DK157137B - PROCEDURE FOR THE PREPARATION OF SUBSTITUTED 3-METHYLENCEPHAM SULPHOXIDES - Google Patents

Description

DK 157137 BDK 157137 B

Denne opfindelse angâr en ny fremgangsmâde til fremstilling af 3-methylencephamsulfoxider, sont er nyttige mellemprodukter ved fremstilling af cephem-antibiotica.This invention relates to a novel process for the preparation of 3-methylencepham sulfoxides, which are useful intermediates in the preparation of cephem antibiotics.

Penicilliner og for nylig cephalosporiner er anerkendt for deres 1103e antibakterielle virkning, og disse midler har fundet udstrakt anvendelse ved behandling af infektionssygdomme. Der foregâr i disse âr en betragtelig forskningsindsats med det mal at kemisk modificere disse forbindelser, idet man ssger efter endnu mere aktive β-lactam-antibiotica. Isser bar man lagt afgzrende vægt pâ at variere C6-acylaminosubstituenten i penicillinforbindelser og bâde C 7-acylamino-substituenten og C3-substituenten i cephem-forbindelser.Penicillins and more recently cephalosporins are recognized for their 1103e antibacterial activity, and these agents have been widely used in the treatment of infectious diseases. These years there is considerable research effort to chemically modify these compounds, searching for even more active β-lactam antibiotics. Issues were essential to vary the C6 acylamino substituent in penicillin compounds and both the C7 acylamino substituent and the C3 substituent in cephem compounds.

l'or nylig bar R.R. Chauvette og P.A. Pennington rapporteret anven-delsen af 3-methylencephamforbindelser, bâde ved fremstilling af 7-amino-desacetoxycephalosporansyre og biologisk aktive derivater deraf [Journal of Organic Chemistry, 38, 2994 (1975)] og til fremstilling af nye 3-methoxy og 3-balogen-cepbemforbindelser [Journal of tbe American Chemical Society, 96, 4986 (1974)]. I bvert til-fælde fremstilledes 3-methylencepham-mellemprodukterne ud fra ce-phalosporansyrer ved fzrst at behandle disse med udvalgte svovl-nucleophiler, sâsom tbiourinstof, thiobenzoesyre, kaliumethylxan-tbat eller natriumthiosulfat og berefter reducere de opnâede pro-dukter, nemlig C3-(substitueret)tbiometbylcepbem-derivaterne, med enten Raney-nikkel i vandig éthanol eller zink i myresyre-dimethyl-formamid. Den pâviste anvendelighed af 3-methylencepham-forbin-delserne som mellemprodukter til nye cephem-antibiotica har igang-sat en efterforskning efter alternative metoder til fremstilling af sâdanne forbindelser ud fra let tilgængelige og 0konomiske ud-gangsmaterialer.Recently, R.R. Chauvette and P.A. Pennington reported the use of 3-methylencepham compounds, both in the preparation of 7-amino-desacetoxycephalosporanoic acid and its biologically active derivatives [Journal of Organic Chemistry, 38, 2994 (1975)], and in the preparation of novel 3-methoxy and 3-balogenic compounds. cepbem compounds [Journal of tbe American Chemical Society, 96, 4986 (1974)]. In each case, the 3-methylencepham intermediates were prepared from cephalosporanic acids by first treating them with selected sulfur nucleophiles, such as thiourea, thiobenzoic acid, potassium ethylxane tbate or sodium thiosulfate, and preparing to reduce the obtained products. substituted) the thiometbylcepbem derivatives, with either Raney nickel in aqueous ethanol or zinc in formic acid dimethyl formamide. The demonstrated utility of the 3-methylencepham compounds as intermediates for novel cephem antibiotics has initiated an investigation of alternative methods for preparing such compounds from readily available and economical starting materials.

Den foreliggende opfindelee angâr en ny fremgangsmâde til fremstilling af 3-methylencephamsulfoxider ved intramolekylær cycli-sering af monocycliske azetidino-2-sulfinylchlorider og sulfin-syrer, sulfinatester, thiosuifinatester, sulfinamid og sulfin-imid-derivater deraf med Friedel-Craft-katalysatorer eller meta-thetisk kationdannende midler. Nogle af azetidinonsulfinsyre-deri-vateme. der anvendes som udeanssmateriale. er i sis: seîv nye.The present invention relates to a novel process for the preparation of 3-methylenecephamsulfoxides by intramolecular cyclization of monocyclic azetidino-2-sulfinyl chlorides and sulfinic acids, sulfinate ester, thiosulfinate ester, sulfinamide and sulfin-imide derivatives thereof with Friedel C -thetic cationic agents. Some of the azetidinone sulfinic acid therein. used as outdoor material. is in sis: seîv new.

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Opfindelsen angâr en fremgangsmâde til fremstilling af 3-methylen-cephamsulfoxider med den i krav 11 s indledning angivne almene formel I. Fremgangsmâden if0lge opfindelsen er ejendommelig ved det i krav l's kendetegnende del anfærte.The invention relates to a process for the preparation of 3-methylene-cephamsulfoxides of the general formula I as set forth in claim 11, the process of the invention being characterized by the characterizing part of claim 1.

DK patentans0gning nr. 3144/78, soin er afdelt fra nærværende ansogning, angâr forbindelser med formlen IIDK patent application no. 3144/78, soin is subdivided from the present application, concerning compounds of formula II

00

IIII

"V _ /x Γ I I 11„V _ / x Γ I I 11

/~\ /N/ ~ \ / N

COORCOOR

•1 hvori R , R og I har samme betydning som defineret i krav 1 med den undtagelse, at X er andet end chlor- brom eller en gruppe med formlen: -Vr7 hvori R6 er -COOR9 eller -COR9, og R7 er -NHCOOR9 eller -NHOOR9.1 wherein R, R and I have the same meaning as defined in claim 1, with the exception that X is other than chloro-bromo or a group of the formula: -Vr7 wherein R6 is -COOR9 or -COR9 and R7 is -NHCOOR9 or -NHOOR9.

I definitionerne refererer alkyl med 1-3 carbonatomer til methyl, ethyl, n-propyl eller isopropyl. Alkyl med 1-10 carbonatomer refererer til methyl, ethyl, propyl, isopropyl, cyclohexyl, sec-butyl, heptyl, octyl, isooctyl, decyl eller menthyl. Halogen-alkyl med 1-6 carbonatomer repræsenterer grupper, sâsom chlormethyl, bromethyl, iodethyl, 2-chlorpropyl, 2-chlorcyclohexyl eller 2-chlorbutyl. AryKC^ - C3 alkyl) omfatter benzyl, 2-phenylethyl, 2-phenylpropyl, 4-chlorbenzyl, naphthylmethyl eller 3-(2-nitro-phenyl)propyl. Eksempler pâ (C^-C^)alkoxycarbonyl' er methoxy-carbonyl, ethoxycarbonyl og isopropoxycarbonyl. Eksempler pâ halogenmethylgrupper er chlormethyl, brommethyl eller iodmethyl.In the definitions alkyl of 1-3 carbon atoms refers to methyl, ethyl, n-propyl or isopropyl. Alkyl of 1-10 carbon atoms refers to methyl, ethyl, propyl, isopropyl, cyclohexyl, sec-butyl, heptyl, octyl, isooctyl, decyl or menthyl. Haloalkyl of 1-6 carbon atoms represents groups such as chloromethyl, bromethyl, iodoethyl, 2-chloropropyl, 2-chlorocyclohexyl or 2-chlorobutyl. Ary (C 1 -C 3 alkyl) includes benzyl, 2-phenylethyl, 2-phenylpropyl, 4-chlorobenzyl, naphthylmethyl or 3- (2-nitrophenyl) propyl. Examples of (C ^-C ^) alkoxycarbonyl 'are methoxycarbonyl, ethoxycarbonyl and isopropoxycarbonyl. Examples of halo methyl groups are chloromethyl, bromomethyl or iodomethyl.

22

Imidogrupper, repræsenteret nâr R er alkenylen med 2-4 carbonatomer, er maleimido, 3-ethylmaleimido eller 3,4-dimethylma-leimido. Imidogrupper, der repræsenteres, nâr R er 1,2-cyclo- 3Imido groups represented when R is the alkenylene having 2-4 carbon atoms are maleimido, 3-ethylmaleimido or 3,4-dimethylmalimido. Imido groups represented when R is 1,2-cyclo-3

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hexenylen eller 1,2-phenylen, er 3,4,5,6-tetrahydrophthalimido ell.er phthalimido.hexenylene or 1,2-phenylene, is 3,4,5,6-tetrahydrophthalimido or phthalimido.

Nâr R" i definitionen repræsenterer en substitueret phenylgruppe, kan R" være en mono- eller disubstitueret halogenphenylgruppe, sâ-som 4-chlorphenyl, 2,6-dichlorphenyl, 2,5-dichlorphenyl, 354-di-cb.lorph.enyl, 3-chlorphenyl, 3-bromphenyl, 4-bromphenyl, 3,4-dibrom-phenyl, 3-*chlor-4-fluorphenyl eller 2-fluorphenyl ; en beskyttet hydroxyphenylgruppe, sâsom 4-benzyloxyphenyl, 3-benzyloxyphenyl, 4-tert-butoxyphenyl, 4-tetrahydropyranyloxyphenyl, 4-(4-nitro-benzyloxy)phenyl, 2-phenacyloxyphenyl, 4-benzhydroxyphenyl eller 4-trityloxyph.enyl; en nitrophenylgruppe, sâsom 3-nitrophenyl eller 4-nitrophenyl; en cyanophenylgruppe, for eksempel 4-cyanophenyl; en mono-eller dialkylsubstitueret phenylgruppe, sâsom 4-methyl-phenyl, 2,4-dimethylphenyl, 2-ethylphenyl, 4-isopropylphenyl, 4-ethylphenyl eller 3-n-propylphenyl; en mono- eller dialkoxyphenyl-gruppe, for eksempel 2,6-dimethoxyphenyl, 4-methoxyphenyl, 3-ethoxyphenyl, 4-isopropoxyphenyl, 4-tert-butoxyphenyl eller 3-ethoxy-4-methoxyphenyl. Endvidere repræsenterer R" disubstituerede phenylgrupper, hvori substituenterne kan være forskellige, for eksempel 3-methyl-4-methoxyphenyl, 3-chlor-4-benzyloxyphenyl, 2-methoxy-4-bromphenyl, 4-ethyl-2-methoxyphenyl, 3-chlor-4-nitro-phenyl og 2-methyl-4-chlorphenyl og lignende disubstituerede phenylgrupper, der har forskellige substituenter.Where R "in the definition represents a substituted phenyl group, R" may be a mono- or disubstituted halo-phenyl group, such as 4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 354-di-cb.-chlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3,4-dibromo-phenyl, 3- * chloro-4-fluorophenyl or 2-fluorophenyl; a protected hydroxyphenyl group such as 4-benzyloxyphenyl, 3-benzyloxyphenyl, 4-tert-butoxyphenyl, 4-tetrahydropyranyloxyphenyl, 4- (4-nitro-benzyloxy) phenyl, 2-phenacyloxyphenyl, 4-benzhydroxyphenyl or 4-benzhydroxyphenyl a nitrophenyl group, such as 3-nitrophenyl or 4-nitrophenyl; a cyanophenyl group, for example 4-cyanophenyl; a mono- or dialkyl-substituted phenyl group, such as 4-methylphenyl, 2,4-dimethylphenyl, 2-ethylphenyl, 4-isopropylphenyl, 4-ethylphenyl or 3-n-propylphenyl; a mono- or dialkoxyphenyl group, for example 2,6-dimethoxyphenyl, 4-methoxyphenyl, 3-ethoxyphenyl, 4-isopropoxyphenyl, 4-tert-butoxyphenyl or 3-ethoxy-4-methoxyphenyl. Furthermore, R "represents disubstituted phenyl groups wherein the substituents may be different, for example 3-methyl-4-methoxyphenyl, 3-chloro-4-benzyloxyphenyl, 2-methoxy-4-bromophenyl, 4-ethyl-2-methoxyphenyl, 3-chloro -4-nitro-phenyl and 2-methyl-4-chlorophenyl and similar disubstituted phenyl groups having different substituents.

Beskyttet amino refererer til en aminogruppe, der er substitueret med en af de almindeligt anvendte aminoblokerende grupper, sâsom tert-butoxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbo-nyl, 4-nitrobenzyloxycarbonyl, 2,2,-trichlorethoxycarbonyl eller 1-carbomethoxy-2-propenyl dannet med methylacetoacetat. lignende aminobeskyttende grupper, sâsom dem, der er beskrevet af J.¥.Protected amino refers to an amino group substituted by one of the commonly used amino blocking groups such as tert-butoxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2,2, -trichloroethoxycarbonyl or 1-carboxy formed with methyl acetoacetate. similar amino protecting groups, such as those described by J. ¥.

Barton i "Protective G-roups in Organic Ohemistry", J.P.W. McOmie, Ed., Plénum Press, New York, N.Y., 1973, kapitel 2, kan ogsâ an-vendes.Barton in "Protective G-roups in Organic Ohemistry", J.P.W. McOmie, Ed., Plénum Press, New York, N.Y., 1973, Chapter 2, may also be used.

Beskyttet hydroxy refererer til let spaltelige grupper, dannet med en hydroxy gruppe,.sâsom fo'rmyloxy, chloracetoxy, benzyloxy, benz-hydryloxy, trityloxy, 4-nitrobenzyloxy, trimethylsilyloxy, phen- 4Protected hydroxy refers to readily cleavable groups formed with a hydroxy group such as formyloxy, chloroacetoxy, benzyloxy, benzhydryloxy, trityloxy, 4-nitrobenzyloxy, trimethylsilyloxy, phenyl

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aeyloxy, tert-butyloxy, metboxymethoxy, tetrabydropyranyloxy og lig-nende. André hydroxybeskyttende grupper inklusive de, der er be-skrevet af C.B. Reese i "Protective Groups in Organic Obemistry", supra, Kapitel 3, kan ogsâ anvendes.aeyloxy, tert-butyloxy, metboxymethoxy, tetrabydropyranyloxy and the like. Other hydroxy protecting groups including those described by C.B. Reese in "Protective Groups in Organic Obemistry," supra, Chapter 3, may also be used.

Carboxylsyrebeskyttende grupper er grupper, der anvendes til at blokere eller beskytte carboxylsyrefunktionen, medens reaktionerne omfatter andre funktionelle grupper i forbindelsen. Sâdanne carb-oxybeskyttende grupper er let fjernelige ved hydrolyse eller ved bydrogenering. Eksempler pâ carboxysyreesterbeskyttende grupper omfatter metbyl, tert-butyl, benzyl, 4-metboxybenzyl, alkanoyloxy-metbyl med 2-6 carbonatorner, 2-iodethyl, 4-nitrobenzyl, diphenyl-metbyl (benzbydryl), pbenacyl, 4-balogenpbenacyl, dimethylallyl, 2,2,2-trichloretbyl, tri(C^ - C^-alkyl)silyl eller succin-imidomethyl. Andre kendte carboxylbeskyttende grupper, sâ-som de, der er beskrevet af E. Haslam i "Protective G-roups in Organic Obemistry", supra, Kapitel 5, kan ogsâ anvendes. Arten af en sâdan esterdannede gruppe er ikke kritisk.Carboxylic acid protecting groups are groups used to block or protect the carboxylic acid function, while the reactions include other functional groups in the compound. Such carboxy protecting groups are readily removable by hydrolysis or by urbanization. Examples of carboxylic acid ester protecting groups include methyl, tert-butyl, benzyl, 4-methoxybenzyl, alkanoyloxy-methyl with 2-6 carbon atoms, 2-iodoethyl, 4-nitrobenzyl, diphenylmethyl (benzbydryl), pbenacyl, 4-balogenpbenacyl, , 2,2-trichloroethyl, tri (C 1 -C 4 alkyl) silyl or succin imidomethyl. Other known carboxyl protecting groups, such as those described by E. Haslam in "Protective G-roups in Organic Obemistry", supra, Chapter 5, may also be used. The nature of such an ester-formed group is not critical.

Nar azetidinonsulfinsyre-derivatet, der anvendes som udgangsmate-riale ved fremgangsmâden, beskyttes med en syrelabil carboxybeskyt-tende gruppe, sâsom 4-metboxybenzyl, benzhydryl, tert-butyl eller tri(alkyl med 1-3 carbonatomer)silyl, er produktet, der fremkom-mer ved cyclisering ifelge opfindelsen, en 3-exometbylencepbam-sulfoxidsyre. Hvis pâ lignende mâde udgangsmaterialet har lignen-de syrelabile bydroxy- eller aminobeskyttende grupper, vil disse grupper sædvanligvis fjemes under de sure betingelser, der fore-ligger ved den omhandlede cycliseringsmetode. Pjernelse af visse syrelabile beskyttende grupper under reaktionsbetingelserne er ikke et kritisk træk ved opfindelsen. De beskyttende grupper pâ azetidinon-udgangsmaterialerne er til stede, fordi det er nedvendigt at beskytte deres precursor-penicillinsulfoxid under fremstillingen af de mellemliggende azetidinonsulfinylhalogenider. Sâledes er det primære formâl med de beskyttende grupper ikke at beskytte de reaktive funktionelle grupper under fremstilling af udgangsmaterialeme. Arten af de beskyttende grupper er ikke kritisk ved den omhandlede fremgangsmâde. Der noteres ingen signifi-kant reaktion af udbyttet af exometbylencepbamsulfoxid, nâr syre- 5When the azetidinone sulfinic acid derivative used as starting material in the process is protected by an acid-labile carboxy-protecting group, such as 4-methboxybenzyl, benzhydryl, tert-butyl or tri (alkyl of 1-3 carbon atoms) silyl, the product obtained is by cyclization according to the invention, a 3-exometbylene cepbam sulfoxic acid. Similarly, if the starting material has similar acid labile bydroxy or amino protecting groups, these groups will usually be removed under the acidic conditions of the present cyclization method. Depletion of certain acid labile protecting groups under the reaction conditions is not a critical feature of the invention. The protecting groups on the azetidinone starting materials are present because it is necessary to protect their precursor penicillin sulfoxide during the preparation of the intermediate azetidinone sulfinyl halides. Thus, the primary purpose of the protecting groups is not to protect the reactive functional groups during the preparation of the starting materials. The nature of the protecting groups is not critical to the method in question. No significant reaction of the yield of exometbylene cepbam sulfoxide is noted when acid

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labile beskyttende grupper fjemes. I sâdanne tilfælde er den eneste forskel, at de opnâede produkter typisk er cephamsyrer i stedet for cephamestere. Da en pâf0lgende omdannelse sædvanligvis foretages, foretrækkes det, at de reaktive funktionelle grupper i produktet forbliver beskyttet under cycliseringsprocessen. Ikke-syrelabile beskyttende grupper foretrækkes derfor. De foretrukne carboxylsyreesterbeskyttende grupper er methyl, 2-iodethyl, 4-nitrobenzyl, 4-balogenphenacyl og 2,2,2-trich.lorethyl.labile protective groups are removed. In such cases, the only difference is that the products obtained are typically cepham acids rather than cepham esters. As a subsequent conversion is usually carried out, it is preferred that the reactive functional groups in the product remain protected during the cyclization process. Non-acid labile protecting groups are therefore preferred. The preferred carboxylic acid ester protecting groups are methyl, 2-iodoethyl, 4-nitrobenzyl, 4-balogenphenacyl and 2,2,2-trichloroethyl.

I de foregâende definitioner er hydroxy-, amino- og carboxylbeskyt-tende grupper ikke komplet defineret. Punktionen af sâdanne grupper er at beskytte den reaktive funktionelle gruppe under fremstil-lingen af udgangsmaterialerne og berefter pâ et senere tidspunkt at blive fjernet uden at 0delægge resten af molekylet. Mange sâdanne beskyttende grupper er velkendte inden for videnskaben.In the foregoing definitions, hydroxy, amino and carboxyl protecting groups are not fully defined. The point of such groups is to protect the reactive functional group during the preparation of the starting materials and, at a later date, attempts to be removed without destroying the rest of the molecule. Many such protective groups are well known in science.

0 •5»0 • 5 »

Repræsentative for acylaminogruppen, R CNÏÏ- er formamido, acetamido, propionamido, butyramido, 2-pentenoylamido, chloracetamido, brom-acetamido eller 5-tert-butoxycarbonylamido-5-tert-butoxycarbonyl-valeramido.Representatives of the acylamino group, R CNÏÏ - are formamido, acetamido, propionamido, butyramido, 2-pentenoylamido, chloroacetamido, bromo-acetamido or 5-tert-butoxycarbonylamido-5-tert-butoxycarbonyl-valeramido.

gg

Belysende for den særlige acylaminogruppe R"CNH- er benzamido, 2,6-dimetlioxybenzaiiiido, 4-chlorbenzamido, 4-methylbenzamido, 3,4-dichlorbenzamido, 4-cyanobenzamido, 3-brombenzamido eller 3-nitro-benzamido.Illustrative of the particular acylamino group R "CNH- are benzamido, 2,6-dimethylioxybenzamido, 4-chlorobenzamido, 4-methylbenzamido, 3,4-dichlorobenzamido, 4-cyanobenzamido, 3-bromobenzamido or 3-nitrobenzamido.

0 3" 30 3 "3

Eksempler pâ acylaminogruppen R^CNH, .nâr R er en gruppe med formlen R" ( og m er 0, er cyclohexa-1,4-dienylacetamido, phenylacetamido, 4-ciilorpbenylacetamido, 3-methoxyph.enylacetamido, 3-cyanophenylacetamido, 3-methylphenylacetamido, 4-bromph.enyl-acetamido, 4-ethoxyphenylacetamido, 4-nitrophenylacetamido eller 3.4- dimethoxyphenylacetamido, og nâr m er 1, er repræsentative acylaminogrupper phenoxyacetamido, 4-cyanoph.enoxyacetamido, 4-chlorpbenoxyacetamido, 3,4-dich.lorpbenoxyacetamido, 2-cblorpben-oxyacetamido, 4-methoxypbenoxyacetamido, 2-eth.oxyphenoxyacetamido, 3.4- dimethylphenoxyacetamido, 4-isopropylphenoxyacetamido, 3-cyano-phenoxyacetamido og 3-nitrophenoxyacetamido.Examples of the acylamino group R ^ CNH when R is a group of formula R "(and m is 0 are cyclohexa-1,4-dienylacetamido, phenylacetamido, 4-cililorbenbenacetamido, 3-methoxyphenylacetamido, 3-cyanophenylacetamido, 3- methylphenylacetamido, 4-bromophenylacetamido, 4-ethoxyphenylacetamido, 4-nitrophenylacetamido or 3,4-dimethoxyphenylacetamido, and when m is 1, representative acylamino groups are phenoxyacetamido, 4-cyanophenoxyacetamido, 4-chloroacetamoxy, 4-chloroacetamoxy, 4-chloro , 2-chlorobenoxyacetamido, 4-methoxypbenoxyacetamido, 2-ethoxyphenoxyacetamido, 3,4-dimethylphenoxyacetamido, 4-isopropylphenoxyacetamido, 3-cyano-phenoxyacetamido and 3-nitrophenoxyacetamido.

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66

Belysende for acylaminogruppen, nâr R er en substitueret arylalkylgruppe med formlen R'’'-GÏÏ-, og W er en beskyttet ¥ bydroxygrappe, er 2-f ormyloxy-2-phenylacetainido, 2-benzyloxy-2-(4-metboxypbenyl)acetamido, 2-(4-nitrobenzyloxy)-2-( 3-cblorphenyl)-acetamido, 2-cbloracetoxy-2-(4-metboxypbenyl)acetamido, 2-benzyl-oxy-2-pbenylacetamido, 2-trimethylsilyloxy-2-(4-cblorpbenyl)acet-amido eller 2-benzbydryloxy-2-phenylacetamido. Repræsentativt for sâdanne grupper, bvori ¥ er en besmyttet amino, er 2-(4-nitro-benzyloxycarbonylamino)-2-pbenylacetamido, 2-(2,2,2-tricbloretboxy-carbonylamino)-2-pbenylacetamido, 2-chloracetamido-2~(1,4-cyclo-hexadien-1-y1)acetamido, 2-(4~metboxybenzyloxycarbonylamino)-2-(4-methoxyphenyl)acetamido, 2-benzbydryloxycarbonylamino-2-pbenyl-acetamido eller 2-(1-carbometboxy-2-propenyl)amino-2-phenylacet-amido.Illustrative of the acylamino group, when R is a substituted arylalkyl group of formula R R - GÏÏ - and W is a protected γ-hydroxy group, 2-formylloxy-2-phenylacetamido, 2-benzyloxy-2- (4-methboxypbenyl) acetamido , 2- (4-nitrobenzyloxy) -2- (3-chlorophenyl) -acetamido, 2-chloroacetoxy-2- (4-methboxypbenyl) acetamido, 2-benzyl-oxy-2-pbenylacetamido, 2-trimethylsilyloxy-2- (4 (chlorobenyl) acetamido or 2-benzbydryloxy-2-phenylacetamido. Representative of such groups, wherein it is a contaminated amino, is 2- (4-nitro-benzyloxycarbonylamino) -2-pbenylacetamido, 2- (2,2,2-tricloroboro-carbonylamino) -2-pbenylacetamido, 2-chloroacetamido-2 ~ (1,4-cyclohexadien-1-yl) acetamido, 2- (4-methoxybenzyloxycarbonylamino) -2- (4-methoxyphenyl) acetamido, 2-benzbydryloxycarbonylamino-2-pbenylacetamido or 2- (1-carbomethoxy) 2-propenyl) amino-2-phenylacet-amido.

-jj

Repræsentative for R , nâr R·*· er en imidogruppe med formlen: 0Representative of R when R · * · is an imido group of the formula: 0

IIII

"V"V

R..-(°) en/ m 2„ 0 er N-acetyl-N-pbenylacetylamino, N-tricbloretboxycarbonyl-N-pbenoxy-acetylamino, N-propoxycarbonyl-N-(4-cblorpbenoxy)acetylamino eller N-(2-bromacetyl)-N-pbenoxyacetylamino.R ..- (°) en / m 2 0 is N-acetyl-N-pbenylacetylamino, N-tricloroethoxycarbonyl-N-pbenoxyacetylamino, N-propoxycarbonyl-N- (4-chlorobenoxy) acetylamino or N- (2- bromoacetyl) -N-pbenoxyacetylamino.

0 3" 30 3 "3

Eksempler pâ acylaminogruppen R CNH-, nâr R er en heteroarylmethyl-gruppe med formlen R,n,-CH2-, er 2-tbienylacetamido, 3-tbienyl-acetamido, 2-furylacetamido, en 2-thiazolylacetamidogruppe med formlen: Π .Examples of the acylamino group R CNH- when R is a heteroarylmethyl group of formula R, n, -CH2- are 2-tbienylacetamido, 3-tbienyl-acetamido, 2-furylacetamido, a 2-thiazolylacetamido group of formula: Π.

\/\ " S CH CNH- 2 7\ / \ "S CH CNH- 2 7

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eller en 3-(2-chlorp]ienyl)-5Hmetliylisoxazol-4-ylamidogruppe med formlen Λ--·.or a 3- (2-chloropyridinyl) -5H-methylisoxazol-4-ylamido group of formula Λ-- ·.

OISLAND

__/~y Γ "\ « L/~cnh"__ / ~ y Γ "\« L / ~ cnh "

XCHXCH

3 1 13 1 1

Repræsentative for R , nâr R er en imidazolidinylgruppe med form-len : 0Representative of R when R is an imidazolidinyl group of the formula: 0

IIII

R"\ /\ I ^ 3 er 2,2-dimethyl-3-nltroso-5-oxo-4~plienyl-1-imidazolidinyl, 2,2-dimethyl-3-nitroso-5-oxo-4-(4-'benzyloxypIienyl)-1-imidazolidinyl, 2,2-dimeth.yl-3-acetyl-5-oxo-4-( 1,4-cyclohexadien-1 -yl) -1 -imidazo-lidinyl eller 2,2-dimetiiyl“3-nitroso-5-oxo-4-(2-th.ienyl)-1-imida-zolidinyl.R 2 is 3,2,2-dimethyl-3-nitroso-5-oxo-4-pyrienyl-1-imidazolidinyl, 2,2-dimethyl-3-nitroso-5-oxo-4- (4- (benzyloxypienyl) -1-imidazolidinyl, 2,2-dimethyl-3-acetyl-5-oxo-4- (1,4-cyclohexadien-1-yl) -1-imidazo-lidinyl or 2,2-dimethyl 3-nitroso-5-oxo-4- (2-th.ienyl) -1-imidazole-zolidinyl.

G-enerelt angâr den omhandlede fremgangsmâde cyclisering af azeti-dinonsulfinsyrederivater afledt af penicillinsulfoxid ved en Rriedel-Craft s-katalysator-induceret intramolekylær reaktion mellem sulfi-nyl og de olefiniske funktioner i azetidinonringen, Denne interne alkylsulfineringsreaktion kan anses som en arialog med Rriedel-Craf t s-acyleringsreaktionen, hvori sulfinylgruppen 0 8G, in general, relates to the process of cyclization of azetidinone sulfinic acid derivatives derived from penicillin sulfoxide by a Rriedel-Craft s catalyst-induced intramolecular reaction of sulfinyl and the olefinic functions of the azetidinone ring with this internal alkyl sulfation reaction. The t-acylation reaction wherein the sulfinyl group is 0 8

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0 n indsættes i stedet for en carbonylgruppe (-C-), og produktet er et sulfoxid i stedet for en keton. I literaturen er beskrevet mindst tre sulfinyleringsreaktioner af Friedel-Crafts-type. Isaer er den intermolekylære arensulfinylering af aromatiske forbindelser, der giver diarylsulfoxider, beskrevet [0. Courtot og J. Erenkiel, C.R. Acad. Sci., 199, 557 (1954); George A. Olah og Jun NisMraura, J. Org. Chem., 39, 1203 (1973); og Irwin B. Douglass og Basil Said Earah, J. Org. Chem., 23, 805 (1958)]. I en analog reaktion reagerer alkyl eller arylsulfenylchlorider med aromatiske carbon-hydrider i nærværelse af aluminiumchloridkatalysatoren til opnâ-else af thioethere i gode udbytter [H. Britzinger og M. langheck, Ber., 86, 557 (1953)]. Omsætningen mellem alkyl eller arylsulfon-syrechlorider og aromatiske forbindelser til opnâelse af sulfoner er underszgt meget grundigt. Se for eksempel George A. Olah, "Friedel-Crafts Chemistry", John ¥iley and Sons,»Inc., New York, N.Y., 1973, pp. 122-12, 146, 507. Der er ikke tidligere beskrevet intramolekylær alkylsulfinylering af den art, der er beskrevet heri. Intramolekylær cyclisering af carboxylsyrer og derivater ieraf med Rriedel-Craft-katalysatorer til fremstilling af cycliske ketoner er imidlertid veldokumenteret i den kemiske literatur. Se William S. Johnson i "Organic Reactions", Roger Adams et al., Eds., John Wiley and Sons, Inc., New York, N.Y., 1944, Kapitel 4, pp. 130-177 og "Eriedel-Crafts Chemistry", supra.0 n is substituted for a carbonyl group (-C-) and the product is a sulfoxide instead of a ketone. The literature describes at least three Friedel-Crafts type sulfinylation reactions. In particular, the intermolecular arenesulfinylation of aromatic compounds giving diarylsulfoxides is described [0. Courtot and J. Erenkiel, C.R. Acad. Sci., 199, 557 (1954); George A. Olah and Jun NisMraura, J. Org. Chem., 39, 1203 (1973); and Irwin B. Douglass and Basil Said Earah, J. Org. Chem., 23, 805 (1958)]. In an analogous reaction, alkyl or arylsulfenyl chlorides react with aromatic hydrocarbons in the presence of the aluminum chloride catalyst to give thioethers in good yields [H. Britzinger and M. langheck, Ber., 86, 557 (1953)]. The reaction between alkyl or arylsulfonic acid chlorides and aromatic compounds to obtain sulfones has been investigated very thoroughly. See, for example, George A. Olah, "Friedel-Crafts Chemistry", John ¥ iley and Sons, Inc., New York, NY, 1973, pp. 122-12, 146, 507. Intramolecular alkyl sulfinylation of the species described herein. However, intramolecular cyclization of carboxylic acids and derivatives thereof with Rriedel-Craft catalysts to produce cyclic ketones is well documented in the chemical literature. See William S. Johnson in "Organic Reactions," Roger Adams et al., Eds., John Wiley and Sons, Inc., New York, NY, 1944, Chapter 4, pp. 130-177 and "Eriedel-Crafts Chemistry" , supra.

Det har nu overraskende vist sig, at den konventionelle Eried’el-It has now surprisingly been found that the conventional Eried'el-

Craft s-acyleringsmetode, inklusive reaktionsbetingelserf oplasnings-midler og katalytiske midler,med held kan anvendes generelt til intramolekylær cyclisering af asetidinonsulfinylchlorider og dérivât er deraf.Craft s-acylation method, including reaction conditions of solvents and catalytic agents, can be successfully used generally for intramolecular cyclization of acetidinone sulfinyl chlorides and derivatives thereof.

Udgangsmateri.alerne ved den omhandlede fremgangsmâde i form af azetidinonsulfinylchlorid afledes fra tilsvarende kendte penicil-linsulfoxidestre ved at omsætte sâdanne estre ved hzj temperatur med et reagens, der tjener som en positiv halogenforbindelser for-• trinsvis en N-halogenimid,sâsom N-chlorsuccinimid . Omdannelsen af 6-imidopenicillinsulfoxidestre til tilsvarende sulfinylchlorider med sulforylchlorid er beskrevet i literaturen [S. Kukolja og S.R. Lammert, Angew. Chem., 12, 67-68 (1973)]. Generelt fremstilles 9The starting materials of the present process in the form of azetidinone sulfinyl chloride are derived from similarly known penicillin sulphoxide esters by reacting such esters at high temperature with a reagent which serves as a positive halogen compounds preferably an N-halogenimide such as N-chloride. The conversion of 6-imidopenicillin sulfoxide esters to corresponding sulfinyl chlorides with sulforyl chloride is described in the literature [S. Kukolja and S.R. Lammert, Angew. Chem., 12, 67-68 (1973)]. Generally manufactured 9

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de omhandlede sulfinylchloridudgangsmaterialer ved at omsætte en penicillinsulfoxidester med ca. 1,1 ækvivalent N-chlorsuccinimid i et t0rt inert organisk oplzsningsmiddel, fortrinsvis 1,1,2-tri-chlorethan eller toluen, ved en temperatur pâ 70 - 120 °C, idet den foretrukne temperatur er afhængig af Cg-substituentens natur. Omdannelsen af Cg-imidopenicillinsulfoxider udfzres sædvanligvis ved 70 - 100 °C, medens lidt hzjere temperaturer (100-120 °C) foretrækkes til sulfinylchloridfremstilling ud fra Cg-acylamino-penicillinsulfoxider. Reaktionen er sædvanligvis tilendebragt pâ 45-90 minutter ved den foretrukne reaktionstemperatur. Peni-cillinsulfoxidester-precusorer til sulfinylchlorider er enten kendte eller let tilgængelige forbindelser, hvoraf mange har været anvendt ved fremstilling af cephemforbindelser. De fremstilles ud fra kendte 7-acylamino og 7-imidopenicillinsyrer ved (1) esteri-ficering og (2) pâfzlgende oxidation, sædvanligvis med metachlor-perbenzoesyre eller natriumperiodat.the present sulfinyl chloride starting materials by reacting a penicillin sulfoxide ester with ca. 1.1 equivalent of N-chlorosuccinimide in a dry inert organic solvent, preferably 1,1,2-trichloroethane or toluene, at a temperature of 70-120 ° C, the preferred temperature being dependent on the nature of the C8 substituent. The conversion of Cg-imidopenicillin sulfoxides is usually carried out at 70-100 ° C, while slightly higher temperatures (100-120 ° C) are preferred for sulfinyl chloride preparation from Cg-acylamino-penicillin sulfoxides. The reaction is usually completed in 45-90 minutes at the preferred reaction temperature. Penicillin sulfoxide ester precusors for sulfinyl chlorides are either known or readily available compounds, many of which have been used in the preparation of cephem compounds. They are prepared from known 7-acylamino and 7-imidopenicillic acids by (1) esterification and (2) subsequent oxidation, usually with metachloroperbenzoic acid or sodium periodate.

