CS236471B2 - Method of cephalosporines production - 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 invention relates to a process for the production of novel cephalosporins.

The present inventors have conducted studies aimed at discovering compounds that have a broad antibacterial spectrum, exhibit excellent antibacterial activity on Gram-positive and Gram-negative bacteria, are stable to bacteria-produced beta-lactamases, have low toxicity, and are well absorbable when administered orally or parenterally excellent therapeutic effect on human and animal diseases. The results of the studies have been to find novel cephalosporins of the general formula I below and their salts having the above-mentioned excellent properties.

The present invention provides a process for the preparation of the novel cephalosporins of the following general formula having a broad antibacterial spectrum, stable to bacterial beta-lactamases, low toxicity, well absorbed by oral or parenteral administration, and excellent therapeutic effects on human and animal diseases .

Other objects of the invention and its advantages are apparent from the following description.

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

The term lower alkoxy means -O-lower alkyl, wherein lower alkyl is as previously defined. The term acyl group means an acyl group of 1 to 12 carbon atoms, for example acetyl, propionyl, butyryl, benzoyl, naphthoyl, pentanecarbonyl, cyclohexanecarbonyl, furoyl, thenoyl and the like. The term acyloxy means -O-ecyl, wherein the acyl group is as previously defined. The term alkylthio means -S-alkyl, wherein alkyl is as defined above. The term alkenyl means an alkenyl group having 2 to 10 carbon atoms, for example vinyl, allyl, isopropenyl, 2-pentenyl, butenyl and the like.

The term alkynyl means an alkynyl group having 2 to 10 carbon atoms, for example ethynyl, 2-propynyl and the like. The term cycloalkyl means a cycloalkyl group having 3 to 7 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. The term cycloalkenyl means a C 5 -C 7 cycloalkenyl group, for example cyclopentenyl, cyclohexenyl and the like. The term eryl means, for example, phenyl, naphthyl, indanyl, and the like, the term aralkyl means lower alkyl, for example, benzyl, phenethyl, 4-methylbenzyl, naphthylmethyl, and the like.

The term heterocyclic group means a heterocyclic group having at least one heteroatom selected from the group consisting of oxygen, nitrogen and sulfur, for example, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiatriazolyl, oxetriazolyl, oxetriazolyl, oxetriazolyl, , pyridyl, 3- (2-methyl-4-methyl-3- (4-pyrrolinyl), N- (methylpiperidinyl), quinolyl, phenazinyl, 1,3-benzodioxolanyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl, cumerinyl and the like. The term halogen atom means fluorine, chlorine, bromine and iodine.

The method according to the invention is as follows:

Process for the preparation of cephalosporins of the general formula I

A — COIMH

(I) where,

R? means 'hydrogen NEB C ^ alkyl, diphenyl-ethyl, phenyl, 2- ^to srboxyfenyl, 1' -pivaloyloxybanzyl, C ^ C ^ acyooyy-alkyl or a group or a group of formula

-CHOR ^and not of -ΟΗΟΟΟΗ ^ ^b wherein R represents ^C ^ and ^o ~ yl, cyclo ^ o ^ fe ^ verifies the NEB to ^a nominal ^P inu ⁷ and H represents a hydrogen atom or Cj_j81kylovou group,

R represents a phenyl, S-thienyl, 2-furyl, C 1-6 alkamilamin, benzoylemine, furoylamine, 1,2,3-triazolyl, 1,2,4-triazolyl or 1,2,3,4-tetrazolyl group, * triazolyl or tetrisolyl groups are attached to the toomethylene group at the 3-position of the cepheum ring by a carbon-carbon bond, and these groups may be substituted with at least one substituent selected from the group consisting of halogen atoms, hydroxyl group, carboxyl group C, alkyl groups C 1-6 alkylthio, C 1-6 alkoxycarbonyl, phenyl, C 1-6 alkanoyl-amino, C 1-6 alkoxycarbonyl-C 1-6 alkyl, kaloalkyl and imino,

R ³ represents a hydrogen atom or a hi- ^{10 g} emt atom. ^Is hydrogen or amino, formylamino, chΊorecetyaεoimovou, bonzylooykarbony! Amino or t »ooylo2yrksrbcmyl6oinovou group and zněmená -Chg- group or a group -C-, where H represents ⁵ -alkyl group N

OR ⁵ e bond / v means that the compound may be with a 1m-Zomltreo or an antisoomer or a mixture of both, or a salt thereof, characterized in that the compound of formula II

(II) wherein ^{R 1c} represents G1o ^of no8kupimt ^{R1 8} denotes a ^thank for NEB protecting SKU ^{p ins} aгbo ^o 1lov ^é hundred · »pins and η ¹ is as defined above, or a salt thereof, reacting a compound of formula III

(III) wherein L * ^8, we changed ^and atoms as ^says to the NEB, and ^{the nose-to-u p} ins ^which can ^b YT ^p o ^p FIPA ^ga interference and ^R2 is dříveuvedený above, or its reactive derivative at the carboxyl group and then, if desired, cleavage of the protecting group, the hydrogen atom at the 4-position of the cephem ring of the carboxyl group located is converted to the meaning of r ', or the product obtained is converted into a salt.

235471 4

In the above formulas, R * represents a hydrogen atom or a C 1-4 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl or the like, diphenylmethyl, phenyl 2-carboxyphenyl, 1'-pivoylloyloxybenzyl, C 1-8 -cyclohexyl-C 1-6 -alkyl such as acetoxymethyl, propionylrneeyl, n-butyrylozymethyl, isobutyrylosyrneethyl, pivaloyloxymethyl, valeryloxymethyl, 1-acetoxymethyl, 1-acetyloxymethyl, 1-acetyloxymethyl, 1-acetyloxymethyl, 1-acetyloxymethyl, 1-acetyloxymethyl; pivaloyloxyethyl, 1-pivaloyl-n-propyl and the like _; pins, a ththalidyl group, or a group of the formula -CHOŘ® or -CHOCOOR® wherein ^R ® stands for "* 7"

O-alkyl ^1, a cyclohexyl or a phenyl radical as mentioned earlier в R · represents hydrogen or C₁₋₄ alkyl previously mentioned significance, such as methoxy-meeyy, etoxymeeyl, propa-nuetl, isopropoxymeeyl., Either the L-oxy-EET ^ Methoxycarbonyl: ethoxycarbortyl, oxyoxyethyl, propo: carbononyl, o-ethyl, isopropoxycarbonyl: ethylene, n-butyloxycarbonyloxymethyl, tert. butyOoxykвrbonyloxymθtyl 1 ^to -шetoxy arЪotn'loxymetyl, 1 "ttoxykaгboϊnloэχrytyУ, 1-propóxykarbornУoxχyeyl 1" iяoproρoxykarbornloxχyeyl, 1-butyloχykθrbollrloэχfetyl and the like · R ^1a represents in ^gratitude for protecting the no ^b with u ^{p to} r ^{b ins} oxyl Sapiną .

Carboixyl protecting groups are those commonly used in the field of penicillins and cephalosporins and include ester-forming groups that can be removed by catalytic reduction, chemical reduction or mild processing, ester-forming groups that are readily removable in living organisms, and other known ester-forming groups Which are readily cleavable by the action of points or alcohol, such as organic silyl groups, phosphorus-containing organic groups, tin-containing organic groups or the like,

Examples of typical carborxyl groups are:

(a) alkyl groups;

b) substituted Closer alkyl groups which are substituted with at least one of the following substituents halogen, nitro, carbalkoxy, acyl, alkoxy, oxo, cycloalkyl and aryl, _{alCylУitsCtpin8} alkyl alkylsulfinyl, alkylsulfonyl, alkoxyC _1-6 alkyl, alkylcarbonyl, alkoxyC 1-6 txt-1,3-ditxol-4-yl, 1-indanyl, 2-indinyl, furyl, pyridyl, 4-imidazolyl, phthalimide, succinimide, acetidine, eziridine, pyrrolidine, piperidine, moofoline, thiophofoline, pyrrole, pyrazolilyl, , i.e., ophthalmic, oxazolil, isoxezclyl, tladiazolil, oxadiazolyl, tiatriazolil, oxatriazolil, triezolil, tetrezolil, pyridyl, quinolil, phenazinyl, benzofujryl, benzoliil, benzothiaxiazolil, benzo thiazolil, benzo thiazolil, benzo thiazole; tlkllpiptrazintvá, S ^ -dime ^! -. 4-methylpiperidine, 2,6-dimethylpiperidine, 3- (2-methyl-4-pyrrolidinyl), Z-4-methylpiperidine, 4-methylpiperidine, 2,6-dimethylpiperidine 1,3-bernzoddoxolanyl, alkylamino, dialkylamino, acyloxiskupina, acylamino, acylthio, dialCyplamintкarbonylová group alkoxikarbonylaminos tajine, alktlyloxysCupine, aryloxy, aralkyloxiskupina, eliclklotxllová group heterociklooxilová group alкtxyCarbonyloχllová group alкenyloэlrkarbtlyloχlsкupina, aryloxykarboinyloxiskupina, aralkyloxikarbonyloxysku.piwa, alicykooo; yrkerboniloxiskuplna, heteroclklttxykarbonyltxlskupinu, alktllloэykarbtnlltvou group aryloxikarbonylovou group aralkyloxyka.rbonylovou group, Alice ^to Oto: lykarbtnllovtu group heteroclklooзykarbolylovtu group alCylanillnovou group and alCylanillnovou 'substituted by halogen, lower alkyl or lower alcohol ^^ rim,

c) cycloalkyl groups, · lower alkyl-substituted alkyl groups or / 2,2-di (lower alCyl) -1,3-ditxolan-44yl / methyl groups,

d) alkenyl groups,

e) alkenyl groups,

f) phenyl, substituted phenyl groups which are substituted with at least one of the substituents listed above under b), or eryl groups of the formula wherein:

X is -CH = CH-O, -CH = C1HS-, -CH ₂ CH ₂ S-, sCH = N-CH 3 N-, -CH = CM-CH = CH-, -CO-CH = CH- CO or CO-CO-CH = CH- or a substituted derivative thereof, wherein the substituents are selected from the substituents listed previously under b), or the formula wherein

У _a represents a lower alkylene group such as - (CH 2) 2 - or a substituted derivative thereof, the substituents of which are selected from those previously mentioned under (b),

g) aralkyl groups which may be substituted by at least one of the substituents mentioned under b) previously,

h) heterocyclic groups which may be substituted by at least one of the substituents mentioned above under b),

i) alicyclic indanyl or phthalidyl groups, or substituted derivatives thereof, wherein the substituent is a halogen atom or a methyl group; elicyclic tetrahydroinaphthyl groups, or substituted derivatives thereof, wherein the substituent. is halogen or methyl; with trityl ^{to-INA 'and} S ^to eholesteryiov oup or bicyclic ^kl jOj- op ^ ^ with ^the cyl oup.

j) alicyclic phthalidylene-lower alkyl or substituted derivatives thereof, wherein the substimene is halogen or lower alkoxy.

The listed protecting groups for the carbonyl group give typical examples of such groups. Any of the groups disclosed in U.S. Patents 3,499,909, 3,573,296, and 3,641,018, and in DOS 2 301,014, 2,253,287, and 2,337,105 can be used.

Of these carboxyl group temples, preferred are carboxyl protecting groups that can be readily removed in living organisms, such as 5-lower alkylsubsulpho-1,3-dioxol-4syl, ecyloxyalkyl, ecylthioalkyl, phthalidyl, indanyl, phenyl a group, substituted or unsubstituted phtelidylidene-lower alkyl groups or groups of the general formulas:

^S CH (CH 2) OH ⁸ -CH ⁰ CO ³ R ⁸ and ^S CH (CH 3) C 00 R ⁸ I 2 rn · ⁶

where

R ⁹ represents ^and linear or branched LoVo sl ^ ^ and ^ eny ^ ^ -ovo an aryl Aral ^{0y salicylic,} ali9 a cyclic or heterocyclic group, K · represents hydrogen or alkyl, R '° · represents hydrogen, halogen or substituted or unsubstituted alkyl,

8 cycloalkyl, aryl or heterocyclic group or -1C22) _n -CJo0R ⁸ wherein R ⁸ is as defined above and n is 0, 1 or 2 am is 0, 1 or 2 »

The aforementioned carboxyl protecting groups particularly include 5-lower alkyl-2-oxo-1,3-dioxol-4-yl groups such as 5-methyl-2-oxo-1,3-dioool-4-yl, 5-ethyl-2- oxo-3-one ₉ dLoxol-4-yl, 5-pгyppl-2-lxoy1,3 diУxol-4-yl-e like groups; tcyloxyalkyl groups such as tert-butyloxymethyl, butyrylylmethyl, butyrylyloxymethyl, 3-isobutyryloxymethyl, tert-butyloxyethyl, 1-tetoxystryl, 1-tetoxy-n-propyl,

1-pivloyl-oxy-n-propyl and the like; ecylthioalkyl groups such as tceeylthioeeeyl, pivlylthioethyl ₉ . beopentyl, p-chloro-benzoyl-thiethyl, 1-methyl-tert-ethyl, 1-piperidyl-ethyl, 1-benzyl-thioeyl, b- (p-chlorobenzimidazol-1-ol); similar groups; the alkoxymethyl group is m < 14 &gt;: x &lt; 14 &gt; C 1-6 cyclohexyloxymethyl groups such as t-cyclocarbonylmethyl, propynylcarbonynyl-3-isoprypo: γ-carbornololylyneeyl, n-buyllycycrbynylyl-cymyl, tr-t-butyl-methyl-methyltyl-2-by-methylmethylltylmethyl; 1-propyloxycarbonyl-1-propynylcarbonyl-1-propynyl-1-propyloxycarbonyl-1-propyloxycarbonyl-1-propyloxycarbonyl-1-propyloxycarbonyl; the C1-4carbonylcarbonyl group is a methylcarbonylmethyl group of a similar group; fidyldyl group; an indenyl group; The exile group t of the flidlidilidentyl group is 2- (6-chlorophthalenediidene) ethyl, 2- (6-chlorophthalenediidene) ethyl, 2- (6-chlorophthalenediidene) ethyl, 2- (6-ethylphenylidene) ethyl t-like groups ·

R ^ ZnTe: the phenyl, 2-tteIyrlovyu, 2-turylovlu, C2 _{^ 1} _alkanny1eeinyekupinu jtko is tcttylaminyváз propionyltmlnová, n buУyryleminyvá, isobuuy 171veleiylkeL-new, isovtltIyιtaminová, 'pivtlyylaminováз hexanes! T podobné'skupiny shrub; furoylamino group; 1,2,3-triazlllyl; 1,2,4-trisstyl. or a 1,2,3,4-thiazolyl group, wherein said trizylyl groups are attached to the C3-methylene group at the 3-position of the cephem ring in which the carbon nitrogen may be substituted with at least one of the substituents in the group. from the group consisting of fluorine, chlorine, bromine, iodine and the like; H, R, R, R, R, R, R, R, R, and R, respectively; C | ^^ 811- ^ 881 ^ 1x11 jtko is -SO ^ ^ tltylc with u ^{p to} int eající C. ^ e ^ ytovou s ^to u ^P inu tofinovtnou for ^R1; C ^ Cltoxycyclennyl group of the jets is С_-е18у1 О-С-saving C, ^ εΙ ^ Ιου ^ def group ^, innovative

O u R; phenyl; C2_ £ tkkancyt & minyvé jtko group is C ^ akkylcCNM- skupint ^wh e C..c EKL ^ ⁱ ^ ^ ^l ^ <^ v ^ á skupint EA výzhte Uve Eny ^d u ^F, C ^ ^e L88yo ktrbynfl- ^{C 1} _-β ^- kl ^8Y LCW ^s SKU ^p ins jtko is C-OC- akkyl. ^ ⁰ _ ^g - ^ i ^ o ^ L ^ C ethicists Bcytové s ^to u ^p in ^Y shown by ^R1;

. O cet ^ l ^ i ^ j ^ inu; e thyloxy group · 3

Г ⁵ - znteená TTOE atom or TTOE the ^ gene is jrto ЗДиг, chloro, ^{b rhyme} jo ^d t ^p • Similarly.

^r 4 ^q 'denoted hydrogen or trinium groups which may be optionally protected · The protective groups of the kine group may be those normally used in the industry! Percillin t Cetyployporinines These groups are represented by the tetral groups which are largely separable, such as trichloride: trbУHr ¹ , ЬЬЬЬymymymymkakakakakakakakarrr benz, benzy Ι ^ ι ^ γΙ ^ ι! p tolutn8ultyвдl »p niryybenzy0ooq8ι: krbony1з of brymbenzyloxyktrbyny1з-L-nitrlteny1sulteny !.» (eyno-, dl or tri) chllracetyl, УrtfUuyгkctУyl, toreyl, Уtrc · amylyχ1karboinrl, Уtrc.buУoxy8krboн ^r 1L »p eeУy: χУbennylo: χУ8artolnr1 , 3з4 ilimtУoxybtnz1lУXyk8rbУny1з-4- (teryLkalo) benzylУoy8krbynrl »4- (4-meУlxyftnylkzy) ^b tnzylyχy8krЬornrl, pyridine-1-oxide-2-yk-2-ture mtУУoyktrblnn1з lyoy8krbynr1, iifenyletУyχ1k8rbynn1, 1,1-iietУylproplχyktrbornl, with op ^ p ^ i ^ i ^ H !! 1-Cyclopropylthioxycarbonyl, succinyl, 1-dimethytyloxycarbonyl, 8-quinylyloxycarbonyl-like groups, the tertiary group of the leaving group being tritium, 2-nitrophenylthienylthiophenylthienylthiophenol-2-nitrophenylphenylthienylthiophenol-2-nitrophenylphenol 2-hydroxy: χ1-5-chlorobenzylidinyl, 2-hydroxy-1-n-methylthylene, 3'-hydroxy-4-pyridylmethyl, 1-methyl: oxycarbonyl-2-propylidenyl-2-carbonyl propyldenedenyl, 3-methylpyrrolidin-2-ylidene, L-acetyl-2-propylidene, 1-benzyl-2-propylidene. 1- [N- (4-ethylphenyl) -2-propyl] -2-propynyl-2-propynyl group; group, 2-thiocyclohexylcyclohexyl group, 2-thiocyclohexylcyclylmethyl group, 2-methylcyclohexyl group, 3,3-di236471 methyl-5'-oxocyclohexyl group, or similar, protecting groups such as di, or similar groups, and the like; or a tri-alkylsilyl group and the like A represents a -CH ₂ - or -C- group, wherein R 6 represents a C 1-4 alkyl group mentioned for R 2

N

MeZ winter compounds in which A represents a -C- patM syn group with anti-ioomers;

N i,

0R ^J as ·. . and mixtures thereof.

of Formula I exists in the form tautw.srů, ^I f R is amino, ^the now obsolete · ^p may be O ^{P at} pH ADS ^chránSn8, yell shows následuuící equilibrium equation

wherein ^R 4 _& ^R 4a mm tfíve her Uve ^d Eny importance e R ^ represents inoskupinu which may be after ^p and ^{d at} pH protected. As the ^p-protecting sku yne ^and Minh UPIN ^{S k R in} the above equation can pouuít balance groups which are conventionally used in cephalosporin and penncilinu ^p Crin. Here especially ^those moonoa ntní ^ groups which are uv © ^d enes at рЛ ^eighth Tautomers also fall within the scope of this invention.

Salts of compounds of formula I or II include salts of basic or acidic groups, which are generally known in the art of cephalosporins and cephalosporins. Particularly include salts with mineral acids such as hydrochloric, nitric, sulfuric and the like acids; salts with organic carboxylic acids such as acetic acid, succinic acid, formic acid, trichloroacetic acid, trifluoroacetic acid, and the like; salts with sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluene-2-sulfonic acid, tolunn-4-sulfonic acid, meestylene sulfonic acid, 2,4,6-trifluoromethylbenzin sulfonic acid, nabalene-1-sulfonic acid, iaphthalene -2-sulfonic acid, phenylmethanesulfonic acid, benzene-1'-disulfonic acid, toluene-1'-disulfonic acid, 18-naphthalene-1,5-disulfonic acid, naphthalene-Z-disulfonic acid, naphthene-2-disulfonic acid, benzene-1,3S-trisuioic acid, benzene-1,2,4-trisuioic acid, naphthalene-1,3,5-trifluoroacetic acid in a similar acid (such as a basic group salt) in an alkali metal salt such as sodium, potassium in the like; alkaline earth metal salts such as calcium, magnesium, the like; ammonium salts; salts with organic bases containing in this nitrogen such as protein, dibenzylamine, N-bennyl-beta-phenethylamine, 1-efenamine, Ν, d-dibeisylntylenediamine, triethylamine, trinethylamine, tributylamine, pyridine, dimeeylanilium, N-mephylmilium, N-mephyllie , diethylamine, dicyclohezylamine in similar (as salts with acidic group).

The following is a detailed description of the process for preparing the compounds of the invention.

The process of the invention is an acylation reaction in which a compound of formula II or a salt thereof reacts with a compound of formula III or a reactive derivative thereof to form a compound of formula I or a salt thereof.

β

Reactive derivatives of the compounds of formula III to the carboocyl group include, in particular, acid halides, acid anhydrides, mixed acid anhydrides, active acid amides, active esters and reactive derivatives formed between the Vilsmeiro reagent and the compound of formula III. As said mixed acid anhydride, mixed monoaltyl carbonate antydrides such as mono-ethylcarbonate, mono-butylcarbonate 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. For example, the active acid amides used may be N-acylsaccharide, N-acylimidezole, N-acyl-4-benzoyl-4-ol, N, N'-dicyclohexyl-N-ecylurea, N-acylstinone and the like. As said active esters, for example, cyanomethyl ethers, substituted phenoxy esters, substituted benzyl esters, substituted thiooyl esters and the like can be used.

As said reactive derivative with a Vilsmeier reagent, reactive derivatives with a Vilsmeier reagent obtained by treating an acid amide such as dimethylforaamide, Ν, dim-dimethylacetamide or similar amides with a halogenating agent such as phosgene, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorous oxyboride, phosphorous pentachloride, trichloromethyl ester of the acid, oxolyl chloride and the like.

When a compound of formula III is used as the free acid or as a salt, the appropriate condensing agent is used. As the condensing agent may pcnuii Ν, Ν'-disubstituovlné carbodiimides such as Ν, Ν * -dicyklohexylklrbodiiiid and the like, compounds as Ν azolido, Ν'tiočyldiiiidszol-etc., Dehyůrateční JEKO agent is N-etoxykerbolpУ- _/ 2-etoχy -1,2-dihydropyridinol, phospholroxy chloride, 11-oxyacetyl and the like, 2-halopyridio salts such as 2-fluoropyridine trifluoride iodide and the like.

The acylation reaction of the invention is usually carried out in an appropriate solvent in the absence or absence of a base. Often, halogenated hydrocarbons such as chloroform, dichloromethane and the like, ethers such as tetrahydrofuran, dioxane and the like, dimethylformamide, diethyl acetyl, acetone, water and their networks are used as the solvent. Among psUjříí used bases for example inorganic bases such as alkali metal hydroxides, hУ ^{<d 'of} the alkali metal β®ačtličitečy'. alkali metal carbonates, alkali metal acetates and the like, tertiary amines such as triethylamine, triethylamine, tributylamine, pyridine, N-mitylpipeaid, ΝΝΧΧ ^ ^, idΙ kol^ kol, collide and the like, secondary amines such as dlcyclohelamine diethylamine and the like.

Usually 1 to several moles of the compound of formula (III) or a reactive derivative thereof per mole of the compound of the formula (II) or a salt thereof are used. The reaction is normally ^and di- ^p rov at a temperature ranging from -50 DEG .about + 4 ° C. The reaction of ^b and ^d is interpreted by ^b. .About ¹⁰ minutes 48 hours.

^^ J ^ 1 ^ z ^e ILD during the acylation reaction ^{of p} ccording to the invention is either with ^the UPIN ^{R, A, R 2} and R ⁸ group is active for the reaction with conventional protecting CTA AICC group during the reaction. After the reaction, the protecting group can be removed by conventional means.

The compound of formula (I) so produced and its salt can be isolated by conventional means.

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

^J es'tl ± ^Z e is obtained by acylation of compounds of Formula I Nina ^ wherein ^R ^ is of allyl, difehylmetyl, phenyl, 2-karb03Qrfextyl, 1 '-pivlloyloDybenzy 1 -C lCsyloзy _^ ~ 561kyl or ftalidilová with oup ^to, or peephole formula -СНОД ^ or - ^ch ° ^{coorR ki -R} e and ^R? IIII oýše UOE en ^{d ý oýznяm, I7,} I7

R ^'R' the compound may be converted in conventional manner to the ^p onídaaící compound or a salt thereof wherein ^R1 is hydrogen; . where the compound of formula I is obtained to ^r1 . ^ represents a driver can be converted into the compound in a conventional manner to the corresponding compound or a salt thereof, wherein ^{R 1} of ⁿ Amen CC ^ alkyl, ^{and e} -methylphenyl yl, phenyl, Z-carboy-phenyl, 1 'pivalate ^ lo ^ běiizyl ^C . EcfJ-oxf-C. al ~ yl ^{n to b} e o ne ^b Sapin of Formula ⁶ or -CHOCOOR -CHOR ⁶ where R ⁶

II ^{R7 R7} and R are as defined above, obtained when the salt of the compound of Formula I of this miíůže be converted in conventional manner into the free compound.

Among the compounds of formula I of this invention are preferably those compounds, E and ^KD is ^- with ^the formula for ^P inu - ^{C -} ^ výhodd network with ^^ ^f ^ y en ^to de R zněměn ^- methyl

N $

OR group. Then there are ^ уИосХпУо ^! especially the son isomers. Another example of preferred compounds of the

There are three compounds wherein R is a substituted 1,2,3-triazyl group, a 1,2,4-triazole group or a 1,2,3,4-tetrazylol group which may be substituted as described above, and are attached to an exomethylene group in the position 3 of the cephem ring by the uhldk-dusdk bond, z^tThese compounds are particularly preferred^-ště vý^hodn^E t^{y kd}E^r2 means^- 1^,2^,4^-trijZVl^y1 or 2- (1,2^,3.4 tetrasolyl, which may be substituted as described above.

