CS236491B2 - 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 also relates to a process for the production of novel cephalaporins.

The present inventors have undertaken studies to discover compounds that have a broad antibacterial spectrum that exhibit excellent antibacterial activity against Gram-positive and Gram-negative bacteria, are ethical to the beta-lactamases produced by the bacteria, have low toxicity, and are well absorbable by oral or parenteral administration and have an excellent therapeutic effect on human and animal diseases. The results of the studies have been to identify novel cephalosporins of the formula I below and their salts having the above-mentioned excellent properties.

It is an object of the present invention to provide novel cephalosporins of the following formula having a broad antibacterial spectrum that are stable to beta-lactamases produced by bacteria that have low toxicity and are well absorbed by oral or parenteral administration and have excellent therapeutic effects on human and animal diseases ·

Further advantages of the invention are apparent from the following description.

In this specification, unless otherwise noted, the term alkyl means a straight or branched alkyl chain of 1 to 14 carbon atoms, for example, methyl, stylish n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl , hexyl, heptyl, octyl, dodecyl and the like. The term alkoxy ⁴ denotes an -O-alkyl group wherein the alkyl group is as defined above. The term lower alkyl denotes a straight or branched chain alkyl group having 1 to 5 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n -butyl, isobutyl, sec-butyl, tert-butyl, pentyl and the like

The term lower alkoxy means -O-lower alkyl, wherein the lower alkyl group is as defined above. The term acyl group means an acyl group having 1 to 12 carbon atoms, for example, acetyl, propionyl, butyryl, benzoyl, naphthoyl, pentanecarbonyl, cyclohexanecarbonyl, furoyl, tenoyl and the like groups. a -O-acyl group wherein the acyl group is as defined above;

The term alkylthio means S-alkyl, where alkyl is as defined above. The term alkenyl means alkenyl of 2 to 10 carbon atoms, for example, vinyl, allyl, isopropenyl, 2-pentenyl, butenyl, and the like. a (C 2 -C 10) vinyl group such as ethynyl, 2-propynyl and the like. Cycloalkyl means a C 3 -C 7 alkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. The term cycloalkenyl means a cycloalkenyl group of 5 to 7 carbon atoms, for example cyclopentenyl, cyclohexenyl and the like. The term aryl refers to, for example, phenyl, naphthyl, indanyl and the like. The term aralkyl means a substituted aralkyl group such as benzyl, phenethyl, 4-methylbenzyl naphthylmethyl and the like. The term heterocyclic group means a heterocyclic group with at least one heteroatom selected from the group consisting of oxygen, nitrogen and sulfur, for example, furyl, thienyl pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, oxazolyl, oxoxazolyl, thiaziazolyl, thiadiazolyl, thiadiazolyl, thiadiazolyl, thiadiazolyl, thiadiazolyl, thiadiazolyl, thiadiazolyl, thiadiazolyl, thiadiazolyl, , tetrazolyl, pyridyl, 3- (2-methyl-4-pyrrolinyl), 4-pyrrolin-3-yl, N-methylpiperidinyl, quinolyl, phenazinyl, 1,3-benzodioxolanyl, benzofuryl, benzothienyl, benzoxazolyl, bensothiazolyl, coumarinyl and similar groups · The term halogen atom means fluorine, chlorine, bromine and iodine atoms ·

The method of the invention is as follows;

Process for the preparation of cephalosporins of the general formula I

d) wherein r 'represents a hydrogen atom, or a C 1-6 alkyl, diphenylmethyl, phenyl, 2-carboxyphenyl, 1'-pivaloyloxybenzyl, C 1-6 -cyloxy-C 1-6 alkyl or a phthalddyl group or a group of the formula -CHO ⁵ or -CHOCOOR ⁵ "

where

R is C 1-6 alkyl, cyclohexyl or phenyl and r 6 is hydrogen or C 1-4 alkyl,

R is phenyl, 2-thienyl, 2-furyl, C 6-6 alkynoyl amino, benzoylamino, furoylamino,

1,2,3-triazolyl, 1,2,4-triazolyl, or 1,2,3,4-tetrazolyl groups, these triazolyl and thiazolyl groups are attached to the exomeeylene group at the 3-position of the cephem ring by a bond carbon-nitrogen bonds and may be substituted by at least one substiuuentem vybrsným from the group consisting of halogen, hydroxyl, carboxyl, C ^ alkyl, C ^ alkylthio, С «^ 1Юх1karbonylové group, phenyl group-alk Grp ins _P C ^ alkoxy, carbonyl-C 1-6 alkoxy, cyano and amino;

^{R5 and} -H Neto phenylamino or amino group and

A is ^a oup of ^the formula - ^to de ^{R4 and} a hydrogen atom of not ^b ^ alkyl groups, and

N

the bond / z 'means that the compound may be in the form of a syn or an anti-isomer, or a salt thereof, characterized in that:. is left. to react a compound of formula II

B ⁷ CH ₂ CO-A-CONH

COOR (II) where

R ^1a represents a znamerrá ^^ ^k u ^b not on ^the ctarónicí Carboxy group: ^χl hunting ^{E is R7 and the} atoms znsmen ^ha and Logen

R and A are as defined above, or a salt thereof with a compound of formula III (III)

S where &

R represents a hydrogen atom or a phenyl or amino group, which may be optionally substituted with a phenyl group; protected, or a salt thereof, and then, if desired, removing the protective group, converting the hydrogen ^ i ^ oxyl in a ^ ^{4-position of} cefemováho ring to another meaning of ^{R 1,} not ^B on the product is converted to s ^ l.

In the above formulas, R ¹ represents a hydrogen atom, a C 1-4 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl and the like; a group; phenyl; 2-carboxyphenyl; 1

a beeroyoybenzyl group; A C 1-4 cyclolo-C-cakkil group such as acetoxyoxyethyl, prilinylnylmethyl, n-butylcycloethyl, 1sobycloxymethyl, pivelocycloxy, valeryl-oxymethyl, 1-acetonylethyl, 1-acetoxy-n-propyl, 1-acetoxy-n-ethyl, n-acetoxy-n-ethyl 1-pivloxyl-n-piperidyl and the like; or a group of the formula -CHOH4 or -CHOCOOR *, wherein R *> is alkyl

R ⁶ R ⁶ group as defined výěe not ^b ^ verifies the females' and ^R6 is not a hydrogen atom by C ^ ^b LdyjOvvou group defined above, an as βοΙο ^] ^^, ethoxy-methyl ^]., Prop ^ ^^ ymmet y, itopropoxyneeyl, butkloxkmetyk, mm to xkk or jtoxk ^k arbonylox; yaej ^y k, propoxcarbsnyloxkmeyk, i sopropoxycarbonyloxymeeyl, b-butkloxk ^k αrblzyloxkmejyk, t erc. butyloxycarbonyloxymethyl, 1-methoxycarblylyl, 1-thioxycarbonyloxy, 1-propoxycarbonyloxyethyl, 1-isopropoxycarbonyl-1,4-butyloxycarbonyloxyethyl and the like.

R is phenyl, 2-phenyl, furyl, C 2-6 alkenylene, such as acetyl amine, propylamino, n-butyrylamino, isobutyrylamino, valeryl amino, isovalerylamino, pivalo]; a mine, hexanoylamino group, likewise, a benzoyl amino group, a firoylamino group, a 1,2,3-trazole group, a 1,2,4-trlazolklo group, or a 1,2,3,4-tetrazolkone group; these triissolyl or tetrazolyl groups are attached to the exomethylene group at the 3-position of the cephem ring by a nitrogen-nitrogen bond.

_Step ^R may be substituted with at least one substituentea you ratfýfa of ^b with ^{at blru, kt} era.

includes halogen atoms such as fluorine, chlorine, bromine, iodine and the like; a hydroxyl group; a C 1-6 alkoxy group, an amine with a skipin; ^^ ^^ C ^ l ^ ii ^ v ^ KLC skupln s ^y as defined for ^R1; cyano; a phenyl group; eLLkyltOuupupin I10 is -β-Ο Ι Ι!! 1, where, Ι Ι yl má ^ ^ zam has the meaning given in ^{r1; 1 carries g} alkoxy carbonyl ^{b y kl} oz alkyl groups ^to j ^ o is C- ^ C ^ alky! having a C 1-4 alkyl _; a group defined by ^{r 1} ; C ^ alkoxy ^ ⁰⁶ ^ arbonyl.- OlkyLové Jato groups ^Y is C, O · elkjd - ^00-0 _ £ ΐώ. ^1] 1 MAA C_ ^j turnbuckle ^and nominal L1 ^{alkyl Y} groups as defined for ^R1; and C ^ álkimoy.aniBostoptak such as C ^ alkyl-C-NR- group maaící inovamou ^d e ^f u ^r1. A is -OTg- or o. AND

N

-C ^- wherein r ⁴ represents a hydrogen atom or a C 1-6 alkenyl moiety as defined for ^{R 1} and the bond z xv represents a syn or antisomer or a mixture thereof.

Group _R 3

or of formula (I);

t exist in the form of rental omen when ^R6 represents phenyl-l Minh Neto ariLnovou group, if not the ^b * FR ⁶ represents phenyl a mine or amino group which may optionally be protected, as shown by the equation of equation:

wherein ^r3 and ^r3z are as defined above and ^r3 and ^r3z are each. an imino group which may optionally be protected. Tautomers are also included within the scope of this invention.

V Хя *

The protecting slkipiny imine groups RJ and R ^j from the equation above, the balance can be used groups which are a common sight in the area! ρεπ ^Ι-ΙΙΙΙ and cephalosporin. Particular include the same moníVvZeníní 'circumscribes groups am.nové groups listed above for R ^a.

Salts of compounds of formula (I) or (II) include those of basic or acidic groups, which are generally used in the chemistry of cephalosporins and cephalosporins. In particular, these include salts with mineral acids, such as, for example, chlorofluoric acid, nitric acid, sulfuric acid, and the like, salts with organic carboxylic acids, such as, for example, oleic acid, succinic acid, formic acid, trifluoric acid, trifluoric acid and the like; salts with sulfonic acids such as methanesulfonic acid, ethanedinic acid, benzenesulfinic acid, tiluene-2-sulfonic acid, tiluene-2-sulfonic acid, bisulfonyl, 2,4,6-trimethylbenzenesulfonic acid, naphthalene-1-sulfonic acid, phosphon-2-sulfonate phenylmethanesulfonic acid, benzene-1,3-disulfonic acid, toluene-1-disulfonic acid, phthalene-1,5-di-fluorophonic acid, n-phthalene-2,6-dilulf () white, naphthalene; 2,3-trisulphonic acid, benzene-1,3,5-trisulphonic acid, benzene-1,2,4-trisulphonic acid, benzene-1,3,5-trisulphonic acid and the like acids (such as basic group salts) ) and are combined with alkali metals such as. for example, sodium, potassium, and the like, with kovyΖΖοο například kovy kovy vá zem vá, h kovy kovy kovy kovy kovy kovy kovy kovy kovy kovy kovy kovy kovy kovy kovy kovy kovy kovy ii ii kovy ii ii ii ii am am am am am am am am am am am am am am am am am am am am am am am amonononon amonononononononononononononononononononononononononononononon s s s son s s s s s such as pricaine, dibenzylamine, N-benzo-beta-phenethylallyl-1-afenamine, N, N-benzylethylenediamine, N, N-benzylethyl, amine, N, N-benzylethyl, amine, N, N-benzylethyl, amine, N, N-benzylethyl. Methylpepidium, N.methylmirpholium, Flight, Cyber, Dicyclic, Lyclohexylamine, and the like (such as salts with an acidic group ·

R 3 represents a hydrogen atom or a carboxyl protecting group. Among the carboxylic acid groups that are commonly seen in Hasen foams and erythrophores, there are ester-forming groups which can be mildly catalyzed by catalytic reduction, chemical reduction or otherwise, ester-sensitive groups readily identifiable in living organisms and other known ester forms skipines which can be readily treated by treatment with water or an alcohol such as organic silyl. groups, organic groups containing a phosphorus atom, orgaic groups tin atom or the like.

Examples of typical carboxyl groups are:

(a) alkyl groups,

(b) substituted lower alkyl skipines which are substituted by at least one of the following substituents: - halogen atom, controlCupiiZ, carbalkixyl, acyl, alkixyl, oxoecipine, cyano, cyanoalkynyl and aryl groups; Alkyl, alkoxycarbinyl, 5-alkyl-2-iodo-1,1'-diixi-4-yl, 1-diidyl, 2-iodine, 2-iodine, 4-alkyl, 4-alkyl Methyl, phthalimido, nuccinimide, aetidium, aziridin, pyrilidin, piperid, moofolin, thiomorphous, pyrrile, pyrazolytic, thiazilyl, and soothing, oxazolytic, iisxazolysilyl, ixxazolyl, thixazolysilyl, ixxazolyl, thixazolylyl, thixazolylyl, thixazolylyl, thioxazolyl, thixazolyl, thixazolyl, thixazolyl, thixazolyl, thixazolyl, thioxazolysate, thiazollyl, thioxazolysate, thiazole , triazilyl, tetrazolylivý, pyridylivý,. Crnolyl, phenazinyl, benzolfuryl, benzotlenyl, benzorazolyl, benzizzizzolyl, cumizyl, N-lower alkylpiperidium, 2,5-dimethyl-pillrolidinyl, 1,4,5,6-tertiarylpyrimidinylmethyl, 4-methylpyrimidinylmethyl, 4-methylpyrimidinylmethyl, 4-methylpyrimidinylmethyl, 4-methylpyrimidinylmethyl, 4-methylpyrimidinylmethyl, -4-3-pyгrOLLí yllvá 4 · pзlτr) _lH-3-N-f lllvá mettlpPpeгidiíyllvá, 1,3-beíZO (Hloxolzíylová, zlkllam.ílvá, МоНу-! mine, acylixyLivá of acylamino, ziyltioιkupiíz, Malki! 236491 aminokea * butoxycarbonyl, alkoxycarbonylamino, alkenyloxy, aryloxy, aralkyloxy, alicyklooxylováj heterocyklooxylová, alkoxykarbon3y.o: carboxylic, áLkanyloxykarbonyloxylová, aryloxykarbonyloxylová, aralkyloxykarbonyloxylová, elicyklooxykarbonyloxylová, heterocylkLooxykartonyloxylová, alkenyloxykarbon-oic acid, aryloxycarbonyl, aralkylojykarbony'Icnéf alicykloiqrkarbonylová, heterocyklooxykarboiwloró) alkylaniLLinová and alkynylanilines substituted by halogen, lower alkyl group an upino or lower alkoxy group;

c) cyld.oalkylové groups, lower alkyl groups or substituted cyklnlkylové [2,2-С1 ^{/ п .ЗД1} O.kyV-l ^^ LoKUHn ^»4 - ^ methyl;

d) alkenyl groups;

o) Hkinyl groups;

f) an Eenyo group, an 8-membered Eeny duipin, wherein the aessoon een ene substitute is selected from subssiiuenites arranged under a), an aryl group of the formula wherein

X is -CH-CH-O, -CH 2 CH-S, -CH 8 CHggS, -CH = LM-, -CH = aH-CH 2 CH 2, -CO CH x CH-CO or -CO-CO CH 3 QH-, or their groups substituted derivatives whose substituents are listed under b) above; or a group of the formula wherein

Y represents a lower alkyl group, such as - (CHg) 4 and - (CHg 4) -, or substituted derivatives thereof, the substituents of which are listed above under b);

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

h) heterocyclic groups which may be substituted by at least one substituent selected from the examples given above under b); .

L) H-cyclic indanyl or phthaldyl groups or substituted derivatives thereof, wherein the substituent is a halogen atom or a methyl group, a H-cyclic tetrahydrofiyl group or a substituted derivative thereof, wherein the substituent is a halogen atom or a methyl group, an irityl group, a dh letterylo group or a bicyclo 4,4,0] -decyllo; '

j) Hicyclic phthalidylsubstituted alkyl group or its ttb · t ± tuool derivatives, wherein the substituent is a halogen atom or a lower alkoxy group;

The abovementioned carboxylic acid moieties are exemplified by the following examples: groups which are listed in U.S. Patent Nos. 3499909 may be used,

3573296, and 3641016, and in the German publications 2301014, 2253287'and 2337105 · '

Of the aforementioned greying groups, carboxyl groups are preferred, those greyhound groups that can be easily removed in living organisms, such as, for example, 5-lower alkyl-2-oxo-1,3-dioxol-4-yl groups, acyloxyOLalkyl groups , acylthioalkyl groups, phthalidyl group, indanyl group, phenyl group, substituted or unsubstituted phthaldehyde, LLd-en-lower alkyl groups or groups of the general formulas

-CH 2 CH-JOR ⁸ , -CHCOCOR ^8, and -CH (CH-ICOOH ⁸ .

L ^{2 M} II ² i ⁹ i ⁹ i '° in which ^R is a linear or branched substituted alkyl or nesubstiuuovanou

O-alkyl, aryl, aralkyl, OL L cyclic or heterocyclic groups,

10

R is hydrogen or alkyl, ^R · represents hydrogen, halogen, or substituted or nesubstiuuovanou alkyl, cycloalkyl, aryl or heterocyclic group ^for NETA ou - (CH ^ -CCOK ⁸ wherein ^{R 8} is defined, ^and the above n denoted by 0 _} 1 or 2 and m number 0,1 or 2.

Preferred carboxyl protecting groups include the S-lower alkyl-2-oxo-1,3-dilxyl-4-yl groups such as 5-methyl-2-lolol-1,3-oxol-4-yl; 5-ethyl-2H-1,3-fluoro-4-yl, 5-methyl-2-fluoro-1,3-fluoro-4-yl and the like, acyloxyalkyl groups such as acetoxymethyl, pivoyoyloxymethyl propionyloxymethyl, butyrylosymethyl, itoeutyryloxymethyl, valerylosylmethyl, acetoxyethyl, 1-acetylpropyl, 1-pivallyl-xyltyl, 1-pyllyl-thioyl, thiylmethyl, thiylmethyl, thiylmethyl, thiyl, thiyl, thiyl, thiyl, thiyl, thiyl, thio, 1-acetylthyl, 1-pyridylthio, 1-enylphenyl, 1-p-chlorene-benzylthyl, and the like, alkoxymethyl groups such as methoxymethyl, ethoxymethyl, propoxymethyl, isobutyl, butyloxy, butyloxymethyl, isobutylmethyl, isobutylmethyl, isobutylmethyl, isobutylmethyl, isopropylmethyl isopentyl like Nappi · metooQrkarbonylcxymeylová, etlxykarbolnFllxymě-yl, propoχykω? eozyllxymetylová, isopropoxykareonyllxymetylová, n eutyloзgrkareonyloχymetyllvá, TTRCA · butyOoxykaebozyloзQmetyllvá, 1-Me's (sУk-ute) lnlOJqre Tylová 1 etlχykareonylo5Qretylová-1-prlpl: χyk8a'te Such groups include, but are not limited to, alkyl, 1-isopropoxycarbonyonyloxy, ethyl, 1-ethyloxycarbonyloxy, and the like, alkoxycarbonylalkyl groups such as methoxycyclohexylmethyl, thioxycarbonylmethyl and the like. similar groups, phthaldyl, indanyl, phenyl and phthalidyl-alkyl groups, such as 2-methylthio, 2- (5-fluorophenyl) ethyl, 2- (6-chlorophthylityl) ethyl, 2- (6- metoa similar groups ·

R ^h is a halogen such as fluorine, clúor, bromo, iodo ^{and R} · represents hydrogen ntao ^{f y} y en ntao amnovou amino group which may be protected Tyr popPípadě ·

As the protecting groups of the group, all of the chromium groups commonly used in the field of pennillins and cephalosporins can be used. o-brombenzyloxykarelnyllvá l-zitlo) fezyltblfezyllvá, mozn-, di- or tχLLchllracttyllvá, trifUloracttylová, foímytová, ttrc.адyloxykareozylová, TTRCA butoзφkareonУLová · p ~ metlχybezžyllxyk & reozylová 4- (the ^y lzlo) benz ^yl 0o: yfcareozylová 4- ( 4.metoχyfezylazl) btzoyllxykarelzyllvá, pyrLdLn lxid-1-yl-2-meloxykбrb) lzylová, 2..jUuφlO] qkC6rb> lzyLová, difθzylmttoχ ^y kareon ^yl group, a 1 ₉ 1-ϋmetylpropoxykareonylová, i8opIoplxykarbonyllvá, 1-cykllpropylttlxykareonylová, phthaloyl,

Succinyl, 1-adamantyloxycarbonynyl, 8-quinolyloxycarbonyl and the like, as well as easily removable stapipines such as the trityl group, 2-nitrophenyl (2-nitrophenyl), 2, n-diolithenylphenyl, 2-hexyloxybenzyl, 2-hexyloxybenzyl 5-Chlorobenzylidene, 2-hexyloxy-1-naphthylmethyl, 3-hydroxy-4-ptridylmethylenediol, 1-ethylbutyl-2-propylidene, 1-ethoxycarbonyl-2-peptide; 3-etlxtkaгb) ont "buttlidenlvá-2, 1-acetyl-2-pnpylidenové ¹ -Ьеп2оуУ - 2- ^{р горуН} enlvá ^{d, 1} - [N - ^ - methoxyphenyl ^ arbamo ^ J - ^^ npyli DENOVO ^- 1 ^[k - (4-metlxyfenyl) kaIbamolt] '- 2 <-prlpyLidenlvá, 2 ^ St ^ TKARA piperidinyl cytLohextlidsnová 2-ethoxycarbonyl 10LlpenttlideilV- ^yl, 2-acettlctkLLohexyLl <eenová, 3,3-dlmettl-5lOoocykLlheχyLidenlvá and similar groups, and other protecting groups im.no Groups such as M- or tri-alkylsilyl and the like groups.

The method of the invention is described in detail below. This method is a ring closure reaction.

Treatment of a compound of formula II or a salt thereof with a thioormimidime or a thiourea of formula III produces a compound of formula I or a salt thereof. This reaction is usually carried out in a solvent. As can be dissolved poidiít any ros uětéfflu ^, k ^t ns than ^{the P} omaluje reScci. Examples of useful solvents include water, methanol, ethanol, acetone, tetrahydrofuran, polyacrylamide, N, dimethylacetamide, N, dimethylacetimide, N-methylpyrrolidone and the like.

They are used either simulated or as a mixture of two or more solvents, although the addition of an acid-binding agent is not particularly necessary, facilitating the degradation of the reagent by avoiding changes in the total skeleton. Acid acceptors for this purpose are inorganic and organic bases, such as alkali metal hydroxides, alkali metal hydrogencarbonates, pyridine, N, N-nitroyllniline, and ^the like. Reaction contours exit through ^p s O I ^of WO C ^P s preferably ¹⁰ to 50 ° C.

One to several equivalents of tL-formamide or thiourea of formula III is used per equivalent of the compound of formula II or its κϋ. The reaction time is usually one to forty-eight hours, preferably one to ten hours. The compound of formula (I) can also be converted in conventional manner to the formula (I). a plildiline compound. JeaSliie Ή one of groups ^{1, - R2} and ^R31 is an active group ^P ro t ^ ^yt reα of ^{the CE. It can be} protected by a conventional protecting group during the reaction. The CuT-forming group can be pushed off after the reaction in a conventional manner. The compound of formula (I) thus produced or a salt thereof is isolated in a known manner.

The present invention includes optical ions, racemic compounds and all crystalline forms and hydrates of the compounds of formula I and salts thereof.

JesStLiže the ring closure Zio ^0- ^ undispersed SLoutanini of formula I, ^R1 is de DEG C ^ slkyL (SL ^by ei ^t lmeeyl, ^phenyl, S ^ ^ irto ^yphenyl, 1'-Benzyl iviloyloj ^ ^C ^^ C ^ iy ^{χt L L-C} ^ Hoyle, Neto rotary group of formula or * -СДОЯ -СДОСОДг ^from e and ^R $ ^{R5 R6} small R ⁶ as defined above, can be converted into these SLouιCeliLna běinýta manner on the poíádll ^ ^ <^: s compound no ^b of a salt, Ote ^R1 is hydrogen. give, if the compound ^ compounds of formula ^kd e ^R1 represents a ^{<eik u} rtže be those Blou ^ Nina switched MUnýta - z ^ Pobe ni corresponding compound Neto - a ¹ salt, ^from e ^r1 zněměná ^'C ^^ ^O ^ 1L У ¹ ny ^ ² ^ -Oirtoxyfenyl, 1' ipiviloylojybenzyl, C-γaeyllxy C1_5llloУ1, Otálidyli or a ^group -CHOR ⁵ n ^e b CHOCtOOOt ^on 'wh ^e R® ¹ R® n. ^j s ⁱⁿ YS ^e d by ^{the nominal currency} profess. profits if 'ae salt

* of a compound of formula (I), can be converted in a conventional manner to its free compound.

Among the compounds of formula (I) obtained according to the invention, those in which A is a group are preferred. Of these, particularly preferred are those in which R ^ _f ^XN N ^ A))) ⁴ znamená is hydrogen or methyl. the methyl group are the most preferred syn-isomers. Further examples of preferred compounds are compounds wherein R ² is a 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3,4-tetrazolyl group which may be substituted in the above manner and connected к exo Of these compounds, those in which R ² is a 1,2,4-triazolyl or 2- (1,2,3,4-tetrazolyl) group which may optionally be substituted as described above are particularly preferred. ·

The compound of formula (II) or a salt thereof, which is used as the starting compound in the process of the invention, is obtained by the reactions shown in the following scheme:

or a carboxyl group derivative thereof, or a salt thereof, or a salt thereof

CH ₃ COCH ₂ COOH (VI)

CH, COCCOOH

Ϊ 'or its reactive derivative ________CHjCOCHgCONH (acylation)

CH ₂ R ² ", COOR ^1, or its salt (acylation), (VIII) or its reactive derivative

(VII)

(IX) formation of a nitroso derivative (and, if desired, alkylation)

*5 * —CH ₂ R ²

COOR ¹ or a salt thereof

halogenation

NH _of CR ^{3a г} к

WITH

(Ila) ring closure (IXI)

AND

or a salt thereof (Ia) (V) or a salt thereof

R ⁷ CH ₂ CO-A-COOH or a reactive (X) derivative thereof

R ⁷ CH ₂ CO-A-CONH

COOR ^1a I (III) ¹ ring closure or a salt thereof

R ³

CH ₂ R ² -COOR 'or a salt thereof wherein R', R ^'8, R ^2, R ^3, R ^3a, R ^4, R ^7, A and ^Y have ^{the ligament} b

S - 9-0, R.

R'3-CSCC-NHI "R" are identical or different, considerable ^ eesjí hydrogen atoms or organic residues which participate in the reaction e - or R ^{1 R} and ^{15 kd} e ^{r1 <7 kt} ns may be the same yCaN- R1 or different, are hydrogen atoms or organic moieties not involved in the reaction, and ^R is a substituted or unsubstituted acyloxy or carbamoolox group.

