SE438855B - 3-HYDROXICROTONIC ACID DERIVATIVES FOR USE AS INTERMEDIATE IN THE SYNTHESIS OF 3-CEFEM SUBSTANCES - Google Patents

Description

10 15 20 25 30 35 7807811-0 2 benzenesulfonyl, and salts thereof.

A lower alkyl group R; has up to 7, preferably up to to 4 carbon atoms, and is especially methyl.

Lower alkyl is, for example, methyl, ethyl, nepropyl, isopropyl, n-butyl, isobutyl, s-butyl or t-butyl, also n-pentyl, isobenzyl, n-hexyl, isohexyl or n-heptyl.

Phenyl lower alkyl is, for example, benzyl, 1-, 2- or 3-phenyl- propyl, diphenylmethyl or trityl. ' Lower alkoxy is, for example, methoxy, ethoxy, n-propyloxy, iso- propyloxy, n-butyloxy, isobutyloxy, s-butyloxy; t-butyloxy, nrpentyloxy or t-pentyloxy. These groups may be sub- such as in halogen lower alkoxy, especially zehalogen low alkoxy, for example 2,2, Z-trichloro-, 2-chloro-, Z-bromo- or 2-iodo-toxic.

Phenyl lower alkoxy is, for example, benzyloxy, 1- or Z-phenylethoxy, diphenylmethoxy or 4,4'-dimethoxydiphenylmethoxy.- Lower alkoxycarbonyl is, for example, methoxycarbonyl, ethoxy- carbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, t-butyloxy- carbonyl or t-pentyloxycarbonyl. Lower alkanoyl is, for example, formyl, acetyl, propionyl or pivaloyl. _ _ 'i I In O-lower alkylphosphono, for example, O-methyl- or O-ethylphosphono- phono, 0,0'-lower alkylphosphono, for example O, O'4dimethylphosphono or 0,0'-diethylphosphono, -O-phenyl lower alkylphosphono, eg O-benzulfosphono, and O-lower alkyl-O'-phenyl lower alkylphosphono, for example O-benzyl-O'-methyl- phosphono. '_ Phenyl lower alkoxycarbonyl is, for example, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, diphenylmethoxycarbonyl or α-4-bi- phenyl-α-methyloxycaronyl.

An etherified hydroxy group R bonyl grouping one, preferably readily cleavable or readily to another functionally converted carboxy group, such as to a carbamoyl or hydrazinocarbonyl group, convertible, esterified such a group Raw is, for example, lower alkoxy, such as methoxy, ethoxy, n-propyloxy or isopropyloxy, which are together with the caroonyl grouping forms an esterified carboxylate group, which especially in 2-cephem compound can be easily transferred to a free carboxy group or to another functional modified carboxy group. 10 15 20 25 50 H0 7807811-0 An etherified hydroxy group Hg, which together with a grouping -C (= O) - forms a particularly easily cleavable, forest- carboxy group, is, for example, 2-halogen lower alkoxy, wherein halogen preferably has an atomic weight above 19. Such a group forms together with the grouping -C (= O) - a by treatment with ke- chemical reducing agents under neutral or slightly acidic conditions looks, for example, with zinc in the presence of aqueous acetic acid, light cleavable, esterified carboxy group or one to such easily transferable, esterified carboxy group and is, for example, 2,2,2-tri- chloroethoxy or 2-iodoethoxy, further 2-chloroethoxy or 2-bromoethoxy, which can be easily transferred to the latter.

An etherified hydroxy group Râ , which together with the group the ring -C (= O) - also constitutes a by treatment with chemical reducing agents under neutral or slightly acidic conditions, for example by treatment with zinc in the presence of aqueous vinegar. acid, further by treatment with an appropriate nucleophilic reagent. such as sodium thiophenolate, readily cleavable, esterified carboxy group is phenacyloxy.

A lower alkyl group R; with up to 7, preferably with up to U carbon atoms, is suitably methyl or also ethyl, n-propyl, hexyl or heptyl. years' I A tri-lower alkylsilyl group R; is preferably trimethylsilyl.

Other readily cleavable hydroxy protecting groups R; is for example d-phenyl lower alkyl, such as benzyl and diphenylmethyl. f an intermediate of formula II is a leaving group Y for example a group -S-Ru or one with the sulfur atom at the pen -S-bonded group -SO 2 -R 5. "A In an intermediate of formula II, R represents 2 shows a etherified hydroxy group, which with the grouping -C (= O) - forms preferred an esterified, especially under the mild condition cleavable, esterified vascular boxing group, with any existing, functional groups in a carboxy protecting group Hg in a manner known per se, for example as specified, may be protected. A group Hg, for example, is special an optionally halogen-substituted lower alkoxy group, such as methoxy, α-polygrenal lower alkoxy, eg t-butyloxy, or 2-halogen lower alkoxy, wherein halogen is, for example, chlorine, bromine or iodine, primarily 2,2,2-trichloroethoxy, 2-bromoethoxy or 2-iodoethoxy, or an optionally substituted, such as lower alkoxy, eg methoxy, or nitro containing, 1-phenyl lower alkoxy group, as optionally, e.g. substituted benzyloxy or diphenylmethoxy, e.g. 7307811-0 g Å oxy, 4-methoxybenzyloxy, U-nitrobenzyloxy, diphenylmethoxy or 4,4'-dimethoxydiphenylmethoxy, furthermore an organic silyloxy or stannyloxy group, such as trilowalkylsilyloxy, e.g. trimethylsilyl oxy, or even halogen, eg chlorine. Preferably denotes in a intermediate of formula II group R? an amino protecting group RQ, such as an acyl group Ac, wherein optionally existing, free, functional groups, such as amino, hydroxy, carboxy or phosphonogroups. per, in a manner known per se may be protected, amino groups for example with the indicated acyl, trityl, silyl or stannyl groups substituted or substituted thio or sulfonyl groups, and hydroxy, carboxy or phosphono groups, for example with indicated ether or ester groups, including silyl or stannyl groups, and R draws hydrogen. “ In an intermediate of formula II, R represents; preferred o lower alkyl, especially methyl, or as hydroxy protecting group preferably a substituted silyl group, especially a trimethyl- silyl group, or an α-phenyl lower alkyl group such as benzyl or diphenylmethyl. _ Z 1 ~ The novel intermediates of formula II, wherein R; significant when hydrogen can be produced by joining an association with the formula a “NH s-y \\? __ ¿(// 3H2V '_ (IV) O __! = a-- --zu ó-cn A 2 5 O = C-R wherein R 1, R 2 and Y are as defined, treating the methylene group for oxidative decomposition with ozone and in it as an intermediate obtained the ozonite of the formula 8. 1 ïvnufg R sew / cn lo '(v) O \ ___C Lz .. 2 \ Û: i / CH _ 3 O = C-R N3> .wii -i., .. 10 15 20 25 30 55 7807811-0 5 A. n n. 2 and Y have the indicated meaning, opposite it to vari Rï, R an enolized oxo group by reductive cleavage and optionally in a obtained compound of formula II ', wherein Y represents a group -S-Ru, transfers the group -S-Ru to a group -SO; -R5 through treatment with a heavy metal sulfinate of the formula Mn (SO 2 -R 5) Å, wherein M represents a heavy metal cation and n represents this valence, and possibly within the definition of the end product transfer an obtained compound to another compound and / or optionally transferring a resulting compound having a salt-forming group to a salt or a salt obtained for free association or to another salt and / or possibly splits one obtained mixture of isomers in the individual isomers.

The new intermediates of formula II, wherein RB lower alkyl or a hydroxy protecting group, can be prepared thereby, denotes that in a compound of the formula: R? , I \ - ln f Icnš (IP) 0. "I '_'._' _: _ N ñ = c-on _ _ A a A 0-0 32 wherein R 1, R 2 and Y are as defined, transfer the enol group by etherification to a represented group -OR? and possibly in a obtained compound of formula II wherein Y represents a group -S-Ru, converts this group -S-Ru to a group -SO 2 -R 5 and / or even- currently within the definition of the final products transfer a received compound to another compound pch / or possibly transfer one obtained compound »with salt-forming group to a salt or a obtained salt in free compound or to another salt and / or even optionally divides a resulting mixture of isomers into the individual the isomers.

For the preparation of lower alkyl ethers and any substituents α-phenylalkylene ethers of formula II are thus used as etherification reactants, for example a corresponding diazo compound R 2 -N 2, for example a diazole alkane such as diazomethane, diazoethane, diazo n-butane or an optionally substituted d-phenyldiazole lower alkane, for example phenyl or diphenyldiazomethane. These reactants were used in the presence of a suitable inert solvent, such as an aliphatic cyclic, cycloaliphatic or aromatic hydrocarbon such as hexane, cyclohexane, benzene or toluene, a halogenated aliphatic carbon hydrogen, eg methylene chloride, a lower alkanol, eg methanol, ethanol or Q » (D _10 15 20 25 30 35 H0 mixture. 7807811-0 f, t-butanol, or an ether such as a lower alkyl ether, e.g. ethyl ether, or a cyclic ether, for example tetrahydrofuran or dioxane, or a solvent mixture and depending on the reactant during cooling, at room temperature or under slight heating, i under an inert gas, such as nitrogen. Furthermore, lower alkyl and optionally substituted α-phenyl lower alkylene ethers of formula II by treating with a reactive ester of further, if necessary, in a closed vessel and / or an enol compound of formula IIf a Suitable esters are in primarily those with strong inorganic or organic acids, for example, hydrohalic acids, such as hydrochloric, bromine, further sulfuric acid or halogenated sulfuric acid corresponding alcohol of the formula Hg-OH. such as mineral acids, hydrochloric or hydroiodic 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, trifluoromethanesulfonic or p-toluenesulfonic acid. These reactions aants, especially lower alkyl sulfate, such as dimethyl sulfate, further lower alkyl fluorosulphate, for example methyl fluorosulphate, or optionally halo- gene-substituted methanesulfonic acid lower alkyl esters, e.g. methanesulfonic acid methyl esters, or even the corresponding α-phenyl lower alkyl esters, for example benzyl and diphenylmethyl esters, such as benzyl or diphenylmethyl halides, such as chlorides or bromides, were used in the presence of a solvent, such as a possible halogenated such as chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbon, tetrahydrofuran, or a lower alkanol, such as ethanol, or a solvent In doing so, one preferably uses suitable for example methylene chloride, an ether such as dioxane or condensing agents, such as alkali metal carbonate or hydrogen bonate, eg sodium or potassium carbonate or bicarbonate (usually together with a sulphate), or organic bases. so- which are usually sterically hindered, tri-lower alkylamines, for example N, N-di- isopropyl-N-ethylamine (preferably together with lower alkyl halo- gene sulphate or optionally halogen-substituted methanesulphonic acid lower alkyl esters), working under cooling, at room temperature. temperature or during heating, -20 ° C to about 50 ° C, and if necessary, in one eg at temperatures of approx closed vessel and / or in an inert gas atmosphere, eg nitrogen. \, "= 10 15 20 25 30 Hu 7807811-0 By phase transfer catalysis (see E.V. Dehmlow, Angewandte Chemie 5 / l97ü, page 187) the etherification reaction can significantly accelerated. As phase transfer catalysts can be used quaternary phosphonium salts and especially quaternary ammonium salts such as optionally substituted tetraalkylammonium halides, for example tetrabutylammonium chloride, bromide or iodide, or also benzyltriethylammonium chloride, in catalytic or up to molar amounts. immiscible solvent may be used, for example an optional halogenated, such as chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbon, such as tri- or tetrachlorethylene, di-, tri- or tetrachloroethane, chlorobenzene, in particular carbon tetrachloride, or also toluene or xylene. As condensing agents suitable alkalis lime metal carbonate or bicarbonate, such as potassium or sodium carbonate or bicarbonate, alkali metal phosphate, eg potassium phosphate barrels, and alkali metal hydroxides, such as sodium hydroxide, can at base-sensitive compounds are titrated to the reaction mixture so that The pH during the etherification remains between 7 and 8.5.

Lower alkylene ethers of formula II can also be prepared by treating an enol compound of formula II 'with a broad same carbon atom with aliphatic character two or three with lower alkyl etherified hydroxy groups of the formula Rë-O containing compound, ie with a corresponding acetal or orthoester, in the presence of one acidic agent. Thus, examples can be used as etherifying agents. for example Qem lower alkoxy lower alkanes, such as 2,2-dimethoxypropane, in being a strong organic sulfonic acid, such as p-toluenesulfonic acid, and a suitable solvent, such as a lower alkanol, e.g. nol, or a lower alkyl or lower alkylene sulfoxide, e.g. tylsulfoxide, or orthomyric acid trialkyl alkyl esters, e.g. acid triethyl ester, in the presence of a strong mineral acid, e.g. acid, or a strong organic sulfonic acid, such as p-toluenesulfonic acid ra, and a suitable solvent, such as a lower alkanol, e.g. ethanol, or an ether, for example dioxane, and thus obtain compounds of formula II, wherein R denotes lower alkyl, eg methyl or ethyl.

Lower alkylene ethers of formula II can also be obtained, if enol compounds of formula II 'are treated with tri-lower alkyl oxonium salts of the formula (R§) 30i? A (; (so-called Meerwein salt), also di-R 10 carbenium salts of the formula (HQO) 2 C fl t) A: ï or dír fl A ':, vari A 5 beteck- 5-halonium salts of the formula (R?), Hal¿t As the organic phase, any one with vat-I can 10 15 20 25 30 35 I: of 78047811-0 when the anion of an acid and Halty denotes a halonium ion, spe- cially a bromonium ion, and R? denotes lower alkyl. It's moving in this case primarily about tri-lower alkyloxonium salts and carbenium or lower alkyl halonium salts, especially the equivalent salts with complex fluorine-containing acids, such as the corresponding tetra- fluoroborate, hexafluorophosphate, hexafluoroantimonate or hexachloroborate roantimonat. Such reactants are, for example, trimethyloxonium or triethyloxonium hexafluoroantimonate, hexachloroantimonate, -hexafluorophosphate or tetrafluoroborate, dimethoxycarenium hexa- fluorophosphate or dimethyl bromonium hexafluoroantimonate. Man an- these excipients are preferably used in an inert solvent solution. agents, such as an ether or a halogenated hydrocarbon, e.g. ether, tetrahydrofuran or methylene chloride, or in a mixture hence, if necessary in the presence of a base, such as an organic base, e.g. one, preferably sterically hindered, tri-lower alkylmin, eg N, N-diisopropyl-N-ethylamine, and under cooling, at room temperature temperature or under slight heating, for example at about -20 ° C to about 5000, if necessary in a closed vessel and / or in an atmosphere of inert gas, such as nitrogen.- Compounds of formula II, wherein the hydroxy protecting group R; is a 2-oxa- or 2-thialiphatic or cycloaliphatic hydrocarbon group, is prepared by acid-catalyzed, for example with a strong mineral acid, such as sulfuric acid or hydrochloric acid catalyzed, storage of α, β-unsaturated, aliphatic or cycloaliphatic ethers or thio- ethers, such as 1-lower alkoxy low alkenes, eg 1-methoxyite or 1-methoxypropylene, 1-lower alkylthio low alkenes, such as 1-methylthioethylene or 1-methylthiopropene, oxa- or thiacyclo-low-alk-2-ones or -2, U-dienes with 5-7 ring atoms, eg 2,5-dihydrofuran, 2H-pyran, 3, U-dihydro-2H-pyran or equivalent analogous sulfur compounds, at the hydroxy group of a compound of formula II ' can be carried out in an excess of the unsaturated ether or ether and optionally 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. hrs Of silyl ethers, which are covered by formula II, i.e. compounds of formula II, wherein Hg represents a substituted silyl group, obtained according to something suitable for silylation of enol groups method, for example by treatment with a suitable silylation agents, such as with a dihalo lower alkyl silane, lower alkoxy lower alkyl 10 20 25 30 7807811-0 9 dihalosilane or tri-lower alkylsilyl halide, for example dichlorodimethyl- silane, methoxymethyldichlorosilane, trimethylsilyl chloride or dimethylsilyl t-butylsilyl 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 1,073,530), a hexa-lower alkyl disilazane, such as hexamethyldisilazane, or with a silylated carboxylic acid amide, such as a bis-trialkylsilyl acetamide, eg with for example bistrimethylsilylacetamide, or trifluorosilylacetamide.

I I a compound of formula II, wherein Bg represents lower alkyl or a hydroxy protecting group and Y represents a group the group -S-RÅ is transferred to a group -SO -R5 by reaction with a heavy metal sulfinate of the formula Mn (SO 2 -R 5); .

In a obtained compound of formula II, a group Ra, R 1, R 2 or R 3; transferred to another group Rï, Rï, Râ or RE, wherein analogous reactions can be used, as indicated for -S-Ru, can the conversion of these groups to compounds of formula IA or clay IV. _ The new, valuable intermediates of formula II can for example, according to the following reaction scheme, Ecologically valuable 75-amino-3-cephem-3-ol-4-carboxylic acid compound of formula IA or the corresponding 78-amino-2-cephem-3-ol-U-car- boxylic acid compounds of formula IB, which as such also are suitable as intermediates.

The procedure shown in the reaction scheme is distinguished compared to hitherto known procedures in that it is deleted from inexpensive, readily available starting materials, such as special l-oxides of the fermentatively manufacturable penicillins G or V and 6-aminopenicillanic acid, the reactive groups of which can protected in any known manner and after the reaction easily re-released and the preparation of those of the present invention required intermediate products are made in high yields. IN É7so7s11-o 10 H8., F) l ~ H H * NH,. S '"X / CHB Steglê 01:? HRS _ / cH5 (III) o = C-Râ s fi eg za, / ¿¶ _ //, / .Z Ra l \ NH ff III S-y 0 H 3 ¶ \\ T = Lc - on (II ') o = c-RQ II'a: Y - -S-RU II'b Y = -soz-R5 ¶ i teg ü Ra.

“NHF * šs-x oš: r_ï: / CH5 \ T == åf «» ~ oR§ (II) o = c-Ra hrs <1 u ' v- < IN l UJ O m | 50 u: <1 n: »<1 IN | m | : U 4: ' Example: Y = -SO-R step 5 10 lay 20 25 åO 7307311-o 11 now _ Ba 1 ~ m: H 'i «~“ nu H 1? “\ ~ ..H_í / Q- 4“ N 5 si == ._ ”i. edlll. - o / 045 o o H5 ow-Rz '° ”°" R2 (IA) '(IB) The starting compounds of formula III are known or can prepared according to known procedures.

Intermediates of the formula Ivs are also known or may be produced in accordance with Dutch Customs Code 72.05.3671.

Intermediate products of the formula Ivb can be obtained from compounds of formula III by reaction with a sulric acid with formula 3502-R5 or a sulronyl cyanide of the formula N50-SO2-H5.

The reaction takes place in an inert solvent or solvent mixture, 2 ex a possible halogenerab, such as chlorinated, ali- Substances, cycloaliphatic or aromatic hydrocarbons, such as pentane, boxes, oclohexene, benzene, toluene, methylene chloride, chloroform or chlorobenzene, elhulazali fi mical, eykloaliphatic or aromatic alcohol such as lower elkenol, for example methanol, ethanol, cyclobexanol or phenol, a polyhydroxy compound, for example a polyhydroxyalkane, such as dihydroxy low volcanic, eg ethylene or propylene glycol, a lower Recon, such as acetone or methyloylkecon, an ether loss solution agents such as diethyl ether, oxane or tetrahydrofuran, a lower carboxylic acid amide, such as dimebylformamide or dimethylacecide omid, a lower dialkyl sulfoxide, such as dimethyl sulfoxide, and the like nsnde or mixtures thereof.

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

The reaction with the sulfonyl cyanide of the formula N5C ~ SO2 ~ R5 isocellated by the addition of halogen anions releasing compounds sp, Suitable balossa anion releasing compounds are, for example guvacernary ammonium halides, in particular chlorides and bromides, as optionally substituted at the lower alkyl groups, e.g. oryl, such as phenyl, mono- or polysubstituted tetralagalkyl- ommonium halide, such as setraethyl or hensyltriethylammonium chloride or bromide. Halogen anion releasing compounds in amounts of about 1 to about 50 molar percent, preferably about 2 ~ about 5 moles fi. ' 10 15 20 ° 5 STAY 35 "H0 7807811-0 12 Compounds of formula IVb may also be obtained thereby, .converting a compound of formula IVa with a heavy metal sulfinate of the formula Mn + (SO2-R5) š, where M constitutes a heavy metal cation and n denote the valence of this cation. Suitable heavy metal sulfinate and thiosulfonate, in particular, are those used the reaction medium has a greater solubility product than those of the reaction medium. formed the heavy metal compounds of the formula Mn + (- S-R4) n.

Suitable heavy metal cations Mn + are especially those which form particularly insoluble sulphides. Among these are marked, for example monovalent or divalent cations of copper, mercury, silver and tin, with copper ++ and silver ++ cations being most suitable.

The heavy metal sulfinate or thiosulfonate can be used things as such or are formed in situ during the reaction, e.g. of a sulfinic acid of the formula HSO? -H5 or a soluble derivative thereof, for example an alkali metal salt, such as the sodium salt, and a heavy metal salt, the solubility of which is greater than that of the corresponding heavy metal sulfinate, for example a heavy metal nitrate, acetate or sulphate, for example silver nitrate, mercury (II) diacetate or copper (II) sulphate, or even a soluble chloride, such as tin (II) - chloride hydrate. ' The reaction of a compound of formula IVa with heavy the number sulfinate of the formula Mn + (SO2-R5) ¿can take place in an inert solvent, in water or in a solvent mixture consisting of water and a water-miscible solvent.

Suitable inert organic solvents are, for example, aliphatic cycloaliphatic or aromatic hydrocarbons, such as pentane, hexane, cyclohexane, benzene, toluene, xylene, or aliphatic, cyclic loaliphatic or aromatic alcohols, such as lower alkanols, eg methanol, ethanol, cyclohexanol or phenol, polyhydroxy compounds compounds such as polyhydroxyalkanes, for example dihydroxy lower alkanes, such as ethylene or propylene glycol, carboxylic acid esters, e.g. carboxylic acid lower alkyl esters such as ethyl acetate, lower ketones, such as such as acetone or methyl ethyl ketone, ethereal solvents, such as such as dioxane, tetrahydrofuran or polyethers, such as dimethoxyethane, lower carboxylic acid amides such as dimethylformamide, lower alkyl nitrite such as acetonitrile, or lower sulfoxides such as dimethyl sulfoxide. In water or especially in mixtures of watercress of the indicated solvents, including in emulsions, the reaction usually significantly faster than in the organic solution The means alone. 10 20 25 STAY H0 7807811-0 15 The reaction temperature is usually at room temperature. but can be lowered for retardation of the reaction or raised for acceleration of it, approximately up to the solvent used boiling point, whereby one can work at normal or even elevated print. IN In a obtained compound of formula IV, a group R or Râ is transferred to another group Râ, 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 steps 2 and 3 or 2a, a compound of formula IV by oxidative decomposition of the methylene group is transferred to a enolized oxo group in a compound of formula II.

The oxidative cleavage of the methylene group in the compound of formula IV to form an oxo group may be by treatment with ozone to form an ozonide compound with formula V. In this case, ozone is usually used in the presence of a solvent, 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 even 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, for example at temperatures of about -90 ° C to about + M0 ° C.

An ozonide of the formula Va obtained as an intermediate can optionally without isolation, is transferred to a compound of the formula Vb and Vc, respectively, by reaction with a heavy metal sulfinate having the meln Mn + (SO 2 -R 5); analogous to the turnover of compounds with meln IVa to compounds of formula IVb and IVc, respectively.

An ozonide of formula V can be reductively cleaved in step 3 to a compound of formula II ', wherein one can use catalytic activated hydrogen, for example hydrogen in the presence of a heavy metal generation catalyst, such as nickel catalyst, further palladium catalyst, preferably on a suitable support, such as calcium carbonate or carbon, or chemical reducing agents, such as heavy metals, including heavy metal alloys or amalgam, zinc, in the presence of a hydrogen donor, such as an acid, e.g. 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, e.g. acetic acid, or a reducing agent. sulphide compound, such as a lower alkyl sulphide, e.g. 10 l5 20 w 30 35 H0 7807811-0 w ' sulfide, a reducing-organic phosphorus compound, such as a phosphine, which may optionally contain substituted, aliphatic or aro- hydrocarbon groups such as substituents, for example trilowalkylphosphine fine, such as tri-n-butylphosphine, or triarylphosphines, such as tri- Uphenylphosphine, further phosphite, which contain as substituents optionally substituted aliphatic hydrocarbon groups, such as trilocal alkylphosphite, usually in the form of the corresponding alcohol adduct compound ar, such as trimethyl phosphite, or phosphoric acid triamides, which as substituents contain optionally substituted ali- phatic hydrocarbon groups, such as hexa-lower alkyl phosphoric acid triamides, eg Ihexamethylphosphoric acid triamide, the latter then preferably in the form of a methanol adduct, or the tetracyanate.

The cleavage of the usually non-isolated ozonide normally takes place under conditions used in its manufacture, ie g in the presence of a suitable solvent or solvent mixture even during cooling or light heating.

Enol compounds of formula II 'may also be present in more ketoform. i I.

An enol compound of formula II'a can be converted to a compound purification of formula II'b by reaction with a heavy metal sulphide. formula Mn + (SO 2 -R 5) Q analogous to the reaction of the compound ar of formula IVa to 'compounds of formula IVb. IN In a obtained compound of formula II ', a group Ra, R 1 or H 3 is transferred to another group Hi, R? or Bg, var- in analogous reactions can be used, as indicated for conversion. the addition of these groups to compounds of formula IA or IB.

According to step 5, according to the invention, obtainable compounds of formula II can be used to prepare 7β-amino-5-cephem I-3-ol-4-carboxylic acid compounds of formula IA, wherein R is hydrogen or an amino protecting group R? and R? is hydrogen or an acyl group Ac or R? and R1 together form a divalent amino protecting group, Rz represents hydroxy or a group Hg, which together with the carbonyl grouping -C (= O) - forms a protected carboxy group, and R 3 represents hydrogen or a group Ro, as well as 1-oxides of 3-cephem compounds of formula IA and the corresponding 2-cephem compounds of formula IB, in which R1, R1, R2 and H3 have or salts of such compounds with salt-forming groups. per. , In 2-cephem compounds of formula IB with double bond in 2,3-position shows the possibly protected carboxy group 10 20 75 30 35 A0 7807811-0 with the formula ~ C (= O) ~ R 2 preferably α-configuration.

Salts are especially those of compounds of formula IA and IB with an acidic grouping, such as a carboxy, sulfo or phosphono group, primarily metal or ammonium salts, such as alkali metal and alkaline earth metal salts, such as sodium, potassium, magnesium or calcium salts, as well as ammonium salts with ammonia or suitable organic amines, wherein for the salt formation in primarily concerns aliphatic, cycloaliphatic, cycloaliphatic political-aliphatic and araliphatic, primary, secondary or terrestrial mono-, di- or polyamines and heterocyclic bases, such as such as lower alkylamines, for example triethylamine, hydroxy lower alkylamines, for example 2-hydroxyethylamine, bis- (2-hydroxyethyl) -amine or tris- (2- hydroxyethyl) -amine, basic aliphatic esters of carboxylic acids, eg A-aminobenzoic acid 2-diethylaminoethyl ester, lower alkylene amines, eg 1-ethylpiperidine, cycloalkylamines, eg bicyclohexylamine, or benzylamines, for example N, N'-dibenzylethylenediamine, further pyridine-type, such as pyridine, collidine or quinoline. Before- 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 organic carboxylic acids or sulfonic acids, for example trifluoro- acetic acid or p-toluenesulfonic acid. Compounds of the formulas IA and IB with an acidic and an alkaline group may also be present in form of internal salts, ie in zwitterionic form. 1-oxides of compounds of formula IA with salt-forming groups can also be then salts, as described.

The compounds of formula IA and IB, respectively, are valuable pharmacological properties or can be used as intermediate for the production of such. Compounds of formula IA, wherein for example R? denotes a N-acyl derivative in pharmacologically active 6B-aminopenam-3-carboxylic acid or 7β-amino-3-cephem-U- carboxylic acid compounds present acyl residue Ac and R 1 denote hydrogen or wherein Râ and Hg together represent one in the 2-position preferably, for example with an aromatic or heterocyclic group, and in the U-position preferably, for example with 2-lower alkyl, such as methyl, substituted 1-oxo-3-aza-1, H-butylene group, R 2 represents hydroxy or a substituted hydroxy group Râ, which together with the carbonyl group forms one easily under physiological conditions cleavable, esterified carboxy group, and H3 represents lower alkyl, wherein in an acyl residue R? any existing, functional groups _ 78iÜ7811-0 16 10 15 20 fl s H0 per, such as amino, carboxy, hydroxy and / or sulfo, usually present in free form, or salt of such compounds with saline forming groups are by parenteral and / or oral administration at low toxicity to microorganisms, such as gram-positive bacteria, such as Staphylococcus aureus, Streptococcus pyogenes and Diplococcus pnedmoniae, (e.g. in mice in doses of about 0.001-about 0.02 g / kg subcutaneously or oral) and gram-negative bacteria, e.g. Escherichia coli, Salmonella typhímurium, Shigella flexneri, Klebsiella pneumoniae, Enterobacter cloacae, Proteus vulgaris, -Proteus rettgeri and Proteus mirabilis (eg in mice at doses of about 0.001-approx 0.15 g / kg subcutaneously or orally), especially also in relation to penicillin-resistant bacteria. These new associations can therefore be used, for example, in the form of antibiotically active preparations for the treatment of similar infections. 7 _ Compounds of formula IE or 1-oxides of compounds of formula IA, wherein H 1, R 1, R 2 and H 3 are in association with the meanings given in formula IA, or compounds of formula IA, wherein R3 has the meaning given, the groups R? and R 1 is hydrogen or Râ denotes an N-acyl derivative from a pharmacologically active one 6β-amino-penam-3-carboxylic acid or 7β-amino-3-cephem-U-carboxylate boxylic acid compounds present acyl residue separate amino protecting group and R? denotes hydrogen or R? and R? together denote a from a 2-position preferably, for example with an aromatic or nheterocyclic group, and in the U-position preferably, e.g. Lower alkyl, such as methyl, substituted 1-oxo-3-aza-1,4-butylene- group separated, divalent amino protecting group and H2 represents hydroxy or R 1a and Hg have the meaning given, R 2 represents a group R 1a, which together with the grouping -C (= 0) - forms one, preferably easily cleavable, protected carboxy group, whereby a dad carboxy group is separated from a physiologically cleavable carboxy ~ group and R3 have the meaning indicated, are valuable intermediates, which in a simple manner, e.g. as will be described, can be transferred to specified, pharmacologically active compounds.

