CH631718A5 - Process for preparing cephem derivatives - Google Patents

Description

The present invention relates to a new process for the preparation of cephem derivatives of the formula z-ch "-co-n:

ch-r cooh in which the substituents have the meaning given in claim 1, and of easily cleavable esters and physiologically acceptable salts of these compounds.

These compounds are known, e.g. from DE-A-23 45 402. They show antibacterial activity and can accordingly be used as medicaments, in particular for combating bacterial infections.

The known production processes for these compounds are not entirely satisfactory. They run through intermediate stages and it is often difficult to obtain the desired products in the required purity and / or in good yield.

The object of the invention was to find a new process for the preparation of compounds of the formula I which does not have the disadvantages of the known processes or only has them to a lesser extent.

This object was achieved by the method according to the invention defined in claim 1.

The optional further processing of the compounds of the formula I obtained by the process according to the invention is defined in claims 2-7.

The process according to the invention includes in particular the possibility of preparing the compounds of the formula I by starting from the inexpensive starting material cephalosporin C and isolating the intermediates which are obtainable in good yields only partly or not at all, that is to say working in a one-pot process.

The radical Z primarily means one, two or four, preferably one, substituted

1,4-dihydro-4-oxo-l-pyridyl. With simple substitution, the substituents in the Z radical are preferably in the 3-position, in the case of two in the 3- and 5- or in the 2- and 6-position, in the case of triple in the 2-, 3- and 5-position. Preferred substituents are Cl and Br, furthermore OH, F, J, no2 and nh2. Alkyl is primarily methyl, but also ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, sec-butyl or tert-butyl. Alkoxy specifically means methoxy, but also ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

In particular, besides the unsubstituted 1,4-dihydro-4-oxo-l-pyridyl, the preferred radicals Z are:

3,5-dichloro, 3,5-dibromo, further 3,5-difluoro, 3,5-diiodine,

3,5-dinitro, 3,5-dihydroxy, 3,5-dimethoxy, 3,5-di-amino, 3-chloro, 3-bromo, 3-nitro, 3-amino, 3- Hydroxy, 3-methoxy, 2,6-dimethyl, 2,6-dimethyl-3,5-dichloro,

2,6-dimethyl-3,5-dibromo, 2,6-dimethyl-3,5-diiodo, 3-chloro

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5-nitro, 3-bromo-5-nitro, 3-chloro-5-amino, 3-bromo-5-amino, 3-chloro-5-hydroxy and 3-bromo-5-hydroxy-l , 4-dihydro-4-oxo-1 pyridyl.

Group Z also represents, for example, the following radicals:

3-fluoro, 3-iodine, 3-ethoxy, 3-n-butoxy, 3-methyl,

3-ethyl, 3-n-butyl, 2,6-dimethyl-3-fluoro, 2,6-dimethyl-3-chloro, 2,6-dimethyl-3-bromo, 2,6-dimethyl 3-iodo, 2,6-dimethyl-3-hydroxy, 2,6-dimethyl-3-nitro, 2,6-dimethyl-3-amino, 2,6-dimethyl-3-methoxy, 2 , 6-dimethyl-3,5-difluoro, 3-chloro-5-methoxy, 3-bromo-5-methoxy-1,4-dihydro-4-oxo-1-pyridyl.

Among the heterocyclic radicals Het, the 1-methyl-tetrazolyl-5 radical and the 5-methyl-l, 3,4-thiadiazolyl-2 radical are preferred.

In the formula II the Q radical preferably denotes a 5-amino-adipinamido radical which is protected on the amino group and / or the free carboxy group, for example a 5-acylamino-adipinamido radical. Since the entire residue Q is split off in the process according to the invention, the nature of the protective groups is not critical.

Examples of protecting groups which are suitable for blocking the amino group in the 5-amino-adipinamido radical include arylcarbamoyl groups, e.g.

Phenylcarbamoyl, 4-chlorophenylcarbamoyl, naphthylcarbamoyl, tolylcarbamoyl, xylylcarbamoyl, mesitylcarbamoyl or cumylcarbamoyl, arylthiocarbamoyl groups, e.g. Phenylthiocarbamoyl, alkoxycarbonyl groups, e.g. Methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, buto-xycarbonyl, tert-butoxycarbonyl, isobutoxycarbonyl, halo-genalkoxycarbonyl groups, e.g. 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,3-dichloropropoxycarbonyl, alkoxy and aryloxyalkoxycarbonyl groups, e.g. 2-methoxyethoxycarbonyl, 2-n-butoxyoxyoxyyl, 2- (2-methoxyethoxy) ethoxycarbonyl, 2-phenoxyethoxycarbonyl, aralkyloxycarbonyl groups, e.g. Benzyloxycarbonyl, alkylcarbamoyl groups, e.g. Methyl carbamoyl or ethyl carbamoyl, N-alkyl-N-aryl-carbamoyl groups, e.g. N-methyl-N-phenylcarbamoyl, arylsulfonyl groups, e.g. Benzenesulfonyl or tosyl, alkanesulfonyl groups such as methanesulfonyl, ethanesulfonyl, propanesulfonyl or butanesulfonyl, arylcarbonyl groups, e.g. Benzoyl, 4-bromobenzoyl, naphthoyl, toluoyl, xyloyl or phthaloyl, alkanoyl groups, e.g. Acetyl, propionyl,

Butyryl, chloroacetyl or bromoacetyl, arylalkanoyl groups such as phenylacetyl or 3-chlorophenylacetyl, e.g. Trialkylsilyl such as trimethylsilyl, p-methoxybenzyloxy, 2-nitrophenylsulfenyl, 2,4-dinitrophenylsulfenyl or arylmercapto such as p-nitrophenylmercapto groups. Benzoyl and p-toluenesulfonyl derivatives are preferred.