Further described is a process for producing a compound of formula II with a material for the process of the invention.

or is a salt which is the default

This compound is obtained as follows:

_R 10 ° ^a

A COOH conversion reaction at the 3-position or is a derivative at the carboaxyl group or a salt thereof (17) _K &apos; and

In a compound of the formula, it is an amino group

A ^N 'j ⁴ ch ₂ y

COOR ' ^and (II) or its salt

IV represents a >> Z group

7> S, or - »O, formulas

/, 12

C = C-NH-

R where R

1 '

which may be the same or different and denote hydrogen atoms or organic residues not involved in the reaction, or a group of formula

C = -, wherein R ¹ and R @ ¹ · ^'the liquor can be the same Neto rvzdí ^{l Уé,} alkyleneoxy means a ^carbon-d ^ ^k u Neto organicW residues that participate in the reaction and R'? represents a sub-substituted acyloxy or a substituted amino group;

Ob

The radical R @ ^v in the compound of the formula IV and in their salts represents an amino group, a group of the formula

= C-NH13 group of the formula R '4 e' ^ ^R15 N = C

A group of the formula R @ ¹ = C @ ¹ -H @ 1 ^from 1.3 is also meant a group ^{of the} formula R @ ¹ which is:

CH-C = N-

1-3 with its isomer.

12 As an organic radical which does not participate the reaction, in the substituents R, R, R ^{43, R '4} and ^{R 5} in the above-mentioned vzorcíc ^h may be ^p OUZ ^ZT Suto ^ tuované no ^b of unsubstituted aliphatic and, if cyclic' eromatic, araliphatic, heterocyclic and ecyl radicals, in particular the following groups are meant:

1. aliphatic residues, such as alkyl and alkenyl groups;

2. cycloalkyl and cycloalkenyl groups;

3. aromatic residues, for example aryl groups,

4. araliphatic radicals, for example aralkyl groups,

5. heterocyclic residues, for example heterocyclic groups,

6. acyl groups: acyl groups which may be derived from organic carboxylic acids. Examples of such acids are aliphatic carboxylic acids, alicyclic carboxylic acids of a cycloaliphatic carboxylic acid, an aromatic group of a substituted carboxylic acid, an aromatic group of a subethoxylated carboxylic acid, an aromatic group substituted oxyeliphatic carboxylic acid, an aromatic group of a substituent. in the case of a sub-substituted alpha-carboxylic acid, a heterocyclic-substituted oxo-α-aliphatic carboxylic acid, or a heterocyclic-substituted thioaliphatic carboxylic acid, an organic carboxylic acid in which the aromatic ring is an aliphatic group or an aliphatic carboxylic acid; a cyclic group attached to the carbonyl group by an oxygen, nitrogen or sulfur atom, an aromatic carboxylic acid, a heterocyclic carboxylic acid, and the like.

As said aliphatic karbonlové acids include mraaennč acid, acetic, propionic, butanoic, isobutene, pentane, methoxy] χyoctoeot, _{meeyVtiooctoeou>} limited, crotonic acid and the like; as said aliphatic carboxy acids. cyclohexanoic acid and the like; said aliphenyleliphatic acids include cyclopentaacetic acid, cyclohexaneacetic acid, cyclohexanepropionic acid, cyclohexanedieneacetic acid and the like.

As the aromatic residue in the above-mentioned organic carboxylic acids, the above-mentioned examples of asylum groups can be used. As the above heterocyclic books, the above examples of heterocyclic groups can be used.

_ l,

Further, the individual groups of which these organic carboxylic acids consist may be substituted substituents such as halogen, tyrol, protected hydrologic, alkyl, alkoxy and acyl, nitro, amino, protected amino, or a protected carboxyl group or the like. ‘

As the amino protecting groups mentioned, U and ^4a may be used.

As the hydroxyl protecting group, all the groups commonly used for protecting the hydroxyl group can be used. In particular, readily removable acyl groups such as benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4-phenylazobenzyloxycarbonyl, 4- (4-bromobenzyloxycarbonyl), 4-nitrobenzyloxycarbonyl, 4- (4-bromobenzyloxycarbonyl) , 1-dimethylpropoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, 1-cyclopropylethoxycarbonyl, 3-chloropropylethoxycarbonyl, 3-chloropropylethoxycarbonyl, 3-chloroethoxycarbonyl, 3-chloro , trityl, methoxymethyl, 2-nitrophenylthio, 2,4-dinitrophenylthio and the like.

All the groups commonly used for carboxyl protecting groups can be used as carboxyl protecting groups. Particular examples are methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, benzyl, diphenylmethyl, trityl, p-nitrobenzyl, p-methoxybenzyl, benzoylmethyl, acetylmethyl, p-nitrobenzoylmethyl, p-bromobenzoyl, methanesulfonylbenzoylmethyl, phthalimidomethyl, trichloroethyl, 1,1-dimethyl-2-propenyl, 1,1-dimethylpropyl, acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, 3-methyl-3-butynyl, succinimidomethyl, 1-cyclopropylethylmethyl, 1-cyclopropylethylethylmethyl, 1-cyclopropylethynyl, 2-ylmethyl-methyl, pyridin-1-oxide-2-yl-methyl, bis (p-methoxyphenyl) methyl and the like; non-metallic compounds such as titanium tetrachloride and silyl compounds such as dimethylchlorosilane, as disclosed in Japanese Patent Laid-Open No. 7073/71 and Dutch Laid-Open Patent Application No. 71 05259.

Derivatives of the compound of formula II on the carboxyl group include, for example:

a) esters: esters which are commonly used in the field of penicillins and cephalosporins can be used. In particular these include the esters mentioned for the substituent R ^first

b) carboxylic anhydrides with N-hydroxysuccinimide, N-hydroxyphthalimide, dimethyl. hydroxylamine, diethylhydroxylemine, 1-hydroxypiperidine, oxime and the like.

c) amides: these include acid amides, N-substituted acid amides and N, N-disubstituted acid amides. Particular mention may be made of N-alkylamides of acids such as N-methylamide of acid, N-ethylamide of acid and the like, N-arylamides of acid such as N-phenylomide of the acid and the like, Ν, Ν-dialkylamides of acids such as N, N-dimethylamide, Ν, Ν-diethylamide, N-ethyl-N-methylamide and the like and acid amides with imidazole, 4-substituted imidazole, triazolopyridone and the like.

As the acyloxy and carbamoyloxy groups for the substituent R, there may be mentioned in particular alkanoyloxy groups such as acetoxyl, propionyloxy and butyryl groups and the like, blkanoyloxy groups such as acryloyloxy and the like, aroyloxy groups such as benzoyloxy and the like a carbamoyloxy group. They may be substituted by one or more substituents such as halogen, nitro, alkyl, alkoxy, alkylthio, acyloxy, acylamino, hydroxyl, carboxyl, sulfemoyl, carbamyol, carbalkoxycarbamoyl, aroylcarbamoyl, carbalkoxysulfemoyl, carbalkoxysulfemoyl, and the like.

In the above substituents on R, the hydroxyl, amine and carboxyl groups may be protected by conventional protecting groups. The protecting groups can be used for the amino-protecting group shown by R ^e and the hydroxyl and carboxyl protecting groups mentioned in groups R to R 6.

Salts of the compounds of formula IV include both acidic and basic salts. In particular, salts of the compounds of formula I or II may be used.

7-Amino-3-substituted methyl-3-cephem-4-carboxylic acid of formula (II) or a salt thereof can be prepared by converting at the 3-position of a cephalosporanic acid of formula (IV) or a derivative thereof to a carboxyl group or a salt thereof with benzene, thiophene, furan ,

C. _r alkylnitriiem, benzonitrile, cyanofurane, I, 2,3-triezolem, 1,2,4-triazole or

1,2,3,4-tetrazole, which may be substituted by the substituents mentioned in R, in an organic solvent in the presence of acids or complex acid compounds and then, if desired, deprotecting the carboxyl group or converting the carboxyl group to salt.

According to this process, a compound of formula IV, a carboxyl group derivative thereof or a salt thereof, is treated with the above-mentioned substituted or unsubstituted benzene. A compound of general formula II or a salt thereof, wherein R ² is the corresponding phenyl. Alternatively, the starting compound is treated in a similar manner ^{8 c} i_5altylnitriiem, benzonitrile or cyanofurane give the compound of formula II or a salt thereof, wherein R ² is the corresponding C ₂ _ ^ alkenoylaminová, benzoylamino or furoylaminová group; or reacting the starting compound with the above substituted or unsubstituted thiophene or furan to form a compound of formula II or a salt thereof, wherein R is the corresponding 2-thienyl or 2-furyl group; or reacting the starting compound with the above 1,2,3-triazole, 1,2,4-triazole or

1,2.3- 4-tetrezol, which may be substituted as previously described on the ring carbon atoms, to give a compound of formula II or a salt thereof, wherein R ² represents the corresponding

1,2.3-triazolyl or 1,2,3,4-tetrazolyl. In all cases mentioned herein, the reaction is carried out in an industrially easy manner so that the product is produced in high yield and in high purity.

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

H

N - N __ _ь N - NH rA _n X _r r ^ N ^ R

H

N - N. N = * N _r > 4 _n x NH

H where o

K represents a hydrogen atom or the aforementioned substituents as in R. If two R groups are present, they may be the same or different.

The triazoles and tetrazoles having different substituents on the ring carbon atoms can, if necessary, be used in the reaction in the form of basic or acid salts. As these basic and acidic salts, the same salts as the carboxyl and amino salts of the compound of formula I or II can be used. Salts of the compounds of formula (IV) may first be isolated and then used or produced in situ.

Protonic acids, Lewis acids and Lewis acid complexes can be used as acids or acid complex compounds in the reaction. Examples of protonic acids are sulfuric, sulfonic and super-acids. means acids which are more than 100% sulfuric acid, including some of the aforementioned sulfuric acid and sulfonic acid. In particular, sulfuric, chlorosulphuric, fluorosulphuric and the like acids, alkylrnono- or alkyldisulphonic acids, for example methanesulphonic acid, trifluoromethanesulphonic acid and the like, aryl mono, aryldi and tert-butylsulphonic acids, for example p-toluenesuccinic acid and the like can be used. magic acid FSO 3 H-SbF 3, FSO 3 H-AsF 3 acid, CH 3 SO 4 · HSSF-, HF-BF 1 H 2 SO 4 -SO 4 and similar superacids. Examples of Lewis acids include barium fluoride.

Lewis acid complex compounds include complex salts of boron trifluoride with dialkyl ethers such as diethyl ether, di-o-p-methyl ether, di-n-butyl ether and the like, corpilexex boron trifluoride salts with amines such as ethylamine, n-propylamine, n-butylamine, tre <tSynoO: .milo? likewise, complex salts of boron trifluoride with carboxylic acid esters such as formic ethyl, ethyl acetate and the like, complex salts of boron trifluoride with aliphatic acids such as acetic acid, propanoic acid and the like, and complex salts of boron trifluoride with nitrates, such as aceto-, nortril, lrQplooOtril and the like,

All solvents which do not adversely affect the reaction can be used as organic solvents. In particular:. n ^ -t ^ ^ r ^ k ^ OAL dreams, such as nitromethane, nitroethenyl, oitropr ^¼ 0lao and the like; organic carboxylic acids, such as formic acid, acetic acid, toifluoroacetic acid, dichloroacetic acid, poolionic acid and the like. acids; ketones such as acetone, methyl keto ketone, ethoxy sisobutslkttoo, and the like; ethers such as diethyl ether, _{diisolroplSléee>} · dioxane tttrahsdrofuolo, etsléoglykoOdimetySééer, anisole and like ethers; esters, such as, for example, trifluoromethyl, diethylcarbonate, methyl acetate, ethyl acetate, ethyl chloroacetate, butyl acetate and the like; such as ιοοι πΟΙγΟΙ, bulysonOttil and the like, and sulfolanes, such as suHo ^, and the like. These solvents may be used alone or in two or more bolds.

Complex compounds composed of these solvents and Lewis acids can also be used as solvents. The acid or complex acid compound is used in an amount of 1 mole or more per mole of the compound of formula (II) or a derivative thereof on the carboxylic acid group or a salt thereof. This ratio may vary according to the conditions. It is particularly preferred to use 2 to 10 moles of acid or acidic complex compound per mole of 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 co-compound compounds.

In the above reaction, 1 or more moles of benzene, thiophene, furan, Cl, is used. 5-alkenyl, bennoontril, cyanofurene, 1,2,3-triazole, 1,2,4-triazole or 1,2,3,4-tetrazole, which may be substituted as a mole of the compound of formula (IV), its carboxylic acid derivative as described above group or its sooi. Especially preferred is a ratio of 1.0 and 5.0 moles per mole of the compound.

^T his reatoe ^are conventionally Eq ^{UNG P} s te ^ o ^ ^{0 and 80} ° C. ^About bvyklou reatoní ^d both a few minutes, and even several tens of hours. If water is present in the reaction mixture, there may be undesirable side reactions, such as lactonization of the starting compound or product, and cleavage of the beta-11-ring in the ring. For these reasons, the reaction system is preferably kept anhydrous. Compliance with this requirement can be achieved by adding an appropriate delta / disintegrating agent, such as a phosphorus compound such as phosphorous pentoxide, polyphosphoric acid, to the reaction system. . phosphorous pentachloride, phosphorous pentachloride, phosphorous oxychloride and the like, an organic silicifying agent, for example, Ο,--bis-triethylsilyl-acetamide, triethylamine, triethylsulfonyl chloride and the like. ethyl chloride, p-toluenesulfonyl chloride and the like, acid anhydride such as acetic anhydride, trifluoroacetic acid and the like. similarly, an inorganic desiccant, for example anhydrous magnesium sulfate, anhydrous calcium chloride, moocecular sieve, calcium carbide and the like, or the like.

When a carboxylic acid derivative of the compound of formula (IV) is used as the starting compound in the above reaction, in some cases, the corresponding compound of formula (II) having a free carboxyl group at the 4-position of the cephem ring can be obtained . A compound of formula II having a free carboxyl group at the 4-position of the cephem ring can also be obtained by removing the group on the carboxyl group in a conventional manner.

• lestlke скОД reacting with this compound, ^{b s} ECN it Formula ^{II, w} e H ^1v represents a hydrogen atom, this compound can be converted in conventional manner into a salt or esterifkovat. If otoc ^ сШ compound of formula ^I above wherein ^{R1 and} esters ynamen ® Cupin tue ^ ^t may formulate it in conventional manner to give a compound of formula II, ^w e R ^b is suddenly vodka. This) compound may be ^p-NIM and further converted to the L & ^b not on the ester. «Testlke the ^ Row compounds OTAC-it ^{II, w} e R ^<18 represents sollUornou s ^ pin ^ can be conventional manner undergo reaction in which the salt is produced a compound of general formula ^{II, wherein R s} represents a hydrogen vodka in popřJ ^ ^ and may further be produced therefrom _β obec1 compound of formula II wherein R · ^α represents an ester group.

When a substituent is attached to benzene, C, 5'-Cllium, b, cyanofuran, thiophene, furan, or 1,2,3-triazole, 1,2,4-triazole, 1,2,4-triazole, 1,2,4-triazole, 1,2,4-triazole, 1,2,4-triazole, 1,2,4-triazole, 1,2,4-triazole -treciol or 1,2,3,4-tetrBzole, which is the reaction component of said reaction, is substituted with a hydroazyl, amine or carboxyl group, then the desired compound is prepared by first protecting these groups with the above protecting groups and then subjecting them to reaction. After completion of the reaction, protect them. remove groups as usual.

If a compound of formula (II) wherein R is a substituted or unsubstituted benzene, 2-thiolyl or 2-furlloe group which is attached to the exomethylene group at the 3-position of the cephem ring by a carbon-carbon bond, is produced, besides the above-mentioned conversion reaction in position 3 of the known method that the Op ^ i ^ i ^ c ^ i ^ iii ^ u as a default maaeriálu opens tiвyold ^d inoeý ring by reaction with 3-л -prop-2-inlliromidem for opening · ring, and then the reaction to create a series dihl ^d roeiediilového ring (Nom-ETE cnlaloзporinoeého skeleton) (see Japanese Patent Publication no. 5393/75, JMC, 20, 1082 (1977); ibid., 20, 1086 (1977) ).

The following are the results of tests on the pharmacological activity of typical compounds obtained by the process according to the invention:

) AnitbaB: Ctrial efficacy

Standard way according to Japanese αhenmtenavntlcké companions Vol.

23, pp. 1-2 (1975)), the culture obtained by culturing the batteries in Heart III broth (manufactured by Eiken Kagakushv) at 37 ° C for 20 hours is seeded on Heart Infusion agar medium (manufactured by Eiken firoia) Kagakusha) and cultured for 20 hours at 37 ° C. Then the growth of ΙβΙ ^ ιΉ is examined visually. Minirnmání inhibitory concentration at which the growth of ^e j inhiioeén ^is referred MI ⁰ Qg). Knnžžtví vaccinated bacterial occiput ^ ¹⁰ ^ ^ EQS ^D ES ^to the cells per ml).

Test compounds:

A. 7- [2- (2-Amino-thiazol-4-yl) -2- (yn) -methoxy] -iminoacetamide] - / [(3-acetamide-12,4-eriazolyl) -methyl] -3-cephem-4-trifluoro-octanoic acid salt carboxylic acids

B. 7- (2- (2-Aminothioyl-4-yl) 2- (lin) meetoxyimino) acetamido] -3- (furan-2-ylcarbonyl) -8-methyl-3-chloro-4-carboxylic acid trifluoro-acetic acid salt,

C. Trifluorooctoeic acid salt with 7- / 2- (2-aminothiazol-4-yl) 2- (8n) -ethoxyethoxycetenido [-3-acetamidomeeyl] -3-cephem-4-carboxylic acid oxylic acid,

D. Trifluoroacetic acid salt with 7- / 2- (2-aminothinzol-4-11-2- (ynn) methoxyiminoacetamide) -3- (4-trifluorophenyl) -3-cellin-4-carboxylic acid,

2—6471

E. 7- (2- (2-Amino-thiazol-4-yl) -2- (syn) imethoxyiminoacetarnido) -3- [2- (1,2,3,4-tetreoolyl) methyl] -3-cepetyl-trifluoroacetic acid salt carboxylic acids,

F. 7-12- (2-8-Thinothiazol-4-yl) -4- (snn) -methoxy-trifluoromethyl-4- (1,2,3,4-tetrazolyl) -phenyl-3-cef trifluoroacetic acid salt em4 - rrbbooylovo acid,

G. trifluoroacetic acid salt 7-12- (2-8iinotirz / L-4-yl) 22- (ann) -meooxyirninorcetгтШоАЗ К-5-8 ^ ^^ - 1, _2,3> 4-tetrazolyl) mely4-4 -cefem44-rrrbooylovic acid,

H. Trifluoroacetic acid salt with 7-12-2 2-ethylthiazole-4-yl) 22- (sin) -ethanol-1-octanol / 12- (5-cyclohexyl) -1,2,3, 4-Tetrazolyl) ethyl-3-cefe44-carboxylic acid,

I. Trifluoric acid salt of 7- [2- (2-dimothiazol-4-yl) -2- (yl) -methoxy] octethoxy] -2- (5-ethyl-1,2,2,4-4- )θίΓ8Ζ0 ^ 1) Fetyl-3-cefem-4-icarbooyl acid,

J. Trifluoroacetic acid salt with 7-12- (2-kineticsolol-4-yl) 24- (S1) -etolyl-octetolphenyl] -1- [2- (5-ethyl-1,2,3,44-tetrazolyl) -ethyl] -3-cephem-4-one --- erboxllovol acid,

K. Trifluoroacetic acid salt with 7-12) - (2-thiothiszol) -4-yl) -4- (lin) -ethoxyolimethylcarbonyl-3- ⁽ -) - chloro-1,2-triazole ) methyl1--3-cefem4 - kiгbooylovoi acid *

L. Trifluoroacetic acid salt with 7-12- (2-chloro-cyclo [-4-11] acetamido) -4- [2- (5-acetamido) -2,3,4-tetrazolyl] ethyl] -3 -Cefem4 - Rarboxylic acid

M. Trifluoroacetic acid salt with 7-12- (2-quinolazol-4-yl) cetamido] -N- (2- (1,2,3,4-methrazolyl) methyl) -3-cephem-4-ar ' OoJyrlovol acid. , k

T ^y's sIouč ^III-1 of Example 10, roll KTA. r position, Cast ^1.2 44trikzo ^ll nominal groups not specifikovánr as 1, 2,4-trikz / butyldimethylsilyl skipinr is NR -x / u ⁺ e; if ^^ / v / u skipini position - · c-FEI / It has not been confirmed which of the ranks of the 1,2,4-tricollol skipin is the nr -x (ethylene) v / l skipini in the c-fern krihi position. Firstly, the 1,2,4-triazolyl ssubstituted polystyrene is specified at the position of the sibstitient in the starting compound used. The same observes in this description, which is not confirmed, which one of the 1,2,4-triczolyl skipines is nrpoj-η nr -x / ethylene / v / l skipini in the - c-fei / weight / krihi position. For example, compounds in which 3-phenyl-1,2,4-triazolyl, 3-feeyllio-1,2,4-triczo, 3-cetylpyrido-1,3-triazolo-1,3-chloro-2,4,4-triazole, -4- to>xykkrboonl-1,2,4'-triczole or p / O / yollyl-on-irr-xornetyleilo> in / u skipini in position - c-fem / weight / krihi, being bonded ------ ((3 -) - 1 - (1, 2,4-triazole) ethyl) ----, --- 3 - / (3-ethylthio-1,2,4-triazole) ethyl] -, -—- 1 (3 1,2-(4-thiazolyl) feeyl------ [(-chloro-1,2,4-triazolyl) ethyl] - n -benzyl- (1 -) - (-) IL) 1 ² 44trikzoOyl) -meeyl / ----. The Νο-ΛΙο^^^^^ ₍ ^ 1 1ol (1 1 1 1 1 1 1 1 1 1 1 1inoinoinoinoinoinoinoinoinoinoinoinoino Eino E E E E E E E EΝ-E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E E,4,4,4,4,4,4,4,4,4,4,4,4,4,4,4,4,4,4,4,4,4,4,4,4,4,4,4,4,4,4,4,4,4,4 Other compounds.

οχ cn O χρ ΙΑ OX o * I o what b O-¹ '' co σχ b- m o- o ^- ' ¹ αχ cn \ o ΙΑ co r- 1 oo b- oo r- οχ n O · " O* O 1 1 O O AND 1 ^AND O\ σχ 00 m ΓΊ r- 1— • X 1 AND l AND ( AND о O O O O O VI οχ VI what 00 VI cn cm b- - _J ř * - _{AND AND} о O O ¹ o ^{x 1} O O ^{AND AND} VI σχ σχ VI г— m m CM - • X · » | 1 1 AND 1 1 о O o ' O O O VI οχ VI VI <n CM _AND о O O O ¹ O O ^{AND 1} VI VI VI 00 οχ oo FROM οχ XO * · b · cm cn IA t- C- cn IA IA ** · 1 AND O O O O CM O O O CM IA VI CM ox IA KO 00 IN- <n Ф— CM CM 1Λ CM CM b ^ IA * «X 1 AND O O O O КО O O O CM IA VI VI cm O\ oo cn IA r— IA СП in- in- b ^ CM • х «Ь <x 1 · » · * 1 о O O O CM о O O O CH КО VI VI VI VI VI VI O IA oo СП what 03 / ко IA · * - IA CM CM ί- b- b " »- the CM · * M O O Ό ο lA n O O O IN- IA kO VI CM VI CM

Я <н H o Ы

ox in xo what σχ IN m и · cm cm the b- c> • X • X • X O O O XO o o - O O O She knows VI 1ГХ VI

ox xo ox n · · ux M СМГЛСМ -

OOe-OlOOOOOO VI C ^M VI

IA

CM u> IA kO CM CM

O

VI o

VI ко IA σ> гп

o VI

IA CM

XO

CM o

IA CM

KO b ^ o

CM o

CM o o

VI xo tA

IA CM

O o CM

Λ

O o

CM A o o

CM _ A A o CM

IA CM xO co b 'o

lA

CM IA - CM cn cn m IA CM

O o CM

-s • H Я й ФЮ 3 P 3 Λ4 O áá

M O O CM Ή CM XO O •C? O b- τ— t- а χο it" O 3 LTX AND Μ- b- «- A4 1 H ι σχ H CM 1 1 3 H H q 1 E4 & H Ό and H 2 EH O·- φ and Φ H G n n h S CD Λ what φ • H • H • H ♦ э • d • H φ O • d H H WITH <*) Φ G WHAT Я what n ri Ή • H 2 no O H O O Φ / □ X> ² IH • H t 8 cH 6 what O ^t ° 0) CD h cH 3 Φ 3 O F) (4 AT • Й • cl • H Φ · Η Φ • H Φ cH ¢ 0 O • H cH cH P O β W я AT E WITH with 8 O O Λ4-Η and •O and • • O O ^{03 G} JD Φ P * 4 O O O • • Η cH rH я Φ > 4 »4 h M M and Μ M * 4 W ω and and and

2. Oral administration

Each test compound is administered orally to mice (ICR, male, 4 weeks of age) at doses of 2 mg per head. The amount of compound in the urine was determined. The results are shown in Table 2. Upon absorption in the living body, all test compounds are easily deprived of the ester group. The corresponding free carboxylic acids are thus obtained. These free carboxylic acids excreted in the urine were quantitatively analyzed and taken as the amount recovered from the urine.

Method of administration: The test compound is suspended in a 0.5% CLIC solution and then administered orally.

Method of performing quantitative analysis: Quantitative analysis is performed using the paper disc test method with the bacteria shown in Table 2.

Compound

к ’ O Obtained back Tested AND from urine (%) ⁺ bacteria -ch ₂ - -CH ₂ OCOC (CH ₃ ) ₃ - N ^Z 1 45.1 M.luteus ATCC9341 -CH ₂ - -CHgOCOCCC ^ Jj 32.0 M.luteus ATCC9341 —C— (syn) II N-OCH ₃ -CH ₂ OCOC (CH ₃ ) ₃ N = N ^Νχ Α = Η ₃ 33.1 M.luteus ATCC9341

-C- (son) -CH-OCOC (CH3), -N 35.0 M.luteus II I ^{3 3} ATCC9341 N-OGH ₃ CH ₃ ^{X x} ₃

• C— (son) II N-OCH ₃ N - N -CH ₂ OCOC (CH ₃ ) ₃

47.0 Kl.pneumoniae • ATCC10031

Note:

⁺ 0 to 4 hours; average value of 5 examples.