The present compounds are suitable for the preparation of 3 ~ cephem compounds of formula IA, wherein R: represents hydrogen or in a fermentative (i.e. s-naturally occurring) or fully synthetically manufacturable, in particular preferably a or bio-, semi- cologically active, such as highly active, N-acyl derivative of a 6β-amino- ponum-1-carboxylic acid or 7β-amino-3-cephem-U-carboxylic acid compound 10 15 20 25 30 35 7807811-0 17 existing acyl group, such as an acyl group of formula A: RI: 0 R (mn c (A) RIII wherein n represents 0 and HI represents hydrogen substituted, cycloaliphatic or aromatic hydrocarbon group or an optionally substituted heterocyclic group, preferably with an aromatic character, a functionally transformed, e.g. or represented, hydroxy or mercapto group or an optionally substituted amino group, or wherein n represents 1, R hydrogen or an optionally substituted aliphatic, cycloal fatisk; cycloaliphatic-aliphatic, aromatic or araliphatic carbon hydrogen group or an optionally substituted heterocyclic or heterocyclic-aliphatic group, wherein the heterocyclic group preferably has an aromatic character and / or a quaternary nitrogen atom, one optionally functionally converted, preferably represented or esterified, hydroxy or mercapto group, an eve- optionally functionally converted carboxy group, an acyl group, a optionally substituted amino group or an azido group, and var and one of the groups RII and RIII represents hydrogen or wherein n denotes 1, RI denotes an optionally substituted, aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or arali phatic hydrocarbon group or an optionally substituted, heterocyclic or heterocyclic-aliphatic group, wherein the heterocyclic the radical group preferably has an aromatic character, RII signifies a possible functionally transformed, e.g. represented, hydroxy or mercapto group, such as a halogen atom, an optionally substituted amino group, an optionally functional one converted carboxy or sulfo group, an optionally O-mono- or 0.0'-disubstituted phosphono group or an azido group and.RIII represents hydrogen or wherein n represents 1, each of the groups RI and RII represent a functionally transformed, preferably etherified or esterified, hydroxy group or any functional 4 carboxy group and RIII represents hydrogen or wherein i n represents 1, R 1 represents hydrogen or an optionally substituted row, aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic- F tical or araliphatic hydrocarbon group and RII and RIII together 1 -10 15 20 25 30 35 such as chlorine, with optionally substituted, such as hydroxy, acyloxy, 78Û7811 "Ü ,. 18 denotes an optionally substituted, by a double bond carbon-bonded, aliphatic, cycloaliphatic, cycloaliphatic aliphatic or araliphatic hydrocarbon group or wherein n represents 1, and RI represents an optionally substituted, aliphatic, cyclo- aliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon group or an optionally substituted heterocyclic heterocyclic-aliphatic group, wherein heterocyclic groups preferably has an aromatic character, R1; denotes an even optionally substituted, aliphatic, cycloaliphatic, cycloaliphatic aliphatic, aromatic or araliphatic hydrocarbon group and RIII hydrogen or an optionally substituted, aliphatic, cyclo- aliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic, hydrocarbon group. '' In indicated acyl groups of formula A denote, for example n 0 and R 1 hydrogen or an optionally, preferably in 1-position, with optionally protected amino, acylamino, wherein acyl in the first hand denotes the acyl residue of a carbonic acid half ester, such as a low alkoxycarbonyl-, 2-halo-lower alkoxycarbonyl- or phenyl-lower alkoxy- 4 g carbonyl group, or one, optionally in salt form, for example alkali metal salt form, the present sulfoamino group, substituted cycloalkyl- group having 5-7 ring carbon atoms, one optionally, preferably with hydroxy, lower alkoxy, eg methoxy, acyloxy, whereby acyl in the first hand denotes the acyl residue of a carbonic acid half ester, such as a low alkoxycarbonyl-, 2-halo-lowalkoxycarbonyl- or phenyl-lowalkoxoxy- carbonyl group, and / or halogen, eg chlorine, substituted phenyl-, naphthyl or tetrahydronaphthyl group, -one optionally, e.g. alkyl, such as methyl, and / or phenyl, which in turn may bear substituents such as halogen, eg chlorine, substituted heterocyclic radical, such as a U-isoxazolyl group, or preferably, eg with an optionally substituted, such as halogen, eg chlorine, containing lower alkyl group N-substituted amino group or n represents I, RI represents an optionally, preferably with halogen, wherein acyl has the stated meaning, and / or halogen, eg chlorine, containing phenyloxy, or with any protected amino and / or 10 l5 20 G5. 50 M0 7807811-0 19 e carboxy substituted lower alkyl group, for example a 5-amino-5-carboxylate propyl group, with optionally protected amino and / or carboxy group, eg silylated, such as tri-lower alkylsilylated, eg trimethylsilylated amino or acylamino group, such as lower alkanoylamino, halo- geno-lower alkanoylamino or phthaloylamino group, and / or silyl- such as tri-lower alkylsilylated, eg trimethylsilylated, or esterified, such as with lower alkyl, 2-halo lower alkyl or phenyl lower alkyl, for example diphenylmethyl, esterified carboxy group, a lower alkenyl group, an optionally substituted, as optionally, for example as acylated hydroxy and / or halogen, eg chlorine, further optionally protected, for example as indicated, acylated amino lower alkyl, such as aminomethyl, or optionally, for example, as indicated, acyl- series of hydroxy and / or halogen, for example chlorine, exhibiting phenyloxy containing phenyl group, one optionally, for example with lower alkyl, such as methyl, or optionally protected, eg acylated in the manner indicated, amino or aminomethyl, substituted pyridyl group, e.g. dyl, pyridinium, eg U-pyridinium, thienyl, eg 2-thienyl, furyl, for example 2-furyl, imidazolyl, for example 1-imidazolyl, or tetrazolyl, for example 1-tetrazolyl, an optionally substituted lower alkoxy group, methoxy, an optionally substituted, such as optionally protected, for example acylated, hydroxy and / or halogen as indicated, such as chlorine, containing phenyloxy group, a lower alkylthio group, e.g. n-butylthio, or lower alkenylthio group, e.g. allylthio, an optionally, for example with lower alkyl, such as methyl, substituted phenylthio-, pyridyl- thio-, eg U-pyridylthio-, 2-imidazolylthio-, 1,2, H-triazol-3-yl- thio-, 1,5, H-triazol-2-ylthio-, 1,2, H-thiadiazol-3-ylthio-, such as 5-methyl-1,2,8-thiadiazol-3-ylthio-, 1,3,4-thiadiazol-2-ylthio-, such as methyl-1,3,4-thiadiazol-2-ylthio-, or 5-tetrazolylthio-, such as 1-methyl-5-tetrazolylthio group, halogen, especially chlorine or bromine, an optionally functionally converted carboxy group, such as lower alkoxycarbonyl, eg methoxycarbonyl or ethoxycarbonyl, cyano or optionally, for example with lower alkyl, such as methyl, or phenyl, N-substituted carbamoyl, an optionally substituted lower alkanoyl- group, for example acetyl or propionyl, or benzoyl group or a azido group and RII and RIII represent hydrogen or n represents 1, RI denotes lower alkyl or an optionally, as with optionally, eg in the manner indicated, acylated hydroxy and / or halogen, e.g. chlorine, substituted phenyl-, furyl-, eg 2-furyl-, thienyl-, e.g. 2- or 5-thienyl, or isothiazolyl, for example 4-isothiazolyl group, denotes any e.g. further a 1,1-cyclohexadienyl group, RII 10 -5 20 25 30 35 7807811-or 20- protected or substituted amino, eg amino, acylamino, such as lower alkoxycarbonylamino, 2-halo lower alkoxycarbonylamino or optionally substituted, such as lower alkoxy, eg methoxy, or nitro containing phenyl lower alkoxycarbonylamino, eg t-butyloxy carbonylamino, 2,2,2-trichloroethoxycarbonylamino, β-methoxybenzyl- oxycarbonylamino or diphenylmethyloxycarbonylamine, arylsulfone nylamino, for example 4-methylphenylsulfonylamino, triethylamino, arylthio- amino, such as nitrophenylthioamino, for example 2-nitrophenylthioamino, or trityltioamino or optionally substituted, such as lower alkoxy- carbonyl, eg ethoxycarbonyl, or lower alkanoyl, eg acetyl, containing 2-propylideneamino, such as 1-ethoxycarbonyl-2-propyl denamino or optionally substituted carbamoylamino, such as xguanidinocarbonylamino, or one, optionally in salt form, e.g. alkali metal salt form, the present sulfoamino group, an azido group, one optionally in salt form, eg alkali metal salt form, or in protected, such as esterified form, for example as lower alkoxycarbonyl, for example methoxycarbonyl or ethoxycarbonyl, or as phenyloxy- carbonyl, eg diphenylmethoxycarbonyl, parent carboxy group, a cyano group, a sulfo group, an optionally functional conversion hydroxy group, with functionally converted hydroxy in particular is acyloxy, such as formyloxy, or lower alkoxycarbonyloxy, 2-halo lower alkoxylcarbonyloxy or optionally substituted, such as lower alkoxy, for example methoxy, or nitro containing phenyl lower alkoxy bonyloxy, for example t-butyloxycarbonyloxy, 2,2,2-trichloroethoxycarbonyl- oxy, U-methoxybenzyloxycarbonyloxy or diphenylmethoxycarbonyloxy, or optionally substituted lower alkoxy, for example methoxy, or phenyl- oxy, an O-lower alkyl or 0,0'-lower alkylphosphono group, e.g. O-methylphosphono or 0,0'-dimethylphosphono, or halogen, e.g. chlorine or bromine, and RIII represents hydrogen or n represents l, R 1 and R 11 each represent halogen, for example bromine, or lower alkoxy. carbonyl, for example methoxycarbonyl, and RIII represents hydrogen or n denotes l, RI denotes an optional, e.g. with optional, as indicated, acylated hydroxy and / or halogen, eg chlorine, substituted_phenyl-, furyl-, e.g. 2-furyl-, or thienyl-, e.g. 2- or 5-thienyl, or isothiazolyl, eg 4-isothiazolyl group, further a 1,1H-cyclohexadienyl group, RII represents an optional, for example, as indicated, protected aminomethyl, and RIII represents hydrogen or n denotes l and each of the groups R ¥, RIII and RIIIr denotes lower alkyl, eg methyl. 10 15 20 30 35 HU 7807811-0 21 The invention primarily relates to intermediate products with which are suitable for the preparation of 7B- (D-u-amino- α-Ra-acetylamino) -3-lower alkoxy-3-cephem-N-carboxylic acids, wherein Ra stands for phenyl, H-hydroxyphenyl, 2-thienyl, 1,1-cyclohexadienyl or 1-cyclohexenyl and lower alkoxy contains up to U of carbon more and for example constitute ethoxy or n-butyloxy, in the first place methoxy, and internal salts thereof and in particular 3- toxi-7β- (D-u-phenylglycylamino) -3-cephem-N-carboxylic acid and the the inner salt thereof; at indicated concentrations, especially orally administration, these compounds exhibit excellent anti- biotic properties both towards gram-positive and especially against gram-negative bacteria at 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 a base an intermediate of formula II, vari Rí, R? and Hg have the meanings given in formula IA, R? stands for lower alkyl or a hydroxy protecting group and Y represents a leaving group, and possibly in a obtained compound with between IA or IB transfers the protected carboxy group of the formula -C (= O) -Râ to free or otherwise protected carboxy group and! - or optionally transfer the protected hydroxy group -O-Bg to a free hydroxy group and / or transfer the obtained free hydroxy group or the protected hydroxy group -O-Bg to a lower alkoxy group -0-RB and / or possibly within the definition of the final products transfer an obtained compound to another compound and / or optionally transferring a resulting compound having a salt-forming group to a salt or a salt obtained for free association or to another salt and / or possibly splits one obtained mixture of isomeric compounds in the individual isomers.

Bases suitable for the cyclization reaction are special strong organic or inorganic bases. It must be emphasized in particular bicyclic amidines, such as diazabicycloalkenes, for example 1,5-diazabicyclo cyclo {H.3.0} non-5-ene or 1,5-diazabicyclo {5.H.0} undec-5-ene, substituted for example with lower alkyl polyunsubstituted guanine diners such as tetramethylguanldine, further metal hashes such as hydrides amides or alcoholates of alkali metals, in particular of sodium, sodium or potassium, for example sodium hydride, lithium dilacyl amides such as lithium propylamide, potassium lower alkoxide such as lium t-butylate. Intermediates of formula II, in which Bg 10 15 20 25 30 H0 i7so7s11-o 22 drawing halogen, eg chlorine, can also be cyclized with a tertiary organic nitrogen base, for example a tri-lower alkylamine, such as triethylamine, wherein the corresponding ester of formula IA and / or IB can be obtained in the presence of an alcohol, such as a lower alkanol, eg t-butanol.

The reaction in step 5 is carried out in a suitable inert solution. agents, for example in an aliphatic, cycloaliphatic or aromatic hydrocarbon such as hexane, cyclohexane, benzene or toluene, is a halogenated hydrocarbon such as methylene chloride, an ether such as a lower alkyl alkyl ether, eg diethyl ether, a lower alkyl alkoxy lower alkane, 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 under slight heating at H0-50 ° C, 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 a 2-benstiazolylthio group, with one of specified bases, for example with 1,5-diazabicyclo {S.4.0} undec-5-ene, may the yield of compounds of formula IA and IB is increased by addition of a sulfinic acid of the formula H-SO 2 -R 5, for example p-toluenesulfinic acid.

In the cyclization reaction in step 5, one can all starting materials and reaction conditions obtain uniform compounds of formula IA or IB or mixtures of compounds of formula IA and IB. Obtained mixtures can on in and of themselves known method is divided, for example by means of suitable division methods, for example by adsorption and fractional elution, including chromium tomography (column paper or plate chromatography) using suitable adsorbents, such as silica gel or aluminum oxide, and eluent, further by fractional crystallization ring, solvent distribution, etc.

Obtained compounds of formulas IA and IB, which are suitable intermediates for the preparation of pharmacological active end products, may be transferred to such active end products through various contingency measures known per se.

In a obtained compound of formulas IA or IB, one can hydroxy protecting group R3 is easily cleaved off and replaced with hydrogen. 2-oxa- or 2-thiaaliphatic or cycloaliphatic hydrocarbon group can be cleaved off, for example, by acid hydrolysis, a silyl or stannyl group by hydrolysis, alcoholysis or acidolysis, e.g. by treatment with water or with an alcohol, such as methanol Split ~ One or ethanol, or even with acid, such as acetic acid. 10 15 20 25 50 H0 7807811-0 25 the addition of an optionally substituted α-phenyl lower alkyl group, e.g. benzyl or diphenylmethyl group, for example by acidolysis, for example by treatment with a suitable inorganic or organic such as hydrochloric acid, sulfuric acid, formic acid or especially trifluoric acid. acetic acid, or by hydrogenolysis, for example by treatment The educational the 5-hydroxy compounds are mainly in 3-cephem form. with hydrogen in the presence of a catalyst such as palladium.

The cleavage of a hydroxy protecting group R; may possibly gas selectively, ie without a carboxy protecting group Râ at the same time split off. _ Enol ethers, ie compounds of formula IA and / or IB, wherein R 5 is lower alkyl is obtained from compounds of the formulas IA or IB, wherein R3 is a hydroxy protecting group, by replacement of this group with hydrogen and subsequent etherification of the free hydroxy group according to any for etherification of enol groups appropriate procedure. Preferably, as the preferred reagent and the optionally substituted hydrocarbon group R3 diazo compound of the formula H3-N2, primarily an optional substituted diazole lower alkane, eg diazomethane, diazoethane or diazo-n-butane, or an optionally substituted u-phenyldiazole alkane, eg phenyl or diphenyldiazomethane. These reagents are used in the presence of a suitable inert solvent, such as an fatty, cycloaliphatic or aromatic hydrocarbon such as hexane, cyclohexane, benzene or toluene, a halogenated aliphatic carbon hydrogen, eg methylene chloride, a lower alkanol, eg methanol methanol or t-butanol, or an ether such as a lower alkyl ether, e.g. ethyl ether, or a cyclic ether, for example tetrahydrofuran or dioxane, or a solvent mixture and depending on the diazore reagent below cooling, at room temperature or under light heating, further if necessary, in a closed vessel and / or under an atmosphere vessels of inert gas, such as nitrogen gas.

Furthermore, enol ethers of the formula IA and / or IB can be formed by treatment with a reactive ester of a lower alkyl group pen or the optionally substituted α-phenyl lower alkyl group, for example a benzyl or diphenylmethyl group, R 3 corresponding to alcohol with the formula R5-OH. Suitable esters are primarily those with strong inorganic or organic acids, such as mineral acids, for example hydrohalic acids, such as hydrochloric acid, hydrobromic acid or hydroiodic acid, further sulfuric acid or halogenated sulfuric acids, e.g. fluorosulfuric acid, or strong organic sulfonic acids, such as 10 15 20 25 30 35 40 thunder cooling, "presence of a strong mineral acid, t 78Û? 811 ', Û i zu optionally, for example with halogen, such as fluorine, substituted sulfonic acids, or aromatic sulfonic acids, such as, for example, 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, Ü CX fi fí ' fluoromethanesulfonic acid methyl ester, is commonly used in the presence of a solvent, such as an optionally halogenated, such as chlorine aliphatic, cycloaliphatic or aromatic hydrocarbon, e.g. methylene chloride, an ether such as dioxane or tetrahydrofuran, or a lower alkanol, such as methanol, or a mixture thereof. Thereby suitable condensing agents are preferably used, such as alkali metal carbonate or bicarbonate, for example sodium or ca- bicarbonate (usually together with a sulfate), or organic bases, such as usually sterically hindered lium carbonate or tri-lower alkylamines, for example N, N-diisopropyl-N-ethylamine (preferably together with lower alkyl halogen sulphate or possibly halogenated substituted methanesulfonic acid lower alkyl esters), working at room temperature or during heating, e.g. at temperatures of about -20 ° C to about 50 ° C, and if so necessary, in a closed vessel and / or in an atmosphere of inert gas, eg nitrogen gas. , ' Enol ethers can also be prepared by treatment with one at the same carbon atom with an aliphatic character two or three companies hydroxy groups of the formula R3-0- containing compound, i.e. with a corresponding acetal or orthoester, in the presence of an acid use gem-low alkoxy low-alkali average. 'Thus you can, for example such as 2,2-dimethoxypropane, in the presence of a strong organic sulfonic acid, such as p-toluenesulfonic acid, and of a suitable solvent such as a lower alkanol, t alkyl or lower alkylene sulfoxide, t e.g. eg methanol, or a diluent ex dimethyl sulfoxide, or orthoformic acid trilowlalkyl esters, orthoformic acid triethyl ester, i ex sulfuric acid, or a strong organic sulfonic acid, such as p-toluenesulfonic acid, and of a suitable solvent, such as a lower alkanol, eg ethanol, or a ether, such as dioxane, as etherifying agents and thus obtain compounds of formula IA and / or IB, wherein R 3 is lower alkyl, eg methyl and ethyl, respectively. 10 15 20 25 30 55 ll O 7807811-0 25 Enol ethers of formula IA and / or IB can also be obtained if intermediates of formula II are treated with (s k Meerwein- salts), as well as di-R O-carbenium salts of the formula (R O) - CI (B G ° j ~ 5 to 1-3) In A or di-H3-halonium salts of the formula (R3) 2Ha1 A tri-R3 oxonium salts of the formula (R3) 3O + .Å9 wherein A (5) represents the anion of an acid and Hal \ 3 represents one This is in the case of take care of tri-lower alkyloxonium salts and lower lower alkoxy carbenium or lower alkyl halonium salts, especially the corresponding salts halonium ion, especially bromonium ion. with complex fluorine-containing acids, such as the corresponding tetrafluoro- borate, hexafluorophosphate, hexafluoroantimonate or hexachloroantioate month. Such reagents are, for example, trimethyloxonium or triethyl ethyl oxonium hexafluoroantimonate, -hexachloroantimonate, -hexafluoro- phosphate or tetrafluoroborate, dimethoxycarenium hexafluorophosphate barrel or dimethylbromonium hexafluoroantimonate. said etherifying agent preferably in an inert solvent, such as an ether or a halogenated hydrocarbon, for example diethyl ether, tetrahydride rofuran or methylene chloride, or a mixture thereof, if any necessary in the presence of a base, such as an organic base, e.g. preferably sterically hindered, tri-lower alkylamine, for example N, N-diiso- propyl-N-ethylamine, and under cooling, at room temperature or under slight heating, for example at about -20 ° C to about 5000, if necessary in a closed vessel and / or in an atmosphere of inert gas, eg nitrogen gas.

Enol ethers of formulas IA and / or IB can also be prepared by treating intermediates of formula II with a 5-substituted 1-RB-triazene compound (ie a compound of the formula subst-N = N-NH-R 5), 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, for example lower alkylphenyl, such as H-methylphenyl. Such triazene compounds are 3-aryl-1-lower alkyltriazenes, for example 3- (U-methylphenyl) -1-methyltrizenes azen, 5- (U-methylphenyl) -1-ethyltriazene, 3- (U-methylphenyl) -1-n-pro- pyltriazene or 3- (H-methylphenyl) -1-isopropyltriazene, further 5-aryl-1- (u-phenyl-lower alkyl) -triazenes, for example 1-benzyl-3- (U-methyl- phenyl) -triazene. These reagents were commonly used in the presence of inert solvents, such as optionally halogenated hydrocarbons or ethers, such as benzene, or solvent mixtures and miracles cooling, at room temperature and preferably at elevated temperature turn, for example at about 20 ° C to about 100 ° C, if necessary 10 15 20 25 30 35 40 carbononyloxy, such as those indicated, for example t-butyloxycarbonyloxy, 7sovs11-0 26 in a closed vessel and / or in an atmosphere of inert gas, e.g. nitrogen. _ In the present compounds free, functional groups can transiently protected in a manner known per se, e.g. free amino acids groups, for example by acylation, tritylation or silylation, free hydroxy or mercapto groups, for example by etherification or esterification, and free carboxy groups, for example by esterification, including silylation, and in a manner known per se, if is desirable, is released alone or jointly after the reaction has taken place. ”Tion. Thus, one can preferably protect, for example, amino-, carboxy or phosphono groups in an acyl group R R? example- shown in form 1 of acylamino, such as those indicated; eg 2,2,2-trichloroethoxycarbonylan fi np-, 2-bromoethoxycarbonylamino3-methoxybenzyloxycarbonylamino-, diphenyl- methoxycarbonylamino or t-butyloxycarbonylamino, in the form of aryl or aryl lower alkylthioamino:, for example, nitrophenylthioamino-, or arylsulfonylamino-, eg 4-methylphenylsulfonylamino-, or in the form of 1-lower alkoxycarbonyl-2-propylidenamino groups and of acyloxy- 2,2,2- trichloroethoxycarbonyloxy or 2-bromoethoxycarbonyloxy, respectively i form of esterified carboxy, such as those indicated, e.g. diphenylmethoxy- carbonyl or 0,0f-disubstituted phosphono, as indicated above, for example 0,0'-lower alkylphosphono, such as OQO'-dimethylphosphono, and afterwards, possibly after conversion of the protecting group, e.g. a 2-bromoethoxycarbonyl to a 2-iodoethoxycarbonyl, on and off known method and depending on the nature of the protection group, if value, e.g. partially, is cleaved, e.g. a 2,2,2-trichloethoxycarbonyl- amino or 2-iodoethoxycarbonylamino group by treatment with a suitable reducing agent, such as zinc in the presence of aqueous acetic acid, a diphenylmethoxycarbonylamino or t-butyloxy- carbonylamino group by treatment with formic acid or trifluoro- acetic acid, an aryl or aryl lower alkylthioamino group by treatment. with a nucleophilic reagent, such as sulfuric acid, an aryl sulfonylamino group by electrolytic reduction, a 1-lower alkoxy carbonyl-2-propylidenamino group by treatment with aqueous mineral acid or a t-butyloxycarbonyloxy group by treatment with formic acid or trifluoroacetic acid or a 2,2,2-trichloroethoxy- carbonyloxy group by treatment with a chemical reducing agent, such as zinc in the presence of aqueous acetic acid response a diphenyl- methoxycarbonyl group by treatment with formic acid or trifluoro acetic acid or by hydrogenolysis or a 0,0'-disubstituted phosphono group by treatment with an alkali metal halide. 10 15 20 25 30 35 H0 7807811-0 27 A compound with a protected, especially esterified, carboxy group with f0Pm @ 1H * C (= 0) -Hg, this can in a manner known per se, eg depending on the group's R of kind, transferred to free carboxy group.

An esterified, for example with a lower alkyl group, especially methyl or ethyl, or with a benzyl group esterified, carboxy group, especially in a 2-cephem compound of formula IB, can be converted to a free carboxy- group by hydrolysis in weakly basic medium, for example by treatment with an aqueous solution of an alkali metal or alkaline earth metal metal hydroxide or carbonate, for example sodium or potassium hydroxide, preferably at a pH of about 9-10, and optionally in the presence of a lower alkanol. a pH of about 9-10, and optionally in the presence of a lower alkanol.

One with a suitable 2-halo lower alkyl or arylcarbonylmethyl group esterified carboxy group can be cleaved, for example by treatment with a chemical reducing agent, such as a metal, such as zinc, or a producing metal salt, such as a chromium (II) salt, for example chromium (II) chloride, usually in the presence of a dehydrating agent, which together with the metal is capable of forming nascent hydrogen, such as an acid, primarily acetic acid and formic acid, or an alcohol, wherein water is preferably added, one with an arylcarbonylmethyl- group esterified carboxy group also by treatment with a nucleophilic, preferably salt-forming, reagents such as sodium thio- phenolate or sodium iodide, one with a suitable arylmethyl grouping esterified carboxy group, for example by irradiation, preferably with ultraviolet light, eg below 290 nm, if the aryl group for example, a possibly in 3-, U- and / or 5-position, for example with lower alkoxy and / or nitro groups, substituted benzyl group or with more long-wave, ultraviolet light, eg over 290 nm, if the arylmethyl group represents, for example, one in the 2-position benzyl group substituted with a nitro group, one with a suitable one substituted methyl group, such as t-butyl or diphenylmethyl, esterified carboxy group, for example, by treatment with an appropriate acidic agent, such as formic acid or trifluoroacetic acid, optionally adding a nucleophilic compound, such as phenol or anisole, an activated esterified carboxy group, further one in anhydride form the present carboxy group by hydrolysis, for example by treatment with an acidic or slightly basic, aqueous medium, such as hydrochloric acid or aqueous sodium bicarbonate or an aqueous potassium phosphate buffer containing pH about Y-about 9, and a hydrogen genolytically cleavable, esterified carboxy group by hydrogenolysis, for example by treatment with hydrogen in the presence of a noble metal catalyst. sator, eg palladium catalyst. 10 15 20 .go EQ, is-si g: 12107311-0 i i '28 A carobxy group protected by silylation can be released on common way, eg by treatment with water or an alcohol.

Compounds of formulas IA or IB may be known per se method to other compounds of formula IA or IB.

A compound with an amino protecting group Râ, especially a light one a cleavable acyl group, may, for example, in a manner known per se cleaved, for example an α-polyg branched lower alkoxycarbonyl group, t-butyloxycarbonyl, by treatment with trifluoroacetic acid and a 2-halo lower alkoxycarbonyl group such as 2,2,2-trichloroethoxy- carbonyl or 2-iodoethoxycarbonyl, or a phenacyloxycarbonyl- group by treatment with a suitable reducing metal or corresponding metal compound, for example zinc or a chromium (II) compound, such as the chloride or acetate, suitably in the presence of an agent, 1 which together with the metal or metal compound gives the nascent they 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) -R 2 preferably represents one, eg by esterification, including by silylation, eg by On reaction with a suitable organic halogenated silicon or halogenated tin (IV) compound, such as trimethylchlorosilane or tri-n-butyltin 'chloride, protected carboxy group, an aoyl group R 1 or R 2, wherein any existing, free, functional groups may be , protected, are cleaved by treatment with an imide halide formation means, reacting the imide halide formed with an alcohol and aspiration of the formed iminoether, a protected, e.g. one with an organic silyl group protected, carboxy group already can released during the course of the reaction.

Imide halide-forming agents in which halogen is attached an electrophilic central atom, are primarily acid halides, such as acid bromides and especially acid chlorides. These are the first hand acid halides of inorganic acids, especially phosphorus acids such as phosphorus oxy-, phosphorus tri- and especially phosphorus halides, eg phosphorus oxychloride, phosphorus trichloride and primarily phosphorus pentachloride, further pyrocatecyl phosphorus trichloride, and acid halides, in particular chlorides, of sulfuric acids or of carboxylic acids such as thionyl chloride, phosgene or oxalyl chloride.