If the carboxy group in the 5-amino-adipinamido residue is protected, it can be in the form of an ester or thioester, e.g. in the form of an alkyl ester (methyl or ethyl ester) or in the form of one of the easily cleavable esters given above.

The radical Q can furthermore mean any other acylamino group having up to 15 C atoms, other than the group Z-ch2-CO-NH, for example formamido, acetamido, benzamido, phenylacetamido, 2- or 3-thienyl-acetamido, these groups can contain any substituents.

The radical Q can furthermore mean the group R2-CHR3- (CH2) 3-C (OR4) = N-. This group is also a functional one

631718

modified 5-amino-adipinamido residue and in this respect particularly preferred.

Here R2 means a free or a functionally modified COOH group, e.g. a COOH group in the form of a silyl ester, e.g. a mono-, di- or (preferably) trialkylsilyl ester, in particular a trimethylsilyl ester group R3 is preferably an acylamino group, the acyl group preferably having the same meaning as given above for acyl in the 5-acylamino-adipinamido radical.

R4 is alkyl with 1-6 C atoms, preferably methyl or ethyl.

In the formula II, the radical R1 denotes a free or a functionally modified COOH group, which e.g. can be in the form of one of the abovementioned easily cleavable esters. Here too, the silyl esters, in particular the tri-methyl silyl esters, are preferred.

The starting materials of formula II are generally known, e.g. from DE-A-22 62 262 and 24 56 528.

Starting materials of the formula II [Q = R2-CHR3- (CH2) 3-C (OR4) = N-] can be obtained, for example, by reacting cephalosporin C [II, Q = HOOC-CH (nh2) - (CH2) 3-CO -NH-, R = OCOCH3, R1 = COOH] or one of its salts, for example the sodium or zinc salt with an N-functionalizing reagent, e.g. an N-acylating agent, for the corresponding derivative II [Q = HOOC-CHR3- (CH2) 3-CO-NH-] which is functionally modified on the primary amino group, preferably the corresponding N-acyl derivative; this can be reacted sequentially with a silylating agent (e.g. chlorotrimethylsilane), an imino halogenating agent (e.g. PCb) and an imino etherifying agent (e.g. methanol). This gives compounds of the formula II in which Q is the preferred group HOOC-CH (NHAcyl) - (CH2) 3-C (OCH3) = N-, or their silylated derivatives.

The acids of formula III are known, e.g. from DE-A-23 45 402. In them the radical Z preferably has the preferred meaning given above.

Suitable functional derivatives of these acids suitable for acylation are, for example the corresponding acid halides, acid anhydrides, activated amides or activated esters, e.g. the acid chlorides, acid azides, the mixed acid anhydrides with an acid such as dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, dialkylphosphoric acid, sulphurous acid, thiosulphuric acid, sulfuric acid, an aliphatic acid, a pentanoic acid, eg an aliphatic acid, a pentanoic acid, an aliphatic acid, an aliphatic carbonic acid Ethylbutyric acid or trichloroacetic acid), an aromatic carboxylic acid (e.g. benzoic acid), or symmetrical acid anhydrides, acid amides with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole, the esters, for example cyanomethyl ester, methoxymethyl ester, vinyl ester p-vinyl ester Propar , 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, methanesulfonylphenyl ester, phenylazophenyl ester, phenylthioester, p-nitrophenyl ester, p-cresylthioester, carboxymethylthioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolylnylthioester, l- or quinolylnylthioester -Hydroxy-2- (1H) -pyridone, N-hydroxysuccinimide or N-hydroxyphthalimide.

The derivatives of the acids of the formula III suitable for acylation can also carry protective groups in the Z radical. In particular, amino and hydroxyl groups on the pyridone radical can be present in a functionally modified form, for example in the form of etherified, esterified or silylated hydroxyl groups (e.g. benzyloxy, acetoxy, trialkylsilyloxy such as trimethylsilyloxy) or benzylated, acylated or silylated amino groups (e.g. benzylamino,

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631 718 4

Benzyloxycarbamoyl, tert-butoxycarbamoyl, formamido, hours; by the action of water (which may be contained in the acetamido, trialkylsilylamino such as trimethylsilylamino molecular sieve, if present, or bis- (trialkylsilyl) amino such as bis- (trimethylsilyl) amino). is) or by addition of an alkanol or alkane thiol with. As protective groups, those which are customary in Pep, preferably 1-6 C atoms, of benzyl alcohol or of tide chemistry and cephalosporin chemistry are very suitable. s hydrochloric acid.

In general, the compound of formula II is expediently used, the diacyl compound

with the acylating agent in the presence of an inert dung, however, during the subsequent, below

Solvent or suspending agent. Cleaved as the solvolysis stage described in the solution, wherein at the same time or suspending agents, in particular coal water is suitable, the protective groups still present are removed, such as benzene; chlorinated hydrocarbons, e.g. io The product obtained is then solvolysed, methylene chloride, chloroform, carbon tetrachloride, 1,2-di- preferably hydrolyzed, and / or hydrogenolysed to give chloroethane, chlorobenzene; Ether, such as diethyl ether, tetrahy- to split off the protective groups still present.

drofuran, dioxane; Ketones such as acetone, butanone; Amides, such as Solvolysis usually takes place at temperatures between dimethylformamide (DMF), dimethylacetamide, phosphorus - 10 and 50 ° C. You can e.g. hydrolyze by acid hexamethyl triamide; Nitriles such as acetonitrile; Sulfoxides, the reaction mixture is simply poured into water. One such as dimethyl sulfoxide; Water; Furthermore, organic or aqueous hydrolysis can also be carried out in weakly basic or inorganic bases. Weakly acidic medium are suitable as organic bases, for example in particular tertiary amines, e.g. Trialkylamines, such as triethyl presence of an alkali metal bicarbonate or trialamine, dialkylbenzylamines, such as N, N-dimethylbenzylamine, kylamine or in the presence of hydrochloric acid or acetic acid. Dimethylaniline or pyridine. As inorganic bases there are 20 With trifluoroacetic acid e.g. tert-butyl ester solvoly e.g. Sodium hydroxide solution or potassium hydroxide solution suitable. It can also be siert.

