NO172584B

NO172584B - PROCEDURE FOR THE PREPARATION OF A 3-HYDROCARBYL-3-CEFEME DERIVATIVE AND COMPOUNDS 3-TRIFLUORMETHANESULPHONYLOXY-3-CEFEM

Info

Publication number: NO172584B
Application number: NO881822A
Authority: NO
Inventors: Stephen R Baker; Vittorio Farina; Jr Chester Sapino
Original assignee: Bristol Myers Squibb Co
Priority date: 1988-04-26
Filing date: 1988-04-26
Publication date: 1993-05-03
Also published as: NO881822D0; NO172584C; NO881822L

Description

Foreliggende oppfinnelse vedrører en fremgangsmåte for fremstilling av et 3-substituert-3-cefemderivat samt forbindelsen 3-trifluormetansulfonyloksy-3-cefem. The present invention relates to a method for producing a 3-substituted-3-cephem derivative and the compound 3-trifluoromethanesulfonyloxy-3-cephem.

U.S. patentnummer 4.591.641 og 4.520.022 beskriver vinyl-substituerte cefalosporiner med 3-((Z)-l-propenyl)- og 7-fenylglycylamido-grupper, som fremgår av strukturformel Å U.S. patent numbers 4,591,641 and 4,520,022 describe vinyl-substituted cephalosporins with 3-((Z)-1-propenyl)- and 7-phenylglycylamido groups, which appear from structural formula Å

hvor 3-propenylgruppen har Z-konfigurasjon. Disse forbindelsene fremstilles ved dannelse av en substituert vinylgruppe i 3-stillingen på cefalosporinkjernen ved omsetting av et 3-halogenmetyl-cefalosporin eller et alkylhalogenid (f.eks. metylhalogenid) med et trifenylfosfin for oppnåelse av et fosforanylmellomprodukt, som deretter omsettes med hhv. et alkylhydrogenkarbonylreagens eller et 3-hydrogenkarbonyl-cefalosporin. Ovennevnte forbindelser fremstilles ved anvendelse av de i U.S. patentnummer 3.769.277, 3.994.884 og 4.107.431 beskrevne fremgangsmåter. where the 3-propenyl group has Z configuration. These compounds are produced by forming a substituted vinyl group in the 3-position of the cephalosporin core by reacting a 3-halomethyl-cephalosporin or an alkyl halide (e.g. methyl halide) with a triphenylphosphine to obtain a phosphoranyl intermediate, which is then reacted with or an alkylhydrogencarbonyl reagent or a 3-hydrogencarbonyl cephalosporin. The above compounds are prepared using those in the U.S. patent numbers 3,769,277, 3,994,884 and 4,107,431 described methods.

I U.S. patentnummer 3.769.277 beskrives fremstillingen av 4-karboksycefalosporiner med formelen ved omsetting av et 3-formyl- (dvs. 3-hydrogenkarbonyl)-cefalosporin med et fosforan med formelen R3P=CR<3>r<4>. I U.S. patentnummer 3.994.884 beskrives fremstillingen av a<3->4-karboksycefalosporin inneholdende en 3-vinylgruppe ved omsetting av den tilsvarende 3-halogenmetylcefalosporinfor-bindelse med et fosfin for oppnåelse av et fosfoniummellom-produkt, omdannelse av fosfoniummellomproduktet til det tilsvarende fosforanylidenmellomprodukt og kobling av fosforanylidenmellomproduktet med formaldehyd. In the U.S. patent number 3,769,277 describes the production of 4-carboxycephalosporins with the formula by reacting a 3-formyl- (i.e. 3-hydrogencarbonyl)-cephalosporin with a phosphorane of the formula R3P=CR<3>r<4>. In the U.S. patent number 3,994,884 describes the production of α<3->4-carboxycephalosporin containing a 3-vinyl group by reacting the corresponding 3-halomethylcephalosporin compound with a phosphine to obtain a phosphonium intermediate, conversion of the phosphonium intermediate into the corresponding phosphoranilidene intermediate and coupling of the phosphoranilidene intermediate with formaldehyde.

I U.S. patentnummer 4.107.431 beskrives fremstillingen av A<3->vinyl- eller substituert vinyl-4-karboksycefalosporiner ved omsetning av et 3-fosforanyliden-cefalosporin med en karbonylforbindelse med formelen R<3>C0R4 eller ved omsetting av et 3-formylcefalosporin med en fosforan med formelen R3P=CR<3>R^. In the U.S. patent number 4,107,431 describes the production of A<3->vinyl- or substituted vinyl-4-carboxycephalosporins by reacting a 3-phosphoranylidene cephalosporin with a carbonyl compound of the formula R<3>COR4 or by reacting a 3-formyl cephalosporin with a phosphorane with the formula R3P=CR<3>R^.

I U.S. patentnummer 3.830.700 beskrives visse 3-arylvinyl-cefalosporiner, som er nyttige som kromogene midler til påvisning av p-laktamaseaktivitet. Forbindelsene som er nyttige ved den omhandlede metoden, fremstilles ved omsetting av et 3-fosforanyliden-cefalosporin med en hydrogenkarbonyl-aryl-(arylaldehyd)-forbindelse eller ved omsetning av et 3-hydrogenkarbonylcefalosporin med en fosforan med formelen (R)3P=CHAr. In the U.S. patent number 3,830,700 describes certain 3-arylvinyl cephalosporins, which are useful as chromogenic agents for the detection of β-lactamase activity. The compounds useful in the subject method are prepared by reacting a 3-phosphoranylidene cephalosporin with a hydrogencarbonyl-aryl-(arylaldehyde) compound or by reacting a 3-hydrogencarbonylcephalosporin with a phosphorane of the formula (R)3P=CHAr.

I U.S. patentnummer 3.983.113, 4.049.806 og 4.139.618 beskrives 3-(heterocyklotio)propenylcefalosporiner med formelen hvor forbindelsene fremstilles ved omsetning av 3-formyl-cefalosporinutgangsforbindelsen med et egnet vinyl-Grignard-reagens for tilveiebringelse av en blanding av a- og 3-hydroksylsomerer av det tilsvarende 3-(l-hydroksy-prop-2-enyl)-cefalosporin etterfulgt av behandling av ovennevnte mellomprodukt med en merkaptosubstituert heterocyklisk forbindelse svarende til SR^-substituenten i nærvær av en liten mengde sterk syre. I U.S. patentnummer 4.112.087 beskrives en forbindelse med samme formel som beskrevet ovenfor bortsett fra, at "<S>R1<11> er erstattet med "OR". In the U.S. patent numbers 3,983,113, 4,049,806 and 4,139,618 describe 3-(heterocyclothio)propenylcephalosporins of the formula where the compounds are prepared by reacting the 3-formyl-cephalosporin starting compound with a suitable vinyl Grignard reagent to provide a mixture of a- and 3 -hydroxyl isomers of the corresponding 3-(1-hydroxy-prop-2-enyl)-cephalosporin followed by treatment of the above intermediate with a mercapto-substituted heterocyclic compound corresponding to the SR^ substituent in the presence of a small amount of strong acid. In the U.S. patent number 4,112,087 describes a compound with the same formula as described above except that "<S>R1<11> is replaced by "OR".

I U.S. patentnummer 4.065.620 beskrives 3-(substituerte )-vinylcefalosporiner fremstilt ved omsetning av en 3-formylcefalosporinforbindelse med en fosforan med formelen In the U.S. patent number 4,065,620 describes 3-(substituted )-vinylcephalosporins prepared by reacting a 3-formylcephalosporin compound with a phosphorane of the formula

R1R2R3P=CH-Y R1R2R3P=CH-Y

ved konvensjonelle Wittig-reaksjonsbetingelser. by conventional Wittig reaction conditions.

I offentliggjort EP-søknad nr. 0.030.630 beskrives 7-acyl-amino-3-vinylcefalosporinsyrederivater fremstilt ved omsetning av en 3-formylcefalosporinforbindelse med en passende fosforan. In published EP application no. 0,030,630, 7-acyl-amino-3-vinylcephalosporin acid derivatives prepared by reacting a 3-formylcephalosporin compound with a suitable phosphorane are described.

I U.S. patentnummer 4.147.863 beskrives cefalosporinderivater med en (l-alkyl-lE-tetrazol-5-yl)vinylgruppe i cefemkjernens 3-stilling. Det beskrives også fremstillingen av mellom-produktet med den gitte 3-vinyl-substituenten ved omsetning av en kjent 3-formylcefalosporin med et Wittig-reagens (fosforanr). In the U.S. patent number 4,147,863 describes cephalosporin derivatives with a (1-alkyl-1E-tetrazol-5-yl)vinyl group in the 3-position of the cephem nucleus. The preparation of the intermediate product with the given 3-vinyl substituent by reaction of a known 3-formylcephalosporin with a Wittig reagent (phosphorane) is also described.