(I) as defined above, Z is S or is amnoskipinu and buy yne of formula ^wherein R ^13, R ¹⁴ and R ^15, the legs be ktwé

The radical ^r 1 'in the compounds of general lupine, the group of the general formula ^{R 1} '

R14

of formula (IV) and (V) and in their salts, am.noa represents a group of the formula ^R @ 1. / r'5 r ¹⁷

Groups of formula ^R1 ^ /

_B14 also includes - a group of the general formula r1; ³

CH isomeric form. As OR ^ n.cké radicals ^{R 15,} R @ ⁴ R @ ¹ and r'® - - R - RFS * in the above formulas that AE participate in the reaction may be used or substituted aliphatic neaubstituované, aiicyklické, arommtické - aralifetické, heterocyclic and acyl residues. In particular:

1. aliphatic radicals: for example alkyl and alkenyl groups,

2. alicyclic radicals: for example, cycloalkyl groups and cycloalkenyl groups;

3 · aromatic radicals: for example aryl groups, ´ 4 · araliphetic 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 said organic carboxylic acids are aliphatic carboxylic acids, alicyclic carboxylic acids, alicycloaliphatic carboxylic acids, aromatic-substituted aliphatic carboxylic acids, aromatic-substituted oxyaliphatic carboxylic acids, aromatic-substituted thioaliphatic carboxylic acids, heterocyclic-substituted aliphatic carboxylic acids, heterocyclic carboxylic acid, heterocyclic group-substituted tioalifatické carboxylic acids, organic carboxylic acids in which the aromatic ring, an aliphatic group or alicyclic group, connected to the carbonyl group, oxygen, nitrogen or sulfur atoms, aromatic carboxylic acids, heterocyclic carboxylic acids and the like _from ·

Such aliphatic carboxylic acids include formic acid, acetic acid. propionic, butanoic, isobutyric *, pentanoic, methoxyacetic, methylthioacetic, acrylic, crotonic and the like · Alicyclic carboxylic acids include cyclohexanoic acid and the like.

The following examples of aryl groups can be used as the aromatic residue in the said organic carboxylic acids. As the heteroxyclic ring, the above-mentioned examples of heterocyclic groups can be used.

The individual groups of these organic carboxylic acids may be further substituted with a substituent such as halogen, hydroxyl, protected hydroxyl, alkyl, alkoxy and acyl, nitro, amino, protected amine, carboxyl, protected carboxyl group or similar groups ·

As amino protecting groups, the protecting groups mentioned for H ^3a can be used.

As the hydroxyl-protecting groups, all the groups usually used for protecting the hydroxyl-group can be used. In particular, these include easily removable acyl groups such as benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxycarbonyl, 3,4-dimethoxycarbonyl 4-phenylazobenzyloxycarbonyl, 4- (4-methoxyphenylazo) benzyloxycarbonyl, t-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromethoxycarbonyl, 2,2,2-tribromethoxy 1-cyklopropyletoxykarbonylové 3-quinolyloxycarbonyl, acetyl, trifluoroacetyl and the like, and benzyl, trityl, methoxymethyl, ^{2-nitrophenylthio,} 2,4 dinitrophenylthio and the like ·

As the protecting groups of the carboxyl group, all the groups usually used for protecting the carboxyl group can be used. In particular, such groups as methyl, ethyl, propyl, isopropyl, tert-butyl, n-butyl, benzyl, diphenylmethyl, trityl, p- nitrobenzyl, p-methoxybenzyl, benzoylmethyl, acetylmethyl, p-nitrofbenzoylmethyl, p-bromobenzoylmethyl, p-methanesulfonylbenzoylmethyl, phthalidomethyl, trichloroethyl, 1,1-dimethyl-2-propenyl, 1,1-dimethyloxymethyl, methyl-3-butynyl, succinimidomethyl, 1-cyclopropylethyl, methylsulfenylmethyl, phenylthiomethyl, dimethylaminomethyl, quinolin-1-oxide-2-ylmethyl, pyridin-1-hydroxide-S-ylmethyl, bia (p-methoxyphenyl) methyl and the like groups; non-metallic compounds, such as titanium diloride and allyl compounds, such as methyl ethyl chloride, as disclosed in Japanese Patent Laid-open No. 7,073/71 and Dutch Laid-Open Patent Application No. 7,075,171. 71 05259.

Among the derivatives of the compound of formula (IV) on the carboxyl group, for example:

a) esters: esters which are commonly used in the field of penaltilins and cephalosporins can be used. ^From here ejména aaPí esters ^{of p} ^ The pellet in the ^R1 substituent.

b) carboxylic anhydrides with N-hydroxysuccinimide, N-hydroxyphthaline, 1-hydroxypiperidine, winter and the like.

(c) amides: these include acid amides, N-substituted acid amides and N, N-disubetituo.

acid amides. Particular mention may be made of J-alkyl amides such as N-methyl amide, N-ethyl amide and the like, N-aryl, dyse, such as N-phenylemide and the need, Ν, dial-dialkyl amides of kyaeHn, such as, for example, N, N-dimethyl Ld acid, Ν, Ν-diethylimide acid, N-ethyl-N-acetylanide acid and the like amidazoles and imidazole, with 4-substituted imidazole, traazolpyridine and the like.

As the acyloxy and cycloalkyloxy groups for the substituent R, there may be mentioned in particular an alkyldyloxy group, such as acetoxy, lopyridyloxy, butyryl and the like; alkenoyloxy groups such as acryldyloxylda and the like; indyloxy-skipines such as benzoyloxy and naphthoxyl groups and the like; and carbamoylphenyl group. They may be substituted by one or more substituents such as halogen, nitro, alkyl and alkyl, alkyltoo, ecyloxy, acylamino, hydroxyl, carboxyl, carbamoyl, carbamoyl, carbamoyl, carbamoyl, aroylker. bamoyl, carbalkoxysulfoyl, aryl, carbamoylphenyl and the like.

In the above substituents on R, the hydroxyl, amine and carboxyl groups can be protected by conventional classifying groups. As chitánncí groups will be pouUít drhncí aminda ^y groups ^{E is} given by ^{d p} and ^p ro ^3e and kartoxylové hydroxyl ^- groups dutáními groups UV-ene from ^{p 13} and ^{Z r1?.}

Among the salts which are mentioned in the above reaction schemes, both salt and acid groups are described, in particular those of formula I or II.

The above process also includes all isomers of meelprodukads, such as syn and monoisomers, tautomers, optical isomers, and the like, as well as mixtures thereof, all crystal forms and hydrates.

The 4-carboxylic acid of formula (V) or its sPi may be prepared by reaction at the 3-position by treatment of cephalosporins. or a carboxylic acid derivative of the formula V or a derivative thereof at the carboxyl group or a salt thereof with benzene, thioene, funus, C1-4, benzene, cyanofuran, 12,3-trazole, 12,4-araaooeea or 1,2,3,4-tetraso, which may be substituted by at least one substituent selected from the group consisting of halogen atoms, hydroxyl group, carboxyl group, amino group, C (alkyl, cyano, halo, C 1-4 alkyl, C 1-4 alkyl, _{C1 ^} alkdoxkkabtonyldaá -carbonyl, C ₁ -C _aLkdoykarbonyУ _1β jálkyloaé C2_gálkanoylβainosktpiny group and (1,2,3-in triaaolt, 12, and 12.3 iuzolu ^^ _s ^ AETR azole are ^those that subbsitueniy Ojén p ^ rt ^for atlonům (in the ring), in organic dissolves in the presence of an acid or acidic co-alkali compound, and optionally, if desired, removing the carboxyl group of the carboxyl group, and / or converting the carboxyl group to sH. If desired, the sub-amino group of the 7-amino group is cleaved in a conventional manner to give the 7-non-substituted-amino group.

According to this process, a compound of formula IV, its derivative at the carboxy group or a salt thereof is treated with benzene 'to me to be substituted subsSituenty said ^p from ^r2 · ZIS ^Ka is a compound of formula V or · R ² represents odppvídající phenyl · radical or treated in a similar way with C ^ alkyl nitriles, benzonitrile or kyanofursnem which may be rnibstituovány substituents mentioned under ^{'R, CD} Mz of ^{d ka} composite of general formula V ^H or wherein ^R2 is opoovídijící

C2_6alk8znylamine, benzoylamine or furoylamine group ·

Or treated in a similar manner with abundant Furen or which can be t ^ ^ and ^ ^ si.t Weights одЬ8 UO2 ^ 1 ^ 1 ^ у mentioned for R to give a compound of formula V or its SDI л wherein ^d represents ndaonídaj c ^{d a} 2-tinyl or 2-ftub group, or a similar treatment with 1,2,3 · triazole, 1,2,4-triazole or 1,2,3, which may be substituted on the carbon atoms by αЬЬЬ ^цццц uvedenými pod under R to form compounds of formula (V) or a mixture thereof, wherein R ² is n-substituted 1,2,3-trimonone, 112,4-triazine, or 1,2, 1,23,4-thiazollyl group. process so that the product is produced in high yield and high purity ·

In these triades and tetrazoles, tautomers escape as described below. Any of these isomers and their mixtures can be used in the reaction.

R H

onamen ^{R and} a hydrogen atom or здЬе ^^ иПу mentioned for ^R2 · If ^b in the formula for betting two R groups may be identical or different ·

The triazides, and tetrazdes, which exhibit tubsitituents on the ring carbon atoms may, if necessary, be used in the reaction in the form of basic or acidic salts. As above, the basic and acidic salts may be the same as the carboxylic acids and The amine groups of the compounds of formula (I) or (II) may be isolated and then ingested or produced in situ.

Acids or acids may be used in the above reaction for example acidic acids, hirsic acids, and the acidic acid compounds. Examples of protonic acids are sulfuric acids. , sulphonic and supercyanic acids, the term tuperkyseliij means acids that are stronger than 100% sulfuric acid, including some of the aforementioned sulfuric acids and uphonic acids.

Particularly, sulfuric acid, chloric acid, fluorosulphuric acid and the like, alkyl mono- or alkyldisulfonic acids, such as petansulphonic acid, trifluorophthalic acid and the like, arylmono, aryldi-optionally tryltrifluoroalkoic acid, pianoic acid, pianoic acid, pianoic acid, pianoic acid, pianoic acid, pianoic acid, pianoic acid and pianoic acid, , chromic acid, medical acid FSO 1 H-SbF ₃ , FSO ₃ H-AsF acid, such as C 10 O-SbF 4, HF-H 3, H 2 SO 4 -SO 3 and the like

The basis for Leras acid is Boo-Trifluoride ·

As the tutoring of the elk acid, the fluoride may be mentioned. boron trifluoride salts such as d.alkylether, diphether / ether, dibutyl ether and the like, such as salts of boron trifluoride with a target such as ethylamine. propylamine, butylamine, triethylamine and the like, are mixed with boron trifluoride with carboxylic acid esters such as, for example, ethyl formate, ethyl acetate, and the like, to form boron trifluoride salts with thiophalic acids. such as acetic acid, propionic acid and the like, and complexes. boron trifluoride salts with nitriles such as acetonitrile, propiinitrile and the like

All organic solvents that do not adversely affect the reaction can be used in this reaction. Particular mention may be made of nitroalkenes such as nitromethane, nitroanene, nionpropene and the like, organic acids such as formic acid, acetic acid, trifluorobutyric acid, dihydroforonic acid, prionic acid and the like; such as, for example, diethyl ether, diallyl ether, dioxane, tetrafluorohydride, atylene glycol ether, and the like, and esters, such as, for example, ethyl fumarate, methacarbunate, meetylate, ethyl acetate, ethyl acetate, butyl acetate, and the like, nitriles such as accaolitrile, buyylonitrile, and m-philanes such as saline and the like.

These solvents can be used alone or in a mixture of two or more. The compounds of these solvents and Lems acids can also be used as solvents. 1 mol or more of acid or cumulative acid compound per ml of compound of formula (II), carboxylic acid derivative or salt thereof is used. This ratio may vary depending on the sub-condition. It is particularly preferred to use from 2 to 10 moles of acid or acid compound per mole of the compound of formula (II). When a complex acid compound is used, it may be used as such, as a solvent or as a mixture of two or more.

Amounts of benzene, thiophene, furan, C-alkylnitrile, benzole, Hu, acid furan, 1,2 _J 3-Oriazol, C, or C are alkyl. 1,2,3,4-te safe, which may be substituted subsSiržanty zahhnuuící selected from halogen atoms, hydroxy <droαylovnu group, a carbon group, aidnoskipinu C-in group, the cyano group, phenyl group, C _β 58kУLttltkUψiuy C ₁ _5eLkknαykarbonuУ-C ₁ _jalLkyll> C2_gιaLkanlylamulskupiny in group a (in 1,2,3-OraezlLž, 1,2,4-1 ^ 0 azmu and 1,2,3,4-OaOrazllž sub8taruaury are attached to carbon atoms of impulsion of As a reactant in the above reaction, 1 molar or more per>> 1 of the compound of formula (IV) or a derivative thereof per carbon group or a salt thereof is preferred. and 5.0 mol per md of the compound of formula IV.

This reaction Eq ^ ^{p <d} s LDE ob ^ ^p s ⁰ to ⁸⁰ ° C. It is usually a time of recollection for some minutes. If water is present in the reaction mixture, there may be unintended side reactions, such as lactluization of the starting compound or product, and cleavage of the percarboxylic ring. For these reasons, the reaction system is preferably kept anhydrous. This can be achieved by adding a suitable deltydrating agent, such as phosphorous supplement, for example phosphorous pentoxide, phospholic acid, phosphorous trichloride, phosphorous trichloride, phosphorous oxychloride, to the reaction system. and the like, an organic reagent such as Ν, Ο-ΜΜΜΙΙΙΙΙΙΙΙΙΧΧΧΧΧ Or, matmatmatltltilyilyilycc, Or Or Or, immatmatltltΙ en en en en en Or, im ΙΙ ^ ^ο ra a podobně a, and the like, an organic acid doride, e.g. litllžei8tžfmuУcihorid and the like anhydaid kysMiny, on-lays antyfrid acetic acid and triLuooroctové lodlЪ ^ _<n> rniuěcí inorganic agent nalíkl ad anhydrous magnesium sulfate, anhydrous calcium choride, mooalku.áraí sieve, calcium carbide and the like, or similar agents.

If the starting compound is a carboxylic acid derivative of the formula (IV), the starting compound is used in the reaction. In some cases, a compound of formula V having a free carboxyl group at the 4-position of the cep es ring can be obtained by the post-reaction process. The starting compound of formula (V), which has a free carbonyl group at the 4-position of the ring, can also be obtained by removing the group on the carboxyl group by the method. ,

If a compound of formula V wherein R ^1a is hydrogen is obtained by this reaction, the compound can be etherified or converted to a salt in a conventional manner. If a compound of formula V wherein R ^1a is an ester group is obtained, the compound can be work up in a conventional manner to produce a compound of formula V wherein R ^1a is hydrogen;

This compound can then be further converted into a salt or optionally another ester. Obtained when the compound of formula V, wherein R ^la represents a salt-forming group, it can be usual manner subjected to a reaction in which the salt compound of Formula V wherein R ^a is hydrogen, and optionally may further produce compound wherein R ^1a is an ester group.

If the substituent on the benzene, C 1-4 alkylnitrile, benzonitrile, cyanofuran, thiophene, furan or on the carbon ring atom of 1,2,3-thirazole, 1,2,4-triazole or 1,2,3,4-tetrazole, which are reactive is substituted by a hydroxyl, amine or carboxyl group, then the desired compound is prepared by first protecting the hydroxyl, amine or carboxyl group with the aforementioned protecting groups, then carrying out the reaction and then removing the protecting group in the usual manner · O

If a compound of formula V wherein R is the above-mentioned substituted or unsubstituted phenyl, thienyl or furyl group, which is attached to the exomethylene group at the 3-position of the cephem nucleus by a CC bond, is prepared, in addition to said conversion reaction at position 3, a known method of opening a thiazolidine ring on penicillin as a starting material, reacting with 3-R-prop-2-ynyl bromide to open the ring, and a series of dihydrothiadine ring reactions (namely, cephalosporin skeleton, see Japanese Patent Laid-Open). No. 5393/75;

J.M.C. 20, 82 (1977) and ibid. 20, 1086 (1977)).

2. The acylation reaction in reaction procedures 1-2 may be carried out in substantially the same manner. By this acylation reaction, a compound of formula V or a salt thereof is treated with a compound of formula VI, VIII or X or a reactive derivative thereof to obtain a compound of formula II, VII or IX or a salt thereof.

In particular, reactive derivatives of compounds of formulas VI, VIII and X include acid halides, acid anhydrides, mixed acid anhydrides, active acid amides, active esters and reactive derivatives between the Vilsmeier reagent and a compound of formula VI, VIII or X. mixed anhydrides of monoalkyl carbonates such as monoethyl carbonate, monoisobutyl carbonate and the like, and mixed anhydrides of lower alkanoic acids optionally substituted with a halogen atom such as pivalic acid, trichloroacetic acid and the like can be used.

N-acylsaccharin, N-acylimidazole, N-acylbenzoylamide, N, N-dicyclohexyl-N-acylurea, N-acylsulfonamide and the like can be used as the active acid amides. For example, cyanomethyl esters, substituted phenyl esters, substituted benzyl esters can be used. , substituted thienyl esters and the like ·

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

When a compound of formula (VI), (VIII) or (X) is used as the free acid or salt, the appropriate coupling agent is used. N, N'-disubstituted carbodiimides such as N, N'-dicyclohexylcarbodiimide and the like can be used azolides such as N, N'-thionyl diimidazole and the like, dehydrating agents such as N-ethoxymethyl-4-ethoxy-1,2-dihydroxycinoline, phosphorus oxychloride, alkoxyacetylene and the like, 2-halo-3-pyridinyl salts, such as, for example, ethyl-2-yloro-iodide, iodo-2-fluoropyridine, and the like.

These acylation reactions are usually carried out in sunny solubilization in the presence of o0o in the absence of oase. Often, halogenated monohydric compounds such as fluorophenium, e.g. dichloromethane and the like, ethers such as tetrahydrofuran, dioxane and the like, dimethylforaamide, dimethylacetamide, acetone, water and mixtures thereof.

Examples of such oases include, for example, inorganic oases, such as alkali metal hydroxides, alkali metal hydrogen carbonates, alkali metal carbonates, alkali metal acetates, and the like, tertiary targets such as trimethylamine, triethylamino, triityl, amine, pyridine, nitride. such as lithium, lithium, collidio, and the like, and di-amines such as dicyclic, amethylene, diethylamino and the like.

In acylation procedures 1-2, typically 1 to several moles of a compound of formula (VI), (VIII), (X) or a reactive derivative thereof is not used, or a mole of a compound of formula (V) is treated at temperatures ranging from -50 to +40 ° C. . The editing time is usually 10 minutes to 48 hours.

Acylation of reaction procedure 3, wherein A is -CH 2 -, yields the compound of formula II wherein A is -CH 2 -, and its salt also by treatment with deteete and halogen by the method of J. Chem. Soc. 587 (1910) and subsequent processing. the product with the compound of formula (Vo) with its compound

Jessiiže the acylation reaction in the process 1 and 2 the recirculation-prepared compound of formula II, ^V II ^of EO IX wherein R ^1a represents Chronic ricupiou kartoxylové lupine, then this compound can be caused ěžoým ^{O O p} em řevésS oa deduction ^^ Compounds The meto OA its salt R ^1a represents a hydrogen atom. Jessiiže the art methods for preparing a compound mentioned ^ ecného formula ^II II oeOo ^IX wherein R ^{1a. p} represents hydrogen and this compound may be vyttýfo ^ cr ^ Roem. lead. to PM ^ ^O vídaící compound not of its ϋύ: wherein ^R · represents ^a 'chrínicí group kartoxylové group. If the salt of formula (II), (VII) or (IX) is formed, the compound can then be converted in a conventional manner to provide the free compound.

Jessiiže s ^{p h} reakcíc these acylating not oěkSerá of ^{R, and R2} and akSivoí skupto ^ for these reactions, protecting after reaction doOu oOvylklou chránOcí group. After the reaction, the protecting group can be protected in a conventional manner.

Thus, the compounds of formula (II), (VII) and (IX) and their salts can be isolated in a conventional manner.

3. If, in the compound of formula (II), the salt thereof is not prepared by acylato by process 2, A is -CH ₂ -, it may be as described below (and optionally followed by O? 1? O). converts to lupine -C- with the outgoing ring closure.

N ^ R ⁴

Nitration may be carried out in a poisonous manner.

The compound of formula (VII) and its salt is converted into the compound of formula (IX) and its salt is dissolved in an oestrosive agent. As the above-mentioned solvents, solvents can be used which react adversely, such as water, acid, acetic acid, oenzene, mmiano, etaool, tetrhydrofurao and the like.

Preferred examples of the regenerating agents are nitric acid and derivatives thereof such as nitrosyl halides, for example nitrosyl chloride, oitrosyl bromide and the like, alkali metal nitrites such as sodium nitrite, potassium nitrite and the like, and alkyl nitrites, e.g. etc. · JesSliže as nitro start agent is salt of DUTs, then the processing is carried out with ¹ 'advantageously be present. inorganic or organic acids such as, for example, hydrochloric acid, sulfuric acid, formic acid, acetic acid and the like.

Although a nitric acid ester is used as the nitrosating agent, the reaction may also be carried out in the presence of a strong base such as an alkali metal alkoxide. Although reaction temperature is not .- CTitcikou magnitude, the envelope is preferably carried out under cooling Neto ^p te ^ lt local ^ones. enyne compounds ^for the ^ CNET formula wherein ^R4 is hydrogen may be readily vynbbt conventional manner · sH These may be the same as the SOH ^ o slouteniny general formula m ^{in some of} R ⁴ is hydrogen. Taloto produced composite obecnéto ntaž formulas ^R4 is hydrogen ^and its ^ ^<h of DEG and may be isolated and purified by known techniques · It is however also possible to poutžt as the starting compound for následujcí reaction without further processing.

4. Following nitrosation, the product is eLCylated. To give a compound of formula m ^{in some} JX ^{of R4} zněmená Ο ^^^ ^^ ι ¹⁰¹ column inu. Rovai Akylace with ^p ^ & í obvy Productio n. way. For example, it may be terminated within a few minutes to a few minutes when carried out in a solvent under cooling or around room temperature. The solvent may be any solvent that does not delay the reaction. The edible solvents include tetrahydrofuran, dioxane, methanol, ethanol, chloroform, mmeylenecchoride, ethyl acetate, butyl acetate, Ν, dim-dimethylamin.d, N, N-dimethylacetamide, water and the like and their solvents. smě ^ s.

As the reagent, for example, methyl chloride, methyl bromide, ethyl bromide, dimethyl acetate, dimethyl ethyl acetate, diazomethane, methylene, methyl p-toluenesulfonic acid and the like are used. If other agents than diazomethyme and palmitate are used, then the reaction is generally carried out in the presence of a base such as an alkali metal carbonate, e.g. sodium, potassium hydroxide and the like, an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or the like, trielylamio, pyridine, methylenediol or the like;

The compounds of formula JX ⁱⁿ which R ⁴ is a C 1-4 column can be readily prepared in a conventional manner. These may be the same SOH SOH as the compound of Formula I. Thus tčeného ANNUAL ^b ^ en ^l dou ^ Nina general formulas IX ^to de ^R4 ιΙΟι ^^^ ^s group and the SOH can be a well known method to isolate and purify. However, it is also possible to use them as starting compounds without further processing for the adjacent reaction.

5. A compound of formula (IIa) or a salt thereof is prepared by treating a compound of formula (IX) or a salt thereof with a halogenated reagent according to the procedure of Method 1. As a compound of formula (II). the reagent can be used with halogens such as chloro, bromo, iodo and the like, sulfuroyl such as sulfide and the like, halogenimide compounds such as N-bromosuccinimide, N-chlorosuccinimide and the like, etc.

Halogenata! the agent is used in a moiety of about one to several moles of agent per m of the compound of formula (IX) or a salt thereof. The reaction is preferably carried out in the presence of Divis Cystine, such as, for example, aluminum cchoride, boiling fluoride, titanium tetrachloride or the like. Any solvent which adversely affects the reaction may be used as the solvent. Apply. can be, for example, tetroxydrofuran, tocan, ethanol, dichloromethane, benzene or the like. These solvents are used either alone or as a mixture of two or more solvents. The treatment is carried out under cooling or elevated temperature, the treatment time is 10 rt.nut to 24 values.

236491 18

The results of testing the pharmacological effect of typical compounds prepared by the method of the invention are as follows:

1. Antibacterial efficacy test

Standard method of the Japanese Chemotherapeutic Society (Chemotherapy, 23.

(1975)), a culture obtained by culturing bacteria in a Heart Infusion broth (manufactured by Eiken Kegakuaha) at 37 ° C for 20 hours, inoculated onto Heart Infusion agar medium (manufactured by Eiken Kagakuahe) and cultured for 20 hours at Deň: 32 ° C. The minimum inhibitory concentration at which bacterial growth is inhibited is termed MIC (µg / ml). The amount of inoculated bacteria was 10 6 cells per plate (10 ⁶ cells per ml).

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

B) 7- [2- (2-Amino-thiazol-4-yl) -2- (syn) -methoxyimino] -acetamido] -3- (furan-2-ylcarboxamido) -methyl-3-cephem-4-carboxylic acid trifluoroacetic acid salt acid,

C) trifluoroacetic acid salt of 7- [2- (2-aminothiazol-4-yl) -2- (syn-methoxyiminoacetamido] -3-acetamidomethyl-3-cephem-4-carboxylic acid,

D) Trifluoroacetic acid salt with 7- [2- (2-aminothiazol-4-yl) -2- (syn) methoxyiminoacet. amido] -3- (4-hydroxybenzyl) -3-cephem-4-carboxylic acid,

E) 7- [2- (2-Aminothiazol-4-yl) -2- (syn-hydroxyiminoacetamide) -3- [2- (5-methyl-1,2,3,4-tetrazolyl) methyl] trifluoroacetic acid salt ] - 3-cep-4-carboxylic acid,

F) Trifluoroacetic acid salt with 7- [2- / 2-aminothiazol-4-yl) -2- (syn) methoxyiminoasetamido] -3- [2- (1,2,3,4-tetrazolyl) methyl] - 3-cef-4-carboxylic acid,

G) 7- [2- (2-Amino-thiazol-4-yl) -2- (syn) -methoxyiminoacetamido] -3- Q- (1,2,3,4-tetrazolyl) methyl] -3- trifluoroacetic acid salt cefem-4-carboxylic acid,

H) Trifluoroacetic acid salt with 7- (2- (2-aminothiazol-4-yl) -2- (syn) -methoxyimino acetamido) -3- [2- (5-amino-1,2,3,4-) tetrazolyl) methyl-3-cephem-4-carboxylic acid,

I) Trifluoroacetic acid salt with 7- [2- (2-amino-thiazol-4-yl) -2- (syn) -methyimino-acetamido] -3- [2- (5-acetamido-1,2,3,4) -tetrazolyl) methyl-3-cephem-4-carboxylic acid,

J) 7-E ^2- (2-Amino-thiazol-4-yl) -2- (syn) -methoxyimino-azetamido] -3- [2- (5-methyl-1,2,3,4-tetrazolyl)] trifluoroacetic acid salt methyl] -3-cep-4-carboxylic acid,

K) Trifluoroacetic acid salt with 7- [2- (2-amino-thiazol-4-yl) -2- (syn) -methoxyiminoacetenes] -3- [2- (5-ethyl-1,2,3,4-tetrazolyl)] ) methyl] -3-cephem-4-carboxylic acid,

L) Trifluoroacetic acid salt with 7- (2- (2-aminothiazol-4-yl) -2- (8-yne) methoxyiminoacetamido) -3- (3-chloro-1,2,4-triazolyl) methyl] -3- cephem-4-carboxylic acid *,

M) 7-Q2- (2-aminothiazol-4-yl) acetamido] -3- [2- (5-ecetamido-1,2,3,4-tetrazolyl) methyl] -3-cephem-4 trifluoroacetic acid salt -carboxylic acid and

N) trifluoroacetic acid salt of 7-Q2- (2-aminothiazol-4-yl) acetamido] -3- | 2 ² - (1 »2,3,4-

-tetrazolyl) methyl] -3-cephem-4-carboxylic acid ·

Note: ⁺ These compounds are produced according to example 2, 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 CN bond but has not been confirmed which of the 1,2,4-triazolyl group nitrogen atoms is attached to the exomethylene group at the 3-position of the cephem ring · In addition, the position of the 1,2,4-triazolyl group substituent is specified by reference to the substituent position in the starting compound used. of this specification where it is not claimed 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 in which 3-methyl-1,2,4-triazolyl, 3- methylthio-1,2,4-triazole, 3-acetemido-1,2,4-triazole, 3-chloro-1,2,4-triazole, 3-ethoxycarbonyl19

-1,2,4-triazole or a similar compound attached to the exomethylene group at the 3-position of the cephem ring are named ^at ---- SD-methyl-bZ-2-methylmethyl] - -, - 3 ^-

- (4-O-methylthio-1,2,4- (2-methyl-1,2,3-diol) methyl) -1- (1-methylthio-1,2,3-dimethylthio) methyl- --- l - ^^ chlorination r 1,2 ^{- r} t r ⁱ zoo ^1-yl) methyl ^11?] - - ^p o ^p Mpadě ---- 3-13 l-j ^ -1 otoxylcrbtony- ^ -tr ^ ^{benzimidazol-1} yl) methyl? ---- • fonkniarUira 1,2,3-tr ^of azolyoovok Slonina substituovacých.