3. Acute toxicity test

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

Table 3

Test compound ^XD 50 (g / kg)

> 30

(son)> 30

The compound of formula (X) and a salt thereof may be administered to humans and animals in the form of free acids, nontoxic salts or physiologically acceptable esters in the treatment or prevention of diseases caused by infections. Preferably, the compounds are administered parenterally in the form of free acids or non-toxic editions or orally in the form of physiologically acceptable esters. In these cases, they can be manufactured in the dosage forms customary for cephalosporin drugs, such as tablets, capsules, powders, granules, fine granules, syrup, injections (including drops), suppositories, or the like. if necessary, diluents and / or auxiliary agents including excipients such as starch, lactose, sucrose, calcium phosphate, calcium carbonate and the like may be used, such as gum arabic, starch, crystalline cellulose, carboaxymtyylcellulose, lygololpolyoyl cellulose and the like, lubricants such as calf, magnesium stearate and the like, and lubricating agents such as kerbetic acid calcium, talc and the like.

When administering the cephalosporiral compositions of the invention by dose, the dose and the number of doses are determined by a number of factors and other factors. Usually, when administered orally or prenitrically, 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 preperative examples, which are not intended to be flawed by the invention.

Reference Example 1

1. Suspend 2.72 g of 7-sminocefelosporanic acid (hereinafter 7-ACA) in 15 ml of anhydrous ecetonitrile. To the resulting suspension was added boron trifluoride diethyl ether complex (5.68 g). The 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% by volume of water). The pH of the solution was adjusted to 3.5 by adding 28% (mono%) aqueous ammonia under ice-cooling. The separated crystals were filtered off, washed first with 5 ml of aqueous 50% acetone and then with 5 ml of acetone. After drying, 2.14 g (79% yield) of 7-amino-3-tetramido-methyl-3-cyclohex-4-hexylic acid having a melting point of ¹⁵⁵ ° ^C (dec.

IR with .delta. (Cm @ -1) cm @ -1: _{C = Q} , 1795, 1640, 1610, 1520.

№ δ spectrum (CF 3 COOD) ppm: 2.37 (3H, s, -CH-), 3.82 (2H, _< s, C 1 H), 4.60 (2H, s, S),> -e ₂ 5.41 (2H, broad s, _C6- H, C2-H),

2. Suspend 2.71 g of 7-amino-3-acetamidomethyl-3-cephem-4-carboxylic acid prepared in paragraph 1 in 30 ml of methanol. To this suspension are added 1.90 g of p-toluenesulfonic acid monohydrate. To the solution was slowly added diphenyldiazomethane (4 g) at room temperature. The resulting mixture was worked at room temperature for 30 minutes. After completion of the reaction, the solvent was removed under reduced pressure with sdeesSils. The residue was dissolved in a mixture of 20 ml of water and 20 ml of ethyl acetate. The pH of the solution was adjusted to 7.0 with sodium bicarbonate. The precipitated crystals are separated, washed thoroughly with water and dried. Gave 2.84 g (yield 65%) of diphenylmethyl 7-imino-3-tcettmidomeSyУ 3-CFSE-4-kc.rboχjlové acid having a melting temperature service ^{from 190} to ¹⁹ 4 ° ^C (dec ^.

^{IR p} ektrum (K8r) cm '': ^q ₌ ^{q 1 758 1 720 1} 0 ^47th

NMR Spectrum (CDCl3) ppm: 1.87 (3H, s, -O2), 3.59 (2H, s, CH2-H), 3.65, 4.27 (2H, ABq, J = 14) c ^p s, S.

4.71 (1H, d, J = 5 Hz, -C-H), 4.89 (1H, d, J = 5 Hz, _C? -H), 6.12 (1H, broad s, -NHCCO) 6.90 (1H, s, -COOO2), 7.36 (10H, s, 2 * 40).

Reference Example 2

The reaction and work-up is carried out in the old-fashioned manner, with trisulfuric acid being used as the reaction solvent. This gives the products listed in Table 4.

TsbuLka. 4

CHjNHCOR ¹⁰

Starting compound

Acid or acid complex b ´ °

Product

Melting point IR spectrum (CC) (cm,, ⁹ C O O) buttrooittil BEj ^ E ^ O *

2-Methylbutyronitrile BF 3 + Et 2 O +

3-ethoxypropio-litrile BŮ ^E OO * acrylooittil cyanoacetic acid HFF.EtgO + benzylkyenid ⁺

-CH ₂ CH ₂ CH ₃ 168 and 170 (rozkL) 1 1 795, 1 610, 1 635 520 CH, 170 to 172 1 795, 1 635 1 J - CHCl ³ CH ³ (mzlk.) 1 620, 1 530 C ^ CH ^ CH ^ ³ 173 to 175 1 800, 1 640 (roztek.) 1 610, 1 530 -CH = CH 2 165 to 167 1 800, 1 650 (yozkk.) 1 615, 1 525 -CHgCOOH 192 to 195 1 755, 1 675 (yozkk.) 1 620, 1 580 -CH3- ^ Q) 185 to 190 1 795, 1 635 (moM.) 1 620, 1 520

ethyl cyanoacetate

-CH2COOCH2CH3

185 to 190 1785, 1730 (mOk) 1610, 1530 chloroacetyl

-ch ₂ ci

185 to 190 1,790, 1,650, (yozkk.) 1,610, 1,515

2-kyanofuyan bennonittil ^^^ t ^ ⁺

200 ei 204 (mOk ·) 1780, 1630 1,590, 1,510 212 to 214 1,793, 1,630 (decomposition ·) 1610, 1520

2-cyanothiophene BE ^ E ^ O *

189-190 1,795, 1,620, (roslck.) 1,530 р-ЮТиг ^! -!.! ^B F ^j . ^E O2 ^{O +}

173-178 1,790, 1,630 (roslck.) 1,615, 1,530 psoanissoil

BF ₃ .Bt ₂ O ⁺

188 ei 193 1790, 1620, (yo ^ Ok.) 1595, 1530 p-Hydyoxybanonnitrile

BF _3. ^^ 2O ⁺

182 to 184 1,795, 1,625 · (yoold ..) 1,600, 1,530

Continuation of Table 4

Starting compound Acid or acid complex and ' ⁰ Product Melting point (° C) IR spectrum (cm ^{-1, V} c = 0) p-cyanobenzenes . st ^ c ⁺ fjBVcooH - 178 to 183 1,800, 1,700, к у s ·! 1 x na (dec.) 1,630, 1-530

B? ₃ .Et ₂ O ⁺

-kytany no -5 -π α ty 1— ^f uren

2-Acid-3-methylthiophene-Et 2 O

ΧΊ 188 to 190 1 780, 1 630 v ^v 3 (rozzie) 1,600, 1,530 ^l3 -x? 175 to 178 1 790, 1.630 (crotch) - 1610, 1530

2-methyl-4-cyeno-5-phenyl-1,2,3-.

-triezol BF 3 < Et 2 O +

193 to 195 (rozkk)

790, 1660

610, 1530

3-Cyenocoumarin

BFyB ^ O *

197 to 199 (rozk.)

790, 1 710

640, 1600,

530

3-4-ky8no metylkurnarin .Е Ы ^ ^ ⁰ *

210-212 (dec) acetone 1 H conc. sulfuric acid

-OH}

155 (rozZk.)

790, 1 710

640, 1600,

530

795, 1 640,

610, 1520

Comment: ^ ^ О .Е means ^sic omplex diets ^^ era with boron trifluoride ^(further uses of ^d e. The same sign) / ++ * Reaction under acθtQn0trilu.

Reference Example 3

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

CHjNHCOR ¹⁰

COOH

Table 5

Compound ^r10

Melting point IR (KBr) cm -1 ^{* 1} : V ¹ _{G = O}

-Q * 167 to 169 (crotch) 1,755, 1,718, 1 642 n 192 to 195 (crotch) 1,755, 1,720, 1 625 218 to 220 (crotch) 1,755, 1,720, 1 638

Reference Example 4

1. Suspend 2.72 g of 7-ACA and 14.2 g of diethyl ether complex with boron trifluoride in 13 ml of sulfolene. 1.0 g of 5-methyl-1,2,3,4-tetrazole was added to the resulting slurry, and the resulting mixture was treated at room temperature for 17 hours. After completion of the reaction, the reaction mixture is poured into 15 ml of ice-water, the pH is adjusted to 3.5 with the addition of 28% aqueous (% humid) ammonia under ice-cooling. The separated flowers were separated by filtration, washed with 5 ml of water, acetone and dried. There was thus obtained 1.76 g of a mixture of 5- _methyl- (5-methyl-1,2,3,4-tetrazolyl) methyl-3S-cephem-4-carboxylic acid and 7-amino-1- (5-methyl-1, 5-methyl-4-carboxylic acid). 2,3,4s (tetrazolyl) methylS-S-cephem-Carboxylic acid in the form of crystals *

2. In 18 ml mmtenólu was suspended 1.76 g of crystals above four (par. 1) and ee suspeozi BC ^{was added} 3 ^{g of 1,1-O} monotydrátu tyseH ^{.p-1-sulfonic} toluenesulfonic. A solution K is formed ^; 4.6 g of difeoyldazzomenane are then slowly added to this solution. The resulting mixture is treated at room temperature for 15 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue thus obtained was dissolved in 30 ml of ethyl acetate and 30 ml of water. The resulting solution was adjusted to pH 8 with sodium bicarbonate. The organic layer was then separated, dried over anhydrous magnesium sulfate and the solvent removed by distillation under reduced pressure. The residue thus obtained was purified by chromatography on silica gel (C-200 silica gel, eluting with 4: 1 hexane-acetyl acetate) to give 0.79 g of diphenylmethyl-23.

4зб47.1 ester 7-liinčoЗ- / 2- (5-ietyl-1,2,3,4-eeΐaalolylčΐeeУyl / -Ceceie - 4-krrboxylovΌ acid, mp ¹⁵⁷ and ^{Z 160} ° C (dec ..) and ^{0 14 g of 7} -iíííičo ^{- 3/1} - ^ - MTY} .- _^1,2,3} 4-teta8lolyl) methyl / -3-em-ce ^{i -} k ^{and s} abboxyllv ^Kyselica táoí temperature of 92 ° C ( decomp.).

9-Amino-η 2 - (3-methyl-1,2,3,4-tetrazolyl) istyl] -3-methyl-4-carboxylic acid diphenylmethyl ester;

IR spectrum ⁽ Kfir) cm ^-1 : V ^{1 1 1 720} ·

NMR Spectrum (CDCl3) ppm:

1.75 (2H, broad s, NH ⁾ , 2.48 (3H, s, CH 3), 3.20 (2H, s, C 1 H -H),

4.70 (1H, d, J = 5Hz, _C6- H), 4.87 (1H, d, J = 5Hz, C2-H, 5.30,

5.72 (2H, ABq, J = 1 Hz),

6.92 (1 H, s,

-CH3 7.30

Diphenylphosphoryl lieSylester ^ 7 ^ III which - ^ - ^/ 1, 2,3, 4-tetrazllyl) ietll / зЗceefem-4-carboxylic acid: t

^IR spe ^k tnm ^(K Br ⁾ cm ^-1 : Γ ^c = ⁰ 1770, 1725. NMR Spectrum (CDCl3) ppm: 1.80 · (2H, s, Kg), 2.15 (3H, s, CH-j), 3.30 (2H, s, Cg-H), 4.70 (1H, d, J = 5 Hz) (Cg-H), 4.85 (1H, d, J = 5Hz, 0-y), 5.00, 5.38 (2H, ABq, J = 16Hz), S), 6.90 (1H , s, -CH3, 7.30 J-CH2-

(10H, s, 2x

In a mixture of 0.5 ml of cisisole and 5 ml of ethyl acetate, a span of 0.462 g of 7-unino-2- (5-methylmethyl-1,2,3-diphenylmethyl) ester was added. 4-Tetrazolyl) -3-methyl-4-carbolylic acid. The resulting solution was subjected to a one hour reaction at lithium temperature. After completion of the reaction, the solvent is distilled off under reduced pressure. 10 ml of water and 10 ml of ethyl acetate were added to the residue. The pH of the solution was adjusted to 8 with 28% aqueous ammonia (% by weight) while cooling the solution with ice. The aqueous layer was separated and the pH adjusted to 3.5 with 2N hydrochloric acid. The precipitated crystals are filtered, first sold with 5 ml of water, then with 5 ml of acetone and then with 5 ml of acetone. 0.26 g of 9-aminčoЗз / ² - (5-miSyУ - 2,3,4-tetrezolyl) ieeyl / ceeei -3-4-ox KLR ^{b yy y} yselin memory ^to a flow temperature of 178 ° C (dec., ^IR spe ^to trum ^(K rr ⁾ cm ¹ : y) ^{5 5 1} 0 ¹ 6 ^ ¹⁵

NMR Spectrum (CF 3 COOD, ppm): 2.70 (3H, s, CH-), 3.73 (2H, s, Ο, -H), 5.40 (2H, s, C-Ha)

ΔΌ -Η), 5.80, 6.12 (2H, ABq, J = 16 Hz), S L ₂ -

From 0.462 g of 7-methyl-1,2,3,4-tetrazolyl-2,4-tetrahydro-4-carboxylic acid ester (7-methyl-1,2,3,4-tetrazolyl) -isulfonic acid ester was obtained in _a sterile manner. 25 g of 7-chromatography ^ o-3/1 - (3-βieyУ--, 2,3,4-t ^ f ^^^] ^ R i) ^ l ^; ^ ^ll ^ ^ll lis1 L / - c ^^ (^ J ^ i-4 ^-k ^ i ^ l ^ ^b ^ LX ^ ^yl LVE Sey ^ tepyote mp ¹⁹⁵ DEG ^C. @ ¹ Oz ^. ^^ ^IR trum ^{(K SR)} cm ^-1: _{C =:} q ⁷⁹ 5,615,530.

Nuclear Magnetic Resonance 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,

- C? -H, 5.57, 5.92 (2H, ABq J = 16 Hz, S ^> ^C H ₂ 236471

Reference Example 5

Dissolve 2.72 g of 7-ACA and 7.1 g of boron trifluoride distylether complex in 19 ml of trifluoroacetic acid. To the resulting solution was added 0.75 g of 1,2,4-triazole. The resulting mixture was allowed to re-react for 7 hours at room temperature. After the reaction, the solvent was distilled off under reduced pressure. To the resulting residue was added 15 mL of water, and the pH of the solution was adjusted to 3.5 by adding 28% (%) water aqueous ammonia under ice-cooling. The separated crystals are filtered off with suction, washed with 5 ml of water, then with 5 ml of acetone and then dried. 2.5 g of 7-sminοrЗз / 1 .- _(J12> 4 trierolyl) methyl / -C-isfem44 aobroзylové acid, mp 149 ° C (dec.) ^IR spelktrum ^{(K Br)} cm ^- ': V _GS0 ¹⁷⁹⁰ »1 ⁶¹ 0 1 53 °.

NMR Spectrum (CF 3 COOD) ppm; 4.0 ° (2H, br s, C ₂ -H), 5.47 (4H, br s, C-H, C7-H,

S), 8.10 (1H, s, N _y ), 9.80 (1H, s, N _y )

Дсн ₂ - / '' H · У ' ¹⁵ ' ·

N N

Reference Example 6

If the following examples are refined through the wall as in Reference Example 1 or Reference Example 2, then the products listed in Table 6 are obtained. Desestering in the same manner as that described in Reference Example 4 (2) and (3) produces the esters and other acids shown in Table 7.

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mp .: 79 to 83 (dec.) m.p .: 220 (dec.)

IR spectrum: 1770, 1720. IR: 1800, 1610, 1530.

NMR: 1.85 (2H _S, -NH,), 3.12 (2H, singlet, NMR: 3.70 (2H, broad s, C ₂ -H), 5.40 (2H,

what

Continuation of Table 7

* * - * ♦ * m Ф

tfx

II

From “> \ l« o

AND

0} «

* - * (XI σχ чО

Semicircle tables 7

\O

mm

X * m * 3 « · » m N N Ol * X X • t what X t- m w- m Ό

o m t * αχ-·

(0 m Г CM O ( ω cn in * <0

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7.30 (ЮН, s, 2 х phenyl)

P

P

O

WITH

P

J

m * o P й and Φ t4 p xn IA fc • ia 0 - O ·> > W m 34 cm ia · « ft ♦ - M ia тем o

Я « « O CM 1 fc XO O xn ia CM · » N M m » CM IA O O II σχ and

and CM ttí τΓ CM CM - r- O M O * · -

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(10H, s, 2 x phenyl group)

Continuation of Table 7

CM

M (M к

IA

см СО к СП со <n 1Г \ ΙΛ * о Λ - OJ « 1 z * x ЭД OJ см о ř- А no

Continuation of Table 7

s <P

Ф H

Ή

Continuation of Table 7

what

Reference Example 7

If the following triazoles are treated in the same manner as in Reference Example 4, paragraph 1, or Reference Example 5, the compounds listed in Table 8 are prepared. The compounds shown in Table 9 were prepared (2.72 g of 7-AGA was used as starting material).

Table 8

Starting triazole (β)

Compound

R ² (g)

COOH

Melting point (° C)

IR spectrum (KBr, cm ’

In ¹ C »Drawbar:

( ⁺ CF, COOD, ppm); Nuclear Magnetic Resonance Spectrum: ^J (CF 3 COOD 3 · + D ₂ O, ppm):

3-Methyl-1,2,4-triazole (0.91) N ~ N A CH ₃ 2.39 195 (dec.) 1 790, 1 610, 1 530 ⁺⁺ 2.60 (3H, einglet, -CH _3), 3.93 (2H, einglet, Cg-H), 5.30 (2H, einglet C ^ -H and _C? -H), 5.10 5.75 (2H, AB quartet, J = 16 Hz, Sx), 9.45 (1H, e, A, CH3-N) 3-chloro- 191 191 1 790, * 3.75 (2H, einglet, Cg-H); -1 »2,4- N - N 1 610, 5.40 (2H, einglet, _C6- H) -triazole - ^ 4, 1.25 (dec.) 1 530 and C ₇ -H), 5.47 and 5.80 (2H, (1,14) AB Quartet, J-16 Hz, S>), 8.50 (1H, AciU- * N singlet, γ _H) N

3-acetemido-1,2,4-triazole (2,5)

CH3OCHN

2.6

150 to 155 1 795, (dec.) 1 680,

610,

540 * 2.43 (3H, einglet, -CH _3), 3.19 (2H, einglet, Cg-H), 5.35 (2H, einglet, e CgeH

C ₇ -H), 5.30 to 5.96 (2H, multiplet,

9.45 (1H, einglet, N

Ун)

N

Continuation of Table 8 ⁽ ^ ΟΓ ^ ΟΟΙι D ppm ^m :

( ⁺ * CF ₃ GOOD + + DgO ppm):

Starting temperature triezol ₂ melting (g) ^{B (g)} (° C)

IR spee @ 1 H-NMR spectrum of the throne (KBr »cm · ¹ ^ C = 0):

3-etoxis-carbon-1,2,4-triazole (1.55)

N — N ‘SA

COOCH ₂ CH

2.3

795,

720, ¹⁷⁶ 1610, ₁₅₃₀ ** 1.50 (3H, triplet, -CH ₂ CH ₃ ),

3.72 (22, Wide 81Оя11П,

Cg-H), 4.65 (22, quaternary, -01¾¾). 5.35 (2H, sin ^ years),

Cg-H and ¢ 7-2), 5.95 (22, Wide Single ^ S>), * ^ CHH ^CH 2

8 »65 (12» singlat »J> —H)

N

3-aenl-Uo-1,2,4-triazole (1,3)

N — N

SCH3

3.4

147 1 770, * 2.75 (32, si-oglet , sSCH.j (dec.) 1 605, 4.00 (22, single !, C ₂ -2), 1 530 5.40 (22, single !, C ₆ - ^H a O, -, 5.2 3 and 5.85 (2H, AB Ovaatet J = 16 Rz, ^S Ί Z ^ C2 ₂ - ), 9.55 (12, e, TO ) - «> TO

4,5-denoxy-1-carbonyl-1,2,3st-2'-triazole (1.94)

AND

N— = N

I 'I

CH3OOC COOCH3

2,0

161 (dec * 3 ^ »55 (2 ^{R» s} single bs! »

795, C ₂ -2), 4.10 <(H, H, 2 x)

725, sCH ₂ ), 5.35 ((H, s, δ, δ).

610, S-1, 5.90 (22, s,

530 Ζ ^ Ό ^ C ₆ sH.and C? SH)

4skyaoos s5-phenils -1,2,3striezol (1,9)

* 3.75 (22, sioglet, C ₂ -2), 5.35 (22, single !, Og-H and O ~ 2), 5.85 (22, wide singlet, S '' Sj),

7.40 to 7.70 (32, m, meta and para feoyl proton),

7.80 to 8.10 (22, a, ortho feoyl protons)

204 2,220, (dec) ⁽ ^ CN ⁾

790,

610,

530 • ²

Melting point (° C)

IR spectrum (KB &^lt; + ^&gt;, ^C &^lt; -1 ^&gt;, ^C &^lt; -1 ^{&gt; ) s}

NMR Spectrum (CDCl3 ppm):

, N = 461-65775, (dec.) 1,720

2.00 (2H, singlet, -NH 4), 3.43 (2H, ainglet, C ₈ -H), 4.70 (1H, doublet, J -5 Hz, C ₆ -H), 4.88 ( 1M, doublet,

J> 5Hz, C _? -H), 5.00 (2H, singlet,

S \), 6.95 (1H, alnglat, -ClO, d ^^ CN ₂ 7.30 (10H, s, pina), 7.85 (1H, s, x Skuna phenyl), 8.07

(1H, ein-et, N)

N

up to 82

770,

720

1.82 (2M, broad ainglet, -Nlg), 3.10 (2H, singlet, C2-H), 4.55 (1H,

J = 5 Hz, C6-M, 4.72 (1K, doublet,

J 5 Hz, C ₇ -K), 4.70 and 5.33 (2H, AB quartet,

J »16 Hz, S-η),

AcHg 6.93 (1H, broad single-CH 2), 7.30 (10H, ai ^, 2 x phenyl) e 7.70 (1H, an si, N)

N

770,

720

2.33 (2H, broad singlet, -Mg-, 2.78 and 3.21 (2H, AB quartet, J »18 Hz, C ₂ -N), 4.71 (1H, doublet, J - 5 Hz, Cd-H), 4.90 (1M, doublet, J 5 Hz, C-H), 5.32 and 5.92 (2H, AB quartet, J 16 Hz, S-η), 6.86 ( 2M,

ACHgsinglet, -CM <x 2), 7.20 '(20H, singlat, x phenyl group, 8.11 1K, set,) -η>

N

Continuation of Table 9

R ² Melting point (° C) IR spectrum (KBr, cm -1, λχ)> ^! MNR spectrum (CDCl3, ppm): N— N 90 (dec) 1 770, 72 ° 2.32 (3H, s, -CH), 3.42 (2H, s, C ₂ -H), 4.70 (1H, doublet, J = 5 Hz, _C6 -H), 4.85 (1H , doublet, J = 5 Hz, _C7 -H), 4.90 (2H singlet, S1), 6.90 (1H, singlet, T2-CH-), Z2-CH3- 7.30 (10H, singlet, 2 x phenyl) 7.85 (1H, singlet, N) У * N Ντς-Ν 167 to 168 COOCH ₂ CH ₃ 1 770, 1 720 1.35 (3H, triplet, -CHgCgj), 2.97 and 3.30 (2H, AB quartet, J = 18 Hz, -C-K), 4.30 (2H, q, -CH ₂ CH ^) 4.60 (1H, doublet, J = 5 Hz, C H _NO), 4.80 (1H, doublet, J = 5 Hz, _C? -H), 5.30 and 5.80 (AB quartet, J » 16 Hz, S (2H, 2H), 6.93 OH, singlet, _J = -CH-) _t 7.30 (10H _f singlet, 2 x phenyl), 7.88 (1H, singlet N) N 'N sch ₃ 80 to 84 (dec.) 1 770, 1 720 1.90 (2H, broad singlet, -NH 2), 2.50 (3H, singlet, -SCH ₃ ), 3.40 (2H, singlet, C 1 H), 4.65 (1H, doublet, J - 5 Hz, C 8 H 11 4.80

(1H, doublet, J «5 Hz, _С? -Н), 4.85 (2H, s, Sk), 6.95 (1H, s,

X ^ ch ₂ 7.27 (ЮИ, singlet, 2 x phenyl purchased), 7.90 (1H, singlet N)

N

Note: This compound was obtained from the starting 4-carboxy-1,2,3-triazole by treatment in the same manner as described in Example 1 above. Article 1 e (2) ·

Reference Example 8

It performs the same reaction as in Reference Example 4 under the conditions indicated in Table 10. It produces the products listed in Table 10.

Table 10

Starting compound Reaction conditions Crude product <g) Eaterification of the crude product * 5 7-ACA 5-Methyl-tetrezo: (G) L acid or acid complex (g) Reaction solvent (ml) Reaction temp. (° C) Reaction time (h) ester a * 1 (g) ester b * 2 (g) 2.72 1.0 BFj.EtgO (7.1) sulfolane (13) 50 4 1.9 * 3 o | o 2.72 1.0 BF ₃ .Bt ₂ O (14.2) ethyl acetate (27) Temp · Places · 20 May 2.1 * 3 0.95 0.15 2.72 1.0 BFj.KtgO (14.2) nitromethane (27) temp. 20 May 1.5 ⁺ 3 0.63 0.1 2.72 0.92 BFyEtjO (7) Trifluoroacetic acid (19) temp · 7 1.5 * 3 0.71 0.05 2.72 1.0 terminal acid] sulfuric (2,5) Acetic acid (27) 60 4 0.4 * 3 0.1 0.03 2.72 1.26 BF ₃ 3.39 ethyl chloroacetate 15 Dec • temp. places. 16 1.44 * 4 - 2.72 2.52 αF ₃ 6.78 ethyl chloroacetate 30 - warm places. 16 1.28 * 4 -

Note: aa: 7-Amino-3- [2- (5-ethyl-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 mixed in b.

* 4 The crude product was composed only of * 5 The crude product obtained by the reaction of tulle was treated in the same manner as in Example 2. This produced the benzhydryl ester of compounds a and h.

Reference Example 9

The same reaction as in Reference Example 5 was carried out from the conditions given in Table 11. The products also shown in Table 11 were made.

