SE438854B - 3-METHYLENOIC ACID DERIVATIVES FOR USE AS INTERMEDIATE IN THE SYNTHESIS OF 3-CEFEM SUBSTANCES - Google Patents

Description

(_71 10 15 35 JU 7807810-2 alkoxycarbonyl groups and wherein X represents oxygen or sulfur and m represents 0 or 1 and Rb represents hydrogen or, when m represents U, optionally with G-polygrane lower alkoxycurhonyl, optionally lower alkoxylcarbonyl, optionally lower alkoxy- or nitro- substituted phenyl] -alkoxycarbonyl, lrilyl or 1-layer-alkoxy- carbonyl-1-propylidene protected amino, optionally with phenyl layer alkyl protected carboxyl or sulfo or optionally branched lower alkoxycarbonyl or formyl protected hydroxy or O-lower alkylphosphono or 0,0'-dialkylphosphono, or a 5-amino- 5-carboxyvaleryl group, if the amino group is optionally protected with lower alkanoyl, halo-lower alkylanoyl, benzoyl or phthaloyl and the carboxy group optionally with phenyl lagalkyl, and wherein R lower alkoxy, Z-hulogen lower alkoxy, phenacyloxy, 1-phenyl- low alkoxy with 1-3, possibly with low alkoxy or nitro sub- substituted phenyl groups, lower alkanoyloxymethoxy, kanoyloxymethoxy, lower alkoxycarbonyloxy or lower alkanoyloxy and Y represents a leaving group, which is hensensulfonyl, p-toluenesulfonyl, O-methoxybenzenesulfonyl, p-methoxyhenesenulfonyl or p-nitrobenzenesulfonyl, and salts thereof.

Legal alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl or t-hutyl, also as n-pentyl, isopentyl, n-hexyl, isohexyl or n-heptyl.

Phenyllugalkyl is, for example, benzyl, 1- or Z-phenylethyl, 1-, Z- or 3-phenylpropyl, diphenylmethyl or trityl.

Legal alkoxy is, for example, methoxy, ethoxy, n-propyloxy, iso- propyloxy, n-hutyloxy, isohutyloxy, s-hutyloxy, t-hutyloxy, n-pentyloxy or t-pentyloxy. These groups may be sub- such as in halogen lower alkoxy, especially 2-halogenated alkoxy. alkoxy, eg 2, Z, 2-tricyclic, 2-chloro-, 2-bromo- or Z-iodo-toxic.

Legal alkoxycaronyloxy is, for example, methoxycarbonyloxy, ethoxycarbonyloxy or t-butyloxycarbonyloxy and low carbonyl is, for example, methoxycarbonyl, ethoxycarbonyl, n-propyloxy- carbonyl, isopropyloxycarbonyl, t-butyloxycarbonyl or t-pen tyloxycarbonyl.

Alkalkanoyl is, for example, formyl, acetyl, propionyl or pivaloyl.

O-lower alkylphosphono is, for example, O-methyl- or O-ethylphosphono- phono, 0,0'-dimalkylphosphono, for example 0.0-dimethylphosphono or 0,0'- diethylphosphono, O-phenyllugalkylphosphono, eg O-hensylphosphono, Och O-lagulkyl-O'-phenyl lagulkylphosphono, 1 ex U-hensyl-O'-methylphosphono. 10 '15 20 25 30 35 lU 7807810-2 3 An etherified hydroxy group RQ together with carbon the nyl grouping one, preferably easily cleavable or easily added another functionally converted carboxy group, such as a carbamoyl or hydrazinocarbonyl group, convertible, esterified carboxy- group. One such group Rê is, for example, legal alkoxy, such as methoxy, ethoxy, n-propyloxy or isopropyluxy, which together with the nyl grouping forms an esterified karhuxi group, which in particular in 2-eefem compounds can be easily transferred to a free carboxy group or to another, functionally converted carboxy group.

An etherified hydroxy group RQ, which together with a -C (= O) - forms a particularly easily cleavable, esterified vessel box group, is, for example, 2-haloalkalkoxy, wherein halogen desvis has an atomic weight of over 19. Such a group forms together with the grouping -C (= O) - one by treatment with chemical reduc- under neutral or slightly acidic conditions, eg with zinc in the presence of aqueous acetic acid, easily splinted carboxy group or to such an easily transferable, carboxy group and is, for example, 1,3, Z-trichloroethoxy or 2-iodo- ethoxy, further 2-chloroethoxy or 2-bromoethoxy, which can be easily transferred race to the latter.

An etherified hydroxy group Rê, which together with the ring -C (= O) - constitutes a possibly by treatment with chemical reducing agents under neutral or slightly acidic conditions, e.g. by treatment with: ink in the presence of aqueous acetic acid, further by treatment with a suitable nucleophilic reagent, e.g. sodium thiophenolate, readily cleavable, esterified carboxy group, is fenacyloxi.

A 1-phenyl lower alkoxy group of 1-3, optionally with lower alkoxy or nitro substituted phenyl groups, together with the grouping -C (= O) - one by irradiation, preferably with ult- raviolet light, under neutral or acidic conditions slightly ester, esterified carboxy group, An aryl group in such an arylmethoxy group group is especially lower alkoxyphenyl, eg methoxyphenyl (wherein methoxyphenyl 3-, 4- and / or 5-position), and / or (where nitro is preferably in oxi primarily star in especially nitrophenyl Z position). Such groups are especially legal alkoxy, e.g. methoxy, and / or nitrobenzyloxy, primarily 3- or 4-methoxybenzyl- oxy, 3,5-dimethoxybenzyloxy, 2-nitrobenzyloxy or 1,5-dimethoxybenzyl 2-nitrobenzyloxy.

An etherified hydroxyl group Rë can also ulge a group, which l0 15 35 ~ l () 7807810-2 together with the grouping -C (= O] - forms an acidic ions, for example by treatment with trifluoroacetic acid or formic acid, easily cleavable, esterified carboxy group. Such a group is in tie a methoxy group in which methyl is polysubstituted optionally substituted piston groups.

The group Rê may also be a substituted hydroxy group, which together with the grouping -C (= U1- forms a bydrolytic, e.g. under weakly basic or slightly acidic conditions estrad carboxy group. Such a group is preferably a series of hydroxy group, which together with the grouping -C (= O) - forms an activated ester group such as nitrophenyloxy, eg 4-nitrophenyl- oxy or 2,4-dinitrophenyloxy, nitrophenyl lagalkoxy, eg 4-nitrophenyloxy benzyloxy.

The Rê group can also be an Eöretrad bydroxy group, which together with the carbonyl grouping of the formula -C (= O) - forms one cleavable under hydrogenolytic conditions, esterified carboxy group, and is, for example, optionally, for example with legal alkoxy or nitro, substituted Ofenophagalkoxy, such as benzyloxy, 4-methoxybenyloxy or 4-nitrobenzyloxy.

The group RQ can also be a represented bydroxy group, which together with the carbonyl grouping -C (= 0) - forms a miracle physiological conditions cleavable, esterified carboxy group, i primarily an acyloxymethoxy group, wherein acyl is, for example, the residue of an organic carboxylic acid, in particular an optionally substituted tuerated lower alkanecarboxylic acid, or wherein acyloxymethyl forms the residue of a lactone. Thus hydroxy groups etherified are legal alkanoyl oxymethoxy, for example acetyloxymethyloxy or pivaloyloxymethoxy, amino lower alkanoyloxymethoxy, especially fl ßamino-lower alkanoyloxymethoxy, eg glycyloxymethoxy, L-valyloxymethoxy, L-leucyloxymethoxy, further phthalidyloxy.

An acyloxy group Râ, which together with the grouping -C (= O) - forms a, preferably hydrolytically, cleavable, mixed anhydride group, contains, for example, the acyl residue of indicated carboxylic acids or carbonic acid bale derivatives and is, for example lower alkanoyloxy, such as acetyloxy or pivaloyloxy.

In an intermediate of formula IVb, Rê is preferably for one, especially under mild conditions, cleavable, contaminated hydroxy group, which with the grouping -C {= O) - forms an esterified carboxy group, whereby any existing functional groups in a carboxy protecting group RÖ in a manner known per se can be l0 20 7807810-2 protected, eg as indicated. A group Râ is, for example, optionally an optionally halogen-substituted lower alkoxy group, such as methoxy, ¿X-polygrenad lower alkoxy, eg t-butyloxy, or Z-halo- gene alkoxy, wherein halogen is, for example, chlorine, bromine or iodine, primarily 2,1,1-trichloroethoxy, 1-chloromethoxy or 2-iodoethoxy, or an optionally snbstitnerated, sn «of laccalloxy, e.g. methoxy, or nitro containing, 1-phenyllogalkoxy group, as appropriate, eg susome indicated, substituted benzyloxy or diphenylmethoxy, for example benzyloxy, 4-methoxybenzyloxy, 1-nitrobenzyloxy, diphenyl- methoxy or 4,4'-dimethoxydiphenylmethoxy.

The present 3-methylene butyric acid derivative can be prepared therein. by, that man n] converts a compound of the formula: Ra l 0 I-I l-l 4 ' _: : _) one; * fr ~ mi) os. . .\' in a- I h o = c-now vari R? and RQ has the indicated meaning, with a sulfinic acid with the formula HSO, -Rg or a sulfonylamide of the formula N = C-SO, -RS or b) reacting a compound of the formula: (IVa) vari Rïoch R? has the specified meaning and R4 represents one optionally substituted aromatic heterocyclic group with up to 15, preferably up to 9, carbon atoms, or at least one ring nitrogen atom and optionally an additional ring heteroatom, such as oxygen or sulfur, which group is attached to the ten group -S- with one of its ring carbon atoms, which is attached to a ring nitrogen atom by a double bond, or an optionally substituted, ali- phatic, eykloaliphatic, araliphatic or aromatic aeyl- or thioacyl group having up to 18 carbon atoms, with a heavy metal sulphide 10 15 ln 7807810-2 formula Mn + (- SO 2 -R 5) n, wherein M represents a heavy metal ion and n denote the valence of this cation, and possibly in a held compound of formula IV transfers a protected carboxy group of the formula -C (= O) -Hg to another protected carboxy group and / el- if desired, transfer a obtained compound to another compound within the definition of the final products and / or, if if desired, transfer an obtained salt-forming compound group to a salt or a salt obtained to a free compound or to another salt and / or, if desired, divide a resulting mixture of isomers in the individual isomers.

The new intermediates of formula IV can be obtained from compounds of formula III by reaction with a sulfinic acid with the formula HSO2-H5 or a sulfonyl cyanide of the formula N50-SO2-Rs.

The reaction takes place in an inert solvent or solvent. mixture, for example an optionally halogenated, such as chlorinated, aliphatic cyclic, cycloaliphatic or aromatic hydrocarbon such as pentane, hexane, cyclohexane, benzene, toluene, methylene chloride, chloroform or chlorobenzene, an aliphatic, cycloaliphatic or aromatic alcohol, such as lower alkanol, for example methanol, ethanol, cyclohexanol or phenol, a polyhydroxy compound, for example a polyhydroxyalkane, such as dihydroxy lower alkane, for example ethylene or propylene glycol, a lower ketone, such as acetone or methyl ethyl ketone, an ethereal solvent such as diethyl ether, dioxane or tetrahydrofuran, a low carboxylic acid amide, such as dimethylformamide or dimethylacetamide, a lower dialkyl- sulfoxide, such as dimethyl sulfoxide, and the like or mixtures hence.

The reaction takes place at room temperature or preferably at room temperature. elevated temperature, for example at the boiling temperature of the solvent used luckily, possibly in an atmosphere of inert gas, such as nitrogen.

The reaction with the sulfonyl cyanide of the formula NEC-SO 2 -H 5 accelerated by the addition of halogen anion releasing compounds.

Suitable halogen anion releasing compounds are, for example, quaternary close to ammonium halides, especially chlorides and bromides, such as optionally substituted at the lower alkyl groups, for example with aryl, such as phenyl, mono- or polysubstituted tetra-lower alkylammonium halides, such as tetraethyl or benzyltriethylammonium chloride, or bromide.

The halogen anion releasing compounds are added in amounts of; about 1 to about 50 mole percent, preferably about 2 to about 5 mole percent.

The groups RH are monocyclic or bicyclic and can for example be substituted with -galkyl, such as methyl or ethyl, : J1 10 15 ' 25 30 35 10 7807810-2 lower alkoxy such as methoxy or ethoxy, halogen such as fluorine or chlorine, or aryl, such as phenyl; Such groups Ru are, for example, monocyclic, five-membered, thiadiazacyclic, thiatriazacyclic, oxadiazacyclic or oxa- triazacyclic groups with an aromatic character, but especially mono- cyclic, five-membered, iiazacyclic, oxazacyclic and thiazacyclic groups with an aromatic character, and / or primarily corresponding to benzdiazacyclic, benzoxazacyclic or benstiazacylic groups in which the heterocyclic moiety is five-membered and aromatic character, wherein in the groups Ru a substitutable ring nitrogen atom, for example, may be substituted with lower alkyl. For- for such groups Ru is 1-methylimidazol-2-yl, 1,3-thiazol 2-yl, 1,1,3-thiadiazol-2-yl, 1,3,3H, 5-thiatriazol-2-yl, 1,3-oxazol-2-yl 2-yl, 1,3, H-oxadiazol-2-yl, 1,3, N, 5-oxatriazol-2-yl, 2-quinolyl, 1-methylbenzimidazol-2-yl, benzoxazol-2-yl and especially benzyl thiazol-2-yl. Other groups RAE are acyl residues of organic boxyl acids or thiocarboxylic acids, such as optionally substituting those, aliphatic, cycloaliphatic, araliphatic or aromatic acyl or thioacyl groups of up to 18, preferably up to to 10, carbon atoms such as lower alkanoyl, e.g. acetyl or propionate nyl, lower thioalkanoyl, for example thioacetyl or thiopropionyl, cycloal cancarbonyl, e.g. cyclohexanecarbonyl, cycloalkantiocarbonyl, e.g. cyclohexantiocarbonyl, benzoyl, thiobenzoyl, naphthylcarbonyl, naphthyl tylthiocarbonyl, heterocyclic carbonyl or thiocarbonyl, such as 2-, 5- or H-pyridylcarbonyl, 2- or 5-tenoyl, 2- or 5-fu- royl, 2-, 3- or U-pyridylthiocarbonyl, 2- or 3-thiotenoyl, 2- or 5-thiofuroyl or correspondingly substituted, for example with lower alkyl such as methyl, halogen such as fluorine or chlorine, lower alkoxy, such as methoxy, aryl, such as phenyl, aryloxy, such as phenyloxy, mono- or polysubstituted acyl or thioacyl groups.

Suitable heavy metal sulfinates are especially those which in the reaction medium used has a greater solubility product than those during the reaction, the heavy metal compounds of the formula formed Mn + (- S-Ru) n. Suitable heavy metal cations Mn + are especially those, which form particularly insoluble sulphides. Among these are noticeable for example monovalent or divalent cations of copper, mercury, silver and tin, with copper ++ and silver * cations being suitable ligast.

The heavy metal sulfinate can be used as such or automotive in situ during the reaction, for example from a sulfinic acid of the formula 10 15 30 40 7807810-2 8 HSO 2 -R or a soluble salt thereof, for example an alkali metal salt, such as the sodium salt, and the fifiunium metal salt, whose solubility is fi pro ' duct is larger than that of the corresponding heavy metal lslsulfinate, e.g. -acetate or -sulfate: Ü ex Sílvernítrat fl or even one a heavy metal nitrate, mercury (II) diacetate or copper (II) sulphate, liquid chlorine, such as cenn (II) chloride dinyrate. g of the formula IVa with heavy metal n + - - 't _ the sulfinate of the formula M (SO 2 R 5) n can take place in an inner Orga I in water or in a solvent mixture consisting of water and a water-miscible solvent. organic solvents are, for example, aliphatic The reaction of a before fi í fl technical solvent, Appropriate inert, cycloaliphatic or aromatic hydrocarbons, such as Pe fl ta fl, hexane, cyclohexane, benzene, toluene, xylene, or aliphatic, cyclohexane aliphatic or aromatic alcohols, such as lower alkanols, e.g. methanol, ethanol, cyclohexanol or phenol, polyhydroxy compounds, such as polyhydroxyalkanes, for example dihydroxylalkanes, such as ethylene or propylene glycol, carboxylic acid esters, for example low carboxylic acid low alkyl esters such as ethyl acetate, coating ketones such as acetone or methyl ethyl ketone, ethereal solvents such as dioxane, tetrahydro furan or polyethers, such as dimethoxyethane, lower carboxylic acid such as dimethylformamide, lower alkyl nitriles such as acetonitrile, or lower sulfoxides, such as dimethyl sulfoxide. In water or especially in mixtures of water and one of the stated solvents, including in emulsions, the reaction usually proceeds substantially faster than in the organic solvent alone.

The reaction temperature is usually at room temperature. but can be slowed down for reaction retardation or accelerated is raised to approximately the boiling point of the solution used the agent, whereby it is possible to work at normal pressure or even increased pressure.

In a obtained new intermediate of formula IV, a group may Rï, so or RA 2 whereby analogous reactions can be used, as indicated for transferred to another group Rï, Rï or Râ, the conversion of these groups into compounds of formula IA or IB.

The new intermediates which can be prepared according to the invention of formula IV can, for example, according to the following reaction scheme transferred to pharmacologically valuable β-amino-3-cephem-3-ol H-carboxylic acid compounds of the formula IA or to them also suitable as intermediates, corresponding to% β-amino-2-cephem-5- _- ___. .__. __. 7807810-2 The oi-U-carboxylic acid compounds of formula IB: The procedure shown in the reaction scheme is distinguished compared to hitherto known procedures thereof, that it is based on inexpensive, readily available starting materials, such as and fermentatively manufacturable penicillins G or V and 6-aminopenicillanic acid, the reactive groups of which in and for known method can be protected and easily re-released after the reaction, and the preparation of the intermediates required according to the invention the products are made in high yield. 7807810-2 10 Rï H H 2 WH; 1 s I ä / “ß ff on o = ~ e-N ¿5 (III) O = C_RA 2 step 2a // Iva Y = _S_RU Ivb Y = -SÛ2 “R5 step 2 a Ra l * Yp H H S_Y l \ NH H 3 s_Y (VI) o = c-ag (v) o = c-now VIa Y 3 “S“ Ru va Y: 'S'Ru vïb - 1 _ -soz-as vb Y _ -soz-R _s: eg H Ra I 3 ung § 9 s-Y "¶ :: 'I c fi š of- N \ ~ O - ~ +> 'fi i-C “OR 1 (II) o = c-RQ IIa Y = -s-nu Iïb = Y _ -soz-RS Ra. Ra. l * NH 3 É S I l \ Nn 5 3 s \ 2 - / \ \ Q É _ ] i] _ * 1: 1 o == Ne / o-RS o ~ o-R5 T ï 0 = c-H2 o = c-RZ (IA) (IB) Starting compounds of formula III are known or can be prepared according to known procedures. 10 15 20 25 STAY 55 H0 7807810-2 11 The compounds of formula IVa are also known or can manufactured according to Dutch patent specification 72 08671.

In steps 2 and 5 or 2a, a compound of formula IV by oxidative decomposition of the methylene group to an oxo group to a compound of formula VI.

The oxidative cleavage of the methylene group in compounds with the formula IV to form an oxo group can be undertaken under formation of an ozonide compound of formula V by treatment with ozone. In this case, ozone is usually used in the presence of a solution. agents such as an alcohol, for example a lower alkanol such as methanol or ethanol, a ketone, for example a lower alkanone, such as acetone, an optional halogenated, aliphatic, cycloaliphatic or aromatic hydrocarbon, for example a halogen lower alkane such as methylene chloride or carbon tetrachloride, or a solvent mixture, including an aqueous mixture even during cooling or light heating, e.g. temperatures of about -90 ° C to about + H0 ° C.

An ozonide of the formula Va can be obtained as an intermediate transferred to a compound of formula Vb, optionally without isolation by reaction with a heavy metal sulfinate of the formula Mn + (-SO-R 5) n is analogous to the reaction of compounds of formula 1Va to compounds of formula IVb.

An ozonide of formula V can be reductively cleaved in step 3 to a compound of formula VI, wherein one can use catalytic ethically activated hydrogen, for example hydrogen in the presence of a heavy generation catalyst, such as nickel catalyst, further palladium catalyst, preferably on a suitable support material, such as calcium carbonate or carbon, or chemical reducing agents, such as reducing heavy metals, including heavy metal alloys or amalgam, eg zinc, in the presence of a hydrogen donor, such as an acid, eg acetic acid, or an alcohol, eg lower alkanol, reducing inorganic salts, such as alkali metal iodides, eg sodium iodide, in the presence of a hydrogen donor, such as an acid, eg acetic acid, or a reducing sulfide compound, such as a lower alkyl sulfide, e.g. dimethyl sulfide, a reducing organic phosphorus compound, such as a phosphine, which may optionally contain substituted aliphatic or aromatic hydrocarbon groups such as substituents, e.g. lower alkylphosphines, such as tri-n-butylphosphine, or triarylphosphines, such as triphenylphosphine, further phosphite, which as substituents contains optionally substituted aliphatic hydrocarbon groups, such as tri-lower alkyl phosphite, usually in the form of the corresponding alcohol 7807810-2 12 compounds such as trimethyl phosphite, or phosphoric acid triamides, which as substituents contain optionally substituted aliphatic hydrocarbon groups, such as hexa-lower alkyl phosphoric acid acid triamides, eg hexamethylphosphoric acid triamide, the latter then preferably in the form of a methanol adduct, or the tetracyanate.

The cleavage of the usually non-isolated ozonide takes place normally under conditions used for its manufacture, ru lO 15 20 25 30 55 ie in the presence of a suitable solvent or solvent mixture, even during cooling or slight heating.

Enol compounds of formula VI may also be present in tautomers ketoform.

An enol compound of formula VIa can be reacted with a heavy metal sulfinate of the formula Mn + (- SO 2 -R 5) n, is converted to a compound of formula VIb analogous to the reaction of compounds with formula IVa to compounds of formula IVb.

In a obtained compound of formula VI, a group R or Râ is transferred to another group Rï, R? or Râ, wherein analogous reactions can be used, as indicated for the conversion of these groups in compounds of formula IA or IB.

In step 4, an obtained enol compound of the formula is converted VI by etherification to a compound of formula II, wherein R; stands for lower alkyl or a hydroxy protecting group, for example as defined for RB under formula IA or IB.

