CS236493B2 - Method of 7-amino-3-substituted methyl-delta 3-cephem-4-carboxyl acid's preparation - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as an intermediate for an antibacterial agent in high purity in high yield easily, by reacting a specific cephalosporanic acid with a triazole or tetrazole in an organic solvent in the presence of an acid or a complex of an acid. CONSTITUTION:A compound shown by the formulaI[R<1> is H or alkoxy; R<2> is NH2, or a group shown by the formula II or III (R<3>-R<7> are organic residue not participating in a reaction); X is optionally substituted acyloxy or carbamoyloxy; Y is S, or S O], derivative at its COOH, or its salt, is reacted with a triazole or tetrazole wherein C in the ring may be substituted, to give a compound shown by the formula IV, its derivative, or its salt. The reaction is carried out in an organic solvent, e.g., nitromethane, etc. in the presence of an acid or a complex of acid (e.g., sulfuric acid, BF3 or its complex compound etc.).

Description

The present invention relates to a process for preparing cephalosporin intermediates.

The 7-amino-3-substituted methyl- N -cephal-4-carboxylic acids of formula I below or salts thereof are suitable intermediates for various cephalosporins, e.g., for the novel cephalosporins of formula III or salts thereof.

(III)

COOR where

A is as defined below;

represents a hydrogen or halogen atom represents a hydrogen atom or an amino group which may be protected or substituted, represents a group of formula -CH 2 - or a group of formula -C-, wherein R ¹ represents an atom

and the bond is syn or an anti-isomer or a mixture thereof, and is a hydrogen atom.

These compounds have an antibacterial spectrum exhibiting excellent antibacterial activity against Gram-positive and Gram-negative bacteria, are still against beta-lactaseases produced by bacteria, are of low toxicity, at the same time are well absorbed by oral or parenteral administration and have excellent therapeutic effect on human and animal diseases.

The present invention provides a novel process for the preparation of 7-amino-4-substituted methyl-4-cephem-4-carboxylic acid or salts thereof.

The invention further relates to the production of novel cephalosporin intermediates obtained by the following process.

Other objects and advantages of the invention are described below.

The present invention provides a process for the preparation of a 7-amino-3-substituted methyl-4-cephen-4-carboxylic acid of formula I

WITH,

(AND)

COOR

phthalidyl, C 1-6 alkoxy-C 1-6 alkyl or a group of the formula -CHOR ^J or -CHOCOOR ^J , wherein R 1 is C 1-6 alkyl, cyclohexyl or phenyl and R 1 is hydrogen or C 1-6 alkyl, and '

R- represents a triazolyl or tetrazolyl group attached to the exornmeylene group at the 3-position of the cephem ring by a carbon-nitrogen bond which may be substituted by at least one substituent selected from the group consisting of halogen atoms, C 1-6 alkyl, C 1-6 alkylthio, alkoxycarbonyl, phenyl ^ ^ ба адоу ш ^^ ^ alkyl, _C-1β 5alklxykarSoouУi C_5 ^ft lkyllvé groups, cyano group and aminostopinu, or show, by reacting a cephalosporanic acid of the formula II wherein

R ⁵

COOH means a C 8-6 alkanoyloxy group, means an aminostopine, a group of the formula R ¹ wherein R ⁷ , R ⁸ and R ⁹ which

OC-NH-,

may be the same or different, znametaií hydrogen atoms, organic radicals which participate in the reaction ^ or a group ^{R, Formula 10 kd} e ^R10 and ^R1 \ which may be

R ¹¹ same or different, znamenej hydrogen atoms or organic residues not participating in the reaction ^, and> Z zněmená> S or>S> 0, or its derivatives at the carboxyl group or its salts or triazoeem tetnzzolem which may be substituted at least one substituent selected from the group zatanující halogen, C ^ alkyl radicals, C_iikУyttltkjut1uy, Ci akkoxykar aryl group, phenyl, C ₂ _galkanoylamino8topiny C _1- 5alklxykarbolnУ- <c_jalkylovlu - group and ^to yanoskupinu aminostopinu in an organic extended ^ Stably in the acid or complexity of the acid compound, and if desired, the carboxyl and amine protecting groups are removed or the product obtained is converted into a salt.

In this specification, unless otherwise indicated, the term alkyl means a straight or branched C 1-6 alkyl chain, for example, methyl, ethyl, n-propyl, 1-propyl, 2-propyl, sec-2-yl, tert-butyl, pent, yl, hexyl, heptyl, octyl, dodecyl and the like.

is hydrogen Neto ^^ ^ alts difenylmeey ^t ^ -nitro ^{with lnzyl,} ftiHtyl, 1 '- ^ valoyi ybenzyl ^ C ^ acyl-yy-C ^ alkyl or a group of formula or -CHOrJ -CHOCOOR- in

- »4 ^{R 5} · ^á znameQ С ^- _ ^- alkyl, cyclohexyl Neto euyl ^f and R is hydrogen or ^ - ^ ^ Vou aUcy quick match. ^{4 V d} efiuici r \ ^r 3 and ^{r 4} znameró term C ^ iltyi napříH. ^ ^T ^ y _methyl) eth-η ^ ^^ ψη иерпру! »N-butyl, i-b ^ Sa ^ 1 ^; ^ l, t ^ butyl, PA-butyl and the like, the term C _s _iacyllxy-Cj- ^ alkyl means for example. ^^ ^ χ ο1? 1 tivailyllxymelyl, trlpiluyloxymelyl, n-Bu ^ yryloxymdyl - ITL-Sutyryloxymeeyl, vallryloxymeeyl 1-acltlxy 1-p-tertyl, 1-pivaloyloxymethyl, 1-pvalyl-ynylpentyl and the like.

Derivatives of the compounds of formula (II) on the carboxyl trace include compounds having carboxylic trace moieties commonly used in the art, such as esters and cephalosporins, and include ester-forming groups that can be removed under mild conditions catalytic reduction, chemical reduction or other treatment; ester-forming groups readily removable in living organisms and other known ester-forming groups which can be easily removed by treatment with water or an alcohol such as organic silyl groups, organic phosphorus-containing groups, tin-containing organic groups or the like

Examples of typical carboxyl protecting groups are:

(a) alkyl groups;

b) substituted lower alkyl groups which are substituted by at least one of the following substituents: halogen, nitro, carbalkoxy, acyl, alkoxy, oxo, cyano, cycloalkyl, aryl, alkylthio, alkylaulfinyl, alkylsulfonyl, alkoxycarbonyl, 5-alkyl- 2-oxo-1 ₄ 3-dioxol-4-yl,

1-indanyl, 2-indanyl, furyl, pyridyl, 4-imidasolyl, phthalimide, aukcinnamide, acetyl, azlridine, pyrrolidine, piperldine, morpholine, thioaorfoline, pyrrolyl, pyrazolyl, thiazolyl, thiazolyl, oxazolio, thiazolyl, oxazolio, oxazolio, thiazolyl, oxazolio, oxazolio, oxetriazolil, triazolyl, tetrazolyl, pyridyl, quinolyl, phenazinyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl, coumarinyl, N-lower alkylpiperazine, 2,5-dimethylpyrrolidine, 1,4,5,6-tetrahydropyrimidinyl, 4-tetrahydropyrimidinyl, 4-tetrahydropyrimidinyl, 6-dimethylpiperidine, 3- (2'-methyl-4-pyrrolinyl)> 3- (4-pyrrolinyl), N- (methylpiperidinyl), 1,3-benzodioxolanyl, alkylamino, dialkylamino, acyloxy, асуlamino, acylthio, dialkylaminocarbonyl, alkoxycarbonylamino, elkenyloxy, aryloxy, erelkyloxy, alicyclooxy, heterocyclooxy, alkoxycarbones Alkoxy, alkenyloxycarbonyloxy, aryloxycarbonyloxy, eralkyloxycarbonyloxy; alicyclooxycarbonyloxy, heterocyclooxycarbonyloxy, alkenyloxycarbonyl, aryloxycarbonyl, arelkyloxycarbonyl, 611cyclooxycarbonyl, heterocyclooxycarbonyl, alkyleniline and alkyleniline substituted with halogen, lower alkyl or lower alkyl;

c) a cycloalkyl group, a lower alkyl-substituted cycloalkyl group, or (2,2-di- (lower alkyl) -1,3-dioxolane-

d) alkenyl groups;

e) alkynyl groups;

f) phenyl, a substituted phenyl group, wherein at least one of the substituents is selected from the substituents mentioned in b) above; or an aryl group of the formula wherein

X is -CH «CH-O-, -CH» CH-S, -CH-N-CH · ®-, -CHCH-CH «CH-, -CO« CH »CH-CO or -CO-CO« CH - CH-, or a substituted derivative thereof, the substituents of which are selected from the substituents mentioned in b) above, or a group of the formula wherein

Y is a lower alkylene group such as - (R 5) 2 - or substituted derivatives thereof, wherein the substituents are made from the examples given under b);

j

g) aralkyl groups which may be substituted with at least a dietary substituent selected from the example given under b);

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

alicyclic indanyl or phthalidyl groups or substituted derivatives thereof, the substituents of which are halogen or methyl; alicyclic tetrahydronaphthyl groups or substituted derivatives thereof substituted with halogen or methyl; a trityl group, a cholesteryl group or a bicyclo [4.4.0] -decyl group;) alicyclic phthalidylidene-lower alkyl groups or substituted derivatives thereof, the substituent of which is halogen or a lower alkyl group;

Said carboxyl protecting groups are typical examples of such groups. any of the groups listed in U.S. Patents 3499909, 3573296 and 1641018, DE-DOS 2301014, 2253287 and 2337105 may be used.