I U.S. patentnummer 4.255.423 beskrives cefalosporinforbind-elser med en substituert eller usubstituert vinylgruppe i cefalosporinkjernens 3-stilling, og disse forbindelser fremstilles ved omsetning av en fosforanylidenforbindelse med en forbindelse inneholdende en karbonylgruppe. Nærmere betegnet kan en fosforanylidenforbindelse med formelen omsettes med en karbonylforbindelse med formelen R2-CO-R3 ^or tllveiebringing av -CH=CR2R3-substituenten i cefemkjernens 3-stilling. In the U.S. patent number 4,255,423 describes cephalosporin compounds with a substituted or unsubstituted vinyl group in the 3-position of the cephalosporin nucleus, and these compounds are produced by reacting a phosphoranilidene compound with a compound containing a carbonyl group. In more detail, a phosphoranylidene compound of the formula can be reacted with a carbonyl compound of the formula R2-CO-R3 ^or tll delivery of the -CH=CR2R3-substituent in the 3-position of the cephem nucleus.

Fra den nærmest beslektede teknikken er det kjent, at forbindelsene med cis(Z)-stereoisomer konfigurasjon foretrek-kes, fremfor forbindelser med trans(E)-stereoisomer konfigurasjon, da førstnevnte forbindelser er i besittelse av større antibakteriell aktivitet. (Se U.S. patentnummer 4.520.022, spalte 16,.linje 23-29). From the closely related technique, it is known that the compounds with cis(Z)-stereoisomer configuration are preferred to compounds with trans(E)-stereoisomer configuration, as the former compounds possess greater antibacterial activity. (See U.S. Patent No. 4,520,022, column 16, lines 23-29).

De hittil kjente og i litteraturen beskrevne fremgangsmåter til fremstilling av 3-(1-propenyl)-3-cefemer gir en blanding av cis(Z)- og trans(E)-isomerer, som krever kostbar separa-sjon for oppnåelse av den foretrukne, mere antibakterielt aktive, cis(Z)-isomer, og det samlede utbytte av ønsket cis(Z)-isomer basert på utgangsmaterialet, er derfor relativt lavt. The methods known to date and described in the literature for the production of 3-(1-propenyl)-3-cephem give a mixture of cis(Z)- and trans(E)-isomers, which require expensive separation to obtain the preferred , more antibacterially active, cis(Z)-isomer, and the overall yield of the desired cis(Z)-isomer based on the starting material is therefore relatively low.

Scott, Crisp & Stille i J. Amer. Chem. Soc. , 106, 4630 (1984) beskriver den palladium-katalyserte kobling av organotinfor-bindelser med elektrofile forbindelser, hvor koblingen er lettet ved tilsetning av sinkklorid. Scott, Crisp & Stille in J. Amer. Chem. Soc. , 106, 4630 (1984) describes the palladium-catalyzed coupling of organotin compounds with electrophilic compounds, the coupling being facilitated by the addition of zinc chloride.

Scott & Stille i J. Amer. Chem. Soc, 108, 3033 (1986) beskriver den palladium-katalyserte koblingsreaksjonen mellom forskjellige vinyl-triflater med organostannaner, som f.eks. vinyltributylstannan, for oppnåelse av et produkt, hvor vinylgruppen er bundet til det karbonatom, som triflatgruppen har forlatt. Scott & Stille in J. Amer. Chem. Soc, 108, 3033 (1986) describes the palladium-catalyzed coupling reaction between various vinyl triflates with organostannanes, such as vinyltributylstannane, to obtain a product, where the vinyl group is bound to the carbon atom, which the triflate group has left.

På grunn av at det er ønskelige å forbedre fremgangsmåtene for fremstilling av 3-vinylcefemderivater med den foretrukne cis(Z )-stereoisomer-konfigurasjonen er det blitt bestemt å anvende en stereo-spesifikk syntesevei for oppbygning av Z-propenyl-sidekjeden i cefemkjernens 3-stilling ved anvendelse av palladium-katalysert kobling av cis(Z)-propenyltributyl-stannan med cefem inneholdende hensiktsmessige funksjonelle grupper. Due to the fact that it is desirable to improve the methods for the preparation of 3-vinyl cephem derivatives with the preferred cis(Z )-stereoisomer configuration, it has been decided to use a stereo-specific synthesis route for building up the Z-propenyl side chain in the cephem core's 3- position using palladium-catalyzed coupling of cis(Z)-propenyltributylstannane with cephem containing appropriate functional groups.

Med utgangspunkt i de lett tilgjengelige 3-hydroksycefemer og derivater derav, herunder trifluormetylsulfonat (triflat) og metansulfonat og klor- og difenylfosfatderivater, ble kobling med ovennevnte organometalliske midler undersøkt. Det viste seg, at ovennevnte koblingsreaksjoner forløp utilfredsstillende, når de ble utført i overensstemmelse med betingelsene anført av Scott & Stille. Kobling mellom difenyl-metyl-7-(fenylacetamido)-3-triflyloksy-3-cefem-4-karboksylat og stannaner var utilfredsstillende, når den ble utført under betingelser beskrevet i litteraturen. Anvendelse av Pd(Pø3)4~ LiCl i THF førte hovedsakelig til 3-klorderivatet av ovennevnte cefem, som lett ble isomerisert til A2-cefemet, mens bare spormengder av det ønskede cefem ble oppnådd. Anvendelse av ZnCl£ i stedet for LiCl gir ikke noe A<2->cefem-biprodukt. Omdannelse av det ønskede produkt forløp imidlertid så langsomt ved utførelse i THF under tilbakekjøling, at det forekom omfattende dekomponering av utgangs-triflatet. Det ønskede produkt, difenylmetyl-7-(fenylacetamido)-3-(Z-l-propenyl)-3-cefem-4-karboksylat, ble deretter oppnådd i et lite utbytte. Based on the readily available 3-hydroxycephems and derivatives thereof, including trifluoromethylsulphonate (triflate) and methanesulphonate and chloro- and diphenylphosphate derivatives, coupling with the above-mentioned organometallic agents was investigated. It was found that the above coupling reactions proceeded unsatisfactorily when carried out in accordance with the conditions stated by Scott & Stille. Coupling between diphenyl-methyl-7-(phenylacetamido)-3-triflyloxy-3-cephem-4-carboxylate and stannanes was unsatisfactory when carried out under conditions described in the literature. Application of Pd(Pø3)4~ LiCl in THF led mainly to the 3-chloro derivative of the above-mentioned cephem, which was readily isomerized to the A2-cephem, while only trace amounts of the desired cephem were obtained. Using ZnCl£ instead of LiCl gives no A<2->cephem by-product. Conversion of the desired product, however, proceeded so slowly when carried out in THF under cooling, that extensive decomposition of the starting triflate occurred. The desired product, diphenylmethyl-7-(phenylacetamido)-3-(Z-1-propenyl)-3-cephem-4-carboxylate, was then obtained in low yield.

Det har nå overraskende vist seg, at kobling mellom 3-trifluormetansulfonyloksy-3-cefemer og visse umettede hydro-C-cn (umettede "hydrokarbyltrialkyltinn") kan medføre til dannelse av en karbon-karbon-binding i cefemkjernens 3-stilling i tilfredsstillende utbytte, og, i tilfelle av 1-alkenyl- og 1-polyalkenylderivatene under oppnåelse av nesten fullstendig stereospesifisitet (dvs. mere enn 99% spesifisi-tet). Dette ble oppnådd ved å utføre koblingsreaksjonen ved romtemperatur i nærvær av et relativt polart aprotiske oppløsningsmiddel, en Pd°- eller Pd<**->forbindelse, visse metallhalogenider og et fosfin. It has now surprisingly been shown that coupling between 3-trifluoromethanesulfonyloxy-3-cephem and certain unsaturated hydro-C-cn (unsaturated "hydrocarbyltrialkyltin") can lead to the formation of a carbon-carbon bond in the 3-position of the cephem nucleus in satisfactory yield , and, in the case of the 1-alkenyl and 1-polyalkenyl derivatives, achieving almost complete stereospecificity (ie more than 99% specificity). This was achieved by carrying out the coupling reaction at room temperature in the presence of a relatively polar aprotic solvent, a Pd° or Pd<**-> compound, certain metal halides and a phosphine.