For the preparation of lower alkyl and optionally substituted the α-phenyl lower alkyl ethenethers of formula II are used as etherifying reagents, for example a corresponding diazo compound, e.g. a diazole alkane such as diazomethane, diazoethane, diazo-n-butane or an optionally substituted u-phenyldiazole lower alkane, e.g. or diphenyldiazomethane. These reagents were used in the presence of a suitable inert solvent, such as an aliphatic, cycloaliphatic hydrocarbon or aromatic hydrocarbon such as hexane, cyclohexane, benzene or toluene, a halogenated aliphatic hydrocarbon, e.g. chloride, a lower alkanol, eg methanol, ethanol or t-butanol, or an ether such as a lower alkyl ether, for example diethyl ether, or a cyclo ether, such as tetrahydrofuran or dioxane, or a solution mixture and depending on the diazo reagent during cooling, at room temperature or under light heating, further, if so necessary, in a closed vessel and / or under an atmosphere of inert gas, eg nitrogen gas. «G \ í 10 15 20 50 35 U0 7807810-2 13 Furthermore, lower alkyl and optionally substituted radea-phenyl lower alkylene ethers of formula II by treating an enol compound of formula VI with a reactive ester of a corresponding alcohol of the formula Hg-OH. Suitable esters are in primarily those with strong inorganic or organic acids, such as mineral acids, such as hydrohalic acids, such as hydrochloric, bromine, hydrochloric or hydroiodic acid, further sulfuric acid or halogenated sulfuric acid tubes, such as fluorosulfuric acid, or strong organic sulfonic acids, as optionally, for example with halogen, such as fluorine, substituted lower alkanesulfonic acids, or aromatic sulfonic acids, such as optionally, for example with lower alkyl, such as methyl, halogen, such as bromine, and / or nitro substituted benzenesulfonic acids, e.g. phonic acid, trifluoromethanesulfonic acid or p-toluenesulfonic acid. These reagents, especially lower alkyl sulfate, such as dimethyl sulfate, further lower alkyl fluorosulphate, eg methyl fluorosulphate, or optionally halogen-substituted methanesulfonic acid lower alkyl esters, e.g. fluoromethanesulfonic acid methyl ester, or even the corresponding e-phenyl- lower alkyl esters, for example benzyl and diphenylmethyl esters, such as benzyl or diphenylmethyl halides, such as chlorides or bromides, are used was usually present in the presence of a solvent, such as an optional halogenated, such as chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbon, for example methylene chloride, an ether such as dioxane or tetrahydrofuran, or lower alkanol, such as methanol, or a solvent mixture. In doing so, one preferably uses suitable condensing agents, such as alkali metal carbonate or hydrogen carbonate, eg sodium or potassium carbonate or bicarbonate (usually together with a sulphate), or organic bases, such as, usually sterically hindered, tri-lower alkylamines, e.g. N, N-diisopropyl-N-ethylamine (preferably together with low alkyl halogen sulphate or optionally halogen-substituted methane sulfonic acid low alkyl esters), working under cooling, at room temperature or during heating, eg at temperatures of about -20 ° C to about 50 ° C, and if necessary in one closed vessel and / or in an atmosphere of inert gas, eg nitrogen gas.

By phase transfer catalysis (see E.V. Dehmlow, Angewandte Chemie 5 / l97U, p 187), the etherification reaction can substantially accelerate reras. Quaternary catalysts can be used as quaternary catalysts. close to phosphonium salts and especially quaternary ammonium salts, such as as optionally substituted tetraalkylammonium halides, e.g. rabutylammonium chloride, bromide or iodide, or even benzyl 10 15 20 25 30 35 H0 78Û781Û "2 14 triethylammonium chloride, in catalytic or up to equimolar quantities. As the organic phase, any with water can not miscible solvents serve, for example a possible halogenated, such as chlorinated, aliphatic, cycloaliphatic or aromatic carbon hydrogen, such as tri- or tetrachlorethylene, di-, tri- or tetrachloro- ethane, chlorobenzene, especially carbon tetrachloride or even toluene or xylene. The alkali metal carbonates suitable as condensing agents or hydrogen carbonate, for example potassium or sodium carbonate or bicarbonate, alkali metal phosphate, eg potassium phosphate, and alkali Potassium metal hydroxides, such as sodium hydroxide, can at base sensitive compounds are titrated to the reaction mixture, to pH below the etherification should remain between 7 and 8.5.

Lower alkylene ethers of formula II can also be prepared by treating an enol compound of formula VI with a wide range of carbon atom with an aliphatic character two or three with lower alkyl etherified hydroxy groups of the formula Bg-O containing compound, i.e. with a corresponding acetal or orthoester, in the presence of an acid average. Thus, for example, it can be used as a desiccant gem-lower alkoxy lower alkanes, such as 2,2-dimethoxy-propane, in the presence of a strong organic sulfonic acid, such as p-toluenesulfonic acid, and a suitable solvent, such as a lower alkanol, eg methanol, or a lower alkyl or lower alkylene sulfoxide, for example dimethyl sulfoxide, or orthoformic acid tria lower alkyl ester, for example orthoformic acid triethyl ester, in the presence of a strong mineral acid, such as sulfuric acid, or a strong organic sulfonic acid, such as p-toluenesulfonic acid, and a suitable solvent, such as a lower alkanol, eg ethanol, or a ether, eg dioxane, and thus obtain compounds of the formula II, wherein R; stands for lower alkyl, eg methyl or ethyl.

Lower alkylene ethers of formula II can also be obtained, if enol compounds of formula VI are treated with tri-lower alkyl oxonium salts of the formula (Rg) 30 GDIÉQ (so-called Meerwein salts), also di-RÉO-carbenium salts of the formula (R§0) 2CH (¿”a§9, or di-R3 halonium salts of the formula (Rg) 2Hal &? A (9, wherein anion of an acid and Hal (§ denotes a halonium ion, spe- bromine ion, and R 1 represents lower alkyl. It's moving primarily tri-lower alkyloxonium salts and dilate alkoxy carbenium or dilahalkylhalonium salts, especially the equivalent salts with complex fluorine-containing acids, such as the corresponding tetra- fluoroborate, hexafluorophosphate, hexafluoroantimonate or hexachloroborate roantimonat. Such reagents are, for example, trimethyloxonium or 10 15 20 25 30 35 ÄO 7807810-2 15 triethyloxonium hexafluoroantimonate, -hexachloroantimonate, -hexafluo- rophosphate or tetrafluoroborate, dimethoxycarbenium hexafluorophosphate barrel or dimethyl bromonium hexafluoroantimonate. It uses des- said etherifying agent preferably in an inner solvent, such as an ether or a halogenated hydrocarbon, for example diethyl ether, tetrahydride rofuran or methylene chloride, or in a mixture thereof, if any necessary in the presence of a base, such as an organic base, e.g. sterically hindered, tri-lower alkylamine, e.g. N, N-diisopropyl- N-ethylamine, and under cooling, at room temperature or below slight heating, eg at about -20 ° C to about 50 ° C, if so necessary in a closed vessel and / or in an atmosphere of inert gas, eg nitrogen gas.

Compounds of formula II, wherein the hydroxy protecting group RÉ is a 2-oxa or 2-thialiphatic or cycloaliphatic hydrocarbon group, produced by acid-catalyzed, for example with a strong mineral ralic acid, such as sulfuric acid or hydrochloric acid, catalyzed storage of <>, ß-unsaturated aliphatic or cycloaliphatic ethers or thioethers, such as 1-lower alkoxy low alkenes, eg 1-methoxyethylene or 1-methoxypropylene, 1-lower alkylthio low alkenes, such as 1-methylthioethylene or 1-methylthiopropene, oxa- or thiacyclo-lowalk-2-ene or -2, Ä-dienes with 5-7 ring atoms, eg 2,3-dihydrofuran, 2H-pyran, 3,4-dihydro-2H-pyran or equivalent analogous sulfur compounds, at the 5-hydroxy group of a compound of formula VI. The addition can be carried out in an excess of the unsaturated ether or ether and possibly in an inert organic solvent, e.g. an aliphatic, cycloaliphatic or aromatic hydrocarbon, such as pentane, hexane, cyclohexane, benzene, toluene and the like, under excluding water.

Of the formula II comprised the silyl or stannyl ethers, i.e. compounds of formula II, wherein R denotes a substituted silyl or stannyl group, is obtained according to something for silylation or stannylation of enol groups by suitable method, for example by treatment with a suitable silylating agent, such as a dihalogen dilaalkylsilane, loweralkoxysalgalkyldíhalosilane or trihydric carbon silyl halide, eg dichlorodimethylsilane, methoxymethyldichlorosilane, trimethylsilyl chloride or dimethyl t-butylsilyl chloride, wherein use such silyl halide compounds preferably in the presence of a base, eg pyridine, with an optionally N-mono-lower alkylated, N, N-lower alkylated, N-tri-lower alkylsilylated or N-lower alkyl-N- tri-lower alkylsilylated N- (tri-lower alkylsilyl) -amine (see for example 10 20 25 30 55 H0 7807810-2 16 British Patent Specification 1,073,530), for example with a hexa-low alkyl silazane, such as hexamethyldisilazane, or with a silylated carboxylate acid amide, such as a bis-tri-lower alkylsilylacetamide, e.g. bis-trimethyl- silyl acetamide, or trifluorosilylacetamide, further with a suitable stannylating agent, such as a bis-trialkyltin oxide e.g. bis- (tri-n-butyl tin) oxide, a tri-lower alkyl tin hydroxide, e.g. triethyltin hydroxide, a tri-lower alkyl low alkoxy tin, tetral coxy-tin or tetra-lower alkyl tin compound, as well as a tri-lower alkyl tin halide, eg tri-n-butyltin chloride (see for example Dutch exposition 67 / lllO7).

A compound of formula IIa, wherein R; denotes lower alkyl or a hydroxy group protecting group, can be reacted with a metal sulfinate of the formula Mn + (- SO 2 -R 5) n is transferred to a compound of formula IIb analogously to the reaction of compounds with formula IVa to IVb.

In a obtained compound of formula II, a group Ra, R Râ or H3 is transferred to another group Ra, Rï, Rê or R b 1, 3, whereby analogous reactions can be used, as indicated for the conversion of these groups to compounds of formula IA or IV.

According to step 5, compounds of formula II can be used for preparation of 7β-amino-3-cephem-3-O1-U-carboxylic acid compounds of formula IA, wherein R 1 and R 2? stands for hydrogen or an acyl group Ac, or Ef and R? together constitute a divalent amino group, H2 stands for hydroxy or a group Bg which together with the carbonyl group -C (= O) - forms a protected carboxy group, and R represents hydrogen or lower alkyl or a hydroxy protecting group H3, as well as 1-oxides of 3-cephem compounds of formula IA and corresponding to 2-cephem compounds of formula IB, wherein R1, Hg, H2 and H5 is as defined, or salts of such compounds with salt-forming groups.

In 2-cephem compounds of formula IB with double bond i 2,3-position shows the possibly protected carboxy group with the formula -C (= O) -R 2 preferably α-configuration.

A lower alkyl group R 5 has up to 7, preferably up to to 4, carbon atoms and is especially methyl or also ethyl, n-propyl, hexyl or heptyl.

A hydroxy protecting group R3 is, for example, a slight cleavage 2-oxa- or 2-thialiphatic or cycloaliphatic hydrocarbon group, an easily cleavable, substituted silyl or stannyl U; 'zh 10 15 20 25 50 35 NO 7807810-2 17 group or an also readily cleavable, optionally substituted rad <1-phenyl lower alkyl group, such as optionally substituted benzyl or diphenylmethyl.

The 2-oxa- or 2-thialiphatic or cycloaliphatic the hydrocarbon group R3 is primarily 1-lower alkoxy-1-lower alkyl or 1-lower alkylthio-1-lower alkyl, such as 1-methoxy-1-ethyl, 1-ethoxy-1-ethyl, 1-methylthio-1-ethyl or 1-ethylthio-1-ethyl, or a 2-oxa- or 2-thialate alkylene or lower alkenylene group having 5-7 ring atoms, such as 2-tetrahydrofuryl, 2-tetrahydropyranyl or 2,3-dihydro-2- pyranyl or a corresponding analogous sulfur compound.

Easily cleavable silyl or stannyl groups RS are preferred substituted with optionally substituted, aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon groups, such as lower alkyl, halo lower alkyl, cycloalkyl, phenyl or phenyl lower alkyl groups, or possibly converted functional groups, such as etherified hydroxy groups, for example lower alkoxy, or halogen, eg chlorine. Typical of such groups are primarily triplicate alkylsilyl such as trimethylsilyl, halo lower alkoxy lower alkylsilyl, such as chloromethoxymethylsilyl, or even tri-lower alkyl stannyl, such as tri-n-butylstannyl.

Other easily cleavable hydroxy protecting groups RB are examples- α-phenyl lower alkyl, such as benzyl and diphenylmethyl, wherein such as substituents on the phenyl nucleus, for example, come into question esterified or etherified hydroxy, such as halogen, eg fluorine, chlorine or bromine, or lower alkoxy, such as methoxy.

Salts are especially those of compounds of formulas IA and IB with an acidic grouping, such as a carboxy, sulfo or phosphono group, primarily metal or ammonium salt, such as alkali metal and alkaline earth metal salts, such as sodium, potassium, magnesium or calcium salts, as well as ammonium salts with ammonium niak or suitable organic amines, primarily for salt formation involves aliphatic, cycloaliphatic, cyclic aliphatic-aliphatic and araliphatic, primary, secondary or tertiary mono-, di- or polyamines, as well as heterocyclic bases such as lower alkylamines, for example triethylamine, hydroxy-lower alkylamines such as 2-hydroxyethylamine, bis- (2-hydroxyethyl) -amine or tris- (2-hydroxyethyl) -amine, basic aliphatic esters of carboxylic acid acids, eg U-aminobenzoic acid 2-diethylaminoethyl ester, lower alkylene amines, eg 1-ethylpiperidine, cycloalkylamines, eg bicyclohexyl- amine, or benzylamines, for example N, N'-dibenzylethylenediamine, further 10 l5 20 25 30 35 NO 7807810-2 pyridine-type bases, such as pyridine, collidine or quinoline. 18 compounds of formulas IA and IB, which have a basic group, can also form acid addition salts, for example with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic acids or sulfonic acids, e.g. acetic acid or p-toluenesulfonic acid. and IB with an acidic and a basic group may also be present in form of internal salts, i.e. in zwitterionic form. of formula IA with salt-forming groups can also form salts. as described.

The associations with pharmacological properties or can be used as intermediates for the production of such. for example Bi stands for a N-acyl derivative in pharmacologically active of 63-aminopenam-3-carboxylic acid or 75-amino-3-cephem-H-carboxylic acid acid compounds present acyl group Ac and R? stands for hydrogen or ler vari R? and R 1 together constitute a 2-position preferred formulas IA and IB respectively show valuable Compounds of formula IA, wherein with, for example, an aromatic or heterocyclic group, and in Ä position preferably, for example with 2-lower alkyl groups, such as methyl, substituted 1-oxo-3-aza-1,4-butylene group, R 2 represents hydroxy or an etherified hydroxy group Râ, which together with the carbonyl the group forms a miracle esterified carboxy group, acyl group R? possibly amino, carboxy, hydroxy free form, or salt off physiological conditions easily cleavable, and H3 represents lower alkyl, wherein in a existing functional groups, such as and / or sulfo, usually present in such compounds with salt-forming groups per are at low toxicity active at parenteral and / or oral administration to microorganisms, such as gram-positive bacteria, eg Staphylococcus aureus, Streptococcus pyogenes and Diplococcus pneumoniae (eg in mice at doses of approx 0.001-about 0.02 g / kg s. c. or p.o.), and gram-negative bacterial rier, eg Escherichia coli, Salmonella typhímurium, Shigella flexneri, Klebsiella pneumoniae, Enterobacter cloacae, Proteus vulgaris, Proteus rettgeri and Proteus mirabilis (eg in mice in doses of about 0.001-about 0.15 g / kg s.c. or p.o.), spe- especially against penicillin-resistant bacteria.

These new compounds may therefore find use in the treatment of the corresponding peripheral infections, e.g. rat. in the form of antibiotic-active preparations Compounds of formula IB or 1-oxides of compounds Before- Compounds of formulas IA 1-oxides of compounds' (IN) 'U 10 15 20 25 STAY 35 U0 7807810-2 19 of formula IA, wherein Ra, Bg, R2 and R3 have in connection with meln IA given the meanings, or compounds of formula IA, wherein R has the indicated meaning, the groups hä and Rï stand for hydrogen or Ra denotes an amino protecting group which is different from one in pharmaco- logically effective N-acyl derivatives of 63-aminopenam-3-carboxylic acid or 7s-amino-3-cephem-H-carboxylic acid compounds present acyl- group, and Rï represents hydrogen or Rï and Rï together a divalent amino-protecting group, which is different from one in 2-position preferably with, for example, an aromatic or heterocyclic group, and in the U-position preferably, for example with 2 lower alkyl, so as methyl, substituted 1-oxo-3-aza-1,1-butylene group, and R 2 is for hydroxy, or R 1 and R 1 have the indicated meaning, R 2 is one group Raw, which together with the grouping -C (= O) - forms a, preferably readily cleavable, protected carboxy group, wherein a thus protected carboxy group is different from a physiological one cleavable carboxy group, and H3 is as indicated, is full intermediates, which in a simple way, e.g. as will described, can be transferred to specified, pharmacologically active associations. ' The invention relates in particular to intermediates of the formula IV, which are suitable for the preparation of 3-cephem compounds with formula IA, wherein R 1 represents hydrogen or preferably an i a fermentative (ie naturally occurring) or bio-, semi- or fully synthetically manufacturable, in particular pharmacological active, as a highly active, 1-acyl derivative of a 6β-aminopenam-5-carboxylate boxylic acid or 7β-amino-3-cephem-N-carboxylic acid compound acyl group, such as one of the acyl groups of formula A, wherein in these R, RII, RIII and n primarily they have as appropriate given meanings, R 1 stands for hydrogen or wherein R and Bg together form a 2-position preferably, e.g. with an aromatic or heterocyclic group, such as phenyl, and in the H-position preferably, for example with two lower alkyl groups, such as methyl, substituted 1-oxo-3-aza-1,1H-butylene group, R 2 is for hydroxy, for optionally, preferably in the α-position, e.g. with optionally substituted aryloxy, such as lower alkoxyphenyloxy, eg α-methoxyphenyloxy, lower alkanoyloxy, eg acetyloxy or pivaloyloxy, u-amino-low alkanoyloxy, eg glycyloxy, L-valyloxy or L-leucyloxy, arylcarbonyl, eg benzoyl, or optionally substituted aryl, such as phenyl, lower alkoxyphenyl, e.g. phenyl, nitrophenyl, e.g. U-nitrophenyl, or biphenylyl, e.g. lO 15 20 25 30 35 H0 7807810-2 20 4-biphenylyl, or in the β-position with halogen, eg chlorine, bromine or iodine, mono- or polysubstituted lower alkoxy, such as lower alkoxy, eg methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, t-bu tyloxy or t-pentyloxy, optionally substituted with lower alkoxy bis-phenyloxymethoxy, eg bis-U-methoxyphenyloxymethoxy, lower alkanoyl- oxymethoxy, for example acetyloxymethoxy or pivaloyloxymethoxy, lower alkanoyloxymethoxy, eg glycyloxymethoxy, phenacyloxy, optionally substituted, phenyl lower alkoxy, especially 1-phenyl lower alkoxy, such as phenylmethoxy, wherein such groups may contain 1-3, optionally, for example with lower alkoxy, such as methoxy, nitro or phenyl, substituted phenyl groups, e.g. syloxy, 4-methoxybenzyloxy, 2-biphenylyl-2-propyloxy, 4-nitroben- syloxy, diphenylmethoxy, N, 4'-dimethoxydiphenylmethoxy or trityloxy, or 2-halo-lower alkoxy, for example 2,2,2-trichloroethoxy, 2-chloroethoxy, 2-bromoethoxy or 2-iodoethoxy, further for 2-phthalidyloxy, also for acyloxy, such as lower alkoxycarbonyloxy, eg methoxycarbonyloxy or ethoxycarbonyloxy, or lower alkanoyloxy, for example acetyloxy or pivaloyloxy, for trilowalkylsilyloxy, eg trimethylsilyloxy, or optionally, for example with lower alkyl, such as methyl, or hydroxy substituted amino or hydrazino, for example amino, lower alkyl or lower alkylamino, such as methylamino or dimethylamino, razino, 2-lower alkyl or 2,2-lower alkylhydrazino, for example 2-methyl- hydrazino or 2,2-dimethylhydrazino, or hydroxyamino and H3 is hydrogen, lower alkyl, especially methyl, or a hydroxy protection group such as tri-lower alkylsilyl, for example trimethylsilyl, or optionally, for example with halogen or lower alkoxy, substituted benzyl or diphenylmethyl, also 1-oxides thereof, further corresponding 2-cephem compounds of formula IB or salts of such compounds with salt-forming groups.

In the first place are in intermediates of formula IV resp in a 3-cephem compound of formula IA and in a corresponding 2-cephem compound of formula IB, further in a 1-oxide of a 3-cephem compound compound of formula IA or in a salt of such a compound with salt-forming groups R? for hydrogen or one in fermentative (ie naturally occurring) or biosynthetically productionable N derivatives of 63-aminopenam-3-carboxylic acid or 7B-amino-3-cephemic 4-carbosylic acid compounds existing acyl group, especially with meln A, wherein RI, RII, RIII and n are primarily such as appropriate specified meanings, such as an option, e.g. hydroxy, substituted phenylacetyl or phenyloxyacetyl group, further an optionally, for example with lower alkylthio, or lower alkenylthio, in E » w w 10 15 20 25 30 35 HO 7807810-2 21 also optionally substituted, such as acylated, amino and / or functionally converted, such as esterified, carboxy, substituted lower alkanoyl or lower alkenoyl group, eg 4-hydroxyphenylacetyl, hexanoyl, octanoyl or n-butylthioacetyl and especially 5-amino- 5-carboxivaleryl, in which the aminoph and / or carboxy groups are currently protected and are present, for example, as acylamino resp esterified carboxy, phenylacetyl or phenyloxyacetyl, or an i high-performance N-acyl derivatives of 6β-amino-penam-3-carboxylic acid or 76-amino-3-cephem-H-carboxylic acid compounds present acyl group, especially with formula A, wherein RI, R, RIII and n are primarily have the meanings given as appropriate, such as formyl, 2-ha logenethylcarbamoyl, for example 2-chloroethylcarbamoyl, cyanoacetyl, phenyl- acetyl, thienylacetyl, for example 2-thienylacetyl, or tetrazolylacetyl, eg 1-tetrazolylacetyl, but especially in the u-position with a cyclo such as cycloaliphatic, aromatic or heterocyclic, i primarily monocyclic group and with a functional group, in primarily amino, carboxy, sulfo or hydroxy groups substitute ~ acetyl, especially phenylglycyl, phenyl optionally being for example with optionally protected hydroxy, such as acyloxy, e.g. optionally halogen-substituted lower alkoxycarbonyloxy or lower kanoyloxy, and / or with halogen, eg chlorine, substituted phenyl, for example phenyl or 3- or N-hydroxy-,} -chloro-U-hydroxy- or 3,5-dichloro-H-hydroxyphenyl (optionally also with protected, such as acylated, hydroxy group) and in which the amino group optionally also may be substituted and, for example, constitutes an optionally in form the present sulfoamino group or an amino group, such as substituents contain a hydrolytically cleavable trityl group or primarily an acyl group, such as an optionally substituted carbamoyl group, such as an optionally substituted ureidocarbon nyl group, for example ureidocarbonyl or N'-trichloromethylureidocarbonyl, or an optionally substituted guanidinocarbonyl group, e.g. guanidinocarbonyl, or one, preferably light, e.g. further action with an acidic agent, such as trifluoroacetic acid reductively, such as by treatment with a chemical reducing agent. part, such as zinc in the presence of aqueous acetic acid, or with catalytic hydrogen, or hydrolytically cleavable or another such a transferable acyl group, preferably a suitable acyl residue of a carbonic acid semi-ester, such as one of those indicated, e.g. halogen- or osenoyl-substituted lower alkyloxycarbonyl groups, for example t-butyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl, 2-chloro- 10 15 20 25 30 35 H0 78Û781Û "2 zz ethoxycarbonyl, 2-bromoethoxycarbonyl, 2-iodoethoxycarbonyl or phenyl acyloxycarbonyl, optionally lower alkoxy- or nitro-substituted fe- lower alkyl alkoxycarbonyl, for example-met-methoxybenzyloxycarbonyl or diphenyl- methoxycarbonyl, or of a carbonic acid halamide, such as carbamoyl or. (hrs N-methylcarbamoyl, further one with a nucleophilic reagent, such as hydrocyanic acid, sulfuric acid or thioacetic acid amide, cleavable arylthio or aryl lower alkylthio group, for example 2-nitrophenylthio or trityltio, an electrolytically reducing cleavable arylsul- phonyl group, for example 4-methylphenylsulfonyl, or one with an acidic part, such as formic acid or aqueous mineral acid, e.g. acid or phosphoric acid, cleavable l-lowD «ndcarbonyl- or 1-lower alkanoyl-2-propylidene group, for example 1-ethoxycarbonyl-2-propylidene the, further u- (1,1-cyclohexadienyl) -glycyl, α- (1-cyclohexenyl) - glycyl, α-thienylglycyl, such as α-2- or u-3-thienylglycyl, u-fu- rylglycyl, such as u-2-furylglycyl, α-isothiazolylglycyl, such as u-4-isothiazolylglycyl, wherein in such groups the amino group may be substituted or protected, for example as indicated for a nylglycyl group, furthermore u-carboxyphenylacetyl or α-carboxytienyl- acetyl, eg u-carboxy-2-thienylacetyl (optionally with functional converted, for example in salt form, such as sodium salt form, or in ester- form such as lower alkyl ester form, for example methyl or ethyl ester form, or phenyl lower alkyl ester form, for example diphenylmethyl ester form, carboxy group), α-sulfophenylacetyl (optionally also with, for example as the carboxy group, functionally converted sulfo group), α-phosphono, α-O-methylphosphono- or α-0,0'-dimethylphosphonophenylacetate tulle, or treated hydroxy group, especially with an acyloxy group in which acyl denotes a, preferably light, for example by treatment with an acidic agent, such as trifluoroacetic acid, or with a chemical production agents, such as zinc in the presence of aqueous acetic acid, cleavable or an acyl group transferable thereto, preferably a suitable acyl residue of a carbonic acid ester, such as one of indicated E for example, optionally halogen- or benzoyl-substituted coxycarbonyl group, for example 2,2,2-trichloroethoxycarbonyl, 2-chloroethoxy- carbonyl, 2-bromoethoxycarbonyl, 2-iodoethoxycarbonyl, t-butyloxycarbyl bonyl or phenacyloxycarbonyl, further formyl), as well as 1-amino- cyclohexylcarbonyl, aminomethylphenylacetyl, such as 2- or nomethylphenylacetyl, or aminopyridinium acetyl, e.g. ridinium acetyl (optionally also with, for example, as indicated, substituted amino group), or pyridylthioacetyl, for example 4-pyridylthioacetyl (u 10 15 20 25 50 7807810-2 for tyl, and Hg stands for hydrogen or Râ and R? together stands for one, in the 2-position preferably, optionally with protected hydroxy, such as acyloxy, for example optionally halogen-substituted lower alkoxy bonyloxy or lower alkanoyloxy, and / or with halogen, eg chlorine, substituted phenyl, for example phenyl or 3- or U-hydroxy-, 3-chloro- --hydroxy- or 3,5-dichloro---hydroxyphenyl (optionally also with protected, eg as indicated, acylated hydroxy group) substituted 1-oxo-3-aza-1,1-butylene group, which in the ü position may contain two lower alkyl, such as methyl, and R 2 is hydroxy, lower alkoxy, especially α-polygrenal lower alkoxy, eg t-butyloxy, further methoxy or ethoxy, 2-halo-lower alkoxy, for example 2,2,2-trichloroethoxy, 2-iodo- ethoxy or readily transferable 2-chloroethoxy or 2-bromo- ethoxy, phenacyloxy, 1-phenyl low alkoxy with 1-3, optionally with low alkoxy or nitro substituted, phenyl groups, e.g. syloxy, 4-nitrobenzyloxy, diphenylmethoxy, 1H, U'-dimethoxydiphenyl- methoxy or trityloxy, lower alkanoyloxymethoxy, e.g. toxi or pivaloyloxymethoxy, α-aminolâgalkanoyloxymethoxy, e.g. glycyloxymethoxy, 2-phthalidyloxymethoxy, lower alkoxycarbonyloxy, e.g. ethoxycarbonyloxy, or lower alkanoyloxy, eg acetyloxy, further tri-lower alkylsilyloxy, eg trimethylsilyloxy, and H3 represents hydrogen, lower alkyl, especially methyl, or a hydroxy protecting group, such as tri-lower alkylsilyl, for example trimethylsilyl, or optionally, for example with halogen, such as chlorine or bromine, or lower alkoxy, such as methoxy, substituted benzyl or diphenylmethyl.

