CS205005B2 - Process for preparing n-acylamino-alpha-arylacetamidocephalosporine - Google Patents

Description

The present invention relates to a process for the preparation of N-acylamino-α-arylacetoamidocephalosporin of the formula I

HQ-A ~ CQNH ~ CH ~ CONH

COOH (II in which

A is a divalent heteroaromatic ring selected from the group consisting of quinoline, isoquinoline, cinnoline, naphthyridine, quinoxaline, pyrazolopyridine, pyridopyrazine, pyridazinopyrimidine, thienopyridine, thiazolopyridine, thazolopyrimidine, pyridopyrimidine, pyridine, pyrimidine, pyridazine, triazine, triazine, triazine, triazine, triazine or more substituents selected from the group consisting of an alkyl group having a total carbon number of 1 to 4, an alkoxy group having a total number of carbon atoms of 1 to 4, an alkanoyl group having a total number of carbon atoms of 2 to 5, an alkoxycarbonyl group having a total number of carbon atoms of 2 to 5, an alkylthio group having a total carbon number of 1 to 4, a mercapto group, a hydroxyl group, an alkoxymethyl group having a total carbon number of 2 to 6, a halogen atom, a phenoxycarbonylamino group, an acetosulfonyl group having a total carbon number of 1 to 4, a phenyl group, a pyridylsulfonyl group, a sulfamoyl group, a carbamoyl group a phenoxycarbonylamino group, an acetoacetylamino group, an alkylamino group having a total carbon number of up to 4, a dialkylamino group in which each alkyl has 1 to 4 carbon atoms, a haloalkyl group having a total carbon number of 1 to 4 , an alkenyl group having a total number of carbon atoms of up to 6, a phenyl group, a pyridyl group and a cycloalkyl group having a total number of carbon atoms of 3 to 6,

R represents a phenyl group substituted with a substituent selected from the group consisting of hydroxyl, amino, hydroxymethyl and ureide, and

X is -OCOCH 3 or -S-Het wherein Het is a member of the group consisting of tetrazol-5-yl, 1,3,4-thiadiazol-5-yl, 1,2,3-triazol-5-yl 1,2,4-triazol-3-yl, 1,3,4-oxadiazol-5-yl, pyridazin-6-yl, at 20,5005, each of which may be substituted with a substituent selected from the group consisting of an alkyl group of 1 to 2 C 1-4 alkyl, mercapto, hydroxymethyl, C 1-4 alkylamino and hydroxyl.

It is known that compounds of the cephalosporin series, such as cephalothin and cephalosin, are very potent and widely used chemotherapeutic agents in the treatment of infectious diseases caused by Gram-positive and Gram-negative bacteria.

However, it is also known that said cephalosporins are virtually ineffective in the treatment of infectious diseases caused by Pseudomonas aeruginosa, which has become widespread in recent years and which are difficult to treat. To date, compounds of the cephalosporin series that are effective in the treatment of an infectious disease caused by Pseudomonas aeruginosa are not commercially available. This drawback is solved by the present invention.

The compounds of the formula I according to the invention are prepared by reacting a carboxylic acid of the formula II

HO — A — COOH (Π) in which A is as defined above, optionally with a reactive carboxylic acid derivative selected from the group consisting of an acid halide, an acid anhydride, an acid azolid, an active ester or an acid azide with a compound of formula III

(IIU wherein R and X are as defined above, or with a salt or derivative thereof, wherein the reaction is carried out at a temperature ranging from -20 ° C to -50 ° C.

The reaction is preferably carried out in the presence of a polar solvent or a non-polar solvent, or in the presence of a mixture of both types of solvents.

An acid halide, an acid anhydride, an acid azolid, a reactive acid ester or an acid azide may be used as the reactive derivative of the compound of formula II.

As a derivative of the compound of formula III, a compound in which the carboxyl group is protected by an easily cleavable group is preferably used.

Examples of suitable heterocyclic rings corresponding to the substituent X include: 1-methyltetrazol-5-yl, 2-methyl-1,3,4-thiadiazol-5-yl, 1,2,3-triazol-5-yl, 1 2,4-triazol-3-yl, tetrazol-5-yl, 2-methyltetrazol-5-yl,

2-mercapto-1,3,4-thiadiazol-5-yl, 2-hydroxymethyl-1,3,4-oxadiazol-5-yl, 2-hydroxymethyl-1,3,4-thladiazol-5-yl, 2-aminomethyl- 1,3,4-thiadiazol-5-yl, 3-hydroxypyridazin-6-yl, 1,3,4-thiadiazol-5-yl, 2-methylamino-1,3,4-thiadiazol-5-yl and the like.