Among the aforementioned protecting groups, carboxyl groups are preferred those which can be readily removed in living organisms, such as 5-lower alkyl-2-oxo-1,3-dioxol-4-yl, acyloxyalkyl, acylthioalkyl, phthalidyl, indanyl, phenyl, substituted or unsubstituted phthalidylene-lower alkyl groups or groups of formulas

-CHtCHp ^ Qfi ³ ', *

-CHOCOOR ^J

-СН (СН,) СООЯ

AND,

R ¹⁵ is a straight or branched, substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, alicyclic or heterocyclic group,

AND*

R 1 represents a hydrogen atom or an alkyl group, r 1 represents a hydrogen atom, a halogen atom or a substituted or unsubstituted alkyl, cycloalkyl, aryl or heterocyclic group - (CH 2 J 4 COOR 4), where iP is as previously defined, n represents Number 0,1 or 2 and m is 0, 1 or 2.

Preferred carboxyl protecting groups include 5-lower alkyl-2-oxo-1,3-dioxol-4-yl groups such as 5-methyl-2-oxo-1,3-dioxol-4-yl, 5- ethyl-2-oxo-1,3-dioxol-4-yl, 5-propyl-2-oxo-1,3-dioxol-4-yl and the like; acyloxyalkyl groups such as acetoxymethyl, pivaloyloxymethyl, propionyloxymethyl, butyryloxymethyl, iso-butyryloxymethyl, valeryloxymethyl, 1-acetoxyethyl, 1-acetoxy-n-propyl, 1-pivaloyloxy-ethyl, 1-pivaloyloxy-n-propyl and the like; acylthioalkyl groups such as acetylthiomethyl, pivaloylthiomethyl, benzoylthiomethyl, p-chlorobenzoylthiomethyl, 1-acetylthioethyl, 1-pivaloylthioethyl, 1-benzoylthioethyl, 1- (p-chlorobenzoylthioethyl) and the like; alkoxymethylmethyl, propoxymethyl, propoxy, butyloxymethyl and the like groups; alkoxycarbonyloxymethyl group such as methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxykarbonyloxymetyl, isopropoxykarbonyloxymetyl, n-butyloxycarbonyloxymethyl, t · butуloxykarbonyloxymetyl, 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl, 1-propoxycarbonylamino bonyloxyetyl, 1-isopropoxykarbonyloxyetyl, 1-butyloxykarbonyloxyetyl like groups; alkoxycarbonylalkyl groups such as methoxycarbonylmethyl, ethoxycarbonylmethyl and the like, phthalidyl group, indanyl group, phenyl group and phthalidylidenealkyl groups such as 2- (phthalidylidene) -ethyl, 2- (5-fluorophthalidylidene) ethyl, 2- (6-chlorophthalidylidene) - ethyl, 2- (6-methoxydthalidylidene) ethyl 1 and similar groups.

Salts of the compounds of formula I or II include salts of basic or acidic groups, which are generally known in the art of penicillins and cephalosporins. In particular, dreams include salts with mineral acids such as hydrochloric acid, nitric acid, sulfuric acid, and the like, salts with organic carboxylic acids such as oxalic 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, toluene-4-sulfonic acid, mesitylenesulfonic acid, 2,4,6-trimethylbenzanesulfonic acid, naphthalea-1-sulfonic acid, naphthalene -2-sulfonic acid, phenylmethanesulfonic acid, benzene-1,3-diaulfonic acid, toluene-3,5-disulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2,6-disulfonic acid, naphthalan-2,7 disulfonic acid, benzene-1,3 »5-trisulfonic acid, benzene-1,2,4-triaulfonová acid, naphthalene-1,3 _t 5-tetraacetic acid and the like acids (such as salts and basic group) and salts в alkali metals such as sodium, potassium and the like; salts with corrosive earth metals such as calcium, magnesium and the like metals; ammonium salts; salts with organic bases containing a nitrogen atom, such as procaine, dibenzylsmin, N-benzyl-beta-phenethylamine, 1-efenamine, Ν, Ν-dibonzylethylenediamine, trletylamine, trimethylamine, tributolamine, pyridine, dimethylanllin, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylsmin and the like (such as an acidic salt).

R represents a triasolyl or tetazolyl group attached to the exomethylene group at the 3-position of the cephem ring by a C-K bond.

The above triazolyl or tetrazolyl groups include 1,2,3-triazolyl,

1,2,4-triazolyl and 1,2,3,4-tetrazolyl groups. Although these triazolyl and tetrazolyl groups find isomers, they may be bonded to the 3-ethoxymethylene group by any ring nitrogen atom. Specific examples are 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,4-triazol-1-yl, 1,2,4-triazol-2-yl ,

1,2,4-triazol-4-yl, 1,2,3,4-tetrazol-1-yl and 1,2,3,4-tetrazol-2-yl.

Further, the triazole and tetrazole groups of R may be substituted with at least one substituent selected from the group consisting of halogen atoms, C 1-4 alkyl groups, C 1-4 alkylthio groups, C 1-4 alkoxycarbonyl groups, phenyl groups, C 2-6 alkanoylanines C 1-6 alkoxycarbobyl-C 1-6 alkyl and amino.

In the meaning of R ^{2, the} term C 1-6 alkyl ** has the same meaning as described for r 1, R ³ and R 4; the term C 1-4 alkylthio means -SC 1-4 alkyl, wherein the C 1-4 alkyl group is as previously defined; the term * C 1-6 alkoxycarbonyl means -OpO-C 1-6 alkyl, wherein C 1-6 alkyl has the previously mentioned meaning; ^R term C ₂ _ ^ ^w alkanoylanino znaBená example, acetylamino, propionylamlnovou, hutyrylaminovou and the like, the term C ^^ ^^ alkoxycarbonyl-C alkyl "means a radical containing Cj- ^ alkoxycarbonyl groups previously mentioned meaning and C ^ alkyXové groups as defined above.

a butyryloxy group and the like.

7

R is an amino group of formula

residues not involved in the reaction or a group of formula R ¹ ® who β q ·

R, R, and R, which may be the same or different, are hydrogen or organic atoms wherein _{R10 and} which may be the same or different are hydrogen atoms or organic residues not involved in the reaction.

As the organic radical R ?, R ^8? * _R 10 _R 11, _wherein Y _8e participate in the reaction, mentioned in the above formulas can be substituted or unsubstituted aliphatic, alicyclic, aromatic, arallfatické, a heterocyclic acyl radicals.

In particular, the following groups should be mentioned:

1 aliphatic radicals: for example alkyl and alkenyl groups,

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

3. aromatic residues: for example aryl groups,

4. arallphatic radicals: for example aralkyl groups,

· Heterocyclic radicals: 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, alicycloaliphatic carboxylic acids, aromatic substituted oxyaliphatic carboxylic acids, aromatic substituted thioaliphatic carboxylic acids, heterocyclic substituted aliphatic carboxylic acids, heterocyclic substituted oxyaliphatic carboxylic acids, heterocyclic substituted thioaliphatic carboxylic acids , organic carboxylic acids in which an aromatic ring, an aliphatic group or an alicyclic group is attached to the carbonyl group by an oxygen, nitrogen or sulfur atom, an aromatic carboxylic acid, a heterocyclic carboxylic acid and the like.

As the above aliphatic carboxylic acids, there may be mentioned formic, acetic, propionic, butanoic, isobutyric, pentanoic, methoxyacetic, methylthioacetic, acrylic, crotonic and the like acids. The above-mentioned alicyclic carboxylic acids include cyclohexanoic acid and the like. The above alicycloaliphatic carboxylic acids include cyclopentanoacetic acid, cyclohexanoacetic acid, cyclohaxesopropionic acid, cyclohexadiene acetic acid and the like.

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

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

As the hydroxyl protecting group, all of the groups commonly used for protecting a hydroxyl group can be used. In particular, readily removable acyl groups such as benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4,4-dimethoxybenzyloxycarbonyl, 4-phenylazobenzyloxycarbonylbenzyloxycarbonylbenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, , 1-dimethylpropoxycarbonyl, iso-propoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromethoxycarbonyl, 2-furfuryloxycarbonyl,

1-adamantyloxycarbonyl, 1-cyclopropylethoxycarbonyl, 3-quinolyloxycarbonyl. Cetyl, trifluoroacetyl and the like, as well as benzyl, trityl, methoxymethyl,

2-nitrophenylthio, 2,4-dinitrophenylthio, 2,4-dinitrophenylthio and the like.

β

As amino protecting groups, those commonly used for protecting amino groups can be used. Particularly, these include easily removable acyl groups such as, for example, trichlorostoxycarbonyl, tribromethoxycarbonyl, benzyloxycarbonyl, p-tolusnaulfomyl, p-nitrobenzyloxycarbonyl, o-bromobenzyloxycarbonyl, o-nitrophenylsulfomyl, tri, chloro, trifluoromethyl, amyloxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4,4-dimethoxybenzyloxycarbonyl, 4- (phenylazo) benyyloxycarbonyl, 4- (4-methoxyphenylaso) benzyloxycarbonyl, 4- (4-netoxyphamylasonyl) methoxy-2-methoxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonylcarbonyloxycarbonylcarbonyloxycarbonyl, 2-furyloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, β-propoxycarbonyl, 1-cyclopropylstoxycarbonyl, phthaloyl, succelnyl, 1-adanantyloxycarbonyl, 8-quinolyloxycarbonyl and similar groups, such as 2-thienyl group, such as triethenyl group, such as triethenyl group 2,4-dinitrophenylthioacin, 2-hydroxybensylidene, 2-hydroxy- 5-chlorobenzylidene, 2-hydroxy-1-naphthyl-methylene, 3-hydroxy-4-pyrydylmethylene, 1-notoxcarbonyl-2-propylidane, 1-ethoxycarbonyl-2-propylidene,

3-ethoxycarbonyl-2-butylidexyl), 1-acetyl-2-propylidene, 1-bensoyl-2-propylldane, 1- (R- (2-methoxyphenyl) carbamoyl) -2-propylldene, 1- (S- (4 (methoxyphenyl) carbomoyl) -2-propylidene, 2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclepentylidene, 2-acstylcyclohexylldene, 3,3-dimatyl-5-oxocyclohexylidene and the like, and other amino-protecting groups such as diyl or tert-butylsilanes similar groups ·

As the carboxyl protecting group, all the groups customarily used for protecting the carboxyl group can be used. In particular, such groups are methyl, stylish, n-propyl, isopropyl, tert-butyl, n-butyl, banzyl, diphegylmethyl, trityl, p-nitrobensyl, p-netoxybensyl, bensoylmethyl, acetylmotyl p-nitrobenzoylmethyl, p-nitrobenzoylmethyl, p-methanesulfonylbensoylmethyl, phthalimidomethyl, trichlorostyl, 1, Udimethyl-2-propenyl, 1,1'-diethylpropyl, α-ethoxymethyl, propionyloxymethyl, pivaloyloxymethyl, 3-aethyl-3-butlnyl, dimethylaminomethyl, succinimidomethylmethyl, succinimidomethylmethyl, succinimidomethylmethyl, succinimidomethylmethyl, succinimidomethylmethyl, succinimidomethylmethyl, succinimidomethyl ethyl, 1-oxide-2-ylmethyl, pyridin-1-oxide-2-yl-astyl, bia (p-aetoxyphenyl) methyl and the like groups} non-metallic compounds such as titanium tetrachloride, and eilyl compounds such as dimethyl chloro and lanceol, such as No. 7073/71; and Dutch Patent Application No. 71 05259 (Unloading).