The present invention relates primarily to intermediate products. compounds of formula IV, which are suitable for the preparation of 3-cell five compounds of formula IA, wherein R 1 represents hydrogen or a acyl group of the formula: Ra-oom cHf-cf (B) in which Ra represents phenyl or hydroxyphenyl, for example 3- or 4-hydroxyphenyl, further hydroxychlorophenyl, eg 3-chloro-U-hydroxy ~ phenyl or 3,5-dichloro-H-hydroxyphenyl, wherein in such groups the hydroxy substituents may be protected with acyl groups, such as optionally halogenated lower alkoxycarbonyl groups, eg t-butyl- oxycarbonyl or 2,2,2-trichloroethoxycarbonyl, also thienyl, eg 2- or 5-thienyl, further pyridyl, eg 4-pyridyl, amino- pyridinium, eg α-aminopyridinium, furyl, eg 2-furyl, iso- 10 15 20 25 30 35 H0 7807810-2 _24 thiazolyl, eg α-isothiazolyl, or tetrazolyl, eg 1-tetrazolyl, or also 1,1-cyclohexadienyl or 1-cyclohexenyl, X is oxygen or sulfur, m stands for 0 or l and Rb stands for wüe aUer, if m is 0, for amino as well as protected amino, such as acylamino, e.g. u-polygrenal lower alkoxycarbonylamino, such as t-butyloxycarbonylamino no, or 2-halo-lower alkoxycarbonylamino, for example 2,2,2-trichloro- ethoxycarbonylamino, 2-iodoethoxycarbonylamino or 2-bromoethoxy- carbonylamino, or optionally lower alkoxy or nitro substituents phenyl lower alkoxycarbonylamino, e.g. U-methoxybenzyloxycarbonyl- amino or diphenylmethoxycarbonylamino, or 5-guanylureido, further sulfoamino or tritylamino, also arylthioamino, e.g. 2-nitrophenylthioamino, arylsulfonylamino, for example H-methylphenylsulfonamino nylamino, or 1-lower alkoxycarbonyl-2-propylideneamino, e.g. 1-ethoxycarbonyl-2-propylideneamino, carboxy or in salt form, e.g. alkali metal salt form, such as sodium salt form, the present boxy, as well as protected carboxy, for example esterified carboxy, such as lower alkyl alkoxycarbonyl, eg diphenylmethoxycarbonyl, sulfo or in salt form, such as alkali metal salt form, eg sodium salt form, present sulfo, also protected sulfo, hydroxy, also protected hydroxy such as acyloxy, for example α-polygrened lower alkoxycarbonyl- oxy, such as t-butyloxycarbonyloxy, or 2-halo-lower alkoxycarbonyloxy nyloxy, such as 2,2,2-trichloroethoxycarbonyloxy, 2-iodoethoxycarbonyl- oxy or 2-bromoethoxycarbonyloxy, further formyloxy, or O-low alkylphosphono or 0,0'-lower alkylphosphono, eg O-methylphosphono or 0,0'-dimethylphosphono, or a 5-amino-5-carboxyvaleryl group, wherein the amino and / or carboxy group may also be present and present, for example, as acylamino, e.g. amino, such as acetylamino, halo-lower alkanoylamino, such as dichloro- acetylamino, benzoylamino or phthaloylamino, or as carboxy, such as phenyl lower alkoxycarbonyl, for example diphenylmethoxy- carbonyl, preferably m representing 1, if Ra represents phenyl, hydroxyphenyl, hydroxychlorophenyl or pyridyl, and m denotes 0 and R b is separated from hydrogen, if Ra is phenyl, hydroxy- phenyl, hydroxychlorophenyl, thienyl, furyl, isothiazolyl, 1,1-lo-cyclo- hexadienyl or 1-cyclohexenyl, R 1 represents hydrogen, R 2 in the first hand stands for hydroxy, further for lower alkoxy, especially α-polygre- lower alkoxy, eg t-butyloxy, 2-haloalkoxy, eg 2,2,2-tri- chloroethoxy, 2-iodoethoxy or 2-bromoethoxy, or optionally, e.g. with lower alkoxy, such as methoxy, substituted diphenylmethoxy, e.g. diphenylmethoxy or U, N''-dimethoxydiphenylmethoxy, further tri-low (n m 10 15 20 25 50 55 HO 7807810-2 25 alkylsilyloxy, for example trimethylsilyloxy, and RB represents hydrogen, lower alkyl, for example methyl, ethyl or n-butyl, as well as tri-lower alkyl silyl, eg trimethylsilyl, further optionally, eg with halogen, such as chlorine or bromine, or lower alkoxy, such as methoxy, substituted benzyl or diphenylmethyl, as well as 1-oxides of such 3-cell five compounds of formula IA, further corresponding to 2-cephem compounds of the formula IB or salts, in particular pharmaceutically only, non-toxic salts of such salt-forming compounds groups such as alkali metal salts, for example sodium salts, or alkaline earth metal salts, such as calcium salts, or ammonium salts, including those with amines, of compounds in which R2 represents roxi and which in the acyl group of formula B contains a free amino- SFUPP- In the first instance in intermediate products of formula IV resp in 3-cephem compounds of formula IA, further in the corresponding 2-cephem five compounds of formula IB and in salts, especially in pharmaceuticals non-toxic, non-toxic salts of such compounds with salt-forming groups, such as those indicated in the preceding paragraph the salts, Râ for hydrogen, for the acyl group of formula B, wherein R? ask- represents phenyl, also hydroxyphenyl, eg H-hydroxyphenyl, thienyl, for example 2- or 5-thienyl, U-isothiazolyl, 1,1-cyclohexadienyl or 1-cyclohexenyl, X is oxygen, m is 0 or 1 and Rb is hydrogen or, if m is 0, amino, also protected amino, such as acylamino, e.g. α-polygrenal lower alkoxycarbonylamino, such as t-butyloxycarbonylamino no, or 2-halo-lower alkoxycarbonylamino, for example 2,2,2-trichloro- ethoxycarbonylamino, 2-iodoethoxycarbonylamino or 2-bromoethoxy- carbonylamino, or optionally lower alkoxy or nitro substitute ~ phenyl lower alkoxycarbonylamino, for example α-methoxybenzyloxycarbonyl- amino or hydroxy, as well as protected hydroxy, such as acyloxy, e.g. α-polygrenal lower alkoxycarbonyloxy, such as t-butyloxycarbonyloxy, or 2-halo-lower alkoxycarbonyloxy, such as 2,2,2-trichloroethoxycarbonyloxy bonyloxy, 2-iodoethoxycarbonyloxy or 2-bromoethoxycarbonyloxy, further formyloxy, or for a 5-amino-5-carboxivaleryl group, in which the amino group and the carboxy group may also be protected and is present, for example, as acylamino, for example lower alkanoylamino, such as acetylamino, halo-lower alkanoylamino, such as dichloroacetyl- amino, benzoylamino or phthaloylamino or as esterified car- box, such as phenyl lower alkoxycarbonyl, eg diphenylmethoxycarbonyl, wherein preferably m represents 1, if Ra is phenyl or hydroxy phenyl, Hg is hydrogen, R2 is primarily hydroxy, further - ~ V I -.- ......_ - .. alla ...__ 10 15 20 30 'löUi / U' V ”' 26 optionally halogen-substituted in the 2-position, eg chlorine, bromine or iodine-substituted, lower alkoxy, especially α-polygrenated lower alkali coxy, eg t-butyloxy, or 2-haloalkalkoxy, eg 2,2,2-tri- chloroethoxy-substituted, such as methoxy-substituted, diphenylmethoxy- for example diphenylmethoxy or ü, H'-dimethoxydiphenylmethoxy, or p-nitro benzyloxy, further trilâgalkylsilyloxy, eg trimethylsilyloxy, and R 3 represents hydrogen, lower alkyl, especially methyl, tri-lower alkyl lyl, e.g. trimethylsilyl, or one optionally with halogen, e.g. chlorine or bromine, or lower alkoxy, for example methoxy, substituted ben- syl or diphenylmethyl group.

The invention primarily relates to intermediate products with which are suitable for the preparation of 7β- (D-α-amino-u- Ra-acetylamino) -3-lower alkoxy-3-cephem-Ä-carboxylic acids, in which Ra stands for phenyl, N-hydroxyphenyl, 2-thienyl, 1,4-cyclohexadienyl or 1-cyclohexenyl, and lower alkoxy contains up to atoms and constitute, for example, ethoxy or n-butyloxy, but in the former methoxy, and internal salts thereof and in particular 5-methoxy-7B- (D-α-phenylglycylamino) -3-cephem-U-carboxylic acid and its inner salt; in the indicated concentrations, these compounds, in particular when administered orally, excellent antibiotic properties both towards gram-positive and especially towards gram-negative bacteria with low toxicity.

According to step 5 of the indicated reaction scheme, compounds of formula IA, their 1-oxides, compounds of formula IB and salts of such compounds having salt-forming groups, by treating with one base a compound of the formula: Ra â \ 5 5 s-Y / i i \\ .__ J /.

El I än; (II) 0: = 1__N \\ ç% 7CsJv0Rg and A O = C'R2 wherein R 1, R 2 and R 3 have the meanings given in formula IA, R; represents lower alkyl or a hydroxy protecting group and Y represents one leaving group and optionally in a obtained compound of the formula IA or IB transfers the protected carboxy group of the formula -C (= 0) -Râ to free or to another protected carboxy group and / or optionally transferring the protected hydroxy group -O-R? to free hydroxy group and / or transfer a obtained free _ .___..-__ f_- fl '_. ru 10 15 20 25 30 35 H0 78078 '\ U "4 z7__ roxy group or the protected hydroxy group -O-R coxy group -O-R 3 and / or optionally within the definition of the products transfer an obtained compound to another compound and / or optionally transferring a obtained compound with salt formation they group into a salt or a salt obtained to free compound or to another salt and / or optionally divides a obtained a mixture of isomeric compounds in the individual isomers.

In an intermediate of formula II, the group -O-Hg may be present in the trans position (crotonic acid configuration) or in the cis position (isocrotonic acid configuration) to the carboxy group.

In an intermediate of formula II, a leaving group is Y for example a group -S-Ru or one with the sulfur atom at the pen -S- bonded group -SO 2 -R 5.

In an intermediate of formula II, R denotes? preferred lower alkyl, especially methyl, or as a hydroxy protecting group preferably a substituted silyl group, especially a trimethyl- silyl group, as well as an α-phenyl lower alkyl group, such as benzyl or diphenylmethyl.

Bases suitable for the cyclization reaction are special strong organic or inorganic bases. Special mention must be made cyclic amidines, such as diazabicycloalkene, for example 1,5-diazabicyclo {3, u, O} non-5-ene or 1,5-diazabicyclo {5, H, O} undec-5-ene, substi- guanidines, for example with lower alkyl polysubstituted such as tetramethylguanidine, further metal bases such as hydrides, amides or alcoholates of alkali metals, in particular of lithium, sodium or potassium, eg sodium hydride, lithium dilalkylamides, such as lithium diisopropylamide, potassium lower alkoxide, such as potassium butylate. Intermediates of formula II, in which Rå represents halogen, such as chlorine, can also be cyclized with a tertiary organic nitrogen base, for example a tri-lower alkylamine, such as triethylamine, corresponding ester of formula IA and / or IB can be obtained in presence of an alcohol, such as a lower alkanol, eg t-butanol.

The reaction of step 5 is carried out in a suitable inert solvent, for example in an aliphatic, cycloaliphatic or aromatic hydrocarbon such as hexane, cyclohexane, benzene or toluene, a halogenated hydrocarbon such as methylene chloride, an ether such as a dialkylalkyl ether, for example diethyl ether, a dialkylalkoxyalkyl ether, such as dimethyloxyethane, a cyclic ether such as dioxane or tetrahydro furan, or even a lower alkanol, eg methanol, ethanol or t-butanol, or in a mixture thereof, at room temperature or 10 15 20 25 30 55 H0 28 under slight heating to 40-5000, possibly in an atmosphere of inert gas, such as nitrogen.

In the treatment of an intermediate of formula II, wherein Y represents a group -S-Ru, for example 2-benstiazolylthio, with one of given bases, for example with 1,5-diazabicyclo [b] the exchange of compounds of formula IA and IB is increased by the addition of a sulfinic acid of the formula H-SO 2 -R 5, for example p-toluenesulfinic acid.

In the cyclization reaction according to step 5, all starting material and reaction conditions obtain uniform compounds of formula IA or IB or mixtures of compounds ar of formula IA and IB. Obtained mixtures can on and for known method is divided, for example by means of suitable separation methods, for example by adsorption and fractional elution, including chromatography (column, paper or plate chromatography) using suitable adsorbents, such as silica gel or alumina, and eluent, further by fractional crystallization tallization, solvent distribution, etc.

Obtained compounds of formulas IA and IB, which are suitable intermediates for the preparation of pharmacologically active agents end products, can through various per se known contingencies measures are transferred to such active end products.

In a obtained compound of formula IA or IB, a hydrogen Roxy protection group R3 is easily cleaved off and replaced with hydrogen. One 2-oxa or 2-thialiphatic or cycloaliphatic hydrocarbon group can be cleaved off, for example, by acid hydrolysis, a silyl or stannyl group by hydrolysis, alcoholysis or acidolysis, for example by treatment with water or with an alcohol, such as methanol or ethanol, or even with an acid, such as acetic acid. The cleavage of an optionally substituted: X-phenyl lower alkyl group, eg benzyl or diphenylmethyl, for example by acidolysis, for example by treatment with a suitable inorganic or organic acid, such as hydrochloric acid, sulfuric acid, formic acid or especially trifluoroacetic acid, or by hydrogenolysis, for example by treatment with hydrogen in the present of a catalyst such as palladium. Formed 3-hydroxy compound ar mainly in 3-cephem form. The cleavage of a hydroxy protecting group H5 can possibly be selected selectively, ie without a carboxy protecting group R2 being simultaneously cleaved.

Enol ethers, ie compounds of formula IA and / or IB, wherein H5 represents lower alkyl, is obtained from compounds of IA or IB, wherein H3 is a hydroxy protecting group, (IL Mr. 10 15 20 25 SO 35 7807810-2 29 by replacing this group with hydrogen and associated ring of the free hydroxy group according to something for etherification of enol groups suitable procedure. Preferably, one thus uses as etherifying reagent a diazo compound of the formula H3-N2, which corresponds to the optionally substituted hydrocarbon group R3, in take care of an optionally substituted diazole alkane, e.g. tan, diazoethane or diazo-n-butane, or an optionally substituted tuerated α-phenyldiazole lower alkane, eg phenyl or diphenyldiazomethane.

These reagents were used in the presence of a suitable inert solution. agents such as an aliphatic, cycloaliphatic or aromatic carbon hydrogen, such as hexane, cyclohexane, benzene or toluene, a halogenated aliphatic hydrocarbon, eg methylene chloride, a lower alkanol, e.g. methanol, ethanol or t-butanol, or an ether such as a diluent alkyl ether, for example diethyl ether, or a cyclic ether, for example tetrahydric rofuran or dioxane, or a solvent mixture and all after diazo reagents during cooling, at room temperature or below light heating, further if necessary, in a closed vessel and / or under an atmosphere of inert gas, eg nitrogen gas.

Furthermore, enol ethers of the formula IA and / or IB can be formed by treatment with a reactive ester of an alcohol with formula RB-OH, which corresponds to the optionally substituted u-phenyl- the lower alkyl group R3, for example benzyl or diphenylmethyl. Suitable est- are primarily those with strong inorganic or organic acids, such as mineral acids, such as hydrohalic acids, such as hydrochloric acid, hydrobromic acid or hydroiodic acid, further sulfuric acid or halogenated sulfuric acids, such as fluorosulfuric acid, or strong organic sulfonic acids, as optional, for example with halogen, such as fluorine, substituted lower alkanesulfonic acids, or aromatic sulfonic acids, as optionally, for example with lower alkyl, such as methyl, halogen, such as bromine, and / or nitro substituted benzenesulfonic acids, e.g. sulfonic acid, trifluoromethanesulfonic acid or p-toluenesulfonic acid.

These reagents, especially lower alkyl sulfate, such as dimethyl sulfate, further lower alkyl fluorosulphate, for example methyl fluorosulphate, or optionally halogen-substituted methanesulfonic acid alkyl esters, e.g. trifluoromethanesulfonic acid methyl ester, is commonly used in the presence of a solvent, such as an optionally halogenated, such as chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbon, for example methylene chloride, an ether such as dioxane or tetrahydrofuran, or a lower alkanol, such as methanol, or a mixture thereof. 10 15 20 25 STAY 35 H0 7807810-2 30 In this case, suitable condensing agents are preferably used, such as alkali metal carbonate or bicarbonate, e.g. or potassium carbonate or bicarbonate (usually together with a sulfate), or organic bases, such as usually steric hindered tri-lower alkylamines, for example N, N-diisopropyl-N-ethylamine (preferably together with lower alkyl halide sulphate or even halogen-substituted methanesulfonic acid lower alkyl esters), when working under cooling, at room temperature or below heating, eg at temperatures of about -20 ° C to approx 5000, and if necessary, in a closed vessel and / or in a atmosphere of inert gas, eg nitrogen gas.

Enol ethers can also be prepared by treatment with at the same carbon atom of aliphatic character two or three companies hydroxy groups of the formula R3-O- containing compound, i.e. with a corresponding acetal or orthoester, in the presence of an acid average. Thus, for example, it can be used as a desiccant lower alkoxy lower alkanes, such as 2,2-dimethoxypropane, in the presence of a strong organic sulfonic acid, such as p-toluenesulfonic acid, and a suitable solvent, such as a lower alkanol, eg methanol, or a lower alkyl or lower alkylene sulfoxide, for example dimethyl sulfoxide, or orthoformic acid tria lower alkyl ester, for example orthoformic acid triethyl ester, in the presence of a strong mineral acid, such as sulfuric acid, or a strong organic sulfonic acid, such as p-toluenesulfonic acid, and a suitable solvent, such as lower alkanol, eg ethanol, or a ether, eg dioxane, and thus obtain compounds of the formula IA and / or IB, wherein R3 represents lower alkyl, eg methyl resp 'ethyl.

Enol ethers of formula IA and / or IB can also be obtained if starting materials of the formula II are treated with tri- H5-oxonium salts of the formula (R5) 30kÃ1lA'C (so-called Meermein salts), also di-B30-carbenium salts of the formula (QUESTION) 2CH 2: 3 or di-R3 halonium salts of the formula (R) 2Hal§¿'A ';, wherein A denotes the anion of an acid and Halíf \ denotes a halonium ion, especially bromonium ion. This is primarily about tri-lower alkyloxonium salts and lower lower alkoxycarbenium or lower alkylhalonium salts, in particular corresponding salts with complex, fluorine-containing acids, such as the corresponding tetrafluoroborate, hexafluoro- rophosphate, hexafluoroantimonate or hexachloroantimonate. Such reagents are, for example, trimethyloxonium or triethyloxonium hexa- fluoroantimonate, hexachloroantimonate, hexafluorophosphate or 'll 10 15 20 25 30 55 H0 7807810-2 '31 tetrafluoroborate, dimethoxycarbonium hexafluorophosphate or dimethyl- bromonium hexafluoroantimonate. These desiccants are used preferably in an inert solvent, such as an ether or a halogenated hydrocarbon, for example diethyl ether, tetrahydrofuran or methyl chlorine chloride, or in a mixture thereof, if necessary in the being a base, such as an organic base, e.g. dangerously hindered tri-lower alkylamine, such as N, N-diisopropyl-N-ethylamine, and during cooling, at room temperature or under slight heating at about -20 ° C to about 50 ° C, if necessary in a closed vessel and / or in an atmosphere of inert gas, e.g. gas.