Foreliggende oppfinnelse vedrører følgelig en fremgangsmåte for fremstilling av et 3-substituert-3-cefemderivat med formelen (I) The present invention therefore relates to a method for the production of a 3-substituted-3-cephem derivative with the formula (I)

hvor where

r! er 1-alkenyl med 2-4 karbonatomer og eventuelt substituert med etoksy, 1-dienyl, 1-alkynyl med 2-4 karbonatomer, metoksyfenyl og N-metylimidazolyl, og r! is 1-alkenyl with 2-4 carbon atoms and optionally substituted with ethoxy, 1-dienyl, 1-alkynyl with 2-4 carbon atoms, methoxyphenyl and N-methylimidazolyl, and

Q er fenylacetyl, en gruppe med formelen Q is phenylacetyl, a group of the formula

der G er fenyl, eventuelt substituert med hydroksy, og G' er amino, eller en gruppe where G is phenyl, optionally substituted with hydroxy, and G' is amino, or a group

der G" er tiazol, som eventuell er substituert med amino eller difenylmetyl eller pivaloyloksymetylesteren derav, kjennetegnet ved at man where G" is thiazole, which is optionally substituted with amino or diphenylmethyl or the pivaloyloxymethyl ester thereof, characterized by

(a) omsetter en utgangsforbindelse med formel (II) (a) reacts a starting compound of formula (II)

der Tf er trifluormetansulfonyloksygruppen, CF3S(0)-, og Q har den ovenfor angitte betydingen, eller difenylmetylesteren eller pivaloyloksymetylesteren derav, i et aprotisk oppløs-ningsmiddel med minst én ekvimolar mengde av en R^-tributyl-tinn i nærvær av 1-10 mol# av en Pd<0-> eller Pd<II->forbindelse og 3-30 mol-# tri(2-furyl)fosfin og 0-7 molekvivalenter ZnCl2 ved 20-65°C i 1-75 timer, og where Tf is the trifluoromethanesulfonyloxy group, CF3S(0)-, and Q has the meaning given above, or the diphenylmethyl ester or the pivaloyloxymethyl ester thereof, in an aprotic solvent with at least one equimolar amount of an R^-tributyltin in the presence of 1-10 mol# of a Pd<0-> or Pd<II-> compound and 3-30 mol-# of tri(2-furyl)phosphine and 0-7 mol-equivalents of ZnCl2 at 20-65°C for 1-75 hours, and

b) utvinner det 3-substituerte 3-cefemderivatet med formel (I) eller difenylmetyl eller pivaloyloksymetylesteren b) recovers the 3-substituted 3-cephem derivative of formula (I) or the diphenylmethyl or the pivaloyloxymethyl ester

derav. hence.

Ved anvendelse av fremgangsmåten ifølge oppfinnelsen er det oppnådd adskillige hittil ukjente forbindelser, som ikke har vært mulig å oppnå ved anvendelse av kjente fremgangsmåter. By using the method according to the invention, several hitherto unknown compounds have been obtained, which have not been possible to obtain by using known methods.

I et annet aspekt angår den foreliggende oppfinnelse et hittil ukjent 3-trifluormetansulfonyloksy-3-cefemutgangs-forbindelse med formelen (II) In another aspect, the present invention relates to a hitherto unknown 3-trifluoromethanesulfonyloxy-3-cephem starting compound of the formula (II)

hvor where

Tf betegner trifluormetansulfonyloksygruppen CF3S(0)_, og Q har den ovenfor angitte betydning eller difenylmetylesteren derav. Tf denotes the trifluoromethanesulfonyloxy group CF3S(0)_, and Q has the above meaning or the diphenylmethyl ester thereof.

3-trifluormetansulfonyloksy-3-cefemutgangsforbindelsen (også benevnt 3-triflyloksy-3-cefem, hvor akronymet "triflyl" eller "triflat" anvendes for betegnelse av trifluormetansulfonyl-gruppen) kan lett oppnåes ut fra kjente 3-hydroksycefemer. 3-triflyloksy-3-cefemutgangsforbindelsen kan på for fagmannen kjent måte være forsynt med forskjellige substituenter på 3- The 3-trifluoromethanesulfonyloxy-3-cephem starting compound (also called 3-triflyloxy-3-cephem, where the acronym "triflyl" or "triflat" is used to designate the trifluoromethanesulfonyl group) can be easily obtained from known 3-hydroxycephems. The 3-triflyloxy-3-cephem starting compound can, in a manner known to the person skilled in the art, be provided with various substituents on 3-

cefemkjernen. Karboksylgruppen i 4-stillingen kan være omdannet til et ester- eller saltderivat derav. I 7-stillingen til 3-cefemkjernen kan en usubstituert eller substituert aminogruppe sitte, hvor substituenten kan være valgt blant en hvilken som helst av de substituenter, som er kjent og beskrevet i litteraturen. Som eksempel kan nevnes, at 4-karboksylgruppen kan være omdannet til difenylmetylkarboksy-latesteren derav og substituenten i 7-stillingen kan være en fenylacetamido- eller t-butyloksykarbonylgruppe. the cephem nucleus. The carboxyl group in the 4-position can be converted to an ester or salt derivative thereof. In the 7-position of the 3-cephem nucleus, an unsubstituted or substituted amino group can be present, where the substituent can be chosen from any of the substituents known and described in the literature. As an example, the 4-carboxyl group can be converted to its diphenylmethylcarboxylate ester and the substituent in the 7-position can be a phenylacetamido or t-butyloxycarbonyl group.

Det aprotiske oppløsningsmiddel som anvendes ved den her beskrevne fremgangsmåten bør være relativt polart. Oppløs-ningsmiddelet kan således være valgt blant l-metyl-2-pyrro-lidinon, tetrahydrofuran (THF), nitriler, såsom acetonitril, dimetylsulfoksyd (DMSO), dimetylformamid (DMF), etere, såsom glyme og dioksan, heksametylfosforsyreamid (HMPA), aceton, nitrometan eller nitrobenzen. Oppløsningsmiddelet er fortrinnsvis valgt blant l-metyl-2-pyrrolidinon, THF, acetonitril, DMSO eller DMF. Oppløsningsmiddelet blir spesielt valgt blant N-metylpyrrolidinon, THF eller acetonitril. Mest foretrukket er oppløsningsmiddelet l-metyl-2-pyrrolidinon. The aprotic solvent used in the method described here should be relatively polar. The solvent can thus be selected from 1-methyl-2-pyrrolidinone, tetrahydrofuran (THF), nitriles, such as acetonitrile, dimethylsulfoxide (DMSO), dimethylformamide (DMF), ethers, such as glyme and dioxane, hexamethylphosphoric acid amide (HMPA), acetone, nitromethane or nitrobenzene. The solvent is preferably chosen from 1-methyl-2-pyrrolidinone, THF, acetonitrile, DMSO or DMF. The solvent is particularly selected from among N-methylpyrrolidinone, THF or acetonitrile. Most preferably, the solvent is 1-methyl-2-pyrrolidinone.

Selv om en hvilken som helst Pd-forbindelse kan anvendes ved den her omtalte fremgangsmåten velges Pd-forbindelsen fortrinnsvis fra en Pd°-forbindelse, såsom bis(dibenzyliden-acetonyl)palladium (Pd(dba)2). eller en Pd<**->forbindelse, såsom Pd(0Ac)2» eller PdCl2- Førstnevnte Pd-reagens (Pd(dba)2) er særlig fordelaktig ved fremgangsmåten ifølge oppfinnelsen. Although any Pd compound can be used in the method described here, the Pd compound is preferably selected from a Pd° compound, such as bis(dibenzylidene-acetonyl)palladium (Pd(dba)2). or a Pd<**-> compound, such as Pd(0Ac)2" or PdCl2- The former Pd reagent (Pd(dba)2) is particularly advantageous in the method according to the invention.

Metallhalogenid, som anvendes i kombinasjon med Pd-forbindelsen ved den omhandlede fremgangsmåten er valgt blant ZnCl2, ZnBr2, LiCl, LiBr, Lii, MgCl2, MgBr2, HgCl2, og bor-, aluminium- eller kadmiumhalogenider (Cl og Br). Metallhalo-genidet velges fortrinnsvis blant ZnCl2 og ZnBr2, spesielt ZnCl2• The metal halide used in combination with the Pd compound in the method in question is selected from ZnCl2, ZnBr2, LiCl, LiBr, Lii, MgCl2, MgBr2, HgCl2, and boron, aluminum or cadmium halides (Cl and Br). The metal halide is preferably selected from among ZnCl2 and ZnBr2, especially ZnCl2•

Følgende reaksjonsskjema viser en typisk utførelsesform for fremgangsmåten ifølge den foreliggende oppfinnelse: The following reaction scheme shows a typical embodiment of the method according to the present invention:

En allmenn eksperimentell metode for utførelse av fremgangsmåten ifølge oppfinnelsen i relasjon til ovenstående reaksjonsskjema er følgende: Triflat III (107 mg, 0,169 mmol) i tørt l-metyl-2-pyrrolidi-non (3 ml) behandles med et egnet stannan (0,20 mmol, i 1 ml l-metyl-2-pyrrolidinon). Sinkklorid (52 mg, 0,38 mmol), Pd(dba)2 (2,45 mg, 0,0042 mmol) og tri-(2-furyl)fosfin (2,0 mg, 0,0085 mmol) tilsettes så. Den mørke oppløsningen omrøres under argon ved 25-50°C i ca. 25 timer. Produktet isoleres ved flammékromatografi på Si02, og karakteriseres ved elementanalyse, <1>H NMR og massespektroskopi. A general experimental method for carrying out the process according to the invention in relation to the above reaction scheme is the following: Triflate III (107 mg, 0.169 mmol) in dry 1-methyl-2-pyrrolidinone (3 ml) is treated with a suitable stannane (0, 20 mmol, in 1 ml of 1-methyl-2-pyrrolidinone). Zinc chloride (52 mg, 0.38 mmol), Pd(dba)2 (2.45 mg, 0.0042 mmol) and tri-(2-furyl)phosphine (2.0 mg, 0.0085 mmol) are then added. The dark solution is stirred under argon at 25-50°C for approx. 25 hours. The product is isolated by flame chromatography on SiO2, and characterized by elemental analysis, <1>H NMR and mass spectroscopy.

