CS236492B2 - Method of cephalosporines preparation - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formulaI(R<1> is H or carboxyl- protecting group; R<2> is aromatic hydrocarbon group, acylamino, etc.; R<3> is H or alkoxy; R<4> is H or halogen; R<5> is H or amino; A is -CH2-, etc.; Z is S,S O; one of dotted lines in the cephem ring is double bond) and its salt. EXAMPLE:7-[2-(2-Aminothiazole-4-yl)acetamido]-3-[2-(5-acetamido-1,2,3, 4-tetrazolyl) methyl]-DELTA<3>-cephem-4-carboxylic acid. USE:An antibacterial agent effective against Gram-positive and Gram-negative bacteria. Stable to beta-lactamse, having low toxicity. PROCESS:A compound shown by the formula II or its salt is reacted with an aromatic hydrocarbon, etc. in an organic solvent in the presence of an acid, etc., to give a compound shown by the formula III. This compound is reacted with a compound shown by the formula IV, to give shown by the formulaI.

Description

The present invention relates to a process for the production of novel cephalosporins.

The present inventors have conducted studies to discover compounds having a broad antibakerial spectrum that exhibit excellent aitibiateial efficacy on Gram positive and Gram-positive bacteria, are stable to bacterial-produced lactamases, have low toxicity, and are well absorbed by oral or parenteral administration and exerted a profound effect on human and animal diseases. The results of the studies have been to find novel cephalosporins of the formula I below and salts thereof having the above-mentioned excellent properties.

The present invention relates to new cephalosporins, formula, milt Wide antltakkerlální spectrum, ^to ter ^E stood ^é towards ^{/ i} - ^and kkaamázám produced by bacteria which Maai low toxicity and are well absoobuuí by oral or parmterálním podáven which IIII excellent therapeutic effects on human and animal diseases. Other objects and advantages of the present invention will become apparent from the following description.

In this specification, unless otherwise indicated, the term alkyl means a straight or branched alkyl chain of 1 to 14 carbon atoms, for example, mert-1, ethyl, n-propl, isopropyl, n-buuyl, isobuuyl, sec-buuyl, tert-butyl. alkyl, pennyl, henorl, heppyl, octyl, and the like; the term alkoxy means -O-allyl stopin, wherein the alkyl stopin is as defined above; the term lower alkyl means a straight or branched chain alkyl group having 1 to 5 carbon atoms, for example meltyl, ectyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, tert-butyl penta and similar traces. Lower alkoxy means -O> lower alkyl, wherein lower alkyl is as defined above. The term "acyl" means an acyl group having 1 to 12 atoms, such as acetyl, propionyl, butyryl, Uenzoyl, naphthoyl, pmtacarbonyl, cyclohexanecarbonyl, furoyl and the like. The term jacyloxy means -O-acyl, wherein acyl is as defined above, the term alkylkylthio means -S-altyl, wherein alkyl is as defined above. denotes C 1-6, for example vinyl, allyl, isopropeins, 2-propyl, totenes; and the like groups The term alkynyl means C2-C10H2O, such as ethynyl, 2-propynyl and the like. The term cyklotí-butyl з..7CЗkPoaltyl ^c is, for example, cyclopropyl, cyklobuuyl cyclohexylmethyl l ^ c ^ o O ^ <^ P ^ r ^ t ^ JL StopIN like.

The term cycloalkrnyl means Cyclycycloylthenyl, cylindrical cyclohexyl and the like. The term nor means, for example, phenyl, naphthyl, indanyl and the like, the term arylalkyl means ar-lower-Otyl, for example bennyl, frectyl, 4-ethyltylene, and the like. n ^a quick match hetrrocyMickou ob descend least hrteroatom selected file zaurrauícího kyssík Zr, nitrogen and sulfur, for example fuiryl, thietyl, pyrroljl, pyrazooyl, thiazoles iíidM60tll·l !, isothijzotyl, oxaazoyl - ^ OX ^ to ^ I thiadien ZOT · УL ^1- thiazolyl, thiazolyl] lyl, oxatoiazotyl, thiazolyl, t-etrazol-1, pyrityl, (2-ethyl-4-ylpyrrole), 3- (4-pyrrolidino), N, N '(mehlpyrrpropyl), quinooyl, phen ainl, 1,3UenzoOioxotшn ^r l Uennztιu'yll UenzotaazOyl, Ueniytkhодztyl, kuamarnyl and the like, and the term halogen means fluorine, chlorine, bromine and iodine.

The process according to the invention is as follows:

A process for the preparation of cephalptsptrils of formula I

where

R ¹ is hydrogen or difenylmetlHrl, phen-l, 2-karboxyfenl, 1-pivaloyloxybenzyl, _e7 acylojx- C <C_5á] Lkyl or ftalityiOovou group or a group of formula -CHOR · ⁵

ηΛο -CHOCOOR ⁵ where

6

R is C 1-4 alkyl, cyclohexyl or phenyl; R is hydrogen or C 1-4 alkyl; ^r2 is C1-4-thienyl-1,2-furyl, 4- and 4-snoyliminostapine, benzoylamino, furoyl-amino, 1,2,3-triazolyl, 1,2,4-triazolyl or 1,2,3,4-terrazolyl, the triazolyl groups are attached to the exomethrlene group at the 3-position of the cephem ring by a nitrogen-to-nitrogen bond, they may be substituted by at least one substituent selected from the group consisting of halogen atoms, hydroxy and a bonding group, carboxyl, C 1-4 -O -kylové group, a C ^ -alkyltbooikupiny, C ^ alkyloxycarbonyl, C2_6aXkyhoylcmino groups, C ^ -C-jalkoxykOTbo.onl jaLkylskupiny, ^kY anoakupinu and amnoelkipinu, ^R znammeiá. foxmylaminosl-pin or chloraceeylaminoskupinu and A represents a group of formula -Г ^to de ^R4 is C ^ al ^ nominal

N

OR ⁴ indicates that the compound bivalve be Syrný-izoneren or anti isomers or srnměí, or sooí, which is characterized by reacting a compound of formula. II

COOR ^'and (II) wherein ^{R 1 S} is hydrogen or Ctrfancí carboxylic acid group, ^{R 3 S} Zn shifts adno2 of ^the now obsolete me to be ^p OPŘ ^beta. ad ^{e C} ^ ir ^o n ^e i ^ a, and ^R is as defined above, thereafter with a compound of formula III

HgHOR⁴. (III) where^r4 Be the above meaning, or its aooi, and then if it is. it third chr. the hydrogen atom of the carboxyl group in the 4-position of the cephem kxu is converted to another meaning of R¹ or the product is converted to mine ·

In výěe uvedlených formula c ^{T, R1} represents a & lta C ^ allyl jtóo is metltl, ethyl, n-propyl, isopropyl, n-bityl, isobutyl, sskkbutyl butyl, pentyl and. similar Groups; diphenylmethyl, phenyl, 2-carboxyphenyl lupine, 1'-pivaoyyooybenzyl, ₇ acyloxy-C 1-6 -cyclohexyl; -5 limited group such as acetoxymethyl нl ^ »^ propioщloxymet tгl, n · butlrlloxlmetlhУ, isobutyrlloxymetlнl» pivtlolloxlnetlhrl vaLtrlloxlββΟηΙ- _l, l-acetozymeetty., 1-acetoxy-n-propyl, 1-pivaL.olloχletltУ>, L, P koylLoylo: χ1-n-propyl and the like, phthalyl group or pattern

-CHOCOOR ⁵ nrto -CHOCOOR ⁵

wherein R is an alkyl group as defined above or a cyclohexyl or phenyl group and R R is a hydrogen atom or an alkyl group as defined above, such as methoxymethyl, ethoxymethyl, propoxyaethyl, isopropoxymethyl, butyloxymethyl, methoxycarbonyl oxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxy, n-butyl oxy -carbonyl oxy methyl terc.butyloxykarbonyloxymethyl, 1-methoxycarbonylethyl, 1-ethoxycarbonyloxyethyl, 1-propoxycarbonyloxyethyl, 1-iaopropoxykarbonylethyl, 1-butyloxykarbonyloxyethyl and the like · R ² is phenyl, 2thienylovou group, a 2-furyl group A C 1-6 phthalkanoylamino group such as an aryl amine, propylamine, n-butyloxylaine, isobutyrylamine, valerylamino, hexanoylamino group and the like; a furoylamino group; 1,2,3-triazolyl, 1,2,4-triazolyl group or a 1,2,3,4-tetrazolyl, said triazolyl groups are attached к exomethylene group at the 3-position of cephem ring carbon nitrogen bond · R ² may be substituted with at least one substituent selected from the group consisting of halogen atoms such as fluorine, chlorine, bromine, iodine and the like; a hydroxyl group; carboxyl, amino, alkyl groups as defined for R ¹ , cyano, phenyl, C 1-6 alkyl thio groups such as -SC 1-4 alkyl, wherein the C 1-6 alkyl group is as defined for R ¹ , C 1-4 alkoxycarbonyl groups such as - COC 4-6 alkyl, wherein the steels λ

The O group is as defined for R ¹ , C 1-6 alkoxycarbonyl-C 1-6 alkyl groups such as C 1-6 alkyl-O-CO-C 1-6 alkyl having alkyl groups as defined for R 1 and C 1-6 alkanoyl amine groups such as Steels 1 -j-NH- having the meanings defined for R '· a represents a group of formula wherein R₁ represents an alkyl group which is as defined for R ¹ and a lower alkylene linkage syn or anti isomer or a mixture thereof ·

A group of formula (I)

_R 3a or II exists in the form of tautomers when R ³ and R ^3a are amino groups which may optionally be protected as shown in the following equation of equilibrium.

where R ³ and R ^3a are as previously defined and R ³ and R ^3a are an imino group which may be optionally protected · Tautomer 4 is also included within the scope of the invention · As the imino protecting group R ³ and R ^3a in the above equation of equilibrium, groups which are used in parallel in the field of penicillin & cephalosporins can be used. In particular, the same groups, which are mentioned as monovalent amino protecting groups, are listed in R ³ ® ·

Salts of the compounds of the formulas II or III include salts of basic or acidic groups which are known in the art of penicillins and cephalosporins. In particular, salts with mineral acids such as hydrochloric, nitric, sulfuric and the like acids, salts with organic carboxylic acids acids such as oxalic acid, succinic acid, formic acid, trichloroacetic acid, trifluoroacetic acid and the like, and salts with sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluene-2-sulfonic acid, toluene-4-sulfonic acid, mesitylene sulfonic acid, 4,6-trimethylbenzenesulfonic / naphthalene-1-sulfonic, naphthalene-2-sulfonic, phenylmethanesulfonic, benzene, 3-disulfonic, toluene-385-disulfonic, naphthalene-1,5-disulfonic, naphthalene-2,6-disulfonic, naphthalene- 2,7disulfonic acid, benzene-1,3,5-trisulfonic acid, benzene-1,2,4-trisulfonic acid, naphthalene-1,3,5-trisulfonic acid and similar acids / as salts with a basic group other alkali metal salts such as sodium, potassium and the like, alkaline earth metal salts and metals such as calcium, magnesium and the like, ammonium salts, nitrogen-containing organic bases such as procaine, dibenzylamine, N-benzyl β-phenethylamine , 1-efenamine, Ν, Ν-dibenzylethylenediamine, triethylamine, trimethylamine, tributylamine, pyridine, dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine and the like (like salts 8 by acidic group) ·

In the above formulas, R is hydrogen or a carboxyl protecting group. Protecting groups for the carboxyl groups which are commonly used in the field of penicillins and cephalosporins include groups forming ester _Ť which can be removed by catalytic reduction, chemical reduction or other treatments under mild conditions; ester-forming groups which can be readily cleaved in living organisms and other known ester-forming groups which can be cleaved by treatment with water or an alcohol such as organic silyl groups, phosphorus-containing organic groups, tin-containing organic groups or the like.

Examples of typical carboxyl protecting groups are:

a) alkyl groups, b) substituted lower alkyl groups wherein the substituent is at least one substituent selected from the group consisting of halogen, nitro, carboxyl, acyl, alkoxy, oxo, acidic, cycloalkyl, aryl, alkylthio, alkylsulfinyl , alkyl and phenyl, alkoxycarbonyl, 5-alkyl- »2-oxo-1,3-dioxol-4-yl,

1- indanyl, 2-indanyl, pharyl, paridyl, 4-imidazolyl, phthalimide, succinimide, acetidine, aziridine, pyrrolidine, piperidine, morpheine, thiomorpholine pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, oxazolyl, oxazolyl, oxazolyl, oxazolyl, oxazolyl, oxazolyl, oxazolyl, oxazolyl, oxazolyl, oxazolyl, oxazolyl, oxazolyl, oxazolyl, oxazolyl, , triazolyl, tetrazolyl, pyridyl, quinolyl, phenazinyl, benzofuryl, benzothienyl, пепгохйzolyl, benzothiazolyl, coumarinyl, N-lower alkyl piperazine, 2,5-dimethylpyrrolidine, 1,4,5,6-tetrahydropyrimidinyl, 4-methylpiperidinyl, 4-methylpiperidinyl -dimethylpipe.vidiswvá ^

2- methyl-4 "pyrrolin'-3-yl, 4-pyrroline""3"_"í yl N-methyl-piperidinyl, 1 ₁ 3 benzodioxolanylová, alkylamino, dialkylamino, acyloxy, acylamino, acylthio, dialkylaminocarbonyl, alkoxycarbonylamino, alkenyloxy »aryloxy group, aralkyloxy group alicyklooxylová, heterocyklooxylová group, alkoxycarbonyloxy, alkenyloxykarbonyloxyskuplna, aryloxycarbonyloxy, alieyklooxykarbonyloxyskupina, heteroeyklooxykarbonyloxyskupina, alkenyloxycarbonyl, aryloxyкarbonylová, aralkyloxycarbonyl, alicyklooxykarbonylová, heterocyclyloxycarbonyl, alkyl, anilino group, and alkyl substituted anilino group halogen, lower alkyl or lower alkoxy;

C 6 cycloalkyl, lower alkyl-substituted cycloalkyl or [2,2-di / lower alkyl] -1,3-dioxol-4-yl] methyl groups;

d) alkenyl groups;

e) alkynyl groups;

f) phenyl, eubetituted phenyl groups containing at least one substituent selected from the group consisting of substituents listed under b); or aryl groups of the formula

wherein X is -CH-CH-CO-, -CH-CH-S--, -C (R) -S-, -CH-N-CH-N-, -CH-C-CHCH-CH- _;

-CO-CH = CH-CO- or -CO-CO-CH = <CCH, or substituted derivatives thereof, the substituents of which are selected from the examples given under b), or the formula

wherein Ϊ represents a lower alkylene group such as - (CH 2) 3 - "C 1-4", or a substituted derivative thereof, wherein the substituent is selected from the examples given under b);

g) aralkyl groups which may be substituted by at least one substituent selected from the examples given under b);

h) heterocyclic traces which may be substituted with at least one substituent selected from the examples given under b) aCyclic indanyl or phthalocyl groups or substituted derivatives thereof, wherein the substituent is halogen or meethyl, and a bicyclic tetrehydronaphthyl group or substituted derivatives thereof, wherein the substituent is halogen or methyl ethyl stop Ιο trityoov * ^and the group ^Y choleater hunting ^and groups Neto BIC ^yk pyrazolo ^[4,4, θ] ^d ®cylov skupna ^á »j / alicyclic ftalidyiiden quick match-lower alkyl, or substituted derivatives thereof wherein the substituent is halogen or a lower alkoxy trace.