Ui 10 7auvu || * ~ 29 The reaction with one of the indicated imide halide-forming agents usually carried out in the presence of a suitable, especially organic, base, primarily a tertiary amine, eg a tertiary aliphatic mono- or diamine, such as a tri-lower alkylamine, e.g. trimethyl-, triethyl 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-pen tylenediamine or N, N, N ', N'-tetramethyl-1,6-hexylenediamine, a mono- or bicyclic mono- or diamine, such as an N-substituted, eg N-lower alkylated, alkylene, azaalkylene or oxaalkylene amine, eg N-methylpiperidine or N-methylmorpholine, further 2,3, ü, 6,7,8- hexahydropyrrolo {1,2-a} pyrimidine (diazabicyclonone DBN), or a tertiary aromatic amine, such as a dialkylalkylaniline, e.g. N, N- dimethylaniline, or primarily a tertiary etherocyclic, mono- or bicyclic base, such as quinoline or isoquinoline, in particular 15 20 v25 30 55 pyridine, preferably in the presence of a solvent such as a optionally halogenated, eg chlorinated, aliphatic or aromatic hydrocarbon, eg methylene chloride. In this case, you can use approximately molar amounts of the imide halide-forming agent and the base; the last however, the latter may also be present in excess or shoots, eg in about 0.2-about 1 times the amount or in one up to 10-fold, especially an approximately 3- to 5-fold excess.

The reaction with the imide halide-forming agent is carried out before during cooling, for example at temperatures of about -5000 to about + 10 ° C, but you can also work at higher temperatures temperatures, ie for example up to about 75 ° C, if the starting material The stability of materials and products allows an elevated temperature.

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, e.g. chlorinated, or in addition hydroxy groups having, lower alkanols, eg ethanol, propanol or butanol, especially methanol, further 2-halogen lower alkanols, eg 2,2,2-trichloroethanol or 2-bromoethanol, and optionally substituted phenyl lower alkanols, such as benzyl alcohol hol. Usually one is used, for example up to about 10 ~ fold, excess alcohol and preferably works during cooling, for example at temperatures of about -5000 to about 10 ° C. 1ow _1ä 20 7307811-0 30, 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 l-about 5, which can be set, if necessary, by adding batch of a basic agent, such as an aqueous alkali metal hydroxide, for example sodium or potassium hydroxide, or an acid, for example a mineral acid or organic acid, such as hydrochloric acid, sulfuric acid acid, phosphoric acid, hydrogen fluoroboride, trifluoroacetic acid or p-total luensulfonic acid. _ I ' 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 a possible halogenated hydrocarbon, e.g. methylene chloride rid, and / or in an atmosphere of inert gas, such as nitrogen.

If you sell it according to the specified procedure obtained The halide halide intermediate with a salt, such as an alkali metal salt .25 30 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 1 are acyl groups.

In a compound of formula IA or IB, wherein both groups R? and R? are acyl groups, one of these groups, preferably desvis_the sterically less hindered, selectively removed, e.g. by hydrolysis or aminolysis.

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

OUT 10 15 20 25 30 7807811-0 51 Some acyl residues R? of an acylamino grouping in accordance with compounds obtainable from the invention, such as a 5-amino-5-carboxylate valeryl group, wherein carboxy is optionally protected, for example by esterification, especially with diphenylmethyl, and / or the amino group protected, for example by acylation, especially with an acyl residue of a organic carboxylic acid, such as halo-lower alkanoyl, such as dichloro- acetyl, or phthaloyl, can also be cleaved by treatment with a nitrosating agent, such as nitrosyl chloride, with a carbocyclic arendiazonium salt, such as benzenediazonium chloride, or with a positive halogen releasing agent, such as an N-halamide or imide, eg 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, e.g. methanol, or in the 5-amino-5-carboxivaleryl group Crude amino group pen is substituted and the carboxy group is protected, for example by and R 1 preferably represents an acyl group, but may also be hydrogen, by standing in an inert solvent such as dioxane and / or a halogenated aliphatic hydrocarbon, eg methylene chloride, and, if necessary, reprocessing of the free or monoacyl the amino compound according to methods known per se.

A formyl group Râ can also be cleaved by treatment with an acidic agent, eg p-sulfonic acid or hydrochloric acid, a weak basic agent, such as dilute ammonia, or a decarbonylation agents, eg tris- (triphenylphosphine) -rodium chloride.

A triarylmethyl group, such as trityl Rα, 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 and R? is hydrogen, one can substitute the free amino group according to i and for known methods, primarily by treatment with acids, so as carboxylic acid, or reactive derivatives thereof. 10 .15 20 25 30 r35i 78Û78i1 "Ü 32 If a free acid, preferably with protected, possibly fine functional groups, such as any amino group, used for acylation, is usually used suitably condensing agents such as carbodiimides, for example N, N'-diethyl-, N, N'-dipropyl-, N, N'-diisopropyl-, N, N'-dicyclohexyl- or N-ethyl- N'-3-dimethylaminopropylcarbodiimide, suitable carbonyl compounds, eg carbonyl diimidazole, or isoxazolinium salts, eg N-ethyl-5- phenylisoxazolinium 3'-sulfonate and N-t-butyl-5-methylisoxazolinium-- perchlorate, or a suitable acylamino compound, for example 2-ethoxy-1- ethoxycarbonyl-1,2-dihydroquinoline. ' IN The condensation reaction is preferably carried out in one of the anhydrous reaction media listed below, e.g. in methylene chloride, dimethylformamide or acetonitrile. IN An amide-forming functional derivative of an acid, preferably with protected groups, if any, such as a any existing amino group, is primarily an anhydride of such an acid, including and preferably a mixed anhydrous rid. Mixed anhydrides are, for example, those with inorganic acids. with halohydric acids, ie corresponding acid halides, eg chlorides or bromides, further with hydrochloric acid, ie 7 corresponding acid azides, with a phosphorus-containing acid, eg phosphoric acid or phosphoric acid, with a sulfur-containing acid, e.g. sulfuric acid, or with cyanohydric acid. Other mixed anhydrides are, for example those with organic acids, such as organic carboxylic acids, such as with optionally, for example with halogen, such as fluorine or chlorine, substituted lower alkanecarboxylic acids, for example pivalic acid or trichloroacetic acid hydrochloric acid, or with half esters, especially lower alkyl half esters, of carbon SYFa, SoS ° m ethyl or isobutyl half esters of carbonic acid, or with Organic, in particular aliphatic or aromatic, sulfonic acids, For example, p-toluenesulfonic acid.

Furthermore, internal anhydride can be used as the acylating agent. there, such as ketenes, eg diketene, isocyanate (ie internal anhydrides of carbamic acid compounds) or internal anhydrides of carboxylic acid compounds with carboxy-substituted hydroxy or amino groups, for example, mandelic acid O-carboxylic anhydride or the anhydride of 1-N-carboxylate aminocyclohexanecarboxylic acid. 10 15 20 25 w_ 7897811-0 33 Other acid derivatives suitable for reaction with free amino group activated esters, usually with protected, possibly present functional groups, such as esters with vinylogenic alcohols (ie enols), such as vinylogenic lower alkanols, or aryl esters, as preferably, for example with nitro or halogen, such as chlorine, substituted phenyl esters, for example pentachlorophenyl, 4-nitrophenyl or 2, U-dinitrophenyl esters, heteroaromatic esters such as benzyl triazole esters, or diacylimino esters, such as succinylimino or ~ Phthalyliminoesters.

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-di-lower alkylaniline, for example N, N-dimethylaniline, or a base of py- type of pyridine, for example pyridine, an inorganic base, for example an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate, e.g. sodium, potassium or calcium hydroxide, carbonate or bicarbonate or an oxirane, for example a lower 1,2-alkylene oxide, such as ethyl lenoxide or propylene oxide.

Specified acylation can be performed in an aqueous or preferably non-aqueous solvent or solvent mixture, for example in a carboxylic acid amide, such as N, N-dialkylalkyl amide, eg dimethylformamide, a halogenated hydrocarbon, eg methylene chloride, carbon tetrachloride or chlorobenzene, a ketone, eg acetone, an ester, eg acetic acid ethyl ester, or a nitrile, eg acetonite ril, or mixtures thereof, and, if necessary, at lowered or elevated temperature and / or in an atmosphere of inert gas, eg nitrogen gas. m 15 20. 25 50 The Ilboxi group of 1 written, including by hydrolysis or alcoholysis¿ 78'07811-0 M In the case of the indicated N-acylation reactions, it can be assumed that compounds of formula IA or IB, wherein R 1 represents lower alkyl or an optionally substituted α-phenyl lower alkyl, eg benzyl or diphenylmethyl, and R 2 is as defined, wherein compounds with free carboxy groups of the formula -C (= O) -R 2, wherein R 2 roxi, can also be used in the form of salts, eg ammonium salts, such as with triethylamine, or in the form of compounds with a genome reaction with a suitable organic phosphorus halide compound, such as with a lower alkyl or lower alkoxyphosphorus dihalide, such as methylphosphoride chloride, ethyl phosphorodibromide or methoxyphosphoric dichloride, protected carboxy group; 1 obtained acylation product, the protected vessel known per se is released, e.g. An acyl group can also be introduced by acylating a compound of formula IA or IB, wherein R? and Rï together denotes a ylidene group (which can also be introduced afterwards, e.g. .by treating a compound wherein R 1 and R 2 are? constitutes hydrogen, with an aldehyde, such as an aliphatic, aromatic or araliphatic aldehyde hyd), for example according to the methods indicated, and hydrolyses acylation the product, preferably in neutral or slightly acidic medium.

In this case, an acyl group can also be introduced step by step. Thus can for example in a compound of formula IA or_IB with a peace amino group introducing a halo lower alkanoyl 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) - or N- (halogen- carbonyl) amino compound with suitable exchange reagents, such as basic compounds, eg tetrazole, thio compounds, eg 2-mercapto-1- methylimidazole, or metal salts, for example sodium azide, or alcohol such as lower alkanols, for example t-butanol, and thus obtain substituted N-lower alkanoyl and N-hydroxycarbonylamino compounds, respectively.

In both reactants, free functional groups can be during the acylation reaction be temporarily protected on in and known per se and after the acylation are released according to i and methods known per se, for example as described. _ The acylation can also take place by replacing an already existing acyl group to another, preferably sterically hindered acyl group group, for example according to the procedure described, by sets the imide halide compound, treating it with a salt of one 10 .Br 20 25 30 35 HQ .carboxy group. 7807811-o .55 acid and hydrolytically cleaves one of those thus obtained. the product existing acyl groups, usually the less steric hindered the acyl group.

Furthermore, one can, for example, react a compound of the formula IA or IB, wherein R? is a substitute, preferably in the u-position, cultured glycyl group, such as phenylglycyl, and R denotes hydrogen, with an aldehyde, eg formaldehyde, or a ketone, such as lower alkanone, for example acetone, and thus obtain compounds of formula IA or IB, wherein R: and R? together with the nitrogen atom constitutes a, in 4-position preferably substituted, in the 2-position optionally substituted tuerad 5-oxo-1,3-diazacyclopentyl group. A In a compound of formula IA or IB, wherein R and R 1 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. g I An amino group can also be protected by the introduction of a silyl and stannyl group. Such groups are introduced on per se known method, for example by treatment with a suitable silylating agent, such as with a dihalo lower alkyl silane, lower alkoxy lower alkyl dihalo- silane or tri-lower alkylsilyl halide, for example dichlorodimethylsilane, methoxy- methyldichlorosilane, trimethylsilyl chloride or dimethyl-t-butylsilyl chloride, using such silyl halide compounds preferably in the presence of a base, eg pyridine, with an optional N-mo- zero-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, British Patent Specification 1,073,550) or with a carboxylic acid amide, such as a bis-trialkylsilyl acetamide, for example bis-trimethylsilylacetamide, or trifluorosilylacetamide, further with a suitable stannylating agent, such as a bis- (tri- lower alkyltin) eoxide, teex bis- (tri-n-butyltin) oxide, a tri-lower alkyltin hydroxide, for example triethyltin hydroxide, a tri low alkoxy tin, tetra low alkoxy tin or tetra low alkyl tin compounds as well as a tri-lower alkyltin halide, for example tri-n-butyltin chloride (see, for example, Dutch Offenlegungsschrift 67/11107).

In a compound of formula IA obtained according to the invention or IB, which contains a free carboxy group of the formula -C (= O) -R 2, lkan such a per se known manner is transferred to a protected Thus esters are obtained, for example, by action with a suitable diazo compound, such as a diazole alkane, .... ... 453 f. 10 20 25 30 35 yo, i_såsom en karbodiimidg. vßßvsw fl- U 36 for example diazomethane or diazobutane, or a phenyldiazole lower alkane, eg diphenyldiazomethane, if necessary, in the presence of a Lewis acid, eg boron trifluoride, or even by reaction with a non-esterification of suitable alcohol in the presence of an esterifying agent, for example dicyclohexylcarbodiimide, as well as bonyldiimidazole, further with an N, N * -dubstituted O- and S-subs- titrated isourea 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 are, for example, lower alkyl, especially isopropyl, cycloalkyl or phenyl, or according to others known and suitable esterification methods, such as the reaction of a salt of acid with a reactive ester of an alcohol and a strong inorganic acid, as well as a strong organic sulfonic acid. We- acid halides, such as chlorides (prepared, for example, nom treatment with ámxækylklanàd);), activated esters (formed for example with N-hydroxy nitrogen compounds, such as N-hydroxysuccin imide) .or mixed anhydrides (obtained, for example, with halogenated formic acid lower alkyl esters, such as chloroformic acid ethyl or chloroformic acid isobutyl ester, or with haloacetic acid halides, such as trichloro- acetic acid chloride) is converted to an esterified carboxy group by reaction with alcohols, optionally in the presence of a base, such as pyridine. _ _ In an obtained compound with an esterified grouping with the formula -C (= 0) -Ra, this can be transferred to another esterified carboxy group with this formylate ex 2-chloroethoxycarbonyl or 2-bromoethoxycarbonyl to 2-iodoethoxycarbonyl by treatment with an iodine salt, such as sodium iodide, in the presence of a suitable solvents such as acetate. ' 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 such as a halide, for example the chloride, of an acid, for example a halogenated amyric acid lower alkyl ester or a lower alkanecarboxylic acid chloride.

* In a compound obtained according to the invention with a free carboxy group of the formula -C (= O) -R 2, such can also be transferred to an optionally substituted carbamoyl or hydrazino car- bonyl group, preferably reacting reactive, in functionally converted derivatives, such as indicated acid halides, esters 10 15 20 ? 5 30 fi_ w_ r7807811-0 37 in general, such as also indicated activated esters, or mixed anhydrides of the corresponding acid with ammonia or amines, including hydroxylamine, 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 one treats compounds of formula IA or IB, wherein R 2 is for hydroxy, or salts such as alkali metal salts, e.g. salts, thereof with a suitable silylation or stannyl such as one of the indicated silylation or stannylation agents. average; see, for example, British Patent Specification 1,073,530 resp Dutch Patent Application 67/17107.

Furthermore, converted functional substituents can be released. in the groups RQ, Bg and / or R2, as substituted amino acids groups, acylated hydroxy groups, esterified carboxy groups or 0.0 'disubstituted phosphono groups, according to per se known methods, such as those described, 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, e.g. acylate or esterify resp substitute. Thus, for example, an amino group can be converted to a sulfoamino group by treatment with sulfur trioxide, preferably preferably in the form of a complex with an organic base, such as a tri-lower alkylamine, eg triethylamine. Furthermore, one can react the mixture obtained by reacting an acid addition sodium salt of an N-guanylsemicarbazide with sodium nitrite, with a compound of formula IA or IB, wherein for example the amino protecting group pen R fi constitutes an optionally substituted glycyl group, and so on method to transfer the amino group to a 3-guanylureido group. Further one can react compounds with aliphatically bound halogen, e.g. with an optionally substituted o-bromoacetyl grouping, with esters of phosphoric acid, such as tri-lower alkyl phosphite compounds, and on thus obtaining the corresponding phosphonophen ions.

Obtained cephem compounds of formula IA and IB can be obtained by oxidation with suitable oxidizing agents, as will be described vase, are converted to 1-oxides of the corresponding 3-cephem compounds with the formula IA. Obtained 1-oxides of 3-cephem compounds with The mixture IA can by reduction with suitable reducing agents, such as for example will be described, reduced to the corresponding 5-cephem compounds of formula IA. In these reactions must taken into account, that, if necessary, free functional groups are l-. ' 'ri ~ -' "rv“ wrr- x - i från ".xu- | er ^ -rn- | x ~ - ^ ---» - t -.,., ..-..-., ,. _..., ..- J ....,.,. .f -, -, -. ~ \. lQ, I * 5 20 _æ ' 30; nß *, o ko] g aa.

I rid. n, the presence or absence of a solvent, such as an optional ..._ .., _ V 7807811-0 ' .m protected and, if desired, subsequently re-released.

Obtained cephem compounds can be isomerized to give the resulting 2-cephem compounds of formula IB or mixtures 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 temporarily transient may be protected, eg as indicated. For example, 2-cephem compounds of formula IB may be used, wherein * the group of the formula -C (= O) -R 2 constitutes a free or protected carboxy- group, wherein a protected carboxy group can also be formed during the reaction. tion. '\ Thus, a 2-cephem compound can be isomerized by meln IB, by treating it with a basic agent and from an optionally obtained equilibrium mixture of 2- and} -cefemfö- purifications isolate the corresponding 3-cephem compound of formula IA.

Suitable isomerizing agents are, for example, organic, volatile bases, such as tertiary heterocyclic bases with aromatic * tical nature and in the first band tertiary aliphatic, azacycloal . phatic or araliphatic bases, such as N, N, N-trilowalkylamines, e: ex Nmnv-crimethiamine, Nm-aimecyi-N-ecylaxftin, NJLN-criel-.yi- amine or N, N-diisopropyl-N-ethylamine, N-lower alkyl azacycloalkanes, toex N-methylpiperidine, or N-phenyl lower alkyl-N, N-lower alkyl alkylamines, eg N-benzyl-N, N-dimethylamine, as well as mixtures thereof, such as The mixture of a pyridine-type base, for example pyridine, and an N, N, N- tri-lower alkylamine, eg pyridine and triethylamine. Furthermore, can also organic or organic salts of bases, in particular of medium- 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, as well as 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 to form a mixed anhydride, such as a carboxylic acid hydride or halide, for example with pyridine in the presence of acetic anhydride In this case, preferably 1 anhydrous medium is used, i halogenated, eg chlorinated, aliphatic, cycloaliphatic cells aromatic hydrocarbon, or a solvent mixture, whereby Thereby 7 10 ; ¿5 20 e25 30 35 NO 7807811-0 59 used as reactants, under the reaction conditions liquid shaped bases can at the same time also serve as solvents, if so is necessary, during cooling or heating, preferably in a temperature range of about -30 ° C to about + 100 ° C, in a atmosphere of inert gas, eg nitrogen gas, and / or in a closed vessel.

The 3-cephem compounds of formula IA thus obtained can in a manner known per se be separated from any still 2-cephem compounds of formula IB, for example by adsorption and / or crystallization. 1 The isomerization of 2-cephem compounds of formula IB can also carried out by oxidizing them in the 1-position, if desired, separates an resulting isomeric mixture of 1-oxy of 3-cephem compounds of formula IA and reduce them accordingly thus obtained the 1-oxides of the corresponding 3-cephem compounds with formula IA.

L As suitable oxidizing agents for the oxidation in the 1-position Inorganic peracids, such as 2-cephem compounds, which has a reduction potential of at least +1.5 volts and which consists of non-metallic elements, organic peracids or mixtures hydrogen peroxide and acids, in particular organic carboxylic acids with a dissociation constant of at least 10-5. Appropriate transition pericardial acids are periodic and persulfuric acid. Organic peracids are the corresponding percarboxylic acids and persulfonic acids, which are added as such or can be formed in situ by the use of at least one equivalent of hydrogen peroxide and one carboxylic acid. Thereby is it is advisable to use a large excess of the carboxylic acid, if, for example, acetic acid was used as the solvent. Suitable peracids are, for example, permyric acid, peracetic acid, pertrifluoro- acetic acid, permaleic acid, perbenzoic acid, monoperphthalic acid or p-toluene persulfonic 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 Z and below, but also larger amounts The effect of the mixture is primarily due to sewing " Suitable mixtures are, for example, those of hydrogen » of the acid. rans strength. peroxide and acetic acid, perchloric acid or trifluoroacetic acid.

Specified oxidation can be carried out in the presence of suitable catalysts. Thus, for example, the oxidation can be catalyzed by the presence of an acid with a dissociation constant of at least . ... n fi d _ Uh 10 .L5 I 20- 30 35 H0 In fluoroacetic acid. olio z to about 20 tf. 7807811-9 uo l0_ $, its effect depending on its strength. As a catalyst suitable acids are, for example, acetic acid, perchloric acid and Usually at least equimolar amounts are used of the oxidizing agent, preferably a slight excess of about The oxidation is carried out under mild conditions. at temperatures of about -50 ° C to about + 100 ° C, preferably about -10 ° C to about + HO ° 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 halohalite compounds, such as cooling hypochlorite, eg t-butyl hypochlorite, which is used in the presence of inert solvents, such as optionally halogenated hydrocarbons, for example methylene chloride, and at temperatures of about -10 ° C to ka + 30 ° C, with periodate compounds, such as alkali metal periodate, for example potassium periodate, which is preferably used in an aqueous containing medium at a pH of about 6 and at temperatures of -10 ° C to about + 30 ° C, with iodobenzene dichloride used in an aqueous medium, preferably in the presence of an mechanical base, eg pyridine, and during cooling, eg at from about -20 ° C to about 0 ° C, or with some other oxidizing suitable for the conversion of a moiety to a sulfoxide array. I ' In the 1-oxides of 3-cephem compounds thus obtained with b in formula IA, especially those compounds in which R1, B1 and R2 has the appropriate meaning given, can the groups Eâ, R? and or H2 is transferred to each other, cleaved or inserted within the 'rade frames. A mixture of isomeric u- and ß-1-oxides can divide read, 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, which contain palladium, platinum or rhodium, and which man possibly using together with a suitable carrier material, such as carbon or barium sulfate; reducing tin, iron, copper or manganese cations, which were used in the form of the corresponding or complexes of inorganic or organic kind, e.g. such as stannous chloride, fluoride, acetate or formate, iron (II) chloride, sulphate, oxalate or succinate, copper (I) chloride, lO _¿5 20 25 30 p? a07s11-0 M1 soat or oxide or manganese (II) chloride, sulphate, acetate or oxide, or as a complex, for example with ethylenediaminetetraacetic acid or nitrilotriethyl fl dwra, xeducing dithionite, iodine or iron - @I) cyanide anions, which were used in the form of the corresponding inorganic or 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, inorganic or organic phosphorus compounds, such as phosphine, further esters, amides and halides of phosphinic acid phosphoric acid or phosphoric acid and these phosphoric acid 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 fine, diphenylphosphinic acid methyl ester; g diphenylchlorophosphine, fe- nyldichlorphosphine, benzenephosphonic acid dimethyl ester, butanephosphonic acidity methyl ester, phosphoric acid triphenyl ester, phosphoric acid trimethyl ester, phosphorus trichloride, phosphorus tribromide, ether, reducing halosilane compounds, which have at least one at the kiel atom_bound hydrogen atom and which in addition to halogen, such as ¥ k1or, bromine or iodine, may also have organic groups, such as Valiphatic or aromatic groups, for example optionally substituted the lower alkyl or phenyl groups, such as chlorosilane, bromosilane, di- or trichlorosilane, di- or tribromosilane, diphenylchlorosilane, di- methylchlorosilane, etc., reducing quaternary chloromethyleneiminium salts, in particular chloromethyleneiminium chlorides or bromides, wherein the iminium group is substituted with a divalent or two valuable organic groups, such as optionally substituted lower alkyl methylene or lower alkyl groups, for example N-chloromethylene-N, N-diethyliminium chloride or N-chloromethylene pyrrolidinium chloride; and complex metal tall hydrides, such as sodium borohydride, in the presence of suitable active agents such as cobalt (II) doride, as well as borane dichloride.

As activating agents, which are used in conjunction with those indicated reducing agents which do not themselves exhibit Lewis acid properties. properties, ie which were primarily used together with the dithio- nitrous, iodine or iron (II] cyanide and non-halogenated, trivalent the phosphorus reducing agents or in the catalytic reduction, special mention may be made of organic carboxylic acid halides and sulfonic acid halides, further sulfur, phosphorus or silicon halides with the same greater hydrolysis constant of the order other than benzoyl chloride, ._. ,, .._____..__. -__ i 10A -zo I 25 sø- g 55 H0 7307811-o A2 eg phosgene, oxalyl chloride, acetic acid chloride or bromide, chlorine 'acetic acid chloride, pivalic acid chloride, H-methoxybenzoic acid chloride, H-cyanobenzoic acid chloride, p-toluenesulfonic acid chloride, methanesulfonic acid hydrochloride, thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide, phenyldichlorophosphine, benzenephosphonic acid-like dichloride, idimethylchlorosilane or trichlorosilane, further suitable acid anhydrous such as trifluoroacetic anhydride, or cyclic sultones, such as ethanesultone, 1,3-propanesultone, 1,4-butanesultone or 1,5-nexansulton.

The reduction is preferably carried out in the presence of solvents. preparations or mixtures thereof, the choice of which is primarily is determined by the solubility of the starting materials and the choice of agents, thus using, for example, lower alkanecarboxylic acids or esters thereof, such as acetic acid and acetic acid ethyl ester, at it the catalytic reduction and, for example, optionally substituted, such as halogenated or nitrated, aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbons, for example benzene, methylene chloride chloride, chloroform or nitromethane, suitable acid derivatives, such as alkanecarboxylic acid esters or nitriles, for example acetic acid ethyl ester or acetonitrile, or amides of inorganic or organic acids such as dimethylformamide, dimethylacetamide or hexamethylphosphoride amide, ethers, for example diethyl ether, tetrahydrofuran or dioxane, acetone, or sulfones, especially aliphatic sulfones, eg dimethyl sulfone or fl tetramethylene sulfone, etc., together with the chemical reducing agents, these solvents being does not contain any water. In doing so, you work usually at temperatures of about -20 ° C to about 100 ° C, when using highly reactive activators The reaction can be carried out at lower temperatures.

In the 3-cephem compounds of the formula thus obtained a f IA can Rl, R? and / or R 2, as described, is transferred to other groups R1, R1 and R2, respectively.

Salts of compounds of formulas IA and IB may be prepared _ set in a manner known per se. Thus one can form sal-s of such compounds with acidic groups, for example by in * treatment with metal compounds, such as alkali metal salts of suitable carboxylic acids, for example the sodium salt of α-ethylcaproic acid, or with ammonia or a suitable organic amine, instead use stoichiometric amounts or only one slight excess of the salt-forming agent. Acid addition salt l0 have 20 25 ' 30 35, In topography) or other suitable separation procedures. .racemat can be divided into the antipodes in the usual way, possibly 1aova11-0 45 of compounds of formulas IA and IB with basic groupings is obtained in the usual way, for example by treatment with an acid or a suitable anion exchange reagent. Internal salts of compounds of formulas IA and IB, which contain a salt-forming amino acid group or a free carboxy group, may for example be formed by neutralization of salts, such as acid addition salts, to it isoelectric point, for example with weak bases, or by treatment with liquid ion exchanger. Salts of 1-oxides of compounds of formula IA with salt-forming groups can be prepared by analogy log way. e p 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 be divided into the individual the isomers according to methods known per se, mixtures of diastereomeric isomers, for example by fractional crystallization adsorption chromatography (column or thin layer chromatography) Obtained after the introduction of suitable salt-forming groupings, e.g. by forming a mixture of diastereomeric salts with optical active salt-forming agent, dividing the mixture into diastases. rheom the salts and conversion of the salts into free compounds or by fractional crystallization from optically active solutions ninßsmedel.

The method also includes such embodiments, according to which compounds obtained as intermediates are used as starting materials and the remaining procedure steps are performed with those or according to which the process is interrupted at any stage; far- re, the starting materials can be used in the form of derivatives or formed during the reaction. r Preferably, such starting materials are used and selected the reaction conditions so as to obtain the compounds which initially indicated as particularly suitable.

In the intermediates which can be prepared according to the invention with formula II the leaving group Y is preferably a group - -SO2R5, wherein R5 has the specified meaning, but especially that as appropriate given meaning. -jm : f 1.5 geo l_25 30 35 49 Clearing of the osmotic pressure and / or buffering agent. horizontal pharmaceutical preparations, which may contain 7807811-0 now Pharmacologically useful compounds of formula IA may for example used in the manufacture of pharmaceutical preparations, containing an effective amount of the active substance together or in admixture with inorganic or organic solid substances 's liquid, pharmaceutically usable carrier materials, 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 ,. it ex lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, and lubricants, eg silica, talc, stea- tartaric acid or salts thereof, such as magnesium or calcium stearate, . and / or polyethylene glycol; tablets also contain binding agents, such as magnesium aluminum silicate, starch, such as corn, * wheat, rice or arrowroot starch, gelatin, tragacanth, methyl cell lulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine eden, and if desired disintegrant, e.g. starch, agar, ginsic acid or salt thereof, such as sodium alginate, and / or effervescent mixtures or adsorbents, colorings, flavorings and sweeteners means. Furthermore, kanwman use the new pharmacological activities The compounds in the form of injectables, for example intravenous digestible or in the form of infusion solutions. 'ings are preferably isotonic, aqueous solutions or t suspensions, whereby these can be produced, for example, before consumption made from lyophilized preparations containing the active substance the substance alone or together with a carrier, eg mannitol} The pharmaceutical preparations may be sterilized and / or excipients, such as preservatives, stabilizers, wetting agents, and / or emulsifiers, solubilizers, salts for Before- other pharmacologically valuable substances, are prepared on-in and for known method, for example by conventional mixing, granulating ring, coating, solution or lyophilization procedures, and contains about 0.1-100%, especially about 1-about 50%, 'lyophilisate up to 100%, of the active substance.