Sluttproduktet kan utvinnes fra koblingsreaksjonsblandingen ved metoder som er konvensjonelle ved cefalosporin- og penicillin-fremstillingen, f.eks. ovenfor ved den allmenne eksperimentelle metoden. The final product can be recovered from the coupling reaction mixture by methods conventional in cephalosporin and penicillin manufacture, e.g. above by the general experimental method.

Den følgende tabellen illustrerer bare noen få representative hydrogenkarbyltributylstannaner, produkter som fremkommer ved reaksjonen derav med triflat III som belyst ovenfor, reaksjonstid og utbytte { <&) av produktet ifølge den foreliggende oppfinnelse. The following table illustrates only a few representative hydrogencarbyltributylstannanes, products resulting from the reaction thereof with triflate III as elucidated above, reaction time and yield {<&) of the product according to the present invention.

Eksempel 5, som belyser fremstillingen av en 3-(desmetyl)-3-cefemforbindelse, faller utenfor den foreliggende oppfinnel-ses rammer, men er tatt med for illustrasjon av anvendelig-heten av fremgangsmåten ifølge oppfinnelsen. Example 5, which illustrates the production of a 3-(desmethyl)-3-cephem compound, falls outside the scope of the present invention, but is included to illustrate the applicability of the method according to the invention.

På grunnlag av de oppnådde resultater som fremgår av eksemp-lene ansees reaksjonstid og -temperaturen i trinn (b) av fremgangsmåten ifølge oppfinnelsen ikke for å være kritisk, og kan variere i området fra 20 til 65°C i 1 til 75 timer, fortrinnsvis 25-50"C i 1-72 timer, avhengig av valget og reaktiviteten av de bestemte reaktanter og katalysator-systemet. On the basis of the results obtained as shown in the examples, the reaction time and temperature in step (b) of the method according to the invention are not considered to be critical, and can vary in the range from 20 to 65°C for 1 to 75 hours, preferably 25-50"C for 1-72 hours, depending on the choice and reactivity of the particular reactants and catalyst system.

De følgende eksempler 1-4 og 6-16 illustrerer bare noen få representative faktiske utførelsesformer for fremgangsmåten ifølge oppfinnelsen. Eksempel A og B belyser fremstillingen av et representativt utgangsmateriale. Alle deler bg prosen-ter er på vektbasis, medmindre annet er anført. The following examples 1-4 and 6-16 illustrate only a few representative actual embodiments of the method according to the invention. Examples A and B illustrate the production of a representative starting material. All parts bg percentages are by weight, unless otherwise stated.

Eksempel A Example A

Dif en vime tvi - 7- f f envlacetamido )- 3- hydroksv- 3- cefem- 4- karbok-s<y>lat Dif en vime tvi - 7- f f envlacetamido )- 3- hydroxysv- 3- cephem- 4- carbox-s<y>late

En oppløsning av 3,38 g (0,006 mol) difenylmetyl-7-amino-3-hydroksy-3-cefem-4-karboksylat, p-toluensulfonsyre-salt<*> og 1,87 g (0,018 mol) natriumbisulfitt i 120 ml tetrahydrofuran og 30 ml vann behandles dråpevis med en oppløsning av 1,41 g (0,009 mol) fenylacetylklorid i 10 ml tetrahydrofuran. Etter endt tilsetning av syrekloridet ble reaksjonsblandingen omrørt ved romtemperatur i 2 timer. Deretter ble tetrahydrofuran fjernet fra reaksjonsblandingen ved redusert trykk og det vandige konstratet ble ekstrahert med etylacetat. Det organiske ekstraktet ble vasket to ganger med 5% natriumbikarbonat og to ganger med saltvann. Til slutt ble det organiske oppløsningsmiddelet fjernet ved redusert trykk, som ga en fast, skumaktig rest. Resten ble kromatografert på 100 g silisiumoksydgel for oppnåelse av 1,85 g (61,6#) defenyl-metyl-7-( f enylace tam i do ) -3-hy drok sy-3-cef em-4-karboksy lat. Det kjernemagnetiske resonansspekteret stemte overens med den ønskede strukturen. A solution of 3.38 g (0.006 mol) diphenylmethyl-7-amino-3-hydroxy-3-cephem-4-carboxylate, p-toluenesulfonic acid salt<*> and 1.87 g (0.018 mol) sodium bisulfite in 120 ml tetrahydrofuran and 30 ml of water are treated dropwise with a solution of 1.41 g (0.009 mol) phenylacetyl chloride in 10 ml of tetrahydrofuran. After the addition of the acid chloride was completed, the reaction mixture was stirred at room temperature for 2 hours. Subsequently, tetrahydrofuran was removed from the reaction mixture under reduced pressure and the aqueous concentrate was extracted with ethyl acetate. The organic extract was washed twice with 5% sodium bicarbonate and twice with brine. Finally, the organic solvent was removed under reduced pressure, yielding a solid, foamy residue. The residue was chromatographed on 100 g of silica gel to obtain 1.85 g (61.6#) of diphenyl-methyl-7-(phenylacetamido)-3-hydroxy-3-cephem-4-carboxylate. The nuclear magnetic resonance spectrum was consistent with the desired structure.

<1>E. Scartazzini & H. Bickel, Heiv. Chim. Acta, 1974, 57, 1919. <1>E. Scartazzini & H. Bickel, Heiv. Chim. Acta, 1974, 57, 1919.

Eksempel B Example B

Difenvlmetvl- 7- ff envlacetamidol- 3-( trifluormetvisulfonvl-oksv)- 3- cefem- 4- karboksylat Diphenylmethyl- 7- ff envlacetamidol- 3-(trifluoromethyl bisulfonyl- oxyl)- 3- cephem- 4- carboxylate

Til 1,57 g (0,00313 mol) difenylmetyl-7-(fenylacetamido)-3-hydroksy-3-cefem-4-karboksylat i 63 ml metylenklorid ble 0,546 ml (0,00313 mol) N,N-diisopropyletylamin tilsatt, og blandingen ble omrørt ved -20°C i 10 minutter under nitrogen-atmosfære. Deretter ble 0,633 ml (0,00376 mol) trifluormetan-sulf onsyreanhydr id tilsatt blandingen og omrøring ved -20°C ble fortsatt i 20 minutter. Reaksjonsblandingen ble fortynnet til et volum på 400 ml ved tilsetting av metylenklorid. Til den organiske oppløsningen ble 100 ml 0,25 N saltsyre tilsatt. Fasene ble separert og metylenkloridfasen ble suksessivt vasket med vann, fortynnet natriumbikarbonat, 0,25 N saltsyre og vann. Det organiske laget ble tørket over magnesiumsulfat. Sulfatet ble fjernet ved filtrering og oppløsningsmiddelet ble fjernet ved redusert trykk for oppnåelse av 1,37 g (69,2$) difenylmetyl-7-[fenylacetamido]-3-(trifluormetylsulfonyloksy)-3-cefem-4-karboksylat. Det kjernemagnetiske resonansspekteret stemte overens med den ønskede strukturen. To 1.57 g (0.00313 mol) of diphenylmethyl-7-(phenylacetamido)-3-hydroxy-3-cephem-4-carboxylate in 63 ml of methylene chloride, 0.546 ml (0.00313 mol) of N,N-diisopropylethylamine was added, and the mixture was stirred at -20°C for 10 minutes under a nitrogen atmosphere. Then 0.633 ml (0.00376 mol) of trifluoromethanesulfonic anhydride was added to the mixture and stirring at -20°C was continued for 20 minutes. The reaction mixture was diluted to a volume of 400 ml by addition of methylene chloride. To the organic solution was added 100 ml of 0.25 N hydrochloric acid. The phases were separated and the methylene chloride phase was washed successively with water, dilute sodium bicarbonate, 0.25 N hydrochloric acid and water. The organic layer was dried over magnesium sulfate. The sulfate was removed by filtration and the solvent was removed under reduced pressure to give 1.37 g (69.2%) of diphenylmethyl-7-[phenylacetamido]-3-(trifluoromethylsulfonyloxy)-3-cephem-4-carboxylate. The nuclear magnetic resonance spectrum was consistent with the desired structure.