Mixtures of the solvents or suspensions mentioned. A hydrogenolysis of functionally modified groups,

means are used. If a salt of a compound, in particular a cleavage of benzyl and carbobenz of the formula I, is to be prepared, oxy radicals can be used as the solvent -this salt serving base can be used, e.g. Triethyldium on carbon or palladium oxide. Appropriately hydroge-amine or aqueous sodium hydroxide solution. nolysed at temperatures between - 10 and + 50 ° C,

The reaction of the compound of formula II with the bond, in particular at room temperature, and in the case of a pressure bond of formula III or its functional derivative between 1 and 100 bar, preferably at normal pressure. It is usually carried out at temperatures between -70 and 30 is possible and often desirable, so the hydrogenolysis to + 100 ° C, preferably between - 50 and + 20 ° C, whereby one should direct that at the same time further reductive changes in the acylating agent are expedient in excess. Molecule done; e.g. can be in a 3 position

In the acylation reaction, a catalyst acetoxymethyl group can also be reduced to a methyl group or a condensing agent added, e.g. Become N-Tri.

methylsilyl-trifluoroacetamide or a carbodiimide, in particular 35 If desired, one can use their dicyclohexylcarbodiimide in the product obtained. In addition, one can work in counter of the formula I according to a molecular sieve known per se from the literature, e.g. a natural method of substituting an R for another substituted or synthetic aluminosilicate zeolite; in this case R and / or a substituent Z against one

In a variant, the reaction is preferably carried out with other Z substituents.

temperatures from 50 to 90 ° C. The 40 is particularly advantageous. For example, it is possible to alkylate a hydroxy group by using Class A synthetic zeolites and treating with an alkylating agent, e.g. X, e.g. of types 3A, 4A, 5 A and 13X, all of which are treated with diazomethane, methyl bromide, methyl iodide, dimethyl

Are trade. The pore size of these zeolites is preferred or diethyl sulfate, ethyl, n-propyl or n-butyl chloride, ranging between 3 and 15Â. The zeolites can be bromide or iodide.

be essentially anhydrous or 0 to 30 weight percent. further, contain a nitro group on the pyridone ring hydrate water. to reduce to the amino group. Basically you can

For the acylation, the reaction mixture, in which all the known per se for the reduction of nitro compound of the formula II has been prepared in situ, can be used as group-appropriate methods, if such are used; this reaction can not be called undesirable changes in the molecule, but it can also be called beforehand under reduced pressure. Catalytic hydrogenation, which vapors, is particularly suitable for the formation of volatile reagents which are used in the acylie e.g. on noble metal catalysts such as palladium in the space-removal reaction. If temperato and normal pressure can be carried out, the reaction mixture is used as such, the reductive conversion of an acetoxymethyl group into one preferably in the heat or with the addition of a methyl group can also be carried out by hydrogenation on DMF, around the unreacted iminohalogenating agent as noble metal catalysts how to perform palladium, being removed. one expediently at low temperatures, but something

If the rest Q in the starting material II works an acylamino-increased pressure (between 2 and 10 bar).

group means can be the primary product of the acylation. If desired, several of the described one can also form a diacyl compound which speaks of the reductive reductive transformations carried out in one step, but which instead of the radical Q become a zch2co-60. For example, hydrogenation of a cephalospo-N (acyl) group (in which Z has the meaning given is ranoic acid I (R = -OCOCH3), which in the remainder Z has a nitro group, and the acyl group of the acylamino group in the remainder Q) is substituted, the corresponding Desacetoxycepha-speaks). As a rule, this diacyl compound is not isosporanic acid I (R = H), which is Z in the rest Z by an amino; to remove the acyl group cleaved group must be substituted.

will. This cleavage can be carried out in various ways. It is also possible to obtain a cephalosporan

take place, e.g. by merely extending the reaction time (in acid of the formula I (R = -OCOCH3) by reaction with the presence of an excess of compound III or its a mercaptan of the formula Het-SH in the corresponding functional derivatives) for a duration of 0.5 to 30 Convict thioether I (R = -SHet). Appropriately sets

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a salt of cephalosporanic acid with a salt of thiol in aqueous acetone at temperatures between 20 and 100 ° C and pH values between 4 and 8 µm. Particularly suitable salts are the alkali metal salts, especially the sodium salts.

A free carboxylic acid I can also be converted into an easily cleavable carboxylic acid ester by esterification. E.g. the tert-butyl ester is obtained by reacting the acids with isobutylene.

Conversely, the acid I can be liberated from a salt or ester obtained, e.g. by solvolysis, especially by acid hydrolysis. The tert-butyl esters obtained particularly advantageously in the synthesis are e.g. split with trifluoroacetic acid at temperatures between 0 and 40 ° C.

The cephem derivatives of the formula I are solid crystalline or amorphous products. They form solid, often crystalline alkali metal, ammonium and alkaline earth metal salts and salts with organic bases such as diethylamine, triethylamine, diethanolamine, N-ethyl-diethanolamine, pyrrolidine, pipidine, N-ethylpiperidine, l- (2-hydroxyethyl) piperidine , Morpholine, procaine, benzylamine, dibenzylamine, l-phenyl-2-propylamine and other amines, as are usually used for the production of cephalosporin salts.

Of the alkali metal salts, the sodium and potassium salts are particularly important. They can be prepared by mixing a solution of an acid I in an organic solvent with a solution of the sodium or potassium salt of a fatty acid, e.g. Diethyl acetic acid or 2-ethyl caproic acid, in a solvent, e.g. Acetone or n-butanol, or a solvent mixture. The salts which precipitate in the course of this or with the addition of ether can be filtered off.