Organic groups denoted by "lower" ("low") include holds, unless otherwise expressly defined, up to 7, preferably up to H carbon atoms; acyl groups contain up to 20, preferably up to 12 and preferably up to 7 carbon atoms. 10 20 25 30 35 NO a / ethyl acetate (5: Û as eluent. i0 ° prepared solution of ššš mg (1,11.mM) of a crude mixture consisting of 00.1 N potassium hydroxide solution. The mixture is further stirred for 5 minutes at _7so7s11-0 H5 The invention is described in more detail in the following examples, in which the temperatures are given in degrees Celsius. The ones given in the examples the cephem compounds have in the 6- and 7-position and the indicated aceti- dinon compounds in 3- and 4-position R-configuration._ _ EXAMPLE 1. To a solution of 153 mg (0.2 mM) of an isomer mixture, consisting of 2-M (p-toluenesulfonylthio) -3-phenoxyacetamido [2-oxaacetyl] thio- din-1-yl] -3-methoxy-crotonic acid p-nitrobenzyl ester and the corresponding iso- crotonic acid ester in a ratio of about QQ1 in a dry tetrahydro- furan is added dropwise over 5 minutes a solution of 60 μl (2 eq) 1,5- diazabicyclo [5.ü.0] undee-5-ene in 1 ml of tetrahydrofuran. After standing at room temperature for 10 minutes, dilute with 20 ml of benzene, cool in an 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, 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 4 g of acid. washed silica gel (2 kg silica gel, stirred three times with 2 l cone. 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 / The fractions that contain the isomer mixture, combine and evaporate in vacuo. You receive a semi-solid isomer mixture (yield 75.5 mg; 74.5% of theory) of 7E »phenoxyacetamido-3-methoxy-cef-3-em-H-carboxylic acid-p-nitrobenzyl- ester and 7β-phenoxyacetamido-3-methoxy-cef-2-em-N-carboxylic acid-p-nitro- benzyl ester in a ratio of about 1: 3, 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 7fi ~ phenoxyacetamido -} - -methoxy-cef-2-em-H-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 1U0.5-1320 (from methylene chloride) ether).

The products can be further processed in the following ways: a wide of 76-phenoxyacetamido-3-methoxy-cef-2-em-ha-carboxylic acid 7β-nitroben- sylester and 76-phenoxyacetamido-3-methoxy-cef-3-em-α-carboxylic acid-pff nitrobenzyls fi er 1 a ratio of about 3 = 1'1 33 m1 uecranyaróïü ' the furan is added with stirring with 16 ml of one to 0? pre-chilled 00, then add 100 ml of ice water and 100 ml of pre-cooled f 1 r .1 .-- | --.- ve-u- ~ u-.n .; .. ... w le ~ e? s07811'0 10 Csï 20_ '25 35 ¶_ is taken under vacuum. 'ne methylene chloride and stirred for a short time. Addition of 01 ml saturated, aqueous sodium chloride solution provides a separation of the da faserna. The organic phase separates 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. - wash twice more with 10 ml of methylene chloride each time. gDe The combined methylene chloride extracts are dried over sodium sulfate and evaporated. The residue is recrystallized from methylene chloride / diethyl ether / pentane to give 75-phenoxyacetamido-3-methoxy-cef-2-em-4a-carboxylic acid .ra with melting point 142-1450; yield 270 mg (67% of theory) ¿ß “* The intermediates can be obtained as follows: a) g A solution of 36.6 g (0.1 M) 6-Phenoxyacetamidopenicillanic acid-1B- oxide, 11.1 ml (0.1 M) of triethylamine and 23.8 g (0.11 M) of p-nitrobenzyl bromide in 200 ml of dimethylformamide is stirred for 4 hours at room temperature below nitrogen solution. The reaction solution is then introduced into 155 l of ice water, precipitated The solution is filtered off, dried and recrystallized twice from ethyl acetate. racetate methylene chloride. The colorless, crystalline 6-phenoxyacetamido- the penicillanic acid nitrobenzyl ester oxide melts at 179-180 °; (yield HH g (88% of theory)., 'g' * _ b) A solution of 5.01 g (10 mM) of 6-phenoxyacetamidopenicillanic acid p- nitrobenzyl ester-1N »oxide and 1.67 g (10 mM) of 2-mercaptobenzothiazole in 110 ml of dry toluene is refluxed for U 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 methylene chloride ether to give 2- [α- (benstiazol-2-yldithio) -3-phenoxyacetyl] amido-2-oxazetidin-1-yl] -3-methylene-butyric acid p-nitrobenzyl ester with melting points 138-1ü1 °; yield 4.5 g (80% of theory).

G) To a solution of 3.25 g (5.0 mM) of 2- [U- (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 (mM) sodium pétoluenesulfinate in 100 ml of the same solvent mixture A light yellow precipitate forms immediately- After - ____.____._ .., _'ning (In 10 min). 1eh stirring 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) -} - phenoxyacetacet- 0 amidofg- oxoazetidin-1-ylc-methylenebutyric acid p-nitrobenzyl ester. Thin- . C- “uu-lnh. ,, ..,., .... ,,. . ..,. b, ._ ,. ¿. . . -. . .., in in 10 (LS 20 gas 30 35 7807811-0 U? layer chromatogram on silica gel (toluene / ethyl acetate 2: 1): Rf value = 0.24; IR spectrum (1 CH 2 Cl 2): characteristic bands at 3.90, 5.56, 5.70, 5.87, 6.23, 6.53, 6.66, 7.40, 7.50, 8.10, 8.72, _9.25, 10.95 um; - 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.

The same compound can also be obtained according to the following methods: ei) T111 a solution of 3.25 g (5.0 mm) 2- [4- (benzc1¿z @ 1-2-y1a1t10) - -3-phenoxyacetamido-2-oxoazetidin-1-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 solution is stirred for 1 hour at room temperature, filtered and further processed. I is grazed as described in Example f c). 2- [4- (p-toluenesulfonylthio) - -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylene-butyric acid-p-nitro- benzyl ester is obtained in quantitative yield.

Silver p-toluenesulfinate is obtained by combining aqueous solutions containing equimolar amounts of silver nitrate and sodium èp-toluenesulfonate as a colorless precipitate. The product is dried under vacuum for 24 hours. _ 0 _ cii) 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 (2,1-b] thiazol-2-yldithio) -3-phenoxyacetamido- α-2-oxaazetidin-1-yl] -3-methylene butyric acid β-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 sulphate and sodium p-toluenesulfinate (2 eq) in water. After filtration, the salt is dried under vacuum for 12 hours at 60 °. ciii) ë- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidine-1- -yl] -3-methylenebutyric acid p-nitrobenzyl ester can also be obtained analogously with Example 1 eI) from 130 mg of 2- [4- (benstiazol-2-yldithio) -3-phenoxyacetacid 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 (2H 2 O) and sodium p-toluenesulfinate in water. After filtration and washing with water, the salt is dried under vacuum for about 12 hours at 50-60 °. civ) 2- [H- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidine-1- γ11-3-methylenebutyric acid β-nitrobenzyl ester can also be obtained analogously with Example 1 (c) from 130 mg of 2-EH- (benzstiazol-2-yldithio) -3-phenoxyacetacid Yes io 15 me 02%, - _30 nd 1 water. ¿Under vacuum for about 12 hours at 50 ~ 609. 7807811'Û w amido-2-oxoazetidin-1-yl] -3-methylenebutyric acid p-nitrobenzyl ester and 102 mg (2 eq) of mercury (II) di-p-toluenesulfinate; yield 67 mg Z (approximately 52.3%). 1 'g Mercury (II) d1-p-toluenesulfinate is obtained by reacting mercury (II) diacetate and sodium p-toluenesulfinate 1 After filtration and washing with water, the salt is dried rev) 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 7'i 10 ml of 1,2-dimethoxyethane (or dioxane) are refluxed for 4.5 hours 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 1 five portions with H5 min 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. The residue is chromatographed on silica gel-thick layer plates with toluene / ethyl acetate (2: 1) to give 2- [4- (p-toluenesul- phonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylenobutyric acid _p_nigf0bensy1eSter; yield 212 mg (59% of theory). cvi) A mixture of 250 mg (0.5 mM) 6-phenoxyacetamidopenioillan 'acid; p-niurobenzylestef-1ß-Oxie, 110 mg (0.61 mm) p-toluenesulronyl- cyanide and 5 mg (0.022 mM) of benzyl triethylammonium chloride in 2 ml Dry, peroxide-free dioxane is stirred under argon for 4.5 hours at 1100 DEG.

The solvent is evaporated off under vacuum and the remaining yellow oil is evaporated. it is chromatographed on acid-washed silica gel. Elution with 50% ethyl acetate in toluene gives 2- [4- (p-toluenesulfonylthio) -3-phenoxylacetamide O-2-oxoazetidin-1-yl] -3-methylenobutyric acid p-nitrobenzyl ester; exchange 1133 mg (42% of theory). ~~ cvii) A mixture of 110 mg (0.61 mM) of p-toluenesulfonyl cyanide and 14.5 mg (0.021 mM) of tetraethylammonium bromide in 1 ml of pure dioxane are stirred » gi at 1100 under argon_i 30 min. Then a suspension 1 is added gave 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 ii H h at 110 ° under argon. The solvent is removed in vacuo. In the crude product is dissolved in ethyl acetate and washed with water and v - -, = ._.,. , - ne a-w-a-'f 10. 15. 20. 25. 30. 35- 7807811-0 H9 saturated aqueous saline solution. The organic phase is dried with magnesium sulfate and liberated in vacuo from solvent to give Crude 2- [N-p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1ryl] -3- methylene butyric acid p-nitrobenzyl ester; yield 3Uß mg. d) In a solution of 1.92 g (3.0 mM) 2- [N- (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 sulfate and evaporated to dryness under vacuum. After recrystallization of the residue from toluene, les 2- [α- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoacetidin-1-yl] - -3-hydroxycrotonic acid p-nitrobenzyl ester, m.p. 159-1600; yield 1.7ü (90 Z of theory). di) According to Example 1 cvii) obtained, crude 2- [4- (p-toluenesulfonylthio) -3- phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylenobutyric acid-p-nitrobenzyl- ester is dissolved in 20 ml of methyl acetate and ozonized at -70 °, 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 0-50. A solution of 300 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 crude product is dissolved in 3 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] -3-hydroxycrotonic acid p-nitrobenzyl ester, m.p. 159-1600; yield 178 -mg (56, z of 'the-theoretical fl e) A solution of 1.93 g of 2- [H- (p-toluenesulfonylthio) -3-phenoxyacetamino- do-2-oxoazetidin-1-yl] -3-oxobutyric acid p-nitrobenzyl ester (3.0 mM) in 15 ml of dry chloroform was cooled to 0 ° and added over the course of 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. a: _. 10. 15. 20. 25. 30. 35.

-H0. 1307811-0 50 The crude product is purified by filtration over Woelm silica gel (activity.

III, 40-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 isomer mixture consisting of 2- [U- (p-toluenesulfonylthio) -3-phenyl- oxyacetamido-2-oxoazetidin-1-yl] -3-methoxycrotonic acid-p-nitrobenzyl- ester and the corresponding isocrotonic acid ester in a ratio of about U: 1; melting point of the mixture 155-156.50; yield 163 g (83% of it theoretical).

EXAMPLE 2. A solution of 279 mg of E- [4- (p-toluenesulfonylthio) -3-phenyl] oxiacetamido-2-oxoazetidin-1-yl] -3-hydroxycrotonic acid diphenylmecyl 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 1 h. The silylated crude product consists of 2, [4- (p-toluenesulfonylthiol-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 ° and put under nitrogen and stirring with 0.069 ml (0.47) mm) 1,5-diazabicyclo [5.4.o] undec-5-ene. After 1 h of reaction was added the solution with 0.3 ml of acetic acid and diluted with chloroform. Chloroform- the solution is washed with dilute sulfuric acid, water and dilute rium bicarbonate solution. The aqueous phases are extracted with chloroform, the combined organic phases are dried over sodium sulfate and evaporated in vacuo. There is obtained crude 7β-phenoxyacetamido-j- hydroxy-cef -} - em-4-carboxylic acid diphenylmethyl ester; Rf value: 0.13 (silica gel; toluene / ethyl acetate 3: 1).

The crude product obtained is taken up and added to Oo with one excess ether solution of diazomethane. After 5 hours the reaction is evaporated the solution is complete and the oily residue is chromatographed on silica gel thick layer plates (toluene / ethyl acetate 3: 1). Silica- gel 1 zone at Rf = 0.19 is extracted with ethyl acetate to give 75- Phenoxyacetamido-3-methoxy-cep-3-em-4-carboxylic acid diphenylmethyl ester melting point 1200 (from ether; IR spectrum (in CHCl 3) 5310, 1775, 1700, 1690, 16oo cm'1; yield 22 mg- __ ”w The intermediate is prepared as follows. a) Of 100 g (27.3 mM) olephenociacetamido-penicillanic acid-1β-oxide, 500 ml of dioxane and 58.4 g (30 mM 2 of diphenylmethyldiazomatane are obtained) about 2 hours 6-phenoxyacetamidopenicillanic acid diphenylmethyl ester-1B- oxide; mp 144-1ü6 ° C. (ethyl acetate / petroleum ether). (fl 10. 15. ao. 25. 30. 35. y separator reg separating about 4.5 ml of water. 7807811-0 51 I b) In analogy to Example 1b) 2- [4- (Benstiazol-2-ylthio) -5- phenoxyacetamido-2-oxoazetidin-1-yl} -3-methylenobutyric acid-diphenylmethyl- ester Melting point 140-1410 (from toluene / ether, from 292 g (55 mM) 6-phenoxyacetamido-penieillanoic acid-diphenylmethyl ester-1β-oxide and 99 g (59.5 mM) 2-mercaptobenstiazole. c) Analogously to Example 1c is obtained from 10 g (14.7 mM) 2- [4- (Benstiazol-2-yldithio) -5-phenoxyacetamido-2-oxoaaetidin-1-yl] -3-methyl- Tylenic butyric acid diphenylmethyl ester 1 50 ml ethyl acetate, 4.92 g (24.98 mm) finely powdered p-toluenesulfinate and stirring for 7 hours at room temperature. 2- [4- (p-toluenesulfonylthio) -5-phenoxyacetamido-2-oxoazetidine -1-yl] -5-methylenobutyric acid diphenylmethyl ester; Rf value = 0.28 (si- lixagel; fi øluen / ecylacëšac 3 = 1); IR spectrum (cHc13> = 1782, 1740, 11695, 1340, 1150 cm -1; yield 9.57 g. 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidine- -1-yl] -5-methylenebutyric acid diphenylmethyl ester can also be prepared on the following sentence '. cl) A suspension of 106.5 g of 6-phenoxyacetamido-penicillanic acid diphenylmethyl ester-1B oxide and 55.8 g of 2-mercaptobenstriazole 1,900 ml of toluene and 9 ml of glacial acetic acid are boiled for 2 hours under nitrogen with 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 50 g of Norit and evaporated. the yellow foam is crystallized from methylene chloride / diethyl ether; melting point 79-820; Rf value = 0.55 (silica gel; toluene / ethyl acetate 5:11. additional amounts of substance can be recovered by crystallization. lysis from methylene chloride / diethyl ether; fgtal yield 109.7 8 (81.3 1 av the theoretical. 1 d) Analogously to item 1d), 10.8 g (1ÉfÉ ”mM) 2- [4- - (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -5-methyl In tylenic butyric acid diphenylmethyl ester in 1 l of methylene chloride and 1.1 eq ozone 2- [N- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] 5 -5-hydroxycrotonic acid diphenylmethyl ester; melting point 142-145 ° (ur ether / pentane); yield 11.5 g.

The ozonation can also be carried out at 0 °: 7807811-o 52 In a solution of 9.23 g (13.8 mM) 2- {ü- (p-toluenesulfonylthio) - -5-phenoxyacetamido-2-oxoazetidin-1-yl} -5-methylenobutyric acid diphenylmethyl ethyl ester in 960 ml of methylene chloride is introduced into 15.2 mM ozone at 0 ° C Almin. 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 obtained 2- [H- (p-toluenesulfonyl) -3-phenoxy-acetamido- 10. (dai) iso 20. 2-oxoazetidin-1-yl-3-hydroxycrotonic acid or diphenylmethyl ester at 13 ~ 138 °; thin layer chromatogram Rf value about 0.46 (silica gel): toluene / ethyl acetate 3: 1). ~ The same compound can also be obtained according to the following methods: A solution of 684 mg (1 mM) of 2-fu- (benstiazol-2-diylthio) -3- phenoxy-2-oxoazetidin-1-yl} -3-hydroxycrotonic acid diphenylmethyl ester in 20 ml of acetone / water 9: 1 (v / v) are stirred at room temperature for 60 minutes with BU1 mg (1.3 mM) silver p-toluenesulfinate. The yellow reaction mixture The mixture is added with 50 ml of acetone and filtered. The filtrate is evaporated, under vacuum and the residue is chromatographed on 30 g of acid-washed silica gel with toluene / ethyl acetate (üzi). Obtained 2-[(p-toluenesulfonyl- thio) -3-phenoxy-acetamido-2-oxoazetidin-1-yl-3-hydroxycrotonic acid dife- nyl methyl ester is recrystallized from ether / pentane and melts at 142-1 e-1u3 °; yield 610 mg (91% of theory). 25. dii) A solution of 72.9 mg (0.1 mM) of the crude ozonide obtained maintained by ozonation of 68.1 mg (0.1 mM) 2- [4- (bënSÜiaZ ° 1-2- -ylthio) -3-phenoxyacetamido (2-oxoazetidin-1-yl] -3-methylenobutyric acid dife nyl methyl ester 1 ethyl acetate and evaporation of the solvent, 1 2 ml Saoetone / water (9: 1) (v / v) is stirred for 1 hour at room temperature 30. 35 :. ' 1 (corr); [dl go = with 35 mg (1.5 eq of silver p-toluenesulfinate. The reaction mixture diluted with 3 ml of acetone and filtered. The filtrate is added with 0.2 ml of dimethyl sulfide and stir for 2 hours at room temperature (to negative Iodine starch reactionï. After removal of the solvent under vacuum, the residue is chromatographed on 3 g of acid-washed silica gel with toluene / ethyl acetate (4: 1). Obtain 2e [4- (pftoluenesulfonylthio) -} - phen- oxiacetamido-2-oxoazetyldin-1-yl] -3-hydroxycarbonic acid diphenylmethyl- ester is recrystallized from ether / pentane and melts at 142-1ü3 °; exchange (38 mg (55% of theory) After recrystallization several times from mecylenecleride / acylcyler a melting point of iuu-1n5 ° is obtained -680 3 1 ° (c = 1; chloroform); thin layer chromatogram: Rf value = 0, B1 '(silica gel; methylene chloride / ethyl acetate 8: 2); UV- 7307811-0 \\ 'l \.> | spectrum (ethyl alcohol): Ķmx = 261 Hm (2 = 14 Ü00) š IR'SPekÜPUm (nujol): characteristic bands at 3.00, 5.56, 5.93, 5.95, 5.05, 6.19, 6.25, 6.514, 6.70, 6.82, 73023 73147; 8:03: 81769 9353! 10,239 10.60, 12.30, 13.26, 111.30 Pm. EXAMPLE 3 A solution of 501 mg (0.462 mM) of 2- [4- (p-toluenesulfonyl) Thio] -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-hydroxycrotonic acid dife- nyl methyl ester 1 3 ml of 1,2-dimethoxyethane are added under nitrogen 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- I tfn, the product is taken up in 3 ml of dried 1,2-dimethoxyethane and added cooling cin o ° with oïovs m1 (o.5o8 mm) 1,5-a1azab1 @ yk1 ° [5.4.o] un- , dec-5-en. After 6 hours reaction time at 0 DEG C. under nitrogen is added 0.3 ml of acetic acid and diluted with methylene chloride. Methylene chloride solvent The mixture is washed successively with dilute sulfuric acid, water and diluted bicarbonate solution. The aqueous phases are extracted with methylene! chloride, the combined organic phases are dried over sodium sulphate, evaporate in vacuo and dry under high vacuum. You get raw 76-Phenoxyacetamido-3-hydroxy-cef-3-em-4-carboxylic acid diphenylmethyl- ester. The solution of the crude product in chloroform is added at 0 ° 15. 20. an excess of a diazomethane solution in ether and allowed to stand for 5 min at 0 °. Then evaporate completely and the residue is chromatographed. applied to silica gel as in Example 2. 7B-phenoxyacetate is obtained. 25-amido-3-methoxy-cep-} -em-4-carboxylic acid diphenylmethyl ester; Rf value (, - = 0.19 (silica gel; toluene / ethyl acetate) 3: 1), melting point 120 ° (from ether); IR spectrum (in CHCl 3): 3310, 1775, 1710, 1690, 1600 cm -1; yield 26 mg.

EXAMPLE 4. A solution of 100 mg (0.15 mM1 of an isomer mixture, 30, consisting of 2- [4- (p-toluenesulfonylthio] -3-phenoxyacetamido-2-oxoazene- thidin-1-yl] -3-methoxy-crotonic acid diphenylmethyl ester and the like isocrotonic acid ester 1 4 ml of dry 1,2-dimethoxyethane, is added under stirring 1 nitrogen atmosphere with 0.045 ml (0.3 mM) 1,5-di8Z fi biOYk10- _ [5.4.0] undec-5-en. The solution is stirred for 40 minutes at room temperature 35, under nitrogen, then cooled with ice and added with 0.1 ml of tiksyra. 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 un, der high vacuum completely from solvent. The oily residue -: _. 4-_u_ .. _ .. 1 * 07807811-0 _51; it is chromatographed on a silica gel thick layer plate (elution medium). part: toluene / ethyl acetate 3: 1; developing once), The two zones at Rf = 0.19 and 0, respectively, Ä is extracted together with ethyl acetate and In W the resulting solution is completely evaporated. You get an oily Product, which consists of β-phenoxyacetamido-3-methoxy-cef-3-em-β-carbon 7 oxylic acid diphenylmethyl ester and isomer 7β-phenoxyacetamido-3-methoxy- -cef-2-em 1H-carboxylic acid diphenylmethyl ester in the ratio 1: 0; Rf- value = 0.14 and 0.32, respectively (silica gel toluene / ethyl acetate 3: 1); IR spectrum - i 09013) 3400, 3310, 1785, 1770, 1750, 1710, 1690, _1630, 1600 cnfï; 10 yield 58 mg.

I i) The ratio of cef-2-em to cef-3-em derivatives obtained depends 0b1.a. on the solvent used for the ring slope, starting material and the concentration of 1,5-diazabicyclo [5.4.0] undec-5-ene and even on the reaction time. The following table lists some reactions, 15 psom is performed analogously to the given example with 100 mg each of an isomeric mixture of about 95% 2- [β- (p-toluenesulfonylthio) -3-phenoxy- acetamido-2-oxoazetidin-1-yl] -3-methoxy-isocrotonic acid-diphenylmethylsyl and about 5% of the corresponding crotonic acid derivatives. Reaction time nppg uniformly to 20 min and the work-up took place analogously with 20 given example. 5 - Kbncentration I f Ratio 'I H - of starting Eq.1 5-diaza- obtained ' Ioånlngsmedel Uateráal bicyclo [5.4.0} -; cef-2-em: »In Yield% weight / volume undec-5-en f cef-3-em- * 5 der fi mt I Acetone 10% 1.5 E ca 3: 2,! 68 lbluen 10% - 1.5 å ca 1: 1 'I 76 »Euylace fi at 10 z 1.5 'i ca 4: 3 g 814 Ethyl acetate 20% 1.3 and about 0: 3 '85 Isobutylmethyl-É ' ketone 20% 1.3 I ca 9:10 65 Mecynnomfom 20 z 1.3 i ca 9: 7 16 »1,2-dimethoxyethane '20 5 1.3 § ca 6: 5 83 ,. in a) The isomer mixture used as starting material can be obtained analogous to Example 1e) from 4 g (6.1 μmM) 2- [4- (p-toluenesulfonyl) 7 thio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-hydroxycrotonic acid Diphenylmethyl ester and an excess ether solution of diazomethane. Your- isomer mixture consisting of 2- [H- (p-toluenesulfonylthio) -3- phenoxyacetamido * 2-oxoazetidin-1-yl] -3-methoxy-crotonic acid diphenylmethyl- 10 15 20 25 30 35 H0 'aii) '7807811-0 55 ester and the corresponding isocrotonic acid diphenylmethyl ester (about 3: 1) > crystallizes from ethyl acetate / pentane and has a melting point of 150-1520; yield 2.14 g.

As intermediate product, use isomer mixture or croton and Isocrotic acid derivatives can also be obtained in the following ways: _, __ m_ “mm_ ~ _ ai) A solution of 698 mg (1 mM) of an isomeric mixture, consisting of: 2- [U- (Benstiazol-2-ylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3- methocycrotonic acid diphenylmethyl ester and the corresponding isocrotonic acid -diphenylmethyl ester in 20 ml acetone / water (9: 1) (v / v) is stirred in 1 h at room temperature with BÜ1 mg (1.3 mM) silver p-toluenesulfinate.

The yellow reaction mixture is diluted with 50 ml of acetone and filtered.

The filtrate is evaporated in vacuo and the residue is chromatographed on 30 g of acid-washed silica gel with toluene / ethyl acetate (2: 1). You receive an isomeric mixture of 2- [U- (p-toluenesulfonylthio) -} - phenoxyacetamido- -2-oxoazetidin-1-yl] -3-methoxy-crotonic acid diphenylmethyl ester and 2- [H- - (p-toluenesulfonylthio) -5-phenoxyacetamido-2-oxoazetidin-1-yl2-3-methyl- oxyisocrotonic acid diphenylmethyl ester; yield 60ü mg (88% of the theory reticent). _ The reaction described under ai) can also, instead of in acetone / water, is carried out in tetrahydrofuran, (stir for about 2U h at room temperature. A solution of 336 mg (0.5 mM) 2-: H- (p-toluenesulfonylthio) -3- phenoxyacetamido-2-oxoazetidin-1-yl) -3-hydroxycrotonic acid diphenylmethyl- ester in 1 ml of ethylene chloride is added at 0 DEG C. with 0.21 ml (1.2 mM) of ethyl acetate. diisopropylamine and 0.12 ml (1.5 mM) of fluorosulfonic acid methyl ester and Stir for 30 minutes at 0 ° and for a further 30 minutes at room temperature.

The reaction mixture is diluted with ethyl acetate, washed with saturated aqueous sodium chloride solution and dilute aqueous sodium bicarbonate solution bonate solution and dried over sodium sulfate. Dwn after evaporation the remaining residue is chromatographed on silica gel. Toluene / ethyl acetate tat (U: 1) first elutes some amount of starting material. With toluene / ethyl acetate (1: 1) is then isolated an isomeric mixture of 2- [α- (p-toluene- sulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxycrotone acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester, yield 190 mg (about 55 l of the theoretical). aiv) A solution of 300 mg (0, UU7 mM) 2- [N- (p-toluenesulfonylthio) -3- phenoxyacetamido-2-oxo-azetidin-1-yl] -3-hydroxycrotonic acid diphenylmethyl- ester in Ä ml acetone is added with 76 mg (0.55 mM) potassium carbonate and 0.088 ml (0.92 mM) of dimethyl sulfate and stir for 5 hours at room temperature.

The solution is diluted with ethyl acetate, washed with water and dried 7 (»10h 15.

A 6.7 g Celite and filter. 27807811-0 _ _ 56 sodium sulfate. After removal of the solvent is recrystallized the residue from ethyl acetate / pentane to give an isomer mixture which stands for 2- [4- (p-toluenesulfonylthio) -5-phenoxyacetamido-2-oxoazetidine-1- 3] methoxy-crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid Ura-diphenylmethyl ester. 2 2 - av) A solution of 6.73 g of 2 - {# + (p-toluenesulfonylthio) -3 Idoamido-2-oxoacetidin-1-yl] -3-hydroxycrotonic acid diphenylmethyl ester (crystalline in tallin) 1 67 m1 ans cecranydrofuran försäbues_v1a -2o ° with 1.57 g N, N'- dinitroso-N, N'-dimethyloxamide and then in 15 minutes with a solution of 0.57 ml (0.51 g) of ethylenediamine in 5 ml of tetrahydrofuran. After the addition Then stir for 1 hour at 0 ° C, add 0.53 ml (11 mM) of glacial acetic acid and "The residue is washed five times with 2 20 ml of tetrahydrofuran each time. Filtrates and washings are combined, evaporate to about 20 g and add 20 ml of hexane. Crystalline The filters are filtered off, washed with tetrahydrofuran / hexane (1: 2) and dried consider high vacuum. IN The crystals consist mainly of 2- [Å- (p-toluenesulfonylthio) -3- -phenoxyacetamido-2-oxoazetidin-1-yl] [3-methoxy-isocrotonic acid- diphenylmethyl ester; yield 6.3 g (92% of theory). 20, 30. 35. 40. lavi) A sample is recrystallized from ethyl acetate / diethyl ether to give the following analysis values = melting point fi 167-169 °; ¿¿jâ ° = -3o ° ¿1 ° t = 1; -methylene chloride); thin layer chromatogram: Rf value = 0.57 (silica jgel; methylene chloride / ethyl acetate / glacial acetic acid 60: 40: 1); UV> spectrum (ethyl alcohol); Q> 45.i _}, max = 260 nm (§ == 16 600); In-spectrum (Nu¿61) = characteristic ristic bands at 2.97, 5.62, 5.90, 6.27, 6.61, 6.66, 7.17, 7.55, 7.70, 7.96, 8.02; 8.20. 8.80, 9.20, 10.26, 12.24, 13.30 um. NMR spectrum (100 MZ; 1 cncl) = δ 2.32 (s / cn3); 2.34 (s / cH5); 3.73 (S / ocH 3); 4.30 / 4.44 (AB; J = 5 / azetidine---CH-); 6.8-7.5 (m / 19 aromatic H, NH) ppm.