The compound is the same as described for the 1,2,4-triazolyl group of compounds.

Table 1

Anibaatteral activity mic (/ ugZmi)

Bekterie

Compound

Cefazoline A B

Е.соИ NIHJ 1.56 £ 0 1 <0.1 <0.1 <0.1 <0.1 50, 1 50.1 B.coli TK3 25 0.39 0.39 0.39 1.56 0.78 <0.1 0.39 (Bacteria with ^: з ^< odлOtLijc: í SenOcilinázo) K. PooomonOao Y-50 1.56 • gO, 1 <0.1 <o, i 0.2 oo, 1 £ 00.1 1SJO, 1 KebiOella opp Y-72 > 200 6.25 1.56 6.25 6.25 3.13 -  - Purchasing Y-41 3.13 0 ^, 2 0.2 0.2 0.78 0.2 250.1 0 2 Entacloacae IID977 > 200 6.25 25 50 25 6.25 12.5 6.25 Ser · marrescens 1ID620 > 200 0.78 0.2 1.56 3.13 3.13 0.39 1.56 Pro-moo · gεrlOi T-216 > 200 0.2 0.39 0.78 0.78 50, 1 <0.1 0.2 Proceedings Т-111 6.25 0.2 0.2 0.39 0.78 0.39 50, 1 0.2 For T-100 mirrailio - SO, 1 50.1 <0, i Sd ' <0.1 - - Pro · vulgaris GN76 > 200 3.13 0.78 6.25 1.56 6.25 0.78 0.78 (Bacteria) c afaloopo rinase) A. · fatc ^ is B-1 100 ALIGN! 50 12.5 12.5 25 3.13 3.13 12.5 Aci · calcoaceticoo A-6 200 25 25 12.5 6.25 50 6.25 25 H AND J TO L M N S0.1 50.1 S01 50.1 <0.1 0.39 0.39 0.78 0.39 0.39 0.39 0.39 1.56 1.56 0.2 <0.1 <0.1 0.2 50.1 0.78 0.39 - - - - - - - 0.39 0.2 <0.39 0.78 0.39 0.78 0.78 12.5 - - - . - - - 0.78 - - - - - - 0.78 - - - - - - 0.39 501 0.2 0.78 0.78 0.78 0.78 - 50.1 <0.1 50.1 £ 0.1 0.39 0.39 1.56 - - - - - - 12.5 - - - - - - 25 - - - - - -

2) ОгПп! administration

Each test compound is administered orally to mice (ICR, male, 4 weeks of age) at doses of 2 mg per unit. The results are shown in Table 2. After absorption in the living body, all test compounds were easily destroyed by the ester trace. The corresponding free carboxylic acids are thus obtained. These free carboxylic acids excreted in the urine were quantitatively determined and taken as the amount 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:

The quantitative analysis shown is performed using the papyrus disc method with the test bacteria in Table 2.

Table 2

HCl.

COOR ¹

Compound

Obtained from urine

Tested bacteria (%) ⁺

-сн ₂ - -CH2OCOC (CH3) ₃ Ан, 32.0 M.luteus ATCC 9341 -C- * (yn)) > -CH, OCOC (CH 2), N = N 33.1 M. luteús II J J -N I ATCC 9341 N-OCH3 ch ₃ N = N -C- seyn) II - (-) (0 (0))). I 3 3 -4 J 35.0 M.luteus ATCC 9341 N-OCH3 CH3 CH3 N — N ^ e, -C- (son) -CH2OCOC (CH3) ₃ 47.0 KL «pneumonine atcC 10031 N-OCH3 / N = N -C- (son) II N-OH -C2 OCCOXCH3 CH ₃ 28.8 M. luteus atcC 9341

Note: * ⁰ to 4 hours:,. ^p Rumer totaot of 5 μΗ ^ · άύ

3) Acute toxicity test

The three 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

(g / kg)

C-CONH

COONa

GCH ₃ (syn)> 3.0

CH ₃ n ₂

COON and ₃

> 3.0

Cl (son)

The compound of formula (I) and its compound can be administered to humans and animals in the form of a free acid, a non-toxic salt, or a physiologically acceptable ester in the treatment or prevention of diseases caused by a bacterium. Preferably, the compounds are administered parenterally in the form of free acids or non-toxic salts or orally in the form of physiologically acceptable esters. In such cases, they may be manufactured in the pharmaceutical formulations customary for cephalosporin drugs such as tablets, capsules, powders, granules, fine granite, syrup, injection (including drops, suppositories, optionally in similar forms). if desired, diluents and / or auxiliary agents including excipients such as starch, lactose, sucrose, calcium phosphate, calcium nitrate and the like, binders such as gum arabic, starch, crystalline cellulose, carboxymethylcellulose, hydroxypropylcellulose, and the like, such as calf, magnesium stearate and the like; and disintegrating agents, such as carboxymethylcalcitm, talc, and the like.

When administering cef ailosporin formulations according to the invention, the dose and the number of doses are determined according to the German and other subjects. Usually, however, when administered orally or parenterally, the composition is administered to adults in an amount of about 50-5000 mg of the cephalosporin compound of the invention one to four times daily.

The present invention is illustrated in more detail by reference examples, examples and preparative examples, which are not intended to illustrate the invention in any way.

Reference Example 1

1. Suspend 2.72 g of 7-amino cepalo epomic acid (hereinafter referred to as 7-ACA) in 15 mL of anhydrous aceeonitrile ee. To the resulting suspension was added boron trifluoride diethyl ether complex (5.68 g). The resulting solution was treated at room temperature for 5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue is dissolved in 20 ml of aqueous acetone (containing 50% v / v). The pH of the solution was adjusted to 3.5 by the addition of 26% (mono-mol% aqueous ammonia under ice-cooling). (79% yield) 7-amino-3-acetamommeyl-3-cefern-4-carboxylic acid having a melting point of 155 ° C (dec.).

IC upectrum (KBi ^. Ra ¹ : ej _e0 1795 ^, 1640, 1610, 1520

Nuclear Magnetic Resonance Spectrum (CF 3 COOD) ppm: 2.37 (3H, s, -CH 3), 3.62 (2H, s, C 8 -H), 4.60 (2H, a, S),

5.41 (2H, broad s, _C6- H, C7-H).

2. Suspend 2.71 g of 7-amino-3-acetimidomeeyl-3-cephem-4-carboxylic acid prepared in paragraph 1 in 30 mL of methanol. To the solution was added diphenyl azide (4 g) at room temperature. The resulting mixture was worked up at room temperature for 30 minutes. After completion of the reaction, the solvent was distilled off under reduced printing. 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 hydrogen carbonate. The precipitated crystals are filtered off, washed well with water and dried. There were obtained 2.64 g (65% yield) dLfcoyleet ^y lcstcru 7-amino-acetamidomethyl-L-b-cffem carloxyo Kyss ^ ^ mp. And ⁹⁰ to 94 · ¹ ° C (dec *). -

IC eprttHM (KBr c ^m_1: ν c _{= 0} 1,756 ^, 1,720 ^, 1,647)

NMR (CDC1 ₃₎ ppm: 1.67 (3H, s, CH _3), 3.59 (2H, s, C-H), 3.65 and 4.27 (2H, ABq,

J = 14Hz, S

), 4.71 (1H, d, J = 5Hz, _C6- H), 4.69 (1H, d, J = 5Hz, C2-H), 6.12 (1H, broad s, - NHCO 3), 6.90 (1H, s, -COOH 2), 7.36 (10H, s, 2x / q).

Reference case 2 ч

The reaction and work-up is carried out in the same manner as in Reference Example 1- (1), except that irilinoacetic acid is the reaction solvent. This yields the products listed in Table 4.

Table 4

соон

Starting compound

Acid or acid complex

Product

Melting point (° C)

Ic (KBr) ^{cm !!} c = 0

♦ butyronitrile BF ₇ .Et _o 0 -CH, CH, CH. 168 to 170 1 795, 1 635, - J (dec.) 1 610, 1 520 ♦ 2-methylbutyronitrile BF ^ _o 0 .Et CH-5 170 to 172 1 795, 1 635, J 2 1 ³ (dec.) 1 620, 1 530 -CHCH ₂ CH ₃ 2 ⁺ BF etoxypropionitrH .Ft ~ _o 0 -CH ₂ CH ₅ OCH ₉ CH 2 173 to 175 1 800, 1 640, <- <· £. □ (dec.) 1 610, 1 530 acrylicones trii ⁺ BFj. Et ^ O -CH = CH ₂ 165 to 167 1 800, 1 650, (dec.) 1 615, t 525 cyanoacetic acid BF ₃ .Et ₂ O -CH ₂ COOH 192 to 195 1 755, I 675, (dec.) 1 620, 1 580 benzyl cyanide ^f BF ₃ .Et ₂ O 185 to 190 (dec.) 1 1 795, 620, 1 635 1 620 ethyl cyanoacetate * BF ₃ .Et ₂ O -CHpGOOCH2CH. 185 to 190 1 785, 1 730, 2 C. J (dec.) 1 610, 1 530 chloroacetonitrile * BF ₇ .Et ₉ 0 -CH ₂ C1 185 to 190 1 790, 1 650, (dec.) 1 610, I 52c 2-cyanofuran * BF ₇ .Et ₉ O 200 to 204 1 780, 1 630, (dec.) 1 590, 1 510 benzonitrile ⁺ BFyEt ₂ O 212 to 214 (dec.) 1 1 793, 610, »630, 1 520 2-cyanothiophene 189 to 190 1 795, 1 620, (dec.) 1 530 b ~ ^ O ^ ~ ch ₃ 1 630, p-tolunitrile BF * EtpO 173 to 178 1 790, 3 ² (dec.) 1 615, 1 530 / θ) - · ₃ β-nor sonithria of BF _in Et 0 188 to 193 Ί 790, 1 620, ³ 2 (dec.) 1 595, 1 530

Table 4 (continued)

Starting compound An acid or acid complex r18 p-hydroxylennons ПгГ1 * BF ₃ .Et2O 'j ⁷ -

Product Melting point (° C) IC (KBr ^{cm -1:} c = 0) OH 182 to 184 (t ·) 1,795, 1,625, 1,600, 1,530

p-cyanobenzoic acid

178 to 183 (decomposition)

800, 1 700,

630, 1530

2-cyano-5-methylfuran * BF ₃ .Et ₂ O

188-190 (dec)

780,

600,

630,

530

2-cyano-3-maeyytiophene ^t BF 3 ^t 20

175 to 178 (rozlk ·)

790, 1 630,

1- 610, 1530

2-methyl-4-cyano-5-phenyl-12,3-triazole

3-cyanocoumarin

3-Cyano-4-methylcoumarin

193-195 1790, 1660, (dec.) 1610, 1530

197 to 199 (rozl. ·)

210 to 212 (decl.) ⁺ * Aceeonityil connects sulfur skins -С «з

155 (dec)

790,

640,

530

710

600

790, 1

640, 1

530

710

600

795,

610,

640

520

Note: ⁺ ^ ⁰ ВРуЕ zněměná complex fiLuoridu ^b oritáho -a ďLetyLátoeem (dial use the same e označeen) · ^{p ++} Reekce rovád e ^ v ^ accton TIL.

Reference Example 3

Reaction and processing. is carried out in the same manner as in Reference Example 1- (2). The compounds listed in Table 5 are also obtained.

-AND

T ch ₂ n / a ¹⁸

COOH

H ₂ N ~ o

o ^J y ^ CH ³ NHCOR ¹⁸

COOCH - / - <g) ₁₂

Table 5

S.Oučenina _H 1S Melting temperature (° C) IR (KBr) cm ^-1 : ^ c = o -at 167 to 169 (rozUl) 1,755, 1,718, 1 642 -IN 192 to 195 (roz ^) 1,755, 1,720, 1 625 φ 218 to 220 (rozk !.) 1,755, 1,720, 1 636

Reference Example 4

1. Suspend 2.72 g of 7-ACA and 14.2 g of diethyl ether-boron trifluoride complex in 13 ml of sulfoline. To the solution (suspension) was added 1.0 g of 5-methyl-112,3,4-tetrazole, after which the resulting mixture was worked at room temperature for 17 hours. After completion of the reaction, the reaction mixture was poured into 15 ml of ice water. The pH of the mixture was adjusted to 3.5 by the addition of 285% aqueous (pot) aqueous ammonia while cooling with ice. The precipitated crystals are filtered off, washed with 5 m of water, acetone and dried. Gain ^{and T} and ^{1 to 76 g} Mixtures of 7-amino-3 £ 2- (5-methyl-1,2,3, 4-tetrazs ^l-yl) methyl] ^{зЗccefem-4-yl} kaг ^b SX ^world kyselka T and ^{2-amino-3 *} -] ^ - ^ ^{5 -meeyl-1, 2, 3,} 4-terrazolyl) methyl] зЗccefem-4-carboxamide ^{l b} sxy ^world in acidulous ^f Orme crystals.

2. 1.76 g of the crystals produced in paragraph 1 are suspended in 16 ml of methanol. 113 g of p-toluenesulfonic acid monohydrate are added to the suspension. A solution is formed. Then 4.6 g of diphenyldisomethane are slowly added to the solution. The resulting mixture is worked for 15 minutes at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue thus obtained is dissolved in a mixture of 30 ml of ethyl acetate and 30 ml of water. The pH of the resulting solution was adjusted to 8 with sodium hydrogen carbonate. The organic layer was then separated, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. This residue was purified by column chromatography (Wako silica gel C200, eluting with 4: ¹ v / v benzene-ethyl acetate). ^In the ýroba ^0.79 g ^^ e ^ triphenylmethyl ™ ^In-amino-3 - ^ ² - (5-methylbenzenesulfonic ¹ 2,3,4ttearaslčyl) letčyl] -. ^{3 -phenyl, and} R ^{b and} eπl44k sx ^Article its acidic ^{and NC,} temperatures up to ¹⁵⁷ Terao

160 DEG C. @ ozkl.) And ^{0, 1, F} 4 ^G II en laetyletteau ^{No. 7} -aminc-3 -] '1- ⁽⁵ -mate ^{No. 1} -1 2, ^{3, 4} - ^t etrezs ^subcontours l) e ^t y ^f ] ~

-3-cephem-4 ^b ar ^to hunt ox ^y ^ ^é tyselta ePlot ^t-t and ⁹² ° ^C án.í ^ ζΉΟ

236491 26

T-amino-4- (4-methyl-1,5,3,4-tetrazolyl) methyl] -phenyl-ethyl-methyl-4-carboxylic acid:

^IR (KBr) cm ^-1: \ k = O ^{1770 '1? 20} ·

NMR Spectrum (CDCl3) ppm:

1.75

4.70

5.30 (2H, br s, NH _2), 2.48 (3H, s, CHY, 3.20 (2H, s, C-H), (1H, d, J = 5Hz, C ₆ - H), 4.87 (1H, d, J = 5Hz, Cy-H),

5.72 (2H, ABq, J = 16Hz,

s, -CJK)

Díenylmee ^ -j ^m aster ⁷ amino-3-0- ^(5-t ee 1.03-yl, ⁴ - ^yl tУгjzolyl) eβtyí] - ³ -ctfee-4-carboxylic acid oxyl ^b:

IR (KBr) cm @ -1: ^ cq ^! 772 ¹ 7 ² 5.

Nuclear Magnetic Resonance Spectrum (CDCl 3 ppm: 1.80 (1H,

5.38

7.30 (2H, s, J), 2.15 (3H, s, CH3) 3.30 (2H, s, C8-H), 4.70 d, J = 5 Hz, C6-H), 4, 85 (1H, d, J = 5 Hz, C-H), 5.00, (2H, ABq, = 16 Hz, S), 6.90 (1H, s, -CH3), s ₂ -

(ЮН, s, 2x

) ·

3. In a mixture of 0.5 [mu] l miOsIu and 5 [mu] l. triПюrodové rozpuutí acid with 0.462 g difenylmetytas ru ^ ⁷ ^ ii ^ -a c ^^ ³ ^ [^^ - ^(5-m Li ^et ^ ^{1, -, 3, 4} -tetjzzolyl) methyl] -3-cephem-4 ^- k; ^s car ^b oiylov kyseltay. The resulting solution was subjected to one hour reaction at room temperature. After completion of the reaction, the solvent was removed under reduced pressure. To the residue were added 10 ml of water and 10 ml of ethyl acetate. The pH of the solution was adjusted to 8 with ice-cooling with 28% aqueous ammonia (% water). The aqueous layer was separated and the pH adjusted to 3.5 with hydrochloric acid under ice-cooling. Vyloučenékrystaly are filtered promyyí first 5 mL of water, then I ^y jctУonu and dried. ZIS ^{ka 0.26 g of 7 m} -j Noo ³ - ^-2 - (5-mdyl-1, ^2, 3, ^4-oxadiazol -Уttrj ^l l) l ^J ee ^yl -3-ceteareth-4-carboxylic acid m.p. 1 * 78 ° C (dec.).

^IR Spedrum (KBr) cm ^-1 :

Vc = o

790, 1610, 1530.

NMR (CF 3 COOO) ppm: 2.70 (3H, s, CH 3), 3.73 (2H, s, (2H, ABq, J = 16 Hz, S-)) / CH ₂ Cl ₂ -H), 5.40 ( 2H, s, C ₍ -H, C7-H), 5.80, 6.12

In the same manner, 0.462 g of 7-amino-3-O- (5-methyl-1,2,3,4-tetezesyl) -ethyl] -cemyl-4-1-carbsillic acid (6-amino-3-ethyl) - (ethyl) -ethyl- 25 g of 7-jmnoo з-1- ^(5-EET-yl 1,2з ³ -ytetraoolye) tylyl - C "CTFE-4-ljarbsillové acid, mp 195 ° C (ROS = H.).

^IR s ^ ktrum (ЮЗг) cm ^{1 1} : ⁹ _{0 =} ° 1 ⁷⁹ 5 ^{, 1 6} ^ ¹ 5 ^

NMR Spectrum (CF 3 COOD) ppm: 2.95 (3H, s, CH 3), 3.90 (2H, broad s, C ₈ -H), 5.45 (2H, s, C ₆ -H), C7-H 5.57, 5.92 (2H, ABq, J = 16 Hz,).

Reference Example 5

2.72 g of 7-ACA and 7.1 g of boron trifluoride diethyl ether complex are dissolved in 19 ml of trifluoroacetic acid. 0.75 g of 1,2,4-triazole is added ^{to the} resulting solution. The resulting mixture is reacted at room temperature for 7 hours. After completion of the reaction, the solvent is distilled off under reduced pressure. 15 ml of water are added to the resulting residue and the pH of the solution is adjusted to 3.5 by adding 28% (w / w) aqueous ammonia under ice-cooling · The precipitated crystals are sucked off, washed with 5 ml of water, 5 ml of acetone and then dried · 2.5 g of 7-amino-3- [j- (1,2,4-triazolyl) methyl] -3 are obtained. m.p. 149 DEG C. (dec.).

IR (KBr) ^cm-1; Vq = Q 1790, 1610, 1530.

NMR Spectrum (CF 3 COOD) ppm; 4.00 ^ H, br s, C-H), 5.47 (4H, br s, C ₆ -H, _C? ~ H

S1), 8.10 (1H, s, _1H ), 9.80 (1H, s, N)

Reference Example 6

If the following tetrazoles are treated in the same manner as in Reference Example 4- (1) or Reference Example 5, the products listed in Table 6 are produced by:

From the products in the table as a reference example, they are listed in Table 7,

Starting compound

BF _? .

Ethyl (esters and carboxylic acids are then produced by esterification and de-esterification in the same manner (2) and (3),

7-ACA

Reaction conditions

Reaction solvent (ml)

Crude product

Yield

Reaction

Reaction temperature (° C)

COOH

R ² (g)

2.72

-CHgCOOCHgCH2

1.72

7.1

CF 3 COOH temp. places.

0.8

N = N

-ri I

4i = |

CH ₂ COOCH 2 CH ₃

2.72

-CHgC00CHgCH ₃

1.6

7.1

CF 3 COOH temp. places.

0.85

2.72

-H

0.77

7.1 sulfolane temp. places ·

1,4 *

l = N

2.72

-Br

1.65

7.1

CF 3 COOH temp. places.

2,2 *

236491 Continuation of Table 6. 6 28 Crude product Bf ,. EtjJO <8) Reaction conditions Yield (8) Starting compound R (8) Reaction solvent (ml) Reaction temperature (° C) Reaction time (h) N-N _ f I 2.72 -SCH ₃ 1 »3 7.1 CF ₃ COOH temp, places. 7 2,0 * -N 1 19 Dec SCH ₃ SCH ₃ Ν = ΛΙ 2.72 -NH ₂ O , 94 7.1 CF ₃ COOH heat places. 7 ’, 3 nh ₂ 19 Dec / I = N _Z N = N 2.72 -CH-CH. 1 , 08 14.2 sulfolane 50 7 1,36 * -Vj 4 13 ch ₂ ch ₃ N = N -u ch ₂ ch ₃ 2.72 -COOCH ₂ CH ₃ 1 , 56 7.1 sulfolane 13 50 7 2,86 * COOCH ₂ CH ₃ ^{N =} 1 COOCH ₂ CH ₃

2.72 -NHCOCH. 1.4 7, ’ GF.GOOH temp. 7 1.0 J 19 Dec places.

NHCOCH ₃ /

Note: ⁺ These products were made as a mixture of 1-substituted and 2-substituted product; the crude products are treated in the same manner as in Example 1 (2); esters of 1-substituted or 2-substituted products are isolated; the properties of these compounds are given in Table 7 ·

-в ²

COOH with ₂ ι *

C0

AND

Сн,

AND

СНз melting point 177 ° C (dec.) Δδ spectrum (KBr, cm -1, Vq_q): 1795 ^, 1735 ^, 1610 "1535"

Nuclear Magnetic Resonance Spectrum (CF 3 COOD) ppm: 1.35 (3H, 1.88 (2H, SirokVo, -NH ₂ ), 1, -CH ₂ CH ₃ ), 3.67 (2H, SirokVo, C2-H), ..... 4.20 (2H, O, -CH ₂ C? OO), 4.35 (2H, q,

4.55 (1H, -C-CH _3), 5.40 (2H, q, (-И, CH), 5.96 (2H, s SirokV, · S).

ЛсН ² 7.23, melting point: 107-110 ° C (rozlk ..)

Ιδ spectrum (KBr, cm -1 ', Y ^ q):

770, 1 '725'

Nuclear Magnetic Resonance Spectrum (dDC +) ppm: 1.20 (3H, t, --CH 2 CH 2 CH 3), - 3.14 (2H, s, C 2 H), 3.85 (2H, s) , -C ^CO00--, 4.10 (2H, q, -CH ₂ CH ₃ , d, J = 5 H 5, C ₆ -H), 4.75 (1H, d, J = 5 Hz, C ₇ - H), 5.27 5.68 (2H, ABq, J = 16 Hs, S @ +), 6.90 (1H, s, -CH3),

A-ch ₂ (10H, ³ , -2)

1 · 1 ·: 73 to 75 ° C (decomposition)

Δδ spectrum: 1770, 1725

Λ ⁾ ΛθΗζ-

NMR Spectrum: 1.80 (2H, SirokV O, -NH _2), 3.22 (2H, q, C ₂ -H), 4.65 (1H, d,

J = 5 Hs, _C6- H), 4.85 (1H, d, J = 5 Hz,

Cy-H), 5.35, 5.80 (2H,

(15Hz, s,

6.90 (1 H,

- @ x3)

O,

ABq, J = 16 Hz, -CH-, 7.23 at 171 ° C (dec.)

Δδ spectrum: 1,790, 1,610, 1,530

NMR Spectrum: 3.75 (2H, s, C ₂ -H), 5.38 (2H, q, C H) CRH 6.02 (2H,

SirokV s,), 7.40 to 7.65 // - ¾.

(3H, m,

H

H

Mp: 79-83 ° C (dec.) IR spectrum: 1770, 1720

NMR Spectrum: 1.85 (2H, o, -NH ₂ ), 3.12 (2H, s, C ₈ -H), 4.60 (1H, d, J = 5 H 5, C ₆ -H), 4, 80 (1H, d, J = 5 Hz, C-H), 5.37, 5.80 (2H, ABq, J = 16 Hz),

Tue: 220 ° C (decomposition)

IR: 1800, 1610, 1530

NMR Spectrum: 3.70 (2H, SirokV s.

C2-H), 5.40 (2H, o,

6.03 (2H, SiOKV a,

Cg-H), 0γ-Η)

^S Ί ⁾ > - <* 27.30 (10H,

N)

N ·

8.80 (1H, 6.97 (1H, s, 1H),

3.

^β »n ^ ~ ^h)

N

Continuation of Table 7

mp: 75 to 78 (dec.) m.p .: 165 (dec) IG Spectrum: 1770, 1720 10 Spectrum: 1790, 1610, 1530 NMR Spectrum: 1.67 (2H, s, -NH ₂ ), NMR Spectrum: 3.60 (2H, broad a, 3.24 (2H, s, C ₂ -H), 4.68 (IH, d, C ₂ -H), 5.40 (2H, s, C ₈ -H), C ₍ H), J = 5 Hz, _C6- H), 4.87 (1H, d, 5.94 (2H, broad a, S) Br J = 5 Hz, C ₇ -H), 5.30, 5.77 (2H, ABq, Л ^СД 2- J = 16 Hz, S), 6.92 (1H, s, Дсн ₂ - -CH-sr), 7.27 (10H, 3.3-0.2)

Л r ·

mp: 96-96 (dec.) IR spectrum: 1770, 1720

NMR Spectrum: 1.65 (2H, s, -NH ₂ ), 3.20 (2H, s, C ₂ -H), 4.75 (1H, d, J = 5 Hz, C ₆ -H), 4 , 88 (1H, d, J = 5Hz, Cl-H), 5.03, 5.67 (2H, ABq, J = 16Hz, S.),

Λ ° Η ₂ 6.98 (1H, e, -CH-c), 7.30 (10H, s,

- (O) x2)

JI = N

Ή

SCH ₃

mp: 195 (dec.) spectrum: 1790, 1610, 1530

N-N

SCH ₃

mp: 64-68 (decomposition) spectrum: 1,770, 1,720

NMR Spectrum: 1.95 (2H, broad s, -NHg), 2.58 (3H, s, -SCHj), 3.18 (2H, s, C ₂ -H), 4.60 (IH, d, J = 5 Hz, _C6- H), 4.80 (1H,

mp: 158-162 (dec.)