Table 11

Starting compound Reaction conditions Product 7-ACA 1,2,4- Acid Reaction Reek. Reek. Name Yield , "4 three. 02-1 ^{(g) (g)} or an acid complex (G) solvent (s) temp. (° C) time (h) (compound) (G)

M.p. (° C)

2.72 0.75 BF-j.EtgO CH-jCN 7.1 20 May

temp. places.

7-Amino-3- [j - (1,2,4-triezolylneeyl) -3-cephem-42,049 149 (dec) carboxylic acid

2.72 0.75 BF3.Et ₂ O CHCl 3 COOH 8 temp. places. 2.72 0.75 concentr. sulfuric acid 5 CHCl 3 COOH 8 temp. places.

7 7-amino-> 3'-iJ- - (1,2,4-triazol-11) meryl] -3-cephem-4-carboxylic acid 2., 0 149 (years) 7 7 ^^ 1 ^ - 3-2 - - (1,2,4-triBzolyl) meryl] -3-cephem-4-carboxylic acid 0.34 149 (rozkki)

2.72 0.75 CH 3 SO 3 H 9.6 CF3COOH 19 Dec temp. places. 2.72 0.75 FSO3H 8 CH3COOH 25 temp. places. 2.72 0.75 CF 3 SO 3 H 12 CH3COOH 25 temp. places. * 2.88 0.76 BF3.Et ₂ O 7.1 CF3COOH 23 temp. places.

7 7-8minco-3ri ^{-1, 2> 4>} t ^RIA - zolyDmeeylJ-3-cephem-4-arboxylic acid diammonium salt 1.31 149 (r-exp. 24 7-emino-3- [1- (1,2,4-triazolyl) meryl] -3-cephem-4-carboxylic acid 1.12 149 (r-skkl) 24 33 - ^^ - 33-1- - (1,2,4-triazolyl) eoryl] -3-phenyl-4-carboxylic acid 1.05 149 (rozkkl) 7 7-amino-1- [1- (1,2,4-triazolylmethyl) -3-cephem-4-carboxylic acid 1.77 149 (r-exp.

Note: * The starting msatriál used Uoxid butyl 7-amino-3-acetate: jqya ^e yl-3-cephem-4-carboxylic acid.

Reference Example 10

If the same reaction and the same treatment as in Example 2 were repeated, replacing the 7-ACA with the starting compounds listed in Table 12, the products also listed in Table 12 were obtained.

Table 12

Starting compound

Product

m.p.

(° C)

7-Amino-3-acetoxy-ethyl-3-cephem-4-carboxylic acid p-nitrobenzyl ester 7-Amino-3- [1- (1,2,4-triazolyl) ethyl] -114-e-p-nitrobenzyl ester

-3-cephem-4-carboxylic acid 116 (dec

770,

708 7-Amino-3-acetoxymethyl-3-cephem-4-carboxylic acid ethyl ester Ethyl ether 1,770, (7-Amino-3-actothiomethyl-3-cephem-4-carboxylic acid, diphenylmethyl) -8-tetramethyl ester

7- (1-Methyl-3- (tetra-triazolyl) methyl) -3-tetem-carbonylbenzoic acid

790

610,

530 <Reference example 11

1. 20 ml of N ^ -dimetyHonamidu was suspended 2.96 g of 7-aminоotз / 2- (5TN · _butyl-1> 2.3, -t> tetiazolyl) methyl / * - C-cefe1t tli8b0oxllзvé acid. The suspension is converted into a solution by the addition of 1.1 g of sulfuric acid under ice-cooling. Then 2.7 g of pivtloylisylmtyl iodide are added to the solution. ^In ýsle ^D in the mixture is left single-sorting at ^0-5 ° ^C · ^C o utončení reactions ae ^ REA the mixture was poured into 250 ml of water and 200 ml ttllicttáУu · Adding sodium tydrogeenuiičitenu e rozyoku pH adjusted to 7.0. The insoluble material was separated. The organic layer was separated and dried over anhydrous magnesium sulfate. The solvent is then removed under reduced pressure. The residue is dissolved in 30 ml of ethyl acetate, and to this solution is added g of dry hydrogen chloride in 30 ml of diethyl ether under cooling in January and under stirring. The precipitated crystals were thoroughly washed with dittyl ether and then recrystallized from chloroform. Prepared 2.72 g (yield 60.9% tydrochloridu pivalзylзxlmeeylt8Уtru 7timinозЗ l - // - t5-tоetylL-1,2,3 -tУeУa8zolyl) meУyl / - ^c -ctfmt-TL ^{3 and} b ^* OJ ^l ^ 1 lзvé ^ 11 ^, ^, Melting projecting into the cavity has the 149 ^th EŽ ¹⁵¹ ° ^C (tozzIl).

IR ^and P ^t lt з ^ u ^ ^m (KBr) с · '. Vc «O 1 773, 1 741 8 1 730.

Nuclear Magnetic Resonance Spectrum (DMSO-d6 ₎ ppm: 1.18 (9H, s, -KCH3, 4), 2.44 (3H, a, -), 3.60 (2M, s, Cg-S), * 5.23 (2H, s, _C6- M, (Cy-H), 5.62 (2N, e1), 5.78,

A ^c M = 5.92 (2H, m, -COOCCMO-).

When different starting compounds are worked up. In the same manner, the compounds and compounds listed in Table 13 and Table 14 are obtained.

Treatment of 7-emino-3- [2- (5-methyl-1,2,3,4-tetrazolyl) methyl] -3-cephem-4-carboxylic acid or 7-amino-3- (3-chloro-1), 2,4-triazolyl) methyl] -3-cephem-4-carboxylic acid as above, substituting N, N-diaethylformamide and triethylamine for acetone and 1,8-diazabicyclo (5.4.0) undecene -7 (DBU), the compounds listed in Tables 13 and 14 were obtained in a yield of 65-90%.

Table 13

Compound R ¹

Melting point (° C)

-CH0C0CH _o CH,

I No 2 3

I o

CH ₃

IR spectrum (КВг, си ’,

9c = 6 ^):

NMR Spectrum

DMSO-d

CDCl3 ₃ CD3OD +

+++ ppa):

Note (processing)

775,

758

1.28 (3H, triplet, J = 7Hz, -CH ₂ CH ₃ ), 1.58 (3H, doublet, J = bHz, CHCHCH ₃ ), 2.02 (2H, broad singlet, -NHg) , 2.51 (3H, s, CH _3), 3.33 (2H,

Broad singlet, C ₂ -H), 4.20 (2H, quartet, J = 7 Hz, _CH2-CH3), 4.90 (2H, bs, _C6-H and _C? -H), 5 62 (2H, broad singlet, s ^ Х сн ₂ from 6.69 to 7.06 (1H, m, ^ ₃ снсн) ++ column chromatography Wako gel, eluting with benzene-ethyl acetate 3: 1 to 101 1 788,

740

1.80 (2H, singlet, NH ₂ >, 2.42 (1.5H, singlet, -CH ₃ ), 2.49 (14H, singlet, -CH ₃ ), 3.27 (1H, singlet, C ₂ -H), 3.30 (1H, s, C ₂ -H), 4.62 to 4.95 (2H, multiplet, C ¹H а С? -Н), 5.30 and 5.65 (2H, AB quartet, J 17 Hz, Sx.), 7.37

Ach ₂ (0.5H, singlet, CHCH), 7.42 (0.5H, singlet, CHCH), 7.54 to 7.87 (4H, multiplet, four phenyl ргЛо) ♦ + Wako silica gel column chromatography C-200, eluting with 3: 1 benzene-ethyl acetate

DMSO-dg

CDCl 3, ⁺⁺ pp 4-4.4.

Note (processing)

Continuation of Table 13

Compound

Melting point (° C)

IR spectrum (KBr, c · ’,

NMR Spectrum

С »о ^)!

-СЮ _? С (СН ₃ ) ₃ 135 e, _{e00 |}

I ⁰ (dec.) 1 735 cm ₃

1.14 (9И, s, --C (CH3) ₃₎

I, 47 (3H, doublet, J »6 Hs,> _CH-CH3), 2.44 (3H, s,

N), 3.49 (2H, br) r -CH ₃

N

The oxalate was formed by adding Siavelic acid to an ethyl acetate solution

++++ -CH ₂ OCH ₂ CH ₃ 125 až 130 (decomposition) 1 790, 1 780

CH-OCCK, and _B 3 107 to 110 1 785, 1 735 O (rozkl ·)

s, C ₂ -N), 4.86 (1H, doublet, J = 6 Hz, C-H), 5.06 (1H, doublet, J »6Hz, _C? -H), 5.50 ( 2H, Wide Singlet,

SX), 6.60 (1H, quartet, J = CH ₂ »6Hz,> _CH-CH3), 7.03 (3H,

Wide Singlet, (♦)

M ₃ N-)

1.18 (3H, triplet, J 7Hz,

-CH ₂ CH ₃ ), 2.47 (3H, singlet, -CH ₃ ), 3.27 (2H, Wide Binglet, C ₂ -H), 3 _t 55 (2H, quartet, J _→ 7 Hz, -CK) > CH ₃ ), 5.08 to 5.68 (6И, multiplet, C ₆ -H, Ογ-Η,

Oxidate was formed by addition of acid · Siavelic acid to ethyl acetate solution ·

-соос ₂ о2.08 (3H, singlet, -OCOCH ₃ ),

2.45 (3H, singlet, N);

3.50 (2H, broad s, C ₂ -H), 4.96 (1H, doublet, J * 6Hz, C ₆ -H), ¢, 11 (1H, doublet, J = 6 Hz · C ₇ « H),

5.58 (2H, wide singlet,

S \), 5.82 (2H, ^ CH ₂ Oxalate formed by addition of kya, Siavel to ethyl acetate solution · singlet, -СООСНО-), 7.66 (3M, Wide singlet, (t) to ₃ n-)

Continuation of Table 13

Compound Temperature IR 8 ^p ektrum NMR .delta. ^DRCs ~ ^d G 'CDCIc HD ₃ 0D + Note R ¹ melting point (° C) (KBr, ce ', ^ C = O): ppm): (treatment)

++++ 117 ež 1 780. 120 1 750 * -CH, OC (CH,) ~ CH ² II ^'233 0 (dec.)

0.87 (3H, triplet, J = 7 Hz, - (CH ₂ ) ₃ CH ₃ ), 1.00 to 1.90 (4H, muuliplet, -CH ₂ CH ₂ O ₂ CH ₃ ), 2.30 to 2.54 (2H, multtplet, -N ₂ N _{2 2} N ₂ ), 2.47 (3H, singlet, N),> - ^CH 3

N

Oxaate is formed by the addition of oxalic acid in ethyl acetate solution.

3.52 (2H, broad singlet, Hg-H),

4.96 (1H, doublet, J = 6Hz, _C6- H), 5.14 (1H, doublet,

J = 6 Hz, H 7 -H) wide single, 5.42 (2H, SA),

ACH ₂ 5.74 (2H, ⁷ ₍ + ^{6 (3H} , ^Η 3 ^Ν) singlet, -0CH ₂ 0-), broad singlet, ~ CHOCO (CH ₂ ) ₃ CH ₃ I ° ^CH3

780,

758

0.92 (3H, triplet, J-6Hx, -H 4 H), 1.12 to 1.70 (4H, BuUtplet, -CH ₂ CH ₂ CCHCH ₂ ),

1.60 (3H, doublet, J = 6Hz,

CCCHCH 3), 1.89 (2H, singlet, -NH ₂ ), 2.52 (3H, singlet, N), 3.32 (2H, broad

Chrornaaogrrfie n. '· Column

WAKO H-200 silica gel, eluting with 5: 1 benzene: ethyl acetate.

s, C ₂ -H), 4.14 (2H, triplet, J = 6 Hz, -CH ₂ HH ₂ HH _{2 3} HH), 4.78 (1H, doublet, J =. 5Hz, C ₆ -H 4.91 (1H, doublet, J = 5Hz, H7-H), 5.44-5.77 (2H, AB quartet, J = 15Hz,

S), 6.96 (1H, J ₂ CH ₂ , J = 6 Hz,> HH-HH 3 ') ++

Half-table 13

Compound

R

Melting point

IR spectrum ^(C) _(ΚΒ γ cm ^"1.

VcsO ^5:

DMO-dg

NMR spectrum .delta.

CDjOD +

++ ppm):

++ ♦

Note ⁽ processing)

++++ -CH ₂ O (CH ₂ ) 3 CH 3 118 až 120 (res.) 1 800, 1 7’00

0.87 (3,, triplet, J - 7 Ht,

-CH ₂ CH ₂ CH ₂ CH 2), 1.10 to 1.75 (4H,

2.48

3.52

СНОССССССС)) -. and

CH ₃

1,770,

750

Note:

++++

Ocalát

-j ^ ch ^ c ^ HI), multtplet, -СН ₂ СН ₂ Сй ₂ СНз), (3H, si ^ let, N), ch ₃

N (2H, Wide Singlet,

22-Ю, 3.64 (2H, triplet, j = 7Hi, -с ₂ with ₂ and _{2 with 2} ) 5.00 (1H, doublet, J = 5 Hz),

C ₆ -H), 5.17 (1H, doublet, J = 5Ht, C 7 -O, 5.44 (2M, singlet, -0С1) 0о), 5.64 (2H, singlet, S1),

A ^cn 2 "

7.83 (3H, (+) - NH ₃ )

Wide Singlet,

1.55 (9H, singlet, --CO3);

1.66 (3H, dubbet, J = 6 Hx-CH-CH-j), 2.20 (2M, s, _NH2), 2.60 (3M, singlet), 3.44 (2H, singlet си ₃

(W, broad A ₂ -И), 4.98 (1H, hollow · *, 5Ifc, _C6- H),

5.1 »- (1H, broad dubbet, C7-H),

5.80 (2H, broad singlet,

S ']), 7.10 (1H, quartet, 6Hg, 6Ha, t-ch).

The addition of Stavelic acid in ethyl acetate solution gave the oxlate.

2—6471

Shouting the trill 1 -

Slolδenink

R '

Melting point (° C)

IR (KBr)

Sl / i-nink

Vc = o

R '

Melting point (° C)

++++

CHOCC (CCH) II 3 3 0 1—6 rž 1 — i (dec 1 i10, 1 780, 1 740 ^CH 2

7i0,

752 ^CH 3

790 ί

720

-CHOCO I ¹¹

I 0 ^CH—

782,

770

- CHOC - (O / I II / ^{0 CH -} 17a,

7—5

Table 14

COOR ¹

Compound

Melting point

IR sрекtrus (КВг, cm ¹ )

9c = o ^} »

NMR Spectrum ( ^DMSO- d6, ppm): CDCl3 **

Note (processing) * 3

-CH 2 OCC (CH ³ ), II ^{3 3} 152 až 155 1 803, 1 750 II 0 (dec.)

»13 (2H, (1H, 5.10 (9H, s, --C (CH3) _3), 3.39 broad s, C-H), 4.90 d, J 5Hz, Cg-H ), (2H,

Wide Singlet,

Oxalate is formed by adding Stevel's acid to ethyl acetate solution «

-CHOCHOCH _o CH, 146-111 ²³ ua

I ⁰

CH ₃

778,

720

5.72 (1 H,

6.28 (3H, doublet, J = 5 Hz, C-H), broad singlet, (+)),

H, K7.89 (1H, singlet,

N

N +1

1.27 (3H, triplet, J = 7 Hz, -CH ₂ CH ₃ ), 1.57 (3M, doublet, J = 6 Hz, J = CHCH ₃ ), 3.22 (2H, broad singlet, C ₂ -M), 4.17 (2H, quartet, J = 7 Hz, -CH ₂ CH ₃ ), 4.70 (1H, doublet, J = 5 Hz, θθ-Η), 4.86 (1H, doublet, 5 Hz, _C? -H), 4.91 and 5.51 (2H, AB quartet, J = 15 Hz, S>), 6.85 (1H, quartet, И сн ₂ ^ J> 6Hz, Z ^ CM-CM ₃ ) 7.73 (1H, singlet, N)

Chromatography on a WAKO C-200 silica gel column, eluting with a 3: 1 mixture of benzene and ethyl acetate.

+2

Continuation of Table 14

Compound

IR Spectrum NMR Spectrum: (ppm):