The mother liquor also contains a small amount of isocrotonic acid derivatives mainly 2- [4- (p-toluenesulfonylthio) -5-phenoxyacetamido-2-oxoazetidine- -1phyl] -3-methoxy-crotonic acid diphenylmethyl ester; as after chromatographic purification on silica gel has a melting point of 146-1Ä8 ° (corr; from ethyl acetate / hexane); NMR spectrum (100 MHz / 1 CDCl 3: δ 2.08 (s / vinyl-CH 3); 2.26 (s / aromatic-cn); 3.70 (S / -ocn); 4.47 (s / -ocH 2 co-); 4.94 (ad / J. = 5 and 8 / azetidine-3-CH-); 5.83 (d / J = 5 / azetidine---CH-); 6.3-7.5 (M / 19) aT0m fi ï1Sk H, -NH ~) PPM; [fl] âO + 210 i 10; (c -1; methylene chloride). A suspension of 6.72 g (10 mmol) of 2- [4- (p-toluenesulfonyl) thio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -5-hydroxycrotonic acid dife- nymethyl ester (crystalline) and 0.36 g (1 mM) of tetra-n-butylammonium .1o. 15. 20. 25, 30. 35.

HO. . 7807811-0 57 ' iodide In 100 ml of toluene, add 3.78 g (30 mM) of dimethyl sulphate and 30 ml of 20% aqueous potassium bicarbonate solution and stirred strongly at room temperature for 4 hours. During the first 15 minutes the solid in solution. The mixture is diluted with toluene and wash with saturated aqueous sodium chloride solution., After drying of the organic phase with sodium sulphate and evaporation is obtained by crystallization from ethyl acetate / diethyl ether 2- [4- (p-toluenesulfonyl- thio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxyisocrotonic acid-di-a phenylmethyl ester. _ avii) A suspension of 3.36 g (5 mM) 2- [α- (p-toluenesulfonylthio) -3- phenoxyacetamido-2-oxoazetidin-1-yl] -3-hydroxycrotonic acid diphenylmethyl- ester (crystalline) in 15 ml of carbon tetrachloride and 10 ml of water are added with 1.08 g (3 mn) of cecrabutylammonium iodide and 1.9 ml (2.52 g, 20 mn) dimethyl sulfate. To the mixture, which is strongly stirred at room temperature, 1 N sodium hydroxide solution is always added with the aid of of an automatic titration device, that the pH remains constant at 7.0.

During the course of 4-5 hours, 1.5-3 eq of sodium naryoxia solution is consumed. Among dilute with ethyl acetate and water and add a small amount of boiling salt. The organic phase is dried over sodium sulfate and evaporated. 1 The residue is crystallized from a small amount of ethyl acetate / hexane (Izl) and ige? 2-15- (P-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-y17-3- methoxyisocrotonic acid-diphenylmethyl estargic yield 2, U g (90% of the reticent). '' The isomer mixture used as intermediate can also be obtained is read via the corresponding 2-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 melt is chromatographed after cooling on 500 g of acid-washed silica gel with toluene / ethyl acetate (6: 1) and then ter (3: 1). 2- [4- (Benzoxazol-2-yldithio) -3-phenoxyacetyl- amido-2-oxoazetidin-1-yl] -3-methylene-butyric acid diphenylmethyl ester in form of a white foam; IR spectrum (methylene chloride): characteristic band at 5.6; 5.75, 5.90 and 6.7 μm. aix) In a solution of 3.35 g of 2- [4- (benzoxazole-2-) cooled to -70 ° yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylenobutyric acid -diphenylmethyl ester in 125 ml of ethyl acetate is introduced into about 1 eq of ozone (1 form of a mixture of 02/03), until some starting material ic- no longer is detectably thin layer chromatographic (silica gel; toluene / ethyl acetate 3: 1). The solution is evaporated in vacuo to about 50 ° C f: \ in 10. ia 20 .: 25.

K 30. 35.

NO. e washed with water. EXAMPLE * S. 7807811-od 5 * 58 1 ml, add 5 ml of dimethyl sulphide and stir until some reaction tion is no longer obtained by potassium iodide starch testing. Among- The residue is evaporated in vacuo, the residue is dissolved in 150 ml of benzene and The organic phase is dried over sodium sulfate * and evaporated. The residue is chromatographed on 150 g of acid-washed silica. gel gel with toluene / ethyl acetate (4: 1) Å 2f [Ä- (benzoxazole- -α-yldithio) -3-phenoxyacetamino-α-oxoazetidin-1-yl] -5-phenyl = rich- = = n- »Acid-diphenylmethyl ester in the form of a white foam; IR spectrum (methyl len chloride) characteristic bands at 5.60; 5.90; 6.0 Hm; uümwe-ljïg. ax) To a solution of 1.7 g of 2- [ÄÅ (benzoxazol-2-yl-dithio) -3- phenoxyacetamido-2-oxoazetidin-1-yl] -3-hydroxycrotonic acid diphenylmethyl ethyl ester in 12.5 ml of methylene chloride is added dropwise at 0 DEG C. stirring an ethereal solution of diazomethane, until no starting material ick = longer is detectably thin layer chromatographic (silica gel; toluene / / ethyl acetate 3: 1) Ä The mixture is evaporated in vacuo and recycled the column is chromatographed on 80 g of acid-washed silica gel with toluene / / ethyl acetate (2: 1). An isomer mixture consisting of 2- [4- (Benzoxazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -34 methoxycrotonic acid diphenylmethyl ester and the corresponding isocrotonic acid phenylmethyl ester in a ratio of about 5: 1; IR spectrum (mean tylene chloride): characteristic bands at 5.60; 5.85 (approach); 5.90; 6.1 + o; 6.65 um; yield 1.27 s- axi) A loose fl ïnå of 68? must (1 mM) of an isomer mixture consisting of of 2- [N- (benzoxazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester In 20 ml of acetone / water (9: 1) (v / v), stir 1 For 90 minutes at room temperature with 350 mg (1.3 mM) of silver-p-toluenesulphide. t.t - R The mixture is filtered through Celite, the filtrate is evaporated your vacuum to 5 ml and extracted with 30 ml of methylene chloride. Methy- The ethyl chloride phase is dried over sodium sulphate and evaporated in vacuo The residue is chromatographed on 30 g of acid-washed silica gel with tgluene / ethyl acetate (1: 1) to give an isomer mixture consisting of 2- [4_ (p_ toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy k t _ carbonic acid diphenylmethyl ester and the corresponding isocrotonic acid + diphenyl methyl ester; yield 610 mg. . 5 _ A solution of 50? may (0.45 mM) of that of Example Ha) obtained, crystallized isomer mixture consisting of 2 - [& - (p_ toluenesulfonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy- crotonic acid-diphenylmethyl ester and the corresponding isocrotonic acid ester 1 4 ml of ÜOPP 112-dimethoxyethane are stirred at room temperature under nitrogen get 78078114] 59 with 0.13U ml (0.9 mM) of 1,5-diazabicycloz5.U.Q; undec-5-ene. After HO 10. 15 20 25. 30! 35. dilute sodium bicarbonate solution. In one reaction, the solution is cooled to 0 DEG C. and added with 0.1 ml of acetic acid. acid and then with 180 mg (1.36 mM) of m-chloroperbenzoic acid (85-pro- centíg). The solution is stirred for 10 minutes at 0 ° under nitrogen, diluted with chloroform and washed with dilute sulfuric acid / sodium thiosulfate, water and dilute sodium bicarbonate solution. chloroform, the combined organic phases are dried overnight. sodium sulphate, evaporated in vacuo and freed from solvents under there high vacuum; yield 27ü 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.

7β-phenoxy-acetamido-3-methoxy-cephalic acid is obtained as an oily residue. c-3-em-H-carboxylic acid diphenylmethyl ester-1-oxide, which crystallizes from methylene chloride / pentane; melting point 115-120 °; 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 dryer of the oily residue, 7β--phenoxyacetamido- 3-methoxy-cep-3-em-α-carboxylic acid diphenylmethyl ester-BK oxide; molten points 175-1800 (from chloroform); yield 12 mg.

The same compounds can also be prepared according to Example i) or -ler ii): i) A solution of 24.7 mg (36 mM) of that of Example 4 a) the crystallized isomer mixture of 2eE4- (p-toluenesulfonyl) thio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-crotonic acid-diphenyl- methyl ester and the corresponding isocrotonic acid ester in 247 ml of dry 1,2-dimethyl oxyethane is stirred at room temperature under nitrogen with 8.22 ml (54 mM) 1,5-diazabicyclo [5.4.0] undec-5-ene. After 40 minutes of reaction, the solution is cooled. to 0 ° and then added with 37.3 ml (108 mM) of permyric acid (prepared from 33 ml of perhydrol (30%) and 100 ml of formic acid).

The solution is stirred for 10 minutes at 0 ° under nitrogen, diluted with chloroform and washed with dilute sulfuric acid / sodium thiosulfate, water and The aqueous phases are extracted with chloroform, the combined organic phases are dried over sodium sulfide. evaporate in vacuo and release from solvent under high pressure vacuum. The obtained crude product is crystallized from methylene chloride / pentane and gives 76-phenoxyacetamido-j-methoxy-1-cef-5-em-4-carboxylic acid diphenyl- methyl ester 16-oxide with melting point 115-1200. l 1o. ~ 20; 25 50. 35- ....... ...._,. u111) 7807811-0 8 60 ii) A solution of 1.5 g (2.19 mM) of the one of Example 4a) crystallized isomer mixture of 2- [4- (p-toluenesulfonyl) thio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-crotonic acid-diphenyl- methyl ester and the corresponding isocrotonic acid ester in 7.5 ml of dry 1,2-dimethyl okietan is stirred at room temperature under nitrogen with 0.43 ml (2.84 mM) 1,5-diazabicyclo [5.4.0] undec-5-ene. ' After 40 minutes of reaction, the solution is cooled. to 0 ° and was added with 0.375 ml (6.55 mm) of acetic acid and with 0.667 ml (458 mM) of 1,2,2-N-peracetic acid; 20 minutes at 0 °. Under nitrogen and then add 0.24 ml of natural The solution is stirred in rium bisulfite solution (20%). Stirring is continued the reaction mixture with 22.5 ml of water. Thereby, the mixture crystallizes The formation of 76-phenoxyacetamido-5-methoxy-cef-3-em-4-carboxylic acid diphenyl- emethyl ester 1B and -1a oxide. The precipitate is filtered off, washed with water water and dried under high vacuum.

To a suspension of 98.8 g (144 mM) of 2- [4- (p-toluenesulfonate)] nylthio-5-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-isocrotonic acid dimethylphenylmethyl ester in 988 ml of 1,2-dimethoxyethane is added at room temperature temperature under a nitrogen atmosphere of 2 minutes with stirring 52.9 ml (216 m fl) 1,5-Diaabicyclo [5.4.0] undec-5-ene. IN for 25 minutes at room temperature, then cooled to 0 DEG C. and added simultaneously with 14.9 ml (595 mM) formic acid and after cooling to -200 dropwise with 149 ml of a mixture of 66 ml of perhydrol (approximately 50% centig) and 134 formic acid (432 mM H 2 O 2). The reaction solution is then stirred after 15 minutes at 120 and then add 37 g of sodium thiosulphide. 7 barrels dissolved in 500 ml of water. In 1 hour, about 300 ml are added at 50 water. After stirring for an additional 2-3 hours at 50, the Itallin, essentially 7β-phenoxyacetamido-3-methoxy-cef-3-em-4-carboxylate oxylic acid-diphenylmethyl ester-1 fi-oxide precipitate, washed with cold water (3 °) and diethyl ether and dried under high vacuum calcium chloride; yield 53.46 g (68% of theory). .

To the filtrate is added with vigorous stirring at 5 ° 7 l of water.

The first oily precipitate, which when standing overnight becomes solid and consisting predominantly of 7β-phenoxyacetamido-3-methoxy-cef-} - em- d-4-Carboxylic acid diphenylmethyl ester oxide, filtered off, washed with ice-cold water and dried under high vacuum over calcium chloride; exchange 23.93 g (30.4% of theory). iv), 34.35 g (50 mM) 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido- -2-oxoazetidin-1-yl] -3-methoxy-isocrotonic acid diphenylmethyl ester suspension their at 200 under a nitrogen atmosphere in 340 ml of tetrahydrofuran (largest The now clear solution is stirred vigorously. '10. 15. 20. 25. 30. 35 UO. 7807811-0 61 in the part is solved). After rapid addition of 11.4 ml (75 mM) of βyaiazabicyx 10 [5,4.0] undec-5-ene stirring solution for 15 minutes at 20 °, is added then with 1.9 ml (30.2 mM) of glacial acetic acid and evaporated to dryness there vacuum at 30 °. The brown, frothy residue is dissolved in 150 ml methylene chloride and washed successively with 60 ml of water, 30 ml of 0.5 N hydrochloric acid, 30 ml of water, 30 ml of 1 M NaHCO 3 solution and 50 ml of water.

The aqueous phases are extracted twice with 10 ml of methylene chloride. rid. 5 The combined, non-dried methylene chloride phases are cooled -100 and slowly add 7.0 ml of peracetic acid / acetic acid (containing containing about 50 mM peracetic acid) (temperature rise up to approx + 10 °). After stirring for 15 minutes at 0-50, the excess peracid is destroyed with an aqueous sodium thiosulfate. The aqueous phase separate and wash with a small amount of methylene chloride. After drying the solution over magnesium sulphate is evaporated in vacuo. The light yellow the residue, consisting of a mixture of 76-phenoxy-acetamido-3-methoxy- cef-5-em-4-carboxylic acid diphenylmethyl ester-1α-oxide and 7β-phenoxyacetamide do-3-methoxy-cef-2-em-4-carboxylic acid diphenylmethyl ester-1-oxide in a holding about 2: 1, dissolved in 120 ml of monoglyme at room temperature and added with 30 ml of water, first 7B-phenylacetamido-3-meth oxy-cef-3-em-4-carboxylic acid diphenylmethyl ester-1B oxide crystallizes out.

The thick crystal porridge is first stirred for 0.5 h, then added in about 5 hours at room temperature and while stirring with 150 ml of water, wherein the corresponding 1d oxide likewise crystallizes out. After total 17 hours stirring is cooled for 1 hour in an ice bath and filtered; the remainder taken with a small amount of cooled monoglyme / water (1: 1.5). The crystals are dried under high vacuum for 16 h over P2O5. 7B-phenoxyacetamido- -5-methoxy-cef-3-em-4-carboxylic acid diphenylmethyl ester-1β-oxide, at which still corresponds to the corresponding 1d oxide; H fi by fi ê 27.23 E- The resulting 1-oxides can be further processed as follows: a) a solution of 150 mg (0.275 mM) of 7β-phenoxyacetamido-3-methoxy-cef- -3-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 0 188 mg (1.37 mM) phosphorus trichloride. The solution is stirred at 0 DEG for 30 DEG 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 7β-phenoxyacetamido-3-methoxy-cef- -5-em-carboxylic acid diphenylmethyl ester is recrystallized from ether; melting point 120 °. .5- Bicarbonate solution. 7so7s11 ~ o 62, ai) A suspension of 5.0 g (9.16 mM) of 75-phenoxyacetamido-5-methoxy- Cef-3-em-4-carboxylic acid diphenylmethyl ester-1a-oxide in 25 ml of methylene chloride »Rid and 1.25 ml of dimethylacetamide are added to Oo after cooling with 1.69 ml (19.5 mM) of phosphorus trichloride. The solution is stirred for 30 minutes at 0 ° C, diluted with ethyl acetate and washed with aqueous sodium hydroxide solution. The aqueous phase is extracted with ethyl acetate. In addition, the combined organic phases are dried over sodium sulfate and concentrated. »Evaporated in vacuo. 10 { 15. '20t 25f 30! 35. ab. melting point 12o °.

In vacuo and the residue crystallizes from acetone / ether.

Obtained crude β-phenoxyacetamido-3-methoxy- .cef-3-em-4-carboxylic acid diphenylmethyl ester is recrystallized from ether; b) A solution of 2.0 g (3.78 mM) of 7β-phenoxyacetamido-3-methoxy-cef- e-cef -} - em-Ä-carboxylic acid diphenylmethyl ester in 5-ml methylene chloride for is added with 0.87 ml of anisole, cooled to 0 ° C and allowed to stand for 1 hour after addition of 1.2 ml of trifluoroacetic acid. The reaction mixture is evaporated You are- 76-phenoxyacetamido-3-methoxy-cef-3-em-4-carboxylic acid with molten item 1700 (decomposition). ' The same compound can be obtained without isolating it under a) specified ester: “, _. _ bi) A suspension of 3.0 g (5.5 mM) of a mixture of 7β-fen- oxiacetamido-3-methoxy-cef-5-em-4-carboxylic acid diphenylmethyl ester-1β- and 1a-oxide in 15 ml of methylene chloride and 0.75 ml of dimethylaoetamide are added. after cooling to 0 ° with 0.966 ml (1.11 mM) of phosphorus trichloride.

The solution is stirred for 40 minutes at 0 °, then added 4.65 ml (61 mM) trifluoroacetic acid and stirred for an additional 30 minutes at 0 ° C.

The reaction mixture is set neutral with saturated sodium bicarbonate. solution and the organic phase is washed with dilute bicarbonate solution. The combined aqueous phases are washed twice ethyl acetate and brought to pH 2.6 with phosphoric acid. Failing TB- phenoxyacetamido-3-methoxy-cef-3-em-4-carboxylic acid is filtered off, washed with water and dried under high vacuum; melting point 1700 (Sunday derdelningl. - bii) A suspension of 55.4 g (97.7 mM) of 75-phenoxyacetamido-5-methoxy- cef-3-em-4-carboxylic acid diphenylmethyl ester-1B oxide (from Example 5 iii) in 320 ml of methylene chloride and 16 ml of dimethyl acetamide are cooled to 0 ° C and slowly add 17.3 ml (19.8 mM) of phosphorus trichloride. After Stirring for 20 hours at 0-50, 80 ml (1.05 M) of trichloroacetic acid are added dropwise. tiksyra. The clear solution is stirred for an additional 20 minutes at 0-5 then diluted with 1300 ml of ethyl acetate and washed successively with -PRO ml 2M dipotassium phosphate solution, 100 ml water and 250 ml semi-saturated, Q 10. 20. 25. 50. 35.

NO. '78 Û7811-Û æ aqueous sodium chloride solution. 76-phenoxyacetamido-5-methoxy-cef- -5-em-4-carboxylic acid is extracted from the organic phase with 700 ml saturated aqueous sodium bicarbonate solution and the aqueous the part is washed twice with 400 ml of ethyl acetate. The organic phases extracted twice with a total of 250 ml of a 50 ml solution saturated aqueous sodium bicarbonate solution, 100 ml of water and 100 ml ml saturated aqueous sodium chloride solution. The combined bicarbonate the extracts are overlaid with 1500 ml of ethyl acetate and the pH of the solution is about 2.5 with vigorous stirring with 20% phosphoric acid. The aqueous phase is extracted twice with 500 ml of ethyl acetate. acetate. The combined organic phases are dried over magnesium sulphate, filtered and evaporated in vacuo. The crystallizing residue it is slurried in 150 ml of ethyl acetate and allowed to stand overnight at -100.

The light yellow crystals of obtained 75-phenoxyacetamido-5-methoxy- 3-em-4-carboxylic acid is filtered off, washed with chilled ethyl acetate rai - and dried under high vacuum to a weight constant; yield 29.28 g, iiii) A solution of 25.9 g of 76-phenoxyacetamido-5-methoxy-cef-5-em-_ -4-carboxylic acid diphenylmethyl ester-1a oxide (from Example 5 iii) i 140 ml of methylene chloride and 7.2 ml of dimethylacetamide are cooled to 0 DEG and Stir further for 20 minutes at 0-50 after slow addition of 7.8 ml phosphorus trichloride. The reaction solution is added dropwise with 56 ml trifluoroacetic acid, is then further stirred at 0-5 ° for 20 minutes and subsequently worked up, as described in Example 5 bii). You are- 7β-phenoxyacetamido-5-methoxy-cef-5-em-4-carboxylic acid in the form of a light yellow crystallized; yield-7.3 S. c) To a suspension of 2.55 g (7 mM) of 7β-phenoxyacetamido-5- methoxy-cef-5-em-4-carboxylic acid and 2.9 ml (22.4 mM) N, N-dimethylaniline in 11 ml of abs methylene chloride is added 0.7 ml (5.7 mM) of dimethyl dichlorosilane under nitrogen at 200 and then stirred for 50 minutes at the same temperature lucky. The clear solution formed is cooled to -200, set to 1.6 g (7.7 mM) of solid phosphorus pentachloride and stirred for 50 minutes. At the same temperature is added in 2-5 minutes a pre-cooled (-20 °) mixture of 0.9 ml (7 mM) of N, N-dimethylaniline and 0.9 ml of n-butanol, then quickly add 10 ml of 1 pre-cooled (-20 °) n-butanol and then Stir for 20 minutes at -20 ° and for 10 minutes without cooling. At about -10 ° 0.4 ml of water are added, stirred for about 10 minutes in an ice bath (0 °), 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 water diluted samples assumed the constant pH 5.5. After 1 h After stirring at 0 DEG C., the precipitate is filtered off, washed with dioxane and stirred. ägs; '10., - 1-5- 20. 25. sodium bicarbonate) :, Ä 788828114) _64 i crystallized from water / dioxane. Obtained 7-amino-3-methoxy-cef-3- em-Carboxylic acid hydrochloride dioxanate has a melting point of more than 3oo ° '; layer chromacogram: Rf value 0.17 (silica gel, systenun-buta- nol / carbon tetrachloride / methanol / formic acid / water 30: H0: 20: 5: 5); yield 1fl2 g. ïci) A suspension of 11.75 g of 93% (corresponding to 10.93 g of 100% %) γβ-phenoxyacetamido-3 = methoxy-cef-3-em-H-carboxylic acid and 13 ml (12.73 g) of N, N-dimethylaniline in H7 ml of abs methylene chloride (dist. over F 2 O 5) is added at + 20 ° under nitrogen with 3.6 ml (3.87 g) tyl-dichlorosilane and then stirred for 30 minutes at the same temperature. The now clear solution is cooled to -180 / -190 and added 7.8 g of solid phosphorus pentachloride, the internal temperature rising 6-10 °. After stirring for 30 minutes in a bath of -20 °, the clear solution is added in about 7 minutes dropwise to a mixture of H7 ml cooled to -20 ° in-butanol and (anhydrous, dried over Sikkan) and U, Ä ml (H, 18 g) di methylaniline. The internal temperature rises to -8 °. Stir in 30 min - initially in bath of -200, later in ice bath (00), so that a final internal temperature of -100 is reached. At this temperature is added dropwise a mixture of Ä7 ml dioxane and 1.6 ml water (time approx 5 minutes). The product then crystallizes slowly. After further After stirring for 10 minutes, the mixture is brought in an ice bath to a pH between 2.2 and 2.4 by portionwise addition of about 9.5 ml of tri-n-butylamine of about 1 hour (first 5 ml) is added in the first 5 minutes and kept at this value. Then filter off, wash in portions with about 30 ml of dioxane and then about 15 ml of methylene chloride and crystalline 7β-amino-3H-methoxy-cef-3-em-N-carboxylic acid hydrochloride dioxanate; melting point above 3000; UV spectrum (in 0.1 N max = 270 nm (2 = 7600); IR spectrum (Nujol): characteristic band at 5.62; 5.80; 5.88; 6.26; 6.55; 7.03; 7, ü5; 7.12; 7.96; 8.1U; 8.26; 8, U5; 8.6Ä; 8.97; 9.29; 10.30; 11.47 * mh = + 13ü 1 1 (c = 1; 0.5 N sodium bicarbonate solution): yield r, ~ tOÜD (_ 9.80 g (89% of theory). 35- '_ NOÅ From the obtained hydrochloride dioxanate it is possible by adding then N sodium hydroxide solution to pH ü, 1 (isoelectric point) to a 20% aqueous solution of the hydrochloride dioxanate the switter ion of Tβ-amino-3-methoxy-cef-3-em-H-carboxylic acid, which filtered and dried has a melting point of more than 300 °; UV spectrum (in 0.1 N sodium bicarbonate solution): λmax = 210 nm (ε, = 7600); thin- "layer chromatogram Rf value identical to that of the hydrochloride ( likagel; same system); B13 go = + 232 ° 2 10 (c = 1; 0.5 N sodium bi- carbonate solution). 10. 20. 25. 50. 35.

HO. ; 7so7a11-0 65 le) A suspension of 1 g (2.82 mM) of 7β-amino-5-methoxy-cef-5-em- -4-carboxylic acid hydrochloride dioxanate in 20 ml of dry methylene chloride at room temperature under a nitrogen atmosphere with 1.65 ml of bis- (tr1- methylsilyl-acetamide. After 40 minutes, the clear solution is cooled 00 and added with 900 mg (4.37 mM) of solid D-d-phenylglycylic acid chloride , hydrochloride. 5 minutes later, 0.7 ml (10 mM) of propylene oxide. The suspension is then stirred for 1 hour at 0 ° C under a nitrogen atmosphere then add 0.5 ml of methanol, whereby 7B4®-α-phenylglycylamino) -5- methoxy-cef-5-em-4-carboxylic 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 7β: D-α-phenylglycylamino) -5-methoxy-cef-5-em-4- carboxylic acid is filtered off, washed with the stage and aliquots and ternas; melting point 1711-176 ° (decomposition), [u] š ° = + 132 ° (e = 0.714; 1 0.1 N hydrochloric acid); thin layer chromatogram (silica1): Rf value approx 0.18 (system n-butanol / acetic acid / water 67:10:23); UV spectrum (1 o, 1 N aqueous sodium bicarbonate solution): Åmax -è 269 nm (á = 7000); IR spectrum (in mineral oil): characteristic bands at 5.72, 5.94, 6.25 and 6.60 mm. 5 di) A suspension of 995 mg (4.52 mM) -76-amino-5-methoxy-cef-5-em- Α-Carboxylic acid (inner salt) in 10 ml of methylene chloride is added with 1.57 (5.6 mM) N, Nèbis- (trimethylsilyl) -acetamide and stirred for 45 minutes at room temperature under a nitrogen atmosphere. The clear solution is cooled 0 ° and added with 1.11 g (5.4 mM) of D-α-phenylglycylic acid hydrochloride chloride. After 5 minutes, 0.4 ml (5.6 mM) of propylene oxide is added. Suspen- The solution is then stirred for 1 hour at 0 ° C under a nitrogen atmosphere and is then added with 0.6 ml of methanol. Crystallized 7B- (D-α-phenyl- glycylamido) -5-methoxy-cef-5-em-4-carboxylic acid hydrochloride is dissolved and dissolved at 00 1 15 ml of water; the solution is adjusted to pH about 4 with 5 ml of 1 N sodium hydroxide solution. The heated solution is brought to pH about 4.8 with triethylamine, then 75- (D-α-phenylglycylamido) -3-methoxy-cef-5-em-4-carboxylic acid crystallizes out in the form of dihydrate.

EXAMPLE 6. To a solution of 0.697 g (1.0 mM) of an isomer mixture consisting of 2- [4- (benstiazol-2-yldithio) -5-phenoxyacetamido-2- oxoazetidin-1-yl] -5-methoxy-crotonic acid diphenylmethyl ester and the like isocrotonic acid diphenylmethyl ester 1 4 ml dry tetrahydrofuran a solution of 0.228 g (1.5 mM) of 1,5-diazabicyclo [5.4.0] is added. 5-en] in 10 ml of tetrahydrofuran. The mixture is stirred for 40 minutes at room temperature. temperature, diluted with 200 ml of benzene and washed successively with The room temperature 10.

Q 15. 20. 25. 30. 35. _ H0. ~ as a firm, 57807811-0 66 ï 1 dilute hydrochloric acid, sodium bicarbonate solution and water. The organic The phase is dried over sodium sulfate and the solvent is removed vacuum. The crude product obtained is chromatographed on 50 g of hydrochloric acid washed silica gel. Toluene / ethyl acetate (7: 1) first elutes 2-mercaptobenstiazole and then 7β-phenoxyacetamido-3-methoxy-cef-2-em-4-carboxylic acid di- phenylmethyl ester: IR spectrum (in CH 2 Cl 2): 5.60; 5.74; 5.90; 8.28 um; yield 0.13 g (2U% of theory). _ ' The resulting ester can be converted to free acid in the following manner: -i) A mixture of 53 mg- (0.1 mM) ¶% -phenoxyacetamido-3-methoxy- cef-2-em-HQ-carboxylic acid diphenylmethyl ester, 0.07 ml of trifluoroacetic acid acid, 0.06 ml of anisole and 0.5 ml of methylene chloride are stirred for 15 hours at 0 ° C.

The mixture is diluted with 5 ml of pentane / diethyl ether (3: 1) and shaken vigorously. tigt. The precipitating white, amorphous 7β-phenoxyacetamido-3-methoxy-cef-2- The em-HW carboxylic acid is filtered off and washed with pentane / diethyl ether (3: 1); IR spectrum (CH 2 Cl 2): 5.60; 5.90; 8.27ßnn; yield 35 mg.