The above list of carboxyl protecting groups provides typical examples of these traces. Any of the traces disclosed in U.S. Patents 3499909, 3573296 and 3641018 and in German Patent Publication Nos. 2301014, 2253287 and 2337105 may be used.

Among the above-mentioned protecting groups for carboxyl, the preferred groups are those which are readily soluble in living organisms, such as, for example, 5-lower alkyl-2-oxo-1,1'-dloxal-6-ol. an alkyl group, an acyloxy alkyl group, an acylthioalkyl group, a phthaldiyl group, an indanyl group, a phenyl group, a substituted or unsubstituted phthalylidene-lower alkyl group or a group of formulas

-CH / CH 2 OR ⁷ , -8

-CHOCOOR ⁷ «8 and -CH / CH ^ CCOOR ⁷ wherein R ⁷ is ^p RIMO or branched-subeti uiovanou nes or 1 ^ lL ^ i ^ ⁱ ^ ^{<^} \ ^ <^ \ ^ ou rM altylovou and ^ en ^ ovo ^ ar ^{t nominal,} arαl · k ^{t nominal,} alicyUckou or heterocyJclictou group, R ⁸ is hydrogen or alkyl Štopl, R₁ is hydrogen, halogen or sub b positioned or unsubstituted alkyl, cylkloalkylovou, aryl or heterocyclic group or ácupinu of formula - (CH 2) CCOR ⁷ , wherein R ⁷ is as defined above, n is 0, 1 or 2 and m is 0, 1 or 2.

Preferred carnitine traces include 5-lower alkyl-2-oxo-1,3-dioxol-4-yl traces such as 5-methyl-2-oxo-113-dioxol-4-yl,

5-ethyl-2-oxo-1,3-dioxol-4-yl, 5-proppyl-2-oxo-1,3-dioxol-4-yl and similar stoppers, such as acetoxymethyl groups, have been reported. methyl, propicinyloxymethyl, butyryloxymethyl ₉ leobinyloxymethyl, valejyloxymethyl. _s Uacetoxyethylová, Uacoto ^ oropolovág 1-pivaloyloxyethyl, 1-β pivaloylotypropylová like, ecylthioalkylové groups such as acetylthoonethylová, plvaloylthoomethylové, benzoic · thiomethyl., p chhorbenzoylthiomethylová, 1-acetylthioethylová, 1 beer & Loylthioethylová,

1-benzooll-haloethyl 1-p-chlorobenzoylthioethyl and the like groups, such as alkoxymethyl groups such as methoxymethylmethylethyl, isopropoxymethyl, butylotymethyl and the like, racycarbonylothoxymethylbutylmethynylmethylsulfonylmethyl, such as methoxymethyl; , propoxycarbonylothymethyl, i sopropotycarbonylothymethyl, n-butylcarbonylothylmethyl ,; tert-butyloxy-bonylothylethyl, 1-methoxycabonynyl-y-thyl? 1-isopropylcarbonylothylethyl, 1-propoxycarbtoinloxyethyl, lisopropoxycarbonyloxyethyl, 1-butylcarbonyloxyethyl and the like, slicycarbonylcarbonyl groups such as methylcarbonyl, methyl, phenylalkyl, phenylalkyl, phenyl, phenyl, methyl, phenyl, phenyl, phenyl, phenyl, methyl, phenyl, methyl, phenyl, methyl, phenyl, phenyl, methyl, phenyl, phenyl, methyl, phenyl, methyl, phenyl and phenyl groups. isaslkylové groups such as 2-ftaLidylidenelhylová, & ^ //. 5 «^: ^ f3-fluoro ^and tái3 ic ^? ^ Z people '. ^ e ^ t ^ y ^ cjvá, 2/6 ~ chlorfteliyylidcEi / Qtbylovó and similar groups ·

3a

R is an amino group which may optionally be protected. As amino protecting groups can be used groups commonly used in the field of penicillins and celiac groups, particularly those readily available from 11/1-acyl groups such as trilocyclopropylcarbonyl, tri bromoethoxycarbonyl , _with p-benzeoэtrkarboouylLová tolιnutuliO> ullová p-nitobbensylotykarbo'nýtová about brombeezzyotykíaiObcnyliová ^ o-uitгo / Gmylthl: / fUAllová, mcow-o! i ~ or trichome /! · Ooetll0 weighing tгiiUoQric ^ / _s tllová formy'Icvá , tercawyLotykarbouylová _P t b _e "oo y karbony'.Lová p-methostyb / luyl, oO yknгboϊnylová _s. 3.4 · -iiiethotlb®mslotknrbonylLOvá _R 4 / feuy1n7o / Ьeuzylotlknгbonylová 4 / 4LtS: tllocyfenylnzo / beuzylotyknrbonylová, -pyridine 1-oxide ~ ~ 2lyl forehead: ykшbomyLová, n ^ furylotykarbonylová, iifeuylm / thotlknrbo: _adenylic> 1.1 ^ ~ ^ i Methylthiocarbonyl, β-propoxycarbonyl, cyclopropyl ethylenecarbonyl, phthaloyl, succinyl, 1-adamanthylthiocarbonyl, β-quinolyol-4-carbonyl, and the like as well as those easily removable groups such as the triethyl group, 2-nitrophenyl-2-thiocarbonyl, 2,4-nitrophenyl, 2,4-nitrophenyl,

2- hydrotybenzylidenová, 2-Hydroxy-T45 ihLorbeuяyl i </ movág ^ 2 ^ l ^ <^ ^ ϊг: йt -Lя ^ ^ ^ nt: ^t lyn1 τlL ^^^ ^ i ^ u ^ oic acid,

3-Hydroxy-4-pyrimidin-1-yl-1-methyl-4-methyl-4-methyl-1-methyl-1-methyl-thiocarbonyl-2-propyl-3-thiocarbonyl-2-butyl φropyl: ideuová, 41 / enc (o'1 ~ -2-propylidene, 1- [LU / second-w / tho: tУf / Uyl / ^b ktгr tmoylj propylidrnová -2-1- [& - / 4 ' ME / hootle / nl / ^s · kaTb propanoyl] ^ ^{-propyijítenovái,} 2 ~ / ^th ot kaτ ^{b l} e ^{t h} onylcyklo У ^L / id NOCs ^and S-eWoty ^^ ^ o ^ lcyklo ρ / nty'Lidenová 2 -ncε ^ tllilkldhetylidsnová _of 3.3 ~ ~ iimethll 5o-o ooolklGheзyli </ euová and the like and other cKTránící anlnoskuuiny groups such as ϋ- or trtalkyltiOová and the like ·

A detailed description of the process according to the invention is given below.

The process according to the invention is a otimation reaction. According to the invention, a compound of formula II or a salt thereof is treated with a compound of formula II or a salt thereof. A compound of formula I or a salt thereof is precipitated. The reaction is usually carried out in a solvent such as water, ethanol; and the like or in jných solvents which adversely necoUvnují г / Псс !, or a mixture of such solvents · The reaction is usually Provo ^p O s to Ю0 ° C | preferably ^p M at ^10-50 ° ^C · ^ St-league in this reaction uses Force compound ^No. enyne ^Y of formula III, the reaction is preferably carried out under příoamnoosi base · These bases include inorganic bases such as · hydroxide an alkali metal, unsaturated sodium hydroxide, potassium hydroxide or the like, a soft earth metal hydroxide, e.g. magnesium hydroxide, calcium hydroxide or the like, an alkali metal carbonate, e.g. sodium silicate, carbonate or the like uHičit an; an alkaline earth metal, such as magnesium carbonate, calcium carbonate or the like, an alkali metal carbonate such as sodium phosphate, potassium hydrogen carbonate or a similar bicarbonate, alkaline earth metal phosphate, such as magnesium phosphate, phosphate, phosphate and an alkali metal hydrogen phosphate such as sodium hydrogen phosphate or potassium hydrogen phosphate or the like hydrogen phosphate, and organic bases such as an alkali metal acetate such as sodium acetate, potassium acetate or the like acetate, a tri alkyl amine such as trimethylamine, triethylamine or like trialkylamine, picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo [4,3, o] -5-nonene-1,4-diazabicyklLo _2, 2] octane, 1,4-diazabicyclo [5, 4,0] -7-undecene and the like.

Compounds of formula I can also be converted to the corresponding desired compound in a conventional manner · Moreover, if the groups ^{R, and} R ² and LP ^and reactive groups in the reaction can then be protected by customary protective groups in any manner during the reaction and the protecting groups can be removed after the reaction by conventional means · The compound of formula I or a salt thereof can be isolated by conventional methods ·

The present invention further includes all optical isomers, racemic compounds and all crystalline forms and hydrates of the compounds of Formula I and their salts.

When oximation gives a compound of formula I wherein R ¹ is C 1-6 alkyl, diphenylmethyl, phenyl, 2-carboxy phenyl, 1'-pivaloyloxy benzyl, C 1-6 acyloxy-C 1-6 alkyl, phthalidyl or a group of formula -CHOR 4 or -CHOCOO.R 6, where R ⁶ and R ⁶ are as defined above, can be this

R ⁶ R ⁶ is converted conventionally into the corresponding compound or salt, where R is hydrogen. If a compound of formula I wherein R is hydrogen is obtained, this compound can be converted conventionally to the corresponding compound or salt thereof, wherein R is hydrogen. R 6 represents C 1-4 alkyl, diphenylmethyl, phenyl, 2-carboxyphenyl, 1'-pivaloyloxybenzyl. C 1-6 alkoxy-C 1-6 alkyl, phthalidal, or -CHOR 4 or -CHCCOOR ¹⁶ R ⁶

Wherein R 5 R is as previously defined. When a salt of a compound of formula (1) is obtained, it can be converted into the corresponding free compound in a conventional manner.

Among the compounds of formula X obtained in the invention are those preferred compounds wherein R represents a methyl _group are more preferred syn isomer · Other examples of preferred compounds are those compounds wherein R _t. especially 1,2,3-triazolyl, 1,2,4-triazolyl or 1,2,3,4-tetrazolyl, wherein these groups may have the above substituents and are attached to the exomethyl group at the 3-position of the cephem ring . Among these compounds, those in which R is a 1,2,4-triazolyl or 1,2,3,4-tetrazol-2-yl group which may contain the abovementioned substituents are particularly preferred.

The compounds of formula (II) which are the starting compounds in the process according to the invention can be prepared as follows:

ch ₂ y

COOH conversion reaction at the 3 / IV position) or a derivative thereof at the carboxyl group or an acylation salt thereof

COOR (V) or its salt (VI) №71— CCOOH

R ^3a - / II \ J ⁰ or a reactive derivative thereof

(VII)

COOR ^, or a salt thereof wherein R ^1a , R ² and R ^3a are as previously defined and > Z is 2 > S or 3? S? 0, R ¹⁰ is 12 amino, a group of the formula R 1 C = C-NH - wherein R ¹² , R ¹³ and R ¹¹ , which may be the same r ' ³ r ¹⁴ or different, represent hydrogen atoms or organic radicals not involved in the reaction, or a group of the formula ^R r' ⁶ wherein R ^{1 '} and R' ^1, which may be the same or different, are hydrogen atoms or organic radicals not involved in the reaction, and R ¹¹ is a substituted or unsubstituted acyloxy or carbamoyloxy group.

The radical R @ ¹ in the compounds of the formulas IV and V and in their salts represents the amino group of the formula R @ ¹ R @ ¹ R @ 2 R @ 4 --C @ NH - and the group

R ¹³ R ¹ R ¹⁸

Group of general formula

R ¹

C = C-NH4 also includes a group of formula

R ¹³ L ^{4 R}

CH-ON, which is its isomer · / I

R ¹³ R ¹⁴

Substituted or unsubstituted aliphatic, alicyclic / aromatic, arallphatic, heterocyclic and acyl radicals may be used as the organic radical R ¹³ , R ¹⁴ , _{and in the} above formulas which do not participate in the reaction. In particular, the following groups are meant:

1. aliphatic residues such as alkyl and alkenyl groups;

2-alicyclic radicals, for example cycloalkyl and eycloalkenyl groups,

· Aromatic residues such as asylum groups,

4. arallphatic radicals, for example aralkyl groups,

5. heterocyclic radicals, for example heterocyclic groups,

6. acyl groups, acyl groups which may be derived from organic carboxylic acids · Examples of such organic carboxylic acids are aliphatic carboxylic acids, alicyclic carbocyclic acids, alicycloaliphatic carboxylic acids, aromatic substituted aliphatic carboxylic acids, aromatic substituted oxyaliphatic carboxylic acids, aromatic a substituted thioaliphatic carboxylic acid, a heterocyclic substituted aliphatic carboxylic acid, a heterocyclyl substituted oxyaliphatic, carboxylic acid, a heterocyclic substituted thioaliphatic carboxylic acid, an organic acid in which an aromatic ring, an aliphatic group or an alicyclic group is attached to the carbonyl atom by a carbonyl group nitrogen or sulfur, aromatic carboxylic acids, heterocyclic carboxylic acids and the like ·

Aliphatic carboxylic acids include formic, acetic, propionic, butanoic, isobutyric, pentanoic, methoxyacetic, methylthioacetic, acrylic, crotonic and the like. Alicyclic carboxylic acids include cyclohexanoic acid and the like. mention cyclopentanoacetic acid, cyclohexanoacetic acid, cyclohexanepropionic acid, cyclohexadiene acetic acid and similar acids ·

The above-mentioned aryl groups may be used as the aromatic radical in the organic carboxylic acids mentioned. The above-mentioned examples of heterocyclic groups may be used as said heterocyclic ring.

The individual groups of these organic carboxylic acids may be further substituted by an aubatituent such as a halogen atom, a hydroxyl group, a protected hydroxyl group, an alkyl, alkoxy and acyl group, a nitro group, an amino group, a protected amino-group, a carboxyl group, a protected carboxyl group. and similar groups ·

As the above amino acid protecting groups, the protecting groups mentioned in R ^3a can be used.

As the hydroxyl protecting group, all of the groups usually used for protecting the hydroxyl group can be used. In particular, readily removable acyl groups such as benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4- (phenylaso) benzyloxycarbonyl, 4- (4-methoxyphenyl) terzo, 4- (4-methoxyphenyl) tert-butyloxycarbonyl. butoxycarbonyl 1,1,1-dimethylpentrocarbonyl, iaopropoxytearbonyl _t- diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, trifluoroacetyl, 1-cyclopropylethoxylcarbonyl similar groups such as benzyl, trityl, methoxymethyl, 2-nitrophenylthio, 2,4-dinitrophenylthio and the like.

As the protecting groups of the carboxyl group, any group usually used for protecting the carboxyl group may be used. these are such as methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, benzyl, diphenylmethyl, trityl, p-nitrobenzyl, p-methoxabenzyl, benzoyl ethyl, acetylmethyl, p-nitrobenzoylmethyl, p- bromobenzoylmethyll-p-methisuufonylbenzoylmethyll, methylthiomethyl, trihloroethyl, 1,1-dimethylethyl-1-propenyl, 1,1-diethylethylpropyl, acetoxyethyl, propionyloxyethyl, pivaloyloxyethyl, succinomethyl-methyl-succinamide; phenylthiometal, diethylaminomethanes, quinolin-1-oxide-4-yl-ether, pyridin-1-oxide-2-yl-methyl-1,1'-methyl-1-oxo-1-oxo-1-oxo-1-oxo-1-oxo γ L / methyl and the like; non-metallic compounds such as titanium tetrachloride; and silyl compounds such as diebethlbhoorilane as disclosed in Japanese Laid-Open Application No. 7073 //? and Dutch Laid-Open Patent Application No. 7 '05259.