Basic compounds of formula I can be converted into the associated acid addition salts with acids in a conventional manner, e.g. into the hydrochloride or citrate. Since the compounds I have no sharp melting points, they are expediently characterized by other physical characteristics, particularly advantageously by their infrared spectra. They show in the infrared spectrum the absorption band of the ß-lactam ring lying at 1760-1800 cm- '. They can also be characterized by their nuclear magnetic resonance spectra and by the thin layer chromatogram. Merck TLC ready-made silica gel F254 can be used for this purpose (plasticizer e.g. dioxane / water 85:15).

The IR spectra ("IR") given in the examples below are recorded in KBr.

example 1

5.2 g of 7- (5-benzamido-adipinamido) -cephalospo-ranoic acid (obtainable by reacting the zinc complex of cephalosporin C with benzoyl chloride / dichlorodimethylsilane / triethylamine in ch2ci2) are added to 80 ml of ch2ci2 and 6 ml of dimethylaniline and 8 are added ml of chlorotrimethylsilane. After cooling to -40 to -50 ° C, 4.4 g of PCh are added. The mixture is stirred at -40 to -50 ° C for 2 hours, 0.4 ml of dimethylaniline and 32 ml of absolute methanol are added, the mixture is stirred at -40 to -50 ° C for 30 minutes and at 20 ° C for a further 30 minutes . The solvent is distilled off, the residue obtained is suspended in 120 ml of ch2ci2 and 10 ml of triethylamine are added. Then, while cooling, 3,5-dichloro-4-pyridon-1-acetyl chloride (prepared in situ from 2.2 g of the acid with SOCl2) is added. The mixture is stirred at 0 ° C. for one hour and at 20 ° C. for a further 15 hours, poured into water, the phases are separated and the aqueous phase (pH 6) is washed with ch2ci2. Hydrochloric acid is then added a little at a time and extracted with ethyl acetate after each addition. From the first fractions (approx. At pH 4) 5-benzamido-adipic acid l-methyl ester is obtained, from the later (approx. At pH 3.5) 7- (3,5-dichloro- 4-oxo-1,4-dihydro-1-pyridylacetamido) cephalosporanic acid, which is crystallized from acetonitrile. IR: 1760, 1730, 1700, 1670, 1600, 1390, 1220 cm- '.

With 4-pyridone-1-acetyl chloride or with 3-methyl, 2,6-dimethyl, 3-methoxy, 3-n-butoxy, 3-hydroxy, 3-fluoro, 3-chloro, 3-bromo, 3-iodo, 3,5-difluoro,

3,5-dibromo, 3,5-diiodo, 2,6-dimethyl-3,5-dichloro,

2,6-dimethyl-3,5-dibromo-, 2,6-dimethyl-3,5-diiodine,

3-nitro-, 3,5-dinitro-, 3-chloro-5-methoxy-, 3-bromo-5-meth-oxy-, 3-chloro-5-nitro-, 3-bromo-5-nitro-, 3-chloro-5-amino, 3-bromo-5-amino, 3-methyl-5-chloro, 3-methyl-5-bromo, 3-chloro-5-hydroxy, 3-bromo-5 -hydroxy-, 3-bromo-5-chloro, 2,3,5-trichloro-, 2,3,5,6-tetrafluoro-, 2,3,5,6-tetrachloro- or 2,3,5- Trifluoro-6-hydroxy-4-pyridone-l-acetyl chloride is obtained analogously:

7- (1,4-Dihydro-4-oxo-1-pyridyl-acetamido) cephalosporanic acid, IR: 3430.1765, 1690, 1645, 1610, 1550, 1405, 1240, 1200 cm-1;

7- (3-Methyl-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -cepha-losporanoic acid

7- (2,6-Dimethyl-1,4-dihydro-4-oxo-1-pyridyl-acetamido) cephalosporanoic acid

7- (3-methoxy-1,4-dihydro-4-oxo-1-pyridyl-acetamido) cephalosporanic acid

7- (3-n-Butoxy-l, 4-dihydro-4-oxo-l-pyridyl-acetamido) cephalosporanic acid

7- (3-Hydroxy-1,4-dihydro-4-oxo-1-pyridyl-acetamido) cephalosporanic acid

7- (3-Fluoro-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -cephalo-sporanoic acid

7- (3-chloro-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -cephalo-sporanoic acid, IR: 1780, 1735, 1680, 1640, 1550, 1390, 1240 cm-1;

7- (3-Bromo-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -cephalo-sporic acid, IR: 1780, 1740, 1680, 1635, 1550, 1235 cm- '; 7- (3-iodo-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -cephalo-sporanoic acid

7- (3,5-difluoro-1,4-dihydro-4-oxo-1-pyridyl-acetamido) cephalosporanic acid

7- (3,5-dibromo-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -cephalosporanoic acid, IR: 1780, 1680, 1630, 1590, 1220 cm- '; 7- (3,5-diiodo-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -cepha-losporanoic acid,

K salt, IR: 1770, 1620, 1580, 1290, 1240 cm- '; 7- (2,6-Dimethyl-3,5-dichloro-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -cephalosporanoic acid

7- (2,6-Dimethyl-3,5-dibromo-1,4-dihydro-4-oxo-1-pyridyl-acetamido) cephalosporanic acid

7- (2,6-Dimethyl-3,5-diiodo-1,4-dihydro-4-oxo-1-pyridyl-acet-amido) -cephalosporanoic acid

7- (3-Nitro-1,4-dihydro-4-oxo-1-pyridyl-acetamido) cephalo-sporanoic acid, IR: 3300.1770, 1710, 1680, 1660, 1590, 1560, 1330, 1250, 1230 cm - ';

7- (3,5-dinitro-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -cephalosporanic acid,

K salt, IR: 1780, 1730, 1680, 1620, 1520, 1330, 1230 cm- '; 7- (3-Chloro-5-methoxy-1,4-dihydro-4-oxo-1-pyridyl-acet-amido) -cephalosporanoic acid