The intermediate product can be obtained as follows: a) In a buffered solution of 681 mg (1.0 mm) 2-Lu- (benstiazol -2-yldithio) -3-phenoxy-acetamido-2-oxo-azetidin-1-yl] 3-methylene-butter- acid-diphenylmethyl ester in 30 ml of ethyl acetate is introduced into 1 eq of ozone (diluted with oxygen). The reaction solution is allowed to warm, evaporate in vacuo to 10 ml, add 1.0 ml of dimethyl sulfide and stir for 15 hours at room temperature. Solvents and solvents shot reagent is removed in vacuo and the residue is chromatographed on 30 g of acid-washed silica gel with toluene / ethyl acetate (üzl) (fractional about 15 ml). 2- [4- (Benstiazol-2-yldithio) -3-phenoxyacetyl- amido-2-oxo-azetidin-1-yl] -3-hydroxycrotonic acid diphenylmethyl ester such as amorphous substance; [Α] D = 1300 3 1 ° (CHCl 3; c = 0.8); IR spectrum: CH 2 Cl 2): 2.95; 5.60; 5.92; 6.04; 8.10 Pm; yield 375 mg. (55% of theory). b) A solution of crude 2- [N- (benstiazol-2-yl-dithio) -3-phenoxyacetyl- amido-2-oxo-azetidin-1-yl] -3-hydroxycrotonic acid diphenylmethyl ester, obtained by ozonation of 681 mg (1.0 mM) of 2- [H-benstiazol-2-yl- 3-Phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylene-butyric acid di- phenylmethyl ester, in 5 ml of methylene chloride was added at 0 DEG C. with an ether containing distilled diazomethane solution (containing 1,3 mM 'diazomethane tan). The mixture is stirred for 1 hour at 0 °, and washed with water; the the organic layer is dried over sodium sulfate. The solvents are removed under vacuum and the residue is chromatographed on 55 U acid washed silica gel with toluene / ethyl acetate (2: 1). An isomer mixture is obtained. of 2- [β- (benstiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidine- 6 .. 10. 15. 20. 25. 30. 55.

HO, 57807811-o 67 -1-yl] -m-methoxycrotonic acid diphenylmethyl ester and the corresponding isocrotone acid diphenylmethyl ester; IR spectrum (in CH 2 Cl 2): 5.60; 5.88; 6.67; 9.15; 9.92 um; yield 514 mg- (74 Z of the theoretical).

EXAMPLE 7. In analogy to Example 4, 200 mg (0.307 mM) are obtained. of an isomeric mixture consisting of 2- [4- (p-toluenesulfonylthio) -5- phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-crotonic acid-2,2,2-trichloro- ethyl ester and the corresponding isocrotonic acid 2,2,2-trichloroethyl ester and 0.09 ml (0.6 mM) of 1,5-diazabicyclo [5.4.0] undec-5-ene for 30 minutes stirring at room temperature 1.5 ml of 1,2-dimethoxyethane an isomer mixture consisting of 76-phenoxyacetamido -} - methoxy-cef-2-em-4-carboxyl- acid 2,2,2-trichloroethyl ester and 76-phenoxyacetamido-3-methoxy-cef-5- em-4-carboxylic acid 2,2,2-trichloroethyl ester (in a ratio of _ ka 1: 1); Rf value = 0.56 and 0.18 (silica gel; toluene / ethyl acetate, respectively) 5: 1). '' ¿ The intermediate 'can be obtained as follows: a) In analogy to Example 1b) 498 mg (1 mM) of 6-phenoxy- acetamido-penicillanic acid 2,2,2-trichloroethyl ester and 200.7 mg (1.2 mM) 2-Mercaptobenstiazole 2- [4- (Benstiazol-2-yldithio) -5-phenoxyacetamido- -2-oxoazetidin-1-yl] -5-methylene butyric acid 2,2,2-trichloroethyl ester; molten point 144 «149 ° (from methylene chloride / pentane); Rf value = 0.5 (silica- gel; -ether). V - ' b) Of 647 mg (1 mM) 2- [4- (Benstiazol-2-yldithio) -3-phenoxyacetyl- amido-2-oxoazetidin-1-ylc-methylenebutyric acid 2,2,2-trichloroethyl ester and 1.2 eq of ozone and subsequent cleavage of the ozonide with di- methyl sulphide, is prepared analogously to Example 6a) 2- [4- ( azol-2-yldithio) -5-phenoxyacetamido-2-oxoazetidin-1-yl] -3-hydroxy- crotonic acid 2,2,2-trichloroethyl ester; melting point 129-150 ° (ether / petroleum leumeter). c) Of 5 g (7.71 mM) 2- [4- (Benstiazol-2-yldithio) -5-phenoxyacet- amido-2-oxoazetidin-1-yl] -3-hydroxycrotonic acid 2,2,2-trichlorethyl ester and an excess of diazomethane is obtained analogously to Example 6b) isomeric mixture consisting of 2- [4- (benstiazol-2-yldithio) -5-phenoxy- acetamido-2-oxoazetyldin-1-yl] -5-methoxy-crotonic acid-2,2,2-trichloroethyl- ester and the corresponding isocrotonic acid 2,2,2-trichloroethyl ester; molten point 170-1740 (1 methylene chloride / ether). d) Of 1.9 g (2.87 mM) of an isomeric mixture consisting of 2- [4- (Benstiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -} - methoxy- crotonic acid-2,2,2-trichloroethyl ester and the corresponding isocrotonic acid-2,2,2- trichlorethyl ester is obtained analogously to Example 1c) by stirring for 5 hours. ring at room temperature with 0.8 g (4.05 mM) of silver p-toluenesulfinate fQ \ l / c \ 15. 20} 25. 30. 35.

H0. Acid is diluted with methylene chloride.

EXAMPLE 9 lenchloride. 7807811-o se E ' in 35 ml of acetonitrile / ethyl acetate (}: 4) an ismer mixture consisting of 2- [4- (p-toluenesulfonylthio) -3> phenoxyacetamido-ε-oxoazetidin-1-yl] -5- methoxycrotonic acid 2,2,2-trichloroethyl ester and the corresponding isocrotonic acid 2,2,2-trichlorethyl ester; mp 155-1589 (from ethyl acetate / ether).

EXAMPLE 8. A solution of 100 mg (0.146 mm) 21h4benst1az ° 1-2-ylamethio) - -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-hydroxycrotonic acid diphenylmethyl Thiester 1 2 ml of dry methylene chloride was added at 0 ° with 0.02 ml (0.16) mM) trimethylchlorosilane. To this solution is added under nitrogen and while stirring 0.047? ml (0.32 mM) 1,5-diazabicyclo [5.4.0] undec-5- and stir for a further 1 hour at 0 ° C. After adding 0.2 ml of vinegar The organic phase is washed successively with dilute sulfuric acid, water and aqueous sodium bicarbonate solution dried over sodium sulfate and evaporated to dryness in vacuo.

Obtained crude 7-phenoxyacetamido-5-hydroxy-cef-3-em- -f4-Carboxylic acid diphenylmethyl ester is dissolved in methanol and added OO with an ethereal solution of diazomethane. After 10 minutes, the solution is evaporated g carefully and the residue is dried under high vacuum.1 The residue is cleaned thick layer chromatographic (toluene / ethyl acetate 3: 1, silica gel). After eluting the silica gel with the zone at Rf_ = 0, f7.with ethyl acetate and in- evaporation of the solution on a rotary evaporator, 7β-phenoxyacetate is obtained. amido-3-methoxy-cef-3-em-4-carboxylic acid diphenylmethyl ester; melting point 120 ° (from ether); yield 5 mg.a ' A solution of 266 mg (0.5 mM) of a crude mixture, consisting of end of 2- [4- (benstiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidine-1- yl} §-methoxy-crotonic acid chloride and 2- [4- (benstiazol-2-yldithio) -3-phenoxy- acetamido-2-oxoazetidin-1-yl] -3-methoxy-isocrotonic acid chloride in 5 ml dry imethylene chloride is added dropwise at 0 ° with stirring over 15 minutes to one solution of 0.10 ml of triethylamine in 0.5 ml of dry t-butanol and 3 ml of methyl After stirring for a further 15 minutes, the reaction mixture is diluted. with methylene chloride, washed with water, dilute hydrochloric acid and again with water, dried over sodium sulfate and evaporated vacuum. The residue is chromatographed on 10 g of acid-washed silica gel with toluene / ethyl acetate (4: 1) as eluent. 'You get Y fi- phenoxyacetamido -} - methoxy-cef-2-em-4-carboxylic acid t-butyl ester; IR- spectrum (1 CH 2 Cl 2): characteristic bands at 5.60; 5.77; 5.90; ”8; 29, um,; _ P fi PXb§_1SQ_¶g * fi§6 Z of the theoretical). The intermediate product can be obtained as follows: a) E E To a solution of 698 mg (1 mM) of a mixture consisting of of 2% [4- (Benzazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] - -3-methoxy-crotonic acid diphenylmethyl ester and 2f [4- (benstiazol-2-yldithio) - 7807811-0 sew -3-phenoxyacetamido-2-oxoazetidin-1-yl] -5-methoxyisocrotonic acid diphenyl- methyl ester 1 Slowly add 1.5 ml of methylene chloride while stirring A mixture of 0.7 ml of trifluoroacetic acid, 0.6 ml of anisole and 2.5 ml methylene chloride. The reaction mixture is stirred for 3 hours at 0 °, shaken with 100 ml of ether / pentane (1: 3) and the precipitate is filtered off. The precipitate consisting of a mixture of 2- [4- (benstiazole-24yldithio) -5-phenoxy- acetamido-2-oxoazetidin-1-yl] -5-methoxycrotonic acid and 2- [- (benstiazol- -2-yldithio) -5-phenoxy-acetamido-2-oxoazetidin-1-yl] -3-methoxy-isocrotone acid, washed with 25 ml of ether / pentane (1: 3) and dried under vacuum; IR spectrum (1 CH 2 Cl 2): characteristic bands at 5.60; 5.80; 5.94; 8.55; 9.95 um_; yield 500 mg (9U Z of the theoretical). b) 1 A solution of 532 mg (1.0 mM) of a mixture consisting of 2- [44-Benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl} 3-methyl- oxycrotonic acid and 2f [4- (benstiazol-2-yldithio) -3-phenoxyacetamido-2-oxo- azetidin-1-yl] -5-methoxy-isocrotonic acid 1 ml of dry dioxane, containing the 10% oxalyl chloride, stirred for 15 hours at room temperature and evaporated Then under vacuum. ~ The solid, non-crystalline residue, which is consists of a mixture of 2- [4- (benstiazol-2-yldithio) -3-phenoxyacetamido- -2-oxoazetidin-1-yl) -3-methoxy-crotonic acid chloride and 2- [4- (benzylazole) -2-yldithio) -5-phenoxyacetamido-2-oxoazetidin-1-yl] -5-methoxy-isocrotone acid chloride, can be further processed without further purification; IR spectrum (in CH 2 Cl 2): characteristic band at 5.58; 5.90; 9.95 um; yield 555 mg.

EXAMPLE 10; A solution of 567 mg (0.5 mM) of a mixture consisting of of 2- [4- (p-nitrobenzenesulfonylthio) -} - phenoxy-acetamido-2-oxoase- thidin-1-yl] -5-methoxy-crotonic acid diphenylmethyl ester and the like isocrotonic acid diphenylmethyl ester, and 152 mg (1.0 mM) of 1,5-diazabicyclo [5.4.0] the undec-5-ene in 10 ml of dry tetrahydrofuran is stirred for 1 # 0 min at room temperature. The reaction mixture is diluted with benzene, washed with dilute hydrochloric acid, water and dilute aqueous sodium 10. 15. 20. 205. Bicarbonate solution, dried over sodium sulfate and liberated in vacuo from solvents. The residue is chromatographed on acid-washed silica gel with toluene / ethyl acetate (7: 1) as eluent, whereby pure 7fi r phenoxyacetamido-3-methoxy-cep-2-em-Ä-carboxylic acid diphenylmethyl ester held, yield 57 mg (22 Z of theory). By elution with toluene / ethyl acetate (2: 1) is then isolated from a mixture which, together with -phenoxyacetamido-3-methoxy-cef-2-em-U-carboxylic acid diphenylmethyl ester also contains 76 »phenoxy-acetamido-3-methoxy-cef-3-em-H-carboxylic acid ~ diphenylmethyl ester5 yield 30 mg. Un Me11anpro0dukgerna1can be prepared as follows: Ms. 10. 15, * 20. for, 30. 35.5 7807811-o 70f; -: a) Of 3ü8; 5 mg (0; 5 mM) of an isomer mixture; consisting of 2- [U- (Benstiazol-2-ylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3- Imethoxycrotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester, and 200 mg (0.68 mM) of silver p-nitrobenzenesulfinate obtained analogously to Example 4 ai) by stirring for 1 hour at 60 ° for 10 hours _ml acetone / water (9í1), a mixture consisting of 2 {[§- (p-nitroben- sensulfonylthio) -3-phenoxy-acetamido-Zsogoaaetidin-1-yl] -3-methoxy- -crotonic acid-diphenylmethyl ester and the corresponding isocrotonic acid-diphenylmethyl ester tyl ester.

Silver-p-nitrobenzenesulfinate is obtained by combining aqueous solutions of equimolar amounts of silver nitrate and natural rium-p-nitrobenzenesulfinate. The precipitate is filtered off and dried. there vacuum for 2Ä h at_50-600. _ _ _ EXAMPLE 11; Of 351.5 mg (0.5 mm) of an isomer mixture¿ beštåenae of 2- [4- (p-methoxybenzenesulfonylthio) -3-phenoxy-acetamido-2-oxoazetidine- -1-yl-3-methoxy-crotonic acid diphenylmethyl ester and the corresponding iso- crotonic acid diphenylmethyl ester, and 152 mg (1 mM) of 1,5-diazabicyclo-5. §.Ä.0fundec-5 is obtained analogously to Example 10 a mixture; existing fde of TE-phenoxyacetamido-3-methoxy-cef-2-em-Ä-carboxylic acid-diphenylmethane tyl ester and 7β-phenoxyacetamido-3-methoxy-ε-3-em-H-carboxylic acid di-5 phenyl methyl ester (yield 270 mg); which can be divided by chromatography in the two isomers; yield of 2-cephem: 133 mg (54%); of 5-cephem: Ä? mg (18% of theory). IN The intermediates' can be obtained as follows: a) Of 697 mg (1 mM) of an isomeric mixture consisting of 2- [Ä- (benzene- thiazol-2-ylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxycrotone acid-diphenylmethyl ester and the corresponding isocrotonic acid-diphenylmethyl- ester, and 361 mg (1.3 mM) of silver p-methoxybenzenesulfinate are obtained analogous to Example Ä ai) by stirring for 1 hour at room temperature in 20 ml acetone / water (9: 1) a mixture consisting of 2- [ü- (p-methoxy- Benzenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy- -crotonic acid-diphenylmethyl ester and the corresponding isocrotonic acid-diphenyl- metvlester; IR spectrum (in CH 2 Cl 2): characteristic bands at 5.60; 5.88: 6.18; 8.76 pm; yield 653 mg (93% of theory).

Silver-β-methoxybenzenesulfinate is obtained by combining aqueous solutions of equimolar amounts of silver nitrate and sodium p-methoxybenzenesulfinate. The precipitate is filtered off and dried under vacuum for 24 hours at 50-60 °. e.g. 10. 15. 20. 25. 30; 35. 7807811-0 71 EXAMPLE 12. Of 356.3 mg (0.5 mM) of an isomer mixture consisting of of 2- [4- (benzenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-P-yl] - -3-methoxy-crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester, and 152 mg (T.mM) 1,5-diazabicyclo [5.4.0] undec-5- one is obtained analogously to Example 10 a mixture consisting of 7B-fen- oxiacetamido -} - methoxy-cef-2-em-4-carboxylic acid diphenylmethyl ester and YE-phenoxy-acetamido-3-methoxy-cef-3-em-4-carboxylic acid diphenylmethyl ester, which can be partitioned by chromatography into the two isomers.

The dairy products can be obtained as follows: a) Of 697 mg (1 mM) of an isomeric mixture consisting of 2- [4- (benzene) tlazol-2-ylthio) -3-phenoxlacetamido-2-oxoazetidin-1-yl] -} - methoxy-1-croton- acid-diphenylmethyl ester and the corresponding isocrotonic acid-diphenylmethyl and 324 mg (1.5 mM) of silver benzenesulfinate are obtained analogously to Example A1) by stirring for 90 minutes at room temperature in 20 ml of acetone / water (9: 1) a mixture consisting of 2- [4- (benzenesulfonyl] -3- phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-crotonic acid-diphenylmethyl- ester and the corresponding isocrotonic acid diphenylmethyl ester; IR spectrum l CH 2 Cl 2: characteristic band at 5.60; 5.88; B, 7pm; yield 6ü2 mg (96% of theory). - In Silverbenzenesulfinate is obtained by combining aqueous - containing solutions of equimolar amounts of silver nitrate and sodium ben- sensulfinate. The precipitate is filtered off and dried in vacuo 24 n at 50-6o °.

EXAMPLE 12. Of an isomer mixture consisting of 2- [4- (p-toluenesul- phonylthio) -3-phenoxy-acetamido-2-oxoazetidin-1-yl] -3-methoxy-crotonic acid -p-nitrobenzyl ester and the corresponding isocrotonic acid ester are obtained with Example 1 by stirring for 12-14 hours at room temperature with ramethylguanidine in tetrahydrofuran is an isomer mixture consisting of: 76-Phenoxyacetamido-3-methoxy-cep-3-em-4-carboxylic acid p-nitrobenzyl ester and 76-phenoxyacetamido-3-methoxy-cep-2-em-4-carboxylic acid p-nitrobenzyl ester.

§§§M§§Q_1§.e A mixture of 104.5 mg (0.15 mM) of an isomer mixture consisting of 2- [α- (benstiazol-2-ylthio) -3-phenoxyacetamido-2-oxoazeti- din-1-yl] -3-methoxy-crotonic acid-diphenylmethyl ester and the corresponding iso- crotonic acid diphenylmethyl ester, 35 mg (0.225 mM) of p-toluenesulfinic acid and 80 mg (0.525 mM) 1,5-diazabicyclo [5.β] undec-5-ene 1 3 ml dry tetra- .beast 7307811-0 i in hydrofuran is stirred for 40 minutes at room temperature. The mixture is diluted Wf with benzene and washed successively with dilute hydrochloric acid, diluted, 10. aqueous sodium chloride solution, 0.5 N sodium hydride solution and again with dilute aqueous sodium chloride solution. The organic The final phase is washed over sodium sulfate and freed from solvent yunder vacuum. Chromatography of the residue on 3.5 g of acid-washed silica gel with toluene ethyl acetate (7: 1) first gives pure 7'-phenoxyacetamido-5- Methoxy-cef-2-em-1H-carboxylic acid diphenylmethyl ester, yield 35.1 mg (üÄ% of the theoretical), Toluene / ethyl acetate (2: 1) then elutes 7β-Phenoxy-acetamido-3-methoxy-cep-3-em-H-carboxylic acid diphenylmethyl- ester; yield 8.4 mg (11% of theory). EXAMPLE 15. A mixture of 11 mg (0.2 mM) 24 [R- (o-methoxybenzene] sulfur '15. phonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-crotonic acid -di-phenylmethyl ester and 61 mg (0.4 mM) of 1,4-diazabicyclo [5.H.Q] undec45- one in 1 ml of dry tetrahydrofuran is stirred for 70 minutes at room temperature.

Work-up analogous to Example 10 gives a crude mixture consisting of 7β-Phenoxyacetamido-3-methoxy-cep-2-em-carboxylic acid diphenylmethyl- tests and 7β-phenoxyacetamido-3-methoxy-cef-3-em-4-carboxylic acid diphenyl- 20. 25. 30. 3-5. methyl ester in a ratio of about ü, ü: 1, which by chromatography The silica gel can be divided into the two isomers analogously to examples 10; yield of 2-cephem: 53%: of 3-cephem: _12_% of the theoretical.

The two compounds are formed in approximately the same ratio, if analogously treating 141 g (0.2 mM) of 2-ÅÄ- (o-methoxybenzenesulfonylthio) - -5-phenoxyacetamidof2-oxoazetidin-1-yl] -3-methoxy-isocrotonic acid nyl methyl ester; yield of 2-cephem: 51%: of 3-cephem: 10% of the reticent. I 7 The two isomeric mauane products can be obtained as follows: a) 3.9 g (5 mM) of an isomeric mixture consisting of 2- [[- (benstiazole) -2-ylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl-3-methoxy-crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester in a ratio of about 4: 1 is stirred at room temperature for 130 minutes with 1.82 g (6.5 mM) of silver-o-methoxybenzenesulfinate 100 ml of acetone / water (9: 1). The mixture is filtered and the filtrate is evaporated in vacuo. The residue is chromatographed on 140 g of acid-washed silica gel with toluene / ethyl acetate (1: 1). 50 ml fractions are collected, of which fractions are Nos. 7-13 contain pure 2- [B- (o-methoxybenzenesulfonylthio) -5-phenoxy- 7 acetamido-2-oxoazetidin-1-yl} -3-methoxy-isocrotonic acid-diphenylmethylsyl 'ter; yield 1.71 g; IR spectrum (CH 2 Cl 2): 5.60; 5.90; 8.72; 9.15 um, HO. and fraction 25 and the following fractions give pure 2- [4- (o-methoxybenzene) sulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxycrotonic acid t? 10. 20. 25. 30. 35. 40. 78-07811-0 73 radiphenylmethyl ester; yield 0.24 g; IR spectrum (CH 2 Cl 2: 5.60; 5.90; 8.20; 8.30; 8.72, 9.80 pm. Fractions 14-24 contain mixtures of the two isomers; yield 1.03 g; total exchange 2.98 g (85% of theory). ' EXAMPEb016. A mixture of 57 mg (1.1 mM) crude 2- [§- (o-methoxyben- sensulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl} -3-methoxyiso- crotonic acid chloride and 43 mg (0.3 mM) of 1,5-diazabicyclo [5.4.0] -5-ene in 2 ml of dry methylene chloride is stirred for 80 minutes at room temperature. lucky. The mixture is diluted with methylene chloride, washed with dilute brine. acid and water, dried over sodium sulfate and freed from solvent under vacuum. The residue is dissolved in 0.5 ml of methylene chloride, add 5 ml of pentane / diethyl ether (3: 1) and shake. The precipitate filtered off and washed with pentane / diethyl ether (311). It exists of fairly pure 7β-phenoxyacetamido-3-methoxy-cef-Zfem-4W-carboxylic acid ra; yield 29 mg (80%).

The intermediate product can be obtained as follows: a) A mixture of 703 mg (1 mM) of pure 2- [4- (o-methoxybenzenesul- phonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-isocrotone acid-diphenylmethyl ester, 0.7 ml of trifluoroacetic acid and 0.66 ml of anisole in 4 ml of methylene chloride is stirred for 3 hours at 0 DEG. The mixture is continued then with 50 ml of pentane / diethyl ether (3: 1) and shake vigorously.

The white precipitate of pure 2-β- (o-methoxybenzenesulfonylthio) -3- -phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-isocrotonic acid from filtered and washed with pentane / diethyl ether (3: 1); IR spectrum (CH 2 Cl 2): 5.60; 5.93; 6.25; 8.72 Pm; yield 100% of the theoretical. b) To a solution of 54 mg (0.1 mM) of 2- [4- (o-methoxybenzenesulfonoph- nylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-isocrotone acid in 0.5 ml of a 10% oxalyl chloride solution in dioxane 1 drop of dimethylformamide is added to dioxane, after which gas evolution takes effect immediately. The mixture is stirred for 2 hours at room temperature and the solvent and excess oxalyl chloride are evaporated in vacuo. The residue is dried under high vacuum to give 2-4- (o-methoxybenzene sulpho- nylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-isocrotone acid chloride in the form of a light orange foam; IR spectrum (CH 2 Cl 2): 5.60; 5.90; 8.70 pm; yield 57 mg (100% of theory) tiska).

EXAMPLE 17. A solution of 200 mg (0.254 mM) 2- [§- (p-toluenesulfonium-) thio) -3- (D-N-t-butyloxycarbonylamino-N * phenylacetylamino) -2-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 P1 (0.38 mM) in7s07811'Û 1 7u_ The 1,5-diazabicyclo- {§.4; Q] undec-5-ene, is then added with ethyl acetate. 10. 20. g 25. <3 30. 35.

HO. with diethyl ether and filtered off. i_under reduced pressure. * tat 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 'nnder vacuum. The residue is chromatographed on silica gel thick layer plates with toluene-ethyl acetate (1: 1) as eluent. You are- »Holds 7fi w (D <& t-butylcarbonylamino-Oßphenylacetylamino-3-methoxy-cef- = 22-em-4% -carboxylic acid diphenylmethyl ester, m.p. 166-168 ° ä (methylene chloride / pentane); thin layer chromatogram (silica1; diethyl ether: Rf value about 0.51; UV spectrum (in ethano1): Anx = 257 nm 1 (EI = 3500); IR spectrum in methylene chloride) § characteristic bands at 552.96; s, e3; 5.74; s, ss fansatsL-sßz; 6.16; 6.64 and 6.72 Pm; "exchange 88 mg; and WG- (D-CX-t-butylcarbonylamino) -d-phenylacetylamino) - , -3-methoxyphosphate-3-em-4-carboxylic acid diphenylmethyl ester with melting point out- 162-163 ° (diethyl ether); thin layer chromatograms Rf value about 0.33 (silica gel; diethyl ether); UV spectrum (in ethanol): Å. Max = 265 nm from; e 600); zso nm (ansats) (¿= e, 200); : Lz spectrum (maf fl ankla- rid); 2.92; 5.58; 5.64 (approach); 5.82; 6.22 and 6.67 μm; yield 25-mg. The obtained compounds can be further processed in the following way: ia) A mixture of 8.8 g of 75- (D-α-t-butyloxycarbonylamino-α-fe- nyl-acetylamino) -3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester, 8.6 ml of anisole and 145 ml of difluoroacetic acid are stirred for 15 minutes at 0 °. then add 400 ml of pre-cooled toluene and evaporate 'der reduced pressure., The residue is dried under high vacuum, digested In this way 1 powder is obtained. * form the trifluoroacetate of 75 '(D-α-phenylglycylamino) -3-methoxy-3-cephem if-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 -5 with a 20% triethylamine solution in methanol, one colorless precipitation is formed. Stir for 1 hour in an ice bath, then add _20 m1 acetane to laser sta 1 16 n at about 1 + °. The colorless folding The mixture is filtered off, washed with acetone and diethyl ether and dried In this way, in the form of a micro- Irocrystalline powder 7B- (D-α-phenylglycylamino) -5-methoxy-3-cephem -4-carboxylic acid as inner salt, which is also present in 1 form : of a hydrate; melting point 174-1760 (decomposition); [α] 25 D = + 149 ° .. (c = 1.03 in 0.1 N hydrochloric acid); thin layer chromatogram (silica gel; , iodine cooling): Rf about 0.56 (system: n-butanol / pyridine / acetic acid) acid / water 40: 24: 6: 30); UV absorption spectrum (1 0.1 N water content tig. sodium bicarbonate solution): λmax = 267 nm (f = 6,200); IR- K 5. 10. 7807811-0 75 spectrum (in minera1o1ja): characteristic bands b1.a. at 5.72 Pm, 5.94 nm, 6.23 Pm and 6.60 Pm. 7 A mixture of 0.063 g of Lä- (D-yrt-butyloxycarbonylamino-M-phenyl- acetylamino) -3-methoxy-2-cephem-4-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 and then evaporated under reduced pressure. The residue is digested with diethyl ether, filtered off and dried; It thus obtained, colorless and powdery trifluoroacetate of 7¿f (D'W'fB fl Y181YCY1 ' amino) -3-methoxy-2-cephem-40β-carboxylic acid is dissolved in 0.5 ml of water and the pH of the solution is adjusted to about 5 by droplet till fi 8V en 10% solution of triethylamine in methanol. Stir for 1 hour In an ice bath, filter the colorless precipitate and dry under high pressure. vacuum. There is thus obtained 7β- (D-α-phenylglycylamino) -3-methoxy-2- cephem-α-carboxylic acid as inner salt; thin layer chromatogram (silica- Gel}: development with iodine): Rf about 0, Ä4 (systemz.n-butanol / pyridine / acetic acid / water 40: 24: 6: 30); UV absorption spectrum (in 0.1 N aqueous sodium bicarbonate solution containing): ion charge = 260 nm. e) To a solution cooled to 0 DEG C. of 0.65 g of 7β- (D-α-t-butyloxy) carbonylamino-α-phenyl-acetylamino) -3-methoxy-2-cephem-4α-carboxylic acid g0-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 50 hours min at 0 DEG C., added with 50 ml of methylene chloride and washed successively with 25 ml each time of a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution. It dries The organic phase over sodium sulfate and evaporates under reduced pressure. 30_chromatogram sad) cat pressure. The residue is crystallized from a mixture of methylene chloride and diethyl ether; There is thus obtained 76- (D-α-t-butyloxycarbonylamino- no-α-phenylacetylamino) -3-methoxy-3-cephem-α-carboxylic acid diphenylmethyl- estaw1 oxide in the form of colorless needles; mp 172-1750; thin-layer (silica gel): Rf about 0.44 (system: acetic acid ethyl ester; _development with iodine vapor); Uvssorption spectrum (1 ethanol): 7 \ max Δ = 277 nm (δ = 7,200); IR absorption spectrum (in methylene chloride): 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.