Derivatives of the compound of formula (IV) on the carboxyl group include, for example: α / esters: flax to slaughter esters, which are usually in the foaming range of foams and eephalosporins. Particularly SERN include esters mentioned for the substituent R, b / anlhycdrid carbonization carboxylic groups with N-hydгo: χyuukcinimidem _f N ^ hycdO ftalirnidern, dimetlhrlhydroxylírninern, diethyLltyc '^^^! ^ L-hydroxy-piperidinern, and oxirnorn podobnýrni, c / aedy: includes acid salts, N-substituted acid arnides and Ν, Ν-ii: acid arnides. Especially NOLalkyl acid amides such as N, N, N, N, N, N-acid, N-ethylarnide and the like, N-arylarnides of the acid, such as N-phonylarnide and the like, N, N-dialkyl acids, such as N, N-dirnethylarnid _acid Ν, Ν-dietyylaeid acid, N-ethyl ^ - ^ N ^ - ^ methyl ^ 8 ^ id acid and the like, amido acids irnidaoolern is substituted ^ irnidazolern, triazolpyrioonern like, ^J as acyloxy and k amo ^ ^ o ^ hunting with ^the u ^L ^ n ^{y P} ro subejtitoent ^R11 is particularly ®l anoyloxylové ^to groups such as acetoxy, propionyloxy and ryloxylová butyl-group, etc., alkenes: ^ yloxy; ^: alkyl groups such as aciryloyloxy and the like, aryloxy groups such as benzoyloxy and phthaloyloxy and the like, and carbanyl groups. One or more substituents may be substituted, such as, for example, atormino, nitro, alkyl and alkoxy, alkylthio, acyloxy, acyl, acyl, carbonyl, corbooyl, sUL2, carbonooyl, carbocoyl, carbocyclocarbolylcarbolycarboxylic acid, carbonylcarbolylcarbolycarboxylic acid, carbonylcarbolylcarbonylcarboloylcarbolylcarbolylcarbolycarboxylic acid, , carbobloxysulf • toll, aryl, carbamooyooyl and similar groups *

In old ^troduction onýc ^substil-h of eluent. ^{R 'h} y be rnohou ^(d Roo rlová ^{χ and} ^ .The new group and kartoocylová protected- běínýrni chránícírni groups. The groups will be chnártcí after ^ Started chrántoí groups arninové utoJ Inja Ul ^ ⁿⁱ nn ^{e p} ro ^R * and ^P ro ^^^ hy ^ o ^ ew and Tajr rqylo UCU ^ ^l ln ^{y n} to protected Uve ^ gr ^ not for ^{R 2} to ^{R 18.}

Among the salts which are mentioned in the above reaction reaction salts, both salts on acidic and basic lupine. In addition, salts of the formula I, II or III may be used.

The present invention also encompasses all isomeric products (e.g., syn and diaminoorneoys), tautorners, optical isomers, and the like, as well as mixtures thereof, all crystal forms and hydrates.

The conversion at the 3-position can be prepared by the 7-substituted or unsubstituted amino-3-carboxylic acid of formula V or a salt thereof by reaction of cefayosporonic acid of formula IV or a carboxylic acid derivative thereof or a salt thereof with benzine, thiophene, C1-4 alkynyltriene, benzonttriol, 4 cyanofuranor, 1,2,3ytriazoyee, 1,2,4-thiazole or 1, 1, 3, 4-tetrazole which may be substituted with at least a iodo substituent selected from the group consisting of the hOLo236492 gene, a hydroxyl group, a carboxyl group, an amino group, an alkyl group, a cyano group, a phenyl group, a C 1-4 alkylthioacin, a C 1-4 alkoxycarbonyl group, ^ alkoxycarbonyl-C ^ _ _1e alkyl groups and Calkanoylaminové, groups / v 1,2,3-triazole, 1,2,4-triazole and 1,2,3,4-tetrazole, these groups are attached to the ring carbon atom к / in an organic solvent in the presence of an acid or a complex acid compound and thereafter, if desired, deprotecting the carboxyl group, or converting the carboxyl group to a salt. If desired, the amino substituent may be removed to provide a 7-unsubstituted amino compound.

According to this process, a compound of formula IV, its derivative at the carboxyl group or a salt thereof is treated в benzene, which can carry the substituents mentioned under R ^2nd A compound of general formula V or a salt thereof, wherein R @ ² is the corresponding phenyl, or is similarly processed starting compound with a C ^^ alkyl nitrile, benzonitrile or cyanofuran, which can carry the substituents mentioned for R ² to give the P

a compound of formula V or a salt thereof, wherein R is a corresponding C _2-6 alkoylamino, benzylamine or furoylamine group; or similarly treated with thiophene or furan, which may carry the substituents mentioned in R ² , to give a compound of formula V or a salt thereof where R is the corresponding 2-thienyl or 2-furyl group or is similarly treated with 1,2,3-triazole, 1,2,4-triazole or 1,2,3,4-tetrazole which may carry the substituents of said for R ² on ring carbon atoms, a compound of formula V or a salt thereof is obtained, wherein R is the corresponding 1,2,3-triazolyl, 1,2,4-triazolyl, or 1,2,3,4-tetrazolyl group; In all these cases, the reaction is carried out in an industrially easy manner, the product is obtained in high yield and high purity »

Tautomers exist in these triazoles and tetrazoles as described below. Any of these isomers or any mixture thereof may be used in the reaction.

H

where R represents a hydrogen atom, or the substituents mentioned previously for R, if two R groups are present, may be the same or different »

Triazoles and tetrazoles having substituents on the ring carbon atoms can be used, if necessary, in the reaction in the form of basic or acidic salts. As the basic and acidic salts, the same salts as the carboxylic acid salts mentioned above can be used; the amino groups of the compounds of formula I, II or III. The salts of the compounds of formula IV can be isolated and then used or can be prepared in situ.

Protonic acids, Lewis acids and Lewis acid complexes can be used as acids or complex compounds in the reaction. Examples of protonic acid are sulfuric acid, sulfonic acid, and super-acid. The term super-acid means acids that are stronger than 100% sulfuric acid, including some of the aforementioned sulfuric acid and sulfonic acid. Particularly, sulfuric, chlorosulfuric, fluorosulfuric and the like sulfuric acids: alkyl / mono- or di-sulfonic acids, such as pentafluoronic acid, trifluoroethane / ethanesulfonic acid and the like; aryl mono, aryldi- or aryltrisioic acids, for example p-toluenesulfonic acid and the like acids: chromic acid, medical acid FSO 3 H-SbFp acid PSO-HAHAsF 2, CF 3 SO 4 -ESbF 3 HF-BF 3, ^ SO 4 -SO 4 and similar superacids . Examples of Leoš acids include boron trifluoride. As the compound of the Leis acid, a boron trifluoride salt with dialkyl ethers such as diethyl ether, dipropyl ether, dibutyl ether and the like, a salt of boron trifluoride salt with amines such as ethylamine, propylamine, butylamine, tri-methanol, and the like, combining a boron trifluoride salt with carbonic acid esters, such as ethyl formate, ethyl acetate, and the like, will complicate the boron trifluoride salt with aliphatic acids such as acetic acid, propionic acid and the like; Boron trifluoride salts have been destroyed, such as, for example, acetoontril, propiooril and the like.

All organic solvents that do not adversely affect the reaction can be used in the art. in particular, nitroalkynes, such as nitro / ethane, oirroethao, oitroiroian and the like; organic carboxylic acids, such as .alpha., acetic, trifluoroacetic, dihloroic, propionic and the like; ketones such as acetone, ethyl ethyl ketone, petroleum isobutyl keroo and the like: ethers such as diethyl ether, diiaoiroyl ether, dioxane, retrofitrole, ethylene glycol dental ether, aUsol and the like: esters such as ethyl formate, diethyl ethyl carbonate , ethyl acetate, butyl acetate, and the like: nitriles, such as acetonitrile, furanyl, and the like, and autolanes, such as sulfolane and the like. ,

These solvents may be used singly or two or more in a mixture. Co-compounds of these solvents and Leisic acids can also be used as solvents. 1 mol or more of the acid or co-compound of the compound is used per mole of the compound of formula (II), a carboxyl derivative thereof, or a salt thereof. This ratio is p / nnt after &lt; Le conditions. It is particularly preferred to use from 2 to 10 moles of acid or of a complex acid compound per mole. Compounds of formula (II). It may be used as such, as a solvent or as a mixture of two or more. more compounds.

A variety of benzene, thiophene, furan, C 1-4 alkyl-tri-tril, banuzoniril, cyanofuran, 1,2,3-triazole, 1,2,4-rriazole or 1,2,3,4-tetrazole, which may carry substituents selected from the group consisting of halogen atoms, hydroxyl group, carboxyl group, and / noslkipinu C | ~ ^ altylové groups, cyano group, phenyl groups, for C ₁ _eLkOo: ^ r''booyl yck-Cl_5alkylové groups and C ₂ _galkano. ylamino groups, wherein the substituents in the 1,2,3-triazole, 1,1'-triazole and 112,3,4-retrazole are attached to the carbon atoms used as the reaction component of the reaction are 1 mole or more per mole of the compound of the general formula IV or a derivative thereof at the carboxyl group, or a salt thereof ₀ Zvváště is preferred to use from 1.0 to 5.0 per 1 mole of the starting compound.

This reaction is carried out at a temperature of 0 to 80 ° C. The usual reaction time is several minutes to several tens of hours. If water is present in the reaction mixture, undesirable side reactions such as lactonization of the starting compound or product and cleavage of the β-lacttrone ring may be feared. For these reasons, the reaction system is preferably kept anhydrous. Compliance with this requirement can be achieved by adding an added detydrating agent such as a phosphorus compound such as phosphorus pentoxide, iolyphosphoric acid, phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride and the like to the reaction system: an organic silylating agent such as N, O -bis s-trimethyl silyl acetamide, trimethylsilylacetamide, trimethylchlorosilane, dimethyldichlorosilane in the like: an organic acid chloride such as n-ethyl chloride, p-toluenesulfonyl chloride and the like: an acid anhydride such as acetic acid anhydride, trifluoroacetic acid and the like: inorganic flavoring agent, for example, anhydrous sulfate. magnesium, anhydrous calcium chloride, molecular sieve, calcium carbide or the like, and similar agents ·

If a non-carboxyl derivative of the compound of formula (XV) is used as the starting compound in the above reaction, the corresponding compound of formula (V) having a free carboxyl group at the 4-position of the cephem ring can be obtained in some cases of the formula V having a free carboxyl group at the 4-position of the cephem ring can also be obtained by removing the non-carboxyl group in a conventional manner.

If this reaction produces a compound of formula V where R ¹ * is hydrogen, then the compound may be conventional manner esterified or make a salt · When preparing a compound of formula V wherein R ^is an ester group, the group can be processed conventional manner to produce a compound of formula V wherein R₁ ^is hydrogen · This compound can then be further converted to a salt or optionally other ester · If a compound of general formula V wherein R ^{l &} represents solitvomou group can be removed in conventional manner to give a compound of formula V, wherein R ^la represents a hydrogen atom, and optionally may further produce a compound of formula V where R ^a is an ester group.

When a substituent attached to benzene, alkyl nitrile, thionitrile, byanofuran, thiophene, furan, or to the carbon atom of the 1,2,3-triazole, 1,2,4-triazole or 1,2,3,4-tetrazole ring, the reactant in said reaction, is substituted by a hydroxyl, amine or carboxyl group, the corresponding compound is obtained by first protecting these groups with the aforementioned protecting groups, then subjecting them to a reaction. After completion of the reaction, the protecting groups are removed by conventional means.

If a compound of formula V wherein R is the above substituted or unsubstituted phenyl, thienyl or furyl group attached to the exomethylene group at the 3-position of the cephem ring by carbon-carbon bonding is formed, then it can be applied to it by a known method in addition to the above conversion reaction at the 3-position, which opens the thiazolidine ring in penicillin as the starting material, by reaction with 3-R * -prop-2-ynyl bromide to open the ring, and a series of dihydrothiazine ring forming reactions, namely the cefelosporin skeleton / see Japanese Patent Laid-Open 5393/75: JMC, 20, 1082 (1977); ibid., 20, 86 (1977).

2. In said acylation reaction, a compound of formula V, or a salt thereof, is reacted with a compound of formula VI, or a reactive derivative thereof, to form a compound of formula VII or a salt thereof.

Particularly reactive derivatives of compounds of formula (VI) include acid halides, acid anhydrides, mixed acid anhydrides, active acid amides, active esters and reactive derivatives between the Vilsmeier reagent and the compound of formula 91. Mixed anhydrides of monoalkyl carbonates such as is monoethyl carbonate, monoisobutyl carbonate and the like; and mixed lower alkenoic anhydrides optionally substituted by halogen such as pivalic acid, trichloroacetic acid and the like. As the active acid amides, for example, N-acyl scourin, N-acylimidazole, N-acylbenzoyl-amide, N, N'-dicyclohexyl-N-acylurea, N-acetylsulfonamide and the like can be used. As said active esters, for example, cyanomethyl esters, substituted phenyl esters, substituted benzyl esters, substituted thienyl esters and the like can be used.

As said reactive derivative with Vielsmeier reagent, reactive derivatives with Vilsmeier reagent obtained by treating an acid amide such as dimethylformamide, N, N-dimethylasetamide or the like amides with a halogenating agent such as phosgene, thionyl chloride, phosphorus trichloride, phosphorus oxychloride can be used. , phosphorus oxybromide, phosphorus pentachloride, trichloromethyl chloroformate, oxalyl chloride and the like ·

When the compound of formula (VI) is used as the free acid or a salt thereof, the appropriate coupling agent is used. N, N * -disubstituted carbodiimides such as Ν, Ν'-dicyclohexylcarbodiimide and the like can be used; azolid compounds such as N, N * -thionyldiimidazole and the like, dehydrating agents such as N-ethoxycarbonyl-2-ethoxy-1,2-dihydroxyquinoline, phosphorus oxychloride, alkoxyacetyl and the like; 2-halopyridinium salts such as methyl-2-chloropyridinium iodide, methyl-2-fluoropyridinium iodide and the like.

These acylation reactions are usually carried out in an appropriate solvent in the presence or absence of a base. Often halogenated hydrocarbons such as chloroform, dichloromethane and the like, ethers such as tetrahydrofuran, dioxane and the like, dimethylformamide, acetone, water and mixtures thereof * The bases used include, for example, inorganic bases such as alkali metal hydroxides, alkali metal bicarbonates, alkali metal carbonates, alkali metal acetates and the like, tertiary amines such as trimethylamine, triethylamine, tributylamine, pyridine, N-methylpiperidine , N-methylmorpholine, lutidine, collidine and the like, and secondary amines such as dicyclohexylamine, diethylamine and the like.

In the acylation reactions mentioned above, 1 to several moles of the compound of formula (VI) or a reactive derivative thereof per mole of the compound of the formula (V) or a salt thereof are usually used. The reaction is conveniently carried out at a temperature in the range of -50 to * 40 ° C. The reaction is usually carried out for 10 minutes to 48 hours.

When the above acylation reaction yields the compound of formula VII wherein R ^1a represents a carboxy protecting group, the compound can be converted in conventional manner to the compound or a salt thereof, wherein R ^a is hydrogen: obtains a compound of formula VII wherein R ^1a represents a hydrogen atom, this compound can be converted in a conventional manner to the corresponding compound or a salt thereof, wherein R ¹ is a carboxyl protecting group. When a salt of a compound of formula (VII) is obtained, it can be converted into the corresponding free compound in a conventional manner.

If during such acylation reactions, some of the R ¹ ®, R @ ² and R @ ® active groups for these reactions, protecting, if desired, any conventional protective group after the reaction and the protecting group can be removed after the reaction in conventional manner.