The 7-amino-3-substituted methyl-3-cephem-4-carboxylic acid of formula I (or salts thereof) can be produced by converting the 3-position of the cephalosporanic acid of formula II or a derivative thereof to the carboxyl group or its salt by treatment with triasolene or tetrazole. which legs have nn ring carbon _м jihli plotting the beaten en those in an organic solvent in the presence of acids or acidic compounds and then, if desired, removing the protecting group of carboxyl group or a carboxyl group is salified. If desired, the 7-amino group substituent can be removed in a conventional manner to give the 7-unsubstituted amino compound.

According to this process, a compound of formula II, a carboxylic acid derivative thereof, or a salt thereof can be treated with a triasolene or tetrazole which may have the above substituents on the ring carbon atoms to give a compound of formula I or a salt thereof, wherein R ² is the corresponding substituted or unsubstituted triasolylovou or tetrazolyl. In all the examples, the reaction is carried out according to an industrial process, so that the product is produced in high yield and in high purity.

As triazole or Tetrasol which may be on a ring carbon substituents LSE use triazole or Tetrasol corresponding substituted triasolové or tetrasolová group for R ^2, namely, triazole or Tetrasol of the formula R ² H wherein R ² is a substituted triasolylovou or tetrazolyl said first for

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

N = N N = N

H where o

R is hydrogen or the substituents mentioned above for R. If the formula contains two R groups, they may be the same or different.

The triazoles and tetrazoles having substituents on the ring carbon atoms can, if necessary, be used in the reaction in the form of basic or acidic salts. As the aforementioned basic and acidic salts, the same salts as those of the compounds of the formulas I or II can be used. Salts of the compounds of formula (XI) may first be isolated and then used, or may be prepared in situ.

Protonic acids, Lewis acids and Lewis acid complexes can be used as acids or acid complex compounds in the above reaction. Examples of protonic acids are sulfuric, sulfonic, and superacids (the term super-acid means acids that are more than 100% sulfuric acid, including some of the aforementioned sulfuric and sulfonic acids). Especially may be used sulfuric acid, chlorosulfonic, fluorsírovou and the like, alkyl mono- or alkyl disulfonic acid, for example methanesulfonic acid, trifluoro ^{ermE Ansi} ^ X ^ ^Eneva acid and the like arylmono-, aryldi- or aryltrisulfonové acid such as p-toluenesulfonic acid and the like acids; perchloric acid, magic acid (FSO ^ H-SbF ^), the acid of formula FSO ^ H ^ AsF, ^CF 3 ^SO 3 ^{H "SbF} 5 ^'HF-BF 3 H ₂ SO ₄ -SO _3, and the like superacids.

Examples of Lewis acids include boron trifluoride. Complex Lewis acid compounds include complex salts of boron trifluoride with dialkyl ethers such as diethyl ether, di-n-propyl ether, di-n-butyl ether and the like complex salts of boron trifluoride with amines such as ethylamine, n-propylamine, n butylamine, triethanolamine and the like, boron trifluoride complex salts with carboxylic acid esters such as ethyl formate, ethyl acetate and the like, boron trifluoride complex salts with aliphatic acids such as acetic acid, propionic acid and the like, and boron trifluoride complex salts with nitriles such as acetonitrile, propionitrile and the like.

All solvents which do not adversely affect the reaction can be used as organic solvents. Particular mention may be made of nitroalkanes such as nitromethane, nitroethane, nitropropane and the like, organic carboxylic acids such as formic, acetic, trifluoroacetic, dichloroacetic, pripionic and the like ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like ketones; _the ethers such as diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, anisole and the like; esters such as ethyl formate, diethyl carbonate, methyl acetate, ethyl acetate, ethyl chloroacetate, butyl acetate and the like; nitrols such as acetonitrile, butyronitrile and the like; and sulfolenes such as sulfolane and the like.

These solvents may be used alone or in a mixture of two or more solvents. Solvents which can also be used are complex compounds formed by these solvents and Lewis acids. The acid or complex acid compound is used in an amount of 1 mole or more per mole of the compound of formula (IX) or a derivative thereof on the carboxyl group or a salt thereof. This ratio may vary according to the conditions. It is especially preferred to use 2 to 10 moles of acid or complex acid compound per mole of compound

236493 10 formula П. When a complex acid compound is used, it can be used as such, as a solvent, or as a mixture of two or more complex compounds.

In the above reaction, 1 or more moles of triazole or tetrazole is used as reactant per mole of the compound of formula (II) its derivative, not the carboxyl group or its salt. Particularly preferred is a ratio of 1.0 to 5.0 mol per 1 mol.

This reaction is usually carried out at temperatures of 0 ° C to 0 ° C. The usual reaction time is from minutes to several tens of hours. If water is present in the reaction mixture, undesirable side reactions such as lactonization of the starting compound or product and cleavage of the beta-latern ring could occur.

For these reasons, the reaction system is preferably kept anhydrous. This must be achieved so that к reaction system may _j adds the appropriate dohydrateční agent such as a phosphorus compound (e.g. phosphorus pentoxide, polyphosphoric acid, phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride and the like), an organic silylating agent (e.g., N, O-bis (trimethylsilyl) aeetamide, trimethylsilylacetamide, trisylphenyl or silane, dimethyldiethlorailane and the like), organic acid chloride (e.g., atyl chloride, p-toluenesulfonyl chloride, and the like), acid anhydride (e.g., acetic anhydride, trifluorotyric acid and the like), inorganic a desiccant (e.g., anhydrous magnesium sulfate, anhydrous calcium chloride, molecular sieve, calcium carbide, and the like), or similar agents.

If a carboxylic acid derivative of the compound of formula (II) is used as the starting compound in the above reaction, then, in some cases, the corresponding compound of formula (III) having a free carboxyl group at the 4-position of the cephem ring can be obtained. The corresponding compound of formula III 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.

If this reaction yields a compound of formula III wherein R ¹ is hydrogen, the compound can be esterified or converted to a salt in a conventional manner. If it is produced from a compound of formula III in which R ¹ is an ester group, it can be worked up in a conventional manner to produce a compound of formula III in which R ¹ is a hydrogen atom. This compound can then be further converted into a salt or, optionally, to another ester. When a compound of formula III in which R * is a salt-forming group is prepared, it can be reacted in a conventional manner to produce salts of a compound of formula III in which R ¹ is hydrogen and optionally can also produce a compound of formula III, wherein R ¹ is an ester group.

If the substituent on the carbon atom in the tetrazole or triazole ring that is the reactant in the above reaction is substituted with an amino group, then the desired compound is prepared by first protecting the group with the above protecting groups. Cancer undergoes reaction · After completion of the reaction, the protecting group is removed by conventional means.

Among the compounds obtained according to the invention is 7-amino-3-substituted ^{methyl-3-cephem} £-4-carboxylic acid of the general formula IV N / - N ^> - CH ₂ R ^In

COOR ¹ (IV) where

2a ^R is as previously defined, and ^{R b} is a 1,2,4-triazolyl or 2- (1,2,3,4-tetrazolyl) group which may be substituted by the above-mentioned substituents, said 1,2,4-triazolyl or 2- (1,2,3,4-eeraazolyl) groups are attached to the exorneeylene group at the 3-position of the cephem ring by a nitrogen-nitrogen bond; a novel intermediate for cephalosporin.

The present invention is illustrated in more detail by the following examples, which are not to be construed in any way.

Example 1 ^X

1 2.72 g of 7-ACA and 14.2 g of diethyl ether 'β-β-boron trifluoride complex are suspended in 13 ml of sulfolane. To the resulting suspension is added 1.0 g of 5-meeyУ-112,3,4-teerez- ^y u, and the resulting mixture was treated for 17 h at míatnoost. After completion of the reaction, the reaction mixture was poured into 15 mL of ice water · adding aqueous 26% (wt ·%) ammonia under ice cooling, the pH is adjusted to 3.5 · precipitated crystals are oddiitrují, promyyí 5 ml of water, acetone and dried in ^y . ^{Z | Ka} 1 ≤ ^{6 g of} a mixture of 7-amino-O- (2- (5 - ^, ^ first-1,2,3,4-eeerizol ^yl) MEA ^ey) -3-cephem-4-kdrbnxy1ooé acid and 7-imino-1- (1- (5-methyl-1,2,3,4-eae-azyl) -yl) -3-chloro-4-carboxylic acid in the form of crystals.

