FI66389B - REFRIGERATION FOR THE FRAMSTATION OF 7BETA-AMINO-2-ELLER -3-CEFEM-3-OL-4-CARBOXYLYRAFOERENINGAR - Google Patents

Description

fiSr ^ l M ADVERTISEMENT, ULICA.SU

JgU · 1 J 1 1 UTLÄGCNI NGSS.KJRIFT Λ5 ö ^ y • Ή® c (**); ylj '11 ^ (51) K * Ju / lm.CL3 C 07 D 501/08, 501/59, 501/60 FINLAND — FINLAND pi) ΡκΜην ^ -ΡΗΜ. ^, 750503 (22) HmkemispUvl - Anaftkningsdag 21.02.75 (23) AlkupUvt — GIMgh «tsdag 21.02.75 (41) Subsidies to the Public - Blivfe offantllg 27.08.75

Patent- och raghteratyralaan Awtiai «thy» oehttSate— pJbSeirad ^ '(32) (33) (31) • Vr »· **)' * tohik«, «- a ^ fctl prior ** 26.02. 7 * »05.06.7 *», 12.08.7 * »Switzerland-Switzerland (CH) 2693/7 *», 7766/7 * », 11 000/7 *» (71) Ciba-Geigy AG, CH- * » 002 Basel, Switzerland-Switzerland (CH) (72) Robert Burns Woodward, Cambridge, Massachusetts, USA (US),

Hans Bickel, Binningen, Switzerland-Schweiz (CH) (7 * ») Oy Jalo Ant-Wuorinen Ab (5 * 0 Method 7 E-amino-2- or -3-cephem-3-ol - *» - carboxyl 1 The present invention relates to a process for the preparation of 73-amino-3-cephem-3-ol. For the preparation of 4-carboxylic acid compounds of the formula R 1 \ (O) n XNH?? ♦ x_ I IÄ O = 1-'Nvy ^ -0 "R 3 o> c - R 2 where n is 0 or 1, represents hydrogen or an acyl group which the formula is 0

Ra - (X), „- CH - 2 B

Rb 2 66389 in which phenyl, hydroxyphenyl, hydroxychlorophenyl, thienyl, pyridyl, aminopyridinium, furyl, isothiazolyl, tetrazolyl or 1, Μ-cyclohexadienyl, where X at the substituents may be substituted by hydroxyl substituents , m is 0 or 1, and is hydrogen, or when m is 0, an optionally protected amino, or a 5-amino-b-carboxy-valeryl residue in which the amino or carboxy group is optionally protected, R 1 represents hydroxy, halogen, lower alkoxy, 2-halo-lower alkoxy, 1-phenyl-lower alkoxy, wherein the phenyl ring may be substituted by a nitro group or diphenyl-lower alkoxy, and R 1 represents hydrogen, lower alkyl, phenyl-lower alkyl or diphenyl-lower alkyl, and the like -combine steiden with the formula

Ra

NH H H

My/%

[| IB

O = -O 3 - r 3 o = c - R 2 wherein R a, R 1 and the same are as defined above, or mixtures of 3-cephem and 2-ceffer compounds of formulas IA and IB, or compounds containing such salt-forming groups. for the preparation of salts.

The process according to the invention is characterized in that the compound of formula

Ri \

^ NH? ? S-Y

^ -Y f 3 II

0 = 1 --- N C! ° r 3

I A

o = c - r 2 wherein Ra is as defined in formula IA, R 1 is as defined for R 2 except for hydroxy, R 0 is lower alkyl, phenyl-3,638,9 lower alkyl, diphenyl lower alkyl or trialempkylsilyl, and Y is a leaving group which is benzthiazol-2-ylthio , benzoxazol-2-ylthio, benzenesulfonyl, p-toluenesulfonyl, o-methoxybenzenesulfonyl, p-methoxybenzenesulfonyl or p-nitrobenzenesulfonyl, is treated with a strong base in an inert solvent at room temperature or with gentle heating at 40-50 ° C optionally in an inert gas atmosphere, and in a manner known per se optionally converting the resulting mixture of 2-cephem (IB) or 3-cephem (IA) or the obtained 2-cephem (IB) by oxidation of 3-cephem to 1-oxide (IA) and optionally converting the resulting 3-cephem compound 1-oxide (IA) by reduction to a 3-cephem compound of formula (IA) and optionally converting the resulting compound to an esterified carboxyl group of formula -C (= O) -R 2. by saponification, or by hydrolysis of the group -C (= O) -Kal to the free carboxyl group or by esterification to another protected carboxyl group and optionally converting the protected 3-hydroxy group in the resulting compound to the free 3-hydroxy group and optionally converting the resulting compound to the free 3-hydroxy group. group by etherification to an etherified 3-hydroxy group, and optionally cleavage in the resulting compound of formula I wherein R 1 represents an acyl residue, treating this acyl residue with an imide halide-forming agent, reacting the resulting imide halide with an alcohol to form the corresponding imino ether, and The protected hydroxy and / or protected amino R 1 optionally present in the hydroxyphenyl residue R in the compound of the formula I, and / or optionally converting the resulting compound containing a salt-forming group into a salt or the resulting salt into a free compound, or to another salt, and / or optionally separating the resulting mixture of isomeric compounds into individual isomers.

The enol derivatives of this invention are 3-cephem-3-ol-resp. Ethers of 2-cephem-3-ol compounds.

In the 2-cephem compounds of formula IB having a double bond at the 2,3-position, the optionally preferred carboxyl group of formula -C (= O) -R 2 preferably has the α-configuration.

The amino-protecting group is a hydrogen-displaceable group, preferably an acyl group Ac, in addition to a triarylmethyl group, especially trityl group, and an organic silyl or organic stanyl group.

The group Ac is preferably a carboxylic acid of an organic carboxylic acid, preferably a carboxylic acid having up to 18 carbon atoms, in particular an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic, araliphatic, acetic acid, heterocyclic or heterocyclic-aliphatic (carboxylic acid)

In particular, the bivalent amino protecting group is a bivalent acyl residue of an organic dicarboxylic acid, preferably a dicarboxylic acid having up to 18 carbon atoms, preferably a diacyl residue of an aliphatic or aromatic dicarboxylic acid, and in addition an amino is preferably bonded to the nitrogen atom via a preferably substituted methylene residue, e.g. containing two lower alkyl groups such as methyl.

The protected carboxyl group is primarily an esterified carboxyl group, however, it may also be a conventional mixed anhydride group or an optionally substituted carbamoyl or hydrazinocarbonyl group.

Together with the -C (= O) grouping, the residue which primarily forms the mixed anhydride group is, for example, halogen, such as chlorine.

The lower alkyl group R 1 preferably contains up to 7, more preferably up to 4 carbon atoms and is especially methyl.

Lower alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and n-pentyl, isopentyl, n-hexyl, isohexyl or n-heptyl.

Phenyl-lower alkyl is, for example, benzyl, 1- or 2-phenylethyl, 1-, 2- or 3-phenylpropyl. Diphenyl prior alkyl is especially diphenylmethyl.

Lower alkoxy is, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, n-pentyloxy or tert-pentyloxy. 2-Halo-lower alkoxy is, for example, 2,2,2-trichloro, 2-chloro, 2-bromo or 2-iodoethoxy. The 1-phenyl-lower alkoxy is, for example, benzyloxy or 1-phenylethoxy.

5 66389

The salts are, in particular, salts of the compounds of formula IA and IB having an acidic group, such as a carboxy group, and are preferably metal or ammonium salts, such as alkali metal and alkaline earth metal, e.g. sodium, potassium, magnesium or calcium salts, as well as ammonium salts with ammonia or suitable organic amines, and in the case of salt formation are preferably aliphatic, cycloaliphatic, cycloaliphatic-aliphatic and araliphatic primary, secondary or tertiary mono-, di- or polyamines, as well as heteros , e.g. hydroxy-lower alkylamines of triethylamine, e.g. 2-hydroxyethylamine, bis- (2-hydroxyethyl) -amine or tri- (2-hydroxyethyl) -amine, basic aliphatic esters of carboxylic acids, e.g. 4-amino-benzoic acid -po-2-diethylaminoethyl ester, lower alkyleneamines, e.g. 1-ethylpiperidine, cycloalkylamines, e.g. bicyclohexylamine, or benzylamines, e.g. N, N * -dibenzylethylenediamine, in addition pyridine-type bases, e.g. pyridine, collidine or Quinoline. Compounds of formula IA and IB having a basic group may also form acid addition salts, e.g. with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulfonic acids, e.g. trifluoroacetic acid or p-toluenesulfonic acid. Compounds of formula IA and IB having an acidic and basic group may also exist as internal salts, i.e. as "cations". The 1-oxides of the compounds of formula IA containing salt-forming groups may also form salts, as described above.

The compounds of the invention have valuable pharmacological properties or can be used as intermediates in the preparation of such compounds. Compounds of formula IA in which n is 0 represent an acyl residue contained in the pharmacologically effective N-acyl derivatives of 6β-amino-penam-3-carboxylic acid or 7β-amino-3-cephem-4-carboxylic acid compounds, denote hydroxy and R 3 denotes lower alkyl, wherein the functional groups optionally present in the acyl residue R 1, such as amino, carboxy, and / or hydroxy, are generally in free form, or salts of such salt-forming compounds, are effective microorganisms when administered parenterally and / or orally, such as gram-positive bacteria, e.g. Staphylococcus aureus, Streptococcus pyogenes and Diplococcus pneumoniae 1 (e.g. in mice at doses of about 0.001 to about 0.02 g / kg sc or po) and gram-negative bacteria, e.g. Escherichia coli, Salmonella typhimurium, Shigella flexneri, Klebsiella pneumonieae1, Enterobacter cloacae, Proteus vulgaris, Proteus rettgeri and Proteus mira against bilis (e.g. in mice from about 0.001 to about 0.15 g / kg s.c. or p.o. doses), in particular also against penicillin-resistant bacteria, while their low toxicity. These new compounds can thus be used, for example, in the form of antibiotically effective preparations for the treatment of similar inflammations.

Compounds of formula IB or 1-oxides of compounds of formula IA wherein n is 1 and the groups and R 1 are of formula IA

or compounds of formula IA wherein R 1 is as defined above, the residue R 1 is hydrogen or R 2 is 6B-amino-penam-3-carboxylic acid or the 7B-amino-3-cephem-4-carboxylic acid compound. An amino protecting group other than the acyl residue contained in the N-acyl derivatives, and R 2 represents hydroxy, are valuable intermediates which can be converted in a simple manner, e.g. as described below, into the above-mentioned pharmacologically active compounds.

The invention relates primarily to the preparation of 7β- (Da-amino-α-Ra-acetylamino) -3-lower alkoxy-3-cephem-4-carboxylic acids, wherein R represents phenyl, 4-hydroxyphenyl, 2-thienyl or 1,4-cyclo 3.

lower alkoxy, and the lower alkoxy contains up to 4 carbon atoms and is, for example, ethoxy or n-butyloxy, but preferably methoxy, and its internal salts and, in particular, 3-methoxy-7g- (Da-phenyl-glycylamino) -3-cephem. In the preparation of 4-carboxylic acid and its internal salt, at the above-mentioned concentrations, especially when administered orally, these compounds have excellent antibiotic properties against both gram-positive and especially gram-negative bacteria, while having low toxicity.

In the starting compound of formula II, the group -O-R ° may be in the trans (corotonic acid configuration) or cis (isocrotonic acid configuration) relative to the carboxyl group.

A

The starting material of the formula II preferably has an etherified hydroxy group which forms an esterified carboxyl group which can be cleaved, in particular under mild conditions, with a -C (= O) group. The group R 1 is, for example, in particular an optionally halogen-substituted lower alkoxy group, such as α-polybranched lower alkoxy, e.g. tert-butyloxy, or 2-halo-lower alkoxy, in which halogen means e.g. chlorine, bromine or iodine, preferably 2.2, 2-trichloroethoxy, 2-bromoethoxy or 2-iodoethoxy, or an optionally substituted, for example, nitro-containing 1-phenyl-lower alkoxy group, such as, for example, benzyloxy or diphenylmethoxy substituted as mentioned above, e.g. benzyloxy, 4-nitrobenzyloxy or diphenylmethoxy or also halogen , e.g. chlorine. In the starting material of the formula II, the radical R 1 preferably denotes an amino-protecting group, such as an acyl group Ac, the free functional groups which may be present, e.g. amino, hydroxy or carboxyl groups, can be protected in a manner known per se, amino groups e.g. acyl, trityl, silyl. or stanynyl, as well as substituted thio or sulfonyl residues, and hydroxy or carboxy groups, e.g. with the abovementioned ether or ester groups, also with silyl or stanynyl groups.

In the starting material of the formula II, R 1 preferably denotes lower alkyl, in particular methyl or, as hydroxyl-protecting group, an α-phenyl lower alkyl group, such as a benzyl or diphenylmethyl group.

Suitable bases for the ring closure reaction are, in particular, strong organic or inorganic bases. Of particular note are bicyclic amidines, such as diazabicycloalkenes, e.g. 1,5-diazabicyclo (4.3.0) non-5-ene or 1,5-diazabicyclo (5.4.0) undec-5-ene, substituted, e.g. by lower alkyl polysubstituted guanidines, such as tetramethylguanidine, further metal bases, such as hydrides, amides or alcoholates of alkali metals, in particular lithium, sodium or potassium, for example sodium hydride, lithium dialyl lower alkylamides, such as lithium diisopropyl alkanamide, potassium Formula II

8 66389

A

Compounds of formula IA and / or IB in which halogen, e.g. chlorine, can also be cyclized with a tertiary organic nitrogen base, e.g. trialminalkylamine, such as triethylamine, to give the corresponding esters of formula IA and / or IB in the presence of an alcohol, e.g. lower alkanol e.g.

The reaction of the invention is carried out in a suitable inert solvent, e.g. an aliphatic, cycloaliphatic or aromatic hydrocarbon such as hexane, cyclohexane, benzene or toluene, a halogenated hydrocarbon such as methylene chloride, dimethyloxyethane, ether such as a lower dialkyl ether, e.g. , such as dioxane or tetrahydrofuran or also a lower alkanol, e.g. methanol, ethanol or tert-butanol, or a mixture thereof, at room temperature or with slight heating to 40-50 °, if desired under an inert gas such as nitrogen.

In the case of a compound of formula II in which Y represents a group -S-R1 +, e.g. a 2-benzthiazolyl residue, one of the abovementioned bases, e.g. 1,5-diazabicyclo (5.4.4) undec-5-ene, can be added by adding H- A sulfinic acid of formula SC1-R1, e.g. p-toluenesulphonic acid, increases the yields of compounds of formula IA and IB.

In the ring-closure reaction according to the invention, depending on the starting material and the reaction conditions, uniform compounds of the formula IA or IB or mixtures of the compounds of the formula IA and IB are always obtained. The resulting mixtures can be separated in a manner known per se, e.g. by suitable separation methods, e.g. by adsorption and fractional elution, also by chromatography (column, paper or plate chromatography) using suitable adsorbents such as silica gel or alumina, and further eluting agents, eluting agents, by division into solvents, etc.

The resulting compounds of formulas IA and IB, which are suitable intermediates for the preparation of more pharmaceutically active end products, can be converted into such active end products by various additional measures known per se.

In the compound of formulas IA or IB obtained according to the invention, the hydroxy-protecting group can be easily cleaved and replaced by hydrogen. The silyl group can be cleaved by hydrolysis, alcohololysin or acidolysis, for example by treatment with water or an alcohol such as methanol or ethanol, or also with an acid such as acetic acid. The cleavage of an optionally substituted α-phenyl-lower alkyl, e.g. benzyl or diphenylmethyl group takes place e.g. by acidolysis, e.g. by treatment with a suitable inorganic or organic acid such as hydrochloric acid, sulfuric acid, formic acid, or especially trifluoroacetic acid, or hydrogenolysis , such as in the presence of palladium. The 3-hydroxy compounds formed are mainly in the 3-cephem form. hydroxy

the cleavage of the protecting group can be performed selectively if desired, ύ A

i.e., without the carboxyl protecting group being cleaved off at the same time.

Enol ethers, i.e. compounds of formula IA and / or IB in which Rg is lower alkyl, are obtained from compounds of formulas IA or IB in which Rg is a hydroxy protecting group, replacing this residue with hydrogen and then etherifying the free hydroxy group according to any method suitable for etherification of enol groups The etherification reagent used is preferably a diazo compound of the formula R3-N2 corresponding to the optionally substituted hydrocarbon radical Rg, preferably an optionally substituted diazo-lower alkane, e.g. diazomethane, diazoethane or diazo-n-butane, in addition optionally substituted α-phenylalkia - or diphenyldiazomethane. These reagents can be used in a suitable inert solvent such as an aliphatic, cycloaliphatic or aromatic hydrocarbon such as hexane, cyclohexane, benzene or toluene, a halogenated aliphatic hydrocarbon, e.g. methylene chloride, lower butanol, ethanol, e.g. such as in the presence of a dialkyl alkyl ether, e.g. diethyl ether, or a cyclic ether, e.g. tetrahydrofuran or dioxane, or a mixture of solvents, and always depending on the diazo reagent while cooling, at room temperature or with little heating, in addition in a sealed vessel and / or inert gas, e.g. .

In addition, enol ethers of formula IA and / or IB can be formed by treating a lower alkyl residue or an optionally substituted α-phenyl lower alkyl, e.g. with a reactive ester of an alcohol of formula Rg-OH corresponding to the benzyl or diphenylmethyl residue Rg. Suitable esters are preferably those obtained from strong inorganic or organic acids, such as mineral acids, e.g. hydrohalic acids, such as hydrochloric, hydrobromic or hydroiodic acids, further sulfuric acid or halogenated sulfuric acids, e.g. fluorosulphuric acid, or strong organic sulfonic acids, such as optionally, e.g. halogen, such as fluorine-substituted lower alkanesulfonic acids, or aromatic sulfonic acids, such as, e.g., optionally, e.g. lower alkyl, such as methyl, halogen, such as bromine, and / or nitro-substituted benzenesulfonic acids, e.g. with these methanesulfonic, trifluoromethanesulfonic or p-toluenesulfonic acids. pomethyl ester, is generally used in the presence of a solvent such as an optionally halogenated, such as chlorinated 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. In this case, suitable condensing agents are preferably used, such as alkali metal carbonates and / or bicarbonate and, e.g. sodium or potassium carbonate or bicarbonate (usually in combination with sulphate), or organic bases, such as generally sterically hindered trialkylalkylamines, e.g. Ν-diisopropyl-N-ethylamine (preferably together with lower alkyl halosulphates or optionally halogen-substituted methanesulphonic acid lower alkyl esters), while working under cooling, at room temperature or under heating, e.g. at a temperature of about -20 to about 50 ° C, if necessary in a closed container and / or an inert gas-e.g. in a nitrogen atmosphere.

Enol ethers can also be prepared by treatment on the same carbon atom of an aliphatic nature with two or three etherified hydroxy groups of formula Rg-O-, i.e. the corresponding acetal or orthoester, in the presence of an acidic substance. Thus, for example, a gem-organic sulfonic acid such as p-toluenesulfonic acid and a suitable solvent such as a lower alkanol, e.g. methanol, or a lower alkyl or lower alkylene sulfoxide, e.g. in the presence of a strong organic mineral acid, e.g. sulfuric acid, or a strong organic sulfonic acid, such as p-toluenesulfonic acid, and a suitable solvent, such as a lower alkanol, e.g. ethanol, or 66389 ether, e.g. dioxane, to give compounds of formula IA and / or IB means lower alkyl, e.g. methyl or ethyl.

The enol ethers of the formula IA and / or IB can also be obtained by treating the starting materials of the formula II with the tri-R 1 -oxonium salts of the formula (R 3) q Cr 2 (the so-called Meerwein salts) and with the di -R 9 -O-carbenium salts or di-R 3 halonium salts of the formula (R 2) 2 HalO 2, in which A 1 represents the anion of the acid and H 2 S-nalonium, in particular bromonium ion, in particular the trialkylalkyloxonium salts, and the corresponding salts of complex, fluorine-containing acids, such as the corresponding tetrafluoroborates, hexafluorophosphates, hexafluoro-antimonate or heksaklooriantimonaatit. such agents are e.g. trimethyloxonium or trietyylioksoniumheksafluoriantimonaatti, -heksaklooriantimonaatti, -hexafluorophosphate or -tetrafluoriboraat-acetate, or dimetoksikarbeniumheksafluorifosfaatti dimetyylibromonium-hexa-hexafluoroantimonate. These ethers the solvents are preferably used in an inert solvent such as ether or a halogenated hydrocarbon, e.g. diethyl ether, tetrahydrofuran. or methylene chloride, or mixtures thereof, optionally with a base such as an organic base, e.g. preferably a sterically hindered trialempalkylamine, e.g.

In the presence of N, N-diisopropyl-N-ethylamine, and with cooling, at room temperature or with little heating, e.g. about -20 to about 50 ° C, if necessary in a sealed vessel and / or under an inert gas, e.g. nitrogen atmosphere.

The enol ethers of formula IA and / or IB can also be prepared by treating the starting materials of formula II with a 3-substituted 1-R 9 -triazene compound (i.e. a compound of formula -N = N-NH-R 3), wherein the substituent on the 3-nitrogen atom means a carbon atom. an organic residue, preferably a carbocyclic aryl residue such as an optionally substituted phenyl residue, e.g. lower alkylphenyl, e.g. 4-methylphenyl. Such triazene compounds include 3-aryl-1-lower alkyl triazenes e.g. 3- (4-methylphenyl) -1-methyltriazene, 3- (4-methylphenyl) -1-ethyltriazene, 3- (i * - methylphenyl) -1-n-propyltriazene or 3- (4-methylphenyl) -1-isopropyltriazene, 3-aryl-1- (α-phenyl-lower alkyl) triazenes, e.g. 3- (4-methylphenyl) -1 benzyl-triazine. These reagents are usually used in the presence of inert solvents such as optionally halogenated hydrocarbons or ethers, e.g. benzene or mixtures of solvents, and under cooling, at room temperature or preferably at elevated temperature, e.g. about 20 to about 100 ° C, if necessary in a closed vessel. and / or in an inert gas, e.g. under a nitrogen atmosphere.

In the process according to the invention, as well as in any further steps which may be carried out, the free functional groups which are not involved in the reaction or in the compounds according to the invention can be temporarily protected in a manner known per se, e.g. free amino groups, e.g. by acylation, tritylation or silylation, free hydroxy or mercaptory groups. e.g. by etherification or esterification and the free carboxyl groups e.g. by esterification, also by silylation and after each reaction carried out in a manner known per se, if desired, if desired, separately or simultaneously. Thus, for example, amino, hydroxy or carboxyl groups in the acyl residue can be protect, e.g., acylamino, such as the aforementioned groups, e.g., 2,2,2-trichloroethoxycarbonylamino, 2-bromoethoxycarbonylamino, 4-methoxybenzyloxycarbonylamino, diphenylmethoxycarbonylamino, or tert-butyloxycarbonylaminoylaminoamino, arylaminoalkylamino; -, e.g. 2-nitrophenylthioamino, or arylsulfonylamino, e.g. 4-methylphenylsulfonylamino, or 1-lower alkoxycarbonyl-2-propylideneamino groups, respectively, acyloxy, such as those mentioned above, e.g. tert-butyloxycarbonyloxy In the form of 2,2,2-trichloroethoxycarbonyloxy or 2-bromoethoxycarbonyloxy groups or esterified carboxy groups such as those mentioned above, e.g. diphenylmethoxycarbonyl groups, and subsequently, optionally after conversion of a protecting group, e.g. in a manner known per se, e.g. in part, and always depending on the nature of the protecting group, e.g. 2,2,2-trichloro toksikarbonyyliamino- or 2-jodietoksikarbonyyliaminoryhmä can be cleaved by treatment with suitable reducing agents, such as by treatment with zinc in aqueous acetic acid in the presence of difenyylimetoksikarbonyyliamino- or tert-butyloxycarbonylamino group muurahals- or trifluoroacetic acid, aryl or aryl-alempialkyylitioaminoryhmä by treatment with a nucleophilic reagent 13 66 389 public, such as sulfurous acid, arylsulfonylamino electrolytic by reduction, the 1-lower alkoxycarbonyl-2-propylideneamino group by treatment with an aqueous mineral acid, respectively, a tert-butyloxycarbonyloxy group by treatment with formic or trifluoroacetic acid, in the presence of a difunctional acetoxyacid, or a 2,2,2-trichloroethoxycarbonyloxy group, by treatment with formic or trifluoroacetic acid or hydrogenolysis.

In the compound of the formula IA or IB obtained according to the invention, in which a protected, in particular esterified, carboxyl group of the formula -C (= O) -1 * 2 can be converted in a manner known per se, e.g. always depending on the nature of the group 1 * 2, carboxyl group. A carboxyl group esterified, e.g. with a lower alkyl residue, especially methyl or ethyl, or a benzyl residue, especially in a 2-cephem compound of formula IB, can be converted to a free carboxyl group by hydrolysis in a weakly basic medium, e.g. by treatment with an alkali metal or alkaline earth metal hydride. with an aqueous solution of sodium or potassium hydroxide, preferably at a pH of about 9-10 and optionally in the presence of a lower alkanol. The carboxyl group esterified with a suitable 2-halo-lower alkyl group can be cleaved, e.g., by treatment with a chemical reducing agent such as metal, e.g. zinc, or a reducing metal salt such as chromium-II salt, e.g. chromium-II chloride, in a conventional manner to present hydrogen in a conventional manner. together with the metal is capable of forming the resulting hydrogen, such as in the presence of an acid, preferably acetic, and formic acid, or an alcohol to which water is preferably added, the carboxyl group esterified by phenylmethyl grouping, e.g., by irradiation, preferably by ultraviolet light, e.g. -, H- or 5-position nitro-substituted benzyl residue, or by longer wavelength ultraviolet light, e.g. more than 290 my, when the phenylmethyl group means 14 66389 2-nitro-substituted benzyl residue, with an appropriately substituted methyl group such as tert-butyl a carboxyl group esterified with a nylmethyl group, e.g. by treatment with a suitable acidic substance such as formic acid or trifluoroacetic acid, optionally adding a nucleophilic compound such as phenol or anisole, an activated esterified carboxyl group, also with hydrochloric acid or aqueous sodium hydrogen carbonate or aqueous potassium phosphate buffer having a pH of about 7-9, and a hydrogenolytically cleavable esterified carboxyl group by hydrogenolysis, e.g. by treatment with hydrogen in the presence of a noble metal, e.g. palladium catalyst.