Eksempler pâ fremstilling af azetidinonsulfinylchloridudgangsma-terialerne anvendt i den omhandlede fremgangsmâde eksemplificeres med fzlgende korte beskrivelse af fremstillingen af 4'-nitrobenzyl-3-methyl-2-(2-chlorsulfinyl-4~oxo-3-acetamido-1-azetidinyl)-3-butenoat: En oplosning af 5 millimol 4'-nitrobenzyl-6-acetamido- penicillanat-1-oxid i 200 ml toluen opvarmes til kogning med til-bagesvaling og terres azeotropt, hvorved ca. 20 ml toluen de-stilleres fra blandingen. Efter kortvarig afkoling af blandingen tilsættes 5,5 millimol N-chlorsuccinimid. Blandingen koges med tilbagesvaling i 90 minutter, hvorefter oplesningen afkeles til stuetemperatur og filtreres. Inddampning i vakuum af filtratet giver 4’-nitrobenzyl-3-methyl-2~(2-chlorsulfinyl-4-oxo-3-acet-amido-1-azetidinyl)-3-butenoat som et skum. Det sâledes opnâede azetidinonsulfinylchloridprodukt kan anvendes i cycliserings-processen ifelge opfindelsen direkte uden oprensning. Eaktisk er det ofte tilfældet, at Eriedel-Craft s-kata_lysatorreagenset tilsaat-tes direkte til den endelige reaktionsblanding af den fremstille-de azetidinonsulfinylchlorid. 1 en reaktion analog med reaktionen mellem penicillinsulfoxidester og N-chlorsuccinimid til opnâelse af azetidinonsulfinylchlorider, 10Examples of preparation of the azetidinone sulfinyl chloride starting materials used in the present process are exemplified by the following brief description of the preparation of 4'-nitrobenzyl-3-methyl-2- (2-chlorosulfinyl-4-oxo-3-acetamido-1-azetidinyl) -3 -Butenoate: A solution of 5 millimoles of 4'-nitrobenzyl-6-acetamido-penicillanate-1-oxide in 200 ml of toluene is heated to reflux and terrazed azeotropically, whereby ca. 20 ml of toluene are distilled from the mixture. After briefly cooling the mixture, 5.5 millimoles of N-chlorosuccinimide are added. The mixture is refluxed for 90 minutes, then the solution is cooled to room temperature and filtered. Evaporation in vacuo of the filtrate gives 4'-nitrobenzyl-3-methyl-2- (2-chlorosulfinyl-4-oxo-3-acetamido-1-azetidinyl) -3-butenoate as a foam. The azetidinone sulfinyl chloride product thus obtained can be used in the cyclization process of the invention directly without purification. Actually, it is often the case that the Eriedel-Craft s catalyst reagent is added directly to the final reaction mixture of the azetidinone sulfinyl chloride produced. In a reaction analogous to the reaction between penicillin sulfoxide ester and N-chlorosuccinimide to obtain azetidinone sulfinyl chlorides, 10

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kan penicillinsulfoxidester med en imidogruppe i C6 omsættes med N-bromsuccinimid til opnâelse af den tilsyarende azetidinonsulfi-nylbromid. Reaktionsbetingelserne for denne omdannelse er identi-ske med de, der anyendes i den foran beskrevne sulfinylchloridfrem-stilling, bvor der anyendes N-chlorsucoinimid. De beskrevne azetidinonsulfinylchlorider og de tilsyarende sulfinylbromider bar ensartet kemisk reaktiyitet med hensyn til cycliseringsmidler-ne, der beskrives nærmere nedenfor.For example, penicillin sulfoxide ester having an imido group in C6 can be reacted with N-bromosuccinimide to give the acidic azetidinone sulfinyl bromide. The reaction conditions for this conversion are identical to those of any of the above-described sulfinyl chloride preparation, if any N-chlorosucoinimide is present. The azetidinone sulfinyl chlorides described and the corresponding sulfinyl bromides exhibited uniform chemical reactivity with respect to the cyclizing agents, which are described in more detail below.

Azetidinonsulfinsyrerne med formlenThe acetetidinone sulfinic acids of the formula

OISLAND

AAAA

œoRœoR

-] hvori R og R er som defineret ovenfor, fremstilles generelt ud fra de tilsyarende sulfinylchlorider yed opslæmning af sulfinyl-chlorid i en etbylacetatoplzsning sammen med en yandig natrium-bicarbonatoplosning yed stuetemperatur i cirka 1 time. Den yan-dige fase, der indebolder suifinsyresaltet, frasepareres, yaskes med ethylacetat, behandles med en anden portion ethylacetat og gzres sur. Den organiske fase frasepareres, yaskes med saltvand, tzrres oyer yandfrit natriumsulfat og inddampes i yakuum til tzr-hed. Sulfinsyrerne isoleres beryed og opnâs normalt som farvelz-se amorfe faste stoffer.wherein R and R are as defined above are generally prepared from the acidifying sulfinyl chloride slurry of sulfinyl chloride in an ethyl acetate solution together with an ambient sodium bicarbonate solution at room temperature for about 1 hour. The final phase containing the sulfinic acid salt is separated, washed with ethyl acetate, treated with a second portion of ethyl acetate and acidified. The organic phase is separated, washed with brine, dried over anhydrous sodium sulfate, and evaporated in dryness to dryness. The sulfinic acids are isolated and usually obtained as colorless amorphous solids.

Repræsentâtiye for de omhandlede sulfinsyrer er fzlgende: 41 -ni trobenzyl-3-metb.y 1-2-( 2-sulf ino-4-oxo-3-pb.enylaeetamido-1 -azetidinyl)-3-butenoat, 21 ,21,2 ’ -tricîiloretb.yl-3-iaetliy 1-2-( 2-sulfino-4-oxo-3-acetamido-1-azetidinyl)-3-butenoat, 2r -iodetby 1-3-meth.y 1-2-( 2-sulfino-4-oxo-3-cb.loracetamido-1-azetidinyl)-3-butenoat, 4 * -methoxybenzyl-3-meth.yl-2-( 2-sulf ino-4-oxo-3-plithalimido-1-azetidinyl)-3-butenoat, 11Representative of the sulphinic acids in question are as follows: 41-N-trobenzyl-3-methoxy-1-2- (2-sulfono-4-oxo-3-pb.enylaeetamido-1-azetidinyl) -3-butenoate, 21, 21 , 2 '-tricilloroethyl-3-methyl-1-2- (2-sulfino-4-oxo-3-acetamido-1-azetidinyl) -3-butenoate, 2-iodoethyl 1-3-methyl-1-2 - (2-sulfino-4-oxo-3-chloroacetamido-1-azetidinyl) -3-butenoate, 4 * -methoxybenzyl-3-methyl-2- (2-sulfino-4-oxo-3- plithalimido-1-azetidinyl) -3-butenoate, 11

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tert-butyl-3-methyl-2-[ 2-sulfino-4-oxo-3-(2-bromacetamido)-1-azetidinyl]-3-butenoat, benzhydry1-3-methyl-2-[ 2-sulfino-4-oxo-3-( 4-cb.lorphenoxyacetainido) -1 -azetidinyl] -3-butenoat, 4 ’ -nitrobenzvl-3-meth.yl-2-[ 2-sulfino-4-oxo-3-(4-nitrobenzyloxycar-bonylamino) -1 -azetidinyl] -3-butenoat, 21, 21, 21-trichlorethyl-3-methyl-2-[2-sulfino-4-oxo-3-(2,2-dimethyl-3-nitroso-5-oxo~4-pbenyl-1-imidazolidinyl)-1 -azetidinyl] -3-butenoat.tert-Butyl-3-methyl-2- [2-sulfino-4-oxo-3- (2-bromoacetamido) -1-azetidinyl] -3-butenoate, benzhydry-3-methyl-2- [2-sulfino-4 -oxo-3- (4-chlorophenoxyacetamido) -1-azetidinyl] -3-butenoate, 4'-nitrobenzyl-3-methyl-2- [2-sulfino-4-oxo-3- (4-nitrobenzyloxycar -bonylamino) -1-azetidinyl] -3-butenoate, 21, 21, 21-trichloroethyl-3-methyl-2- [2-sulfino-4-oxo-3- (2,2-dimethyl-3-nitroso-5 -oxo-4-pbenyl-1-imidazolidinyl) -1-azetidinyl] -3-butenoate.

2T -iodethyl-3-metb.yl-2-[ 2-sulfino-4-oxo-3-acetamido-1-azetidinyl]-3-butenoat og 41 -nitr obenzyl-3-nieth.yl-2-[ 2-sulf ino-4-oxo-3-( 4-chlorbenzamido ) -1 -azetidinyl] -3-butenoat.2T-iodoethyl-3-methyl-2- [2-sulfino-4-oxo-3-acetamido-1-azetidinyl] -3-butenoate and 41-nitro-obenzyl-3-methyl-2- [2- sulfino-4-oxo-3- (4-chlorobenzamido) -1-azetidinyl] -3-butenoate.

Det mâ erkendes, at andre derivater af azetidinonsulfinylchlorider, indbefattende sulfinatestre, tbiosulfinatestre, blandede carboxyl-og suifonanhydrider og sulfinamid og sulfinimid-derivater deraf, kan fremstilles ud fra sulfinsyrerne og fra deres precursor sulfinylchlorid. Sâdanne derivater kan fremstilles ved velkendte metoder, anvendt ved fremstilling af carboxylsyre-derivater, for eksempel estre, tbioestre, anbydrider, amider og imider fra carb-oxylsyrer og farboxylsyrechlorider. Nogle azetidinonsulfinimid-derivater er fremstillet direkte fra penicillinsulfoxider [S.It is recognized that other derivatives of azetidinone sulfinyl chlorides, including sulfinate esters, thiosulfinate esters, mixed carboxyl and sulfon anhydrides and sulfinamide and sulfinimide derivatives thereof, can be prepared from the sulfinic acids and from their precursor sulfinyl chloride. Such derivatives can be prepared by well known methods used in the preparation of carboxylic acid derivatives, for example esters, thioesters, anhydrides, amides and imides from carboxylic acids and farboxylic acid chlorides. Some azetidinone sulfinimide derivatives are prepared directly from penicillin sulfoxides [S.

Terao, T. Matsuo, S. Tsushima, N. Matsumoto, T. Miyawaki og M. Miyamoto, J. Cbem. Soc. (C), 1304 (1972)]. Sâdanne derivater kan cycliseres til 3-metbylencepbamsulfoxidforbindelser ved meto-den og de betingelser, der er beskrevet heri.Terao, T. Matsuo, S. Tsushima, N. Matsumoto, T. Miyawaki, and M. Miyamoto, J. Cbem. Soc. (C), 1304 (1972)]. Such derivatives can be cyclized to 3-methylene cepbam sulfoxide compounds by the method and conditions described herein.

12 DK 157137 B12 DK 157137 B

Azetidinonsulfinsyreestre (sulfinater) med formlen: -v y ΑΛ 6oor 1 4 hvori R og R har samme betydning som defineret ovenfor, og R er (Οχ - C1Q) alkyl, aryl (C-j-c^alkyl) eller (Οχ-Οζ)halogenalkyl, fremstilles ud fra foran beskrevne azetidinonsulfinylchlorider ved at omsætte sulfinylchloridet med den tilsvarende ((3χ-(2χφ)-alkanol, aryl (ci~C3 alkanol) eller (C^C^)halogenalkanol.Azetidinone sulfinic acid esters (sulfinates) of the formula: -VY oor 6oor 1 4 wherein R and R have the same meaning as defined above and R is (Οχ - C11) alkyl, aryl (Cjc alkyl alkyl) or (Οχ-Οζ) haloalkyl, is prepared from from the above-described azetidinone sulfinyl chlorides by reacting the sulfinyl chloride with the corresponding ((3χ- (2χχ)) -alkanol, aryl (Ci-C3 alkanol) or (C ^-C ^) haloalkanol.

Typisk fremstilles sulfinylsyreesterne ved at tilsætte den onskede alkohol direkte til reaktionsblandingen, hvori azetidinonsulf inylchloridet er fremstillet ud fra et penicillin-suif oxid. Sulfinsyreesteren isoleres herefter under anvendelse af standardteknik inklusive inddampning, krystallisation og kromatografi.Typically, the sulfinyl acid esters are prepared by adding the desired alcohol directly to the reaction mixture in which the azetidinone sulf inyl chloride is prepared from a penicillin-sulfur oxide. The sulfinic acid ester is then isolated using standard techniques including evaporation, crystallization and chromatography.

Eksempler pâ alkoholer, der kan anvendes ved fremstilling af sul-finsyreestre, er methanol, éthanol, 2-propanol, cyclohexanol, 4-chlor-cyclohexanol, seo-hutanol, n-heptanol, menthol, benzyl-alkohol, 2-phenylethanol, 3-phenylpropanol, 2-chlorbenzylalkohol, 4-methoxybenzylalkohol, 2-(4-nitrophenyl)éthanol, 2-chlorethanol, 2-bromethanol, 3-bromcyclohexanol, 4-chlorbutanol eller 3-chlor-propanol.Examples of alcohols that can be used in the production of sulfinic acid esters are methanol, ethanol, 2-propanol, cyclohexanol, 4-chloro-cyclohexanol, seo-hutanol, n-heptanol, menthol, benzyl alcohol, 2-phenylethanol, 3 -phenylpropanol, 2-chlorobenzyl alcohol, 4-methoxybenzyl alcohol, 2- (4-nitrophenyl) ethanol, 2-chloroethanol, 2-bromoethanol, 3-bromocyclohexanol, 4-chlorobutanol or 3-chloropropanol.

Repræsentative for azetidinonsulfinsyreestre er 4 ’ -nitrohenzyl-3-Diethyl-2-( 2-isobutoxysulf inyl-4-oxo-3-acetamido-· 1-azetidinyl)-3-hutenoat benzhydryl-3-methyl-2-[ 2-(2-chlorpropoxysulfinyl)-4-oxo-3-phenoxy-acetamido-1-azetidinyl]~3“hutenoat 2’,2T,2'-trichlorethyl-3-methyl-2-[2-(2-hrornethoxysulfinyl)-4-oxo-3“(2-formyloxy-2-phenylacetamido)-1-azetidinyl]“3-hutenoatRepresentatives of azetidinone sulfinic acid esters are 4 '-nitrohenzyl-3-diethyl-2- (2-isobutoxysulfinyl-4-oxo-3-acetamido-1-azetidinyl) -3-hutenoate benzhydryl-3-methyl-2- [2- ( 2-Chloropropoxysulfinyl) -4-oxo-3-phenoxy-acetamido-1-azetidinyl] -3-hutenoate 2 ', 2T, 2'-trichloroethyl-3-methyl-2- [2- (2-chloromethoxysulfinyl) -4- oxo-3 '(2-formyloxy-2-phenylacetamido) -1-azetidinyl] "3-hutenoat

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2 ’ -iodethyl-3-me thyl-2-[ 2- ( 4-hrombenzyloxysulfinyl ) -4-oxo-3-phthal-imido-1-azetidinyl]-3-butenoat tert-butyl-3-methyl-2-(2-methoxysulfinyl-4-oxo-3-'benzyloxycar'bonyl-amino-1-azetidinyl)-3-butenoat 4 ' -chlorphenacyl-3-methyl-2-[ 2-( 2-ph.eny lis opropoxy suif inyl) -4-oxo- 3-( 2-chlorbenzamido ) -1 -azetidinyl] -3-butenoat 4 ’ -methoxybenzyl-3-methyl-2-[ 2-cyclohexyloxysulfinyl-4-oxo-3-(2,2-dimethyl~3-nitroso-5-oxo-4-phenyl-1-imidazolidinyl)-1-aze-tidinyl] -3-butenoat og methyl-3-methyl-2-[ 2-( 3-phenylpropoxysulfinyl)-4-oxo-3-(4-chlor-phenoxyacetamido)-1 -azetidinyl] -3-butenoat.2'-iodoethyl-3-methyl-2- [2- (4-thrombenzyloxysulfinyl) -4-oxo-3-phthalimido-1-azetidinyl] -3-butenoate tert-butyl-3-methyl-2- ( 2-methoxysulfinyl-4-oxo-3-benzyloxycarbonyl-amino-1-azetidinyl) -3-butenoate 4 '-chlorophenacyl-3-methyl-2- [2- (2-phenylpropoxy suphinyl) -4-oxo-3- (2-chlorobenzamido) -1-azetidinyl] -3-butenoate 4'-methoxybenzyl-3-methyl-2- [2-cyclohexyloxysulfinyl-4-oxo-3- (2,2-dimethyl) 3-nitroso-5-oxo-4-phenyl-1-imidazolidinyl) -1-aze-tidinyl] -3-butenoate and methyl-3-methyl-2- [2- (3-phenylpropoxysulfinyl) -4-oxo-3 - (4-Chloro-phenoxyacetamido) -1-acetidinyl] -3-butenoate.

Azetidinonthiosulfinatestre med formlen:Azetidinone thiosulfinate esters of the formula:

OISLAND

» 5 /SR5 A4 Îoor 1 5 hvori R og R er som defineret ovenfor, og R er (Cj^-CgJalkyl, aryl eller aryl (C-^-C^alkyl ) fremstilles ud fra nævnte azetidi- nonsulfinÿlchlorider ved omsætning med tilsvarènde (C^-C^)alkyl- thiol, arylthiol eller aryl(C^-C^alkyl)thiol. Thiosulfinat- estre fremstilles 'og isoleres pâ kendt mâde. Fremstilling af disse forbindelser er direkte analog med fremstilling af car- boxylsyreestre ud fra carboxylsyrechlorider.Wherein R and R are as defined above and R is (Cj-Cggalkyl, aryl or aryl (C --C C alkyl) is prepared from said azetidinone sulfinyl chlorides by reaction with the corresponding ( C 1 -C 4 alkylthiol, arylthiol or aryl (C 1 -C 4 alkyl) thiol. Thiosulfinate esters are prepared and isolated in known manner. Preparation of these compounds is directly analogous to the production of carboxylic acid esters from carboxylic acid chlorides. .

Repræsentâtive for thioler eller mercaptaner, der kan anvendes ved fremstilling af azetidinonthiolsulfinatestre, er methanthiol, ethanthiol, 2-propanthiol, 2-meth.yl-2-propanth.iol, cyclohexan-thiol, 2-pentanthiol, 1-hutanthiol, thiophenol, 4-chlorthiophenol, 2-phenylethanthiol og benzylmercaptan.Representative of thiols or mercaptans which can be used in the preparation of azetidinone thiol sulfinate esters are methanethiol, ethanethiol, 2-propanethiol, 2-methyl-2-propanethiol, cyclohexanethiol, 2-pentanthiol, 1-hutanthiol, thiophenol, 4 -chlorothiophenol, 2-phenylethanthiol and benzylmercaptan.

Repræsentantive for de omhandlede azetidinthiolsulfinatestre er fzlgende:Representatives of the azetidinethiol sulfinate esters in question are as follows:

H DK 157137 BH DK 157137 B

4 ’ -nitrobenzyl-3-methy1-2-( 2-methylthiosulfinyl-4-oxo-3-f orm-amido-1-azetidinyl)-3-butenoat 2,-iodethyl-3-methyl-2[ 2-(2-methyl-1-propanthiosulfinyl)-4-oxo- 3-(4-methoxybenzyloxycarbonylamino)-1-azetidinyl]-3-butenoat 2’ , 2’ ,2' -trichlorethyl-3-methyl-2-[ 2-( 1-hexanthiosulfinyl)-4-oxo-3- ( 4-trifluormethylbenzamido ) -1 -azetidinyl] -3-butenoat benzhydryl-3-methyl-2-[ 2-benzylthiosulfinyl-4-oxo-3-(4-methyl-phenoxyacetamido)-1-azetidinyl]-3-butenoat og tert-butyl-3-methyl-2-[ 2-phenylthiosulfinyl-4-oxo-3-(4-nitrobenzyl-oxycarbonylamino)-1-azetidinyl]-3-butenoat.4 '-nitrobenzyl-3-methyl-2- (2-methylthiosulfinyl-4-oxo-3-formamido-1-azetidinyl) -3-butenoate 2, -iodoethyl-3-methyl-2 [2- (2 -methyl-1-propanthiosulfinyl) -4-oxo-3- (4-methoxybenzyloxycarbonylamino) -1-azetidinyl] -3-butenoate 2 ', 2', 2 '-trichloroethyl-3-methyl-2- [2- (1) -hexanthiosulfinyl) -4-oxo-3- (4-trifluoromethylbenzamido) -1-azetidinyl] -3-butenoate benzhydryl-3-methyl-2- [2-benzylthiosulfinyl-4-oxo-3- (4-methyl-phenoxyacetamido) -1-azetidinyl] -3-butenoate and tert-butyl-3-methyl-2- [2-phenylthiosulfinyl-4-oxo-3- (4-nitrobenzyl-oxycarbonylamino) -1-azetidinyl] -3-butenoate.

Suifinamid og sulfinimid-derivater af de omhandlede azetidinon-sulfinylchlorider er repræsenteret ved formlen: 0 fi Il R6 ΡΛ /_N>7 I î h / \/>Suifinamide and sulfinimide derivatives of the subject azetidinone sulfinyl chlorides are represented by the formula: 0 fi ll R6 ΡΛ / _N> 7 I î h / \ />

COORCOOR

hvori R og R har samme betydning som defineret ovenfor, og hvori Γ τη (a) R° er hydrogen, og R' er hydrogen, R" har samme betydning som 8 o defineret ovenfor, eller en gruppe med formlen -NHR , hvori R er aminocarhonyl, (C^-C^iâlkylaminocarbonyl, (C^-C^)alkoxycar-bonyl, '(C^-C^Jalkylcarbonyl eller tosyl; eller hvori (b) R® og sammen med det nitrogen, hvortil de er bundet, danner en imidogruppe med formlen 0wherein R and R have the same meaning as defined above and wherein Γ τη (a) R ° is hydrogen and R 'is hydrogen, R "has the same meaning as 8 o defined above, or a group of the formula -NHR wherein R is aminocarhonyl, (C 1 -C 4 alkylaminocarbonyl, (C 1 -C 3) alkoxycarbonyl, '(C 1 -C 3 alkylcarbonyl or tosyl) or wherein (b) R 2 and together with the nitrogen to which they are attached , forms an imido group of formula 0

IIII

y \2 \/ •y \ 2 \ / •

IIII

0 ? hvori R har samme betydning som defineret ovenfor.0? wherein R has the same meaning as defined above.

G-enerelt fremstilles azetidinonsulfinamider og sulfinimider ud fra tilsvarende sulfinylchlorider pâ samme mâde,som carboxamider og carboximider fremstilles fra carboxylsyrechlorider, dvs. ved atIn general, azetidinone sulfinamides and sulfinimides are prepared from corresponding sulfinyl chlorides in the same manner as carboxamides and carboximides are prepared from carboxylic acid chlorides, ie. by

15 DK 157137 BDK 157137 B

omsætte syrechloridet med 1—2 ækvivalenter af en tilsvarende aminbase. Typisk udfores denne reaktion ligesom den foran be-ekrevne sulfinsyreester- og tMoester-reaktion i et Inert organisk oplasningsmiddel, sâsom benzen, toluen, methylenchlorid, diloro-form eller ethylacetat. kzlgende tabel illustrerer de særlige baser, der anvendes ved fremstilling af de individuelle sulfinamider og sulfinimider; < / Π * A/reacting the acid chloride with 1-2 equivalents of a corresponding amine base. Typically, this reaction is carried out like the sulfuric acid ester and tMoester reaction described above in an inert organic solvent, such as benzene, toluene, methylene chloride, diloroform or ethyl acetate. The following table illustrates the particular bases used in the preparation of the individual sulfinamides and sulfinimides; </ Π * A /

COORCOOR

_X_______ Amin - base -snh2 NH4C1_X_______ Amine - base -snh2 NH4C1

OISLAND

-SNHR" R"~NH-SNHR "R" ~ NH

0 0 0 -snhnhcnh2 h2nnhcnh2 0 0· 0 -SNHNHCNH (C^C^ alkyl H2NNHCNH (Cj-C^lkyl)0 0 0 -snhnhcnh2 h2nnhcnh2 0 0 · 0 -SNHNHCNH (C ^C ^ alkyl H₂NNHCNH (Cj-C ^ alkyl)

0 0 O0 0 O.

-SNHNHCO(C1-C3alkyl) H2NNHCO(C-j-C^lkyl) 0 0 0 -SNHNHC (C1-C3alkyl) H^NHC (C-j-C^lkyl) 0 0 0 " " // \ Il y*--*\-SNHNHCO (C1-C3alkyl) H2NNHCO (C-j-C1-6alkyl) 0 0 0 -SNHNHC (C1-C3alkyl) H ^ NHC (C-j-C1-6kyl) 0 0 0 "" // \ Il y * - * \

-SNHNHS-·. ,·-0Η H0NNHS-»f >-CH-SNHNHS- ·. , · -0Η H0NNHS- »f> -CH

+ ·“· 3 2 4. \—/ 3+ · “· 3 2 4. \ - / 3

0 O0 O

2 (? ^R2 kTn^ \r2 5 52 (? ^ R2 kTn ^ \ r2 5 5

DK 157157 BDK 157157 B

Succinimidosulfinylazetidinoner kan ogsâ fremstilles efter fel-gende reaktionssekvens: rv A ris /-<j π A — π f çf \/ HOAc, dmf, δ c/ \ / x Îoor Lor A; ÎoorSuccinimidosulfinylazetidinones can also be prepared by the following reaction sequence: rv A rice / - <j π A - π f çf \ / HOAc, dmf, δ c / \ / x Loroor Lor A; Îoor

Penicillinsulfoxidesteren opvarmes i dimethylformamid til ca.The penicillin sulfoxide ester is heated in dimethylformamide to ca.

105 °C med overskud af N-trimethylsilylsuccinimid i nærværelse af eddikesyre. Azetidinonsulfenimid, der herved opnâs, oxideres med m-chlorperbenzoesyre til opnâelse af den tilsvarende sulfinimid-forbindelse.105 ° C with excess N-trimethylsilylsuccinimide in the presence of acetic acid. Acetidinone sulfenimide thus obtained is oxidized with m-chloroperbenzoic acid to obtain the corresponding sulfinimide compound.

Repræsentative for azetidinonsulfamider og sulfinimider er: 4 ’ -nitrobenzyl-3-metbyl-2-(2-phth.aliinidosulfinyl-4-oxo-3-pbenyl-acetamido-1-azetidinyl)-3-butenoat 2 ’ -iodeth.yl-3-met]iyl-2-[ 2-(4-chloranilinsulfinyl)-4-oxo~3-plienoxy-acetamido-1-azetidinyl]-3-butenoat benzhydryl-3-methyl-2-[2-carbamylh.ydrazosulfinyl-4-oxo-3-(4-nitro-benzyloxycarbonylamino)-1-azetidinyl]-3-butenoat 4 *-cblorpbenacyl-3-methy1-2-(2-etbylcarbamyl-hydrazosulfinyl-4-oxo-3-formamido-1-azetidinyl)-3-butenoat tert-butyl-3-metbyl-2-[2-carboethoxybydrazosulfinyl-4-oxo-3-(2-formyloxy-2-pbenylacetamido)-1-azetidinyl]-3-butenoat 2^2^21 -tricbloretbyl-3-me tby 1-2-( 2-propionylbydrazosulf iny 1-4-oxo-3-pbth.aliiiiido-1 -azetidinyl) -3-butenoat 17Representatives of azetidinone sulfamides and sulfinimides are: 4 '-nitrobenzyl-3-methyl-2- (2-phthalinidosulfinyl-4-oxo-3-pbenyl-acetamido-1-azetidinyl) -3-butenoate 2'-iodoethyl. 3-Methyl-2- [2- (4-chloroaniline sulfinyl) -4-oxo-3-plienoxyacetamido-1-azetidinyl] -3-butenoate benzhydryl-3-methyl-2- [2-carbamylhydrazosulfinyl] 4-oxo-3- (4-nitro-benzyloxycarbonylamino) -1-azetidinyl] -3-butenoate 4 * -carborbenacyl-3-methyl-2- (2-ethylcarbamyl-hydrazosulfinyl-4-oxo-3-formamido-1- azetidinyl) -3-butenoate tert-butyl-3-methyl-2- [2-carboethoxybydrazosulfinyl-4-oxo-3- (2-formyloxy-2-pbenylacetamido) -1-azetidinyl] -3-butenoate 2 -tricycloroethyl-3-methyl-1- (2-propionylbydrazosulfinyl) 1-4-oxo-3-pbthalisyl] -1-azetidinyl) -3-butenoate 17

DK 157137 BDK 157137 B

methyl-3-metliyl-2-[ 2-(4-tolylsulfonylh.ydrazosulfinyl)-4--oxo-3-(2-chlorbenzamido ) -1 -aze tidinyl] -3-butenoat 4'-me th.oxybenzyl-3-methy 1-2-( 2-succinimido suif inyl-4-oxo-3-pr opion-amido-1-azetidinyl)-3-butenoat 4 ' -nitrobenzyl-3-metb.yl-2-[ 2-(4-meth.oxyanilinosulfinyl) -4-oxo-3-pïienoxyacetamido-1-azetidinyl] -3-butenoat 2' -iodeth.yl-3-meth.yl-2-(2-oarbometh.oxy]iydrazosulfinyl-4-oxo-3-chloracetamido-1 -azetidinyl) -3-butenoat og 2' ,2', 2 '-trichloretb.yl-3-metliyl-2-[2-acetylh.ydrazosulf inyl-4-oxo-3-( 2-tert-butoxycarbonylamino-2-phenylacetamido ) -1 -azetidinyl] -3-butenoat.methyl 3-methyl-2- [2- (4-tolylsulfonylhydrazosulfinyl) -4-oxo-3- (2-chlorobenzamido) -1-azidinyl] -3-butenoate 4'-methoxybenzyl-3 -methyl 1-2- (2-succinimido sulfinyl-4-oxo-3-propionamido-1-azetidinyl) -3-butenoate 4 '-nitrobenzyl-3-methyl-2- [2- (4) -methoxyanilinosulfinyl) -4-oxo-3-pienoxyacetamido-1-azetidinyl] -3-butenoate 2'-iodoethyl-3-methyl-2- (2-oarbomethoxy) hydrazosulfinyl-4-oxo-2 3-chloroacetamido-1-azetidinyl) -3-butenoate and 2 ', 2', 2 '-trichloroethyl-3-methyl-2- [2-acetylhydrazosulfinyl-4-oxo-3- (2-tert -butoxycarbonylamino-2-phenylacetamido) -1-azetidinyl] -3-butenoate.

Foruden de foran beskrevne sulfinamider kan andre sulfinamider anvendes som udgangsmaterialer ved den omhandlede cycliserings-proces. Især kan azetidinonsulfinamider med formleme: 0 NHCOOR^ ο NHCOR^ Π 1 H 1 R1 5-N-C00R9 R1 ; .^S^NCOr9 xn » Yi i ry . / va 6oor COOR 1 9In addition to the sulfinamides described above, other sulfinamides can be used as starting materials in the process of cyclization. In particular, azetidinone sulfinamides of the formulas: 0 NHCOOR ^ ο NHCOR ^ ^ 1 H 1 R1 5-N-C00R9 R1; . ^ S ^ NCOr9 xn »Yi in ry. / from 6oor COOR 1 9

Irvori R og R bar samme betydning som ovenfor, og R er alkyl med 1-6 carbonatomer eller phenyl, cycliseres under den omhandlede fremgangsmâdes sure betingelser til opnâelse af de tilsvarende 3-meth.ylenceph.amsulfoxider. Sâdanne azetidinonsulfinamider er kendte forbindelser. [S. Terao et al., supra]. De fremstilles direkte fra penicillinsulfoxider ved omsætning med azodicarboxy-later eller diacyldiimider. Med noget mildere reaktionsbetingel-ser (i forbold til de reaktionsbetingelser, der anvendes ved sulfinylhalogenidfremstilling) ved fremstilling af disse azetidinonsulfinamider kan der anvendes et bredere spektrum af penicil- Ί linsulfoxid-udgangsmaterialer. Sâledes kan R foruden de be-skrevne grupper repræsentere en -amidgruppe med formlen 0 R''f'CHgONH-,Where R and R have the same meaning as above, and R is alkyl of 1-6 carbon atoms or phenyl, cyclization is performed under the acidic conditions of the process of the present invention to obtain the corresponding 3-methylencephalam sulfoxides. Such azetidinone sulfinamides are known compounds. [S. Terao et al., Supra]. They are prepared directly from penicillin sulfoxides by reaction with azodicarboxylates or diacyldiimides. With somewhat milder reaction conditions (in the case of the reaction conditions used in sulfinyl halide preparation) in the preparation of these azetidinone sulfinamides, a wider range of penicillin-sulfin oxide starting materials can be used. Thus, in addition to the described groups, R may represent an amide group of the formula 0 R''f'CHgONH-,

DK 157137 BDK 157137 B

hyori R1 1 1 1 er en heteroarylgruppe, blandt andet omfattende 2-tliienyl, 3-th.ienyl, 2-furyl, 3-furyl, 2-th.iazoyl eller 4-isoxa-zolyl.hyori R1 1 1 1 is a heteroaryl group including, inter alia, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-thiazoyl or 4-isoxazolyl.

Eksempler pâ sulfinamid-udgangsmaterialer afledt direkte af peni-cillinsulfoxider og azodicarboxylater eller diacyldiimider er fzl-gende: 4 ’ -nitrobenzyl-3-meth.yl-2-[ 2-(N ,N ’ -dicarbotert-butoxyhydrazosul-finyl)-4-oxo-3-(2-tliienylacetaïïiido)-1-azetidinyl]-3-butenoat 2 ’ -iodethyl-3-nethyl-2-[ 2-(N ,N1 -dibenzoylbydrazosulfinyl)-4-oxo-3-pb.enoxyacetamido-1 -azetidinyl] -3-butenoat 2^2^21 -trichlorethyl-3-met]iyl-2-[ 2-(N,N ' -dicarboethoxybydra-zosulfinyl)-4-oxo-3-pb-enylacetamido-1-azetidinyl] -3-butenoat benzhydryl-3-ïïietliyl-2-[ 2-(N,N' -dicarbometh.oxyh.ydrazosulfinyl)-4-οΧο-3-( 2-f ormyloxy-2-pb.enylacetamido ) -1 -azetidinyl] -3-butenoat og 4 ' -cb.lorph.enacyl-3-meth.yl-2-[ 2-(N ,N ' -dicarbopropoxyhydrazosulfi-nyl)-4-oxo-3-acetamido-1-azetidinyl]-3-butenoat.Examples of sulfinamide starting materials derived directly from penicillin sulfoxides and azodicarboxylates or diacyl diimides are as follows: 4 '-nitrobenzyl-3-methyl-2- [2- (N, N' -dicarbutert-butoxyhydrazosulphinyl) -4 -oxo-3- (2-thienylacetamido) -1-azetidinyl] -3-butenoate 2'-iodoethyl-3-methyl-2- [2- (N, N1-dibenzoylbydrazosulfinyl) -4-oxo-3-pb.eneoxyacetamido -1-azetidinyl] -3-butenoate 2, 2, 21-Trichloroethyl-3-methyl-2- [2- (N, N '-dicarboethoxybydrazosulfinyl) -4-oxo-3-pb-enylacetamido-1 -azetidinyl] -3-butenoate benzhydryl-3-methylethyl-2- [2- (N, N '-dicarbomoethoxyhydrazosulfinyl) -4-oxo-3- (2-formyloxy-2-pbhenylacetamido) - 1-azetidinyl] -3-butenoate and 4'-cblorophenacyl-3-methyl-2- [2- (N, N'-dicarbopropoxyhydrazosulfinyl) -4-oxo-3-acetamido-1- azetidinyl] -3-butenoate.