2 · V 18 ml of methanol was suspended 1.76 g of the crystals produced above (in par. 1) and to the suspension were added 1.13 g mm (> ^y yrátu of p-toУudOsu1fonooé. A solution to which was added slowly 4 , 6 g diphenyl ^y ddzoomdeaou. the resulting mixture was processed for 15 minutes at místnoost. After completion of the reaction the solvent under reduced pressure nddeateluje. the residue was dissolved in SME whose 30 ml atylicatátu and 30 ml of water. the pH. of the resulting solution - with adjusted with sodium h ^y drogenoULličiiшaem to 8. the organic layer was then oddděí, dried over anhydrous magnesium sulfate and the solvent under reduced pressure oddeesiluje. the resulting residue was vyčiatí four biological mieogaiií-column (Wako-gel C-H-200-el UCE mixtures benozdo-deУacetát 4: 1 OBB / OOB ·). There were obtained 0.79 g of 7-amine N difdoy1metylasteru --- (2- (5-ethyl-1,2,3 -eeetr8Z01 ^y i) deУy-) -Зaiaiem4 _BTE-β ki} ylooé acid, mp 157-160 ° C (rozkk.) and 0.14 g of 7 eifdoy1metyldtteru -dminoo - (1- (5-112,3,4-meeyУ eetriz-yl) ieaeУ) -3-Cdfd ^ -4 ^to Dr. -X ^{b Y 1} oo ^s mp ⁹² ° C ^{(dec kl).}

7-Imino-α (2 - (- mdaeУ-1,2,3,4.eaeriZ-УyУ) ieeeУ) -3-cefdm-4-carboxylic acid

IR spektaum ^(ИВг cm ^-1 _in C _S0): 1 1 77 ^ 720th

NMR Spectrum (ppmρ ppm):

1.75 (2H, br s, NH _2), 2.48 (3H, s, CH-j), C ₂ -H), 4.70 (1H, d, J = 5 Hz / Cg-H) 4.87 (1 H,

5.30 and 5.72 (2H, ABq, J = 16 Hz, S)

-CH3), 7.30 (10H, s,

3.20 (2H, s, d, J = 5 dec, C-H),

6.92 (1 H, s,

D ^ ^ eny nape ster ⁷ -μ ^ ο-3-U - ^ - ^one of methyl 1-2,3,4 tatriZO ^{- yУ)} Mee ^ey) - ^'3 -cdfdm-4-carbo ^{about χ1Уo} Vé kysdliny:

IR (KBr cm ^-1 : ⁹ _CsO 1770 ^, ₁₇₂₅ )

NMR (CDCl 3) ppm: H 80 (2H, s, -NH), 2.15 (3H, s, -CH 3), 3.30 (2H, s, Ο, -H), 4.70 (1H) , d,

J = 5 Ht, CggH), 4? 85 (1Щ d, J = 5 Hit, C? -H), 5.00, 5.38 (2H, ABq, J = 16 Hz,

S1), 6.90 (1H, s, -CH3), 7.30 (10H, s, J / Q1-x2).

> - ^C H ₂ - \ _V

3 * In a mixture of 0.5 · 1 anionic acid and 5 ~ 1 trifluoroacetic acid, 0.462 g of diphenylaethylether 7-emino-3- (2- (5-ethyl-1,2,3,4-tetraoolyl) ethyl) -3-methyl-3-phenoxy is added. -Euro) -ylic acid. The resulting solution was allowed to react at room temperature for 1 hour. After finishing it. 10% water and ethyl acetate are added to the residue. The pH of the solution is adjusted with 28% vine · anonirken (h · ooano%) nr. 8, the solution being cooled with ice. The aqueous layer was odddSÍ and the pH was adjusted with ice cooling 2K · HCl · 3.5 NR KRYSTOL re precipitated are filtered, for a) it is first five) liters of water Poton ⁵ 'nl Bcetonu and ^y with Subi. Z ^and waits 0.26 g of 7-anilOoЗ- (22 (the fifth _(and etjl »í1,2,3,4-tetrrιkoljl) neSyj) -3-4-eafin karloxylrvé kyselily, mp 178 ° C (dec) ·

IR spectra (ЮЗг, cn ^{1 1} , ^3.o): 1 ⁷⁹⁰ · ^{1 61} O ' ¹ 53 °

NMR (CF3COOD in ppm): 2.70 (3H, s, CH), 3.73 (2H, s, CGH), 5.40 (2H, q, CGH, _C? -H)

5.80, 6.12 (2H, ABq, J «16 Hz, S <) · ^¹H 2Stejrýn caused as shown sh ^ rr from 0.462 g dm ^ s ^ phenyl ^ i ^ l ^^ ^ leeteru 7.1п1ю 4 - ((- (5-methyl-1,2,), 4-tetracrlyl) net) (-3-effen-4-carbonyl) acid produces 0.25 g of 7-anino -) - ^{1 (} - (5-methyl-1,2,2LЗ ⁽ 4e ^{t e} eezololyl ^ethyl) -3-cephem (44-Meb ^{r y} O2 LLOV tysel-ins, U ^t · ¹⁹⁵ ° C (dec).

IR (0 · ^ ^{c '1):} _CS0 ^1795, 1 6 ^ 1 530th

NMR (CP 3 COOD, ppn): 2.95 (3H, s, CH 3), 3.90 (2H, broad s, Cg-H), 5.45 (2H, e, Cg-H and

C7-H), 5.57 and 5.92 (2H, [delta], J &lt; 16 &gt; Hz, Su).

^ CHgPex 1 r d 2

Dissolve 2.72 g of 7-ACA and 7.1 g of the diethylene-boron-methylene complex in 19 µl of trifluoroacetic acid. To the solution of the solution was added 0.75 g. Resulting. The mixture is allowed to react for 7 hours. After the end reaction, the solvent was removed from the reduced printing. K vyslataánu. 15 ml of water was added to the residue and the pH of the solution was adjusted to 3.5 with 28% (tip%) of aqueous TOnneM. zr cooling January. The precipitated crystals were aspirated, washed with 5 [mu] l of water, then the acetone was dried. It is obtained. 2.5 g of 7-amino (3- (1- (1,2,4-11-1 ^ 1011)) ethyl) -3- (4-methyl) -tynyl, mp 149 ° C (гоЛЬ).

IR (KBr, i » ^'1): 790- 1, 1610, 1 530th

NMR Spectrum (CV ₃ COOD, ppn): 4.00 (2H, broad s, Cg-H), 5.47 (4H, broad a, Cg-H, C 1 H -H), 8.10 (1H 9.80 (1H,

Ad 3

The following tetreaoly can be caused by it. as in Example 1 (1) or (2), the board is obtained as shown in Table 1. and the carboxylic acids listed in Table 2.

а м н л

а Я

(О о сГ

г- t-

♦ о

СМ

см г * см

см ьсм см ьсГ см ř— см

2.72 -IBL · 0.94 7.1 CF-COOH temp ^β at.

£ 35 ю о φ ф ж ** She knows 1 о г-4 α 2 3 ю ♦ * 31

си řοΓ

<\ Γ

СМ t (XJ

ф С о. д ф о ю о ф а <s о л а N гЧ Ф

Table 2

COOH melting point: 107-110 ° C (dec.) Melting point: 177 ° C (dec.) IR spectrum (KBr, ca -1, 9 g * ₀ ):

770, 1725

NMR Spectrum (CDCl3, ppa):

1.20 (3H, t, CHgCH _3), 1.88 (2H, broad s, NHG), 3.14 (2H, s, C ₂ -H) 3.85 (2H, s, CH ₂ COO) 4.10 (2H, quartet, CHgCHj), 4.55 (1H, J «на 5, Cg-H), 4.75 (H, and J-5 Hs, _C? -H) 5.27 and 5.68 (2H, AB quartet, < J &gt; 16 Hs,),

-CHg

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

795, 1735, 1610, 1535

Nuclear Magnetic Resonance Spectrum (CF 3 COOD, ppm): 1.35 (3H, t, CH 3 CH 3), 3.67 (2H, broad s, Cg-H), 4.20 (2H, s, CH 3 COO), 4.35 (2H, quercat, CH ₂ CH ₃ ), 5.40 (2H, α, C 8 -H, C 1 -H), (2H, Wide α,),

Xch ₂ 5.96

6.90 (1H, s, -CHxr), 7.23 (10H, x phenyl group)

mp: 73-75 ° C (dec

IR: 1770, 1725

NMR: 1.80 (2H, broad s, -NHg), 3.22 (2H, s, C ₂ -H) 4.65 (1H, s, J »5 Hs, -C-H) 4.85 (1H , d, J = 5 Hs, _C? -H), 5.35 and 5.80 (2H, AB quartet, J »16 Hs, S-.), 6.90 (1H, s, ₂ Sacha mp: 171 ° C (roskl.)

IR: 1790, 1610, 1530

NMR: 3.75 (2H, s, C ₂ -H), 5.38 (2H, Ογ-Η), 6.02 (2H, broad and,

J-CJL, 7.40 to 7.65 (3H, a, phenyl protons in, C ₆ -H),>, meta and para) 7.85 to 8.10 (2H, a, phenyl ortho)

-CH), 7.23 (15 Hs, s, 3x phenyl group) tit .: 79 to 83 ° C (dec.)

IR: 1,770, 1,720 ”

NMR: 1.85 (2H, s, -NHg), 3.12 (2H, einglet, Sg-H), 4.60 (1H, doublet,

mp: 220 ° C (dec.)

IR: 1800, 1610, 1530.

NMR: 3.70 (2H, br s, C-H), 5.40 (2H, s, C-H, _C? -H), 6.03 (2H, br s), 8.80 (1H , s, * <.)

Λ "

N

-CH 2 O), 7.30 (10H, s, 2x phenyl # group), 8.43 (1H,

N

Continuation of Table 2

mp: 75 to 77 ° C (dec.)

IR: 1770, 1720

NMR: 1.87 (2H, s, -NHg), 3.24 (2H, s, C ₂ -H), 4.68 (1Й, d,

J 7 Hz, C ₆ -H), 4.87 (1H, d, J = 5 Hz, C ₇ -H), 5.30 (2H,

AB quartet, J = 16 Hz, 5.77

S), 6.92 (1H, [alpha], -CH3),

mp: 165 ° C (dec.)

IR: 1790, 1610, 1530 3.60 (2H, broad and C ₂ -H), C ₆ -H and _C? -H) with ₄ ),

5.40 (2 H, s,

5.94 (2H, broad 8,

H ₂ 7.27 (10H, s, 2x Ph)

mp: 96-98 ° C (dec.)

IR: 1770, 1720.