For example, the carboxyl group protected by silylation or stannylation can be liberated in a conventional manner, e.g., by treatment with water or alcohol.

The compounds of the formula IA or IB obtained can be converted into other compounds of the formula IA or IB in a manner known per se.

In the resulting compound, the amino protecting group R 1, especially the easily cleavable acyl group, can be cleaved in a manner known per se, e.g., an α-polybranched lower alkoxycarbonyl group such as tert-butyloxycarbonyl by treatment with trifluoroacetic acid, and -iodoethoxycarbonyl or phenenyloxycarbonyl group by treatment with a suitable reducing metal or similar metal compound, e.g. zinc or a chromium II compound such as chloride or acetate, preferably together with the metal or metal compound in the presence of a hydrogen-forming substance, especially an aqueous acid-forming substance.

In addition, in the resulting compound of formula IA or IB, wherein the carboxyl group of formula -C (= O) -R 2 is preferably present, e.g. by esterification, also by silylation, e.g. by reaction with a suitable organic halosilicon or halotin-IV compound such as trimethylchlorosilane or a carboxyl group protected with tri-n-butyltin chloride, an acyl group R 1 a in which any free functional groups present are optionally protected, is liberated by treatment with an imide halide-forming ane, reacting the formed imide halide with an alcohol and cleaving the carboxyl-protected organic ether, can be released and during the reaction.

Imide halide-forming substances in which the halogen orv is attached to an electrophilic central atom are, above all, acid halides, such as acid bromides and especially acid chlorides. Such substances are, in addition to acid halides of inorganic acids, in particular phosphorus-containing acids, such as phosphorus oxy, phosphorus tri- and especially phosphorus pentahalides, in particular phosphorus oxychloride, phosphorus trichloride and chlorides such as thionyl chloride, phosgene or oxalyl chloride.

The reaction with one of the abovementioned imide halide-forming agents is usually carried out with a suitable, especially organic base, preferably a tertiary amine, e.g. a tertiary aliphatic mono- or diamine, such as a trialkylalkylamine, e.g. trimethyl, triethyl or N, N-di- isopropyl-N-ethylamine, in addition to N, N, N ', N * -tetra-lower alkyl-lower alkylenediamine, e.g.

N, N, N ', N * -tetramethyl-1,5-pentylenediamine or N, N, N', N * -tetramethyl-1,6-hexylenediamine, a mono- or bicyclic mono- or diamine such as In addition to an N-substituted, e.g. N-lower alkylated alkylene, aza-alkylene or oxa-alkyleneamine, e.g. Nm-ethyl-piperidine or N-methyl-morpholine, 2.3> 4> 6,7,6- hexahydro-pyrrolo [1,2-a] pyrimidine (diazabicyclonone; DBN) or a tertiary aromatic amine such as a dialkylalkylaniline, e.g. N, N-dimethylamine or primarily a tertiary heterocyclic, mono- or bicyclic base such as quinoline or in the presence of an isoquinoline, especially pyridine, preferably using a solvent such as an optionally halogenated, e.g. chlorinated, aliphatic or aromatic hydrocarbon, e.g. methylene chloride. In this case, approximately equimolar amounts of the imide halide-forming agent and the base are used; however, the latter may also be used in excess or undercut, e.g. from about 0.2 to about 1-fold, or up to 10-fold, especially from about 3-5-fold excess.

The reaction with the imide halide-forming agent is preferably carried out under cooling, e.g. at a temperature of about -50 ° to + 10 ° C, however higher temperatures, i.e. 66389, i.e. up to 75 ° C, may be used if the stability of the starting materials and products allows a higher use of temperature.

The imide halide product, which is usually further used without isolation, is reacted according to the invention with an alcohol, preferably in the presence of one of the aforementioned bases, to give the imino ether. Suitable alcohols are, for example, aliphatic, as well as araliphatic alcohols, preferably optionally substituted, such as halogenated, e.g. chlorinated or additional hydroxy-containing parent alkanols, e.g. ethanol, propanol, or butanol, in particular methanol, in addition to 2-halo-lower alkanols, e.g.

2,2,2-trichloroethanol or 2-bromoethanol, and optionally substituted phenyl lower alkanols such as benzyl alcohol. Usually, for example, up to 100 times the excess of alcohol is used, and it is preferred to work at the same time under cooling, e.g. at a temperature of about -50 ° to + 10 ° C.

The iminoether product is most preferably cleaved without isolation.

Cleavage of the iminoether can be accomplished by treatment with a suitable hydroxy compound, preferably by hydrolysis, in addition to alcoholysis, whereby the latter, using an excess of alcohol, can be performed immediately after formation of the iminoether. In this case, water or an alcohol, in particular a lower alkanol, e.g. methanol or an aqueous mixture of an organic solvent, such as alcohol, is preferably used. In general, work is carried out in an acidic medium, e.g. at a pH of about 1 to 5 hours, which can be adjusted, if necessary, by the addition of a basic substance, such as aqueous alkali metal hydroxide, e.g. sodium or potassium hydroxide, or an acid, e.g. mineral acid, or an organic acid, such as hydrochloric acid. , sulfuric acid, phosphoric acid, boron hydrofluoric acid, trifluoroacetic acid or p-toluenesulfonic acid.

The three-step process described above for the prevention of an acyl group is most preferably carried out without isolation of imide halide and iminoethyl intermediate products, usually in the presence of an organic solvent inert to the reaction components, such as optionally halogenated hydrocarbons, e.g. methylene chloride or e.g. in a nitrogen atmosphere.

17 66389

Certain acyl residues of the acylamino group in the compounds obtainable according to the invention, such as, for example, the 5-amino-5-carboxyvaleryl residue, in which the carboxyl is optionally protected, e.g. by esterification, in particular diphenylmethyl, and / or the amino group is protected, e.g. by acylation, in particular acyl carboxylic acid such as halo-lower alkanoyl, such as dichloroacetyl or phthaloyl, may also be cleaved by treatment with a nitrosating agent such as nitrosyl chloride, a carbocyclic arenediazonium salt such as benzenediazonium chloride or a positive halogen donating agent such as halogen, With N-bromosuccinimide, preferably in a suitable solvent or solvent mixture such as formic acid together with a nitro or cyano lower alkane and adding to the reaction product a hydroxyl-containing substance such as water or a lower alkanol, e.g. methanol, or if a 5-amino-5-carboxyvaleryl residue where the amino group is substituted and the carboxyl group is protected, e.g. by esterification, it can be cleaved by standing in an inert solvent such as dioxane or a halogenated aliphatic hydrocarbon, e.g. methylene chloride and, if necessary, treating the free or monoacylated amino compound in a manner known per se.

In the compound of formula IA or IB thus obtained, in which R 1 represents hydrogen, the free amino group can be substituted by methods known per se, in particular acylation by treatment with acids such as carboxylic acids or their reactive derivatives.

If a free acid is used for the acylation, preferably with protected, optionally present functional groups, such as an optionally present amino group, suitable condensing agents, such as carbodiimides, for example Ν, Ν'-diethyl-, Ν, Ν'-dipropyl, N, N'-diisopropyl, N, N'-dicyclohexyl or N-ethyl-N'-3-dimethylaminopropylcarbodiimide, suitable carbonyl compounds, for example carbonyldiimidazole or isoxazolinium salts, e.g. N- ethyl 5-phenylisoxazolinium 3'-sulfonate and N-tert. -butyl 5-methylisoxazolinium perchlorate, or a suitable acylamino compound, e.g. 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline.

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

The amide-forming functional derivative of the acid, preferably having protected, optionally present groups, such as an optionally present amino group, is primarily an anhydride of such an acid, including, and most preferably, a mixed anhydride. Mixed anhydrides are, for example, those obtained from inorganic acids, in particular hydrohalic acids, i.e. the corresponding acid halides, e.g. chlorides or bromides, further nitric acids, i.e. the corresponding acid azides, phosphoric acid, e.g. phosphoric acid or phosphoric acid, , e.g. with sulfuric acid, or cyanobutyric acid. Other mixed anhydrides are, for example, those obtained from organic acids such as organic carboxylic acids, such as halo-substituted lower alkanecarboxylic acids substituted by halogen, such as fluorine or chlorine, e.g. pivalic or trichloroacetic acid or carbonic acid, or with an isobutyl lipoester, organic, in particular aliphatic or aromatic sulfonic acids, e.g. p-toluenesulfonic acid.

In addition, internal anhydrides such as ketenes, e.g. diketene, isocyanates (internal anhydrides of carbamic acid compounds) or internal anhydrides of carboxylic acid compounds having carboxy-substituted hydroxy or amino groups such as mandelic acid-O-carboxylic acid-O-carboxylic acid-O-carboxylic acid compounds can be used as acylating agents. siaminocyclohexanecarboxylic anhydride.

Other suitable acid derivatives which can be reacted with free amino groups are activated esters which generally contain protected, optionally present functional groups, such as esters with vinylic alcohols (i.e. enols), such as vinylogical lower alkanols, or aryl esters, such as preferably with nitro or halogen-substituted phenyl esters, e.g. pentachlorophenyl, 4-nitrophenyl or 2,4-dinitrophenyl ester, heteroaromatic esters such as benztriazole ester, or diacyliminoesters such as succinylimino or phthaliminoester.

Other acylation derivatives include, for example, substituted formimino derivatives such as substituted N, Ν-dimethylchloroformimino derivatives of acids, or N-substituted N, N-diacylamines such as N, N-diacylation aniline.

19 66389

The acylation with an acid derivative such as an anhydride and especially an acid halide can be carried out with an acid scavenger, for example an organic base such as an organic amine, e.g. a tertiary amine such as trialkylalkylamine, e.g. triethylamine, N, N-dialkylalkylaniline, e.g. -dimethylaniline, or a pyridine-type base, e.g. 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 in the presence of an oxirane, for example a lower 1,2-alkylene oxide such as ethylene oxide or propylene oxide.

The above acylation may be carried out in an aqueous or, preferably, anhydrous solvent or solvent mixture, for example a carboxylic acid amide such as N, N-dialkylalkylamide, e.g. dimethylformamide, a halogenated hydrocarbon, e.g. methylene chloride, carbon tetrachloride or chlorobenzene, ketone, ketone. in ethyl acetate, or in a nitrile, e.g. acetonitrile or mixtures thereof and, if necessary, at reduced or elevated temperature and / or in an inert gas, e.g. in a nitrogen atmosphere.

The above-mentioned N-acylation reactions can be started from compounds of the formula IA or IB in which Rg is lower alkyl or an optionally substituted α-phenyl-lower alkyl, e.g. benzyl or diphenylmethyl group and R2 is the same as above, the compounds of the formula -C (= O) -R 2 free carboxyl groups in which R 2 represents hydroxy can also be used with salts, e.g. ammonium salts, such as triethylamine, or in the form of a compound which reacts with a suitable organic phosphorus halide compound, such as a lower alkyl or lower alkoxyphosphoride halide, such as a carboxyl group protected with methylphosphorus dichloride, ethylphosphorus dibromide or methoxyphosphorus dichloride; in the obtained acylation product, the protected carboxyl group can be liberated in a manner known per se, e.g. as described above, also by hydrolysis or alcoholization.

In both reaction components, during the acylation reaction, the free functional groups can be temporarily protected in a manner known per se and, after acylation, liberated in a manner known per se, e.g. as described above.

The resulting kefem compounds of formulas IA and IB can be converted to the corresponding 1-oxides of the 3-cephem compounds of formula IA by oxidation with suitable oxidizing agents such as those mentioned below. The 1-oxides obtained from the 3-cephem compounds of the formula IA can be reduced to the corresponding 3-cephem compounds of the formula IA by reduction with suitable reducing agents, such as those mentioned below. In these reactions, care must be taken to ensure that the free functional groups are protected, if necessary, and are subsequently released if desired.

The resulting cephem compounds can be isomerized. Thus, the resulting 2-cephem compounds of formula IB or the resulting mixtures of 2- and 3-cephem compounds can be converted to the corresponding 3-cephem compounds of formula IA by isomerization of the 2-cephem compound of formula IB, or 2- and 3-cephem compounds. a mixture of compounds in which the free functional groups are optionally temporarily protected, e.g. as mentioned above. In this case, for example, 2-cephem compounds of the formula IB can be used, in which the group of the formula - (3 (= O) -1) denotes a free or protected carboxyl group, whereby the protected carboxyl group can also be formed during the reaction.

Thus, a 2-cephem compound of formula IB can be isomerized by treatment with a basic substance and the corresponding 3-cephem compound of formula IA can be isolated from an equilibrium mixture of 2- and 3-cephem compounds which may be obtained.

Suitable isomerization agents include, for example, organic nitrogen-containing bases, such as tertiary heterocyclic bases of an aromatic nature, and preferably tertiary, aliphatic, azacycloaliphatic or araliphatic bases, such as N, N, N-trimethylamine, N, N-dimethyl ethylamine, N, N, N-triethylamine or N, N-diisopropyl-N-ethylamine, N-lower alkyl azacycloalkane, e.g. N-methylpiperidine, or N-phenyl-lower alkyl-N, N-di-lower alkylamine , e.g. N-benzyl-N, N-dimethylamine, and mixtures thereof, such as a mixture of a pyridine-type base, e.g. pyridine, and N, N, N-trialempalkylamine, e.g. a mixture of pyridine and triethylamine. In addition, inorganic or organic salts of bases can also be used, in particular salts of medium-strong bases with weak acids, such as time metal or ammonium salts of lower alkanecarboxylic acids, e.g. sodium acetate, triethylammonium acetate or N-methylpiperidine emetate or .

2i 66389

The above isomerization with basic substances is carried out, for example, in the presence of a derivative of a carboxylic acid suitable for the formation of a mixed anhydride, such as in the presence of a carboxylic acid anhydride or halide, e.g. with pyridine in the presence of acetic anhydride. In this case, it is preferable to work in an anhydrous medium with or without a solvent, such as optionally halogenated, e.g. chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbon, or a solvent mixture, in which case liquid bases used as reactants can also act simultaneously as solvents. by cooling or heating, preferably at a temperature of about -30 to about 100 ° C, in an inert gas atmosphere, e.g. nitrogen gas, and / or in a sealed container.

The 3-cephem compounds of the formula IA thus obtained can be separated from the 2-cephem compounds of the formula IB which may still be present in a manner known per se, for example by adsorption and / or crystallization.

The isomerization of the 2-cephem compounds of the formula IB can also be carried out by oxidizing them in the 1-position and, if desired, separating the resulting isomeric mixture of the 1-oxides of the 3-cephem compounds of the formula IA and the 1-oxides of the corresponding 3-cephem compounds of the formula IA thus obtained. is reduced.

Suitable oxidizing agents for the oxidation of 2-cephem compounds in the 1-position are inorganic peracids having a reduction potential of at least +1.5 volts and consisting of non-metallic elements, organic peracids or mixtures of hydrogen peroxide and acids, in particular such organic carboxylic acids, 5 with a dissociation constant of 10 or more. Suitable inorganic peracids include periodic and sulfuric acid. Organic peracids are the corresponding percarboxylic and persulfonic acids used as such or prepared in situ using at least one equivalent of hydrogen peroxide and carboxylic acid. In this case, it is expedient to use a large excess of carboxylic acid when using, for example, acetic acid as a solvent. Suitable peracids are, for example, perforic acid, peracetic acid, pertrifluoroacetic acid, permaleic acid, perbenzoic acid, monoperphthalic acid or p-toluene persulfonic acid.

66389 22

The oxidation can also be carried out using hydrogen peroxide with catalytic amounts of an acid having a dissociation constant of -5 to at least 10, in which case lower concentrations, e.g. 1-2%, and less but also higher amounts of acid can be used. In this case, the effectiveness of the mixture depends primarily on the strength of the acid. Suitable mixtures are, for example, mixtures of hydrogen peroxide with acetic acid, perchloric acid or trifluoroacetic acid.

The above oxidation can be carried out in the presence of suitable catalysts. Thus, oxidation with percarboxylic acids can be catalyzed by the use of an acid having a dissociation constant of -5 to at least 10, the efficiency of the acid depending on its intensity.

Suitable acids for the catalyst are, for example, acetic acid, perchloric acid and trifluoroacetic acid. Generally, at least equimolar amounts of oxidizing agents are used, preferably a small excess of about 10% to 20%. The oxidation is performed under mild conditions, e.g. at a temperature of about -50 to about + 100 ° C, preferably at a temperature of about -10 to about + 40 ° C.

The oxidation of 2-cephem compounds to the 1-oxides of the corresponding 3-cephem compounds can also be carried out by treatment with ozone, further with organic hypohalogen compounds such as lower alkyl hypochlorites, e.g. tert-butyl hypochlorite used in inert solvents such as optionally halogenated hydrocarbons. e.g. in the presence of methylene chloride, and at a temperature of about -10 to about 30 ° C, periodate compounds such as alkali metal periodates, e.g. potassium periodate which is preferably used in an aqueous medium at a pH of about 6, and about -10 to about + 30 ° C: at i, iodobenzene dichloride used in an aqueous medium, preferably in the presence of an organic base, e.g. pyridine, and cooling, e.g. at about -20 to about 0 ° C, or any oxidizing agent suitable for converting a thio group to a sulfoxide group.

In the 1-oxides of the 3-cephem compounds of the formula IA thus obtained, in particular in those compounds in which the groups R1a and R2 have the abovementioned preferred meanings, the groups R1a and / or R2 can be interchanged within the definitions, cleaved or joined, The isomeric mixture of and β-1 oxides can be separated, e.g. by chromatography.

23 6 6389

The reduction of the 1-oxides of the 3-cephem compounds of the formula IA can be carried out in a manner known per se by treatment with a reducing agent, if necessary in the presence of an activating agent. Suitable reducing agents are: catalytically activated hydrogen using noble metal catalysts containing palladium, platinum or rhodium and optionally used with a suitable support such as carbon or barium sulphate; reducing tin, iron, copper or manganese cations used in the form of corresponding compounds or complexes of an inorganic or organic nature, e.g. tin II chloride, fluoride, acetate or formate, iron II chloride, as sulphate, oxalate or succinate, copper I chloride, benzoate or oxide, or manganese II chloride, sulphate, acetate or oxide, or as complexes, for example with ethylenediaminetetraacetic acid or nitrilotriacetic acid; reducing agents dithionite, iodine or iron II cyanide anions used in the form of corresponding inorganic or organic salts, such as alkali metal, e.g. sodium tax potassium dithionite, sodium or potassium iodine or iron II cyanide, or corresponding acids , such as in the form of hydroiodic acid; reducing trivalent inorganic or organic phosphorus compounds, such as phosphines, in addition to esters, amides and halides of phosphine, phosphonic acid or phosphoric acid, and phosphorus-sulfur compounds corresponding to these phosphoric oxygen compounds, the organic residues being preferably aliphatic, aromatic or aralic; . optionally substituted lower alkyl, phenyl or fenyylialempialkyyliryhmiä, such as e.g. trifenyylifos-olefin, tri-n-butylphosphine, difenyylifosfiinihappometyyliesteri, difenyylikloorifosfiini, fenyylidikloorifosfiini, bentseenifosfonihap-podimetyyliesteri, butaanifosfonihappometyyliesteri, phosphorous-trifenyyliesteri, fosforihapoketrimetyyliesteri, phosphorus trichloride, phosphorus tribromide, etc .; reducing halosilane compounds containing at least one hydrogen atom bonded to a silicon atom and which, in addition to halogen such as chlorine, bromine or iodine, may also contain organic residues such as aliphatic or aromatic groups, e.g. optionally substituted lower alkyl or phenyl groups such as chlorosilane, bromosilane, bromosilane, or trichlorosilane, di- or tribromosilane, diphenylchlorosilane, dimethylchlorosilane, etc .; reducing quaternary chloromethyleneiminium salts, especially chlorides or bromides, wherein the iminium group 66389 24 is substituted by one bivalent or two monovalent organic residues, such as an optionally substituted lower alkylene or lower alkyl group, such as N-chloro iminium chloride or N-chloromethylene-pyrrolidinyl chloride; and complex metal hydrides such as sodium borohydride in the presence of suitable activating agents such as cobalt II chloride or borane dichloride.

As activating agents used in combination with the abovementioned reducing agents which do not themselves have Lewis acid properties, i.e. which are used primarily in combination with dithionite, iodine or iron II cyanide and non-halogenated trivalent phosphorus reducing agents or in the catalytic reduction, in particular organic carboxylic and sulphonic acid halides, in addition to sulfur, phosphorus or silicon halides having a second or higher degree of hydrolysis constant equal to that of benzoyl chloride, e.g. phosgene, oxalyl chloride, acetic acid chloride or bromic acid, chloroacid chloride, chloride; pivaliinihappokloridi, 4-methoxy-benzoic acid chloride, 4-syaanibentsoehappokloridi, p-toluenesulfonic acid chloride, methanesulfonic acid chloride, thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide, fenyylidikloorifosfiini, bent-seenifosfonihappodikloridi, dimetyylikloorisilaani or trichloro-silane, in addition to suitable acid anhydrides such as trifluoroacetic anhydride, or cyclic sultons such as ethane sultone, 1,3-propane sultone, 1,4-butane sultone or 1,3-hexane sultone.

The reduction is preferably carried out in the presence of solvents or mixtures thereof, the choice of which depends primarily on the solubility of the starting materials and the choice of reducing agents; thus, for example, lower alkanecarboxylic acids or their esters, such as acetic acid and ethyl acetate, are used in the catalytic reduction, and e.g. acid derivatives such as lower alkane carboxylic acid esters and nitriles, e.g. acetic acid ethyl ester or acetonitrile or amides of inorganic or organic acids, e.g. sulfones, especially aliphatic sulfones, e.g. dimethyl sulfone, tetra-66389 methylene sulfone, etc. together with chemical reducing agents, these solvents preferably containing no water at all. In this case, the work is usually carried out at a temperature of about -20 to about 100 ° C, in which case, if highly reactive activators are used, the reaction can also be carried out at lower temperatures.

In the 3-cephem compounds of the formula IA thus obtained, R1a and / or R2, as described above, can be converted into other groups R1a resp. R2.

The salts of the compounds of formula IA and IB can be prepared in a manner known per se. Thus, salts of such acid-containing compounds may be formed, e.g., by treatment with metal compounds such as alkali metal salts of suitable carboxylic acids, e.g., the sodium salt of α-ethyl-caproic acid, or ammonia or a suitable organic amine, preferably using a stoichiometric excess or only a small amount. Acid addition salts of compounds of formula IA and IB containing basic groups are obtained in a conventional manner, e.g. by treatment with an acid or a suitable anion exchange reagent. Internal salts of compounds of formula IA and IB containing a salt-forming amino group and a free carboxyl group may be formed, e.g., by neutralizing salts, such as acid addition salts, to an isoelectric point, e.g., with weak bases, or by treatment with liquid ion exchangers. Salts of the 1-oxides of the salt-forming group-containing compounds of formula IA can be prepared in a similar manner.

The salts can be converted into the free compounds in a conventional manner, the metal or ammonium salts, e.g. by treatment with suitable acids, and the acid addition salts, e.g. by treatment with suitable basic substances.

The resulting mixtures of isomers can be separated into the individual isomers by methods known per se, mixtures of diastereomeric isomers, e.g. by fractional crystallization, adsorption chromatography (column or thin layer chromatography) or using another suitable separation method. The resulting racemates can be resolved into the antipodes in a conventional manner, optionally after the addition of suitable salt-forming groups, e.g., by mixing diastereomeric salts with optically active salt-forming agents, separating the mixture into diastereomeric salts, .

Such starting materials are preferably used and the reaction conditions are chosen so as to obtain compounds which are initially preferred.

In the starting materials of the formula II, the leaving group Y is preferably benzene, p-toluene, o-methoxybenzene, p-methoxybenzene or p-nitrobenzenesulfonyl, in particular benzene, p-toluene, p-methoxybenzene or p-nitrobenzenesulfonyl.

The process according to the invention is characterized in comparison with previously known processes in that it can be starting from inexpensive, readily available starting materials, in particular 1-oxides of fermentable penicillins G or V and 6-aminopenicillanic acid, the reactive groups of which can be protected in a known manner and are readily liberated after the reaction and that the intermediates required according to the invention are prepared in high yields.

The starting materials of the formula II used according to the invention can be prepared, for example, according to the following reaction formula.

66389

Ra q

NH? *} I. NH H H S_Y

% / S \ yCH ^ Step 1 Ή ».

° -N =. / \ CH- 0 = L_N

I 3 V-c - ch3 (III) 0 = C-S ^, 0 = C-I ^ / IVa: Y β -S-R ^

Step 2a and IVb: Y 2 -SO 2 -R 5

Step 2

Ra Rl \

KNH H H Step 3 £, S-Y

T — f CH '. 1 (Ί n — I J, I 3 ° = * - N ° \ ν ° '° Η n 3 (VI) oJ-R * <V> 0 = C “4

Via: Y »~ S-R ^ Va: Y * -S-R ^

Vlb; Y = -SO 2 -R 5 Vb: Y = -SO 2 -R 5

Step 4 In the compounds of formulas IVa, IVb, Va, Vb, Via, ^ VIb, Ha and Hb, R® represents benzthiazol-2-NHHHcvyl or benzoxazol-2-yl and X: Y Rg represents phenyl, p- toluyl, ^ 9¾ o-methoxyphenyl, p-methoxyphenyl NN - = _ C ~ -Or | tal P-nitrophenyl.

(II) o = c-r.a

If: Y = -S-R.