(KBr, cm -1 ', ^CDCl 3 ⁺² ((° c) у _{с = 0} ),

Note (processing) +

CHOCOCH _o CH. 1 Feb ^{2 3} 1 ⁰ 67 ež 70 1 780, 1 760 CH ₃

+5

1.32 (3H, triplet, J = 7Hz, -CH ₂ CH ₃ ), 1.59 (3H, doublet, J = 6Hz, J = CH-CH ₃ ), 1.86 (2H, einglet, - NHG), 3.20 (2H, einglet, _C2-H), 4.20 (2H, quartet, J = 7 Hz, -CHgCH ^), 4.87 (1H, doublet, J = 5 Hz, _C? -H), 4.72 (1H, doublet, J = 5Hz, _C6- H), 4.99 and 5.52 (2H, AB quartet, J = 15Hz,

~~~ S]), 6.95 (1H, quartet, J = CH ₂ = 6 Hz, = CH-CH _3), 7.75 (1H, s, N)

H

N +2

Ohromatography on a column

Weko 0-200 silica gel. elution of a 3: 1 mixture of benzene and ethyl acetate * 3

-CH ₉ O (CH ₀ ), CH, 128 to ² 2 3 3 ₁₃₅

773,

720

0.90 (3H, triplet, J = 7 Hz, -CH ₂ ) ₃ CH ₃ ), 1.15 to 1.71 (4H, multiplet, -C 1 H 2 CH 2 Cl 2 CR 3) 3.30 to 3.65 (4H , multiplet, _C2 -H), and CH ₂ CH ₂ CH ₂ CH _3), 4.95 to 5.40 (6H, multiplet, -OCH O- _С л -Н C. HaS-^) 8 * 01 (1 H,

Z 2 H 6 (einglet, N), 8.84 (3H, singlet, broad), -NH 4)

The oxalate is formed by adding Stevelic acid to an ethyl acetate solution solution.

+3

-CHOCCCCH.). 132 to 1,782,

II ^JJ 137 1 740

I o

CH ₃

1.17 (9H, s, -CÍCHpp 150 (3H, d, J = 6Hz, -CH-), 3.49 (2H, ^c §3

Broad e, (C ₂ -H), 4.97 to 5.19 (4H, α, C ₆ -H), C ₇ -M, S-η),

Oh ₂ from 6.70 to 7.08 (1H, и, -CH-), 8.04 сн ₃ (1H, s, N)

Add acetic acid to the ethyl acetate solution to form oxalate

Note: + optical isomer +3 oxalate> 4 upper component +3 lower component

Example 1

1. Dissolve 2.72 g of 2- (2-t-amyloxycarboxamidothiazol-4-yl) acetic acid in 40 ml of anhydrous methylene chloride. Add 1.06 g of N-methylmorpholine to the solution. The reaction mixture is then cooled to -35 ° C and 1.12 g of ethyl chlorocarbonate is added to the mixture. It is left at -35 to -25 ° C for 1.5 hours. 4.62 g of 7-emino-3- [2- (5-methyl-1,2,3,4-tetrazolyl) methyl] -3-cephem-4-carboxylic acid diphenylmethyl ether is added to the reaction mixture. The reaction mixture is worked up for 1 hour at 3030 to -20 ° C, then for an additional hour at -10 to 10 ° C. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue thus obtained is dissolved in a mixture of 40 ml of ethyl acetate and 30 ml of water. The organic layer was separated, mixed with 30 µl of water and the pH of the solution was adjusted to 1.5 by addition of 2N hydrochloric acid under ice-cooling.

The organic layer was separated, mixed with 30 ml of water and adjusted to pH 7.0 by addition of sodium bicarbonate under ice-cooling. The organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diethyl ether was added to the residue. The precipitated crystals are filtered off, washed thoroughly with diethyl ether and then dried. 6.52 g (yield 91.1%) of diphenylmethyl ether of 7- [2- (2-tert-amyloxycarboxamidothiazol-4-yl) acetamido] -3- [2- (5-methyl-1,2,3), m.p. 4-Tetrazolyl) methyl] -3-cephem-4-carboxylic acid having a melting point of 103-105 ° C (dec.).

IR spectrum (KBr) cm ^-1 ; In _{C 0} 1780, 1720, 1675.

NMR Spectrum (CDCl 3) ppm: 0.90 (3H, t, J 7 Hz, C 1 H 6 CH 3 -C), 1.48 (6H, s, CH 3), 1.92

(2H, Q, J = 7 Hz, CH ₃ CH ₂ -C-), 2.44 (3H, s, N

N (2Я, broad s, C ₂ -H), 3.62 (2H, β, N -n-CH _2), 3.08

4.85 (1H, d, J = 5Hz, _C6- H), 5.50 5.90 (3H, m, S

C ₇ -H), 6.53 (1H, s, 1H-d), ^{6.88 OH} · ⁷ · ²⁵

S H (10H ♦ 9)

2.72 g of 2- (tert-bicyclo-4-cyano-cycloalkyl-thiazol-4-yl) -acetic acid are suspended in 30 ml of anhydrous benzene. 2.54 g of oxazooyl chloride are added to the suspension under ice-cooling. The reaction mixture is then treated for one hour at the same temperature. After completion of the reaction, the solvent is distilled off under reduced pressure. The resulting residue was dissolved in 5 mL of anhydrous MMC. The resulting solution was added dropwise to a solution of 4.62 g of fifanylmethylattaos 7-amino- [2- (5-methyl-1,2,3,4-tetrazolyl)] data with β-3-aephthaloroxylic acid and 1.times. 21 g in 40 ml of ^{DEH b} EFTA metylenchlortou at -50 to -45 ° C. ^p o is displaced ^d přikapáid ^{characterized} by solution processes, ^and 3 ⁰ minutes at -4 ⁰ ° C, ³⁰ minutes at - ²⁰ and ^from the -10 ° C ^t β finally, R₁ ce ^t min at 0 ° C. After completion of the reaction, the solvent is removed under reduced pressure. The resulting residue was dissolved in 40 mL of atylarolate and 30 mL of water and the organic layer was separated. To this layer was again added 30 ml of water and the pH of the resulting bile. was adjusted to 1.5 with 2N hydrochloric acid under ice-cooling.

The organic layer was then separated, 30 ml of water was added thereto, and the pH of the resulting mixture was adjusted to 7.0 with sodium hydrogen chloride under ice-cooling. The organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The precipitated crystals are filtered, washed thoroughly with diethyl ether and dried. 6.69 g (93.5% yield) of fifaoyldethylattars 7- / 2- (2-methyl-2-oxo-oxo-oxo-thiazol-0-yl) -ceramaddf-0 - / - (55mdtet-), 2,3,4- tetrazolyl) datyl] -3-rafad-4-carboxylate having a melting point of ⁰ to ¹⁰⁵ ° C.

The physical properties of this compound were identical to those of the compound produced above. .

2. In a mixture of 32 ml of trifluoroacetic acid and 10 ml of anole, 6.52 g of 7-dimethylaminocarbonyl-thiazol-4-yl) acatadiazo-3-ol were dissolved. 2- [5-Datyl-1,2,3,4'-thiazolyl] -amino-4-amino-4-lactolylic acid prepared as described in paragraph 1 above. room temperature. After completion of the work-up, the solvent is filtered off under reduced pressure. The resulting crystals were separated and thoroughly dried and the phthalyl was dried thoroughly to give 4.61 g (92.1% yield) of the triacetoacetic acid salt of 7- (2-22aa-p-10-naphthalen-4-yl). (R) -Difo [-3] 2- (5-detyl-1,2,3'-acetyl) -ethyl- (3-aadiazol-4-carboxylic acid) having an melting point of 184-187 ° C (decomposition) ^IR spectrum ^(KR cm -1): 1765, 1655, 1630.

Vc = o

IR spectrum (HMSO +) ppm; 2.43 (3H, s, H-zz-CH3), 3.45 (4H, ba, O, -H);

5.08 (1H, d, J = 4 Hz, _C6- H), 5.50 to 5.90 (3M, m, S)

In the same way, the following compound of the trifluoroacetic acid salt is prepared.

7- [2- (2-Amino-4-thiazolyl) -acathoido] -3-acetamifomidyl-3-cepheid-4-keoboxylic acid. th d 153 ° ^and from 154 ° C (means).

3. Suspend 5.5 g of trifluoroacetic acid salt of 7- / 2- (2-aminothiezol-4-yl) acetamido] -3- / 2- (5-methyl-1,2,3,4) in water (30%). (tetrazolyl) Betyl] -3-cep-4-carboxylic acid. To the suspension was added ice water (0 ml) of 1N aqueous sodium hydroxide solution. The reaction mixture was cooled. The eluent was evaporated to dryness. Give 4j1 g -výtěžek 83.4%) of sodium 7- SOU / 2--2 - emanated-d- ^ ^- ^ H-CE Eido ^^ - U-mity ^- - ^{- 2} 3> ^and 4- - ⁱ г) ZLI ^{- l)} f eeyl / -3-ce ^- eu4- ^to Erbo ^o yl acid ester, mp teplot- -8 / -87 ° C EŽ -rozkl).

IR spectrum ^-KB * ⁾ cm ^-1 : Voo ^- ' ⁷⁶⁰ > ^{- 660} » ^{- 610} *

NNR Spectrum - ^^ ^00- °) ^{рр в:} г, 4Х (3H, β, -C) 3.40 - / -, broad s, C / -), 3.62 - / -, s, H CH ₂ -), 4.93 -I-, d, J 5 -z, C ₆ -H), 5, (5-6,0)

(3H, α, C ₇ -H, S

ch ₂ <

6.09 (1H, 8, N)

), 8.80 (1H, d, J at 8Hz, -СОЮ! -.

Otejnýe manner, the compounds ..: sodium 7 - // - / ² -afinltiezll 4 - L) c-t-oiOo / L3-a - ^d Tafi blfe-yll3- cefefl4- * ^b ar ^{to s} ooylbv acid: mp ^ ^ plo ^- 55 2 ^- 5 ° ^{C for 8}

IR ^spe ktru -KB ^{f 0) - »-1} - 755 680 I EŽ - 590

NMR Spectrum: -D 10 ppm: 1.98-3И,

- / 3,5g s, s,

-СОСИ ₃ ), '3.16, 3.56 - / -, ABq, J = -a -z, C / -), N CC ---, 3.84, 4.15 - / - ABq, J = -4 -z

) ·

5.0 / -I-, d, J 5 -z, Сб--), 5.57 -1-, d, J »5 -z, ^with xC ₇ -), - 6.40 -1И, s , N)

Example -d - ²

1. Dissolve 1.7 g of 2- (2-chloro-2-methyl-k-oboxelidobtazbb-4-yl) -butyric acid in 30 ml of anhydrous ooeylene chloride. To the solution of ee was added 1.06 g of N-i-ylmooroline. The reaction mixture was cooled to -35 ° ^C. Then ^there was added ^{1, 1} / ^g -Ι ^-1 - ¹¹ ^ ¹ -! ^^^^ fteakčití mixture zpгaclvává ^{1, p} s 5 Todina EŽ -35 - / 5%. ^p btbm to re-KBI mixture bchl- ^d I N -4 ⁰ ° ^C. (a solution of 96 g of 7-) amino-1- (2 - ((- phenyl-1,2,3,4-octol) zyl) phenyli) -zc-iu is prepared (a child's ocular salt is prepared) The suspension was suspended in 30 ml of anhydrous ol-ylene chloride. To this suspension was added with ice Z- -hlazení 6.1 g 0 ^ - ^^ / ^ 11-1-181 ^ 1 - ^ ^ βοΙΟ - the mixture of bis- ^beta racbváv ⁴⁰ minutes at 5 - ¹⁰ ° ^F Flow ⁰ does not make up the desired solution.

He pk Exemplary of PE to shoř- made re-CTION srnl-s, wherein teplot- udržuje'n- ⁰ -4 -2 -3 ⁰ ° ^{C. P} o when ^K - ^P nor ^- re rises ^to the mixture being processed. ¹ hour s ⁰ -2 -3 -ЗД ° ^C and ^about 81 ° h s ^p taplotě - ¹⁰ -2 ¹⁰ ° ^{C. p} terminating œ sets Kaspersky AV ^1- solvent odtoesHuje z- reduced thickness-ku. 40 ml of t-tate-40 ml of water are added to the residue. The pH of the solution was adjusted to 7.5 by addition of the hydrogen sulphite. The aqueous layer was separated, mixed with 40 o! The n-value was adjusted by adding ² N hydrochloric acid from ice-cooling. The organic layer was separated, poured over 30 ml of water - dried over magnesium sulfate. The solvent was removed under reduced pressure. 5.07 g (92.2% yield) of 7- / 2- (2-tert-amyloxycarboxamidothiazol-4-yl) ecetareido / -3- / 2 were obtained. - _{(5-methyl-1,2,3>} 4-tetrazolyl) methyl / -3-cefetn-4-yl} carboxylic acid, ^and has ktee ^еер у / 1.6 еи point C ^from 142 ° C ^(dec.) .

^P ektrum IR ^(KBr) cm: Q = ^Vq '775 1 720 1 675th

Nuclear Magnetic Resonance Spectrum (D 2 SO 4 -CO 3) ppm: 0.68 (3H, t, J = 7 Hz, CH / CH ₂ -CC), 1.40 (6H, s, CH ₃ (2H, q, J = 7 Hz, CH (CH 2 -C-), 2.45 (3H, s, N), 46 (2H, t, s, C ₂ -H), 54 (2H, s, N)

5.08 (1 H,

O, J = 5 Hz, C ₆ -H), 5.6 µl (2H, s (1H,

O, J = 5 Hz, C ₇ -H), 6.76 (1H,

8.75 (1 H, d,

J =. 8 Hz, -CONM

2 · In the mix! 25 ml of ethyl acetate were dissolved in 8 ml of anis / l and 5.07 g of 7- / 2c (2-ethylcyclohexylcarbonylmethyl) -O- (5-methylsulfonic acid) were dissolved in 5 ml. 2,3,4-Theeaazolyl) ethyl 1 (C3-Cem-4-) carbotolic acid produced according to (1). The resulting compound (1) is treated for 0 minutes at room temperature. Upon completion of the reaction, the reaction was enhanced under reduced pressure. The crystals were added to the sample and the crystals were collected and survived. thoroughly Oieeyléeteei and dries. 4.72 g (yield 9%, 1%) of 7- (2- (2-thiothiazole-4-yl) acetic acid) are obtained (5% e-1,2,3). 4- tra ^ zllyl) ieet0 / -3-CCEE-4'cc ^to the ^b / ^oyy verifies ^{kt EE} te ^ has / have a ^melting, 4 ^{and 8, 8} 7 ° ^C - (e / zkl.b

The physical properties (IR and NMR spectra) of these compounds were identical to the physical properties of the compound of Example 1. (2).

Example. and O /

By using the starting compounds listed in Table 15, the reaction of both 1 and 2 gives the same compounds as shown in Table 15. 52

Table 1?

trifluoroacetic acid

_Z Nj-CHjCONH —η-HjN J, - ΝχχΑ.

^x s J 7 ch ₂ y ²

COOH

Compound

Melting point (° C)

IR spectrum, (KBr, cm -1 ⁾ , \ W ^:

NMR spectrum (DMSO-D 6 +, CD 4 OD, DMSO-d 6 + D 6 O ⁺⁺ , CF 4 COOD ⁺⁺⁺⁺ ; ppm):

115 1 780, (l-ozkl.) I 670,

630

1.27 (3H, triplet, J 7 Hz, -CH ₂ CH ₃ )

2.84 (2H, quertet, J = 7Hz, -CH3jCH3)

3.20 to 3.80 (4H, multiplet, Cg-e)

5.13 (1H, doublet,

J => Hz, c ₆ -H), multiplet, e

5.45 to 5.33 (3K

6.53 (1H, singlet,

152 f 775, (dec.) 1 670,

630 ⁺ 1.30 (3H, triplet, J = 7Hz, CH3H3), δ.94 (211, quartet, δ = 7Hz, -4 '). 3.45 (2H, s, C ₂ -H), 3% (2H, ainglet N -RR-CHy), 5, and 2 (1H,

П s

doublet, J = 5 Hz, C ^-H), 5.25 to 5.95 (3H, β-γ, γ-ε S'-η), δ ^K 'CH ₂ 6.56

(1H, doublet, J = 8Hz, -CONH)

Continuing Table 15

Compound

Melting point (° C)

IR spectrum, (KBr, cm -1 ⁾ , С С = 0 ^):

ApК apektruai (DMSO-D ^ ♦, CD ^ OD \ ΰΜ30 ~ ₆ + DgO **, CFjCOOD ** ⁺⁺ 5 ppss):

137 to 1 770 —N 140 1 740 (rozkl ·) 1 670 1 630 COOCH ₂ CH ₃

⁺ 1, 36 (3H, triplet, J «7 Иг, -CH ₃ CH _3), 3.47 (2H, broad s, C ₂ -H), 3.70 (2H, singlet, H - j -CH ₂ ),

4.41 (2H, quartet, .delta. = 7 Hz, CH3 CH2), 5.08 (1H, doublet, J = 5Ha, _C6- H),

5.50 to 5.80 (ЗЯ, multiplet, 0γ ~ Κ and S), 6.48 (1H, singlet,

, W ~ N

- <I> = N

COOCH ₂ CH ₃

149 to 1775,

154 1740, (dec.) 1670, 630

1.36 (3H, triplet, J = 7 Hz, -CH3CH3),

3.50 (2H, broad singlet, C 1 H), 3.71 (2H, singlet, Н-- _Г СИ _? ·.), 4.40 (2K, phi>·> s quartet, J - 1 Hz 5CH (CH3CH3), 5.06 (1H, doublet, J ~ 5 Hz, _C6 -H), 5.60 to 5.85 (1H, Bultiplet, Si), 6.47 (1H, singlet, ' ^S ') ^ CH ₂ ~ ^Й Т ~) _s / \

133 1 770, (dec.) 1 670,

630 ⁺ 3.55 (4H, Wide Singlet, Cyli and _N - CH.-), 5.05 (1Я, doublet,

WITH

J * 5Hz, C ₆ -H), 5.50 to 5.80 (3H, ruptured) ₅ ^ Чи ₂ -

7.40 to 8.10 (5H * miltiplet, phenyl)

236471 Continuation of Table 15 54 Compound Temperature IR spectrum, NMH spectrum (DMSO-D6 +, CD3OD ⁺⁺⁺ , R ² melting point (° C) (KBr, cm -1 ', ^ Ca (P ^: DMSO-dg + D ₂ O **, CF 3 COOD **** ·, ppm):

148 1 778, (rozkl ·) 1 710, 1 668

* 3.44 (2H, br ainglet, C ₂ -H), (2H, broad singlet, N CHg-)

3.56

5.08

5.42

WITH

(1H, doublet, J »5 Hz, -C-H) EŽ 5.93 (3H, multiplet, and C ₇ -H), 6.57 (1H, s _2, s, N

), 8.90 (1H, singlet,

N), 9.13 (1H, doublet,

N ^ \ H

J · 8 Hz, -CONH-)

100 to 1780,

102 1710 (dec ·) * 1 670 3.60 (2H, broad singlet, C ₂ -H)

3.68 (2H, broad singlet, H-JH-) -

5.06 (1H, doublet, J = 5 Hz, Cg-H), 5.30 to 5.85 (3H, multiplet,

S and C _? -H), 6.59 (1H, CH ₂ einglet N

WITH

), 9.15 (1H, singlet,

N1), 9.17 (1H, ₃ doublets, J = 8 Hz, ^{> N)}

H

-COHH-)

NHCOCH3

143 I 770, ₆₉₀ ,

665,

630 * 2.10 (ЗИ, singlet, -CH ₃ ), 3.50 (4H, Wide singlet, C 8 H 11 N CH ₂ -),

WITH

5.10 (tH, doublet, J 5 Hz, Cg-H),

5.50 to 5.85 (3H, multiplet, S ^ ch ₂ ·),

and C ₇ -H), 6.50 (1H, singlet, H)

WITH

9.05 (1H, doublet, J * 8 Hz, -COH-) (° C)

Continuation of Table 15

Compound

R ²

Melting point

IR SPE ^to tiuim NMR "SPE ^for trum ^{(D N} J0-D ^{6 +} CD OD ⁺⁺⁺ · (R B · cm" ^{1 for} the DMO d _o + D ^g O ** CF COOD ^{+++ +} ; ppm):

^ C = O ^{) s}

185 1 770, ⁺⁺ 3.47 (2H, broad eingltУ ^, ¢ -, - 4), (rozkC.) 1 665, 1 o30, 3.55 (2H, s, N - _rr-CH2 -), 5.10 with (1H, Dubbet, J = 5Hz, C ₆ -H), ^5.45 (2H, wide singles, S \) ^ CH ₂ - 5.50 (1H, Dubbet, J = 5Hz, Cr-H), 6.55 / 1 ΤΪ «Ιησί \ (IH, s, n π) _S AH

107 1 765, -Ц, (rozkC ·) 1 665, 1 630 SCH3

⁺ 2.60 (3H, broad), -CH ₃ , 3.55 (4H broad singlet, C ' ₂ -H, N CH 2 -),

WITH

5.05 (IH, dubbet, J = 5Hz, C ₆ _H), 5.50 to 5.80 (3H, muttjpl ^ l ^ LT, Cy-H and S '"У), 6.55 (IH, sing ^ t, ^ Ч ₂ -

SCH ₃

107 1,776, ((^ (^ zz ^ C ·) 1 665)

630 ^{++ 2,} 70 (ЭЩ -CH ^ · 3.35 (2H, br-t eingLe, Cg-H), 3.50 (2H, s, N

WITH

Cl ^ -)

5.10 (1H, doublet, J 5Hz, _C6- H), 5.30 (2H, singles, S &gt;), 5.70 (1H, doublet, J = 5Hz, Cy-H)

6.60 (1H, singles, N

with

236471 Continuation of Table 15 56 Compound K ² Melting point (° C) IR spectrum (KBr, cm -1, ^V c = O ^): Nuclear Magnetic Resonance Spectrum (DM 50 -D ₆ +, CD 3 OD ·, D 2 SO 4 ^- + D ^g O ** C 2 COOD ⁺⁺⁺⁺ ; ppa):

_{/ N} = N 150 to 1 770 153 1 665 1 630 CH ₃

⁺ 2.49 (3H single, -CH ₃ ), 3.40 (2H single, C 8 -H), 3.52 (2H, single, N CH) -), 5.05 (XH, oak,

WITH

J => 5 Hz, C ₆ -H), 5.28 (2H, broad single band), 5.62

Duct value, J = 5 Hz,

C7-H), 6.49 (XH, single, (XH,

J = 8Hz, N)

WITH

9.03 (XH, doublet, J »8 Hz, -CONH-)

120 ež

123 (dec.)

СН ₂ СООСН ₂ СНз

765,

730,

665,

630 ^{+ 1,} 20 ^(3-tri-p l ^e t, J 7 Hs, -C ^H C ^Cн)

3.42 (2H, Broad singular, Cg-Η), 3.50 (2H, Broad singular, H — n-CHg-), 4.00

S>

(2H, singly, -CH 3 COOOO), 4.02 (2H, ketamine, J 7 H 5, -CH ₃ CH ₃ ), 5.05 · (1H, dbst, J = 5 Hz, CH), 5 , 15 and ·

5.65 (2H, AB quart, J = 14 Hz,

S), 5.70 (1H, hollow-t, J = 5 Hz,

Αη ₂ C ₇ -H), 6.50 (1H, and Helem, N —---)

S хЧи

119 1770, * 1660, * 1 · 630 * 3.43. (2H, Wide ^ С ^п ^ 1 ^ ^| ^ 1П,

3.52 (2H, broad single, N - C - N ₂ -),

WITH-

5.02 to 5.35 (3K, C ₆ -H and S), 5.63 (1H, sod,

), 8.47 (1H, singlet, I.I.)

N

CH 2 J 5 Hz, C 2 H, 6.55 (1H, singlet), 7.95 (1H, singlet, (° C)

Continuation of Table 15

Compound

Melting point

IR spectrum (KBr, cm &^lt; -1 &gt;, [delta] = 0 ^):

NMB spectrum (BMSO ~ D ₆ +, CD 4 OD *** 'DJÍSO-d ₆ + Dj, 0 **, CFjCOOD **** 5 рря)

144 to 1765,

146 1665, (dec.) 1630 * 2.23 (3H, singlet, -CH ₃ ), 3.45 (2H, Wide Singlet, 3.58 (2H, Wide Singlet, N

WITH

5.05 to 5.20 (3H, multiplet, C ^ «H eS) »

5.70

6.60 (1H, doublet, J = 5Hz, (1H, singlet, N,

C ₍ H) _v

8.38 (1H, singlet, N) > ^H

133 1 765, (dec.) 1 665,

630 ** 2.50 (3H, singlet, --CH3), 3.50 (2H,

Broad singlet, C 1 H, 3.60 (2H,

Broad singlet, m '- _n-CH2 -), 5.05 (1H, doublet, J »5Hz, C ₆ -H), 5.10 (2H, s, S), 5.65 (1H,

Λ ₂ doublet, J = 5 Hz, singlet, N

WITH

C ₇ -H), 6.60 (1H,), 8.40 (1H, singlet ^N COOCH3CH3)

155 to 1765,

158 1725, 1660,

630

N * 1.34 (3H, triplet, J = 7Hz, -CH ₂ CH)

3.41 (2H,

.. ". ,,>

(2H, broad s, C ₂ -H), 3.53 bs, N CHj-), 4.38

S q, J *> 7 Hz, -CH ₂ CH ₃ ), = 5 Hz, C ₆ -K), 5.50 to 5.85 (3H, multiplet, C 6 -H 8 S (2H, d, J)

5.10 (Й1, (1H, singlet, M

S singlet, N)

N

), 6.55 ch ₂ ), 8.14 (1H,

236471 Continuation of Table 15 58 Compound Temperature _TAC) ^R (° C) IR spectrum, NMR spectrum (DMSO-D6 +, CD3 OD ⁺⁺⁺ ' ^(KBr ' cm @ -1, DM3 O-d6 @ + ⁺⁺ , C @ 3 Cood ^{++++ and} ppm)): ^V C = O> ^:

140 1 765, (гогк1 «) 1 665,

630 ^{++ 3,} 47 (2H einglet broad _t, C-H)

3.65 (2H,

Cl einglet, N

WITH

СИ ₂ -)

3.10 (1H, doublet, J = 3Hz, _C6- H),

3.10 and 5.40 (2H, AB quartet, J = 16 Hz, S-1), 6.65 (1H, einglet)

N

WITH

), 8.02 (1H, br. E. ^, N)

N

/ N \ —N N 137 to 140 1 775 1 730 cOocHj ^cooch 3 1 640

* ³ 49 ^(2H Wide singly Cg-H)

3.70 (2H, singlet, N CH3 -),

3.82 (3H, s, _OCH3), 3.87 (3H, s, OCH3), 5.06 (1H, dullet, J = Hk 5, C ₆ -H), 5.32 to 5, 85 (3H, multtplet, Sx and C-H),

6.51 (1H, singlet, N)

WITH

and

9.03 (1H, dullet, J = 8Hz, -CONH)

115 1 770, (dec.) 1 670,

630 * ^3, 55 (4H, br single-Cg-H CH _2), 5.05 (1H, doublet,

J 5Hz, C ₆ -H), 5.50 EŽ 5.80 (3H, m, _C? -H, S η) * ΧΗ 6.55 · (1H, s, N), 7.40 8.20

(5H, multtplet, phenyl group)

Continuation of Table 15

Compound

Melting point (° C)

IR spectrum, (KBr, cm ** ¹ ,

Vc = O ^);

NMR (DMSO-D _O + CD OD · ⁴ * ⁴ * ⁴ "DMSO-d _o + DGO CF COOD ^ ⁴⁴ ^ ррту

NHCOCH3

180 1 770 (dec.) 1 690 1 670 1 630

-NHCCH ₀ Cl 1 2

O

124 až

125 (dec)

770,

660,

630 ⁺ 3.50 (2H, broad single !, Cg-H),

3.55 (2H, singlet, N CH3 -),

3.91 and 4.15 (2H,

WITH

AB quartet, J = 13 Hz

137 to 1 760, 1 660, (dec.) 1 640

<усн ₂ >> 4.10

5.03 (1H, d, (2H, s, C1CH ₂ -), 5 Hz, _C6 --H), 5.65 (1H, doublet of doublets, J = 5 Hz,

-CONH-)

9.01 (1H, doublet)

8inglet _a

J = 8 Hz * 3.58 (2H, singlet, N CH 8 -),

3.62 and 3.84

S (2H, AB quartet, J = 12Hz,

C ₂ -H), 4.18

S>),

Λ ₂ to 4.53 (2H, multiplet, 5.05 (1H, doublet, J = 5 Hz),

C ₈ -H), 5.67 (1H, doublet of doublets, J = 5 Hz, J = 8 Hz, C ₇ -H), 6.57 (1H, singlet, N

S), 7.22 to 8.03 (5H multiplet, benzoyl group), 8.60 to 8.92 (1H, multiplet,> -CH ₂ NHCO-),

9.02 (1H, doublet, J = 8Hz, -CONH-)

23о471

Continuation of Table 15

Compound Teplote IR spectrum, NMK spectrum (DI4SO-D, +, CD.OD '* ·' * '* ’ h ² melting point (° C) (KBr, cn ', V ocP » J J DmSCi <3 ₀ + D ₂ O ⁺⁺ , CFjCOOD · * · ⁺⁺⁺ ; ppn)