De typer reagenser, der er egnede til at udfzre intramolekylær sulfinylering yed den omhandlede fremgangsmâde, falder i det væ-sentlige sammen med de forbindelser, som man anerkender er i stand til at udf0re acyleringsreaktioner af Eriedel-Crafts-typen. Et grundigt overblik oyer Eriedel-Crafts-acyleringer og beslægtede reaktioner samt katalysatorer dertil er beskreyet af G-eorge A.The types of reagents suitable for carrying out intramolecular sulfinylation by the process of the invention essentially coincide with the compounds which are recognized to be capable of performing Eriedel-Crafts type acylation reactions. A thorough overview of Eriedel-Crafts acylations and related reactions as well as catalysts thereto is described by G-eorge A.

Olah. i "Eriedel-Crafts diemistry", John Wiley and Sons, New York, Ν.Γ., 1973.Olah. in "Eriedel-Crafts Diemistry", John Wiley and Sons, New York, 1973, 1973.

Egnede reagenser, der kan anvendes ved den omhandlede fremgangsmâde til intramolekylær cyclisering af næynte azetidinon-sulfinyl-chlorider og suifinylbromider, er de konyentionelle Eriedel-Crafts-katalysatorer, omfattende katalysatorer af Lewis-syrertypen, katalysatorer af Brznsted-protonsyre-typen og metathetisk kationdannen-de midler. Eoretruk.ne blandt katalysatorer af Lewis-typen er metalhalogenider. Katalysatorer af Br0nsted-protonsyre~typen om-fatter sure chalcogenider (især sure oxider), konjugerede Friedel-Craft s'“katalysatorer med formlen HMA^ g og bâde organiske og uor-ganiske katalysatorer af Bronsted-typen.Suitable reagents which can be used in the present process for the intramolecular cyclization of nickel-azetidinone sulfinyl chlorides and sufinyl bromides are the conventional Eriedel-Crafts catalysts, comprising Lewis acid type catalysts, Brznsted methionic acid catalysts and Brznsted protonic acid catalysts. the means. The features of Lewis-type catalysts are metal halides. Bronsted protonic acid catalysts include acid chalcogenides (especially acid oxides), conjugated Friedel-Craft's catalysts of the formula HMA, and both Bronsted organic and inorganic catalysts.

19 DK 157137 B19 DK 157137 B

Cyclisering af nævnte azetidinonsulfinsyrer, estre, thioestre, ami-der og imider udfzres med katalysatorer af Brznsted-protonsyre-typen.Cyclization of said azetidinone sulfinic acids, esters, thioesters, amides and sometimes is carried out with Brznsted protonic acid type catalysts.

Katalysatorer af lewis-typen er ejendommelige ved nærværelsen af en ledig orbital, der kan acceptere et frit elektronpar, enten et frit, dvs. pâ et oxygen, svovl eller halogenatom, eller et elektronpar i en n-orbital i en forbindelse af lewis-typen til dan-nelse af en kovalent binding. Eksempler pâ egnede metalhalogenid-katalysatorer af lewis-typen er aluminiumchlorid, stannichlorid, stannibromid, zinkchlorid, zinkbromid, antimonpentachlorid, titan-tetrachlorid, ferrichlorid, galliumtrichlorid, zirconiumtetra-cblorid, mercurichlorid, cbromtricblorid og lignende metalfor-bindelser, der bar katalytisk virkning af Eriedel-Crafts-typen. Eoretrukne katalysatorer er stannichlorid, zinkchlorid, zinkbromid, zirconiumtetrachlorid og titantetrachlorid. Stannichlorid er den foretrukne.Lewis-type catalysts are peculiar to the presence of a free orbital capable of accepting a free electron pair, either a free, i.e. on an oxygen, sulfur or halogen atom, or an electron pair in an n-orbital in a lewis-type compound to form a covalent bond. Examples of suitable Lewis-type metal halide catalysts are aluminum chloride, stannous chloride, stannous bromide, zinc chloride, zinc bromide, antimony pentachloride, titanium tetrachloride, ferric chloride, gallium trichloride, zirconium chloride chloride and mercuric chloride, mercuric chloride, mercuric chloride -Crafts type. Easily extracted catalysts are stannous chloride, zinc chloride, zinc bromide, zirconium tetrachloride and titanium tetrachloride. Stannous chloride is preferred.

Katalysatorer af Brznsted-typen adskiller sig fra de sure haloge-nider af lewis-typen derved, at den elektronaccepterende evne skyl-des en positivt ladet enhed, nemlig en proton. Eksempler pâ egnede organiske Brznsted-protonsyre.-katalysatorer er methansulfon-syre, ethansulfonsyre, trifluoreddikesyre, trichloreddikesyre, dichloreddikesyre og lignende organiske syrer. Egnede uorganiske Brznsted-protonsyre-katalysatorer til fremgangsmâden omfatter svovl-syre, phosphorsyre, polyphosphorsyre, perchlorsyre, chlorsulfonsyre, fluorsulfonsyre og lignende protonsyrekatalysatorer. Eore-trukne katalysatorer af Brznsted-protonsyre-typen er methansulfon-syre, trifluoreddikesyre, phosphorsyre, svovlsyre og polyphosphorsyre.Brznsted-type catalysts differ from the Lewis-type acid halides in that the electron accepting ability is due to a positively charged entity, namely a proton. Examples of suitable organic Brznsted protonic acid catalysts are methanesulfonic acid, ethanesulfonic acid, trifluoroacetic acid, trichloroacetic acid, dichloroacetic acid and similar organic acids. Suitable inorganic Brznsted protonic acid catalysts for the process include sulfuric acid, phosphoric acid, polyphosphoric acid, perchloric acid, chlorosulfonic acid, fluorosulfonic acid and similar protonic acid catalysts. Eor-drawn catalysts of the Brznsted protonic acid type are methanesulfonic acid, trifluoroacetic acid, phosphoric acid, sulfuric acid and polyphosphoric acid.

Chalc.ogenid-katalysatorer omfatter. en lang række faste'ôxider og sul-fider. Olah, i "Eriedel-Orafts Chemistry" supra, har rapporteret, at hvad Eriedel-Craft-s-acyleringskatalysatorer angâr, sâ synes sure, faste chalc ogenid-katalysatorer at'være de mest attraktive katalysatorer i fremtiden. Blandt de sure châlcogenider foretrækkes sure oxider eller blandede sure oxider til den omhandlede fremgangsmâde. Repræsentativt for sâdanne sure oxider er alumina, silica, C^O^, P2Ü^, TiO^, A^O^CoO og AlgO^’MnO. Phosphorpentoxid foretrækkes. Generelt er dehydratiserede châlcogenider inaktive som katalysatorer vedChalcogenide catalysts include. a wide variety of solid oxides and sulphides. Olah, in "Eriedel-Orafts Chemistry" supra, has reported that as far as Eriedel-Craft-s acylation catalysts are concerned, acidic, solid chalc andenide catalysts appear to be the most attractive catalysts in the future. Among the acidic chalcogenides, acidic oxides or mixed acidic oxides are preferred for the present process. Representative of such acidic oxides are alumina, silica, C 2 O 2, P 2 U 2, TiO 2, A 2 O 2 CoO and AlgO 2 MnO. Phosphorus pentoxide is preferred. Generally, dehydrated chalcogenides are inactive as catalysts

20 DK 157137 BDK 157137 B

Priedel-Crafts-acyleringerT- tilsætning af smâ mængder (1-5%) vand aktiverer imidlertid den katalytiske aktivitet Los disse ka-talysatorer. Absorberede protoner synes at være væsentlige for den katalytiske virkning af disse sure katalysatorer. Yirkningen af vand peger pâ, at Brsnsted-aciditet er ansvarlig for den katalytiske virkning bos disse sure chalogenider ~F.E. Condong i "Catalysts", Vol. VI, ed. P.H. Emmet, Reinhold Publ. Corp. New York, N.Y.However, Priedel-Crafts acylationsT addition of small amounts (1-5%) of water activates the catalytic activity Los these catalysts. Absorbed protons appear to be essential for the catalytic action of these acidic catalysts. The action of water indicates that Brsnsted acidity is responsible for the catalytic effect of these acidic chalogenides ~ F.E. Condong in "Catalysts", Vol. VI, ed. P. H. Emmet, Reinhold Publ. Corp. New York, N.Y.

(1953), p.43]. Disse cbalcogenider klassificeres derfor’i den fore-liggende beskrivelse som Brsnsted-protontype-katalysatorer.(1953), p. 43]. These cbalcogenides are therefore classified in the present description as Brsnsted proton type catalysts.

Det mâ ogsâ bemærkes, bvilket under tiden er tilfældet Yed Eriedel-It must also be noted, because in the meanwhile the case is Yed Eriedel-

Craft s-type-acyleringer, at et metalhalogenid af Lewis-typen kan anvendes sammen med en Bronsted-protonkatalysator, idet den effek-tiYe katalysator er en konjugeret Eriedel-Crafts-syrekatalysator af typen HMA^ g. Aktivitet af Brsnsted-syre-typen antages at være ansvarlig for Yirkningen af denne type katalysator. I den forelig-gende beskrivelse vil en sâdan konjugeret katalysator klassificeres som Bronsted-katalysator. Eksempler pâ sâdanne konjugerede syrekatalysatorer HBB^, ÏÏAICI^, HAsEg og HAlBr^.Craft s-type acylations that a Lewis-type metal halide can be used with a Bronsted proton catalyst, the effective catalyst being a conjugated Eriedel-Crafts acid catalyst of the HMAMAg type. Brsnsted acid type activity is believed to be responsible for the operation of this type of catalyst. In the present disclosure, such a conjugated catalyst will be classified as Bronsted catalyst. Examples of such conjugated acid catalysts HBB ^, ICAICI ^, HAsEg and HAlBr ^.

Selv om deres virkning i ordets grundlæggende betydning ikke er katalytisk (idet de generelt forbruges i den kationdannende re-aktion) er metatbetisk kationdannende midler,især vandfri S0lv-salte, sâsom sslv-p-toluensulfonat, sslvpercblorat, sslvphospbat, solvtetrafluorborat, solvtrifluoracetat og lignende sslvforbindel-ser, effektive "katalysatorer" ved den ombandlede cyclisering af azitidinonsulfinylbalogenider. Szlvsaltene virker som metatbetisk kationdannende forbindelser, nâr de omsættes med balogenider og ikke som syrer. Den foreslâede mellemliggende suifiniumkation fremkommer sâledes ud fra sulfinylcîiloridet ved cbloridf jernelse med solvkationen og ikke ved en syre-basereaktion, hvilket er tilfældet med de foran beskrevne katalysatorer. Det uoploselige bi-produkt szlvcblorid udfældes. Solv-p-toluensulfonat er en foretruk-ken metatbetisk kationdannende forbindelse i den ombandlede frem-gangsmâde.Although their effect in the basic sense of the word is not catalytic (generally consumed in the cation-forming reaction), metathetic beta cationic agents, especially anhydrous silver salts, such as sslv sslv compounds, effective "catalysts" in the rebranded cyclization of azitidinone sulfinyl balogenides. The silver salts act as metathetic cationic compounds when reacted with balogenides and not as acids. The proposed intermediate sufinium cation thus emerges from the sulfinylciloride by chloride removal with the solvation cation and not by an acid-base reaction, as is the case with the catalysts described above. The insoluble by-product silver chloride precipitates. Solv-p-toluenesulfonate is a preferred metatabetic cation-forming compound in the remanded process.

Metatbetisk kationdannende midler er kun effektive med azetidinon-sulfinylbalogenid-udgangsmaterialer. Sâdanne midler er ikke eg-nede til cyclisering af andre tilsvarende sulfinsyre-derivater.Metathetic cationic agents are effective only with azetidinone-sulfinylbalogenide starting materials. Such agents are not suitable for cyclization of other corresponding sulfinic acid derivatives.

21 DK 157137 B21 DK 157137 B

Sâdanne andre sulfinsyrederivater cycliseres under anvendelse af en katalysator af Bronsted-protonsyretypen.Such other sulfinic acid derivatives are cyclized using a Bronsted protonic acid type catalyst.

Azetidinonsulfinylhalogenid-udgangsmaterialeme kan sâledes cycliseres ved omsætning med en Lewis-syre i form af et metalhalogenid, en katalysator af Bronsted-protonsyre-typen eller en en metathe-tisk kationdannende forbindelse. De bedste udbytter af 3-methylen-cephamsulfoxider ud fra azetidinonsulfinylchlorider opnâs, nâr der anvendes en metalhalogenidkatalysator af Lewis-syre-typen. Imidlertid opnâs ogsâ gode udbytter med katalysatorer af Bronsted-protonsyre-typen og metathetisk kationdannende forbindelser. Metalhalogenidkatalysatorer af Lewis-typen foretrækkes ved frem-gangsmâden ifolge opfindelsen, nâr azetidinonsulfonylchloriderne og sulfinylbromiderne anvendes som udgangsmateriale. Katalysato-rer af Bronsted-protonsyre-typen foretrækkes ved den omhandlede fremgangsmâde, nâr azetidinonsulfinsyrer og tilsvarende sulfinat-estre, thiosulfinatestre, sulfinamid og sulfinimider anvendes som udgangsmaterialer.The azetidinone sulfinyl halide starting materials can thus be cyclized by reaction with a Lewis acid in the form of a metal halide, a Bronsted protonic acid catalyst or a metathetic cation-forming compound. The best yields of 3-methylene-cepham sulfoxides from azetidinone sulfinyl chlorides are obtained when using a Lewis acid metal halide catalyst. However, good yields are also obtained with Bronsted-protonic acid-type catalysts and metathetic cation-forming compounds. Lewis-type metal halide catalysts are preferred in the process of the invention when the azetidinone sulfonyl chlorides and sulfinyl bromides are used as starting material. Bronsted-protonic acid-type catalysts are preferred by the process of the present invention when azetidinone sulfinic acids and corresponding sulfinate esters, thiosulfinate esters, sulfinamide and sulfinimides are used as starting materials.

Enhver af en lang række torre inerte organiske oplosningsmidler kan anvendes som medium ved den omhandlede cycliseringsproces.Any of a wide variety of dry inert organic solvents can be used as a medium in the process of cyclization.

Yed inert organisk oplosningsmiddel forstâs et organisk oplos-ningsmiddel, der under processens hetingelser ikke reagerer enten med reaktanter eller produkter. Da sulfinylchloridudgangsmateri-alerne ligesom andre reagenser af halogenidtypen kan hydrolysere og kan angribes af andre protiske forbindelser, f.eks. alkoholer og aminer, skal fugtighed og andre sâdanne protiske forbindelser fjernes fra reaktionsmediet. Et tort aprotisk organisk oplosnings-middel foretrækkes derfor. Spormængder af vand,som findes i kom-mercielt torre oplosningsmidler, kan tolereres. Imidlertid foretrækkes det at udfore den omhandlede fremgangsmâde under vandfri betingelser. Egnede oplosningsmidler omfatter for eksempel aroma-tiske carbonhydrider, sâsom benzen, toluen, xylen, chlorbenzen, nitrobenzen, nitromesitylen; halogenerede alifatiske carbonhydrider, sâsom chloroform, methylenchlorid, carbontetrachlorid, 1,2-dichlorethan (ethylenchlorid), 1,1,2-trichlorethan, 1,1-di-brom-2-chlorethan,og andre oplosningsmidler, som fagmanden ved er egnede for Eriedel-Crafts-type-reaktioner, omfattende blandt andet carbondisulfid og nitromethan, Eoretrukne oplosningsmidler er aromatiske carbonhydrider og halogenerede alifatiske carbonhydri- 22By inert organic solvent is understood an organic solvent which does not react either with reactants or products during the process heat. Since the sulfinyl chloride starting materials, like other halide reagents, can hydrolyze and can be attacked by other protic compounds, e.g. alcohols and amines, moisture and other such protic compounds must be removed from the reaction medium. A tort aprotic organic solvent is therefore preferred. Trace amounts of water found in commercially dry solvents can be tolerated. However, it is preferred to carry out the present process under anhydrous conditions. Suitable solvents include, for example, aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene, nitrobenzene, nitromesitylene; halogenated aliphatic hydrocarbons such as chloroform, methylene chloride, carbon tetrachloride, 1,2-dichloroethane (ethylene chloride), 1,1,2-trichloroethane, 1,1-dibromo-2-chloroethane, and other solvents suitable for the skilled artisan Eriedel-Crafts type reactions, including carbon disulfide and nitromethane, among others, Eorthrown solvents are aromatic hydrocarbons and halogenated aliphatic hydrocarbons.

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der. De mest foretrukne opl0sningsmidler er benzen og toluen. Blandt de lialogenerede alifatiske carbonhydrider foretrækkes methylenclilorid, etbylenclilorid og 1,1,2-trichloretlian.there. The most preferred solvents are benzene and toluene. Among the lialogenated aliphatic hydrocarbons, methylene chloride, ethylene chloride and 1,1,2-trichloroethlian are preferred.

Temperaturen, ved hvilken den ombandlede fremgangsmâde udfores, er afbængig af den særlige katalysator eller middel, der anvendes. Temperaturen ma være tilstrækkelig h0j til at udvirke cyclisering af udgangsmaterialet. Det er velkendt for fagmanden, at forskel-lige Briedel-Crafts-reagenser èr effektive ved forskellige tempera-turer, f.eks. til at fuldende en given acylering. Endvidere vides det, at denne sammenliæng ogsâ kan- genfindes selv inden for en særlig klasse Briedel-Crafts-reagenser. Den omhandlede fremgangsmâde kan udferes generelt ved en temperatur pâ 5 - 150 C.The temperature at which the resampled process is carried out is dependent on the particular catalyst or agent used. The temperature must be sufficiently high to effect cyclization of the starting material. It is well known to those skilled in the art that different Briedel-Crafts reagents are effective at different temperatures, e.g. to complete a given acylation. Furthermore, it is known that this correlation can also be found even within a particular class of Briedel-Crafts reagents. The process of the present invention can generally be carried out at a temperature of 5 - 150 ° C.

Cyclisering af Mie azetidinonsulfinsyrederivater og sulfinylha-logenider kan udfores med katalysatorer af Bronsted-protonsyre-ty-pen i et inert organisk oplosningsmiddel ved en temperatur pâ 70 -115 °C, typisk ved kogetemperaturen for det medium, bvori cyeli-seringen udfores.Cyclization of Mie azetidinone sulfinic acid derivatives and sulfinyl halogenides can be carried out with catalysts of the Bronsted protonic acid type in an inert organic solvent at a temperature of 70 -115 ° C, typically at the boiling temperature of the medium before which the cyclization is carried out.

Altemativt kan et af de for beskrevne azetidinonsulfinylderivater cycliseres til tilsvarende exometliylencepbamsulfoxider ved at op-lose det i en organisk Bronsted-protonsyre, sâsom methansulfon-syre, trifluormethansulfonsyre, trifluoreddikesyre, trichloreddi-kesyre eller dichloreddikesyre. Den tid, der kræves for cyclisering under sâdanne betingelser, afhænger af naturen af sulfinyl-derivatet, den særligt anvendte syre og reaktionstemperaturen. Typisk cycliseres azetidinonsulfamid og sulfimidderivater pâ 5-10 minutter ved stuetemperatur i methansulfonsyre, medens cyc-liseringen af suifinsyrerne, estrene og thioestrene er tilendebragt efter 30 minutter ved stuetemperatur.Alternatively, one of the azetidinone sulfinyl derivatives described above can be cyclized to corresponding exometliylene cepbam sulfoxides by dissolving it in an organic Bronsted protonic acid, such as methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, trichloroacetic acid or dichloroacetic acid. The time required for cyclization under such conditions depends on the nature of the sulfinyl derivative, the particular acid used and the reaction temperature. Typically, azetidinone sulfamide and sulfimide derivatives are cyclized for 5-10 minutes at room temperature in methanesulfonic acid, while the cyclization of the sufic acids, esters and thioesters is completed after 30 minutes at room temperature.

Cyclisering af foran beskrevne azetidinonsulfinylbalogenider ud-fores fortrinsvis ved en temperatur pâ 10-115 °C. Nærmere be-stemt udfares reaktionen helst ved 20-85 °C og allerîielst ved en temperatur, der primært afhænger af oploseligheden og den I katalytiske aktivitet af det specielt anvendte cycliseringsmiddel* Nâr der anvendes en katalysator af Bronsted-protonsyre-typen (in-klusive sure clialc.ogenid-katalysatorer og konjugerede Fridel-Crafts-syrekatalysatorer), ligger det foretrukne temperaturomrâde pâ 70-Cyclization of azetidinone sulfinyl balogenides described above is preferably carried out at a temperature of 10-115 ° C. Specifically, the reaction is preferably carried out at 20-85 ° C and most preferably at a temperature which depends primarily on the solubility and catalytic activity of the particular cyclizing agent used * When a Bronsted protonic acid type catalyst (inclusive) is used. acidic calycogenide catalysts and conjugated Fridel-Crafts acid catalysts), the preferred temperature range is 70

23 DK 157137 B23 DK 157137 B

115 °C typisk ved kogepunktstemperaturen for det medium, cycliseringen udf0res i. Imidlertid udf0res cyclisering af meth.yl-3-methyl-2-( 2-chlorsulf inyl-4-oxo-3-phthalimido-1-azetidinyl)-3-butenoat i ren polyphosphorsyre ved stuetemperatur. Wâr den in-tramolekylære sulfinylering udfzres ved hjælp af en metâthetisk kationdannende forbindelse, udf0res den fortrinsvis ved 20-80 °C og helst ved stuetemperatur. Nâr der anvendes et metalhalogenid-katalysator af Lewis-syretypen afhænger den foretrukne temperatur, ved hvilken fremgangsmâden udf0res, af den individuelle metalha-logenidkatalysator. Sâledes udfzres cycliseringen, nâr stanni-chlorid, stannibromid eller antimonpentachlorid anvendes, ved temperaturer fra 10 til 40 °C, belst ved stuetemperatur. Nâr titantetrachlorid, hvilket er en væske, der ogsâ er opleselig i de fleste reaktionsopl0sningsmidler, anvendes, foretrækkes en temperatur pâ 40 - 100 °C til omdannelsen. Nâr der anvendes andre metalhalogenid-katalysatorer af Lewis-typen end de, der er nævnt her, ved fremgangsmâden, foretrækkes generelt temperatùrer pâ 40-115 °Ç; en temperatur pâ 40-85 °C er den mest foretrukne.115 ° C typically at the boiling temperature of the medium in which the cyclization is carried out. However, cyclization of methyl 3-methyl-2- (2-chlorosulfonyl-4-oxo-3-phthalimido-1-azetidinyl) -3-butenoate is performed. in pure polyphosphoric acid at room temperature. When the intramolecular sulfinylation is carried out by a metathetic cation-forming compound, it is preferably carried out at 20-80 ° C and preferably at room temperature. When a Lewis acid type metal halide catalyst is used, the preferred temperature at which the process is carried out depends on the individual metal halide catalyst. Thus, the cyclization is carried out when stannous chloride, stannous bromide or antimony pentachloride is used, at temperatures of 10 to 40 ° C, at room temperature. When titanium tetrachloride, which is a liquid which is also soluble in most reaction solvents, is used, a temperature of 40 - 100 ° C is preferred for conversion. When Lewis-type metal halide catalysts other than those mentioned herein are used in the process, temperatures of 40-115 ° C are generally preferred; a temperature of 40-85 ° C is the most preferred.

Nâr stannichlorid anvendes som cycliseringsmiddel i den omhandlede fremgangsmâde i et toluenmedium, kan et mellemprodukt i form af stannichlorid-sulfinylhalogenidkompleks isoleres ved simpel filtre-ring af reaktionsblandingen. Komplekset kan terres og oplagres, eller det kan opleses i ethylacetat og vaskes successivt med hydro-genchloridsyre, vand og saltvand til opnâelse af den tilsvarende exomethylenc ephamsulfozi d.When stannous chloride is used as a cyclizing agent in the process of a toluene medium, an intermediate in the form of stannous chloride-sulfinyl halide complex can be isolated by simple filtration of the reaction mixture. The complex can be terraced and stored, or it can be dissolved in ethyl acetate and washed successively with hydrogen chloride acid, water and brine to obtain the corresponding exomethylenc ephamsulfozi d.

l'or at sikre fuldstændig cyclisering af sulfinylhalogenidet anvendes mindst en stekiometrisk (mol pr. mol) mængde af katalysa-toren af lewis-syre-typen eller af det metâthetisk'kationdannende stof. Yed at anvende mindre end en ækvivalent af sâdanne midler opnâs lavere udbytter af 3-nietbylencepbamsulfoxidet, og en del af sulfinylchloridet forbliver ureageret. Typisk vil den mængde ka-talysator, der anvendes, dække fra lidt over en ækvivalent til cirka to ækvivalenter pr. mol sulfinylchlorid. Cirka 1,1 ækviva-lent met alliai ogenid af lewis-syre-typen eller af det metâthetisk kationdannende middel anvendes for hvert mol azetidinonsulfinyl-halogenid. Selv om mindre end stokiometriske mængder af en kata-lysator af Brsnsted-protonsyre-typen' kan anvendes for at fuldende cycliseringen af enten sulfinylchlorid eller andre sulfinsyre- 24To ensure complete cyclization of the sulfinyl halide, at least one stoichiometric (mole per mole) amount of the Lewis acid type catalyst or of the metathetic cation forming agent is used. By using less than one equivalent of such agents, lower yields of the 3-nitylbenzepepam sulfoxide are obtained and part of the sulfinyl chloride remains unreacted. Typically, the amount of catalyst used will cover from a little over one equivalent to about two equivalents per moles of sulfinyl chloride. Approximately 1.1 equivalents of the Lewis acid-type alloy ogenide or of the metathetic cation-forming agent are used for each mole of azetidinone sulfinyl halide. Although less than stoichiometric amounts of a Brsnsted protonic acid catalyst can be used to complete the cyclization of either sulfinyl chloride or other sulfinic acid.

DK 157137 BDK 157137 B

derivater, anvendes typisk en ækvivalent mængde eller lidt mere af en sâdan sur katalysator. Som anfsrt ovenfor kan cycliseringen ogsâ udferes i en ren protisk syre, hvilket er en foretrukken metode.derivatives, an equivalent amount or a little more of such an acidic catalyst is typically used. As mentioned above, cyclization can also be carried out in a pure protic acid, which is a preferred method.

Reaktionstiden under de foran beskrevne betingelser vil ligge pâ 5 minutter til 2 timer, idet reaktionstiden i nogen grad er afhæng-ig af de særlige reaktanter, det anvendte oplzsningsmiddel og den temperatur, ved hvilken reaktionen udfores. Sædvanligvis vil re-aktionen være tilendebragt, efter at reaktanterne har været i kon-takt med hinanden, ved den foretrukne temperatur i 45-90 minutter; imidlertid er kortere reaktionstider bekvemme under visse betin-gelser. Reaktionsblandingen kan let fslges, f.eks. ved sammenlig-nende tyndtlagskromatografi for at bestemme, livornâr cycliserings-reaktionen er tilende'bragt.The reaction time under the conditions described above will be from 5 minutes to 2 hours, the reaction time being to some extent dependent on the particular reactants, the solvent used and the temperature at which the reaction is carried out. Usually, after the reactants have been in contact with each other, the reaction will be completed at the preferred temperature for 45-90 minutes; however, shorter reaction times are convenient under certain conditions. The reaction mixture can be readily followed, e.g. by comparative thin layer chromatography to determine when the cyclization reaction is complete.

Den mekanisme, der gzr, at man ved den omhandlede fremgangsmâde opnâr det znskede résultat, er ikke endnu fuldstsendigt klarlagt, men et mellemprodukt af en sulfiniumion 0The mechanism by which the desired result is obtained by the process in question has not yet been fully clarified, but an intermediate of a sulphinium ion.

VÂ . r\ AVÂ. r \ A

' A Λ Y CHs y- CH*'A Λ Y CHs y- CH *

(JOOR COOR(JOOR COOR

eller et kompleks deraf, livori C2-substituenten pâ azetidinon-ringen eror a complex thereof, the livori C2 substituent on the azetidinone ring

* X:M* X: M

i .. , S-0:M eller — S-0 (M = H+ eller metalhalogenid af lewis-syre-typen) er det mesr sand-synlige. Oyclisering af deutereret sulfinylchlorid fremstillet ud fra metfryl-6-pbthalimido-3P-meth.yl~3a-trideuteriometliylpenam*-3-carboxylat-la-oxid (R.D.G·. Cooper, Journal of the American Chemicalin .., S-0: M or - S-0 (M = H + or Lewis acid metal halide), the mesr is visible. Oyclization of Deuterated Sulfinyl Chloride Prepared From Methylryl-6-pbthalimido-3β-methyl ~ 3α-trideuteriometliylpenam * -3-carboxylate-la-oxide (R.D.G. Cooper, Journal of the American Chemical

25 DK 157137 BDK 157137 B

Society, 92, 5010 (1970)] med stannichlorid giver meth.yl-7-ph.th.al-imido-2,2-dideuterio-3-methylencepliam-4-carboxylat-1-oxid.Society, 92, 5010 (1970)] with stannous chloride affords methyl 7-phthalal imido-2,2-dideuterio-3-methyleneepliam-4-carboxylate-1-oxide.

0 Π O0 Π O

Il O # Il /V\ >. (\\ /\/>Il O # Il / V \>. (\\ / \ />

1 ΛΛ-Τ Γ vv D N1 ΛΛ-Τ Γ vv D N

X* ο SnCU ° ^X * ο SnCU ° ^

Loch, ^ î'0lgende er repræsentative for de omdannelser, der kan opnâs ved fremgangsmâden ifzlge opfindelsen: t ert-butyl-3-meth.y 1-2-( 2-ch.lor suif inyl-4-oxo-3-phtlialimido-1-azetidinyl)-3-butenoat fra tert-butyl-6-pbth.alimidopenicillanat-sulfoxid cycliseres til 7-pbtbalimido-3-nietliylencepliaïïi-4-carboxyl-syresulfoxid; benzyl-3-methyl-2-( 2-cb.lorsulfinyl-4-oxo-3-benzyloxycarbonylaniino- 1-azetidinyl)-3-butenoat,afledt af benzyl-6-benzyloxycarbonyl-amino-penicillanat-sulfoxid, cycliseres til benzyl-7-benzyloxy-carbonylamino-3-iQetliylencepliam-4-carboxylat-sulfoxid; 4 ' -metboxybenzyl-3-methyl-2-( 2-sulf ino-4-oxo-3-ph.enoxyacetamido- 1-azetidinyl)-3-butenoat, afledt af 4' -metb.oxybenzyl-6-plienoxy-acetamidopenicillanatsulfoxid, cycliseres til 7-pbenoxyacetamido-3-methylencephem-4-carboxylsyresulfoxid; 2' ,2' ,2' -trichlorethyl-3-methyl-2-(2-chlorsulfinyl) -4-oxo-3-phenyl-acetamido-1-azetidinyl)-3-butenoat, afledt af 2’,2',2’-trichlor-ethyl-6-pîienylacetamidopenicillanatsulfoxid, cycliseres til 2^2^2^ trichlorethyl-7-plienylacetainido-3-metliylencepb.ani-4-carboxylatsulf-oxid; 4 ’ -nitrobenzyl-3-me thyl-2-[ 2- (N ,N * -di ( carbomethoxy)liydrazosul-finyl)-4-oxo-3-(2-tbienylacetainido)-1-azetidinyl]-3-butenoat, afledt af 4,-nitrobenzyl-6-(2-tMenylacetamido)penicillanatsulfoxid, cycliseres til 41 -nitrobenzy 1-7-( 2-thienylacetamido) -3-meth.ylen-The following are representative of the conversions that can be obtained by the process of the invention: tert-butyl-3-methyl-1-2- (2-chloro suifinyl-4-oxo-3-phthalimido) -1-azetidinyl) -3-butenoate from tert-butyl-6-pbthalimidopenicillanate sulfoxide is cyclized to 7-pbtbalimido-3-methylene cephalin-4-carboxylic acid sulfoxide; benzyl-3-methyl-2- (2-chlorosulfinyl-4-oxo-3-benzyloxycarbonylamino-1-azetidinyl) -3-butenoate derived from benzyl-6-benzyloxycarbonylamino-penicillanate sulfoxide is cyclized to benzyl. 7-benzyloxy-carbonylamino-3-iQetliylencepliam-4-carboxylate sulfoxide; 4 '-Metboxybenzyl-3-methyl-2- (2-sulfino-4-oxo-3-phenoxyacetamido-1-azetidinyl) -3-butenoate, derived from 4' -methoxybenzyl-6-plienoxyacetamidopenicillanate sulfoxide , is cyclized to 7-pbenoxyacetamido-3-methylene cephem-4-carboxylic acid sulfoxide; 2 ', 2', 2 '-trichloroethyl-3-methyl-2- (2-chlorosulfinyl) -4-oxo-3-phenyl-acetamido-1-azetidinyl) -3-butenoate, derived from 2', 2 ', 2'-trichloro-ethyl-6-pienylacetamidopenicillanate sulfoxide, cyclized to 2 ^ 2 ^ 2 ^ trichloroethyl-7-plienylacetamido-3-methylenecepbanyan-4-carboxylate sulfide oxide; 4'-Nitrobenzyl-3-methyl-2- [2- (N, N * -di (carbomethoxy) -hydrazosulphinyl) -4-oxo-3- (2-thienylacetamido) -1-azetidinyl] -3-butenoate , derived from 4, -nitrobenzyl-6- (2-phenylacetamido) penicillanate sulfoxide, is cyclized to 41-nitrobenzy 1-7- (2-thienylacetamido) -3-methylene