NMR: 1.85 (2H, s, -NHg), 3.20 (2H, s, C ₂ -H), 4.75 (1H, d, J = 5Hz, C ₆ -H), 4.88 (1 H, d,

J = 5 Hz, C ₇ -H), 5.03 and 5.67 (2H, AB quartet, J »16 Hz)

S-η), 6.98 (1H, a, -CH <), * A <h ₂ 7.30 (ЮН, a, 2x phenyl group)

mp: 64-68 ° C (dec.)

IR: 1770, 1720.

NMR: 1.95 (2H, broad and, -NH ₂₎ 2.58 (3H, s, -SCH _3), 3.18 (2H, s, C ₂ -H), 4.60 (1H, d, J »5 Hz, C ₆ -H), 4.80 (1H, d, J» 5 Hz, C ₇ -H), 5.25ι (· 2Η, AB quartet,

5.72J t, m.x 195 ° C (dec.)

IR: 1790, 1610, 1530.

NMR: 2.68 (3H, s, -SCH-j), C ₂ -H), 5.28 (2H, s, C ₆ -H), (2H, s,

3.62 (2H, a, C ₇ -H), 5.80

J = 10 Hz, S-. ), 6.90 (1H, [alpha], <+> - CH2)

-CH <. ), 7.25 (Ι0Η, s, 2x phenyl group)

Continuation of table δ. 2

/ N = n -N | / = ^N

SCHj

T: T: 158-102 (dec

IR: 1760, 1710.

NMR 1.75 (2H, broad s, -NH 3), 2.58 (3H, s, -SCH-j), 3.10 (2H, s, C 2 H), 4.60 (1H, d, J = 5 Hz, C ₆ -H), 4.80 (1H, d, J 5 Hz, C ₇ -H), 4.97, 5.47 (2H, AB querret, J = 16 Hz, S < ),--CH ₂ ^, -CH (h 7 ^, 25 s, 2x phenyl group)

mp: 174 (rodei.)

IR: 1795, 1610, 1530.

NMR: 2.87 (3H, s, -SC ^), C ₂ -H), 5.35 (2H, s, C ₆ -H, (2H,

3.63 (2 H, s,

(C7-H), 5.60

6.93 (1H, s (юн,

mp ^: 115 ° C (dec.)

IR: 1,770, 1,720, ·

^{NMR: + 3,} 10 (2 br ^s ^ »^ N), t, t ¹ .: 95 DEG C. (dec.) IR: 1795, 1615 - 1530.

NH ₂

3.43 (2H, s, C2-H), 4.85 (1H, d, J = 5Hz, C6-H), 5.05 (1H, d,

J = 5 Hz, C 7 -H), 5.30 (2H, s,

NMR: 3.75 (2H, broad s, Cg-H), 5.35 (2H, s, Cg-H, C7-H), 5.80 (2H, broad s,

^6, 06 (2H, br ^s,

K), 6.90 (1H, s, -CH 2),

7.35 (10H, s, 2x phenyl group)

^mp: 142 ^and from 143 ° C (decomposition

mp: 198-202 ° C (dec

IR: 1775, 1725.

IR: 1795, 1561.5, 1530.

CH2CH3

NMR: 1.32 (3H, t, -CH ₂ CH ₂ ), 1.75 (2H, broad s, -NH), 2.85 (2H, quartet, -CH ₂ CHh), 3.17 (2H, s, C ₂ -H), 4.67 (1H, d, JJ = 5Hz, Cg-H), 5.27, 5.70 (2H,

NMR: 1.48 (3H, t, --CH3), 3.10 (2H, quartaret, --CH2 CH2), 3.75 (2H, s, C6 - H),

5.40 (2H, s, C ₆ -H, C ₇ -H), 5.85, Sy <0

AB quartet, J = 16Hz,

(2H, AB quartet, S

6.93 (1H, s, -CH3), 7.30 (10H, s, 2x phenyl)

COOH

CH2CH3

mp: 82-83 ° C (dec.)

IR: 1770, 1720.

NMR: 1.20 (3H, t-CH3H3), 1.90 (2H, broad s, -N)), 2.50. (2H, quartet, -C1-CH2), 3.25 (2H, s, C8-H); 4.70 (1H, d, J = 5 Hz, _C6- H), 4.90 (1H, d, J * 5 Hz, O-6), 5.02, 5.40 (2H, AB quartet) J »Í16Hz,), 6.90 (1H, 8, -CHO, -CH ₂ ^ * mp: 195-197 ° 0 (roakl).

IR: 1795, 1610, 1530.

NMR: 1.57 (3H, t, -CH ₂ CO ₃ ), 3.30. (2H, q, -CH = CH), 3.83 (2H, s, C ₂ -H)

5.40 (2H, s, Cg_H, _C? -H), (2H, AB quartet, JM6 Hz,

5.53, 5.92

7.28 (10H, s, 2x phenyl group)

mp: 165-167 ° C (dec

mp: 158 ° 0 (dec.)

IR: 1775, 1735, 1710.

u I r °

CH3

NMR: 1.38 (3I, triplet, -CH ₂ Cg ₃ ), 1.72 (2H, α, -NH ₂ (3.25 (2H, broad s, C ₂ -H)) 4.32 (2H , quartet, -CyCl}, 4.70 (1H, d, J-JHz, C ₆ -H), 4.82 (1H, d, J 5 ', 2', C ₇ -H), 5.40 , 5.90 (2H, 'aB quartet,

IR: 1800, 1735, 1610, 1530.

NMR: 1.50 (3H, t, -C ^C C), 3.55, 3.90 (2H, AB quartet, J J ₁₈ Hz, C ₂ -H),. 4, '60 (2H, q, -CH ₂ CCH), 5.40 (2H,

C 6 -H, (C 7 -H), 6.05 (2H, broad e),

8,

)>

J »16 Hz,

6.90 (1H, a, --CH3), 7.30 (10H, e, 2x. Phenyl group)

c = o

I (3

AND

CH ₂ I

CH ₃

140 DEG-142 DEG C. (dec. 770, 1735, 1720).

mp: IR: 1

142 ° C (dec. 800, 1.740, 1610, 1530

mp .:

IR: 1

NMR: 1.42 (3H, triplet, -CH 2 Cl 2), NMR: 1.50 (3H, triplet, -CH 3), 1.80 (2H, e, -NH ₂ ), 3.20 (2H, s, * ------.

C ₂ -H), 4.45 (2H, quartet, -CH 2 CH 3), 4.70 (1H, d, J 5 Hz, C ₆ -H), 4.85 (1H, d, J 5 Hz), C7-H), 5.90 (2H, AB quartet, J-16 Hz, S), 6.90 (1H,

IN

3) 70 (2H, broad 8, C.-Η), 4.55 (2H, quertet, -CJgCCHP, 5.40 (2h, s, _C6- H, C7-Ю), 6.02 (2H, broad s) = CH _2, CH), 7.30 (10H, s, 2x Ph)

c = o CH3

mp: 106 to 108 ° C (dec.) IR: 1770, 1720, 1700.

NMR ^1, 95 (2H, br and, -IfflJ '2.20. (3H, s, COCH3), 3.20 * (2H, br s, C2-H), 4.67 (1H, d, J = 5 Hz, C ₅ , H) 5.32, 5.68 (2H, AB quartet, J = 16 Hz, S @ +), .delta _. 6.90 (1H, s, -CH3), 7.25 (10H, 3, 2 × phenyl group), 9.75 (1H, broad s,> NH)

mp: 179 ° C (dec.)

IR: 1790, 1690, 1610, 1530.

NMR: 2.42 (3H, s, -CH 3), 3.70 (2H, s, C 2 H), 5.40 (2H, s, C ₆ -H, O ₇ -H),

5.95 (2H, broad s, 3H). 5ch ₂ -

mp: 147-150 ° C (dec.) IR: 1770, 1720.

3.30 (2Η, broad s, -NH ₂ ), 4.87

5.04 (1 H,

5.35 (2H, broad), 6.91 (1H, s,

NMR:

3.47 (2Η, broad s, C2-H) (1H, d, J = 5 Hz, _C6- H), d, J = 5 Hz, &lt; 1 & gt _; -H) ₉ cal with S.

[.Alpha.] D @ 23 = _2- (CH-), 7.34 (10H, s, 2 * phenyl), 9.22 (1H, s,

Note: * mSubstituted in DM10-dg as solvent.

Example 4

When the following triazoles are treated in the same manner as in Example 1 (1) or Example 2, the compounds listed in Table 3 are obtained. as shown in Table 4 (2.72 g of 7-ACA was used as the starting material).

(Note: The bond position of the 1,2,4-triazolyl group is not specified because

The 1,2,4-triazolyl group is attached to the exomethylene group at position 3 of the cephem ring by a carbon-nitrogen bond, but it has not been confirmed which of the 1,2,4-triazolyl group nitrogen atoms is attached to the exomethylene group at position 3 of the cephem ring . However, the position of the 1,2,4-triazolyl group substituent is specified by reference to the position of the substituent in the starting compound used.

The same is true in this description, where it is not confirmed which nitrogen atom of the 1,2,4-triazolyl group is attached to the exomethylene group at the 3-position of the cephem ring. triazolyl, 3-methylthio-1,2,4-triezolyl, 3-acetamido-1,2,4-triazolyl-3-chloro-1,2,4-triazolyl. 3-ethoxycarbonyl-1,2,4-triezolyl or a similar group attached to the exomethylene group at the 3-position of the cephem ring, designated 3- ([(3-methyl-1,2,4-triazolyl) methyl)] - 3 - [(3-methylthio-1,2,4-triazoles dimethyl) - -, ^M - -3- (3-methylthio-1,2,4-triazol) methyl] -, -3 - [(3-acetamido-1,2,4-triezolyl) methyl] -, - -3 - [(3-chloro-1,2,4-triazolyl) methyl] -, or - -3 - [(3-ethoxycarbonyl-1,2,4-triazolyl) methyl] -. The nomenclature of the 1,2,3-triazolyl-substituted compounds is the same as above for the 1,2,4-triazolyl-substituted compounds.