B

lib: Y = ~ SO 2 -R 5 66389 28

The starting compounds of formula III are known or can be prepared according to known methods.

Compounds of formula IVa are also known or can be prepared according to NL patent publication 72.08671.

The compounds of formulas IVb, Va, Vb, Via, VIb, Ha and Hb, in which R1a, and Y have the same meaning as in formula II, are new.

Compounds of formula IVb may be prepared from compounds of formula III by reaction with a sulphinic acid of formula HSC 4 -R 1 -R 2, or a sulphonyl cyanide of formula NfC-SC 2 -R 2. The reaction takes place in an inert solvent or solvent mixture, for example optionally halogenated, such as chlorinated, aliphatic, cycloaliphatic, or aromatic hydrocarbon, such as pentane, hexane, cyclohexane, alcohols such as benzene, toluene, methylene chloride, alpha, toluene, methylene chloride, chloroform or chlorobenzene. e.g. in methanol, ethanol, cyclohexanol or phenol, in a polyhydroxy compound, e.g. in a polyhydroxyalkane such as dihydroxy lower alkane, e.g. in ethylene or propylene glycol, in a lower ketone such as acetone or methyl ethyl ketone, or dimethylacetamide, a lower dialkyl sulfoxide such as dimethyl sulfoxide and the like, or mixtures thereof.

The reaction takes place at room temperature or, preferably, at an elevated temperature, e.g. at the boiling point of the solvent used, if desired under an inert gas atmosphere such as nitrogen gas.

The reaction with the sulfonyl cyanide of the formula N = C-SO 2 -R 5 can be accelerated by the addition of halogen anion-forming compounds. Suitable halogen anion-forming compounds are, for example, quaternary ammonium halides, such as, for example, chlorides, and bromides, such as those optionally substituted on lower alkyl groups, e.g., aryl, such as phenyl, mono- or polysubstituted tetra-lower alkylammonium halides, such as tetra -triethyl 29 66389 ammonium chloride or bromide. The halogen anion-forming compounds are added in amounts of about 1 to about 50 mol%, preferably about 2 to about 5 mol%.

Compounds of formula IVb may also be prepared by reacting a compound of formula IVa with a heavy metal sulphinate of formula M (SC> 2-R5) n, wherein M represents a heavy metal cation and n represents the valence of this cation. Suitable heavy metal sulfinates are, in particular, those in which the reaction medium used has a higher solubility input than the heavy metal compounds of the formula Mn + (- S-R4) n formed in the reaction. Suitable heavy metal cations Mn are in particular those which form particularly sparingly soluble sulphides. Such are, for example, monovalent or divalent cations of copper, mercury, silver and tin, with copper and silver cations being preferred.

The heavy metal sulfinate can be used either as such or formed in situ during the reaction, for example from a sulfinic acid of the formula HSO 4 -R 9, or from its soluble gut, e.g.

an alkali metal such as a sodium salt, and a heavy metal salt having a solubility yield greater than that of a heavy metal sulfinate, for example a heavy metal nitrate, acetate or sulphate, e.g. silver nitrate, mercury silver II diacetate or copper II sulphate or also soluble , such as stannous chloride dihydrate.

The reaction of a compound of formula IVa with a heavy metal sulfinate of formula Mn + (SO 2 -R 5) n may take place in an inert organic solvent, water or 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, cycloaliphatic or aromatic alcohols, such as lower alkanols, e.g. lower alkanols, e.g. polyhydroxyalkanes, e.g. dihydroxy-lower alkanes, such as ethylene or propylene glycol, carboxylic acid esters, e.g., lower alkanecarboxylic acid alkyl esters, e.g. dimethoxyethane, lower carboxylic acid amides such as dimethylformamide, lower alkyl nitriles such as acetonitrile or lower sulfoxides such as dimethyl sulfoxide. In water, or in particular in a mixture of water and one of the aforementioned solvents, including emulsions, the reaction usually takes place considerably faster than in an organic solvent alone.

The reaction temperature is usually room temperature, but can be lowered to slow down the reaction or raised to accelerate the reaction, up to about the boiling point of the solvent used, whereby normal or elevated pressure can be worked.

In the obtained compound of formula IV, the group R 1a A a A 1 or R 2 can be converted into another group R 1 or R 2, in which case the corresponding reactions mentioned for the conversion of these groups in the compounds of formula IA and / or IB can be used.

In steps 2 and 3 or 2a, the compound of formula IV can be converted to the compound of formula VI by oxidative decomposition of the methylene group to an oxo group.

Oxidative cleavage of the methylene group in compounds of formula IV to form an oxo group can be accomplished by treatment with ozone to form an ozone compound of formula V. In this case, ozone is usually used in the presence of a solvent such as an alcohol, e.g. a lower alkanol such as methanol or ethanol, a ketone, e.g. a lower alkano such as acetone, optionally halogenated aliphatic, cycloaliphatic or aromatic hydrocarbon, e.g. , also in the presence of an aqueous mixture, and by cooling or slightly heating, e.g. at a temperature of about -90 to 0 ° C.

Optionally, the intermediate ozonide of formula Va can be converted to compounds of formula IVb without isolation by reaction with Mn + (a heavy metal sulfinate of formula IV) in a manner similar to the conversion of compounds of formula IVa to compounds of formula IVb.

31 66389

The ozonide of formula V may be reductively cleaved in step 3 to give the compound of formula VI, using catalytically activated hydrogen, e.g. hydrogen in the presence of a heavy metal hydrogenation catalyst such as nickel, further palladium catalyst, preferably with a suitable support such as calcium or chemical scavengers such as reducing heavy metals, as well as heavy metal teas or amalgams, e.g. zinc, in the presence of a hydrogen donating agent such as an acid, e.g. acetic acid, or an alcohol, e.g. lower alkanol, e.g. in the presence of a donating agent such as an acid, e.g. acetic acid, or reducing sulfide compounds such as a dialkylalkyl sulfide, e.g. dimethyl sulfide, a reducing organophosphorus compound such as phosphine, which may contain optionally substituted aliphatic or aromatic hydrocarbons. residues as substituents, such as trialempkylphosphines, e.g. tri-n-butylphosphine, or triarylphosphines, e.g. triphenylphosphine, further phosphites containing optionally substituted hydrocarbon residues in the form of substituents, e.g. phosphoric acid triamides containing optionally substituted aliphatic hydrocarbon residues as substituents, such as hexa-lower alkyl-phosphoric acid triamide, e.g. hexamethylphosphoric acid triamide, the latter preferably in the form of a methanol adduct, or tetrasyanoethane. Usually, cleavage of uninsulated ozonide normally occurs under the conditions used to prepare it, i.e., in the presence of a suitable solvent or solvent mixture, both under cooling and with low heating.

The enol compounds of formula VI may also be in tautomeric keto form.

The enol compound of formula Via can be reacted with the formula

With Mn + (SO-Rc) heavy metal sulfinate in the same manner as mentioned above for the conversion of compounds of formula IVa to compounds of formulas IVb, to compounds of formula VIb.

32 66389

The resulting compound of formula VI may be grouped or converted to another group of formula or R 1, wherein the corresponding reactions used to convert these groups in compounds of formulas IA or IB may be used.

In the fourth step, the resulting enol compound of formula is converted by etherification to a compound of formula II.

For the preparation of lower alkyl and optionally substituted α-phenyl-lower alkyl enol ethers of the formula II, for example, the corresponding diazo compound is used as the etherification reagent, e.g. These reagents are used in a suitable inert solvent such as an aliphatic, cycloaliphatic or aromatic hydrocarbon such as hexane, cyclohexane, benzene or a halogenated aliphatic hydrocarbon of toluene, e.g. methylene chloride, lower butanol, e.g. methanol or ethanol, e.g. , such as a lower alkyl ether, e.g. diethyl ether, or a cyclic ether, e.g. tetrahydrofuran or dioxane, or a mixture of solvents, and always depending on the diazo reagent while cooling, at room temperature or with low heating, further, if necessary, in a sealed vessel and / or inert gas, e.g. -rissä.

In addition, lower alkyl and optionally substituted α-phenyl lower alkyl enol ethers of formula II can be prepared by treating an enol compound of formula VI with a reactive ester of the corresponding alcohol of formula R 30 -OH. Suitable esters are preferably those obtained with strong inorganic or organic acids, such as mineral acids, e.g. hydrohalic acids, such as hydrochloric, hydrobromic or hydroiodic acid, further sulfuric acid or halosulphuric acids, e.g. fluorosulphuric acid, or strong organic sulphonic acids, optionally halogenic acids. such as fluoro-substituted precursal sulfonic acids, or aromatic sulfonic acids such as e.g. optionally, e.g. lower alkyl such as methyl, halogen such as bromine and / or nitro substituted benzenesulfonic acids, e.g. methanesulfonic, trifluoromethanesulfonic or p-sulfoniculfonic These reagents, in particular 66389 lower alkyl alkyl sulphates, such as dimethyl sulphate, further lower alkyl fluorosulphates, e.g. methyl fluorosulphate, or optionally halogen-substituted methanesulphonic acid lower alkyl esters, e.g. benzyl or diphenylmethyl halides, such as chlorides or bromides, are commonly used in a solvent such as an optionally halogenated, such as chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbon, e.g. methylene chloride, ether, such as dioxane or tetrahydrofuran, or in the presence of a solvent mixture. In this case, suitable condensing agents, such as alkali metal carbonates, e.g. sodium or potassium carbonate or bicarbonate (usually in combination with sulphate), or inorganic bases, such as normally sterically hindered tri-lower alkylamines, e.g. N, N-diisopropyl, are preferably used. ethylamine (preferably in combination with lower alkyl halosulphates and optionally halogen-substituted methanesulphonic acid lower alkyl esters) while working under cooling, at room temperature or heating, e.g. at about -20 to 50 ° C, and, if necessary, in a sealed vessel and / or inert gas atmosphere, and / or inert gas. .

By phase transfer catalysis (p. E.V. Dehmlow, Angewandte Chemie 5/1971 +, p. 187), the etherification reaction can be considerably accelerated. As phase transfer catalysts, quaternary phosphonium salts and in particular quaternary ammonium salts, such as optionally substituted tetraalkylammonium halides, e.g. tetra-butylammonium chloride, bromide or iodide, or also benzyltriethylammonium chloride can be used as equivalents or catalysts. As the organic phase, any water-immiscible solvent can be used, for example optionally halogenated, such as chlorinated aliphatic, cycloaliphatic or aromatic hydrocarbons, such as tri- or tetrachlorethylene, di-, tri- or tetrachloroethane, chlorobenzene, especially carbon tetrachloride, especially carbon tetrachloride. Suitable alkali metal carbonates or bicarbonates as condensing agents, e.g. potassium or sodium carbonate or bicarbonate, and alkali metal phosphates, e.g. potassium phosphate and alkali metal hydroxides, e.g. sodium hydroxide, can be added to the is about 7-8.5.

Lower alkyl enol ethers of formula II may also be prepared by treating an enol compound of formula VI on the same carbon atom of an aliphatic nature with a compound containing two or three hydroxy groups of formula R 30 -O-etherified, i.e. in the presence of the corresponding acetal or orthoester. Thus, for example, gem-lower alkoxy-lower alkanes such as 2,2-dimethoxypropane, a strong organic sulfonic acid such as p-toluenesulfonic acid, and a suitable solvent such as lower alkanol, e.g. methanol or a lower alkyl or lower alkylene sulfoxide, e.g. dimethyl sulfoxide, e.g. in the presence of an orthomole formic acid trialempkyl alkyl ester, e.g., orthomuric acid triethyl ester, and a strong mineral acid, e.g. sulfuric acid or a strong organic sulfonic acid such as p-toluenesulfonic acid and a suitable solvent such as a lower alkanol, e.g. ethanol, e.g. ethanol or ether. , and thus to obtain compounds of formula II in which R 30 represents lower alkyl, e.g. methyl versus ethyl.

The lower alkyl enol ethers of the formula II can also be obtained by treating the enol compounds of the formula VI with trialemalkyloxonium salts of the formula (R30) 3O2P (so-called Meerwein salts) and with di-RgO-carbonium salts of the formula (R3KCH2A®) or di-R-halonium compounds of formula (R ~ 0) 9Hal 2.

Θ ö 1 J

salts wherein A represents an acid anion and Hal represents a halonium, especially bromonium ion and R 30 lower alkyl. Suitable are, in particular, trialemium alkyloxonium salts, as well as dialempialkoxycarbenium or dialempkylalkonium salts, in particular the corresponding salts with complex, fluorine-containing acids, such as the corresponding tetrafluoroborates, hexafluorophosphates, hexafluorantimonate teas or hexachloranthimones. Such reagents are, for example, trimethyloxonium or triethyloxonium hexafluoroantimonate, hexachloroantimonate, hexafluorophosphate or tetrafluoroborate, dimethoxycarbenium hexafluorophosphate or dimethyl bromonium hexafluorantimonate. These etherifying agents are preferably used in an inert solvent such as ether or a halogenated hydrocarbon, e.g. in diethyl ether, tetrahydrofuran or methylene chloride, or mixtures thereof, if necessary in the presence of a base such as an organic base, e.g. preferably a sterically hindered trialempalkylamine, e.g. N, N-diisopropyl-N-ethylamine and cooling, at room temperature or with low heating, e.g. about -20- to about 50 ° C, if necessary in a sealed vessel and / or under an inert gas, e.g. nitrogen atmosphere.

A compound of formula IIa wherein R30 represents lower alkyl or a hydroxy protecting group may be converted to compounds of formula IVb by reaction with a heavy metal sulfinate of formula Mn + (- SO2 - Rr) 2 5n in a manner similar to the conversion of compounds of formula IVa to compounds of formula Hb.

In the obtained compound of formula II, the group R 1, R 2 or R 3 can be converted into another group R 1, R 2 or R 3, in which case the corresponding reactions mentioned for the conversion of these groups in the compounds of formulas IA or IV can be used.

The pharmacologically acceptable compounds according to the invention can be used, for example, to form pharmaceutical preparations containing an effective amount of the active ingredient together or in admixture with inorganic or organic, solid or liquid, pharmaceutically acceptable carriers suitable for enteral or parenteral administration.

Thus tablets or gelatin capsules containing the active ingredient in combination with diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine are used; and lubricants, e.g. diatomaceous earth, talc, stearic acid or its salts, such as magnesium ** or calcium stearate, and / or polyethylene glycol; tablets also contain binders, e.g. magnesium aluminum silicate, starches such as corn, wheat, rice or arrowroot starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone and, if desired, disintegrants, disintegrants if desired. such as sodium alginate, and / or effervescent mixtures, or adsorbents, colorants, flavors and sweeteners. The novel pharmacologically active 66389 compounds can also be used in the form of injectables, e.g., intravenous preparations or infusion solutions. These solutions are preferably isotonic aqueous solutions or suspensions, which can be prepared before use, e.g. from lyophilized preparations containing the active ingredient as such or in combination with a carrier, e.g. mannitol. The pharmaceutical preparations can be sterilized and / or contain auxiliaries, e.g. preservatives, stabilizers, wetting and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers. These pharmaceutical preparations may, if desired, contain other pharmacologically valuable substances and are prepared in a manner known per se, e.g. using conventional mixing, granulating, granulating, solvent or lyophilizing methods, and contain from about 0.1 to 100%, in particular about 1 - about 50%, and lyophilisates always 100% of active ingredient, In this specification, "lower" organic residues, unless otherwise specified, contain not more than 7, preferably not more than 4, carbon atoms; acyl residues contain up to 20, preferably up to 12 and primarily up to 7 carbon atoms.

The following examples illustrate the invention; temperatures are given in degrees Celsius. In the examples, said cephem compounds have the R configuration in the 6- and 7-positions and said azetidinone compounds in the 3- and 4-positions. In the examples, the carboxylic acid is referred to as carboxylic acid.

Example 1:

To a solution of 133 mg (0.2 mmol) of a mixture of isomers containing 2- (4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoacetidin-1-yl) -3-methoxy-crotonic acid p-nitrobenzyl ester and the corresponding isocrotonic acid ester in a ratio of about 4: 1 in 4 ml of dry tetrahydrofuran are added within 5 minutes. a solution of 60 μΐ (2 equivalents) of 1,5-diazabicyclo (5.4.o) undec-5-ene in 1 ml in tetrahydrofuran. Allow to stand at room temperature for 40 minutes, then dilute with 20 ml of benzene, cool in an ice bath and stir for 10 minutes with 10 ml of 10% citric acid solution. The organic layer is separated, washed successively with saturated brine, 10% sodium bicarbonate solution and brine. The solution, dried over magnesium sulphate, is concentrated in vacuo and the residual yellow oil is purified by chromatography filtration on 4 g of acid-washed silica gel (2 kg of silica gel are stirred 3 times with 2 liters of concentrated hydrochloric acid each time for 10 minutes, decanted, decanted, decanted). , washed with methanol and activated for 60 hours at 120 °) using benzene / ethyl acetate 5: 1 as eluent. The fractions containing the isomer mixture are combined and concentrated in vacuo. A semi-solid mixture of isomers consisting of 7β-phenoxyacetamido-3-methoxy-cef-3-em-4-carboxylic acid p-nitrobenzyl and 7β-phenoxyacetamido-3-methoxy-cef-2-em-4-carboxylic acid is obtained. p-nitrobenzyl ester in a ratio of about 1: 3, which can be separated into both isomers on a VJoelm silica gel (activity III) with benzene / ethyl acetate 5: 1. The faster mobile 76-phenoxyacetamido-3-methoxy-cef-2-em-4-carboxylic acid p-nitrobenzyl ester is recrystallized from methylene chloride ether and has a melting point of 129-131.5 °. The slower mobile 7β-phenoxyacetamido The melting point of 3-methoxy-cef-3-em-4-carboxylic acid p-nitrobenzyl ester is 140.5-142 ° (from methylene chloride / ether).

38 66389 The starting materials can be prepared as follows: a) A solution of 36.6 g (0.1 mmol) of 6-phenoxyacetamido-penicillanic acid-113-oxide, 11.1 ml (0.11 mol) of triethylamine and 23.8 g (0.11 mol) of p-nitrobenzyl bromide in 200 ml of dimethylformamide, stirred for 4 hours at room temperature under nitrogen gas. The reaction solution is then added to 1.5 liters of ice water, the precipitate is filtered off, dried and recrystallized twice from ethyl acetate / methylene chloride. Colorless crystalline 6-phenoxyacetamidopenicillanic acid p-nitrobenzyl ester-1β-oxide melts at 179-180 °, b) A solution of 5.01 g (10 mmol) of 6-phenoxyacetamido-penicillanic acid p-nitrobenzyl ester-1β-oxide and 1.67 g (10 mmol) of 2-mercaptobenzthiazole in 110 ml of dry toluene are refluxed for 4 hours under reflux under a nitrogen atmosphere. The solution is concentrated to about 25 ml by distillation and diluted with about 100 ml of ether. The separated product is recrystallized from methylene chloride / ether to give 2- (4- (benzthiazol-2-ylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methylenebutyric acid p-nitrobenzyl ester, having a melting point of 138-141 °.

c) To a solution of 3.25 g (5.0 mmol) of 2- (4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methylenebutyric acid p-nitrobenzyl ester in 200 ml of acetone / water 9: 1 (v / v), 1.06 g of finely ground silver nitrate are added. Immediately thereafter, a solution of 890 mg (5 mmol) of sodium p-toluenesulfinate in 100 ml of the same solvent mixture (within 10 minutes) is added. In this case, a pale yellow precipitate immediately forms. After stirring for 1 hour at room temperature, filter by adding Celite. The filtrate is diluted with water and extracted twice with ether. The combined ether extracts are dried over sodium sulfate and concentrated to give a pale yellow solid 2- (4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methylenebutyric acid p-nitrobenzyl ester. Thin layer chromatogram on silica gel (toluene / ethyl acetate 2: 1): Rf value = 0.24; IR spectrum (s): characteristic bands: 3.90, 5.56, 5.70, 5.87, 6.23, 6.53, 6.66, 7.40, 7.50, 8.10 , 8.72, 9.25, 10.95μ.

The product can be used in the next reaction without further purification.

66389

The same compound can also be prepared by the following methods.

ci) To a solution of 3.25 g (5.0 mmol) of 2- (4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methylenobutyric acid p-nitrobenzyl ester in 200 ml of acetone / water 9: 1 (v / v), 1.58 g (1.2 equivalents) of silver p-toluenesulfinate are added in portions over 10 minutes. The suspension is stirred for one hour at room temperature, stirred and further treated as described in Example 1c). 2- (4- (p-Toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methylenebutyric acid p-nitrobenzyl ester) is obtained in quantitative yield.

Silver p-toluenesulfinate is obtained as a colorless precipitate by combining aqueous solutions containing equimolar amounts of silver nitrate and sodium p-toluenesulfinate. The product is dried under vacuum for 24 hours.

cii) 2- (4- (p-Toluenesulfonylthio) -3-phenoxyacetamido-2-oxo-azetidin-1-yl) -3-methylenebutyric acid p-nitrobenzyl ester can also be prepared from Example 1ci) from 3.25 g, respectively 2- (4- (Benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methylenobutyric acid p-nitrobenzyl ester and 1.87 g (2 equivalents) of copper II-di- p-toluenesulfinate in quantitative yield.

Copper II-di-p-toluenesulfinate is obtained by reacting copper sulfinate with sodium p-toluenesulfinate (2 equivalents) in water. After filtration, the salt is dried under vacuum for 12 hours at 60 °.

ciii) 2- (4- (p-Toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methylenebutyric acid p-nitrobenzyl ester can also be prepared from Example 1ci) from 130 mg of 2- ( 4-Benzthiazol-2-yl-dithio) -3-phenoxy-acetamido-2-oxo-azetidin-1-yl) -3-methylene-butyric acid p-nitro-benzyl ester and 85 mg (2 equivalents) of stannous di-p-toluenesulfinate.

Stannous di-p-toluenesulfinate is obtained by reacting stannous chloride (2H2O) with 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- (4- (p-Toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methylenobutyric acid p-nitrobenzyl ester "O 66389 can also be prepared from Example 1ci) from 130 mg of 2- ( * 4- (Benzothiazol-2-yl-dithio) -3-phenoxy-acetamido-2-oxo-azetidin-1-yl) -3-methyl-butyric acid p-nitro-benzyl ester and 102 mg (2 equivalents) of mercury-II-di-p -tolueenisulfinaattia.

Mercury II-di-p-toluenesulfinate is obtained by reacting mercury-p-toluenesulphate with sodium p-toluenesulfinate in water. After filtration and washing with water, the salt is dried under vacuum for about 12 hours at 50-60 °.

(cv) A solution of 517 mg (1.02 mmol) of 6-phenoxyacetamido-penicillanic acid p-p-nitrobenzyl ester 1-oxide and 187 mg (1.2 mmol) of p-toluenesulphonic acid in 10 ml of 1,2-dimethoxyethane. (or dioxane) is heated for 4.5 hours using 3.5 g of molecular sieve 3A and under reflux under a nitrogen atmosphere, followed by the addition of 308 mg (1.98 mmol) of p-toluenesulphonic acid dissolved in 2 ml of 1,2-dimethoxyethane in five portions. Every 45 minutes. After 4.5 hours, the reaction mixture is poured into 100 ml of 5% 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 sulfate and evaporated. The residue is chromatographed on silica gel thick plates with toluene / ethyl acetate 2: 1 to give 2- (4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methylenobutyric acid p-nitrobenzyl ester.

(cvi) A mixture of 250 mg (0.5 mmol) of 6-phenoxyacetamidopenicillanic acid p-nitrobenzyl ester 1β-oxide, 110 mg (0.61 mmol) of p-toluenesulfonyl cyanide and 5 mg (0.022 mmol) of benzyl tri- ethyl ammonium chloride in 2 ml of dry, peroxide-free dioxane, is stirred under argon for 4.5 hours at 110 °. The solvent is evaporated off under vacuum and the residual yellow oil is chromatographed on acid-washed silica gel. Elution with 30% ethyl acetate in toluene gives 2- (4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methylbutyric acid p-nitrobenzyl ester.

cvii) A mixture of 110 mg (0.61 mmol) of p-toluenesulfonyl cyanide and 4.5 mg (0.021 mmol) of tetraethylammonium bromide in 1 ml of pure dioxane is stirred at 110 ° under an argon atmosphere for 30 minutes. A suspension of 250 mg (0.5 mmol) of 6-phenoxyacetamidopenicillanic acid p-nitrobenzyl ester 1β-oxide in 1 ml of dioxane is then added and the remaining solution is stirred for 4 hours at 110 ° under argon. The solvent is removed in vacuo, the crude product is dissolved in ethyl acetate, washed with water and saturated aqueous brine. The organic phase is dried over magnesium sulfate and the solvent is removed in vacuo to give crude 2- (4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methylbutyric acid p-nitrobenzyl ester.

d) To a solution of 1.92 g (3.0 mmol) of 2- (4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methylenebutyric acid p- nitrobenzyl ester in 30 ml of dry methyl acetate, 1.1 equivalents of ozone are introduced at -78 ° within 33 minutes. Immediately thereafter, excess ozone is removed with a stream of nitrogen (15 minutes at -78 °). 2.2 ml of dimethyl sulfide (10 equivalents) are added and the solution is warmed to room temperature. After standing for 5 hours, the solvent is distilled off in vacuo and the remaining colorless oil is dissolved in 100 ml of benzene. The benzene solution is washed 3 times with 50 ml portions of saturated brine, dried over magnesium sulfate and evaporated to dryness in vacuo. After recrystallization of the residue from toluene, 2- (4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoacetidin-1-yl) -3-hydroxy-crotonic acid p-nitrobenzyl ester, m.p. 159-160 °.

di) The crude 2- (4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methylenebutyric acid p-nitrobenzyl ester obtained according to Example 1cvii) is dissolved in 20 ml of methyl acetate and ozonate at -70 ° until the thin layer chromatogram shows that no starting material is present. A stream of nitrogen is then passed through the solution and this is heated to 0-5 °. A solution of 300 mg of sodium bisulphite in 5 ml of water is added and stirred for about 5 minutes until no ozone is detected on the potassium iodide-starch paper.