7- (3-Bromo-5-methoxy-1,4-dihydro-4-oxo-1-pyridyl-acet-amido) -cephalosporanoic acid

7- (3-Chloro-5-nitro-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -cephalosporanic acid, Na salt, IR: 1770.1660.1610.1380, 1335.1240 cm- ' ;

7- (3-bromo-5-nitro-1,4-dihydro-4-oxo-1-pyridyl-acet-

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amido) -cephalosporanic acid, IR: 1780, 1730, 1650, 1610, 1530, 1380, 1330, 1230, 1070, 1040 cm- '; 7- (3-Chloro-5-amino-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -cephalosporanoic acid, IR: 3410.1770, 1630.1560, 1370, 1250 cm- ';

7- (3-Bromo-5-amino-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -cephalosporanoic acid, Na salt, IR: 3420.1765.1625, 1560.1375.1260 cm - ';

7- (3-Methyl-5-chloro-1,4-dihydro-4-oxo-1-pyridyl-acet-amido) -cephalosporanoic acid

7- (3-methyl-5-bromo-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -cephalosporanic acid, IR: 1770.1740.1695.1650, 1610.1560, 1390.1270, 1245 cm- '; 7- (3-Chloro-5-hydroxy-1,4-dihydro-4-oxo-1-pyridyl-acet-amido) -cephalosporanoic acid

7- (3-bromo-5-hydroxy-1,4-dihydro-4-oxo-1-pyridyl-acet-

amido) cephalosporanic acid

7- (3-bromo-5-chloro-1,4-dihydro-4-oxo-1-pyridyl-acet-

amido) -cephalosporanic acid, IR: 1760,1685,1630,1595,

1375.1220 cm- ';

7- (2,3,5-trichloro-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -cephalosporanic acid, IR: 1785.1740.1680.1625, 1560.1465.1440.1395, 1240.1170 cm- '; 7- (2,3,5,6-tetrafluoro-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -cephalosporanic acid, Na salt, IR: 1770.1700.1650, 1615.1520, 1485,1400,1245,1125 cm- '; 7- (2,3,5,6-Tetrachloro-1,4-dihydro-4-oxo-1-pyridyl-acet-amido) -cephalosporanic acid, IR: 1790, 1730, 1700,1530, 1400,1340,1235 , 1040 cm- ';

7- (2,3,5-trifluoro-6-hydroxy-l, 4-dihydro-4-oxo-l-pyridyl-acetamido) -cephalosporanic acid, Na salt, IR: 3450.1770, 1685, 1615, 1490, 1405.1245, 1115.1035.970 cm- '.

Example 2

6.06 g of 7- [5- (N-phenylcarbamoylamino) adipon-amido] -3- (5-methyl-l, 3,4-thiadiazol-2-yl-mercaptomethyl) -3-cephem-4- are added carboxylic acid to 80 ml dichloromethane, add 6 ml dimethylaniline and 8 ml chlorotrimethylsilane and boil the mixture for one hour. After cooling to -40 to -50 ° C, 4.4 g of phosphorus pentachloride are added. The mixture is stirred at the same temperature for 2 hours, 0.4 ml of dimethylaniline and 32 ml of absolute methanol are added, the mixture is stirred at -40 to -50 ° C. for 30 minutes and at 20 ° C. for a further 30 minutes. The solvent is distilled off, the residue obtained is suspended in 120 ml of dichloromethane and 10 ml of triethylamine are added. A mixed acid anhydride is then added with cooling, which has been prepared conventionally from 6.7 g of 3,5-dichloro-l, 4-dihydro-4-oxo-l-pyridylacetic acid and 6 g of trichloroacetyl chloride. The mixture is stirred at 0 ° C. for one hour and at 20 ° C. for a further 15 hours, evaporated, dilute hydrochloric acid is added and the mixture is extracted with ethyl acetate. The organic phase is extracted with aqueous sodium hydrogen carbonate solution, the extract is mixed with ethyl acetate and the mixture is acidified with hydrochloric acid. The organic phase is separated off, washed with water, dried over sodium sulfate and evaporated. 3- (5-Methyl-l, 3,4-thiadiazolyl-2-mercaptomethyl) -7- (3,5-dichloro-1,4-dihydro-4-oxo-1-pyridyl-acetamido) is obtained by adding acetonitrile ) -3-cephem-4-carboxylic acid. IR: 1770, 1690, 1640, 1590, 1380 and 1220 cm- '.

Analogously, with the corresponding mixed acid anhydrides, 4-pyridone-1-acetic acid, 3-chloro, 3,5-dibromo, 3-bromo-5-nitro, 3-chloro-5-nitro, 3 -Bromo-5-amino-, 3-chloro-5-amino- or 3-bromo-5-chloro-4-pyridone-l-acetic acid are available:

3- (5-methyl-l, 3,4-thiadiazolyl-2-mercaptomethyi) -7- (l, 4-

dihydro-4-oxo-1-pyridyl-acetamido) -3-cephem-4-carboxylic acid, Na salt, IR: 1760.1685.1640, 1605.1545, 1395.1380, 1365, 1200 cm- ';

3- (5-methyl-l, 3,4-thiadiazolyl-2-mercaptomethyl) -7- (3-chloro-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3-cephem-4- carboxylic acid, IR: 1780, 1700, 1640, 1550, 1380, 1220 cm- ';

3- (5-methyl-l, 3,4-thiadiazolyl-2-mercaptomethyl) -7- (3,5-dibromo-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3-cephem-

4-carboxylic acid, K salt, IR: 1760, 1690, 1620, 1590, 1390, 1360, 1220 cm- ';