The compound thus prepared and a salt thereof may be isolated by conventional means.

The results of the pharmacological activity tests of typical compounds prepared by the method of the invention are shown below:

1 · Antibacterial activity

Standard method of the Japanese Chemotherapeutic Society / Chemotherapy, 23,

1-2 (1975), a culture which is obtained by culturing bacteria in Heart Infusion broth (manufactured by Eiken Kagakusha) at 37 ° C for 30 hours is seeded on

Heart Infusion agar medium (manufactured by Eiken Kagakusha) and cultured at ° C for 20 hours. The growth of bacteria is then evaluated visually. The minimum inhibitory concentration at which bacterial growth is inhibited is indicated by MIC (µg / ml). The number of inoculated bacteria was Ю ⁴ cells per plate (10 ^ cells / ml) ·

Test compounds:

A. Trifluoroacetic acid salt with 7- [2- (2-aminothiazol-4-yl) -2- [syn] methoxjiminoacetamido] -3 - [[3-acetamido-1,2,4-triazolyl] methyl] -3 -cephem-4-carboxylic acid ⁺ ,

B. Trifluoroacetic acid salt with 7- [2- (2-aminothiazol-4-yl) -2- [syn] -methoxyiminoacetamido] -3- (furan-2-ylcarboxamido) methyl-3-cephem-4-carboxylic acid acid,

C. trifluoroacetic acid and 7- [2- (2-aminothiazol-4-yl) -2- [syn] -methoxyiminoecetamido] -3-acetamethyl-3-cepham-4-carboxylic acid salt,

Trifluoroacetic acid and 7- [2- (2-aminothiazol-4-yl) -2- [syn] -methoxyiminoacetamido] -3- (4-hydroxybenzyl) -3-cephem-4-carboxylic acid D,

E. Trifluoroacetic acid salt and 7- [2- (2-aminothiazol-4-yl) -2- (sine) -methoxyiminoacetamido] -3- [2- (1,2,3,4-tetrazolyl) methyl] -3 -cephem-4-carboxylic acid,

F. Trifluoroacetic acid salt and 7- [2- (2-aminothiazol-4-yl) -2- [syn] -methoxyiminoacetamido] -3- [1- (1,2,3,4-tetrazolyl) methyl] -3 -cephem-4-carboxylic acid,

G, trifluoroacetic acid salt and 7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamido] -3- [2- (5-amino-1,2,3,4-tetrazolyl)] methyl-3-cephem-4-carboxylic acid,

H. Trifluoroacetic acid salt and 7- [2- (2-aminothiazol-4-yl) -2- (8yn) -methoxyiminoacetamido] -3- [2- (5-acetamido-1,2,3,4-tetrazolyl)] methyl] -3-cephem-4-carboxylic acid,

I. trifluoroacetic acid salt and 7- [2- (2-aminothiazol-4-yl) -2- [syn] -methoxyiminoacetamido] -3- [2- (5-methyl-1,2,3,4-tetrazolyl) methyl] ] -3-cephem-4-carboxylic acid _t trifluoroacetic acid salt of 7- [2- / 2-aminothiazol-4-yl / -2- / son / -methoxyiminoacetamido] -3- [2- / 5-ethyl-1 2,3,4-tetrazolyl / methyl-3-cephem-4-carboxylic acid,

K. Trifluoroacetic acid salt and 7- [2- (2-aminothiazol-4-yl) -2- [syn] -methoxyiminoacetamido] -3 - [[3-chloro-1,2,4-triazolyl] methyl] -3 -cephem-4-carboxylic acids *,

Note: * These compounds are produced according to Example 3, etc. The bonding position of the 1,2,4-triazolyl group is not specified because the 1,2,4-triazolyl group is attached to the exomethylene group at the 3-position of the cephem ring by a carbon-nitrogen bond but ; it has not been established which of the nitrogen atoms of the 1,2,4-triazolyl group is attached to the exomethylene group at the 3-position of the cephem ring. In addition, the substituent position of the 1,3,4-triazolyl group is specified by reference to the substituent position in the starting compound used. The same is true in this specification where it is not confirmed which nitrogen atom of the 1,2,4-triazolyl group is attached to the exomethylene group at the 3-position of the cephem ring. For example, compounds wherein 3-methyl-1,2,4-triazole, 3-methylthio-1,2,4-trioazole, 3-acetamido-1,2,4-triazole, 3-chloro-1,2, 4-triazole, 3-ethoxycarbonyl-1,2,4-triezole or a similar compound attached to the exomethylene group at the 3-position of the cephem ring are named --- -3 - [(3-methyl-1,2,4-triazolyl)] methyl] ----, ---- 3 - [[3-methylthio-1,2,4-triazolyl] methyl] ---, -3- [[3-isothimido-1,2,4- triazolyl / methyl] ---- ”, --- 3 - [/ 3-chloro-1,2,4-triazolyl / methyl] - --- or ---- 3 - [[3-ethoxycarbonyl-1], 2,4-triazolyl / methyl] ----

The nomenclature of the 1,2,3-triazolyl-substituted compounds is the same as in the example given by the 1,2,4-triazolyl-substituted compounds.

T a b u 1 к а 1

Antibacterial potency MIC (µg / ml)

as as oo tt— <* з · - m ί- ** 0k «К «К O O O 1 O 1 1 1 ο O 1 1 1 vi vi Vl as OO oo r— 1 * 3 CM Ι- ί- tt— «К l · ^ O O O 1 Ο 1 1 AND ο O 1 1 1 IN" pr.n. Os as tt— · - m CM · » 0b • 4 «К W O O O 1 O 1 1 1 O O 1 1 1 μ pr.n. VI as tt— n in- CM r— <k · « «К •to M O O O AND O 1 1 1 O O 1 1 1 pr.n. pr.n. Vl Vt oo and\ oo oo as SO in*· ί- CM AND ί- ί- AND AND M * •to Ф O ο O 1 O CM ο ο O 1 tt- CM AND VI * " CM as and Sat oo tt- · - CM CM and CM CM ί- AND •to n tt » Рч O O O 1 O Sat O O F ο CM AND pr.n. VI CM as oo AND r- ♦ - »- r and r- · - ί- · - CM M O O O 1 O CM O O O 1 ο rn SO VI Vl VI - pr.n. Vl Sat and 00 00 oo Sat AND r— AND CM CM ί- —- ί- ί- r- AND CM «К •to • к R 0k AND O O Sat ο and ο ο O tt- AND SO Vl CM VI CM as AND SO what as AND «R- r- CM CM AND ί- * 3 · - CM AND AND •to «К O O O O Sat O O w— ο O O SO CM CM VI VI and VI and\ Sat as 00 <* 3 · - AND CM CM 1 * 3 CM ί- AND 0k «4 Г » * 4 03 / O O O »- O AND O O O O ο CM AND and Vl CM vt * " CM as AND AND oo rn «- í *> · - CM CM CM ί- CM CM · - »- «К •to tt » 4 O O O SO O Sat ο O O O O AND VI VI VI AND CM and H in N 0 Sat SO AND * 4 and AND CM tt •to O W— AND in O O O O Sat 1 O O O CM O O O O O O O CM CM CM CM CM · - CM AND AND AND AND AND Ή 1 O □ Ή Í4 T> and 5 φ tt □ • H and Ό ř « • rl O φ and ♦ * 3 φ and O JM N x> CM 0 XB SO 0 « Sat O 0 1 0 • rl in- O —z • rl «4 гЧ »4 O CM in t- q Sat w O (4 ω tt and l- •in t- H > - \ o O 0 9 » 1 1 1 as H 1 1 C- and 0 M X X X q 1 H E4 SS ω AT ® H 0 H O O 1 • H tt and tt H tí 0 0 r4 04 / ♦> "-OF z-x 0 tx 0 tt • rl • H • H 0 0 tt 3 • H 0 H « O * 4 r4 r4 -rl V4 0 Q JB N tí and O no 0 • rl t4 h tt • H 0 M XB O 0 O O tt 0 0 O 0 AT H O X 64 а r-4 в 0 O Ml 0 0 Ц) 0 O α> • rl 3 r-4 3 O at. P r4 V4 no H • H • rl • rl r4 tt tt гЧ 0 O i4 • H 0 O tt 0 t. r4 r4 • rl Й • rl and O with а В а> V4 0 AT q> O O O and W and T> ^ 4 ♦> O AT rl Yeah 0 ДЧ and • tt « 4-> ř < O O o ó • • rl 0 03 M M φ a o з a p tt </) € 4 0 « b (4 p 04 0 « 3 I.E X C O <* ·

2. Oral administration

Each test compound is administered orally to mice / ICR, male, 4 weeks of age at doses of 2 mg per head. The amount of compound in the urine is determined. The results are shown in Table 2. Upon absorption in the living body, all test compounds are easily deprived of the ester group. The corresponding free carboxylic acids are thus obtained. These free carboxylic acids excreted in the urine are quantified, reported as recovered from the urine. Method of administration:

The test compound is suspended in a 0.5% CMC solution and then administered orally.

Method of quantitative analysis:

Quantitative analysis is performed using the paper disc method with the test bacteria shown in Table 2.

φ

φ

Ен

0)

P X »

σκ ϋ ϋ Ен i φ a a

and

Pl 00 »?

m

O

IfS

A-CONH

W

M M

XJ •

E"

3. Acute toxicity test

Two test compounds were intravenously administered to mice (ICR, male, 4 weeks of age) to test for their acute toxicity. The results are shown in Table 3.

Table 3

Test compound

N-jt — C - CONH J

OCH ₃ / вуп /

50О ₅₀ / g / kg

COONa> 3.0

C-CONH

COONa (syn)> 3.0

The compound of formula I and its salt may be administered to humans and animals in the form of a free acid, non-toxic salt or physiologically acceptable ester in the treatment or prevention of diseases caused by bacterial infections. a physiologically acceptable ester. In such cases, they may be prepared in such dosage forms as are customary for cefelosporin drugs such as tablets, capsules, powders, granules, fine granules, syrup, injections including drops, suppositories and the like. Diluents and / or auxiliary agents, including excipients such as starch, lactose, sucrose, calcium phosphate, calcium carbonate and the like, binders such as acacia, starch, crystalline cellulose, carboxymethylcellulose, hydroxypropylcellulose and the like, lubricants such as talc, magnesium stearate and the like, and disintegrating agents such as carboxymethylcalcium, talc and the like.

When administering cephalosporin compositions of the invention to humans, the dose and number of doses are determined appropriately according to the disease and other factors. Usually, however, when administered orally or parenterally, the composition is administered to adults in an amount of about 50-5000 mg of the cecalosporin compound of the invention one to four times daily.

The invention is illustrated in greater detail by reference examples, examples and comparative examples, which are not intended to be limiting but merely illustrative.

Reference Example 1

1. Suspend 2.72 g of 7-aminocephalosporinic acid (hereinafter referred to as 7- (CA)) in 15 mL of anhydrous acetonntril. To the resulting suspension was added boron trifluoride diethyl ether complex (5.68 g). The resulting solution was left at room temperature for 5 hours. After the solvent was removed under reduced pressure. The residue was dissolved in 20m aqueous acetone (containing 50% v / v) and adjusted to pH 3.5 by adding 28% (w / w) aqueous ammonia under ice-cooling. The precipitated crystals are filtered off, washed first with 5 ml of aqueous 50% acetone and then with 5 ml of acetone. After drying, 2.14 g / 79% / 7-imino-3-tcetťmidomeethlL ^"3-cephem-4 -ktrboχylové acid ^kt ER ^and M ^and it toplotu ^{th 155} ° C / dec ^ /.

IR spectrum / KBr / cm ^{-1: 1 7} 95, ^{1 640, 1 61} 0 ¹ 5 ²⁰ ·

Nuclear Magnetic Resonance Spectrum (CF ₃ COOD) ppm: 2.37 (3H, s, -CH 2, 3.82 (2H, s, C ₂ -H), 4.60 (2 N, s, S),

5.41 (2H), broad s, _C6- H, C2-7.

2. In 30 tó. 2.71 g of 7-amino-3-acetamidomethyl-3-cephem-4-carboxylic acid obtained in paragraph 1 above are suspended in methanol. To this suspension is added 1.90 g of p-toluenesulfonic acid monohydrate. Diphenyldiasomethane (4 g) was added at room temperature. The resulting mixture is worked for 30 minutes at room temperature. After the reaction, the solvent was removed under reduced pressure. The residue was dissolved in a mixture of 20 mL of water and 20 mL of ethyl acetate. The pH of the solution was adjusted to 7.0 with sodium bicarbonate. The precipitated crystals are filtered off, washed thoroughly with water and dried. There were obtained 2.84 g / yield 65% / 7-difenylmetlhlesteru tm.no acetealidomethyl-3-3 "Effem ·· 4-yl ^^ -carboxylic acid which ^has a temperature T, ^and the ^190-194 ° ^C / юШ ./.

IR / KBr / ^c m sv _CA0 ¹ 1 ⁷⁵⁸ 1 720 1 647th

NMR / CDCl 3 ppm: 1.87 (3H, s, -CH 2, 3.59 / 2H, s, C 1 H-H, 3.65, 4.27 (2H), Bq, J = 14 cps,

Лсн _2О ^ 00 ⁰ ^ 6 ^, 90/1 ^H ^ 00Η ^ / ₁ , 7 ^, 36/10 ^ - (O) * 2 /.

/ 10H.

Reference Example 2

The reaction and work-up is carried out in the same manner as in Reference Example 1 except that trifluoroacetic acid is used as the reaction solvent. The products thus obtained are shown in Table 4.

Table 4

Starting compound butyronitrile

2-methylbutyroriitrile

2-ethoxypropionitrile acrylonitrile cyanoacetic acid benzylcyanide ethylcyanoacetate chloroacetonitrile

2-cyanofuran benzonitrile

2-cyanothiophene p-tolunitrile p-anisonitrile p-hydroxybenzonitrile p-cyanobenzoic acid 2-cyano-5-methylfuran h ₂ n

ch ₂ nc ¹⁰

COOH

Acid й ° or complex product

Melting point (° 0) of acid

IR (KBr) e ® ^sv

* BF ₃ .Et ₂ O -ch ₂ ch ₂ ch ₃ ⁺ BF ₃ .Et ₂ O CK ₃ -CHCH ₂ CH ₃ BF ₃ .Et ₂ O -CH ₂ CH ₂ OCH ₂ CH ₃ ⁺ BF ₃ .Et ₂ O -CH = CH ₂ ⁺ BF ₃ .Et ₂ O -CH ₂ COOH ⁺ BF ₃ .Et ₂ O ⁺ BF ₃ .Et ₂ O -CH ₂ COOCH ₂ CH ₃ * BF ₃ Et Et ₂ O -CH ₂ Cl * BF ₃ .Et ₂ O * BF ₃ .Et ₂ O xz * BF ₃ .Et ₂ O * BF ₃ .Et ₂ O - @> ~ ch ₃ * BF ₃ .Et ₂ O - ^ 0 ^ -och ₃ * BF ₃ .Et ₂ 0 ~ ^ O ^ ~ oh * BF ₃ .Et ₂ O * BF ₃ .Et ₂ O

168 to 170 635, (rozkl ·) 1610, 1520 170 to 172 1,795, 1,635, (dec.) 1,620, 1,530 173 to 175 1,800, 1,640, (dec.) 1610, 1530 165 to 167 1,800, 1,655 «, (rozkl ·) 1,615, 1,525 192 to 195 1,755, 1,675, (dec.) 1,620, 1,580 185 to 190 1,795, 1,635, (dec.) 1,620, 1,520 185 to 190 1,785, 1,730, (rozkl ·) 1610, 1530 185 to 190 1,790, 1,650, (dec.) 1610, 1520 200 to 204 1,780, 1,630, (rozkl ·) 1590, 15Ю 212 to 214 1,793, 1,630, (dec.) 1610, 1520 169 to 190 (dec.) 1,795, 1,620, 1 530 173 to 178 1,790, 1,630, (rozkl ·) 1,615, 1,530 188 to 193 1,790, 1,620, (rozkl ·) 1,595, 1,530 182 to 184 1,795, 1,625, (rozkl ·) 1,600, 1,530 178 to 183 1,800, 1,700, (rozkl,) 1,630, 1,530 188 to 190 1,780, 1,630, (dec.) 1,600, 1,530

Table 4 continued

2-cyano-3-methylthiophene

2-methyl-4-chloro-5-phenyl-1,2,3-triazole ⁺ BF ³ · Et ² O

175-178 (dec.)