The mixture is diluted with ethyl acetate, the aqueous phase is separated and the organic phase is washed with water, dried over magnesium sulphate and the solvent is removed in vacuo. 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 is evaporated in vacuo. The residue is recrystallized from methanol to give 2- (4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-hydroxycrotonic acid p-nitrobenzyl ester, m.p. 159-160 °.

e) A solution of 1.93 g of 2- (4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-oxobutyric acid p-nitro-42,6389 benzyl ester (3.0 mmol) ) In 15 ml of dry chloroform, cooled to 0 ° and within 10 minutes add 6 ml of ethereal diazomethane solution (0.75 molar, corresponding to 1.5 equivalents). The mixture is stirred for 2 hours at 0 °, the excess diazomethane is removed with a stream of nitrogen and the solvent is removed in vacuo. The crude product is purified by filtration on Woelm silica gel (activity III, 40-fold amount) with benzene / ethyl acetate 5: 1. The colorless oil obtained after distilling off the solvent crystallizes on standing. After recrystallization from methylene chloride / ether, a mixture of isomers is obtained consisting of 2- (4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxy-crotonic acid p-nitrobenzyl ester and the corresponding isocrotonic acid ester in a ratio of about 4: 1. The melting point of the mixture is 155-156.5 °.

Example 2:

A solution of 279 mg of 2- (4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-hydroxycrotonic acid diphenylmethyl ester (0.428 mmol) in 4 ml of chloroform and 1 ml of hexamethyl -disilazane, heated at reflux for 1 hour, evaporated in vacuo and the oily residue dried under high vacuum for one hour. The silylated crude product consists of 2- (4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-trimethylsilyloxy-crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester.

The crude product obtained is dissolved in 3 ml of dry chloroform, cooled to 0 [deg.] C. and 0.069 ml (0.47 mmol) of 1,5-diazabicyclo (5.4.4) undec-5-ene are added with stirring under a nitrogen atmosphere. After a reaction time of one hour, 0.3 ml of acetic acid is added to the solution and diluted with chloroform. The chloroform solution is washed with dilute sulfuric acid, water and dilute sodium bicarbonate solution. The aqueous phase is extracted with chloroform, the combined organic phases are dried over sodium sulfate and evaporated in vacuo. Crude 7β-phenoxyacetamido-3-hydroxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester is obtained. Rf value 0.13 (silica gel; toluene / ethyl acetate 3: 1).

The crude product obtained is dissolved in methanol and an excess of ethereal diazomethane solution is added at 0 °. After a reaction time of 5 minutes, the solution is completely evaporated and the oily residue is chromatographed on silica gel thick-layer plates (toluene / ethyl acetate 3: 1). The silica gel of the band with an Rf value of 0.19 is extracted with 1.3 66389 ethyl acetate to give 78-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester; melting point 120 ° (from ether), IR spectrum (CH / Clg); 3310, 1775, 1700, 1690, 1600 cm-1.

The starting material is prepared as follows: a) 100 g (27.3 mmol) of 6-phenoxyacetamido-penicillanic acid 1β-oxide, 500 ml of dioxane and 58.4 g (30 mmol) of diphenylmethyldiazomethane are obtained for about 2 hours. after 6-phenoxyacetamidopenicillanic acid diphenylmethyl ester-1β-oxide; mp 144-146 ° (ethyl acetate / petroleum ether).

b) 292 g (55 mmol) of 6-phenoxyacetamido-penicillanic acid diphenylmethyl ester-1β-oxide and 99 g (59.5 mmol) of 2-mercaptobenzthiazole 2- (j + - (benzthiazole) 2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylene-butyric acid diphenylmethyl ester, mp 140-141 ° (from toluene / ether).

c) According to Example 1c) 10 g (14.7 mmol) of 2- (4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methylbutyric acid diphenylmethyl ester are obtained In 50 ml of ethyl acetate, 4.92 g (24.98 mmol) of finely ground silver p-toluenesulfinate with stirring for 7 hours at room temperature with 2- (4- (p-toluenesulfonylthio) -S-phenoxyacetamido-4-oxoazetidine). ni-1-yl) -3-methylenebutyric acid diphenylmethyl ester, Rf value = 0.28 (silica gel, toluene / ethyl acetate 3: 1); IR spectra (CHCl 3): 1782, 1740, 1695, 1340, 1150 cm -1.

2- (4- (p-Toluenesulfonylthio) -3-phenoxyacetamido-2-oxo-azetidin-1-yl) -3-methylbutyric acid diphenylmethyl ester can also be prepared as follows: ci) A suspension of 106.5 g of 6 -phenoxyacetamido-penicillanic acid diphenylmethyl ester-1β-oxide and 33.8 g of 2-mercaptobenzthiazole in 900 ml of toluene and 9 ml of glacial acetic acid are boiled under a nitrogen atmosphere for 2 hours using a water extractor to give about 4.5 ml of water. The solution is cooled to room temperature, a total of 85.5 g of silver p-toluenesulfinate is added portionwise over one hour and then further stirred at 22 °. The mixture is filtered through Hyflo and the filtrate is washed twice with saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate, concentrated in vacuo to about 1 liter, decolorized with 30 g of Norit and evaporated. The resulting yellow foam is recrystallized from methylene chloride / diethyl ether. Melting point 79-82 °, Rf value = 0.55 (silica gel; toluene / ethyl acetate 3: 1). Additional compound is obtained from the mother liquors by crystallization from methylene chloride / diethyl ether.

d) According to Example 1d), 10.8 g (16.2 mmol) of 2-O- (p-toluenesulfonylthio) -S-phenoxyacetamido-4-oxoazetidin-1-yl] -3-methylenobutyric acid diphenylmethyl ester are obtained in 1 liter of ethylene chloride and 1.1 equivalents of ozone 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-hydroxy-crotonic acid diphenylmethyl ester; melting point 142-143 ° (from ether / pentane).

Ozonation can also be performed at 0 °.

To a solution of 9.23 g (13.8 mmol) of 2- (4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methylenebutyric acid diphenylmethyl ester 960 in ml of methylene chloride, 15.2 mmol of ozone are passed in at 0 ° within 19 minutes. To the clear reaction solution is added 10 ml of dimethyl sulfide and stirred for 20 minutes at 5 °. Concentrate in a water-jet vacuum and dry the residue under high vacuum to give a pale yellow foam which is crystallized from methylene chloride / hexane; The resulting 2- (4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-hydroxycrotonic acid diphenylmethyl ester has a melting point of 1334-138 °. Thin layer chromatogram: Rf value 0.45 (silica gel; toluene / ethyl acetate 3: 1).

The same compound can also be prepared according to the following methods.

di) A solution of 684 mg (1 mmol) of 2- (4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-hydroxy-crotonic acid diphenylmethyl ester in 20 ml of acetone / water 9: 1 (v / v), is stirred with 341 mg (1.3 mmol) of silver p-toluenesulfinate for 60 minutes at room temperature. To the yellow reaction mixture is added 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 4: 1. The resulting 2- (4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-hydroxycrotonic acid diphenylmethyl ester is recrystallized from ether / pentane and melts at 142-143 °.

(dii) A solution of 72.9 mg (0.1 mmol) of crude ozonide obtained by ozonation of 68.1 mg (0.1 mmol) of 2- (4- (benzthiazole-6 63 8 9 2-ylthio) - 3-Phenoxyacetamido-2-oxo-azetidin-1-yl) -3-methyl-butyric acid diphenylmethyl ester in ethyl acetate and evaporation of the solvent in 2 ml of acetone / water 9: 1 (v / v) is stirred with 35 mg (v / v). 1.3 equivalents) of silver p-toluenesulfate for 1 hour at room temperature. The reaction mixture is diluted with 3 ml of acetone and filtered. 0.2 ml of dimethyl sulfide are added to the filtrate and stirred for two hours at room temperature (until a negative iodine-starch reaction). After removal of the solvent in vacuo, the residue is chromatographed on 3 g of acid-washed silica gel with toluene / ethyl acetate 4: 1. The resulting 2- (4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-hydroxycrotonic acid diphenylmethyl ester is recrystallized from ether / pentane and melts at 142-143 °. Recrystallization again from methylene chloride / diethyl ether gives a melting point of 144-145 ° (corrected): (a) -68 ° + 1 ° (c = 1; chloroform); thin layer chromatogram: Rf value = 0.81 (silica gel; methylene chloride / ethyl acetate 8: 2); UV spectrum (ethyl alcohol): = 261 nm (ε = 14 400); IR spectrum (nujol): characteristic bands: 3.00; 5.56; 5.93; 5.98; 6.06; 6, 19, 6.25, 6.54, 6.70, 6.82, 7.02, 7.47, 8.03, 8.76, 9.53, 10.23, 10.60, 12.30; 13.26, 14.30 μ.

Example 3:

To a solution of 301 mg (0.462 mmol) of 2- (4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-hydroxycrotonic acid diphenylmethyl ester in 3 mL of 1 , 2-dimethoxyethane, add 0.12 ml of bis-trimethylsilylacetamide (0.508 mmol) under a nitrogen atmosphere and stir for one hour at room temperature. The solution is completely evaporated and the oily residue is dried under high vacuum for 1 hour. The silylated crude product is dissolved in 3 ml of dried 1,2-dimethoxyethane and, after cooling to 0 [deg.] C., 0.075 ml (0.508 mmol) of 1,5-diazabicyclo (5.4.4) undec-5-ene are added. After a reaction time of 6 hours at 0 ° and under a nitrogen atmosphere, 0.3 ml of acetic acid are added and the mixture is diluted with methylene chloride. The methylene chloride solution is washed successively with dilute sulfuric acid, water and dilute bicarbonate solution. The aqueous phases are extracted with methylene chloride, the combined organic phases are dried over sodium sulfate, evaporated in vacuo and dried under high vacuum. Crude 7 8-phenyacetamido-3-hydroxy-cef-3-em-4-carboxylic acid diphenylmethyl ester is obtained. To a solution of the crude product in chloroform at 0 ° is added an excess of ethereal diazomethane solution and allowed to stand for 5 minutes at 0 °.

It is then completely evaporated and the residue is chromatographed on silica gel as in Example 2. 73-Phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester is obtained; 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, 16Θ -1 -1 cm

Example 4:

To a solution of 100 mg (0.15 mmol) of a mixture of isomers consisting of 2- (4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxy-crotonic acid diphenylmethyl ester and from the corresponding isocrotonic acid ester in 4 ml of dry 1,2-dimethoxyethane, 0.045 ml (0.3 mmol) of 1,5-diazabicyclo (5.4.4) undec-5-ene are added under stirring under a nitrogen atmosphere. The solution is stirred under a nitrogen atmosphere at room temperature for 40 minutes, then cooled with ice and 0.1 ml of acetic acid are added. The solution diluted with methylene chloride is washed successively with dilute sulfuric acid, water and dilute bicarbonate solution. The aqueous phases are extracted with methylene chloride. The combined organic phases are dried over sodium sulfate. evaporate and remove the solvent completely under high vacuum. the oily residue is chromatographed on a silica gel thick-layer plate (eluent toluene / ethyl acetate 3: 1, developed once). Both, with an Rf value of 0.19 resp. The 0.4 zones are co-extracted with ethyl acetate and the resulting solution is completely evaporated. An oily product consisting of 7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester and its isomeric 76-phenoxyacetamido-3-methoxy-cef-2-em-4-carboxylic acid is obtained. diphenylmethyl ester in a ratio of 1: 4. Rf value = 0.14 resp. 0.32 (silica gel), toluene / ethyl acetate 3: 1); IR spectrum (in CHCl 3): 3400, 3310, 1785, 1770, 1750, 1710, 1690, 1630, 1600 cm -1.

i) The ratio between the kef-2-em and kef-3-em derivatives obtained depends, inter alia, on the solvent used to close the ring, the concentrations of the starting material and 1,5-diazabicyclo (5.4.0) undec-5-ene and also the reaction extender. The following table shows some of the reactions performed according to the example described above, each using 100 mg of a mixture of isomers consisting of 47 66389 of about 95% 2- (4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidine-1 -yl) -3-methoxy-isocrotonic acid-diphenylmethyl ester and about 5% of the corresponding crotonic acid derivative. The reaction time was 20 minutes in each case, and further work-up was carried out according to the example described above.

Starting Material Equivalents The ratio obtained for kef-2-

Solvent concentration 1,5-diazabicyclo em: cef-3-em / w / v (5.4.o) undec-5-derivative ene

Acetone 10% 1.5 ~ 3: 2

Toluene 10% 1.5 -1: 1

Ethyl acetate 10% 1.5 -4: 3

Ethyl acetate 20% 1.3 -4: 3

Isobutyl methyl ketone 20% 1.3 ~ 9:10

Methyl chloroform 20% 1,3-9: 7 1,2-dimethoxyethane 20% 1,3 ~ 6: 5 a) The isomer mixture used as starting material can be prepared from 4 g (6.14 mmol) 2 according to Example 1e). - (4- (p-Toluenesulfonylthio) -3-phenoxyacetamido-2-oxo-azetidin-1-yl) -3-hydroxycrotonic acid diphenylmethyl ester and excess ethereal diazomethane solution. The resulting mixture of isomers consisting of 2- (4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxy-crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester (about 3: 1) crystallizes from ethyl / pentane and a melting point of 150-152 °.

The mixture of isomers used as a starting material, i.e. a crotonic and isochrotonic acid derivative, can also be prepared in the following manner.

ai) A solution of 698 mg (1 mmol) of a mixture of isomers consisting of 2- (4- (benzthiazol-2-ylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxy-crotonic acid diphenylmethyl ether and the corresponding isocrotonic acid diphenylmethyl ester in 20 ml of acetone / water 9: 1 (v / v) are stirred with 341 mg of 48 66389 (1.3 mmol) of silver p-toluenesulfinate for 1 hour at room temperature. 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 acidic silica gel with toluene / ethyl acetate 2: 1. A mixture of isomers consisting of 2- (4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxychromoacid diphenylmethyl ester and 2- (4- (p-toluenesulfonylthio) -3- tert-noksiasetamido-2-oxo-azetidin-1-yl) -3-methoxy-isocrotonic diphenylmethyl ester.

aii) Instead of acetone / water, the reaction described in ai) can be carried out in tetrahydrofuran, stirring for about 24 hours at room temperature.

aiii) To a solution of 336 mg (0.5 mmol) of 2- (4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxo-azetidin-1-yl) -3-hydroxy-crotonic acid diphenylmethyl ester 4 ml of ethylene chloride, add at 0 ° 0.21 ml (1.2 mmol) of ethyl diisopropylamine and 0.12 ml (1.5 mmol) of fluorosulphonic acid methyl ester and stir for 30 minutes at 0 °: and further for 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, and dried over sodium sulfate. After evaporation, the residue is chromatographed on silica gel. Toluene / ethyl acetate 4: 1 first elutes some starting material, Toluene / ethyl acetate 1: 1 then isolates the isomer mixture consisting of 2- (4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) - 3-methoxy-crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester.

aiv) To a solution of 300 mg (0.447 mmol) of 2- (4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-hydroxycrotonic acid diphenylmethyl ester in 4 ml of acetone is added 76 mg (0.55 mmol) of potassium carbonate and 0.088 ml (0.92 mmol) of dimethyl sulfate and stirred for 5 hours at room temperature. The solution is diluted with ethyl acetate, washed with water and dried over sodium sulfate. After removal of the solvent, the residue is crystallized from ethyl acetate / pentane to give a mixture of isomers consisting of 2- (4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxy-crotonic acid diphenylmethyl ester and the corresponding isocrotic acid -difenyylimetyyliesteristä.

«4 49 66389 av) To a solution of 6.73 g of 2- (4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-hydroxycrotonic acid poly-diphenylmethyl ester (crystalline) 67 in ml abs. tetrahydrofuran, 1.57 g of N, N'-dinitroso-N, N'-dimethyloxamide are added at -20 °, followed by a solution of 0.57 ml (0.51 g) of ethylenediamine in 5 ml within 15 minutes. in tetrahydrofuran. After the addition, stir for 1 hour at 0 °, add 0.53 ml (11.4 moles) of glacial acetic acid and 6.7 g of Celite and filter. The residue is washed 5 times with 20 ml of tetrahydrofuran each time. The filtrate and washings are combined, evaporated to about 20 g and 20 ml of hexane are added. The crystals are filtered, washed with tetrahydrofuran / hexane 1: 2 and dried under high vacuum.

The crystals consist mainly of 2- (4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxyisocrotonic acid diphenylmethyl ester. The sample is recrystallized from ethyl acetate / diethyl ether to give the following analytical values: melting point 167-169 °; (α) J = -30 ° + 1 ° (c = 1, methylene chloride); thin layer chromatogram: Rf value = 0.57 (silica gel); methylene chloride / ethyl acetate / glacial acetic acid 60: 40: 1); UV spectrum (ethyl alcohol):? max = m (ε = 16,600); IR spectrum (nujol): characteristic bands at 2.97, 5.62, 5.90, 6.27, 6.61, 6.66, 7.17, 7.53, 7.70, 7.96, 8.02, 8.20, 8.80, 9.20, 10.26, 12.24, 13.30μ, NMR spectrum (100 Megahertz / in CDCl 3): 62.32 (s / CH 3); 2.34 (s / CH 2); 3.73 (S / OCH 3); 4.30 / 4.44 (AB; J = 5 / azetidine-4-CH-); 6-8-7.5 (m / 19 aromatic H, NH) ppm,

The mother liquor contains, in addition to a small amount of isocrotonic acid derivative, mainly 2- (4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-roxo-azetidin-1-yl) -3-methoxy-crotonic acid diphenylmethyl ester, which, after chromatographic purification, has a melting point 146-1 in silica gel. ° (corrected), ethyl acetate / hexane); NMR spectrum (100 Megahertz / in CDCl 3): 62.08 (s / vinyl-CH 2 Cl 2); 2.26 (s / aromatic-CH3); 3.70 (S / -OCH 3); 4.47 (s / -OCH 2 CO-); 4.94 (dd / J = 5 and 8 / azetidine-3-CH-); 5.83 (d / J = 5 / azetidine-4-CH-), 6.8-7.5 (m / 19 aromatic H - NH-) ppm; (aj ^ 0 = + 21 ° + 1 ^;) c = 1; methylene chloride).

avi) To a suspension of 6.72 g (10 mmol) of 2- (4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-hydroxycrotonic acid diphenylmethyl ester (crystalline) and 0.36 g (1 mmol) of tetra-n-butylammonium iodide in 100 ml of toluene, 3.78 g (30 mmol) of dimethyl sulphate in 30 ml of 20% aqueous potassium carbonate solution are added and the mixture is stirred vigorously for 4 hours at room temperature. . During the first 15 minutes, the solid dissolves. The mixture is diluted with toluene and washed with saturated aqueous sodium chloride solution. After drying the organic phase over sodium sulfate and evaporation, crystallization from ethyl acetate / diethyl ether gives 2- (4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxyisocrotonic acid diphenylmethylmethyl

avii) To a suspension of 3.36 g (5 mmol) of 2- (4- (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, 1.08 g (3 mmol) of tetrabutylammonium iodide and 1.9 mL (2.52 g, 20 mmol) of dimethyl sulfate are added. To the vigorously stirred mixture at room temperature, an amount of 1N sodium hydroxide is added in each case with an automatic titrator so that the pH remains constant at 7.0. 1.5-2 equivalents of sodium hydroxide are consumed in 4-5 hours. The mixture is diluted with ethyl acetate and water and a little salt is added. The organic phase is dried over sodium sulfate and evaporated. The residue is crystallized from a small amount of ethyl acetate / hexane 1: 1 to give 2- (4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxyisocrotonic acid diphenylmethyl ester.

The starting isomer mixture can also be prepared via the corresponding 2-benzoxazole derivatives as follows: aviii) A solution of 10 g of 6-phenoxyacetamido-penicillanic acid diphenylmethyl ester-10-oxide and 3 g of 2-mercaptobenzoxazole in 25 ml of dry tetrahydrofuran is completely evaporated in vacuo. The remaining foam is heated in a water jet vacuum for 70 minutes at 120 ° (oil bath temperature). After cooling, the melt residue is chromatographed on 500 g of acid-washed silica gel with toluene / ethyl acetate 6: 1 and then 3: 1. 2- (4- (Benzoxazol-2-yl-dithio) -3-phenoxy-acetamido-2-oxo-azetidin-1-yl) -3-methyl-butyric acid diphenylmethyl ester is obtained in the form of a white foam; IR spectrum (methylene chloride): characteristic bands: 5.6, 5.75, 5.90, 6.7 μ.

51 66389 Aix) to a solution cooled to -70 ° containing 3.35 g of 2- (4- (benzoxazol-2-yldithio) -3-phenoxyacetamido-2-oxoacetidin-1-yl) -3-methylene- butyric acid diphenylmethyl ester in 125 ml of ethyl acetate, about one equivalent of ozone (in the form of a CO 2 / Og mixture) is passed until it can be shown by thin layer chromatography (silica gel; toluene / ethyl acetate 3: 1) that no starting material is present. The solution is evaporated in vacuo to about 50 ml, 5 ml of dimethyl sulphide are added and the mixture is stirred until no more reaction is obtained in the potassium iodide-starch test. The mixture is evaporated in vacuo, the residue is dissolved in 150 ml of benzene and washed with water. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on 150 g of acid-washed silica gel with toluene / ethyl acetate 4: 1. 2- (4- (Benzoxazol-2-yl-dithio) -3-phenoxy-acetamido-2-oxo-azetidin-1-yl) -3-hydroxy-crotonic acid diphenylmethyl ester is obtained in the form of a white foam; IR spectrum (methylene chloride); characteristic lines: 5.60, 5.90, 6.0μ.

ax) To a solution of 1.7 g of 2- (4- (benzoxazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-hydroxycrotonic acid diphenylmethyl ester in 12.5 ml of methylene chloride is added at 0 [deg.] C. while stirring the ethereal diazomethane solution until it can be shown by thin layer chromatography (silica gel; toluene / ethyl acetate 3: 1) that no starting material is present. The mixture is evaporated in vacuo and the residue is chromatographed on 80 g of acid-washed silica gel with toluene / ethyl acetate 2: 1. A mixture of isomers consisting of 2- (4- (benzoxazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxycrotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester in a ratio of 5: 1 is obtained; IR spectrum (methylene chloride) characteristic bands: 5.60, 5.85 sh, 5.90, 6.40, 6.65μ.

axi) A solution of 682 mg (1 mmol) of a mixture of isomers consisting of 2- (4- (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) are stirred with 350 mg (1.5 mmol) of silver p-toluenesulfinate for 90 minutes at room temperature.

OD

mode. The mixture is filtered through Celite, the filtrate is evaporated in vacuo to 5 ml and extracted with 30 ml of methylene chloride. The methylene chloride phase is dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed on 30 g of acid-washed silica gel with toluene / ethyl acetate 1: 1 to give a mixture of isomers consisting of 2- (4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxy crotonic acid diphenylmethyl ester and the corresponding iso-crotonic acid diphenylmethyl ester.

Example 5:

A solution of 300 mg (0.45 mmol) of the crystalline isomer mixture obtained according to Example 4a) consisting of 2- [4- (p-toluenesulfonylthio-3-phenoxacetamido-2-oxoazetidin-1-yl) -3-methoxy- From crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid ester in 4 ml of dry 1,2-dimethoxyethane, stir at room temperature under nitrogen with 0.134 ml (0.9 mmol) of 1,5-diazabicyclo (5.4 g) undec-5-ene. After a reaction time of 40 minutes, the solution is cooled to 0 ° and 0.4 ml of acetic acid are added, followed by 180 mg (1.36 mmol) of m-chloroperbenzoic acid (85%) and the solution is stirred for 10 minutes at 0 ° C under nitrogen. dilute with chloroform and wash with dilute sulfuric acid / sodium thiosulfate, water and dilute sodium bicarbonate solution The aqueous phases are extracted with chloroform, the combined organic phases are dried over sodium sulfate, evaporated in vacuo and the solvent is removed under high vacuum. on thick-layer plates (vinegar ester as a fluid, once developed). The silica gel of the zone with an Rf value of 0.51 is extracted with ethyl acetate, the solution obtained is concentrated and the residue is dried under high vacuum. 7β-Phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester-1β-oxide is obtained as an oily residue, which is crystallized from methylene chloride-pentane, m.p. 115-120 ° C.

Extraction of the silica gel of the zone with an Rf value of 0.22 with ethyl acetate, evaporation of the solution on a rotary evaporator and drying of the oily residue gives 73-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester-1α-oxide, m.p. ° (chloroform).

The same compounds can also be obtained according to Example i) or ii): i) A solution of 24.7 mg (36 mmol) of the crystalline isomer mixture obtained according to Example 4a) consisting of 2- (4- (p-toluenesulfonylthio) - 3-Phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxy-crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid ester in 247 ml of dry 1,2-dimethoxyethane are evaporated at room temperature under nitrogen with 8.22 ml (54 mmol). ) 1,5-diazabicyclo (5.4.o) undec-5-ene. After a reaction time of 40 minutes, the solution is cooled to 0 ° and then 3.73 ml of formic acid are added, followed by 37.3 ml (108 mmol) of perforic acid (prepared from 33 ml of perhydrol (30%) and 100 ml). formic acid). The solution is stirred for 10 minutes at 0 ° under nitrogen gas, diluted with chloroform and washed with dilute sulfuric acid / sodium thiosulfate, water and dilute sodium bicarbonate solution. The aqueous phases are extracted with chloroform, the combined organic phases are dried over sodium sulfate, evaporated in vacuo and the solvent is removed under high vacuum. The obtained crude product is crystallized from methylene chloride / pentane to give 73-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester-1β-oxide, m.p. 115-120 °.

ii) A solution of 1.5 g (2.19 mmol) of the crystalline isomer mixture obtained according to Example 4a) consisting of 2- (4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl ) -3-methoxy-crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid ester in 7.5 ml of dry 1,2-dimethoxyethane, stirred at room temperature under nitrogen with 0.43 ml (2.84 mmol) of 1,5-diazabicyclo (5.4. 0) undec-5-ene. After a reaction time of 40 minutes, the solution is cooled to 0 ° and 0.375 ml (6.55 mmol) of acetic acid are added, followed by 0.667 ml (4.8 mmol) of 7.2N peracetic acid. The solution is stirred for 20 minutes at 0 ° under nitrogen, then 0.24 ml of sodium bisulphite solution (20%) is added. While stirring vigorously, 22.5 ml of water are added to the reaction mixture. A mixture of 76-phenoxyacetamido-3-methoxy-cef-3-em-4-carboxylic acid diphenylmethyl ester-1β- and -1a-oxide crystallizes out.