A cold solution of 1.30 g of 7β- (n-α-u-buuyioxycarbonate) Nylamino-α-phenylacetyl-amino) -} - methoxy-3-cephem-4-carboxylic acid diphenyl- methyl ester-1-oxide in 50 ml of dimethylformamide is 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 h0_hydrogen phosphate solution; the aqueous mixture is extracted two 10. e.g. 15. 20, Q; 25. 30. 635. 6 s) ao; 7807811-0 76 š «2 _, 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 gel. íkagel; elute with diethyl ether amorphous LG- (D-q-butyloxycarbonylamino- no-M-phenylacetyl-amino) 43-methoxy-3-Cef @ ñ * 4'k? ester as a thin layer chromatographically pure substance; Rf is 0.39 (system: diethyl ether development with iodine); EX] D =: 1 i_1o (c = 0.981 in chloroform); UV absorption spectrum (1 ethane blue): aå = 264 nm (δ = 6300); IR absorption spectrum (in methylene chloride) ristic path at 2.94 μm, 5.62 μm, 5.84 μm, 5.88 μm, 6.25 μm, and 6.70 um. _ 3 f- ' 6 "The intermediate ikan is obtained as follows: A solution cooled to -150 g of 31.2 g (0.12 mM) of D-N-b-butyl oxycarbonylphenylglycine and 16.7 ml (0.12 mM) of triethylamine 1,300 ml tetrahydrofuran is 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 5 of 21.6 g (0.1 mM) of 6-aminopenicillanic acid and 15.4 ml (0.11 mM) ethylamine in 300 ml of tetrahydrofuran / water (2: 1). The reaction mixture Stir for 1 hour at 0 DEG C. and for 2 hours at room temperature, maintaining the pH constant at about 6.9 by the addition of triethylamine; Reaction mixture is adjusted at 5 ° to pH 2.0 with phosphoric acid, saturated with sodium chloride and extracted three times with 500 ml of ethyl acetate each time; 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-butyloxycarbonylampicillin has in thin layer chromaugram an af value of about 0.65 (silica gel ethyl acetate / n-bucan01- / pyridine / aß fi ic acid / varnen 42 = 21 = 21 = 6 = 1o); yield 59-22 81 f) A solution of 57.22 g of crude N-t-butyloxycarbonyl-ampicillin in 100 ml of glacial acetic acid are added in 10 minutes with 21.6 ml of 30% hydrogen peroxide. oxide (0.25 M) and stirred for 2.5 hours at room temperature. Reaction mixture The solution is then poured into 2 l of ice water, in the form of a volumetric precipitate obtained N-t-butyloxycarbonyl-ampicillin-1-oxide from felt-_ 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 (s1likage1; ethyl acetate / n-butanol / pyridine / acetic acid / water 42: 2l: 2l: 6: 10) Rf-ver- 1 of about 0.30.

A mixture of 67.7 g of crude N-t-butyloxycarbonyl-ampicillin-1- oxide 1 380 ml of dioxane are added with a solution of 42 g- (0,3 Mdiphenyl- diazomethane.1 130 ml of dioxane and stir for 2.5 hours at room temperature. Ef- 5. 10. 15. '2o ,. 25. 50. 7807811 ~ 0 77 The addition of 5 ml of glacial acetic acid is evaporated in vacuo. treated with petroleum ether, the petroleum ether extract is discarded and refilled the column is crystallized from methylene chloride / ether / hexane. You get N ~ t- butyloxycarbonyl-ampicillin-1-oxide-diphenylmethyl ester with melting point 1e4-166 °; [ k1oríd): characteristic bands at 2.91; 2.94; 5.54; 5.69; 5.82 (an- clause); 5.88; 6.60; 6.68 Pm; thin layer chromatogram: Rf value approx 0.23 (silica gel toluene / ethyl acetate 3: 1); yield 32 g ($ 51 of it theoretical). , _. h) A mixture of 11.2 g (17.7 mM) of N-t-butyloxycarbonyl-ampicillin cillin-1-oxide-diphenylmethyl ester and 3.26 g (19.5 mm) of mercaptobenzene thiazole in 170 ml of toluene is boiled for 3 hours in a reflux apparatus with water. 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 (ansatsh 5.91 and 6.71 μm; Yield 9.24 g 1) A solution of 2.54 g (5.0 mm) 2- [4- (benzylazol-2-yl) -10) - -3- (α-t-butyloxycarbonylamino-α-phenyl-acetylamino) -2-oxoazetidin-1-yl] -3-methylene-butyric acid diphenylmethyl ester in 30 ml of acetone / water (9: 1) is added to 00 with 0.868 g (3.46 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 amorphous 2- [4- (p-toluenesulfonylthio) -3- (α-t-butyloxycarbonyl- amino-α-phenylacetylamino) -2-oxoazetidin-1-yl] -3-methylene-butyric acid diphenylmethyl ester; thin layer chromatogram: Rf value about 0.33 (silica kagel; toluene / ethyl acetate 3: 1); IR spectrum (methylene chloride): characteristic rist bands at 2.93; 5.57; 5.70; 5.82; 6.21; 6.65 um; yield 2.30 g.

J) In a solution cooled to -700 of 2.30 g (3.0 mM) 2- [4- (p-toluene) sulfonylthio) -3- (α-t-butyloxycarbonylamino-α-phenylacetylamino) -2-oxoazine thidin-1-yl] -3-methylene-butyric acid-diphenylmethyl ester 1 230 ml of methylene- 35_chloride, an ozone-oxygen gas stream (0.5 mM ozone per minute) is initiated 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- [α- (p-toluenesulfonate) nylthio) -3- (α-t-butyloxycarbonylamino-α-phenyl-acetylamino) -2-oxo- uz_azetidin-1-yl] -3-hydroxycrotonic acid diphenylmethyl ester with melting point ïio. 20 .; a; round.. * -182-184 ° - UV spectrum (Ethanol): λmax = 259 nm Yspectrum (methylene chloride): i '-Rf-dvärae 7 '; spectrum (ethanol) Å i'k10ria) 7_Rf value about 0.54 (silica gel; toluene / ethyl acetate system 1: 1) and Amorphous 7β-phenylacetamido-3-methoxy-cep-3-em-4-carboxylic acid-diphenylmethyl- 1 "> ¿f: yty1ester; UV spectrum (ethanol): Ä Δ 5 '' d (ε: δ 6350]; 282 nm (f = 5600) (approach); IR spectrum (methylene chloride): diving characteristic band at 2¿94; 5.63; 5.83; 5.94; 6.26; 6.66 pm, "Rf value about 0.37 (silica1; system toluene / ethyl acetate 1: 1) in a f 7go7s11š ° ii 78 (E- 13mm; In- characteristic band at 2.92; 5.59; 5.85; 5.92; 6.05 (approach); 6.18; 6.68 um; thin layer chromatogram: about 0.55 (silica gel: toluene / ethyl acetate 1: 1); u fl mme1,60g k) A solution of 0.5 μg (0.7 mM) 2- [4- (p-thuenesulfonylthio) -3- J '(q-t-butyloxycarbonylamino-α-phenylacetylamino) -2-oxo-azetidin-1-yl] - 6-5-Hydroxycrotonic acid diphenylmethyl ester in 20 ml of methylene chloride / methanol ONTÖTGS At 0 ° C with an excess of an ethereal diazomethane Pre- (1: 1) solution for 15 minutes and then evaporated in vacuo. comparative layer chromatography of the residue on silica cable with toluene / ethyl acetate (1: 1) as eluent and elution of the 1 UV violet The visible zone gives 2- [4- (p-t-butenesulfonylthio) -3- (u-t-butyloxycar- = bonylamino-c-phenylacetylamino-2-oxoazetidin-1-yl} -3-methoxy-crotonic acid diphenylmethyl ester, which is recrystallized from methylene chloride / diethyl ether / 1 / hexane; mp 204-206 °; 1UV4 spectrum (ethanol): λ max = 259 nm (E = 16 000); Ira spectrum (Nujoih characteristic path at , d2,9}; 5.58; 5.80; 5.84; 5.93, t 6.24; 6.57 um; thin layer chromatogram: \ Rf value about 0.33 (silica gel: toluene / ethyl acetate 1: 1).

EXAMPLE 18. A mixture of 670 mg (1 mM) 2- [4- (p-toluenesulfonylthio) - 51-3-phenylacetamido-2-oxoazetidin-1-yl] -3-methoxy-crotonic acid-diphenylmethyl methyl ester, 6.7 ml of 1,2-dimethoxyethane and 0.22 ml of 1,5-diazabicyclo [5.0] the undec-5 is stirred for 25 minutes at room temperature fl under a nitrogen atmosphere.

The reaction mixture is diluted with toluene and washed successively with .52 N hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated 1t, aqueous sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. Layer chromatography on silica gel with toluene / ethyl acetate (1: 1) 7β-phenyl- The residue gives after preparative thickening acetamido-3-methoxy-cef-2-em-α-carboxylic acid diphenylmethyl ester with 7 ”melting point 166-1690 (from methylene chloride / hexane); yield 430 mg; UV- §0 .; K max = 258 nm (2: = 400); IR spectrum (methylene- ¿Characteristic band at 2.93; 5.62; 5.13; 5.93; 6.66 Pm; max = zss mn (2- 6350), 264 nm ratio of 8: 1, yield S4 mg.

In the further processing can take place as follows: 10. 15. 20. 25. 30. 35. 57807311-0 79 73-Phenylacetamido-3-methoxy-cep-2-em-4-carboxylic acid diphenylmethyl analogous to Example 17c) can be converted to 7B-phenylacetamide -3-methoxy-cef-3-em-4-carboxylic acid diphenylmethyl ester-1-oxide with molten points 152-155 ° (from acetone / diethyl ether); Rf value = 0.31 (silica gel; system: ethyl acetate); UV> spectrum (1 95% ethanol1): Ülmax = 288 nm (¿f = 3610) and approach at 51 = 247 nm; IR spectrum (methylene chloride rid): characteristic bands at 2.94; 5.59; 5.81; 5.95; 6.22 and 6.61 Mm. , A purer product, consisting essentially of 7β-phenylacetate amido-5-methoxy-cef-3-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) -3- 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, 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. extracted with 10 ml of methylene chloride, the organic extracts and stirred for 15 minutes in an ice bath at 0 DEG C. with 2.24 ml of .DELTA. peracetic acid. The reaction mixture is then added with a solution. 1.50 g (6 mM) of sodium thiosulphate pentahydrate in 20 ml of water and stir for 10 minutes; the aqueous phase is separated. The organic the phase is washed surface-layer with 10 ml of water, dried over sodium sulfate and evaporate under vacuum. Crystallization of the solid residue from methyl chloride / petroleum ether gives 'H3-phenyla0ê17amide »3" m @ 1 = 0Xi "0ef'5'Gm'Ü' carboxylic acid diphenylmethyl ester 1p oxide, m.p. 175 ~ 176 ° C; hours layer chromatogram (silica gel) = Rf'Value Ca 0,1 (fi0 lUeH / e fi ylace fi at l: l); UV spectrum (a2nol): - Åmax = 279 hm (Ö = 7300) š IR'SP @ kÜPUm (meÜY1en " chloride) in characteristic bandxid 2,9Ä; 5.56, 5.78; 5,915 6> 20š5; 57 fl m} yield 3.31 g.

From the 1-oxides can be obtained analogously to Example 17e) 7fi-phenylacetamido-3-methoxy-cep-3-em-carboxylic acid diphenylmethyl ester.

From this one can obtain by pre-filtration analogously to Example 17a) crude 7fi + phenylacetamido-3-methoxy-cef-3-em-4-carboxylic acid, which can be by chromatography on silica gel, containing 5 3 Water »WGÛ methylene chloride, containing 30-50% acetone and subsequent lyo- filtration of dioxane; UV spectrum (in 95% ethanol): ._....._..._._.._...._ ..

Q 10 .; isf f 20. 225; 17307811-O At o °, heated to 15 ° and Spaces with uooimi chloroform. the aqueous phase is separated off and the organic phase is washed 80 From the 1-oxides can be obtained analogously to Example 17e) Γβ-phenylacetamido-3-methoxy-cep-3-em-carboxylic acid diphenylmethyl ester.

From this, by saponification analogous to Example 17a) can be obtained crude 76-phenylacetamido-3-methoxy-cef-3-em-4-carboxylic acid, which can be chromatograph on silica gel, containing 5% water, with amethylene chloride, containing 30-50% acetone and subsequently lyophilization from dioxane; Uvespectrum (1 95-PP00 @ HÜï8 et8n0l) = } \ '= 265 nm (¿f = 5800); IR spectrum (methylene chloride): characteristic rigid band at 3.03; 5.66; 5.7 fl; 5.92; 6.21; And 6.67 pm- Me11an products_can be obtained from the following 'I way: J _ _ - 9 9 E a) A mixture of 37.24 g (0.1 M) of potassium salt of penicillin G- 90 ml of water, 7.3 ml of acetone and 150 ml of chloroform are added stirring at 0 DEG C. 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 32.5 ml of 10% sulfuric acid and 28 ml of 40% percent peracetic acid. After the addition is complete, stir for 30 minutes The oessive with 300 ml of 5% aqueous sodium bisulfite solution, 300 ml saturated aqueous sodium bicarbonate solution and 300 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 50} .IR spectrum (methylene chloride): diphenylmethyl ester-1B oxide; melting point 1390; thin layer chromatogram (silica gel): Rf value about 0.40 (system: toluene / ethyl acetate 1: 1); characteristic bands at 2.94; 5.56; 5.70; 5, 92 and 6.57 U-m; yield 48.03 g (about 92 'of the theoretical) lb) A mixture of 5.165 g (10 mM) of 6-phenylacetamidopenicillanic acid di- 9-Phenylmethyl ester-16-oxide in 50 ml of toluene and 0.5 ml of glacial acetic acid are added with 1.83 g (11 mm) 350 HO. 2-mercaptobenstiazoloçhlmkas2h: in one with a water- separator equipped with reflux boiler. In case of cooling crisis tallies 2- [4- (benzazole-εddition) -3-phenylacetamido-2-oxoazetidine-1-, -yl] -3-methylene-butyric acid diphenylmethyl ester spontaneously. After encircling1 ~ * crystallization once from methylene chloride / diethyl ether crystals are obtained with a melting point of 134-136 °; thin layer chromatogram (silica gel): Rf- value about 0.52 (system: toluene / ethyl acetate 1: 1); UV spectrum (etancl): Λmax 269 nm, (f: 12_700); IEI spectrum (methylene chloride f: characteristic 4% _ further processing. The filtrate is filtered off over Hyflo and washed with toluene. 10. 7807811-0 81 band at 2.90; 5.60; 5.72; 5.92 and 6.61 μm; yield 3.27 g.

Ci The product obtained under b) need not be isolated for After cooling, the reaction diluent can be diluted immediately. mixture with 30 ml of toluene, add 3.95 g (15 mM) of silver-p-toluene. ensulfinate and stir for 2 hours at room temperature. Outcome, yellow fold d Filtrauet ut- shake with saturated aqueous sodium chloride solution, wipe dry sodium sulfate and evaporated in vacuo. The evaporation residue is take 1 toluene and add petroleum ether. The precipitate is felted and recrystallized from ethyl acetate / petroleum ether. Received 2f [α- (p-toluenesulfonylthio5-5-phenylaoetamido-2-oxoazetidin-1-yl] -3- Methylene butyric acid diphenylmethyl ester has a melting point of 75 °; thin- 15 layer chromatogram (silica gel): Rf value about 0.47 (system: toluene / / ecylacecac 1 = 1); : IV spectrum (1 ethanol »Å max = 259 nm (É- 4500); IR spectrum (methylene chloride): characteristic bands at 2.92; 5.62; 5,743 5.94 And ÖÄÖÖ Hm; yield 4.05 g. d) A solution of 655 mg (1 mM) of 2- [4- (p-toluenesulfonylthio) -3-phenylacet- 2 amido-2-oxoazetidin-1-yl]] - 3-methylene-butyric acid diphenylmethyl ester in 65 .ml methylene chloride is treated at -65 ° with a mixture of ozone and oxygen 20. 25; 30. 35. 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 from 2- [4- (p-toluenesulfonylthio) -j-phenylacet- amido-2-oxoazetidin-1-yl] -3-hydroxy-crotonic acid diphenylmethyl ester can be further processed without further purification; Rf value about 0.46 (silica- gel; system: toluene / ethyl acetate 1: 1 »IR spectrum (methylene chloride): characteristic bands 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 was added at 0 ° with 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: tolucn / 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 of 2- [4- (p- -toluenesulfonylthio) -3-phenylacetamido-2-oxoazetidin-1-yl] -3-methoxy- -isocrotonic acid diphenylmethyl ester. .'75 10; -f15. 20. 25: 30. than _the 7807811-0 82 EXAMPLE 19. To a solution of 6.06 g (10 mm) of a biananing (3 = 1) of isomer 2? [H- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazeti- , din-1-yl) -3-methoxy-crotonic and -isocrotonic acid benzyl ester and 2.35 g (15 mM) p-toluenesulfinic acid in 200 ml of abs tetrahydrofuran is added room temperature while cooling 5.20 ml (55 mM) 1,5-diazabicyclo [5.ü.0] - undec-5-en. The mixture is further stirred for 40 minutes at room temperature. is added with 500 ml of methylene chloride and washed successively with 200 ml 0.5 N hydrochloric acid, 200 ml water, 200 ml 0.5 N sodium bicarbonate gnat solution and 200 ml of water. The methylene chloride phase is dried overnight rium sulphate and evaporated in vacuo. The residue is chromatographed on 200 g of acid-washed silica gel with toluene / ethyl acetate (3: 1), Ysphenoxyacetamido-3-methoxy-cep-2Hem-Hd-carboxylic acid benzyl ester with a melting point of 1U8-151 ° is obtained by adding diethyl ether to the fractions; IR spectrum (methylene chloride): characteristic bands at 5.60; 5.75; 5.90; 8.25 pmgfo fl lšo = + 284 ° f 19 (c = 1; chloroform); exchange aus g. aa - _- Toluene / ethyl acetate (2: 1) also elutes with diethyl ether precipitable W: -phenoxyacetamido-3-methoxy-cef-3-em-H-carboxylic acid-benzyl- ester, m.p. 89-910; IR spectrum (methylene chloride): characteristic teriscal bands at 5.60; 5.85; 5.90 Pm; [sq š ° = + 47 ° ¿1 ° (c = 1; chloroform; yield 0.80 g (18 Z of theory).

I -The ratio cef-2-em- to cef-3-em compound amounts to about 3: 1. 5 I The compounds can be further processed as follows: A solution prepared at 0 ° of 454 mg (1 mM) of a mixture (about 5: 1) of 7β-phenoxyacetamido-3-methoxy-cef-2-em-4α-carboxylic acid benzyl ester and 7β-phenoxyacetamido-3-methoxy-1-cep-5α-4-carboxylic acid benzyl ester in 50 ml of tetrahydrofuran is added with stirring 15 ml of 1 pre-cooled 0.1 N potassium hydroxide solution. The mixture Stir for 5 minutes at 0 DEG C., then add 100 ml of ice water and 100 ml of pre-cooled methylene chloride and stir vigorously. Additive of any amount of saturated aqueous sodium chloride solution more a separation into two phases. The methylene chloride phase is separated and the aqueous phase is washed with an additional 50 ml of methylene chloride. the aqueous phase is overlaid with 50 ml of methylene chloride, with 10 ml of 2 N hydrochloric acid and shake. After separation of the organic phase is extracted twice more with 30 ml of methyl The combined methylene chloride extracts are dried The thesis the len chloride each time. \O/ , _ 10. 15. 20. 57807811-0 83 over sodium sulfate and evaporated in vacuo; yield 320 mg (88% of the theoretical). The white foam obtained crystallizes on addition of chloroform and diethyl ether to give Zt-phenoxyacetamido-5'-methoxy-cef- -2-em-43-carboxylic acid with a melting point of 1U2 ° (decomposition); IR- spectrum (KBr): characteristic bands at 5.65; 5.75; 5.95 pm- / MellanPr ° duk fi en = can be prepared as follows; To a solution of 36.6 g (0.1 M) of 6-phenoxyacetamido-penylc111an- acid-10-oxide in 150 ml of dry dimethylformamide is added while cooling with The lead value is 20 ml (14.6 s: 0.145 M) of ethylamine and 17 ml (24.5 g, 01143 M) benzyl bromide. and then poured onto ice water.

The mixture is stirred for 20 hours at room temperature. The precipitate is removed, washed with about 1000 ml of water, dried under vacuum for 2 days at 40, then 1,200 ml of methylene chloride are taken up and another is dried once with sodium sulfate. It after evaporation of the solvent under vacuum remaining, the white foam was dissolved in 150 ml of ethyl acetate and must then stand first at room temperature and then at wherein pure 6-phenoxyacetamidopenicillanic acid benzyl ester-1β-oxide crystallizes; melting point 159-1400; IR spectrum 4 (methylene chloride): characteristic trajectory at 5.55; 5.75; 5.90 um; [ajšo = + 174 ° and 1 ° (c 1; chloroform). -2o °, From the mother liquor can be obtained by chromatography of 250 g with acid washed silica gel obtain additional amounts of crystalline benzyl ester-oxide with toluene / ethyl acetate (1: 1); total yield ü0.2 g ~ (88% of theory). 25. 30. 35- HO. n b) 4.56 g (10 mM) of 6-phenoxyacetamido-penicillanic acid benzyl ester; oxide and 1.84 g (11 mM) of 2-mercaptobenstiazole are refluxed in 100 ml of toluene for 5 hours (bath temperature 1350). The mixture is allowed to stand, at 2-LN- (benstiazol-2-yldithio) -3-phenoxyacetamido-2-oxoacetidin-1-yl -3-methylene-butyric acid-benzyl ester crystallizes out. The crystals of nutschas, washed with 50 ml of toluene and dried under high vacuum. Give- chromatography of the mother liquor of 70 g with acid washed silica gel with toluene / ethyl acetate (3: 1) may be additional amounts of crystalline product _ recovered; melting point of pure product 150 to about 1530; IR spectrum rum (methylene chloride): characteristic bands at 5.60; 5.75; 5.90 Pm; BX} š0 = -1120 3 10 (c = 1; chloroform); total yield 5.3U g (88 l of it theoretical). - c) By a solution of 6.60 g (10 mM) 2-β- (benstiazol-2-yldithio) -5- Phenoxy-acetamido-2-oxoazetidin-1-yl-5-methylene-butyric acid benzyl ester in 500 ml of methylene chloride a mixture of oxygen and ozone was passed through long at -200, that the starting material becomes completely ozonized .. 10. 0, e. 0 Q 150 I 020 ..

- Q, 25. 30; 07807811-0 6 any ozonide is no longer detectable with potassium iodide starch. evaporate in vacuo to a volume of about 20 ml. t 5.90; 6.00; 8.75 um; [01§ ° = Z (39% of theory). 84 (control by thin layer chromatography: silica gel; toluene / ethyl acetate) _ tat 1: 1). : To the mixture is then added 50 ml of 10%, aqueous sodium bisulfate solution and stir until (5 min), that To to the mixture is added 300 ml of water and the product is distributed between them both formed phases. The organic phase is dried over sodium sulphate and freed from solvents. The residue is triturated with 1 100 ml of ether / tan (1: 1), then 2- {4- (benstiazol-2-yldithio) -3-phenoxy-acetamido- -2-oxoazetidin-1-yl] -5-hydroxy-crotonic acid benzyl ester crystallizes out Melting point 58-62 °; IR spectrum (methylene chloride): characteristic band at 5.60; 5.90; 6.00 um; [ç] šO = -920 ¿1 ° (c = 01; chloroform); yield 5.48 g (90% of theory). " D) 6.08 g (0.01 M) 2- [4- (Benstiazol-2-yldithio] -3-phenokiacetamido- -2-oxoazetidin-1-yl] -3-hydroxy-crotonic acid benzyl ester and 5.50 g (0.01} M) silver p-toluenesulfinate is stirred in 200 ml acetone / water (9: 1) for 60 minutes at room temperature. The yellow precipitate formed filtered off over Cdlit, the residue is washed with acetone and filtered The product then partitioned between ethylene chloride and dilute aqueous sodium hydroxide solution. rium sulphate solution. The organic phase is dried over sodium sulphate and The solvent is evaporated off under vacuum. The residue is taken up in 70 ml ethyl acetate, optionally under heating, filtered from any amount insoluble and evaporated again. By adding 100 ml of ether / pentane at 0 ° crystallizes 2- [4- (p-toluenesulfonylthio} 5-phenoxyacetamido-2- oxoazetidin-1-yl] -3-hydroxy-crotonic acid benzyl ester with melting point 151-152 ° C; IR spectrum (mecylene10r1d) = characteristic bands at 5.60; -16 ° 3 1 ° (c = 1; x10form \; uubyce 5.31 e) To a solution of 5.97 s (0.01 M) of pure 2 - {} - (p-toluenesulfonyl) thio) -3-phenoxyacetamidof2-oxoazetidin-1-yl] -3-hydroxy-crotonic acid-benzyl sylester in 50 ml of methylene chloride is added dropwise at 0 DEG C. with stirring. An ethereal solution of diazomethane until the starting materials are complete constantly methylated (control: thin layer chromatography on silica gel; 35-toluene / ethyl acetate 1: 1). excess diazomethane is neutralized by one drops of glacial acetic acid (excess glacial acetic acid is avoided), after which The mixture is evaporated in vacuo. The yellow, foam-like residue crystallized from diethyl ether / pentane (1: 1) to give 6-one isomer mixture, consisting of 2- [U- (p-toluenesulfonylthio) -3- f \ 10; "15. 20. 25.

STAY. 35-- 7807811-0 85 -phanoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-chromato-acid ester and 2- [β- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazeti- din-1-yl-3-methoxy-isocrotonic acid benzyl ester in the ratio approx 3: 1; yield 5.72 g (9ü% of theory).

By repeated chromatography on silica gel with toluene / acetic acid raecyl ester (1 = 1) the two isomers can be skiigas. Erhaiien e- [4- (p- toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy- crotonic acid benzyl ester has a melting point of 166-1680; [a] š0 = -} 6 ° i 1 ° (c = 1; chloroform); IR spectrum (methylene chloride): characteristic band at 5.60; 5.80; 5.90; 8.72 um; NMR spectrum (chloroform): characteristic terrestrial bands at 2.12 (s); 5.00 (dd); 5.90 (d) ppm; thin-layer chromatogram: Rf value about 0.10 Lsil1kage1); toluene / ethyl acetate (1: 1).

Obtain 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidine -1-yl] 43-methoxyisocrotonic acid benzyl ester has a melting point of 59-63 °; [α] D = -1 ° _4 _-_ 1 ° (c = 1; chloroformh IR spectrum (methylene chlorideh) characteristic bands at 5.60; 5.87 approach; 5.90; 8.72 um; NMR- spectrum (chloroform); characteristic band at 2.32 (s); 5.45 (d, d); * 5.72 (d) ppm; thin layer chromatogram: Rf value about 0.13 (silica gel; toluene / ethyl acetate 1š1).

EXAMPLE 20. A solution of 534 mg (1 mm) of a mixture consisting of 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] - -3-methoxy-isocrotonic acid methyl ester and 2- [4- (p-toluenesulfonylthio) -3- phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-crotonic acid methyl ester 1 a ratio of about 4: 1 in 20 ml of tetrahydrofuran is added stirring with 302 mg (2 mM) of 1,5-diazabicyclo [5.A] O undec-5-ene and stirring. stir for 1 40 min. The mixture is diluted with 70 ml of methylene chloride and washed taken successively with dilute hydrochloric acid, water, diluted, aqueous sodium bicarbonate solution and again with water. The organic phase dried over sodium sulfate and evaporated in vacuo. The remaining cro- matographed on 15 g acid-washed silica gel with toluene / ethyl acetate (2: 1) and then (1: 1), first pure 75-phenoxyacetamido -} - methox1-eef- = 2-em-ha-carboxylic acid methyl ester eluent yield 115 mg (35% of the theoretical). IR spectrum (in methylene chloride): characteristic band at 5.60; 5.70; 5.90; 8.25 .mu.m, and then pure β-phenoxyacetacid amido-3-methoxy-cef-3-em-U-carboxylic acid methyl ester; exchange bra mg (9 Z of the theoretical); IR spectrum (in methylene chloride): characteristic ethical band at 5.50; 5.85; 5.90; 7.10 pm, in the form of colorless foams.

The obtained compounds can be further processed as follows: 10. 15 :. 20. '7s07s11-of and 85 To a solution of 382 mg of 7β-phenoxyacet- f cooled in an ice bath amido-3-methoxy-cef-2-emfigecarboxylic acid methyl ester in 30 ml of tetrahydride Rofuran is added with stirring to 15 ml of cooled 0.1 N aqueous potassium chloride. hydroxide solution. After 5 minutes, add 100 ml of water and 70 ml of ethylene chloride and the mixture is acidified by adding 10 ml of 1 N aqueous containing hydrochloric acid. The methylene chloride phase is separated and the aqueous the aqueous phase is extracted with 30 ml of methylene chloride. The joint bodies The organic phases are dried over sodium sulphate and evaporated in vacuo. É The residue is crystallized from chloroform / diethyl ether to give 7B-Phenoxyacetamido-3-methoxy-cef-2-em-HOcarboxylic acid - m.p. 'ten 1420 (SÖ fl dePde1 fl ï fl š) 5 yield 32Ä mg (89 1 of the theoretical). The same compound with melting point lü2 ° (decomposition) is obtained read, about 7§-phenoxyacetamido-3-methoxy-cef-3-em-4-carboxylic acid methyl- ester, as described, is saponified with 0.1 N potassium hydroxide solution; yield 87% of theory. "1 '' - - The intermediate samples can be prepared as follows: a) A solution of 19.25 g (50 mM) of 6-phenoxyacetamido-penicillanic acid g, methyl5gep-lß-oxide and 9 μg (55 mM) 2-mercaptobenzothiazole in 500 ml The dry toluene is refluxed for 8 hours and then evaporated in vacuo. the riddle is dissolved under heating (about 80 °) in 400 ml of ethyl acetate, treated with 0.2 g of activated carbon and discarded by an electric suction dehaired glass interplate. Upon cooling, 2-Ca4benstia2ol-2- is separated. 25 .: 30. 35.1 Yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylene-butyric acid methyl ester having a melting point of 132 to about 13 H °. From the mother liquors' additional amounts of this compound can be obtained (melting point 135) to about 1370); total yield 80% of theory). b) Through a solution of 20.6 g (ÜÛ NM) 2 '[h' (beH $ fi íaZ ° l'2'Y1åíÜí0) '3 * phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylene-butyric acid methyl ester in H00 ml of acetone is passed a mixture of oxygen and OZOH At «20 °» until thin layer chromatographic (silica gel, toluene / ethyl acetate III) not no longer any starting material is detectable. The mixture is added , then with H0 ml of dimethyl sulphide and stir for three days at room temperature. temperature, until some ozone is no longer detectable with potassium iodide -starch. The mixture is evaporated in vacuo and the liquid recycled the pillar is poured onto H00 ml of ice water. The precipitate is filtered off, washed : with 200 ml of ice water, dried under vacuum and brought to 0 ° to crystallize 7so7s11-o 37 'tallize from diethyl ether / pentane. Obtained 2- [U- (benstiazol-2-yldi- .5. ' 10. 20. 25. 30. 35.