193 to 195 (dec.)

790, 1 630,

610, 1.530

790, 1. 660,

610, 1530

3-kiaookumario * BF ₃ .Et ₂ O

3-kyaoo-4-methilkumiuio * BFyEt ₂ O

ro 0 197 to 199 (dec.) 1,790, 1,710, 1,640, 1,600, 1. -530. CHo 1 m 210 to 212 1,790, 1,710, (rozkk ..) 1,640, 1,600, О 1 530

* ⁺ acetoo ^o tril conc, sulfuric acid

-CH ₃

155 1,795, 1,640, (cr.) 1,610, 1,520

Note РуЕ ^ ^ ⁰ is ^the omp ^ ^p ^ .ex .ettyletoeru boritifo and fluoride ^{(hereinafter aeP} sing ^and equal sign) ** Reaction ^aeP Rovai ^d ^ I in acetone for example, acrylonitrile.

Reference Example 3

The reaction and work-up is carried out in the same manner as in Reference Example 1-2. They also yield the compounds which are listed in Table 5.

Table 5

Compound Melting point IR / kg / cm 2: ^v c = 0

R ¹⁰ / ° С /

-AT 167 to 169 (decomposition) 1,755, 1,718, 1,642 -at 192 to 195 (dec.) 1,755, 1,720, 1,625 ~ <2> 218 to 220 (dec.) 1,755, 1,720, 1,638

Reference Example 4

1. Suspend 2.72 g of 7-AA and 14.2 g of diethyl ether-boron trifluoride complex in 13 ml of aulolane. 1.0 g of 5-methyl-1,2,3,4-tetrazole was added to the solution / suspension and the resulting snow was left at room temperature for 17 hours. After completion of the reaction, the reaction mixture is poured into 15 ml of ice water. · Add 28% aqueous ($ w / w) ammonia under ice-cooling and adjust the pH of the mixture to 3.5. 1.76 g of 7-amino-3- [2- (5-methyl-1,2,3,4-tetrazolyl) methyl] -3-cephem-4-carboxylic acid and 7-amino-3- [1] are obtained. - [5-methyl-1,2,3,4-tetrazolyl] methyl] -3-cephem-4-carboylic acid in the form of crystals.

2 · 1.76 g of the crystals produced are suspended in 18 µl of methanol. 1.13 g of p-tolusnaulfonic acid monohydrate are added to the slurry. Allow 15 minutes at room temperature. After completion of the reaction, the solvent is distilled off under reduced pressure. The residue is dissolved in a mixture of 30 ml of ethyl acetate and 30 ml of water. The organic layer is then separated, dried over anhydrous magnesium sulfate and the solvent is removed by distillation under reduced pressure. 1 v / v /· 0.79 g of diphenylmethyl ethyl 7-amino-3- [2- / 5-methyl-1,2,3,4-tetrazolyl / methyl] -3-cephem-4- is obtained. 157 DEG-160 DEG C. (dec.) and 0.14 g of 7-amino-3- [1- (5-methyl-1,2,3,4-tetrazolyl) methyl] -3-cephem diphenylmethyl ester 4-carboxylic acids, m.p. 92 DEG C. (dec.) ·

7-Amino-3- [2- (5-methyl-1,2,3,4-tetrazolyl) methyl] -3-cofem-4-carboxylic acid, diphenylmethyl ester:

IR / µg / cm * ^{* 1} : 1,770, 1,720

NMR (CDCl ₃₎ / ppm: 1.75 (2 N, broad α, -ЖН ₂ ), 2.48 (ЗН, o, -CH 2, 3.20 (2 N, s, C ₂ -H), 4.70) 1Н, d, J »5Hz, С _б -Н /, 4.87 / 1Н, d, J« 5Hz, C _? -H /, 5.30, 5.72 / 2Н, ABq, J »16Hz, Д /, 6.92 / 1Н, ·, -СНСГ /, 7, зо / ЮВ, e ^ Q ^ x2 /.

PLfsaylBethFl® · ¹ · ^ 7-Mdiw3- [i- / 5-nethX ·! _f 2 _t 3 _t 4 * tertiaryl / Beyl] -3-tert-4-carbonyl xylic acid (s):

XB (BB) o: in _Ce0 1.770, 1725

MB / CFe / pp ·: 1.80 / 2Н, s, -юу, 2.15 / 3Н, s, -ay ». 3.30 / 2N, s, C ₂ -H, 4.70 / 'N, d, J-5Hs, Cg-H 4.85 /' N, d, J 5Hs, γγ-Ή 5.00, 5, 38 / 2Н, ABq J 6 Ha, S /,

6.90 (1N, a, -CH ~), 7.30 (OH),

In this case, 0.5 to 0.5 g of isol and 5 e of acetic acid are dissolved in 0.462 g of 7-aniline-2-oxyl-2-oxo [2- (5-methylthio) -2-oxo-2-ol]. 3,4-thiazololyl-ethyl] -3-cephtho-4-carboxylic acid The reaction mixture was allowed to react for one hour at room temperature. the reaction is stopped and the rospomocer is old at the pressure of the pressure · To the remainder ae. add 10 L of water and 10 L of ethyl acetate · 28% aqueous ammonia (% density) // ee pH of the solution is adjusted (e h / r 8 s cooling of ice solution) · Water layer ae separated and pH ae aa ice cooling) · Treats 2N hydrochloric acid / hour / hour 3.5 · Excludes crystals and then filters, firstly · 5/1 water, then / 5 / l - aceto / u and then exits · Gets ae 0.26 g of 7-Mrinoo3H-2- / 5-ethFl ^ L ^ ^ .ljáttetrzollyViieUiiy -CF ^ IRAM-aíbtoisrlťvré to ^yj ^ <^ ^{e ^: l /} s · tepUta th / '78 ^- C dec ·

XB / KBr / c · ^{-1: v} _c> j 1790 ¹ 6l0, 1530

N ‰ / C ^ COC »/ pp ·: 2.70 / 3N, s, -Cy, 3.73 / 2N, t, Cg-V, 5.40 / 2N, t, Cg-H, c ₇ -H /, 5.80, 6.12 / 2Н, ABq, J 16Hs, 8 / ·

Existing method · 0.462 g of diphthyl / thi-tetrazol-7-acetone-α [5-α-5-α-1,2,3,4-tetlyl-thiyl] (α-α-fto-4 ") 0.25 g 7- · mm> t-. [1, / 5-ol-3 1-1.2 ^{4 -} tetraκtly ^{/ m h} rt Уιl] -3-tefom- ^- l · ^r ABTO] ^y ^ rlová аеИ / у, teptoU th / t 195 ° C Aoskl ¹ / ·

XB / IBT "/"^'in φ ^-0 l 795, 1615, 1530

MB / CT-jCOOD / pp · 2.95 / 3Н, t, -CY, 3.90 / 2Н, broad t, C H ₂ ', 5.45 / 2Н, t, -C H, 5.57; 5.92 / 2Н, ABq, J - 16Mt, - 8 / ·

BeTan / Example 5

In 19/1 of trifluoroacetic acid and dissolve 2.72 g of 7-ACA and 7.1 g of boron trifluoride complex. · 0.75 g of 1,2,4-trlazole are added to the mixture and SMt ae is added. Allows to react for 7 h / s of temperature / (οΙ / ^ ι ^ · 1 · After completion of the reaction and remembering to de-filter and to remove the rapid press · K ^ • ^ι ^ Ι / ο the evaporator and add '5 / water' · pH of solution and adjust (3.5) add 28% (% 28%) of water and cooling and eliminate crystals and leave to stand, pour 5/1 of water, bake 5/1 • ceto / u · then the mixture is obtained with 2.5 g 7 ·· ιOιmoЗ- [1ι- / ^/ 1 _t ^2ι4 - ^| J · wlyly ^{/ m} retyl] -3-r < ^r / - ⁴ - - · RR ^of иι Nominal ^y ^ 001 ^, · pulsation th / s 149 ° C Ao ·! ¹ / ^XB · / "Br / cm ^-1: v _{c> 0} and W 1 6 l ° 1 53 ⁰

IB / CP3COC® (pp): 4.00 (2 N, broad t, C ₂ -H), 5.47 (4 N, broad t, Cg-H, C _? H, ^8/8 7 ° / 'Н, ^•,

N.

/ iH · Vaz

Reference Example 6

If the successor of the tetresol is treated in the same manner as in Reference Example 4- (1) or Reference Example 5, the products listed in Table 6 are obtained. of Example 4- (2) and (3) are esters and carboxylic acids listed in Table 7.

2.72 -NH 4 0.94 7.1 CP 3 COOH temp.

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Reference Example 7

If the following triazoles were treated in the same manner as in Reference Example 4- ( ¹ ) or Reference Example 5, the compounds shown in Table 8 were obtained. Carboxylic acids were esterified in the same manner as in Reference Example 4- (2). The compounds listed in Table 9 are obtained. (2.72 g of 7-ACHA is used as starting material).

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Note: * This compound was prepared using 4-carboxy-1,2,3-triazole as starting compound by the same reaction and treatment as in Reference Example 4- (1) and (2).

Reference example β

By the same reaction as in Reference Example 4, the results shown in Table Ю are obtained under the conditions given in Table Ю.

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Note: 1-Oxide-7-amino-3-acetoxymethyl-3 * cephem-4-carboxylic acid was used as starting compound

Reference Example 10

By repeating the reaction and work-up described in Example 2, substituting 7-ACA for the starting compound listed in Table 12, the products also listed in Table 12 are obtained.

Table 12

Starting compound Product Melting point (° C) IR (KBr) cm ^-1 : ⁱⁿ C = O p-nitrobenzyl ester p-nitrobenzyl ester 114 to 116 1,770, 1,708 7-amino-3-acetoxymethyl 7-amino-3- / 1-d, 2,4-tria- (rozkl ·) -3-cephem-4-carboxylic acid zolyl) methyl] -3-cephem-4- acid carboxylic acids 7-Amino-3- ethyl ester 7-amino- ethyl ester 68 to 72 1 770, -acetoxymethyl-3-cephem [1- (1,2,4-triazolyl)] (rozkl ·) 1 720 4-carboxylic acids methyl] -3-cephem-4-carbo- xylic acids dlphenylmethyl ester 7-Amino-Z- [1- / 1,2,4-triazole- • 149 1,790, 1,610, 7-Amino-3-acetoxymethyl- yl / methyl] -3-cephem-4- (rozkl ·) 1 530 -3-cephem-4-carboxylic acid -carboxylic acids acid

Reference Example 11

1. 2.96 g of 7-amino-3- [4- (5-methyl-1,2,3,4-tefcrazolyl) methyl} -3-cephem-4-carboxylic acid are suspended in 20 ml of Ν, Ν-dimethylformamide. The suspension is converted into a solution by adding 1.1 g of triethylamine under ice-cooling. Then 2.7 g of pivaloyloxymethyl iodide are added to the solution. The resulting mixture is treated for one hour at 0-5 ° C. After completion of the reaction, the reaction mixture is poured into a mixture of 250 ml of water and 300 ml of ethyl acetate. Separate and dry over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure. The residue is washed with diethyl ether, dissolved in 30 ml of ethyl acetate and to this solution is added a solution of 1 g dry hydrogen chloride in 30 ml of diethyl ether · Wash thoroughly with diethyl ether and then recrystallize from chloroform. 2.72 g (60.9% yield) of 7-amino-3- [2- / 5-methyl-1,2,3,4-tetrazolyl] methyl pivaloyloxymethyl ester hydrochloride are obtained. -3-Cephem-4-carboxylic acid having a melting point of 149-151 ° C (dec.).

IR / KBr / cm ^"1:> _{'c, 0} 1773, 1741, 1730

NMR (d ₆ -DMSO) ppm: 1.18 (9N, s, -С / СNуу, 2.44 (ЗН, s, -CH-j), 3.60 (2N, α, С ₂ -Н), 5.23 (2H, α, C ₆ -H, γγ-δ, 5.62 (2Й, α, S), 5.78 to 5.92 (2 N, δ, -COOCH 3 O-).

Лв ₂ 45

X »

When the various starting compounds are treated as described above, the corresponding compounds are shown in Tables 13 and 14.

When 7-amino-3- [2- (5-ethyl-1,2,3,4-tetrazolyl) methyl] -3-cephem-4-carboxylic acid or 7-amino-3-carboxylic acid is used in the above reaction. (3-chloro-1,2,3,4-triazolyl) methyl] -3-cephem-4-carboxylic acid, substituting Ν, Ν-dimethylformamide and triethylamine for acetone and 1,8-diaza-bicyclo) 5 → 4 → 0 (undecenum-7 (DBU)), the compounds listed in Tables 13 and 14 are obtained in a yield of 65 to 90%.

Table

«Η о. гЧ • Η Μ Μ> Μ • Η 1 sec ο а ♦ * φ vt а g ♦ * о and φ η гЧ ϋ ω Ф ti

Melting point IR spectrum NMR spectrum (dg-DMSO ⁺ ) ppm Note (° C) (KBr, cm -1) (CDCl, **)

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o ί-

ο ř-

Compound Melting point IR (KBr) NMR (d 6 -MISO 2) Note r '(° C) cm ^-1 : (CDCl ³ * ² ) (treatment) 0 0 = 0 ppm

<*? Ř

CM in +

Note: optical isomer; 3 oxalate, 4 upper component * 5 lower component

Example 1

1 · Dissolve 2,49 g of 2- (2-difluorocylamide-thiooal-4-4У) glyoxylic acid in 13 ml of dim, Ν- »dimethyllacttamide · To the solution is added dropwise 3.07 g of phosphorus xychtoride at · -20 ° C · Result The mixture was treated for 1 hour with pM -20 to -10 ° C. Then was added 4.62 g of di-nil / © ^;! ^^ ™ 7-AMIA-3- p- methyl ² -75 · ^t y ^l -1, ^{2, 3,} 4 ^e e ^r r ^o o ^l y ^m / ^{e thickness} t yϊ] -3-cephem-4kkrr ^about oxyl ^{- 1} · Výsledsiá acid mixture treated ^with e 3 ° min · ^{t o} - ^10CA annum ^for 30 minutes at ROOM ^ i. After ^u · kon.čeaí reaction. se. The reaction mixture is poured into a mixture of 40 ml of water / 60 ml. The pH of the mixture was adjusted to 7.0 by the addition of sodium pyrophosphate. The organic layer was separated, washed with 30 mL of water, and dried over anhydrous magnesium sulfate. Rszpouut & ^ llo is ddesiluje vacuo · added to the residue precipitated crystals diettyletter · · oodfitrují to afford 6.35 g / yield: 91.6% / diftnllmethylt8ttru 7- ^[2 зchUokaзttkmidothikZoU 2-2 --- yigglyoxylamdoo- ³ - [2 - (5-methyl-1,2,3) -tethoxybenzyl-3-cephem-3-carboxylic acid, m.p. 115-119 ° C;

IR / KBr / ^c m "'i 1780 ^1720, 1670

NMR (d ₆ -IMSOO ppm: 2.46 / 3H, s, -CH 2, 3.62 (2H, broad s, C ₂ -H), 4.47 (2H, s, C ₁ CH ₂ -), 37 (H, d, J = 5Hz, C6-H), 5.63 (2H, broad s, S), 6.06 (1H), dd, J = 5Hz, J = 8Hz,

C _? ^- H ^/ 7.07 / 1И ^with -CH ^ 7 ^ 1/10 ^ bs, -_ / q \ x2 /, 8.52 / 1H, 8, N ^ /, ^ ^0, was 07/1 H .alpha., d, J = 8 Hz, --COONH].