-NHC (CH-) .CH, 1 O 1 05 bž 1 08 (dec.) 1 76p 1 660 1 640

⁺ Ο, Θ7 (3H, triplet, J = 7Hz, -CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 1.05 to 1.70 (6H, multiplet, -CH ₃ Cl ₂ C ₂ Cl ₂ CH ₃ ), 2 .08 (2H, triplet, J = 7Hz),

-CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 3.41 (2H, broad singlet, C ₂ -H), 3.17 (2H, singlet,

4.01 (2H, broad singlet,

WITH

), 5.00 (1H, doublet)

CH 6 = 5 Hz, C ₆ -H), 5.63 (1H, doublet of doublets, J = 5 Hz,

6.55 (1H, singlet,

J = 0 Hz, C _? -H),

OH, broad singlet, 4-CH 2 NHCO-)

II ^{22 3}

О

114 to 176>,

116 16.00, (dec.) 1640 * 0.84 (3H, triplet, J = 7 Hz,

-CH ₂ CH ₂ CH ₃ ), 1.18 to 1.82 (2H, multiplet, -CH 2 HgCH 2), 2.05 (2H, triplet, J = 7 Hz, -CH ₂ CH ₃ CH 2), 3.42 ( 2H, broad singlet (Cg-H),

3.15 (2H, singlet,

CHg-4, 3.85 to 4.26 (2H, rultiplet, S

5.01 (1H, doublet, J = 5Hz, CH2 -H), 5.70 (1H, doublet of doublets, J = 5Hz, J = 8Hz,

8.07 (1H, triplet, J = 6 &lt; -1 &gt;)

CHgNHCO-)

Checking Table 15 Compound

Melting point (° C)

IR spectrum (KBr, cm &lt; -1 &gt;,

In c = q) ’

NMR Spectrum (DMSO-D _6, CD-iOD ***, DMSO-d ₆ * D ₂ O * ^Ψ , CF-jCOOD ppm):

175 to 1780,

17o 1710, (ro2kl.) 1665, ούΟ lól to 1 760,

163 1 710 (dec)

620

155 1,760, (dec) 1,660,

630 * 8z 3.03 3.57 (6H, aultiplet, _C2-H, S-η), and _N-t-CH2 -), ^{4.87: г} ° сн ₂ ^ - S (1H, doublet, J = 5 Hz, C &apos; -H), 5.32 to 5.70 (1H, multiplet, C1-H), 6.25 to 7.61 (4M, multiplet, N)

H H

8.20 (ΊΉ, broad singlet, 1 -CH ₂ NHCO-), 8.81 (1H, doublet, J = 8 Hz, -CONH-) ⁺ 3.04 to 3.83 (6И, aultiplet, C ₂ - H ε 3 '> - and also N - CH _{2 -} , ^X CH ₂ 5.00 (1H, doublet, <T = 5Hz, C 1 H -), 5.36 to 5.72 (1H, multiplet, C _? -H), 6.24 to 7.39 (H), multiplet, N

With protons of phenolic group), 8.96 (1H, doublet, J = 8 Hz, -CONH-)

*** ⁺ 3.43 (2H, broad s, C ₂ -H), (2H,

3.86 singlet, N

4.20 (2H,

S multiplet,

'2 ch ₂ -)

)

5.22

6.05 (1H, ^CH2 doublet, J = 5Hz, C, -H), multiplet, Cy-H), 6.62, 7.22 (5H, (1H, (1H, slnglet, N)

Wide singlet, phenyl group)

IR spectrum, NMR ^spe ktrum (DMSO-D6 ^{+ +++} 0D3OD ^{(KBr, cm-DM>} Since ^G + D ² 0 К CR COOD ^{+ ++} *; ^PP n):

^In c = o ° *

Continuation of Table 15

Compound

R ²

Melting point (° C)

184 (angry)

765,

710,

620 ++++

3.12 to 4.12

(6H, muutppet,

5.00

5,57

6.45 (1H, (1H, (1H, doublet, J = 5Hz, C6-H), doublet, J = 5Hz, C2-H), singlet, N

WITH

7.30 (1H, doublet ®),

7.52 (1H, doublet) J = 3.5 Hz,

COOCH3

151 až 1 768, 153 1 705, (roz ^) 5 1 620

^{+++ 3} 15 and 3.48 (2 ^t ^ AB KVE ^tet, J = 18 Hz, _C2 --H), 3.62, singlet

CH 2 -), 3.82 (3H, singlet,

-OC1), 3.60 and 4.03 (2H, AB quartet, J = 15 Hz, S), 5.08 (1H,

CH 2duWet, J = 5 Hz, C 8 -H), 5.68 (1H, duWet, J = 5 Hz, C 7 -H), 6.54 (1H, singlet, N), 7.53 (1H, duHet,

J = 3.5Hz

COOCH3

7.67 (1H, duHet, J = 3.5Hz, 'S')

COOCH3 ⁾

Proceed to Table 16

Compound Temperature IR spectrum, NM ^R spectrum (DkSCo ^С ^ ОС ⁺⁺ +, R ^{2 th} C) ^(KBr »cm 'DMCO-d-4 Dgo ⁺⁺ CJř.HO) EYE ^++++; ppm.): VocPi

..

183 až 1 765 187 1 710 (rozzil) 1 5 610

⁺⁺⁺ 3.45 (2H, broad singlet, Cg-H),

3.64 '' · (2H, singlet, N - J - H - H ₂ '), p

3.90 (2H, broad singlet,

4.92 (1H, doublet, J = 5Hz, C.-H), > 51 (1H, doublet, J = 5Hz, H +),

6.19 (1H, doublet, J = 4 ^{Hz) 0} COOH

Hz, (1H, doublet, J = 4)

Example 4

At -27 ml Ν, Ν-dimetylfmnamidu rozpuutí with 5.5 g of 7- / 2-22 - tert _e ayyloykkarboxamidotiazol-4-yl) acetamido / 3- / 2- (5-methyl-1, 2,3, 4-Tetralyl Jettyl-4-acetylic acid as exemplified in Example 2- (1) To this solution was added 1 g of triethylmine and 2.9 g of pivlylphoylmethyl iodide from ice-cooling, and the resulting mixture was worked up for 30 minutes. The reaction mixture was poured into 250 ml of water and 250 ml of ethyl acetate and adjusted to pH 7.0 by the addition of sodium hydrogencarbonate.The organic layer was separated, washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. 02 g of 7- pivaloylooymetytesteru / 2 · (22teerc.amylooylarboxotidetiazzt-4-yl) -3- -acetemideO / 2 - (> - вett ^r L-1 _of 2,3,4-tteratllyl) methyl / -3-eefeю-- The carbonic acid is a crude product, which is dissolved in 30 ml of trifluoroacetic acid without further purification, and this solution is treated for 30 minutes at a temperature after the reaction is complete. The solvent was removed by filtration under reduced pressure, and 80 ml of water and 80 ml of ethyl acetate were added to the residue. The pH of the solution was adjusted to 7.0 by addition of sodium bicarbonate under ice-cooling. The organic layer was separated, dried over anhydrous magnesium sulfate and 0.8 g of dry hydrogen chloride in 20 ml of diethyl ether was added while stirring. Kle-brightened powder precipitates. This powder was decanted, washed thoroughly with ethyl ether, and recrystallized from ethyl acetate. 3.82 g of 7- [2- (2-aminothiazol-4-yl) acetemyl] -2- (> - methyl 1-1,2,3,4-aterolyl) methylthiazol-4-yl] methyl-p-methyl-4-methylbenzyl hydrochloride are obtained. thy acid, mp 146-148 ° C (dec.) [R spectrum (КБг) cm ^"1 \) qq ^1762, 1750 1 B70

NMR (DMSO-d _6, ppm): 1.15 (9H, s, -C (CH ^)

5.26 to 5.79

С ₂ -Н), 3.62 (2Н, з

ι

С _? -Н), 5.87 (2Η, s, -ОСН ₂ О-),

J * 5 Hz, C ₆ -N),), 9.23 (1 N, d, J = 8 Hz, -CONH-),

Example 5

When the compounds listed in Tables 16 and 17 are treated in the same manner as described in Example 4, the corresponding compounds listed in Tables 16 and 17 are obtained.

Table 16

HCl

CH ₂ CONH _p

Serving

M.p.

(° C) o

СООСН ₂ ОСС (СН ₃ ) ₂ o

IR (KBr, NMR ( ⁺¹ DMSO-d 6, * ² COCl ³ , t ³ O ₂ O; pp ·):

си ’» J).

ⁱⁿ c «o '·

-Q

CH ₂ CH ₃

124 to 1780,

127 1750 (dec.) * 1 1670 1.15 (9H, -CXCH _{3) 3);}

1.26 (3H, triplet, J = 7Hz)

-CH ₂ CH _3), 2.83 (2H, quartet, J »7 Hz, -C-CH), 3.52 (2H, s, C ₂ -N), 3.62 (2H, s,

CH ₂ -), 5.14 (1H, doublet,

J = 5 Hz, C ₆ -H), 5.46-6.00 (5H, multiplet,

-OCH ₂ 0- a

2—6471

Continued Ιο

Sloič-iinr

IR (KBr, NMR ( ^+, IMSO-d ₆ , ⁺² CDCl ₃ , ⁽ ppm)):

(° C) cm ¹ , ^ С = сО:

112 rž 1 7β0, 115 1 750, (rozUt 1 1 670

1 ^{+ 1,} 17 (9 ^ s, -C (CH ⁽⁾ ₃₎ EŽ 3 i6 4H, fUiltppe-t, C ₂ H e N

S ^, 3.32

t

5.12 (1H, duibet, J = 5Hz, (.H-H), 5.39-6.00 (5H, fuiltplet, S)

CyH r -Ο ^ Οο-, 6.59 · (HH, singlet,

i, ii ( ¹ H, singlet, N h ¹

9.19 (1H duibet, J = and Hz, -CCNH-) N = N = ^N-L

NHCOCH3

165 1 7i0, (rozUt 1 1 750, 1 630

+2 +4 ₂ »

2.25 (-H,

3.65 (4H, (9H, singlet, -C (CH _{( 3} ) ₃ )),

-C0CH (, singlet), fuittppet, C ₂ ^HQ

3,20 rž

4.91 (1H, Oubbet, J = 5Hz, C, -H),

5.20? 6.00 (5H, fuit-tppe ^ t,

-OCHOC- r C _? -H), 6.1i (1H, singlet, N = 1)

-NI = N

1-7 rž 1770.

139 1740, (mt 1660

^{+2, +4 1,} 29 (9H, eiiOLet - ((^ H)

3.24 to 3.60 (4H, fuittplet, C2-H,

CH2-)

90 (1H, OubbLcCl., J =

C ₆ -H), 5.15 (1H, fuittplet, Cy-H), 5.7C δ 5.95 (4H, fuiliplet, S)

-ΟΟ ^ Ο-,

7.81 (1H, 1, 25 (1H, singlet, H)

WITH

6.14 (1H, singlet, N

>

singletj—— 1

NMR ( ⁺¹ DMSO-d6, ⁺² CDCl-1, ⁺³ D2O; ppm):

Continuation of Table 16

Compound

Tt.

(° C)

120 8Ž 1 770, 132 1 745, (dec.) ! 660

^{+2, +4} 1.13 (9H, s, --C (CH3) ₃₎

3.16 (2H, s, C ₂ -H), 3.41 (2H,

3.72 (2H, doublet,

J = 15 Hz

S>), 4.83 (IH, d, "Асн J = 5Hz, C H _O), 5.40 to 6.00 (5H, mltij ^ l <^ 1 t, -OC ^ Clo, _nh _{2 C?} -H), 7.10 (3H, rnultiplet, phenyl, 7.83 (1H, d, J = 8 Hz, -COINH-, 6.06 (H,

-NHICCH3

135 to 1778,

138 1750, (dec.) 1680 s

620

^{+3.1 ,} 20 (9H, single C 1 -C (CH ₃ ) ₃ ) (3H, singlet, -COCH 3), - 3.33 to ^, 2.0 ¹

4.38 (6H, C 1 H-N, N

WITH

WITH

5.09 (1H, doublet, J = 5 Hz,

C 6 H, 5.64 (1H, doublet, J = 5 Hz, C ₆ -H), 5.81 (2H, broad singlet, -OC 4 O-), 6.64 (1H, singlet, N )

Note: ⁺² means that ^P s ^P NMR with ^the e-ira was uífcito příaluStoé year ouStS ^{d p} lo way) e indicated in the heading of this table knameiná, ^from an NMR data refer s.ouče e ^ ny to ^the now obsolete there was no hydrochloric acid

Table 17

IR spectral WR spectrum (IMSO-d 6, ppm):

melting, o (0q) (ЮЗгу um i ⁹ c = o ') ^:

131 to 1 780 133 1 725 -CH} (tzkl.) 1 665

2.45 (3H, einglet, N), 3.40 ^CH3

N? 3.70 (4H, mU Uplet, N

WITH

_CH2 and C2-H.), 3.77 (3H, s, -OCH ^,

5.10 (1H, doublet, J = 5Hz, _C6- H),

5.50 to 5.85 (3H, muUtplet, S \

C, -H), 6.25 (1H, singlet, N

WITH

8.89 (1H, doublet, J = 8 Hz, -CONH-)

152 to 1,780,

153 1 750,

680

2.42 (3H, s, N), 3.45? ^{"Сн з}

N to 3.80 (4H, uuUltplet, N CH 2 -)

S and C2-H), 5.12 (1H, doublet, J = 5 Hz, _C6- H), 5.45-5.90 (3H, murttplet,

S '-η and C-H), 6.60 (1H, singlet,), 7.61 (1H, singlet,

S H

7.55 to 8.00 (4H, uuUtplet, phenyl, 9.25 (1H, doublet, J = 7 Hz, -CONH-)

Note: ⁺ H ^yr tohlorid.

1. Acylation according to Example 2- (1) ·· produces the following compound:

Example 6

7- [2- (2-chloro-acetimidothiazol-4-yl) -ethoxy] -3 - [(3-chloro-1,2,4-triazolyl) methyl] -3-cephem-4-carboxylic acid, m.p. 120 to 122 ° C (dec.)

IR spectrum (KBr) cm ^-1 : δ C = O ^{1,775 7 7.0 1 1,680 1 1,650} . NMR spectrum (DMSO-d 6) ppm: 3.43 (2H, s, C 8 -H), 3.60 (2H, s,

4.32 (2 H, s,

6.97 (IH, · »·, H), 8.95 (IH, d, J = 8Hz, ^К 'Т'^>' ^{8.03 (1K} ' _S A

-CONH-).

Example 7

1 · 3.1 5 g of 2- (2-tert-amyloxycarboxsmidothiazol-4-yl) -2- (syn) methoxyiminoacetic acid are dissolved in 16 ml of Ν, Ν-dimethylacetsamide. 1.69 g of phosphorus oxychloride are added dropwise to this solution at -20 ° C. The resulting mixture was stirred at the same temperature for 1.5 hours. A solution of 3.16 g of 7-emino-3 - [(3-chloro-1,2,4-triazolyl) methyl] -3-cephem-4-carboxylic acid and 6-methyl-6-carboxylic acid is then added dropwise at -30 to -20 ° C. 1 g of N, O-bis (trimethylsilyl) acetamide in 32 ml of anhydrous methylene chloride. The reaction mixture is then left at the same temperature for 1 hour, at 0 to 10 ° C for 30 minutes and at room temperature for 30 minutes. After completion of the reaction, the methylene chloride was distilled off under reduced pressure. The residue thus obtained is mixed with 80 ml of water and 100 ml of ethyl acetate. The organic layer was then separated, 80 ml of water were added and the pH was adjusted to 7.0 by addition of sodium bicarbonate. The aqueous layer was separated, 80 ml of ethyl acetate was added thereto, and the pH was adjusted to 1.5 by adding 2N hydrochloric acid with cooling. The organic layer was separated, washed first with 50 ml of water, then with 50 ml of saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. MgSO4 and the solvent was distilled off under reduced pressure. Diethyl ether was added to the residue. The resulting crystals were collected by filtration to give 5.62 g (yield 91.8%) of 7- / 2- (2-tert-amyloxycarboxanidothiazol-4-yl) -2- (syn) -methoxyiminoBetamido / -3- / (3- chloro-1,2 ₍ 4-triazolyl) methyl] -3-cephem-4-carboxylic acid, m.p. 198 DEG-200 DEG C. (dec.)

IR spectrum (KBr) cm -1 4180, 1720 and 1670.

Nuclear Magnetic Resonance Spectrum (DMSO-d 6) ppm: 0.89 (3H, t, J = 7 Hz, -CH 2 CH 2),

q, J in 7 Hz,

-OCH ₃ ), 4.96

2. Dissolve 5.62 g of 7- / 2- (2-tert-ayloxycarboximidothiazol-4-yl) -2- (syn) -methoxy-inonoaocCBtododo3- (ЗзсС1ог-1,2,4) in 30 mL of trifluoroacetic acid The mixture was left at room temperature for 30 minutes at room temperature. After completion of the reaction, the solvent was removed from the reduced pressure.

Diethyl ether was added to the residue. The resulting castles were filtered, washed thoroughly with diethyl ether and dried. 5.23 g (93.1% yield) of trifluoroacetic acid thaeleate salt and 7- / 2- (4-methyl-thiazol-4-yl) -2- (sya) -methyloquinoline-3-chloro-3 (3-zClL1-) are obtained. 112.4 ^tri8Zol-yl) meeyl / ^{-3-cephem-4-yl} sβ kertooylové to ¹¹ and ^y is now obsolete ^for having ^a melting ^{point of 162} ° C (dec.

IR (KBr) ^c m ^{1: V} _c _ ₀ 1778, 1715, 1670, 1630

NMK (dg-DMSO) ppm

3.48 (2H, broad, e, CyH), 3.93 (3H, s, -OCH 3),

Δ _6- α), C ₆ -H), 5.78 (1H, dd, J = 5 Hz)

4.98 to 5.42 (3H, m, J = 8 ', t'), 6.91

N

9.74 (1H, d, J = 8Hz, -CO 3 -).

Example '

Dissolve 3.15 g of 2 '(2-tert-amyloyycarboximidothiazol-4-yl) -2,2- (ayn) -etloyyl-acetic acid in 40 mL of anhydrous methylene chloride. To the solution was added 1.06 g of N-methylmorpholine. The reaction mixture was warmed to -35 ° C. Then when it к ^d and ^{1.12 g of} eVlchlorkcrtunáts. mixture zprccov ^{a r} tofóny at ^1.5 - ³ 5 CZ - ² 5 ° C. Hom ^P 'at 4.62 ^gf ^ i ⁱ CA meth ^yl LCS ^{y t} 7зcminal3з CRL-2- (5-meCy 1-1,2,3,4'tCetra! Lola)) methyl / зЗ-icfel34 - karbloylové acid. The resulting mixture was zpracoróvá 1 totUnu at -3 ° ^and -20 ° C. ^p Otom the pulse tc ^ REA ^KCN mixture slowly increases and eventually the reaction mixture is kept 3 hours' at locally ^ Ti. After completion of the reaction, the solvent was removed under reduced pressure. 50 ml of ethyl acetate and 40 ml of water were added to the residue. The organic layer is separated, 40 ml of water are again added and the pH of the solution is adjusted from ice-cooling by addition of 2N hydrochloric acid to 1.5. The organic layer is then stated, add 40 ml water and the pH under ice cooling adjusted to 7.0 by adding sodium enaU1lčitanl 1ydrΌ ^g. The organic layer was separated, dried over anhydrous magnesium sulfate and dissolved in vacuo. The residue was treated with (6%) to give 7.06 g (93.0% yield) of di ^, cetylmethyl ether. 7- / 2- (2-terc.emy1ll: o1sabox8xCdofiazcZol-Y1L ') 2 з (S1N) зшetl: oyiminalJCcC8шSdfO-3- / 2- (5-metylз1, 2,3,4-tetrazlL ^yl) meth ^y l / з3cCifea 4-kcrblo ^{1 l} to ¹ l ^é sβ and ^{if one which} has a melting point of ^94-99 DEG ^C. @ ozkl).

IR (KBr) ^{cm -1:} \) _c _ ₀ 1 ⁷⁹⁰ 1 725 1 685th

NMR (dyDMSO) ppm: 0.87 (3H, t, J = 7Hz, -CH 2 CH 3), 1.44 (6H, s, CH 3), 1.75 (2H, q, J = 7Hz, - WHOSE

CH ₃

-CH 2 CH 3), 2.4 (3H, s, N), 3.46 (2H, broad s, C ₂ -H), 3.81 (3H, s, ^{3 %} ).

N

-OCH 3), 5.15 (1H, d, J = 5Hz, C ₆ -H), 5.47 (2H, Wide e, S), δx5-CH 2 2.87 (1H, dd, J = 5 Hz, J = 8 Hz, CyH), 6.84 (1H, e, O = CH-), 6.93 to 7.52 (11H, m, Q, Q, X, N '-, -), 9, 61 (1H, d, J = 8 Hz), -COINk-, 11.66 (1H, S, 4 H, broad s, -COINH 2/6471)

2. The compound obtained in (Ostavcl 1) undergoes reaction and reaction as described in Example 1 - (1) · The following is produced:

5.07 g (91.9% yield) with / Li eaifSuor acid / зt / IE 7- / 2- (2-Ciinoleвzzl-4-yl) -2C (зyn) - ^ ee / χtiii olaзeeeido ^N / C // 2c (5-methyl-112, [1,4-tetkazztyl) methyl] -3-cefl4C-carbtoylthioic acid.

Melting point: 12/125 ° C (e / g)

(KBe) cm · ¹ : 9 ^ 1 790 ^, 1720 ^, 16/5

NMR (CD 3 OD) ppm: 2.45 (1H, 1H)

5.10 (1H,

O,

N - (-) (1, 44 (2H, Si, Cg-H), (99 UH, s, -00 ')). N

J = 5 Hz

C ₆ -H), 5.50, 5.81 (2H, ABq, J = 14 Hz, S)

5.80 (1 H,

O,

J = 5 Hz

O

C7-HI, 6.9 / (1H, s, N)

is subjected to the reaction and processing striped in the example

Э. Sl / apprenticeship acquired in / 2

1- (1). Produced by:

S (7c / 2- (2kei / no / thiazolecyl) 2C- (ton) -methoxy) -acetic acid-C (2- (5) -eyl-1,2,3,4-tetrazole) salt) methyl (3-chloro-C-carbonyloxy) acid.

Melting point: 18/187 ° C (e / g)

IR (KBe) ^{cm -1:} 9 °; ₌ o 17 ^ 1665 ^, 1610

NMR 10g-DuSO-Dg-) ppm: 2.50 ((H, s, N), [α] D = -CH ₃

N

0 (0¾). 5.12 (1H, O, J = 1 Hz, (2H, Si, C ₂ -H))

C ₆ -H), 5.66 (2H, Si, s, (3H, s,

5.74 - (1H, O, J = 5Hz, C ₇ -h),

6.83 (1 H, s, N)

In the same way, the following results are obtained:

S / she salt of 7- / ceiiootiallO 2-22 · 4-tl) -C (. (Ton) ^mf eloэyiiioteceteiiioO / C - / (3cзhO / t-1 _J 2,4c ctriθzotyl) letylCзЗ-cephem-CC kerbtoyO % of acid.

Melting point: 168 ° C (e / g)

IR (KBE) ^m_1 c ^{'> C} ₌ ^{O 1760, 1670,} 1605

NMR (D 6 O) ppm: 3.30 (2H, broad s, Cg-H), 3.97 (3H, s, -OCH 2),

WITH

Example 9

6.13 g of trifluoroacetic acid salt and 7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamido] - [(3-chloro-1,2,4) -benzene] are suspended in 25 ml of water. "Triezolyl) methyl] -3" C 1-6 -amino-4-carboxylic acid. Sodium bicarbonate was added to the suspension under ice-cooling to adjust the pH of the suspension to 3.0. At this pH the suspension becomes a solution. Concentrated hydrochloric acid is then adjusted to pH 2.5 from the same temperature as above. Crystals are separated. Filter, wash thoroughly with water, acetone and dry. 4.71 g (94.5% yield) of 7- [2- (2-aminothiazol-4-yl) -2- (syn -) - methoxyiminoacetamido] -3- (3-chloro-1,2,4) are obtained. 3-Cephem-4-carboxylic acid, triazolyl) wetyl, m.p. &gt; 200 ° C.

IR (KBr) cm -1: V _{c = 0} 1765, 1660, 1625

NMR (d 6 -D 1 H 2 O) ppe: 3.44 (2H, broad s, Cg-H), 3.85 (3H, s, -OCH 4), 5.20 (2H, broad s,

8.04 (1 H,

6.71 (1 H, a,

C, -H),, -CONH-)

J 8 Hz,), 7.16 (2H, broad a, -Ж,),

Z ^-11

N

The following compound was prepared in the same manner:

7- / 2- (2-aminothiazol-4-yl) -2- (8-yne) methoxyiminoacetamide / 3- (2- (5-methyl-1,2,3,4-tetrazolyl) methyl) -3-Cephem-4-carboxylic acid.

Melting point:> -200 ° C

IR (KBr) cm '* ^ _{c "0} 1 765» 660 625 I

Example 10

Compounds listed in Table 18 were prepared by acylation in the same manner as in Example 7- (1) or Example 8- (1).

-H

Melting point (° C)

IR spectrum (KBr, cm -1 ⁾ ,

CH. 1 ^J CH.CH.C-OCONH- 180 až 1 780, ^{3 2} I 183 1 710, CH ₃ (dec.) 1 670

NHCOCH3

CUCHgCONMore than 1,780

200 $ 1,710

640

-H

C1CH ₂ CONH147 to 1780,

150 1,720 (dec)

650

CH ₂ CH ₃

CH-CH.C _OCONH-CH3

104 to 1 780, 109 1 720, (dec.) 1 680

-CH ₂ -f- (O) ₂ ) -N ‘ \ ^ = w CH. 1 ^J CH.CH.C-OCONH- 4 130 to 132 (dec) 1 780, 1 720, 1 680 - ^CH2 ~ t ~ ^ O ^ · ₂ -NHCOCH3 CH. ¹³ CH.CH.C-OCONH- 4 163 (dec) in 1 780, 1 720, 1 680 WITH 1 620

Continuation of Table 18

-R

Melting point (° C)

IR spectrum (KBr ^): c = o ^):

^CH 3 165 až 1 780, CH, CH 2 C-OCONH ^J 1 166. (тЫ.) 1 1 720, 680 CH. 5 3 1 620

-ch ₂ -h () ₂ (o) - OH

CH-, ¹³ CH.CH-C-OCONH- 98 to 1 780, ^{3 2} 1 105 1 723, CHj ^ oz ^.) 1 680

^CH 3 CHC-OCONH ^CH 3 to 1775,

101 1720, (dec. 1670

ClCHgCONH.

156 to 1780,

157 174 5 (dec.) 1680,

655

Example 11

In the same reaction procedure as in Example 7 or 8, the compounds listed in Table 19 and Table 20 were prepared.

Table 19

COOH

OCH ₃ (syn isomer)

Compound R

Melting point (° C)

IR spectrum (KBr, си ^-1 ,

NMR Spectrum (DMSO-d6, ppm):

^ C «(P ⁵

-Q ch ₂ ch ₃

153 to 1 775, 158 1 670, 1 630

1.27 (3H, triplet, J 17 Ha, -CH 5 CH 3),

2.82 (2H, quartet, J = 7 Hz, -CHgCHp,

3.43 (2H, s, C ₂ -H), 3.85 OH, s, _OCH3), 5.13 (IH, d, J "5Hz, C ₆ -H), 5.5 5 EŽ 9 (3H, multiplet

and C ₇ -H), 6.74 (1H, singlet, N - n -), 9.64 sA (1H, doublet, J ae Hz, -CONH-)

-Q

NHCOCH3

156 to 1 765,

159 1 700, 1 665,

630

2.10 (3H, singlet, -000µ). 3.44 (2H, singlet, C ₂ -И), 3.82 (3H, singlet, -00µ), 5.14 (1H, doublet, J = 6Hz, C ₆ -H), 5.55 to 5, 85 (3H, multiplet, S X. and C?-H), 6.72 (1H, ^CH ₂ singlet, N

9.05 (1H, doublet, J = 8 Hz)

-CONH-), 11.02 (1H, singlet, -CONH-)

135 1 770, (dec.) 1 705,

665,

630 [solvent: CD-Dep: 3.50 (2И, s, C ₂ -H), 3.98 (3H, singlet, -00¾), 5.00 to 5.50 (3H, multiplet, S \ and C 1 H-5.80

Ah ₂ (1K, doublet, J = 5 Hz, C ₇ -H), 7.01 (1H, singlet, K = n), 7.97 (IH, singlet,

S / 'н

Continuation of Table 19

NMR Spectrum (DMSO-d6, ppm):

IR spectrum

№. cm ^- '

Melting point (° C)? ⁰ = ° ^!

Compound ^r2

N = N - N ^X N = J

142 (rozk.)

775,

660,

630