Ю spectrum: 1760, 1710

NMR Spectrum: 2.68 (3H, s, -SCH ^), 3.62 (2H, s, C ₂ -H), 5.28 (2H, s,

NMR Spectrum: 1.75 (2H, broad and, -NH _2),

2.58 (3H, s, -SCH _3), 3.10 (2H, s, C ₂ -H), 4.60 (IH, d, J »5Hz, C ₆ -H), 4.80 ( IH, d,

J (5Hz, C ₇ -H),

7.25 (10H, s,

4.97, 5.47 (2H, ABq, J = 6 Hz, 6.93 (Ή, s, -CH2c)),

M.P .: 174 (dec.) &lt; 1 &gt; G spectrum: 1795, 1610, 1530

NMR Spectrum: 2.87 (3H, s, -SCH3),

3.63 (2H, s, C ₂ -H), 5.35 (2H, s,

Continuation of Table 7

melting point: 115 (dec.)

N = N q

nh ₂

Spektδ Spectrum: 1,770, 1,720

NMR 8PE ^to trum: з, 1 ^{0 (2H,} s ^ Siro, -N ^Hg) 3.43 (2H, s, C ₂ -H), 4.85 (1H, d, J = 5 Hz,

11: 195

Ic ^ ktrum: ^{1795, 1615,} 1 53 ⁰ · NMR Spectrum: 3.75 (2H, br s,

C ₆ -H), 5.05 (1H, d, J = 5Hz, (2H, s,

6.06

C ₇ -H),

5.30

C ₂ -H), 5.35 (2H,

5.80 (2H, broad s, _C6- H, C7-H),

N = N

CHj

CH3

CH ₂ CH 3 (2H, br s, N), 6.90 (1 H, _3> H ₂ ^N

N, CX), 7.35 (10H,

mp: 142 to 143 (dec.)

IR: 1775, 1725

mp: 198 · to 202 (dec.)

IC spectrum: 1795, 1615, 1530

NMR Spectrum: 1.32 (3H, t, -CH ₂ (C) ₃ ), 1.75 (2H, broad s, -NH ₂ ), 2.85 (2H, q, -CH ₂ CH 3), · 3 17 (2H, s, C ₂ -H), 4.67 (1H, d, J = 5 Hs, _C6 -H), 4.82 (1H, d, J = 5 Hs, C ₇ -H) 5.27, 5.70 (2H, AJq, S), 6.93 (1H, s,

NMR Spectrum: 1.48 (3H, t, --CH2 CH2), 3.10 (2H, q, --CH2 CH3), 3.75 (2H, s,

C ₂ -H), 5.40 (2H, 6.10 · (2H, A3q, br _s, C ₆ -H, Ο-Η)

5,85,

J = 16 Hz

-CH- =

5-ca ₂ C, 7.30 (10H, _a , - (O) * ² )

mp: 82-83 (roalk ,.) δδ: 1,770, 1,720

NMR Spectrum: 1.20 (3H, t, CH) CH _3), 1.90 (2H, br s, NH _2), 2.50? 2H, q, -CH =), 3.25 (2H , s, C ₂ -H), 4.70 (1H, d, J = 5 Hs, _C6 -H), 4.90 (1H, d,

mp: 195-197 (r ^ zl ^ L,)

Δδ spectrum: 1795, 1610, 1530

NMR Spectrum 1.57 (3H, t, -CH ₂ CH) 3.30 (2H, q, -CH ₂ CCH), 3.83 (2H, s, C ₂ -H), 5.40 (2H, s, C ₆ -H, C? -H,> 53 5.92 (2H, AB q, J = 16 Hz,

J = 5 Hz, J = 16 Hs, C-H),

5.02, 5.40 (2H,), 6.90 (1H,

Ο ₂ -CH - = :), 7.28 (ЮН, 8,

A3q, e2)

Continuation of Table 7 Clay

O = O I o I

CH2 I

CH3

mp: 165-167 (dec.)

IR: 1775, 1735, 1710

NMR Spectrum: 1.38 (3H, t, -C ^ CH ^, 1.72 (2H, s, _NH2), 3.25 (2H, br

Δ, C ₂ -H), 4.32 (2H, q, -CK 2 CH 3), 4.70 (1H, d, J = 5 Hz, C ₆ -H), 4.82 (1H, d,

m.p .: 158 (dec.)

IR: 1800, 1735, 1610, 1530 NMR spectrum: 1.50 (3H, t, CH ₂ CH _3), 3.55, 3.90 (2H, AB q, J = 18 Ha, C 4 -H), 4.60 (2H, q, -CH ₂ CH ₃ ), 5.40 (2H, s, C ₆ -H), C ₆ -H), 6.05 (2H, broad s, ^S) Y '> - ^C H ₂ -

N = N

O-O

AND

CH ₂

I ^FROM CH3

mp: 140-142 (dec)

IR: 1770, 1735, 1720

NMR Spectrum: 1.42 (3H, t, -CEgCCH), 1.80 (2H, s, -NH ₂ ), 3.20 (2H, s, C2-H), 4.45 (2H, q, -CH 2 CH 3), 4.70 (1H, d,

J = 5 Hz, C ₆ -H), 4.85 (1H, d, J = 5 Hz, C ₇ -H), 5.35, 5.90 (2H, ABq, J = 16 Hz,

S.), 6.90 (1H, [alpha], --CH-- =),

Α ^- 7.30 (10H, s. - ^ 22) t, t: 142 (dec.)

IR: 1800, 1740, 1610, 1530 NMR Spectrum: 1.50 (3H, t, --CH2 CH2);

3.70 (2Щ broad ^s, C? H), ^4, 55? ^2H, q, -OHCH _3), 5.40 (2H, s, C-H,

C7-H), 6.02 (2H, broad s, S

mp: 106-108 (means ·) / H · IM spurnim: 1775, 1720 _l 1700 \ _{Ν Η} NMR цюНУвд 1.95 (br 2Щ ° ^- NH ₂₎ · FJH 2.20 (3H, s CCOCH3) 3 ^ 0 (2H, Airola CO · ^{C β} H _2)> 4.67 (1H, d, J = 5 Hz, C H ^g), L 'ЦН 4.22, <1 J = 5Hz ^, C ^- H) ^, 5.2g ^,

CH3 (2H, AB q, J = 16 Hz, S ·,), 6.90> - ^{С Й2.} (1H, s, --CH2 -) = 7.25 (10H, S)

m.p .: 179 (dec.)

IR: 1790, 1690, 1610, 1530 NMR spectrum: 2.42 (3H, s, -CH3), 3.70 (2H, s, C2-H), 5.40 (2H) , s, C ₆ -H,

C7-H), 5.94 (2H, broad s, S)

Ζ - <$ 2-

x2). 9.75 (1И, broad s, p »NH) mp: 147-150 (dec.) Ντ = Ν IM 1 IR: TTTO L 720 ^{N MR} pelktTuim: ⁺ 3.30 ^(2H, bs ^O, -N ^) - 3.47 (2H, Oiroký s, C ₂ -H), 4.87 (1H, d, \ = N J = 5 Hz, C ₈ H), 5.04 (1H, d, J = 5 Hz, C ₇ -H), 5.35 (2H, broad s, S),> -ch ₂ - 6.91 ( 1H, s, (C, CH-), 7.34 (10H, s,

^P labeled and ^{AMK: +}

Vo '> 2), 9.22 (1H, s, N)' - ^ ^- ^ ^H

N-solvent for dg-MSO.

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). ). Compounds listed in Table 9 were prepared (2.72 g of 7-AHSA was used as the starting compound).

AND

Table 8

COOH

Starting triazole (G) Compound (g) K ² Melting temperature (° C) IC (KBr) e · · ¹ Vc = o NMR ( ⁺ CF ₃ COOB) ... ppm (** cf ₃ cooihd ₂ °) 3-methyl- 195 1 790, * ⁺ 2.60 (3H, a, -CH ₃ ), 3.93 (2H, a, -1,2,4- (rozkl ·) 1 610, C ₂ -H), 5.30 (2H, s, C ₆ -H, Cy-H) - triazole CH ₃ 1 530 5.10, 5.75 (2H, ABq, J = 16Hz, 0.91 2.39 S), 9.45 (1H, a, N) _M- H

3-chloro-1,2,4-triazole 1,14

191 (dec)

Cl

790,

610,

530 * 3.75 (2H, s, C ₂ -H) с -и _6,

J = 16Hz

5.40 (2 H, a,

Cy-H), 5.47, 5.60 (2H, ABq,), 8.50 (1H, s,

1,25

H

3-acetemido- N - N 150 to 1 795, -1,2,4-triazole- NHCOCH ₃ 155 (dec) 1 680, 1 610 2.52 1 540

»»

2.6 * 2.43 (3H, s, -Oty, 3.19 (2H, s, C ₂ -H), 5.35 (2H, s, C ₆ -H, C ₇ -H), 5, 30-5.95 (2H, m, S),

CHg-

5.45 (1H, a, N)) - H N

3-ethoxycarbonyl-1,2,4-triazole

1.55

COOCH ₂ CH ₃

2.3

176 (dec)

795,

720,

610,

530 ** 1.50 (3H, t, -CH ₂ CH ₃ ), broad e,

5.35 (2H, broad s,

from ₂ 236491

Continuation of Table No. β

Default triazd Compound (g) p Temperature week i ⁰ (ffiiO <Ά ⁽ ° 0Β) PP) (G) iT Ά Ά ° (^ COOD ^ O)

3-methyl- N — N 147 I 770, * ² 75 (3H, ^s, - = CH ^{3)) 4,} 00 (2 ^ s -tlo-1,2,4- (rozkk ·) I 605, (GH), 5.40 (2H, s, C ₆ -H, C ₇ -H) -triazd SCH3 I 530 5.23, 5.85 (2H, ABq, J = 16Hz, 1.3 3.4 S), 9.55 (1H, s, N) J_CH _second X »^ 2 N

N -dimethoxycarbonyl-1,2,3- - triazd Z ^N S О CO ^ cooch ₃ 2.0 I61 (rozl. ·) I 795, I 725, I 610, I 530 * ^3, 55 (2 broad ^s ^ C ^ Hh ^4, 10 (s 6H, -CH 2 - x2), 5.35 (2H, s, S), A-OH, 5.90 (2H, s (gH C7-H) 4-kynto-5β-1,1,2,3-traazd 1.9 iF © 204 (rozkki) 2 200 I 790, I 610, * ³ 75 (2H ⁸ C2 ^{- H), 5,} 35 ^{(2H, s,} C-H, C7-H), 5.85 (2H, br 8, S), 7.40 to 7.70 (3H , m, Л-с ₂ - I 530 -H 1.3 - (0> -h 1 _H , 7.80-8.10 (2H, m,

ti

Table 9

COOH

-R ²

Melting point (° C)

IR (KBr) ^{cm -1} = c

NMR (CDCl3) ppm:

N = N

up to 1,775

1,720 (dec)

2.00 (2H, s, -NH ₂ ) m 3.43 (2H, s, (1H, d, J = 5Hz, _C6 -H), 4.88 (1H,

C _r H), 5.00 (2H, s,

-CH2O, 7.30 (10H,

x2) _ø 7.85

C ₂ H, 4.70 d, J 5 Hz, 6.95 (1H _t , up to 1,770)

720 (Ш, s, N),

N

8.07 (b, s, N)

N

1.82 (2H, br s, NH ₂₎ 3, Ю (2H, C ₂ -H)

4.55 (1H, d, J = 5Hz, _C6- H), 4.72 (1H, d,

J = 5 Hz, C ₇ -H),

4.70, 5.33 (2H, ABq, J = 16)

6.93 (1H, broad s, -CH3)

Hz

7.30 (10H, s,

96 to 1 770, 2.33 (2H, broad s, -NHg), 2.78, 3.21 (2H, 101 1 720 AB q, J = 18Hz, C ₂ -H, 4.71 (1H, d, J = 5 Hz, -C-H) (dec.) 4.90 (1H, d, J = 5Hz, _C7 -H), 5.32. 5.92 (2H, / - \ ABq, J = 16 Hz, S @ 1. 6.86 (2H, s, --CH3) СООСН-Ч --- - <o)> ₂ Д-сн ₂ - x2), 7.20 (20H, s, ^x4) * ⁸ '' ^{(, H} ' ⁸

N)

(dec.)

770,

720

C _r H),

2.32 (3H, s, -CH3), 3.42 (2H, s, (1H, d, J = 5Hz, _C6- H), 4.85 (1H,

C ₂ -H), 4.70 d, J = 5 Hz,

6.90 (1H, s,> CH-), 7.30 (10H, s,

(1 H, s, N)

N

Continuation of Table 9

Melting point (° C)

IR (KBr) ^{cm -1} C = ^o

NMR (CDCl 3) ppm:

COOCHjCHj

167 'to

168

770,

720

1.35 (3H, t, J = 18 Hz, C ₂ -. (1 H, Ц, J = 5 1 C ₇ -H), 5.30, 6.93 (1H, s, 7.88 (1H, s,

Z = -CH-, 7.30 (10H,

-CH ₂ CH ₃ ), 2.297, 3.30 (2H, ABq, H), 4.30 (2H, q, -CH ₂ SN-), 4.60 Hz, C ₆ -H), 4.80 (1H , d, J = 5Hz,

5.80 (2H, ABq, J = 16Hz, S)

»

up to 1,770

1 720 (dec.) Broad s, -NH ₂ , 2.50 (3H, a, -SCH 3, s, C ₂ -H), 4.65 (1H, d, J = 5 Hz, C (H), d, J = 5 Hz, C 7 -H), 4.85 (2H, s, H), 6.95 (1H, s, H = -CH), 7.27 (10H, s, H = -CH);

1.90

3.40

4.80 (2H, (2H, (1 H,

x2), 7.90 (1 H, s, N 1)

N

Note: ⁺ ^ This merged and the CIS ^of ANA at ^p ou ^at -tarbojqy APPLICATION ^ ^- 3-triazole as starting materials as described in Referential Example 4- (1) and (2) ·

Reference Example 8

The same reaction as in Reference Example 4 was carried out under the conditions indicated in Table 10. The products listed in Table 10 were prepared.

Table 10

Starting compound

Reaction conditions

7-ACA 5-methyl- Acid Reaction Reaction Reaction Crude Esterifikace * (G) -tetrazole or com- solvent- temperature time product raw product (G) Acid plex (g) body (° C) (h) (G) Ester (a) * ¹ (g) Ester (b) + ² (g) 2.72 1.0 BF _{3 <} Et ₂ O 7.1 sulfolane 13 50 4 1,9 ⁺³ 0.3 / 0.7 2.72 1.0 BF _{3 <} Et ₂ O 14.2 ethyl acetate 27 Mar: temp. mi st. 20 May 2,1 ⁺³ 0.95 / 0.15 2.72 1.0 ^BF 3 ' ^Et 2 ° 14.2 nitromethane 27 Mar: temp. mi st. 20 May 1,5 ⁺³ 0.63 / 0.1 2.72 0.92 BF _y Et ₂ 0 7.1 trifluoroacetic acid 19 Dec temp. places. 7 1,5 ⁺³ 0.71 / 0.05 2.72. ',O conc. h ₂ Sat ₄ 2.5 acetic acid 27 Mar: 60 4 0,4 ⁺³ 0.1 / 0.03 2.72 1.26 BF ₃ 3.39 ethyl chloroacetate 15 Dec temp. mi st. 16 1.44 * ⁴ - 2.72 2.52 BF ₃ 6.78 ethyl chloroacetate temp. places. 16 1,28 ⁺⁴ -

Note: ⁺¹ (a): 7-amino-3- (2- (5-methyl-1,2,3,4-tetrazolyl) methyl) -3-cephem-4-carboxylic acid +2 (b): 7 -amino-3- (1- (5-methyl-1,2,3,4-tetrazolyl) methyl) -3-cephem-4-carboxylic acid * 3 The crude product was a mixture of (a) and (b).

+4 Raw product consisted of ·

The crude product obtained by the reaction was treated in the same manner as in Reference Example 4- (2) to give the benzhydryl ester (a) and (b).

Reference Example 9

The same reaction was performed as in Reference Example 5 under the conditions given in Table 11. The products shown in Table 11 were obtained.

Table 11

Starting compound Reaction conditions product

1,2,4- -triazole (g) Acid or acid complex Reaction solvent (ml) Reaction temperature (° C) Reaction time (h) Name of the product (g) Melting point (° C) 0.75 BF ^ .EtnO CH 2 CN temp. 7 7-amino-3- 2.02 149 3 2 3 mi st. - (1- (1,2,4- (dec.) 7.1 20 May -triazolyl) methyl) -3- -cephem-4-carboxylic acid

2.72 0.75

BF ₃ .Et ₂ O

7.1

CHCl 3 COOH temp. 7 beds ·

7-amino-3- 2.0 - (1- (1,2,4-triazolyl) methyl) -3-cephem-4-carboxylic acid 149 (decomposition)

2.72 0.75 konc.HgSO ^ 5 CHCl ₂ COOH 8 temp. places. 7 7-Amino-3- (1- (1,2,4-triazolyl) methyl) -3-cephem-4-carboxylic acid 0.34 149 (dec) 2.72 0.75 с ₃ эо ₃ н CF ₃ COOH 19 temp. places. 7 7-Amino-3- (1- (1,2,4-triazolyl) methyl) -3cephem-4-carboxylic acid 1.31 149 (dec) 2.72 0.75 FSO ₃ H 8 ch ₃ cooh 25 temp. places. 24 7-Amino-3- (1- (1,2,4-triazolyl) methyl) -3-cephem-4-carboxylic acid 1.12 149 (dec) 2.72 0.75 CF ₃ SO ₃ H 12 ch ₃ cooh 25 temp. places. 24 7-Amino-3- (1- (1,2,4-triazolyl) methyl) -3-cephem-4-carboxylic acid 1.05 149 (dec) * 2.88 0.76 BF _3> EtgO 7.1 CF ₃ COOH 23 temp. places. 7 7-Amino-3- (1- (1,2,4-triazolyl) methyl) -3-cephem-4- - carboxylic acid 1.77 149 (dec)

Note: * 7-Amino-3-acetoxymethyl-3-cephem-4-carboxylic acid 1-oxide was used as starting material.

Reference Example 10

The same reaction was performed as in Reference Example 5 except that the 7-ACA was replaced by the starting compounds listed in Table 12 to produce the products listed in Table 12.

Table 12

Starting compound Product Tt, (° C) IR (KBr) cm " ¹ : ⁹ c = o ^0-y oiУrsbtnz les tr ^y 7 ^ and in jcttsiymetyl- ^^ -3-3- cephem-4-k: jrbsχllsvá acid O-N-triazolyl-3- ^y -amino-3 [eta] &lt; 1 &gt; ⁽ 1 &apos; -triazolylmethyl) -3-cephem-4-carboxylic acid 114 to 116 (dec) 1 770, 1 708, tУlltsУtr ^{jeinosЗ-7-yl} Jct O) xymeeyl- 3- ceph em-4-carboxylic acid-ium ťtytester ^^ 0-30) (¼) 2 ⁴ - ^yl rijzol ^l l) -EE ^y-yl] - ³ -C ef em 4- to jrtoxllsvé acid 68 to 72 (rozk) 1 770, 1 720 7-Amino-3- (10-oxo-6,6-di-1-ol) diphenyl] ethyl ester (4) Larboxylic acids 7-amino-3- [01- (1,2, ¹ .4- ^]? ^ ^L ^ J ^^ i ^mt-yl] - ³ -cefem- 4-carboxylic acid 149 ‘ (dec) 1 790, 1 610

acid

Reference Example 11¹. Ve^{10 m} N^,N-^d^: ^ me^y^^l^^ Lfom ^ and ^:^idu is suspended^{2.96 g 7}-and^mno-3^{) 2}- (5-eet^yli1,^-, 3^,4 -tetrazoles⁾)methyl^-зЗ-.ctfem4^-l^andarbox^ylsv^E Susp ^ ΙΙο ^ Suspension is made^atmelting^{1,1 gt}r^and^ ¢ ^ tJ^andjm^and^ ot₍ converted into a solution with ice cooling. Then 2.7 g of pivyloyloiymet was added to the solution^yljodidt ·^INý81e^dn^and the mixture is from^pgulls^andin^and they're going totan^při^WITH to⁵ Deň: 32 ° C. After completion of the reaction, the reaction mixture was poured into 250 ml of water and 200 ml of ethyl acetate. The pH of the solution was adjusted to 7.0 by the addition of sodium hydrogen carbonate. The insoluble material is removed. Separate the organic layer and dry over anhydrous sulfate R 2^yThe soap is then stripped under reduced pressure. Z ^ b ^^yek se prom^yThe solution is 1 g of dry hydrogen chloride in 30 ml of diethyl ether with stirring and ice-cooling. The precipitated crystals were washed thoroughly with diethyl ether and then washed with chloroform. Gets^ká se^{2.72 (v}ý^yThat^1 6°,⁹ %) tydrochlord-th^pivjls^ylsx^yeeeylestert^7-a ^ d ^ i ^ c ^ —3—⁰^ - - (⁵-ee^yyl-¹,^-зЗ,^-t^tE^yjzoi^lye) tt^ly13-Зtct^Eem-^-kaabbox^ywhich has a melting point of ‘³M.p. 49-151 ° C (dec.).

IR (KBr) cm '': V _c = o '773, 1 741 1 730th

Nuclear Magnetic Resonance Spectrum (JMStOdg) ppm: 1.18 (9H, s, -C (CH ₃ ) j), 2.44 (3H, s, -Cit), 3.60 (2H, s, C 1 H), δ 25 (2H, _s , C 8 -H, 07-ю, 5, δ> (2H, s, S), 5.78 to 5.92

D <2 (2H, m, -COOCH2 O).

If the various starting compounds are treated in the same manner as above, the corresponding compounds shown in Table 13 and Table 14 are prepared.

236491 40

If in the same. T reaction are employed BE-amino ^ - ^ - methyl- ^{1, 2) 3,4-ее} г гаго! у1) у п ^ ^ -3-cephem-4-carboxylic acid, or. 7-Amino-3-fluoro-1,2,4-triazolyl) methyl] -3-cephem-4-carboxylic acid and N, N-dimethylformamide and triethylamine are replaced by acetone. and 1,8-diaa-bicyclo (5.4.0) non-enene-7 (DBU), the corresponding compounds are obtained in yields of 65 and 90%. The resulting compounds are shown in Tables 13 and 14.

Table 13

Compound

R ¹

Temperature iC (KBr) The NMR (d ₆ -DMSO ⁺⁾ thaw cm-l _O * ⁺ CDCl _ppm. 0 ppm. CD ₃ QD ⁺⁺ + (° C) ^ C «O

Note (processing)

-chococh ₂ ch ₃

775, 1.28 (3H, t, J = 7Ha, -CH ₂ CH 3), Column chromatography 758 1.58 (3H, d, J = 6Ha, 2CHHCH3), grafie (Wako silHa- 2.02 (2H, broad s, -NH ₂ ), 2.51 C-200 gel; elution (3H, s, -CH 3), 3.33 (2H, broad benzenetyl- s, C ₂ -H), 4.20 (2H, q, J = 7 Ha -CHgCCH), 4.90 (2H, br 8, C ₆ -H, C 7 -H), 5.61 (2H, broad s,), 6.69 and 7.06 (IH, acetate = 3: 1) m, 3 = —CHCH3) ++

98 ai 1 788 101 1 740

-СНОСС (ССн) п

^CH 3

135 ai 1 600

137 1 735 (dec)

Column chromatography (Wako silicogel C.200; - eluent

-NH 2), 2.42 (1.5H,

2.49 (1-.5H, s -Cty, 8, _C2 -H), 3.30 (1H,

4.62 to 4.95 (2H, m, Cc-H, [beta] -feaf: C-H-effetyl acetate, 5.30, 5.65 (2H, ABj, = 3: 1))

J = 17 Ha, S), 7.37 (0.5H, oh ₂ s, ЭСН), 7.42 (0.5H, s, = cCH),

1.80 (2H, s, -C ^), 3.27 (1H, C (-H)),

7.54

1.14 (3 H, (3 H,

8,

α 7.87 (4H, m,

) ♦ + (9H, s, d

8, year J = 6 Hz,

J = 6 Hz, year s,

To the ethyl acetate solution was added oxalic acid to form oxalate.

-C (CH3) 3), 1.47 J = 6-Hz, (cHH-Cl), 2.44 (N), 3.49 (2H, 6N)

Cg-H),

C ₆ -H),

Cy-H),

4.86

5.06

5.50 (1H, d, (1H, d, (2H, bs)), 6.80 (1H, ch ₂ q, J = 6Hz, 4-CH-CH ₃ ), 7.03 (3H, br s, - HN-) + J

8,

NMH (d -iMí ^g ^ O ^{*) CDCl} ₃ ^{++ p} pm:

CDjOD ⁺⁺ *

Advancing .table 13

Compound

Temperature 10 (KBr) melting.

(° C)

Note (processing)

- ^ 0 (¾ ^ ⁴⁴⁴⁴ 125 to 130)

790,

780 (dec)

1.18 (3H, t, J = 7Hz, -CH ₂ CH ₃ ),

2.47 (3H, s, -CH 3), 3.27 (2H, broad s, C ₂ -H), 3.55 (2H, q,

J = 7 Hz, -CH 2 CH 3), 5.08 to 5.68 (6H, m, C ₆ -H, C ₇ -H,

Oxalic acid was added to the ethyl acetate solution to form the oxalate.

-COOCHgCO, +++

-OCCHO, ^{0 J}

-CHgOCCH3 ⁴⁴⁴⁴ 107 to 1 785 II 110 1 735 0 (crotch)

2.45 (3H,

2.08 (3H, s,

N

3.50 '(2H, br s, C ₂ -H), 4.96 (1H, d, J = 6 Hz · C ₆ -H), 5.11 (1H, d, J = 6 Hz, C7 -H), 5.58 (2H, broad s,

Sat), 5.82 (2H, s, ^t ° - ^S 2 ')

-COOCH ₂ O), 7.66 (3H, broad s,

H3N -)

Oxalic acid was added to the ethyl acetate solution to form oxalate.

++++

-ch ₂ C (ch ₂ ) ₃ ch ₃

117 až 1 780 120 1 750 (rozkkl)

0.87 (3H, t, J = 7'Hz, - (CH ₂ ) ₃ CH ₃ ),

1.00 to 1.90 (4H, m, β-CH ₂ CH ₃ ), 2.30 to 2.54 (2H, m, -CH ₂ CH ₂ CH ₂ CH ₃ ), 2.47 (3H, s,

N), 3.52 (2H, broad s,

N

To form oxalate, acetic acid was added to the ethyl acetate solution.

C ₂ -H), 4.96 (1H, d, J = 6Hz,

C ₆ -H), 5.14 (1H, d, J = 6Hz, C ₇ -H), 5.42 (2H, broad s.