Enol ethers of formula IA and / or IB can also be prepared by treating starting materials of formula II with a 3-substituted 1-RB-triazene compound (ie a compound of the formula subst-N = N-NH-H5), the substituent at the 3-nitrogen atom being one over a carbon atom bonded organic group, preferably a carbocyclic aryl group, such as an optionally substituted phenyl group, e.g. lower alkylphenyl, such as H-methylphenyl. Such triazene compounds are 5-aryl-1-lower alkyltriazenes, for example 3- (4-methylphenyl) -1-methyltriazen, 3- (U-methylphenyl) -1-ethyltriazene, 3- (U-methylphenyl) -1-n-propyltrizen azen or 3- (N-methylphenyl) -1-isopropyltriazene, further 5-aryl-1- (d-phenyl lower alkyl) -triazenes, eg 1-benzyl-3- (H-methylphenyl) -tri- azen. These reagents are usually used in the presence of inert solutions. agents, such as optionally halogenated hydrocarbons or ethers, eg benzene, or solvent mixtures, and during cooling, at room temperature and preferably at elevated temperature, e.g. at about 20 ° C to about 100 ° C, if necessary: in a closed vessels and / or in an atmosphere of inert gas, eg nitrogen gas.

In the present proceeding and its contingency measures, if necessary, in the reaction non-participating, free functioning groups in the starting material or in those according to the invention obtainable compounds in a manner known per se transient protected amino acids, for example by acylation, tritylation or silylation, free hydroxy or mercapto groups for example by etherification or esterification and free carboxy groups. per for example by esterification, including silylation, and always according to the reaction taken in a manner known per se, if desired. worth, released alone or jointly. Thus, one can prefer protect, for example, amino-, hydroxy-, carboxy- or phospho- groups in an acyl group R for example in the form of acylamines 10 15 20 25 30 35 RO 7807810-2 32 such as those indicated, for example, 2,2,2-nicloroethoxycarbonylamino, 2-bromo- ethoxycarbonylamino, U-methoxybenzyloxycarbonylamino, diphenylmethoxy- carbonylamino or t-butyloxycarbonylamino, in the form of aryl or aryl lower alkylthioamino, for example 2-nitrophenylthioamino, or arylsulfonyl nylamino, for example 4-methylphenylsulfonylamino, or 1-lower alkoxycarbonyl nyl-2-propylideneamino and acyloxy, respectively, such as those indicated, e.g. tyloxycarbonyloxy, 2,2,2-trichloroethoxycarbonyloxy or 2-bromo- ethoxycarbonyloxy, or in the form of esterified carboxy, as given, for example diphenylmethoxycarbonyl groups, or 0,0'-disubstitution phosphono, such as those indicated, for example 0,0'-dialkylphosphono, such as 0,0'-dimethylphosphono, and afterwards, optionally after conversion of the protecting group, for example a 2-bromoethoxycarbonyl group to a 2-iodine ethoxycarbonyl group, for example partially known per se depending on the nature of the protection group, such as a 2,2,2-tri- chloroethoxycarbonylamino or 2-iodoethoxycarbonylamino group by treatment with suitable reducing agents, such as zinc in the presence of aqueous acetic acid, a diphenylmethoxycarbonylamino- or t-butyloxycarbonylamino group by treatment with formic acid or trifluoroacetic acid, an aryl or aryl lower alkylthioamino group through treatment with a nucleophilic reagent, such as sulfuric acid, an arylsulfonylamino group by electrolytic reduction, a 1-lower alkoxycarbonyl-2-propylideneamino group by treatment with aqueous mineral acid or a t-butyloxycarbonyloxy group through treatment with formic acid or trifluoroacetic acid or a 2,2,2- trichloroethoxycarbonyloxy group by treatment with a chemical reducing agents, such as zinc in the presence of aqueous acetic acid, or a diphenylmethoxycarbonyl group by treatment with formic acid or trifluoroacetic acid or by hydrogenolysis or a 0,0'-di- substituted phosphono group by treatment with an alkali metal halid.

In a compound obtainable according to the invention with a protected, especially esterified, carboxy group of the formula -C (= O) -R in a manner known per se, for example after the group's R 'type, breed to free carboxy group. An esterified, for example with a lower alkyl K group, especially methyl or ethyl, or with a benzyl group estrad, carboxy group, especially in a 2-cephem compound of the formula IB, can be converted to a free carboxy group by hydrolysis in weak alkaline medium, for example by treatment with an aqueous solution an alkali metal or alkaline earth metal hydroxide or carbonate, for example sodium or potassium hydroxide, preferably at m m 10 15 20 30 55 HO 7807810-2 33 a pH of about 9-10, and optionally in the presence of a lower alkanol.

One with a suitable 2-halo lower alkyl or an arylcarbonylmethyl- group esterified carboxy group can be cleaved, for example, by action with a chemical reducing agent, such as a metal, e.g. zinc, or a reducing metal salt, such as a chromium (II) salt, for example chromium (II) chloride, usually in the presence of a hydrogen releasing part, which together with the metal has the ability to form nascent hydrogen, such as an acid, primarily acetic acid and formic acid, or an alcohol, preferably adding water, a carboxy group esterified with an arylcarbonylmethyl group is also present by treatment with a nucleophilic, preferably salt-forming, reagents such as sodium thiophenolate or sodium iodide, one by one suitable arylmethyl grouping esterified carboxy group for example by irradiation, preferably with ultraviolet light, e.g. der 29O nm, if the arylmethyl group, for example, constitutes an optional i 3-, H- and / or 5-position, eg with lower alkoxy and / or nitrous oxide ro groups, substituted benzyl group, or with more long-wave ultraviolet light, for example above 290 nm, if the arylmethyl group vis denotes one in the 2-position with a nitro group substituted benzyl group, one with an appropriately substituted methyl group, such as t-butyl or diphenylmethyl, esterified carboxy group for example by treatment with a suitable acidic agent, such as formic acid or trifluoroacetic acid, optionally with the addition of a nucleophilic purification, such as phenol or anisole, an activated, esterified carboxy group, further an anhydride form carboxy group through hydrolysis, for example by treatment with an acidic or weakly basic, aqueous agent such as hydrochloric acid or aqueous sodium bicarbonate or an aqueous potassium phosphate buffer with pH about 7-about 9, and a hydrogenolytic cleavable, esterified box group by hydrogenolysis, for example by treatment with hydrogen in presence of a noble metal catalyst, eg palladium catalyst.

One, for example, protected by silylation or stannylation carboxy group can be released in the usual way, for example by treatment with water or an alcohol.

Obtained compounds of formula IA or IB can be in and is known per se to be transferred to other compounds of formula IA or IB.

In a compound obtained, for example, an amino protecting group may RA or Hg, especially an easily cleavable acyl group, on i and l known method is cleaved off, for example a u-polygranically lower alkoxy 10 15 20 50 55 HO 7807810-2 34 J bonyl group, such as t-butyloxycarbonyl, by treatment with tri- fluoroacetic acid and a 2-halo lower alkoxycarbonyl group, such as ~ 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl, or a phenacyloxycarbonyl group by treatment with an appropriate reduction metal or equivalent metal compound, such as zinc or a chromium (II) compound, such as the chloride or acetate, suitably in presence of an agent which, together with the metal or metal the compound forms nascent hydrogen, preferably in the presence of aqueous acetic acid.

Furthermore, in a obtained compound of formula IA or IB, wherein a carboxy group of the formula -C (= O) -H 2 is preferably do one, eg by esterification, including by silylation, e.g. by reaction with a suitable organic halogenated silicon or halo- gene (IV) compound, such as trimethylchlorosilane or tri-n-butyl- tin chloride, protected carboxy group, an acyl group R 1 or R 2, wherein any existing, free, functional groups may be protected, cleaved by treatment with an imide halide formation agent, reaction of the imide halide formed with an alcohol and cleavage of the formed iminoether, a protected one, e.g. with an organic silyl group protected, the carboxy group can already be released. during the course of the reaction.

Imide halide-forming agents in which halogen is attached to a electrophilic central atom, are mainly acid halides, such as bromides and especially acid chlorides. In the first place may be mentioned acid halides of inorganic acids, in particular phosphorus-containing acids such as phosphorus oxy-, phosphorus tri- and especially phosphorus pentahali such as phosphorus oxychloride, phosphorus trichloride and in the first place phosphorus pentachloride, further pyrocatecyl phosphorus trichloride and acid suffering, in particular chlorides, from sulfur-containing acids or from boxyl acids, such as thionyl chloride, phosgene or oxalyl chloride.

The reaction with one of the indicated imide halide-forming agents is usually carried out in the presence of a suitable, especially organic, base, primarily a tertiary amine, for example a tertiary aliphatic mo- no- or diamine, such as a tri-lower alkylamine, e.g. trimethyl-, tri- ethyl or N, N-diisopropyl-N-ethylamine, furthermore an N, N, N ', N'-tetra- lower alkyl lower alkylenediamine, for example N, N, N ', N'-tetramethyl-1,5-pentyl lendiamine or N, N, N ', N'-tetramethyl-1,6-hexylenediamine, a mono- or bicyclic mono- or diamine, such as an N-substituted, e.g. N-lower alkylated, alkylene, azaalkylene or oxaalkyleneamine, e.g. N-methylpiperidine or N-methylmorpholine, further 2,3,4,6,7,8-hexases (ju 10 15 20 25 30 U0 7807810-2 35 hydropyrrolo {1,2-a} pyrimidine (diazabicyclonone; DBN), or a tertiary aromatic amine, such as a dialkylalkylaniline, e.g. N, N-di- methylaniline, or primarily a tertiary heterocyclic mono- or bicyclic base, such as quinoline or isoquinoline, especially pyridine, preferably in the presence of a solvent such as a optionally halogenated, eg chlorinated, aliphatic or aromatic hydrocarbon, such as methylene chloride. In this case, you can use approx. equimolar amounts of the imide halide-forming agent and base; however, the latter may also be present in excess or shots, for example in an amount of about 0.2 to about 1 times the amount of base or further in an approximately 10-fold, especially an approximately 3-fold 5-fold excess.

The reaction with the imide halide-forming agent is carried out before preferably under cooling, for example at temperatures of about -50 ° C to about + 10 ° C, but you can also work at higher temperatures temperatures, ie up to about 7500, if the starting material the stability of materials and products allows for an increased temperature lucky.

The imidhalide product, without which it is usually further processed insulation, is reacted according to the invention with an alcohol, preferably in the presence of one of the indicated bases, to iminoethers. Suitable alcohols are, for example, aliphatic and araliphatic alcohols. primarily optionally substituted, such as halogenated, for example chlorinated, or additionally hydroxy groups exhibiting, nols, eg ethanol, propanol or butanol, especially methanol, further 2-halogen lower alkanols, for example 2,2,2-trichloroethanol or 2-bromethanol, and optionally substituted phenyl lower alkanols, such as benzyl alcohol. Usually you use one for example up to about 100-fold excess of alcohol and work for during cooling, for example at temperatures of about -50 ° C to about 10%.

The iminoether product may conveniently be subjected to cleavage without insulation. The cleavage of the iminoether can be achieved by treatment with a suitable hydroxy compound, preferably by rolys, further by alcoholysis, the latter being able to take place di- immediately after iminoether formation using an excess of the alcohol. In this case, water or an alkali is preferably used. alcohol, especially a lower alkanol, eg methanol, or an aqueous mixture of an organic solvent, such as an alcohol.

One usually works in an acidic medium, for example at a pH of approx 10 15 20 25 30 55 H0 7807810-2 36 l-about 5, which can be set, if necessary, by adding batch of a basic agent, such as an aqueous alkali metal hydride oxide, for example sodium or potassium hydroxide, or an acid, for example a mineral acid, or organic acid such as hydrochloric acid, sulfuric acid, acid, hydrogen fluoroborate, trifluoroacetic acid or p-toluenesulfonic acid. acid. _ The described three-step procedure for cleavage of a acyl group is conveniently carried out without isolation of imide halide and iminoether intermediates, usually in the presence of an organic solvent which is inert to the reactant. such as an optionally halogenated hydrocarbon, e.g. chloride, and / or in an atmosphere of inert gas, such as nitrogen.

If you sell it according to the specified procedure obtainable the imide halide intermediate with a salt such as an alkali metal salt of a carboxylic acid, especially a sterically hindered carboxylic acid, instead of with an alcohol, one obtains a compound with meln IA or IB, wherein both groups R? and R? are acyl groups.

In a compound of formula IA or IB, wherein both groups R? and R 1 are acyl groups, one of these groups may, preferably the sterically less hindered, is selectively removed, e.g. rolys geller aminolys.

In a compound of formula IA or IB, wherein the R together with the nitrogen atom constitutes a phthalimido group, this example by hydrazinolysis, ie by treating such a compound hydrazine, is converted to the free amino group.

Certain acyl groups Râ in an acylamino grouping in accordance with compounds obtainable from the invention, such as a 5-amino-5-carboxy- leryl group, in which carboxy is optionally protected, for example by esterification, especially with diphenylmethyl, and / or the amino group exem- pelvis by acylation, especially with an acyl residue of an organic carboxylic acid, such as halo-lower alkanoyl, such as dichloroacetyl, or phthaloyl, can also be cleaved by treatment with a nitroseran the agents, such as nitrosyl chloride, with a carbocyclic arendiazole nium salt, such as benzenediazonium chloride, or with a positive halogen releasing agent, such as an N-halamide or imide, e.g. N-bromosuccinimide, preferably in a suitable solvent or solvent mixture, such as formic acid, together with a nitro- or cyano-lower alkane and addition to the reaction product of a hydroxyl-containing agent, such as water or a lower alkanol, for example methanol, or, if in the 5-amino-5-carboxivaleryl group R (IN) w 10 15 20 25 30i 35 H0 7807810-2 57 the amino group is substituted and the carboxy group protected exemplary by esterification, and R 1 is preferably an acyl group, but may also denote hydrogen, by standing in an inert solvent, such as dioxane or a halogenated aliphatic hydrocarbon, e.g. tylene chloride, and if necessary, reprocessing of the free or the monoacylated amino compound as is known per se methods.

A formyl group Raw can also be cleaved by treatment with an acidic agent, for example p-toluenesulfonic acid or hydrochloric acid, a weakly basic agent, such as dilute ammonia, or a decoction bonylating agents, eg tris- (triphenylphosphine) rhodium chloride.

A triarylmethyl group, such as trityl, R 2a can be cleaved for example by treatment with an acidic agent, such as a mineral acid, eg hydrochloric acid.

In a compound of formula IA or IB, wherein R 1 and R 2 are hydrogen, one can substitute the free amino group according to i and for known methods, primarily acylate by treatment with acids, such as carboxylic acid, or reactive derivatives thereof.

If a free acid, preferably with protected, possibly existing functional groups, such as a possible amino group, used for acylation, is commonly used suitable condensing agents, such as carbodiimides, eg N, §'-di- ethyl, N, N'-dipropyl-, N, N'-diisopropyl-, N, N'-dicyclohexyl- or N-ethyl-N'-5-dimethylaminopropylcarbodiimide, suitable carbon nyl compounds, for example carbonyldiimidazole, or isoxazolinium salts, eg N-ethyl-5-phenyl-isoxazolinium-3'-sulfonate and N-t-butyl-5- methyl isoxazolinium perchlorate, or a suitable acylamino compound, for example 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline.

The condensation reaction is preferably carried out in one of the following anhydrous reagents, for example in methylene chloride, dimethylformamide or acetonitrile.

An amide-forming functional derivative of an acid, preferably with protected, possibly existing groups, such as a any amino group present, is primarily an anhydril of such an acid, including and preferably a mixed anhydrous rid. Mixed anhydrides are, for example, those with inorganic acids, especially with hydrohalic acids, ie the corresponding acid hali ~ there, for example chlorides or bromides, further with hydrochloric acid, i.e., corresponding acid azides, with a phosphorus-containing acid, e.g. or phosphoric acid, with a sulfur-containing acid, e.g. 10 15 20 25 30 35 U0 7807810-2 38 acid, or with hydrocyanic acid. Other mixed anhydrides are examples such as those with organic acids, such as organic carboxylic acids, as an optionally, for example with halogen, such as fluorine or chlorine, substitute lower alkanecarboxylic acids, for example pivalic acid or tri- chloroacetic acid, or with half esters, especially lower alkyl half-esters of carbonic acid, such as ethyl or isobutyl halves of carbonic acid, or with organic, in particular aliphatic or aromatic, sul- phonic acids, eg p-toluenesulfonic acid.

Furthermore, internal anhydride can be used as the acylating agent. such as ketenes, for example diketene, isocyanate (ie internal anhydride carbamic acid compounds) or internal anhydrides of carboxyl ~ acid compounds with carboxy-substituted hydroxy or amino group such as mandelic acid O-carboxane anhydride or the anhydride of 1 ~ N- carboxyamino-cyclohexanecarboxylic acid. å Other acid suitable for reaction with the free amino group derivatives are activated esters, usually with protected, optionally functional groups present, such as esters with vinylogens alcohols (ie enols), such as vinylogenic lower alkanols, or aryl esters, such as preferably, for example with nitro or halogen, such as chlorine, substituted phenyl esters, e.g. pentachlorophenyl-, 4-nitrophenyl or 2,4-dinitrophenyl esters, heteroaromatic esters such as bone striazole esters, or diacylimino esters, such as succinylimino or phthalylimino esters.

Other acylation derivatives are, for example, substituted forms imino derivatives, such as substituted N, N-dimethylchloroformimino derivatives of acids, or N-substituted N, N-diacylamines, such as an N, N-diacylamine acylated aniline.

The acylation with an acid derivative, such as an anhydride and especially with an acid halide, can be carried out in the presence of an acid binding agents, for example an organic base such as an organic amine, eg a tertiary amine, such as trilowalkylamine, eg triethylamine, N, N-lower alkylaniline, eg N, N-dimethylaniline, or a base of pyridine type, e.g. pyridine, an inorganic base, e.g. an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate, for example sodium, potassium or calcium hydroxide, carbonate or bicarbonate, or an oxirane, for example a lower 1,2-alkylene oxide, such as as ethylene oxide or propylene oxide.

Specified acylation can be performed in an aqueous or preferably non-aqueous solvent or solvent sub-mixture, for example in a carboxylic acid amide, such as N, N-lower alkyl-γ n » 10 15 20 25 50 7807810-2 39 amide, eg dimethylformamide, a halogenated hydrocarbon, eg methylene chloride, carbon tetrachloride or chlorobenzene, a ketone, for example an acetone, an ester, eg acetic acid ethyl ester, or a nitrile, eg acetonite or mixtures thereof, and if necessary in the case of reduced elevated temperature and / or in an atmosphere of inert gas, e.g. nitrogen.

In the indicated N-acylation reaction one can start from the compound ar of formula IA or IB, wherein H3 represents lower alkyl or a optionally substituted α-phenyl lower alkyl group, eg benzyl or diphenylmethyl, and R 2 has the stated meaning, wherein compounds with free carboxyl groups of the formula -C (= O) -R 2, wherein H 2 represents hydrogen roxi, can also be used in the form of salts, for example ammonium salts, such as as with triethylamine, or in the form of a compound having a genome reaction with a suitable organic phosphorus halide compound, such as a lower alkyl or lower alkoxyphosphoric dihalide, eg methylphosphoric dichloride, ethyl phosphorus dibromide or methoxyphosphorus dichloride, protected carboxy group; in the acylation product obtained, the protected the boxing group is released in a manner known per se, e.g. written, including by hydrolysis or alcoholysis.

An acyl group can also be introduced by acylating a compound of formula IA or IB, wherein R? and Râ together stands for a ylidene group (which can also be introduced afterwards, e.g. by treating a compound wherein R and Hg is hydrogen, with an aldehyde, such as an aliphatic, aromatic or araliphatic aldehyde hyd), for example according to the specified methods, and that hydrolyze the acylation product, preferably in neutral or slightly acidic medium.

In this case, an acyl group can also be introduced step by step. Thus For example, in a compound of formula IA or IB with one free amino group introduce a haloalkanoyl group, eg bromoacetyl, or for example by treatment with a carbonic acid dihalide, such as phosgene, a halocarbonyl group, eg chlorocarbonyl, and react an N-halo-lower alkanoyl- and N-halogen-carbon- bonylamino compound with suitable exchange reagents, such as basic compounds, eg tetrazole, thio compounds, eg 2-mercapto-1-methyl- thylimidazole, or metal salts, eg sodium azide, or alcohol such as lower alkanols, for example t-butanol, and thus obtain substituted N-lower alkanoyl and N-hydroxycarbonylamino compounds nings. 10 15 20 25 30 35 HO 7807810-2 40 In both reactants, free functional groups can be per transient in a manner known per se be protected under acy- the reaction and after the acylation is released by i and for known methods, for example as described.

The acylation can also take place by replacing an already existing one acyl group to another, preferably sterically hindered acyl group, for example according to the described process, by preparing the imide halide compound, treat it with a salt of an acid and hydrolytically cleaves one of the products thus obtained. existing acyl groups, usually the sterically less hindered the acyl groups.

Furthermore, one can, for example, react a compound of the formula IA or IB, wherein R? denotes a, preferably in the a-position, substituted, glycyl group such as phenylglycyl, and R 5 is hydrogen, with an aldehyde, for example formaldehyde, or a ketone, such as nol, eg acetone, and thus obtain compounds of formula IA or IB, wherein Eâ and R? together with the nitrogen atom forms a, in the Ä position preferably substituted, in the 2 position optionally substituted, 5-oxo-1,3-diaza-cyclopentyl group.

In a compound of formula IA or IB, wherein R is hydrogen, the free amino group can also be protected by the introduction of a triarylmethyl group, for example by treatment with a reaction agent. gene ester of a triarylmethanol, such as trityl chloride, preferably in the presence of a basic agent, such as pyridine.

An amino group can also be protected by the introduction of a silyl and stannyl group. Such groups are introduced on per se known by treatment with a suitable silylating agent, e.g. as with a dihalo-low-alkylsilane, lower-alkoxy-alkyl-dihalo- silane or tri-lower alkylsilyl halide, for example dichlorodimethylsilane, methoxy- methyldichlorosilane, trimethylsilyl chloride or dimethyl-t-butylsilyl chloride chloride, using such silyl halide compounds preferably in the presence of a base, eg pyridine, with an optionally N-mono-low alkylated, N, N-lower low-alkylated, N-tri-lower alkyl-silylated or N-lower alkyl-N-tri-lower alkylsilylated N- (tri-lower alkylsilyl) -amine (see, for example, British Patent Specification 1,075,530) or with a silylated carboxylic acid amide, such as a bistro-lower alkylsilylacetamide, for example bis-trimethylsilylacetamide, or trifluorosilylacetamide, with a suitable stannylating agent, such as a bis- (tri-lower alkyl tin) oxide, for example bis- (tri-n-butyltin) oxide, a tri-lower alkyltin- hydroxide, for example triethyltin hydroxide, a tri-low alkyl low alkoxy tin, W W 10 l5 20 25 30 55 ÄO 7807810-2 4T tetra low alkoxy tin or tetra low alkyl tin compound, also a tri-lower alkyltin halide, eg tri-n-butyltin chloride (see for example Dutch Official Gazette 67/11107).

In a compound of formula IA obtained according to the invention or IB, which contains an fi in carboxy group of the formula -C (= O) -Ra, such a device known per se can be transferred to a protected one Thus esters are obtained, for example, by such as a diazole lower alkane, carboxy group. document with an appropriate diazo compound, for example diazomethane, or diazobutane, or a phenyldiazole lower alkane, for example diphenyldiazomethane, if necessary in the presence of a Lewis acid, such as boron trifluoride, or even reaction with a ring suitable alcohol in the presence of an esterifying agent, such as a carbodiimide, for example dicyclohexylcarbodiimide, as well as carbonyldiimide dazole, further with an N, N'-disubstituted O- and S-substituted isocarbamide or isothiourea, wherein an O and S substituent for example lower alkyl, especially t-butyl, phenyl lower alkyl or cycloalkyl and N- and N'-substituents, for example, are lower alkyl, especially isopropyl, cycloalkyl or phenyl, or according to some other known and suitable esterification process, such as reaction of a salt of the acid with a reactive ester of an alcohol and a strong inorganic acid, as well as a strong organic sulfonic acid.