3.51 (2H, br single. C ₂ -H), 3.91 (3H, singlet, -ОЮН3), 5.23 (1B, duo ^. J ~ 5 Hz, -C-H) - 5.77 (2B, broad single .0), .delta. CHg5.85 (1H, doublet, J = 5 Hz, J = 7 Hz,

C _? -H, 6.85 (1B, sunslet, Bn -), 7.93 (3H, (+) ^δ wide single. -NH)), 8.95 (1H, single.), 9.76 (1H, d) m / z, J = 7 Hz, -CONH-

N

150 (rozk.)

775,

660,

630

3.52 (2H, broad single, C8-H), 3.90 (3H, singlet, -OCH3), 5.17 (1H, duMe, J = 5H4, C8-H), 5.43 (2H , wide single.)

A _C h ₂ _

5.81 (1H, doublet of doublets, J = 5 Hz, J = 8 Hz, C-H, 6.29 (3H, broad single. (+)), 6.81 ⁷ '- ¹ ¾), 9, 31 (1 H, single.

1H, single.

121 to

125 (dec

775

670

630 nh ₂

N), 9.67 (1H,

N dutoet, J = 8 Hz, -CONH-) single. C ₂ -H), 3.88 (3H, 5.18 (1H, duHet, J = 5 Hz),

3.53 (2H, broad singlet, -OC)),

C ₆ -H), 5.48 to -5.88 (3H, muuttppe, 5'-H), 6.83 (1H, single, N

with

9.66 (1H, doublet, J = 8 Hz, -COH-)

Continuation of Table 19

NMR Spectrum (DKSO-d6, ppm):

Melting point (° C)

Compound R ²

IR spectrum (KBr, ^cm-1, Vo ^<P!

181 1,775, (decomposition) 1,710,

665,

630

2.51 (3H, s, -SCH _3), 3.50 (2H, Miroku s, C ₂ -H), 3.93 (3H, s, -O CH₃), 4.96 EŽ 5.34 (3H, multiplet, S \ e

C ₆ -H), 5.80 (1H, doublet of doublets, J »5 Hz J = 8 Hz,

C ₇ -H), 6.85 (1H, einglet, N)

)

8.40 (1 H, einglet,

WITH

N), 9.69 ( «X, d, / ~ ^K

N

J and 8 Hz,

C0NH-)

NHCOCH3

168 to 1,775,

180 1,710, (roskl ·) 1,680 s

630

_COCH3), 3.42 (2H, br

2.02 (3H, einglet, einglet, C ₂ -H), 3.86 (@ 3 H einglet, -O CH₃), 4.75 to 5.55 (3H, multiplet, S)

V (C ₆ -X), 5.68 (1H, doublet of doublets, J = 5 Ks, J = 8 Hz, C ₇ -H), 6.76 (1H, singlet, X),

WITH

8.24 (1H, einglet, N), 9.60 (1X, doublet, χ-χ)

N

J 8 Hz, -C0NX-)

141 ež 1 778, 144 1 710, (rozkl ·) 1 670

CH ₃ [solvent: CD ₃ OD]: 2.39 (ЗИ, einglet, -CH ₃ ), 3.56 (2Я, broad singlet, C 1 H), 4.03 (3H, singlet, -OCH ₃ ), 4, 92 to 5.37 (3K, multiplet, S in C ^-H), 5.86 (1H, doublet, CHCH ₂ J · 5Hi, γ-Η), 7.00 (1X, einglet, K-tt-) ), sA

8.63 (1H, singlet, N) 7 ^M

К

ΊΊ

Continuation of Table 19

NO spectrum (DluO-dg, pp ·):

IR spectrum (K8r, ca '’,

Melting point . 2

Compound ^R2 (° C)

Vc = o ^):

-NHCO

183 1 778, (dec.) 1 710 1 630 1 630

3.52 (2H, broad s, C ₂ -H), 3.62

4.27 (2H, multiplet,), 3.88 (3H,

Z-CIL, singlet, -OCH 3), 5.07 (1H, doublet, J = 5 Hz, C 1 H), 5.75 (1H, doublet of charge, J - 5 Hs,

J = 8Hz, J = 2Hz, _7-H e,

J = 4Hz

6.54 (1H, doublet of doublets, •),

6.81 (1H, singlet, N)

WITH

duUet,

7.73 (1H, doublet,

8.25 to 8.67 (1H, muUiplet, - ^ 00-),

9.64 (1H, doublet, J = 8Hz, -COH-)

-IHCOCH

166 1 775, (dec.) 1 710 <7

620 (3H, singlet, C (C 1 H)) 3.42 (2H, broad, 22 °) H}, 3.86 (3H, settle, -0CH 3) _t .......),

CH ₂ 5.08 (1H, doublet, J = 5 Hz, C ₆ -H), 5.67 (1H, doublet of doublets, J = 5 Hz, J = 8 Hz, C 4 H), 6.79 (1H singlet, N), 7.84-8.26

1.85 singlet, C 1-4 -H), 3.86 (3H, singlet, -OCH 3) 3.60 to 4.21 (2H, muHiplet, S

(1H, auuttplet, -NHO), 9.64 (1H, doublet, J = 8Hz, -CO ‰ -)

236471 Continuation of Table 19 78 2 Compound ^R Temperature spektuum №R IR spectrum (DKSO-d₆, ppm) ^t, and ^Ni (KBr, ^cm-1 (M ° by _^C.dbd.O:

137 ež 1 760, —Nhco— ^ Q ^ 141 (rozkn) 1 660, 1 630

3.51 (2H, 'broad s, C ₂ -H), 3.85 (3H, s, OCH)), 4.08 to 4.50 (2H, dtiplet, S \.), 5.09 ( IH, doublet, J = 5 Hz, δ ₂ Cg-H), 5.71 (IH, doublet, doublet, J = 5 Hz,

J = 8 Hz, C 2 H, 6.78 (1H, singlet, N -) -,

S Z)

7.20 to 7.98 (5H, dtiplet, phenyl protons), 8.39 to 9.34 (4H, multtplet, (+) and

-NH3

-NHCC-), 9.59 (1H, doublet, J 8 Hz, -CONH-)

155 to 1 770,

159 1 710 (dec

620

3.09 and 3.50 (2H, AB quartet, J = 18 Hz,

C ₂ -H), 3.50 EZ 4.16 (2H, m, 'S ^{_(λ 0Η} ₂ 3.82 (3H, s, -OCCH), 5.10 (IH, d, J - = 5Hz , C ₆ -H), 5.61 (IH, doublet of doublets, J = 5 Hz, J = 8 Hz, C ₇ -H), 6.73 (IH, settle, N), 7.19 (5H, Broad singlet , phenyl

with proton), 9.57 (1H, doublet, J = 8 Hz, -CONH-)

165 1,770, (swarm.) 1,710

630

3.05 to 4.14 (4H, multiplet, CgH and S)

) ⁾

3.82 (3H, s, _OCH3), 5.10 (IH, d, J = 5 Hz, С ^ -Н), 5.65 (IH, doublet of doublets,

J = 5 Hz, AB quartet

(4H,

6.75 (1H, singlet, N

WITH

9.55 (1H, doublet, J = 8 Hz, -C0NH-) _{СТэ еоов.н} ^ ТГ ^"Н Л = 7,

8-N CH 3 R 4 (son Isomer) \ COOH

OCH ₃

Table 20

R ²

XR spectrum (KBr, cw ',

7 770, - 1 665, I 630, / N = N ⁴ CH ₂ COOCH ₂ CH ₃

770, 1,730, 1,665, 1,630

770, I 665, > 630

770, 665, 1630

SCH ₃

775, 1660, 1630

CH ₂ CH ₃ >775,>665,> 630 _Z N = N

COOCH ₂ CH ₃

770, 1730, 1670, 1630, N = N

- <I

COOCH ₂ CH ₃

775, 1,740, 1,670, 1,630

Continuation of Table 20

IR spectrophotometer ^(K Br _t cm -1), c ^ 5

^N COOCH ² CH ₃ 1,775, 1,725, 1,660, 1,630 1,775, 1,730, 1,665, 1,630 2S ^coocH3 1,775, 1,670, 1,630 AAcooH 1-770, 1710 to 1620 AX 1,770, 1,710 to 1,620 COOCH3 'COOH 1,770, 1,710 to 1,620

Example 12

· 1 in 50 ml of anhydrous Met ^ r ^p is enchlorito uutí ^{3, 7} ° C

-5 - chloro-o-RTLA -.- 4-yl / -2 l (· yn) · eβ tolymвιtoooctové-acid-alloyed · To the solution was added 1.06 g of ^N-r meeylmoo olltu. the mixture was cooled to -35 ° ^C · ^{P "for the} addition ^{of 1} * ^{12 g} etylchlsrkarbonátu. The resulting mixture was treated for 2 hours at -30 to -20 ° C. Then a solution of 4.37 g of 7-amino-3-acetamidolmryl-3-cepham-4-carboxylic acid diphenylmethylester in a dropwise manner was added dropwise to the reaction emission. 50 ml of anhydrous chloroform, the resulting SRNC Disregarding 3 hours at temp-tc místnosb ^to d ^y has been treated for ¹ hour at -20 temp tc-e ^F -ΊΟ DEG C. After reaction the solvent ufončení -ddeestluje under reduced pressure. The residue was dissolved in 50 ml of ethyl acetate and 40 ml of water. The organic layer was separated and 40 ml of water was added again. The pH was adjusted to 1.5 by the addition of 2N hydrochloric acid under ice-cooling. The organic layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. Diethyl ether was added to the residue. The precipitated crystals were filtered off to give 6.50 g. ) yeeoxχiminl> tcctaImddO-3 "actУtmiddtlltyl - зceftm- · 4) Carboxyltvá acid having a temperature T ^ i ¹ 36 ° C (^ rtzkl

IR (KBr) cm &^lt; -1 &gt; ₌ 1780, 1720 ^, 1680 to 1640

NMR (d 6 -SO 2) ppms 1.85 (3H, e, -CCH 3), 3.51 (2H, broad s, · C, -H), δ || 3 2 o

3.71 to 4.35 (2H, m,

3.39 (3H,

4.

(2H, s, (о) -с _{2 2} s, -OOH ₃ ), 5.14 (1H, d, J), 5.86 (1H, dd, J = 5Hz, = 5Hz, C6-H) ), 5.21

J 8 Hz, C 7 -H), 6.88 (1H, s, CH -); 6.98 to 7.67 (15H, m,

x3), 7.78-8.21 (1H, m,

-NHCO-), 9.69 (1H, d, J = 8Hz, -COIN).

2. Spread 0.79 g of 7- / 2 - (- tololytolycarboxadido) -5-cUl (:> rtotol-4-yl) (· (2-chloromethyl-4-trifluoromethyl-acetyl) -3-acetyl-4-carboxylic acid) in a 15 mL port. 1.33 g of aluminum chloride was added to the resultant solution under ice-cooling, and the resulting mixture was worked up at 5-10 ° C for 2 hours. Sodium cyanobutyric acid · Insoluble material is washed with water (30 ml of ethyl acetate), 50 ml of detyltetyl acetone are added and the pH is adjusted to 2.0 by addition of 2N hydrochloric acid. anhydrous magnesium sulfate · The solvent was evaporated under reduced pressure, diethyl ether was added to the residue, and the precipitated crystals were collected by filtration to give 0.37 g (yield 75.7%) of 7- / 2- (2-imino-5-chlorothiazole-4). (-Yl) -2- (syn) methoxlidinoa Cido-3-acetadido-ethyl-3'-Cofed-4-carbotylic acid having a melting point of 148-152 ° C (dec.)

IR (KBr) ^{cm -1:>) C} = _O 1770, 1710, 1630 1620

NMR (d 6 -DMSO) ppm: 1.83 (3H, s, -COCH 3), 3.42 (2H, broad s, C 1 H), 3.84 (3H, s, -COH-1),

3.70-4.22 (2H, m, S), 5.02 (1H, d, J = 5Hz, _C6- H), 5.67 (1H,

Х <ø ₂ -.

d, J = 5 Hz, C 7 H, 7.85-8.21 (1H, m, -NHCO), 9.46 (1H, d, J 8 Hz, -CO 1 N-)).

Example 13

The same reaction and work-up as in Example 8- (1) and (2) was repeated except that 2 * (2-ter) amino (1-carboxylate) -diazol-4 *) yl) * - 2 ((Uln) -methyl) pyridine. The acid is bonded to 2- (tert-butyl) -2e (ln) -tetolymilic acid to give the compounds listed in Tables 21 and 22.

Table 21

Melting point <° C)

IR spectrum (КВт, си ’,

Vc = o>

NMR Spectrum (CDCl3, ppm):

102 to 1785,

104 1730, 1680 dec

3.14 (2H, broad singlet, Cg-H),

3.90 (3H, singlet, -OCH 3), 4.77 and

5.34 (2H, AB quartet, J = 15 Hz,

), 4.94 (IH, d, _CH2 J = 5Hz, C ₆ -H), 5.88 (IH, doublet of doublets, J = 5 Hz, J = 8.5 Hz, Cy-H), 6 82 (1H, singlet, > * CH-), 7.18 (10H, broad singlet, 2 * phenyl · group), 7.54 (1H, doublet, J 2 Hz,

N

WITH

)>

8.11 (1H, doublet, J = 8.5Hz, -CONH-), 8.58 (IH, doublet, J = 2Hz,

H) p

106 1780,

109 1730 1630

2.44 (3H, singlet, N), 3.20 - ^CH3

N (2H, broad singlet, C8-H, 3.98 (3H, singlet, -OCH)), 4.97 (1H, doublet, J * 6 Hz, C, -H), 5.30 and 5.70 (2H, AB quartet, J »15 Hz, S), 5.92 (IH, doublet of CH 2 doublets, J = 6 Hz, J at 8 Hz, Cy-H), 6.89 (IH, singlet, Z) Δ CH-), 7.25 (10H, broad singlet, 2 x phenyl protons), 7.65 (1H, doublet, J = 2 Hz, N @ -) -, 7.74 (1H, doublet, J in. 8 Hz, _S A

-CONH-), 8.67 (1H, doublet, J = 2 Hz, 4 ')

with

Table 22

Melting point (° C)

IR spectrum (KBr, cm ^-1 VcsO ^):

NMR Spectrum (DMSO-d6, ppm):

N — N - ^ 4 130 to 140 (dec) 1 780, 1 715, 1 670 3.39 (2H, broad s, C ₂ -H), 3.33 (3H, s, -O CH₃), 4.38 (1H, doublet, J = 5 Hz, -C-H), 5.12 (2H ₂ - 5.79 (1H, doublet of doublets, J = 5 Hz, J = 8 Hz, _C7 -H), 7.83 (1H, doublet, J = 2Hz, N- —Π—), 7.93 (1H, singlet, N), 9 N with' , 02 (1H, doublet, J = 2Hz, N ) q 9.56 (1H, doublet, J = 8.5 Hz) О -CONH-)

129 ež

134 (dec)

780,

720,

675

2.44 (3H, singlet, N), 3.41

CH ₃ (2H, broad singlet, C 8 -H), 3.86 (ЗЙ, singlet, -OCH ₂ ), 5.14 (1H, doublet, J = 5 Hz, C ₆ -H), 5.60 (2H , wide singlet,

5.81 (1H, doublet of doublets, J = 5 Hz,

J = 8.5 Hz, C ₇ -H),

7.86 (1 H,

9.07 (1H, doublet, doublet,

9.63 (1H, doublet,

J = 8.5 Hz, -COH-)

H4kU d 14

1. Dissolve 6.13 g of 7- / 2- (2-tert-arnyl-carboxxemidotin-4-yl) -2- (syn) -rneoxyl-iminoacetaeidodo3 - / (3- Chloro-112,4-triazol-4-yl-methyl-3-methyl-4-carboxylic acid, while cooling with ice, 1 g of aluminum and 2.9 g of plvaloyloxy-iodide are added to the obtained solution. The reaction mixture was poured into a mixture of 300/1 water and 300/1 ethyl ethyl acetate, and the pH of the reaction mixture was adjusted to 7.0 with sodium bicarbonate. The mixture was then separated, washed with 100/1 of water, 100/1 of saturated sodium chloride solution and dried over anhydrous (sulphate / magnesium), and the solvent was distilled off under reduced pressure. diisopropyl ether was dried and dried, yielding 6.6 g (90.8% yield) of piveloyloxymethyltretrole 7- / 2- (2-ethoxy) -llylolcarboxa/ieoyl-0-4-c (1) c2- (syn) (c) eraoχiroi / oaoehamido / eO-cЧЗ (cChl Lo1 _t 2 (44CroloCyl) (η 3) -3-cefe-4C4-carboxylic acid *

@ 1 H (KBr) h ^{/ @ 1} : ⁹ DEG C. ₌ 1.790, 1775 DEG, 1720, 1675

NMR (CBCl 3) pp /: 0.96 (3H, t, J = 7 Hz, -0.3 '). 1.30 (9H, s, -0 (¾ '). 1.57 (6H, s, 0¾). », 91 (2H, q, J = 7Hz, -1'), 3.33 (2H, broad). , C ₂ -H), 4.02

-C ₃ and ₃ (3H, s, -0 (¾)).

4.89 to 5.34 (3H, J, S)

C ₆ -H), 5.70 to 6.27 (3H, -, -COOCH--,

C ₇ -H), 7.14 (1H, s, N)

WITH

90 (1 H, s, N), 9.31 (1 H,

d, J =. 8 Hz, -CO 2 h ".

2. It dissolves in 33/1 of trefluoroacetic acid. 6.6 g of p-ooyloxymethyl-7- (2- (2-erccyl) -l-3-carboxoxeidet08az0-C4yl) -2- (lynC-carbohydrate / inoβahrte / de) -CC (3-chloro-1,2,4-> trikooУol) The resulting solution was treated for 30 minutes at room temperature, after completion of the reaction, the solvent was distilled off under reduced pressure, to which the residue was added 80/1 of water and 80/1 of carbonate. / hl ^{<erogeruhlOčitanu} of cooling O ^ e ^ e ^ t ^ / solution pH was adjusted to 7.0. the organic layer was dried over anhydrous odddlí and / Si ^ i ^ i ^ i ^ i ^ /.. hořečnetý /. to a solution of A solution of dry hydrogen chloride in an alcoholic solution was added with stirring and ice-cooling to give a white powder, which was separated, thoroughly washed and dried to give 5.2 g (yield 88). 2% l pivelolloyl hydrochloride 7- / 2- (2ea / inoaieksu-4-yl) -2- (ayn) -eaxyl yol / inhthalate / de - -C - / (3-fluoroc4,2 ₉ 4-amino) (11) ealyl-free-e-144-erbolylic acid which melts 134-136 ° C (dec ·).

IR (KB ") ^{c /} '_ ^1: 1790, ^1755, 1680

NMR (dg-IMSO). pp /:

1.17 (9H, s, -0 ((3 ', 3')), 3.49 (2H, high s, 3 ''), 3.93 (3H, 2 ', -0').

4.95 ež. 5.40 (3H, J, S, Cg-), 5.60-6.02 (3H, J, -00000000).

C ₇ -H), 6.91 (1H, s,

s, N.), 8.83. (1H, d, J &gt; 9 Hz, ✓- ^a)

N

-coim- "

Example 15

K. stirring 8 ml anhydrous meeelnnchloridu and 2.2 ml of Ν, Ν-dimneylacetamidu at 0 DEG C was added ^and the 3, ^{7 g} N-diethyl-du ^^ orečného. Výsledrá mixture of ^p rβcov ^{é é} in 3 ⁰ minutes ^ye same interior temperatures. ^p and ^k ^ REA it was cooled to -Ί5 and ^F -W ° C. ^instance ID, ^{and thereto 2,} 4 ^{g of} 2- (2-вminitinzol-4-II) 2 - (SNN) mnetoyiiminooctoeé acid. The resulting mixture was worked from the same fence for 20 minutes. Otom ^{p to} t-ETO Smee at - ¹⁰ ° C APE ^BC-4, 4 ^{7 g} of pívslolloχlmenelnttnru 7-amino-3- / ² - (2-metll-1, 2,3,4-tetrθzolyl) // methyl 3-lefem-cobagyloylic acid and 1.01 g in 20 ml of anhydrous men- chloid. After the dropwise addition, the mixture is y ^p RACO ^{é é} in 3 ⁰ minutes at - ¹⁰ ° C, ³⁰ minutes at ⁰ ° C in ^Pb .sIšíc ^{1 30} minutes enploe místaosti ^l. After completion of the reaction, the solvent was distilled off under reduced pressure. 50 ml of water in 50 ml of acetic acid were added to the residue. The pH of the solution was adjusted to 7.0 by addition of sodium hydrogen nitrate. The organic layer was separated, washed with 30 ml of water, 30 ml of saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Diethyl ether was added to the residue. Excreted to those became filtered out. 5.1 g (86% yield) of the alloyloyloyl ester of 7- / 2- (2-eminothiazol-4-yl) -2- (ynn) -methoxy-4-dimethylamino-3- (2- (5-methyl-112,3,4-)) was obtained. Methyl tert-azoolyl) methylphosphoric oxoic acid having a content of ^{127 to 12} . ⁸ ° C (dec.)

IR (KBr) cm ^{_ '9 0} 1 7Θ0 c_, 1743, 1675

Η ^: £ Ο ^ β4 16

When the various starting compounds are treated in the same manner as in Example 14 at 15, the corresponding compounds shown in Tables 23, 24 and 25 are obtained.

Table 23

Compound R ²

OCH3

Melting point

IR spectrum (KB ·, C ^_1 ,

Wall Spectrum (DMSOd |), ppm)

CH3

144 až

148 (separation)

790,

750,

675

singlet, C2-H), 3.96 (3H, singlet, -00µ),> 19 (1H, dutobet, J = 5Hz, C ₆ -H), 5.39 to δ, ΟΟ ( ^5H , m, m, t, et, S, ^Cy - ^H

-OClHCo-, 6.96 (1H, singlet, N-π-), 9, B4 (1H, J = 8 Hz, -CO3-);

Continuation of Table 23

8Ó

Compound R ² Melting point (° C) IR spectrum (KBr, cm "’, c = o ’ NLIR spectrum (DMSO-d 6, ppm): -(O) 119 bž 123 (dec) 1 780, 1 740, 1 670 1.15 (9H, s, --C (CH3) _3), 3.10 e 3.60 (2H, AB quartet, J = 10 Hz, _C2 --H), 3.50

4.22 (2H, multiplat, S)

^c 6), 3.93 (3H,

_CH2 s, _OCH3), 5.17 (1H, doublet, J = 5 Hz, _C6 --H), 40 5 to 6.02 (3H, multiplet, -OCHgOa _C? -H), 6.92 (1H, singlet, N) 7.21

(5H,

9.85

S broad singlet, protons of phenyl group), (1H, doublet, J = 8 Hz, -CONH-)

144 až

146 (dec)

780,

745,

660

1.16 singlet, (9H, singlet, -C (CH ₃ ) ₃ , 2.39 (3H,), 3.56 (2H, Broad singlet, CH ₃ )

N

C ₂ -H), 3.88 (3H, singlet, -OCH 3) 5.46 (3H, multiplet, S

₃ ), 4.05 to (C ₆ -H),

5,52

6.86 to 6.01 (3H, multiplet, -0CH ₂ 0- and _C? -H), (1H, s, N), 7.80 (1H, sin-

S gel, N), 9.74 (1H, doublet, J = 0 Hz),

Z ~ ^H

N (-CONH-)

N — N ^ A ?A

SCH ₃

135 8 *

137 (dec)

1.17 (9H, singlet, glet, -SCH ₃ ), 3.52 3.93 (3H, singlet, multiplet, S

-C (CH ₃ ) ₃ ), 2.49 (3H, sin (2H, Broad singlet, C ₂ -H), 4.87 to 5.38 (3H,

5.50 to 6.05 ¹ 3'3 ^Ъ

-OCH ₃ ), and C ₆ -H), н ₂ <

(3H, multiplet, -OCH ₂ O- C _8? -H), 6.92 (1H, s, N-π-) .8,50 (1H, s,

S ^ H

N), 9.80 (1H, doublet, J = 8Hz, -CONH-)

N

Continuation of Table 23

2 Compound R Temperature IR spectrum thaw (KBr, cm ", NMR Spectrum (DMSO-d6, ppm): (° C) ’Λ’ 0 = 0 '

-NHCOCH3

133 8ž

135 (dec)

780,

740,

680 l

620

1.16 (9H, s, --C (CH3) _3), 1.81 (3H, singlet, -COCH ^) 3.46 (2H, broad singlet, (C ₂ H), 3.61 4.18 (2H, multiplet,

S), 3.80 (3H, singlet, -OCH3),

= 5 Hz, C ₆ -H),> 48 e to -COOCH ₂ - e C _? -H), 6.66-), 7.12 (2H, broad

5.05 (1H, doublet, J

6.00 (3H, multiplet, (1H, singlet, N)

WITH

singlet, -NH ₂ ), 7.78 to 8.09 (1H, multiplet,

-NHCO-), 9.45 (1H, doublet, J = 8Hz, -CONH-)

130 to 1780,

132 1745, 1665

3.50 (2H, broad

1.21 (9H, s, -CCCH ^) ^, s, C ₂ -H), 3.90 (3H, s, -OCH ^), 4.88 to 5.30 (3H, m, λ e

^X CH ₂ C ₆ -H), 64 to 6.04 (3H, multiplet, -COOCH ₂ e C ₇ -H), 6.72 (1H, singlet, N '-), 7.83 (1H , singlet, N), 8.37 (1H, singlet,

N), 9.46 (1H, doublet, J = 8Hz, -CONH-) > ^-H

N

Note:

Hydrochloride

Table 24

(son isomer)

R Melting point (° C)

NMR spectrum IR (KB ^ cm '', ^Y = C, ^P 0 'NMR (DMSO-d₆, ppm):

+ -CH. 154 1 785, J (rozkU) 1 730, 1 655

2.48 (3H, s, N) / ^- ¾

N

3.53 (2H, broad singlet, Cg-H), 3.81 (3H, singlet, -00 (00 ')), 3.96 (3H, singlet, -001'), 5.23 (1H, 2 iubbet, J = 5 Hz, _C6- H), 5.61 (2H,

5.83 (1H, iubube-t

Wide Singlet, S

dubbet, J = 5 Hz, J = 8 Hz, C-H), 6.95 (1H, singlet, N), 9.88 (1H, dubbet,

WITH

J = .8 Hz, -CONH-)

-CHgOCCH.

II

O

121 to

124

1780,

745,

2.10 (3H, singlet, -00 (00¾). 2.46 (3H, singlet, N), 3.52 (2И, Wide singlet,> - ^CH 3

N

C ₂ -H), 3.82 (3H, sinet, -001 '). 5.19 (1H, d ₆ -butyl, J χ 5 Hz, C ₆ -H), 5.59 (2H, broad singlet, s

5.78 (1H, doublet of doublets,

J 5 5 Hz, J χ 8 Hz, γγ-Η), 5.83 (2H, singlet, -COOCl ⁰ -) · ⁶ · ⁶⁹ ('H, singlet, N), 7.12

(2H, broad singlet, -N)), 9.55 (1H, dubbet,

J χ 8 Hz, -CO1OH-)

Continuation of Table 24

IR apectrum (KB. Св ’,

Melting point (° C)

NMR Spectrum (DMSOd6, ppm):

^ ^C »Cp>

166 to 1 -775,

168, 1745, (1040) 1665

2.41 (3H, single. N - CH. -), 3.58 (2H,

N wide single. C ₂ -H), 3.93 (3H, single, -OCH 3, 5.19 (ΪΗ, δЬЫ, J - 5 Bz, Cg-B), 5.62 (2H, broad single), 5.78 (IB, doublet of doublets, J = 35 Hz, J = 8 Hz, single. N

WITH

), 7.62 (1B

CI-H), 6.88 (1H, single.

H, 7.67 to 8.00 (4H, m / e).

Y four phenyl protons) 9.80 (1H, duMe, J = 8 Hz, -CONH-),

-CHOCOCM,

I ^{11 4}

I 0

CH ₃

130 to 1780,

136 1775, (гоШ1) 1665, ° H ₃

1.20 (3B, triple. J = 7Hz, -CH ₂ <CH>, 1.51 (3H, doublet · J. J = -6Hz, ΗΗΟοΗΗΟ ^), 2.45 (3B, single. N) , 3.55 (2B, wide single.

z ~ “3

N

Cg-H), 3.85 (3B, singular -OCH) 4.16 (2H, quartet, J = 7 Hz, -0.10), 5.20- (IB, duMe.

J = 5 Hs, Cg-B), 5.55 (2B, broad single).

S - -)), 5.81 (IH, doublet of doublets,

J = 5 Hz, J = 8 Hz, ΟΟ -)), 6.72 (1H, single. N '-), 6, β1 - (1B, quart. J = 6 Hz, = cHWHj), 9.60 (1B, duWe. J = 8Hz, -CONH-)

236471 Continuation of Table 24 90 R Temperature melting point (° C) IR spectrum ⁽ KBr, cm -1), NMR spectrum (DMSO- ₁₆ , ppm):?

-CHOCCCCCH)

II ^{3 3} 0

CH3

127 to 1780,

130 1740, 1675

T

1.14 (9H, singlet, --CH2), 1.48 (3H, dubbet, J = 5.5 Hz, = CH - CH3), 2.45 (3H, singlet, N @ +); 3.48 (2H, broad singlet,

Z — _3

N

C ₂ -H), 3.82 (3H, singlet, -OCH 3), 5.19 (1H, doublet, J = 5 Hz, C ₆ -H), 5.54 (2H, broad singlet,), 5, 83 (1H, doublet dubbet, = CH ₂ J = 5 Hz, J = 8 · Hz, C7-H), 6.69 (1H, singlet, quartet, J = 5.5 Hz,

), 6.86 (1H, .dbd.CH-CH3)

9.56 (m), 7.11 (1H, doublet, (2H, broad singlet, -NH 1), J = 8 Hz, -CO 1 H 2 -).