5.74 (2 H, s,

-OCH 2 Oc), 7.66 (3H, broad s,

-L. H ₃ N -) + '

-CHOCCOCCh))> CH ₇ | II JJ

I o

CH ₃

780,

758

0.92 (3H, t, J = 6Hz, - (CHhHhCH _3), 1.12 and 1.70 (4H, m, ⁰ ≤ -¾¾¾ 1.60 (3H, d, J = 6Hz, CCHH- _CH3), 1.89 (2H, 3, -NH ₂₎ 2.52 (3H, s, H> - ^C ^>

N

3.32 (2H, br s, C ₂ -H), 4.14 (2H, · t, J = 6Hz, -¾¾) CH 2 CH _3), 4.78 (1H, d, Л = 5Hz, C ₆ -H), 4.91 (1H, d, J = 5 Hz, C7-H), 5.44, 5.77 (2H, ABq, J = 15 Hz, S &gt;), 6.96 (1H, q,

J = 6 Hz, CH = CH-CH ₃₎ ++

Column chromatography (Wako silica gel. C-200; eluent benzene: ethyl acetate = 5: 1)

Note (processing)

Continuation of Table 13

Compound Temperature iC (KBr) NMR (d ₆ -LMSO ⁺ ) H ’ melting point (° C) cm "\) in _{c = 0} CDCl ₃ * ⁺ ppm: CD ₃ FROM ⁺⁺⁺

++++

-сн ₂ О (с ₂ ) ₃ сн ₃

116 až

120 (dec)

800,

700

0.87 (3H, t, J = 7 Hz, -CH ₂ CH ₂ CH ₂ CH ₃ ), 1.10 to 1.75 (4H, m, -CH ₂ CH ₂ CH ₂ CH ₃ ),

2.48 (3H, s, N *);

Oxalic acid was added to the ethyl acetate solution to form oxalate.

3.52 (2H, br s, C ₂ -H)

3.64 (2H, t, J = 7Hz, -CH ₂ CH ₂ CH ₂ CH ₃ ), 5.00 (1H, d, J = 5Hz, _C6 -H), 5.17 (1H, d,

J = 5Hz, C _? -H), 5.44 (2H, s, -OCH O ₂ ~), 5.64 (2H, s,

s, -NH ₃ )

7.83 (3H, broad

-CHOCOC (CH3).

I á ³

CH ₃

770,

750

1.55 (9H, s, -C (CH ₃ ) ₃ ), 1.66 (3H, d, J = 6 Hz, CH-CH ₃ ), 2.20 (2H, s, -NH ₂ ), 2 60 (3H, 8)

N ). 3.44 (2H, broad s from ^-0 ' ³ N C ₂ -H), 4.98 (1H, d, J «5 Hz, C ₆ -H), 5.11 (1H, d, J = 5 Hz, C ₇ -H), 5.80 (2H, wide 8,

), 7.10 (q, q,

^Л- С Й2J = 6Hz,> CH-CH ₃₎ ++

Note: Oxolate.

Compound R ¹ Melting point (° C) IR (KBr) cm &lt; -1 &gt;; ^F c = o ++++ -CHOCC (CH _7). . 136 to 1 810, | Λ ³³ 138 • to 1,780, CH ₉ I * (kiss) 1 740 čh ₂ -CHOCC (CH K • II 3 ^J - 1 790 2 (о)! 1 720 -снос * - <O> | 3 ^{x 7} - 1 775, 1 735 ^CH 3

Compound R ¹ Melting point (° C) IRCKBi *) cm?:. ^ C = O -CHCO— O - 1 780, 1 752 ch ₃ -CHOCO -. 0 - 1 782, 1 770 CH ₃

Table 14

Compound Temperature iC (KBr) NMR (d ₆ -rM30 ⁺¹⁾ R ¹ thaw ^cm ' ^: or> ο CDCl ^{2 ppm} (° C)

Note (processing)

* 3 -CH 2 _O (CH 2) ² O ^{13 33} 0 152 až 155 / dec) 1 803 1 750

1.13 (9H, s, -C (CH3) _3), 3.39 (2H, br s, C ₂ -H), 4.90 (1H, d, J = 5Hz, C ₆ -H) , 5.10 (2H, broad s,

), 5.72 (1H,

Oxalic acid was added to the ethyl acetate solution to form oxalate.

d, J = 5 Hz, C _? -H), 6.28 (3H, broad s, H-5S-), 7.89 (1H, s,

♦ CH0C0CH ₉ CH, 146 to 1 778, 1 II ^{2 3} 148 1 720 1 ⁰ CH ₃

1,27

1.57

3.22 (2H, (1 H,

5.51 (3H, t, J = 7Hz, -CH ₂ CH ₃₎ (3H, d, J = 6Hz, -CHCH ₃ ^), (2H, br s, C ₂ -H), 4. 17 q, J = 7 Hz, -CH ₂ CH ₃ ), 4.70 d, J = 5 Hz, C ₍ H), 4.91,

Column Chromatography (Wako silica gel C-200 * eluent benzene: ethyl acetate = 3: 1) (2H,

-СНОСОСНЛЛЦ

II ^{2 3 0}

CH ₃ to

780,

760

1.32 (3H, t, J = 7Hz, -CH ₂ CH ₃ ),

1.59 (3H, d, J = 6Hz,>_CH-CH3);

1.86 (2H, 8, -NH ₂ ), 3.20 (2H, e, C ₂ -H), 4.20 (2H, q, J = 7 Hz, -CH ₂ CH ₃ ), 4.72 (1H, d, J = 5Hz, _C6 -H), 4.87 (1H, d, J = 5Hz,

Column chromatography (Wako silica gel G-200; eluent benzene: ethyl acetate ^with 3: D)

C ₍ H), 4.99, 5.52 (2H, ABq,

J = 15 Hz, S), 6.95 (1H, ch ₂ q, J = 6 Hz,> CH-CH ₃ ), 7.75 (1H, s,

+2

Stavolic acid adds to the ethyl acetate solution solution to form oxalate ·

236491 44 Continuation Table 14 Compound Temperature iG (KBr) NMR (dg-IMSO * ¹ ) CDCl ₃ ⁺² PP " ^: Note R ¹ melting point (° C) ^c ® '' ^! 4> o (treatment

+3 -CH ₂ O (CH ₂ ) ₃ CH ₃ 128 až 1 773, 135 1 720

0.90 (ЗН, i, J = 7Hz,

- (CH ₂ ) ₃ CH ₃ ), 1.15 to 1.71 (4H, m, 3.30 to 3.00H);

3.65 (4H, m, C ₂ -H) -¾¾.

CH ₂ CH ₃ ), 4.95 to 5.40 (6H, m, -OCH 8 O-,

c ₆ - ^H »

_С г н 8.01 (1H, 8,

N), 8.84 (3H, broad s,

+

N

+

+3 -CHOCC (CH), 132 to 1 782, 1.17 (9H, a, -C (CH3) _3), 1.50 To create p ³³ 136 1 740 (3H, d, J = 6Hz, -CH-), 3.49 oxalate with 4h, к ethylacotátovéau CH 2 -3 (2H, broad and C ₂ -H), 4.97 to 5.19 (4H, m, C ₆ -H, _C? -H, s), 6.70 to 7.08 Д-СНз- (1H, α, -CH-), 8.04 (1H, α, ch ₃ oxalic acid is added to the solution N) > -a N

Note:

+ optic isomer * 3 oxalate

4 * 4 upper component

4 * 5 lower component

Reference Example 12

1.45 g of 3-oxo-2-ethoxyimino-butyric acid, 2.0 g of 1-oxybenzotetrazole and 4.63 g of diphenylmethyl ester of 7-amino-SQ (s-chloro-1,2,4-triszolyl) are dissolved in 50 .mu.l of anhydrous tetrihydrofuran. ) metcefem4 4k arboxy ^{e l} b ^s k / get. R> ZTO is cooled ^to 5 ° C. ^p and added thereto 2.5 g Ν, Ν'-dicyclohexylcarbodiimide. The resulting mixture was worked for thirty minutes at the same temperature and 5 hours at room temperature. After completion of the reaction, the insoluble material was filtered off. the foo-solvent is removed from the filtrate by distillation under reduced pressure. Ethyl acetate (40 ml) was added to the residue. Insoluble matter may be recovered / filtered. The nitrate is initially a 5% (aqueous solution) aqueous sodium bicarbonate solution, water, and dried over anhydrous magnesium sulfate.

The supernatant was decrystallized under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (Wako silica gel - C-200, eluting with 8: 1 benene-ethyl acetate). To afford 3.7 g (yield 62.8%) dichlorodiethylsilane ^ -phenyl ^^ t ^ ^ Leste 7- ^{(2-methoxyimino-3:} ^ Oxo tyremiiJo) -3 - ^ (3-cM.oir · 1 ^1, 2, ^{4 (} triazolyl) ethyl] '. -CN ^{F 3 nm-4} -karboxyluvé maajcí acid mp 102-103 ° C (rozzk.).

IC spectrum (KBr) cm -1: 9 _{c =} q 1775, 1740, 1670.

NMR Spectrum (IMSOdg ppm:

2.31 - (3H, s,

4.00 (3H, s,

4.), ^ —ch ₂ 8, -ch <),

COCH3), 3.47 (2H, br s, C ₂ -H), -OC ^), 4.90 to 5.40 (3H, m, - C H, 5.89 (1H, dd, J8 Hz, J = 5 Hz, - C - H)

7.50 (10H, i, 7.95 (1H,

J-h,

6.93 (1H, s, N ⁾

9.43 (1H, d, J = 8Hz, -CONH).

If the same procedure is followed, the following compound is produced:

difn- líβnylester V ^y - ^ - ^ mino- methoxynaphthalene oxotutyramido) - ³ - ^{2) (5-1 meeyli ^^ j ^^^ azolyl) íenylL) -S-4-Cefn kaгboχyluvé acid. Mp 88-90 ° C (dec.).

IC ktnmUKBr) «jm ^- '·: V ^ 1775» 1720 ^- 1685 1 670th

NMR (JMSQdg ppm): 2.27 (3H, s, C ₂ -H)

5.42 (2H, s, -COCHh), 2,37- (3H, s, N), 3.46 (2H, br> - ^ ^{н з}

N s, -OCH 3), 5.10 (1H, d, J = 5Hz, -C ₆ -H), S), 5.82 (1H, dd, J = 5Hz,

_CH2 (1H, s,> CH--, 7.17 (10H, broad s), - 9.27 (1H, d, J = 8 Hz, -COUH).

3.93 (3H, broad s,

J = 8Hz, Cy-H), 6.82 ^2x

Reference Example 13

1. Suspend 2.96 g of 7-amino-3- (β-chloro-1,2,4-triezolyl) methyl] -3-cephem-4-carboxylic acid in 90 µl of anhydrous methylene chloride. 1.7 g of diketene and 2.02 g of triethylamine. The mixture is then treated at 5 to 10 ° C for 4 hours. After completion of the reaction, 100 ml of water are added to the reaction mixture. To this aqueous layer, add 100 of ethyl acetate and adjust the pH to 1.0 by adding 2N hydrochloric acid. After removing a small amount of undissolved material, the organic portions are separated and dried over anhydrous magnesium sulfate. Approximately 1.6 g of diphonyldiazomethane is slowly added thereto with stirring.

The resulting mixture is treated for about 30 minutes. After completion of the reaction, the solvent is distilled off under reduced pressure. Isopropyl ether is added to the residue. The precipitated crystals are filtered off, washed thoroughly with isopropyl ether and then dried. 3.3 g (yield 60.4%) of diphenylmethyl ester 7- (3-oxobutyramido) -3-Q3-chloro-1,2 are produced. , 4-triazolyl) methyl] -3-cephem-4-carboxylic acid, m.p. 75-77 ° C (dec ·) · IR (KBr) cm ^"1: \) c ₌ Q 1775, 1720 , 1 670.

Nuclear Magnetic Resonance Spectrum (JDMSO-d ₆ ) ppm: 2.17 (3H, s, -COCH 3), 3.48 (4H, broad s, C 8 -H, -COCH 8 CO-), 5.00-5.40 (3H, m, C ₆ -H, S), 5.86 (1H, dd, J 1 -CH 2 J = 8 Hz, J = 5 Hz, C ₇ -H), 6.99 (1H, s,> CB-), 7.36 (1H, s, 8.05 (IH, s, N), 9.12 (IH, d, J = 8Hz,

-CONH-).

Following the same procedure, the following compound was prepared: 7- (3-oxobutyramido) -3- [2- (5-methyl-1,2,3,4-tetrazolyl) methyl] -3-cephem-4-carboxylic acid diphenylmethyl ester acid. Melting point: 84-86 ° C (dec.) IR (KBr) ¹ Ca: ή> ο ^{1780 »1720» 1670} ·

Nuclear Magnetic Resonance Spectrum (O 2 SO-d 6) ppa: 2.06 (3H, s, -COCH 3), δ, 31 (3H, s, N), 3.34 (2H, v,> —OI)

N

-COCH 3 CO-), 3.46 (2H, broad 8, C ₂ -H), 5.00 (1H, d, J = 5 Hz, C ₆ -H), 5.31 (2H, broad s, S) , 5.63 СIH, dd, J «5 Hz,

CH ₂ J = 8 Hz, C _r H), 6.71 (1H, z,> CB-), 7.06 (10H, broad 8, 2x> ⁸ » ^{75 <1H} » ^d > ^{J 8 Hz} »- ^C0Wl ·) ·

Second Dfenylmetylester 7- (3-oxo-butyramido) -3-Q (3-chloro- N 1j2,, 4tri-tolyl) methyl] -3 ^- c ^e f ^<m »k18elin1 -4-carboxylic acid, prepared in paragraph 1 ' It is processed in the same manner as in Example 5 below. Difen1leety1estet give 7 - (- · hydtlX1imino 3-oxlbut1r ^and ϊ * ^m in) - [j ^3- (3-chllr-1, ^2, 4 t rio ^{r l} o y ^{l e)} 6 t yϊ ^l] -> ct ^e 4- eπl4 ^and rrЪox ^l llvé tyselin ^{1 to} tery mp 108-110 ° C (dec ^-).

iC with ktm (KBr) cm ¹ : · 9 _ε _ ₀ 1,780, 1,720, 1,680.

Nuclear Magnetic Resonance Spectrum (QiSO-dg) ppm:

2.32 (3H, s, -COCC ₃₎ '3.44 (2H, br g, C-H), 4.90 to 5.40 (3H, m, C ₆ H, S), 5 88 (1H, dd, J = 8Ha, J = 5Hz,

Δ-ch ₂ CrH, 6.94 (1H, s, -CH 2), 7.33 (10H, s, 2χ-Zq)),

8.00 (1H, s, N), 9.30 (1H, d, J = 8Hz, -CO1-, 12.82)

N (1 H, s, = N-OH).

s,> -CH), 7.11 (10H, SiO 2, 2x)

Following the sterile procedure as described above, the following compound was produced:

Diphenyl ^ ^ ster MTY 7- ⁽² - ^H1D rox mijl- ^{1i '3} -oxo ^b utyram ^{id o)} -3- ⁽² - ^(1,2, 3,4-tetrazolyl) ee ^{t J} yl -3-ce: ^{e ee-4-one} karblx llvé acids ¹ * :, mp ^{102 105} ° ^C (ro ^ L ^ ^ L.) ^ic ^ ktrum ^(KBr) cm ^"1 ≠ Y _{c = 0} 1 ^{1 72} 2 ^{1 68} °.

Nuclear Magnetic Resonance Spectrum (IW & δ ₆ ) ppm: 2.25 (3H, s, -COCH) 2.35 (3H, s, N), 3.44 (2H, broad> ^CH 3)

N 5, C ₂ -H), 5.05 (1H, d, J = 5'Hz, C ₆ -H), 5.37 (2H, broad s, 3 '), 5.76 (1H, dd, J = 5 Ho, J = 8 Ho, C-H), 6.71 (1H,

JL-Ofe), 9.04 * (1H, d,

J = 8 Hs, -CO 2 H).

Third DifnylmeVí.ester ⁷ - ^{(- 1} -h ^1d imijo RLX-3-lxlbutyrшni ^d o) - ^ - ^-) 3 chloir.1,2 4-triaooiyL) ^{metylj--cephem-4-carboxylic} acid ¹ and ^ ma ^ diphenylmethyl ester ^{1 7} - ^{(2-hydroxy-d-Tox 1} ieijo- ³ -lxl taeidol ^b u ^{t 1} - ^ (2- ^{(S-methyl- 1} - ^{1,2, 3,} E-tetrazoles) mttyl ^J] з ^- em -tf f ^- l ^{1 l é} -karblx acids ¹ ^^ rave No in paragraph 2 were subjected to reaction and treatment in the same manner as described in Example 5- (3) mentioned below ZIS * · ^ka ditenyLmet.yl .eater ⁷ - ^(- -eetlxyieiln) · oxobutyyrmido l.3) - 3Γ (3-cM.lr- ^{1, 2, 4 -třiazlly))} ettyl] ^-c з cephem 4 ^- to ^{1 l, and} l ^s arblx acid having Melting point ¹⁰² and ^{Z 10} 3 ° ^{C (dec k)} and ^ 01 ^ 1 ¹ 17 ester ^{of 7} - ^{(- 1} -methyl ^t lx ieinOl ³ -lXlbutyrtm ^ed o) - ^- з ^- 22-5 ~ ^e me y ^{1-1, -, 3, 4} -tetrezo ^1y).) Me ¹ Y ^J- з ^- ctefeI 4 ^- l ^{and 1 l} l ^é arblx kyselta ^1, having a melting point ⁸⁸ and ^from 90 ° C (dec ³ -) . The properties (10 and NMR spectra) of these compounds are identical to the physical properties of the compounds that were shown in Reference Example 42.

Reference Example 14

In 120 ml of dry Dissolve 5.89 g dlfeoylaetyllstlrt 7- ^{(2--altdxyiaino} 3 · ^d b DXO yгaαi ^{t i} o) dЗ- ^[- 22 (5-AEL l- ^{t 1.2)} 3, ^{t 4} · ltrazdlyl ) Iltyl ^- 3-cephim-4-carbonyl ^and looic acids. To this solution was added 1.34 g of others. To the solution was added 5.00 g of lyridine nitrile perbromy at room temperature. The resulting mixture was stirred at this temperature for 30 minutes. After completion of the reaction, the solvent was removed under reduced pressure. 50% ethyl acetate and 50% water were added to the residue. The small allodynia insoluble matter is filtered off. The organic layer was filtered, washed with water, dried with magnesium sulfate and finally the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (W-silica gel O-20C, eluting with a 9: 1 mixture of benzene and ethyl acetate). There were obtained 4.13 g (yield 61.8%) DLF mylme the sten-7- (4 - boa - ^{2 t} dxyiaino -ae-3-oxo- butyraldehyde »to) -3-Q ² - (5) 0 ⁽ 1- ⁽ 3,4,4-tetrahydro-1- ^yl ) -ethyl] -3- [eta] -4-cartoxylic acid) having a melting point of 80-82 ° C (dec.)

Example 1

A solution of 0.46 g of chlorine in 5 µl of light carbon tetrachloomide was added dropwise at -30 ° C to a solution of 0.55 g of diketene in 10 µl of white chloride ^and chloride. The resulting mixture was treated at -30 to -20 ° C for 30 minutes. There was thus obtained acid chloride solution · In <Accordingly the pH ≤ ^l avi aus ^1.48 g Nal Va ^ oo ^ ^{-3- (5-methoxy ethyl} - 1, ^2, 3, ⁴ - ^t L ^{t y} y ^y RAID ) Alta ^yl] - ^{l -C} lo ^IA-3 -kartoxylové acid in 20 »blaaddehd to this suspension is added

2.12 g of N-O-bis (trialtylsulfonyl) chloride while cooling with Ted and the mixture was treated for 1 hour at room temperature. The reaction mixture is then added to -40 ° C. To this cooled mixture was prepared a Chorita acid solution prepared above. After the dropwise addition, the temperature was raised and the mixture was treated at 0-5 ° C for 1 hour. After completion of the reaction, the solvent dddilat ^y TJL as «níženého pressure. The residue was broken down in 30 ml of ethyl acetate and 20 ml of water. The organic layer was separated. The mixture was filtered, washed successively with 20 ml of water and 20 ml of a saturated aqueous solution of sodium and dried over anhydrous magnesium sulphate.

RnzpoиЗИё <Ио dddilailtjl under reduced pressure. To the residue was added iiltylttlr »precipitated crystals are ddifltrutí ,, proimyí ϋ positively iilt ^yy éleeea and dried. Produced 1.85 g

-phenyl-4-carbonyldaic acid having a melting point of 98-101 ° C (dec).

iC spectrum №1 cm -1 ': 9c = 0 ^{1 1 72} 5 ^{1 668}

Nuclear Magnetic Resonance Spectrum (H 2 SO-dg ppa: 2.44 (3H, s, -CH 2)), 3.42 (2H, broad s, Og-H), 3.56 (2H, s,

-COOHgOO-, 4.52 (2H, s, -C 1 CH) -), 5.08 (1H, d, J 5 Hz),

V ^δ »5.31 to 5.89 (3H, a, S, c _r H),

2. Dissolve 0.82 g of 7- (4-chloro-3-oxobutyramyl) -3- ( ^2- (5 -)) - 1- (1 - 1) in 6-chloro-2-ol, the 3,4-lttrzoo ^y y ^{i) y} LT yl] -3-OLFE 4- ^to KTB oз ^{d y t} _ ιloa acidulous Ayro ^b lm ^s in paragraph ¹

To this solution was added 0.167 g of thiocortic acid. The solution was treated at room temperature for two hours. After completion of the reaction, the reaction mixture is poured into 5 L of water and the pH of the solution is adjusted to 5.0 with sodium bicarbonate (while cooling with ice). The preferred precipitate is washed first with water, then with acetone and finally with diethyl ether. There was obtained 0.77 g (yield - 88.3% 7- (O 2 - (2-aloalkylthiazol-4- ^yl ) acetamyl) -) -. 4-TLT »aao0yl) aieyl] ^-3-Cole-4-yl kartox LDA ^e acid - to TTA ^ AA ^ p.otu point ²⁰³ and ^{from 208} ° C @ ZLD.).

Ιδ spectrum ^(K Br) cm ^-1 : ^{1 - 1 6} 5C ^{1 625} .

Nuclear Magnetic Resonance Spectrum (IMSO-d ₆ ) ppm: 2.34 (3H, s, -CH ₃ ), 3.40 (4H, broad a, C ₂ -H), N-n-CH ₂ -),

WITH

4.92 (IH,

WITH

d, J = 5Hz, C ₆ -H), 5.18 to 5.80 (3H, m, _C? -H), 6.10 (IH, s, N-I] -) 8 68 (1 H, d, MHz)

CHg-CONH-).

If thioformamide is used instead of thiourea, the following compound is produced as described above:

7-C ^2- (thiazol-4-yl) acetamido] -3- [2- (5-phenyl-1,2,3,4-tetrazolyl) methyl} -3-cephem-4-carboxylic acid. Melting point: 140-142 ° C (dec.).

IC spectrum (KBr) cm ^-1 : 9 _{C = O} 1775, 1720, 1660.

Nuclear Magnetic Resonance Spectrum (IMSO-dg) ppm: 2.44 (3H, s, -CH),

_N-jj-CH2 -), 5? 06

WITH

3.44 (2H, br s, C ₂ -H), 3.79 (2H, s (IH, d, J = 5Hz, C ₆ -H), 5.60 (2H, br s,

)

5,6 až

(1H,

5.8 (1H, m, C ₇ -H), 7.45 (1H, d, J = 2Hz, λ d, J = 2Hz,), 9.00 to 9.25 (1H, m,

WITH

-CONH-),

P r 1 k 1 a d 2

If the starting compounds listed in Table 13 were processed in the same manner as in Example 1, the corresponding compounds listed in Table 15 were prepared.

Table 15 trifluoroacetic acid ·

COOH

Compound Temperature IR (KBr) dg-EMSO * R ² thaw (° C) с » ¹ 'at 0 = 0 NMR (++ ₊₊₊₊ ) ppm dg-INSO 4 O, CF 3 COOD

N = N

115 (decomposition)

CH ₂ CH ₃

780,

670,

630 * 1.27 (3H, t, J = 7 Hz, -CH₂-CH₃), 2.84 (2H, q, J = 7Hz, -CH ₂ CH _3), 3.20 to 3.80

C ₂ -H, NH ₂ -, 5; 13 (1 H, d,

(4H, m, J = 5Hz)

WITH

C ₆ -H), 5.54 to 5.85 (3H, m, _0? -Η,

6.53 (1H, [alpha], N) s

152 (dec)

775,

670,

630 * 1.30 (3H, t, J = 7Hz, -CH3CH3), 2.94 (2H, q, J = 7Hz, -CH3CH3), 3.45 (2H, a, C1-H3), 3 56 (2H, ¢, N ----- CH ₂ -), 5.12 (1H, d,

J = 5Hz, C ₆ -H), 5.25 to 5.85 (3H, m, _C? -H, s), 6.56 (1H, s, N-N-), ca ₂ - S - ^ H

9.14 (1H, d, J = 8Hz, -CONH-)

-q соосн ₂ ch ₃

137 to

140 / dec)

770,

740,

670,

630

N = N

COOCH ₂ CH ₃

149 až 1 775, 154 1 740, (DIF) 1 670, 1 630

* 1.36 (3H, t, J = 7Hz, -CH ₂ CH _3), 3.47 (2H, broad and C ₂ -H), 3.70 (2H, s, _N-N-CH2 -),

WITH

4.41 (2H, q, J = 7Hz, -C1-CH2), 5.08 (1H, d, J = 5Hz, C8HH), 5.50-5.80 (3H, m, _C7 -H) s \), 6.48 (1H, s, N-ц-) -CH ₂ * 1.36 (3H, t, J = 7Hz, -CH ₂ CH _3), 3.50 (2H, broad s , C ₂ -H), 3.71 (2H, s, N - H -C ₂ -) with -Λ

4.40 (2H, q, J »7 Hz, -CHgCHj), 5.06 (1H, d, J = 5 Hz, -C-H), 5.60 to 5.85 (3H, m, _C? -H , S1), 6.47 (1H, a, N - n -)

J_CH ₂ - sXh

Continuation of Table 15

Melting point (° C) IR (KBr) cm ^-1 ; s) ^F C = 0 X 444. d ₆ -DMSO, CD 3 OD NMR ( ₊ ) ppm: d ₆ -IMSOD ₂₀ , CF 3 COOD 133 (decomposition) 1 770, 1 670, ⁺ 3.55 (4H, broad and C ₂ -H) · -ц N-CH-), S 1 630 5.05 (1H, d, J = 5Hz, _C6- H), 5.50-5.80 (3H, m, Cy-H1), 6.55 (1H, s, Y- ₂₎ - N - (-) -, 7.40 to 8.10 (5H, m, - &gt;) 148 (dec) 1 778, 1 710, 1 668 ⁺ 3.44 (2H, broad and C ₂ -H), 3.56 (2H, br β, N-y CH ₂ -), 5.08 (1H, d, J = 5Hz, C ₆ -H), 5.42 to 5.93 (3H, m, Vol., Cy-H), 6.57 (1H, s, N-π-), s) -CH ₂ - S -AH 8.90 (1H, a, 1H), 9.13 (1H, d, J = 8 Hz) Л -CONH-)

100 to 1780,

102 1710 (dec.) * 1 670 3.60 (2H, broad and C ₂ -H), 3.68 (2H, br β N OJa-), 5.06 (1H, d, J = 5 Hz ,

WITH

C ₆ -H), 5.30 to 5.85 (3H, m, S)

), ^ Lch ₂ C _? -H), 6.59 (1H, a, N-d 6), 9.15 (1H, a, SH

N), 9.17 (1H, d, J = 8Hz, -CONH-)

H

NHCOCH ₃

143 ¹ 770, (dec.) ’690 T 665, 1 630

⁺ 2.10 (3H, s, -CH ₃ ), 3.50 (4H, broad s,

C ₂ -H, N-n-CH ₂ -), 5.10 (1H, d, J = 5 Hz, S + -)

C ₆ -H), 5.50 to 5.85 (H, M, S \, -Chg-.

c _r H),

6.50 (1 H,

8,

9.05 (1 H, d, J = 8 Hz, -CONH-)

Continuation of Table 15

Compound

IR (KBr) m.p. 1.times. cm @ -1: [.alpha.] D @ 20 = .delta.