Furthermore, acid halides, such as chlorides (prepared for example by treatment with oxalyl chloride), activated esters (formed for example with N-hydroxy nitrogen compound, such as N-hydroxysuccinimide) or mixed anhydrides (obtained, for example, with haloformic acid) lower alkyl esters such as chloroformic acid ethyl or chloroformic acid isobutyl ester, or with haloacetic acid halides, such as trichloroacetic acid chloride) by reaction with alcohols, optionally in the presence of a base, such as pyridine, is converted to the esterified carboxy group.

In an obtained compound with an esterified grouping with formula -C (= O) -H 2, this can be transferred to another esterified carboxy group of this formula, for example 2-chloroethoxycarbonyl or 2-bromoethoxycarbonyl to 2-iodoethoxycarbonyl by treatment with an iodine salt, such as sodium iodide, in the presence of a suitable solvent agents such as acetone, Mixed anhydrides can be prepared by reacting a compound of formula IA or IB with a free carboxy group of the formula -C (= O) -R 2, preferably a salt, especially an alkali metal salt, for example the sodium salt, or the ammonium salt, for example the triethylammonium salt thereof, with a reaction-prone derivative 10 15 20 25 30 35 HO 7807810-2 42 such as a halide, e.g. the chloride, of an acid, e.g. a halogenated formic acid lower alkyl ester or a lower alkanecarboxylic acid chloride.

In a compound obtained according to the invention with a free boxing group of the formula -C (= O) -H2, such can also be transferred to optionally substituted carbamoyl or hydrazinocarbonyl group, wherein one is preferably reactive prone to reaction, functional converted derivatives, such as indicated acid halides, general esters, such as also indicated activated esters, or mixed anhydrides of the corresponding acid with ammonia or amines, including hydroxyl amine, or hydrazines.

A vessel protected with an organic silyl or stannyl group boxing group can be formed in a manner known per se, for example by treating compounds of formula IA or IB, wherein H2 is roxi, or salts such as alkali metal salts, eg sodium salts thereof, with a suitable silylating or stannylating agent, as one of the indicated silylating or stannylating agents; see for example, British Patent Specification 1,073,530 and Dutch patent the publication 67/17107.

Furthermore, according to methods known per se, e.g. the described, release converted functional substituents in the groups R 1, R 2 and / or R 2, as substituted amino groups, acylated hydroxy groups, esterified carboxy groups or 0,0'-di- substituted phosphono groups or functionally convert free functional substituents in the groups Râ, R? and / or R 2, such as free amino, hydroxy, carboxy or phosphono groups, according to i and methods known per se, for example aoylera resp esterify resp substitute them. Thus, for example, an amino group can be converted to sulfoamino group by treatment with sulfur trioxide, preferably in the form of a complex with an organic base, such as a tri- lower alkylamine, eg triethylamine. Furthermore, the reaction the mixture obtained by reacting an acid addition salt of an H-guanylsemicarbazide with sodium nitrite, with a compound containing formula IA or IB, wherein for example the amino protecting group R an optionally substituted glycyl group, and thus transfer the amino group to a 3-guanylureido group. Furthermore, you can sell compounds with aliphatically bonded halogen, for example with an optional substituted α-bromoacetyl grouping, with esters of phosphoric acid such as tri-lower alkyl phosphite compounds, and thus obtain corresponding phosphono compounds.

Obtained cephem compounds of formula IA and IB can be obtained by HL 'hrs 10 15 20 25 35 40 7807810-2 43 oxidation with suitable oxidizing agents, such as those which will described, are transferred to 1-oxides of the corresponding 3-cephem compound ar of formula IA. Obtained 1-oxides of 3-cephem compounds with formula IA can be reduced by reduction with suitable reducing agents, e.g. those which will be described are reduced to the corresponding 5 ~ cefem- compounds of formula IA. In these reactions, one must consider, that if necessary, free functional groups are protected and, if desired, subsequently re-released.

Obtained cephem compounds can be isomerized. to give the resulting 2-cephem compounds of formula IB or mixture of 2- and 3-cephem compounds to the corresponding 3-cephem compounds of formula IA, by isomerizing one 2-cephem compound of formula IB or a mixture consisting of a 2- and 3-cephem compound, wherein free functional groups may be temporarily protected, for example as specified. Where- for example, 2-cephem compounds of the formula IB can be used, wherein the group of the formula -C (= O) ~ R 2 is a free or protected carboxy group, wherein a protected carboxy group can also be formed Thus can there reaction. _ Thus, a 2-cephem compound of the formula can be isomerized IB, by treating it with a basic agent and from one any equilibrium mixture of 2- and 3-cephem compounds obtained isolates the corresponding 3-oefem compound of formula IA.

Suitable isomerizing agents are, for example, organic nitrogen. venaltic bases, such as tert heter & a.heterocyclic bases with aromatic character, and in particular tertiary aliphatic, azacycloalipa- tical or araliphatic bases, such as N, N, N-tri-lower alkylamines, eg N, N, N-trimethylamine, N, N-dimethyl-N-ethylamine, N, N, N-triethylamine amine or N, N-diisopropyl-N-ethylamine, N-lower alkyl azacycloalkanes, for example N-methyl-piperidine, or N-phenyl-lower alkyl-N, N-lower alkyl-amino n-benzyl-N, N-dimethylamine, as well as mixtures thereof, such as as the mixture of a pyridine-type base, for example pyridine, and a N, N, N-trilagalkylamine, eg pyridine and triethylamine. Furthermore, can also inorganic or organic salts of bases, in particular of strong to strong bases with weak acids, such as alkali metal or ammonium salts of lower alkanecarboxylic acids, for example sodium acetate, triethylammonium acetate or N-methylpiperidine acetate, and others analogous bases or mixtures of such basic agents are used.

The stated isomerization with basic agents can, for example, carried out in the presence of a derivative of a carboxylic acid, which is suitable 10 l5 20 25 55 H0 7807810-2 44 to form a mixed anhydride, such as a carboxylic acid anhydride or halide, for example with pyridine in the presence of acetic acid hydride. In this case, one preferably works in anhydrous medium, in the presence or absence of a solvent, such as an eventual halogenated, eg chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbon, or a solvent mixture, when used as reactants, under the reaction conditions liquid bases can at the same time also serve as solvents, if this is necessary, during cooling or heating, preferably in a temperature range of about -3000 to about 10000, in a atmosphere of inert gas, eg nitrogen gas, and / or in a closed vessel.

The 5-cephem compounds of formula IA thus obtained can in a manner known per se be separated from any yet 2-cephem compounds of formula IB, for example by adsorption and / or crystallization.

The isomerization of 2-cephem compounds of formula IB can also carried out by oxidizing them in the 1-position if desired, distinguishes an resulting isomer mixture from 1-oxides from 3-cephem compounds of formula IA and reduce them the 1-oxides of the corresponding 5-cephem compounds thus obtained with the formula IA.

As suitable oxidizing agents for the oxidation in the 1-position The formation of 2-cephem compounds involves inorganic peracids, which exhibits a reduction potential of at least +1.5 volts and consists of non-metallic elements, organic peracids or mixtures of hydrogen peroxide and acids, in particular organic carboxylic acids, with a dissociation constant of at least 10_5. Suitable inorganic per- acids are periodic and persulfuric acid. Organic peracids are corresponding percarboxylic acid and persulfonic acids, which are added as such or can be formed in situ using at least one equivalent of hydrogen peroxide and a carboxylic acid. In doing so, it is it is possible to use a small excess of the carboxylic acid, if acetic acid was used as the solvent. Suitable peracids are for example permyric acid, peracetic acid, pertrifluoroacetic acid, peracetic acid maleic acid, perbenzoic acid, monoperphthalic acid or p-toluene persul- fonic acid.

The oxidation can also be carried out using hydrogen peroxide with catalytic amounts of an acid with a dissociation constant of at least 10_5, whereby lower concentrations can be used concentrations, eg 1-2% and smaller, but also larger amounts of (II 10 15 20 30 35 H0 7807810-2 45 syran. In this case, the effect of the mixture depends primarily on the acidity strength. Suitable mixtures are, for example, those of hydrogen peroxide and acetic acid, perchloric acid or trifluoroacetic acid.

The stated oxidation can be carried out in the presence of suitable talysators. Thus, for example, the oxidation with percarboxylic acid acids are catalyzed by the presence of an acid with a dissociation constant of at least 10-5, its effect depending on its strength.

Suitable catalysts as catalysts are, for example, acetic acid, chloric acid and trifluoroacetic acid. Usually at least oak vimolar amounts of the oxidizing agent, preferably a small amount surplus of about 10% to about 20%. The oxidation is carried out under mild conditions, eg at temperatures of about -5000 to about + 10 ° C, preferably about -1 ° C to about + 10 ° C.

The oxidation of 2-cephem compounds to 1-oxides of the corresponding 3-cephem compounds can also be implemented by treatment with ozone, further with organic hypohalite compounds, such as low cooling hypochlorite, for example t-butyl hypochlorite, which is used in the present inert solvents, such as optionally halogenated hydrocarbons for example, methylene chloride, and at temperatures of about -10 ° C to about + 50 ° C, with periodate compounds, such as alkali metal per iodate, eg potassium periodate, which is preferably used in one aqueous medium at a pH of about 6 and at temperatures of about -10 ° C to about +} 0 ° C, with iodobenzene dichloride, as one use in an aqueous medium, preferably in the presence of an organic base, for example pyridine, and during cooling, for example at temperatures of about -20 ° C to about 0 ° C, or with something else oxidizing agent, which is suitable for the conversion of a call a sulfoxide array.

In the 1-oxides of 3-cephem compounds thus obtained of formula IA, especially in such compounds in which Bi, R? and R has the meanings given as appropriate, the groups n1, R1 and / or R2 are transferred to each other within the defined but, split off or introduced. ß-1-oxides can be divided, eg chromatographically.

The reduction of 1-oxides of 3-cephem compounds of the formula IA can be implemented in a manner known per se through treatment with a reducing agent, if necessary in the presence of one activating agents. As a reducing agent in question: catalytic activated hydrogen, using noble metal catalysts, containing palladium, platinum or rhodium and which may be A mixture of isomeric α- and 10 15 20 25 35 HO 7807810-2 46 use together with a suitable carrier material, such as carbon or barium sulphate; reducing tin, iron, copper or manganese cations, which were used in the form of corresponding compounds or complexes of inorganic or organic kind, for example as igniters GI) chloride, fluoride, acetate or formate, ferric chloride, sulphate, oxalate or succinate, copper (I) chloride, benzoate or oxide, or manganese (II) chloride, sulphate, acetate or oxide, or such as complexes, for example with ethylenediaminetetraacetic acid or nitrilotriacetic acid; reducing dithionite, iodine or iron (II) - cyanide anions, which were used in the form of the corresponding inorganic electricity organic salts, such as alkali metal salts, e.g. or potassium dithionite, sodium or potassium iodide or iron-II- cyanide, or in the form of corresponding acids, such as hydroiodic acid; reducing trivalent inorganic or organic phosphorus compounds, such as phosphines, further esters, amides and halides of phosphinic acid phosphoric acid or phosphoric acid, as well as these phosphoric oxygen compounds corresponding to phosphorus sulfur compounds, wherein organic groups are primarily aliphatic, aromatic or araliphatic. groups, for example optionally substituted lower alkyl, phenyl or phenyl lower alkyl groups such as triphenylphosphine, tri-n-butylphosphine, diphenylphosphinic acid methyl ester, diphenylchlorophosphine, phenyldichloro- phosphine, benzenephosphonic acid dimethyl ester, butanephosphonic acid methyl ester, phosphoric acid triphenyl ester, phosphoric acid triphenyl ester methyl ester, phosphorus trichloride, phosphorus tribromide, etc., reducing halosilane compounds, which exhibit at least one but bonded hydrogen atom and which in addition to halogen, such as chlorine, bromine, or iodine, may also have organic groups, such as aliphatic or aromatic groups, for example optionally substituted lower alkyl or phenyl groups such as chlorosilane, bromosilane, di- or trichloro- silane, di- or tribromosilane, diphenylchlorosilane, dimethylchlorosilane, etc.; reducing quaternary chloromethyleneiminium salts, especially chlorides or bromides, wherein the iminium group is substituted with a divalent or two monovalent organic groups, as appropriate substituted lower alkylene or lower alkyl groups, such as N-chloromethane Tylene-N, N-diethyliminium chloride or N-chloromethylenepyrrolidinium chloride rid; and complex metal hydrides, such as sodium borohydride, in the presence of suitable activating agents, such as cobalt II chloride, as well as as borane dichloride.

As activating agents, which are used in conjunction with those of the indicated reducing agents, which themselves do not exhibit Lewis acid (II q, 10 15 20 25 30 35 40 7807810-2 47 properties, ie primarily together with ditionite, iodine or ferrous cyanide- and non-halogen-containing, trivalent phosphorus-reducing by the catalytic reduction, is special organic carboxylic acid and sulfonic acid halides, further sulfur, phosphorus or silicon halides having the same or greater hydrolysis concentration other than benzoyl chloride, eg phosgene, oxalyl chloride chloride, acetic acid chloride or bromide, chloroacetic acid chloride, pivalin acid chloride, H-methoxybenzoic acid chloride, α-cyanobenzoic acid chloride, p-toluenesulfonic acid chloride, methanesulfonic acid chloride, thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide, phenyldichloro- phosphine, benzenephosphonic acid dichloride, dimethylchlorosilane or trichlorosilane, further suitable acid anhydrides, such as trifluoro- acetic anhydride, or cyclic sultones, such as ethanesultone, 1,3-propanesultone, 1,3-butanesultone or 1,3-hexanesultone.

The reduction is preferably carried out in the presence of solution solution. agents or mixtures thereof, the choice of which is primarily determined of the solubility of the starting materials and the choice of reducing agent, thus, for example, lower alkanecarboxylic acids or esters are used thereof, such as acetic acid and acetic acid ethyl ester, in the catalytic and reduced, for example, optionally substituted, such as halogenated or nitrated, aliphatic, cycloaliphatic, aerobic mathematical or araliphatic hydrocarbons, such as benzene, methylene chloride, chloroform or nitromethane, suitable acid derivatives such as lower alkane carboxylic acid esters or nitriles, for example acetic acid ethyl ester or acetonitrile, or amides of inorganic or organic acids, for example dimethylformamide, dimethylacetamide or hexamethylphosphoramide, ethers, eg diethyl ether, tetrahydrofuran or dioxane, ketones, eg acetone, or sulfones, especially aliphatic sulfones, e.g. dimethyl sulfone or tetramethylene sulfone, etc., together with those chemical reducing agents, these solvents being preferred does not contain any water. You usually work with that at temperatures of about -20 ° C to about 10 ° C, with at reversal of highly reactive activator reaction can be carried out at lower temperatures.

In the 3-cephem compounds of the formula thus obtained 1A, R 1, R 5 and / or H 2, as described, can be transferred to ra groups Râ, R? resp R2.

Salts of compounds of formulas IA and IB can be prepared read in a manner known per se. Thus one can form salts of such compounds with acidic groups, for example by treatment with 10 15 20 25 30 35 7807810-2 48 number compounds, such as alkali metal salts of suitable carboxylic acid tubes, for example the sodium salt of α-ethylcaproic acid, or with ammonia or a suitable organic amine, using preferably stoichiometric amounts or only a slight excess of it the salt-forming agent. Acid addition salts of compounds of IA and IB with basic groupings are usually obtained method, for example by treatment with an acid or a suitable anion bytarreagens. Internal salts of compounds of formulas IA and IB, which contain a salt-forming amino group and a free carboxy- group, can be formed, for example, by neutralizing salts, as acid addition salts, to the isoelectric point, e.g. with weak bases, or by treatment with liquid ion exchangers.

Salts of 1-oxides of compounds of formula IA with salt-forming groups can be prepared in an analogous manner.

Salts can be transferred to free compounds in the usual way, metal and ammonium salts, for example by treatment with suitable acids and acid addition salts, for example by treatment by appropriate basic means.

The resulting mixtures of isomers can, per se known methods are divided into the individual isomers, mixtures of diastereomeric isomers, for example by fractional crystallization adsorption chromatography (column or thin layer chromatography) topography) or other appropriate separation procedures. Obtained the racemate can be divided into the antipodes in the usual way, possibly after the introduction of suitable salt-forming groupings, e.g. by forming a mixture of diastereomeric salts with optical active salt-forming agents, dividing the mixture into the astereomeric salts and conversion of the salts in the free radicals or by fractional crystallization from optical solvents.

The method also includes such embodiments, according to which compounds obtained as intermediates are used as starting materials and remaining procedural steps are performed with those or in which the process is interrupted at any stage; further can the starting materials are used in the form of derivatives or formed below the reaction.

Preferably, such starting materials are used and selected r_n the reaction conditions so as to obtain compounds which contain indicated as particularly suitable. 10 15 20 25 STAY 35 7807810-2 49 In the intermediates of formula II, the leaving group is Y is suitably a group -SO 2 -R 5, wherein H 5 has the indicated but especially the meaning given as appropriate.

The pharmacologically useful compounds of formula IA can be used, for example, for the preparation of pharmaceutical preparations containing an effective amount of the active substance together with or in admixture with inorganic or organic, solid or liquid, pharmaceutically usable carriers, which are suitable for enteral or preferably parenteral administration ring. Thus, tablets or gelatin capsules are used, as exhibits the active substance together with diluent, eg lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, and lubricants, eg silica, talc, stearin acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol; tablets also contain binder demedy, for example magnesium aluminum silicate, starch, such as maize, wheat, rice or arrowroot starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolytic lidon, and any disintegrants, such as starch, agar, alginate, acid or a salt thereof, such as sodium alginate, and / or effervescent mixtures, or adsorbents, dyes, flavorings and sweetener. Furthermore, one can use the new ones, pharmacologically active compounds in the form of injectables, for example intravenously administrable, preparations or infusion solutions.

Such solutions are preferably isotonic, aqueous solutions. or suspensions, which may be prepared before consumption, for example from lyophilized preparations, which contain the active substance alone or together with the rare, eg mannitol. The pharmacological granules may be and / or contain excipients, such as preservatives agents, stabilizers, wetting agents and / or emulsifying agents, solubility mediators, salts for regulating the osmotic pressure and / or buffering agent. The present pharmaceutical preparations which may contain other pharmacological deful substances, are produced in a manner known per se, e.g. by conventional mixing, granulating, coating, solution or lyophilization processes, contains approx 0.1-100%, especially about 1 to about 50%, lyophilisate up to 100% of the active substance. 10 15 20 25 30 H0 7807810-2 so Organic groups denoted by "low" ("lower") contain smiles here, unless otherwise expressly defined, up to 7, preferably up to U, carbon atoms; acyl groups contain up to 20, preferably up to 12 and primarily up to 7 carbon atoms.

The invention is described in more detail in the following examples; tempe- the temperatures are given in degrees Celsius. The cephemes given in the examples the compounds have in the 6- and 7-position and the indicated azetidinone the compounds in 3- and Ä-position R-configuration.

EXAMPLE 1. To a solution of_155 mg- (0.2 mM) of an isomer mixture, consisting of 2-H-p-toluenesulfonylthio) -5-phenoxyacetamido-2-oxaazeti- din-1-yl] -j-methoxy-crotonic acid p-nitrobenzyl ester and the corresponding iso- crotonic acid ester in a ratio of about 4: 1 to 4 ml of dry tetrahydro furan is added dropwise in 5 minutes a solution of 60 μl (2 eq) 1.5- diazabicyclo [5.4.0] undec-5-ene 1 1 ml tetrahydrofuran. After standing at room temperature for 40 minutes dilute with 20 ml of benzene, cool 1 ice bath and stirred for 10 minutes with 10 ml of a 10% citric acid solution.

The organic layer is separated and washed in order of saturated cooking. saline solution, 10% sodium bicarbonate solution and brine, The solution dried over magnesium sulphate is evaporated in vacuo and the resulting yellow oil is purified by chromatography on washed silica gel (2 kg silica gel, stirred three times with 2 l concl hydrochloric acid each time for 10 min, decanted, washed neutral with dist. water, washed with methanol and activated for 60 hours at 1200) with benzene / / ethyl acetate (5: 0 as eluent. The fractions containing the isomer mixture, combine and evaporate in vacuo. You receive a semi-solid isomer mixture (yield 75.5 mg; 7Ä, 5% of theory) of 7'»phenoxyacetamido-3-methoxy-cef-3-em-Ä-carboxylic acid-p-nitrobenzyl- ester and Ysphenoxyacetamido-3-methoxyphsec-2-em-H-carboxylic acid-p-nitro- benzyl ester in a ratio of about 1: 5, which mixture can be is divided into the two isomers on Woelm silica gel (activity III) with benzene / ethyl acetate (5: 1). The faster migrating 7fl Pfenoxyacetamido-3- -methoxy-cef-2-em-Ä-carboxylic acid p-nitrobenzyl ester is recrystallized from methylene chloride / ether and has a melting point of 129-131.5 ° C. The long- co-migrating Tβ-phenoxyacetamido-3-methoxy-cef-U-carboxylic acid-p- the nitrobenzyl ester has a melting point of 1U0, 5-1U2 ° (from methylene chloride / ether).

The products can be further processed in the following ways: Oo prepared solution of 555 mg (1.11 mm) of a crude mixture consisting of of 73-phenoxyacetamido-3-methoxy-ε-2-em-4α-carboxylic acid-p-nitroben- a wide ru 10 15 20 25 STAY 7807810-2 51 sylester and 75-phenoxyacetamido-5-methoxy-cef-5-em-4-carboxylic acid-p- nitrobenzyl ester in a ratio of about 5: 1 in 33 ml of tetrahydro The furan is added with stirring with 16 ml of a pre-cooled to 0 DEG 0.1 N chelium hydroxide solution. The mixture is further stirred for 5 minutes at Oo, then add 100 ml of ice water and 100 ml of pre-cooled methylene chloride and stirred for a short time. Addition of 1 ml saturated, aqueous sodium chloride solution provides a separation of the the phases. The organic phase is separated, the aqueous phase washed once more with 20 ml of methylene chloride, then supernatant with 50 ml of methylene chloride and acidified with 20 ml of 2 N hydrochloric acid. After shaking The organic phase is separated off and the hydrochloric acid solution is extracted. Rinse twice more with 10 ml of methylene chloride each time. The The combined methylene chloride extracts are dried over sodium sulfate and evaporated. taken under vacuum. The residue is recrystallized from methylene chloride / diethyl ether / pentane to give 76-phenoxyacetamido-3-methoxy-cef-2-em-α-carboxylic acid ra with melting points 1112-11450; yield 270 mg (67% of theory) - The new intermediates are obtained as follows: a) A solution of 36.6 g (0.1 M) of 6-phenoxyacetamidopenicillanic acid-1β- oxide, 11.1 ml (0.11 M) of triethylamine and 23.8 g (0.1 M) of p-nitrobenzyl bromide in 200 ml of dimethylformamide is stirred for N h at room temperature under nitrogen. The reaction solution is then introduced into 1.5 l of ice water, precipitated The mixture is filtered off, dried and recrystallized twice from ethyl acetate. acetaz-methylene chloride. The colorless, crystalline 6-phenoxyacetamide the penicillanic acid p-nitrobenzyl ester 1E oxide melts at 179-1800; -__ v. šutbåte UU g (88% -of the theoretical). b) A solution of 5.01 g (10 mM) of 6-phenoxyacetamidopenicillanic acid p- nitrobenzyl ester-oxide and 1.67 g (10 mM) of 2-mercaptobenzothiazole in 110 ml of dry toluene is refluxed in Ä h under a nitrogen atmosphere. Loose- The mixture is evaporated by distillation to about 25 ml and diluted with about 100 ml of ether. The separated product is recrystallized from the methylene chloride ether to give 2- [H- (benzothiazol-2-yldithio) -3-phenoxyacetate amido-2-oxazetidin-1-ylβ-3-methylene-butyric acid p-nitrobenzyl ester with melting point 138-iülo; yield 5.5 g (80% of theory). o) To a solution of 3.25 g (5.0 mM) 2- [- (benstiazol-2-yldithio) - -3-phenoxyacetamido-2-oxazetidin-1-yl) -3-methylenobutyric acid-p-nitrobenzyl ester in 200 ml of acetone / water (9: 1) (v / v) is added 1.06 g of fine powder silver nitrate. Immediately thereafter, a solution of 890 mg is introduced (meth) sodium p-toluenesulfinate in 100 ml of the same solvent mixture (in 10 min). A light yellow precipitate forms immediately. After 20.