Analyse for C29<H>23N207S2F3: Analysis for C29<H>23N207S2F3:

Beregnet: C: 55,06$, H: 3,66$, N: 4,43$, S: 10,14$ Calculated: C: $55.06, H: $3.66, N: $4.43, S: $10.14

Funnet : C: 55,28$, H: 3,66$, N: 3,94$, S:.10,68$ Found : C: $55.28, H: $3.66, N: $3.94, S: $10.68

Eksempel 1 Example 1

Dif envlmetvl - 7- ff envl ac et am idol - 3- ( Z- l- propenyl- 3- cefem- 4-karboksylat Dif envlmetvl - 7- ff envl ac et am idol - 3- ( Z- l- propenyl- 3- cephem- 4-carboxylate

En oppløsning av 0,226 g (0,00358 mol) difenylmetyl-7-[fenylacetamido]-3-(tri fluormetylsulfonyloksy )-3-cef em-4-karboksylat, 0,130 g (0,00039 mol) Z-l-propenyl-tri-n-butylstannan, 0,0033 g (0,000014 mol) tri(2-furyl)fosfin og 0,0041 g (0,000007 mol) palladium(0)-bis(dibenzylidenaceton) i 4 ml tetrahydrofuran ble avgasset under argonatmosfære og redusert trykk i 30 sekunder. Deretter ble det på en gang tilsatt en oppløsning av 0,097 g (0,00072 mol) sinkklorid i 1 ml tetrahydrofuran. Reaksjonsblandingen ble omrørt ved romtemperatur i 16 timer. Deretter ble blandingen fortynnet med etylacetat og vasket med den fortynnede ammoniumklorid-oppløsningen. Det organiske oppløsningsmiddelet ble fjernet ved redusert trykk og erstattet med acetonitril. Acetonitril-oppløsningen ble vasket 3 ganger med n-pentan, og opp-løsningsmiddelet ble igjen fjernet ved redusert trykk. Resten ble kromatografert på silisiumoksyd gel for oppnåelse av 0,123 g(65$) difenylmetyl-7-[fenylacetamido]-3-(Z-l-propenyl)-3-cefem-4-karboksylat. Det kjernemagnetiske resonansspekteret stemte overens med den ønskede strukturen. A solution of 0.226 g (0.00358 mol) of diphenylmethyl-7-[phenylacetamido]-3-(trifluoromethylsulfonyloxy)-3-cephem-4-carboxylate, 0.130 g (0.00039 mol) of Z-1-propenyl-tri-n -butylstannane, 0.0033 g (0.000014 mol) tri(2-furyl)phosphine and 0.0041 g (0.000007 mol) palladium(0)-bis(dibenzylideneacetone) in 4 ml tetrahydrofuran were degassed under an argon atmosphere and reduced press for 30 seconds. A solution of 0.097 g (0.00072 mol) of zinc chloride in 1 ml of tetrahydrofuran was then added all at once. The reaction mixture was stirred at room temperature for 16 hours. Then the mixture was diluted with ethyl acetate and washed with the dilute ammonium chloride solution. The organic solvent was removed under reduced pressure and replaced with acetonitrile. The acetonitrile solution was washed 3 times with n-pentane, and the solvent was again removed under reduced pressure. The residue was chromatographed on silica gel to obtain 0.123 g (65%) of diphenylmethyl-7-[phenylacetamido]-3-(Z-1-propenyl)-3-cephem-4-carboxylate. The nuclear magnetic resonance spectrum was consistent with the desired structure.

Eksempel 2 Example 2

Difenvimety1- 7- ffenvlacetamidol- 3-( 1- propenvl )- 3- cefem- 4-karboksvlat Diphenvimethyl 1- 7- phenvlacetamidol- 3-( 1- propenyl )- 3- cephem- 4-carboxvlate

En blanding av 1,03 g (0,00162 mol) difenylmetyl-7-[fenylacetyl]-3-(trifluormetylsulfonyloksy)-3-cefem-4-karboksylat, 0,533 g (0,00162 mol) (1-propynyl)-tri-n-butylstannan, 0,665 g (0,00488 mol) sinkklorid, 0,030 g (0,00013 mol) tri(2-furyl)fosfin og 0,00727 g (0,000032 mol) palladium(II)-acetat i 30 ml tørt N,N-dimetyl-formamid ble oppvarmet ved 65°C i 2 timer og ved romtemperatur i 19 timer under nitrogenatmos-fære. Reaksjonsblandingen ble fortynnet med etylacetat og den organiske oppløsningen ble vasket fem ganger med vann. Etylacetat ble fjernet ved redusert trykk og resten oppløst i acetonitril. Den organiske fasen ble vasket to ganger med n-pentan og acetonitrilet ble fjernet ved redusert trykk. Resten ble renset ved reversfase-kromatografi for oppnåelse av 0,281 g(30$) difenylmetyl-7-[fenylacetamido]-3-(1-propy-nyl )-3-cef em-4-karboksylat . Det kjernemagnetiske resonansspekteret stemte overens med den ønskede strukturen. A mixture of 1.03 g (0.00162 mol) diphenylmethyl-7-[phenylacetyl]-3-(trifluoromethylsulfonyloxy)-3-cephem-4-carboxylate, 0.533 g (0.00162 mol) (1-propynyl)-tri -n-butylstannane, 0.665 g (0.00488 mol) zinc chloride, 0.030 g (0.00013 mol) tri(2-furyl)phosphine and 0.00727 g (0.000032 mol) palladium(II) acetate in 30 ml dry N,N-dimethylformamide was heated at 65°C for 2 hours and at room temperature for 19 hours under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate and the organic solution was washed five times with water. Ethyl acetate was removed under reduced pressure and the residue dissolved in acetonitrile. The organic phase was washed twice with n-pentane and the acetonitrile was removed under reduced pressure. The residue was purified by reverse phase chromatography to obtain 0.281 g (30$) of diphenylmethyl-7-[phenylacetamido]-3-(1-propynyl)-3-cephem-4-carboxylate. The nuclear magnetic resonance spectrum was consistent with the desired structure.

Analyse for C31<H>26<N>2O4S: Analysis for C31<H>26<N>2O4S:

Beregnet: C: 71,24$, H: 5,02$, N: 5,36$, S: 6,14$ Calculated: C: $71.24, H: $5.02, N: $5.36, S: $6.14

Funnet : C: 71,23$, H: 5,02$, N: 5,03$, S: 6,11$. Found : C: 71.23$, H: 5.02$, N: 5.03$, S: 6.11$.

Eksempel 3 Example 3

DifenyImety1- 7- ffenylacetamidol- 3-( 2- metyl- l- propenyl 1-3-cefem- 4- karboksylat DiphenyImethyl- 7- phenylacetamidol- 3-( 2- methyl- l- propenyl 1-3- cephem- 4- carboxylate

En blanding av 0,105 g (0,000166 mol) difenylmetyl-7-[fenylacetamido ]-3-(trifluormetylsulfonyloksy)-3-cefem-4-karboksylat, 0,070 g (0,002 mol) (2-metyl-l-propenyl)tri-n-butylstannan, 0,052 g (0,00038 mol) sinkklorid og 0,0039 g (0,000016 mol) tri(2-furyl)fosfin i 4 ml tørt l-metyl-2-pyrrolidinon ble avgasset i 30 sekunder under argonatmosfære. Deretter ble det på en gang tilsatt 0,0049 g (0,000008 mol) palladium(0)-bis(dibenzyliden-aceton). Reaksjonsblandingen ble omrørt ved romtemperatur i 19 timer. Deretter ble reaksjonsblandingen fortynnet med etylacetat og den organiske fasen vasket med fortynnet ammoniumklorid. Etylacetatet ble fjernet ved redusert trykk og erstattet med acetonitril. Den organiske oppløsningen ble vasket med n-pentan og acetonitril ble fjernet ved redusert trykk. Resten ble kromatografert på silisiumoksydgel for oppnåelse av 0,0603 g(66$) difenylmetyl-7- [f enylacetamido] -3- ( 2-metyl-l-propenyl )-3-cefem-4-karboksylat. Det kjernemagnetiske resonansspekteret og massespek-teret stemte overens med den ønskede strukturen. A mixture of 0.105 g (0.000166 mol) diphenylmethyl-7-[phenylacetamido]-3-(trifluoromethylsulfonyloxy)-3-cephem-4-carboxylate, 0.070 g (0.002 mol) (2-methyl-1-propenyl)tri- n-Butylstannane, 0.052 g (0.00038 mol) zinc chloride and 0.0039 g (0.000016 mol) tri(2-furyl)phosphine in 4 ml of dry 1-methyl-2-pyrrolidinone were degassed for 30 seconds under an argon atmosphere. Then 0.0049 g (0.000008 mol) of palladium(0)-bis(dibenzylidene-acetone) was added all at once. The reaction mixture was stirred at room temperature for 19 hours. Then the reaction mixture was diluted with ethyl acetate and the organic phase was washed with dilute ammonium chloride. The ethyl acetate was removed under reduced pressure and replaced with acetonitrile. The organic solution was washed with n-pentane and acetonitrile was removed under reduced pressure. The residue was chromatographed on silica gel to obtain 0.0603 g (66$) of diphenylmethyl-7-[phenylacetamido]-3-(2-methyl-1-propenyl)-3-cephem-4-carboxylate. The nuclear magnetic resonance spectrum and mass spectrum were consistent with the desired structure.