Examples of non-toxic pharmaceutically acceptable salts derived from the compounds of Formula I include: sodium salt, potassium salt, calcium salt, magnesium salt, triethylamine salt, diethanolamine salt, morpholine salt, procaine salt, L-arginine salt, L-lysine salt and the like.

Since the--carbon atom of the side chain (phenylglycine residue), attached in formula I at position 7, is an asymmetric carbon atom, there are two optically active isomers of the compound of formula I. These two isomers (D-diastereomer and L- therefore, the diastereomer J and the DL form are also within the scope of the invention, with the preferred diastereomer being the D-diastereomer.

Inert solvents which may be used in the reaction between the compound of formula II and the compound of formula III include polar solvents such as: dichloromethane, chloroform, acetone, tetrahydrofuran, dioxane, acetonitrile, methylisobutylketone, ethanol, dlmethylformamide, dimethylacetamide, dimethylsulfoxide , nitromethane, hexamethylphosphoric triamide, sulfonate and the like, or non-polar solvents such as: benzene, toluene, petroleum ether, n-hexane and the like or mixtures thereof.

These solvents may be used in combination with water.

In the form of reactive carboxylic acid derivatives of the formula II, mixed acid anhydrides or symmetrical acid anhydrides can be used, such as: dialkyl phosphoric acids, dibenzylphosphoric acids, halophosphoric acids, dialkylphosphoric acids, methanesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, aliphatic carboxylic acids pivalic acid, pentanoic acid, isopentanoic acid and 2-ethylbutanoic acid), acid azolides with imidazole, substituted imidazoles, dimethylpyrazole, triazole and the like, and active esters such as: cyanomethyl ester, methoxymethyl ester, vinyl ester, propargyl ester, p-nitrophenyl ester, p-nitrophenyl ester, p-nitrophenyl ester 4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, methanesulfonylphenyl ester, p-nitrophenylthioester, carboxymethylthioester, pyridylester, piperidyl ester, 8-quinolinthioester, and esters with 1-hydroxy-2 (1H) -pyridone, N-hydroxysuccinide and N-hydroxyphthalimide.

When the compounds of formula (II) are used as the free acid (or salt thereof) of the carbonyl group, trichloroethyl ester group, then it is preferred to carry out the reaction in the presence of a coupling agent such as: Ν, Ν'-dicyclohexylcarbodiimide, N-cyclohexyl- N-morpholinoethylcarbodiimide, N-cyclohexyl-N- (4-diethylaminocyclohexyl) carbodiimide, N, N'-diethylcarbodiimide, N, N'-diisopropylcarbodiimide, N-ethyl-N- (3-dimethylaminopropyl) carbodiimide, N, N'- carbonyldi- (2-methylimidazole), pentamethylenketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine, 2-ethyl-7-hydroxybenzisoxazolium salt, 2-ethyl-5- (m-sulfonyl) isoxazole hydroxide, (chloromethylene) dimethylammonium chloride and the like.

As already mentioned, amidating agents commonly used in the peptide industry in the manufacture of penicillin and cephalosporin can be used in the process of the invention.

Examples of salts of compounds of formula III include: alkali metal or alkaline earth metal (e.g., sodium, potassium, calcium and the like) salts of acids of formula III, organic ammonium salts (such as triethylamine-derived salts, trimethylamine, choline, collidine and the like) of acids of formula III and salts of organic sulfonic acids such as toluenesulfonic acid, naphthalenesulfonic acid and tetralinsulfonic acid derived from acids of formula III.

Examples of derivatives of the compounds of formula III include carboxyl derivatives in which the carboxyl group is protected by esterification or amidation and thus by an ester or amide group or in the form of an anhydride group.

After carrying out the acylation reaction under mild reaction conditions, the carboxyl protecting group may be removed, for example, by solvolysis, such as hydrolysis or alcoholysis, catalytic hydrogenation, reduction, oxidation, nucleophilic substitution, photochemical reaction or enzymatic reaction.