STAY. 35. . cii) 7807810-2 52 Stirring for 1 hour at room temperature is filtered while adding Celite.

The filtrate is diluted with water and extracted twice with ether.

The combined ether extracts are dried over sodium sulfate to give evaporation pale yellow solid 2- [4- (p-toluenesulfonylthio) -5-phenoxyacet- amido-2-oxoazetidin-1-yl] -methylenebutyric acid p-nitrobenzyl ester. Thin- layer chromatogram on silica gel (toluene / ethyl acetate 2 = 1) = Rf-Woven = 0.24; aIR spectrum (in CH 2 Cl 2): characteristic bands at 5.90, 5.56, 5.70, 5.87, 6.23, 6.53, 6.66, 7.40, 7.50, 8.10, 8.72, 9.25, 10.95 11min ' yield 2.9 g (91% of theory). The product can easily purification is used in the subsequent reaction. - _ _ The product can be used in the subsequent reaction without further purification. hrs The same compound can also be obtained according to the following methods: ci) To a solution of 3.25 g (5.0 mM) 2- [4- (benstiazol-2-yldithio) - -5-phenoxyacetamido-2-oxoazetidin41-yl] -3-methylenobutyric acid-p-nitro- benzyl ester in 200 ml of acetone / water (9: 1) (v / v) is added 1.58 g (1.2 eq) silver p-toluenesulfinate portionwise over 10 min. Suspen- The reaction is stirred for 1 hour at room temperature, filtered and further processed. grazed as described in Example 1 c). 2- [4- (p-toluenesulfonylthio) - -5-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylene-butyric acid-p-nitro- benzylses are obtained in Lcvancicativc exchange. I _ Silver p-toluenesulfinate is obtained by combining aqueous containing solutions of equimolar amounts of silver nitrate and sodium¿ ' -p-toluenesulfonate as a colorless precipitate. The product is dried ' under vacuum for 24 hours. 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] - -3-methylene butyric acid p-nitrobenzyl ester can also be obtained analogously to Example 1 ci) of 3.25 g of (2,4-benzothiazol-2-ylditiol-3-phenoxyacetamido- -2-oxaazetidin-1-yl] -3-methylene butyric acid p-nitrobenzyl ester and 1.87 g (2 eq.) Copper (II) di-p-toluenesulfinate in quantitative yield.

Copper (II) di-p-toluenesulfinate is obtained by reacting copper sulfate and sodium p-toluenesulfinate (2 eq) in water. After After filtration, the salt is dried under vacuum for 12 hours at 600 DEG. ciii) 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidine-1- -yl] -3-methylenebutyric acid p-nitrobenzyl ester can also be obtained analogously with Example 1 ci) from 150 mg of 2- [4- (Benstiazol-2-yldithio) -j-phenoxyacet- amido-2-oxoazetidin-1-yl] -3-methylenobutyric acid p-nitrobenzyl ester and 85 mg (2 eq) of stannous di-p-toluenesulfinate.

Tin (II) di-p-toluenesulfinate is obtained by reacting stannous chloride (2H2O) and sodium p-toluenesulfinate in water. After v 20. _ b] L 71 HO.

Qcvii 7807810-2 53 filtration and washing with water, the salt is dried under vacuum for about 12 n at 50-6o °. civ) 2- [U- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidine-1- yl] -3-methylenebutyric acid p-nitrobenzyl ester can also be obtained analogously with Example 1 ci) from 130 mg of 2- [H- (benstiazol-2-yldithio) -5-phenoxyacetyl- amido-2-oxoazetidin-1-yl] -5-methylenobutyric acid p-nitrobenzyl ester and 102 mg (2 eq) of mercury (II) di-p-toluenesulfinate; yield 67 mg (about 52.5%).

Mercury (II) di-p-toluenesulfinate is obtained by reacting mercury (II) diacetate and sodium ~ p-toluenesulfinate in water. After filtration and washing with water, the salt is dried under vacuum for about 12 hours at 50-600. cv) A solution of 517 mg (1.02 mM) of 6-phenoxyacetamidopenicillanic acid -p-nitrobenzyl ester-1B oxide and 187 mg (1.2 mM) p-toluenesulfinic acid in 10 ml of 1,2-dimethoxyethane (or dioxane) is refluxed for 0.5 h in the presence of 3.5 g of a molecular sieve 3A and under a nitrogen atmosphere, then an additional 308 mg (1.98 mM) of p-toluenesulfinic acid, dissolved in 2 ml of 1,2-dimethoxyethane, add in five portions over 45 minutes interval. After 4.5 hours, the reaction mixture is poured into 100 ml of 5-pro- cent, aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases are washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulphate and evaporated. layer plates with toluene / ethyl acetate (2: 1) to give 2- [4- (p-toluenesul- The residue is chromatographed on silica gel-thick ~ phonylthio) -E-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylene butyric acid -p-n1grQb @ nsy1eSner; yield 212 months (59% of theory).

A mixture of 250 mg (0.5 mM) of 6-phenoxyacetamidopenicillan acid p-nitrobenzyl ester 1B oxide, 110 mg (0.6l mM) p-toluenesulfonyl cyanide and 5 mg (0.022 mM) benzyl triethylammonium chloride 1 2 ml dry, peroxide-free dioxane is stirred under argon for 4.5 hours at 1100.

The solvent is evaporated off under vacuum and the remaining yellow oil is evaporated. is chromatographed on acid-washed silica gel. Elution with 50% ethyl acetate in toluene gives 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamino- do-2-oxoazetidin-1-yl] -5-methylenebutyric acid p-nitrobenzyl ester; Exchange 133 mg (M2% of theory). ' cvii) A mixture of 110 mg (0.61 mM) of p-toluenesulfonyl cyanide and H, 5 mg (0.021 mM) of tetraethylammonium bromide in 1 ml of pure dioxane are stirred at 1100 under argon for 50 min. Then a suspension is added of 250 mg (0.5 mM) of 6-phenoxyacetamidopenicillanic acid p-nitrobenzyl- ester-1% oxide in 1 ml of dioxane and the resulting solution is stirred in H h at 1100 under argon. The solvent is removed in vacuo. The crude product is dissolved in ethyl acetate and washed with water and 10 15 30 55 RO 78Û78¶0-2 , S4 saturated aqueous saline solution. The organic phase is dried with magnesium sulfate and liberated in vacuo from solvent to give Crude 2- [U-p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidine-1:11] -3- methylene butyric acid p-nitrobenzyl ester; exchange BRÅ mg.

The intermediate obtained can be processed as follows: Ö) In a solution of 1.92 S (3.0 mM) 2- [U- (p-toluenesulfonylthio) -3-phenyl] oxiacetamido-2-oxoazetidin-1-yl] -3-methylenebutyric acid p-nitrobenzyl ester in 30 ml of dry methyl acetate, 1.1 eq of ozone is introduced at -780 in 33 minutes.

Immediately afterwards, excess ozone is removed by means of a stream of nitrogen (15 min at -780). 2.2 ml of dimethyl sulfide (10 eq) are added and the solution heated to room temperature. After standing for 5 hours, the solution is distilled off. the agent under vacuum and residual colorless oil is taken up in 100 ml benzene. The benzene solution is washed with 3 x 50 ml portions of saturated boiling brine, dried over magnesium sulphate and evaporated to dryness under vacuum. After recrystallization of the residue from toluene, les_2- [H- (p-toluenesulfonylthio) -B-benoxyacetamido-2-oxoacetidin-1-yl] - -3-hydroxycrotonic acid p-nitrobenzyl ester, m.p. 159-1600; yield 1.7Ä 3 (90% of theory). _ ~ di) According to Example 1 cvii) obtained, crude 2- [4- (p-toluenesulfonylthio) -5- phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylenobutyric acid-p-nitrobenzyl- ester is dissolved in 20 ml of methyl acetate and ozonized at -700, until slightly starting material no longer remains according to thin layer chromatogram.

Then a stream of nitrogen gas is passed through the solution and this is heated O-50. A solution of 500 mg of sodium bisulfite in 5 ml of water is added. and stir for about 5 minutes, until no ozonide is detected bar with potassium iodide starch paper. The mixture is diluted with ethyl acetate, the aqueous phase is separated and the organic phase washed with water, dried over magnesium sulfate and freed from solvent under vacuum. The hair product is dissolved in 5 ml of methylene chloride and 15 ml of toluene are added. The precipitate is filtered off and the filtrate evaporate in vacuo. The residue is recrystallized from methanol and gives 2- [4- (p-toluenesulfonylthio) -3-phenoxy-acetamido-2-oxoazetidin-1-yl] - -34hydroxycrotonic acid p-nitrobenzyl ester, m.p. 159-1600; Yield 173 mg (56% of theory). 9) A solution of 1.95 g of 2- [4- (p-toluenesulfonylthio) f5-phenoxyacetamide do-2-oxoazetidin-1-yl] -3-oxobutyric acid p-nitrobenzyl ester (3.0 mM) in 15 ml of dry chloroform are cooled to 0 DEG C. and added over time 10 min with 6 ml of an ethereal solution of diazomethane (0.75 M), corresponding 1.5 eq). The mixture is stirred for 2 hours at 0 DEG, excess diazomethane is removed. is removed with a stream of nitrogen and the solvent is removed in vacuo 10. 20. 2s._ 35.

H0. " 7807810-2 55 The crude product is purified by filtration over Woelm silica gel (activity III, H0-fold amount) with benzene / ethyl acetate (5: 1). The following tillation of the solvent obtained, the colorless oil crystallizes when standing. After recrystallization from methylene chloride / ether is obtained an isomeric mixture consisting of 2- [H- (p-toluenesulfonylthio) -3-phenyl- oxiacetamido-2-oxoazetidin-1-yl] -3-methoxycrotonic acid p-nitrobenzyl ester and the corresponding isocrotonic acid ester in a ratio of about u: 1; melt melting point 155-156.5 °; yield 163 g (83 2 of it theoretical). g __ M _ “m_ M_ EXAMPLE 2. A solution of 79 mg of eel [Å- (§-to1uènšuifonyíɧ $ §-5-ren- oxiacetamido-2-oxoazetidin-1-yl] -5-hydroxycrotonic acid diphenylmethyl- ester (0.428 mM) in 4 ml of chloroform and 1 ml of hexamethyldisilazane reflux for 1 hour and evaporate in vacuo; the oily the residue is dried in a high vacuum for 1 hour. The silylated crude product consists of 2,, [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazeti- din-1-yl] -3-trimethylsilyloxycrotonic acid diphenylmethyl ester and corresponding isocrotonic acid diphenylmethyl ester.

The crude product obtained is taken up in 3 ml of dry chloroform and cooled to 0 DEG C. and added under nitrogen and stirring with 0.069 ml (0.47) mM) 1,5-diazabicyclo [5.4.0] undec-5-ene. After 1 H reaction is continued the solution with 0.5 ml of acetic acid and diluted with chloroform. the solution is washed with dilute sulfuric acid, water and dilute nat- W rium bicarbonate solution. The aqueous phases are extracted with chloroform, the combined organic phases are dried over sodium sulfate and evaporated in vacuo. 7β-phenoxyacetamido-j- hydroxy-cef-3-em-4-carboxylic acid diphenylmethyl ester; Rf value: 0.13 (silica gel; toluene / ethyl acetate 3:11.

The crude product obtained is taken up and added to Oo with one After 5 hours the reaction is evaporated Chloroform- excess ether solution of diazomethane. the solution is complete and the oily residue is chromatographed on silica gel thick layer plates (coiuen / euyiacecat 3: 1). siiika- gel in the zone at Rf = 0.19 is extracted with ethyl acetate to give TB phenoxyethoamido-3-methoxy-cep-} -em-4-carboxylic acid diphenylmethyl ester melting point 120 ° (from ether; IR spectrum (1 CHCl 3) 3510, 1775, 1700, 1695, 1600 Cm'1; yield 22 mg. is prepared as follows: al Av 100 g (27.3 mM \ 6-phenoxyacetamido-penicillanic acid-1β-oxide, 500 ml of dioxane and 58.4 g of (BC mM) diphenylmethyldiazomatane are obtained about 2 hours 6-phenoxyacetamidopeniolylanic acid diphenylmethyl ester-1B- oxide; mp 144-1M6OC (ethyl acetate / petroleum ether).

The intermediate product 10 15 20 25 STAY 35 78Û781Û ~ 2 56 b) In analogy to Example 1b), 2- [4- (benstiazol-2-ylthio) -5- phenoxyacetamido-2-oxoazetidin-1-yl] -5-methylenobutyric acid diphenylmethyl- GSÉSP; mp 140-1Ä1 ° (from toluene / ether), from 292 g (55 mM1 6-phenoxyacetamido-penicillanic acid diphenylmethyl ester-15-oxide and 99 g (59.5 ml) 2-mercaptobenstiazole. IN analogous to Example 1c is obtained from 10 g (14.7 mM) of 2- [4- (Benstiazol-2-ylditic) -3-phenoxyacetamido-2-oxoaeetidin-1-yl] -} - Tylenic butyric acid diphenylmethyl ester in 50 ml of ethyl acetate, 4.92 g (24.98 mM) finely powdered p-toluenesulfinate and stirring for 7 hours at room temperature. 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidine -1-yl] -5-methylenobutyric acid diphenylmethyl ester; Rf ~ value = 0.28 (si- likagel; toluene / ethyl acetate 5:11; IR spectrum (CHCl 3): 1782, 17 ° C, 1695, 1340, 115o cm -1; yield 9.57 g. 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidine- -1-yl] -3-methylenebutyric acid diphenylmethyl ester can also be prepared on as follows:. ci) A suspension of 106.5 g of 6-phenoxyacetamido-penicillanic acid diphenylmethyl ester-1B oxide and 35.8 g of 2-mercaptobenstriazole in 900 ml of toluene and 9 ml of glacial acetic acid are boiled for 2 hours under nitrogen with water. separator, separating about 4.5 ml of water. The solution is cooled to room temperature, is added in 1 hour portionwise with a total of 85.5 g of silver p-toluenesulfinate and then stirred for a further 2 hours at 220. The mixture is filtered through Hyflo and the filtrate is washed twice with saturated aqueous sodium chloride solution. The or- The organic phase is washed over magnesium sulphate, evaporated in vacuo to about 1 l, decolorized with 30 g of Norit and evaporated. the yellow foam is crystallized from methylene chloride / diethyl ether; melting point 79-320; Rf value = 0.55 (silica gel; toluene / ethyl acetate 3: 1). Ur mo- additional amounts of substance can be recovered by crystallization. methylation chloride / diethyl ether total yield 109.7 g (81.8% of the theoretical.

The intermediate obtained can be further processed as follows: d) Analogously to Example 1d) is obtained from 10.8 g (16.2 mM) 2- [4- - (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -5-methyl- tylene butyric acid diphenylmethyl ester in 1 l of methylene chloride and 1.1 eq ozone 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-hydroxycrotonic acid diphenylmethyl ester; melting point 142-1Ä3 ° (ur ether / pentane); yield 11.5 g.

The ozonation can also be carried out at Oo: 10 15 20 25 EO HO 7807810-2 57 In a solution of 9.23 g (13.8 mM) 2- [N- (p-toluenesulfonylthio) - -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylenobutyric acid diphenylmethyl tyl ester in 960 ml of methylene chloride in 15.2 mM ozone at 00 on 19 my. The clear reaction solution is added with 10 ml of dimethyl sulfide and stirred for 20 minutes at 50. After evaporation under water jet vacuum and drying of the residue under high vacuum gives a light yellow foam-like product; which crystallizes from methylene chloride / hexane; melting point of the obtained 2- [H- (p-toluenesulfonyl) -3-phenoxy-acetamidido- .2-oxoazetidin-1-yl] -3-hydroxycrotonic acid diphenylmethyl ester at -138O; thin layer chromatogram Rf value about 0, ü6 (silica gel): toluene / ethyl acetate 3: 1).

EXAMPLE 3. A solution of 301 mg (0.462 mM} 2- [4- (p-toluenesulfonyl) thiol-3-phenoxyacetamido-2-oxoazetidin-1-yl] -5-hydroxycrotonic acid nyl methyl ester in 3 ml of 1,2-dimethoxyethane was added under nitrogen with 0.12 ml of bis-trimethylsilyl acetamide (0.508 mM) and stirred at room temperature temperature for 1 h. The solution is completely evaporated and the oily the residue is dried for 1 hour under high vacuum. The silylated crude the product is taken up in 5 ml of dried 1,2-dimethoxyethane and added cooling to 0 DEG C. with 0.075 ml (0.508 mM, 1,5-diazabicyclo [5. dec-5-en. After 6 hours reaction time at 0 DEG C. under nitrogen is added 0,) ml of acetic acid and dilute with methylene chloride. Methylene chloride solvent The solution is washed successively with dilute sulfuric acid, water and dilute bicarbonate solution. The aqueous phases are extracted with methylene chloride, the combined organic phases are dried over sodium sulphate, evaporated in vacuo and dried under high vacuum. You get raw TB-phenoxyacetamido-5-hydroxy-cef-} -em-4-carboxylic acid diphenylmethyl- ester. The solution of the crude product in chloroform is added at 0 DEG an excess of a diazomethane solution in ether and allowed to stand for 5 min at OO. Then evaporate completely and the residue is chromatographed. on silica gel as in Example 2. 76-Phenoxyacetate is obtained. amido-3-methoxy-cef-3-em-4-carboxylic acid diphenylmethyl ester; Rf value = C, 19 (silica gel; toluene / ethyl acetate 5: 1), m.p. 120 ° (ur. eeer); IR spectrum (in CHCl 3) = 3310, 1775, 1710, 1690, 1600 @ m -1; yield 26 mg.

EXAMPLE 4. A solution of 100 mg (0.15 mM) of an isomer mixture, consisting of 2- [α- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxacazene- thidin-1-yl] -3-methoxy-crotonic acid diphenylmethyl ester and the like isocrotic acid ester in ml ml dry 1,2-dimethoxyethane, is added under stirring in a nitrogen atmosphere with 0.045 ml (0.3 mm) 1,5_diazab1® yk1o- [5.4.0] undec-5-en. The solution is stirred for 40 minutes at room temperature 10 15 20 25 30 55 H0 7807810-2 58 under nitrogen, then cooled with ice and added with 0.1 ml of The solution diluted with methylene chloride is washed successively with dilute sulfuric acid, water and dilute dicarbonate solution. The the aqueous phases are extracted with methylene chloride. The United States the organic phases are dried over sodium sulphate, evaporated and freed from high vacuum completely from solvent. The oily residue tiksyra. it is chromatographed on a silica gel thick layer plate (elution medium). part: toluene / ethyl acetate 3: 1; development once). The two zones at Rf = 0.19 and 0.10, respectively, is extracted together with ethyl acetate and the resulting solution is completely evaporated. You get an oily product consisting of 7β-phenoxyacetamido-3-methoxy-cef-3-em-H-carbon oxylic acid diphenylmethyl ester and isomer 7β-phenoxyacetamido-5-methoxy- -cef-2-em-H-carboxylic acid diphenylmethyl ester in the ratio 1: ü; Rf- value = 0.1U and 0.32, respectively (silica gel toluene / ethyl acetate 321); IR spectrum 1 cHc13) 5000, 5510, 1785, 1770, 1750, 1710, 1690, 1650, 1600 cm -1; yield 58 mg.

The isomer mixture used as intermediate is obtained via the corresponding benzoxazole derivatives as follows: aviii) A solution of 10 g of 6-phenoxyacetamido-penicillanic acid-diphenyl- methyl ester-15-oxide and 3 g of 2-mercaptobenzoxazole in 25 ml of dry tetra- hydrofuran is completely evaporated in vacuo. Remaining foam heated under a water jet vacuum for 70 minutes to 1200 (oil bath temperature). The molten residue is chromatographed after cooling 500 g of acid-washed silica gel with toluene / ethyl acetate (6: 1) and then ter (3: 1). amido-2-oxoazetidin-1-yl] -3-methylene-butyric acid diphenylmethyl ester in form of a white foam; I fl f spectrum (methylene chloride): characteristic band at 5.6; 5.75, 5.90 and 6.7 μm. aix) Analogously to Example 1 c) - 1 iv) or analogously to Example pile 2 c) is transferred 2- {H- (benzoxazol-2-yldithio) -3-phenoxyacetamino- 2- [4- (Benzoxazol-2-yldithio) -3-phenoxyethyl] is obtained. do-2-oxoazetidin-1-yl} -3-methylenobutyric acid diphenylmethyl ester to 2- {N- (p-toluenesulfonylthio) -5-phenoxyacetamido-2-oxoazetidine-1- yl} -3-methylenebutyric acid diphenylmethyl ester, as in Example 2 d) transferred to 2- {4- (p-toluenesulfonylthio) -5-phenoxyacetamido-2- oxoazetidin-1-yl} -3-hydroxycrotonic acid diphenylmethyl ester. a) The isomer mixture used as intermediate can be obtained read analogously to Example 1e) from H g (6.1H mM) 2- {4 "(P" CO sulfonylthio) -5-phenoxyacetamido-2-oxoazetidin-1-yl} -3-hydroxy- crotonic acid diphenylmethyl ester and an excess ether solution of diazomethane. Obtained isomer mixture consisting of 2- {U ~ (p-to- 10 15 20 25 STAY 55 HO 7807810-2 _59 luenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl -3-methoxy- crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenyl nyl methyl ester (about 3: 1) crystallizes from ethyl acetate / pentane and has a melting point of 150 "152O5 UÜÜYÜG 2: 4 å- EXAMPLE 5. A solution of 300 mg (0.45 mM) of that of Example 4a) obtained, crystallized isomer mixture consisting of 2- [Ä- (p- toluenesulfonylthio-5-phenoxyacetamido-2-oxoazetidin-1-yl] -5-methoxy- crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid ester in A ml of dry 1,2-dimethoxyethane is stirred at room temperature under nitrogen with 0.3 H ml (0.9 mM) of 1,5-diazabicyclo [5.U.iundec-5-ene. After HO min reaction, the solution was cooled to 0 ° C and added with 0.1 H ml of acetic acid. acid and then with 180 mg (1.36 mM) of m-chloroperbenzoic acid (85-pro- centig). The solution is stirred for 10 minutes at 0 ° C under nitrogen, diluted with Chloroform and wash with dilute sulfuric acid / sodium thiosulfate, water and dilute sodium bicarbonate solution. The aqueous phases are extracted chloroform, the combined organic phases are dried overnight. sodium sulphate, evaporated in vacuo and freed from solvents under there high vacuum; yield 27U mg. The product obtained is divided into silica gel thick layer plates (eluent ethyl acetate; developed once).

The silica gel in the zone with Rf = 0.51 is extracted with ethyl acetate, it is The solution is evaporated and the residue is dried under high vacuum.

As the oily residue, 7 = -phenoxy-acetamido-3-methoxy-cef- -3-em-H-carboxylic acid diphenylmethyl ester-1; oxide, which crystallizes from methylene chloride / pentane; melting point 115-12o °; yield 132 mg.