If the same procedure is followed, a compound is obtained:

diftn meth ^ll ^ ^t le8ttr 7- [2- / 2зch ^on oaзee ^and ιmidut kzul- · ^{TL -} -y ^{/ 6} g ^l OO yl bromide ^and - ^^ / L-cWor- ¹ 234trkazol ^y l / ^ll mttΗ 4343 t ^{and TM-4 to} arbuχylov acidified ^é ^ · ¹

121-123 ° C (dec.)

IR / KBr / ^c · ' ¹ :> _{σ0 1775} , 1720, ₁₆₆₃

NMR / DGJ-MSO / pp ·: 3.52 / 2H, br s, C-H /, 4.43 / 2H, s, ₂ C1CH - /, 4.94 to 5.57 / 3H, m, C ₆ -H, S], 5.98 (1H), dd, J = 5h, J = 8Ha, C-IH ', 7.00 (1H, s, ZCH-), 7.07 to 7.67

Ν '

2 0.84 g of methoxyamino tyridine chloride are dissolved in 30 ml of methanol. 0.76 g of triethylamine is added to the solution. 3.46 g of diphenylmethyl ethyl ether 7- [2- / 2- is then added. chloro KCET ^{to about} mdoUhtakO -4- ^y l / gl ^{y l} OX limite ^d at ^0-3 ^ - / S-meth ^{1-1, 2 »3, 4} - dr ^ l ^ / methyl-butyl] ^ -Jce The resulting mixture was treated at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. · The organic layer is separated, washed with 20% water, and dried with the aid of magnesium sulphate. The solvent is distilled off under reduced pressure. . ^Zí s ^k se se ^2,80 / výt ^ rt ^77,6 % ^^ βηγΙ / ^ ΗΙ ^^ τα 7- [ ² - ^2- cth ^u oaззeam ^id U4 ttlazUl444 ^y 1 / - ² - / 8 ^y n / -met ^t o ^χl ieinoaзetklι ^k . ^d u] -3 ^ - / 5-Metta ^{1-1, 2-4-t} ^ l ^ resonator / methyl] -3-еefem4 - // IIci k8rbuχlluvé acid mp 129-132 ° C / rozkkl / ·

IR / KBr / ев '' I _CE0 in 780, 1720, 1675

4.38 / 2H, s, гга ₂ - /, 5.26 / 1H, d, J «5Hz,

NMR (dg-IMSO) ppm: 2.44 (3H, s, -C./, 3.53 (2H), broad a, C ₂ -H 3.88 (Z 2, a, -OCH 3), ----_ '.......'', CW 5.55 (2H, broad s, S), 5.96

В <2 2в, CHCH- /, 7.00 to 7.63 (ПН, / 1H, dd, J = 5Wz, J = 8Hb, ^ τΗ /, 6.92 / 1H, Nj = 7, 9.73 / 1H, d, J-8Hz, -СОШ- /.

S J

The following compounds are produced in the same manner:

diphenylmethyl 7- [2- / 2-chloroethanoethanol-4-yl] -2-o-4-yl] -2- (8-ylamino) acetonitrile] -3 [(3-chloro-1,2) _> 4-triasolyl / ethyl] -3-cephem-4-carboxylic acid

Melting point: 120 to 124 ° C (dec.)

IB / KBr / ^s ': ^£ ' ⁰ 1,780 ^, 1,720 ^, 1,675

NMR (d ₆ -IMSO) ppm: 3.50 (2Ы, broad e, C C-V, 3.90 (3H) α, ,ΟΟΟ), 4.41 (2H, α, C ^ C /), 4.99 to -, 41 / ...., m, C ₆ -, S /, 5,981 (1H), dd, J = 5Hz, J 8Hz, C 1 H, 6.96 (1H, eZfCH) _N, 7.03-7.67 / U. n, _ / q \ x2, N = - ^2, 7.99 (1H, t, J = -), 9.73 (1H, d, J = 8 & z, -COHH);

S и K

3. In 10 ml of Ν-ethylmethylfuel. Dissolve ^2.0 g ^ .fenylmethylesteru 7- [2- / 2-chloroacetate ^and .doo ^th azoo ^4-yl-1 / -2 / s ^with y / ^c -meehooyiminnaoa EII ^and to] - ^o - [2- / 5-ma ^et V ^y i ¹ i ^2> 3,4-t'eteazo.yi / nmttyil] -e-eefeim44-krbooxylové acid, which was prepared in paragraph 2 of this Example. To this mixture was added 0.27 g of thioacetate. Mixture. The reaction mixture is poured into 20 m. of water and 30 .mu.l of ethyl acetate. The pH is adjusted to 7.0 by the addition of sodium bicarbonate. The organic layer was separated, washed with water (15%) and saturated aqueous sodium chloride (15%), dried over anhydrous magnesium tritium, and the solvent was removed under reduced printing. Ee To the residue, diethyl ether was added and deposited crystals · · · section thorns 1.45 g / yield: ^81.0% dfenyaiettyletteru ⁷ - ^[2 2 ² 2 ^i-м .not ^about lazol-4- ^{yl 2} 22- yn ^e / ² · e ^o hoxyiad ^No4 acetarnidoj-l- [2- / 54aethУ-1 »2,3,4 4tetrazolyl ² · methyl] -L-hУ 32Cefelm4l · carboxy χylové acid, m.p. 102-105 ° C / decl /·. *

IB / KBr / о »“ ¹ : Ъ.0 1,778 ^, 1,720 »1,660

NMR (d 6 -IMSO) pp: 2.43 (3), s, -Cly, 3.45 (2H), broad α, Cg-V, 3.84 (3H, α, -OCCl 3), 5.29 (1H) d, J = 5Hz, C8 H7, 5.52, (2H, broad t, S), 5.93 (1H), dd, J = 6Hi, J8He, CH2 -, 6.78 (1H), ^and N @ + -, 6.91: 1. > CH ^ 7.3 ^2/10. br ,, β / θ)> χ ^{2/9, 6} · 4 '-' / 1H, d, J = 8Hz, -COJNH /.

In the same way the following compound is obtained:

^diphenyl-l r ^e thyl you 7- ^[2- / ² -ani notOiazol242 ^/ l ² 2 ^{4 /} ./y ⁿ / L / - eOOo · ^{y n} r 1i ^and noιю ei · ^t · ^u ol ³ ^ J ^ M-or-1,2,4-triazolyl- ^2- ethyl] 23-aphenyl-42-carboxylic acid ·

Melting point: 118-122 ° C / dec

IR / KBr ^{2 cn} &quot; _Ca0 1,775, 1,720 ^, 1,660 · 'ϋ · - · · к

^ -f ^ ^9, 67 / ^{1H, d,} J 8,

NMR (d 6 -DMSO) ppm: 3.42 (2H, broad s, C ₂ -H), 3.84 (3H, s, -ОС), 4.99 to 5.39 (3H, m, S, C ₆₎ -H /, 5.92 / 1H, dd, J = 5Hz, J = 8Hz, 0 ^, 6.77 / 1H, s, Nj- /, 6.97 / 1H, s,> - ^cg 2 "

ICH ^ 7 ^, 34 / 10H broad iq - ^ Q ^ x2 ^ ^/ , 8,01 (1Н),

N 8 »

N

-CONH / <

4. The compounds obtained in paragraph 3 are treated in the manner indicated in the table with trinocuccinic acid known as: 15/1 / ·

Table 155/1 /

Trifluoroacetic acid ^0CH 3 COOH / son of Izom · / 2 compound (R) melting point ^/ ° C / .N = N —N I CH3 162 / rozkl · / N77N -t0-k ^N Cl 123 to 125 / nostrils · /

5 / i / ^UL-yl acetic acid benzyl ester; 7- [2- / ^2-th and ^m .not azo ^t - yl ⁴ / 22- / 8 ⁿ n / -mβtht ^; yininooccttaidoJo3- [22/5-net ^t yl-1> ^{2, 3,} 4 - te ^of ratolyl / · tthyl] - ^c · f c · вн ^ k ^and OR ^at about ^y f0ovou tyaelinou and salt tysell MnooiOctc ^ ^ 7- ^[2-2 2tlmintt ^h Ltzol-4- ^yl [22- / ly] -1-hexyl [ ^1,2-a ] -1,2,4,4-thiisol-1- ^yl ] -attnyl]- Cetylphosphoric acid is reacted with 1N hydroxide solution sodium or a saturated aqueous solution of sodium thyrogene sulfite, then. Purified by Aberrant XAD-2 column (eluent lead) to give the compounds listed in Table 15 (2):

Table 15/2 /

/ son Izo ··· /

Melting point / ° с /

IH / КВг / '*' C 'o

NMR (dg-MiSO-D ₂₀ ⁺ ) ppm / J> ₂₀ ** /

183 až 187 ./rozkl./

760, 1 665,

610 * 2,50 / ЗН, _e ,> -Ca ₃ /,

N

3.30 / 2Н, broad а, C ₂ -H /, 3.91 / ЗН, 8, -OCH ₃ Z, 5.12 / 1Н, d, J «5Hz, C ₆ -H /,

5,66 / 2Н, wide 8, S /,

168 / rozlcl · /

760, 1 670,

605

5.74 / «H, d, J = 5H« _C? -H /, 6.83 (1H).

S й

3,30 / 2Н, Wide and,

Cg-H /, 3.97 (ЗН, and, -OCH 3),

4.93 to 5.60 / ЗН, n,

S, Cg H, 5.77 H, d,

J »5 N, C ₇ -H /, 6.91 /« H, e, N ~ j —— /, 7.96 / 1 N, s,

With fl> a /

N / ii) 6.13 g of the trifluoroacetic acid salt of 7- [2- (2-aminothiasol-4-yl) -2- [syn-methoxyiminoacetamido] -3 - [(3-chloro-1)] are suspended in 25 ml of water. 2,4-triazolyl / ethyl] -3cephem-4-carboxylic acid · Sodium bicarbonate is added to this suspension with ice-cooling to adjust the pH of the suspension to 8.0 · At this pH the suspension becomes a solution · Concentrated hydrochloric acid The pH is then adjusted to 2.5 at the same temperature, whereupon crystals are precipitated, the crystals are filtered off, washed thoroughly with acetone and dried. aminothiazol-4-yl] -2- (Bromo) -methoxyiainoacetamido] -3- [[3-chloro-1,2,4-triazolyl] methyl] -3-cephem-4-carboxylic acid having a melting point greater than 200 ° C ·

IR ABr / cm: · 765, 1660, 1625

NMR (d 6 -MISO) ppm: 3.44 (2 N, Broad 8, C 8 -H), 3.85 (З N, a, -OCH 3), 5.20 (2 N, Broad a,

Л /, 5,20 / 1Н, d, J «6Ht, Cg-H /, 5,78 / 1Н, dd, J« 6Ha, J 8Hz, Oj-H /, 6,7 «/« Η, e, «2 _M

Я-ТГ- /. 7, 6 (2H), broad and -NHg (8.04 (1H), s, 6H, 9.60 (1H, d, JH, -CONH). S Д ^H

The following compound was prepared in the same manner:

Melting point: > 200 ° C

IH / KBr / cm ^-1: v _{c, 0} 1 765, 1 660, 1 625th

7- [2- (2-aminothiazol-4-yl) -2- [syn] -methoxyiminoacetamido] -3- [2- (5-methyl-1,2,3,4-tetrazolyl) methyl] -3-cephem -4-carboxylic acid ·

Example 2

By using different starting compounds with the same reaction as in Example 1, the corresponding compounds are shown in Table 16.

Table 16

Trifluoroacetic acid N ~ A CONH —1 --- OCH3 COOH / son izonse / Я ² R ² R ²

-q

CH ₃ .N = N

-H

SCH ₃

-TN

COOCHjCHj

-Q

NHCáCHj

N = N i

SCH ₃

N = N

CH2COOCH2CH3

N = N

AJ * 4 nh ₂

-Cl

2 CH ₃

_N-CH3 N = N .M

-in

CH ₂ CH ₃

N = N

COOCH ₂ CH 3

N - ^ - N

SCH ₃

N-ttAI

NHCOCHj

-IHiCOCHj

COOH

N — N

COOCH ₂ CH ₃

COOCH3 - NH - at

COOH

соосн ₃ соосн ₄

- @ НОН

Example 2

By the same reaction and using different starting compounds of the procedure of Example 1, the corresponding compounds shown in Table 16 are obtained.

WITH.

ДИ

Η л

Ε4

1А КО • н «К О КО ио м 8 > Ы <п а. 0 <ь А н ш • 5 <*? 00 к ΛΙ м- оо * 7 * гп «К А Я1 м II <Л I / о 1Л м L / 1Л ►э 1 г \ м <м *** 2. « η 0 •

о. α

хо Ж - m no • О Ж N * см 9 Я —- А со tt— А СМ М> А II о хо <п Л » 0 к ох N Z-ч А 34 * СПС- А  ,

Γ'σ) t- ΰ А 1 / ^И м см / й ак II Ьс см • к • «к η 0 ХО 1 ^v w N ) Ы ж 0 • э Μ Т5 r " СМ СЙ 0 • ХО я к • о о СП no no * о ЧУ ж · » ί- ί- м м ο WITH * 1 «К со со т см А ί-

8.25 to 8.67 Cl (n, -KHCO-), 9.64 <1Ж

-CONH-)

<х а

й

о m ЧО о о сГ см чо Г ^ »\ О ЧО - - <- * 1Л О ь · ЧО t- t— -

1О 1Г \ ζ-χ О Я ~

N ΙΑ О

О СП чО г · о о о см ь- Q) е- - - Г » о О еř- Ř

Table 16 continued

Trifluoroacetic acid

/ son izoaer /

IR / KBr / cm ^-1 :

^V> C = Q

IR / ХВг / cn '¹;

VC = Q

N = N N I 1 770, 1 665, 1 630 СН3 N = N 1 770, 1 730, 1 665, 1 630 СН2СООСН2СН3

_From N = N - NI БСН3 1 1 770, 630 1 665, N = N 1 775, 1 660, 1 630 БСН3

770, 1 665,

63Q,

n = n 1775 ,, «. 665 —N 1 1 630 СН2СН3

77Q, 1 730,

670, 1_ 630,

СООСН ₂ СНз

775, 1 670,

630

N = N i

СООСН2СН3

775, 1 740,

670, 1630

-У

COOH

770,171O

620

775, 1,725,

660, 1630

СООСН2СН3

770, 1,710,

620 / N

775, 1 730,

665, 1630

770, 1710

620

СООСН3

СООСН3

COOH

Example 3

Using the various starting compounds, the corresponding compounds shown in Tables 17, 18 and 19 are obtained according to the example.

ia IA

O

1 = »<0

Д4

A jq a

CCONH

« * о CA Μ O 10 10 ’Ф 10 * 3 • Ol 0 CM it m σι <n ΓΊ it / —Ч lA cn Я Я · » no CM OF"" O Я and 1 1 «* Ю W Q со & M it O ЭД Μ h lA σι • H XO II * □ τ- M • CM it * - Ό

№

CO CM

И и о

I (0

CM ’ф) N

O

OO 1A aí <*? (AND

lA O O fr- t- 10 10 10 10 - - - _л O O ΙΑ lA IN- t * · IN- - - - * O Φ © as WHAT OO ř- -

10 CM • Φ · z-ч « * 3 AND А what and Μ N N σι O ’Ф О »- (4 ’Ф Сч * - ’Ч *»

SKK here O «rt / *> 1 WHAT t ·> 1 40 4_Z CM it ř- of". ад O CM O EJ No. * Ό M WS O E WITH 5 CM O of — 4 AND 00 m O M 1 1 0 <4 * II O

AND

bulka 17 continued

СО

О

ДЧ гЧ

В

А

Η

(And IA VO

About CH ί-

OO

СП

ж

А

СП ΙΑ

СП 1А

С— гп СО ч

1А о 1Л О О «Ъ й · » • č II • н МО МО Я1 хх Я ж * ГП л СМ Ό см я / '\ хх XX о жж · » СП 1А Я см X * 1А КО OJ ω Я СП (А

СП ΙΑ

О II смо О Я 40 • к я о hj XX • -э ХЧ о 1 1 04 / СП см * СП 44 я ж • 4 X Ό O (М *, ♦ * о ϋ СО W • О * t- XX см 1 04 / СП • 4 Я1 44 *

TΑ tчо о СП ΓΙΑ СО к а 18 continued

В О со Е4 а й • Н Й

Φ ю д о гЧ <М ω о3

A4

Η

Л &

о.