Silyl ester, organotin ester, toluenesulfonylethyl ester, p-nitrobenzyl ester, benzyl ester, phenacyl ester, 2-furylmethyl ester, diphenylmethyl ester, substituted diphenylmethyl ester, triethylbutyl ester, triethylbutyl ester, triethylbenzyl ester a benzoylmethyl ester group, a dimethylmethyleneaminoester group, a p-nitrophenyl ester group, a methylsulfonyl ester group, a methylthiophenyl ester group, a t-butyl ester group, a 4-picolyl ester group, an iodoethyl ester group, a trichloroethyl ester group, a phthalimidomethyl ester group, a 3,5-dimethylmethyl ester group, , 2-nitrobenzyl ester group, 2,2'-dinitrobenzyl ester group, acetyloxy-coophyl group

said groups being formed from carboxyl protecting groups commonly used in the peptide, penicillin and cephalosporin industry.

In the case of the silyl ester group, other optional substituents of a compound of formula III, such as, for example, hydroxyl and amino, may optionally be silylated.

Salts derived from hydrochloric acid, p-toluenesulfonic acid, naphthalenesulfonic acid or tetralinsulfonic acid may also be used in the case of these derivatives of the compounds of formula III.

Compounds of formula (III) may be readily prepared by procedures described, for example, in U.S. Patent 3,634,416 and 3,634,418, Dutch Patent No. 70/05519, Canadian Patent No. 873,869, Japanese Patent Application Publication No. 14457/1971. .

The novel cephalosporins of the formula I have been found to have potent antimicrobial activity against gram-positive and gram-negative bacteria and exhibit excellent pharmacokinetic properties. For these reasons, the compounds are useful as chemotherapeutic agents for the treatment of infectious diseases in humans, poultry and cattle.

The compounds of the formula I exhibit excellent antimicrobial activity against bacteria against which the cephalosporin series compounds known so far have little activity. Such bacteria are, for example, Pseudomonas aeruginosa, Indole-positive Proteus, Serratia and Enterobacter aerogenus.

Cephalosporins of formula I having a phenyl group substituted with at least one substituent selected from the group consisting of ureido, amine, hydroxymethyl, or hydroxyl (= the general substituent R) are much better distributable in serum and urine than similar compounds without said compounds. substituents.

The compounds of formula I may be administered intramuscularly or intravenously, for example in the form of solutions, suspensions and the like.

Pharmaceutical formulations containing a compound of formula I as an active ingredient can be prepared by mixing a compound of formula I with one or more pharmaceutically acceptable carriers or diluents, for example, water.

A typical dose of a compound of Formula I is 400 mg to 20 g / day, preferably about 500 mg to 2 g / day; this amount is administered in a single dose or in divided doses (usually in divided doses) and is calculated for an adult (about 60 kg of body weight).

In order that the invention may be more fully understood, the following non-limiting examples illustrate the invention. All parts, percentages and ratios herein are by weight, by weight, and by weight unless otherwise indicated.

He did

Preparation of 7- [D-α- (4-hydroxypyridine-3-carboxamido) -α-β-ureidophenylacetamido] cephalosporanic acid

To a solution of 4.63 g of 7- (Da-amino-β-ureidophenylacetamido) cepalosporic acid and 2.02 g of triethylamine in 80 ml of dimethylformamide is added 2.36 g of 4-hydroxypyridine-3-carboxylic acid N-hydroxysuccinimide ester, with stirring. The reaction mixture is stirred at ambient temperature for 3 hours, then 1.66 g of sodium 2-ethylhexanoate is added and after 10 minutes 200 ml of dichloromethane and 100 ml of diethyl ether are added to precipitate crystals.

The separated crystals were collected by filtration and then washed with diethyl ether. The product thus obtained is then dissolved in water and the pH of the solution is adjusted to 2 by adding 3N aqueous hydrochloric acid solution while cooling with ice, also with stirring. The precipitated crystals are recovered by filtration, then washed with water and dried over phosphorus pentoxide under reduced pressure. This procedure yields

2.6 g of the title compound, m.p. 200-206 ° C.

The sodium salt of the compound of the invention is obtained by dissolving the free acid in dimethylformamide and adding an equimolar amount of sodium 2-ethylhexanoate to the resulting solution. Diethyl ether was added to the reaction mixture to precipitate crystals.