3- (5-methyl-1,3,4-thiadiazolyl-2-mercaptomethyl) -7- (3-bromo-5-nitro-l, 4-dihydro-4-oxo-l-pyridyl-acetamido) -3- cephem-4-carboxylic acid, Na salt, IR: 1770, 1695, 1650, 1620, 1375, 1330, 1230 cm- ';

3- (5-methyl-l, 3,4-thiadiazolyl-2-mercaptomethyl) -7- (3-chloro-5-nitro-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3- cephem-4-carboxylic acid, Na salt, IR: 1765, 1660, 1620, 1385, 1330, 1235 cm- ';

3- (5-methyl-1,3,4-thiadiazolyl-2-mercaptomethyl) -7- (3-bromo-5-amino-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3- cephem-4-carboxylic acid, IR: 1780, 1680, 1600, 1560, 1470, 1370, 1280, 1250, 1200 cm- ';

3- (5-methyl-1,3,4-thiadiazolyI-2-mercaptomethyl) -7- (3-chloro-5-amino-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3- cephem-4-carboxylic acid, IR: 1780, 1670, 1590, 1555, 1460, 1365, 1270, 1245, 1190 cm- ';

3- (5-methyl-l, 3,4-thiadiazolyl-2-mercaptomethyl) -7- (3-bromo-5-chloro-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3- cephem-4-carboxylic acid, IR: 1770.1690.1620.1390.1235 cm- '.

Analogously, from the corresponding 7- (5-N-phenyl-carbamoylamino-adipinamido) -3-HetSCH2-3-cephem-4-car-bonic acids:

3- (1-methyltetrazolyl-5-mercaptomethyl) -7- (1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3-cephem-4-carboxylic acid, Na salt, IR: 1755.1680, 1640.1610.1405.1370.1205 cm- '; 3- (l-methyltetrazolyl-5-mercaptomethyl) -7- (3-chloro-l, 4-dihydro-4-oxo-1-pyridyl-acetamido) -3-cephem-4-carboxylic acid, IR: 1770, 1690, 1630, 1530, 1360, 1200 cm- '; 3- (1-methyltetrazolyl-5-mercaptomethyl) -7- (3,5-dichloro-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3-cephem-4-carboxylic acid, K- Salt, IR: 1770, 1690, 1630, 1590, 1220 cm- '; 3- (1-methyltetrazolyl-5-mercaptomethyl) -7- (3,5-dibromo-1,4-dihydro-4-oxo-1-pyridyI-acetamido) -3-cephem-4-carboxylic acid, K- Salt, IR: 1765, 1630, 1600, 1390, 1360, 1220 cm- '; 3- (l-MethyltetrazolyI-5-mercaptomethyl) -7- (3,5-diiodo-l, 4-dihydro-4-oxo-1-pyridyl-acetamido) -3-cephem-4-carboxylic acid, K- Salt, IR: 1760, 1660, 1610, 1570, 1390, 1360, 1210 cm-1;

3- (l-methyltetrazolyl-5-mercaptomethyl) -7- (3-bromo-5-chloro-l, 4-dihydro-4-oxo-l-pyridyl-acetamido) -3-cephem-4-car-bonic acid, IR: 1755, 1680, 1620, 1595, 1385, 1355, 1220 cm- '; 3- (l-methyltetrazolyl-5-mercaptomethyl) -7- (3-chloro-5-nitro-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3-cephem-4-car-bonic acid, Na salt, IR: 1770.1660.1620.1335.1240.1180 cm- ';

3- (l-methyltetrazolyl-5-mercaptomethyl) -7- (3-bromo-5-nitro-l, 4-dihydro-4-oxo-l-pyridyl-acetamido) -3-cephem-4-car-bonic acid, Na salt, IR: 1765, 1650, 1610, 1365, 1330, 1230 cm- ';

3- (l-methyltetrazolyl-5-mercaptomethyl) -7- (3-chloro-5-amino-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3-cephem-4-carboxylic acid, IR: 3415, 1780, 1670, 1590, 1560, 1470, 1405, 1365, 1270, 1240, 1180 cm-i;

3- (l-methyltetrazolyl-5-mercaptomethyl) -7- (3-bromo-5-amino-1,4-dihydro-4-oxo-l-pyridyl-acetamido) -3-cephem-4-

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carboxylic acid, IR: 1780, 1680, 1600, 1560, 1475, 1400, 1370, 1280, 1250, 1190 cm-1;

3- (1-methyl-1,2,4-thiadiazolyl-5-mercaptomethyl) -7- (3-chloro-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3-cephem-4- carboxylic acid, IR: 1780,1695, 1640,1550,1365,1295,1220 cm- ';

3- (3-methyl-l, 2,4-thiadiazolyl-5-mercaptomethyl) -7- (3,5-dichloro-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3-cephem-

4-carboxylic acid, K salt, IR: 1765.1685, 1590.1485.1362, 1295.1225 cm- ';

3- (3-methyl-l, 2,4-thiadiazolyl-5-mercaptomethyl) -7- (3,5-dibromo-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3-cephem-

4-carboxylic acid, K salt, IR: 1760, 1675, 1625, 1595, 1475, 1360, 1290, 1220 cm- ';

3- (3-methyl-l, 2,4-thiadiazolyl-5-mercaptomethyl) -7- (3-bromo-5-chloro-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3- cephem-4-carboxylic acid, IR: 1770, 1680, 1630, 1610, 1400, 1365, 1300, 1230 cm- ';

3- (3-methyl-l, 2,4-thiadiazolyl-5-mercaptomethyl) -7- (3-chloro-5-nitro-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3- cephem-4-carboxylic acid, Na salt, IR: 1765.1655, 1615.1365, 1330, 1290, 1230 cm- ';