HO. _11 ... ____t_ .. _c) EXAMPLE 21. thio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-hydroxycrotonic acid methyl- ester has a melting point of 127 to about 1300; yield 16.5 g (80 ß of the theoretical); IR spectrum (in methylene chloride): characteristic band at 5.60; 5.90; 6.00; 8.10 pm. By chromatography of mother liquor on silica gel with toluene / ethyl acetate (3: 1) can be additional amounts (1.5 g: 7 l of the theoretical) product is recovered. _ To a solution of 4.85 g (0.0l M) 2-1 U- (benstiazol-2-yldithio) - -3-phenoxyacetamido-2-oxoazetidin-1-yl7-3-hydroxy-crotonic acid-methyl- ester in 50 ml of methylene chloride is added at 0 ° with stirring so much ether solution of diazomethane, that no starting material no longer is detectable by thin layer chromatography (silica gel: toluene / ethyl state lll) after 15 min stirring. Excess diazomethane is neutralized with a minimum amount of acetic acid and the mixture is evaporated in vacuo. the residue consists of a mixture of 2-1-U- (benstiazol-2-yldithio) -3- Phenoxy-acetamido-2-oxoazetidin-1-yl-17-ylgmate 2-15- (Benstiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl7-3-_ methoxy-crotonic acid methyl ester in a ratio of about 0: 1; IR- spectrum (in methylene chloride): characteristic bands at 5.60; 5.85; 5,905. 9.05; 10.00 pm; exchange 100 1 of the theoretical. g g d) A mixture of 5.03 (0.0l M) of a mixture consisting of 2-15- (Benstiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl7-3- methoxy-isocrotonic acid methyl ester and the corresponding crotonic acid methyl ester in a ratio of about 4: 1, 3.50 g (0.0l3 M) of silver-p-toluene sulfinate and 200 ml of acetone / water (9; 1) are stirred at room temperature in H0 min and then filtered through Cellulite. Filter residues washed with acetone and the combined filtrates evaporated in vacuo to a volume of about 20 ml. After adding 100 ml of methylene chloride and 100 ml of dilute aqueous sodium sulfate solution are shaken through, the aqueous phase is separated and the methylene chloride phase is dried over sodium sulfate and evaporated in vacuo. The remainder is torn down purify at 0 ° with diethyl ether / pentane and filter. You receive a mixture of 2-15- (p-toluenesulfonylthio) -} - phenoxyacetamido-2-oxo- azetidin-1-yl7-3-methoxy-isocrotonic acid methyl ester and 2-β- (p4toluene- sulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl7-3-methoxy-croton- acid methyl ester in a ratio of about 0: 1 in the form of a white powder; IR spectrum (in methylene chloride) characteristic bands at 5.60; 5.85; 5.90; 8.75 pm; yield 3.95 g (7% of theory).

A solution of 731 mg (1 mM) of a mixture (lzl) is consisting of 2- [β- (p-toluenesulfonylthio) -3-phenoxy-acetamido-2-oxoase- Otidin-1-yl7-3-benzyloxy-crotonic acid p-nitrobenzyl ester and the corresponding rs 1 ío ,,. - 150 20. 5 25, _30. , 35. 7so7s} 1-0 88 the -isocrotonic acid p-nitrobenzyl ester is stirred for exactly 35 minutes at room temperature in a mixture of 0.185 ml (1.2 mM) of 1,5-diazabicyclo- [5.H.Q7undec-5-ene in 20 ml of dry tetrahydrofuran. The mixture for- is added with 50 ml of methylene chloride and washed successively with diluent hydrochloric acid, water and dilute aqueous sodium bicarbonate solution.

The organic phase is dried over sodium sulfate and evaporated vacuum. The residue is chromatographed on 25 mg with acid washed silica gel with toluene / ethyl acetate (3: 1); yield 396 mg (7051 of the theoretical tiska). A mixture of cef-2-em and cef- The 5-3-cm compound in a ratio of about 3: 1, which mixture By repeated chromatography can be divided into the pure isomers, to give 7β-phenoxyacetamido-3-benzyloxy-cef-2-em-Ux- I, carboxylic acid p-nitrobenzyl ester, m.p. 160-1620 (diethyl peter / pentane); IR spectrum (methylene chloride): characteristic bands at 5.6; 5.7; 5.9; 7.4 Pm; and 75-phenoxyacetamido-3-benzyloxy-cef- 5-3-em-Ä-carboxylic acid p-nitrobenzyl ester in the form of a colorless fskum; IR spectrum (methylene chloride): characteristic bands at 5.6; 5.8 approach; 5.9; 7.9; 8, u um. ' The resulting isomer mixture can be further processed as follows: Obtained isomer mixture consisting of 7β-phenoxyacetamido-3- Benzyloxy-cef-2-em-NV-carboxylic acid p-nitrobenzyl ester and 7fi-ph Acetamido-3-benzyloxy-cef-3-em-H-carboxylic acid p-nitrobenzyl ester in a ratio of about 3: 1 is dissolved in 8 ml of trifluoroacetic acid and Stir for 90 minutes at room temperature. The reaction mixture is evaporated. taken under vacuum and residues of trifluoroacetic acid are torn several times with toluene. The residue is chromatographed on 20 g of acid-washed silica gel with toluene / ethyl acetate (3: 1) (566 mg), the 7β-phenoxyacetamido- -5-hydroxy-cef-3-em-H-carboxylic acid p-nitrobenzyl ester is obtained in In the form of a colorless foam; IR spectrum (methylene chloride): characteristic ethical band at 2.95; 3.3; 5.6; 5.75 approach; 5.9; 5.95 approach; 5.55, 7.5; 8.15; 8.3 Pm. NMR spectrum (deuterochloroform): characteristic teristic bands at 3, H = (2H, AB q, J = 17Hz), H, 57_ (2H, S), 5.06 ' (1H, d, J = 5Hz '), 5.35 (ZH, AB q, J =' 1U Hz), 5.7 (1H, dd, J = 5, § 10 Hz), 6.8-8, u (10H, C), 11, u_ (1H, br.s.) ppm; yield Hold mg (83% ev.ê9E-ës ° f2PiSKê> - The intermediate nanica is prepared as follows: b 10, 15. 20. 25; 30. 35. and dried under high vacuum. 7807811-0 89 free a solution of 1.282 g (2 mM) z-ßï- (p-tølruenesulfonylthiok 2 -3-phenoxyacetamido-2-oxoazetidin-1-yl7-5-hydroxycrotonic acid-p-nitro- benzyl ester in H ml dest dioxane is added 30 ml of an "in situ" - prepared solution of 1.2 g (about 10 mM) of phenyldiazomethane in ether (prepared from N-benzyl-N-nitrotoluenesulfonamide) at room temperature.

The mixture is refluxed for 6 hours at the bath temperature N50, diluted with 100 ml of methylene chloride and then washed with 100 ml of water. The organic phase is dried over sodium sulphate, evaporated in vacuo The resulting yellow oil is chromatographed on 100 g with acid washed silica gel with toluene / ethyl acetate (3: 1) and (2: 1) such as eluent. An isomer mixture consisting of 2- [E- (p-toluenesulfonylthio) -3-phenoxy-acetamido-2-oxoazetidin-1-yl] -3 * benzyloxy-crotonic acid p-nitrobenzyl ester and 2-1E- (p-toluenesulfonyl- thio) -3-phenoxyacetamido-2-oxoazetidin-1-yl7-3-benzyloni-isocrotonic acid fp-nitrobenzyl ester in a ratio of about 1: 1 (yield 1.1H g: 78% of theory), which mixture can be divided into the Separate the isomers, as before, by repeated chromatography; IR- spectrum of the faster migrating crotonic acid derivative (methylene- chloride): characteristic bands at 5.6; 5.80; 5.90; 8.75 pm; NMR- spectrum (deuterochloroform): characteristic bands at 2.2 (s), 5.05 (dd), 5.93 (d) ppm; thin layer chromatogram: Rf value about 0.3 (silica gel; toluene / ethyl acetate 2: 1) š iR spectrum of the slower migrating isocrotonic acid derivative (methylene chloride): terrestrial bands at 5.6; 5.85 approach; 5.90; 8.75 Pm; NMR spectrum (deuterochloroform): characteristic bands at 2.5 (s), 5.41 (dd), 5.77 (d) ppm; thin layer chromatogram; Rf value about 0.25 (silica1; toluene / ethyl acetate 2: 1).

EXAMPLE 22. H05 mg (0.5 mM) of an isomer mixture consisting of of 2-15- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidine -1-yl7-3-diphenylmethoxy-crotonic acid p-nitrobenzyl ester and the like isomeric isocrotonic acid ester in 8 ml of dry tetrahydrofuran, containing 0.9 ml (0.6 mM) of 1,5-diazabicyclo [.]. exact H5 min at room temperature. The yellow reaction mixture dilute with 25 ml of methylene chloride and wash with 0.5 N hydrochloric acid, water and dilute aqueous sodium bicarbonate solution. The organic the phase is dried over sodium sulphate and evaporated.

An isomer mixture consisting of 7F-phenoxyacetate is obtained. amido-3-diphenylmethoxy-cef-2-em-H-carboxylic acid p-nitrobenzyl ester and 7β-Phenoxyacetamido-3-diphenylmethoxy-cef-3-em-N-carboxylic acid-p-nitro- K _ . '} - 0-10. one 15. 20, 525 ;, 30 "., W 55y _ up. EXAMPLE 23. 7807811-o 90 'bansyl ester; IR spectrum (methylene chloride): characteristic bands at 5.60; 5.70; 5.90; 6.55; 7,110 Fm; yield 3140 ng (98 z of the theoretical).

The resulting isomer mixture of the two compounds can be further processed as follows: _ A solution of 340 mg of the resulting isomer mixture, which consists of 7fi-phenoxyacetamido-3-diphenylmethoxy-cef-2-em-carcarboxylic acid acid-p-nitrobenzyl ester and 7β-phenoxyacetamido-3-diphenylmethoxy-cef-3- em-4-carboxylic acid p-nitrobenzyl ester in a mixture of 0.5 ml of tri- fluoroacetic acid and 9.5 ml of methylene chloride are stirred for H0 min at room temperature. The mixture is evaporated in vacuo, the residue being was added with toluene and evaporated again. The residue obtained (concentrated also contains trifluoroacetic acid) chromatographed on 15 washed silica gel with toluene / ethyl acetate (3: 1) to give 7B-Phenoxyacetamido-3-hydroxy-cef-3-em-H-carboxylic acid-p-nitrobenzyl- ester, IR spectrum (methylene chloride): characteristic bands at 2.95; 5.5; 5.6; 5.75 approach; 5.9; 5.95 approach; 6.55; 7.16; 8.15; 8.3 pm; NMR spectrum (deuterochloroform); characteristic band at 3.4 (ZH, AB q, J '17az), 14.57 (2H, s), 5.06 (m, d, J = sfiz), 5.35 (an, AB q, J 11: Hz), 5.7 (1H, aa, J = 5, 10, Hz), 6.8-8.1x (10H, e), 11.14 (m, br. S.) Ppm; yield 170 mg (70 z of theory). i ell ellanproduct can be obtained as follows: To a solution of 6 mg (1 mM) of)-ZU- (p-toluenesulfonylthio) -3-phenoxyacetyl- amido-2-oxoazetidinyl-7-hydroxy-crotonic acid p-nitrobenzyl ester in 0.5 ml of dest dioxane is added to a solution of 350 mg (1.75 mM) diphenyl- diazomethane in 0.3 ml of dioxane and the reaction mixture was heated to The mixture is evaporated in vacuo IN! 5o ° without stirring .i 36 n. the remaining dioxane is stripped off with toluene by re-evaporation and the residue is chromatographed on 20 g of acid-washed silica gel with toluene / ethyl acetate (7: 1) and 3: 1).

An isomer mixture consisting of 2-β- (p-toluene- sulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl7-3-diphenylmethoxy- crotonic acid p-nitrobenzyl ester and 2-15- (p-toluenesulfonylthio) -3- phenoxyacetamido-2-oxoazetidin-1-yl7-3-diphenylmethoxy-isocrotonic acid-p- nitrobenzyl ester; IR spectrum (methylene chloride): characteristic bands at 5.6; 5.85 approach; 5.9; 5.25; 5.55; 7, "3; 8.75 Pm; u fi byte 725 må (90% of theory). _ A solution of 933 mg (1.5 mM) of an isomer mixture is prepared consisting of 2-15- (benstiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazeti- din-1-yl7-3-benzyloxy-crotonic acid methyl ester and the corresponding isocrotonic , acid methyl ester in a ratio of about 1: 1 and 350 mg (2.25 mM) p-toluenesulfinic acid in 30 ml of dry tetrahydrofuran is added with 800 v- ß- Ln-mu »num- 10. q 15. 20. 25. ü. 30. 35.

H0. 7907811-U 91 i mg (5.25 mM) 1,5-diazabicycloal.H.Q7undec-5-ene and stirred for exactly H0 min at room temperature. The reaction mixture is diluted with 100 ml of benzene and washed with dilute aqueous hydrochloric acid, water, dilute aqueous sodium hydroxide solution and again with water.

The benzene phase is dried over sodium sulfate and evaporated in vacuo.

By chromatography with toluene / ethyl acetate (5: 1) on silica gel an isomer mixture consisting of 7β-phenoxyacetamido-3-benzyloxy- cef-3-em-H-carboxylic acid methyl ester and β-phenoxyacetamido-3-benzyloxy- cef-2-em-U-carboxylic acid methyl ester; IR spectrum (methylene chloride): characteristic bands at 5.60; 5.72; 5.85 approach; 5.90 Pm.

The intermediate can be prepared as follows: A solution of 483 mg (1 mM9 2-β (benstiazol-2-yldithio) -3-phenyl oxiacetamido-2-oxoazetidin-1-yl7-3-hydroxy-crotonic acid methyl ester in 1.5 ml of methylene chloride / diethyl ether is added with 960 mg (approximately 8 mM) phenyldiazomethane and stirred for 20 hours at 0 DEG. The mixture is diluted with methylene chloride and washed with water. The organic the phase is dried over sodium sulphate, evaporated in vacuo and dried in high vacuum. The residue is chromatographed on 10 g with acid washed silica gel with toluene / ethyl acetate (2: 1) to give an isomer mixture consisting of 2-β- (benstiazol-2-yldithio) -3-phenoxyacetamido-2-oxoase- thidin-1-yl7-3-benzyloxy-crotonic acid methyl ester and the corresponding iso- crotonic acid methyl ester in a ratio of about 1: 1; IR spectrum (mean tylene chloride): characteristic bands at 5.6; 5.85 approach; 5.9 approach; 9.9 pm; yield HUD mg (79% of theory).

EXAMPLE Zü. Analogously to Example 5 d) one can by reaction of 1.16 g (3 mM) of 7β-amino-3-methoxy-cef-3-em- obtained according to the invention -U-carboxylic acid hydrochloride dioxanate with 1.5 ml (6.2 mM) bis- K (trimethylsilyl) -acetamide and then a) with 765 mg (3.6 mM) of D-Nemino- -Oê (2-thienyl) -acetic acid hydrochloride obtain 7β-β-O3amino- thienyl) -acetylamine-3-methoxy-3-cephem-α-carboxylic acid in the form of internal salt; melting point 140 ° (decomposition); thin layer chromatography on ¶Likage1; identification with iodine): Rf about 0.22 (system: n-butanol / acetic acid / water 67:10:23) and Rf about 0.53 (system: isopropanol acid / water 77:14:19); UV absorption spectrum: λmax = 235 nm (δ = 1 11 uoo) and Å approach = 272 mn (5 = 6100) in 0.1 N salicic acid without Ämax = 238 nm (6 = 1123cc) and Äansats = 267 mn (E = 6590) in 0.1 N aqueous sodium bicarbonate solution; b) with 940 mg (,.5 mM) D-Kramino- (1,4-cyclohexadienyl) -acetic acid hydrochloride obtain 7B- [δ-Gramino-β (1,1-cyclohexadienyl) -acetylamine] -3-methoxy-3-cephem- -H-carboxylic acid in the form of inner salt; melting point 170 ° (decomposition); 7807811-0 i 92 thin layer chromatogram (silica gel identification with iodine): Rf approx 660.19 (nebutanol / acetic acid / water system 67:10:23) and Rf about 0.58 (system: isopropahol / formic acid / water 77: fl: 19); UV absorption spectrum room: Åmax 267 nm (2 = 6300) in 0.1 N hydrochloric acid and Åmax = 268 nm 6522 (f; 6600) in 0.1 N aqueous sodium bicarbonate solution; Eijšo._ + 8S ° i 10 (c = 1.06; 0.1 N hydrochloric acid); and in ,, c) with 800 mg (3.6 mM) of D-M-amino-H-hydroxy-phenylacetic acid hydrochloride Chloride to obtain 7F- [D - β-amino- (4-hydroxyphenyl) -acetylamino] -3-methoxy- ¿_, -Sfcefem---carboxylic acid in the form of inner salt; mp 243-2üU, 5 ° 10. _ (sintering begins from 2310) (decomposition); thin layer chromatogram 2i (silica gel; identification with iodine): Rf about 0.23 (system: n-buta- (Phenol / acetic acid / water 67:10:23) and Rf about 0.57 (system: isopropane) .Znol / formic acid / water (77: 4: 19); UV absorption spectrum: Åmax = 228 51 nm_ (âI = 12000) and 271_nm (i = 6900) in 0.1 N aal fi acid ° çh.Ämax 5 iS._1227 nm (É6 = 10500) and Ä approach f 262 nm (Z = 8009) in 0.1 N aqueous Containing sodium bicarbonate solution; + = 165 ° 1 1 ° (c = 1.3; 0.1 , .lvN hydrochloric acid),, 2 f EXAMPLE 25. Analogously, the following compounds can be prepared from suitable, Intermediate inventions obtained according to the invention: 6 6α, 6β, β-amino-5-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester; five-layer chromatogram (silica gel): Rf ä 0.17 (system: ethyl acetate; 6] 'development with iodine); ultraviolet absorption spectrum (in 95 ~ percent agree, watery atano1) = Ä, max = 258 am (2 = 5700); infrared "sorption spectrum (in dioxane): characteristic bands at 2.87 μm, D25, ¿ä5.62 Pm and 6.26 Fm; 3-n-Butyloxy-Tβ-phenylacetylamino-3-cephem-4-carboxylic acid dife- “Lr ~ Åny1matyiaatar; amäitpunk fi 168-17o °; [ag š ° = + 55 ° 3 1 ° (0 = 0,38 i fichloroform); ultraviolet absorption spectrum (in 95% water Jšàhaltig ethanol) :. ä max = 26Ä nm (âÉ = 7500); infrared absorption spectrum 6'¶ 65o¿f§rum (1 methyl1ank10rid) = characteristic bands at 2.98; 5.62; 5.81; ï¿f5.92; 6.25 and 6.62 Pm; 7, 3-, 3-n-butyloxy-W- (D-β-butyloxycarbonylamino-N-phenyl-acetyl- if fl amino) -3-cephem-4-carboxylic acid diphenylmethyl ester; λ = = 110 in 1 ° (c = 0.98 in chloroform); ultraviolet absorption spectrum (in 95- lpfocentig vatteñhaltig etano1): Ätmax = 26fl nm (Ei: 6100); infra_ 2 red absorption spectrum (in methylene chloride): characteristic bands at * f2.88, 5.63; 5.8U, (approach); 5.88, 6.26 and 6.71 μm; 6-3-n-butyloxy-7β- (D-K-phenyl-glycylamino) -3-cephem-U-carboxylic acid; Melting point 1U1 ¥ 1ü2 °; thin layer chromatogram (silica1): Rf approx. _§0Åfg0,21 (system: ethyl acetate / pyridia / acetic acid / water 62: 21: 5: 11); 10. 15. 20. 25. 30. 35.

HO. 78078114 93 ultraviolet absorption spectrum (in 0.1 N aqueous sodium hydrogen carbonate solution):; \ max = 267 nm (ä = 7300); 3-methoxy-7β-phenylacetylamino-3-cephem-α-carboxylic acid methyl ester; melting point 171-17 ° C after recrystallization from methylene chloride and hexane fl ijšo = + 102 ° 2 1 ° (c = 0.95 in chloroform); ultraviolet soprtion spectrum (in 95 ~% aqueous ethanol):) \ max = 265 nm (§: = 6250); infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94; 5.62; 5.76; 5.95; 6.2ü and 6.65 Fm; 3-ethoxy-¶% - (D-q-t-butyloxycarbonylamino-M-phenyl-acetylamino) - -3-cephem-4-carboxylic acid diphenylmethyl ester; thin layer chromatography (silica gel): Rf about 0.28 (system: toluene / ethyl acetate 3: 1); ultra- violet absorption spectrum (in 95% aqueous ethanol): Λmax = 258 mn (2 = 7000) and λmax = 261: nm (2 = 6900); infrared- absorption spectrum (in methylene chloride): characteristic bands at 2.96; 5,6Ä; 5.90; 6.28 and 6.73 Pm; 3-ethoxy-W1- (D-Gz-phenyl-glycylamino) -3-cephem-α-carboxylic acid; thin layer chromatogram (silica gel): Rf about 0.1? (system: ethyl- tat / pyridine / acetic acid / water 62: 21: 6: 11); u1traviolettabsorptions ~ spectrum (in 0.1 M aqueous sodium bicarbonate solution): Å = 263 rm (ä = 5500); 3-Benzyloxy-WQ- (D-Oct-butyloxycarbonylamino-ussophenyl) -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); 3x3š0 = + 7 ° 1 10 (c = 0.97 in chloroform); Ultraviolet absorption spectrum (in 95% aqueous ethanol): Amax = ass mn <í = 6800) och 261: mn <§ = 6000) och A ansats = 280 nm (Å = 6500); infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96; 5.63; 5.88; 6.26 and 6.72pm; 3-Benzyloxy-7β- (D-M-phenyl-glycylamino) -3-cephem-H-carboxylic acid in zwitterionic form; thin layer chromatogram (silica1): 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 resolution h max = 266 nm (ä = 6500); ê ê- (5-benzoylamino-5-diphenylmethoxycarbonylvalerylamino) -3- -methoxy-3-Ophem-U-carboxylic acid diphenylmethyl ester; thin-layer chrome togram (silica gel): Rf = 0, ü5 (system: toluene / ethyl acetate 1: 1); Ultraviolet absorption spectrum (in 95% aqueous ethanol): Recess = 258 nm (f = 71450), 2614 mn (ï = 7050) and 268 nm (2, = 6700); Infrared absorption spectrum (in methylene chloride): characteristic rist bands at 5.65; 5.78; 6.03 and 6.6H Pm; 10. 15. 20. 25. 30. 35.

H0. 7807811-0 9Ä 7fi- (D-dft-butyloxycarbonylamino-acphenyl-acetylamino) -3-methoxy- -3-cephem-4-carboxylic acid; thin layer chromatogram (silica gel); iden- iodination): Ef about 0.64 (system: n-butanol / acetic acid / aqueous at 67:10:23); ultraviolet absorption spectrum (in 95% water tenanol ethanol) :, λ max = 26ü nm (:: = “4100); infrared absorption spectrum (in methylene chloride): characteristic bands at 3.00; 5.6ü; 5.92; 6.25 and 6.72 μm; 7β- [D-Qr-butyloxycarbonylamino-N- (2-thienyl) -acetylamino] -3- -methoxy-3-cephem-α-carboxylic acid diphenylmethyl ester; thin layer chromato- gram (silica gel): identification with ultraviolet light λ = 25N nm); Rf about 0.51: (system: diecylethernafoç] go = + 26 ° i 1 ° (c = 0.86 i chloroform); ultraviolet absorption spectrum (in 95 ~% water ethanol content): λmax = 2140 nm (λ = 12500) and 280 nm (f: 6000); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.9U; 5.62; 5.85; 6.26 And 6.72 Pm; Wi-: D-i-t-butyloxycarbonylamino-N; (1,1-H-cyclohexadienyl) -acetyl- amino: -3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester; thin-layer chromatogram (silica gel identification with diethyl ether): Rf about 0.39 (system: diethyl ether); UNQ go = + 1 ° 3 10 (c = 0.7fl5 in chloroform); Ultraviolet absorption spectrum (in 95% aqueous ethanol): ., \ max = 263 nm (2 = 66700) and Å approach = 280 nm (¿f = 6300); infra- red absorption spectrum (in methylene chloride): characteristic bands at 2.96; 5.6U; 5.86; 5.90 (approach); 6.27 and 6.73 Pm; N-D-α-t-butyloxycarbonylamino-0% (H-hydroxyphenyl) -acetylamine -3-methoxy-3-cephem-H-carboxylic acid diphenylmethyl ester; thin-layer chrome togram (silica gel; identification with iodine): Rf about 0.35 (system: toluene / ethyl acetate (1: 1); Q {] š0 about -1 ° 1 10 (c = 0.566 in chloroform); Ultraviolet absorption spectrum (in 95% aqueous ethanol): Å (maX = 276 nm (â ~ = 7Ä00); infrared absorption spectrum (in methylene chloride): characteristic band at 2.83; 2.96; 5.60; 5.86; 5.91 (shoulder); 6.23; 6.28; 6.65 and 6.72 Pm: 7α-β-N-t-butyloxycarbonylamino-? (H-isothiazolyl) -acetylamino- -3-methoxy-2-cephem-45-carboxylic acid diphenylmethyl ester; melting point 1700 (after crystallization from a mixture of methylene chloride and pentane); ÜÅJ go = + 1ü7O 1 10 (9 = 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): λmax = 248 nm (λ = 10700); infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96; 5.63; 5.75; 5.87; 6.18 and 6.72 Pm; 7807811-0 95 7β- [D-M-t-butyloxycarbonylamino-N- (H-isothiazolyl) «acetylamino] - -3-methoxy-3-cephem-H-carboxylic acid diphenylmethyl esterBK] go = + 260 1 51 ° (c = 0.65 in chloroform); thin layer chromatogram (silica gel identical iodination): Rf about 0.1 (system: toluene / ethyl acetate 1: 1); ultraviolet absorption spectrum (in 95% aqueous eta- nol): λ max = 250 nm (2: = 12200) and 280 nm (f = 5900); infrared- absorption spectrum (in methylene chloride): characteristic bands at e2.9H; 5.65; 5.71 (approach); 5.88; 6.28 and 6.73 Pm.

Claims (1)

7807811-0 Qlo PATBNrKRÄV 3. 3-Hydroxycrotonic acid derivatives for use as intermediates in the synthesis of 3-cephem compounds with antibiotic properties, characterized by the formula: nl _ LNHÉ 1:25 'Y __ f; (II), 0 ORQ-í I A o-c-az vari R? represents hydrogen, an acyl group of the formula O II na- (znm-ca-c- kw). B wherein Ra represents phenyl, hydroxyphenyl, hydroxychlorophenyl, thienyl, pyridyl, aminopyridinium, furyl, isothiazole / tetrazolyl or 1,4-cyclohexadienyl and wherein in these groups the hydroxy substituents may be protected with optionally halogenated lower alkoxycarbonyl groups and wherein and m represents 0 or 1 and Rb represents hydrogen or, when m represents 0, optionally with α-polygrened lower alkoxycarbonyl, optionally lower alkoxy- or nitrosubstituted Å phenyl lower alkoxycarbonyl, trityl or 1-1 lower alkoxycarbonyl-2-propylidene protected amino, optionally protected with phenyl lower alkyl icarboxy or sulfo or optionally with α-polygrened lower alkoxycarbonyl or formyl protected hydroxy, or O-lower alkylphosphono or 0,0'-lower alkylphosphono, or a 5-amino-5-carboxyvaleryl group, in which the amino group is optionally a protected with lower alkanoyl, halo lower alkanoyl, benzoyl or phthaloyl and the carboxy group optionally with phenyl lower alkyl, and wherein R xi, Zahalogen lower alkoxy, phenacyloxy, 1-phenyl lower alkoxy of 1-3, optionally substituted with lower alkoxy or nitro, phenyl groups, lower alkanoyloxymethoxy, u-amino-lower alkanoyloxymethoxy, lower alkoxycarbonyloxy or lower alkanoyloxyphenylalkyl; a leaving group consisting of benzthiazol-Z-ylthio, benzoxazol-2-ylthiobenzenesulfonyl, p-toluenesulfonyl, o-methoxybenzenesulfonyl, p-methoxybenzenesulfonyl or p-nitrobenzenesulfonyl, and salts thereof. 7807811-0 9? Z. Compounds of formula II according to claim 1, k e n n e - t e c k n a d e thereof, that R? denotes phenylacetyl or phenoxyacetyl, Rê denotes p-nitrobenzyloxy, diphenylmethoxy, Z, 2,2-trichloroethoxy or methoxyR? represents hydrogen, methyl or trimethylsilyl and Y represents benzestiazol-2-ylthio, benzoxazol-2-ylthio, p-toluenesulfonyl, p-nitrobenzenesulfonyl, p-methoxybenzenesulfonyl, benzenesulfonyl or o-methoxybenzenesulfonyl.