26 DK 157137 B26 DK 157137 B

cepham-4-carboxylatsulfoxid; benzb.ydryl-3-metliyl-2-[ 2-chlorsulfinyl-4-oxo-3-(2,2-dimeth.yl-3-nitroso-5-oxo-4-pb.enyl-1-imidazolidinyl)-1-azetidinyl]-3-butenoat, afledt af benzhydryl-6-(2,2-dimeth.yl-3-nitroso-5-oxo-4-ph.eny 1-1-imidazolidinyl)penicillanatsulfoxid [h.etacillin-benzh.ydrylester], cycliseres til 7-(2,2-dimeth.yl-3-nitroso-5-oxo-4-ph.enyl-1-imida-zolidinyl)-3-meth.ylenceph.am-4-carboxylsyresulfoxid; 2 ,-iodeth.yl-3-meth.yl-2-(2-sulfino-4-oxo-3-ckloracetamido~1-aze-tidinyl)-3-butenoat, afledt af 2 '-iodetliyl-ô-cîiloracetaniïdopeni-cillanatsulf oxid, cycliseres til 2 ’-iodeth.yl-7-ch.loracetamido-3-me th.y lenc eph.am-4-car boxy lat suif oxid; dimeth.ylallyl-3~metliyl-2-(2-clilorsulfinyl-4-oxo-3-maleiïïiido-1-azetidinyl)-3-butenoat, afledt af dimethylallyl~6-maleimidopeni-cillanatsulfoxid, cyclideres af dimeth.ylallyl-7-maleimido-3-meth.ylenceph.am-4-carboxylatsulfoxid; succinimidometliyl-3-meth.yl-2-(2-ch.lorsulfinyl-4-oxo-3-cyanoacet-amido-1-azetidinyl)-3-butenoat, afledt af succinimidômethy1-6-cyanoacetamidopenicillanat-sulfoxid, cycliseres til succinimido-meth.yl-7-cyanoacetamido-3-metliylenceph.em-4-carboxylat-sulfoxid; 4 ' -nitrobenzyl-3-meth.yl-2-[ 2-sulfino-4-oxo-3-(4-nitrobenzyloxy-carbonylamino)-1-azetidinyl]-3-butenoat, afledt af 4,-nitrobenzyl~ 6- (4-nitrobenzyloxycarbonylamino)penicillanatsulfoxid, cycliseres af 4’-nitrobenzyl-7-(4-nitrobenzyloxycarbonylamino)-3-methylen- cepbam-4-carboxylatsulfoxid; 4 ’ -nitrobenzyl-3-meth.yl-2-[ 2-ch.lorsulfinyl-4-oxo-3-(4-ch.lorbenz-amido)-1-azetidinyl]-3-butenoat, afledt af 4'-nitrobenzyl-7-(4-chlorbenzamido)penicillanatsulfoxid, cycliseres til 4f-nitrobenzyl- 7- ( 4-cblorbenzamido ) -3-meth.ylencepliem-4-carboxylatsulf oxid ; benzhydryl-3-meth.yl-2-[2-ch.lorsulfinyl~4-oxo-(2-tert-butoxycarbo-nylamino-2-pbenylacetamido)-1-azetidinyl]-3-butenoat, afledt af benzhydryl-6-(2-tert-butoxycarbonylamino-2-phenylacetamido)peni-cillanatsulfoxid, cycliseres til 7-(2-amino-2-ph.enylacetamido)-3-meth.ylencepham-4-carboxylsyresulfoxid;cepham-4-carboxylatsulfoxid; benzbydryl-3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (2,2-dimethyl-3-nitroso-5-oxo-4-pybenyl-1-imidazolidinyl) -1 -azetidinyl] -3-butenoate derived from benzhydryl-6- (2,2-dimethyl-3-nitroso-5-oxo-4-phenyl-1-imidazolidinyl) penicillanate sulfoxide [etacillin-benzh. yeast ester], cyclized to 7- (2,2-dimethyl-3-nitroso-5-oxo-4-phenyl-1-imidazolidinyl) -3-methylenecepham-4-carboxylic acid sulfoxide; 2, -iodoethyl-3-methyl-2- (2-sulfino-4-oxo-3-chloroacetamido-1-aze-tidinyl) -3-butenoate, derived from 2'-iodo-dimethyl-α-siloroacetanyidopenic acid cillanate sulfide oxide, cyclized to 2'-iodoethyl-7-chloroacetamido-3-me thylene eph.am-4-car boxy lat suf oxide; dimethylallyl-3-methyl-2- (2-chlorosulfinyl-4-oxo-3-maleido-1-azetidinyl) -3-butenoate, derived from dimethylallyl ~ 6-maleimidopenicillanate sulfoxide, is cyclized by dimethylallyl-7- 3-maleimido-4-meth.ylenceph.am carboxylatsulfoxid; succinimidomethyl-3-methyl-2- (2-chlorosulfinyl-4-oxo-3-cyanoacetamido-1-azetidinyl) -3-butenoate, derived from succinimidomethyl-6-cyanoacetamidopenicillanate sulfoxide, is cyclized to succinimido meth.yl-7-cyanoacetamido-3-metliylenceph.em-4-carboxylate sulfoxide; 4 '-nitrobenzyl-3-methyl-2- [2-sulfino-4-oxo-3- (4-nitrobenzyloxy-carbonylamino) -1-azetidinyl] -3-butenoate, derived from 4-nitrobenzyl ~ 6- (4-nitrobenzyloxycarbonylamino) penicillanate sulfoxide, cyclized by 4'-nitrobenzyl-7- (4-nitrobenzyloxycarbonylamino) -3-methylene cepbam-4-carboxylate sulfoxide; 4'-Nitrobenzyl-3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (4-chlorobenzamido) -1-azetidinyl] -3-butenoate, derived from 4'- nitrobenzyl-7- (4-chlorobenzamido) penicillanate sulfoxide, cyclized to 4f-nitrobenzyl-7- (4-chlorobenzamido) -3-methylenecepliem-4-carboxylate sulfide oxide; benzhydryl-3-methyl-2- [2-chlorosulfinyl-4-oxo- (2-tert-butoxycarbonylamino-2-pbenylacetamido) -1-azetidinyl] -3-butenoate, derived from benzhydryl-6- (2-tert-butoxycarbonylamino-2-phenylacetamido) penicillanate sulfoxide, cyclized to 7- (2-amino-2-phenylacetamido) -3-methylencepham-4-carboxylic acid sulfoxide;

27 DK 157137 B27 DK 157137 B

4 ’ -me thoxybenzyl-3-methyl-2-[ 2-chlorsulf inyl-4-oxo-3- ( 2-benzyloxy- 2-phenylacetamido)-1-azetidinyl]-3-butenoat, afledt fra 4’-methoxy-benzyl-6-(2-benzyloxy-2-phenylacetamido)penieillanatsulfoxid, cyc-liseres til 7-(2-benzyloxy-2-phenylacetamido)-3-methylencepham-4-carboxylsyresulfoxid; 2 ', 2 *, 2 ’ -trichlorethyl-3-methyl-2-[ 2-chlorsulfinyl-4-oxo-3-( 2-benzyloxy-2-phenylacetamido ) -1 -azetidinyl] -3-butenoat, afledt fra 2 ', 2f, 2 ' -trichlorethyl-6-(2-benzyloxy~2-phenylacetamido)penicil-lanatsuifoxid, cycliseres til 2',2'^’-trichlorethyl^-^-benzyl-oxy^-phenylacetamido )-3-methylencepham-4-carboxylatsulfoxid; 4 r-nitrobenzyl-3-methyl-2-(2-isopropoxysulfinyl-4-oxo-3-benzamido- 1 -azetidinyl)-3-butenoat, afledt af 4,-nitrobenzyl-6-benzamido-penicillanatsulfoxid, cycliseres til 4'-nitrobenzyl-7-benzamido-3-methylencepham-4-carboxylatsulfoxid; 2 ' -iodeth.yl-3-meth.yl-2- ( 2-cyclohexyloxysulf inyl-4-oxo-3-chlor-acetamido-1-azetidinyl)-3-butenoat, afledt af 21-iodethyl-6-chlor-acetamidopenicillanatsuifoxid, cycliseres til 2,-iodethyl-7-chlor-acetamido-3-methylencepham-4-carboxylatsulfoxid; 2 ’, 2 ' ,2'-trichlorethyl-3-methyl-2-[N,N'-di(carboethoxy)hydrazo-sulfinyl-4-oxo-3-(2-thienylacetamido)-1-azetidinyl]-3-butenoat, afledt af 2',2',2’-trichlorethyl-6-(2-thienylacetamido)penicilla-natsulfoxid, cycliseres til 2’,2',2’-trichlorethy1-7-(2-thienylacetamido )-3-methylencepham-4-carboxylatsulfoxid; methyl-3-methyl-2-[2-carbamylhydrazosulfinyl-4-oxo-3-(3-nitrophen-oxyacetamido)-1-azetidinyl]-3-butenoat, afledt af methyl-6-(3-nitrophenoxyacetamido)penicillanatsulfoxid, cycliseres til methyl- 7-(3-nitrophenoxyacetamido)-3-methylencepham-4-carboxylatsulfoxid; benzhydryl-3-methyl-2-[2-(4-chloranilinsulfinyl)-4-oxo-3-(4-nitro-benzyloxÿcarbonylamino)-1-azetidinyl]-3-butenoat, afledt af benz-hydryl-6-(4-nitrobenzyloxycarbonylamino)penicillanatsulfoxid, cycliseres til 7-(4-nitrobenzyloxycarbonylamino)-3-methylencepham- 4-carboxylsyresulfoxid; 284 '-methoxybenzyl-3-methyl-2- [2-chlorosulfonyl-4-oxo-3- (2-benzyloxy-2-phenylacetamido) -1-azetidinyl] -3-butenoate, derived from 4'-methoxyphenyl benzyl-6- (2-benzyloxy-2-phenylacetamido) penylillanate sulfoxide, cyclized to 7- (2-benzyloxy-2-phenylacetamido) -3-methyleneepham-4-carboxylic acid sulfoxide; 2 ', 2 *, 2' -trichloroethyl-3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (2-benzyloxy-2-phenylacetamido) -1-azetidinyl] -3-butenoate, derived from 2 2,2,2-Trichloroethyl-6- (2-benzyloxy-2-phenylacetamido) penicillanatsuifoxide is cyclized to 2 ', 2' - (- trichloroethyl - (- - benzyl-oxy-phenylacetamido) -3-methylencepham -4-carboxylatsulfoxid; 4 r-Nitrobenzyl-3-methyl-2- (2-isopropoxysulfinyl-4-oxo-3-benzamido-1-azetidinyl) -3-butenoate, derived from 4, -nitrobenzyl-6-benzamido-penicillanate sulfoxide, is cyclized to 4 ' -nitrobenzyl-7-benzamido-3-methylenecepham-4-carboxylatsulfoxid; 2 '-iodoethyl-3-methyl-2- (2-cyclohexyloxysulfinyl-4-oxo-3-chloro-acetamido-1-azetidinyl) -3-butenoate, derived from 21-iodoethyl-6-chloro acetamidopenicillanatsu nitric oxide, cyclized to 2, -iodoethyl-7-chloro-acetamido-3-methylene cepham-4-carboxylate sulfoxide; 2 ', 2', 2'-trichloroethyl-3-methyl-2- [N, N'-di (carboethoxy) hydrazo-sulfinyl-4-oxo-3- (2-thienylacetamido) -1-azetidinyl] -3- butenoate, derived from 2 ', 2', 2'-trichloroethyl-6- (2-thienylacetamido) penicillanate sulfoxide, cyclized to 2 ', 2', 2'-trichloroethyl 1-7- (2-thienylacetamido) -3-methylencepham -4-carboxylatsulfoxid; Methyl 3-methyl-2- [2-carbamylhydrazosulfinyl-4-oxo-3- (3-nitrophenoxyacetamido) -1-azetidinyl] -3-butenoate derived from methyl 6- (3-nitrophenoxyacetamido) penicillanate sulfoxide is cyclized. to methyl 7- (3-nitrophenoxyacetamido) -3-methylencepham-4-carboxylate sulfoxide; benzhydryl-3-methyl-2- [2- (4-chloroaniline sulfinyl) -4-oxo-3- (4-nitro-benzyloxecarbonylamino) -1-azetidinyl] -3-butenoate, derived from benzhydryl-6- (4 -nitrobenzyloxycarbonylamino) penicillanate sulfoxide, cyclized to 7- (4-nitrobenzyloxycarbonylamino) -3-methyleneepham-4-carboxylic acid sulfoxide; 28

DK 157137 BDK 157137 B

4 ’ -nitrobenzyl-3-met:hyl-2-( 2-p:lltfralimidosulfinyl-4-oxo-3-p}lenyl-acetamido-1-azetidinyl)-3-butenoat, afledt af 4,-nitro'benzyl-6-phenylacetamidopenicillanatsulfoxid, cycliseres til 4,-nitro'benzyl-7-pb.enylacetamido-3-methylencepliaï)i-4-car'boxylatsulfoxid; 21 -iode thyl-3-metliy 1-2- ( 2-br omsulf inyl-4-oxo-3-plit]ialimido-1 -azetidinyl)-3-butenoat, afledt af 2,-iodeth.yl-6-phtlialimidopeni-cillanatsulfoxid, cyclideres til 2,-iodethyl-7-plithalimido-3-me thylencepliam-4-carboxylatsulf oxid ; 4! -ni troT3enzyl-3-metliy 1-2-( 2-ph.enyltliiosulf iny l-4“OXo-3~plienoxy-acetamido-1-azetidinyl)-3-butenoat, afledt af 41 -nitrobenzyl-β-phenoxyacetamidopenicillanatsulfoxid, cycliseres til 4'-nitrobenzyl-7-pîienoxyacetamido-3-nietliylencepliaiii-4-carboxylatsulfoxid; phenacyl-3-m.et]iyl-2-[ 2-( 2-phenylethylthiosulf inyl) -4-oxo-3-( 2-benzyloxy-2-ph.enylacetamido ) -1 -azetidinyl] -3-butenoat, afledt af ph.enacyl-6- ( 2-benzyloxy-2-ph.enylacetamido ) penicillanatsulf oxid, cyclieeres til ph.enacyl-7-(2-benzyloxy-2-plienylacetaniido)-3-methylencepbLam-4-carbo:xylatsulfoxid; tert-butyi-3-methyl-2-[ 2~metbylcarbamylliydrazosulfinyl-4-oxo-3-(4-metlioxyplienylacetaniido)-1-azetidinyl]-3-butenoat, afledt af tert-butyl-6- ( 4-me tboxyphenylacetamido ) penicillanatsulf oxid, cy c-t lisérés til 7-(4-methoxyplaenylacetainido)-3~metliylencepliain-4-carb-oxylsyresulfoxid; trimeth.ylsilyl-3-met]iyl-2-(2-carboinethoxyhydrazosulfinyl-4-oxo-3-plieny lacet ami do-1 -azetidinyl) -3-butenoat, afledt af trimethyl-silyl-6-ph.enylacetamidopenicillanatsulfoxid, cycliseres til 7-plienylacetamido-3-methylencepham-4-car'boxylsyresulfoxid; og 4 ' -dilorplienacyl-3-metliyl-2-[ 2-( 2-ch.loreth.oxysulfinyl)-4-oxo-3~ formamido-1-azetidinyl]-3-butenoat, afledt af 4' -cblorph.enacyl-6-formamidopenicillanatsulfoxid, cycliseres til 4'-clilorplienacyl-7-formamido-3-metliylencepliam-4-car'boxylatsulfoxid.4'-Nitrobenzyl-3-methyl-2- (2-piperidimalosidosulfinyl-4-oxo-3-p} lenyl-acetamido-1-azetidinyl) -3-butenoate, derived from 4, -nitro'benzyl 6-phenylacetamidopenicillanate sulfoxide, cyclized to 4, -nitro'benzyl-7-pb.enylacetamido-3-methyleneceplia) -4-carboxylate sulfoxide; 21-Ide thyl-3-methyl 1-2- (2-bromosulfinyl-4-oxo-3-plit] alimido-1-azetidinyl) -3-butenoate, derived from 2, iodoethyl-6-phthalimidopenia -cillanate sulfoxide, is cyclated to 2, -iodoethyl-7-plithalimido-3-methylethylcepliam-4-carboxylate sulfide oxide; 4! -NitroT3enzyl-3-methyl 1-2- (2-phenylthiolsulfinyl-4β-OXo-3-pienoxyacetamido-1-azetidinyl) -3-butenoate, derived from 41-nitrobenzyl-β-phenoxyacetamidopenicillanate sulfoxide, is cyclized to 4'-nitrobenzyl-7-pienoxyacetamido-3-methylene cephalin-4-carboxylate sulfoxide; phenacyl-3-methyl] 2- [2- (2-phenylethylthiosulfonyl) -4-oxo-3- (2-benzyloxy-2-phenylacetamido) -1-acetyl] -3-butenoate, derived of phenylacyl-6- (2-benzyloxy-2-phenylacetamido) penicillanate sulfide oxide, cyclized to phenylacyl 7- (2-benzyloxy-2-plienylacetanido) -3-methylene cepbLam-4-carboxylate sulphoxide; tert-butyl-3-methyl-2- [2-methylcarbamyl] dirazosulfinyl-4-oxo-3- (4-methylioxyplienylacetanyl) -1-azetidinyl] -3-butenoate, derived from tert-butyl-6- (4-methyl-tboxyphenylacetamido) penicillanate sulfide oxide, which is licensed to 7- (4-methoxyplaenylacetamido) -3-methylenecepliain-4-carboxylic acid sulfoxide; trimethylsilyl-3-methyl-2- (2-carboinethoxyhydrazosulfinyl-4-oxo-3-plienylacetamido-1-azetidinyl) -3-butenoate, derived from trimethylsilyl-6-phenylacetamidopenicillanate sulfoxide, is cyclized to 7-plienylacetamido-3-methylene cepham-4-carboxylic acid sulfoxide; and 4 '-dilorplienacyl-3-methyl-2- [2- (2-chloroethoxysulfinyl) -4-oxo-3-formamido-1-azetidinyl] -3-butenoate derived from 4'-chlorophenacyl -6-formamidopenicillanate sulfoxide, is cyclized to 4'-chloroplienacyl-7-formamido-3-methylenecepliam-4-carboxylate sulfoxide.

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DK 157137 BDK 157137 B

Udbyttet af produkterne vil variere afhængigt af de særlige reak-tanter, der anvendes, de relative mængder af reagenseme og de andre femævnte reaktionsbetingelser.The yield of the products will vary depending on the particular reactants used, the relative amounts of the reagents and the other five-mentioned reaction conditions.

Produktet, der fremstilles ved den omhandlede fremgangsmâde, kan isoleres og oprenses ved at anvende kendt teknik. Denne omfatter kromatografisk separering, filtrering, krystallisation eller om-krystallisation.The product produced by the process of the present invention can be isolated and purified using known techniques. This includes chromatographic separation, filtration, crystallization or recrystallization.

De mest foretrukne sidekæder, repræsenteret ved R i ovennævnte formel, ved den omhandlede fremgangsmâde er de sidekæder, der finies i penicilliner, der fremstilles direkte ved fermentering, primært phenylacetamido og phenoxyacetamido-sidekæder. Sâdanne penicilliner kan esterificeres og oxideres (ikke nedvendigvis i den rækkefslge) til respektive penicillinsulfoxidestre,ud fra hvilke sulfinylchloridmellemprodukterne og andre udgangsmaterialer til den omhandlede fremgangsmâde kan afledes. Det mâ bemærkes, at de fernævnte foretrukne sidekæder ogsâ foretrækkes primært af 0ko-nomiske grunde. Pencillinprecursorer, der har sâdanne sidekæder, er let tilgængelige og relativt billige, og fordelen ved at udfsre den omhandlede fremgangsmâde med de beskrevne sulfinyl-mellempro-dukterudledt herfra mâ være helt klar. Naturligvis kan penicillin-sulfoxider, der har de kendte sidekæder, let fremstilles (ved acylering af 6-APA eller 6-APA-estre og pâfelgende oxidation) og anvendes ved den omhandlede fremgangsmâde.The most preferred side chains, represented by R in the above formula, in the process of the present invention are the side chains fined in penicillins produced directly by fermentation, primarily phenylacetamido and phenoxyacetamido side chains. Such penicillins can be esterified and oxidized (not necessarily in the order) to respective penicillin sulfoxide esters from which the sulfinyl chloride intermediates and other starting materials of the process can be derived. It should be noted that the aforementioned preferred side chains are also preferred primarily for economic reasons. Pencillin precursors having such side chains are readily available and relatively inexpensive, and the advantage of carrying out the process of the present invention with the described sulfinyl intermediates must be quite clear. Of course, penicillin sulfoxides having the known side chains can be readily prepared (by acylation of 6-APA or 6-APA esters and subsequent oxidation) and used in the process of the invention.

De fremstillede produkter i form af 3-methylencephamsulfoxider er nyttige som mellemprodukter ved fremstilling af antibiotiske forbindelser. Sulfoxiderne kan reduceres ved kendte metoder, typisk med phosphortrichlorid eller phosphortribromid i dimethyl-formamid til opnâelse af den tilsvarende 3-methylencephamforbin-delse, der omdannes i hnjt udbytte til desacetoxycephalosporiner med formlen: J-Kh-The products prepared in the form of 3-methylene cepham sulfoxides are useful as intermediates in the preparation of antibiotic compounds. The sulfoxides can be reduced by known methods, typically with phosphorus trichloride or phosphorus tribromide in dimethylformamide to obtain the corresponding 3-methylene cepham compound which is converted in high yield to desacetoxycephalosporins of the formula:

COORCOOR

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DK 1571 37 BDK 1571 37 B

ved behandling med triethylamin i dîmethylacetamid. [Robert R. Chauvette and Pamela A. Pennington, J. Org. Chem. 38, 2994 (1973)]. Desacetoxycephalosporinestre omdannes til aktive antibiotica ved spaltning af esterfunktionen. Deesterificeringen kan opnâs afhæng-igt af den beskyttende gruppes natur ved en lang række kendte meto-der omfattende (1) behandling med en syre, sâsom trifluoreddike-syre, myresyre eller hydrogenchloridsyre; (2) behandling med zink og en syre, sâsom myresyre, eddikesyre eller hydrogenchloridsyre: eller (3) hydrogenering i nærværelse af palladium, platin, rhodium eller en forbindelse heraf, i en suspension eller pâ en bærer, sâsom bariumsulfat, carbon eller alumina.by treatment with triethylamine in dimethylacetamide. [Robert R. Chauvette and Pamela A. Pennington, J. Org. Chem. 38, 2994 (1973)]. Desacetoxycephalosporin esters are converted to active antibiotics by cleavage of the ester function. The deesterification can be obtained depending on the nature of the protecting group by a variety of known methods comprising (1) treating with an acid such as trifluoroacetic acid, formic acid or hydrochloric acid; (2) treatment with zinc and an acid such as formic acid, acetic acid or hydrochloric acid: or (3) hydrogenation in the presence of palladium, platinum, rhodium or a compound thereof, in a suspension or on a support such as barium sulfate, carbon or alumina.

Alternativt kan exomethylencephamforbindelserne anvendes ved frem-stilling af nye cephemantibiotika med formlen:Alternatively, the exomethylene cepham compounds may be used in the preparation of novel cephem antibiotics of the formula:

R1 SR1 S

\ _ /\\ _ / \

COOHCOOH

hvori Y for eksempel er chlor, brom eller methoxy. Sâdanne kemiske omdannelser af 3-exomethylencephamforbindelser er beskrevet i den kemiske litte.ratur [Robert R. Chauvette and Pamela A. Pennington, Journal of the American Chemical Society, 96, 4986 (1974)].wherein Y is, for example, chlorine, bromine or methoxy. Such chemical conversions of 3-exomethylenepepham compounds are described in the chemical literature [Robert R. Chauvette and Pamela A. Pennington, Journal of the American Chemical Society, 96, 4986 (1974)].

Generelt omdannes exomethylencephamforbindelserne ved lavt tempe- raturozonolyse til 3-hydroxycephemforbindelser, der herefter be- handles med diazomethan i methylenchlorid/ether ved stuetempera- tur til opnâelse af 3-methoxycephemderivater. 3-halogencephem- forbindelser afledes fra 3-hydroxycephemestre ved behandling med * et halogeneringsmiddel, sâsom thionylchlorid eller phosphortri-bromid i dimethylformamid. Tilsvarende cephemsyrer har kraftig antibakteriel virkning.Generally, at low temperature ozonolysis, the exomethylene cepham compounds are converted to 3-hydroxycepheme compounds, which are then treated with diazomethane in methylene chloride / ether at room temperature to obtain 3-methoxycepheme derivatives. 3-Halogen Cephem compounds are derived from 3-hydroxycephem esters by treatment with * a halogenating agent such as thionyl chloride or phosphorous tribromide in dimethylformamide. Corresponding cephemic acids have potent antibacterial activity.

••

Palgénde eksempler illustrerer nærmere fremgangsmâden ifolge op-findelsen. I eksemplerne og præparationeme er nuclear-magnetisk resonansspektrum forkortet med nmr. nmr-spektrene blev opnâet pâ en Varian Associates ï-60 Spectrometer, idet der anvendtes tetra-The following examples further illustrate the method according to the invention. In the examples and preparations, the nuclear magnetic resonance spectrum is shortened by nmr. The nmr spectra were obtained on a Varian Associates 60-60 Spectrometer using

31 DK 157137 B31 DK 157137 B

methylsilan som referencestandard. De kemiske skift er udtrykt i δ-værdier i dele pr. million (ppm),og koHlingskonstanterne (j) er udtrykt som Hz i svingninger pr. sekund.methylsilane as a reference standard. The chemical shifts are expressed in δ values in parts per unit. million (ppm), and the cooling constants (j) are expressed as Hz in oscillations per minute. second.

EKSEMPEL 1EXAMPLE 1

Methyl-7-phtHalimido-3-methylencephem-4-çartoxylat-1_-oxid A. StanniohloridMethyl 7-phthalimido-3-methylene cephem-4-quartoxylate-1-oxide A. Stannous chloride

En blanding af 18,8 g (50 rnmol) methyl-6-phthalimidopenicillanat-sulfoxid og 6,7 g (50 rnmol) N-clilorsuccinimid i 1 liter ter car-tontetraclilorid kogtes i 70 minutter. Det râ produkt afkeledes til stuetemperatur, filtreredes, vaskedes med vand (1 x 500 ml) og tzrredes over magnesiumsulfat. Oplzsningsmidlet afdampedes i vakuum til torlied. nmr-spektret angav en fuldstændig omdannelse til sulfinylchloridet.A mixture of 18.8 g (50 µmol) of methyl 6-phthalimidopenicillanate sulfoxide and 6.7 g (50 µmol) of N-chlorosuccinimide in 1 liter terontontetracliloride was boiled for 70 minutes. The crude product was cooled to room temperature, filtered, washed with water (1 x 500 ml) and dried over magnesium sulfate. The solvent was evaporated in vacuo to dry. the nmr spectrum indicated a complete conversion to the sulfinyl chloride.

nmr (GDCl^) δ 1997 (tred s, 3) 3,86 (s, 3) 5,05 (to. s, 2) 5,2 (d, 1, J=2 Hz) 5,77 (d, 1, J=4 Hz) 5,9 (d, 1, J=4 Hz) 7,83 (m, 4)nmr (GDCl 2) δ 1997 (third s, 3) 3.86 (s, 3) 5.05 (two s, 2) 5.2 (d, 1, J = 2 Hz) 5.77 (d, 1, J = 4 Hz) 5.9 (d, 1, J = 4 Hz) 7.83 (m, 4)

Produktet oplestes i 1 liter tzr methylenclilorid, og 6 ml (50 rnmol) vandfri stanniclilorid tilsattes. Den fremkomne oplosning omrertes i 45 minutter, vaskedes med 1N hydrogencliloridsyre (2 x 200 ml) og terredes over magnesiumsulfat. Inddampning i vakuum gav 18,4 g (98,4$) af en blanding af R- og S-sulfoxider (ca. 3:2 ved nmr) som et lyst gult skum. En del af derme "blanding (1,26 g) adskiltes ved kromatografi over silicagel, idet der anvendtes chloroform/etliylacetat som oplesningsmiddel. Eraktionerne 6-10 indeîioldt- ren R-sulfoxid (340 mg), der omkrystalliseredes fra methylendilorid/cycloîiexan (smp. 201-202 °C).The product was dissolved in 1 liter of methylene chloride and 6 ml (50 µmol) of anhydrous stannic chloride was added. The resulting solution was stirred for 45 minutes, washed with 1N hydrochloric acid (2 x 200 ml) and triturated over magnesium sulfate. Evaporation in vacuo gave 18.4 g ($ 98.4) of a mixture of R and S sulfoxides (about 3: 2 at nmr) as a light yellow foam. A portion of this mixture (1.26 g) was separated by chromatography over silica gel using chloroform / ethyl acetate as the solvent. The reactions 6-10 contained ethyl R-sulfoxide (340 mg) which was recrystallized from methylene diloride / cyclohexane (m.p. 201-202 ° C).

nmr (CDCl^) δ 3,62 og 4,12 (ABq., 2, J=14 Hz) 3,85 (s, 3) 4,88 (d, 1, J=4,5 Hz)nmr (CDCl3) δ 3.62 and 4.12 (ABq., 2, J = 14 Hz) 3.85 (s, 3) 4.88 (d, 1, J = 4.5 Hz)

32 DK 157137 B32 DK 157137 B

nmr (CDCl^) δ 5,25 (Br, s, 1) (forts.) 5,58 ^ 5,97 (d, 1, J=4,5 Hz) 7.84 (ïïl, 4) massespektrum m/e 374, 358, 346, 298, 287, 239, 220. ir (Or): 1780, 1745 og 1390 cm"1.nmr (CDCl 3) δ 5.25 (Br, s, 1) (cont.) 5.58 ^ 5.97 (d, 1, J = 4.5 Hz) 7.84 (µl, 4) mass spectrum m / e 374 , 358, 346, 298, 287, 239, 220. ir (Or): 1780, 1745 and 1390 cm

Analyse Beregnet for C 17H14N2°6S (574,37: C 54,54 - H 3,77 - N 7,48 - 0 25,64 - S 8,56 fundet: C 54,41 - h 4,06 - N 7,26 - 0 25,59 - S 8,41Analysis Calculated for C 17 H 14 N 2 O 6 S (574.37: C 54.54 - H 3.77 - N 7.48 - 0.25.64 - S 8.56 found: C 54.41 - h 4.06 - N 7 , 26 - 0 25.59 - S 8.41

Eraktionerne 11-18 indelioldt en Blanding af R- og S-sulfoxider, og fraktionerne 19-35 gav 210 mg af S-sulfoxidet, der omkrystal-liseredes fra methyleneHlorid/cycloHexan.Fractions 11-18 divided a mixture of R and S sulfoxides and fractions 19-35 gave 210 mg of the S sulfoxide which was recrystallized from methylene chloride / cyclohexane.

nmr (CDCl^) δ 3,63 (s, 2) 3,82 (s, 3) 4,90 (d, 1, J=4,5 Hz) 5,32 (s, 1) 5,46 (Br, s, 1) 5,64 (d, 1, J=4,5 Hz) 5,77 (s, 1) 7.84 (m, 4) massespektrum m/e 374, 358, 346, 298, 287, 239, 200.nmr (CDCl 3) δ 3.63 (s, 2) 3.82 (s, 3) 4.90 (d, 1, J = 4.5 Hz) 5.32 (s, 1) 5.46 (Br , s, 1) 5.64 (d, 1, J = 4.5 Hz) 5.77 (s, 1) 7.84 (m, 4) mass spectrum m / e 374, 358, 346, 298, 287, 239, 200th

ir (Or): 1775, 1745, 1725, 1390, 1205, 1111, 1051, 730 og 715 -1 cm .ir (Or): 1775, 1745, 1725, 1390, 1205, 1111, 1051, 730 and 715 -1 cm.

Analyse Beregnet for Ο^γΗ^^Οβδ: C 54,54 - H 3,77 - N 7,48 fundet: C 54,33 - H 3,76 - N 7,36.Analysis Calculated for ΟΟ γΗΗΟδδ: C 54.54 - H 3.77 - N 7.48 found: C 54.33 - H 3.76 - N 7.36.

B. TitaniumtetracBloridB. Titanium TetracBloride

En oplssning af 0,41 g metB.yl-3-methy 1-2-(2-chlorsulfinyl-4-oxo- 3-pkthalimido-1-azetidinyl)-3-Butenoat og 0,12 ml titantetrachlo-A solution of 0.41 g of methyl B. 3-methyl 1-2- (2-chlorosulfinyl-4-oxo-3-pctthalimido-1-azetidinyl) -3-butenoate and 0.12 ml of titanium tetrachloride

33 DK 157137 B33 DK 157137 B

rid i 30 ml ter 1,2-dichlorethan kogtes med tilhagesvaling i 30 minutter. Blandingen afkeledes til stuetemperatur, vaskedes med 1N hydrogenchloridsyre og saltvand og t0rredes over magnesium-sulfat. Inddampning i vakuum til tzrhed gav 0,34 g methyl-7-phthalimido-3-methylencepham-4-carhoxylat-1-oxid.Stir in 30 ml ter 1,2-dichloroethane boiled at reflux for 30 minutes. The mixture was cooled to room temperature, washed with 1N hydrochloric acid and brine, and dried over magnesium sulfate. Evaporation in vacuo to dryness gave 0.34 g of methyl 7-phthalimido-3-methylene cepham-4-carhoxylate-1 oxide.

C. AluminiumchloridC. Aluminum chloride

En hlanding af 0,41 g methyl-3-methyl-2~(2-chlorsulfinyl-4-oxo-3-phthalimido-1-azetidinyl)-3-butenoat og 0,13 g aluminiumchlorid kogtes med tilhagesvaling i 30 ml ter 1,2-dichlorethan. Blandingen afkzledes til stuetemperatur, yaskedes med 1N hydrogenchlorid-syre og saltvand og terredes over magnesiumsulfat. Inddampning i vakuum til terhed gav 0,35 g 3-methylencephamsulfoxid som et gult skum.A mixture of 0.41 g of methyl 3-methyl-2 ~ (2-chlorosulfinyl-4-oxo-3-phthalimido-1-azetidinyl) -3-butenoate and 0.13 g of aluminum chloride was refluxed in 30 ml of ter 1 , 2-dichloroethane. The mixture was cooled to room temperature, washed with 1N hydrochloric acid and brine and triturated over magnesium sulfate. Evaporation in vacuo to dryness gave 0.35 g of 3-methylene cepham sulfoxide as a yellow foam.

D. ZinkhromidD. Zinc chromide

En hlanding af 0,41 g methyl-3-methyl-2-(2-chlorsulfinyl-4-oxo-3-phthalimido-1-azetidinyl)-3-hutenoat og 0,27 g zinkhromid i 30 ml ter methylenchlorid kogtes med tilhagesvaling i 1‘ time. Blandingen afkzledes til stuetemperatur, vaskedes med 1N hydrogen-chloridsyre og tzrredes over magnesiumsulfat. Inddampning i vakuum til terhed gav en hlanding af R- og S-3-methylencepham-sulfoxid som et gult skum.A mixture of 0.41 g of methyl 3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phthalimido-1-azetidinyl) -3-hutenoate and 0.27 g of zinc chromide in 30 ml of methylene chloride was refluxed. for 1 hour. The mixture was cooled to room temperature, washed with 1N hydrochloric acid and dried over magnesium sulfate. Evaporation in vacuo to dryness gave a mixture of R- and S-3-methylene cepham sulfoxide as a yellow foam.

E. AntimonpentachloridE. Antimony pentachloride

En oplesning af 0,41 g methyl-3-methyl-2-(2-chlorsulfinyl-4-oxo-3-phthalimido-1-azetidinyl)-3-hutenoat og 0,12 g antimonpentachlorid omrertes ved stuetemperatur i 60 minutter. Reaktionshlan-dingen vaskedes med 1N hydrogenchloridsyre og saltvand, tzrredes over magnesiumsulfat og inddampedes i vakuum til tzrhed til op-nâelse af den znskede 3-methylencephamsulfoxid som et gult skum. nmr-prektret af produktet var ringe, Œil hekræftelse af nærvæ-relse af cephamsulfoxid oplzstes reaktionsproduktet i 3 ml di-methylformamid og omsattes med 0,09 ml phosphortrichlorid. Efter hlandingen var omrzrt ved 0 °0 i 30 minutter udhældtes den pâ en is/vand-hlanding. Det gule hundfald, der herved dannedes, opsam-ledes ved filtrering og tzrredes under vakuum. Et nmr-spektrum af produktet (0,15 g) viste, at det var methyl-7-phthalimido-3-methylencepham-4-carhoxylat.A solution of 0.41 g of methyl 3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phthalimido-1-azetidinyl) -3-hutenoate and 0.12 g of antimony pentachloride was stirred at room temperature for 60 minutes. The reaction mixture was washed with 1N hydrochloric acid and brine, dried over magnesium sulfate and evaporated in vacuo to dryness to give the desired 3-methylene cepham sulfoxide as a yellow foam. The nmr spectrum of the product was low, to confirm the presence of cepham sulfoxide, the reaction product was dissolved in 3 ml of dimethylformamide and reacted with 0.09 ml of phosphorus trichloride. After the stirring was stirred at 0 ° for 30 minutes, it was poured onto an ice / water mixture. The yellow droplet thus formed is collected by filtration and dried under vacuum. An nmr spectrum of the product (0.15 g) showed it to be methyl 7-phthalimido-3-methylene cepham-4-carhoxylate.

34 DK 157137 B34 DK 157137 B

(CDC15) δ 3,47, 3,96 (ABçl, 2, J=17 Hz, Cg-H) 3,87 (s, 3, C4-ïï) 5,20 (d, 1, J=4,5 Hz) 5,80 (d, 1, J=4,5 Hz) 7,83 (m, 4).(CDCl15) δ 3.47, 3.96 (ABçl, 2, J = 17 Hz, Cg-H) 3.87 (s, 3, C4-) 5.20 (d, 1, J = 4.5 Hz) 5.80 (d, 1, J = 4.5 Hz) 7.83 (m, 4).