Table 3

Default triaso (β)

Compound (e &gt;)

R ²

3-methyl-1,2,4-triezole

0.91 * V

2.39

COOH

Temperature, melting (° C)

IR (KBr)

CaO

NMR ( ⁺ CF 3 COOD, pp.) ⁺⁺ CF 3 COOD + D ₂ O, ppn)

195 • (dec.)

790,

610,

530 ⁺⁺ 2, go (3 H, -CH ₃ ), 3.93 (2H, e,

C ₂ -H), 5.30 (2H, C ₈ -H, C ₇ -H), 5.10, 5.75 (2H, AB quartet, Jal 6 Яж,

3-chloro-1, 2,4-triezole »14

1,25

1790, 1610,

530 * 3.75 (2H,., C ₂ -H), 5.40 (2H, s,

Cg-H, C ₇ -H), 5.47, quartet, J> 16 Ha, S

5.80 (2 H, AB

), 8.50 (1Я, and

Continuation of Table 3

Výcbozx triazole (G) Compound (g) R ² Melting point (° C) IR (KBr) -1 Cl at C ^ 0 3-acetamido- 150 to 1 795, -1,2,4-tris- N - N 155 (dec) 1 1 680, 610, zol 2.52 1 540 NHCOCH3 2.6 3-ethoxy- 176 1 795, kerbonyl- (rozk-to ·) 1 1 720, 610, “1,2,4- -triazole 1.55 N-i-N 1 530. СООСН ₂ СНз

2.3

Ш (^ CF ^ OOD ppm) ⁺⁺ CF ³ COOD + D ₂ ^O, and ^{PP) + 2} 43 (3 H, and ^{-CH-j), 3,} 19 (2Щ ^s, C2-H), 5, 35 (2H, s, _C6- H, C7-H), 5.30 to 5.95 (2H, m, S.), 9.45 (CHt (1H, s, N)) -N ^- N ⁺ 1 , 50 (3H, t, 3/4). ^3, 72 (2H, br s, C ₂ -H), 4.65 (2H, q, -CH ₂ CCh), 5.35 (2H, s, C ₆ -H, C? -H), 5.95 (2H, broad a,), 8.65. ^5/4 ch ₂ (1 H, 3, λ) λ ^κ

3-methylthio-1,2,4-triazole 1.3 N — N XA ^N 'SCH3 147 (dec) 1 770 1 605 1 530 3.4

⁺ 2.75 (3H, α, -SCH ₃ ε, 4.00 (2H, α, C ₂ -H), 5.40 (2H, α, C ₆ -H, C 2 -H), 5.23 , 5.85 (2H, AB quartet, J-16 Hz,

4,5-dimethoxycarbonyl-1,2,3-triazole, 94

161 (res.) Cy = COOCH3

COOCH3

795,

725,

610,

530 ^{+ 3,} 55 (br 2Щ C ₂ -H), ⁴ l <f (6H, s, 2 x-CH₂), 5.35 (2H, s,

5.90 (2H and

C ₆ -H), S-N)

4-Cyano-5-phenyl-1,2,3-triazole

1.9

CN

204 (rozkki)

530

220, ⁽ CN ⁾

790,

610,

530 ^{+ 3,} 75 (2H, s

(Cg-H, C ₇ -H),

^, C ₂ -H), ^5, 35 (2H, and 5.85 (2H, broad s, 7.40 to 7.70 (3H, n,

), 7.80 to 8.10 (2H, η,

Table

Melting point (° C)

IR (KBr) cm -1: at _c-0

NMR (CDCl3) ppa:

to 65 1,775, (dec.) 1,720 to 82 1,770, (dec.) 1,720, 2.00 (2H, a, -NH,), 3.43 (2H, a, Cg-H), 4 .70 TTnrfd, J = 5 Hz, [delta _] -H), 4.88 (1H, d, J = 5 Hz),

_C7 -H), 5.00 (2H, a, S), 6.95 (1H, s,

Н, -CH (·), 7.30 (10H, a,

(1H, s,

8,0 _χ ), 8.07

x2), 7.85 (1 H, 8,

(2H, Broad a, (1H, d, J = 5 Hz, Cg-H), _C7- H), 4.70, 5.33 (2H, ABq,

1.82

4.55

6.93 (1 H,

Wide s, • NHg), З.Ю (2H, в, C ₂ -H),

4.72 (1H, d, J &gt; 5 Hz,

J »16 Hz,),), 7.30 (10H, a,

-CH x 2), 7.70 (1H, 8,

up to 101 (dec.)

770,

720

1,770, (roskl.) 1,720

-NHg), 2.78 (3.21 (2H, AB

5.32, 5.92), 6.86 (2H,

2.33 (2H, quartet, J = 18Hz, Cg-H), 4.71 (1H, Hz)

C ₈ -H), 4.90 (1H, d, J = 5Hz, C ₇ -H), (2H, AB quartet, J = 16Hz, S

Wide e, e, -CH <x 2), 7.20 (20H, β (1H,

x 4), 8.11 e, (3H, e, -CH ₃ ), 3.42 (2H, s, C 8 -H), #, 70 d, J -5 Hz, C 8 -H), 4.85 ( 1H, d, _C7 -H), 4.90 (2H, [nu] C, 1.90)

2.32 (1 H,

J = 5 Hz, (1H, e,> CH-), 7.30 (Ι0Η, β, (1H, s,) x 2), 7.85

Continuation of Table S. 4 -R ² Melting point (° C) IR (KBr) ^c '' ^c = o NMR (CDC1 ₃₎ ppm: N — N 167 až 1 770, 1.35 (3H, t, CH ₂ CH _3), 2.97, 3.30 (2H, ABq, ”COOCHjCH, 168 1 720 J = 18 Hz, _C2 --H), 4.30 (2H, q, -CHgCHj), 4.60 (1H, d, J = 5Hz, C ₆ -H), 4.80 (1H, d, J = 5 Hz, C ₇ -H), 5.30, 5.80 (2H, ABq, J = 16 Hz, S-_), * dc H ₂ - 6.93 (1H, S, P-CH-) 7.30 (10H, s, - 7.88 (1H, s, N) N) N — N 80 to 1 770, 1.90 (2H, broad s, -NH ₂ ), 2.50 (3H, a, -SCH 3), N SCH ₃ 84 (rozkki) 1 720 3.40 (2H, s, C ₂ -H), 4.65 (1H, d, J = 5Hz, C ₆ -H), 4.80 (1H, d, J = 5Hz, C ₂ -H ), 4.85 (2H, s, s ^.), 6.95 (1H, s, 7.27 (10H, ₽ = ^ * - s ₂ - s, x2), 7.90 (1H, s ,) N

. ^ Note that this and the ^one of Maniña Tyl zíakána výctozíto 4- ^b ar ^to the ^xy - ^L ^ L ^ TR ^ from stejtym ůдоЪпш from ^p to that described in Example 1- (1) and (2).

Example 5 t

The reaction is carried out in the old manner as in Example 1 under the conditions given in Table 5. The results are summarized in Table 5

к \

• · нр • * НР аю а » о ‘В with L ° L 0 • Η * 0 Η ► t * Й * » О '· о Φ ο см И * »- М Р СП ΦΡ Jřs J? · φ ф * 5 Φ ·

N t- £ £ £ £ см <м м см см

см t * σι см t <м

fe o °

A4

N

N

M OS O <fc

Axis O -M- fc

N O fc

The reaction is carried out in the same manner as in Example 2 with the conditions given in Table 6, the results obtained are also summarized in Table 6.

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M>

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M * - *> Ф «Ю &

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1ХА 10 е * ίο * о

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

Example 7

If the same reaction and the same treatment as in Example 1 were repeated, replacing the 7-ACA with the starting compounds listed in Table 7, the products listed in Table 7 were also obtained.

Table 7

Starting compound Product M.p. (° C) IR (KBr) cm ' »^ ^C = o p-oitofbenzzlesteo 7-amino- p-oiУofbenzylesУer 7-emino- 114 až 1 770, (3-Acetyl-3-methyl-3-cefθm) -3- / 1 - (1 -, -, 44-yr ^ 1) - 116 1 708 -4-carboxylic acids meetH-S-cell-4-carboxylic acid 4ΓΟΖΚ1 · J acid Ethyl ester 7-emino-3-aceto- eУllesteo V-eminn-3- / 1- (1,2,4- 68 ež 1 770, x ^ i ^ eet ^ y -3-cef em ^ -carbo- - ri8zoly ^{y l) l} l -eet / ^- -3-ce ^e ee-4- 72 (crotch) 1 720 xylic acids -carboxylic acids lileolleeeylester 7- ^ 1П1по- 7-ethoxyphenyl-1- (1,2,4-oxazolyl) - 149 1 790, / 3-lcetfxleeeyl / 3 / cefee-3 / ethyl-3-methyl-4-kerbenzyl (opzzI.) 1 1 610, 530 -carboxylic acids acid

Example 8. To a suspension of 2.96 g of 7-amino-3- [2- (5-inyl-1,2,3,4-tetrazolyl) methyl] -3-methyl-4-carboxylic acid in 15 ml of N, N-dimethylformamide is added 1.34 g selicylaldehydu. The mixture was left at room temperature for 1 hour. The reaction mixture was then cooled with ice. 0.96 g of trielylminine and 2.42 g of plvllfllleleylyl were added. The mixture was allowed to react for 20 minutes. After completion of the reaction, the mixture was poured into a mixture of 150 ml of water and 150 ml of ethyl acetate. The pH is adjusted to 7.3 with sodium bicarbonate, the organic layer is separated, washed twice with 100 µl of water and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure. Isopropyl alcohol was added to the residue. The resulting rats were removed. The product is recrystallized from isopropyl alcohol. 2.73 g (53.1% yield of 7 / (2-ethylphenylphenylbenzene) -ZZ / 22 (5) ethyl-1,2,3,4 (tetrazolyl) pivelolphenylmethyl ester 7 / (2-ethylphenylphenylbenzene) ester) methyl (α) -cephene (4) -carbonyl (4-carboxylic acid) 136 DEG-137 DEG C. (dec.)