The precipitate is filtered off, washed with water and dried under high vacuum.

iii) To a suspension of 98.8 ml (98.8 mmol) of 2- (4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxyisocrotonic acid diphenylmethyl ester: 1,2-dimethoxyethane is added at room temperature under a nitrogen atmosphere over 2 minutes while stirring 32.9 ml (216 mmol) of 1,5-diazabicyclo (5.4.0) undec-5-ene. The clear solution is stirred for 25 minutes at room temperature, then cooled to 0 °, at the same time 14.9 ml (395 mmol) of formic acid are added and, after cooling to -20 °, 149 ml of a mixture of 66 ml of perhydrol (~ 0.30%) and 134 ml of formic acid (432 mmol). The reaction solution is then stirred for 15 minutes at 0 [deg.] C. and then 37 g of sodium thiosulphate dissolved in 500 ml of water are added. 300 ml of water, stirring is continued for 2-3 hours at 5 [deg.] C., after which the precipitate consisting mainly of 7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carbonic acid diphenylmethyl ester-13-oxide is filtered off and washed with cold water. , (3 ° C) and diethyl ether and dried under high vacuum over calcium chloride.

At the same time, 7 liters of water are added to the filtrate with vigorous stirring at 5 °. First, an oily precipitate which solidified after standing overnight, consisting mainly of 76-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester-1a-oxide, is filtered off, washed with ice-cold water and dried under high vacuum over calcium chloride.

iv) 34.35 g (50 mmol) of 2- (4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxyisocrotone-frappo-diphenylmethyl ester are suspended at 20 ° under a nitrogen atmosphere. 340 ml of tetrahydrofuran (most of which is soluble). 11.4 ml (75 mmol) of 1,5-diazabicyclo (5.4 °) undec-5-ene are added rapidly, after which the solution is stirred for 15 minutes at 20 °, then 1.9 ml (30.2 mmol) of ) glacial acetic acid and then evaporated to dryness in vacuo at 30 °. The brown, foamy residue is dissolved in 130 ml of methylene chloride, and washed successively with 60 ml of water, 30 ml of 0.5N hydrochloric acid, 30 ml of water, 30 ml of 1m NaHCO3 solution and 30 ml of water. The aqueous phases are extracted twice with 10 ml of methylene chloride.

The combined, non-dried methylene chloride phases are cooled to -10 ° C and 7.0 ml of peracetic acid / acetic acid (containing about 50 mmol) of peracetic acid are slowly added; temperature rise to a maximum of about + 10 °. Stir for 15 minutes at 0-5 ° after which the excess peracid is discarded with aqueous sodium thiosulfate. The aqueous phase is separated and washed with a small amount of methylene chloride. After drying the solution over magnesium sulphate, it is evaporated in vacuo. A pale yellow residue consisting of 78-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester 1-oxide and 70-phenoxyacetamido-3-methoxy-cef-2-em- From a mixture of 4-carboxylic acid diphenylmethyl ester-1-oxide in a ratio of about 2: 1, dissolve in 120 ml of monoglyme at room temperature, 30 ml of water are added, whereupon 73-phenyltetamido-3-methoxy-cef-3-em-4- carboxylic acid, diphenylmethyl-13-oxide. The thick crystalline porridge is first stirred for 1/2 hour, then 150 ml of water are added over about 5 hours at room temperature while stirring, whereby the corresponding 1α-oxide also crystallizes. Stir for a total of 17 hours, then cool in an ice bath for 1 hour, filter and wash the residue with a small amount of chilled mono-glyme / water 1: 1.5. The crystals are dried under high vacuum for 16 hours under P 2 O 4. 73-Phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester-13-oxide is obtained, which still contains the corresponding 1α-oxide. The resulting 1-oxides can be further treated as follows: a) To a solution of 150 mg (0.275 mmol) of 73-phenoxy-acetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester-18-oxide in 3 ml: in methylene chloride and 0.1 ml of dimethylformamide, 188 mg (1.37 mmol) of phosphorus trichloride are added after cooling to 0 °. The solution is stirred at 0 ° for 30 minutes, diluted with methylene chloride and washed with sodium bicarbonate Resil solution. The aqueous phase is extracted with methylene chloride, the combined organic phases are dried over sodium sulfate and evaporated in vacuo. The obtained crude 70-phenoxy-acetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester is crystallized from ether; melting point 120 ° i ai) To a suspension of 5.0 g (9.16 mmol) of 73-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester-1a-oxide in 25 ml: After cooling to 0 °, 1.69 ml (19.3 mmol) of phosphorus trichloride are added. The solution is stirred at 0 ° for 30 minutes, diluted with ethyl acetate and washed with aqueous sodium bicarbonate solution. The aqueous phase is extracted with ethyl acetate, the combined organic phases are dried over sodium sulfate and evaporated in vacuo. The crude 73-phenoxyethido-3-methoxy-ceph-3-em-1-carboxylic acid di-phenylmethyl ester obtained is recrystallized from ether; melting point 120 °.

b) To a solution of 2.0 g (3.78 mmol) of 78-phenoxyacetamido-3-methoxy-cef-3-em-4-carboxylic acid diphenylmethyl ester in 5 ml of 56 6 6 3 8 9 methylene chloride is added 0, 87 ml of anisole, cooled to 0 °, 1.2 ml of difluoroacetic acid are added and allowed to stand for 1 hour. The reaction mixture is concentrated in vacuo and the residue is crystallized from acetone / ether. 73-Phenoxyacetamido-3-methoxy-cef-3-em-4-carboxylic acid is obtained, melting point 170 ° (decomposes).

The same compound can also be obtained without isolating the ester according to a): bi) To a suspension of 3.0 g (5.5 mmol) of 73-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester-1β A mixture of - and 1α-oxide in 15 ml of methylene chloride and 0.75 ml of dimethylacetamide is added, after cooling to 0 DEG, 0.966 ml (1.11 mmol) of phosphorus trichloride. The solution is stirred at 0 ° for 40 minutes, then 4.65 ml (61 mmol) of trifluoroacetic acid are added and further stirred at 0 ° for 30 minutes. The reaction solution is neutralized with saturated sodium bicarbonate solution and the organic phases are washed with dilute bicarbonate solution. The combined aqueous phases are washed 2. · times with ethyl acetate and adjusted to pH 2.6 with phosphoric acid. The precipitated 73-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid is filtered off, washed with water and dried under high vacuum, m.p. 170 ° (decomposes).

bii) A suspension of 53.4 g (97.7 mmol) of 7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester-1β-oxide (from Example 5iii) in 320 ml of methylene chloride and in 16 mL of dimethylacetamide is cooled and 17.3 mL (19.8 mmol) of phosphorus trichloride is slowly added. Stir for 20 minutes at 0-5 °, then add 80 ml (1.05 mmol) of trifluoroacetic acid dropwise. The clear solution is stirred for 20 minutes at 0-5 °, then diluted with 1,300 ml of ethyl acetate and washed successively with 240 ml of 2M dipotassium phosphate solution, 100 ml of water and 250 ml of half-saturated aqueous sodium chloride solution. 73-Phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid is extracted from the organic phase with 700 ml of saturated aqueous sodium bicarbonate solution and the aqueous phase is washed twice with 400 ml of ethyl acetate. The organic phases are extracted twice with a total of 250 ml of a solution of 50 ml of saturated aqueous sodium bicarbonate solution, 100 ml of water and 100 ml of saturated aqueous sodium chloride solution. 1500 ml of ethyl acetate, pH of the solution, are poured onto the combined Jaikarbonate extracts

57 6 6 3 8 9 is adjusted at the same time with vigorous stirring to 20% with phosphoric acid. The aqueous phase is extracted twice with 500 ml of ethyl acetate. The combined organic phases are dried over magnesium sulphate, filtered and evaporated in vacuo. The crystalline residue is slurried in 130 ml of ethyl acetate and allowed to stand overnight at -10 °. The slightly yellowish crystals of the obtained 70-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid are filtered off, washed with chilled ethyl acetate and dried under high vacuum to constant weight.

biii) A solution of 2,9 g of 7fS-phenoxyacetamido-3-methoxy-cef-3-em-4-carboxylic acid diphenylmethyl ester-1a-oxide (from Example 5iii)) in 140 ml of methylene chloride and 7.2 ml of dimethylacetamide , cooled to 0 °, 7.8 ml of phosphorus trichloride are slowly added, followed by further stirring for 20 minutes at 0-5 °. To the reaction solution is added dropwise 36 ml of trifluoroacetic acid, then stirred at 0-5 ° for 20 minutes and worked up as described in Example 5 bii). 73-Phenoxyacetamido-3-methoxy-cef-3-em-4-carboxylic acid is obtained in the form of a pale yellow crystalline precipitate.

c) To a suspension of 2.55 g (7 mmol) of 78-phenoxyacetamido-3-methoxy-cef-3-em-4-carboxylic acid and 2.9 ml (22, * + mmol) of N, N-di -methylaniline in 11 ml of absolute methylene chloride, 0.7 ml (5.7 mmol) of dimethyldichlorosilane are added in nitrogen gas at 20 [deg.] C. and further stirred for 30 minutes at the same temperature. The resulting clear solution is cooled to -20 °, 1.6 g (7.7 mmol) of solid phosphorus pentachloride are added and stirred for 30 minutes. At the same temperature, a mixture of 0.9 ml (7 mmol) of N, N-dimethylaniline and 0.9 ml of n-butanol, pre-cooled (¢ -20 °) is added over 2-3 minutes, followed by the rapid addition of 10 ml of precooled ( -20 °) n-butanol and then stir for 20 minutes at -20 ° and 10 minutes without cooling. At about -10 ° add 0.4 ml of water, stir for about 10 minutes in an ice bath (0 °), then add 11 ml of dioxane and, after further stirring for 10 minutes at 0 °, about 4.5 ml of tri-t-butylmine are added portionwise until the sample diluted with water has a constant pH of 3.5. Stir for 1 hour at 0 °, then filter the precipitate, wash with dioxane and recrystallize from water / dioxane.

The resulting 7β-amino-3-methoxy-ceph-3-em-4-carboxylic acid hydrochloride dioxanate has a melting point above 300 °, thin layer chromatogram: Rf value 0.17 (silica gel; system n-butanol / h ') tetrachloride / methanol / non-monetary acid / water 30: 40: 20: 5: 5).

δβ 66389 (ci) To a suspension of 11.75 g of 95% (corresponding to 10.93 g of 100%) of 78-phenoxyacetamido-3-methoxy-cef-3-em-4-carboxylic acid and 13.4 ml ( 12.73 g) of N, N-dimethylaniline in 47 ml of abs. methylene chloride (distilled from P 2 O 3), add 3.6 ml (3.87 g) of dimethyldichlorosilane at + 20 ° under nitrogen and then stir for 30 minutes at the same temperature. The clear solution is cooled to -18 to 19 ° and 7.8 g of solid phosphorus pentachloride are added, raising the internal temperature to -10 °. After stirring for 30 minutes in a -20 ° bath, the clear solution is added dropwise over about 7 minutes to a mixture cooled to -20 ° with 47 ml of n-butanol (anhydrous, dried over silica) and 4.4 ml (4.18 g). dimethyl aniline. In this case, the internal temperature rises to -8 °. Stir for 30 minutes, first in a -20 ° bath, then in an ice bath (0 °) so that a final internal temperature of 10 ° is reached. At this temperature, a mixture of 47 ml of dioxane and 1.6 ml of water (takes about 5 minutes) is added dropwise. In this case, the product crystallizes slowly. Stirring is continued for 10 minutes, after which the mixture in the ice bath is adjusted to pH 2.2-2.4. .

It is then filtered, washed portionwise with about 30 ml of dioxane, then with about 15 ml of methylene chloride to give crystalline 7g-amino-3-methoxy-cef-3-em-4-carboxylic acid hydrochloride dioxanate. ; melting point above 300 ° C; UV spectrum (in 0.1 N sodium bicarbonate): λ males = "V = 7600"; IR spectrum (Nujol): characteristic bands: 5.62, 5.80, 5.88, 6.26, 6.55, 7 .03, 7.45, 7.72, 7.96, 8.14, 8.26, 8.45, 8.64, 8.97, 9, 29, 10.40, 11, 47 np; ) ^ = + 134 ° + 1 ° (c = 1; 0.5N sodium bicarbonate solution).

From the hydrochloride dioxanate obtained, by adding 2N sodium hydroxide to a 20% aqueous solution thereof to pH 4.1 (Gsoelectric point), 7β-amino-3-methoxy-ceph-3-em-4-carbonic acid double ion can be obtained. , filtered and dried, having a melting point above 300 °. UV spectrum (in 0.1N sodium bicarbonate solution) λ = 270 nm (e = 7600). Thin layer chromatogram: Rf value identical to the Rf value of the hydrochloride (silica gel, similar system); (a) = + 232 ° + 1 ° (c = 1; 0.5N sodium bicarbonate solution).

59 6 6 3 8 9 d) To a suspension of 1 g (2.82 mmol) of 73-amino-3-methoxy-cef-3-em-4-carboxylic acid hydrochloride dioxanate in 20 ml of dry methylene chloride is added room at room temperature under a nitrogen atmosphere 1.65 ml of bis- (trimethylsilyl) acetamide. After 40 minutes, the clear solution is cooled to 0 ° and 900 mg (4.37 mmol) of solid D-α-phenyl-glycyl acid hydrochloride are added. After 5 minutes, 0.7 ml (10 mmol) of propylene oxide are added. The suspension is then stirred for 1 hour at 0 ° under a nitrogen atmosphere, then 0.5 ml of methanol are added to precipitate 73- (D-α-phenylglycylamino) -3-methoxy-cef-3-em-4-carboxylic acid hydrochloride. crystalline. The hydrochloride is filtered off, dissolved in 9 ml of water and the solution is adjusted to pH 4.6 with 1N sodium hydroxide. The precipitated hydrate of the inner salt of 73- (D-α-phenylglycylamino) -3-methoxy-ceph-3-em-4-carboxylic acid is filtered off, washed with acetone and diethyl ether and dried, m.p. 174-176 ° (decomposes); (α) D = + 132 ° (c = 0.714, in 0.1 N hydrochloric acid); thin layer chromatogram (silica gel): Rf value ~ 0.18 (system: n-butanol / acetic acid / water 67:10:23): UV spectrum (in 0.1 N aqueous sodium bicarbonate solution) λ ^ = 269μ (ε = 7000); IR spectrum (in mineral oil): characteristic bands: 5.72, 5.94, 6.23 and 6.60y.

di) To a suspension of 993 mg (4.32 mmol) of 73-amino-3-methoxy-cef-3-em-4-carboxylic acid (internal salt) in 10 ml of methylene chloride is added 1.37 ml (5 , 6 mmol) of N, N-bis- (trimethylsilyl) acetamide and stirred for 45 minutes at room temperature under a nitrogen gas atmosphere. The clear solution is cooled to 0 ° and 1.11 g (5.4 mmol) of D-α-phenylglycyl chloride hydrochloride are added. After 5 minutes, 0.4 ml (5.6 mmol) of propylene oxide are added. The suspension is then stirred for 1 hour at 0 ° under a nitrogen atmosphere, after which 0.6 ml of methanol are added. The crystallising 73- (Da-phenylglycylamido) -3-methoxy-cef-3-em-4-carbonic acid hydrochloride is filtered, dissolved in 15 ml of water at 0 ° and the solution is adjusted to pH 5 with 5 ml of 1N sodium hydroxide. about 4. The solution warmed to room temperature is adjusted to a pH of about 4.8 with triethylamine, whereby 73- (Da-phenylglycylamido) -3-methoxy-cef-3-em-4-carboxylic acid precipitates in the form of the dihydrate. Example 6:

To a solution of 0.697 g (1.0 mmol) of 2- (4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxy-60 6 6 3 8 9 crotonic acid a mixture of isomers of diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester in 4 ml of dry tetrahydrofuran, a solution of 0.228 g (1.5 mmol) of 1,5-diazabicyclo (5.4.o.) undec-5-ene in 10 ml is added: in tetrahydrofuran. The mixture is stirred for 40 minutes at room temperature, diluted with 200 ml of benzene and washed successively with dilute hydrochloric acid, sodium bicarbonate solution and water. The organic phases are dried over sodium sulfate and the solvent is removed in vacuo. The crude product obtained is chromatographed on 30 g of acid-washed silica gel. Toluene / ethyl acetate 7: 1 elutes first 2-mercaptobenzthiazole followed by 7β-phenoxyacetamido-3-methoxy-cef-2-em-4-carboxylic acid diphenylmethyl ester. IR spectrum (in CH 2 Cl 2): 5.60, 5.74, 5.90, 8.28μ. The ester obtained can be converted into the free acid as follows: i) A mixture of 53 mg (0.1 mmol) of 7β-phenoxyacetamido-3-methoxy-ceph-2-em-4α-carboxylic acid diphenylmethyl ester, 0.007 ml of trifluoroacetic acid, 0.06 ml of anisole and 0.5 ml of methylene chloride are stirred for 15 hours at 0 °. The mixture is diluted with 5 ml of pentane / diethyl ether 3: 1 and shaken vigorously. The precipitated white amorphous 76-phenoxyacetamido-3-methoxy-cef-2-em-4a-carboxylic acid is filtered off and washed with pentane / diethyl ether 3: 1. IR spectrum (CH 2 Cl 2): 5.60, 5.90, 8.27μ.

The starting material can be prepared as follows: a) In a -70 ° cooled solution of 681 mg (1.0 mmol) of 2- (4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidine-1 -yl) -3-methylene-butyric acid diphenylmethyl ester in 30 ml of ethyl acetate, 1 equivalent of ozone (diluted with acid) is passed. The reaction solution is allowed to warm, concentrated in vacuo to 10 ml, 1.0 ml of dimethyl sulfide are added and stirred for 15 hours at room temperature. The solvent and excess reagent are removed in vacuo and the residue is chromatographed on 30 g of acid-washed silica gel with toluene / ethyl acetate 4: 1 (fractions a 15 ml). 2- (4- (Benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxo-azetidin-1-yl) -3-hydroxycrotonic acid diphenylmethyl ester is obtained as a solid amorphous product: (a) ^ = 130 ° + 1 ° (CHCl 3: c = 0.8) IR spectrum (CH 2 Cl 2): 2.95, 5.60, 5.92, 6.04, 8.10μ.

no 66389 b) To a solution of crude 2- (4- (benzthiazol-2-yl-dithio) -3-phenoxyacetamido-2-oxo-azetidin-1-yl) -3-hydroxycrotonic acid diphenylmethyl ester obtained by ozonation of 681 mg (1.0 mmol) of 2- (4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxo-azetidin-1-yl) -3-methylenebutyric acid diphenylmethyl ester In 5 ml of methylene chloride, a solution of ethereal, distilled diazomethane (containing 1.3 mmol of diazomethane) is added at C °. The mixture is stirred for 1 hour at 0 °, washed with water and the organic layer is dried over sodium sulfate. The solvent is removed in vacuo and the residue is chromatographed on 35 g of acid-washed silica gel with toluene / ethyl acetate 2: 1. An isomeric mixture of 2- (4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoacetidin-1-yl) -3-methoxy-crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester is obtained. IR spectrum (in CH 2 Cl 2): 5.60, 5.88, 6, 67, 9.15, 9.92μ. Example 7:

According to Example 4, 200 mg (0.307 mmol) of 2- (4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxy-crotonic acid 2,2,2-trichloroethyl ester and a mixture of isomers of the corresponding isocrotonic acid 2,2,2-trichloroethyl ester, and 0.09 ml (0.6 mmol) of 1,5-diazabicyclo (5.4.4) undec-5-ene with stirring for 30 minutes at room temperature in 3 ml 1, 2-Dimethoxyethane from 78-phenoxyacetamido-3-methoxy-cef-2-em-4-carboxylic acid 2,2,2-trichloroethyl ester and 7B-phenoxy-acetamido-3-methoxy-cef-3-em-4-carboxylic acid-2 , A mixture of isomers of 2,2-trichloroethyl ester (in a ratio of about 1: 1). The Rf value is 0.36 resp.

0.18 (silica gel; toluene / ethyl acetate 3: 1).

The starting material can be prepared as follows: a) 498 mg (1 mmol) of 6-phenoxyacetamido-penicillanic acid 2,2,2-trichloroethyl ester and 200.7 mg (1.2 mmol) of 2 are obtained, respectively. -Mercapto-benzthiazole 2- (4- (Benz-thiazol-2-yl-dithio) -3-phenoxy-acetamido-2-oxo-azetidin-1-yl) -3-methylene-butyric acid 2,2,2-trichloro-ethyl ester, m.p. 144 -149 ° C (methylene chloride / pentane), Rf value = 0.5 (silica gel: ether).

b) Correspondingly to Example 6a), 647 ng (1 mmol) of 2- (4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoacetidin-1-yl] -3-methyleneacetic acid 2,2 , 2-trichloroethyl ester and 6,668,389 of 1.2 equivalents of ozone followed by cleavage of the ozone diide with dimethyl sulfide 2- (4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3 -hydroxycrotonic acid 2,2,2-trichloroethyl ester, mp 129-130 ° (ether / petroleum ether).

c) According to Example 6b) 5 g (7.71 mmol) of 2- (4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-hydroxycrotonic acid-2.2 , 2-trichloroethyl ester and an excess of diazomethane from 2- (4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxy-crotonic acid 2.2.2-trichloroethyl ester and the corresponding isocrotonic acid-2 , A mixture of isomers of 2,2-trichloroethyl ester; melting point 170-174 ° (methylene chloride / ether).

d) According to Example 1c), 1.9 g (2.87 mmol) of 2- (4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxy-crotonic acid are obtained A mixture of isomers consisting of -2,2,2-trichloroethyl ester and the corresponding isocrotonic acid 2,2,2-trichloroethyl ester, with stirring for 5 hours at room temperature with 0.8 g (4.05 mmol) of silver p-toluenesulfinate in 35 ml of acetone triyl / ethyl acetate 3: 4 2- (4- (p-Toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxy-crotonic acid 2.2.2-trichloroethyl ester and the corresponding isocrotonic acid-2.2 A mixture of isomers consisting of 2-trichloroethyl ester; melting point 155-158 ° (from ethyl acetate / ether).

Example 8:

To a solution of 100 mg (0.146 mmol) of 2- (4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-hydroxy-crotonic acid diphenylmethyl ester in 2 mL of dry methylene chloride dia, 0.02 ml (0.16 mmol) of trimethylchlorosilane are added at 0. To this solution, 0.0477 ml (0.32 mmol) of 1,5-diazabicyclo (5.4.O) undec-5-ene are added with stirring under nitrogen. and further stirred for 1 hour at 0 [deg.] C. 0.2 ml of acetic acid are added and the mixture is diluted with methylene chloride, 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.

The crude 76-phenoxyacetamido-3-hydroxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester obtained is dissolved in methanol and an ethereal diazomethane solution is added at 0 °. After 10 minutes, the solution is carefully evaporated and the residue is dried under high vacuum. The residue is purified by thick layer chromatography (toluene / ethyl acetate 3: 1, silica gel). After eluting the silica gel zone with an Rf value of 0.17 with ethyl acetate and evaporating the solution on a rotary evaporator, 7f} -phenoxyacetamido-3-methoxy-cef-3-em-4-carboxylic acid diphenylmethyl ester is obtained; melting point 120 ° (from ether).

Example 9:

A solution of 266 mg (0.5 mmol) of 2- (u- (benzthiazol-2-yl-dithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxy-crotonic acid chloride and 2- A crude mixture of (u- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxyisocrotonic acid chloride in 5 ml of dry methylene chloride is added at 0 ° with stirring for 15 minutes. dropwise to a solution of 0.10 ml of triethylamine in 0.5 ml of dry tert-butanol and 3 ml of methylene chloride. 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 sulphate and evaporated in vacuo. The residue is chromatographed on 10 g of acid-washed silica gel using toluene / ethyl acetate (4: 1) as eluent. 76-Phenoxyacetamido-3-methoxy-cef-2-em-4-carboxylic acid tert-butyl ester is obtained, IR spectrum (in CH 2 Cl 2): characteristic bands: 5.60, 5.77, 5, 90, 8.29μ.

The starting material can be prepared as follows: a) To a solution of 698 mg (1 mmol) of 2- (4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxy-crotonic acid 1.5 ml of a mixture of diphenylmethyl ester and 2 - (* + - (benzthiazo-2-yl-dithio) -3-phenoxy-acetamido-2-oxo-azetidin-1-yl) -3-methoxy-isotrotonic acid-diphenylmethyl ester: methylene chloride, a mixture of 0.7 ml of trifluoroacetic acid, 0.6 ml of anisole and 2.5 ml of methylene chloride is slowly added with stirring at 0 °. 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. A precipitate consisting of 2- (4- (benzthiazol-2-yl) thithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxy-crotonic acid and 2- (4- (benzthiazol-2-yl) Ylyldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxyisocrotonic acid is washed with 25 ml of ether / pentane 1: 3 and dried in vacuo. IR spectrum (CI / CH 2): characteristic δ: 5.60, 5.80, 5.94, 8.55, 9.95μ.

b) A solution of 532 mg (1.0 mmol) of 2- (4- (benzthiazol-2-6,6,689yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxy-crotonic acid and a mixture of 2- (4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxyisocrotonic acid in 5 ml of dry dioxane containing 10% oxalyl chloride is stirred for 15 hours at room temperature. temperature and then evaporated in vacuo. A solid non-crystalline residue consisting of 2- (4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxy-crotonic acid chloride and 2- (4- (benzthiazole) 2-yldithio-3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxyisocrotonic acid chloride, can be further processed without further purification IR spectrum (in CH 2 Cl 2): characteristic lines 5.58, 5.90, 9.95.