/ ·>

о

Ό i

* · * O Т / й · o * 8 к - * 2 ¹ ~ 1 II К M M o

x-s t o o Ш * - * M O t * № \ 0 * O и · « O Ъ «

> N * * o

ΙΑ

K0

KO

t

o ίCKI o co røkko

ο 4A СО КО b-K0

b ·

IA in b '

1Л IA

CO b ~ b- CO ιΑ bIA O CO 00-ко

O b * r- O ia WHAT b- b * KO -

bulka 18 continued

IA <*)

b ·

IA r4 r4 <0 Л4 H « O lA O IA (M

<0 • 0

and

V4 £

Ρ

Ρ ο

X

MC4 Μ · o tf>

ο řΜΟ

W

CD

ΙΑ CM

к а 19 continued

* см я Ш о GQ -Γ- гл СЛ - ΙΑ К «* v © М z ~ k 01 No. сл о я СЛ м о 1Л 1 СП ® КО «К ί- л / X 1Л ο -г- СЛ О О О \ 1 СЛ л см Ό О stl ж / η ο- о < N СО LA со ι СМ Я ad

if ►о СП W * -V сл О ' КО AND • к СЛ • к II * d о Х-Ч * -г Д СЛ * 1 М 1А ί- «К «I - аР ο • о о ® со X-Z 1 я w Í— и 1А см • ъ Í О ' w СП * “Γ- л сл «Ъ ΟΟ о со Z ** 4 * о • к

Example 4

A solution of 2.5 g of aeeitylenesulfonic acid dihydrate in 20 [mu] l of ethyl acetate was added to a solution of 5.93 g of 7- [2- [2-a] inothlazol-4-yl-2-yl] -ethoxylino-methanesethanido] pivaloyloxy-ethyl ester. * [2- (5-methyl-1,2,3,4-tetrazolyl) ethyl] -3-cephen-4-carboxylic acid in 50 µl ethyl acetate. The precipitated crystals are filtered off, washed with ethyl acetate and dried. 7.39 g (93.2% yield) of selenium sulfonic acid with pivaloyloxyaethyl ester * 7- [2- (2-aainothiazol-4-yl) -2-syn] methoxyiminoacetenido] -3- [2- (5-Bethyl-1,2,3,4-tetrazolyl) -ethyl] -3-cephen-4-carboxylic acid, m.p. 218-220 ° C (dec).

IB / KP / d ': v _c _ ₀ 1 782, 1 745, 1 680

/, 2,43 / ЗН, 8, * -> - qH ₃

ΔК / dg-DMSO / ppa: 1.15 / 9N, α, -C / CH ₃ / γ, 2.14 (3H, s, CH ₃

2.53 / 6Н, and,

3,52 / 2Н, wide in, С ₂ -Я /, 3,93 / ЗН, and, -OCHy, 5,20 / 1Н, d

J 5H, C ₆ -H /, 5.56 / 2N, broad α, S /, 5.78 / 1N, dd, J 5Hz, J 8N, γγ-Η /, '. i | ·. Η v * í! : -yw; J · .Ji! . . t

5.85 / 2Н, 8, -COOOHgO- /, 6.50 / ЗН, broad а, -fa ₃ /, 6.75 / 2Н, and,

Sat ₃ - /, 6,93 / 1Н, 8,

Κ-χ— /, 9,81 / 1Н, d, J ´ 8H «, -CONH- /. S ^ S

Example 5

I. 1.72 g of 2-aninothlazol-4-yl-glycolylic acid are suspended in 6 µl of H, N-dimethylformaldehyde. 3.3 g of phosphorus oxychloride were added dropwise to the resulting suspension at -20 ° C, and the reaction mixture was allowed to react at -5 ° C for 3 hours. Next, a suspension of 5 g of selenium acid with plvaloylmethyl methyl ester 7-anino-3- [2- (5-methyl-1,2,3,4-tetrazolyl) ethyl] -3-cepham-4-carboxylic acid in 20 ml was prepared. of anhydrous nethylene chloride, 1.01 g of triethylalanine at -30 ° C is added to the resulting suspension. This suspension was added dropwise to the above reaction mixture at -30 to -20 ° C. The resulting mixture was allowed to react for 1 hour at the same temperature and then at 30 ° C to 30 ° C for 1 hour. After completion of the reaction, the methylene chloride was distilled off under reduced pressure, and 60 µl of ethyl acetate was added to the residue. The pH was adjusted to 4.0 with sodium bicarbonate.

Insoluble matter was removed and the organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by column chromatography (eluent: benzene-ethyl acetate = 2: 1). 3.5 g (62.1% yield) of pivaloyloxynotyl ³ '[[2-a] -nothiazol-4-yl] -glyoxilamido] -3- [2- (5-methyl-1, 2-methylpyrrolidin-1-yl) ester] are obtained.

2,3,4-tetrazolylmethyl-3-cephem-4-carboxylic acid having a melting point of 99-102 ° C.

IR ABr / _CB 's in _CbQ 1,785, 1,745, 1,685, 1,660

H \

NMR (d ₆ -BMSO) ppa: 1.21 (9 N, a, -C (CH ₃ ) ·), 2.54 (Н N, a,> -CH ₃ ), 3.65 (2 N, broad a,

N

C ₂ -H /, 5.40 (1N, d, J) 5Ha, Cg-H /, 5.81 (2N), broad а, 5.88 to 6.25 (ЗН,,

C ₇ -H, -OCl 2 O- /, 7.59 / 2Н, aro, -NH ₂ /, ^{8 '07 /, H} «·» ^М ПСГ ^/ » ¹⁰ »' ° ^/ ' ^H ' ^d > ^J “ ^9Hz · s д

-С0КН- /. In the same way, the following compounds were obtained:

7- [[2-Aminothiazol-4-yl] -glyoxylamido] -3- [2- (5-methyl-1,2,3,4-tetrazolyl) methyl] -3-cephem-4-carboxylic acid pivaloyloxyethyl ester / yield 61%.

Melting point 106-109 ° C (dec.).

IR (KBr / cm &^lt; -1 &gt;): [nu] _C-O 1780, 1740, 1680, 1660.

NMR (d 6 -DMSO) ppm: 1.18 / 9N, s, -C / Gγy, 1.56 / ЗН, d, J * 6Hz, -СН- /, 2.51 / ЗН, s,

^ CH ₂ - /, 5.80 to 6.15 / 1Н, ø, C _r H /, 6.90 to 7.25 / 1Н,, -СД- /, 7.54 / 2Н, broad a, CH ₃

-NH ₂ / 8.03 / 1Н, а, Nj ^ - ^{/,, 0> 07 / H »4} - ^9Hz> -С0ЯН- /.

pivaloyloxyethyl 7 - [(2-aminothiazol-4-yl) -glyoxylaidid-3-yl] -3- (chloro-1,2,4-triazolyl) methyl] -3-cephem-4-carboxylic acid (60% yield).

Melting point: 111-114 ° C (dec.).

IR (KBr / cm &^lt; -1 &gt;): [nu] _C-O 1780, 1740, 1680, 1660.

NMR (d6 -DMSO) ppa: 1.19 (9N, s, -C (CH3)), 1.56 (ZN, d, J = 6Hz, -СN-), 3.57 (2N), Wide a, ch ₃ с ₂ -и /, 5.17 to 5.52 / ЗН, n, Cg-H, ^ Lch ₂ - /, 6.85 to 7.28 / 1Н, n, -СН- /, 7.55 / 2 N, broad ch ₃ a, -NH ₂ /, 8.03 (1 N, a / Nu -), 8.24 / 1 N, a, S &

TO·

9.85 / 1N, d, J = 9H, -СОНН- /.

-carboxylic acid and methoxyamine hydrochloride are added under ice-cooling, the reaction mixture is then reacted for 12 hours at a temperature of 15 to 20 ° C. After the reaction, the reaction mixture was poured into a mixture of 250 ml of water and 250 ml of ethyl acetate. The pH was adjusted to 4.0 with sodium bicarbonate, the organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Diethyl ether was added to the residue. The precipitated crystals are filtered off. 4.7 g (yield 84.7%) of 7- [2- / 2-aminothiazol-4-yl] -2- (syn) -methoxyiminoacetamido] -3- [2- / 5-methyl-1] pivaloyloxyethyl ester are obtained. 2,3,4-tetrazolyl (methyl) -3-cephem-4-carboxylic acid having a melting point of 127 to 128 ° C (dec.).

In the same way the following compounds were obtained: 7- (2- (2-aminothiazol-4-yl) -2- [syn] -methoxyiminoacetamido) -3- [2- / 5-methyl-1,2,3,4-] pivaloyloxyethyl ester tetrazolyl (methyl) -3-cephem-4-carboxylic acid (85% yield) ·

Melting point: 127-130 ° C (dec.).

7- [2- (2-Aminothiazol-4-yl) -2- (syn) -methoxy-iminoacetamido-chloro-1,2,4 ** triazolyl] methyl] -3-cephem-4-carboxylic acid pivaloyloxyethyl (yield 84%) i

145-147 ° C.

These compounds have the same physical properties as the products obtained in Example 3.

Example 6. AND

2.2 g of 2-fornanidothiazol-4-yl-glyoxylic acid are suspended in 6.6 ml of Ν, Ν-dimethylacetamide and 1.8 g of phosphorus oxychloride are added dropwise to the resulting suspension at -20 ° C, at this temperature. The reaction mixture is left to stand at room temperature for 2 hours. Next, 5 g of weed acid are suspended with plvaloyloxymethyl ester 7-anino-3- [2- (5-methyl-1,2,3,4-tetrazolyl) ethyl] -3-cephem-4- of carboxylic acid in 20 µl of anhydrous methylene chloride, at -30 ° C, 1.01 g of triethylamine is added to the resulting suspension. The resulting mixture was then added dropwise at -30 ° C to -20 ° C to the above reaction mixture. The resulting mixture was allowed to react at the same temperature for 1 hour. After the reaction, methylene chloride was removed by distillation under reduced pressure. 70 µl of water and 70 µl of ethyl acetate were added to the residue. The pH was then adjusted to 3.5 with sodium hydrogen carbonate. insoluble matter · The organic layer is separated, washed with water and saturated aqueous sodium chloride in turn, then dried over anhydrous magnesium sulfate · The solvent is then distilled off under reduced pressure · Diothyl ether is added to the residue and the precipitated crystals are collected by filtration · Washed and recovered with 4.74 g (80.1% yield) of 7 - [[2-Fornanidothiazol-4-yl] -glyoxylamide] -3- [2 * / 5-methyl-

1,2,3,4-tetrazolyl (methyl) -3-cephem-4-carboxylic acid, m.p. 129 DEG-132 DEG C. (dec.).

IR (KBr / cm &lt; ^-1 &gt;): [nu] _{C-Q =} 705, 1755, 1695, 1670

NMR (d 6 -DMSO) ppm: 1.16 / 9N, s,

С / СНуу, 2.47 / ЗН, s,>

• CH ₃ /,

3,57 / 2Н, wide, and »

C ₂ -H /, 5.29 / 1N, d, <5Hs, C ₆ -H /, 5.65 / 2N, broad

C ₇ -H, -OCHgO- /, 8,44 / 1Н, and, Nj— /, ⁸ .59 / 1Н, and, НС- /, 9,95 / 1Н,

12.37 (1H, broad a, -CONH-).

1.20 / 9Н, β »

5.50 / ЗН, «·

8.26 / 1N, e>

-C / CH _3/3 / 1.56 / ЗН, d, J »6Hz, -СН- / 3.67 / 2Н, br e, Cg-H / 5.17 .Z ca ₃

Cg-H, ^ СЦ ₂ - /, 5.83 to 6.18 / 1Н, а, С _? -В /, 6.93 to 7.30 (1N, e, -Cfl-),

CH-i

8.64 / 1Н, s, N-д— /, 8.81 / 1Н, а, НС- /, 10.18 / 1Н, d, J «9Hz,

W S Ц o

-CONH- /, 12.97 / 1Н, broad s, -ННСО- /.

2) In 25 µl of Ν, Ν-dinethylacetamide, 5.92 g of pivaloyloxynotyl ester 7 [(2-fornanidothiazol-4-yl) -glyoxylamido] -3- [2- / 5-methyl-4,2,3,4-tetrazelyl] are dissolved. (methyl) -3-cephem-4-carboxylic acid and, under cooling in January, 1.67 g of methoxyamine hydrochloride are added to the resulting solution. The reaction mixture is then reacted for 3 hours at 15-20 ° C. After completion of the reaction, the reaction mixture is poured into a mixture of 250 µl of water and 250 µl of ethyl acetate. The organic layer is separated, washed first with water and then with saturated sodium chloride solution in water. After drying with anhydrous magnesium sulphate, the solvent is distilled off under reduced pressure. diethyl ether was added to the residue, and the precipitated crystals were collected by filtration, yielding 5.27 g (yield 84.9%) of pivaloyloxymethyl ethyl-7- [2- (2-fornanidothiazol-4-yl) -2- (8-yl) methoxyiminoacotamido] -3- [2- (5-methyl-1,2,3,4-tetrazolyl) methyl] -3-cephen-4-carboxylic acid, m.p. 132-135 ° C;

IR (KBr / cm &lt; -1 &gt;): [ _{nu] C, 1785, 1752} , 1680

NMR (d ₆ -DMSO) ppm: 1.2% (9N, a, -C (CH 2 Z 2), 2.51 (ЗN, a, J) -CH ₃ ), 3.61 (2 N, broad a,

C ₂ -B / ', 3.97 / 3H, β, -OCH 3, 5.38 / 1H, d, J = 5Hz, C 4 H 7, 5.77 (2H, broad s, S),'

6.05 / 2H, s, -OCH ^ OA 6.11 / UI, dd, J - 5 Hz, J - 8 Hz, C H ₂ / 7.60 / 1И and N / -7

S 2

8.73 (1H, s, 1H), 10.00 (1H). d, J = 8Hz, - ^ CON ^ /, 12.63 (1H), broad s, -CXNH-Λ

O

The following compounds are prepared in the same way:

¹ '-pi.va ^ j ^ oxyethylester 7 - (/? - ^T FO iaamidoo laao ^of M ~ ^- l / -g ylamide ^ly by ^x / 3 - »[2- / 5" Me tíhl- ¹ 2, ^3, 4-te ^of i'ezol ^et / mith ^c] - ^»e -eeí ^EDI" 4bkarbo ⁱⁿ rlové acid.