Analyse for C32H30N2O4S: Analysis for C32H30N2O4S:

Beregnet: C: 71,35$, H: 5,61$, N: 5,20$, S: 5,95$. Calculated: C: $71.35, H: $5.61, N: $5.20, S: $5.95.

Funnet : C: 70,97$, H: 5,67$, N: 5,07$, S: 5,42$. Found : C: 70.97$, H: 5.67$, N: 5.07$, S: 5.42$.

Eksempel 4 Example 4

Difenvlmetvi- 7- Tfenylacetamido]- 3-( p- metoksvfenvl)- 3- cefem- 4-karboks<y>lat Diphenylmethyl- 7- phenylacetamido]- 3-( p- methoxyphenyl)- 3- cephem- 4-carbox<y>late

En blanding av 0,1029 g (0,000163 mol) difenylmetyl-7-[f enylacetamido]-3-(tri fluormetylsulfonyloksy ) -3-cef em-4-karboksylat, 0,0775 (0,000195 mol) (p-metoksyf eiiyl )tri-n-butylstannan, 0,044 g (0,00032 mol) sinkklorid og 0,00378 g A mixture of 0.1029 g (0.000163 mol) of diphenylmethyl-7-[phenylacetamido]-3-(trifluoromethylsulfonyloxy)-3-cephem-4-carboxylate, 0.0775 (0.000195 mol) (p- methoxyethyl)tri-n-butylstannane, 0.044 g (0.00032 mol) zinc chloride and 0.00378 g

(0,000016 mol) tri(2-furyl)-fosfin i 4 ml tørt l-metyl-2-pyrrolidinon ble avgasset i 30 sekunder under argonatmosfære. Deretter ble det på en gang tilsatt 0,0047 g (0,000008 mol) palladium(0)-bis(dibenzyliden-aceton). Reaksjonsblandingen ble omrørt ved 50°C i 5,5 timer og ved romtemperatur i 16 timer. Reaksjonsblandingen ble fortynnet med etylacetat, og den organiske oppløsningen ble vasket med fortynnet ammoniumklorid. Etylacetatet ble fjernet ved redusert trykk og erstattet med acetonitril. Den organiske fasen ble vasket med n-pentan og acetonitril ble fjernet ved redusert trykk. Resten ble kromatografert på silisiumoksydgel for oppnåelse av 0,0548 g(57$) difenylmetyl-7-[fenylacetamido]-3-(p-metoksyfenyl)-3-cefem-4-karboksylat. (0.000016 mol) of tri(2-furyl)-phosphine in 4 mL of dry 1-methyl-2-pyrrolidinone was degassed for 30 seconds under an argon atmosphere. Then 0.0047 g (0.000008 mol) of palladium(0)-bis(dibenzylidene-acetone) was added all at once. The reaction mixture was stirred at 50°C for 5.5 hours and at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate, and the organic solution was washed with dilute ammonium chloride. The ethyl acetate was removed under reduced pressure and replaced with acetonitrile. The organic phase was washed with n-pentane and acetonitrile was removed under reduced pressure. The residue was chromatographed on silica gel to obtain 0.0548 g (57%) of diphenylmethyl-7-[phenylacetamido]-3-(p-methoxyphenyl)-3-cephem-4-carboxylate.

Det kjernemagnetiske resonansspekteret stemte overens med den ønskede strukturen. The nuclear magnetic resonance spectrum was consistent with the desired structure.

Analyse for C35H30<N>2O5S: Analysis for C35H30<N>2O5S:

Beregnet: C: 71,16$, H: 5,12$, N: 4,74$ Calculated: C: $71.16, H: $5.12, N: $4.74

Funnet : C: 70,95$, H: 5,18$, N: 4,70$ Found : C: $70.95, H: $5.18, N: $4.70

Eksempel 5 ( sammenligningseksempel) Example 5 (comparison example)

Difenvlmetvl- 7- rfenylacetamidol- 3-( desmetyl )- 3- cefem- 4-karboksylat Diphenylmethyl-7-rphenylacetamidol-3-(desmethyl)-3-cephem-4-carboxylate

Til en blanding av 0,100 g (0,000158 mol) difenylmetyl-7-[fenylacetamido]-3-(trifluormetylsulfonyloksy )-3-cefem-4-karboksylat, 0,065 g (0,00047 mol) sinkklorid, 0,00293 g (0,000012 mol) tri(2-furyl)fosfin og 0,0007 g (0,000003 mol) palladium(II)-acetat i 3 ml tørr tetrahydrofuran under argonatmosfære ble porsjonsvis tilsatt 0,216 g (0,00074 mol) tri-n-butyl-tinn-hydrid. Reaksjonsblandingen ble omrørt ved 65"C i 2 timer. Reaksjonsblandingen ble så fortynnet med metylenklorid og den organiske oppløsningen ble vasket med- n-pentan, og oppløsningsmiddelet ble fjernet ved redusert trykk. Resten ble kromatografert på silisiumoksydgel for oppnåelse av 0,053 g (68,5$) difenylmetyl-7-[fenylacetamido]-3-(desmetyl )-3-cefem-4-karboksylat. Det kjernemagnetiske resonansspekteret stemte overens med den ønskede strukturen. To a mixture of 0.100 g (0.000158 mol) diphenylmethyl-7-[phenylacetamido]-3-(trifluoromethylsulfonyloxy )-3-cephem-4-carboxylate, 0.065 g (0.00047 mol) zinc chloride, 0.00293 g (0 .000012 mol) tri(2-furyl)phosphine and 0.0007 g (0.000003 mol) palladium(II)-acetate in 3 ml dry tetrahydrofuran under an argon atmosphere were added portionwise 0.216 g (0.00074 mol) tri-n- butyl tin hydride. The reaction mixture was stirred at 65°C for 2 hours. The reaction mixture was then diluted with methylene chloride and the organic solution was washed with n-pentane, and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel to obtain 0.053 g (68, 5$) diphenylmethyl-7-[phenylacetamido]-3-(desmethyl )-3-cephem-4-carboxylate The nuclear magnetic resonance spectrum was consistent with the desired structure.

Analyse for C2s<H>24^2°4S: Analysis for C2s<H>24^2°4S:

Beregnet: C: 69,40$, E: 4,99$, N: 5,78$, S: 6,62$. Calculated: C: $69.40, E: $4.99, N: $5.78, S: $6.62.

Funnet : C: 68,04$, H: 4,96$, N: 5,52$, S: 6,60$. Found : C: 68.04$, H: 4.96$, N: 5.52$, S: 6.60$.