Example 10:

A solution of 367 mg (0.5 mmol) of 2- (4- (p-nitrobenzenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxy-crotonic acid diphenylmethyl ester and the corresponding iso -crotonic acid diphenylmethyl ester and 152 mg (1.0 mmol) of 1,5-diazabicyclo (5.4.o) undec-5-ene in 10 ml of dry tetrahydrofuran are stirred for 40 minutes at room temperature. The reaction mixture is diluted with benzene, washed successively with dilute hydrochloric acid, water and dilute sodium bicarbonate solution, dried over sodium sulfate and the solvent is removed in vacuo. The residue is chromatographed on acid-washed silica gel using toluene / ethyl acetate 7: 1 as eluent to give pure 7β-phenoxyacetamido-3-methoxy-ceph-2-em-4-carboxylic acid diphenylmethyl ester. Elution with toluene / ethyl acetate 2: 1 then isolates a mixture which, in addition to 78-phenoxyacetamido-3-methoxy-ceph-2-em-4-carboxylic acid diphenylmethyl ester, also contains 78-phenoxyacetamido-3-methoxy-cef-3- em-4-carboxylic acid, diphenylmethyl ester.

The starting material can be prepared as follows: a) According to Example 4ai) 348.5 mg (0.5 mmol) of 2- (4- (benzthiazol-2-ylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3 -methoxy-crotonic acid diphenylmethyl ester and the corresponding isomeric mixture of isociotonic acid poly-diphenylmethyl ester, and 200 mg (0.68 mmol) of silver p-nitrobenzenesulfinate with stirring for 1 hour at 60 ° in 10 ml of acetone / water 9: 1 mixture of 2- (4- (p-nitrobenzenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxy-crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester.

65 66389

Silver p-nitrobenzenesulfinate is obtained by combining aqueous solutions containing equimolar amounts of silver nitrate and sodium p-nitrobenzenesulfate. The precipitate is filtered off and dried under vacuum for 24 hours at 50-60 °.

Example 11:

According to Example 10, 351.5 mg (0.5 mmol) of 2- (4- (p-methoxybenzenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxy-crotonic acid diphenylmethyl ester and a mixture of isomers of the corresponding isocrotonic acid diphenylmethyl ester and a mixture of 152 mg (1 mmol) of 1,5-diazabicyclo (5.4.0) undec-5-ene consisting of 76-phenoxyacetamido-3-methoxy-cef-2-em From 4-carboxylic acid diphenylmethyl ester and 76-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester, which can be separated into both isomers by chromatography.

The starting materials can be prepared as follows: a) According to Example 4ai) 697 mg (1 mmol) of 2- (4- (benzthiazol-2-ylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxy are obtained, respectively. -chrotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester isomer mixture and 361 mg (1.3 mmol) of silver p-methoxybenzenesulfate, with stirring for 1 hour at room temperature in 20 ml of a 9: 2 mixture of acetone and Tone / water consisting of (-4- (p-Methoxy-benzenesulfonylthio) -3-phenoxy-acetamido-2-oxo-azetidin-1-yl) -3-methoxy-crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester. IR spectrum (in CH 2 Cl 2): characteristic bands: 5.60, 5.88, 6.18, 8.76μ.

Silver p-methoxybenzene sulfinate is obtained by combining aqueous solutions containing equimolar amounts of silver nitrate and sodium p-methoxybenzene sulfinate. The precipitate is filtered off and dried under vacuum at 50-60 ° for 24 hours.

Example 12:

According to Example 10, an isomeric mixture of 336.3 mg (0.5 mmol) of 2- (4-benzenesulfonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxy-crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester is obtained. and 152 mg (1 mmol) of a mixture of 1,5-diazabicyclo 5.4.0 undec-5-ene consisting of 76-phenoxy-acetamido-3-methoxy-ceph-2-em-4-carboxylic acid diphenylmethyl ester and 7f -phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester, which can be separated into both isomers by chromatography.

The starting materials can be prepared as follows: a) According to Example 4ai) 697 mg (1 mmol) of 2- (4- (benzthiazol-2-ylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxy are obtained, respectively. -chrotonic acid diphenylmethyl ester and the corresponding isomeric mixture of isocrotonic acid diphenylmethyl ester and 32 * + mg (1.3 mmol) of silver benzenesulfinate by stirring for 90 minutes at room temperature in 20 ml of a 9: 1 mixture of acetone / water consisting of 2 - (4-Benzenesulfonylthio-3-phenoxy-acetamido-2-oxo-azetidin-1-yl) -3-methoxy-crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester. IR spectrum (in CH 2 Cl 2): characteristic bands 5.60, 5.88, 8.74μ.

Silver benzene sulfinate is obtained by combining aqueous solutions containing equimolar amounts of silver nitrate sodium benzene sulfinate. The precipitate is filtered off and dried under vacuum for 24 hours at 50-60 °.

Example 13:

According to Example 1, a mixture of 2- (4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxycrotonic acid p-nitrobenzyl ester and the corresponding isocrotonic acid ester can be obtained by stirring with tetramethyl for 12-14 hours at room temperature. in tetrahydrofuran, a mixture of isomers consisting of 7- (3-phenoxyacetamido-3-methoxy-cef-3-em-4-carboxylic acid p-nitrobenzyl ester and 78-phenoxyacetamido-3-methoxy-ke-2-em-4-carboxylic acid -p-ritrobent cause of ester.

Example 14:

A mixture of 104.5 mg (0.15 mmol) of 2- (4- (benzthiazol-2-ylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxy-crotonic acid diphenylmethyl ester and a mixture of isomers of the corresponding isocrotonic acid diphenylmethyl ester, 35 mg (0.225 mmol) of p-toluenesulfinic acid and 80 mg (0.525 mmol) of 1,5-diazabicyclo (5.4.4) undec-5-ene in 3 ml of dry tetrahydrofuran , stirring for 40 minutes at room temperature. The mixture is diluted with henzene, washed successively with dilute hydrochloric acid, dilute aqueous sodium chloride solution, 0.5N sodium hydroxide solution and again with dilute aqueous sodium chloride solution, 67 6 6 3 8 9

The organic phase is dried over sodium sulfate and the solvent is removed in vacuo. Chromatography of the residue on 3.5 g of oxygen-washed silica gel with toluene / ethyl acetate 7: 1 first gives pure 73-phenoxyacetamido-3-methoxy-ceph-2-em-4a-carboxylic acid diphenylmethyl ester. Toluene / ethyl acetate 2: 1 is then eluted with 73-phenoxyacetamido-3-methoxy-cef-3-em-4-carboxylic acid diphenylmethyl ester.

Example 15:

A mixture of 141 mg (0.2 mmol) of 2- (4- (o-methoxybenzenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxy-crotonic acid diphenylmethyl ester and 61 mg (0.4 mmol) of 1,4-diazabicyclo (5.4.4) undec-5-ene in 4 ml of dry tetrahydrofuran are stirred for 70 minutes at room temperature. Example 10 is further treated as follows to give 73-phenoxyacetamido-3-methoxy-ceph-2-em-4a-carboxylic acid diphenylmethyl ester and 73-phenoxyacetamido-3-methoxy-cef-3-em-4-carbonic acid ester. a crude mixture of diphenylmethyl ester in a ratio of about 4.4: 1, which can be separated into both isomers by chromatography on silica gel according to Example 10.

Both compounds are obtained in essentially the same ratio by treating 141 g (0.2 mmol) of 2- (4- (o-methoxybenzenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxyisocrotonic acid diphenylmethyl ester in a similar manner .

Both isomeric starting materials can be obtained as follows: a) 3.49 g (5 mmol) of 2- (4- (benzthiazol-2-ylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxy- a mixture of isomers of crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester in a ratio of about 4.1 is stirred with 1.82 g (6.5 mmol) of silver o-methoxybenzene sulfinate in 100 ml of acetone / water 9: 1 , 130 minutes at room temperature. 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. Collect 50 ml fractions of which fractions 7-13 contain pure 2- (4- (o-methoxybenzenesulphonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxyisocrotonic acid diphenylmethyl ester, IR spectrum (in): 5.60, 5.90, 8.72, 9.15μ, and fraction 25 et seq. of pure 2- (4- (o-methoxybenzenesulfonylthio) -3-phenoxyacetamido-2-oxoacetidine.ini-1 -yl) -3-methoxy-crotonic acid diphenylmethyl ester, IR spectrum 68 66389 (in CH 2 Cl 2): 5.60, 5.90, 8.20, 8.30, 8.72. 9,80μ. Fractions 14-24 contain a mixture of both isomers.

Example 16:

A mixture of 57 mg (0.1 mmol) of crude 2- (4- (o-methoxybenzenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxyisocrotonic acid chloride and 43 mg (0, 3 mmol) 1,5-diazabicyclo (5.4.0.) Undec-5-ene in 2 ml of dry methylene chloride, stirred for 80 minutes at room temperature. The mixture is diluted with methylene chloride, washed with dilute hydrochloric acid and water, dried over sodium sulfate and the solvent is removed in vacuo. The residue is dissolved in 0.5 ml of methylene chloride, 5 ml of pentane / diethyl ether are added 3: 1 and shaken. The precipitate is filtered off and washed with pentane / diethyl ether 3: 1. It consists of almost pure 7- (3-phenoxy-acetamido-3-methoxy-cef-2-em-4a-carboxylic acid.

The starting material can be prepared as follows: a) A mixture of 703 mg (1 mmol) of pure 2- (4- (o-methoxybenzenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxyisocrotonic acid -diphenylmethyl ester, 0.7 ml of trifluoroacetic acid and 0.66 ml of anisole in 4 ml of methylene chloride are stirred for 3 hours at 0 °. 50 ml of Penta / diethyl ether are then added to the mixture and shaken vigorously. The white precipitate of pure 2- (4- (o-methoxybenzenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxyisocrotonic acid is filtered off, washed with pentane / diethyl ether 3: 1. IR spectrum (in CH 2 Cl 2): 5.60, 5.93, 6.25, 8.72μ.

b) To a solution of 54 mg (0.1 mmol) of 2- (4- (o-methoxybenzenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxyisocrotonic acid in 0.5 ml: 10% oxalic solution in dioxane, a drop of dimethylformamide in dioxane is added, immediately evolving gas. The mixture is stirred for 2 hours at room temperature and the solvent and excess oxalic chloride are evaporated in vacuo. The residue is dried under high vacuum to give 2- (4- (o-methoxybenzenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxyisocrotonic acid chloride as a faint orange foam. IR spectrum (in CH 2 Cl 2): 5.60, 5.90, 8.70μ.

69 66389

Example 17:

A solution of 200 mg (0.254 mmol) of 2- (4- (p-toluenesulfonylthio) -3- (Da-tert-butyloxycarbonylamino-α-phenylacetylamino) -2-oxoazetidin-1-yl) -3 -methoxy-crotonic acid diphenylmethyl ester in 2 ml of dimethylformamide, stirred with 57 μl (0.38 mmol) of 1,5-diazabicyclo (b.4.o) undec-5-ene for 30 minutes at room temperature, then added ethyl acetate and washed with water and 2N hydrochloric acid until the acid reaction and saturated aqueous sodium chloride solution until neutral. The organic phase is dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed on silica gel thick-layer plates with toluene / ethyl acetate 1: 1 as eluent.

There is obtained 78- (Da-tert-butyloxycarbonylamino-α-phenylacetylamino) -3-methoxy-cef-2-em-4a-carboxylic acid diphenylmethyl ester, m.p. 166-168 ° (methylene chloride / pentane); thin layer chromatogram (piogram); diethyl ether): Rf value 0,50.51, UV spectrum (in ethanol): λ = 257 my (s = 3500); IR spectrum (methylene chloride): characteristic lines at 2.96, 5.63, 5.74, 5.85 (shoulder), 5.92, 6.16, 6, 64 and 6.72y; and 78- (D-α-tert-butyloxycarbonylamino-α-phenyl-acetylamino) -3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester, m.p. 162-163 ° (diethyl ether); thin layer chromatogram: Rf value: 0,0.33 (silica gel; diethyl ether); UV spectrum (in ethanol) = 265 my (e = 6600); 280 my (olake) (ε = 6200); IR spectrum (in methylene chloride): 2.92, 5.58, 5.64 (shoulder), 5.82, 6.22 and 6.67y.

The obtained compounds can be further treated as follows: a) A mixture of 8.8 g of 7β- (Da-tert-butyloxycarbonylamino-α-ferrylacetylamino) -3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester , 8.6 ml of anisole and 145 ml of trifluoroacetic acid, are stirred for 15 minutes at 0 [deg.] C., then 400 ml of precooled toluene are added and the mixture is evaporated under reduced pressure. The residue is dried under high vacuum, extracted with diethyl ether and filtered. There is thus obtained 7β- (D-α-phenyl-glycylamino) -3-methoxy-3-cephem-4-carboxylic acid trifluoroacetate in powder form, which is dissolved in 20 ml of water. Wash twice with 5 ml of ethyl acetate each time and adjust the pH to about 5 with a 20% solution of triethylamine in methanol to give a colorless precipitate. Stir for one hour in an ice bath, add 20 ml of acetone and allow to stand for 16 hours at about 4 °. The colorless precipitate is filtered off, washed with acetone and diethyl ether and dried under reduced pressure. There is thus obtained 3- (D-α-phenyl-glycylamino) -3-methoxy-3-cephem-4-carboxylic acid as an internal salt in the form of a microcrystalline powder which is further in the form of a hydrate, m.p. 174-176 ° (dec.); (a) = +149? (c = 1.03 in 0.1 N hydrochloric acid); thin layer chromatogram (silica gel; evolution with iodine): Rf 0, 0.36 (system: n-butanol / pyridine / acetic acid / water 40: 24: 6:30); ultraviolet absorption spectrum (in 0.1 N aqueous sodium hydrogen carbonate solution): λ ^ = 267y (ε = 6200); infrared absorption spectrum (in mineral oil): characteristic lines at 5.72μ, 5.94μ, 6.23μ and 6.60μ.

b) A mixture of 0.063 g of 73- (D- (x-tert-butyloxycarbonylamino-α-phenylacetylamino) -3-methoxy-2-cephem-4a-carboxylic acid diphenylmethyl ester, 0.1 ml of acetone and 1.5 ml of ml of trifluoroacetic acid, allow to stand for 15 minutes at 0 ° and then evaporate under reduced pressure. The residue is extracted with diethyl ether, filtered and dried. The colorless, powdered trifluoroacetate of 73- (Da-phenyl-glycylamino) -3-methoxy-2-cephem-4a-carboxylic acid thus obtained is dissolved in 0.5 ml of water and the pH of the solution is adjusted to about 5 by dropwise addition of 10% triethylamine solution. methanol. Stir for 1 hour in an ice bath, filter off the colorless precipitate and dry under high vacuum. There is thus obtained 73- (Da-phenyl-1H-glycylamino) -3-methoxy-2-cephem-4a-carboxylic acid as an internal salt, thin layer chromatogram (silica gel; evolution with iodine): Rf ~ 0.44 (system: n-butanol / pyridine) acetic acid / water 40: 24: 6:30); ultraviolet absorption spectrum (in 0.1 N aqueous sodium hydrogen carbonate solution: = 260μ.

c) To a solution cooled to 0 ° of 0.63 g of 7β- (D-α-tert, butyloxycarbonylamino-α-phenylacetylamino) -3-methoxy-2-cephem-4α-carboxylic acid diphenylmethyl ester in 25 ml methylene chloride, a solution of 0.20 g of 3-chloroperbenzoic acid in 5 ml of methylene chloride is added. The mixture is stirred for 30 minutes at 0 °, 50 ml of methylene chloride are added and the mixture is washed successively with 25 ml of saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution each time. The organic phase is dried over sodium sulfate and evaporated under reduced pressure.

71 66389 The residue is crystallized from a mixture of methylene chloride and diethyl ether; There is thus obtained 7β- (D-α-tert-butyloxycarbonylamino-α-phenylacetylamino) -3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester-1-oxide in the form of colorless needles, m.p. 172-175 °; thin layer chromatogram (silica gel): Rf -0.44 (system: acetic acid ethyl ester; evolution with iodine); ultraviolet absorption spectrum (in ethanol): = 277 my (e = 7200); infrared absorption spectrum (in methylene chloride): characteristic bands: 2.96y, 5.56y, 5.71y, 5.83y ;, 5.90y, G, 27y and 6.67y.

d) to a solution cooled to -10 ° containing 1.30 g of 76- (D-α-tert-butyloxycarbonylamino-α-phenylacetylamino) -3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester- 1-oxide in 30 ml of dimethylformamide, 2.80 g of phosphorus trichloride are added while protecting from air. After standing for 15 minutes, the reaction mixture is poured into a mixture of ice and aqueous dipotassium hydrogen phosphate solution; the aqueous mixture is extracted in each case with 100 ml of ethyl acetate. The organic extract is washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. The residue is chromatographed on silica gel; elute with diethyl ether from amorphous 7β- (Da-tert-butyloxycarbonylamino-α-phenylacetylamino) -3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester as a thin layer chromatographically pure product, Rf = 0.39 (system: diethyl ether, evolution on iodine vapor) (a) ^ = 1 ° + 1 ° (c = 0.981 in chloroform); ultraviolet absorption spectrum (in ethanol): λ = 264y (ε = 6300; infrared absorption spectrum (in methylene chloride): characteristic bands 2.94y, 5.62y, 5.84y, 5.88y, 6.25y and 6.70y.

The starting material can be prepared as follows: e) in a -15 ° cooled solution of 31.2 g (0.12 mmol) of DN-tert-butyloxycarbonylphenylglycine and 16.7 ml (0.12 mmol) of triethylamine in 300 ml tetrahydrofuran, add 16.5 ml (0.12 mmol) of chloroformic acid isobutyl ester and stir for 30 minutes at -10 °. A solution of 21.6 g (0.10 mmol) of 6-aminopenicillanic acid and 15.4 ml (0.11 mmol) of triethylamine in 300 ml of tetrahydrofuran / water 2: 1 is then added. The reaction mixture is stirred for 1 hour at 0 ° and 2 hours at room temperature, keeping the pH constant at about 6.9 by the addition of triethylamine. The reaction mixture is adjusted to pH 2.0 at 5 ° 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 sulfate and evaporated. The crude N-tert-butyloxycarbonyl-ampicillin obtained in the form of a pale yellow foam has an Rf value of 0,0.65 (silica gel; ethyl acetate / n-butanol / pyridine / acetic acid / water) in the thin layer chromatogram 42: 21: 21: 6: 10 ).

(f) To a solution of 57.22 g of crude N-tert-butyloxycarbonyl-ampicillin in 100 ml of glacial acetic acid, 21.6 ml of 30% hydrogen peroxide (0.25 mol) are added over 10 minutes and the mixture is stirred for 2.5 minutes. hours at room temperature. The reaction mixture is then poured into 2 liters of ice water, the N-tert-butyloxycarbonyl-ampicillin-1-oxide formed as a fluffy precipitate is filtered off, washed thoroughly with water and dried in vacuo. Extraction of the filtrate with ethyl acetate can give more crude N-tert-butylcarbonyl-ampicillin-1-oxide. Thin layer chromatogram (silica gel; ethyl acetate / n-butanol / pyridine / acetic acid / water 42: 21: 21: 6: 10) Rf value -0.30.

g) To a mixture of 67.7 g of crude N-tert-butyloxycarbonyl-ampicillin-1-oxide in 380 ml of dioxane is added a solution of 42 g (0.23 mol) of diphenyldiazomethane in 130 ml of dioxane, and stirred for 2.5 hours at room temperature. Add 5 ml of glacial acetic acid, then evaporate in vacuo. The residue is extracted with Petro-ether, the petroleum ether extract is discarded and the residue is crystallized from methylene chloride / ether / hexane. N-tert-butyloxycarbonyl-ampicillin-1-oxide-diphenylmethyl ester is obtained, melting point 164-166 °, (a) ^ = + 117o + 1 ° (c = 1, CHCl3); IR spectrum (in methylene chloride): characteristic bands 2.91, 2.94, 5.54, 5.69, 5.82 (shoulder), 5.88, 6.60, 6.68y, thin layer chromatogram mi: Rf value ~ 0.23 (silica gel; toluene / ethyl acetate 3: 1).

h) A mixture of 11.2 g (17.7 mmol) of N-tert-butyloxycarbonyl-ampicillin-1-oxide-diphenylmethyl ester and 3.26 g (19.5 mmol) of mercaptobenzthiazole in 170 ml of toluene is boiled for 3 hours. hours in a reflux condenser using a water separator and then evaporated. The residue is chromatographed on silica gel using toluene / ethyl acetate 3: 1 as eluent to give amorphous 2- (4- (benzthiazol-2-yldithio) -3- (α-tert-butyloxycarbonylamino-α-phenylacetylamino) -2-oxoazetidin-1-yl ) -3-methylene-butyric acid diphenylmethyl ester, thin layer chromatogram: Rf value 0,0.37 (silica gel; toluene / ethyl acetate 3: 1); IR spectrum (methylene chloride): characteristic bands 2, 94, 5, 64, 5.76, 5.86 (shoulder), 5.91 and 6.71μ.

73 6 6 3 8 9 i) To a solution of 2.34 g (3.0 mmol) of 2- (4- (benzthiazol-2-yldithio) -3- (α-tert-butyloxycarbonylamino-α-phenyl- acetylamino) -2-oxoazetidin-1-yl) -3-methylene-butyric acid diphenylmethyl ester in 30 ml of acetone / water 9: 1, 0.868 g (3.46 nunol) of silver toluene sulphinate are added at 0 ° and stirred for 1 hour in an ice bath. The precipitate formed is filtered off, the filtrate is dissolved in toluene and shaken with saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulfate and, after evaporation, amorphous 2- (4- (p-toluenesulfonylthio) -3- (α-tert-butyloxycarbonylamino-α-phenylacetylamino) -2-oxoazetidin-1-yl) -3-methylene is obtained. -butyric acid diphenylmethyl ester, thin layer chromatogram: Rf value 0,0.33 (silica gel; toluene / ethyl acetate 3: 1); IR spectrum (methylene chloride): characteristic bands 2.93, 5.57, 5.70, 5.82, 6.21, 6.65y.

j) to a -70 ° cooled solution of 2.30 g (3.0 mmol) of 2- (4- (p-toluenesulfonylthio) -3- (α-tert-butyloxycarbonylamino-?-phenylacetylamino) -2 -oxoazetidin-1-yl) -3-methyl-butyric acid diphenylmethyl ester in 230 ml of methylene chloride, a stream of ozone / oxygen (0.5 mmol of ozone per minute) is introduced over 7 minutes. 1 ml of dimethyl sulphide are added, after which the solution is further stirred for 1 hour without cooling and then evaporated in vacuo. The residue is recrystallized from methylene chloride / ether / hexane to give 2- (4- (p-toluenesulfonylthio) -3- (o-tert-butyloxycarbonylamino-α-phenylacetylamino) -2-oxoacetidin-1-yl) - 3-Hydroxy-crotonic acid-diphenyl lime style ester with a melting point of 182-184 °. UV spectrum (ethanol): (max = = = 3400); IR spectrum (methylene chloride): Characteristic bands 2.92, 5.59, 5.83, 592, 6.03 (shoulder), 6.18, 6.68y; thin layer chromatogram: Rf value 0,50.55 (silica gel; toluene / ethyl acetate 1: 1).

k) A solution of 0.54 g (0.7 mmol) of 2- (4- (p-toluenesulfonylthio) -3- (α-tert-butyloxycarbonylamino-α-phenylacetylamino) -2-oxoazetidine -1-yl) -3-hydroxycrotonic acid diphenylmethyl ester in 20 ml of methylene chloride / methanol 1: 1, stirred at 0 ° with an excess of ethereal diazomethane solution for 15 minutes, then evaporated in vacuo. Preparative layer chromatography of the residue on silica gel using toluene / ethyl acetate 1: 1 as eluent and eluting the band visible under UV light gave 2- (4- (p-toluenesulfonylthio) -3- (α-tert-butyloxycarbonylamino-α-phenyl) -phenyl 2-Oxo-azetidin-1-yl) -3-methoxy-crotonic acid diphenylmethyl ester, recrystallized from methylene chloride / diethyl ether / hexane, melting point 204-206 ° C, UV spectrum (ethanol): = 259 my (e = 16000 ); IR spectrum (Nujol): characteristic bands 2.93, 5.58, 5.80, 5.84, 5.93, 6.24, 6.57y, thin layer chromatogram: Rf value 0,0.33 (silica gel; toluene) / ethyl acetate 1: 1).

Example 18:

A mixture of 670 mg (1 mmol) of 2- (4- (p-toluenesulfonylthio) -3-phenylacetamido-2-oxoazetidin-1-yl) -3-methoxy-crotonic acid diphenylmethyl ester, 6.7 ml 1,2-Dimethoxyethane and 0.22 ml of 1,5-diazabicyclo (5.4.4) undec-5-ene are stirred for 25 minutes at room temperature under a nitrogen atmosphere. The reaction mixture is diluted with toluene and washed successively with 2N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. After preparative thick layer chromatography on silica gel with toluene / ethyl acetate 1: 1 76-phenylacetamido-3-methoxy-ceph-2-em-4a-carboxylic acid diphenylmethyl ester, m.p. 166-169 ° (methylene chloride / hexane), is obtained from the residue. ): = 258 my (ε = 4500), IR spectrum (methylene chloride): characteristic bands 2.93, 5.62, 5.73, 5.93, 6.66y, Rf value 0,50.54 (silica gel; system toluene / ethyl acetate 1: 1) and amorphous 76-phenylacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester, UV spectrum (ethanol): λ ^ = 258 my (ε = 6350), 264 my (e = 6350), 282 my (ε = 5600) (shoulder), IR spectrum (methylene chloride): characteristic bands 2.94, 5.63, 5.83, 5.94, 6.26, 6, 66y, Rf ~ 0.37 (silica gel; toluene / ethyl acetate 1: 1 system), 8: 1.