NMR (.delta.4.4U.) PP ^{m /} z = -rMSO + DgO, CF3COOD ****

/ • = 7 185 1 770 (rozkl ·) 1 665 nh ₂ 1 630

** 3.47 (2H, Broad a, Cg-H), 3.55 (2H, ₄ , N-w-CH2), 5.10 s

(1H, d, J = 5Hz, _C6- H), 5.45 (2H, broad, S), 5.70 (1H, d, J = 5Hz, [gamma] -),

CH ~ 2

6.55 (1 H, a, N)

WITH

_from N = N

SCH ₃

107 1 765, (dec.) 1 665,

630 * 2.60 (3H, a, -CH3), 3.55 (4H, broad a,

C 8 -H, N-Ir-CH 8 -, 5.05 (1H, d, J -5 Hz,

WITH

Cg-H), 5.50 to 5.80 (3H, m, C _r H,

SK), 6.55 (1H, [alpha], N-rr-)

CH3-S ^^ H

107 1 776, (dec.) 1 665, 1 630

** 2.70 (3H, ·, -CH _3), 3.35 (2H, broad and C ₂ -H), 3.50 (2H, s, Nj-CHg-), 5.10 (1H, d, J = 5 Hz, _C6- H), 5.30 '(2H, a,

S), 5.70 (1H, d, J «5 Hz, _C? -H) сн ₂ 6.60 (1H, β, Ν-Π- ')

S ^ H

CH ₃

150-16770, 1531665, (dec.) 1630 * 2.49 (3H, a, -CH, 3.40 (2H, a, Cg-H)),

3.52 (2H, a, N - CH -), 5.05 (d, d,

WITH

J = 5 Hz, Cg-H) #. 28 (2H, broad a,

S1), 5.62 (1H, dd, J = 5 Haj

-CH 8 (J = 8 Hz, C 1 H), 6.49 (1H, a,),

H

9.03 (1H, d, J »8Ha, -C0NB-)

Continuation of Table 15

Compound

Melting point (° C)

IR (KBr) cm ^-1 : 'J' c = from _A- IWSO ⁺ , CD, OD ⁺⁺⁺

NMR ( ^{b J} ) ppm:

d ₆ -IMSO + D ₂ O ⁺⁺ , CF ₃ COOD ⁺⁺⁺⁺

N = N '

CH ₂ COOCH ₂ CH ₃

120 to 1765,

123 1730, 1665,

630 * 1.20 (3H, t, J = 7Hz, -CH ₂ CH _3), 3.42 (2H, (br s, C ₂ -H), 3.50 (2H, br s,

N CH 3 -), 4.00 (2H, s, -CH ₂ COO-),

119 1 770, (dec.) 1 660,

630

* 3.43 (2H, broad and C ₂ -H), 3.52 (2H, br s, N- CH ₂ -), 5.02 to 5.35 (3H, s

m, Cg-H,

C-H),

N) 7.95 (1 H,

CH ₃

144 to 1765,

146 1665, (dec.).

* 2.23 (3H, s>, -CH ₃ ), 3.45 (2H, Wide 3, C ₂ -H), 3.58 (2H, broad а, К CHg-),

WITH

5.05 to 5.20 (3H, m, C 8 H, S)

)>

CH ₂ 5.70 (1H, d, J = 5 Hz, _C? -H), 6.60 (1 H, 3 Ν -ц-), 8.38 (1H, β, N) S H ^ \ ~ -

133 1 765, (dec.) 1 665,

630

⁺⁺ 2.50 (3H, s, -CH ₃ ), 3.50 (2H, broad s, C ₂ -H), 3.60 (2H, broad s, N CH ₂ -),

WITH

5.05 (1H, d, J = 5Hz, Cg-H), 5.10 (2H, s,

S), 5.65 (1H, d, J = 5 Hz, _C? -H)

CH26.60 (1 H, 3, N), 8.40 (1 H, s, N)

N

CONTROLLING TABLES 15

Compound

R ²

Melting point (° C)

IR (KBr) cm ^-1 : Ώ ^y C = 0 dr-IMS0 ⁺ , CD, OD ⁺⁺

NMH ( ^{£ 0} ) ppra:

d ₆ -mso + and ₂ o ⁺⁺ , cf ₃ cood ⁺ * ⁺⁺

COOCH ₂ CH ₃

155 to

158 (dec)

765,

725,

660,

630 ⁺ 1.34 (3H, t, J = 7Hz, -CH ₂ CH ₃ ), 3.41 (2H, broad s, C ₂ -H), 3.53 (2H, broad e, CHa-), 4.38 (2H, q, J = 7Hz)

6.55 (1 H, s,

-Cg ₂ CH ₃ ), 5.10 (1H, d, J = 5 Hz, C ₆ -H), 5.50 to 5.85 (3H, m, C ₇ -H)

140 (dec)

765,

665,

630 ⁺⁺ 3.47 (2H, br e, C ₂ -H), 3.65 (2H, s, N --- ^ - ¾.), 5.10 (1H, d, J = 5 Hz, -C -H),

WITH

5.10, 5.40 (2H, ABq, J = 16Hz, S).

J-CH ₂ 5.70 (IH, d, J = 5 Hz, _C? -H), 6.65 (IH, s, H-π-), 8.02 (1H, s, N)

A> -ϊ)

AND

_COOCH3 COOCH3

137 to

140 (dec)

775, 730, 640

3.49 (2H, broad and C ₂ -H), 3.70 (2H, s, CHg-), 3.82 (3H, s, _OCH3), 3.87

-COH ₃ ), 5.06

5.32 to 5.85 (3H, m,

6.51 (1H, [beta], N

-CONH-)

153 (dec)

770,

670,

630 * 3.55 (4H, wide s,

C ₂ -H, N

CHg),

NHCOCH3

160 (dec)

770,

690 670,

630

5.05 (IH, d, J = 5 Hz, (3H, m, C H _R, S

with

CG-H), 5.50 to 5.80), 6.55 (IH, A, CH _2), 7.40 to 8.20 (5H, m,

)

Continued Tables 15

Compound Temperature IR (KBr) d ₆ -BSsO, CDgaD R ² thaw (° C) cm ¹ : \) * C = O NMR ++ ++++) PPm: d ₆ -aM ₁₀ OD 10, CF 3 COOD

-NHCCH, -C1

II ²

124 až 1 770, 125 1 660, (dec.) 1 630

* 3.50 (2H, broad s, C2 ^_--H), 3.55 (2H, s,

3,91,

4.15 (2H, A3q, J = 12 Hz, &gt;)

4.10 (2H, s, CLCH ₂ -), 5.03 (1H, d,

J = 5 Hz

J = 5 Hz, _C6- H), 5.65 (1H, dd,

H = 6 Hz, γ-Η), 6.53 (1H, s, 9.01 (1H, J = 8Hz, -CON1H-)

У37 to 1760,

141 1 660, (dec.) 1640

m, CH3 (NHHO), 9.02 (1H, d, J = 8Hz, -CONH-)

-NHC (CH ₂₄₃ o

105 až 1 765, * 0.87 (3H, t, J = 7Hz, ¾¾¾¾¾) 108 1 660, 1.05 to 1.70 (6H, m, - (¾¾¾¾)). (rozlk.) 1 640 2.08 (2H, t, J = 7Hz, ¾¾¾¾¾). 3.41 (2H, broad s, Cg-H), 3.57 (2H, a

4,01>

>

(2H, broad s);

- CH 2 O 5.63 (1H, dd, <6.55 (1H, s, N)

5.00 (1H, d, J = 5Hz, _C6- H),

J = 5

Ж> —CH, NHC (O).

Hz, J = 8 Hz, C _? -H),), 8.10 (ΊΗ, W,

Continuation of Table 15

Compound

R ² Temperature IR (KBr) d ₆ -Uis ^»+ CDgOO *** cm '. NMH (· ₊₊₊₊ ) ppm

(° C) In _Ce0 d ₆ -n ^ K * D2 ° * ⁺ »CFjCOOD *

114 až 1 765, 116 1 660, (rozlk ·) 1 640

* 0.84 (3H, t, J = 7 Hs, -CH ² CЯ ^- Cg 3) ^, 1.18 to 1.82 (2H, о, -СНдО ^ СС ^, 2.05 (2H, t J = 7) Hz -Ca »CH 2 CH _3), 3.42 (2H, br s, C ₂ -H), 3.51 (2H, s, N-π dL) 3.85 AI

S '

4.26 (2 H, m.

° = 5Ha, _C6- H), 5.7 ° (1H,

5.01 (1H, d, dd, J 5 Ha, ° = 6Hz, δ-1), 6.5 ° (1H,

8.07 (1 H, t, J = 6 Hz, σ-ТТуТ)

175 až 1 780, 176 1 710, '(ro ^ Hi) 1 665, 1 660

* 3.03 i 3.57 (6H, s, C ₂ -H,

008, -, 4.87 (1H, d,

WITH

5.32 to 5.70 (1H, β, C _r H), (4H,

CH ₂ J = 5Hz ^_C6-H), 6.25 i 7.61 И)

8.20 (1H, Wide and,,> —СНуЩССО-, 8.81 (1H, d, 0 «8 Hz -CONH)

161 to 1 760

163, 1 710 (roll) l

620

5.36 to 5.72 (1H, m, O- ^B &apos;, ^e , 2 * to 7.39 (5H, m, N ' -O-O)), 8.96 (1H,

S (H = d, J = 8 Hz, -CONH)

Continuation of Table 15

Compound R ² Melting point (° C) IR (KBr) ^{cm &} lt ^; -1 &gt; -BMSO d ₆ ⁺ CD ₂ OD * NMR ⁺⁺ (++ +4.4.4. ppm): d ₆ "-DMSO + D ₂ O, CF, COOD 155 (dec) 1 760, 1 660, 1 630 ⁺⁺⁺⁺ 3.43 (2H, br s, C ₂ -H), 3.S6 (2H, 8, N-ir CHg-), 4.20 (2H, m, S) 7- 7 S ^c ^ 2 5.22 (1H, d, <J "5Hz, Cg-H), 6.05 (1H, m, _C? -H), 6.62 (1H, s, N -J-) 7.22 (5H, SH wide with —ξθγ) » —4 _S JI — COOH 184 (dec) 1 765, 1,710 Z 1 620 ⁺⁺⁺ * 3.12 to 4.12 (6H, m, C ₂ -H, J-S ^ ~ CHg- ^{К У} С Й2-) ^{S »00 <H} · ^{d> J = 5} · ^{Kz C} 6- ^H > S

f (1 H, 8,

5.57 (1H, d, J = 5Hz, C _r H), 6.45 N-π-), 7.30 (1H, d, J = 3.5Hz,

COOH

7.52 (1 H, d,

- * L _with JLcooh

J = 3.5 Hz, -C1-COOCH3

151 až 1 768, ⁺⁺⁺ 3,15, 153 1 705 3.62 (2H (dec.) 2 (. -осн,),: 1 620 J WITH

C ₂ -H),

3.48 (2H, AB q, J = 18 Hz, 8, --- N | pCH ₂ -), 3.82 (3H, 8,

3.60, 4.03 (2H, ABq, J x 15 Hz,), 5.08 (1H, d, J = 5 Hz, _C6- H), ch ₂ 5.68 (1H, d, J = 5 Hz C ₇ -H) 6.54 (1H, s,

N), 7.53 (1H, d, J = 3.5Hz, g)

COOCH;

7.67 (1H, d, J = 3.5Hz)

Xol · COOH

183 až

187 (rozkl,)

765,

710 l

610

⁺⁺⁺ COOCH3 3.45 (2H, br s, C ₂ -H), 3.64 (2H, q, NJ-CH2-), 3.90 (2H, br s,

S), 4.92 (1H, d, J = 5Hz, _C6- H),

Λ-α ₂ 5.51 (1H, d, J = 5Hz, C ₇ -H), 6.19 (1H, d, J = 4Hz, H-γ--,

JJ / COOH)

6.48 (1H, a, w '), 6.97 (1H, d, J = 4 Hz, is ^A H)

COOH

Example 3

1. A solution of 1.92 g of bromine in 12 ml of anhydrous methylene chloride is added dropwise at -30 ° C to a solution of 1.26 g of diketene in 20 ml of anhydrous methylene chloride. The reaction mixture is worked for 30 minutes at -30 to -20 ° C. Then, the reaction mixture is added dropwise to a solution of 4.62 g of 7-amino-3- [2- (5-methyl-1,2,3,4-tetrazolyl) methyl] -3-cephem-4-carboxylic acid diphenylmethyl ester and 4 g of N (O-bis) trimethylsilyl) acetamide in 50 ml of anhydrous chloroform at -30 ° C or below · After being charged from the reaction mixture, it is worked for 30 minutes at -30 to -20 ° C and then for 1 hour at -10 to 0 Deň: 32 ° C. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in 60 ml of ethyl acetate and 60 ml of water. The organic layer was separated, washed with 30 ml of water, then 30 ml of saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate. the solvent was distilled off under reduced pressure. Diethyl ether is added to the residue. The precipitated crystals are filtered off to give 5.92 g (yield 94.7%) of diphenylmethyl 7- (4-bromo-2-oxobutyramido) -3- [2- (5-methyl-1,2) -ethyl ester. 3- _l- 4-tetrazolyl) methyl-3-cepea-4-carboxylic acid, m.p. 82-85 ° C (dec.) ·

IC spectrum (KBr) cm ¹ : 1780, 1722, 1690, up to 1650.

NMR (CDCl @) in ppm: 2.42 (3H, s, N), 3.19 (2H, br s, C ₂ -H), 3.62 (2H, s, ^3> - ₃ ° Η

N

-COCH ₂ CO-), 3.97 (2H, s, BrCH ₂ -), 4.86 (1H, d, J = 5 Hz, Cg-H),

2. Dissolve 6.52 g of diphenylmethyl 7- (4-bromo-3-oxobutyrsmido) -3-C2- (5-methyl-1,2,3,4-tetrazolyl) methyl] - in 30 ml of-, Ν-dimethylformamide. 3-cephem-4-carboxylic acid and 1.67 g of N-phenylthiourea. The solution is worked up at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was washed with diethyl ether, then mixed with 100 ml of ethyl acetate and 50 ml of water. The pH of the mixture was adjusted to 7.5 by addition of a saturated aqueous sodium bicarbonate solution. The organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure. 5.9 g of diphenylmethyl 7- [2- (2-phenylsaminothiazol-4-yl) acetamido] -3- (2- (5-methyl-1,2,3,4-tetrazolyl) methyl) -3H-3- (2- (5-methyl-1,2,3,4-tetrazolyl) ester) are obtained. cefem-4-carboxylic acids as a crude solid product ·

Dissolve in 59 ml of sol without further purification. 59 ml of trifluoroacetic acid are added dropwise to this solution. The reaction mixture was worked up at room temperature for 30 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure. Diethyl ether was added to the residue. Addition of diethyl ether precipitates crystals from the solution, which are sucked off, washed thoroughly with diethyl ether and dried. There was thus obtained the salt of trifluoroacetic acid with 7- (2- (2-phenyl-amino-thiazol-4-yl) -amethyl-3- [2- (5-methyl-1,2,3,4-tetrazolyl) methyl) -3-cep-4-carboxylic acid having a melting point of 165-169 ° C (dec.)

IC spectrum (KBr) cm -1: V _{c = 0} 1775, 1660, 1625

NMR (IMSO-d₆, ppm): 2.42 (3H, β, N-j-j-CH), 3.47 (2H, br s, C ₂ -H), 3.53

N (2H, s, N-n-CHg-), 5.07 OH, d, J = 5 Ha, Cg-H), 5.59 (2H,

S wide and,

), 5.80 (1H, dd, l = 5Hz, l = 6Hz, Ο-γ-Η), 6.53 (IH, a,

Example 4

1. ^The suspension of ^2.96 g of 7-amino-3- [2-) 55) ietyl-) ¹ _l 2,3-tetrazolyDmeVylJ ^JT-cephem-4) -carboxylic acid in 15 ml of N, N) is dimetilfrnnamidu 1.34 g of sucrose is added. The mixture was treated at room temperature for 1 hour. The reaction mixture was cooled with ice and 0.96 g of triethylamine and 2.42 g of pivlloyloxymethyl were added. The resulting mixture was worked up for 20 minutes. After completion of the reaction, the mixture was poured into brine (150 mL) of water and 150 mL of ethyl acetate. The pH was adjusted to 7.3 with sodium bicarbonate. The organic layer was separated, washed twice with 100 mL of water and dried over anhydrous magnesium sulfate. The solvent was then removed under reduced pressure. Iopropyl alcohol was added to the residue. The precipitated crystals are filtered. The product is recrystallized from isopropyl alcohol. There were obtained 2.73 ^{g (thee} obstructions above ^53, 1%) of ^l pivl LZX ^{y y} y ^{y e} me ^t et ERU T - ^ - b ^ roxybeezVideneaiino) - ^{'-.; 2} -methyl-1,2,3,4-ethyl-1-methyl-methyl-cellulose-1-carboxylic acid having a temperature of 136-137 ° C (m.p.);

IC spectrum ⁽ KBr) cm ^-1 : ^9q -o ¹ Π0, ^1,765 > ^1,750 ·

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) ppm: 1.13 (9H, s, -CjCl ^), 2.51 (3H, s, N --Cц C) 3.30.

C ₂ -H), 5.06 (1H, d, J = 5Hz, C ₆ -H), 5.32 (1H, d, J = 5Hz, 5.38, 5.82 (2H, ABq, l = 16 Hz, s (2H, s,

-OCH ₂ O-, 6.70-7.50 (4H _rm ,

C ₍ H),), 5.91 (2H, broad s, cn ₂ ), 8.49 dH, s, -CHAU)

2, 50 mm srnmsi 4N kyselioy cCh.orovo <hydrohalic acid and 25 ml (detyléteru rnmchá the fan 1 at ^10-15 ° C, ^5.14 jvaloVox eeylesteru ⁷ ^ - ^{(l 2} -h ^b lroxy- Benzyl ^{mu m} but eoll ) - ^{) з)} 2- ⁽⁵ ) mityl-1,2,5,5-tetrazolomethyl--C-6-carboxylic acid prepared in paragraph 1. The aqueous layer was then separated and washed with two 30 ml portions of diethyl ether. 100 ml of diethyl ether are then added to the aqueous layer and the pH is adjusted to 7.0 by adding 28% (% by weight) of aqueous ammonia on ice. The organic layer was separated and dried over anhydrous magnesium sulfate. A solution of - 1 g - dry hydrogen chloride in 20 ml of d-ethyl ether was then added with stirring and ice-cooling. A white color powder is formed. This powder was filtered off, washed with ether and recrystallized from chloroform. To afford 3.67 g (yield 82.2%) of the hydrochloride of ^l beer ^al LZX ^y Me y ^{l e t} et ERU T aráno- ³ - N - (5-οθ ^ 1. 1,2,3, ⁴ ' tetrazole Lemel ^{y y} 2 ^l 3-cephem-b-carboxylic acid which has a - táoí temperature of 149-151 ° C (dec.).

^iC spe ^k trum (KBr) cm ^-1 : ⁹ ° _C ^{1 77} 3, ¹ 741, ¹ 730.

Nuclear Magnetic Resonance Spectrum (LM? SOd ₆ ) ppm: 1.18 (9H, s, -C (CH ₃ ) ₃ ) _δ 2.44 (3H, s, N), 3.60 (2H, s,

N

C2-H). 5.23 (2H, s, C8-H, CH2 -H), 5.62 (2H, s, S),

Д_сн ₂ .

5.78 to 5.92 (2H, m, -COOCH ₂ O-).

3. Dissolve 1 g of dikcti in 20 nL of anhydrous leidenesside. To this solution was added dropwise a solution of 0.85 g of chlorine in 9 mL of anhydrous trichloromethane at -30 ° C. Thereafter, the slurry is worked at -30 to -20 ° C for 30 minutes. Reikční mixture P ^ i moats -40 ° C to a solution of 4.47 g of hydroxylamine cMoridu ^about Laαlcyloχym · tyltsttru AMNOTE 7-3- [J2 (5-meeyli 1,2,3,4-1 ^^ 1 The compound of formula (2) and 2.43 g of Ν, Ν-dimethyl-lithium in 50 ml of anhydrous methyl chloride are added and the temperature of the mixture is raised. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in 50 mL of ethyl acetate and 30 mL of water. The organic layer was separated, washed with water, saturated sodium hydroxide solution in water. The mixture is dried over magnesium sulphate and the solvent is removed under reduced pressure.

The oily product was dissolved in 15 mL of 0.76 g of thioionic acid and the mixture was worked up at room temperature for 2 hours. Upon completion of the retention, the reaction mixture was poured into a mixture of 150 mL of water and 150 mL of ethyl acetate. The pH of the solution was adjusted to 7.0 by adding sodium hydrogencarbonitonate. Organic layer (cddel1). Dried over anhydrous magnesium sulfate and concentrated under reduced pressure to a volume of 50 mL (organic layer). Then a solution of dry hydrogen chloride in the touchtex is added, with stirring and ice water. A white-colored powder is formed. This powder was collected, washed well with methylether. and recrystallized from ethyl states. 4.4 g (yield 75,0-%) ^of 1c iv ^{α y y} LCX ^{methylthiophenyl} yУtsttru ⁷ -p ² - ^(2-m and ^the .nt INZO ^c - ⁴ - ^yl acetate ^{and 3-áQ-} - ^ - ⁽⁵ -MS ^t t ^y ^ ^{Ll, 2,} _l ^3, 4- ^{t y} t x ^ nkcly1) mttyí] - 4-Зctefeπ 4kαabЪcxylové Kresliny, melting - point 146-148 ° C (logics., @ 1 C (KBr) cm @ -1: H = .delta.782, 1750, 1670

NMR (H 2 O-d 6) ppm: 1.15 (9H,

3.62 (2H, s, -C (CH3) _3), 2.46 (3H, s, N_CH) »- ^3» 51 (2H, s »C ^ -H)

N

CH), 5.15 (1H, d, J = 5 Hz, _C6- H), 5.26-5.79 s, N

(3 H, m, S)

WITH

Δ, δ 7 (H), 5.87 - (28, s, 2 H, 2 H, δ 6.62 1H, s, N), ω 6 -

S H

9.23 (1H, d, J = 8 Hz, -COH-).

Example 5.

1. Dissolve 2,2 g of diketene and this solution in 25 ml of anhydrous Chodride.

^EP Rik ^APS stream x ^ 1.85 ^g of chlorine in ² 0 mL tazvotého ^ trachlomdanu at - ³⁰ ° ^C. YSL Nu ^SD treated solution st 30 minutes * of -30 to -20 ° C. ИЧ -30 - ° C or lower temperature, we mix oozing řikn ^{p p} s to ^9.63 g roztoto Mf ^ y ^ T etylMtoro sáiNbJÍljt ^{3) Ch1CC1) 1, -) 4} -trjkco1 ^yl) m ¢ butyl] - C-csf01-44carbylic acids and 4 g bis (triistylsiyll - t)

100 ^{mL of} N ^- methyl A Chord. Dreaming st ^ rncovává nut ^{30 m p} s - ³⁰ - ° C to - ²⁰ ° ^C and one hour at 0-10 ° C. After completion of the reaction, the solvent is cedeetiluís under reduced printing.

The residue is dissolved in 100 L of ethyl acetate and 80 L of water. The organic layer was partitioned with 50-1 of water, 50 L of saturated aqueous sodium chloride solution and dried over magnesium sulphate. Then, under reduced pressure, the residue is distilled off.

To the residue and e - add άLiscorcppУether. The precipitated crystals are cdelltrjíí · ZT give 10.7 g (89 ^ full of ^heaviness, 2 ") dLfety.1etylesteru 7 - (^ - ^3- ch1cr- · Cx) ^b u ^jyy de rα ^{m) з3 c) (C 3} -C lo · ^a) 2 ^{2) μ) t} R ^{1 m »e} 1 ^y) SRN-4 - carboxylic Μΐ ^! ^ ^ having a temperature of ⁷³ s and ⁷⁵ ° C.

IC vrttnm (KBr) ^c rn'í ^Hc * ₀ I 780, I 7 R I ^{69 0-1}

Severography, n. P., MOST

Price- 2,40 Kčs

Nuclear Magnetic Resonance Spectrum (CDClyDiO) ppm: 3.19 (2 N, wide ₂ , _2- N), 3.50 ( ₂ N, ₂ , -СОСН ₂ СО-), 4.12 (2 N, (2 N,

Δ, С1СН ₂ -), 4.88 (1H, d, J = 5Hz, Cg-H), 4.82, 5.35 ABq, J = 15Hz, S), 5.72 (1H, d, J = 5 Hz, CyH)

J - CH ₂ (IH, 8,> CH -), 7.26 (10H, 8, 2x> - »)

N

6.90

8, К

). 7.71 (1Н,

2. Dissolve 6 g of diphenylmethyl 7- (4-chloro-3-ozobyramido) -3- [β-chloro-1,2,4-triazolyl) methyl] -3-cephem-4-carboxylic acid diphenylmethyl ester in 40 ml of acetic acid. To this solution is added dropwise a solution of 1 g of sodium nitrite in 6 ml of water over 1 hour under ice-cooling. The stoes was then treated at room temperature for 2 hours. After completion of the reaction, the reaction mixture is poured into 600 ml of water. The precipitated crystals are filtered off with suction, washed thoroughly with water and dried. 5.24 g (yield 83.3%) of diphenylmethyl 7- (4-chloro-2-hydroxyimino-3-oxobutyramido) -3-Q3-chloro-1,2-ester are obtained. 4-triazolyliminyl-3-cephem-4-carboxylic acid having a melting point of 93-95 ° C (decomposition);

IC spectrum (KBr) cm ^-1 , _{= 0} 1780, 1720, 1700 to 1650.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ -D ₂ O) ppm: 3.20 (· 2Η, broad a, C ₂ -H), 4.59 (2H, s, C ₁ CH ₂ -), 4.93 (1H, d, J = 5 Hz, Cg-H), 4.79, 5.16 (2H, ABq, Λ16 H2, S),

Δ-α ₂ 5.78 (1H, d, J = 5 Hz, C _r H), 6.90 (1H, α, β ZCH-), 7.24 (10H, α, 2x __ / Z \), 7.71 (1 H, s, N).

\ 2 / Z- *

N

3. 6.29 g of diphenylmethyl 7- (4-chloro-2-hydroxyimino-3-oxobutyramido) -3- [β-chloro-1,2,4-triazolyl) methyl] are dissolved in 35 ml of Ν, Ν-dimethylformamide. - 3-cep-4-carboxylic acid. The solution was ice-cooled. 1.5 g of sodium carbonate and 2.1 g of dimethyl sulfate were added thereto. The mixture is then treated at 5-10 ° C for 1 hour. After completion of the reaction, the reaction mixture was poured into 600 ml of water. The separated crystals were filtered and purified by chromatography on a W-C silica gel C-200 column, eluting with 9: 1 benzene-ethyl acetate. 2.7 g (42% yield) of diphenylmethyl 7- (4-chloro-2- (syn) -methoxyimino-3-oxobutyramido) -3- (3-chloro-1,2,4-triazolyl) methyl ester are obtained. Of? -3-cephem-4-carboxylic acid having a melting point of 102-104 ° C (dec.).

IC spectrum (KBr) cm ^-1 : δ _{c = 0} 1,782, 1,720, 1,690, 1,670.