Eksempel 6 Example 6

Dif envlmetyl- 7- ff enylacetamidol - 3- etenvl- 3- cefem- 4-karboksylat Diphenylmethyl- 7- ff enylacetamidol - 3- ethenyl- 3- cephem- 4-carboxylate

En blanding av 0,4645 g (0,00073 mol) difenylmetyl-7-[fenylacetamido] - 3-(trifluormetylsulfonyloksy)-3-cefem-4-karboksylat, 0,279 g (0,00088 mol) etenyl-tri-n-butylstannan, 0,200 g (0,00146 mol) sinkklorid og 0,0068 g (0,000029 mol) tri(2-furyl)fosfin i 6 ml tørt l-metyl-2-pyrrolidinon ble avgasset under argonatmosfære i 30 sekunder. Deretter ble det på en gang tilsatt 0,0084 g (0,000014 mol) palladium(0)-bis-(dibenzyliden-aceton). Reaksjonsblandingen ble omrørt ved romtemperatur i 1 time. Deretter ble reaksjonsblandingen fortynnet med etylacetat og den organiske oppløsningen ble vasket med fortynnet ammoniumklorid. Etylacetat ble fjernet ved redusert trykk og erstattet med acetonitril. Den organiske fasen ble vasket med n-pentan og acetonitrilet fjernet med redusert trykk. Resten ble krystallisert fra etanol/metylenklorid for oppnåelse av 0,320 g (85$) difenylmetyl-7-[fenylacetamido]-3-etenyl-3-cefem-4-karboksylat. Det kjernemagnetiske resonansspekteret stemte overens med den ønskede strukturen. A mixture of 0.4645 g (0.00073 mol) diphenylmethyl-7-[phenylacetamido]-3-(trifluoromethylsulfonyloxy)-3-cephem-4-carboxylate, 0.279 g (0.00088 mol) ethenyl-tri-n-butylstannane , 0.200 g (0.00146 mol) of zinc chloride and 0.0068 g (0.000029 mol) of tri(2-furyl)phosphine in 6 mL of dry 1-methyl-2-pyrrolidinone were degassed under an argon atmosphere for 30 seconds. Then 0.0084 g (0.000014 mol) of palladium(0)-bis-(dibenzylidene-acetone) was added all at once. The reaction mixture was stirred at room temperature for 1 hour. Then the reaction mixture was diluted with ethyl acetate and the organic solution was washed with dilute ammonium chloride. Ethyl acetate was removed under reduced pressure and replaced with acetonitrile. The organic phase was washed with n-pentane and the acetonitrile removed under reduced pressure. The residue was crystallized from ethanol/methylene chloride to give 0.320 g (85%) of diphenylmethyl 7-[phenylacetamido]-3-ethenyl-3-cephem-4-carboxylate. The nuclear magnetic resonance spectrum was consistent with the desired structure.

Analyse for C30<H>26<N>2O4S: Analysis for C30<H>26<N>2O4S:

Beregnet: C: 70,56$, H: 5,13$, N: 5,49$, S: 6,28$. Calculated: C: 70.56$, H: 5.13$, N: 5.49$, S: 6.28$.

Funnet : C: 70,22$, H: 5,13$, N: 5,21$, S. 6,41$. Found : C: 70.22$, H: 5.13$, N: 5.21$, S. 6.41$.

Eksempel 7 Example 7

Difenylmetvl- 7- rf enylacetamidol- 3-( l- etoksv- l- etenyl1- 3-cefem- 4- karboksylat Diphenylmethyl-7-rf-enylacetamidol-3-(1-ethoxy-1-ethenyl1-3-cephem-4-carboxylate

En blanding av 0,200 g (0,00031 mol) difenylmetyl-7-[fenyl-ace tamido] - 3-trif luorme ty lsul f onyloksy )-3-cefem-4 -karboksylat, 0,115 g (0,000318 mol) (1-etoksyvinyl)-tri-n-butylstannan, 0,090 g (0,00066 mol) sinkklorid og 0,00293 g (0,000012 mol) tri(2-furyl)fosfin i 6 ml tørt l-metyl-2-pyrrolidinon ble avgasset i 30 sekunder under argonatmosfære. Deretter ble det på en gang tilsatt 0,0035 g (0,000006 mol) palladium(0)-bis-(dibenzyliden-aceton). Reaksjonsblandingen ble omrørt vad romtemperatur i 19 timer. Deretter ble reaksjonsblandingen fortynnet med etylacetat og den organiske oppløsningen ble vasket med fortynnet ammoniumklorid. Etylacetatet ble fjernet ved redusert trykk og erstattet med acetonitril. Den organiske oppløsningen ble vasket med n-pentan og acetonitril ble fjernet ved redusert trykk. Resten ble kromatografert på silisiumoksydgel for oppnåelse av 0,092 g (52$) difenylmetyl-7- [fenylacetamido]-3-(1-etoksy-l-etenyl )-3-cefem-4-karboksylat. Det kjernemagnetiske resonansspekteret stemte overens med den ønskede strukturen. A mixture of 0.200 g (0.00031 mol) diphenylmethyl-7-[phenyl-acetamido]-3-trifluoromethylsulfonyloxy )-3-cephem-4-carboxylate, 0.115 g (0.000318 mol) (1 -ethoxyvinyl)-tri-n-butylstannane, 0.090 g (0.00066 mol) zinc chloride and 0.00293 g (0.000012 mol) tri(2-furyl)phosphine in 6 ml of dry 1-methyl-2-pyrrolidinone were degassed for 30 seconds under an argon atmosphere. Then 0.0035 g (0.000006 mol) palladium(0)-bis-(dibenzylidene-acetone) was added all at once. The reaction mixture was stirred at room temperature for 19 hours. Then the reaction mixture was diluted with ethyl acetate and the organic solution was washed with dilute ammonium chloride. The ethyl acetate was removed under reduced pressure and replaced with acetonitrile. The organic solution was washed with n-pentane and acetonitrile was removed under reduced pressure. The residue was chromatographed on silica gel to obtain 0.092 g (52%) of diphenylmethyl-7-[phenylacetamido]-3-(1-ethoxy-1-ethenyl)-3-cephem-4-carboxylate. The nuclear magnetic resonance spectrum was consistent with the desired structure.

Analyse for C32<H>30<N>2O5S: Analysis for C32<H>30<N>2O5S:

Beregnet: C: 69,29$, H: 5,45$, N: 5,05$, S: 5,78$. Calculated: C: 69.29$, H: 5.45$, N: 5.05$, S: 5.78$.

Funnet : C: 69,24$, H: 5,54$, N: 4,89$, S: 5,60$. Found : C: 69.24$, H: 5.54$, N: 4.89$, S: 5.60$.

Flere cefemderivater ble fremstilt i alt vesentlig som beskrevet ovenfor ved fremgangsmåten ifølge oppfinnelsen, bortsett fra at den anvendte triflat (Tf)-derivatet ble erstattet med 7-[2-(4-hydroksyfenyl)-2-aminoacetamido]- eller 7-[(Z)-2-(2-aminotiazol-4-yl )-2-metoksyimino-acetamido]-3-hydroksy-3-cefem-4-karboksylsyre samt visse estere derav, og at de i nedenstående tabell anførte hydrokarbyl-tributylstan-naner ble anvendt. Dé i følgende tabell anførte utgangs-triflater (Tf) er forbindelsene som nedenfor er betegnet med "V" og "VI (a,b)", hvori alle sure setene er beskyttet på konvensjonell måte. Etter koblingsreaksjonen for oppnåelse av den ønskede 3-hydrokarbylsubstitusjonen på cefemkjernen, kan beskyttelsesgruppene fjernes ved anvendelse av konvensjonell teknikk. Passende karbonylbeskyttende grupper omfatter aralkylgrupper, såsom benzyl, metoksybenzyl og difenylmetyl(benzhydryl), alkyl, såsom t-butyl, og halogenalkyl, såsom 2,2,2-trikloretyl eller lignende. Passende amin- og hydroksy-beskyttende grupper omfatter trityl- og acylgrupper, såsom kloracetyl, formyl, t-butoksykarbonyl og karbobenzyl-oksy eller lignende. Det er åpenbart, at "Q" i formelen vist i tabellen betegner cefemkjernen som stammer fra triflåtene "V"og "VI (a,b)", og RI betegner den umettede alkylgruppe fra stannanen. Several cephem derivatives were prepared essentially as described above by the method according to the invention, except that the triflate (Tf) derivative used was replaced with 7-[2-(4-hydroxyphenyl)-2-aminoacetamido]- or 7-[( Z)-2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamido]-3-hydroxy-3-cephem-4-carboxylic acid and certain esters thereof, and that the hydrocarbyl-tributylstannanes listed in the table below was applied. The starting triflates (Tf) listed in the following table are the compounds denoted below by "V" and "VI (a,b)", in which all acid sites are protected in a conventional manner. After the coupling reaction to obtain the desired 3-hydrocarbyl substitution on the cephem nucleus, the protecting groups can be removed using conventional techniques. Suitable carbonyl protecting groups include aralkyl groups, such as benzyl, methoxybenzyl and diphenylmethyl (benzhydryl), alkyl, such as t-butyl, and haloalkyl, such as 2,2,2-trichloroethyl or the like. Suitable amine and hydroxy protecting groups include trityl and acyl groups, such as chloroacetyl, formyl, t-butoxycarbonyl and carbobenzyloxy or the like. It is obvious that "Q" in the formula shown in the table denotes the cephem nucleus derived from the triflates "V" and "VI (a,b)", and RI denotes the unsaturated alkyl group from the stannane.