The work-up can be carried out as follows: 76-Phenylacetamido-3-methoxy-cef-2-em-4a-carboxylic acid * -diphenylmethyl ester can be modified according to Example 17c) 73-phenylacetamido-3-methoxy-cef-3-em-4- to carboxylic acid diphenyl methyl ester 1-oxide, m.p. 152-155 ° (from acetone / diethyl ether), Rf 0.31 (silica gel; system: ethyl acetate), UV spectrum (in 95% ethanol): λ = 288 my (e = 3610) 66389 and shoulder λ = 247 mu; IR spectrum (methylene chloride): characteristic bands 2.94, 5.59, 5.81, 5.95, 6.22 and 6.61μ,

A purer product consisting essentially of 7β-phenylacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester-13-oxide can be prepared as follows.

A solution of 6.7 g (10 mmol) of 2- (4- (p-toluenesulfonylthio) -3-phenylacetamido-2-oxoazetidin-1-yl) -3-methoxyisocrotonic acid diphenylmethyl ester in 67 ml: ssa abs. tetrahydrofuran, stirred with 2.28 ml (15 mmol) of 1,5-diazabicyclo (5.4.o) undec-5-ene for 15 minutes at 20 °, 0.7 ml of glacial acetic acid are added and then evaporated in vacuo, an oily dark residue is dissolved in 30 ml of methylene chloride and washed successively with 15 ml of water, 10 ml of 0.5N hydrochloric acid, 10 ml of saturated aqueous sodium bicarbonate solution and 10 ml of water. The aqueous phases are extracted with 10 ml of methylene chloride, the organic extracts are combined and stirred at 0 ° with 2.24 ml of 40% peracetic acid for 15 minutes in an ice bath. A solution of 1.50 g (6 mmol) of sodium thiosulfate pentahydrate in 20 ml of water is then added to the reaction mixture, stirred for 10 minutes and the aqueous phase is separated. The organic phase is washed once more with 10 ml of water, dried over sodium sulphate and evaporated in vacuo. Crystallization of the solid residue from methylene chloride / petroleum ether gives 7,3-phenylacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester-β-oxide, m.p. 175-176 °; thin layer chromatogram (silica gel): Rf value 0,10.1 (toluene / ethyl acetate 1: 1); UV spectrum (ethanol): λιη &] <. Ε = 279 my (ε = 7300); IR spectrum (methylene chloride): characteristic bands at 2.94, 5.56, 5.78, 5.91, 6.20, 6.67μ.

According to Example 17d), 7β-phenylacetamido-3-methoxy-ceph-3-em-carboxylic acid diphenylmethyl ester can be obtained from the 1-oxides.

The latter can be saponified according to Example 17a) to give crude 73-phenylacetamido-3-methoxy-ceph-3-em-4-carboxylic acid, which can be purified by chromatography on silica gel (containing 5% water) with methylene chloride containing 30-50% acetone and followed by lyophilization from dioxane, UV spectrum (in 95% ethanol): = 265 my (ε = 5800); IR spectrum (methylene chloride di): characteristic bands at 3.03, 5.60, 5.74, 5.92, 6.24, and 6.67y.

76 6 6 3 8 9 The starting materials and intermediates can be prepared as follows: a) To a mixture of 37.24 g (0.1 mol) of penicillin G potassium salt in 90 ml of water, 7.3 ml of acetone and 150 ml of chloroform are added while stirring at 0 ° for 40 minutes 19 4 ml of 40% Peracetic acid. After 15 minutes, 28 g (0.15 mol) of benzophenone hydrazone are added portionwise at the same temperature, followed by 6.3 ml of 1% aqueous potassium iodide solution and finally, dropwise over 1.5 hours, a mixture of 32.5 ml of 10% sulfuric acid and 28 ml. ml of 40% peracetic acid. At the end of the addition, stir for a further 30 minutes at 0 °, warm to 15 ° and dilute with 400 ml of chloroform. The aqueous phase is separated and the organic phase is washed successively with 300 ml of 5% aqueous sodium bisilphite solution, 300 ml of saturated aqueous sodium bicarbonate solution and 300 ml of saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. The evaporation residue is recrystallized from ethyl acetate / petroleum ether to give 6-phenylacetamidopenicillanic acid diphenylmethyl ester-1B-oxide, m.p. 139 °; thin layer chromatogram (silica gel): Rf value -0.40 (toluene / ethyl acetate system 1: 1), IR spectrum (methylene chloride): characteristic lines at 2.94, 5.56, 5.70, 5, 92 and 6.57μ.

(b) To a mixture of 5.165 g (10 mmol) of 6-phenylacetamidopenicillanic acid diphenylmethyl ester-1B-oxide in 50 ml of toluene and 0.5 ml of glacial acetic acid is added 1.83 g (11 mmol) of 2-mercapto- benzthiazole and boil for 2 hours in a reflux condenser equipped with a water separator. Upon cooling, 2- (4- (benzthiazol-2-yldithio) -3-phenylacetamido-2-oxoazetidin-1-yl) -3-methylenobutyric acid diphenylmethyl ester crystallizes spontaneously. Recrystallize once from methylene chloride / diethyl ether to give crystals with a melting point of 134-136 ° C. Thin layer chromatogram (silica gel): Rf 0.52 (toluene / ethyl acetate 1: 1 system); UV spectrum (ethanol): λ. = 269 sec (ε = 12700); IR spectrum (methylene chloride): characteristic bands at 2.90, 5.60, 5.72, 5.92 and 6.61p.

(c) The product obtained in (b) need not be isolated for further processing. After cooling, the reaction mixture can be diluted directly with 30 ml of toluene, 3.95 g (15 mmol) of silver p-toluenesulfinate are added and stirred for 2 hours at room temperature. The precipitated yellow precipitate is filtered off in Hyflo and the residue is washed with toluene. The filtrate is shaken with saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. The evaporation residue is dissolved in toluene and petroleum ether is added. The precipitate is filtered off and recrystallized from ethyl acetate / petroleum ether. The obtained 2- (U- (p-toluenesulfonylthio) -3-phenylacetamido-2-oxoazetidin-1-yl) -3-methylenebutyric acid diphenylmethyl ester has a melting point of 75 °; thin layer chromatogram (silica gel): Rf value 0,0.47 (toluene / ethyl acetate system 1: 1), UV spectrum (ethanol): = 259 my (e = 4300); IR spectrum (methylene chloride): characteristic bands at 2.92, 5.62, 5.74, 5.94 and 6.63μ.

d) A solution of 655 mg (1 mmol) of 2- (4- (p-toluenesulfonylthio) -3-phenylacetamido-2-oxoazetidin-1-yl) -3-methylenebutyric acid diphenylmethyl ester in 65 ml of methylene chloride , is treated at -65 ° with an ozone / oxygen mixture until the mixture turns slightly blue. 0.5 ml of dimethyl sulphide are added, then the mixture is allowed to warm to room temperature and evaporated in vacuo. The resulting crude 2- (4- (p-toluenesulfonylthio) -3-phenylacetamido-2-oxoacetidin-1-yl) -3-hydroxy-crotonic acid diphenylmethyl ester, Rf ~0.46 (silica gel; toluene / ethyl acetate system 1: 1), IR spectrum (methylene chloride): characteristic bands at 2.95, 5.60, 5.98, 6.18, 6.61μ. can be processed without further purification.

e) The crude product obtained in d) is dissolved in 20 ml of methanol and at 0 ° ethereal diazomethane solution is added until a permanent yellow coloration. The solvent is evaporated off in vacuo and the residue is purified by preparative thick layer chromatography on silica gel with toluene / ethyl acetate 1: 1 as eluent. 2- (4- (p-Toluenesulfonylthio) -3-phenylacetamido-2-oxoazetidin-1-yl) -3-methoxy-crotonic acid diphenylmethyl ester is obtained. Rf value 0,20.2 (silica gel; toluene / ethyl acetate system 1: 1), IR spectrum (methylene chloride): characteristic bands at 2.94, 5.61, 5.96, 6.24, 6.62μ and small amounts of 2- (4- (p-toluenesulfonylthio) -3- phenylacetamido-2-oxoazetidine-1-yl) -3-me-methoxy-isocrotonic acid, diphenylmethyl ester.

78 66389

Example 19:

To a solution of 6.06 g (10 nunols) of isomeric 2- (4- (p-toluenesulfonylthio) -3-phenoxyetamido-2-oxoazetidin-1-yl) -3-methoxy-croton and isocrotonic acid benzyl ester 3: 1-mixture and 2.33 g (15 mmol) of p-toluenesulphonic acid in 200 ml of absolute tetrahydrofuran are added at room temperature while stirring 5.20 ml (35 mmol) of 1,5-diazabicyclo (5.4.o) undec-5-ene . The mixture is further stirred for 40 minutes at room temperature, 500 ml of methylene chloride are added and the mixture is washed successively with 200 ml of 0.5N hydrochloric acid, 200 ml of water, 200 ml of Q, 5N sodium bicarbonate and 200 ml of water. The methylene chloride phase is dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed on 200 g of acid-washed silica gel with toluene / ethyl acetate 3: 1 to give diethyl ether fractions to give 76-phenoxyacetamido-3-methoxy-ceph-2-em-4a-carboxylic acid benzyl ester, m.p. 148. -151 °. IR spectrum (methylene chloride): characteristic bands at 5.60, 5.75, 5.90, 8.25y; (α) D = + 284 ° + 1 ° (c = 1; chloroform).

Toluene / ethyl acetate 2: 1 also elutes with diethyl ether precipitated 7B-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid benzyl ester, m.p. 89-91 °; IR spectrum (methylene chloride): characteristic bands at 5.60, 5.85, 5.90; (α] D = + 47 ° + 1 ° (c = 1; chloroform).

The ratio of kef-2-em to kef-3-em is about 3: 1.

The compounds can be further treated as follows: to a solution prepared at 0 ° with 454 mg (1 mmol) of 76-phenoxyacetamido-3-methoxy-cef-2-em-4a-carboxylic acid benzyl ester and 7fS-phenoxyacetamido-3- about 3: 1 of a methoxy-cef-3-em-4-carboxylic acid benzyl ester in 30 ml of tetrahydrofuran is added with stirring, 15 ml of precooled 0.1 N potassium hydroxide solution. The mixture is further stirred for 5 minutes at 0 °, then 100 ml of ice water and 100 ml of precooled methylene chloride are added and the mixture is stirred vigorously. Addition of slightly saturated aqueous sodium chloride solution causes separation into two phases. The methylene chloride phase is separated off and the aqueous phase is washed with a further 30 ml of methylene chloride. Pour 50 ml of methylene chloride into the aqueous phase, add 10 ml of 2N hydrochloric acid and shake. After separation of the organic phase, 30 ml of methylene chloride are extracted twice more in each case. The combined methylene chloride extracts are dried over sodium sulfate and evaporated in vacuo. The white foam obtained crystallizes on addition of chloroform and diethyl ether to give 73-phenoxyacetamido-3-methoxy-cef-2-em-4oc-carboxylic acid with a melting point of 142 ° (decomposition). IR spectrum (KBr): characteristic lines at 5, 65, 5.75, 5.95μ.

The starting material can be prepared as follows: a) To a solution of 36.6 g (0.1 mol) of 6-phenoxyacetamidodenicillanic acid 16-oxide in 150 ml of dry dimethylformamide is added, under cooling with tap water, 20 ml of (14.6 g, 0.145 mol) triethylamine and 17 ml (24.5 g, 0.143 mol) benzyl bromide. The mixture is stirred for 20 hours at room temperature and then poured into ice water. The precipitate is filtered off with suction, washed with about 1000 ml of water, dried under vacuum at 40 ° for 2 days, then dissolved in 200 ml of methylene chloride and dried once more with sodium sulphate. After evaporation of the solvent in vacuo, the remaining white foam is dissolved in 150 ml of ethyl acetate and then allowed to stand first at room temperature, then at -20 °, whereby pure 6-phenoxyacetamido-penicillanic acid benzyl ester 1 H-oxide crystallizes, m.p. 139-140 °; IR spectrum (methylene chloride); characteristic lines at 5.55, 5.75, 5.90, (a) ^ = + 174 ° + 1 ° (c = 1, chloroform).

Chromatography of the mother liquor on 250 g of acid-washed silica gel with toluene / ethyl acetate (1: 1) gives more crystalline benzyl ester-1β-oxide.

b) 4.56 g (10 mmol) of 6-phenoxyacetamido-penicillanic acid benzyl ester 1-Boxide and 1.84 g (11 mmol) of 2-mercaptobenzthiazole are heated in 100 ml of toluene under reflux for 5 hours (bath temperature 135 °). The mixture is allowed to stand, whereupon 2- (4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methylenebutyric acid benzyl ester crystallizes. The crystals are filtered off with suction, washed with 50 ml of toluene and dried under high vacuum. Chromatography of the mother liquor on 70 g of acid-washed silica gel with toluene-ethyl acetate (3: 1) gives an additional crystalline product. The melting point of the pure product is 150 ~ 153 °; IR spectrum (methylene chloride): characteristic bands 5.60, 5.75, 5.90μ; (α) D = -112 ° + 1 ° (c = 1, chloroform).

c) Through a solution of 6.06 g (10 mmol) of 2- (4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -80,6389 3-methylene -butyric acid benzyl ester in 300 ml of methylene chloride, run at -20 ° until the oxygen / ozone mixture is completely ozonated (checked by thin layer chromatography, silica gel, toluene / ethyl acetate 1: 1). 50 ml of a 10% aqueous sodium bisulphite solution are then added to the mixture and stirred until 5 ozide can no longer be detected with potassium iodide starch. 300 ml of water are added to the mixture and the product is partitioned between the two phases formed. The organic phase is dried over sodium sulfate and the solvent is removed. The residue is triturated in 100 ml of ether-pentane (1: 1) at 0 ° to give 2- (4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3- hydroxy-crotonic acid benzyl ester crystallizes, melting point 58-62 °, IR spectrum (methylene chloride): characteristic bands ry / \ 5.60, 5.90, 6.00μ, (α] ρ § -92 ° + 1 ° (c = 1, chloroform).

d) 6.08 g (0.01 mol) of 2- (α- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoacetidin-1-yl) -3-hydroxy-crotonic acid benzyl ester and 3, 50 g (0.013 mol) of silver p-toluenesulphinate are stirred in 200 ml of acetone-water (1: 1) for 60 minutes at room temperature. The yellow precipitate formed is filtered off with Celite, the residue is washed with acetone and the filtrate is evaporated in vacuo to a volume of about 20 ml. The product is then partitioned between methylene chloride and dilute aqueous sodium sulfate. The organic phase is dried over sodium sulfate and the solvent is evaporated off under vacuum. The residue is dissolved in 70 ml of ethyl acetate, if necessary with heating, filtered off with a small amount of insoluble product and re-evaporated. Addition of 100 ml of ether-pentane at 0 ° crystallizes 2- (u- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoacetidin-1-yl) -3-hydroxy-crotonic acid benzyl ester with a melting point of 151- 152 °; IR spectrum (methylene chloride): characteristic bands at 5, 60, 5.90, 6, 00, 8.75, (α) D = -16 ° + 1 ° (c = 1, chloroform).

e) To a solution of 5.97 g (0.01 mol) of pure 2- (α- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxazetidin-1-yl) -3-hydroxy-crotonic acid benzyl ester in 50 ml in methylene chloride, is added dropwise at 0 ° while stirring the ethereal diazomethane solution until the starting material is completely methylated (control: thin layer chromatography on silica gel, toluene / ethyl acetate 1: 1). Excess diazomethane is neutralized with a few drops of glacial acetic acid M 66389 (excess acetic acid to be avoided), after which the mixture is evaporated in vacuo. The yellowish foamy residue is crystallized from diethyl ether / pentane (1: 1) to give 2- (4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxy-crotonic acid benzyl ester and 2- A mixture of isomers of (4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxyisocrotonic acid benzyl ester in a ratio of about 3: 1.

Repeated chromatography on silica gel with toluene / acetic acid ethyl ester 1: 1 can separate both isomers. The obtained 2- (4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxy-crotonic acid benzyl ester has a melting point of 166-168 °; (a) = 3636 ° + 1 ° (c = 1, chloroform), IR spectrum (methylene chloride): characteristic lines at 5.60, 5.80, 5.90, 8.72μ; NMR spectrum (chloroform): characteristic bands at 2.12 (s); 5.00 (dd); 5.90 Cd) ppm, thin layer chromatogram: Rf value -0.10 (silica gel; toluene / ethyl acetate 1: 1).

The obtained 2- (4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxyisocrotonic acid benzyl ester has a melting point of 59-63 °, (a) = -1 ° + 1 ° ( c = 1, chloroform), IR spectrum (methylene chloride): characteristic bands at 5.60, 5.87, sh, 5.90, 8.72μ, NMR spectrum (chloroform): characteristic bands at 2.32 ( s), 5.45 (d, d), 5.72 (d) ppm, thin layer chromatogram: Rf value 0,0.13 (silica gel, toluene / ethyl acetate 1: 1).

Example 20:

To a solution of 534 mg (1 mmol) of 2- (4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxyisocrotonic acid methyl ester and 2- (4- ( p-Toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxy-crotonic acid methyl ester in about 4: 1 in 20 mL of tetrahydrofuran is added with stirring 302 mg (2 mmol) of 1.5- diazabicyclo (5.4, θ) undec-5-ene and stir for 40 minutes. The mixture is diluted with 70 ml of methylene chloride and washed successively with dilute hydrochloric acid, water, dilute aqueous sodium bicarbonate solution and again with water. The organic phase is dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed on 15 g of acid-washed silica gel with toluene / ethyl acetate 2: 1 and then 1: 1, eluting first with pure 7fS-phenoxyacetamido-3-methoxy-cef-2-em-4a-carboxylic acid methyl ester, IR- spectrum (in methylene chloride): characteristic bands at 5.60, 5.70, 5.90, 8.25μ, followed by «2,666389 of pure 7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid. methyl ester, IR spectrum (in methylene chloride): characteristic lines: 5.60, 5.85, 5.90, 7.10μ, as a colorless foam.

The obtained compounds can be further treated as follows: To a solution cooled in an ice bath containing 382 mg of 7β-phenoxyacetamido-3-methoxy-ceph-2-em-4a-carboxylic acid methyl / ester in 30 ml of tetrahydrofuran is added, with stirring, 15 ml of cooled O , 1 N aqueous potassium hydroxide solution. After 5 minutes, 100 ml of water and 70 ml of methylene chloride are added and the mixture is acidified by adding 10 ml of 1N aqueous hydrochloric acid. The methylene chloride phase is separated off and the aqueous phase is extracted with 30 ml of methylene chloride. The combined organic phases are dried over sodium sulfate and evaporated in vacuo. The residue is crystallized from chloroform / diethyl ether to give 76-phenoxyacetamido-3-methoxy-cef-2-em-4a-carboxylic acid, m.p. 142 ° (decomp.).

The same compound having a melting point of 142 ° (decomposed) is obtained by saponification of 7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid methyl ester as described above with 0.1 N potassium hydroxide solution.

The starting materials can be prepared as follows: a) A solution of 19.25 g (50 mmol) of 6-phenoxyacetamido-penicillanic acid methyl ester-1β-oxide and 9.4 g (55 mmol) of 2-mercaptobenzthiazole in 500 ml of dry toluene, boil for 8 hours under reflux and then concentrate in vacuo. The residue is dissolved with heating (about 80 °) in 400 ml of ethyl acetate, treated with 0.2 g of activated carbon and suction filtered through electrically heated sintered glass. On cooling, 2- (4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methylenebutyric acid methyl ester with a melting point of 132-134 ° is isolated. Additional of this compound (melting point 135-137 °) can be obtained from the mother liquors.

b) Through a solution of 20.6 g (40 mmol) of 2- (4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methylenebutyric acid methyl ester In 400 ml of acetone, the ozone / oxygen mixture is passed at -20 ° until no starting material (silica gel, toluene / ethyl acetate 1: 1) can be detected by thin layer chromatography. 40 ml of dimethyl sulphide are then added to the mixture and the mixture is stirred for 3 days at room temperature until no ozone can be detected with potassium 66389 iodide starch. The mixture is concentrated in vacuo and the liquid residue is poured into 400 ml of ice-water. The precipitate is filtered off, washed with 200 ml of ice water, dried in vacuo and recrystallized at 0 ° from diethyl ether / pentane. The obtained 2- (4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-hydroxycrotonic acid methyl ester has a melting point of 127-130 °; IR spectrum (in methylene chloride): characteristic bands 5.60, 5.90, 6.00, 8.10μ. Chromatography of the mother liquors on silica gel with toluene / ethyl acetate 3: 1 gives more product.

c) To a solution of 4.85 g (0.01 mol) of 2- (4- (benzthiazol-2-ylthio) - (3-phenoxyacetamido-2-oxoacetidin-1-yl) -3-hydroxycrotonic acid methyl ester in 50 ml of methylene chloride, is added at 0 ° with stirring until the ethereal diazomethane solution is stirred until, after stirring for 15 minutes, no starting material can be detected by thin layer chromatography (silica gel, toluene / ethyl acetate 1: 1). Excess diazomethane is neutralized with as little acetic acid as possible and the mixture is evaporated in vacuo. The residue consists of 2- (4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxyisocrotonic acid methyl ester and 2- (4- (benzthiazol-2-yldithio) From a mixture of 3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxy-crotonic acid methyl ester in a ratio of about 4: 1. IR spectrum (in methylene chloride): characteristic bands: 5.60, 5.85, 5.90 , 9.05, 10.00μ.

d) A mixture of 5.03 g (0.01 'mol) of 2- (4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxyisocrotonic acid -methyl ester and the corresponding crotonic acid methyl ester in a ratio of about 4: 1, 3.50 g (0.098 mol) of silver p-toluenesulfinate and 200 ml of acetone / water 9: 1, stirred for 40 minutes at room temperature and then filtered through Celite. through. The filter residue is washed with acetone and the combined filtrates are concentrated in vacuo to about 20 ml. 100 ml of methylene chloride and 100 ml of dilute aqueous sodium sulphate solution are added, followed by shaking, the aqueous phase is separated and the methylene chloride phase is dried over sodium sulphate and evaporated in vacuo. The residue is purified by trituration at 0 ° with diethyl ether / pentane and filtered. 2- (4- (p-Toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxyisocrotonic acid methyl ester and 2- (4- (p-toluenesulfonyl lithio) -3-phenoxyacetamido are obtained. - 2-oxoacetidin-1-yl) -3-846389 methoxy-crotonic acid methyl ester in a ratio of about 4: 1 in the form of a white powder. IR spectrum (in methylene chloride): characteristic bands. 5.60, 5.85, 5.90, 8.75y.

Example 21:

A solution of 731 mg (1 mmol) of 2- (4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-benzyloxy-croton and the corresponding isocrotone p-nitrobenzyl ester 1: 1 mixture is stirred in a mixture of 0.185 ml (1.2 mmol) of 1,5-diazabicyclo (5.4.4) undec-5-ene in 20 ml of dry tetrahydrofuran over a period of exactly 35 minutes at room temperature. To the mixture is added 50 ml of methylene chloride and washed successively with dilute hydrochloric acid, water and dilute aqueous sodium bicarbonate solution. The organic phase is triturated with sodium sulfate and evaporated in vacuo. The residue is chromatographed on 25 mg of acid-washed silica gel with toluene / ethyl acetate 3: 1. A mixture of cef-2-em and cef-3-em is obtained in a ratio of about 3: 1, which can be separated by chromatography on pure isomers to give 78-phenoxyacetamido-3-benzyloxy-cef-2-em-4a-carboxylic acid. p-nitrobenzyl ester with a melting point of 160-162 ° (diethyl ether / pentane); IR spectrum (methylene chloride): characteristic bands of 5,6, 5,7, 5,9, 7,4y, and 7β-phenoxyacetamido-3-benzyloxy-ceph-3-em-4-carboxylic acid p-nitrobenzyl ester in the form of a colorless foam , IR spectrum (methyl-1-ene chloride): characteristic bands 5.6, 5.8 sh, 5.9, 7.9, 8.4μ.

The resulting mixture of isomers can be further treated as follows: 7H-phenoxyacetamido-3-benzyloxy-cef-2-em-4a-carboxylic acid p-nitrobenzyl ester and 78-phenoxyacetamido-3-benzyloxy-cef-3-em-4-carboxylic acid-p The 3: 1 mixture of isomers of nitrobenzyl ester is dissolved in 8 ml of trifluoroacetic acid and stirred for 90 minutes at room temperature. The reaction mixture is evaporated in vacuo and the trifluoroacetic acid residues are repeatedly removed with toluene. The residue is chromatographed on 20 g of acid-washed silica gel with toluene / ethyl acetate (3: 1) to give 78-phenoxyacetamido-3-hydroxy-ceph-3-em-4-carboxylic acid p-nitrobenzyl ester in the form of a colorless foam, IR spectrum (methylene chloride). ): characteristic bands 2.95, 3.3, 5.6, 5.75 sh, 5.9, 5.95 sh, 6.55, 7.45, 8.15, 8.3 μ; NMR spectrum (Deuterochloroform): characteristic bands: 3.4 (2H, AB q, J = 17 Hz), 4.57 (2H, s), 5.06 (1H, d, J = 5 Hz), δ, 35 (2H, AB q, J = 14 Hz), 5.7 (1H, dd, J = 5, 10 Hz), 6.8-8.4 85 66389 OOH, c), 11.4- (1H, br.s.) ppm.

The starting material can be prepared as follows:

To a solution of 1.282 g (2 mmol) of 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-hydroxy-crotonic acid p-nitrobenzyl ester in 4 ml: 30 ml of an in situ solution of 1.2 g (about 10 mmol) of phenyldiazomethane in ether (prepared from N-benzyl-N-nitrotoluenesulfonamide) is added at room temperature.