By extraction of the silica gel in the zone at Rf = 0.22 with ethyl acetate, evaporation of the solution on a rotary evaporator and drying the oily residue can be obtained T fi rphenoxyacetamido- 3-methoxy-cef-3-em-H-carboxylic acid diphenylmethyl ester oxide; molten point 175-180 ° (from chloroform); yield 12 mg.

The resulting 1-oxides can be further processed as follows: a) a solution of 150 mg (0,275 mM) 75-phenoxyacetamido -} - methoxy-eef- -5-em-4-carboxylic acid diphenylmethyl ester-1B oxide in 3 ml of methylene chloride and 0.1 ml of dimethylformamide is added after cooling to 0 ° C 188 mg (1.7 mM) phosphorus trichloride. The solution is stirred at 0 ° C for 30 h min, diluted with methylene chloride and washed with aqueous sodium bicarbonate. carbonate solution. The aqueous phase is extracted with methylene chloride. the combined organic phases are dried over sodium sulphate and concentrated evaporate in vacuo. Obtained crude TB-phenoxyacetamido -} - methoxy-ce5- -3-em-4-carboxylic acid diphenylmethyl ester is recrystallized from ether; melting point 12 °. 10 15 20 25 30 35 HO 7807810-2 so b) A solution of 2.0 g (3.78 mM) of 76-phenoxyacetamido-3-methoxy-cef- -cef-3-em-4-carboxylic acid diphenylmethyl ester in 5 ml of methylene chloride was added with 0.87 ml of aniseed, cooled to 0 ° and allowed to stand for 1 1 n addition of 1.2 ml of trifluoroacetic acid. under vacuum and the residue crystallizes from acetone / ether. 7fi-phenoxyacetamido-3-methoxy-cef-5-em-4-carboxylic acid with molten point 170 ° (decomposition). c) To a suspension of 2.55 g (7 ml) of 7β-phenoxyacetamide The reaction mixture is evaporated You are- methoxy-cef-5-em-4-carboxylic acid and 2.9 ml (22 μM) N, N-dimethylaniline in 11 ml of abs methylene chloride is added 0.7 ml (5.7 mM) of dimethyl dichlorosilane under nitrogen at 20 ° and then stirred for 50 minutes at the same temperature The resulting clear solution is cooled to -200, set at 1.6 g (7.7 mM) of solid phosphorus pentachloride and stirred for 30 minutes. At the same temperature is added in 2-3 minutes a pre-cooled (-200) mixture of 0.9 ml (7 mM) of N, N-dimethylaniline and 0.9 ml of n-butanol, then 10 ml of pre-cooled (-200) n-butanol are added rapidly and then reconstituted. Stir for 20 minutes at -20 ° and for 10 minutes without cooling. At about -100 1 0.4 ml of water are added, the mixture is stirred for about 10 minutes in an ice bath (0o), 11 ml dioxane is then added and after a further 10 minutes stirring at 00, about 4.5 ml of tri-n-butylamine are added portionwise, until i water diluted samples assumed the constant pH 3.5. After 1 h 1 stirring at 0 DEG C., the precipitate is filtered off, washed with dioxane and stirred. crystallized from water / dioxane. Obtained 7β-amino-3-methoxy-cef-5- lucky. em-U-carboxylic acid hydrochloride dioxanate has a melting point of more than 5000; thin layer chromatogram: Rf value 0.17 (silica gel system: n-buta- nol / carbon tetrachloride / methanol / formic acid / water 30: HO: 20: 5: 5); yield 1, ¶2g.

From the obtained hydrochloride dioxanate it is possible by adding 2 N sodium hydroxide solution to pH U (1 (isoelectric point) to a 20% aqueous solution of the hydrochloride dioxanate the switter ion of fl G-amino-3-methoxy-cef-3-em-U-carboxylic acid, which filtered and dried has a melting point of more than 3000; UV spectrum (in 0.1 N sodium bicarbonate solution): λ max = 270 nm (δ = 7600); thin- layer chromatogram: Rf value identical to that of the hydrochloride ( likagel; same system); EQJ go = + 232 ° j 10 (c = 1; 0.5 N sodium bi- carbonate solution). , d) A suspension of 1 g (2.82 mM 75-amino-3-methoxy-cef-3-em- -4-carboxylic acid hydrochloride dioxanate in 20 ml of dry methylene chloride for at room temperature under a nitrogen atmosphere with 1.65 ml of bis- (tri- methylsilyl) -acetamide. After 40 minutes, the clear solution is cooled And was added with 900 mg (,, 37 mM) of solid D-d-phenylglycylic acid lO 15 20 25 STAY 35 NO 61 7807810-2 hydrochloride. 5 minutes later, 0.7 ml (10 ml) of propylene oxide. The suspension is then stirred for 1 hour at Go under a nitrogen atmosphere is then added with 0.5 ml of methanol, where 7β (4-α-phenylglycylamino) -3- methoxy-cef-3-em-4-carhoxylic acid hydrochloride precipitates in crystalline form.

The hydrochloride is filtered off and dissolved in 9 ml of water; the solution is set read at pH 4.6 with 1 N sodium hydroxide solution. The result is dihydrate of the inner salt of 7B4®-α-phenylglycylamino) -} - methoxy-cef-3-em-Ä- carboxylic acid is filtered off, washed with acetone and diethyl ether and torkas; melting point 17% -1760 (decomposition); [α] D 20 = + 1320 (C = 0.714; in 0.1 N hydrochloric acid cunnsxixus chromatogram (Silicaeelh Rf value approx 0.18 (system n-butanol / acetic acid / water 67:10:23); UV spectrum (in 0.1 N aqueous sodium bicarbonate solution) = max = 269 nm (§ = 7000); IR spectrum (in mineral oil): characteristic bands at 5.72, 5.94, 6.23 and 6.60 μm.

EXAMPLE 6. A solution of 200 mg (0.254 mM) 2- [§- (p-toluenesulfonyl )- thio) -3- (D-M-t-butyloxycarbonylamino-ophenylacetylamino) -Z-oxoase- thidin-1-yl] -3-methoxy-crotonic acid diphenylmethyl ester in 2 ml of dimethyl- formamide is stirred for 30 minutes at room temperature with 57 μl (0.38 mM) 1, S-diazabicyclo- {§.§: Olundec-5-en, is then added with ethyl acetate. and washed with water and 2 N hydrochloric acid to acidic reaction and with saturated aqueous sodium chloride solution to a neutral reaction. tion. The organic phase is dried over sodium sulfate and evaporated under vacuum. The residue is chromatographed on silica gel thick layer. plates with toluene-ethyl acetate (111) as eluent. You are- holds 7β- (D <§t-butylcarbonylamino-OFphenylacetylamino-3-methoxy-cef- -2-em-4d-carboxylic acid diphenylmethyl ester, m.p. 166-1689 (methylene chloride / pentane); thin layer chromatogram (silica gel; diethyl- ether: Rf value about 0¿§1; UV spectrum (in ethanol): λmax = 257 nm (§ == 3500); IR spectrum in methylene chloride): characteristic bands at 2.96; 5.63; 5.74; 5.85 (approach), 5.92; 6.16; 6.64 and 6.72 Pm; out- byte 88 mg; and W3- (D-Q-1-butylcarbonylamino) -d-phenylacetylamino) - -3-methoxy-cef-3-em-4-carboxylic acid diphenylmethyl ester with melting point 162-163 ° (diethyl ether); thin layer chromatogram: Rf value about 0.33 (silica gel; diethyl ether); UV spectrum (in ethanol):> \ nmx = 265 nm (â == 6 600); 280 nm (ansats) (2: = 6 200); IR spectrum C1 methylene chloride ride); 2.92; 5.58; 5.64 (approach); 5.82; 6.22 and 6.67 μm; yield 25 mg.

Obtained compounds can be further processed as follows: a) A mixture of 8.8 g of 76- (D-α-t-butyloxycarbonylamino-α-fe- nyl-acetylamino) -3-methoxy -} - cephem-α-carboxylic acid diphenylmethyl ester, 8.6 ml of anisole and 145 ml of difluoroacetic acid are stirred for 15 minutes at 0 10 15 20 25 30 35 40 7807810-2 62 then add 400 ml of pre-cooled toluene and evaporate reduced pressure. The residue is dried under high vacuum, digested with diethyl ether and filtered off. In this way, in powder- form the trifluoroacetate of 7β- (D-α-phenylglycylamino) -} - methoxy-β-cephem -4-carboxylic acid, which is dissolved in 20 ml of water. You wash twice with 25 ml of acetic acid ethyl ester each time and adjust the pH to approx With a 20% triethylamine solution in methanol, one colorless precipitation is formed. Stir for 1 hour in an ice bath, then add ao mi aeeton and let stand 1 16 n at about 4 °. The colorless folding The mixture is filtered off, washed with acetone and diethyl ether and dried under reduced pressure. In this way, in the form of a micro- Rocrystalline powder IB- (D-α-phenylglycylamino) -5-methoxy-3-ol -4-carboxylic acid as inner salt, which is also present in form of a hydrate; melting point 174-176 ° (decomposition); [α] 25 D = + 149 ° (c Q 1.05 1 0.1 N hydrochloric acid); thin layer chromatogram (silica gel front iodine cooling): Rf about 0.56 (system: n-butanol / pyridine / acetic acid) acid / water 40: 24: 6: 30); UV absorption spectrum (in 0.1 N water s sodium bicarbonate solution): 7l x = 267 nm (E = 6 200); IR- spectrum (in mineral oil): characteristic bands i.a. at 5.72 Pm, 5.94 μm, 6.23 μm and 6.60 μm. _ b) A mixture of 0.063 g of Za- (D-act-butyloxycarbonylamino-erphenyl) acetylamino) -3-methoxy-2-cephem-10-carboxylic acid diphenylmethyl ester, 0.1 ml of anisole and 1.5 ml of trifluoroacetic acid are allowed to stand for 15 minutes at 0 DEG and then evaporated under reduced pressure. The residue is digested with diethyl ether, filtered off and dried. What is thus obtained, colorless and powdery trifluoroacetate of 7β- (D-Q & phenylglycyl- amino) -3-methoxy-2-cephem-4Dicarboxylic acid is dissolved in 0.5 ml of water and the pH of the solution is adjusted to about 5 by dropwise addition of a 10% solution of triethylamine in methanol. Stir for 1 hour in an ice bath, the colorless precipitate filters out and dries under high vacuum. There is thus obtained T fi- (D-o-phenylglycylamino) -3-methoxy-2- cephem-α-carboxylic acid as inner salt; thin layer chromatogram (silica- ëeï! ff fi f fl kall fl inä with JOdhRf about 0.44 (system: n-butanoi / pyriain / acetic acid / water 40: 24: 6: 30); UV absorption spectrum (in 0.1 N aqueous containing sodium bicarbonate solution):: K t = 260 pm _ n _ ansa s ^ ' c) T111 a cooled solution of 0.63 g 7s_ (n_a - = - buty10xi_ carbonylamino-α-phenyl-acetylamino) -5-methoxy-2-cephem-4α-carboxylic acid diphenylmethyl ester In 25 ml of methylene chloride is added a solution of 0.20 g 3-chloroperbenzoic acid in 5 ml of methylene chloride. The mixture is stirred for 30 hours min at 0 °, add 50 ml of methylene chloride and wash successively 10 15 20 25 30 35 HO 63 7807810-2 with 25 ml each time of a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. It dries the organic phase over sodium sulphate and evaporates under reduced pressure. cat pressure. the residue is crystallized from a mixture of methylene chloride and diethyl ether; 7α- (D-o-t-butyloxycarbonylamino- no-α-phenylacetylamino) -3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl- este »1-oxide 1 form of colorless needles; melting point 172-175 °; thin-layer chromatogram (silica gel): Rf about 0.44 (system: acetic acid ethyl ester; development with iodine vapor); UV absorption spectrum (in ethanol): 7 = 277 nm (f: = 7 200); IR absorption spectrum (in methylene chloride): m characteristic bands at 2.96 μm, 5.56 μm, 5.71 μm, 5.83 μm, 5.90 μm, 6.27 um and 6.67 um. d) A solution of 1.30 g of 7B- (D-α-t-butyloxycarbonate) cooled to -100 nylamino-d-phenylacetyl-amino) -} - methoxy -} - cephem-4-carboxylic acid diphenyl- methyl ester-1-oxide in 50 ml of dimethylformamide was added with 2.80 g of phosphorus trichloride under exclusion of air. After 15 minutes standing, pour the reaction mixture on a mixture of ice and an aqueous dipotassium ear Hydrogen phosphate solution; the aqueous mixture is extracted two times with 100 ml of acetic acid ethyl ester each time. The organic extract The solution is washed with a saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated. The residue is chromatographed on silica kagel; eluting with diethyl ether amorphous 7fl- (D-Q-butyloxycarbonylamino- no-X-phenylacetylamino) -3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl- ester as a thin layer chromatographically pure substance; Rf about 0.39 (system: diethyl ether; development with iodine vapor); Qx] D = 10 1 10 (c = 0.951 in chloroform); UV absorption spectrum (in ethanol): _Ämax = 264 nm (f fl = 6500); IR absorption spectrum (in methylene chloride}: characteristic istic bands at 2.94 μm, 5.62 μm, 5.84 μm, 5.88 μm, 6.25 μm, and 6.70 um.

The intermediate is obtained as follows: ) A to -15 ° cooling solution of 51.2 g (0.12 mm) o-H -: -: 1: y: - xicarbonyl-phenylglyoin and 16.7 ml (0.12 mM) of triethylamine in 300 ml etrahydrofuran was added with 16.5 ml (0.12 mM) of chloroformic acid isobutyl- ester and stirred for 30 minutes at -100. Then a solution is added of 21.6 g (0.10 mM) of 6-aminopenicillanic acid and 15.4 ml (0.11 m fl) ethylamine in 500 ml of tetrahydrofuran / water (2: 1). The reaction mixture Stir for 1 hour at 0 DEG and 1 2 hours at room temperature, maintaining the pH constant at about 6.9 by the addition of triethylamine. Reaction mixture The setting is set at 50 to 2.0 with phosphoric acid, measured with sodium (D (J Kf xloride = and extracted three times with 500 ml of ethyl acetate each time; 10 15 20 25 STAY 35 H0 7807819-2 64 the organic phase is washed with saturated aqueous sodium chloride solution. dried over sodium sulphate and evaporated. In the form of light yellow foam obtained, crude N-t-butylcycarbonylampicillin has in thin layer chromate an Ef value of about 0.65 (silica gel; ethyl acetate / n-butanol / pyridine / acetic acid / water 42: 21: 21: 6: 10) ¿«ÅQ1? ~ fí22j. f) A solution of 57.22 g of crude N-t-butyloxycarbonyl-ampicillin in 100 ml of glacial acetic acid was added in 10 minutes with 21.6 ml of a 30% hydrogen peroxide. oxyš (0.25 M) and stirred for 2.5 h at room temperature. Reaction mixture The mixture is then poured into 2 l of ice water, in the form of a volumetric precipitation of the N-t-butyloxycarbonyl-ampicillin-1-oxide precipitated washed, washed well with water and dried under vacuum. Through extracts addition of the filtrate with ethyl acetate, additional amounts of crude N-t-butyl carbonyl-ampicillin-1-oxide is obtained; thin layer chromatogram (silica gel; ethyl acetate / n-butanol / pyridine / acetic acid / water 42: 21: 21: 6: 10 of about 0.30. g) A mixture of 67.7 g of crude N-t-butyloxycarbonyl-ampicillin-1- oxide in 380 ml of dioxane is added with a solution of 42 g (0,2 Mdiphenyl- diazomethane in 150 ml of dioxane and stirred for 2.5 hours at room temperature. Ef- The addition of 5 ml of glacial acetic acid is evaporated under vacuum. petroleum ether, the petroleum ether extract is discarded and the column is crystallized from methylene chloride / ether / hexane. One obtains N-t- butyloxycarbonyl-ampicillin-1-oxide-diphenylmethyl ester with melting point 164-166 °; 5§> <] šo = + 117 ° '¿1 ° (c = 1; cHc13); xxx spectrum (methylene chloride): characteristic bands at 2.91; 2.94; 5.54; 5.69; 5.82 (an- satsj; 5.88; 6.60; 6.68 Pm; thin layer chromatogram: Rf value approx 0.23 (silica gel; toluene / ethyl acetate 3: 1); yield 32eg (51% theoretical). h) A mixture of 11.2 g (17.7 mm) of N-c-butyloxycarbonyl-ampi- cilinin-1-oxide-direnylmethyl ester and 3.26 g (19.5 mm) of merxaptobenzene thiazole in 170 ml of toluene is boiled for 5 hours in a reflux apparatus with aqueous separator and then evaporated. The residue is chromatographed on silica gel with toluene / ethyl acetate 3: 1 as eluent and give amorphous 2- [4- (benstiazol-2-yldithio) -3- (α-t-butyloxycarbonylamino-α- phenylacetylamino) -2-oxoazetidin-1-yl] -3-methylene-butyric acid diphenylmethyl tyl ester. Thin layer chromatogram: Rf value about 0.37 (silica gel; toluene / ethyl acetate 3: 1); IR spectrum (methylene chloride): characteristic band at 2.94; 5.64; 5.76; 5.86 (approach); 5.91 and 6.71 μm; U fl WTe9fP4g- 1) A solution of 2.34 g (3.0 mm) of 2- [u- (benzciazo-2-ylaicide] -5- (α-t-butyloxycarbonylamino-α-phenyl-acetylamino) -2-oxcazetidin-1-yl] - -3-methylene-butyric acid diphenylmethyl ester in 30 ml acetone / water (9: 1) for! of the 10 15 20 25 50 ÄO EXAMPLE 7- 7807810-2 65 is added to 00 with 0.868 g (3.6 mM) of silver toluenesulfinate and stirred for 1 hour in an ice bath. The precipitated precipitate is filtered off. The filtrate taken up in toluene and shaken out with saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulfate and yields evaporation of amor fl 2- [4- (p-toluenesulfonylthio) -5- (α-t-butyloxycarbonyl- amine-d-phenylacetylamino) -2-oxoazetidin-1-yl] -3-methylene-SMOPSYT & - diphenylmethyl ester; thin layer chromatogram: Rf value about 0.55 (silica cinnamon. tcluen / ethyl acetate 3; 1); IR spectrum (methylene chloride): characteristic c l - risnisxa band at 2.95; 5.57; 5.70; 5.82; 6.21; 6.65 Em; yield 2.50 21- ' Obtained intermediate product can be further processed at folJ & HÖ @ way: _ 3) In a solution cooled to -700 of 2.50 g (5.0 mM) 2- [4- (p-toluene) sulfonylthio) -5- (α-t-butyloxycarbonylamino-d-phenylacetylamino) -2-oxoazine thidin-1-yl] -5-methylene-butyric acid diphenylmethyl ester in 250 ml of methylene chloride is introduced into an ozone-oxygen stream (0.5 mM ozone per minute) for 7 minutes.

After adding 1 ml of dimethyl sulfide, the solution is stirred for 1 hour without cooling and then evaporated in vacuo. The remainder is crystallized from methylene chloride / ether / hexane to give 2- [4- (p-toluenesulfonate) Nylthio) -5- (α-t-butyloxycarbonylamino-α-phenyl-acetylamino) -2-oxo- azetidin-1-yl] -5-hydroxycrotonic acid diphenylmethyl ester with melting point 1824819; vil spectrum (Enanone: λmax = 259 nm (<ï = 13400), In- spectrum (methylene chloride): characteristic bands at 2.92; 5.59; 5.85; 5.92; 6.05 (approach); 6.18; 6.68 um; Rf - value about 0.55 (silica gel: A solution of 0.54 g (0.7 mM) of 2- [4- (p-toluenesulfonylthio) -5- (α-t-butyloxycarbonylamino-d-phenylacetylamino) -2-oxo-azetidin-1-yl] - -5-hydroxycrotonic acid-diphenylmethyl ester in 20 ml of methylene chloride / methanol (1 = 1) solution for 15 minutes and then evaporated in vacuo. Pre- comparative layer chromatography of the residue on silica cable with toluene / ethyl acetate (1: 1) as eluent and eluting it in UV violet the clearly visible zone gives 2- [4- (p-toluenesulfonylthio) -5- (α-t-butyloxycar- bonylamino-α-phenylacetylamino-2-oxoazetidin-1-yl] -5-methoxy-crotonic acid thin layer chromatogram: ONTÖTGS At OOC with an excess of an ethereal diazomethane 4 diphenylmethyl ester, which is recrystallized from methylene chloride / diethyl ether / / hexane; melting point 204-2060; UV spectrum (ethanol): imax = 259 nm (Es = 16,000); IR spectrum (Nujol): characteristic bands at 2.95; 5.58; 5.80; 5.84; 5.95; 6.24; 6.57 um; thin layer chromatogram: Rf value about 0.55 (silica gel: toluene / ethyl acetate 1: 1).

A mixture of 670 mg (1 mM) 2 - [& - (p-toluenesulfonylthio) - -5-phenylacetamido-2-oxoazetidin-1-yl] -5-methoxy-crotonic acid-diphenylmethyl toluene / ethyl acetate 1: 1); Lnbyte1, ÖÛ E- 10 15 20 25 50 35 40 7807810- "2 66 tyl ester, 6.7 ml of 1,2-dimethoxyethane and 0.22 ml of 1,5-diazabicyclo [5.4.0] the undec-5 is stirred for 25 minutes at room temperature under a nitrogen atmosphere.

The reaction mixture is diluted with toluene and washed successively with 2 N hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. The residual residue gives after preparative tgock- _ layer chromatography on silica gel with toluene / ethyl acetate (1: 1) 7S-phenyl- acetamido-5-methoxy-cef-2-em-4d-carboxylic acid diphenylmethyl ester with melting point 166-16 ° (from methylene chloride / hexane); yield 430 mg; UV- spectrum (ethanol) λmax = 258 nm (δ = 400); IR spectrum (methylene- chloride): characteristic bands at 2.93; 5.62; 5.73; 5.95; 6.66 Pm; Rf value about 0.54 (silica1; toluene / ethyl acetate system 1: 1) and Amorphous 7β-phenylacetamido-3-methoxy-cep-3-em-4-carboxylic acid diphenylmethyl tylestergic UV spectrum (ethanol): λmax = 258 nm (α = 6350), 264 nm (á: = 6350), 282 nn1 ([f = 'S60O) (ansats); IR spectrum (methylene chloride) characteristic bands at 2.94; 5.63; 5.83; 5.94; 6.26; 6.66 pm, _ Rf value about 0.37 (silica gel; system toluene / ethyl acetate 1: 1] in one, ratio of 8: 1, yield 54 mg. x The further processing can take place as follows: 5 75-Phenylacetamido-5-methoxy-cep-2-em-40-carboxylic acid diphenylmethyl analogous to Example 17c) can be converted to 7S-phenylacetamido- -5-Methoxy-cep-} -em-4-carboxylic acid diphenylmethyl ester-1-oxide with melt- points 152-1550 (from acetone / diethyl ether); Rf value = 0.51 (silica gel; system: e: ylacetate); UV spectrum (in 95% ethanol) = Ülnax = 288 nn (Öfà 5610) and approach at Fi = 247 nm; IR spectrum (methylene chloride rich characteristic band at 2.94; 5.59; 5.81; 5.95; 6.22 and 6.61 um.