Example 2

Preparation of 7- [D-α- (4-hydroxy-1,5-naphthyridine-3-carboxamido) -a- (p-ureidophenyl) acetamido] cephalosporanic acid

A solution of 4.63 g of 7- (Da-amino-p-ureidophenylacetamido) cephalosporanic acid and 2.02 g of triethylamine in 100 ml of dichloromethane is cooled with ice and 2.45 g of 4-hydroxy-1-hydrochloride hydrochloride are added thereto under stirring. 5-naphthyridine-3-carboxylic acid. After stirring the reaction mixture for 20 minutes, 1.01 g of triethylamine and 30 ml of dimethylformamide were added and the reaction mixture was allowed to react for 15 hours with stirring at the same temperature.

The insoluble material was then filtered off and the filtrate was extracted with three 30 ml portions of aqueous sodium bicarbonate. The resulting aqueous extract was cooled with ice and its pH adjusted to 2 by the addition of 3 N aqueous hydrochloric acid with stirring. The precipitated crystals are collected by filtration, then washed with water and dried over phosphorus pentoxide under reduced pressure. 2.4 g of the title compound of melting point 263 DEG-271 DEG C. are obtained.

The product can be converted to the corresponding sodium salt by known methods. Example 3

Preparation of 7- [D-α- (4-hydrocinnoline-3-carboxamido) -α- (β-ureidophenylacetamido) cephalosporanic acid.

CONH-CH-CQNH

CH _of 0C0CH ₅

COOH

NHC0NH _z

1.90 g of 4-hydroxycinnoic acid are dissolved in 160 ml of anhydrous dimethylformamide. lin-3-carboxylic acid at ambient temperature (about 20-30 ° C) and with stirring. To this solution was then added 1.78 g of carbonyldiimidazole and the resulting reaction mixture was stirred for 30 minutes. Thereafter, 2 g of triethylamine and 4.63 g of 7- (Da-amino-p-ureidophenylacetamido) -cephalosporanic acid were added to the reaction mixture, and the mixture was allowed to react for 3 hours at ambient temperature with stirring. 3.64 g of a 50% solution of sodium 2-ethylhexanoate in n-butanol is then stirred for 10 minutes.

The reaction solution is subsequently poured into acetone and the precipitated crystals are then dissolved in water, the resulting solution is cooled with ice and its pH is adjusted to 2 by the addition of a 2 N aqueous hydrochloric acid solution with stirring. The precipitated crystals are collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure. 3 g of the title compound of melting point 228 DEG-235 DEG C. are obtained.

This compound can be converted to the corresponding salt by methods known per se.

Example 4

Preparation of 7- [N- (4-hydroxypyridine-3-carboxamido) -a- (p-ureidophenyl) acetamido] -3- (2-methyl-1,3,4-thiadiazol-5-yl) thiomethyl-3 -cephem-4-carboxylic acid

OH

CO 2 -CW-COA / VJ - ^,

LJ As cr Y-kci-fs.s-hsA

COOH

CH.

nhconh ^

To a mixture of 5.35 g of 7- (D-amino-p-ureidophenylacetamido) -3- (2-methyl-1,3,4-thiadiazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid, 2 2.00 g of triethylamine and 80 ml of dimethylformamide were added 2.36 g of 4-hydroxypyridine-3-carboxylic acid N-hydroxysuccinimide ester. The reaction mixture was allowed to react for 3 hours at ambient temperature with stirring, then 1.66 g of sodium 2-ethylhexanoate was added, followed by 200 ml of acetone and 100 ml of diethyl ether for 10 minutes to precipitate crystals.

The separated crystals are collected by filtration, washed with diethyl ether and dissolved in water. The resulting solution was then treated by adding 2 N aqueous hydrochloric acid solution with ice-cooling to adjust the pH of the solution to 2. The precipitated crystals were collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure. 3.2 g of the title compound of melting point 233 DEG-240 DEG C. are obtained.

This compound can be further converted to the corresponding sodium salt by methods known per se.

Example 1 a d 5

Preparation of 7- [D-α- (4-hydroxypyridine-3-carboxyamido) -α- (β-ureidophenyl) acetamido] -3- (1-methyltetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid

The compound was prepared according to the same procedure as described in Example 4, using 7- (D-α-amino-β-ureidophenyl-acetamido) -3- (1-methyltetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid.

Melting point: 235-245 ° C.