The mixture is refluxed for 6 hours at a bath temperature of 45 °, diluted with 100 ml of methylene chloride and then washed with 100 ml of water. The organic phase is dried over sodium sulfate, evaporated in vacuo and dried under high vacuum. The yellow oil obtained is chromatographed on 100 g of oxygen-washed silica gel using toluene / ethyl acetate 3: 1 and 2: 1 as eluent. Obtained from 2- (4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-benzyloxy-crotonic acid p-nitrobenzyl ester and 2- (4- (p-toluenesulfonylthio) -3- a mixture of isomers of phenoxyacetamido-2-oxoazetidin-1-yl) -3-benzyloxy-isocrotonic acid p-nitrobenzyl ester in a ratio of about 1: 1, which can be separated into the individual isomers by repeated chromatography as above. IR spectrum of the faster moving crotonic acid derivative (methylene chloride): characteristic bands; 5.6, 5.80, 5.90, 8.75μ; NMR Spectrum (Deuteroclordbrm): characteristic bands: 2.2 (s), 5.05 (dd), 5.93 (d) ppm; thin layer chromatogram: Rf value 0,3.3 (silica gel; toluene / ethyl acetate 2: 1); IR spectrum of the slower isocrotonic acid derivative (methylene chloride): characteristic bands: 5.6, 5.85 sh, 5.90, 8.75 μ; NMR spectrum (deuterochloroform): characteristic bands 2.5 (s), 5.41 Cdd), 5.77 (d) ppm; thin layer chromatogram: Rf value 0,0.25 (silica gel; toluene / ethyl acetate 2: 1). Example 22: 405 mg (0.5 mmol) of 2- (4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-diphenylmethoxy-crotonic acid p-nitrobenzyl ester and the corresponding isomeric isocrotonic acid The ester isomer mixture is dissolved in 8 ml of dry tetrahydrofuran containing 0.9 ml (0.6 mmol) of 1,5-diazabicyclo (5.4.0) undec-1-ene and stirred for exactly 45 minutes at room temperature. The yellow reaction mixture is diluted with 25 mL of methylene chloride and washed with 0.5 N hydrochloric acid, water and dilute aqueous sodium bicarbonate. The organic phase is dried over sodium sulfate and evaporated.

86 66389

Obtained from 73-phenoxyacetamido-3-diphenylmethoxy-ceph-2-em-4a-carboxylic acid p-nitrobenzyl ester and 73-phenoxyacetamido-3-diphenylmethoxy-cef-3-em-4-carboxylic acid p-nitrobenzyl ester, IR spectrum (methylene chloride ): characteristic lines 5.60, 5.70, 5, 90, 6, 55, 7.40y.

The resulting isomeric mixture of both compounds can be further treated as follows:

A solution of 340 mg of 73-phenoxyacetamido-3-diphenylmethoxy-ceph-2-em-4a-carboxylic acid p-nitrobenzyl ester and 73-phenoxyacetamido-3-diphenylmethoxy-cef-3-em-4-carboxylic acid p- the resulting mixture of isomers of nitrobenzyl ester in a mixture of 0.5 ml of trifluoroacetic acid and 9.5 ml of methylene chloride is stirred for 40 minutes at room temperature. The mixture is evaporated in vacuo, toluene is added to the residue and evaporated again. The residue obtained (still containing trifluoroacetic acid) is chromatographed on 15 g of acid-washed silica * toluene / ethyl acetate 3: 1 to give 73-phenoxyacetamido-3-hydroxy-ceph-3-em-4-carboxylic acid p-nitrobenzyl ester. ; IR spectrum (methylene chloride): characteristic bands: 2.95, 3.3, 5.6, 5.75 sh, 5.9, 5.95 sh, 6.55, 7.45, 8.15, 8, 3μ; NMR spectrum (Deuterochloroform): characteristic bands: 3.4 (2H, AB q,} = 17 Hz), 4.57 (2H, s), 5.06 (1H, d,} = 5 Hz), δ, 35 (2H, AB q,} = 14 Hz), 5.7 (1H, dd,} = 5, 10 Ha), 6.8-8.4 (10H, c), 11.4 (1H, br . s.) ppm.

The starting material can be prepared as follows:

To a solution of 641 mg (1 mmol) of 2- (4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-hydroxycrotonic acid p-nitrobenzyl ester, 0.5 mL in distilled dioxane, a solution of 350 mg (1.75 mmol) of diphenyldiazomethane in 0.3 ml of dioxane is added and the reaction mixture is heated at 50 [deg.] C. for 36 hours without stirring. The mixture is evaporated in vacuo, the residual dioxane is removed by repeated evaporation with toluene and the residue is chromatographed on 20 g of acid-washed silica gel with toluene / ethyl acetate (7: 1) and (3: 1).

Obtained from 2- (4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-diphenylmethoxy-crotonic acid p-nitrobenzyl ester and 2- (4- (p-toluenesulfonylthio) -3- phenoxyacetamido-2-oxoazetidin-1-yl) -3-diphenylmethoxyisocrotonic acid p-nitrobenzyl ester, IR spectrum (methylene chloride): characteristic bands: 5.6, 5.85 sh, 5.9, 6.25, 6.55, 7.43, 8.75p.

87 6 6 3 8 9

Example 23:

To a solution of 933 mg (1.5 mmol) of 2- (4- (benzthiazol-2-yldithio) -3-phenoxyacetamido ** 2-oxoazetidin-1-yl) -3-benzyloxy-crotonic acid methyl ester and the like a mixture of isomrotonic acid methyl ester in a ratio of about 1: 1 and 350 mg (2.25 mmol) of p-toluenesulphonic acid in 30 ml of dry tetrahydrofuran, 800 mg (5.25 mmol) of 1,5-diazabicyclo (5.4. o) undec-5-ene and stir for exactly 40 minutes 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. Chromatography on toluene / ethyl acetate (5: 1) on silica gel gives 76-phenoxyacetamido-3-benzyloxy-ceph-3-em-4-carboxylic acid methyl ester and 78-phenoxyacetamido-3-benzyloxy-cef-2-em-4-carboxylic acid methyl ester: IR spectrum (methylene chloride): characteristic bands: 5.60, 5.72, 5.85 sh, 5.90p.

The starting material can be prepared as follows:

To a solution of 483 mg (1 mmol) of 2- (4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-hydroxy-crotonic acid methyl ester in 1.5 mL: In methylene chloride / diethyl ether, 960 mg (about 8 mmol) of freshly distilled phenyldiazomethane are added and the mixture is stirred for 20 hours at 0 °. The reaction mixture is diluted with methylene chloride and washed with water. The organic phase is dried over sodium sulfate, evaporated in vacuo and dried under high vacuum. The residue is chromatographed on 10 g of acid-washed silica gel with toluene / ethyl acetate (2: 1) to give 2- (4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoacetidin-1-yl) -3- a mixture of isomers of benzyloxy-crotonic acid methyl ester and the corresponding isochrotonic acid methyl ester in a ratio of about 1: 1; IR spectrum (methylene chloride): characteristic bands: 5.6, 5.85 sh, 5.9, 9.9 y.

Example 24:

Example 5d) can be obtained, respectively, by reacting 1.16 g (3 mmol) of the 7β-amino-3-methoxy-ceph-3-em-4-carboxylic acid hydrochloride dioxanate obtained according to the invention with 1.5 ml ( 6.2 mmol) of bis- (trimethylsilyl) acetamide followed by 88 66389 a) with 765 mg (3.6 nunoles) of Da-amino- (2-thienyl) -acetic acid chloride hydrochloride 78- (Da- amino-α- (2-thienyl) -acetylamino) -3-methoxy-3-cephem-4-carboxylic acid in the form of an internal salt, m.p. 140 ° (decomp.); thin layer chromatogram (silica gel; identification with iodine): Rf 0, 0.22 (system: n-butanol / acetic acid / water 67:10:23) and Rf 0,5 0.53 (system: isopropanol / formic acid / water 77: 4:19); ultraviolet absorption spectrum: λ ^ = 235 my (ε = 11400) and = 272 my (e = 6100) in 0.1 hydrochloric acid, and λ = 238 my (e = 11800) and λ = 267 my (ε = 6500) in 0.1 N aqueous sodium hydrogen carbonate solution.

b) with 940 mg (4.5 nunols) of Da-amino- (1,4-cyclohexadienyl) -acetic acid hydrochloride, 78- (Da-amino-α- (1,4-cyclohexadienyl) -acetylamino) -3-methoxy-3-cephem-4-carboxylic acid in the form of an internal salt, m.p. 170 ° (decomp.); thin layer chromatogram (silica gel; detection with iodine): Rf ~ 0.19 (system: n-butanol / acetic acid / water 67:10:23) and Rf - 0.58 (system: isopropanol / formic acid / water 77: 4: 19 ); ultraviolet absorption spectrum: = 267 my (ε = 6,300) in 0.1N hydrochloric acid, and λ ^ = 268 my (ε = 6600) in 0.1N aqueous sodium hydrogen carbonate solution, (a) ^ = + 88 ° + 1 ° (c = 1 , 06; 0.1N hydrochloric acid) and c) with 800 mg (3.6 mmol) of Da-amino-4-hydroxyphenyl-acetic acid chloride hydrochloride, 78- (Da-amino-α- (4-hydroxy- phenyl) -acetylamino) -3-methoxy-3-cephem-4-carboxylic acid in the form of an internal salt, m.p. 243-144.5 ° (sintered from 231 °) (decomposed); thin layer chromatogram (silica gel; detection with iodine):

Rf ~ 0.24 (system: n-butanol / acetic acid / water 67:10:23) and

Rf - 0.57 (system: isopropanol / formic acid / water 77: 4: 19); ultraviolet absorption spectrum: = 22 8 my (e = 12000) and 271 my (ε = 6900) in 0.1 N hydrochloric acid, and = 227 my (ε = 10500) and λ,, = 262 my (ε = 8000) in 0.1 N aqueous sodium - in bicarbonate solution, (a) p = + 165 ° +1 (c = 1.3; 0.1 N hydrochloric acid).

Example 25:

Correspondingly, the following intermediates can be prepared from suitable intermediates according to the invention: 89 66389 7 0-Amino-3-methoxy-3-cephem-4-carboxylic acid diphenyl lime style ester, thin layer chromatogram (silica gel): Rf = 0/17 (system: ethyl acetate, evolution with iodine); ultraviolet absorption spectrum (in 95% aqueous ethanol): Xmakg = 258 my (e = 5700); infrared absorption spectrum (in dioxane); characteristic bands 2.87 μ, 5.62 μ and 6.26 μ, 3-n-butyloxy-70-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester, m.p. 168-170 °, (ot) = + 55 ° ± 1 ° (c = 0.38 in chloroform); ultraviolet absorption spectrum (in 95% aqueous ethanol): λ ks = 264 m (e = 7300); infrared absorption spectrum (in methylene chloride): characteristic bands 2.98 μ, 5.62 μ, 5.81 μ, 5.92 μ, 6.25 μ and 6.62 μ; 3-n-Butyloxy-7β- (D-α-tert-butyloxycarbonylamino-α-phenyl-acetylamino) -3-cephem-4-carboxylic acid diphenylmethyl ester, (α) D = + 11 ° ± 1 ° (c = 0.98 in chloroform); ultraviolet absorption spectrum (in 95% aqueous ethanol): μg = 264 my (ε = 6100); infrared absorption spectrum (in methylene chloride): characteristic bands 2.88 y, 5.63 y, 5.84 y (shoulder), 5.88 y, 6.26 y and 6.71 μ; 3-n-butyloxy-70- (D-α-phenyl-glycylamino) -3-cephem-4-carbonic acid, m.p. 141-142 °; Thin layer chromatogram (silica gel):

Rf ^ 0.21 (system; acetic acid ethyl ester / pyridine / acetic acid / water 62: 21: 6: 11); ultraviolet absorption spectrum (in 0.1 N aqueous sodium hydrogen carbonate solution): ^ j ^ s = 267 my (ε = 7300); 3-methoxy-70-phenylacetylamino-3-cephem-4-carboxylic acid methyl ester. mp 171-174 ° after recrystallization from methylene chloride and hexane; (a) ^ ° = + 102 ° ± 1 ° (c = 0.95 in chloroform); ultraviolet absorption spectrum (in 95% aqueous ethanol): ^ majcS = 265 my (ε = 6250); infrared absorption spectrum (in methylene chloride): characteristic bands 2.94 μ, 5.62 μ, 5.76 y, 5.93 y, 6.24 y and 6.65 μ; 3-Ethoxy-70- (Da-tert-butyloxycarbonylamino-α-phenyl-acetylamino) -3-cephem-4-carboxylic acid diphenylmethyl ester, thin layer chromatography (silica gel): Rf ^ 0.28 (system: toluene / acetic acid ethyl ester) : 1); ultraviolet absorption spectrum (in 95% aqueous ethanol): = 258 my (ε * 7000) and \ naks = 264 my (ε = 6900); inf crab absorption spectrum (in methylene-90 66389 chloride): characteristic bands 2.96 y, 5.64 μ, 5.90 μ, 6.28 μ and 6.73 μ; 3-Ethoxy-78- (Da-phenyl-glycylamino) -3-cephem-4-carboxylic acid, thin layer chromatogram (silica gel): Rf ^ 0.17 (system: ethyl acetate / pyridine / acetic acid / water 62: 21: 6: 11); ultraviolet absorption spectrum (in 0.1 molar aqueous sodium hydrogen carbonate solution): λ = 263 m (ε = 5500); 3-Benzyloxy-7β- (Da-tert-butyloxycarbonylamino-α-phenyl-acetylamino) -3-cephem-4-carboxylic acid diphenylmethyl ester, thin layer chromatogram (silica gel; evolution with iodine): Rf 'v- n λ 0.34 ( system: toluene / acetic acid ethyl ester 3: 1); (a) D = + 7 ° ± 1 ° (c = 0.97 in chloroform); ultraviolet absorption spectrum (in 95% aqueous ethanol): λιη0] ς8 = 258 my (e = 6800), and 264 my (ε = 6800), and Xo ^ aJce = 280 my (ε = 6300); infrared absorption spectrum (in methylene chloride): characteristic bands 2.96 y, 5.63 y, 5.88 y, 6.26 y and 6.72 y; 3-Benzyloxy-7β- (Da-phenyl-glycylamino) -3-phospha-4-carboxylic acid in zwitterionic form, thin layer chromatogram (silica gel): Rf = 0.17 (system; ethyl acetate / pyridine / acetic acid / water 62: 21: 6 : 11); ultraviolet absorption spectrum (in 0.1 N aqueous sodium hydrogen carbonate solution): λ = 266 my (e = 6500); 7β- (5-Benzoylamino-5-diphenylmethoxycarbonyl-valeryl-amino) -3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester, thin layer chromatogram (silica gel): Rf = 0.45 (system: toluene / acetic acid) ethyl ester ; ultraviolet absorption spectrum (in 95% aqueous ethanol): ^ 0iake = 258 μ U (ε = 7450), 264 my (e = 7050) and 268 my (e = 6700), infrared absorption spectrum (in methylene chloride): characteristic lines 5.65 y, 5.78 y, 6.03 μ and 6.64 μ; 7 β- (Da-tert-butyloxycarbonylamino-α-phenylacetylamino) -3-methoxy-3-cephem-4-carboxylic acid, thin layer chromatogram (silica gel; identification with iodine): Rf 'v 0.64 (system -butanol / acetic acid / water 67:10:23); ultraviolet absorption spectrum (in 95% aqueous ethanol): Xmaics = 264 my (ε = 4100); infra-red absorption spectrum (in methylene chloride): characteristic bands 3.00 y, 5.64 y, 5.92 y, 6.25 y and 6.72 y; 91 66389 70- (Da-tert-butyloxycarbonylamino-α- (2-thienyl) -acetylamino) -3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester, thin layer chromatogram (silica gel: identification by UV light λ = 254 m) ; Rf ^ 0.34 (system: diethyl ether); (a) p0 = + 26 ° ± 1 ° (c = 0.86 in chloroform); ultraviolet absorption spectrum (in 95% aqueous ethanol): * majcS = 249 my (ε = 12,500) and 280 my (ε = 600); infrared absorption spectrum (in methylene chloride): characteristic bands 2.94 y, 5.62 y, 5.85 y, 6.26 y and 6.72 y; 70- (D-α-tert-butyloxycarbonylamino-α- (1,4-cyclohexadienyl) acetylamino) -3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester, thin layer chromatogram (silica gel; identification with diethyl ether) : Rf 'v * 0.39 (system: diethyl ether); (a) D = + 1 ° ± 1 ° (c = 0.745 in chloroform); ultraviolet absorption spectrum (in 95% aqueous ethanol): λ = 263 my (ε = 6700) and? Qiafce = 280 my (ε = 6300); infrared absorption spectrum (in methylene chloride): characteristic bands 2.96 y, 5.64 y, 5.86 y, 5.90 y (shoulder), 6.27 y and 6.73 y; 70 O- (D-α-tert-butyloxycarbonylamino-α- (4-hydroxyphenyl) acetylamino) -3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester, thin layer chromatogram (silica gel; identification with iodine): ΛΛ

Rf ^ 0.35 (system: toluene / ethyl acetate 1: 1); (ex) D 'v. -1 ° ± 1 ° (c = 0.566 in chloroform); ultraviolet absorption spectrum (in 95% aqueous ethanol): λmax = 276 my (ε = 7400); infrared absorption spectrum (in methylene chloride): characteristic bands 2.83 y, 2.96 y, 5.64 y, 5.86 y, 5.91 y (shoulder), 6.23 y, 6.28 y, 6.65 y and 6.72 y; 70- (D-α-tert-butyloxycarbonylamino-α- (4-isothiazolyl) acetylamino) -3-methoxy-2-cephem-4α-carboxylic acid diphenylmethyl ester, m.p. 170 ° (after crystallization from a mixture of methylene chloride and pentane); (a) p = + 147 ° ± 1 ° (c = 0.79 in chloroform); thin layer chromatogram (silica gel; identification with iodine); Rf ^ 0.68 (system: toluene / ethyl acetate 1: 1); ultraviolet absorption spectrum (in 95% aqueous ethanol): = 248 my (ε * 10700); infrared absorption spectrum (in methylene chloride): characteristic bands 2.96 y, 5.63 y, 5.75 y, 5.87 y, 6.18 y and 6.72 y; 70- (D-a-t-butyloxycarbonylamino-α- (4-isothiazolyl) acetylamino) -3-methoxy-3-cephem-4-carboxylic diphenylmethyl

Claims (8)

92 66389 ester, (α) ρ® = + 26 ° ± 1 ° (c = 0.65 in chloroform); thin layer chromatogram (silica gel; identification with iodine): Rf ^ 0.43 (system: toluene / ethyl acetate 1: 1); ultraviolet absorption spectrum (in 95% aqueous ethanol): * max = 250 πιμ (ε = 12200) and 280 my (e = 5900); infrared absorption spectrum (in methylene chloride): characteristic bands 2.94 y, 5.65 y, 5.71 y (shoulder), 5.88 y, 6.28 y and 6.73 y. A process for the preparation of 7β-amino-3-cephem-3-ol-4-carboxylic acid compounds of the formula (0) n "H?? 1" - 0 = J-Nvy ^ "" ° "R 3 O = C - r 2 wherein n is 0 or 1, R 1 represents hydrogen or an acyl group of formula 0 R - (X) - CH - C - B s. m | R b wherein R represents phenyl, hydroxyphenyl, hydroxychlorophenyl, thienyl, pyridyl , aminopyridinium, furyl, isothiazolyl, tetrazolyl or 1,4-cyclohexadienyl, in which case the hydroxyl substituents in these radicals may be protected by acyl radicals, X represents oxygen, m is 0 or 1, and is hydrogen, or when m is 0, optionally protected amino, or a 5-amino-5-carboxy-valeryl residue in which the amino or carboxy group is optionally protected, R 7 represents hydroxy, halogen, lower alkoxy, 2-halo-lower alkoxy, 1-phenyl-lower alkoxy, where the phenyl gas may be substituted with nitro or diphenyl lower alkoxy, and R 3 represents hydrogen, lower alkyl, phenyl lower alkyl or 93 66389 diphenyl-lower alkyl, as well as the corresponding 2-cephem compounds of the formula R, \ NH HHN—, οΙΖί L0-K3 o = C - R2 where Ra, R2 and R1 have the same meanings as defined above, or the 3- for the preparation of mixtures of cephem and 2-cephem compounds, or salts of such compounds containing salt-forming groups, characterized in that the compound of formula Ra 1 \ HH NH V. S-Y CH, I Ϊ 3 11 o = 1-N C / vwOR® 0. C to R * a .A wherein R1 is as defined in formula IA, R2 is the same as R2 except for hydroxy, R1 is lower alkyl, phenyl-lower alkyl, diphenyl-lower alkyl or trialempkylsilyl, and Y is a leaving group which is benzthiazol-2. -ylthio, benzoxazol-2-ylthio, benzenesulfonyl, p-toluenesulfonyl, o-methoxybenzenesulfonyl, p-methoxybenzenesulfonyl or p-nitrobenzenesulfonyl, treated with a strong base in an inert solvent at room temperature or with gentle heating at 0 ° C in an inert gas atmosphere and in a manner known per se, optionally converting the resulting mixture of 2-cephem (IB) and 3-cephem (IA) or the obtained 2-cephem compound (IB) by oxidation of the 3-cephem compound to 1-oxide ( IA) and optionally converting the resulting 3-cephem compound 1-oxide (IA) by reduction to a 3-cephem compound of formula (IA), and optionally converting the resulting compound to an esterified carboxyl group of formula -C (= O) -R 2. by saponification, or by hydrolysis of the group -C (= O) -Hal to the free carboxyl group or by esterification to another protected carboxyl group, and optionally converting the protected 3-hydroxy group -ORg to the free 3-hydroxy group in the resulting compound and optionally converting the free 3-hydroxy group in the obtained compound by etherification to an etherified 3-hydroxy group, and optionally cleaving in the resulting compound of formula I wherein an acyl residue, treating this acyl residue with an imide halide-forming agent, reacting the formed imide halide with an alcohol optionally releasing the protected hydroxy and / or protected amino R 1 present in the resulting compound of formula I at the hydroxyphenyl residue R a, and / or optionally converting the resulting compound containing a salt-forming group into a salt or the resulting salt free compound or another salt, and / or optionally separating the resulting mixture of isomeric compounds into the individual isomers. Process according to Claim 1, characterized in that bicyclic amidine is used as the base. Process according to Claim 1 or 2, characterized in that a diazabicycloalkene, such as 1,5-diazabicyclo (5.4.0) undec-5-ene, is used as the base. Process according to Claim 1, characterized in that a substituted guanidine, such as tetramethylguanidine, which is polysubstituted by lower alkyl, is used as the base. Process according to Claim 1, characterized in that a trialkylalkylamine, such as triethylamine, is used as the base. 95 66389 A process for the preparation of 78-amino-3-cephem-3-ol-4-carboxylic acid with the formula R? \ (0) n NH? ? ί N: _ f IA o —o - R3 o = c - r2 i is selected from 0 or 1, the same or an acyl group having the formula 0 R - (X) - CH - C - B am, * or the same R phenyl, hydroxyphenyl, hydroxychlorophenyl, thienyl, 3. pyridyl, aminopyridinium, furyl, isothiazolyl, tetrazolyl or Ι, Ί-cyclohexadienyl, varvid i dessa rester hydroxylsubituituerna can be substituted with an acyl ester, X is substituted for 0, with 0 except for 0, optionally amino, or, if appropriate, 5-amino-5-carboxy-valeryl, and a single amino-carboxy group, optionally different, R2 is hydroxy, halogen, alkoxy, 2-halo-alkoxy, 1-phenylgene alkoxy, a variety of phenyl rings having the substituent on a nitro group, or a diphenylgroup alkoxy, and an alkyl group, an alkyl, phenylglylalkyl, or a diphenylgearkyl, as well as 2-cephem-phenyl derivatives of the form R - o = C - R2 96 66389 is selected from the group consisting of R2 and R ^ betecknar decamma som ovan, eller blandningar in the case of 3-cephem and 2-cephem-formulations with the formulation IA and IB or for the formulation of the present invention with the corresponding salt group-form, which is meant by the formulation NH? ? SY o 0 = 1-NIAO - c - 4 a A i is selected from the group consisting of formula IA, R2 is a period of time with R2, with the corresponding amount of hydroxyl, R ° is a group of alkyl, phenyl-alkylalkyl, diphenylgealkyl, or trihydroalkylsilyl, and a group consisting of benzthiazol-2-ylthio, benzoxazol-2-ylthio, benzenesulfonyl, p-toluenesulfonyl, o-methoxybenzenesulfonyl, p-methoxybenzenesulfonyl or p-nitrobenzenesulfonyl, treated with starch inert heating medium at room temperature or below velocity up to 40-50 ° C, optionally in an inert gas atmosphere, and in the case of an inert gas atmosphere at a temperature equal to or less than 2 degrees Celsius (IB) and 3-cef for the conversion of the genome to the 2-cephem (IB) genome by oxidation to the 1-oxide to the 3-cephem (IA), and optionally to the conversion of the 1-oxide to the 3-cefem (IA) ) genomic reduction to 3-cephem derivatives of formula (IA), and optionally to other compounds of the carboxyl group the form of the -C (= O) -R2 genome is replaced by a group -C (= O) -Hal genome hydrolysed to a carboxyl group or a genomic group to give a carboxyl group, and optionally to give a solution of the 3-hydrophilic group. the group -0R ° to the 3-hydroxyl group, which may have been converted to the 3-hydroxyl group, to the 3-hydroxyl group, and optionally to the group of the 3-hydroxyl group acylrest, denyl acylrest genom behandling med ett imidhalogenid-bildande ämne, omsättning av den bildade imidha-logeniden med en alcohol to motsvarande iminoeter och solvolys av den bildade iminoetern, och eventuellt frigörs i en erhällen förening med formuleln I i