148 to 1785,

152 1730, (rosdck.) 1675

0.88

1.05

2.45 (3H, triplet, J = 7Hz, - (C 1 H 6 _{CH 3} )), to 1.75 (4H, muuttppet, -CH 8 _{CH 8 CH} 8 CHCH), (3H, singlet, N _CH ), 3.45 (2H ,

Z 3

N triplet, J = 7Hz, —CHgCHgCCHCC.j), 3.55 (2H, broad singlet, C2-H), 3.87 (3H, singlet, -OCH3), 5.23 (1H, dubbet, J = 5 Hz, C ₆ -H), 5.43 (2H, singlet, -COOCC ₂ O-), 5.62 (2H, broad singlet, S), 5.86 (1H, doublet).

dubbet, J χ 5 Hz, J = 8 Hz, C7-H), 6.74 (1H, singlet, N), 9.63 (1H, dubbet,

WITH

J χ 8 Hz, -CONH-)

.Continuing Table 24

IR Spectrum (Kfir, cm ^-1 , к '

Melting point

NMR Spectrum (EMS-d, ppm):

(° C) ^ 0 = 0 ¹

107 to < 108 1 780, 1 760, 1 670 -CH-OCtCH-UC, 11 ³ o

0.87 (3H, - triplet, J = 7 Hz, - (-, -) -),

1.0 to 1.7 (4H, uullippet, -CH ₂ CHhCCh ^GH 3),

2.25 to 2.55 (2H, ΒΒ ^ ^, -CH ₂ CHhCHhCH ₃ ),

2.45 (3H, s, «j ^ j-CH ^3» 3.33 ^(2H> sili years singlet, C, - ^), 3.85 (3H, s,

-OHH ₃ ), 5.20 (1H, doublet,

5.58 (2H, broad singlet, (2H, singlet, -OCH inulttplet, γγ-H,

125 to 1780, 1307, 1760, (dec.) 1667

J = 5 Hz, _C6- H),

S - (), 5.88 (ch ₂ O -), 5.73 to 5.97 (IH, .70 (IH, singlet, N).

WITH

7.18 (2H, broad singlet, -NH), 9.60 (1H, doublet, J = 9 Hz, -CONH-)

-HHOHO (CH 3) -HH-.

i li 2 3 3 ⁰

CHj

0.87 (3H, triplet, J = 6Hz)

1.15 to 1.70 (4Η, mulliplet, 1.53 (3H, doublet, J ~ 6Hz, (3H, singlet, N-C)), 3.54 (2H, široký wide

N singlet, C 8 -H), 3.86 (3H, singlet, -OCH 3), 4.11 (2H, triplet, J = 6 Hz, - =, 2 =, =, = .3), 5.23 (IH, doublet, J = 5Hz, _C6- H), 5.59 (2H, broad singlet, S), 5.85 (IH, doublet, doublet, J = 5Hz, J = 8Hz, C) ? -H, 6.76 (1H, singlet, N '-), 6.81 (1H, quartet,

S A

128 to 1,780,

135 1 755

665

- (=, 3 = 3)

CC3), ^ ch-cc,)? 2.46

J = 6Hz, == 0, - = 3), 9.65 (1H, doublet, J = 8Hz, -CONH)

-CHOCO (CH3) i 3 3 0

CH ₃

1.41 (9H, flight) J = 7 V-ch ₃ ⁾ 'N singlet, -С (СННз), 1.51 (3H, drlHz, r = cCH-CH3), 2.50 (3H, singlet, 3 , 56 (2H, broad singlet, Cg-H),

3.92 (3H, singlet, -OHH 3), 5.29 (1H, doublet, J = 5 Hz, C ₆ -H), 5.63 (2H, broad singlet, S &gt;), 5.92 (IH, doublet of doublets, J = 5 Hz,

J = 8 Hz, C7-H), 6.84 (1H, singlet, N

WITH

6.91 (1H, quartet, J = 7Hz, 3 ==, - =,), 9.75 (IH, doublet, J = 8Hz, -NHCO-)

Note: * НУгосШог ^.

Table 24 (continued)

J '

Melting point

IR (KBr) cm ”:

c> o

R '

Melting point (° C)

IR (KBr) cm ^-1 :

% = 0

-CHOCC (CH),

I V ³³

CHCh,

140 to 1785,

142 1745, 1675 dec

-CHOCO

I p

137 to

140

782,

750,

670

CH ₃

153 ež

157 (dec)

785,

745,

680

CH 2

-CHOCO

780,

770,

680

-СНОС- <°> o

125 1 780 (dec.) 1 740 1 675

123 ež

129 (dec)

780,

740,

665 ^GH 3

-CHOCCCCH-), + 150 ež 1 793 | ÍI 3 3 160 1. 742 ⁰ (dec.) 1 675

CH)

COOH

16β 1 780, (dec) 1 710,

675 ++

Toifluoo * acetic acid salt

T ьЪ lulka 25

(son isomer)

Melting point ( ⁰ C)

IR spectrum cm -1 ' ^{, V} C = 0 ^P '

Nuclear Magnetic Resonance Spectrum (DKSCOcd, ppm):

-CH ₂ O (CC ₂ ) ₃ CH ₃ 125 až 130 1 780, 1 722, 1 670

+

-CHOCOCH _o CHq

I ll ²³

I ° CH ₃

133 to 1 778,

135 1 755

670

0.87 (3H, triplet, J = 7 dec, - (OH, 3 ')), 1.15-1.58 (4H, m / z), 3.45 (2H,

Wide singlet, C2-H), 3.48 (2H, triplet, J = 7Hz, -C1-C6-C4-C4), 3.83- (3H,-singlet, -OCH3), 5.10 ( 1H, diubet, J = 5 Hz, _C6- H), 5.25 (1H, doublet of doublets, J ~ 5 Hz, J = 8 Hz, C2-H), 5.30 (2H, singlet, -C00CC) ₂₀ °), 2.41 (2H, broad singlet, Sk), 6.71 (1H, singlet, N '-),

ACH ,. ^- S ^^ H

7.18 (2H, broad singlet, -NH 4), 8.01 (1H, singlet, N), 9.57 (1H, J = 8 Hz, -CON 1 -)> -H

N

1.23 (3H, triplet, J = 7 Hz, -C = CH ·)), 1.52 (3H, (dubst J »5Hz, sc _g of H-CH _3), 3.49 (2H, br singlet, C-2-H), 3.84 (3H, singlet, -CCC ₃ ), 4.19 (2H, quartet, J = 7 Hz, -CH ₂ CH ₃ ), 4.95 to 5.52 ( 3 H, muuttppet, C ₆ -H, S), 5.81 (1H, 4 oh ₂ doublet of doublets, J = 5 Hz, J = 8 Hz, C 2 -H), 6.71 (1H, singlet., N ), 6.76 (1H, querteeX,

WITH

J = 5 Hz, s-H1-CH-), 7.16 (1H, broad singlet, -HH-), 8.04 (1H, singlet, N), 9.60 (1H,

N duubet, J = 8Hz, -COH-)

Note: ⁺ opticty igOrne ^

^{J +} 1 as the starting compound used in the top composition Tyl-13 manufactured tebulce

Continuation of Table 25

Melting point (° C)

IR spectrum (KBr, cm '', Ус = <Р ’

NMR spectrum (DMSO-d6, ppm);

OCC -CH (CH,), II and ^JJ Q 1 CH ₃ 145 to 147 1 780, 1 742 » 1 670 1.17 (9H, s, -C (CH ₃ ) ₃ ), 1.52 (3H, -C 1 H -), 3.54 (2H, Broad a, C 8 H), d, J = 6 Hz, 3.92 (3H, s, 1, s) (C ₇ -H), 6.05 m, -CH-) CH ₃ -OCH ₃ ), 4 5.07 (1H, (1H, a, N) . 98 to 5.50 (3H, m. _C6- H) dd 7 J x 5 Hz, J = 8 Hz, -), 6.97-7.24 (1H, WITH ^ч ц 1 CH ₃ 0.24 (1 H, with, N, .delta., 9.78 (1H, d, J = 0 Hz N -CONH-).

Example 17

By the same reaction and treatment as in Example 14- (1), the compounds shown in Table 26 were prepared.

Table 26

-R ²

(son isomer)

OCH ₃

Melting point (° C) to 81 (° C)

COOCH ₂ OCOC (CH3) ₃

IR spectrum (KBr, cm -1 ', 9cx (P »

785,

750,

675

NLIR spectrum (CDCl3, ppm):

1.20 (9H, s, -C (CH _{3> 3>;} 3.25 s, C ₂ -H), 3.98 (3H, s, and 5.45 (2H, AB quartet, J = 15 Hz (2H, br -OCH _3), 5.00 S \) ₂ Ah 5.84 (2H, »

J -0 Hz, C _? -H), 7.60 (1H, doublet, N), 7.75

(1H, singlet),

N ~

7.93 (1H, doublet, doublet, J with 2 Hz,

J = 0 Hz, -CONH-, h - () s

8.77 (1 H,

5.03 (1H, doublet, J = 5 Hz, _C6 -H), singlet, -OCH2O-), 5.91 (1H, doublet of doublets)

J x 5 Hz,

J = 2 Hz

1R spectrum (^τ ^ c ¹ ,

Continuation of Table 26

R ²

Melting point (° C)

NMR spectrum (DMO-δ, ppm);

to 1785,

1745, (crotch) 1675

1.20 (9H, s, --C (CH3) _3), 2.47 (3H, s, N ^ __ _CH 3) 2 H, 0 (2H, br tinglet,

N

C ₂ -H), 3.98 (3H, t sinkL ^ -O CH₃), 5.04 (1H, doublet, J - 5 Hz, _C6 --H), 5.39 e 5.76 (2H, AB quaternet, J = 15 Hz, S (i), 5.85 (2H,

AND

CH ₂ single (-OCMhO-), 5.94 (1H, doublet of doublets, J = 5 Hz, J = 8 Hz, C 7 -H), 7.69 (1H, doublet, J = 2Hz, N -), 7 , 91 (1H, doublet, J = 8Hz)

= J

-CO№H), 8.77 (1H, doublet, J = 2 Hz, H — C)

O

To a solution of 5.93 to l-oxoyloxymethyl iter- [2- (2-eminothiazol-4-yl) 22- (son) -methoxyiminoacetamide] -3- [2- (5-methyl-1,2,3,4-) -] -. tetrazole)) methyl / ~ --cefem 4lkarboxylové-acid in 50 ml _eiyl> ccetáil solution to 2.5 dihydrate meestylensulfonové acid in 20 ml etylacetáuu; The precipitated crystals are filtered off, washed with ethyl acetate and dried. There was obtained 7.39 k (yield 93.2%) of the meestylene sulfonic acid salt of the pivaloyl (a) -oxyl ester] (2- (2-aminothiazol-4-yl)) - 2- (zinc) -metoxyiminooccSβc IDF ^ / 3- / 2- (5-τηeeyl-1, ^{2,3,4-tstrθzoly))} methyl / зЗ-cef®τ) 44 l ^c _r ^y catching box y8el ^{e r i} ny ^to a now obsolete ^{lot-218 and} 22 ⁰ ° ^C (dec ^).

IR (KBr) cm -1; ⁹ _{C = O} 1,782, 1,745, 1,680

NMR (d ₆ -DMOO) ppm: 1.15 (9H, s, -C (CH 3) 3), 2.14 (3H, s,

(3H, s, -OCH 3), 5.20 (1H,

3.52 (2H, broad s, C ₂ -H), 3.93

5.78 (1H, dd d, J = 5Hz, J = 5Hz, J)

C ₆ -H), 5.56 (2H, broad s, = 8 Hz, C ₇ -H), 5.85 (2H, s,

-C-OCCl ³ -, 6.50 (3H, broad s, H 2 N-N-).

H, 93 UH, β, N

WITH

9.81 (1H, d, J = 8Hz, -CO 2 H 1 H)

2—6471

Example 19

1. 5 ml njn-dimetylecetemidu was dissolved 2.4 g of 2- (2-formamidotiazol-4-yl) -2- (syn) -metoxyiminooctové acids ¹ · К te resulting solution at -5 ° was added dropwise ^{1 q, 7 g} ftsf 0: 0: ^ 1111 ^^. The mixture is allowed to react at a temperature of -5 to ⁰ DEG C. for 1 hour. In addition, a suspension of 5 g of Stavetic acid salt with pivaloiloxymethylether (T-amino-1- (2-55-methyl-1,2,3,34-tetazolyl)) is prepared. nie1yl / -C-cefe444 aaroo3irlc) at · acid in 35 ml · etilacetáts ^the resulting suspension přtaá ^1.0 1 ^g Trie-amine at - ³⁰ ° C. ^To the suspension was kapkác ^hours at - ^{30 o u} - ²⁰ ° ^C at c and ^d supra Uve Measured reaction mixture and transmits ^ ack mixture was reacted at the same temperature for 1 hour. After the reaction, water (12 ml) was added and the organic layer was separated. Then 12 ml of water and the pH is adjusted to 4.0 · hy ^d rog nuhličirinβm sulfate. The organic layer was separated and dried with anhydrous magnesium sulfate. The solvent was then removed from the vacuum. The diethyl ether and the rat body were added to the residue to give 5.65 g (91% yield) of 7- / 2- (2-thiomethyl-ethyl) -44y1-pivaloylthoxymethyl ester 42- (syn). 454mert1-1> 2 | 3,4-retaolo1yl) me1yl / -Cecefe444-kвr0oJ1) World taplttě ^counting of I ³² to И5 ^C ^ tzkU

IR (KBr cm &^lt; -1 & gt _;: V &lt; ^{0 &gt};

NMR (d₆-DMSO) ppm: 1.20 (9H s, -CCCCj) _J), 2.51 (s 3H, N) 3.61 (2H, br and,> ^-CH3

N

C24-) | 3.97 (3H, s-OC ₃ ), 5.38 (1H-d, J 5 H 5, C ₆ -H), 5.77 (2H, broad s, S) - 6.05 (2N, s, -0.0420-), 6.11 (1H, dd, J = 5 Hz,

J = 8 Hz-C ₇ -H), 7.60 (1H-s-N

), 8.73 (1H, s, H "), 10.00 (1--,

O

S d, J = 8 Hz, -CON--, 12.63 (1H- broad s, COJN!)

The following compounds were collected in the same manner: 1- [2- (2'-formido) azelt-4-yl] -4,4-ylamino-4-oxo-oxo-acetonitrile-O - / (3-chloro-C, 1,4-4γ-α-O) (1) 4 ', 4'-f-cephem-4-carboxylic acid (crystalline acetic acid, 90% yield).

151-154 ° C.

IR (KB ·) cm '': ^-0 TTU 785 · 1 1 5 7 * ,. 1,680

NMR (d 6 -DMSO) ppm: 1.17 (9H- s, -CH 2) 4)

1.53 (3H, d, J 16 Ho, -CH-), 3.50 (2H, broad

0¾ ^s l

3.90 (3H, s, -OCHpi 4.93 to 5.46 (3-by-m-C ₆ S -H-

5.92 (1H, 7.40 (1H, (1H-d-J dd, J = 5-z, J = 8 Hz, C7-H)) 6.83 to 7-08 (1H-m,), 8- 04 (1H-s-N), 8-8 (1H-s, N -), Z-II

S 'N 0

Hz-COICI--, 12-64. (1H, broad s, -CONH-.

a, N

-CH-),

I CH3 9-75

23647!

7- [2- (2-Formamidothiazol-4-yl) -2- (n-methoxymethoxyiminoacetamido) -3-] - 2- (5-methyl-1,2,3-tetrazolyl) methyl] -pivaloyloxyethyl ester methyl-3-re-fem-.4-carboxylic acid (recrystallized from thiazole), yield 92%.

Melting point: ²⁰³ DEG- ²⁰⁵ DEG C. (.alpha.) .Alpha. (KBr) cm @ ^-1 ; ^9c '° 17S0, 1750, 1725, 1680 №R (d ₆ -Di.SO) ppn: 1.19 (9-, s, -0 ((¾¾). 1.53 (3H, d, J = 6 Hz, -CH-), 2.50 (3H, s,

N), 3.71 (2H, broad s, C, -), 4.00 (3-, s, -00¾). 5.35 (1 H,

-¾ * ^J (1 H, d, J = 6 Hz)

CS ^-)

5.68 (2H, broads,

6.02 (1 H, dd,

J = 6 Hz, J = 9 Hz, C, -), 7.08 (1H, m, -CH--), 7.58 (1H, ⁷ 'Γ ° b)

8.70 (1H, s, HC--), 9.99 (1H, d, J = 9Hz, -CON4 -), 12.70 (1H)

O s, N

WITH

(1H, Shirols,

CO ^ ^ ”).

^/, In ⁶⁶ mL of methanol and 6.55 ^g was sispendijc 1 * - ^p Ivalo ^y lox ^y e lestfcri ^the T - ^ - ^ - fomcamidotiazol-4 '' -yl) -2- (ynn) -τηe0ox 0oinoocceteido ^y / ~ · 3- / <(^ - ^ <^ I ^ 3.oj ^ —1 ^ Л-ыЧкгоХу). 4-Ethyl-3-C, 4-la carboxylic acid and 4.2 ml of 12N chloroform-acid were added to this suspension from ice-cooling. ^In ýsle ^d n sc Necmi ^and the mixture react for ^{2 hours} by ^{d p} s ^ ins ploité ^{5 and} 10 ° C. ^The reaction mixture was poured into 660 ml of water. Pal is pumped to pH 5.0 with sodium bicarbonate and the depicted filtrate is filtered off. 5.73 g (91.4% yield) of 1 ' -pivaloyloxyethyl ester 7-12-2 2a-aminothiazzl-4-yl) - (- (2-chlorobenzoyl-iminoacetamide) -3 - / (3-chloro-1,2) are obtained, m.p. 4-tr ^y y azo ^e) ethyl ^ / ^ - iefer ^ - ^ ^ ew ^ly arbox Selin ^yl mp ^{145 147} "C.

The physical (IR and NMR) of this compound is identical to the prodil obtained in Example 16.

Annex 1 a d 20

1. Follow the same procedure in Example 14 or 15 to obtain the following compound:

pivFaloylzxymeeyУesteo 7 - // ~ (/ - aminrZiiZkZl-4yУ) - / - (syn) · ethoxyimino8-tamido / · '-з / 2- (5-methyl-1, /, 3,4 ·) triazoles)) methyl-Zecefem44kkerbzxylic acids.

Tann 99 ^and temperature of 102 ° C (dec.)

IR (KBr) ^{cm @} -1 ^:. ^ ^c ₌ ^o 1,785, 1,745, 1,675, 1,615

2. From the compounds obtained in (1) above, the compound is obtained by the method described in Example 18: MeCylene Sulfonic Acid Salt with Pivaloyl Crecyl 7- / 2 - ((2-eminothiazole) (4- (1-yyl)) - 2- (syn-ethoxyimido-acetamide) -3 (72) - ((- ethyl-1,2,3,4-tetrazolyliinctyl) -? --Ceifem-4-laoboxylovol acid).

Melting points ^: &gt; 190 ° C

IR (KBr)? ^C = O ^1780, 1745, 1 ⁶ 80th

Preperation example 1

The composition below is prepared by first mixing and spreading the main component with Isktose. An aqueous solution of hydroxypropylcellulose is added to the mixture. The resulting mixture is bent, dried and dusted. The powder is mixed with magnesium stearate which has been premixed with starch, and then the resulting mixture is made into tablets.

7- (2- (2-Amino-thiazol-4-yl) -2- (syn) -wetoxyimino-acetamido) -1- (2- (5-methyl-1,2,3,4-tetrazolyl) methyl) methyl) pivaloyloxymethyl ester hydrochloride 3-cefem-

.alpha.-carboxylic acids 130 mg lectose 20 May mg starch 44 mg hy droxy propyl ce lul ó za 5.4 mg magnesium stearate 0.6 mg 200 mg / tablet

If other compounds are used instead of said compound, tablets may be prepared in a similar manner.

Preparation example 2

The composition of which is given below is prepared by mixing part of the starch and rubbing it with magnesium stearate. The blended mixture is mixed with the remaining starch, hydroxypropylcellulose and the main component. Capsules are prepared in a conventional manner from the mixture obtained.

7- (2- (2-Amino-thiazol-4-yl) -2- (syn) -methoxyiminoacetamido) -3- [2- (5-methyl-1,2,3,4-tetrazolyl) methyl] hydrochloride pivaloyloxymethyl ester hydrochloride -3-cephem

-4-carboxylic acids 136 mg starch 54 mg hydroxypropylcellulose 6 mg magnesium stearate 4 mg

200 mg / capsule

If other compounds are used instead of said compound, similar capsules can be prepared in a similar manner.

Preparation example 3

The composition below is made by first mixing the main component with lactose and triturating the mixture. An aqueous solution of hydroxypropyl cellulose was added to the ground mixture. The resulting mixture is bent and dusted. 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-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamido) -3- / 2- (5-methyl-1,2,3,4-tetrazolyl) mesitylene sulfonic acid pivaloyloxymethyl ester salt methyl 3-cephem-4-carboxylic acid lactose

130 mg

Starch hydroxypropylcellulose magnesium stearate mg mg

5.4

0.6 mg mg

200 mg / tablet

If other compounds are used instead of said compound, similar tablets may be prepared in a similar manner.

Preparation example 4

The composition below is made by mixing a portion of the starch and triturating it with magnesium stearate. The blended mixture is mixed with the remaining starch, hydroxypropylcellulose and the weed component. A capsule is prepared from the mixture obtained in a conventional manner

Formulation mesitylenesulfonic acid salt and pivaloyloxymethyl ester

- [2- (2-Amino-thiazol-4-yl) -2- (synyl) -methoxyimidazo] -3- [2- (5-methyl-1,2,3,4- &lt; / RTI &gt; tetrazolyl) methyl] -3-cephem-4-carboxylic acid 136 mg Starch 54 mg hydroxypropylcellulose 6 mg magnesium stearate 4 mg

200 mg / capsule

When other compounds are used for the above compounds, similar capsule formulations can be prepared in a similar manner.

Preparation Example 5

Sodium bicarbonate mixture with 7- / 2- (2-eminothiazol-4-yl) -2- (syn) methoxyimino-

8cetamido / 3- / 2- (5-methyl-1 ₃ 2,3,4-tetrazolyl) methyl / -3-cephem-4-carboxylic acid was treated in a conventional manner so as to obtain a lyophilized sterile sodium salt. Injections are made by dissolving one gram of sodium salt in 20 ml of physiological saline.

100 ALIGN!

Preparation example 6

Injections which were diluted prior to use were prepared by dissolving 1 gram (strength) of the lyophilized product prepared according to Comparative Example 5 in 4 ml of a 0.5% (w / v) aqueous solution of hydrochloride.

Preparation example 7

Injection is made by dissolving 1 g (strength) of the oily product produced according to Preparation Example 5 in 20 ml of a 5% glucose solution.

In addition, other compounds (free carboxylic acids) of the formula I according to the invention may also be formulated in the lipidized products (sodium salts) or in the injections, if the procedure is the same, as in Preparation Examples 5 to 7.

Claims (5)

A process for the preparation of spores of the general formula I (I) wherein r 1 represents a hydrogen atom or a C 1-6 alkyl, phenyl, 2-carboxyphenyl, 1'-C 1'-C 1'-oxybenzyl, C 1'-C ^в У У!! -C ^ -alkyl, furdyl, or a group of formula -CHOOR ⁶ or ^- -CHOCOOR ⁶ where 6 7 R 0 represents a C 1-6 alkyl, cycloheyl or phenyl group and R 1 represents a hydrogen atom or an alkyl group; R ² is phenyl, 2-tlenyl, 2-furyl, C2_ _б elktnoylaminvskupiyu, benzvylaminv8kupiyu, furoyl amino, 1,2,3-zolyXovou Itri, 1,2,4-triezolyVovvt or 1,2,3,4-tetrjlvlflovou group, they are attached to the exornetylene group at the 3-position of the cephem ring by a carbon-nitrogen bond and can be substituted by at least one substituent selected from the group consisting of halogen atoms, hydroxy, C 1-6 alkyl, C 1-4 alkylthio, C 1-4 alkoxycarbonyl, phenyl, C 6-6 alkanoylamino, C 1-7 alkanoylamino; R @ ³ is hydrogen or halogen, ^R @ ⁴ is hydrogen, amino or formylamino, chloroacetyl, benzyloycarbonylthienylcarbonyl or tert-amylcarbonyl; amino represents a group of the formula -CH ₂ - or a group of the formula -C-, OR 101 represents a C 1-4 alkyl group and the bond ^aaa means that the compound may be a son or an anti-isoner, or mixtures thereof, or a pharmaceutically acceptable salt thereof, characterized by. by reacting a compound of formula II COOR (II) wherein ^h0 is amino, ^h ' ⁹ is hydrogen ^; in the case of a carboxyl group 2 's ^to u ^when n ^y and ^R has the abovementioned meaning, ^b not a salt thereof, with a-nino ou ^ of formula ^b ecného X'II R ^4a -A-COOH R3 (III) wherein R ⁸ is hydrogen NETIO aminos ^to oup ^which may Tyr ^p OPr i ^p j ^ga is driven to ^R3 and A mm her defined above, or its reactive deriváeern at the carboxyl group and, if desired, deprotected, hydrogen atom in the carboxyl group at position 4 of cephem ruhu ^to the ^p ieve ^d e a different meaning of ^{R 1,} or the product ^P, reversible e ^d into a pharmaceutically acceptable salt thereof. 2. The process of clause 1, wherein the process is based on a compound of the above. of the general formulas to give compounds of formula I wherein R is 1, 4-triazolyl, 3-methyl-1 H, 4-triazolyl, 3-methylthio-1,2,4-triazolyl, 3-ethoxykaabooyl-1,2,44-triazolyl, 3 chloro-1, 2,4 - ^^ ^ & 1у1 3-acetylaminno1, 2,44triazolyl, 4,5 ''^'bdlmetoo'ykaronyny1,2,33trió'zooyl, 4tkyeno 5-tfenyl-1-З 1,2,3,4,4-dimethyl-1,1,5-methyl-15-ethyl-1,2,3,4-triazol-5-yl 1,2,3 _> 4-trrazolyl, S-amine! , 2,3,4 - ^^^ (3111, ^ -etoxykarbony1-1, ^{2,3,4-tetra-,} and ^ o ^; ^ t., 5-phenyl-l S.čcetyljminool, 2,3,4- · ^^^^} ^. or 5 'ttoxykar ^b oon1ϊ ⁿ ity1-1, 2,3,4 ~ e rttiaiolyl other subot1tutn.ry ϋ · ί above above known. 3. A process according to claim 1 or 2, wherein A is starting from compounds of the above formulas, to form compounds of formula I, wherein the group is of the formula -CH3 and the other substituents are as defined above. 4. A method according to claim 1 or 2, vyznnjčuící in that starting from the compound of the above formulas to form a compound of formula I wherein A represents a group of formula -C- ^ undispersed ^wh e ^r3 and ligament and ^b / vw have the above significance Eny Uve ^{d b} in the one and the other ^da ^ i i N) i 5 OR ³ substituents are as defined above, 5. The process of any one of claims 1 to 4, wherein the reaction is carried out at a temperature of -50 to 40 ° C.