3- (3-methyl-l, 2,4-thiadiazolyl-5-mercaptomethyl) -7- (3-bromo-5-nitro-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3- cephem-4-carboxylic acid, Na salt, IR: 1770, 1700, 1650, 1620, 1530, 1370, 1335, 1300, 1235 cm- '; 3- (3-methyl-1,2,4-thiadiazolyl-5-mercaptomethyl) -7- (3-bromo-5-amino-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3- cephem-4-carboxylic acid, IR: 1780, 1680, 1605, 1560, 1365, 1280, 1245, 1200 cm-1;

3- (3-methyl-l, 3,4-oxadiazolyl-2-mercaptomethyl) -7- (3,5-dichloro-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3-cephem-

4-carboxylic acid, K salt, IR: 1755, 1675, 1580, 1470, 1380, 1345, 1210 cm- ';

3- (5-methyl-1,3,4-oxadiazolyl-2-mercaptomethyl) -7- (3,5-dibromo-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3-cephem-

4-carboxylic acid, K salt, IR: 1760, 1680, 1620, 1590, 1380, 1350, 1210 cm- ';

3- (5-methyl-l, 3,4-oxadiazolyl-2-mercaptomethyl) -7- (3,5-diiodo-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3-cephem- 4-carboxylic acid, K salt, IR: 1760.1675, 1605, 1345, 1200 cm- ';

3- (tetrazolyl-5-mercaptomethyl) -7- (3,5-dichloro-1,4-dihydro-

4-oxo-1-pyridyl-acetamido) -3-cephem-4-carboxylic acid, K salt, IR: 1760, 1630, 1590, 1220 cm- ';

3- (tetrazolyl-5-mercaptomethyl) -7- (3,5-dibromo-l, 4-dihydro-

4-oxo-1-pyridyI-acetamido) -3-cephem-4-carboxylic acid, K salt, IR: 1760, 1630, 1590, 1220 cm- '; 3- (l, 2,3-triazolyl-4-mercaptomethyl) -7- (3,5-dichloro-l, 4-dihydro-4-oxo-l-pyridyl-acetamido) -3-cephem-4-carbon- acid, K salt, IR: 1760, 1680, 1630, 1590, 1360, 1220 cm- '; 3- (1,2,3-triazolyl-4-mercaptomethyl) -7- (3,5-dibromo-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3-cephem-4-carbon- acid, K salt, IR: 1760, 1620, 1590, 1390, 1360, 1220 cm- '; 3- (l, 2,3-triazolyl-4-mercaptomethyl) -7- (3,5-diiodo-l, 4-dihydro-4-oxo-1-pyridyl-acetamido) -3-cephem-4-carbon- acid, K salt, IR: 1760.1670.1620.1360.1220 cm- '; 3- (l, 2,3-triazolyl-4-mercaptomethyl) -7- (3-bromo-5-amino-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3-cephem-4- car-bonic acid, IR: 1770, 1685, 1655, 1600, 1550, 1270, 1240, 1190 cm- ';

3- (4-methyloxazolyl-2-mercaptomethyl) -7- (3,5-dichloro-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3-cephem-4-carboxylic acid, K- salt

3- (4-methyloxazolyl-2-mercaptomethyl) -7- (3,5-dibromo-l, 4-dihydro-4-oxo-1-pyridyl-acetamido) -3-cephem-4-carboxylic acid, K- salt

3- (1 -Oxidopyridinio-2-mercaptomethyl) -7- (3,5-dibromo-1,4-dihydro-4-oxo-1-pyridyl-acetamido) -3-cephem-4-carbon-

acid, K salt, IR: 1760, 1680, 1620, 1580, 1470, 1350, 1220 cm- '.

Example 3

a) Analogously to Example 1, 3-benzylamino-4-pyridone-1-acetyl chloride gives the 7- (3-benzylamino-4-oxo-1, 4-dihydro-1-pyridyl-acetamido) cephalosporanic acid, which is in crude form is processed further.

b) A solution of 479 mg of 7- (3-benzylamino-4-oxo-1,4-dihydro-l-pyridyl-acetamido) -cephalosporanic acid in 100 ml of methanol is added to 300 mg of 5% Pd carbon at 25 ° C and hydrogenated 1 bar until the end of the hydrogen uptake. It is filtered, evaporated and 7- (3-amino-4-oxo-l, 4-dihydro-l-pyridylacetamido) -cephalosporanic acid is obtained, IR: 3350, 1780, 1670, 1540, 1390, 1240, 1080, 1040 cm. '.

Example 4

To a slurry of 6.85 g of 7- (D-5-p-toluenesulfone-amido-adipinamido) -3- (5-methyl-l, 3,4-thiadiazolyl-2-mer-captomethyl) -3-cephem- 4-carboxylic acid methoxymethyl ester [obtainable by tosylating the sodium salt of 7- (D-5-amino-adipinamido) -3- (5-methyl-l, 3,4-thiadiazolyl-2-mer-captomethyl) -3-cephem- 4-carboxylic acid, conversion into the bis-dicyclohexylamine salt and esterification with chloromethyl methyl ether] and 7.5 g of powdered “molecular sieve 4A” (particle size approx. 27 pm; hydrated to 17 ± 2% water) in 85 ml of 1,2-dichloroethane with stirring, a freshly prepared solution of 3,5-dichloro-4-pyridone-1-acetyl chloride (obtained by dropwise addition of 2.3 ml of thionyl chloride to a solution of 7 g of 3,5-dichloro-4-pyridone-1-acetic acid in 40 ml DMF at -40 ° C) added. The slurry is heated to 65 ° C. for 16 hours with stirring and while introducing nitrogen, cooled and left to stand for 2 hours after adding 0.8 ml of methanol. The mixture that

3- (5-methyl-1,3,4-thiadiazolyl-2-mercaptomethyl) -7- (3,5-dichloro-l, 4-dihydro-4-oxo-l-pyridyl-acetamido) -3-cephem-

Contains 4-carboxylic acid methoxymethyl ester, is filtered and the residue washed with cold methanol. The filtrate and washing liquids are combined and cooled to 0 ° C. A solution of 20.8 ml of concentrated hydrochloric acid and 23.6 ml of methanol, cooled to 0 ° C., is added, the solution is warmed to 15 ° C. and stirred at 15 ° C. for a further 3 hours. The pH of the mixture is first adjusted to 2 to 2.5 by introducing gaseous ethylene oxide and then to 5 to 6 by adding solid NaOH. The mixture is filtered, the organic phase is separated off and the aqueous phase, which contains the sodium salt of the desired product, is acidified with hydrochloric acid. The crude 3- (5-methyl-l, 3,4-thiadiazolyl-2-mercaptomethyl) -7- (3,5-dichloro-1,4-dihydro-4-oxo-1-pyridylacetamido) -3-cephem obtained -4-carboxylic acid is crystallized from acetonitrile; IR: 1770, 1690, 1640, 1590, 1380, 1220 cm- '.