Melting point: ¹³⁶ to ¹³⁹ ° C (decomposition)

IR / KBr / ^c m-4 in _{Cs0 1755-174, 1690-1655}

NMR (d 6 -IMSO) ppm: 1.19 (9H, s, -C (CH 2), 1.56 / 3H, d, J = 6Hz, -CH), 2.53 (3H, s,

Chj

CHχ> -CHy, 3.67 / 2H, broad s, CyV, 5.42 / 1H, d, J = 5Hz, C ^ H / 5.75 / 2H, broad s, ^ 1-¾¼ 6.06 / 1И , dd, J = 9Hz, Cy-H, 6.95-7.35 (1H, α, - ^ - 1), 8.68 (1Щs), 'CH ₃

Nj = -, ^{8 *} , 83 (3) HC- (3 ') (1H, d, J = 9Hz, -COIN), 12.82 (1H, broad s, -NHCCO), HO ¹ ''; ^ρi va ^l k ^y lkχ ^y et / ^l leater 7 - [/ 2 ™ ^k oιαa8 ^o LdGthíazol “ ⁴ “ ^y l / “. gl ^y o2 ^y la «aido]«> ³ ~ ^ -d / lor-1,2'4 ^t гiazk ^ll l / oet / pl] ^ - 3 “CΟfeO” 4-kt ^ lr ^b o :: ι ^{χ lkV é} acid ^1,

Melting point: 141 - 143 ° ^C (decomposition)

IR (KBr / cm &lt; ^-1 &gt;): [nu] _C-O 1785 * 1745 * 1690 * 1665.

NMR (d ₆ -IMSO) ppm:

In the same way ae the following compounds are obtained:

1- '· ^ p: ^ л ^ 8 ^ · k ^ ^y lox ^ ^, e ^t /^].es ^t er T- ^ -ZS ^ ïímímasddcthi.azol- ⁴ - ^yl / - ^ 2 7 7a ^y Ώ / -oe ^{t /} k ^χy ioinoacetaoidok * ~ 3- [ ³ 3-c ^/ lcr ™ !? ^, 4 "taiozo ^ly0 / It / ^y th lJ-. ^c e ^l ce ^of E4 @ '· The hinge ^of ox ^yl May ^{/ yt} Sze in ^the $ ^83/2 oojící having ^a melting ^{point from 154} and ¹⁵¹ ° ^{C / s to} r of the uninstallation ^and NO oetl / Mn ^ / ·

IR (KBr) α ¹ : δ ^C _{1785 +} 1745 + 1680

NMR (dg-1MSO) ppa: 1.17 / 98, s, -C (dyy) 1.53 (3H, d, J = 6Hz, -CH), 3.50 (2H, broad s, C CH ₃ s) 'C ₂ -H', 3.90 / 3H, 8 ', -OCH 3, 4.93 to 5.46 (3H), and, C ₆ -H, S', 5.92 (1d), dd, J = 5Hz, . > ^C H ₂ “ _K

J = 3Hs, _C7 -HH, 6.83 to 7.08 (1H, a, 7.40 (1H, u, N-), 0.04 (1H, a,

CH 3 S H W

8.50 (1H, s, HCC), 9.75 (1H, d, J = 8,000, -COUH), 12.64 (1H, broad α, -COUH).

я

7 '[2- / 2-Formraidothiazol-4'-yl] -2- (3-yne) -methoxyimino.cetimidoy-3- [2- (5-methyl-1,2,3,4-tetrazolyl) O'-plvaloyloxy] ethyl ester (ethyl) -3-cephem-4-carboxylic acid (85% yield) having a melting point of 203-205 ° C (dec.).

IR (KBr) / cm * ¹ : [nu] _C-O 1790, 1750, 1725, 1680

NMR d6-DMSO / ppm; 1.18 / 9Н, e, -С / СНуу, 1.53 / ЗН, d, J 6Hz, -СН /, 2.50 / ЗН, s, ^ -CH ₃ /, 3.71 / 2Н, Wide s , C ₂ -H / M M <> (ЗН, s, -OCH-j), 5.35 (1N, d, J = 6Hz, Cg-H), 5.68 (211), broad s, S /, 6.02 / 1Н, dd, J = 6Hz, J = 9Hz, γγ-ΗΖ, 7.08 / 1Н, в, - (j! H- /, ^ cn ₂ сн ₃

7.58 / 111, e, N <J - /, 8.70 / 1Н, в, H ^ ~ /, 9.99 / 1H, d, J = 9Hz, -CONH- /, 12.70 / 1Н , s ^ 'h 0 wide з, -С01Ш- /.

3. In 66 ml of ethanol, 6.55 g of 7- (2- [2- (2-forma-midothiaxol-4-yl) -2- (3-methyl-ethoxy) amino] acetamido) -3- (3-chloro-2-carboxylic acid) are obtained. R, 2 _S 4-triezolyl / methyl "3 * ~ ~ cefeHi 4-carboxylic acid obtained in paragraph 2, and under ice cooling, 4.2 ml of 12N hydrochloric acid к this suspension. The resulting shifts were allowed to react at 5-10 ° C for 2 hours. The reaction was then poured into 660 ml of water and the pH adjusted to 5.0 with sodium bicarbonate. The precipitated crystals are filtered off, yielding ⁴ εе 5.73 g / yield 91 _with 4''-pivfiloyloxyethyl ester 7 * 2 '. / 2-aninothiazole / methyl-3-cefem * »

M.p. 145-147 ° C.

The following compounds are obtained in the same way:

7- [2- / 2-Caminothiazol-4-yl] -2- (8-yne / methoxyiminoacetyl) -ido] -3- [2- / 5-methyl-1,2,3,4 "tetrazolyl / methyl] pivaloyloxymethyl ester - 3-Cephem-4-carboxylic acid having a melting point of 127 to 128 ° C (dec.).

'-pivaloyloxy ethylene ster 7 »[2- / 2-aBinothiazol-4-yl / -2- / ayn / -methoxylminoacetamidoJ ->» 3 2- / 5-methyl-1,2,3 _of 4-Tetrazolyl / metbyl -3-Cephem-4-carboxylic acids having a melting point of 127-130 ° C (dec.).

The physical characteristics of these compounds are identical to those obtained in Example 3.

Example 7

1. In the same manner as in Example 6, 7- [2- [2- (1-Thinothiazol-4-yl) -2- [syn] -ethoxyiminoncetemido] -3- [2- (5-methylthio) -1- [2- (5-methylthio ^)] - pivaloyloxymethyl ester is obtained. 2,3,4-tetrazolyl / methyl] -3-cephem-4-carboxylic acid.

Melting point: 99-102 ° C (dec.).

IR / kg / cm ' ¹ : * _{с = 0} 1,785, 1,745, 1,675, 1,615

2. In the same manner as in Example 4, the following compound is obtained from the compound prepared in paragraph:

mesitylenesulfonic acid salt with pivaloyloxymethyl ethyl 7- [2- / 2-aminothiazol-4-yl] -2- (8'-ethoxyiminoacetamido) -3- [2- / 5-methyl-1,2,3,4-totrazolyl] methyl -3-Cephenyl-4-carboxylic acid.

Melting point: &gt; ¹⁹ ° C.

IR / kg / cm &^lt; -1 &gt;: in _{G = 0} 1780, 1745, t 680.

Preparation example 1

The composition, the composition of which is given below, is prepared by first mixing the main component and spreading it with lactose. An aqueous solution of hydroaxypopylcellulose was added to the mixture. The resulting mixture was washed, dried and dried. The powder is mixed with magnesium atearate which has been premixed with starch. Tablets are then prepared from the resulting mixture.

Composition ^H ydrochlorid Pivate ^ o ^ tester methyl 7- [2- / 2-aainpth ± azpl-4-yl / · "2 / son / -methoxyiainoacetí ^m L ^d P ^Ί -3-2- / 5 ·· шethy ¹ 1 · _s 2,

3,4 “tetrazole ^y / meth ^y lJзЗce®m-4-carboxylic acid 113 mg lactose 20 mg starch 444 rag Hydroxypropylcellulose 5.4 mg magnesium stearate 0,6 mag 200 mAablet

If other compounds are used in place of the above compound, similar tablets may be prepared in a similar manner.

Preparation example 2

The composition below is made by mixing a portion of the starch and triturating it with magnesium stearate. This comminuted mixture is mixed with the remaining starch with hydrooxypropylcellulose and the active ingredient. Capsules are prepared in a conventional manner from the mixture obtained.

Composition trihydrochloride Pivato ^ ^ ^ ox ethLesteru ⁷ - [2 -. / 2-iminothiazol- '~ 4- ^y 1 ^ - ² ^ / ^{/ Y} n ^/ - ^ aietho ^x Ln y ^im ^ i ^ (^ (^' and ^t ^ i ^ (^ oJ- ³ - ^[2 - / 5 «methyl ^1, 2,3,4-eetrazol ^yl / meth ^yl] з3ctefem44o ^and arbpχ ^yl pv ^Star kyseldny I ³⁶ mg starch '54 mg hydrpxypr ^ yleelulpza magnesium stearate4 · mg

200 ·

If other compounds are used instead of the above compound, similar capsule formulations can be prepared in a similar manner.

Preparation example 3

The composition below is prepared by first mixing the main component with lactose and adding an aqueous solution of hydroxypropylcellulose to the comminuted mixture. The resulting mixture is bent and dusted. The powder is mixed with magnesium stearate which has been previously spread with Starch. Then the resulting mixture is made into tablets ·

The composition of a mosquitylenesulfonic acid salt in pivaloyloxymethyl ester

7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamido] -3- [2- (5-methyl-1,2,3,4-tetrazolyl) ethyl] -3 " Cefem-4-carboxylic acids 130mg lactose 20mg starch 44mg hydroxypropylcellulose 5.4 mg magnesium stearate 0.6 mg

200 mg / tablet

If other compounds are used instead of the above compound, similar tablets are obtained in a similar manner.

Preparation example 4

The composition below is prepared by mixing a portion of the starch and triturating it with magnesium stearate. The thus ground mixture is mixed with the remaining starch, hydroxypropylcellulose ^from Zou as the main component. Capsules are prepared in a conventional manner from the mixture obtained.

Formulation mesitylenesulfonic acid salt with pivaloyloxymethyl ester of 7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamido] -3- [2- (5-ethyl-1,2,3,4-tetrazolyl)] methyl] -3-cefem-4-carboxylic acid 136 mg starch 54 mg hydroxypropylcellulose 6 mg magnesium stearate 4 mg

200 mg / capsule

If other compounds are used instead of the above compound, similar formulations can be prepared in a similar manner

Preparation Example 5

A mixture of ^d hydrogennLhld.či.tanu therefrom T - ^ - ^ - minothiazol - ^ - VAS-Zsyn / maetho ^ iminoacetamido] -3- ^f 2- / 5-Me ^eth li1,2,3,4 ^"e trrazilyl / eetyyl ^{-3-cephem-3 and} 4- arboxylovou acid was treated in a conventional manner to obtain lyofilZzovíná sterile sodium salt. Injections are prepared by dissolving one gram (strength) of sodium salt with 20 ml of saline.

Preparation example 6

Injections, which are diluted before use, are prepared by dissolving one gram (strength) of the lyophilized product produced according to Preparation Example 5 with 4 ml of 0.5% (w / v) by volume / aqueous solution of lidocaine hydrochloride.

Preparation Example 7 By injecting one gram (strength) of the liophilized product produced according to Preparation Example 5 in 20 ml of a 5% glucose solution, an injection is made.

Other compounds (free carboxylic acids) of the formula I according to the invention can also be formulated in the lyophilized products (sodium salts) or by injection in the same manner as in Preparation Examples 5-7.

Claims (3)

1. A process for preparing 1 cefalcsporinů general formula (I) wherein ^R1 is ^a hydrogen vofóto not a C ^{b g} pLkyl ^_lβ, iffeΏy ° ¢ ϊtl ^l m ^{l l.,} Phenyl, .alpha.-Tort βιφΐ ^ f, 1 '4pioalzylzx ^lb eΏzy ^{l C} иγa ylz ¢: r ^{χ C} и58LL] ^kгl, ί. ^{»1 101} 1 NEFA-group of the formula -CHOR R ⁶ Or wherein R ^y represents a C 1-6 alkyl group and R represents a hydrogen atom or ^{r 6} 'o C ^ an alkyl radical ^R represents ^{phenoxy-yl zozu, zozu,} C_ ^G and ^LK 'aюoylíminooou ^benzoyl ^ and ^ ine _9: fUroylninzoou, 1,2,3-triítδzlylovzu 1 _with 2,4-or 1,2,3 trlazzllloozu , 4 The 4-tetrazzlyl group, said triazolyl group and the tetrazolyl group are attached to the exomeric group at the 3-position of the cephem ring by a carbon-nitrogen bond and may be substituted by at least one substituent selected from the group consisting of: zahrnnjjcí from halo atom, hydroxyl group, carboxyl group, aminostopinu C ^^ aHilové group kyanostopinu, Festová group, a C aHylthl of group C ^ _lw alloxykarbonylové group ^{O βε,} alkozy ^χ Уlr bzyl- ^{R 4 and} 1βв5l L ^Star StopIN ylzo ^l and C ₂ _ ^o anoy ^g and ^l and ^m .nostopiny ^R3 represents adaoshpinu, formylam.no tracks well, chloracetylimlnoskupinu and A means a trace of the formula toe ^r4 means a ^C _- ^a a ^{l of} cyloozo a stop and a bond ^b a а remelts N IR ⁴ Antl or syn-isomer or a mixture thereof, or salts thereof, characterized in that a compound of formula II (II) Y = CH ₂ »2 COOR ^1a wherein R ^1a represents a hydrogen atom or a carboxyl protecting group, R 10 represents an amino 2 group which may optionally be protected and R is as defined above, or a salt thereof, reacted with a compound of formula III (III) And where R is as defined above, or with a salt thereof, and then, if desired, the protecting group is removed, the hydrogen atom of the carboxyl group at the 4-position of the cephem ring is converted to another meaning specified in R 6, or the product is converted to salt · 2. A process according to claim 1, wherein R @ 1 is 1,2,4-triazolyl, 3-methyl-1,2,4-triazolyl, 3-methylthio-l, 2,4-triazolyl, 3-ethoxycarbonyl-1,2,4-triazolyl, 3-chloro-1,2,4-triazolyl, 3-acetylamino-1,2,2-triazolyl, 4,5-dimethoxycarbonyl-1, 2,3-triazolyl, 4-cyano-5-phenyl-1,2,3-triazolyl, 1,2.3.4-Tetrazolyl, 5-methyl-1,2,3,4-tetrazolyl, 5-ethyl-1,2,3,4-tetrazolyl, 5-methylthio-1,2,3,4-tetrazolyl, 5- amino-1,2,3,4-tetrazolyl, 5-ethoxycarbonyl-1,2,3,4-tetrazolyl, 5-phenyl-1,2,3,4-tetrazolyl, 5-acetylamino-1,2,3, 4-tetrazolyl or 5-ethoxycarbonylmethyl- 1.2.3.4-tetrazolyl and other substituents have the meaning given above. 3. Process according to claim 1 or 2, characterized in that the reaction is carried out at a temperature of 0 to 100 ° C.