NMR Spectrum (CDCl 3 D 6 O) ppm:

3.20 (2H, br s, C ₂ -H), 4.05 (3H, s, -O CH₃), 4.50 (2H, s, ClCHy), 4.95 (IH, d, J = 5 Hz (Cg-H), 4.82, 5.36 (2H, ABq,

J = 15 Hz

d, J = 5 Hz

C _r H), 6.95 (1H, [delta],

N = CH-), 7.35 (δ N, 8, 2x)

), 7.72 (1H, s,

4. Dissolve 6.43 g of diphenylmethyl 7- (4-chloro-2- (syn) -methoxyimino-3-oxobenzoyl) -3-oxo-4- (4-chloro-2- (syn) -methoxy) -3- (4-chloro-2-carboxylic acid) ester in 48 ml. O (3-COOH-1,2,4-triazolyl) methyl-3-cellulose-4-carboxylic acid and -1 g of thiourea. The resulting solution was treated at room temperature for 2 hours. After completion of the reaction, the reaction mixture was poured into a mixture of 600 m and 600 m of ethyl acetate. The pH was adjusted to 6.7 by the addition of sodium bicarbonate. The organic layer was separated, the aqueous layer was extracted with two 300-portions of ethyl acetate. Wash the organic layers two times with 800 m of water each time and dry with anhydrous magnesium sulfate. The solution was distilled off under reduced pressure. Methyl ether was added to the residue. The precipitated crystals are filtered off. Detects 5.8 ⁷ g ^(TEI weighing ek ^{88%) -} ^ n phenyl ester of 7- (2- (2 ^^ ^{thiaz ol-4-yl} *) - ² - ^(Tyn) -metos ^χy - ⁱ mlnsacetш ^eie0 ->. ⁰ 3 · cHos- ^112, 4-tri azooyl) Mee ^^^ - cephem * -4kkarboxylové - acids having a melting counting: s 155 to 157 ° C (rozzii).

ICs (ψ.ΙϋΓΐΜ (KBr) ce ': ⁵ _Cb0 1,781, 1,725 ^, _1-672 ).

NMR spectrum (CDCl Igo, ppm): 3.20 (2H, broad s, C ₂ -H), 3.86 (3H, s, -OCCj), J = 5Hz, C ₆ -H), 4.82 5.41 (2H, ABq, J = 16 Hz, S)

4.99 (1 H, d.

5.96 (1H, d, J = 5 Hz, O 2 -), 6.62- (1H, s, (1H, s, CH-), 7.28 (10H, s, 2x

N

), 7.71 (1H, s,

5 «The SMMS 35 mi ^ LNY irf1hoosocSové acid and 10 mi tnitslh rozpussí with 6.65 g diphenhydramine ^y1 m ⁷ - ^[2 - (2-imino itzsl- ^{with 4} - ^yl) - ^{- (.} (8yn) -No ^with oxyiminstcettвido] - ^- з0 ( ^3cl .olr.

-1,2,4 ttгiιo · o ^exch) etУ ^{yl 3} - ^c-н efef ^{kt Ib} by: ^y ιlové tysel! ^. The resulting ^{- tozí-1} is treated for 1 hour at mÍ8ttlosti. After completion of the reaction, the slurry was separated under reduced pressure. Diethyl ether was added to the residue. The precipitated crystals are filtered off, washed thoroughly with diethyl ether and dried. There were obtained 5.71 g (yield 93.2%) with ^ oi ^ using TFA trifluoroacetic acid 7-C ^{the second (2 e} -t nntiaaol ^44y-yl-2- (S ^y n) -methoxy ^yl minsacnttmi of ^d ] - ³ - ^(3-Cl .os ^r · 1.2 ⁴ -tltaslУ ^y e) ntУ ^{cefEF-yl-4-ltarSorybovou} souring having a melting point of 162 (comp.

IC / KP / ^{c c} _{0 0} 1 778, 1 7 ^ ^- 1 670 ^, 1 630.

NMR (d 6 -O 2 SO) ppm: 3.48 (2H, broad s, C 1 H), 3.93 (3H, s, -OCH 3), 4.98-5.42 (3H, m,

C ₆ -H),

5.78 (1H, dd, J = 5 Hz, J = 8 Hz, C, H), 6.91 (1H,

Np-), 8.02 (1H, s ^Z 'H', N), 9.74 (1H, d, J = 8 Hz, -COUH- / N).

6. i) »1 kyeeli trfiu.wroatové ee ^ 7 - ^ - (2-minstit« sl- -y1--2s ⁴⁾ βyn) ^MEI about чrim ⁱ n ^s · ^tc etι ^and LMD ^d d] - ^{з 0} - 3Ch.olr · ^l - ^{4-trazsoУye)} ntУyl ³⁾ efef ^c) l- ^{'s 1} Kae oзyi ^with oτsh ^for ye ^<e lin react ^oh "and 1N aqueous sodium hydroxide or eodného saturated aqueous Iyer sodium bicarbonate, then purified by column chromatography on Anmerlite XAD-2 (water elution) to give the following compound:

s ^o d mi 7-02- (2 · ^t e ^ln Si ^t zS-4yy) - ² - (s; ^y ϋ-m · ts: ^χy i ^m .noacett ^m dq] -3- ^{C (} 3 · ^Cl1 ^ Even Ί ^{r> - 4))} t ^{l AA} oУ ^yl) meУ ^yl] -Cecefe- ^- l ^{t AE) y} lsvé tyssliny. 168 ° C (dec.).

br s, C ₂ -H), 3.97

iC spectrum / Kg / cm cm 9θ ₌ θ 1 760, 1 670, 1 605.

NMR spectrum (D ₂ 0, ppm):

3.30 (2H, (3H, m, S (1H, s, N)

WITH

5.77), 7.96 (1H, (3H, s, (1H, d,

-0CH ₃ ) _? 4.93 to 5.60

J 5 Ha, C _? (H), 6.91 ii) 6.13 g of the trifluoroacetic acid salt of 7- [2- (2-aminothiazol-4-yl) -2- (syn) methoxyiminoacetamido] -3- [ 3-chloro-1,2,4 * (triazolyl) methyl] -3-cephem-4-carboxylic acid. Sodium bicarbonate was added to the suspension under ice-cooling to adjust the pH of the suspension to 8.0 and the suspension went into solution. The pH is then adjusted to 2.5 with concentrated hydrochloric acid at the same temperature and crystals are formed. The crystals are filtered off, washed thoroughly with water, then with acetone and dried. 4.71 g (94.5% yield) of 7 - [? - (2-amino-thiazol-4-yl) -2- (syn) -methoxyiminoacetam-3- (3-chloro-1,2) are obtained. (4-triazolyl) methyl-3-cephem-4-carboxylic acid having a melting point greater than 200 ° C.

IR (KBr) cm ^- ': V _{c = 0} 1765, 1660 1 625th

NMR (d₆-MSO)? Ppm: 3.44 (2H, br s, C ₂ -H), 3.85 (3H, s, _OCH3), 5.20 (2H, broad s, S), 5, 20 (IH, d, J = 6 Hz, -C-H), 5.78 (1H, dd, J = 6 Hz, J = 8 Hz, _C? -H), 6.71 (IH,> CH ₂ ), 8.04 (1H, s, N), 9.60 (1H, d, J = 8Hz, -CONH-).

S Η N), 7.16 (2H, broad s, -NH ₂₎

S, N

Example 6

1. Dissolve 2,24 g of 4-bromo-3-oxo-2-methoxyiminobutyric acid, 2,0 g of 1-oxybenztriazole and 4,62 g of 7-amino-3-p-chlorophenyl methyl ester in 50 ml of anhydrous tetrahydrofuran. -1,2,4-triazolyl) methyl] -3-cephem-4-carboxylic acid. The solution is cooled to 5 and 2.5 g of Ν, Ν'-dicyclohexylcarbodiimide are then added to the solution. The resulting mixture was worked up at 5 ° C for 30 minutes and at room temperature for 5 hours. After completion of the reaction, the insoluble material was filtered off. The solvent was distilled off from the filtrate under reduced pressure. Ethyl acetate (40 ml) was added to the residue. A small amount of undissolved material was removed by filtration. The ethyl acetate solution was then washed with 5% (w / w) aqueous sodium bicarbonate solution, water, and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue obtained is chromatographed on a column of Wako silica gel C-200, eluting with 9: 1 benzene-ethyl acetate. 3.65 g (54.6%) of diphenylmethyl 7- (4- rom ^{b-3-methoxyimino-3-oxo-butyremido)} -3- (3-chloro-1,2, 4-triazolyl) methyl 3-Cephem-4-carboxylic acid having a melting point of 91-94 ° C (dec.).

XC spectrum (KBr) cm -1 ¹ : 1780, 1720, 1680.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO) ppm: 3.55 (2H, broad s, C ₂ -H), 3.84 (3H, s, -OCH-j), 4.16 (2H, s, BrCH ₂ - ), 4.99 to 5.53 (3H, m, S \, C ₆ -H), 5.87 (1H, CH ₂ dd, J = 5 Hz, J = 8 Hz, C ₇ -H), 7 Δ (1H, s, δ TCH-), 7.40 (10H, broad α, 2x / ~D), 8.04 (1H, s, N), 10.01 (1H, d,

Л2 / Z ~ ^H

N

J = 8Hz, -CONH-).

Following the same procedure, the following compounds are obtained;

7- (4-bromo-2-methoxyimino-3-oxobutyramido) -3- (2- (5-methyl-1,2,3,4-tetrazolyl) methyl) diphenylmethyl ester xylic acid ·

M.p .: 80-82 ° C (dec.) Spectrum (KBr) cm -1 ¹ : 9 _{C = 0} 1780, 1720, 1680.

NMR spectrum (GDCl3) ppm:

2.41 (3H, s, N) ), 3.16 (2H, broad, and _C? -H), 4.00 (3H, s, > - -ch ₃ ^г. N -OCH ₃ ), 4.25 (2H, , α, BrCH ₂ -), 4.88 (1 N, d, J = 5 Hz, C 8 -H), 5.38 (2H, broad s, S ), 5.78 (1H, dd, J = 5Hz, J = 8Hz, сн ₂ - Γγ-δ, 6.81 (1H, s, J = -CH-), 7.18 (10H, broad a, 2x -; 9.10 (1H, d, J * 8) Hz, -CONH-).

)

2. When treated with 7- [4-bromo-2- (ayn) -methoxyimino-3-oxobutyriddd}} - 2- (5-methyl-1,2,3,4-tetrazolyl) methyl] -3-phenyl-methyl ester -cephem-4-carboxylic acid obtained as described in Example 5- (4) and (5) above to give the following compound:

7- [2- (2-Amino-thiazol-4-yl) -2- (syn) -methoxyiminoacetamido] -3- [2- (5-ethyl-1,2,3,4-tetrazolyl) methyl] -3- cephem-4-carboxylic acid. Melting point: 102 to 1 ° C (dec.).

IR (KBr) cm ^-1 :

9c = o ’

778, 1720, 1660.

NMR (d ₆ -O ₄ SO) ppm: 2.43

5.29 (3H, s, (1 H, d,

-CH ₃ ), 3.45 (2H, broad s, Cg-H), 3.84 (3H, s, -OCH 2, J = 5 Hz, C ₆ -H), 5.52 (2H, broad ( 1H, dd,

J = 5

CH-),

7.32 ООН, Wide s, 2χ), 5.93

Hz, J = 8 Hz, C ₇ -H), 6.78 (1H,

7- [2- (2-Aminothiazol-4-yl) -2- (syn) -methoxyiminoacetemido] -3-trifluoroacetic acid salt - [2- (5-methyl-1,2,3,4-tetrazolyl) (methyl) -3-cephem-4-carboxylic acid. Melting point: 123-125 ° C (dec.).

(KBr) cm ^-1 : 9 _{С = О} 1,790.1

720-1,635.

NMR (CDCl 3 OD) ppm: 2.45 (3H,

3>

5.10 (1 H, d,

N - j chy, 3.44 (2H, br and C ₂ -H), 3.99 (3H, s, -O-J) N

J = 5 Hz, Cg-H), 5.50, 5.81 (2H, ABq, J = 14 Hz, S), _- δ 5.80 (1H, d,

J = 5 Hz, C ₇ -H), 6.93 (1H, s, N-π-sA)

).

3. Processes- !! trifluorodové acid salt 7- [2- (2-.8ΜηοΗΒΖθ1 ~ 4 · ^ 1.) - 2- (83η) metoxyiminoacetarnidó] - ³ - ^^ - methyl · - ¹ ггагоТуЗЭтеу ^^ / ^ гЗзЗисе- ет- By acid treatment as in Example 5- (6), (i) and (ii), the compounds listed in Table 16 are obtained.

T ab č lka 16

(syn isomer) and compound no.

On

Melting point (° C) IC (KBr) µm ¹ : ^J * C = Q

183-187 (dec) 1,776,

665,

61Q> 2QQ 1,765

66Q,

625

Example 7

The various starting compounds were exchanged in the manner described in Example 5 to give the deprotecting compounds shown in Table 17.

Table 17 trifluoroacetic acid

(son isomer)

Compound Temperature IR (KBr) R ² melting point (° C) cm ¹ : \) ^y OO

NMR (d6-EMSO) ppm:

-q CH ₂ CH ₃ 153 to 159 (decomposition) 1 775, 1 670, 1 630 1.27 (3H, t, J = 6Hz, -CH ₂ CH _3), 2.82 (2H, q, J «7 Hz, -CH ₂ CH _3), 3.43 (2H, s, C ₂ -H), 3.85 (3H, a, -OCH ₃ ), 5.13 (1H, d, J = 5 Hz, (C 8 -H)), 5.5-5.9 (3H, m, S C ₇ -H), 6.74 (1H, a, N = JJ-), 9.64 (1H, d, J = 8 Hz, -CONH) -q NHCOCH3 156 až 159 (dec) 1 765, 1 700, 1 665, 1 630 2.10 (3H, α, -COCH ₃ ), 3.44 (2H, α, C ₂ -H), 3.82 (3H, α, -OCH ₃ ), 5.14 (1H, d, J = 6 Hz, Cg-H), 5.55 to 5.85 (3H, m, S-D ₂ - C ₇ -H), 6.72 (1H, α, β-P)>% 05 (1H , d, J = 8 Hz, -CONH-), 11.02 (1H, α, -CONH-)

135 1,770, (decomposition) 1,705,

665,

630 solvent: CDCl 3 OD

3.50 (2H, s, C ₂ -H), 3.98 (3H, s,

-och ₃ ), C ₆ -H),

5.80 (1 H, d, J = 5 Hz,

7.97 (1H

H

<.и, л-р "

Continuation of Table 17

Compound Temperature Ιδ (KBr) NMR (dg-WSO) ppm B ² thaw (° C) ^{cm: 9c} = ⁰

142 1 775, (dec.) 1 660,

630

3.51 (2H, SirokO, (-)), 3.91 (3H, o, C 1 H), 3.91 (3H, 10O, -), 5.23 (1H, d, J) = 5 H 5, C ₆ -H), 5.77 (2H, SiO 2 V,

J = 5 Hs

J = 7Hz, C _? -H), 6.85 (1H,

7.93 (3H, SiOKV a,

N), 9.76 (1H, d,) - »

-NH ₃ h 8.95 (1 H,

J = 7 Hs, -CONH-10,

N = N 110 ' 1 775, -and (c ^ rosk.) 1 660, 1 630

3.52 (2H, SirokV o, Cg-H), 3.90 (3H, O, C-H 3.90 (3H, ^a, -OCH ^, ^5, 17 ^{(1H, d,} J = 5 Hs, C ₆ -H), 5.43 (2H, SirokV o,

S), 5.81 (1H, dd, J = 5 Hs, J = 8 Hs,

( _RH ), 6.29 s,

N

WITH

(3H,

9.31

SirokV δ, -NH 3), 6.81 ‘(1H, (1H, δ, N), 9.67 (Ш, Z-1)

N d, J = 8 Hs, -CONH-)

N = N -N 121 to 1 775 ⁴ n = 4 125 1 670 and (crotch) 1 630 nh ₂

3.53 (2H, SirokV a, (-H), 3.88 (3H, a,

-OCH ³ ), up to 5.88

5.18 (1H, d, J = 5Hs, (-H)) (3H, m,

Cy-H1, 5.48

6.83 сд ₂ (1H, s,

-CONIH.)

9.66 (1 H, d, J = 8 Hs,

181 (rozl.)

775

710 1,665

630

2.51 (3H, s, - :( 113), 3.50 (2H, SirokV s, C ₂ -H), 3.93 <3H, a, OCH3), 4.96 to 5.34 (3H , m, S., _C6- H), 5.80 (1H, dd,

₂ -D ₂ J = 5 Hs, J = 8 Hs, СрН), 6.85 (1H, o, N)

S _

8.40 (1H, d, N), 9.69 (1H, d, J = 8 Hs, > - *)

N

-C0NH-), 3.42 (2Н, Åroky а,

-OCH, 4.75 to 5.55

Cg-H), 5.68 (1H, dd,

Table continuation 17 Compound R ² Melting point (° C) IG (KBr) ^cm -1 ¹ 0 = 0 NMR (dg-MSO) ppm: ΛΙ — N NHCOCH3 168 až 180 (dec) 1 775, 1 710, 1 680 1 630 2.02 (3H, s, COCH ₂ C H), 3.86 <3H, s, (3H, m, s Дсн ₂ -

J = 5 Hz, J = 8 Hz, C <-H), 6.76 (1H, β, N7)

>

S fl.

8.24 (1H, β, M), 9.60 (1H, d, J = 8Hz,

N

-CONH-)

141 to

144 (dec)

778. 1,710, 1,670,

630 solvent:

CD ₃ OD

2.39 (3H _t s, -CH _3), C ₂ -H), 4.03 (3H, 8 (3H, m,

3.56 (2H, s Simko, -OCH _3), 4.92 to 5.37

C ₆ -H), 5.86 (1H, d,

J »5Hz, C _? -H), 7.00 (1H,

8.63 (1 H, 8, N)

N

π — π i -NHCO-φ ^<Г02к1 · ' 1 778, 1 7Ю 1 630

8.25 to 8.67 (1H, m, -NHCO-), 9.14 (1H, d, J = 8Hz, -COH-)

Continuation of Table 17

Compound Melting point Ic (KBr) -1. NMR (d 6 -IMSO) δ r R ² (° C) ^ca · C = o

-NHCOCH 166 1 775, 1.65 (3H, s, -COCH ₃ ), 3.42 (2H, Wide e, 3 (dec.) 1 710 C ₂ -H), 3.86 (3H, s, -OCH ₃ ), 3.60-4.21 (2H, m, S), 5.08 (1H, d, J = 5 Hz, 1 620 / -CHa- C ₆ -H), 5.67 (1H, dd, J = 5 Hz, J = 8 Hz, _C? -H)

6/79 (1H, s, N-n--), 7.84-8.26 (1H, m, -NHCO-), 9.64 (1H, <3, J = 8 Hz, -CONH-)

-NHCO

137 to 1760,

141 1660, 1630

3.51 (2H, br s, C ₂ -H), 3.85 (3H, s, -OCH _3), 4.08 to 4.50 (2H, m, S),

5.09 (1H, d, J = 5Hz, _C6- H), 5.71 (1H, dd,

J = 5 Hz, J = 8 Hz, Cy-H), 6.78 (1H, s, N &apos;) _y with H

7.20 to 7.98 (5H, m, θ, 39 ^ai)

9.34 (4H, m, -NH ₃ , -NHCO-), 9.59 (1H, d, J = 8 Hz, -COH-)

155 to 1 770,

159 1 710 (dec)

620

3.09, 3.50 (2H, to 4.16 (2H, m,

AB q, J = 18 Hz, _C2 --H), 3.50), 3.82 (3H, d,

-OCH ₃ ), 5.10 (1H, (1H, dd, J = 5Hz, * 7.19)

S H (1 H, d,

9.57

J = 8d, J = 5Hz, _C6- H), 5.61 J = 8Hz, Cy-H), (5H,

6.73 (1 H,),

Hz,

-CONH-)

, 165 —Ζθ \ -ΟΗ (dec.) 1 770, 1 710 1 630

3.05 to 4.14 (4H, m,

C ₍ H), S

3.82

C ₆ -H)

-OCH ₃ ),

CB ₂ 5.10 (1H, d, J = 5Hz, > 0-)

6.75 (1 H, s, N)

(3H, 8,. 5.65 (1H, J = 5Hz, J = 8Hz, Cy-H)

6.62, 7.01 (4H, ABq, J = 8Hz)

J = 8Hz,

S H

-CONH-)

Table 17 (continued)

trifluoroacetic acid

H ₂ N

(son isomer)

COOH

IC (KBr R ² iC (KBr) ^{cm 1} H c = o ^cm -1 4c = O

i 770, 1 665, ΛΙ = Ν Ή 1 770, 1 665, 1 630 sch ₃ 1 630

CH ₂ COOCH ₂ CH ₃

770,

730,

665,

630

775,

660 and 630

770,

665,

630

-at. 1 770, 1 730 C00CH ₂ CH ₃ 1 670, 1 630

775,

665,

630

775,

670,

630

/ N = N "IN 1 775, / 1 740 COOCH ₂ CH ₃ 1 670 1 630

COOH

770, 1 710 г.

620

COOCHjCH,

775,

725,

660,

630

COOCHj

770,

710 l

620

Severography, n. P., MOST

Price 2,40 Kčs

R ² 10 (KBr) ^{cm 1: 9} c = o R ² iC (KBr) ^{cm -1 c c} = 0 - N N ^^ COOCH, 1 775, 1 730, Xi 1 770, 1 710 COOCH3 ^J 1 6651 COOH 1 630 l 1 620

Example 8

1. Dissolve 6.25 g of 7- (4-bromo-3-oxobutyramido) -1,3) 2- (5-methyl-1,2,3,4-tetrazolyl) methyl] -3-methyl ester in 40 mL of acetic acid. -cephem-4-carboxylic acid, prepared in Example 3- (1). To this solution was added dropwise a solution of 1 g of nitrous sodium in 6 ml of water while cooling with ice over 1 hour. The reaction mixture was then worked up at room temperature for 2 hours. After completion of the reaction, the reaction mixture was poured into 600 µL of water. The precipitated crystals are filtered off, washed with water and dried. 5.43 g (83.0% yield) of dipeolmethyletter 7) (4-bromo--2 (hydroJmino-min)) 3 (:)) are obtained. 3.4) УeУrazol ^yl) methyl ^{azetidinyl] з)} ceefim-4-carboxylic ^b ox ^l ^ ew ^ βθ -Ο ^ ^kt projecting into the cavity of my ^t e ^p lo ^t ^ u ^th eye ⁹⁷ and ^{of the 100} ° C.

IR (CDCl3) ^cm -1:? ₌ 1,780, 1,720, 1,695-1,650.

NMR Spectrum (CDCl3) ppm: 2.49 (3H, s, N), 3.23 (2H, s, C2-H}, 4.42 (2H, s, BrCH ₂ -) / ^- N ¾ ^Z 4.92 (1H, d C = 5 Hz, C ₆ -H), 5.32, 5.70 (2H, ABq C = 16 Hz, S-1), 5.78 (1H d, C = 5 Hz, C 4 H) Δ 6.89 ( ₁₃ ° C ^{-, Ca} 2 '__ 7.23 (10 °, s, 2x - / q'), 9.10 (1H, d, C = 8 Hz, -CONH -),

2. 35 Il Ν, Ν-dimeУlL.aceУmidu dissolved 6.54 g difeoylmetyletteru 7- ^(4-b-2-ROM tyďroxyimiio- oxohbutiaaito ^) ^o)) - ^{[(2- ((5} -Met ^yl - ¹ 2, ^{3, 4} (te ^t tetrazol ^l) methyl] - ^{3-cephem-4 b} ar ^{to 1} OX the nominal selioy ^y and 1 g of thiourea. Rnzyok is treated for 2 hours at ROOM ^ i. After completion of the reaction, The reaction mixture is poured into a mixture of 500 ml of water and 500 ml of ethyl acetate, the pH of the solution is adjusted to 7.0 with sodium carbonate, the organic layer is separated, and the aqueous layer is reextracted twice with 200 ml of ethyl acetate. anhydrous magnesium sulfate. RoppuutědLo the () ddstУluje under reduced pressure. the residue was purified by column chromeaouг0aií WSío silikEigeLu C-200, eluted. with methanol SMMS chlorofomiu Merum ^ v ^ ^1. ZísW ^{3.2 g (HE LZ} e ^{k 50.7%)} dL ^{[EO y} lmetyletteru 7- ^{[2- (2} -afl tooiia ^ ^ - ^ y ¹⁾ *) ² - (SLN) - ^h ydroo ^l im ^and about nuacetm ^id] - ³ - [2- ^(5-methyl-1 - ^1,2, 3-tetr azotyl) methyl] -3-c ^[e em-4 ^b ar ^to oo1luv ^e i ^ S ^^^ ^{Li-1, k} has the ^Ter ^ fence mp ¹⁶ 4 ° C (rozlk). ^IC ektrum ^(KBr) cm ^{-1: q} ₌ ¹ Q ⁷⁸ 0 ^{1 7} 31 ¹ б ⁷ !

NMR Spec (d6-MISO) ppm: 2.40 (3H, s, N d,

C = 5 Hz, >), 3.41 (2H, broad -¾)

Cg-H), 5.20-6.10 (3H, m, S s, C2-H), 5.14 (1H,

6.63 (1 H, s,

2x

N - (-) -, 6.90 (1H, s,.

S H), 9.46 (1H, d, J = 8Hz, -CONH-)

CH-),

X., C ₇ -H),

7.28 (ЮН, s,

3) 6.31 g of diphenylmethyl 7- (2- (2-aminothiazol-4-yl) -2- (syn) -hydroxyiminoacetamido) -3-Q2- (5-dimethylamino-thiazol-4-yl) ester are dissolved in a mixture of 32 ml of trifluoroacetic acid and 10 ml of anisole. -methyl-1,2,3,4-tetrazolyl) methyl] -3-cephem-4-carboxylic acid · This solution is treated at room temperature for 1.5 hours · After completion of the reaction, the solvent is distilled off under reduced pressure. diethyl ether is added. The precipitated crystals are filtered off, washed thoroughly with diethyl ether and dried. There are obtained 5.33 g (yield 92.1%) of the trifluoroacetic acid salt of 7- [2- (2-8ШP-thiazol-4-yl) -2- (syn) -hydroxyiniinoacetamido ] -3- [2- (5-methyl-1,2,3,4-tetrazolyl) methyl] -3-cephem-4-carboxylic acid, m.p. 175 ° C (dec.) ·

IR (KBr) cm ^"1: Ό _CEQ 1770, 1680, 1 630th

Nuclear Magnetic Resonance Spectrum (dg-IMSO) ppm: 2.43 (3H,

(2H, br s, C ₂ -H), 5.13 (1H, d,

J »5 Hz, Cg-H), 5.26-5.95 (3H, m,

CHgC _r H), 6.67 (1H,

9.48 (1H, d, J = 8 Hz, -CONH-).

If the procedure is as described above, the following compounds are prepared:

Trifluoroacetic acid salt with 7-? 2- (aminothiazol-4-yl) -2- (3-yne) hydroxyiminoacetemido] -3-benzyl-3-cephem-4-carboxylic acid, m.p. 139 ° C (dec.)

IR (KBr) cm _@ ^-1 : _{Ca @ 1760} , 1710, 1660.

Nuclear Magnetic Resonance Spectrum (dg-IMSO) ppm: 3.40

5.18 (1H, (4H, and trifluoroacetic acid salt of 7- {2- (2-amino-azol-4-yl) -2- (syn) -hydroxylamino-acetamido) -3-acetothiomethyl-3-cephem-4-carboxylic acid ,

IR (KBr) cm ^"1: oo ^{'1 1} ^ ¹ ^ ¹ ^ 20th

8 »S

С1H ,. d, J 4 Hz, C ₆ -H), 5,8, N -), 7,25 (5H, s,

^s ".

m, -CONH-, -NH)

4. The trifluoroacetic acid salt of 7- [2- (2-aminothiazol-4-yl) -2- (eyn) -hydroxyiniinoacetamide (Bido) -3-aza-thiimidomethyl-3-cephem-4-carboxylic acid, which was produced in paragraph 3 by treatment with the same by the method of Example 5- (6) gave the following compound: 7- [2- (2-aminothiazol-4-yl) -2- (syn) -hydroxyiminoacetamide] -3-oefene-4-carboxylic acid sodium salt. Melting point above 200 ° C.