Example 5

1 g of sodium salt of cephalosporin C, 1 g of Linde molecular sieve 4A (in powder form; water content 15%) and 1 ml of 3,5-dichloro-4-pyridone-1-acetyl chloride are added in succession to 20 ml of 1,2-dichloroethane. The mixture is boiled for 8 hours with stirring. It is filtered and the molecular sieve extracted with methanol. The extract is evaporated; it consists of crude 7- (3,5-dichloro-4-oxo-l, 4-dihydro-l-pyridyl-acetamido) -cephalosporanic acid.

Example 6

5.6 g of N- (2-n-butoxyethoxycarbonyl) cephalosporin C are suspended in 30 ml of methylene chloride and 2.2 g are added

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Triethylamine and 4.72 g of dimethylaniline. 5.43 g of chlorotrimethylsilane is slowly added to the mixture, which is then stirred at 0-5 ° C. for one hour. Then 2.7 g of PCb are added, the mixture is stirred at -40 to -30 ° C for one hour, then at -20 to -10 ° C for a further hour. After adding 12.7 ml of absolute methanol, the mixture is stirred at -20 to -10 ° C for two hours and then left at -20 ° C overnight. Then 6.53 g of dimethylaniline and dropwise a mixture of 25 ml of methylene chloride and 2.9 g of 3,5-dichloro-4-pyridone-1-acetyl chloride are added, the temperature being kept at from -30 to -20.degree . It is stirred for a further 2.5 hours at the same temperature and finally mixed with 40 ml of ice water; the pH is adjusted to 2.0 with sodium hydrogen carbonate. The mixture is stirred for a further 30 minutes, separated, 40 ml of water are added to the organic layer and then, with stirring, aqueous sodium bicarbonate solution up to pH 7.5. The aqueous layer, which separates from the organic layer, is mixed with ethyl acetate and brought to pH 2.0 with 2N hydrochloric acid. The ethyl acetate layer which separates again is separated off, washed with water, dried and evaporated. Treatment of the residue with ether gives 7- (3,5-dichloro-4-oxo-1,4-dihydro-1-pyridyl-acetamido) -cephalosporanic acid.

B

Claims (7)

631718 2. The method according to claim 1, characterized in that alkylating a hydroxy group in the compound of formula I obtained. 2nd PATENT CLAIMS 1. Process for the preparation of cephem derivatives of the formula Z-CH2-CO-nil_ ^ cooh in which Z is an unsubstituted or a 1,4-dihydro-4-oxo-1-substituted one or more times by alkyl or alkoxy with 1-4 C atoms, OH, F, Cl, Br, J, no2 and / or NH2-substituted pyridyl radical, and RH, -OCOCH3 or -SHet, where Het is 3-methyl-l, 2,4-thiadiazolyl-5,5-methyl-l, 3,4-oxadiazolyl-2, 5-hydroxymethyl-1,3, 4-oxadiazolyl-2,5-methyl-1,3,4-thia-diazolyl-2,5-hydroxymethyl-1,3,4-thiadiazolyl-2, tetra-zolyl-5, l-methyltetrazolyl-5, l, 2,3-triazolyl-4,4-methyl-oxazolyl-2 or l-oxidopyridinio-2, mean, and of their trialkylsilyl esters with 1-4 C atoms in the alkyl groups, tert-butyl, benzyl , Benzhydryl, trichloroethyl, benzoylmethyl, p-methoxybenzyl, methoxymethyl or pivaloyloxymethyl esters and physiologically acceptable salts of these compounds, characterized in that a compound of the formula ch_r in which Q is different from the group Z-ch2-CO-NH Acylamino group with 1-15 C atoms or the group R2-CHR3- (CH2) 3-C (OR4) = N-, where R2 is COOH or a e is a functionally modified COOH group, R3 is a functionally modified nh2 group, and R4 is alkyl having 1-6 C atoms, and R1 is COOH or a functionally modified COOH group, with an acid of the formula Z-ch2-COOH (III) or reacted with a functional derivative of such an acid suitable for acylation and the product obtained is then solvolysed and / or hydrogenolyzed. 3. The method according to claim 1, characterized in that a nitro group is reduced to an amino group in the compound of formula I obtained. 4. The method according to claim 1, characterized in that an acetoxymethyl group is reduced to a methyl group in the compound of formula I obtained. 5. The method according to claim 1, characterized in that in the compound of formula I obtained an acetoxy group by treatment with a thiol of the formula Het-SH or a corresponding mercaptide in the rest -S-Het. 6. The method according to claim 1, characterized in that one obtained a compound of formula I with a free carboxyl group to a trialkylsilyl ester with 1-4 C atoms in the alkyl groups, tert-butyl, benzyl, benzhydryl, trichloroethyl, , Esterified benzoylmethyl, p-methoxybenzyl, methoxymethyl or pivaloyloxymethyl ester. 7. The method according to any one of the preceding claims, characterized in that one liberates the acid from a salt or ester obtained or converts an acidic or basic compound obtained into one of its physiologically acceptable salts.