1. Mercurichlorid1. Mercury Chloride

En blanding af 0,20 g methyl-3-methyl-2-(2-chlorsulfinyl-4~oxo-3-phthalimido-1-azetidinyl)-3-butenoat og 0,14 g mercurichlorid i 10 ml ter 1,2~dichlorethan kogtes med tUbage s valing i 1 time. Blandingen afkzledes til stuetemperatur, vaskedes med 1N hydrogen-chloridsyre, terredes over magnesiumsulfat og inddampedes i vakumm til tzrhed til opnâelse af 0,14 g 3-methylencephamsulfoxid som en blanding af R- og S-sulfoxidisomere.A mixture of 0.20 g of methyl 3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phthalimido-1-azetidinyl) -3-butenoate and 0.14 g of mercuric chloride in 10 ml of 1.2 ~ dichloroethane was boiled with tUbage's whey for 1 hour. The mixture was cooled to room temperature, washed with 1N hydrochloric acid, triturated over magnesium sulfate and evaporated in vacuo to dryness to give 0.14 g of 3-methylene cepham sulfoxide as a mixture of R and S sulfoxide isomers.

G. EerrichloridG. Eerichloride

Ben samme procedure blev anvendt som under E med den undtagelse, at 0,08 g ferrichlorid anvendtes som katalysator i stedet for mercurichlorid. Sammenlignende tyndtlagskromatografi bekræfte-de omdannelsen af sulfinylchlorid til 3-methy1encephamsulfoxid.Ben the same procedure was used as under E except that 0.08 g of ferric chloride was used as a catalyst instead of mercuric chloride. Comparative thin layer chromatography confirmed the conversion of sulfinyl chloride to 3-methyleneephamsulfoxide.

H. ZirconiumtetrachloridH. Zirconium tetrachloride

Den samme metode blev fulgt som under E med den undtagelse, at 0,12 g zirconiumtetraclilorid anvendtes som katalysator i stedet for mercurichlorid. Sammenlignende tyndtlagskromatografi bekræf-tede en ren omdannelse af sulfinylchlorid til 3-methylencepham-sulfoxid. nmr-spektret af produktet var identisk med produktet under A ovenfor.The same method was followed as under E with the exception that 0.12 g of zirconium tetracliloride was used as a catalyst instead of mercuric chloride. Comparative thin layer chromatography confirmed a pure conversion of sulfinyl chloride to 3-methylene cepham sulfoxide. the nmr spectrum of the product was identical to the product under A above.

I. PolyphosphorsyreI. Polyphosphoric acid

Me thyl-3-methyl-2-(2-chlorsulfinyl-4-oxo-3-phthalimido~1-azeti-dinyl)-3-butenoat (0,20 g) omrzrtes i ca. 27 g polyphosphorsyre i 20 minutter. Isvand og ethylacetat (25 ml) sattes til reaktions-blandingen, Den organiske fase frasepareredes og vaskedes suc-cessivt med vand, vandig natriumbicarbonat og saltvand, t0rredes over magnesiumsulfat og inddampedes i vakuum til terhed til opnâelse af methyl-7-phthalimido-3-methylencepham-4-carboxylat-1-oxid (0,05 g) som et hvidt skum.Methyl 3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phthalimido-1-azetidinyl) -3-butenoate (0.20 g) was stirred for ca. 27 g of polyphosphoric acid for 20 minutes. Ice water and ethyl acetate (25 ml) were added to the reaction mixture, The organic phase was separated and washed successively with water, aqueous sodium bicarbonate and brine, dried over magnesium sulfate and evaporated in vacuo to give methyl 7-phthalimido-3 methylene cepham-4-carboxylate-1-oxide (0.05 g) as a white foam.

35 DK 157137 BDK 157137 B

J. SvovlsyreJ. Sulfuric acid

En oplesning af 0,20 g meth.yl-3-metliyl-2-(2-c]2lorsulfinyl~4-oxo-3-phthalimido-1-azetidinyl)-3-butenoat og 2 drâber koncentreret svovlsyre i 10 ml ter 1,2-dicb.loretlian kogtes med tilbagesvaling i 1 time. Reaktionsblandingen afkeledes, vaskedes med saltvand, terredes over magnesiumsulfat og inddampedes i vakuum til ter-lied til opnâelse ai 0,09 g ai et farvelest skum, hvis nmr-spek-trum viste, at det primært var den enskede 3-meth.ylenceph.am~ sulfoxid.A solution of 0.20 g of methyl 3-methyl-2- (2-c] chlorosulfinyl-4-oxo-3-phthalimido-1-azetidinyl) -3-butenoate and 2 drops of concentrated sulfuric acid in 10 ml of ter 1 The 2-dicb.loretlian was refluxed for 1 hour. The reaction mixture was cooled, washed with brine, triturated over magnesium sulfate and evaporated in vacuo to give 0.09 g of a colorless foam, the nmr spectrum of which was primarily the individual 3-methylenceph. amulphoxide.

K. MethansulfonsyreK. Methanesulfonic acid

Samme metode blev anvendt som under I, dog anyendtes 0,03 ml methansulfonsyre i stedet for syoylsyre. Produktet, der identi-ficeredes ved nmr-spektroskopi, yar den enskede 3-methylencepham-sulfoxid.The same method was used as under I, however, 0.03 ml of methanesulfonic acid was substituted for syoyl acid. The product identified by nmr spectroscopy is the individual 3-methylene cepham sulfoxide.

1. Prifluoreddikesyre1. Prifluoroacetic acid

En oplesning af 0,29 g methyl-3-methyl-2(2-chlorsulfinyl-4-oxo-3-phthalimido-1-azetidinyl)-3-butenoat i 10 ml trifluoreddike-syre kogtes med tirbagesyaling i 30 minutter og inddampedes i vakuum til terhed. Produktet oplestes i 20 ml ethylacetat. Den fremkomne oplesning vaskedes successiyt med vand i natriumbicar-bonat tre gange, vand og saltvand og terredes over magnesium-sulfat og inddampedes i vakuum til terhed til opnâelse af methyl- 7-phthalimido-3-methylencepham-4-carboxylat-1-oxid.A solution of 0.29 g of methyl 3-methyl-2 (2-chlorosulfinyl-4-oxo-3-phthalimido-1-azetidinyl) -3-butenoate in 10 ml of trifluoroacetic acid was boiled with turbial acid for 30 minutes and evaporated vacuum to dryness. The product is dissolved in 20 ml of ethyl acetate. The resulting solution was washed successively with water in sodium bicarbonate three times, water and brine and triturated over magnesium sulfate and evaporated in vacuo to give methyl 7-phthalimido-3-methylene cepham-4-carboxylate-1 oxide.

M. Selv-p-toluensulfonatM. Self-p-toluenesulfonate

Selv-p-toluensulfonat (0,80 g) sattes til en oplesning af 1,0 g methyl-3-methyl-2-(2-chlorsuifinyl-4-oxo-3-phthalimido-1-azeti-dinyl)-3-butenoat i 75 ml ter toluen. Reaktionsblandingen omrer-tes ved stuetemperatur i 2,5 timer og filtreredes. Piltratet blev inddampet i vakuum til terhed, og remanensen oplestes i 50 ml etbylacetat. Oplesningen vaskedes i vakuum til terhed. Produktet identificeredes ved nmr-spektroskopi som methyl-7-phthalimido-3-metbylencepbam-4-carboxylat-1-oxid.Self-p-toluenesulfonate (0.80 g) was added to a solution of 1.0 g of methyl 3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phthalimido-1-azetidinyl) -3- butenoate in 75 ml of toluene. The reaction mixture was stirred at room temperature for 2.5 hours and filtered. The filtrate was evaporated in vacuo to dryness and the residue was dissolved in 50 ml of ethyl acetate. The solution was washed in vacuo to dryness. The product was identified by nmr spectroscopy as methyl 7-phthalimido-3-methylene cepbam-4-carboxylate-1-oxide.

5S DK 157137 B5S DK 157137 B

WS3XBEL 2WS3XBEL 2

Methyl-72phthalimido-2_2_2-dideuterio-3-metli2lence£ham-4;-car'box2la'tMethyl 72phthalimido-2_2_2-dideuterio--3-metli2lence £ him-4; -car'box2la't

En blanding af 3,76 g (10 mmol) methyl-6p-phthalimidopenicillanat-sulfoxid, 5 ml deuteriumoxid og 500 ml tar carbontetrachlorid kog-tes med tilbagesvaling i 3 timer. Easerne separeredes, og den organiske fase tarredes over magnesiumsulfat. Inddampning i va-kuum gav 3,59 g af et h.vidt, amorft skum. nmr-spektret viste deuterium (H ) inkorporeret i 2a-meth.ylgruppen, og resten af hy- -j drogenet (H ) i denne gruppe var pâ mindre end 29 $ (ved intégration). Massespektralanalyse gav falgende deuteriumfordeling i 2a-metbylgruppen: dQ, 5,8$; d-^, 20,5$; d2, 41,3$; d^, 32,4$+ 2$.A mixture of 3.76 g (10 mmol) of methyl 6β-phthalimidopenicillanate sulfoxide, 5 ml of deuterium oxide and 500 ml of tar carbon tetrachloride is refluxed for 3 hours. The phases were separated and the organic phase was triturated over magnesium sulfate. Evaporation in vacuo gave 3.59 g of a white amorphous foam. The nmr spectrum showed deuterium (H) incorporated in the 2α-methyl group, and the remainder of the hydrogen-H (H) in this group was less than $ 29 (by integration). Mass spectral analysis yielded decreasing deuterium distribution in the 2α-methyl group: dQ, $ 5.8; d- ^, $ 20.5; d2, $ 41.3; d ^, $ 32.4 + $ 2.

Omkrystallisation fra acetone/dietiiyletîier gav farvelase prismer, smp. 148-151 °C.Recrystallization from acetone / diethyl ether gave colorase prisms, m.p. 148-151 ° C.

Massespektrum, m/e 379, 378, 377, 376, 361, 360, 359, 358, 302,/301, 300, 299.Mass spectrum, m / e 379, 378, 377, 376, 361, 360, 359, 358, 302, / 301, 300, 299.

ir (KBr) 1800, 1775 og 1725 cm"1.ir (KBr) 1800, 1775 and 1725 cm -1.

nmr (CDCl^·) δ 1,83 (d, 3) 3.85 (s, 3) 4,62 (s, 1) 4.85 (d, 1, J=4,5 Ha) 5.86 (d, 1, J=4,5 Hz) 7,83 (m, 4)nmr (CDCl3) δ 1.83 (d, 3) 3.85 (s, 3) 4.62 (s, 1) 4.85 (d, 1, J = 4.5 Ha) 5.86 (d, 1, J = 4.5 Hz) 7.83 (m, 4)

Analyse beregnet for C17H16M2°6S (376,387)· 054,25 - H 4,28 - N 7,44 - 025,50' S 8,52 fundet: C 54,05 - H 4,28 - N 7,26 - 0 25,61 - S 8,53.Analysis calculated for C 17 H 16 M 2 ° 6S (376.387) · 054.25 - H 4.28 - N 7.44 - 025.50 S 8.52 Found: C 54.05 - H 4.28 - N 7.26-0 25.61 - S 8.53.

En oplasning af 0,57 g (1,5 mmol) methyl-2p-metbyl-2o;-trideuterio-methyl-ôp-pbthalimidopenicillanat-l-oxid og 0,20 g (1,5 mmol) N-chlorsuccinimid kogtes i 30 minutter i 25 ml tar 1,1,2-tricblor-ethan, afkaledes, vaskedes med vand (1 x 50 ml), saltvand (1 x 50 ml) og tarredes over magnesiumsulfat. Oplosfringsmidlet afdampedes 37 DK 1571378 i vakuum og gav 0,69 g af en blanding af R- og S-sulfinylchlorid soin et lyst gult amorft skum. Denne blanding opl0stes i 25 ml ter methylenchlorid,og 0,20 (1,7 mmol) vandfri stannichlorid til-sattes» Den fremkomne blanding omrortes i 50 minutter, vaskedes med 1N hydrogenchloridsyre, t0rredes over magnesiumsulfat og ind-dampedes i vakuum til opnâelse af 0,57 g af en blanding af R- og 3-sulfoxider soin et gult skum» Det sâledes opnâede stof oplostes i 4 ml for Η,Ν-dimethylformamid, afk0ledes i et isbad,og 0,14 ml (1,6 mmol) phosphortrichlorid tilsattes» Efter 35 minutter udhæld-tes den râ blanding pâ vand og isklumper og omrortes. Det frem-komne bundfald opsamledes ved filtrering og torredes under vakuum. TJdbyttet var 0,38 g. nmr-spektret viste kun et meget smalt signal for Cg-stilling (<10$ af det teoretiske ved nmr intégration), medens signalet for exomethylen C1^-stillingen var normal, hvilket angav selektiv inkorporering af deuterium i C2-stilling. Masse-spektralanalyse gav folgende deuterium-fordeling i C2-stilling: d^, 2,2$; d^, 25,5$, d2, 72,3$ - 2$. Omkrystallisation fra methylenchlorid/cyclohexan gav farvelose krystaller med et smelte-punkt pâ 198-201 °C (dekomponering).A solution of 0.57 g (1.5 mmol) of methyl-2β-methyl-20-trideuterio-methyl-β-pbthalimidopenicillanate 1-oxide and 0.20 g (1.5 mmol) of N-chlorosuccinimide was boiled for 30 minutes. minutes in 25 ml take 1,1,2-tricloro-ethane, cool off, wash with water (1 x 50 ml), brine (1 x 50 ml) and tar over magnesium sulfate. The solvent was evaporated in vacuo to give 0.69 g of a mixture of R and S-sulfinyl chloride soin a light yellow amorphous foam. This mixture was dissolved in 25 ml ter of methylene chloride and 0.20 (1.7 mmol) of anhydrous stannous chloride was added. The resulting mixture was stirred for 50 minutes, washed with 1N hydrochloric acid, dried over magnesium sulfate and evaporated in vacuo 0.57 g of a mixture of R- and 3-sulfoxides formed in a yellow foam »The substance thus obtained was dissolved in 4 ml for Η, Ν-dimethylformamide, cooled in an ice bath, and 0.14 ml (1.6 mmol) phosphorus trichloride was added »After 35 minutes, pour the raw mixture onto water and ice clumps and stir. The resulting precipitate was collected by filtration and dried under vacuum. The TJ yield was 0.38 g. The nmr spectrum showed only a very narrow signal for Cg position (<10 $ of the theoretical at nmr integration), while the signal for the exomethylene C1 position was normal, indicating selective incorporation of deuterium into the C2-position. Mass spectral analysis gave the following deuterium distribution at C2 position: d 2, $ 2.2; d ^, $ 25.5, d2, $ 72.3 - $ 2. Recrystallization from methylene chloride / cyclohexane gave colorless crystals with a melting point of 198-201 ° C (decomposition).

Massespektrum m/e 360, 273, 174.Mass Spectrum m / e 360, 273, 174.

ir (KB ) 1770, 1740 og 1710 cm”1.ir (KB) 1770, 1740 and 1710 cm ”1.

nmr (ODOl^) δ 3,80 (s, 3) 5,32 (m, 3) 5,46 (d, 1, J=4,5 Hz) 5,67 (d, 1, J=4,5 Hz) 7,83 (m, 4).nmr (ODO1) δ 3.80 (s, 3) 5.32 (m, 3) 5.46 (d, 1, J = 4.5 Hz) 5.67 (d, 1, J = 4.5 Hz) 7.83 (m, 4).

Analyse beregnet for C^H^NgO^S (358,372); C 56,98 - H 3,94 - N 7,82 - 0 22,32 - S 8,95Analysis calculated for C ^ HH ^NgO ^S (358,372); C 56.98 - H 3.94 - N 7.82 - 0.22.32 - S 8.95

Eundet: C 56,96 - H 3,85 - N 7,94.Found: C 56.96 - H 3.85 - N 7.94.

EKSEMPEL· 3 4 ' ~nitrobenzyl-7-piienoxyacetamido-3-methylenceph.em-4--carboxylat-1~ DM^oxid_____ A. Stannichlorid 38EXAMPLE 3 4 '- Nitrobenzyl-7-pienoxyacetamido-3-methylene cephem-4 - carboxylate-1 ~ DM 2 oxide _____ A. Stannous chloride 38

DK 157137 BDK 157137 B

penicillanat-1-oxid og 500 ml tsr toluen kogtes med tilbagesvaling i 10 minutter, idet der anvendtes en Dean-Stark fælde for at fjer-ne spormængder af vand. Herefter tilsattes 1,8 g N-chlorsuccin-, imid, og blandingen kogtes med tilbagesvaling i 90 minutter og afksledes til ca. 50 °0. Den fremkomne oplzsning af sulfinyl-chlorid tilsattes 1,8 ml vandfri stannichlorid. Blandingen omrzr-tes ved stuetemperatur i 90 minutter. Herefter tilsattes 100 ml vand og 100 ml ethylacetat. Den organiske fase frasepareredes og vaskedes (1N*HC1, vandig natriumhydrogencarbonat, saltvand) og tzrredes over magnesiumsulfat. Inddampning i vakuum til tzrhed gav et produkt, der krystalliserede fra ethylacetat til opnâelse af 2,16 g (36$)af det nævnte produkt). En przve omkrystalliseredes fra etliylacetat/acetone, hvilket gav store prismer (smp. 200-201 °0): nmr (CDCl^) δ 3,5 og 3,75 (ABq., 2, J=14 Hz) 4,55 (s, 2) 4,83 (d, 1, J=4,5 Hz) 5,3 (s, 2) 5,33 (s, 1) 5,5 (s, 1) 5,78 (s, 1) 5,94 og 6,1 (q, 1, J=4,5 Hz og 8,0 Hz) 6,9 - 8,3 (m, 9).penicillanate-1-oxide and 500 ml of tsr toluene were refluxed for 10 minutes, using a Dean-Stark trap to remove trace amounts of water. Then 1.8 g of N-chlorosuccinic, imide was added and the mixture was refluxed for 90 minutes and separated to ca. 50 ° 0. The resulting solution of sulfinyl chloride was added with 1.8 ml of anhydrous stannous chloride. The mixture is stirred at room temperature for 90 minutes. Then, 100 ml of water and 100 ml of ethyl acetate were added. The organic phase was separated and washed (1N * HCl, aqueous sodium bicarbonate, brine) and dried over magnesium sulfate. Evaporation in vacuo to dryness afforded a product which crystallized from ethyl acetate to give 2.16 g ($ 36) of said product). A sample was recrystallized from ethyl acetate / acetone to give high prisms (mp 200-201 ° 0): nmr (CDCl 3) δ 3.5 and 3.75 (ABq., 2, J = 14 Hz) 4.55 ( s, 2) 4.83 (d, 1, J = 4.5 Hz) 5.3 (s, 2) 5.33 (s, 1) 5.5 (s, 1) 5.78 (s, 1) ) 5.94 and 6.1 (q, 1, J = 4.5 Hz and 8.0 Hz) 6.9 - 8.3 (m, 9).

Analyse beregnet for 023H21N3°8S (499,5): C 55,31 - H 4,24 ·- N 8,41 - 0 25,62 - S 6,42Analysis calculated for 023 H21 N3 ° 8S (499.5): C 55.31 - H 4.24 · N 8.41 - 0.25.62 - S 6.42

Pundet: C 55,06 - H 4,14 - N 8,30 - 0 25,62 - S 6,26.Pound: C 55.06 - H 4.14 - N 8.30 - 0.25.62 - S 6.26.

B. Zinkchlorid 4 ' -nitrobenzyl-3-methy1-2-( 2-chlorsulf inyl-4-oxo-3-phenoxyacet-amido-1-azetidinyl)-3-butenoat fremstilledes ved at koge en op-lzsning af 1 g 4'-nitrobenzyl-6-phenoxyaeetamidopenicillanatsulf-oxid og 0,27 g N-chlorsuccinimid i 40 ml 1,1,2-trichloretlian i 30 minutter. Herefter tilsattes 0,27 g zinkchlorid. Blandingen kogtes med tilhagesvaling i yderligere 45 minutter. Efter afksling af blandingen til stuetemperatur vaskedes med 1N hydrogenchlorid-syre to gange, tzrredes over magnesiumsulfat og inddampedes i va-kuum til tzrhed. nmr-spektret af produktet viste, at det var det znskede produkt, nemlig 4,-nitrobenzyl-7-phenoxyacetamido-3-B. Zinc chloride 4 '-nitrobenzyl-3-methyl-2- (2-chlorosulfonyl-4-oxo-3-phenoxyacetamido-1-azetidinyl) -3-butenoate was prepared by boiling a solution of 1 g of 4 -Nitrobenzyl-6-phenoxyethylenetamidopenicillanate sulfoxide and 0.27 g of N-chlorosuccinimide in 40 ml of 1,1,2-trichloroethlian for 30 minutes. Then 0.27 g of zinc chloride was added. The mixture was boiled at reflux for an additional 45 minutes. After quenching the mixture to room temperature, wash with 1N hydrochloric acid twice, dry over magnesium sulfate and evaporate in vacuo to dryness. the nmr spectrum of the product indicated that it was the desired product, namely 4, -nitrobenzyl-7-phenoxyacetamido-3

39 DK 157137 B39 DK 157137 B

metliylencepham-4-carboxylat-1-oxid.metliylencepham-4-carboxylate-1-oxide.

C. Sslv-p-toluensulfonatC. Sslv-p-toluenesulfonate

En opl0sning af 1 g 4’-nitrobenzyl-ô-phenoxyacetamidopenicillanat- i-oxid og 0,27 g N-chlorsuccinimid i 10 ml tzr toluen kogtes i 1 time. Sslv-p-toluensulfonat (0,61 g) sattes til den varme op» lo'sning. Blandingen omrortes i 45 minutter, medens der afkoledes til stuetemperatur. Reaktionsblandingen filtreredes, vaskedes med vand to gange og saltvand, t0rredes over magnesiumsulfat og inddampedes i vakuum til tzrlied til opnâelse af 0,43 g 4'-nitro-benzyl-7-plienoxyacetamido-3-metIiylencepliam--4-carboxylat-1-oxid (med nogle urenheder i) soin et gult skum.A solution of 1 g of 4'-nitrobenzyl-o-phenoxyacetamidopenicillanate i-oxide and 0.27 g of N-chlorosuccinimide in 10 ml of toluene was boiled for 1 hour. Sslv-p-toluenesulfonate (0.61 g) was added to the warm solution. The mixture is stirred for 45 minutes while cooled to room temperature. The reaction mixture was filtered, washed with water twice and brine, dried over magnesium sulfate and evaporated in vacuo to dry, to give 0.43 g of 4'-nitrobenzyl-7-plienoxyacetamido-3-methylenecepliam-4-carboxylate-1-oxide. (with some impurities in) soin a yellow foam.

EKSEMPEl· 4 ïil en opl0sning af 23,1 g 4f-nitrobenzyl-3“met]iyl-2-(2-chlor-sulfinyl»4-oxO"3-pti-tlialimidO“1“azetidinyl)-3“t)utenoat i 400 ml didilormetiian ved stuetemperatur sattes 6,1 ml vandfri stanni-chlorid. En stigende mængde bundfald noteredes, efterhânden som reaktionen skred frem. Efter 45 minutters reaktionstid vaskedes blandingen med 1N syoylsyre, yand, natriumbicarbonatoplssning og saltyand. Den organiske fase tzrredes og inddampedes i yakuum til tzrlied til opnâelse af 16,72 g (78fo) af det nseynte produkt.EXAMPLE 4 A solution of 23.1 g of 4f-nitrobenzyl-3-methyl-2- (2-chlorosulfinyl-4-oxo-3-p-tialialimide (1-azetidinyl) -3-t) 6.1 ml of anhydrous stannous chloride were added in 400 ml of didiloromethane at room temperature, and an increasing amount of precipitate was noted as the reaction progressed. After 45 minutes of reaction, the mixture was washed with 1N syoyl acid, yan, sodium bicarbonate solution and brine. in yakuum to dry to give 16.72 g (78fo) of the visible product.

R- og S-sulfoxid-isomerene separeredes ved fraktioneret omkrystal-lisation fra acetone og dichlormethan.The R and S sulfoxide isomers were separated by fractional recrystallization from acetone and dichloromethane.

R-sulfoxidet opnâedes som farvelzse prismer, der blev blzde ved 155 °0 og smeltede fuldstændigt ved 213 °C;The R-sulfoxide was obtained as colorless prisms which bleed at 155 ° C and completely melted at 213 ° C;

Massespektrum m/e 495, 479, 367, 343.Mass spectrum m / e 495, 479, 367, 343.

nmr (CDClj) δ 3,58 og 4,10 (Abq, 2, J=13 Hz) 4,87 (d, 1, J=4,5 Hz) 5,33 (s) 5,57 (m, 2) 5,95 (d, 1, J=4,5 Hz) 7,4 - 8,4 (m, 8, ArE).nmr (CDCl 3) δ 3.58 and 4.10 (Abq, 2, J = 13 Hz) 4.87 (d, 1, J = 4.5 Hz) 5.33 (s) 5.57 (m, 2 ) 5.95 (d, 1, J = 4.5 Hz) 7.4 - 8.4 (m, 8, ArE).

4°4 °

°K 157137 B° K 157137 B

Analyse beregnet for C^^H^N^OgS (495,5): C 55,76 - H 3,46 - N 8,48 - 0 25,83 - s 6,47Analysis calculated for C ^^ HH ^ NN ^O₂S (495.5): C 55.76 - H 3.46 - N 8.48 - 0.25.83 - s 6.47

Eundet: C 55,50 - H 3,45 - N 8,65 - 0 25,17 - S 6,32.Found: C 55.50 - H 3.45 - N 8.65 - 0.25.17 - S 6.32.

S-sulfoxidet isoleredes soin farvelose prismer (smp. 190—192 °0): ir (mull) 1780, 1775, 1741 og 1728 cm"1.The S-sulfoxide was isolated in colorless prisms (mp 190-192 °): ir (mull) 1780, 1775, 1741 and 1728 cm -1.

nmr (CDClj) δ 5,5 og 3,7 (ABq, 2, J=15 Hz) 4,9 (d, 1, J=4,5 Hz) 5,34 (s, 2) 5,46 (m, 2) 5,6 (d, 1, J=4,5 Hz) 5.8 (s, 1) 7,4 - 8,4 (m, 8).nmr (CDCl 3) δ 5.5 and 3.7 (ABq, 2, J = 15 Hz) 4.9 (d, 1, J = 4.5 Hz) 5.34 (s, 2) 5.46 (m , 2) 5.6 (d, 1, J = 4.5 Hz) 5.8 (s, 1) 7.4 - 8.4 (m, 8).

Analyse beregnet for G23H17N5°8Sî G 55,76 - H 3,46 - N 8,48 - 0 25,83 - S 6,47Analysis calculated for G23H17N5 ° 8Si G 55.76 - H 3.46 - N 8.48 - 0.25.83 - S 6.47

Eundet: 0 55,58 - H 3,62 - N 8,25 - 0 25,19 - S 6,18.Found: 0 55.58 - H 3.62 - N 8.25 - 0 25.19 - S 6.18.

BKSEMPEL 5 2’ , 21 ,2' -triclilorethyl-7-pHenylacetamido-3-metliylencep]iam-4-carlD- ___oxjjflat-l^-oxid__________________________________________EXAMPLE 5 2 ', 21, 2' -triclilorethyl-7-pHenylacetamido-3-methylenecep] amine-4-carlD-___ oxyjflate-1'-oxide __________________________________________

En blanding af 1,0 g 2',2’,2f-tricblorethyl-7-phenylacetamido-penicillanat-1-oxid, 0,5 g N-chlorsuccinimid og 80 ml tzr toluen kogtes med tilbagesvaling i 90 minutter, afksledes og vaskedes .(vand og saltvând). Een fremkomne oplzsning af sulfinylchlo-rid tilsattes 0,28 ml vandfri stannichlorid. Den fremkomne blan-ding omrzrtes i 90 minutter. Efter vask med vand og saltvand ind-dampedes oplzsningsmidlet i vakuum til torhed. Produktet krystal-liseredes fra ethylacetat-ether til opnâelse af det nævnte produkt som farvelsse prismer; smp. 187-189 °C.A mixture of 1.0 g of 2 ', 2', 2f-tricloroethyl-7-phenylacetamido-penicillanate-1-oxide, 0.5 g of N-chlorosuccinimide and 80 ml of toluene was refluxed for 90 minutes, separated and washed. (water and salt water). A solution of sulfinyl chloride obtained was added to 0.28 ml of anhydrous stannous chloride. The resulting mixture is stirred for 90 minutes. After washing with water and brine, the solvent was evaporated in vacuo to dryness. The product was crystallized from ethyl acetate ether to give the product as colorful prisms; mp. 187-189 ° C.

nmr (ŒDCl^) δ 3,5 og 3,81 (ABq, 2, J=14 Hz) 3,63 (s, 2) 4.8 (m, 2) 4.9 (d, 1, J=4,5 Hz)nmr (ŒDCl ^) δ 3.5 and 3.81 (ABq, 2, J = 14 Hz) 3.63 (s, 2) 4.8 (m, 2) 4.9 (d, 1, J = 4.5 Hz)

41 DK 157137 B41 DK 157137 B

5,37 (s, 1) 5,5 (s, 1) 5,82 (s, 1) 5,9 og 6,07 (çl, 1, J=4,5 Hz og 10,0 Hz) 7,0 (d, NH, J=10 Hz) 7,33 (s, 5) EKSEMPEl· 6 .Me th.yl-7- ( 2,2-dimethyl-3-nitroso-5“Oxo-=4-phenylimi iazolidin-1 -y 1) -3-metHylencegham-4~car6oxylat-1i-oxid____5.37 (s, 1) 5.5 (s, 1) 5.82 (s, 1) 5.9 and 6.07 (çl, 1, J = 4.5 Hz and 10.0 Hz) 7, 0 (d, NH, J = 10 Hz) 7.33 (s, 5) EXAMPLE 1 6. Me thyl-7- (2,2-dimethyl-3-nitroso-5 'Oxo- = 4-phenylimidazolidine) -1-yl) -3-methylenecegham-4-carboxylate-1i-oxide ____

En blanding af 0,896 g N-nitrosohetacillin-sulfoxid-methylester og 0,536 g N-chlorsuccinimid i 55 ml tzr benzen kogtes under til-bagesvaling i en nitrogenatmosfære'i 1 time. Reaktionsblandingen afkzledes, og en 5 ml prove af blandingen blev inddampet i vakuum til tzrhed. nmr-spektret af remanensen stemte med strukturen af det znskede mellemprodukt. Re.sten af reaktionsblandingen afkzle-des under nitrogen i et isbad, og der tilsattes 0,33 ml stanni-chlorid. Et lyst orange bundfald dannedes med det samrne. Efter omrzring af blandingen i 2 timer og 15 minutter ved stuetemperatur tilsattes 5,5 ml dimetbylacetamid og 55 ml ethylacetat. Een frem-komne oplzsning vaskedes med vand og saltvand, tzrredes over cal-ciumsulfat og inddampedes i vakuum til torhed til opnâelse af 1,3 g af en gui olie. Produkteb oplzstes i metbylenchlorid og pâ-fortes pâ fire præparative tyndtlagskromatografiplader. Pladerne udvikledes med en 1:1 blanding af benzen og ethylacetat. To pri-mære bând blev noteret. Det ene havde en lavere Rf-værdi, hvilket var repræsentativt for den znskede forbindelse. 3-methylencepham-sulfoxid (en blanding af R- og S-sulfoxider) isoleredes ved eks-traktion af det endelige identificerede bând med acetonitril: nmr (CECl^) § 2,07 (s, 6, gem-dimethyl) 3,73 (s, 3, C00CH3) 4,7 - 5,6 (m) 7,3 (s, ArH).A mixture of 0.896 g of N-nitrosohetacillin sulfoxide methyl ester and 0.536 g of N-chlorosuccinimide in 55 ml of benzene was boiled under reflux in a nitrogen atmosphere for 1 hour. The reaction mixture was cooled and a 5 ml sample of the mixture was evaporated in vacuo to dryness. the nmr spectrum of the residue corresponded to the structure of the desired intermediate. The residue of the reaction mixture was cooled under nitrogen in an ice bath and 0.33 ml of stannous chloride was added. A bright orange precipitate formed with the concn. After stirring the mixture for 2 hours and 15 minutes at room temperature, 5.5 ml of dimethylbylacetamide and 55 ml of ethyl acetate were added. A resultant solution was washed with water and brine, dried over calcium sulfate and evaporated in vacuo to dryness to give 1.3 g of a crude oil. The product was dissolved in methylene chloride and applied to four thin-layer preparative chromatography plates. The plates were developed with a 1: 1 mixture of benzene and ethyl acetate. Two primary tapes were noted. One had a lower Rf value, which was representative of the desired compound. 3-methylenecepham sulfoxide (a mixture of R and S sulfoxides) was isolated by extraction of the final identified band with acetonitrile: nmr (CEC1) § 2.07 (s, 6, gem-dimethyl) 3.73 (s, 3, C00CH3) 4.7 - 5.6 (m) 7.3 (s, ArH).

42 DK 157137 B42 DK 157137 B

EKSEMPEL 7 4 ' -nitrolDenzyl-3-metliyl-2-(2--sulfino-4-oxo--3-phthalimido-1-azeti-__dinyl2-5;fbutenoatEXAMPLE 7 4'-NitrolDenzyl-3-methyl-2- (2-sulfino-4-oxo-3-phthalimido-1-azetidinyl) -5-bututenate

En opl0sning af 49,7 g (0,1 mol) 4'-nitrobenzyl-6-ph.thalimidope-nicillanat-1-oxid og 13,4 g (0,1 mol) N-chlorsuccinimid i 1,5 li-ter 1,2-dichlorethan kogtes med tilbagesvaling i 90 minutter.A solution of 49.7 g (0.1 mole) of 4'-nitrobenzyl-6-phthalimidope nicillanate 1-oxide and 13.4 g (0.1 mole) of N-chlorosuccinimide in 1.5 liters 1,2-dichloroethane was refluxed for 90 minutes.

Efter afk0ling af reaEtionsklandingen vaskedes med vandog salt-vand, og der tsrredes over magnesiumsulfat. Oplzsningsmidlet ind-dampedes i vakuum til tsrlied til opnâelse af 52,0 g af azetidi-nonsulfinylclilorldproduktet: nmr (ODCl^) § 1,97 (s, 3) 5,05 (s, 1) 5,4 (s, 2) 5,76 (d, 1, J=5 Hz) 5,91 (d, 1, J=5 Hz) 7,83 (m, 8, ArH).After cooling the reaction mixture, wash with water and brine, and boil over magnesium sulfate. The solvent was evaporated in vacuo to give 52.0 g of the azetidine nonsulfinyl chloride product: nmr (ODCl 2) § 1.97 (s, 3) 5.05 (s, 1) 5.4 (s, 2) 5.76 (d, 1, J = 5 Hz) 5.91 (d, 1, J = 5 Hz) 7.83 (m, 8, ArH).

Dette produkt omdannedes til sulfinsyren ved at opslæmme det i en etliylacetatoplzsning med en 5$ oplzsning af natrium'bicar'bonat ved stuetemperatur i 2 timer. Den vandige fase tilev gjort sur med saltsyre i nærværelse af ethylacetat, hvilket efter separering og torring over magnesiumsulfat og inddampning i vakuum af den organiske fase gav'den onskede sulfinsyre som et farvelost skum: nmr (ODOl^) § 1,92 (s, 3) 4,88 (s, 1, J=4,5 Hz) 5,00 (s, 2) 5,18 (kred s, l) 5,38 (s, 2) 5,67 (d, 1, J=4,5 Hz) 7,5-8,3 (m, 9, ArH).This product was converted to the sulfinic acid by slurrying it in an ethyl acetate solution with a 5 $ solution of sodium bicarbonate at room temperature for 2 hours. The aqueous phase was acidified with hydrochloric acid in the presence of ethyl acetate, which after separation and drying over magnesium sulfate and evaporation in vacuo of the organic phase afforded the desired sulfinic acid as a colorless foam: nmr (ODO1) § 1.92 (s, 3) 4.88 (s, 1, J = 4.5 Hz) 5.00 (s, 2) 5.18 (cr s, l) 5.38 (s, 2) 5.67 (d, 1) J = 4.5 Hz) 7.5-8.3 (m, 9, ArH).