A purer product, consisting essentially of 7B-phenylacetate amido-5-methoxy-cef-5-em-4-carboxylic acid diphenylmethyl ester-1B oxide, can be obtained as follows: A solution of 6.7 g (10 mM) 2- [4- (p-toluenesulfonylthio) -5- phenylacetamido-2-oxoazetidin-1-yl] -5-methoxyisocrotonic acid diphenyl- methyl ester in 67 ml of abs tetrahydrofuran is stirred at 200 for 15 minutes with 2.28 ml (15 mM) of 1,5-diazabicyclo [5.4.0] undec-5-ene, add> with 0.7 ml of glacial acetic acid and then evaporated in vacuo. The oily one the dark residue is dissolved in 30 ml of methylene chloride and shaken out successively with 15 ml of water, 10 ml of 0.5 N hydrochloric acid, 10 ml of saturated aqueous sodium bicarbonate solution and 10 ml of water. The aqueous phases extracted with 10 ml of methylene chloride, the organic extracts and stir for 15 minutes in an ice bath at 0 DEG with 2.24 ml of 40%. 10 15 20 25 50 35 40 7807810-2 67 Deracetic acid. The reaction mixture is then added with a solution. 1.50 å (6 HM) fl abrium fi iSulfate pentahydrate in 20 ml water and stir for 10 minutes; the aqueous phase is separated. The organic the phase is washed Mxeüigare with 10 ml of water, dried over sodium sulphate and evaporate under vacuum. Crystallization of the solid residue from Methyl flfl-doridylpetrdmmneter gives 7fi-phenylaoetamido-3-methoxy-cef-3-em-4-- carnoxylic acid diphenylmethyl ester-β-oxide, m.p. 175 DEG-176 DEG C. layer chromatogram (silica gel): Ef value approx. 0.1 (toluene / ethyl acetate 1: 1); UV spectrum (aenol): λmax = 279 nm (δ = 7300); IR spectrum (methylene ~ chloride): karahteristishamnínafid 2,9q; 5.55, 5.75; 5.91; 5.20¿6.57 Fm; yield 3.31 g From the 1-oxides can be obtained analogously to examples 7B-phenylacetamido-3-methoxy-cef-3-em-carboxylic acid diphenylmethyl ester.W From this one can obtain by saponification analogous to example öe) crude TE-phenylacetamido-3-methoxy-cef-5-em-4-carboxylic acid, which can be by chromatography on silica gel, containing 5% water, with methylene chloride, containing 30-50% acetone and subsequently lyophilization from dioxane; UV spectrum (in 95% ethanol): § \ maX = 265 nm (¿f = 5800); 1H spectrum (methylene chloride): characteristic rist bands at 3.03; 5.6o, 5.714; 5.92-, 6.211; and 6.67 Fm.

Starting materials and intermediates can be obtained from way: a) A mixture of 57.24 g (0.1 M) potassium salt of penicillin G- in 90 ml of water, 7.5 ml of acetone and 150 ml of chloroform were added stirring at 0 DEG for 40 minutes with 19.4 ml of 40% peracetic acid.

After a further 15 minutes, the portion is added at the same temperature. 28 g (0.15 M) of benzophenone hydrazone, then 6.3 ml of 1% aqueous potassium iodide solution and finally in 1.5 hours dropwise a mixture of 52.5 ml of 10% sulfuric acid and 28 ml of 40% percent peracetic acid. After the addition is complete, stir for 30 minutes at 0 DEG C., heat to 150 DEG C. and dilute with 400 ml of chloroform. The the aqueous phase is separated and the organic phase is washed cessively with 500 ml of 5% aqueous sodium bisulfite solution, BCC ml saturated aqueous sodium bicarbonate solution and 500 ml saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated in vacuo. The evaporation residue is recrystallized from ethyl acetate / petroleum ether to give 6-phenylacetamidopenicillanic acid diphenylmethyl ester-1β-oxide; melting point 1590; thin layer chromatogram (silica gel): Rf value about 0.40 (system: toluene / ethyl acetate 1:13; IR spectrum (methylene chloride): characteristic bands at 2.94; 5.56; 10 15 20 25 50 35 HO 78Û78¶0 ~ 2 68 5,705 5.92 and 6.57 um; yield 48.05 g (about 92% of theory) b) A mixture of 5.165 g (10 mM) of 6% phenylacetamidopenicillanic acid di- phenylmethyl ester-1β-oxide in 50 ml of toluene and 0.5 ml of glacial acetic acid are added with 1.85 g (11 mM) of 2-mercaptobenzothiazol è ygkesgh in one with an aqueous separator equipped with reflux boiler. When cooling crisis- ' tallies 2- [4- (Benzuezole-qq-dithio) -5-phenylacetamido-2-oxoazetidine-1- -yl] -5-methylene-butyric acid diphenylmethyl ester spontaneously. After recrystallization crystallization once from methylene chloride / diethyl ether crystals are obtained with melting point 134-1560; thin layer chromatogram (silica gel): Rf- value about 0.52 (system: toluene / ethyl acetate 1: 1); UV> spectrum (ethenol): λ max 269 nm (2 '= 12 700); IR spectrum (methylene chloride): characteristic band at 2.90; 5.60; 5.725 5.92 and 6.61 μm; yield 3.27 g.

C] The intermediate obtained under b) need not be isolated for further processing. After cooling, the reaction diluent can be diluted immediately. mixture with 50 ml of toluene, add 5.95 g (15 mM) of silver-p-toluene. ensulfinate and stir for 2 hours at room temperature. Outcome, yellow fold The filtrate shake with saturated aqueous sodium chloride solution, wipe dry filtered off over Hyflo and washed with toluene. sodium sulfate and evaporated in vacuo. The evaporation residue is taken in toluene and added with petroleum ether. The precipitate is filtered off. and recrystallized from ethyl acetate / petroleum ether. Received Ethyl (p-toluenesulfonylthio) -5-phenylacetamido-2-oxoazetidin-1-yl] -5- methylene butyric acid diphenylmethyl ester has a melting point of 750; thin- layer chromatogram (silica gel): Rf value about 0.47 (system: toluene / / ethyl acetate 1: 1); UV spectrum (in ethanol):) \ max = 259 nm (ë_ = Ä500); Ill spectrum (methylene chloride characteristic band at 2.92, - 5.62, - 5,? Ä; 5.94 and 6.65 μm; yield 4.05 g. 0 fql_ The intermediate obtained can be further processed on o way: d) A solution of 655 mg (1 mM) of 2- [4- (p-toluenesulfonylthio) -5-phenylacetate amido-2-oxoazetidin-1-yl]] - 5-methylene-butyric acid diphenylmethyl ester in 65 ml of methylene chloride is treated at -65 ° with a mixture of ozone and oxygen to light blue staining. After addition of 0.5 ml of dimethyl sulfide allow the mixture to warm to room temperature and evaporate under vacuum. Obtained crude 2- [4- (p-toluenesulfonylthio) -5-phenylacet- amido-2-oxoazetidin-1-yl] -5-hydroxy-crotonic acid diphenylmethyl ester 'can be further processed without further purification; Rf value about C, 46 (silica- gel; system: toluene / ethyl acetate 1: 1 »IR spectrum (methylene chloride): characteristic trajectory at 2.95; 5.60; 5.98; 6.18; 6.61 um; yield 744 mg. e) The crude product obtained under d) is dissolved in 20 ml of methanol and 10 15 20 25 35 UO 7807810-2 69 is added at 0 DEG to an ethereal solution of diazomethane to the residue yellowing. After evaporation of the solvent in vacuo the residue is purified by preparative thick layer chromatography on silica kagel with toluene / ethyl acetate (1: 1) as eluent. You are- contains 2- [4- (p-toluenesulfonylthio) -3-phenylacetamido-2-oxoazetidine- -1-yl] -3-methoxy-crotonic acid diphenylmethyl ester; Rf ~ value about 0.2 (silica gel; system: boluen / ethyl acetate 1: 1); IR spectrum (methylene chloride): characteristic bands at 2.94; 5.61; 5.96; 6.24; 6.62 pm; yield 522 mg (90% of theory); plus small amount 2- [§- (p- -toluenesulfonylthio) -3-phenylacetamido-2-oxoazetidin-1-yl] -3-methoxy- -isocrotonic acid diphenylmethyl ester.

EXAMPLE 8. In analogy to Example 5 d), by reaction of 1.16 (3 me) of 7β-amino-3-methoxy-cef-3-em- obtained according to the invention -Q-carboxylic acid hydrochloride dioxanate with 1.5 ml (6.2 mM) bis- (trimethylsilyl) -acetamide and then a) with 765 mg (3.6 mM) of D-U -vc- (z-ßienyl) -acetic acid kioria-neydrochioria obtain vp- [ü-oé-amino- thienyl) -acetylamine-3-methoxy-3-cephem-α-carboxylic acid in the form of internal salt; melting point 140 ° (decomposition); thin layer chromatography on likagel; identification with iodine): Rf about 0.22 (system: n-butanol / tic acid / water 67:10:23) and Rf about 0.53 (system: isopropanol / mire ~ acid / water 77: ä: l9); UV absorption spectrum:> Lmax = 235 nm (Ö = 1 11 1100) and 1 approach = 272 mn (5 = 6100) in 0.1 N saitsyr-a and Åmax = 238 nm (6 = 11800) and Vkansats = 267 mn (6 = 6500) in 0.1 N aqueous sodium bicarbonate solution; b) with 9ü0 mg (0.5 mM) D - amino> amino- (1,1H-cyclohexadienyl) -acetic acid hydrochloride obtain 7B-š-Oßamino-G & (1,1-cyclohexadienyl) -acetylamine-3-methoxy-3-cephem -U-carboxylic acid in the form of inner salt; melting point 1700 (decomposition); thin layer chromatogram (silica gel; identification with iodine): Ef approx 0.19 (system n-butanol / acetic acid / water 67:10:23) and Rf about 0.58 (system: isopropanol / formic acid / water 77: Ä: 19); UV absorption spectrum max 267 nm (E, = 6300) in 0.1 N hydrochloric acid and Ämax = 268 nm (f = 6600) in 0.1 N aqueous sodium bicarbonate solution; + 88 ° 1 10 (c = 1.06; 0.1 N hydrochloric acid); o c h c) with 800 mg (3.6 mM) of D-Weamino-4-hydroxy-phenylacetic acid hydrochloride chloride to give Tfi-LD-Q-amino-β (4-hydroxyphenyl) -acetylamino] -3-methoxy- -3-cephem-U-carboxylic acid in the form of inner salt; melting point 2ü3-2üü, 5 ° (sintering starts from 2310) (decomposition); thin layer chromatogram (silica gel; identification with iodine): Rf about 0.24 (system: n-buta- nol / acetic acid / water 67:10:23) and Rf about 0.57 (system: isopropane zero / formic acid / water (77: U: 19); UV absorption spectrum:; \ max = 228 Inch! 7807810-2 70 ' nm _ (í = 12000) and 271 nm (i = 6900) 1 0.1 N coincidence and Amax = 227 nm (i = 10500) and Å approach = 262 nm (2 = 8000) 1 0.1 N aqueous sodium bicarbonate solution containing [QJÉO = + 165 ° 1 10 (c = 1.5; 0.1 N hydrochloric acid).

EXAMPLE 9. Analogously, from suitable, according to the invention intermediate products the following compounds are prepared: Y fi-amino-5-methoxy-5-cephem-4-carboxylic acid diphenylmethyl ester; IN thin layer chromatogram (silica gel): Ef = 0.17 (system: ethyl acetate 1) development with iodine); ultraviolet absorption spectrum (in 95'Pbocen- aqueous ethanol): λ (max = 258 nm (Z = 5700); infrared sorption spectrum (in dioxane): characteristic bands at 2.87 μm, 5.62 Fm and 6.26 Fm; 5-n-Butyloxy-7β-phenylacetylamino-5-cephem-U-carboxylic acid dife- nylmesyieszer; mp 168-170 °; [ chloroform); ultraviolet absorption spectrum (in 95% water ethanol content): Å_max = 264 nm (Et = 7500); infrared absorption spectrum rum (in methylene chloride): characteristic band at 2.98; 5.62; 5.81; 5.92; 6.25 and 6.62 Pm; 5-n-butyloxy-7% - (D-Q-t-butyloxycarbonylamino-N-phenyl-acetyl- amino) -5-cephem-4-carboxylic acid diphenylmethyl ester; j xjso = '+ 110 3 1 (0 = 0.98 in chloroform); ultraviolet absorption spectrum (in 95- max = 2614 mn (E = 6100); infra- red absorption spectrum (in methylene chloride): characteristic bands at 2.88; 5.65; 5.8Ä (approach); 5.88, 6.26 and 6.71 μm; _ 5-n-butyloxy-7β- (D-M-phenyl-glycylamino) -3-cephem-α-carboxylic acid; melting point 1ü1-1U2 °; thin layer chromatogram (silica gel): If approx 0.21 (system: ethyl acetate / pyridine / acetic acid / water 62: 21: 5:11); ultraviolet absorption spectrum (in 0.1 N aqueous sodium hydrogen carbonate solution):) \ max = 267 nm (â = * 7500); 5-methoxy-β-phenylacetylamino-5-cephem-α-carboxylic acid methyl ester; mp 171-17 ° after recrystallization from methylene chloride and hexane fi jšo = + 1020 1 10 (c = 0.95 in chloroform); ultraviolet soprtion spectrum (in 95 * Percent aqueous ethanol):) \ maX = 265 nm (δ: = 6250); Infrared absorption spectra (in methylene chloride): characteristic band at 2.93; 5.62; 5.76; 5.95; 6.2 Å and 6.65 Pm; 3-ethoxy-¶% - (D-Q-t-butyloxycarbonylamino-N-phenyl-acetylamino) - -5-cephem-H-carboxylic acid diphenylmethyl ester; thin layer chromatography (silica gel): Rf about 0.28 (system: toluene / ethyl acetate 5: 1); ultra- Violet absorption spectrum (in 95% aqueous ethanol): O percent aqueous ethanol):> \ = 258 nm (f = 7000) and Åmax = 261! nm (f: 6900); infrared- IIIaX 7807810-2 71 absorption spectrum (in methylene chloride): characteristic bands at 2.96; 5.6ü; 5.90; 6.28 and 6.73 μm; 3-ethoxy-N- (D-phenyl-glycylamino) -3-cephem-N-carboxylic acid; thin layer chromatogram (silica gel): Rf about 0.17 (system: ethyl acetate ~ 1 tat / pyridine / acetic acid / water 62: 21: 6: 11); ultraviolet absorption spectrum (in 0.1 M aqueous sodium bicarbonate solution): Å = 265 nm <â = 5500); 3-Benzyloxy-¶% - (D-Oct-butyloxycarbonylamino-o-phenyl-acetyl- amino) -3-cephem-4-carboxylic acid diphenylmethyl ester; thin layer chromato- grams (silica gel development with iodine): Rf about 0.3H (system: toluene / ethyl acetate 3: 1); ÜxJšO = + 7 ° f 10_ (c = 0.97 in chloroform); _ Ultraviolet absorption spectrum (in 95% aqueous ethanol): Amax = 250 mo <í = 6000) ooh zon om <§ = 6800) ooo Aansats = 280 nm (_ = 6300); infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96; 5.63; 5.88; 6.26 and 6.72 μm; 3-Benzyloxy-7β- (D-Ophenyl-glycylamino) -3-cephem-U-carboxylic acid in zwitterionic form; thin layer chromatogram (silica gel): Rf = 0.17 (system: ethyl acetate / pyridine / acetic acid / water 62: 21: 6: 11); ultraviolet light absorption spectrum (in 0.1 N aqueous sodium bicarbonate solution): Å.maX = 266 nm (â = 6500); 7% - (5-benzoylamino-5-diphenylmethoxycarbonylvalerylamino) -3- -methoxy-3-cephem-H-carboxylic acid diphenylmethyl ester; thin-layer chrome togram (silica gel): Rf = 0.05 (system: toluene / ethyl acetate 1: 1), Ultraviolet absorption spectrum (in 95% aqueous ethanol): Approach = 258 om (f: 71450), 2614 om (j = 7050) ooh 268 om (2_ = 6700); Infrared absorption spectrum (in methyl chloride): characteristic rist bands at 5.65; 5.78; 6.03 and 6.6U Pm; 75- (D-6-t-butyloxycarbonylamino- fenphenyl-acetylamino) -3-methoxy- -3-cephem-H-carboxylic acid; thin layer chromatogram (silica1); iden- iodination): Rf about 0.6U (system: n-butanol / acetic acid / aqueous at 67:10:23); ultraviolet absorption spectrum (in 95% water containing ethanol): λmax = 26U nm (: = 100100); infrared absorption spectrum (in methylene chloride): characteristic bands at 3.00; 5.6H; 5.92; 6.25 and 6.72 Pm; 75-: D-β-Butyloxycarbonylamino-β- (2-thienyl) -acetylamino-5- -methoxy-3-cephem-H-carboxylic acid diphenylmethyl ester; thin layer chromato- gram (silica gel): identification with ultraviolet light Å ~ = 25ü nm); Rf about 0.3U (system: diethyl ether); EQ go = + 260 3 10 (c = 0.86 i chloroform); ultraviolet absorption spectrum (in 95% water haitig ethanol »- ^ _ = 2110 nm_ (¿f = 12500) ooh 280 om (f = 6000); maX 10 15 20 25 STAY 35 7807810-2 72 Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.93; 5.62; 5.85; 6.26 and 6.72 Pm; H5-iD <1-t-butyloxycarbonylamino-Nk (1,1-cyclohexadienyl) -acetyl- amino] -3-methoxy-5-cephem-α-carboxylic acid diphenylmethyl ester; thin-layer chromatogram (silica gel; identification with diethyl ether): Rf about 0.39 (system: diethyl ether); ßX1 šo = + 10 1 1 ° (c = 0.745 in chloroform); Ultraviolet absorption spectrum (in 95% aqueous ethanol): Å max š 263 nm <2; 26700) and Ä approach = 280 mn red absorption spectrum (in methylene chloride): characteristic bands at 2.96; 5.6U; 5.86; 5.90 (approach); 6.27 and 6.73 μm; 73-: D-3-t-Butyloxycarbonylamino-0% (4-hydroxyphenyl) -acetylamine -3-methoxy-3-cephem-U-carboxylic acid diphenylmethyl ester; thin-layer chrome _togram (silica gel; identification with iodine): Ef about 0.55 (system: toluene / ethyl acetate 1: 1); Ultraviolet absorption spectrum (in 95% aqueous ethanol): Λmax = 276 nm (λ = 7400); infrared absorption spectrum (in methylene g chloride): characteristic band at 2.85; 2.96; 5.6B; 5.86; 5.91 (shoulder); 6.23; 6.28; 6.65 and 6.72 Pm: 7β-ED-N-t-butyloxycarbonylamino-1- (4-isothiazolyl) -acetylamino- -3-methoxy-2-cephem-HN-carboxylic acid diphenylmethyl ester; melting point 1700 (after crystallization from a mixture of methylene chloride and pentank; ÅÜJM šo = + 1H7 ° j 10 (c = 0.79 in chloroform); thin layer chromatogram (silica gel identification with iodine): Rf about 0.68 (system: toluene / / ethyl acetate 1: 1); ultraviolet absorption spectrum (in 95% aqueous ethanol): Atmax = 248 nm (= = 10700); infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96; 5.65; 5.75; 5.87; 6.18 and 6.72 μm; Y fi- ÄD-d-t-butyloxycarbonylamino-d- (Ü "β-thiazolyl) -acetyleminol ' -5-methoxy-5-cephem-4-carboxylic acid diphenylmethyl ester? (C = 0.65 in chloroform); thin layer chromatogram (silica gel; identical iodination): Rf about 0.1 H3 (system: toluene / ethyl acetate 1: 1); ultraviolet absorption spectrum (in 95% dry aqueous solution). no1) = f'-max = 250 nm (Z = 12200) and 280 nm (Z = 5900); infrared- absorption spectrum (in methylene chloride): characteristic bands at 2.9ü; 5.55; 5.71 (approach); 5.88; 6.28 and 6.73 Pm. __ '- ,.

Claims (7)

43, 7807810-2 PATE§l§ß§¶, 1. 3-methylene butyric acid derivative for use as an intermediate in the synthesis of 5-cephem compounds with antibiotic properties, characterized by the formula: a * ÄN 12 f: H / \ § ___ § / S'Y | (IV) o = ._. L H \ - š-z-cn3 O: -rg vari R? represents hydrogen, an acyl group of the formula: Ra - (X) m - FH - C ~ (B), Rb wherein Ra represents phenyl, hydroxyphenyl, hydroxychlorophenyl, thienyl, pyridyl, aminopyridinium, furyl, isoamyl, tetrazolyl or 1,4-cyclohexadienyl and wherein in such groups the hydroxy substituents may be protected with optionally halogenated lower alkoxycarbonyl groups and wherein X represents oxygen or sulfur and m represents 0 or 1 and R b represents hydrogen or, when m represents O, optionally with α-polygrenated lower alkoxycarbonyl, optionally lower alkoxycarbonyl, optionally lower alkoxy- or nitro-substituted phenyl lower alkoxycarbonyl, trityl or 1-lower alkoxycarbonyl-2-propylidene protected amino, optionally with phenyl lower alkyl protected carboxy or sulfo or optionally with α-polybranched lower alkoxycarbonyl or formyl protected hydroxy or O-lower alkylphosphono or O , O'-di-lower alkylphosphono, or a 5-amino-5-carboxivalivalyl group, wherein the amino group is optionally protected with lower alkanoyl, halo lower alkanoyl, benzoyl or fta loyl and the carboxy group optionally with phenyl lower alkyl, and wherein R lower alkoxycarbonyloxy or lower alkanoyloxy and Y represents a leaving group consisting of benzenesulfonyl, p-toluenesulfonyl, O-methoxybenzenesulfonyl, p-methoxybenzenesulfonyl or p-nitrobenzenesulfonyl, and salts thereof. Z. Compounds of formula IV according to claim 1, k e n n e - t e c k n a d e thereof, that R? represents hydrogen, phenoxyacetyl, D-α-t-butyloxycarbonylamino-d-phenylacetyl or phenylacetyl, 7α7s10-2 2, Z, 2-tril chloroethoxy. 3. A process for the preparation of 3-methylene butyric acid compounds according to claim 1, characterized in that a) a compound of the formula: a O R 5 g H 2 / z 2 / CH 3 (III), O = --- $ CH \. 3 O = ¿-RA vari R? and R 1a has the meaning given in claim 1, with a sulfinic acid of the formula H1Y or a sulphonyl cyanide of the formula NšCY, wherein Y has the meaning given in claim 1, or b) a compound of the formula: a R 1 a * f: - - ssR H \: ____ ñ / 4 I (Ivalr o = --- NH \ .- fi_ aæ fi3 o = ¿-now where R? And Râ have the meaning given in claim 1 and R4 represents benstiazole or benšoxazole with a heavy metal sulfinate of the formula Mn + (-Y) n, wherein M represents a heavy metal cation and n represents the valence of this cation, and optionally in a obtained compound of formula IV transfers the protected carboxy group of formula -C (= O) -R e to another protected carboxy group and / or optionally within the definition of the final products transfer a obtained compound to another compound and / or optionally transfer a obtained compound having a salt-forming group to a salt or a salt obtained to a free compound or to another salt and / or optionally obtained mixture of isomers in the individual isomers. 75. 7807810-2 4. A process according to claim 3, characterized in that the reaction of a starting material of formula (III) with a sulfinic acid or a sulfonyl cyanide in a solvent or a solvent mixture is carried out. Process according to Claim Å or 4, characterized in that the reaction of the starting materials of the formula (III) is carried out with a sulfinic acid of the formula HY in an inner solvent at the reflux temperature of the solvent used. 6. A process according to claim 3, characterized in that as a heavy metal cation Mn + in a heavy metal sulfinate of the formula Mn + (~ Y) n one or two-fold cations of copper, mercury, silver or tin are used. Process according to either of Claims 3 and 6, characterized in that the reaction of the starting materials of the formula IVa is carried out with a heavy metal sulfinate of the formula Mn + (-Yln in an inert solvent, in water or in a solvent mixture consisting of water and a water-miscible solvent. __ .___. _.._.___....._-......_._._-_-._._-.