Eksempel 15 Example 15

Dif eny Ime ty 1- 7- f envlacetamldo- 3-( N1- metvl- 2- lmidazolvl 1-3-cefem- 4- karboksylat Dif eny Ime ty 1- 7- f envlacetamldo- 3-( N1- metvl- 2- imidazolvl 1-3- cephem- 4- carboxylate

En blanding av 0,4645 g (0,00073 mol) difenylmetyl-7-fenylacetamido -3-trifluormetylsulfonyloksy-3-cefem-4-karboksylat, N<1->metyl-2-imdiazolyl-tributylstannan (0,271 g, 0,00073 mol), sinkklorid (0,020 g, 0,00146 mol) og tri(2-furyl)fosfin (0,0068 g, 0,000029 mol) i tørt l-metyl-2-pyrrolidinon (5 ml) ble avgasset under argonatmosfære, og palladium(0)-bis(di-benzyliden-aceton) (0,0084 g, 0,000014 mol) ble tilsatt. Reaksjonsblandingen ble omrørt ved romtemperatur natten over. Deretter ble etylacetat (30 ml) tilsatt og en fortynnet ammoniumkloridoppløsning. Det organiske laget ble vasket 3 ganger med vandig ammoniumklorid, tørket og inndampet. Acetonitril (30 ml) ble satt til resten, og oppløsningen ble vasket 3 ganger med pentan og deretter inndampet. Resten ble renset ved kromatografert på silisiumoksydgel under eluering med etylacetat og heksan. Utbytte: 0,767 g (19$) difenylmetyl-7-f enyl-acetamido-3-(N1-metyl-2-imidazolyl )-3-cefem-4-karboksylat. <*>N-NMR-spekteret stemte overens med den ønskede struktur. A mixture of 0.4645 g (0.00073 mol) diphenylmethyl-7-phenylacetamido -3-trifluoromethylsulfonyloxy-3-cephem-4-carboxylate, N<1->methyl-2-imdiazolyl-tributylstannane (0.271 g, 0.00073 mol), zinc chloride (0.020 g, 0.00146 mol) and tri(2-furyl)phosphine (0.0068 g, 0.000029 mol) in dry 1-methyl-2-pyrrolidinone (5 mL) was degassed under an argon atmosphere, and palladium(0)-bis(di-benzylidene-acetone) (0.0084 g, 0.000014 mol) was added. The reaction mixture was stirred at room temperature overnight. Then ethyl acetate (30 ml) was added and a dilute ammonium chloride solution. The organic layer was washed 3 times with aqueous ammonium chloride, dried and evaporated. Acetonitrile (30 mL) was added to the residue and the solution was washed 3 times with pentane and then evaporated. The residue was purified by chromatography on silica gel eluting with ethyl acetate and hexane. Yield: 0.767 g (19$) of diphenylmethyl-7-phenylacetamido-3-(N1-methyl-2-imidazolyl)-3-cephem-4-carboxylate. <*>The N-NMR spectrum was consistent with the desired structure.

Forbindelsene med formel (I), som blir fremstilt ved fremgangsmåten ifølge den foreliggende oppfinnelse kan tilveie-bringes som farmasøytisk akseptable syreaddisjons- og basesalter, hvor henholdsvis anionet eller kationet ikke bidrar signifikant til toksisiteten av saltet, og hvor The compounds of formula (I), which are produced by the method according to the present invention, can be provided as pharmaceutically acceptable acid addition and base salts, where respectively the anion or the cation does not contribute significantly to the toxicity of the salt, and where

-saltene er forenlige med konvensjonelle, farmasøytisk - the salts are compatible with conventional, pharmaceutical

akseptable bærere og andre konvensjonelle adjuvanser og tilsetningsstoffer, som vanligvis anvendes ved fremstilling av farmasøytiske preparater for oral eller parenteral administrasjon. Syreaddisjonssaltene dannes på konvensjonell måte ved omsetting av forbindelser med formel (I) med mineralsyrer, som f.eks. saltsyre, brombrintsyre, fosforsyre eller svovelsyre, eller med organiske karboksylsyrer eller sulfonsyrer, som f.eks. eddiksyre, sitronsyre, maleinsyre, ravsyre, benzosyre, vinsyre, askorbinsyre, metansulfonsyre, etansulfonsyre, p-toluensulfonsyre eller lignende. acceptable carriers and other conventional adjuvants and additives, which are usually used in the preparation of pharmaceutical preparations for oral or parenteral administration. The acid addition salts are formed in a conventional manner by reacting compounds of formula (I) with mineral acids, such as e.g. hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or with organic carboxylic acids or sulphonic acids, such as e.g. acetic acid, citric acid, maleic acid, succinic acid, benzoic acid, tartaric acid, ascorbic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid or the like.

Farmasøytisk akseptable basesalter dannes på konvensjonell måte ved omsetning av forbindelsene med formel (I) med alkalimetallbaser (Na, K) og jordalkalimetallbaser (Ba, Zn, Mg), fortrinnsvis med alkalimetallbaser, som f.eks. fortynnede oppløsninger av natriumhydroksyd, kaliumkarbonat og natriumbikarbonat. Farmasøytisk akseptable basesalter dannes også på konvensjonell måte ved omsetning med aminer, som f.eks. trietylamin, dibenzylamin, N,N'-dibenzyletylendiamin, prokain eller lignende aminer. Pharmaceutically acceptable base salts are formed in a conventional manner by reacting the compounds of formula (I) with alkali metal bases (Na, K) and alkaline earth metal bases (Ba, Zn, Mg), preferably with alkali metal bases, such as e.g. dilute solutions of sodium hydroxide, potassium carbonate and sodium bicarbonate. Pharmaceutically acceptable base salts are also formed in a conventional manner by reaction with amines, such as e.g. triethylamine, dibenzylamine, N,N'-dibenzylethylenediamine, procaine or similar amines.

Farmasøytisk akseptable estere omfatter slike estere, som er aktive i seg selv, eller som fungerer som pro-legemidler ved hydrolyse i kroppen for oppnåelse av det aktive antibiotikum. Egnede estere av sistnevnte type omfatter fenacyl, acetoksy-metyl, pivaloyloksymetyl, O-acetoksybenzyl, 3-ftalidyl, 5-indalyl, metoksymetyl, benzyloksy-metyl, glycyoksymetyl, og andre estere kjent ved cefalosporin- og penicillinfremstil-ling. Pharmaceutically acceptable esters include such esters, which are active in themselves, or which function as prodrugs upon hydrolysis in the body to obtain the active antibiotic. Suitable esters of the latter type include phenacyl, acetoxymethyl, pivaloyloxymethyl, O-acetoxybenzyl, 3-phthalidyl, 5-indalyl, methoxymethyl, benzyloxymethyl, glycyoxymethyl, and other esters known in cephalosporin and penicillin manufacture.

Den følgende tabellen illustrerer aktiviteten av flere representative forbindelser fremstilt ved fremgangsmåten ifølge den foreliggende oppfinnelse. The following table illustrates the activity of several representative compounds prepared by the method of the present invention.

Claims

1. Process for the preparation of a 3-substituted-3-cephem derivative of the formula (I) where r! is 1-alkenyl with 2-4 carbon atoms and optionally substituted with ethoxy, 1-dienyl, 1-alkynyl with 2-4 carbon atoms, methoxyphenyl and N-methylimidazolyl, and Q is phenylacetyl, a group of the formula where G is phenyl, optionally substituted with hydroxy, and G' is amino, or a group where G" is thiazole, which is possibly substituted with amino or diphenylmethyl or the pivaloyloxymethyl ester thereof, characterized by (a) reacting a starting compound of formula (II) where Tf is the trifluoromethanesulfonyloxy group, CF3S(0)-, and Q is the above-mentioned meaning, or the diphenylmethyl ester or the pivaloyloxymethyl ester thereof, in an aprotic solvent with at least one equimolar amount of an R^-tributyltin in the presence of 1-10 mol$ of a Pd°- or Pd<II-> compound and 3-30 mol$ tri(2-furyl)phosphine and 0-7 molar equivalents of ZnCl2 at 20-65°C for 1-75 hours, and b) recovering the 3-substituted 3-cephem derivative of formula (I) or diphenylmethyl or the pivaloyloxymethyl ester thereof.

2. Method according to claim 1, characterized in that the reactants in step (a) are reacted at 25-50°C for 1-72 hours.

3. Method according to claims 1-2, characterized in that the Pd compound used in step (b) is bis(dibenzylidene-acetonyl) palladium or palladium(II) acetate.

4. Method according to claims 1-3, characterized in that the Pd compound used is bis(dibenzylidene-acetonyl) palladium.

5. The compound 3-trifluoromethanesulfonyloxy-3-cephem, characterized in that it has the formula where Tf denotes the trifluoromethanesulfonyloxy group CF3S(0)_, and Q has the meaning stated in claim 1 or the diphenylmethyl ester thereof.