43 DK 157137 B43 DK 157137 B

EKSEMPEL· 8 2^2^2^ trichloreth.yl-7-piienoxyacetamido-5“nLethylencepliam-4-EXAMPLE 8 2 2 2 2 2 Trichloroethyl-7-pienoxyoxyacetamido-5-ethylene cepliam-4

En blanding af 4,82 g (10 mmol) 2’, 2',2'-trichlorethyl-6-phenoxy-acetamidopenioillanat-1-oxid, 150 ml ter toluen og 2,0 (11 mmol) i'I“Ciilorph.thalimi 1 kogtes mod tilbagesvaling i 60 minutter, idet 1er anvendtes en Dean-Siark-kilde. En 5 ml prsve af blandingen inddampedeSc nmr-spektret viste en fuldstændig omdannelse fil isn ventede sulfinylehlorid.A mixture of 4.82 g (10 mmol) of 2 ', 2', 2'-trichloroethyl-6-phenoxy-acetamidopenioillanate-1-oxide, 150 ml of ter toluene and 2.0 (11 mmol) of 1 'Ciilorph. Thalimi 1 was refluxed for 60 minutes, using a Dean-Siark source. A 5 ml sample of the mixture evaporated the Sc nmr spectrum showed a complete conversion to expected sulfinyl chloride.

En oplzsning af sulfinylchlorid i toluen afkoledes til ca. 40 °C, og 1,4 ml stannichlorid tilsattes. Blandingen omrortes i 60 minutter og vaskedes herefter successivt med 1N saltsyrer vandig natriumhydrogencarbonat og saltvand og tzrredes over magne-siumsulfat. Efter âfdampning af oplesningsmidlet tilsattes 30 ml ehloroform, og det uoplzselige phthalimid filtreredes fra. Eiltratet inddampedes til torhed, og det gule amorfe produkt tor-redes i vakuum. ïïdbytte 3,4 g (70 pet.) af det onskede produkt.A solution of sulfinyl chloride in toluene was cooled to ca. 40 ° C and 1.4 ml of stannous chloride were added. The mixture is stirred for 60 minutes and then washed successively with 1N hydrochloric acid aqueous sodium bicarbonate and brine and dried over magnesium sulfate. After evaporation of the solvent, 30 ml of ehloroform was added and the insoluble phthalimide was filtered off. The filtrate was evaporated to dryness and the yellow amorphous product dried in vacuo. Exchange 3.4 g (70 pet.) of the desired product.

mur (0D015) δ 3,56 og 3,80 (ABq., 2, J=14 Hz) 4.48 (e, 2) 4,75 (m, 2, CH2CC13) 4,89 (d, 1, J=4,5 Hz) 5,33 (s, 1) 5.48 (s, 1) 5,78 (s, 1) 5,9 og 6,07 (l, 1, J=4,5 Hz) 6,8 - 7,4 (m, 5, ArH) 8,1 (d, NH, J=10 Hz).wall (OD015) δ 3.56 and 3.80 (ABq., 2, J = 14 Hz) 4.48 (e, 2) 4.75 (m, 2, CH2CC13) 4.89 (d, 1, J = 4 5.33 (s, 1) 5.48 (s, 1) 5.78 (s, 1) 5.9 and 6.07 (1.1, J = 4.5 Hz) 6.8 - 7 , 4 (m, 5, ArH) 8.1 (d, NH, J = 10 Hz).

EKSEMPEL 9EXAMPLE 9

Methyl~3-methyl-2-(2-sulfino-4~oxo-3~ph.th.alimido-1-azetidinyl)-3-butenoat_____________________________________________Methyl ~ 3-methyl-2- (2-sulfino-4-oxo-3 ~ ph.th.alimido-1-azetidinyl) -3-butenoate _____________________________________________

En blanding af 3,76 g methyl-6-phth.alimidopenicillanatsulfoxid og 1,4 g N-chlorsuccinimid i 250 ml tzr (calciumchlorid) carbon-tetraciilorid kogtes med tilbagesvaling i 70 minutter. Blandingen afkzledes til stuetemperatur, filtreredes, vaskedes med vand ogA mixture of 3.76 g of methyl 6-phthalimidopenicillanate sulfoxide and 1.4 g of N-chlorosuccinimide in 250 ml of tzr (calcium chloride) carbon tetracyl chloride was refluxed for 70 minutes. The mixture was cooled to room temperature, filtered, washed with water and

44 DK 157137 B44 DK 157137 B

til tzrhed gav metliyl-3--metliyl-2-(2-chlorsulfinyl-4-oxo-3-pliÎIial-imido-1-azetidinyl)-3-Putenoat som et hvidt skum (se eksempel 1A).to dryness gave methyl 3-methyl-2- (2-chlorosulfinyl-4-oxo-3-piperidial-imido-1-azetidinyl) -3-putenoate as a white foam (see Example 1A).

Œil en oplzsning af 0,20 g sulfinylchlorid i 25 ml chloroform sattes 2 draper vand. Blandingen kogtes med tilPagesvaling i 30 minutter, afkaledes, t0rredes over magnesiumsulfat og inddampedes i vakuum til t0rlied til opnâelse af det nævnte produkt i form af et farvelsst skum.To a solution of 0.20 g of sulfinyl chloride in 25 ml of chloroform was added 2 drops of water. The mixture was boiled under reflux for 30 minutes, cooled, dried over magnesium sulfate and evaporated in vacuo to dry, to give the product as a colorless foam.

nmr (CLCl^) δ 1,93 (s, 3, -CHj) 3.80 (s, 3, -C00CH5) 4,88 - 5,15 (m, 4, C^-H, =CH2, β-laetam H) 5,70 (d, 1, J=5,0 Hz, β-lactam H) 7.80 (m, 4, ArH).nmr (CLCl s) δ 1.93 (s, 3, -CH₂) 3.80 (s, 3, -C00CH5) 4.88 - 5.15 (m, 4, C ^-H, = CH₂, β-laetam H ) 5.70 (d, 1, J = 5.0 Hz, β-lactam H) 7.80 (m, 4, ArH).

Sulfinylchloridet omdannedes ogsâ til den nævnte sulfinsyre ved henstand ved stuetemperatur i luften i 2 dage.The sulfinyl chloride was also converted to the said sulfinic acid upon standing at room temperature in the air for 2 days.

EKSEMPEL 10EXAMPLE 10

Methyl-7-phthalimido~3-meth.yleneepham-4-carPoxylat~1-oxid __£f£a_azetidinon-sulfins2re2____________________________ A. PhosphorpentoxidMethyl 7-phthalimido ~ 3-methyleneepham-4-carpoxylate ~ 1-oxide __ £ for a-azetidinone sulfinic acid 2 ____________________________ A. Phosphorus pentoxide

En oplosning af 0,10 g methyl-3-methy 1-2-(2-sulfino-4-oxo-3“Phthal-imido-1-azetidinyl)-3-Putenoat og 0,04 g phosphorpentoxid i 20 ml 1,2-dichlorethan omrzrtes ved stuetemperatur i 1 time. En tic af reaktionsPlandingen indicerede kun spormængder af methylencepham-sulfoxid. Blandingen kogtes med tilPagesvaling i 30 minutter, afk0ledes til stuetemperatur og Plandedes med 25 ml ethylacetat og 50 ml saltvand. Den organiske fase separeredes fra, vaskedes med vandig natriumPicarPonat og saltvand og tsrredes over magne-siumsulfat. Inddampning i vakuum til tzrhed gav 0,04 g af det nævnte produkt som et hvidt skum.A solution of 0.10 g of methyl 3-methyl 1-2- (2-sulfino-4-oxo-3β-phthalimido-1-azetidinyl) -3-putenoate and 0.04 g of phosphorus pentoxide in 20 ml of 1, 2-Dichloroethane is stirred at room temperature for 1 hour. One tic of the reaction mixture indicated only trace amounts of methylene cepham sulfoxide. The mixture was boiled under reflux for 30 minutes, cooled to room temperature and plated with 25 ml of ethyl acetate and 50 ml of brine. The organic phase was separated, washed with aqueous sodium PicarPonate and brine, and dried over magnesium sulfate. Evaporation in vacuo to dryness gave 0.04 g of said product as a white foam.

B. SvovlsyreB. Sulfuric acid

Samme metode Plev fulgt som i eksempel 1 (J), dog anvendtes 0,20 g meth.yl-3--meth.yl~2- ( 2-suif ino-4-oxo-3-phthalimido-1 -aze tidinyl ) -3-Puten at som udgangsmateriale i stedet for sulfinylchloridet.The same method was followed as in Example 1 (J), however, 0.20 g of methyl-3-methyl-2- (2-sulfino-4-oxo-3-phthalimido-1-aze tidinyl) was used. -3-Pillow as a starting material instead of the sulfinyl chloride.

45 DK 157137 B45 DK 157137 B

G. PolyphosphorsyreG. Polyphosphoric acid

Den samme metode blev fulgt som i eksempel 1 (I), dog anvendtes 0,20 g methyl-3-methyl-2-(2-sulfino-4”Oxo*™3~pAitlialiiiiido-1“azeti-dinyl)-3-butenoat som udgangsmateriale i stedet for sulfinylchlo-ridet. Reaktionen gav 0,10 g af det snskede produkt.The same method was followed as in Example 1 (I), however, 0.20 g of methyl 3-methyl-2- (2-sulfino-4 ”Oxo * ™ 3-p-aryl-aliido-1” azeti-dinyl) -3- butenoate as a starting material instead of the sulfinyl chloride. The reaction gave 0.10 g of the soaked product.

D. TrifluoreddikesyreD. Trifluoroacetic acid

Den samme metode blev fulgt som beskrevet i eksempel 1 (L), dog anvendtes 0,20 g methyl-3-methyl-2-(2-sulfino-4-oxo-3“Phth.alimi~ do-1-azetidinyl)“3-butenoat som udgangsmateriale i stedet for den tilsvarende sulfinylchlorid. Et nmr-spektrum af produktet viste, at det znskede produkt var h.ovedkomponenten„ EKSEMPEL· 11 4! -nitrobenzyl-3-metliyl-2-[ 2-cîilorsulf inyl-4-oxo~3- (N-phenoxyace-tyl-N-( 2,2,2-trichloreth.oxycarbonyl) amino )-1-azetidinyl] -3-bu-tenoat^ _ __ A. En blanding af 4,855 g (10 mmol) 4'-nitrobenzyl-6-pbenoxy-acetamido-2,2-dimetbylpenam-3-carboxylat, 16,94 g (80 mmol) 2,2,2-trich.loretbylch.lorformat, 18 ml N,0-(bis-trimetbylsilyl)trifluor-metbylacetamid og 20 ml methylenchlorid fremstilledes. Blandingen benstod ved stuetemperatur natten over. Blandingen opvarmedes til kogning med tilbagesvaling i 7 timer, hvorefter den igen fik lov at stâ ved stuetemperatur natten over. Opvarmningen blev fortsat i yderligere 6 timer. Blandingen inddampedes til en remanens, og denne oplzstes i benzen, og den fremkomne oplssning sattes til et stort overskud af heptan. Det fremkomne uoploselige stof blev filtreret fra og oplzstes i benzen og kromatograferedes over sili-cagel, idet der anvendtes benzen-ethylacetat som elueringsmiddel. Deropnâedes 4' -nitrobenzyl-6-[N-phenoxyacetyl-M-(2,2,2-trich.lor-eth.oxycarbonyl)amino]-2,2-dimetbylpenam-3-carboxylat (4,76 g, 72 pet.) som produkt: nmr (CDCl^) § 1,41 (s, 3) 1,62 (s, 3) 4,61 (s, 1) 4,84 (à, 1, J=12 Hz)The same method was followed as described in Example 1 (L), however, 0.20 g of methyl 3-methyl-2- (2-sulfino-4-oxo-3 "Phthalimido-1-azetidinyl)" was used. 3-butenoate as starting material instead of the corresponding sulfinyl chloride. An nmr spectrum of the product showed that the desired product was the main component "EXAMPLE · 11 4! -nitrobenzyl-3-methyl-2- [2-chlorosulfonyl-4-oxo-3- (N-phenoxyacetyl-N- (2,2,2-trichloroethoxycarbonyl) amino) -1-azetidinyl] -3 -Butenoate A mixture of 4.855 g (10 mmol) of 4'-nitrobenzyl-6-pbenoxyacetamido-2,2-dimethbylpenam-3-carboxylate, 16.94 g (80 mmol) 2.2 , 2-Trichloroethyl chloroformate, 18 ml of N, O- (bis-trimethylbylsilyl) trifluoromethylacetamide and 20 ml of methylene chloride were prepared. The mixture was left at room temperature overnight. The mixture was heated to reflux for 7 hours, then allowed to stand at room temperature overnight. The heating was continued for another 6 hours. The mixture was evaporated to a residue and dissolved in benzene and the resulting solution was added to a large excess of heptane. The resulting insoluble matter was filtered off and dissolved in benzene and chromatographed over silica gel using benzene-ethyl acetate as eluant. 4'-Nitrobenzyl 6- [N-phenoxyacetyl-M- (2,2,2-trichloro-ethoxycarbonyl) amino] -2,2-dimethbylpenam-3-carboxylate (4.76 g, 72 pet. .) as product: nmr (CDCl3) § 1.41 (s, 3) 1.62 (s, 3) 4.61 (s, 1) 4.84 (à, 1, J = 12 Hz)

46 DK 157137 B46 DK 157137 B

nmr (GDGlj) δ 4,99 (d, 1, J=12 Hz) (forts,) 5,20 2^ 5.30 (s, 2) 5,56 (s, 2) 6.8- 7,4 (m, 5) 7,53 (d, 2, J=9 Hz) 8,22 (d, 2, J=9 Hz).nmr (GDGlj) δ 4.99 (d, 1, J = 12 Hz) (contd) 5.20 2 ^ 5.30 (s, 2) 5.56 (s, 2) 6.8- 7.4 (m, 5 ) 7.53 (d, 2, J = 9 Hz) 8.22 (d, 2, J = 9 Hz).

B. Sulfoxidfremstilling Œil ca. 75 ml acetone sattes 2,54 g (3,84 mmol) af ovennævnte produisit. Blandingen afkzledes ved -70 °C, og et overskud af ozon ledtes til reaktionsblandingen i en mængde pâ 1,17 mmol pr. minut i 10 minut ter, hvorunder realrtionen llev lia. Blandingen llev holdt ved -70 °G i 35 minutter, livorefter der opvarmedes til stue-temperatur. Oplosningsmidlet f jemedes i vakuum til opnâelse af 2,76 g 4’-nitro'benzyl-6-[N-p]ienoxyaeetyl-N-(2,2,2-tricliloretli-oxycarbonyl)amino] -2,2-dimeth.ylpenam-3-car'boxylat-1-oxid.B. Sulphoxide Preparation Œil ca. 75 ml of acetone was added 2.54 g (3.84 mmol) of the above product. The mixture was cooled at -70 ° C and an excess of ozone was passed to the reaction mixture in an amount of 1.17 mmol per ml. minute for 10 minutes, during which the realtion lived lia. The mixture was kept at -70 ° G for 35 minutes, then warmed to room temperature. The solvent is in vacuo to give 2.76 g of 4'-nitro'benzyl-6- [Np] eneoxyyaethyl-N- (2,2,2-tricliloroethoxycarbonyl) amino] -2,2-dimethylpenamide. 3-car'boxylat-1-oxide.

nmr (CBCl^) δ 1,22 (s, 3) 1,62 (s, 3) 4,60 (s, 1) 4,78 (d, 1, J=5 Hz) 4.93 (s, 2) 5,26 (s, 2) 5.30 (s, 2) 5.93 (d, 1, J=5 Hz) 6.8- 7,4 (m, 5) 7,51 (d, 2, J=9 Hz) 8,20 (d, 2, J=9 Hz).nmr (CBCl ^) δ 1.22 (s, 3) 1.62 (s, 3) 4.60 (s, 1) 4.78 (d, 1, J = 5 Hz) 4.93 (s, 2) δ , 26 (s, 2) 5.30 (s, 2) 5.93 (d, 1, J = 5 Hz) 6.8- 7.4 (m, 5) 7.51 (d, 2, J = 9 Hz) 8.20 (d, 2, J = 9 Hz).

G. SulfinylchloridfremstillingG. Sulfinyl chloride preparation

Til 40 ml tsrbenzen sattes 792 mg (ca. 1 mmol) af ovennævnte produit og 155 mg (ca. 1,2 mmol) N-cHlorsuccinimid. Ben fremkomne Tolanding opvarmedes til kogning med tillagesvaling i 1 time. Et nmr-spektrum af reaktionsllandingen gav nærværelsen af nævnte forlindelse.To 40 ml of tetrabenzene were added 792 mg (about 1 mmol) of the above product and 155 mg (about 1.2 mmol) of N-chlorosuccinimide. Legs obtained Tolanding were heated to boiling with boil for 1 hour. An nmr spectrum of the reaction landing gave the presence of said compound.

47 DK 157137 B47 DK 157137 B

nmr (CDCl^) δ 1,92 (s, 3) 4,89 (s, 1) 4,96 (s, 2) 5,05 (s, 2) 5.25 (s, 2) 5.26 (s, 1) 5.34 (s, 2) 5.64 (d, 1, J=5 Hz) 5,95 (d, 1, J=5 Hz) 6,10 (d, 1, J=5 Hz) 6.8- 7,5 (m, 5) 7,56 (d, 2, J=9 Hz) 8.23 (d, 2, J=9 Hz).nmr (CDCl 3) δ 1.92 (s, 3) 4.89 (s, 1) 4.96 (s, 2) 5.05 (s, 2) 5.25 (s, 2) 5.26 (s, 1) 5.34 (s, 2) 5.64 (d, 1, J = 5 Hz) 5.95 (d, 1, J = 5 Hz) 6.10 (d, 1, J = 5 Hz) 6.8- 7.5 (m , 5) 7.56 (d, 2, J = 9 Hz) 8.23 (d, 2, J = 9 Hz).

D. Omdannelse til 4'-nitrohenzyl-7-[N-plienoxyacetyl-N-(2,2,2--tri-“ chlorethoxycarbonyl)amino] ^-methylencephamH-carboxylat-l -oxid ________________D. Conversion to 4'-Nitrohenzyl-7- [N-plienoxyacetyl-N- (2,2,2-trichloroethoxycarbonyl) amino] -methylencephamH-carboxylate-1-oxide ________________

Til reaktionsTolandingen ira, (C) ovenfor, afkslet til stuetempera-tur, tilsattes 390 mg (1,5 mmol) stannichlorid. Blandingen hold-tes ved stuetemperatur i 75 minutter, og 5 ml methanol folev til-sat. Yderligere henzen tilsattes, og den fremkomne Blanding va-skedes tre gange med en blanding af H01 og vandig natriumchlorid. Benzenfasen separeredes fra, tsrredes over natriumsulfat og ind-dampedes i yakuum til tsrhed. Hemanensen kromatograferedes oyer silicagel (15 $ vand) med en benzen-ethylacetat-elueringsmiddel til opnâelse af 246 mg exomethylencephamsulfoxid: nmr (CDCl^) δ 3,42 (d, 1, J=15 Hz) 3,98 (d, 1, J=13 Hz) 4.64 (d, 1, J=5 Hz) 4,94 (s, 2) 5,25 (s, 2) 5,30 (s, 2) 5.34 (s, 1) 5,47 (s, 1) 6,04 (d, 1, J=5 Hz) 6.8- 7,4 (m, 5) 7,55 (d, 2, J=9 Hz) 8.23 (d, 2, J=9 Hz)eTo the reaction mixture, ira, (C) above, cooled to room temperature, 390 mg (1.5 mmol) of stannous chloride was added. The mixture was kept at room temperature for 75 minutes and 5 ml of methanol folev was added. Further henzene was added and the resulting mixture was washed three times with a mixture of H01 and aqueous sodium chloride. The benzene phase was separated, dried over sodium sulfate and evaporated in dryness to dryness. The residue was chromatographed on silica gel (15 $ water) with a benzene-ethyl acetate eluent to give 246 mg of exomethylene cepham sulfoxide: nmr (CDCl3) δ 3.42 (d, 1, J = 15 Hz) 3.98 (d, 1, J = 13 Hz) 4.64 (d, 1, J = 5 Hz) 4.94 (s, 2) 5.25 (s, 2) 5.30 (s, 2) 5.34 (s, 1) 5.47 (s, 2) s, 1) 6.04 (d, 1, J = 5 Hz) 6.8- 7.4 (m, 5) 7.55 (d, 2, J = 9 Hz) 8.23 (d, 2, J = 9 Hz) ) e

DK 157137 BDK 157137 B

4-8 EKSMPEIi 12 4'-BrompB.enacyl-7-plienoxyacetamido-3--methylencep]iam-4“CarBoxylat~ __ 1-oxid ___________ _ _______4-8 EXAMPLE 12 4'-Bromine.Benacyl-7-plienoxyacetamido-3-methyleneceptinam-4 “Carboxylate ~ __ 1-oxide ___________ _ _______

Til 200 ml tsrret toluen sattes 5,6 g (10 mmol) 4’-BrompBenacyl- 6-ph.enoxyacetamido-2,2-dimetîiylpenam~3-carBoxylat-1-oxid og 5,2 g (50 mmol) natriumBisulfit. Blandingen opvarmedes til kogning, og 1,5 g (11 mmol) N-cBlorsuccinimid tilsattes. Den fremkomne Blanding omrsrtes og kogtes med tilBagesvaling i 1 time, afksledes i et isBad, og der tilsattes 1,3 g (11 mmol) stannichJLorid. Den fremkomne Blanding omrsrtes ved stuetemperatur i 2 timer og ud-hældtes i en Blanding af ethylaeetat og vand. Den organiske fase separeredes fra og vaskedes successivt med 5i° hydrogencBlorid, 5i« natriumBicarBonatoplssning og saltvand. Blandingen tsrredes over magnesiumsulfat. Efter inddampning til næsten tsrhed i va-kuum opsamledes 1,75 g (31$) af det nævnte produkt i krystallinsk tilstand. nmr-analyse af produktet stemte med strukturen af den onskede forBindelse.To 200 ml of dried toluene was added 5.6 g (10 mmol) of 4'-Bromobenacyl-6-phenoxyacetamido-2,2-dimethylpenam-3-carboxylate-1-oxide and 5.2 g (50 mmol) of sodium bisulfite. The mixture was heated to boiling and 1.5 g (11 mmol) of N-cblorosuccinimide was added. The resulting mixture was stirred and refluxed for 1 hour, separated in an ice bath and 1.3 g (11 mmol) of stannous chloride was added. The resulting mixture was stirred at room temperature for 2 hours and poured into a mixture of ethyl acetate and water. The organic phase was separated and washed successively with 5 µl of hydrogen chloride, 5 µl of sodium bicarbonate solution and brine. The mixture is dried over magnesium sulfate. After evaporation to near dryness in a vacuum, 1.75 g (31 $) of said product was collected in crystalline state. nmr analysis of the product corresponded to the structure of the desired compound.

Analyse Beregnet for C24H21N2°7SBr: 051,35 - H 3,77 - N 4,99 - Br 14,23Calcd for C24H21N2 ° 7SBr: 051.35 - H 3.77 - N 4.99 - Br 14.23

Bundet: C 51,03 - H 3,91 - N 5,10 - Br 14,46.Found: C, 51.03; H, 3.91; N, 5.10; Br, 14.46.

EESEMPEL 15 ^-pîienoxyacetamido-^-methylencepliam-^-carBox^lsïÎËzllSïiâ Œil 200 ml tsrret toluen sattes 4,95 g (10 mmol) 4'-metBoxyBenzyl- 6-phenoxyacetamido-2,2-dimetB.ylpenam-3-carBoxylat-1-oxid og 5,2 g (50 mmol) natriumBisulfit. Blandingen opvarmedes til kogning med tilBagesvaling, og der tilsattes 1,5 g (11 mmol) N-cBlorsuccinimid. Blandingen omrsrtes og kogtes en time, livorefter der afksledes i et isBad, og der tilsattes 1,3 g (11 mmol) starmichlorid. Blandingen omrsrtes ved stuetemperatur i 2 timer, Bvorefter den udBældtes i en Blanding af etBylacétat og vand. Den organiske fase separeredes fra og vaskedes successivt med 5$ Bydrogenchlorid og saltvand. Den organiske fase ekstraBeredes med 5$ natriumBicarBonat-oplssning. Ekstrakten opslæmmedes med ethylaeetat og Blev gjort sur til pH 2,5. Ethylacetatfasen frasepareredes og vaskedes med 49EXAMPLE 15 ^ -pienoxyacetamido - ^ - methylenecepliam - ^ - carBoxylsisylsilic acid 200 ml of dry toluene was added 4.95 g (10 mmol) of 4'-methoxyoxybenzyl-6-phenoxyacetamido-2,2-dimethyl.bipylate-3-carboxyl 1-oxide and 5.2 g (50 mmol) of sodium bisulfite. The mixture was heated to reflux and 1.5 g (11 mmol) of N-clorosuccinimide was added. The mixture was stirred and boiled for one hour, then quenched in an ice bath and 1.3 g (11 mmol) of starch chloride was added. The mixture was stirred at room temperature for 2 hours, after which it was precipitated in a mixture of ethyl acetate and water. The organic phase was separated and washed successively with 5 $ of hydrogen chloride and brine. The organic phase was added with 5 $ sodium bicaronate solution. The extract was slurried with ethyl acetate and acidified to pH 2.5. The ethyl acetate phase was separated and washed with 49

DK 157137 BDK 157137 B

vand, t0rredes over magnesiumsulfat og koncentreredes i vakuum til et lille volumen, hYorfra 1,3 g (35$) af det næYnte produkt Blev opnâet i form af krystaller, Analyse af produktet ved iqælp af nmr viste, at produktet stemte med det 0nskede produkt.water, dried over magnesium sulfate and concentrated in vacuo to a small volume, yielding 1.3 g ($ 35) of the title product Was obtained in the form of crystals, Analysis of the product using nmr showed that the product matched the desired product .

Analyse Beregnat for C^gH^N20gS; C 52,74 - H 4,43 - N 7,69 Jundetî 0 52,99 - H 4,64 - N 7,51.Analysis Calculated for C ^ gH ^N₂O₂S; C 52.74 - H 4.43 - N 7.69 Yearly 0 52.99 - H 4.64 - N 7.51.

EKSEMPEL 14EXAMPLE 14

Benzhydryl-3-meth.yl--2-[ 2-ch.lorsulfinyl-4-oxo-3-plienoxyaoetamido- _„llâ^£ÎiÊiB2iiz5“^ntenoat__________;_______________________________ A. Til 800 ml tsrret toluen sattes 20 g BenzB.ydryl-6-plienoxy-aoetamido-2,2-dimetB.y35penam-3~carBoxylat-1 -oxid. Blandingen kog-tes med tilBagesvaling i et System, der havde en Dean-Stark-vand-fælde til azeotropisk fjernelse af fugtighedo Blandingen til-sattes 12,2 g N-cBlorsuccinimid. Eogning med tirbagesYaling fortsattes i 1,5 timer. Produktet Blev analyseret ved nmr-analyse, hvilket viste, at det var det rigtige produkt: nmr (GDG1^) δ 1,88 (s, 3) 4.53 (s, 2) 4,90 (s, 1) 5,14 (s, 2) 5.54 (a, 1, J=4 Hz) 6,24 (g., 1, J=4 Hz og 8 Hz) 6,95 (s, 1) 7,15-7,4 (m, 15) 8,0 (d, 1, J=8 Hz).Benzhydryl-3-methyl-2- [2-chlorosulfinyl-4-oxo-3-plienoxy] ethamido [11.1] BiiiB₂iiz5 ntenoate __________; ______________________________ A. To 800 ml of dry toluene was added 20 g of BenzB.ydryl -6-plienoxy-aoetamido-2,2-dimethy.by35penam-3-carboxylate-1 oxide. The mixture was refluxed in a System which had a Dean-Stark water trap for azeotropic removal of moisture. The mixture was added 12.2 g of N-clorosuccinimide. Increase with tirbage sealing was continued for 1.5 hours. The product was analyzed by nmr analysis, showing that it was the correct product: nmr (GDG1 +) δ 1.88 (s, 3) 4.53 (s, 2) 4.90 (s, 1) 5.14 ( s, 2) 5.54 (a, 1, J = 4 Hz) 6.24 (g., 1, J = 4 Hz and 8 Hz) 6.95 (s, 1) 7.15-7.4 (m, 15) 8.0 (d, 1, J = 8 Hz).

B. Omdannelse til exometHylensulfoxidB. Conversion to ExometHylene Sulfoxide

Ted at fslge proceduren Beskrevet i eksempel 13 ovenfor cyclise-redes azetidinonsulfinylclilorid fra (A) med stannichlorid til 7-phenoxyacetamido-3-metliylencep]iam-4“Car‘boxylsyre=1"=oxid.To follow the procedure described in Example 13 above, azetidinone sulfinyl chloride from (A) is cyclized with stannous chloride to 7-phenoxyacetamido-3-methylenecep] amine-4 “Carboxylic acid = 1” = oxide.

50 DK 157137 B50 DK 157137 B

EKSEMPE1 15 2 ' , 2 ’ , 2 * triclilor e tbyl-3-metb.yl-2-[ 2-cb.lorsuif inyl-4-oxo-3- (4- nitr°benz2l222!2Ë£ÏâSiâ-2i“lz®:Zi®ÎiÉiri21l“5i^HÎÊ«2§Î___________ A. En blanding af 300 ml 1,1,2-trichloretlian og 10,26 g 2^2^2^ trichloretliyl-6- ( 4-nitrobenzyloxycarbamido ) -2,2-dimet]iylpenam-3--carboxylat-1-oxid fremstilledes. Blandingen kogtes med fjernelse af ca. 75 ml af opl0sningsmidlet for at giye et tort reaktionsme-dium. Blandingen afkzledes, og propylenoxid tilsattes, hyorefter der tilsattes 4 g N-cblorsuccinimid. Temperaturen hæyedes til 102° C, og blandingen kogtes med tilbagesvaling i 2,5 timer. En preve af reaktionsblandingen bley fjernet, og oplzsningsmidlet bley afdampet. En nmr-analyse af remanensen stemte oyerens med strukturen af den snskede forbindelse.EXAMPLE 1 2 ', 2', 2 * Tricliloroethyl-3-methyl-2- [2-chlorofluorophenyl-4-oxo-3- (4-nitrobenz2,2222) 2H-SiS-2i A mixture of 300 ml of 1,1,2-trichloroethlian and 10.26 g of 2 ^ 2 ^ 2 ^ trichloroethyl-6- (4-nitrobenzyloxycarbamido) -2, The mixture was boiled with removal of about 75 ml of the solvent to give a dry reaction medium. The mixture was cooled and propylene oxide was added, followed by the addition of 4 g of N-2-dimethylamino-3-carboxylate-1-oxide. The temperature was raised to 102 ° C and the mixture was boiled at reflux for 2.5 hours, a preve of the reaction mixture was removed and the solvent was evaporated An NMR analysis of the residue matched the structure of the compound.

nmr (CDClj) δ 1,94 (bs, 3) 4,83 (s, 2) 5,25 (s, 2) 5,0-5,4 (m, 3) 6,2 (d, 1, J=4 Hz) 7.55 (d, 2, J=8 Hz) 8,24 (d, 2, J=8 Hz).nmr (CDCl 3) δ 1.94 (bs, 3) 4.83 (s, 2) 5.25 (s, 2) 5.0-5.4 (m, 3) 6.2 (d, 1, J = 4 Hz) 7.55 (d, 2, J = 8 Hz) 8.24 (d, 2, J = 8 Hz).

B. Omdannelse af 2* ,2’ , 2’-tricb.loretb.yl-7-(4-:nitrobenzyloxycarb- amido ) -3-methylencepb.am-4-carboxylat-1 -oxid_B. Conversion of 2 *, 2 ', 2'-trichloroethyl ether-7- (4-: nitrobenzyloxycarbamido) -3-methylenecepbam-4-carboxylate-1-oxide

En del svarende til ca. en tredjjedel af reaktionsblandingen fra (A) oyenfor inddampedes, og remanensen oplostes i 100 ml torret methylencblorid. Ben fremkomne blanding tilsattes 5 ml stanni-chlorid. Blandingen behandledes som beskreyet i eksempel 12 til opnâelse af 700 mg 3-metb.ylencepbamsulfoxid: nmr (CDCl^) δ 5,60, 3,88 (ABçl, 2, J=15 Hz) 4,82 (s, 2) 4,94 (d, 1 J=4,5 Hz) 5,23 (s, 2) 5,40 (s, 1) 5.56 (s, 1) 6,37 (d, 1, J=10 Hz) 7,46 (d, 2, J=9 Hz) 8,20 (d, 2, J=9 Hz).A portion corresponding to approx. one third of the reaction mixture from (A) was evaporated and the residue dissolved in 100 ml of dried methylene chloride. Bone resulting mixture was added 5 ml of stannous chloride. The mixture was treated as described in Example 12 to give 700 mg of 3-methylbenzepepam sulfoxide: nmr (CDCl3) δ 5.60, 3.88 (ABçl, 2, J = 15 Hz) 4.82 (s, 2) 4 , 94 (d, 1 J = 4.5 Hz) 5.23 (s, 2) 5.40 (s, 1) 5.56 (s, 1) 6.37 (d, 1, J = 10 Hz) 7, 46 (d, 2, J = 9 Hz) 8.20 (d, 2, J = 9 Hz).

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DK 157137 BDK 157137 B

EKSEMPEl 16 4,~nitrobenzyl-2-methyl~2-(2-chlorsulfinyl-4“Oxo-3-acetamiciO'-1-azetidin2l2"2"5HÎSïï£âÎ.^____________________ A. 500 ml toluen opvarmedes i et udstyr, der liavde en Dean-Stark-vandfælde til azeotropisk fjernelse af yand. Til den fremkomne terrede toluen sattes 1,0 g (2,4 mmol) 4î~nitroDenzyl-6-acetamido- 2,2-dimethylpenam-3-oarboxylat-1-oxid. Den fremkomne blanding kogtes igen, idet der anyendtes en vandfælde for at fjerne yder-ligere mængder yand. Blandingen afk0ledes, og 400 mg (2,9 mmol) N-chlorsuccinimid tilsattes. Blandingen kogres med tilbagesvaling 1 finie. En preve af blandingen blev taget ud, og opl0snlngsmidlet blev fjernet. Produktet, der kerved bley opnâet, yiste sig at væ-re det rigtige produkt: nmr (CDCl^) § 1,86 (bs, 3) 2,04, 2,09 (2s, 3) 4.80 (m, 1) 5,2 (m, 2) 5,28 (s, 2) 5,63 (m, 1) 6,05 (d, 1, J=4 Hz) 7,4-8,4 (q., 4, ArH).EXAMPLE 16 4, ~ Nitrobenzyl-2-methyl ~ 2- (2-chlorosulfinyl-4 "Oxo-3-acetamycin-1-azetidin2,2" 2 "5HÎSïï ^ ^. ____________________ A. 500 ml of toluene was heated in a device which to a dean-Stark water trap for azeotropic removal of yand To the resulting terrained toluene was added 1.0 g (2.4 mmol) of 4'-nitroDenzyl-6-acetamido-2,2-dimethylpenam-3-oreboxylate-1 oxide The resulting mixture was boiled again, adding a water trap to remove further quantities of the mixture. The mixture was cooled and 400 mg (2.9 mmol) of N-chlorosuccinimide was added. The mixture was refluxed with 1 fin. The product thus obtained was claimed to be the correct product: nmr (CDCl3) § 1.86 (bs, 3) 2.04, 2.09 (2s, 3) ) 4.80 (m, 1) 5.2 (m, 2) 5.28 (s, 2) 5.63 (m, 1) 6.05 (d, 1, J = 4 Hz) 7.4-8, 4 (q., 4, ArH).