IR (KBO-.cm &lt; -1 &gt;): [nu] _C-O 1,770 ^, 1765 to 1750

NMR (CDCl ₃ ) δ: 1.23 (9H, s, -C (CH ₃ ) ₃ ), 2.51 (3H, s, N 1 -y CC ₃ ) 3.30 (2H, s, C ₂ -H), N

5.08 (2H, (4H, (1H, d, J = 5Hz, _C6- H)), ABq, J = 16Hz,

% 8.49 (1H,

5.32 (1H, d, J = 5 Hz, C7 / H), 5.38,), 5.91 (2H, br -OCH ₂ O-), 6.70 s, -CH = K).

5.82 to 7.50

2 · In a mixture of 50 ml of 4N hydrochloric acid and 25 ml of diethyl ether, 5.14 g of 7- (2-hydroxybenzynylidenemine) -33 / 2- (5-methyl-1,2,3) piveloyloxymethyl ester is stirred for 1 hour at 10 to 15 ° C. The aqueous layer is separated off with two 30 ml portions of diethyl ether. 100 ml of diethyl ether are then added to the aqueous layer and the pH is adjusted to pH = 4 (tetrrezllyl) methyl-3 -cephern-4-carboxylic acid. 7.0 by adding 28% (Moisture%) aqueous ammonia under ice cooling · The organic layer is separated and dried over anhydrous magnesium sulfate · A solution of 1 g of dry hydrogen chloride in 20 ml of diethyl ether is added under stirring and ice-cooling. It is filtered, washed with methylene chloride and recrystallized from chloroform. 3.67 g (yield 82.2%) of pivalzyl-oxy-oyl ester hydrochloride of 7-aminozZZ - ((- ((- / - alpha-112,3,4-aminoazzlyl)) are obtained. 149 DEG-151 DEG C. (decomposition) of (4-carboxylic acid) (4-carboxylic acid) l ·) ·

IR (KBr) cm ^-1 : [nu] _C-Q 1773 ^, 1741, 1730

NMR (d6-MSO) δ: 1.18 (9H, α, -CÍCHCH), 2.44 (3H, s, N &lt;), 3.60 (2H, α, Cg-H), 5.23 > ^C fe

(2H, s, C ₆ -H, _C? -H), 5.62 (2H, br s), 5.78 EŽ 5.92 (2H, s,

CH “2

-COOCHgO-),

Example 9

2.96 g of 7-aminobenzoyl-2- (5-methyl-1,2,3,4-triazol-3-yl) -3-chloro-4-carbonyl] -sulfuric acid are suspended in 20 ml of Z, Ν / dimethylaminamide. 1.1 g of trleyleamine are converted into solution under ice-cooling. Then 2.7 g of pivelsylxynethyl iodide are added to the solution. The resulting mixture is treated for one hour at 0-5 ° C. After the reaction has ended, the reaction mixture is poured into 250 ml of water and 200 ml. ml of sodium hydrate · pH of the solution is adjusted to 7.0 by addition of sodium hydrogen carbonate · Insoluble matter is desulphurized · The organic layer is separated and dried over anhydrous magnesium sulphate. to this solution is added a solution of 1 g of anhydrous hydrogen chloride in 30 ml of diethyl ether under ice-cooling and stirring. The separated crystals are washed thoroughly with methylene chloride and then retarylated from chloroform to give 2.72 g (yield 60, 9 pivaloylxyoxyeayl chloride ester 7 (amino) -O (3 (4 - ((5-aryl-1,2,3,4-entrylyl) methyl)) -3-α (4) -benzylbenzyl hyde, having a melting point of 149 to 150%; 151 ° C (гоДО. ·) IR (KBr, m ^-1 ) in _CsQ : 1,773, 1,741 · 1,730 ·

NMR (-MKOdg) ppm: 1.18 (9H, s, -Cl 2), 2.44 (3H, s, -CH-), 3.60 (2H, s, Cg-H), 5, 23), 5.78 to 5.92 (2H, m (2H, s, C ₆ -H, C ₇ -H), 5.62 (2H, s, s ·

By the above reaction using various starting compounds, the corresponding compounds are prepared, which are listed in Table 8 and Table 9.

In the processing of 7 .alpha. - (2- (5-lmayl-1,2,3,4-tetrazolyl) methyl) 3-α-biphenyl-4-lactobenzyl acid or 7 .alpha.-3- (3-chloro-1-carboxylic acid). (2) 4-Acetyl-3-methyl-3- (4-methylbenzyl) thelines by the above reaction substituting Ν, Ν / dioanyiZoaoid and tarieayaaoio for acaoneone and »8 / β-azobicylolo (·4.0) 7 (o) ee4.0 —BJ), the compounds listed in Table 8 and Table 9 are obtained in a yield of 65-90%.

Table 8

COOR

'SSouUenina Temperature IR (KBr NMR (d ₆ -IMSC ⁺ ) ^pp rn ^r1 melting point (° C) ^cm_ ' ^{: Vc} = 0 (CDC1 ₃ ⁺ *) (CD ₃ QD ⁺⁺⁺⁾

Note (processing)

-CHOCOCH "CH - ^{F 3} I ² II 0 1 775, 1 758 1.28 (3H, t, J = 7Hz, -CH 2 Cl 2), 1.5 [deg.] (3H, d, J = 6 Hz, CHCH3), Column Chromatography (Weko l CH3 2.02 (2H, broad s, -NH 3), silkcarel C-200; 3 2.51 (3H, a, -CH 3), 3.33 (2H, eluent: Br s, C ₂ -H), 4.90 (2H, benzene: ethyl- Wide s, C ₆ -H,. C7-H 5.61 (2H, br s, S.) ^^ н ₂ - 6.69 to 7.06 (1H, m, ^ ífCHC) ++ acetate 3: 1)

to

101

788,

740 (2H, s, -NH 2), 2.42 (1H, Ί ₃ ), 2.49 (1, 5H, s, -CH ₃ ),

1.80 s, -CH 3

3.27 (1H, s, C ₂ -H), 3.30 (1H, s, C ₂ -H), 4.62 to 4.95 (2H, m, C ₆ -H, C 7 -H), 5 , 30, 5.65 (2H, Aj, J = 17 Hz, S)

^7, 37 (0.5H, s (0.5H, s, (4H,

) · Column chromatography (Weko silica gel C-200; eluent bennznneeylacetate 3: 1)

7.87

7 ^, 42 (CH), 7.54 e>m>)

++++ ++

-CHOCC (CHHh

II ³³

^CH 3.

135 to 1 800,

137 1735 (broad), 14 (9H, s, - (β3) 3), 1.47 (3H, d, J = 6Hz, CH-CayC, 2.44 (3H, s, K), 3 .49 (2H,

A ^H 3

N oxalate was formed after addition of oxalic acid to the ethyl acetate solution

Broad s, Cg-H), 4.86 (1H, d,

J = 6 Hz, Cg-H), 5.06 (1H, d,

J = 6 Hz, C7-H, 5.50 (2H, broad s, S)

6.80 (1H, q, J = 6Hz, C, -CH-Cl), 7.03 (3H, broad ^H-1 -)

NMR (d 6 -DMSO ⁺ ) ppm (CDCl ₃ ⁺⁺

CD ₃ FROM ⁺⁺⁺ )

Continuation of table δ. β

Compound

Melting point (° C)

IR (KBr) δ ¹ : _c

Note (processing)

-CHgOCHgCl2

125 až 1 790, 1.18 (3H, t, J = 7Hz, -CH 2 Cl 2), oxolate 130 (dec.) 1 780 2.47 (3H, s, -CH ₃ ), 3.27 (2H, oxalic acid Wide α, C ₂ -H), 3.55 (2H, q, of ethyl acetate flow J = 7 Hz, -CH ₂ CH ₃ ), 5.08 to 5.68 (6H, m, C ₆ -H, C ₇ -H, -COOCH 8 O-, X ¹ * 444

-CH _o 0CCH_ 107 to 1 785, J 110 (dec) t 735

2.08 (3H, s, _{M &gt}; ³⁾

Cg-H), 4.96 C-H), 5.58 S '),

CH ₂ -COOCH, O-), -H ₃ N-)

-CH _{o O} (CH _o ) .CH.

^{23 3} o

117 až

120 (dec)

780,

750

-CH0C0 (CH _{O) 7} CH. ²³³ 1 780, 1 758 CH ₃

and, -OflCH _3), 2.45 (3H, 0), 3.50 (2H, br s,

(1H, d, J «6 Hz, (2H, wide 8, 5.82 (2H, s, 7.66 (3H, broad s, J = 7 Hz, - (0¾) ^)

>

oxalate was formed by the addition of oxalic acid to the ethyl acetate solution

0.87 (3 H, t,

1.00 to 1.90 (4H, m, -CHjCggCUgCH _3), 2.30 to 2.54 (2H, s, CH ₂ CH "CH ₉ CH), 2.47 (3H, s, N \) ,

Z ³

3.52 (2H, broad e, Cg-H), 4.96 (1H, d, J = 6Hz, _C6- H), 5.14 (1H, d,

J «6Hz, C ₇ -H), 5.42 (2H, br s), 5.74 (2H, s, -OCH ₂ O-),> ca ^ ₂ 7.66 (3H, broad and, H _{3 (} f) +

0.92

1.12 to 1.70 (4H, m, -CHgCHgCH, CH _3), CH _3), (3H, oxalate oxalic acid addition к solution of EtOAc (3H, t, J = 6Hz, -сн _{2) 3} сц ₃ ),

......