IR (KBr) cm ^-1 : δ, δ 1750, 1680, 1665, 1660.

Nuclear Magnetic Resonance Spectrum (DgO) ppm: 1.98 (3H,

4.20 (2H, s, -COCH-), 3, ABq, J = 14 Hz,

29 3.62 (2H, AB q, J = 18 Hz, _C2 --H), 3.86,), 5.11 (1H, d, J = 5Hz, C ₆ -H)

5.76 (1H, d, J = 5Hz, C-H), 6.84 (1H, s, N-n ----).

з ^Л н

Example lad .o

By treating the various starting compounds in the same manner as in Example 5, the corresponding compounds shown in Tables 18, 19 and 20 are obtained.

Table 18

Compound +

CH3

OCH3

N-т — CCONH · * ^{U i}

COOCH2OCOC (CH3) ₃ (syn isomer)

Melting point (° C) iC (KBr)

-t, ^cm · c = o

144 až 1 790, 148 1 750, (rozkl) 1 675

NMR (dg-IMSO) ppm:

1.17 (9H, s, -CfCl ^), 2.46 (3H, s,

---- --- P N CH3), 355 (2H, šiooký s, C ₂ -H)

N

3.96 (3H, s, -OCH 3), 5.19 (1H, C ₆ -H), 5.39-6.00 (5H, m, S d, J = 5 Hz,

C _r H, -OCH ₂ (O),

6.96 (1 H,

9.84

S f (1 H, d, J = 8 Hz, -CONH-)

119 to 1780,

123 1740, (rezHi) 1670

1.15 (9H, s, - ^ (^ 3) 3), 3.18, 3.60 (2H, AB q, J = 18 Hz, _C2 --H), 3.58 to 4.22 (2H, m,

3.93 (3H, s, -OCH 3), 5.17 (1H, d, J = 5 Hz, C ₆ -H), 5.48-6.02 (3H, m, -OCH ₂ O, C? H?); -H, 6.92 (1H, s, N-d 6),), 9.85 (1H,

7.21 (5H, broad s, d, J = 8 Hz, -CONH-)

IC (KBr) ^m- · c = o

Continuation of Table 18

AND

Compound

Melting point (° C)

NMJT (dg-MISO). ppm:

+ 144 až 1 780 N — N -ΦΙ 146 (rozl.) 1 745 1 660 CH,

Δ, 16 (9Η, 3, -CCC ^), 2.39 (3H, s,

3.56 (2I,

Wide with,

C ₂ -H)

-OCH 3), 4.85 to 5.46 (3I, m,

5.52 to 6.01 (3 H, m, - CH • _i) oc7-H), 6.86 (1H, s, Иц-), 7.80 (1H, s,

S H +, 9.74 (1H, d, J = 8Hz, -CONH)

N.

+ 135 až 1 785 N — N 137 (rozia ·) 1 745 1 672 SCH3

1.17 (9I, s, --C ^ 3), 2.49 (3I, s, - ^ 3),

3.52. (2H, broad s, C ₂ -I) .3,93 (3H, m,

-00H ₃ ), 4.87-5.38 (3H, S

-NHCOCH

133 až

135 (rozki ·)

780, 740, 680

620

130 to 1780,

132 1745, 1665

Note: ity itydíOcM.orid, -OCHO, C7-H),

N -), 8.50 (1I, 8, H >,

N

C ₆ -H, 5.50-6.05 (3I, m _: 6.92)

9.80 (1H, (1H, ^s >)

d,

with H J = 8. Hs, -C0NH-)

1.16 (9H, s, -C (J 3) 3), 1.81 (3H, s, -COCH 3),

3.46 (2H, broad and C ₂ -I), 3.61 to 4.18 (2H, m, S (1H,

d, J = 5 Hz

3.80 (3H, s, -OCl 3), 5.05 m, C ^-COOCH »2 · C, - -.

C ₆ -D, 5.48 to 6.00 (3I, H, 6.66 (1I, s, N-π --- γ)

7.12 (2I, broad s, -NH 2), 7.78-8.09 (1I, m, -NHCCO), 9.45 (1H, d, J = 8 Hs, -CONH.)

1.21 (9I, S, C (C _{3) 3),} 3.50 (2H, s Biroký C ₂ -I) ,. 3.90 (.s ,. 3I, -OCH _3), 4.88 to 5.30

A ⁰ ”. -COOCHi-, 7.83 (1I (3H, m, (3I, m, X '· s --- C ₆ -I), 5.64 to 6.04

A0H2C ₇ -H), 6.72 (1H,. 8, p.?

> D, 8.37 (1 H, 8,

N), 9.46 (1H, d, J = 8 is, -CONH-)

Г N

Table 19

(son isomer)

R ¹ Temperature lC (KBr) NMR (d ₆ -IMSO) ppm: thaw -1. (° C) cm:. \ C = 0

- ^с з з

154 1 785 (dec.) 1 730 1 655

2.48 (3H, s, N); 3.53 (2H, broad s,

CH ₃

N c ₂ -H), 3, ei (3H, s, -sulf ₃ ), з, 9a (зн, β, -OCH ₃ ), 5.23 (1N, d, J = 5 Hz, C ₆ -H) ), 5.61 (2H, broad s, S), 5.83 (1H, dd, J = 5Hz, cg ₂ J = 8Hz, γγ-Η), 6.95 (1H, s, 9.88) (1H, d, J = 8Hz, -CONH-)

-CH ₀ OCCH 121 to 1 7801 ² «3 124 1 745, 0 (dec.) 1 670

2.10 (3H,

3.52

5.19 (2H, (1 H,

3, -OGCH 3), 2.46 (3H, s, N), ^J ₃

N s, C ₂ -H), 3.82 (3H, s, -OCH ₃ ), Hz, C ₆ -H), 5.59 (2H, broad s, (1H, dd, J = 5 Hz, J) = 8 Hz,

Wide d, J = 5). 5.78> CH ₂ C ₇ -H), 5.83 (2H,

N-d--, 7.12 (2H, broad s

H

J = 8 Hz, -CONH-, s, -COOCH ₂ O-), 6.69 (1H, s, -NH ₂ ), 9.55 (1H, d,

166 to 1 775,

168 1,745, (dec) 1,665

2.41 (3H, s, N); 3.58 (2H, broad s,

N

C ₂ -H), 3.93 (3H, s, -OCH ₃ ), 5.19 (1H, d,

J = 5 Hz, C ₆ -H) _g 5.62 (2H, broad s, S), δ D ₂ (1H, dd, J = 5 Hz, J = 8 Hz, C 4 H), 6.88 S , M-l ---, 7.62 (1H, s, HOO),

5.78 (1 H,

7.67 to

), 9.80 (1H, d,

J = 8Hz, -CONH-)

NMR (dg-IMSO) ppm:

Continuation of Table 19

R ¹ Melting point (° C) iC (KBr) cm @ -1 ^: c = 0 OHOCCCCH,), 127 až 1 780 » 1 A ³³ 130 1 740 » 1 (rozU) 1 675

CH ₃

1.14 (9H, s, -C (CH3) _3), 1.48 (3H, d, J = 5.5 Hz,> CH-CH), 2.45 (3H, s, N) 3, 48 '(2 H,

From ^CH3

N

Br s, C ₂ -H), 3.82 (3H, s, - -0CH3), 5.19 (1H, d, J = 5Hz, C ₆ -H), 5.54 (2H, br 8 S), 5.83 (1H, dd, J = 5Hz, J = 8Hz,

CrH), 6.69 (1H, s, N-p—) »6 '86 (1H, q,

S fl.

J = 5.5Hz, Qt-CH-j), 7'11 (2H, Wide,

-NH 2), 9.56 (1H, d, J = 8Hz, -COMH-)

-CHOCOCH-CH

J

130 to 1780,

136 1 775, 1 665

1.20 (3H, t, J = 7 Hz, --CH2 CH3), J = 6, (CH-CB3), 2.45 (3H,

CH3

1.51 (3 H, d,

3.55 (2H, broad s, C2-H); 3.85 (3H, s, -OCH3), 4.16 (2H, q, J = 7 Hz, --CH3), 5.20, ( 1H, d, J = 5 Hz, _C6- H), 5.55 (2H, Broad a,), 5.81 (1H, dd, J = 5 Hz, <J = 8 Hz,> ^CH 2 -) C 6 H 7 6.72 (1H, q, J = 6 Hz, J 2 H ₂ -CH ₃ ), 9.60 -d, J 8 Hz, -CONH) (1H, C = H);

-C2 OCCH3 ^ CH3

148 to 1 785,

152-1703, (dec) 1675

0’88 (3H,

1.75 (4H, ^N -)

QH.J

N

t, J = 7 Hz, - (CH3) -, 1.05 to m, --CH2 CH2 --CH3), 2.45 (3H, a, 3.45 (2H, t, J); -7 Hz, -C ^C CC CC),

3.55 (2H, br 8, C ₂ -H), 3.87 (3H, s »-OCHh) '5.23 (1H, d, - J = 5 Hs, -C-H), 5.43 ( 2H, a,

-COOC4 O) 5.62 (2H, br s, S)

5.86 (1H, dd, J = 5Hz, J = 8Hz, [gamma] -), 6.74 (1H, [alpha], 'N' -), 9.63 (1H, d, J = 8Hz, -CCJOU)

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Price 2,40 Kčs

Lc (KBr)

NMR (dg-IMSO ·) ppm:

Table continuation

R ¹

-CH 2 OC (CH) ₃ on зCH

Temperature

107 to

108 c * ¹

C-0

780, 1,760.

>

670

0.87 (3-, t, J-7 Hz, - (C 1 -C 7) 1.0 to 1.7 (4H, m, -CH 8 CH 8 CClCCH 3, 2.25 to 2.55 (2H, m, -C 9 H 8 CCHCl 2, 2) 45 (3H, s)

N), 3.33 (2H, br, C, -H), fi ⁰ ₃ ²

3.85 (3H, 8, -OCH-), 5.20 (1H, d, J-5 Hz, Cg-H),

5.88 (2 H, s,

-ОС-Оо ´, 5.73 to 5.97 '(1H, ж, C? -H), 6.70 (1H, α, H-γ), 7.10 (2H, broad and, -BHg),

S H

9.60 (1H, d, J-9Hz, -COH)

-CH000 (CC ₂ , ₃ CH ₃

I ⁰

C)

135 až 1 780, 130 1 760, (dec.) 1 667

0.87 (3H, t, J = 6 Hz, - (C-OjCH)), 1.15 to 11.5

1.70 (4H, d, -CHoCH-OC-CHc), 1.53 (3H, d,

J-6 Hz, ZZ237 (CH-CH3), 2.46 (3-s, S-O-N-3),

N

3.54 (2H, br 8, C ₂ -H), 3.86 (3, s, -OC-j

4.11 (2H, t, J-6 Hz, -COgC-CH-OC-j), 5.23 (1H, d, J-5 Hz, _C6- H), 5.59 (2H, broad s,

S), 5.85 (1H, dd, J-5Hz, J-8Hz,

C ₇ -H), 6.76 (1H, α, N 4 -),

S-'4

-OHOCOC (OH ₃ ) ₃ I o

OH3

128 až 1 780, 135 1 755, 1 665

1.41 (9H, a, JCHH-C- ₃ ),

-C (C- ₃ ) ₃ ), 1.51 (3H, d, J = 7 Hz),

2.50 (3H, a, N), 3.56

N (2H, br s, C ₂ -H), 3.92 (3H, s, -O CH₃

5.29 (1H, d, J-5Hz, Cg-H), 5.63 (2H, broad a, ^5.92 O-dd, J-5 Hz, J-8 -z)

C 6 ^{- 6.84 ( 1H ,} .631 (1H, q,

S H

J-7 Ηζ, 2Ξ = (Cg-C-3), 9.75. (1H, d, J = 8Hz,

-Н-ССМ

CM * o O * · O o O oo OA t * oo b SJ b- b 49 t * b

O O <a «O O LA oo KO «0 b b b KO- b b KO *> - IN-

ЯЯ и • о «Яi

Г 22 г ·

s £ з b b kO * * о o ua -e ь t- KO * <n σκ C—

σκ

A e <

Table . 20 May

COOR

JY-T- C - CONH ^{н НГ д}

AND

OCH ₃ R ¹ Temperature IR (KBr) thaw cn ¹ : _% ^{l (} ° C) y C = O .030 (03) 30¾ 1 78Q, 130 1 722, 1 670

(son i cmer)

NMR (dg-IMSO) ppm:

0.87 (3H, t, J = 7H ;, - (C ^ KCl3)) · 1.15-1.58 (4H, a, -Ο ^ Η ^ ΗηΟ ^), 3.45 (2h, Wide with,

C ₂ -H), 3.48 (2H, t, J = 7 Hz),

3.83 (3H, s, -0 _<3 3H), 5.10 (1H, d, J "5Hz, C ₆ -H), 5.25 (1H, dd, J» 5 Hs J «8 Hz,? -?), 5.30 (2H, s, -COOH 4 O--), 5.41 (2H, broad s, S), ^c -T), 7.18 (2H, broad s,

6.71 (1H, s, N-1-A) »

-NH ₂ ), 8.01 (1H, s, 1H), 9.57 (1H, d, J-8Hz,

N

-CONH-) ♦

rCHBCOCH ₂ <CH ₃ ^133-135

778,

755,

670

03¾

1.23 (3H, t, J = 7 Hz, -CHgCH), J = 5 ta,. CH-CH3), 3.49. (2H, 3.84 (3H, s, -003) 4.19 (2H, 4.95-5.52 (3H, m, Cg-H, S)

1.52 (3H, d broad q, J = 7);

t +1

^s , C ₈ -H, Hz, -CH ₂ CH ₃ ),), 5.81 (1H, cHgdd, J = 5 Hz, J = 8 Hz, C ₇ -H), 6.71 (1H, s, N -rj—),. AND

S H

6.76 (1H, q, J = 6 Hz, 2ZZ CHCl3) 7.16 (1H, broad s, J = -), 8.04 (1H, s, K.), 9.60 (1H, d, J »8 Hz,

N

-СО ^ ИН)

R ¹ Temperature i ^C (KBr) mp ca '':.

(° C) ° C

NMR (dg-DMSO) ppa:

.ch OCC (CH3) ₃

II '

O

145 aí

H7 ch ₃

780,

742,

670

1.17 (9H, a, -C (CH _{3) 3,} - 1.52 (3H, d, J = 6Hz, -CH-), 3,54- (2H, br j, C _r H) 3.92 (3H, ·,

0H ₃ .

-OCH 3), 4.98 to 5.50 (3H, α, C 8 H, S)

5.87 (1H, dd, J-5 Hz, J-8 Hz, 0-OD),

N -), 6.97 to 7.24 (1H, a, -CH-),

H

6.85 (1 H, ·,

8.24 (1H, j), 9.78 (1H, d, J = 6 Hz, -oh).

♦♦ > CH ₂ OCOC (CH ₃ ) ₃ 134 ai 1 790, 136 1 755, (rozo.) 1 680

1.17 (9H, z,

3.93 (3H, a,

-0 (O) 3), 3.49 (2H, broad)

-OCH3), 4.95 aí 5.40 (3H, s · C ₂ -H), with _{Ps> C)} ^ CCHg-

J »9 Hz, -CONH-)

^ znfaka: ^{4 *,} h ^y drlc llprid * ^{i 'j} as a starting material was joouHta Horm Uve ^ NS tobulce 13

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Example 10

To a solution of 5.93 g of 7-2- (2-chloro-4'-yl) -2 '(tnn) -α-oxyl-11-leyeaaido] -3- [2- (5-nettl-1,2 _l) 3,4-Ethyltetyl-3-epiphenyl-4,4-labloxy-oxoic acid in 50 µl of ethyl acetate is added a solution of 2.5 g of methyl-hexyloxylic acid dihydrate in 20 µl of ethyl acetate. The precipitated crystals of DFI ^ ^ ^ Trujillo her prom ^ yjí etyllcetáten and Vyssh · ae give 7.39 g (93.2% výiěžek) salts neeiiyl «mttflonloé acid siolllyll) ymeeyletteren tilzll-4tyl> 2s _(β yn) - 3-Cephen-3-carboxylic acid, which has a melting point of ²¹⁸ to ²²⁰ ° ⁽ (ω));

If el elctx- ^ (KB *) св'H _Сй0 1,782, 1,745, 1,680

Nuclear Magnetic Resonance Spectrum (dg-DMSO) ppn: 1.15 (9H, s, - ((CH 2 OH (3H, s, »)), 2.53 (6H, s)

For ^CS 3

N

), 2.43

2.52 ’(2H, y

Br s, C ₂ -H), 3.93 (3H, s, ^ -OO), 5.20 (IH,

C ₆ -H), 5.56 (2H, broad s, S.), 5.78 (1H, d, J = 5 Hz, C 6 dd, J-5 H 5,

J = 8 Hz, C ₇ -H), 5.85

H ₃ N-), 6.75 (2H, s,

(2H, s,, -СООСС ^ о), 6.50 (3H, broad s,

9.81 (1H, d, J = 8 Hz, -COMi-Example 11)

If siolloylxyxyl ester of β-ω-ω [1,2- (4-methyl) -1,2,3,4-tetrololyl] ethyl] -3-cephen-4-carboxylic acid is used and treated in a manner such as: described in Example ¹² - ⁽¹⁾ and Example 2 ^ (0, ztoká ^with iolll ^t llxyntyle8ter 7- ^ 2- (2- ^ 1 ^ 0 ^ μοΙ-4 -?) - 2- (syn) - hyteoxyininoaceianido] - 3- [2- (4-Chloro-4- (4-tetrololyl) -ethyl)] - 3-cefl-4-carboxylic acid. This compound was further treated in ethyl acetateTen solution with a solution of dry hydrogen chloride in diethyl ether. Hydrocchorid piolLoyLoxyмeytesteru give 7- ^[-) (2-aminotilкll) '4) · yl) -2- ^{(t n} n) ^{appointing-hydroxy-r n t} RIM lllcetamido] ^-Зз) 2. ⁽⁵⁾ _and eeyt-1 2,3,4) tetrafazolylmethyl] 44-alaxylic acid, which has a melting point of 142 DEG-145 DEG C. (dec.),

Ic ^ ktrun (KBr) cm ^{"1:) 1765, 1750, 1675} vc ·« of

NMR spectrum (d₆-DMSO) in ppm: 1.20 (9H, s, -C (CCh) _3), 2.49 (3H, s, H), 3.55 (2H, br s, C ₂ -H ), 5.26 (1H, d, J > 5 (-Η), 5.63 (2H, broad a, (2H, broad s, S)

), 5.78 to 5.95 (3H, force, C ₇ -H, -СОЮЗОВ-, 6.84 OH,>,

J (7H, -COHOH).

-), 9.76 OH, d, J 1

Example 12

1. In the same manner as in Example 5, the following compound is obtained:

IIL ^{p l} o ^{y t} IIx meeyl · stlг 7- L ² ~ ⁽ⁱ 2lЦ nltilZl1l4l ^tl) -2- (and ⁿ⁾ - ^I · tox · ΠLilllc etl * d ⁰ and ^{d-3- [[2-} (5ET ^t LL ¹ 2.3 | 4teetiZlltyl) · ty e ^{J e} · зlceo l4lo ^l b ^l OU ^t1 lli ^ ^é tyselin temperature T ^- ^ 99 i ^of 102 ° C (Rozo.).

IR (KBr) «T ^{1 C-0} 1785, 1745, 1675, 1 615th

2. Same! as in Example 10, the compounds prepared by 1) are obtained by the following compounds:

salt of kyseliny8ϋϋ 00χ »00 α00οηι ^ s with plural yloxtodontyleatoron 7- [2- (2 <-1 *. 112,3,4-tetrlZlltl) Deιt ^yl - 3 · ^eeeel-4-yl bed method iablox acid. Warmify point Md 190 ° C.

IC (KBr) c · ^{1 CeQ 1780} , 1745, 1680.

Preparation example 1

The composition according to the composition is shown below to produce a tick, that is to say, the ear fungus is reduced first and also to the liquid. Aqueous solution of polycellulose may be added to the mixture. The resulting mixture is dried and dried. The pellets were coated with the 'stearate' magnesium, which had previously been spread with starch and pellets to form tablets.

AND

Means

7- (2- (2-methyl-4-methyl) -4 (2-yl) 22-ol) - [3- (2- (5-methyl-1,2,3, < 4 &gt; -ethyl) -1,3-tetrylsilyl] -eyl-3-ol-4-ol) The carboxylic acids 130g are 20 * starch 44sg of magnesium starch and magnesium stearate 0.6 vd.

200 sg / tibleti

If other compounds are killed in place of the compound, other tablets can be made.

Preparation Example 2

The composition of the composition is shown below and produced by mixing a portion of starch with a magnesium stearate. The comminuted mixture thus remains with starch, with hydroxylpropplcellulozous with the main component. Capsules are obtained from the above process.

7- (2- (2-Amino-oxol-4-yl) -2- (8-yne) -oxyoxyiminoacetamide) 2- (5) -ethyl-12,3,4-tetrahydro-dimethyl-methyl-pivaloyloxyacetyl hydrochloride N-carboxylic acid 136 mg starch 54 mg lydroxwrooyl cellulose - 6 mg magnesium stearate 4 mg

200 m ^ capsules

If other compounds are used instead of the above compounds, similar capsules may be prepared in a similar manner.

Prepara & u example 3

The composition shown below is made by first mixing the Havrt component with the lactose and triturating the mixture. An aqueous solution of lipopropyl cellulose is added to the comminuted mixture. The resulting mixture is bent and dropped. The powder is mixed with magnesium stearate which has been premixed with starch and then the resulting mixture is made into tablets.

Composition 7- (2-) - (2-aninoththiazol-1-yl) -2- (syn) -methoxyimnoacetiamdoo-3- [2- (4-methyl-1,1'-triazolyl) ethyl] ethyl-methanesulfonic acid salt of pivaloyloxymethyl ester -3-Citric ---- carboxylic acids lactose starch hydroxypropylcellulose magnesium stearate

130 mg mg mg

5.4 mg

0.6 mg

200 m / tablet

If ae uses other compounds instead of said compound, similar tablets will be made in a similar manner.

Preparing Example 4

The composition, the composition of which is given below, is prepared by mixing part of the starch. and comminuted with magnesium atearate * The comminuted mixture is mixed with the remaining starch, hydroxypropyl cellulose and the main component. A band is formed from the mixture obtained in a conventional manner.

Composition meeitlleniuϊfonlvé acid salt plvalllllxlmatyleetaritt 7- ^{[2- (2-t} and ^m nol azz l4 ^l-yl) -2- (8 ^L o) -metoxyiminoac etrmi0o] -3- [2- (5- ^ 1- ·· 1,2,3,4-tetrsaoyl) ethoxy-4-dimethoxy-4-carboxylic acid starch lyophilisates

136 mg mg mg mg

200 mg of capsule

236491 84

If other compounds are used instead of the above compounds, the capsules can be prepared in a manner known per se.

Preparation Example 5

SMTE hydrogeen ^ iditan sodium ⁷ - [2- (2 - α ^{t 0} Nol ajo l4 ^l-yl) - ² - (n · ^y) -metlxyiyinljcetaaOid] -33 2- (5-oatyl 1.2 3,4-Tetrazolyl) methyl] -3-cephalobenzyl-4-carboxylic acid is treated in the usual manner to obtain a sterile sterile sodium hall. Injection is effected by dissolving one gram (strength) of sodium salt in 20 m of physiological saline.

Preparative Example 6 _f . Injections which were diluted prior to use were prepared by dissolving one gram (strength) of the lyophilized product withdrawn according to Preparation Example 5 in 4 µL of a 0.5% (mol / mol) aqueous solution of lidocaine hydrochloride.

Example 7 of one gram ([mu] l) of the product produced according to Preparation Example 5 in 20 [mu] l of a 5% glucose solution causes injection.

Further, the compounds (free carboxylic acids) of the formula (I) according to the invention can also be formulated in the injection products (sodium salts) in the injections, but in the same way as in ^the case ^of lipoproteins. of Preparation Examples 5 to 7.

Claims (5)

A process for the preparation of a compound of formula I (I) wherein R is hydrogen, neOo .C ^^ tlky !, difenyloetyl, phenyl, 2-carboxamide ^ o ^; ^^ «n ^] ,, 1 * -oivjll ^yl ox ^y Oшsyl ^C | cyloxy ^ -C ^ alkyl-methoxy group of formula ⁹ -CfflOB meto -CHOCOOR ^9, where R ⁹ ''^'R6 represents ^L6 C ^ 1 ^ 2 cyclohexyl methoxy phenyl and represents hydrogen metho ^ C- alkyl group, 5 ’ R ² represents phenyl 2 2-enyl those у ^ 2 ^^ ^C ₂ _ ^o αl ^to αno ljniУOikuolnu ^{y O y} aιyκo ^{laninoskupiyu,} HrtylaniLnoikuoiol, 1,2,3-tгjalol lovll ^yl, 1,2,4-triazol-jaloУylvvlu neOo. 1,2,3,4-tetrazolyl, 'said Ezo t ^ ^ ew oeOo tetrαzll ltvé ^Y groups are attached to extmetyleotvé group in position 3 cefenového. The ring of the carbon-carbon bond and the legs can be substituted by at least one substituent selected from the group consisting of halogen atoms, hydroxy groups, cartoxyl groups, allyl groups. C_ ^ alkyl, kyamoalmpinu, phenyl, C_salyyltliakuoio ^y C ^ alkozykartonylové group C1_5αlktxykαrOtnyl C1_5αlkyltvé-groups, and _C2 ^ _G lkaoo Lanin ^ ^ alkyl groups, R ³ represents a hydrogen atom or a phenylamine or amino group and represents a group of the formula -CH Or a group of the formula wherein R ⁴ is a hydrogen atom or an alkyl group and the bond is a son or an anti-isomer or a salt thereof, or a salt thereof, characterized in that the compound of formula II is reacted R ⁷ CH ₂ CO -А -ССЖЖ COOR (II) where R ^1a represents a hydrogen atom or a carboxyl protecting group, Ry represents a halogen atom and R and A are as defined above, or a salt thereof, with a compound of formula III н, ^нса 3а (iii) II p where R ^3a represents a hydrogen atom or a phenylamine or amine group which may be optionally protected and then, if desired, deprotecting, converting the hydrogen atom of the carboxyl group at the 4-position of the cephem ring to R ', or converted to salt _e 2. A process according to claim 1, wherein R is 1,2,4-triazolyl, 3-methyl-1,2,4-triazolyl, 3-ethylthio-1, 2,4-triazolyl, 3-ethoxycarbonyl-1,2,4-troazolyl, 3-chloro-1,2,4-triazolyl _with 3-cetylamino-1,2,4-triazolyl, 4,5-dimetoycarbonyl-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-ethoxy, carbonyl-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 the other substituents have the meaning given above · 3. A process according to claim 1 or 2, wherein A is -CH2- and the other substituents are as defined above. 4. A method according to claim 1 or 2, wherein the formula II. wherein A is -O-, wherein ~ a II N is derived from a bond and has the meaning given in 1, and the other meaning given above. 5. A process according to any one of claims 1 to 4, wherein the reaction is carried out at a temperature of from 0 to 100 ° C.