B. Omdannelse til 4,-nitrobenzyl-7-acetamido-3-met3iylencep2iam-4- ~ carboxylat-1-oxid_____________________________B. Conversion to 4, -nitrobenzyl-7-acetamido-3-methylenecep 2-amine-4-carboxylate-1-oxide

Reaktionsblandingen fra (A) ovenfor afkoledes i et isbad, og 1 ml stannichlorid tilsattes. Blandingen bley holdt i 2 timer ved stue~ temperatur, livorefter den inddampedes i yakuum til tzrhed. Den fremkomne remanens oplestes i ethylacétat, og ethylacetatblandin-gen yaskedes en gang med en blanding af HCl og en yandig natrium-ekloridblanding og 2 gange med yandig natriumcîilorid, torredes oyer magnesiumsulfat og inddampedes i yakuum til tærhed. Remanen-sen opl0stes i en minimal mængde etbylacetat, og efter henstand natten oyer opsamledes krystaller af 3-methylenceph.amsulfoxidet: nmr (CDCl^) δ 1,92 (s, 3) 3.80 (bs, 2) 5,00 (d, 1, J=4 Hz) 5j32 (s, 2)The reaction mixture from (A) above was cooled in an ice bath and 1 ml of stannous chloride was added. The mixture was kept at room temperature for 2 hours, then evaporated in dryness to dryness. The resulting residue was dissolved in ethyl acetate, and the ethyl acetate mixture was washed once with a mixture of HCl and an aqueous sodium chloride mixture and twice with anhydrous sodium chloride, dried over magnesium sulfate and evaporated to dryness. The residue was dissolved in a minimal amount of ethyl acetate and, after standing overnight, crystals of the 3-methylene encephal sulfur oxide: nmr (CDCl 3) δ 1.92 (s, 3) 3.80 (bs, 2) 5.00 (d, 1, J = 4 Hz) 5j32 (s, 2)

52 DK 157137 B52 DK 157137 B

nmr (CDCl,) 5,45-5,80 (m, 5) (forts.) 7’60 . <d’ 2’ J=8 Hz) 7,86 (a, 1, J=9 Hz) 8,20 (d, 2, J=8 Hz).nmr (CDCl3) 5.45-5.80 (m, 5) (continued) 7'60. <d '2' J = 8 Hz) 7.86 (a, 1, J = 9 Hz) 8.20 (d, 2, J = 8 Hz).

EKSEMPEL 17 4’-nitrobenzyl-7-pbenoxyacetamido-3-methylencepham-4-carboxylat-__1_-oxid__iEomplex_isolering2___________________________________ 750 ml toluen kogtes i 15 minutter, idet der anvendtes en Lean-Stark-vandfælde. Den znskede toluen tilsattes 55 ml propylen-oxid, 25 g 4'-nitrobenzyl-6-plienoxyacetamidopenicillanat-1-oxid og 7,37 g N-chlorsuceinimid. Reaktionsblandingen kogtes med tUbage s valing ved 100 °C i 2 timer, bvorefter 120 ml toluen destilleredes fra blandingen. Efter afkeling tilsattes 7,3 ml stanniclilorid. Eiltrering af reaktionsblandingen gav 17,1 g af et orangefarvet komplex, der oplestes i ethylacetat og vaskedes med vandig HCl og saltvand. Etbylacetatoplæsningen tzrredes og ind-dampedes i vakuum til tzrhed til opnâelse af 6,9 g af det znskede produkt.EXAMPLE 17 4'-Nitrobenzyl-7-pbenoxyacetamido-3-methylene cepham-4-carboxylate-1-oxide-epoxide insulation 2 750 ml of toluene was boiled for 15 minutes using a Lean-Stark water trap. The desired toluene was added 55 ml of propylene oxide, 25 g of 4'-nitrobenzyl-6-plienoxyacetamidopenicillanate-1-oxide and 7.37 g of N-chlorosuceinimide. The reaction mixture was boiled with Tuber's boiling at 100 ° C for 2 hours, after which 120 ml of toluene was distilled from the mixture. After cooling, 7.3 ml of stannic chloride was added. Eiltration of the reaction mixture gave 17.1 g of an orange complex which was dissolved in ethyl acetate and washed with aqueous HCl and brine. The ethyl acetate solution was dried and evaporated in vacuo to dryness to obtain 6.9 g of the desired product.

EKSEMPEL 18EXAMPLE 18

Methyl-3-methyl-2- ( 2-br omsulf inyl-4-oxo-3-pb.thalimido-1 -azetidinyl) -__3-bntenoat A. En blanding af 1,88 g metbyl-6-pb.tb.alimido-penieillanat-1-oxid og 890 mg N-bromsuccinimid i 150 ml carbontetracblorid kog-tes med tilbagesvaling i 80 minutter. Reaktionsblandingen afkz-ledes, vaskedes med vand og saltvand over vandfri magnesiumsulfat og inddampedes i vakuum til tzrbed til opnâelse af 1,82 g af det znskede produkt: nmr (GDCl^) δ 1,92 (bs, s) 3,82 (s, 3, C00CH3) 5,0-5,35 (m, s) 5,8-6,2 (m, 2, β-lactam H) 7,80 (bs, 4, ArH).Methyl 3-methyl-2- (2-bromosulfinyl-4-oxo-3-pb.thalimido-1-azetidinyl) -1,3-bentenoate A. A mixture of 1.88 gmethyl-6-pb.tb. alimido-penicillanate-1-oxide and 890 mg of N-bromosuccinimide in 150 ml of carbon tetracloride are refluxed for 80 minutes. The reaction mixture was cooled, washed with water and brine over anhydrous magnesium sulfate and evaporated in vacuo to dryness to give 1.82 g of the desired product: nmr (GDCl 2) δ 1.92 (bs, s) 3.82 (s , 3, C00CH3) 5.0-5.35 (m, s) 5.8-6.2 (m, 2, β-lactam H) 7.80 (bs, 4, ArH).

53 DK 157137 B53 DK 157137 B

Azetidinonsulfinylbromidet ovenfor opl0stes i 20 ml methylenchlorid, 0,6 ml stannichlorod sattes til opl0snlngen. Efter 45 minutter ved stuetemperatur Yaskedes reaktions'blandingen med vand og salt-vand, tzrredes over vandfri magnesiumsulfat og inddampedes i vakuum til tsrhed til opnâelse af 1,15 g methyl-7-pntiialimido-3-met]iylen-cepliam-4-carT30zylat-1-oxid (en blanding af R- og S~sulfoxidiso-mere). Eor den mest forekommende isomer; nmr (CDCl^) δ 3,64, 4,20 (ABq, 2, J=13 Hz, C2-H) 3.84 s, 3, 000CH3) 4,90 (d, 1, J=4,0 Hz, β-lactam H) 5,3-5,7 (m, 5) 5,97 (d, 1, J=4,0 Hz, β-lactam H) 7.84 Cbs, 4, Arïï).The acetidinone sulfinyl bromide above was dissolved in 20 ml of methylene chloride, 0.6 ml of stannous chloride was added to the solution. After 45 minutes at room temperature, the reaction mixture was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo to dryness to give 1.15 g of methyl 7-pentylimido-3-methylene-cepliam-4-carotinozylate. -1-oxide (a mixture of R- and S-sulfoxide isomer). Eor the most abundant isomer; nmr (CDCl ^) δ 3.64, 4.20 (ABq, 2, J = 13 Hz, C 2 -H) 3.84 s, 3,000CH 3) 4.90 (d, 1, J = 4.0 Hz, β -lactam H) 5.3-5.7 (m, 5) 5.97 (d, 1, J = 4.0 Hz, β-lactam H) 7.84 Cbs, 4, Aria).

EKSEMPEL 19 4 ' -nitroPenzyl-3-meth.yl-2-[ 2-isopropyltMosulfinyl-4-oxo-5-pHen-oxyacetamido-1-azetidinyl2-3-butenoat____ A. Til en opl0sning af 10 g 4'-nitrobenzyl-3-neth.yl-2-(2-clilor~ sulfinyl-4-oxo-3-pRenoxyzcetamido-1-azetidinyl)-3-'buten:oat i 450 ml toluen sattes 1,9 ml isopropylmercaptan og 3,5 ml propylenoxid. Blandingen Henstod adskillige dage Yed stuetemperatur og inddampedes i Yakuum til terïied til opnâelse af en olie, der kromatogra-feredes ουθγ silica-gel, idet der anvendtes toluen-etîiylacetat som elueringsmiddel. En total mængde pâ 6,62 g af det znskede pro-dukt lleY isoleret; nmr (CDCl^) δ 1,40 (d, 6, J=6,0 Hz, S0H(CH3)2) 2,01 (s, 3) 3,55 (m, 1, S0H(0H5)2) 4,60 (s, 2, sidekæde 0H2) 5,1-5,4 (m, 3) 5,33 (s, 2, ester CH2) 6,20 (dd, 1, J=4?5 og 10,0 Hz, β-lactan H) 6,9-8,3 (m, 9, ArH) 8,6 (d, 2, J=10,0 Hz, NH).EXAMPLE 19 4'-NitroPenzyl-3-methyl-2- [2-isopropylthosulfinyl-4-oxo-5-pHene oxyacetamido-1-azetidinyl] -3-butenoate ____ A. To a solution of 10 g of 4'-nitrobenzyl 3-Methyl-2- (2-chloro-sulfinyl-4-oxo-3-penoxyzcetamido-1-azetidinyl) -3-butene: in 450 ml of toluene was added 1.9 ml of isopropyl mercaptan and 3.5 ml of propylene oxide . The mixture was allowed to stand for several days at room temperature and evaporated in Yakuum to give an oil which was chromatographed on silica gel using toluene-ethyl acetate as the eluent. A total amount of 6.62 g of the desired product is isolated; nmr (CDCl 3) δ 1.40 (d, 6, J = 6.0 Hz, SOH (CH 3) 2) 2.01 (s, 3) 3.55 (m, 1, SOH (OH) 2) 4 , 60 (s, 2, side chain OH2) 5.1-5.4 (m, 3) 5.33 (s, 2, ester CH2) 6.20 (dd, 1, J = 4? 5 and 10.0 Hz, β-lactane H) 6.9-8.3 (m, 9, ArH) 8.6 (d, 2, J = 10.0 Hz, NH).

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DK 157137 BDK 157137 B

B. Qmdannelse til exomethylencephamsulfoxidB. Formation for Exomethylene Cepham Sulfoxide

Det nævnte produkt (682 mg) oplzstes i 3,4 ml methansulfonsyre.Said product (682 mg) was dissolved in 3.4 ml of methanesulfonic acid.

Efter 30 minutter udhældtes oplzsningen i en skilletragt, der in-deholdt ethylacetat og mættet vandig natriumbicarhonatoplesning.After 30 minutes, the solution was poured into a separatory funnel containing ethyl acetate and saturated aqueous sodium bicarbonate solution.

Den organisée fase frasepareredes, vaskedes successivt med vandigt natriumbicarbonat, vand og saltvand (2 gange) og tzrredes over vand-fri magnesiumsulfat. Produktet krystalliseredes fra ethylacetat ved henstand natten over. I ait 60 mg af det znskede produkt iso-leredes. Produktet var 4'-nitrobenzyl-7-*phenoxyacetamido-3-methyl-encepham-4-carboxylat-1-oxid.The organic phase was separated, washed successively with aqueous sodium bicarbonate, water and brine (2 times) and dried over anhydrous magnesium sulfate. The product was crystallized from ethyl acetate on standing overnight. A total of 60 mg of the desired product was isolated. The product was 4'-nitrobenzyl 7- * phenoxyacetamido-3-methyl-encepham-4-carboxylate-1-oxide.

EKSEMPEl· 20 4 ’ -nitrobenzyl-3-methyl-2-(2-tert-butylthiosulfinyl-4-oxo-3-phen-oxyacetamido-1~azetidinyl)-5-butenoat___ A. Per fulgtes samme metode som beskrevet i eksempel 19, idet der anvendtes 2,4 ml tert-butylmercaptan i stedet for isopropylmercap- tan. 4,69 g af det znskede produkt blev isoleret efter kromatogra- fi; nmr (CDCl^) § 1,43 (d, 9, tert-butyl) 2,01 (s, 3) 4,57 (s, 2, sidekæde -CH^) 5,0-5,4 (m, 5) 6,20 (dd, 1, J=4,0 og 11,0 Hz, β-lactam H) 6,8-8,2 (m, 9, ArH) 8,64 (s, 1, J=11,0 Hz, NH).EXAMPLE 1 4'-Nitrobenzyl-3-methyl-2- (2-tert-butylthiosulfinyl-4-oxo-3-phenoxyacetamido-1-azetidinyl) -5-butenoate __ A. Per the same method as described in Example 19 was followed. , using 2.4 ml of tert-butyl mercaptan instead of isopropyl mercaptan. 4.69 g of the desired product were isolated by chromatography; nmr (CDCl ^) § 1.43 (d, 9, tert-butyl) 2.01 (s, 3) 4.57 (s, 2, side chain -CH ^) 5.0-5.4 (m, 5 ) 6.20 (dd, 1, J = 4.0 and 11.0 Hz, β-lactam H) 6.8-8.2 (m, 9, ArH) 8.64 (s, 1, J = 11 , 0 Hz, NH).

B. Qmdannelse til exomethylencephamsulfoxid 700 mg af det znskede produkt oplzstes i 3,5 ml methansulfonsyre.B. Preparation for Exomethylene Cepham Sulfoxide 700 mg of the desired product is dissolved in 3.5 ml of methanesulfonic acid.

Ved at fzlge samme metode som heskrevet ovenfor opnâedes 190 mg 4 ' -nitro‘benzyl-7-phenoxyacetamido-3~methylencepham-4-car'boxylat-1 -oxid.Following the same method as described above, 190 mg of 4'-nitro'benzyl-7-phenoxyacetamido-3-methylene cepham-4-carboxylate-1-oxide was obtained.

55 DK 157137 B55 DK 157137 B

EKSEMPEL· 21 4 ’ -nitroPenzyl-3-methyl-2- ( 2-me'fch.oxysulf inyl-4“OXO~3-phenoxyacet-amidO”1-azetidinyl2-3-butenoat________________________ A. Til en oplosning af 4,-nitro‘benzyl-3--iiiet}iyl-2-(2-clilorsulfi-nyl-4-oxo-3-phenoxyacetamido-1-azetidinyl)-3-Putenoat, afledt af 10 g 4,-n.itroPenzyl-6-phenoxyacetamidopenicillanat-1-oxid og 2,68 H-chlorsuccinimid i 400 ml toluen sattes 25 ml ter·methanol. ReaktionsPlandingen omrertes ved stuetemperatur natten over og vastedes successivt med vandig natriumPicarPonat (2 gange), vand og saltvand (2 gange). Inddampning i vakuum til terhed gav 10 g af det urene enskede produkt, der oprensedes ved kromatografi over syrevasket silicagel, idet der anvendtes toluen-ethylacetat som elueringsmiddel. Produktet isoleredes som en Planding af isome-rene (R- og S-sulfinater). Eor den mest forekomne isomer: nmr (CDC13) δ 1s90 (s, 3) 3,74 (s, 3, -0Cïï3) 4,52 (s, 2, sidekæde CH2) 4.8- 5,3 (m, 5) 5,32 (s, 2, ester CH2) 5,76 (dd, 1, J=5,0 og 9,0 Hz, β-lactam H) 6.8- 8,2 (m, 9, ArH).EXAMPLE 21 4 '-nitroPenzyl-3-methyl-2- (2-methoxyphysulfinyl-4 “OXO ~ 3-phenoxyacetamido) 1-azetidinyl-2-butenoate ________________________ A. For a solution of 4, - nitro'benzyl-3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phenoxyacetamido-1-azetidinyl) -3-putenoate, derived from 10 g of 4, -nitroPenzyl-6- phenoxyacetamidopenicillanate-1-oxide and 2.68 H-chlorosuccinimide in 400 ml of toluene were added 25 ml of ter · methanol The reaction mixture was stirred at room temperature overnight and successively fastened with aqueous sodium PicarPonate (2 times), water and brine (2 times). vacuum to dryness yielded 10 g of the crude single product which was purified by chromatography over acid washed silica gel using toluene-ethyl acetate as the eluent. The product was isolated as a mixture of isomers (R and S sulfinates). occurring isomers: nmr (CDCl3) δ 1s90 (s, 3) 3.74 (s, 3, -0Cl3) 4.52 (s, 2, side chain CH2) 4.8-5.3 (m, 5) 5.32 ( s, 2, ester CH 2) 5.76 (dd, 1, J = 5.0 and 9.0 Hz, β-lactam H) 6.8- 8.2 (m, 9, ArH).

B. Omdannelse til exomethylecephamsulfoxid 590 mg af det nævnte produkt oplestes i 2,0 ml methansulfonsyre. Efter 30 minutter ved stuetemperatur oparPejdedes Plandingen som Peskrevet i eksempel 19 til opnâelse af 0,13 g (40$) 4*-nitroPen-zyl-7-phenoxyacetamido-3-methylencepham-4-carPoxylat-1-oxid.B. Conversion to Exomethylecephamsulfoxide 590 mg of said product is dissolved in 2.0 ml of methanesulfonic acid. After 30 minutes at room temperature, the mixture was prepared as described in Example 19 to give 0.13 g ($ 40) of 4

EKSEMPEL· 22 4! -nitroPenzyl-3-methy1-2-(2-methyloxysulfinyl-4-oxo-3-phenoxy- _J^22Î22iÉ2lll222Îiâiïïïiil2lÎ2E£2£2âÎ____ A. Samme metode Plev anvendt som Peskrevet i eksempel 21, idet dog 3,12 g (20 mmol) menthol anvendtes i stedet for methanol. Produktet i form af sulfinatester isoleredes ved kromatografi pâEXAMPLE · 22 4! -NitroPenzyl-3-methyl-2- (2-methyloxysulfinyl-4-oxo-3-phenoxy) -j 2 menthol was used instead of methanol. The product in the form of sulfinate ester was isolated by chromatography on

56 DK 157137 B56 DK 157137 B

en syreyasket silicagelkolonne, idet der anyendtes toluen-ethyl-acetat soin elueringsmiddel. Produktet isoleredes som en Blanding af isomerene R- og S-sulfinater og for den mest forekommende iso- mer : nmr (CDCl^) δ 0,6-24, (m, 18, mentyl H) 1,86 (s, 3) 3,98 (Bs, 1) 4,52 (s, 2, sidekæde CH£) 4.72 (d, 1, J=5,0 Hz, β-lactam H) 4.8- 5,2 (m, 3) 5,36 (s, 2, ester 0Η2) 5.72 (dd, 1, J=5,0 og 9,0 Hz, β-lactam H) 6.8- 8,2 (m, 9, ArH) 7,85 (d, 1, J=9,0 Hz, -NH).an acid-washed silica gel column, using toluene-ethyl acetate soin eluent. The product was isolated as a mixture of the isomers R and S sulfinates and for the most common isomer: nmr (CDCl3) δ 0.6-24, (m, 18, menthyl H) 1.86 (s, 3) 3.98 (Bs, 1) 4.52 (s, 2, side chain CH 2) 4.72 (d, 1, J = 5.0 Hz, β-lactam H) 4.8 - 5.2 (m, 3) 5, 36 (s, 2, ester 0Η2) 5.72 (dd, 1, J = 5.0 and 9.0 Hz, β-lactam H) 6.8- 8.2 (m, 9, ArH) 7.85 (d, 1 , J = 9.0 Hz, -NH).

B. Omdannelse til exomethylencephamsulfoxid 906 mg af næynte produkt oplzstes i 4,6 ml methansulfonsyre. Ef-ter 30 minutter yed stuetemperatur oparBejdedes reaktionsBlandingen som Beskreyet i eksempel 19. Omdannelse til 4'-nitroBenzyl-7-ph.enoxyacetamido-3-metB.ylenceph.am-4-carBoxylat-1-oxid Bekræftedes yed sammenlignende tyndtlagskromatografi og nmr-spektroskopi.B. Conversion to Exomethylene Cepham Sulfoxide 906 mg of the nude product is dissolved in 4.6 ml of methanesulfonic acid. After 30 minutes at room temperature, the reaction mixture was prepared as described in Example 19. Conversion to 4'-nitroBenzyl-7-phenoxyacetamido-3-meth.ylencepham-4-carboxylate-1 oxide was confirmed by comparative thin layer chromatography and nmr. spectroscopy.

EKSEMPEL 23 4 ' -nitroBenzyl-3-metRy 1-2-( 2-anilinsulf inyl-4-oxo-3-plienoxyacet- __amido-^-azetidinyl^-^-Butenoat_____ A. Til en oplzsning af 4,-nitroBenzyl-3-metliyl-2-(2-chlorsulfinyl- 4-oxo-3-pB.enoxyacetamido-1-azetidinyl)-3-Butenoat, afledt fra 10 g 4,-nitroBenzyl-6-pB.enoxyacetamidopenicillanat-1-oxid og 2,68 g N-chlorsuccinimid i 400 ml toluen sattes 3,6 ml anilin. Efter 5 minutter yed stuetemperatur yaskedes Blandingen med 2 gange yand og saltyand, tsrredes oyer yandfri magnesiumsulfat og inddampedes i yakuum til tsrhed til opnâelse af det næynte produkt: nmr (CBCl^) δ 1,96 (s, 3) 4,5 (s, 2, sidekæde CH2) 5,34 (s, 2, ester CH2) 5,0-5,3 (m, 3)EXAMPLE 23 4'-NitroBenzyl-3-Methyl 1-2- (2-aniline sulfinyl-4-oxo-3-plienoxyacetamide) - azetidinyl ^ - ^ - Butenoate -methyl-2- (2-chlorosulfinyl-4-oxo-3-p.Benoxyacetamido-1-azetidinyl) -3-butenoate, derived from 10 g of 4, -nitroBenzyl-6-pB.enoxyacetamidopenicillanate-1-oxide and 2, 68 g of N-chlorosuccinimide in 400 ml of toluene were added 3.6 ml of aniline. After 5 minutes at room temperature, the mixture was washed with 2 times yand and salts, dried over anhydrous magnesium sulfate and evaporated in dryness to dryness to give the nitrate product: nmr (CBCl δ 1.96 (s, 3) 4.5 (s, 2, side chain CH 2) 5.34 (s, 2, ester CH 2) 5.0-5.3 (m, 3)

57 DK 157137 B57 DK 157137 B

nmr (CDCl^) δ 6,8-8,4 (m, 14, ArH) .nmr (CDCl ^) δ 6.8-8.4 (m, 14, ArH).

(forts.) B. Omdannelse til exomethylencephamsulfoxid 2,07 g af ovennævnte produkt oplsstes i 10 ml methansulfonsyre. Efter 30 minutter hældtes oplzsningen langsomt i en kold Plan-ding af mættet vandig natriumPicarPonat og ethylacetat. Ethylaoe-tatfasen separeredes, vaskedes successivt med vandig natriumPicarPonat 2 gange, 2 gange med vand og 2 gange med saltvand, tor-redes over vandfri magnesiumsulfat og inddampedes i vakuurn til tzrhed. 4'-nitroPenzyl-7-phenoxyacetamido-3-methylencepham-4-carP-oxylat-1-oxid (373 mg, 21$) krystalliseredes fra ethylacetatop-lzsningen af det urene produkt.(cont.) B. Conversion to Exomethylene Cepham Sulfoxide 2.07 g of the above product is dissolved in 10 ml of methanesulfonic acid. After 30 minutes, the solution was slowly poured into a cold solution of saturated aqueous sodium PicarPonate and ethyl acetate. The ethyl acetate phase was separated, washed successively with aqueous sodium PicarPonate twice, twice with water and 2 times with brine, dried over anhydrous magnesium sulfate and evaporated to dryness in vacuo. 4'-NitroPenzyl-7-phenoxyacetamido-3-methylencepham-4-carp-oxylate-1-oxide (373 mg, 21 $) was crystallized from the ethyl acetate solution of the crude product.

EKSEMPEL 24EXAMPLE 24

Me thyl-3-methy1-2-(2-N-succinimidosulfinyl-4-Oxo-3-phenylacet-__a2i^2lll§5ËÎiâiSZi2l5-Putenoat_________________________ A. En oplzsning af 2,55 g (7 mmol) 4'-nitroPenzyl-6-phenylacet-amidopenicillanat-1-oxid, 5,6 ml (34 mmol) N-trimethylsIlylsuecin-imid og 0,18 ml eddikesyre i 41 ml dimetPylacetamid omrzrtes i 3,5 timer ved 105 °C. Efter afkoling udhældtes reaktionsPlan-dingen i en kold Planding af 50 ml ethylacetat og 150 ml vand. Vandfasen ekstraheredes to gange med ethylacetat. Ethylacetat-ekstrakterne Plandedes, vaskedes med vand, tzrredes over vandfri magnesiumsulfat og inddampedes i vakuum til tzrhed til opnâelse af 3,3 g methyl-3-methyl-2-(2-N-succinimidothio-4-oxo-3-phenyl-acetamido-1-azetidinyl)-3-Putenoat: nmr (CDCl^) δ 1,84 (s, 3) 2,78 (s, 4, succinimido) 3.65 (s, 2, sidekæde CH^) 3,74 (s, 3, C00Cïï5) 4.66 (s, 1) 5,0-5,5 (m, 4, β-laetam H + olefinisk CB^) 7,26 (s, 5, Arïï) 7,58 (d, 1, J=8,0 Hz, -MH).Methyl-3-methyl-2- (2-N-succinimidosulfinyl-4-oxo-3-phenylacetyl) -2,211,115SÎiSZi215-Putenoate ______________________________ A. A solution of 2.55 g (7 mmol) of 4'-nitroPenzyl-6 -phenylacetamidopenicillanate-1-oxide, 5.6 ml (34 mmol) of N-trimethylsilylsuecin imide and 0.18 ml of acetic acid in 41 ml of dimethylPylacetamide was stirred for 3.5 hours at 105 ° C. a cold mixture of 50 ml of ethyl acetate and 150 ml of water. The aqueous phase was extracted twice with ethyl acetate. The ethyl acetate extracts were washed, washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness to give 3.3 g of methyl 3-methyl. -2- (2-N-succinimidothio-4-oxo-3-phenyl-acetamido-1-azetidinyl) -3-putenoate: nmr (CDCl3) δ 1.84 (s, 3) 2.78 (s, 4) , succinimido) 3.65 (s, 2, side chain CH ^) 3.74 (s, 3, C00CCï5) 4.66 (s, 1) 5.0-5.5 (m, 4, β-laetam H + olefinic CB ^) 7.26 (s, 5, Ary) 7.58 (d, 1, J = 8.0 Hz, -MH).

58 DK 157137 B58 DK 157137 B

Ovennævnte sulfinimid oplzstes i 50 ml metbylenchlorid ved 0 °0 og oxideredes med 1,48 g m-chlorperbenzoesyre. Efter 1 time ved 0 °C vaskedes reaktionsblandingen successivt med mættet vandig natriumbicarbonat, vand og saltvand, tzrredes over vandfri magne-siumsulfat og inddampedes i vakuum til tzrbed til opnâelse af det nævnte produkt: nmr (CDCl^) δ 1,86 (s, 3) 2,60 (s, 4j suceinimido H) 3,54 (s, 2, sidekæde CH2) 3,78 (s, 3, C000ïï3) 4,8-5,2 (m, 3) 5,6-5,9 (m, 1, β-lactam H) 6,04 (d, 1, J=5,0 Hz, β-lactam H) 7,3 (s, 5, ArH).The above sulfinimide was dissolved in 50 ml of methylene chloride at 0 ° and oxidized with 1.48 g of m-chloroperbenzoic acid. After 1 hour at 0 ° C, the reaction mixture was washed successively with saturated aqueous sodium bicarbonate, water and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo to dryness to give the product: nmr (CDCl3) δ 1.86 (s, 3) 2.60 (s, 4j suceinimido H) 3.54 (s, 2, side chain CH 2) 3.78 (s, 3, C000 3) 4.8-5.2 (m, 3) 5.6-5 , 9 (m, 1, β-lactam H) 6.04 (d, 1, J = 5.0 Hz, β-lactam H) 7.3 (s, 5, ArH).

B. Omdannelse til exometh.ylencephamsulfoxid 469 mg, 1 mmol, af nævnte produkt oplzstes i 2,3 ml methansulfon-syre. Efter 30 minutters ved stuetemperatur udh.ældtes oplzsningen langsomt i en blanding af mættet vandig natriumbicarbonat og ethyl-acetat. Etïiylacetatfasen separeredes fra og vaskedes successivt med vandig natriumbicarbonat, vand og saltvand, tzrredes over vandfri magnesiumsulfat og inddampedes i vakuum til tzrhed. Omdannelsen til metliyl-7-pb.enylacetamido-3-metliylencepliam-4-carb-oxylat-1-oxid bekræftedes ved sammenlignende tyndtlagskromatogra-fi og nmr-spektroskopi.B. Conversion to Exomethylene Cepham Sulfoxide 469 mg, 1 mmol, of said product is dissolved in 2.3 ml of methanesulfonic acid. After 30 minutes at room temperature, the solution was poured slowly into a mixture of saturated aqueous sodium bicarbonate and ethyl acetate. The ethyl acetate phase was separated and washed successively with aqueous sodium bicarbonate, water and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo to dryness. The conversion to methyl 7-pb.enylacetamido-3-methylenecepliam-4-carb oxylate-1 oxide was confirmed by comparative thin layer chromatography and nmr spectroscopy.

EKSEMPEl· 25 4_' -nitrobenzyl-3-metliyl-2-[ 2-(N, N* -dicarboethoxyliydrazosulfinyl)-__4-ogo-3-phenoxgacetamido-1 -azetidinyl] -3-butenoat______________ A. En oplzsning af 10 g 4'-nitrobenzyl-6-ph.enoxyacetamidopenicil-lanat-1-oxid i 300 ml tzr 1,1,2-trichloreth.an kogtes med tilbage-svaling og tzrredes under anvendelse af en vandfælde. Efter ca.EXAMPLE 1 4'-Nitrobenzyl-3-methyl-2- [2- (N, N * -dicarboethoxylidrazosulfinyl) -1,4-ogo-3-phenoxgacetamido-1-azetidinyl] -3-butenoate ______________ A. A solution of 10 g of 4 -Nitrobenzyl-6-phenoxyacetamidopenicil lanate-1 oxide in 300 ml of 1,1,2-trichloroethane was refluxed and dried using a water trap. After approx.

50 ml af oplzsningsmidlet var destilleret, afkzledes blandingen, og 6 ml diethylazodicarboxylat tilsattes. Reaktionsblandingen kogtes i 45 minutter, hvorefter den inddampedes i vakuum til tzr-hed. Remanensen behandledes med hexan for at fjerne overskud af 5950 ml of the solvent was distilled off, the mixture was cooled and 6 ml of diethyl azodicarboxylate was added. The reaction mixture was boiled for 45 minutes, then evaporated in vacuo to dryness. The residue was treated with hexane to remove excess of 59

DK 157137 BDK 157137 B

diethylazodicarboxylat. Tderligere tzrring gav det nævnte produit soin et urent gult gummiagtigt stof, der ikke yderligere op-rensedes fzr omdannelse til exometHylencephamsulfoxid: mm? (ODOlj) δ 1,40 (t, 3, J=7 Hz, CH2CH5) 1,95 Cbs, 3) 3,8-4,7 (m, 6) 5.0- 5,6 (m, 5) 6,7-8,4 (m, 9, ArH).diethylazodicarboxylate. Further drying said product gave an impure yellow rubbery substance which was not further purified for conversion to exometylene cepham sulfoxide: mm? (ODOlj) δ 1.40 (t, 3, J = 7 Hz, CH 2 CH 5) 1.95 Cbs, 3) 3.8-4.7 (m, 6) 5.0-5.6 (m, 5) 6, 7-8.4 (m, 9, ArH).

B. Omdannelse til exomethylensulfoxidB. Conversion to Exomethylene Sulfoxide

Et gram af produktet fra (A) ovenfor oplzstes i 20 ml methan-sulfonsyre. Blandingen omrzrtes ved stuetemperatur i 20 minutter, hvorefter den udhældtes î en natriumcliloridoplzsning. Een vandige oplzsning ekstraheredes med 20 ml ethylacetat, Ethylacetatekstrak-ten vaskedes med vandig natriumbicarbonat, torredes over magnesi-umsulfat og inddampedes i vakuum til tzriied. Remanensen opren-sedes ved præparativ tyndtlagskromatografi under anvendelse af silicagel udviklende 90$ ethylacetat-benzen. I ait 160 mg af produktet blev isoleret: 4’ -nitrobenzyl-7-pb.enoxyacetamido-3-meth.yl- encepham-4-carboxylat-1-oxid.One gram of the product from (A) above is dissolved in 20 ml of methanesulfonic acid. The mixture was stirred at room temperature for 20 minutes, then poured into a sodium chloride solution. An aqueous solution was extracted with 20 ml of ethyl acetate, the ethyl acetate extract was washed with aqueous sodium bicarbonate, dried over magnesium sulfate and evaporated in vacuo to dry. The residue is purified by preparative thin layer chromatography using silica gel producing 90 $ ethyl acetate benzene. A total of 160 mg of the product was isolated: 4 '-nitrobenzyl-7-pb.enoxyacetamido-3-methyl-encepham-4-carboxylate-1-oxide.

EKSEMPEL 26 4_' -nitrobenzyl-3-methyl-2-[ 2- (N ,N ‘ -dicarbo-tert. butoxyhydrazosul-__ÎÎ2;yÎiliz2S2z2zâ2®Î§S^É:2“lz2:z2^ÎÉ:ÎS!:2[ilz5-butenoat _ A. I overensstemmelse metoden beskrevet i eksempel 25 omsattes 820 mg 4,-nitrobenzyl-6-acetamidopenicillanat-1-oxid med 465 mg ditert-butylazodicarboxylat til opnâelse af næimte produkt: nmr (CDCl^) δ 1,50 s, 18, tert-butyl) 1,90 (bs, 3) 0 2,00 (s, 3, CH^CNH-) 5,40 (s, 2, ester CH2) 5.0- 6,0 (m, 5) 7,6-8,4 (m, 4, ArH).EXAMPLE 26 4'-Nitrobenzyl-3-methyl-2- [2- (N, N '-dicarbo-tert.butoxyhydrazosul-2 ÎÎ2; yÎiliz2S2z2zâ2®Î§S ^ É: 2 “lz2: z2 [ilz5-Butenoate A. In accordance with the method described in Example 25, 820 mg of 4-nitrobenzyl-6-acetamidopenicillanate-1 oxide was reacted with 465 mg of ditert-butyl azodicarboxylate to give the title product: nmr (CDCl3) δ 1.50 s, 18, tert-butyl) 1.90 (bs, 3) 0. 2.00 (s, 3, CH 2 CNH-) 5.40 (s, 2, ester CH 2) 5.0 - 6.0 (m, ) 7.6-8.4 (m, 4, ArH).