1.60 (3H, d, J = 6Hz,> CH1,89 (2H, s, _NH2), 2.52 S, N)> 3.32 (2H, Si> ^H 3

N 5, C ₈ -H), 4.14 (2H, t, J = -Ca ₂ CH ₂ CH ₂ CH ₃ ), 4.78 (1H, 5 Hz, C ₆ -H), 4.91 (1H, d, 1z, C ₇ -H), 5.44, 5.77 (2H, J = 15 Hz, S-), 6.96 column chromatography (Wako silica gel Q-200; eluent: benzene: ethyl acetate 5: 1)

Continuation of Table 8

Compound R ¹ Melting point (° C) IK (KBr) ^cm -1 ^: c = 0 NMH (dg-DbiSO *) ppm (CDCl ₃ ⁺⁺ ) (CD ₃ OD ⁺⁺⁺ ) Note (processing ++++ -CH _o O (CH _o ) .CH _q 118 až 1 800, 0.87 (3H, t, J = 7Hz, -CH ₂ CH ₂ - oxalate was formed £ C. J J 120 (dec) 1 700 CH ₂ CH ₃ ), 1.10 to 1.7, (4H, и, addition of weedic acid -СН ₂ СН ₂ СЦ ₂ СН ₃ ), 2.48 (ЗН, s, to ethyl- )> 3.52 (2H, broad s,> ^сн з acetate

C ₂ -H), 3.64 (2H, t, J = 7 Hz, _2- s ₂ and _2- s ₃ ), 5.00 (1H, d, J = 5 Hz, Cg-H), 5, 17 (1 H, d,

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

S), 7.83 <3H, broad s,

CH ₂ NH ₃₎ +

-CHOCOCCCH3)

I ^p

CH ₃

770,

750 (9H, s, -C / CH _{3) 3,} 1.66 d, J »6 Hz, _CH-CH3), 2.20 s, _NH2), 2.60 (3H, s); 3.44 (2H, broad s,

1.55 (3H, (2H, ...)

> ^сн з

NT

C ₂ -H), 4.98 (1H, d, J = 5 Hz,

C ₆ H), 5.11 (1H, d, J = 5 Hz),

C ₇ -H), 5.80 (2H, broad s), 7.10 (1H, q,

CH ₂ -

J = 6Hz,> CH-CH ₃₎ ++

Note:

++++ oxalate

Table 8 (continued)

Compound R ¹ Melting point (° C) IR (KBr) ^cm-1 • 900 Compound R ¹ Melting point (° C) IR (KBr) cm- ’ C = O ♦ +++ -CHOCC '(CH,) I ^«33 136 to 138 1 810, 1 780, - 1 780, 1 752 0 (rozkl ·) 1 740 v * ⁿ 3 no CH ₂ CH ₃ -CHOJC (CH3) ₃ - 1 790 -CH0C0- <O> CH, O - 1 782, 1 770 (o). · 1 720 □ 1 775, 1 735

and

Table 9

Compound

Melting point (° C)

-CH-OCCCCH.). 152 to ^{2 3 3} 155

-CHOCOCH, CH, 146 and ²³ 14 ·

O ch ₃

IR (KBr) cm • 3;

750

77 ·,

720

NMH (d6-DMSO) ppm

CDC1 ₃ * ² )

1.13 (9H; -C (CH3) _3), 3.39 (2H, bs, _C2 --H), 5.10 (2H, br ^s>), 5.72 (IH, d, J «5 Hs,> 2C ₇ -H), 6.2 · (3H, broad a, H ₃ M-),

7 · 9 (IH,

1.27 (3H, t, d7 Hs, -ch ₂ ch ₃ ),

1.57 (3H, d, J-6Hs, X 1 HCH 3), 3.22 (2H, broad a, C 8 -H), 4.17 (2H, q, J 17 Hb, -0 '). 4.70 (1H, d, J = 5 Hb, Cg-H), 4, 6 (IH, d, J = 5 Hb, C ₇ -H), (2H, ABq, 11 * 15 Hs)

Note (work-up) oxalate was prepared by the addition of Acid Buffer to an ethyl acetate solution of column chromatography (Wako silica gel C-200;

• Benzenzotyl acotate 3: 1 meadow reagent

* 4

Continuation of table δ. 9

Compound

Temperature IC (KBr) -1 cm _for melting (° C) C = O

NMB (d6-DMSO ⁺¹ ) ppm

CDC1 ₃ ⁺²

Note (treatment) (1H, q, J = 6 Hs > CH-CHO,

7.73 (1H, s, N &lt; + &gt;) / -N N +2

-CH ₂ OCC (CH ₃ ) ₃ I <5 to

780,

760

CH ₃

1.32 (3H, t, J = 7Hz, -CH ₂ CH ₃ ), 1.59 (3H, a, J = 6Hz,> CH-CH ₃ ), 1.86 (2H, s, -NH ₂ ), 3.20 (2H, s, Cg-H), 4.20 (2H, q, J = 7Hz, -e2CH-j), 4.72 (1H, d, J = 5Hz, C ₆ -H), 4.87 (1H, α, column chromatography (Weka silica gel C-200, eluent benzene: ethyl acetate 3: 1))

J = 5 Hz, C ₇ -H), 4.99,

J = 15 Hz, S-), <D _{2 2} 5.52 (2H, ABq,

6.95 (1 H, q,

J = 6 Hz,> CH-CH3), 7.75 (1H, s,) ⁺ 2 N @ +

_About 0 -CH (CH _a) 128 EŽ

₁₃₅

773,

720

0.90 (3H, t, J = 7Hz, -fHg] -JCHp,

EŽ 1.15 1.71 (4H, m, -CH ₂ CH ₂ CH ₃ CIJ ₂₎

3.30 to 3.65 (4H, m, Cg-H),

-Ci ₂ CH ₂ CH ₂ CH ₃ ), 4.95 m, -OCHgO-, Cg-H, C ₇ oxalate was prepared by adding oxalic acid to an ethyl acetate solution of up to 5.40 (6H)

)

8.01 (1H, s, N.), 8.84 / 2N,

У

Broad s, -NH ₃ ) ⁺ 3

-CHOCC (CH3). 132-1 782 H J ^JJ 136 1740

I ⁰

CH ₃

1.17 (9H, s, -C (CH ₃ ) ₃ , 1.50 (3H, d, J = 6 Hz, -CH-), 3.49 (2H, broad s, C ₃ oxalate) was prepared by addition of acid Magnesium to ethyl acetate solution

C ₂ -H)

C ₇ -H, 4.97-5.19 (4H, m, C ₆ -H,

6.70 to 7.08 / 1N, m, -CH-), 8.04 / 1N,

Ih

Note: * optical isomer ⁺ 3 oxalate ⁺ 4 upper component * 5 aol component

Claims (7)

SUBJECT OF THE INVENTION Process for the preparation of 7-amino-3-substituted-methyl-1-cephem-4-carboxylic acid of the general formula I h ₂ ni --- Τ ^δ Ί - ^ Y ^ CH ³ R ² COOR ¹ (I) where R ¹ represents a hydrogen atom or a C 1-6 alkyl, diphenylmethyl, p-nitrobenzyl, 1-pivaloyloxybenzyl, phthalidyl, C 1-6 acyloxy-C 1-6 alkyl group or a group of the formula -CHOR 4 or -CHOCOOR; R * R * wherein R 1 is C 1-6 alkyl, cyclohexyl or phenyl, R 1 is hydrogen or C 1-6 an alkyl group; R represents a triazolyl or tetrazolyl group attached to the exomethylene group at the 3-position of the cephem ring by a carbon-nitrogen bond, which group may be substituted by at least one substituent selected from the group consisting of halogen atoms, C 1-4 alkyl, C 1-4 alkylthio, C 1-4 alkylthio; alkoxycarbonyl, phenyl, C 2-6 alkanoylalamino, C 1-6 -alkoxycarbonyl-C 1-4 alkyl, cyano and amino, or salts thereof, characterized in that the cephalosporanic acid of formula II is re-reacted COOH (II) where R ⁵ R ⁶ represents a C _2-6 alkanoyloxy group, 7 amino group of the formula R \ _e "n £ bo different, represent hydrogen response, or a group of the formula R? Where C = N, K ^{11 are} different, are hydrogen or Z is 8 or SO, where R 2, βθ and R 4, which may be the same OC-NH-, or organic residues not participating wherein R ^{10 n} R e, which may be identical or organic residues not participating in the reaction, or a derivative thereof at the carboxyl group or its salt, triazole and tetrazole, which may be substituted by at least one substituent selected from the group consisting of halogen atoms, C ^ alkyl, C ^ alkylthio, _e ^ alkoxycarbonyl, phenyl, -C ^ elkanoylaminoskupiny, _ $ alkoxy carbonyl 1-C ^ ^ alkyl, cyano, and amino, in an organic solvent in the presence of an acid or a complex acid, and then, if necessary, removing the carboxyl or amino protecting group, or converting the product into a salt. 35 236493 2. A process for the preparation of a 7-amino-3-substituted methyl-- ³ -cephem- ^4- carboxylic acid or a salt thereof according to claim 1, which process starts from compounds of the above formulas to give compounds of the above formula. wherein R * is a 1,2,4-triololyl or 2- (1,2,3,4-tetrazolyl) group attached to the exomeeylene group at the 3-position of the cephem ring by a carbon-nitrogen bond, which group may be substituted by a halogen atom, C * C1-6alkyl, C1-6alkoxy, C1-6alkoxy, C1-4alkoxy, Eenyl, C1-4alkoxy, C1-4alkoxy, C1-4alkoxy, C1-4alkoxy, C1-4alkoxy, C1-4alkoxy alkyl, cyano or amino. 3. A method according to claim 1 or 2, characterized in that said acid or complex compound of the acid in which the reaction is carried out is a protonic acid, a Lewis acid or a complex compound of a Lewis acid. 4. The process of claim 3, wherein said protonic acid in which the reaction is carried out is sulfuric, sulfonic or superfluoric acid. 5. The method of claim 3, wherein said Lewis acid or Lewis acid complex in which the reaction is carried out is Ogtrieltotide or a compound thereof. ^{6. bp} mouth of Ravy ^{beta.-amino-l} ^ I ^ Bufa alkoxylated methyl-Δ ³ .- -cefem- ⁴ -carboxylic ^{about l} b ^s oxy acid or salt thereof according to any one of claims 1-5, professes ^ JCI The method of claim 1, wherein the starting compound is a compound wherein C is acetoxy. 7. A method according to any one of claims 1 to 6, in that the reaction is effected ^p s t ^ 0 EŽ ture of 80 ° C.