60 DK 157137 B60 DK 157137 B

B. Omdannelse til exomethylensulfoxidB. Conversion to Exomethylene Sulfoxide

Bet nævnte produkt fra (A) oplzstes i 15 ml metBansulfonsyre, og efter 10 mi mit ter yed stuetemperatur udkældtes det i en mættet yandig natriumchloridoplzsning. Ben vandige opl0sning ekstrahe-redes med ethylacetat, og den organiske ekstrakt yaskedes med yandig natriumBicarBonat, tzrredes oyer magnesiumsulfat og inddampedes i yakuum til tzrked. Eromatografisk oprensning af remanensen gay 90 mg (12fo) 4,-:ni'troBenzyl-7-acetamido-3-meth.ylencepHam-4-carB-oxylat-1-oxid: 0 nmr (CBCl^) δ 2,04 (s, 3, CH^CNH-) 3,66 (Bs, 2, 0H2-H) 4,90 (d, 1, J=4,0 Hz, 06-H) 5,26 (s, 3, C^-H + ester CH2) 5,45, 5,74 (2s, 2 = CH2) 5,92 (dd, 1, J=4,0 og 8,0 Hz, 0?-Η) 6,97 (d, 1, J=8,0 Hz, -NH) 7,4-8,4 (m, 4, ArH).The said product from (A) was dissolved in 15 ml of metansulfonic acid and after 10 ml of room temperature it was precipitated in a saturated aqueous sodium chloride solution. Bone aqueous solution was extracted with ethyl acetate and the organic extract was washed with rich sodium bicarbonate, dried over magnesium sulfate and evaporated to dryness in a vacuum. Eromatographic purification of the residue gay 90 mg (12fo) 4, -: nitroBenzyl-7-acetamido-3-methylenepept-4-carB-oxylate-1-oxide: 0 nmr (CBCll) δ 2.04 (s 3.66 (Bs, 2, OH 2 -H) 4.90 (d, 1, J = 4.0 Hz, 06-H) 5.26 (s, 3, C H + ester CH2) 5.45, 5.74 (2s, 2 = CH2) 5.92 (dd, 1, J = 4.0 and 8.0 Hz, O? -Η) 6.97 (d, 1 , J = 8.0 Hz, -NH) 7.4-8.4 (m, 4, ArH).

EESEMPBl· 27 21 ,2? , 2 ’ -tricH.loretH.yl-7-( 2-tB.ienylacetamido ) -5-meth.ylenceph.am- ___________EESEMPBl · 27 21, 2? , 2 '-tricyl chloroethyl-7- (2-t.bienylacetamido) -5-methylencephalamide

En oplzsning af 1 g 2’ ,2’ ,2’-trichloretliyl-ô-^-tliienylaeetaiiiidoJ-penicillanat-l-oxid og 525 mg ditert-ButylazodicarBoxylat i 50 ml 1,1,2-trich.lorethan kogtes med tilBagesvaling i 45 minutter. Re-aktionsBlandingen afkzledes og inddampedes i yakuum til tzrBed. Remanesen, der Reryed Bley opnâet, oplzstes i metRansulfonsyre, og efter 15 minutter yed stuetemperatur udBældtes den sure oplzsning i mættet yandig natriumclilorid. Ben yandige oplzsning eks-traheredes med ethylacetat. Ben organiske fase yaskedes med na-triumBicarBonatoplzsning, tzrredes oyer magnesiumsulfat og inddampedes i yakuum til tzrBed til opnâelse af 72 mg (7$) af det næynte produkt:A solution of 1 g of 2 ', 2', 2'-trichloroethyl-α-β-methylene ethyl acetate-penicillanate-1-oxide and 525 mg of ditert-butyl azodicarboxylate in 50 ml of 1,1,2-trichloroethane was refluxed for 45 minutes. minutes. The reaction mixture was cooled and evaporated in a vacuum to dryness. The residue obtained by Reryed Bley was dissolved in methanesulfonic acid and after 15 minutes at room temperature, the acidic solution was precipitated in saturated aqueous sodium chloride. Bone-containing solution was extracted with ethyl acetate. Bone organic phase was washed with sodium BicarBonate solution, dried over magnesium sulfate and evaporated in yakuu to dry bed to obtain 72 mg ($ 7) of the nitrate product:

61 DK 157137 B61 DK 157137 B

nmr (ODOl^) δ 2,87 (las, 2, C2-H) 3,75 (s, 2, sidekæde CH2) 4,80 (s, 2, ester CH2) 5,28 (d, 1, J=4,0 Hz, 06-H) 5,46, 5,77 (2s, 2, =CH2) 5,90 (dd, 1, J=4,0 og 8,0 Hz, Ογ-Η) 6,8-7,3 (m, 3, ArH).nmr (ODO1) δ 2.87 (las, 2, C2-H) 3.75 (s, 2, side chain CH2) 4.80 (s, 2, ester CH2) 5.28 (d, 1, J = 4.0 Hz, 06-H) 5.46, 5.77 (2s, 2, = CH 2) 5.90 (dd, 1, J = 4.0 and 8.0 Hz, Ογ-Η) 6.8 -7.3 (m, 3, ArH).

EKSEMPEL· 28 4'-nitrobenzyl-3“meth.yl~2-[ 2-(N,N’ -Ηϊΐ3βηζο3τ11ΐ3ΓΗΓΕΖθ8π1ΐΐιιγ1)-4-___oxo-3-ghenox2ace tamido-1 -aze tidiny ll“3-but gnoatœc=____________ A. Ifzlge metoden beskrevet i eksempel 25 omsattes 10 g 4’-nitro-benzyl-6-pb.enoxyacetamidopenicillanat-1-oxid med 7,8 g dibenzoyl-diimid i ter 1,1, 2-trich.loretban.EXAMPLE 28 4'-Nitrobenzyl-3 "Methyl ~ 2- [2- (N, N '-Ηϊΐ3βηζο3τ11ΐ3ΓΗΓΕΖθ8π1ΐΐιιγ1) -4 According to the method described in Example 25, 10 g of 4'-nitro-benzyl-6-pbeneoxyacetamidopenicillanate-1-oxide was reacted with 7.8 g of dibenzoyl-diimide in ter 1,1,2-trichloroethane.

B. Omdannelse til exomethylensulfoxidB. Conversion to Exomethylene Sulfoxide

Et gram urenset produkt fra (A) ovenfor oplæstes i 20 ml methan-sulfonsyre. Efter 20 minutter udhældtes blandingen i 300 ml mæt-tet vandig natriumcb orid. Den vandige oplzsning ekstraberedes med 20 ml etbylacetat, og den organiske ekstrakt vaskedes med natriumbicarbonatoplzsning, tsrredes over magnesiumsulfat og ind-dampedes i vakuum til tzrlied. 90 mg (40$) af 4!-nitrobenzyl-7-phenoxyaeetamido-3-met]iylencepbam-4-4-carboxylat-1 -oxid blev isole-ret ved præparativ tyndtlagskromatografi.One gram of crude product from (A) above is dissolved in 20 ml of methanesulfonic acid. After 20 minutes, the mixture was poured into 300 ml of saturated aqueous sodium chloride. The aqueous solution was extracted with 20 ml of ethyl acetate, and the organic extract was washed with sodium bicarbonate solution, dried over magnesium sulfate and evaporated in vacuo to dry. 90 mg (40 $) of 4-nitrobenzyl-7-phenoxyethylenetamido-3-methylene cepbam-4-4-carboxylate-1 oxide was isolated by preparative thin layer chromatography.

EKSEMPEL· 29 4’-nitrobenzyl-3-metbyl-2-(2-acetylbydrazosulfinyl-4-oxo-3-pben-_«.°2Zacetamido-1 -aze tidiny 1) -3-butenoat ____ _ A. Til en oplosning af 4,-nitrobenzyl-3-metb.yl-2-(2-cblorsulfinyl- 4-oxo-3-phenoxyacetamido-1-azetidinyl)-3-butenoat (afledt fra 50 g 4f“nitrobenzyl-6-phenoxyacetamidopenicillanat-1-oxid og 15 g N-chlorsuccinimid i 1000 ml 1,1,2-trichlorethan) ved stuetempera-tur tilsattes 14,8 g acetylhydrazido Efter omrsring i 30 minutter ved stuetemperatur vaskedes blandingen tre gange med 500 ml 62EXAMPLE 29 4'-Nitrobenzyl-3-methyl-2- (2-acetylbydrazosulfinyl-4-oxo-3-pben-2,4-acetamido-1-aze tidiny 1) -3-butenoate _____ A. For a solution of 4, -nitrobenzyl-3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phenoxyacetamido-1-azetidinyl) -3-butenoate (derived from 50 g of 4'-nitrobenzyl-6-phenoxyacetamidopenicillanate-1- oxide and 15 g of N-chlorosuccinimide in 1000 ml of 1,1,2-trichloroethane) at room temperature were added 14.8 g of acetylhydrazido. After stirring for 30 minutes at room temperature, the mixture was washed three times with 500 ml of 62

DK 157137 BDK 157137 B

portioner mættet natriumchloridopl0sning, tsrredes over magnesium-sulfat og inddampedes i vakuum til tsrhed. Remanensen oplostes i ethylacetat. Ved lienstand i kzleskab opnâedes 29 »7 g (52$) af nævnte produit i form af krystaller: 0 ninr (CBCl^) δ 1,94 (s, 6, CR^C- + allylisk CH3) 4.65 (s, 2, sidekæde CH2) 4,9-5,4 (m, 5) 5.55 (s, 2, ester CH2) 6.8- 8,4 (m, 9, ArH).portions of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo to dryness. The residue was dissolved in ethyl acetate. On refrigerator reclining, 29 »7 g ($ 52) of said product was obtained in the form of crystals: 0 ninr (CBCl)) δ 1.94 (s, 6, CR₂C- + allylic CH3) 4.65 (s, 2, side chain CH2) 4.9-5.4 (m, 5) 5.55 (s, 2, ester CH2) 6.8-8.4 (m, 9, ArH).

B. Omdannelse til exomethylensulfoxid lo gram af nævnte produkt opl0stes i 20 ml methansulfonsyre. Ef-ter 15 minutter ved stuetemperatur udhældtes den sure opl0sning i en skilletragt indeholdende 200 ml ethylacetat, 250 ml mættet natriumclilorid og 250 ml mættet natriumbicarbonatoplzsning. Ben organiske fase separeredes fra, vaskedes med natriumbicarbonat-opl0sning, t0rredes over magnesiumsulfat og inddampedes i vakuum til t0rhed. Remanensen oplzstes i en minimal mængde ethylacetat, og ved henstand krystalliserede 879 mg (51$) af 4’-nitrobenzyl- 7-phenoxyacetamido-3-methylencepham-4-carboxylat-1-oxid.B. Conversion to exomethylene sulfoxide 100 grams of said product was dissolved in 20 ml of methanesulfonic acid. After 15 minutes at room temperature, the acidic solution was poured into a separatory funnel containing 200 ml of ethyl acetate, 250 ml of saturated sodium chloride and 250 ml of saturated sodium bicarbonate solution. Bone organic phase was separated, washed with sodium bicarbonate solution, dried over magnesium sulfate and evaporated in vacuo to dryness. The residue was dissolved in a minimal amount of ethyl acetate and, upon standing, crystallized 879 mg (51 $) of 4'-nitrobenzyl-7-phenoxyacetamido-3-methylene cepham-4-carboxylate-1-oxide.

EKSEMPEL· 50 41-nitrobenzyl-3-methy1-2-(2-carbomethoxyhydrazosulfinyl-4-oxo-3-__pheno^acetamido=1_-azetidinyl)-3-hutenoat____ A. Yed at fzlge metoden beskrevet i eksempel 29 omsattes carbo-methoxyhydrazid (4,5 g) med sulfinylchlorid afledt af 15 g 4'-ni-trobenzyl-6-phenoxyacetamidopenicillanat-1-oxid til opnâelse af . det nævnte produkt som et gult gummiagtigt produkt: nmr (GBCl^) δ 1,92 (hs, 3) 3.66 (s, 3, COOCÏÏ^) 4.56 (s, 2, sidekæde CH2) 4.8- 5,6 (m, 7, ester CH2, β-lactam H, olefinish H) 6,7-8,4 (m, 9, ArH)EXAMPLE 50 41-Nitrobenzyl-3-methyl-2- (2-carbomethoxyhydrazosulfinyl-4-oxo-3-pheno-acetamido = 1-azetidinyl) -3-hutenoate ____ A. Following the method described in Example 29, carbomethoxyhydrazide (4.5 g) with sulfinyl chloride derived from 15 g of 4'-nitrobenzyl-6-phenoxyacetamidopenicillanate-1-oxide to give. said product as a yellow rubbery product: nmr (GBClCl) δ 1.92 (hs, 3) 3.66 (s, 3, COOCÏÏÏÏ) 4.56 (s, 2, side chain CH2) 4.8-5.6 (m, 7 , ester CH2, β-lactam H, olefinish H) 6.7-8.4 (m, 9, ArH)

63 DK 157137 B63 DK 157137 B

B. Omdannelse til exomethylensulfoxidB. Conversion to Exomethylene Sulfoxide

Yed at fzlge metoden beskrevet i anden del af eksempel 29 cycli-seredes det nævnte produkt, i ait 640 mg, i methansulfonsyre (10 ml) til opnâelse af 240 mg (45$) af produktet 4’-nitrobenzyl-7-pbenoxyacetamido-3-met]iyl-encepham-4-carboxylat-1-oxid.Following the method described in the second part of Example 29, said product was cycled to a total of 640 mg in methanesulfonic acid (10 ml) to give 240 mg (45 $) of the product 4'-nitrobenzyl-7-pbenoxyacetamido-3 -met] iyl-encepham-4-carboxylate-1-oxide.

EKSEMPEl· 51 4,-nitrobenzyl-3-meth.yl-2-(2-tolylsulf onyIh.ydrazosulfinyl-4-oxo-__3-EHenox£acetamido-2-^____ A. Yed at felge metoden beskrevet i eksempel 29 omsattes 18 g tosylbydrazid med sulfinylchlorid afledt af 30 g 4'-nitrobenzyl-6-pbenoxyacetamidopenicillanat-1-oxid til opnâelse af det nævnte produkt som et gult gummiagtigt stof, der ikke krystalliserede.EXAMPLE 1 4 4-Nitrobenzyl-3-methyl-2- (2-tolylsulfonylhydrazosulfinyl-4-oxo-3-EHenoxylacetamido-2 - ____ A. To rim the method described in Example 29, reaction 18 g of tosylbydrazide with sulfinyl chloride derived from 30 g of 4'-nitrobenzyl-6-pbenoxyacetamidopenicillanate-1 oxide to give the product as a yellow non-crystalline gummy substance.

B. Yed at fzlge metoden beskrevet i anden del af eksempel 29 cycliseredes nævnte produkt i 150 ml methansulfonsyre til opnâelse af 7?0 g (23$) af 4 *-nitrobenzyl-7-pbenoxyacetamido-3-metbyl-en-c epbam-4-carboxylat-1-oxid.B. Following the method described in the second part of Example 29, said product was cyclized in 150 ml of methanesulfonic acid to obtain 7.0 g (23 $) of 4 * -nitrobenzyl-7-pbenoxyacetamido-3-methyl-en-c 4-carboxylate 1-oxide.

EKSEMPEL· 52 41-nitrobenzyl-3-methyl-2-(2-aminosulfinyl-4-oxo-3-pbenoxyacet-__amido-2-azetidin^l)=3-butenoat_______________________________ A. Til en oplzsning af 5 g 4’-nitrobenzyl-3-methyl-2-(2-chlor-sulfinyl-4-oxo-3-phenoxyacetamido-1-azetidinyl)-3--butenoat i to-luen sattes en oplesning af 5 g natriumcyanat i 100 ml vand. Ef-ter 1 time ved stuetemperatur frasepareredes den organiske fase, - der tzrredes over magnesiumsulfat og inddampedes i vakuum til tsrbed til opnâelse af en blanding af nævnte produkt og 4’-nitro-benzyl-6-pbenoxyacetamido-penicillanatsulfoxid. Eor det nævnte produktî nmr (CDCl^) δ 1,96 (s, 3) 0 4,55 (s, 4, sidekæde Cïï2 * =SNH2) 4,88 (d, 1, J=4,5 Hz9 β-lactam H)EXAMPLE 52 41-Nitrobenzyl-3-methyl-2- (2-aminosulfinyl-4-oxo-3-pbenoxyacetamido-2-azetidine [1) = 3-butenoate ______________________________ A. To a solution of 5 g of 4'-nitrobenzyl -3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phenoxyacetamido-1-azetidinyl) -3-butenoate in toluene was added a solution of 5 g of sodium cyanate in 100 ml of water. After 1 hour at room temperature, the organic phase was separated, dried over magnesium sulfate and evaporated in vacuo to dryness to give a mixture of said product and 4'-nitrobenzyl-6-pbenoxyacetamido-penicillanate sulfoxide. Eor said product nmr (CDCl ^) δ 1.96 (s, 3) δ 4.55 (s, 4, side chain Cïï₂ = SNH₂) 4.88 (d, 1, J = 4.5 Hz9 β-lactam H)

64 DK 157137 B64 DK 157137 B

nmr (CDCl^) ô 7,74 (d, 1, J=9,0 Hz, -Nïï) (forts.) 6,9-8,4 (m, 9, Arïï).nmr (CDCl ^) δ 7.74 (d, 1, J = 9.0 Hz, -Niï) (cont.) 6.9-8.4 (m, 9, Aïï).

Analyse "beregnet for C23H24N4°8S: C 53,48 - H 4,68 - N 10,85 - 0 24,78 - S 6,21For C 23 H 24 N 4 ° 8 S: C 53.48 - H 4.68 - N 10.85 - 0.24.78 - S 6.21

Eundet: C 53,69 - H 4,77 - N 10,62 - S 5,90 B. Omdannelse til exomethylensulfoxidFound: C 53.69 - H 4.77 - N 10.62 - S 5.90 B. Conversion to Exomethylene Sulfoxide

Ved at fzlge metoden Beskrevet i anden del i eksempel 29 eyclise-redes nævnte produkt i metliansulfonsyre til opnâelse af 4!-nitro-Benzyl-7-pB.enQxyacetamido-3-nietliylenceph.aiii-4~carBoxylat-1-oxid.Following the method described in the second part of Example 29, said product is cyclized in methanesulfonic acid to give 4-nitro-benzyl-7-p.Benoxyxyacetamido-3-nitliylenecephi-4-carboxylate-1 oxide.

Claims (26)

1. Fremgangsmâde til fremstilling af subtituerede 3-methylen-cephamsulfoxider med den almene formel: 0 11 RV /\ Π T i /“\ /V COOR' kendetegnet ved, at en forbindelse med formlen: 0 vA M II L· underkastes en intramolekylær cyclisering i nærværelse af en Friedel-Crafts-katalysator af Lewis-syre-typen, en Friedel-Crafts-katalysator af Bronsted-protonsyre-typen eller et metathe-tisk kationdannende middel i et tort inert organisk oplosnings-middel eller oplost i en organisk Bronsted-syre, hvorhos i ovennævnte formler R er en carboxylsyrebeskyttende gruppe, R' er R eller hydrogen, R^- er (1) en imidogruppe med formlen: DK 157137 B <>' 11 0 2 hvori R er alkenylen med 2-4 carbonatomer, alkylen med 2-4 carbonatomer, 1,2-phenylen eller 1,2-cyclohexenylen, (2) en amidogruppe med formlen: 0 ?» R^CNH- 3 hvori R er (a) hydrogen, alkyl med 1-3 carbonatomer, halogenmethyl eller 3-(2-chlorphenyl)-5-methylisoxazol-4-yl, (b) benzyloxy, 4-nitrobenzyloxy, 2,2,2-trichlorethoxy, tert-butoxy eller 4-methoxybenzyloxy, (c) gruppen R", hvor R" er 1,4-cyclohexadienyl, phenyl eller phenyl substitueret med 1-2 substituenter uafhængigt valgt blandt halogen, beskyttet hydroxy, nitro, cyano, trifluorme-methyl, alkyl med 1-3 carbonatomer og alkoxy med 1-4 carbonatomer , (d) en arylalkylgruppe med formlen: R" - (0) -CH0-m 2 hvori R" har samme betydning som defineret ovenfor, og m er o eller 1, (e) en substitueret arylalkylgruppe med formlen: DK 157137 B R'''CH- i W hvori R' ' 1 er R" soin defineret ovenfor, og W er beskyttet hydroxy eller beskyttet amino, (3) en imidogruppe med formlen: 0 2" V . R"-(0) CH C m 2lt 0 hvori R" og m har samme betydning som defineret ovenfor, 2 ' og R er alkyl med 1-3 carbonatomer, halogenalkyl med 1-6 carbonatomer, alkoxy med 1-3 carbonatomer eller trichlor- ethoxy, eller 0 (4) en imidazolidinylgruppe med formlen: Il R,yV- /—\. Y CH 3 hvori R" har samme betydning som defineret ovenfor,, og Y er acetyl eller nitroso; og X er (i) chlor eller brom, (ii) en gruppe med formlen -OR^, hvor R^ er hydrogen, alkyl med 1-10 carbonatomer, arylalkyl med 1-3 carbonatomer i alkyldelen eller halogenalkyl med 1-6 carbonatomer, 5 5 (iii) en gruppe med formlen -SR , hvor R er alkyl med 1-6 DK 157137 B carbonatomer, aryl eller arylalkyl med 1-3 carbonato-mer i alkyldelen; eller R6 (iv) en gruppe med formlen -Kr , hvori N. 7 R 6 7 (a) R er hydrogen, og R er hydrogen, R" som defineret O ovenfor eller en gruppe med formlen -NHR , hvor g R er aminocarbonyl, alkylaminocarbonyl med 1-3 carbonatomer, alkylcarbonyl med 1-3 carbonatomer i alkyldelen, alkoxycarbonyl med 1-3 carbonatomer i alkyldelen eller tosyl; eller (b) R^ er -COOR^ eller -COR^, og R^ er -NHCOOR^ eller 9 9 -NHCOR , hvori R er alkyl med 1-6 carbonatomer eller phenyl; eller 6 7 (c) R , R7 og det nitrogenatom, hvortil de er knyttet, tilsammen danner en imidogruppe med formlen: -<> II 0 2 hvori R har samme betydning som defineret ovenfor, og nâr X er som defineret under (iv) (b), kan 3 R desuden være en heteroarylmethylgruppe med formlen R'11'CH^-, hvor R'1'' er 2-thienyl, 3-thie-nyl, 2-furyl, 3-furyl, 2-thiazolyl eller 5-isoxa-zolyl; med de begraensninger, at nâr X er brom, er R^ kun en imidogruppe med formlen: DK 157137 B © II 0 at nâr der anvendes en metathetisk kationdannende forbindelse eller en Lewis-syre, er X kun chlor eller brom; og at nâr R er er en syrelabil carboxylsyrebeskyttende gruppe, er produk-tet et 3-methylencepham-4-carboxylsyresulfoxid.A process for the preparation of substituted 3-methylene cepham sulfoxides of the general formula: 0 11 RV / \ \ T i / "\ / V COOR 'characterized in that a compound of the formula: 0 vA M II L is subjected to an intramolecular cyclization in the presence of a Lewis acid-type Friedel-Crafts catalyst, a Bronsted-protonic acid-type Friedel-Crafts catalyst or a metathetic cation-forming agent in a tort inert organic solvent or dissolved in an organic Bronsted acid in which in the above formulas R is a carboxylic acid protecting group, R 1 is R or hydrogen, R 2 - is (1) an imido group of the formula: wherein R is alkenylene having 2-4 carbon atoms , alkylene having 2-4 carbon atoms, 1,2-phenylene or 1,2-cyclohexenylene, (2) an amido group of the formula: R 3 CNH-3 wherein R is (a) hydrogen, alkyl of 1-3 carbon atoms, halomethyl or 3- (2-chlorophenyl) -5-methylisoxazol-4-yl, (b) benzyloxy, 4-nitrobenzyloxy, 2.2 , 2-trichloroethoxy, tert-butoxy or 4-methoxybenzyloxy, (c) the group R "wherein R" is 1,4-cyclohexadienyl, phenyl or phenyl substituted with 1-2 substituents independently selected from halogen, protected hydroxy, nitro, cyano , trifluoromethyl, alkyl of 1-3 carbon atoms and alkoxy of 1-4 carbon atoms, (d) an arylalkyl group of the formula: R "- (O) -CHO-m 2 wherein R" has the same meaning as defined above, and m is o or 1, (e) a substituted arylalkyl group of the formula: wherein R '' 1 is R '' soin defined above and W is protected hydroxy or protected amino, (3) a imido group of formula: 0 2 "V. R "- (0) CH C m 2lt 0 wherein R" and m have the same meaning as defined above, 2 'and R are alkyl of 1-3 carbon atoms, haloalkyl of 1-6 carbon atoms, alkoxy of 1-3 carbon atoms or trichloro - ethoxy, or 0 (4) an imidazolidinyl group of the formula: II R, yV- / - \. Y is CH 3 wherein R "is as defined above, and Y is acetyl or nitroso; and X is (i) chlorine or bromine, (ii) a group of the formula -OR ^ wherein R 1 is hydrogen, alkyl with 1-10 carbon atoms, arylalkyl of 1-3 carbon atoms in the alkyl moiety or haloalkyl of 1-6 carbon atoms, (iii) a group of the formula -SR wherein R is alkyl of 1-6 carbon atoms, aryl or arylalkyl having Or R 6 (iv) a group of formula -Kr wherein N. 7 R 6 7 (a) R is hydrogen and R is hydrogen, R "as defined O above or a group having the formula -NHR wherein g R is aminocarbonyl, alkylaminocarbonyl of 1-3 carbon atoms, alkylcarbonyl of 1-3 carbon atoms in the alkyl moiety, alkoxycarbonyl of 1-3 carbon atoms in the alkyl moiety or tosyl; or (b) R 1 is -COOR 2 or -COR 2, and R 1 is -NHCOOR 2 or 9 9 -NHCOR wherein R is alkyl of 1-6 carbon atoms or phenyl; or (7) (c) R, R7 and the nitrogen atom to which they are attached together form an imido group of the formula: - <> II 0 2 wherein R has the same meaning as defined above and where X is as defined under (iv) (b), R 3 may additionally be a heteroaryl methyl group of the formula R'11'CH2 - wherein R'1 '' is 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-thiazolyl or 5-isoxazolyl; with the limitations that when X is bromine, R 2 is only an imido group of the formula: when a metathetic cation-forming compound or a Lewis acid, X is only chlorine or bromine; and when R is an acid-labile carboxylic acid protecting group, the product is a 3-methylenepepham-4-carboxylic acid sulfoxide. 2. Fremgangsmâde if0lge krav 1, k. endetegnet ved, at der anvendes en metathetisk kationdannende forbindelse.A method according to claim 1, characterized in that a metathetic cation-forming compound is used. 3. Fremgangsmâde ifolge krav 1 eller 2, kendetegnet ved, at den metathetiske kationdannende forbindelse er et vandfrit solvsalt.Process according to claim 1 or 2, characterized in that the metathetic cation-forming compound is an anhydrous solvate salt. 4. Fremgangsmâde ifolge ethvert af kravene 1-3, kendetegnet ved, at det metathetiske kationdannende stof er solv-p-toluensulfonat.Process according to any one of claims 1-3, characterized in that the metathetic cation-forming substance is solv-p-toluenesulfonate. 5. Fremgangsmâde ifolge ethvert af kravene 1-4, kendetegnet ved, at reaktionstemperaturen er 20-80 °C.Process according to any one of claims 1-4, characterized in that the reaction temperature is 20-80 ° C. 6. Fremgangsmâde ifolge krav 1, kendetegnet ved, at der anvendes en metalhalogenidkatalysator af Lewis-syre-typen.Process according to claim 1, characterized in that a Lewis acid metal halide catalyst is used. 7. Fremgangsmâde ifolge krav 1 eller 6, kendetegnet ved, at katalysatoren er aluminiumchlorid, stannichlorid, stannibromid, zinkchlorid, zinkbromid, antimonpentachlorid, titantetrachlorid, ferichlorid, galliumtrichlorid, zirconium-tetrachlorid, mercurichlorid eller chromtrichlorid.Process according to claim 1 or 6, characterized in that the catalyst is aluminum chloride, stannous chloride, stannous bromide, zinc chloride, zinc bromide, antimony pentachloride, titanium tetrachloride, ferichloride, gallium trichloride, zirconium tetrachloride, mercuric chloride or mercuric chloride. 8. Fremgangsmâde ifolge ethvert af kravene 1, 6 eller 7, DK 157137 B kendetegnet ved, at oplosningsmidlet er et aromatisk carbonhydrid eller et halogeneret alifatisk carbonhydrid.Process according to any one of claims 1, 6 or 7, characterized in that the solvent is an aromatic hydrocarbon or a halogenated aliphatic hydrocarbon. 9. Fremgangsmâde ifolge ethvert af kravene 1 eller 6-8, kendetegnet ved, at der anvendes 1,1 aekvivalent metal-halogenid-katalysator i et aromatisk carbonhydridoplosnings-middel eller et halogeneret alifatisk carbonhydridoplosnings-middel ved en temperatur pâ 10-115 °C.Process according to any one of claims 1 or 6-8, characterized in that 1.1 equivalent metal halide catalyst is used in an aromatic hydrocarbon solvent or a halogenated aliphatic hydrocarbon solvent at a temperature of 10-115 ° C. . 10. Fremgangsmâde ifolge ethvert af kravene 1 eller 6-9, kendetegnet ved, at der anvendes stannibromid, stan-nichlorid eller antimonpentachlorid ved en temperatur pâ 10-40 °C.Process according to any one of claims 1 or 6-9, characterized in that stannous bromide, stannous chloride or antimony pentachloride is used at a temperature of 10-40 ° C. 11. Fremgangsmâde ifolge ethvert af kravene 1 eller 6-10, kendetegnet ved, at reaktionen udfores ved stue-temperatur med stannichlorid.Process according to any one of claims 1 or 6 to 10, characterized in that the reaction is carried out at room temperature with stannous chloride. 12. Fremgangsmâde ifolge ethvert af kravene 1 eller 6-9, kendetegnet ved, at reaktionen udfores med aluminium-chlorid, zinkchlorid, zinkbromid, ferrichlorid, galliumtri-chlorid, zirconiumtetrachlorid, mercurichlorid eller chromtri-chlorid ved en temperatur pâ 40-115 °C.Process according to any one of claims 1 or 6-9, characterized in that the reaction is carried out with aluminum chloride, zinc chloride, zinc bromide, ferric chloride, gallium trichloride, zirconium tetrachloride, mercuric chloride or chromium trichloride at a temperature of 40-115 ° C. . 13. Fremgangsmâde ifolge krav 1 eller 6-9, kendetegnet ved, at titantetrachlorid anvendes ved en temperatur pâ 40-100 °C.Process according to claims 1 or 6-9, characterized in that titanium tetrachloride is used at a temperature of 40-100 ° C. 14. Fremgangsmâde ifolge krav 1, kendetegnet ved, at der anvendes en katalysator af Bronsted-protonsyre-typen.Process according to claim 1, characterized in that a Bronsted-protonic acid-type catalyst is used. 15. Fremgangsmâde ifolge krav 1-14, kendetegnet ved, at reaktionen udfores i et aromatisk carbonhydridoplos-ningsmiddel eller et halogeneret alifatisk carbonhydridoplos-ningsmiddel ved en temperatur pâ 70-115 °C. 1 Fremgangsmâde ifolge ethvert af kravene 1, 14 eller 15, DK 157137 B kendetegnet ved, at Bronsted-protonsyre-katalysatoren er methansulfonsyre, ethansulfonsyre, trifluoreddikesyre, trichloreddikesyre, dichloreddikesyre, svovlsyre, phosphor-syre, polyphosphorsyre, perchlorsyre, chlorsulfonsyre eller fluorsulfonsyre.Process according to claims 1-14, characterized in that the reaction is carried out in an aromatic hydrocarbon solvent or a halogenated aliphatic hydrocarbon solvent at a temperature of 70-115 ° C. Process according to any one of claims 1, 14 or 15, characterized in that the Bronsted protonic acid catalyst is methanesulfonic acid, ethanesulfonic acid, trifluoroacetic acid, trichloroacetic acid, dichloroacetic acid, sulfuric acid, phosphoric acid, hydrochloric acid, polyphosphoric acid, perchloric acid, perchloric acid, 17. Fremgangsmâde if0lge ethvert af kravene 1, 14 eller 15, kendetegnet ved, at der anvendes en konjugeret Frie-del-Crafts-syrekatalysator af typen HMA^A process according to any one of claims 1, 14 or 15, characterized in that a HMA-type Free Part Crafts acid conjugate is used. 18. Fremgangsmâde ifelge krav 17, kendetegnet ved, at Friedel-Crafts-katalysatoren er HBF^, HAlCl^, HAsFg eller HAlBr4.Process according to claim 17, characterized in that the Friedel-Crafts catalyst is HBF₂, HAlCl₂, HAsFg or HAlBr4. 19. Fremgangsmâde ifolge ethvert af kravene 1, 14 eller 15, kendetegnet ved, at der anvendes et surt chalcogenid.Process according to any one of claims 1, 14 or 15, characterized in that an acidic chalcogenide is used. 20. Fremgangsmâde ifolge krav 19, kendetegnet ved, at det sure chalcogenid er phosphorpentoxid.Process according to claim 19, characterized in that the acidic chalcogenide is phosphorus pentoxide. 21. Fremgangsmâde ifolge krav 1 eller 14, kendetegnet ved, at forbindelsen med formlen II oploses i methansulfonsyre, ethansulfonsyre, trifluoreddikesyre, trichloreddikesyre eller dichloreddikesyre ved stuetemperatur ©g hol-des i oplosningen i ca. 10-30 minutter.Process according to claim 1 or 14, characterized in that the compound of formula II is dissolved in methanesulfonic acid, ethanesulfonic acid, trifluoroacetic acid, trichloroacetic acid or dichloroacetic acid at room temperature. 10-30 minutes. 22. Fremgangsmâde ifolge ethvert af kravene 1 eller 14-21, 4 kendetegnet ved, at X er en gruppe med formlen -OR , 5 en gruppe med formlen -SR eller en gruppe med formlen R6 / "N\r7.A process according to any one of claims 1 or 14-21, 4 characterized in that X is a group of formula -OR, 5 a group of formula -SR or a group of formula R6 / "N \ r7. 23. Fremgangsmâde ifolge ethvert af kravene 1-21, kendetegnet ved, at X er chlor. DK 157137 BA process according to any one of claims 1-21, characterized in that X is chlorine. DK 157137 B 24. Fremgangsmâde ifolge ethvert af kravene 1-21, kende-t e g n e t ved, at X er brom.A method according to any one of claims 1-21, characterized in that X is bromine. 25. Fremgangsmâde if0lge ethvert af kravene 1-23, kende-t e g n e t ved, at R1 er en amidogruppe med formlen . 0 3" R CNH-, 3 og R er en arylalkylgruppe med formlen R"-25. A process according to any one of claims 1-23, characterized in that R1 is an amido group of the formula. 0 3 "R CNH-, 3 and R is an arylalkyl group of formula R" - 26. Fremgangsmâde ifolge ethvert af kravene 1-25, kende- t e g n e t ved, at R er methyl, tert-butyl, benzyl, 4-methoxy-benzyl, alkanoyloxymethyl med 2-4 carbonatomer, 2-iodethyl, 4-nitrobenzyl, diphenylmethyl (benzhydryl), phenacyl, 4-halogen-acyl, dimethylallyl, 2,2,2-trichlorethyl, tri(C^-C^alkyl)-silyl eller succinimidomethyl.Process according to any one of claims 1-25, characterized in that R is methyl, tert-butyl, benzyl, 4-methoxy-benzyl, alkanoyloxymethyl with 2-4 carbon atoms, 2-iodoethyl, 4-nitrobenzyl, diphenylmethyl ( benzhydryl), phenacyl, 4-haloacyl, dimethylallyl, 2,2,2-trichloroethyl, tri (C 1 -C 6 alkyl) silyl or succinimidomethyl. 27. Fremgangsmâde ifolge ethvert af kravene 1-26, kende-t e g n e t ved, at R er benzhydryl, 4-methoxybenzyl, tert-butyl eller tri(C^-C^alkyl)silyl, og R' er hydrogen.A process according to any one of claims 1-26, characterized in that R is benzhydryl, 4-methoxybenzyl, tert-butyl or tri (C 1 -C 4 alkyl) silyl, and R 1 is hydrogen.