Example 6

Preparation of 7- [N- (4-hydroxypyridine-3-carboxamido) -a- (p-ureldophenyl) acetamido] -3- (2-methyl-1,3,4-thiadiazol-5-yl) thiomethyl-3- cephem-4-carboxylic acid

OH

Iconh-ch-conh

CX °

r '' č? -N

N — N

CH3S- ^ S- ^ CH4

COOH

ŇHCONH _Z

A mixture of 1.21 g of sodium 7- [Da- (4-hydroxypyridine-3-carboxamido) -α- (p-ureidophenyl) acetamido] cephalosporanate, 0.20 g of sodium bicarbonate, 0.36 g of 2-methyl-5- mercapto-1,3,4-thiadiazole and 25 ml of phosphate buffer (0.1 N KHaPCH-Ol N NaHPOi; 2: 1 v / v; pH: 6.3) are stirred for 6 hours at 60 ° C. The resulting solution was then cooled with ice and its pH adjusted to 2 by the addition of aqueous hydrochloric acid (3N).

The precipitated crystals are collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure. 0.62 g of the title compound is obtained.

The prepared compound can be converted into the corresponding sodium salt in a known manner.

The melting point of the obtained compound ranges from 233 to 240 ° C.

Example 7

Preparation of 7- [D-α- (4-hydroxy-1,5-naphthyridine-3-carboxamido) -α-p-aminophenylacetamido cephalosporanic acid

To a mixture of 4.20 g of 7- (Dap-aminophenylacetamoyl) cephalosporanic acid, 2.02 g of triethylamine and 50 ml of dimethylformamide are added 2.87 g of 4-hydroxy-1,5-naphthyridine-3-carboxylic acid ester with N-hydroxysuccinimide, after which the resulting mixture is stirred for two hours at ambient temperature. The insoluble matter is filtered off and 100 ml of dichloromethane and 300 ml of diethyl ether are added to the filtrate.

The separated crystals were collected by filtration, washed with diethyl ether and dried over phosphorus pentoxide under reduced pressure. 4.7 g of the triethylamine salt of the title compound are obtained. This compound was dissolved in dimethylformamide and sodium 2-ethylhexanoate was added 1.1 times molar relative to the title compound. After addition of acetone to the reaction solution, the sodium salt of the title compound is separated in crystalline form. Mp 250-262 ° C.

Example 8

Preparation of 7- [D-α- (4-hydroxypyridine-3-carboxamido) -α-m-aminophenylacetamido] cephalosporanic acid

CONH - CH - CONH

¹ y 2 CH ₂ OCOCH ₃

COOH νη _λ

To a mixture of 4.20 g of 7- [Dam-aminophenylacetamido] cephalosporanic acid, 2.02 g of triethylamine and 50 ml of dimethylformamide was added 4-hydroxypyridine-3-carboxylic acid ester with N-hydroxysuccinimide, and the resulting mixture was stirred for two hours at ambient temperature. Subsequently, 1.66 g of sodium 2-ethylhexanoate was added to the reaction mixture, and after a further 10 minutes, 100 ml of dichloromethane and 200 ml of diethyl ether were added to precipitate crystals.

The separated crystals are collected by filtration, washed with diethyl ether and dried over phosphorus pentoxide under reduced pressure. 4.5 g of the sodium salt of the title compound are obtained. Melting point 220-229 ° C.

Example 9

Preparation of 7- [Da- (4-hydroxy-1,5-naphthyridine-3-carboxamido) -op-aminophenylacetamido] -3- (2-methyl-1,3,4-thiadiazol-5-yl) thiomethyl -3-cephem-4-carboxylic acid

The compound is obtained in the same manner as in Example 1 except that 7- (D-n-p-aminophenylacetamido) cep alosporanic acid is replaced by 7- (Dap-aminophenylacetamido) -3- (2-methyl-1,3). (4-thiadiazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid. Mp 249-260 ° C.

Example 10

Preparation of 7- [D - N- (4-hydroxy-1,5-naphthyridine-3-carboxamido) -α-m-aminophenylacetamido] -3- (1,3,4-thiadiazol-5-yl) thiomethyl- 3-cephem-4-carboxylic acid

A mixture of 1.18 g of 7- [D - N - (4-hydroxy-1,5-naphthyridine-3-carboxamido) - N - m-aminophenylacetamido] -cephalosporanic acid, 0.368 grams of sodium bicarbonate, 0.32 g of 2- mercapto-1,3,4-thiadiazole and 25 ml phosphate buffer (0.1 N ΚΗζΡΟί-Ο, Ι N NaHPCU; 2: 1 v / v; pH 6.3) was stirred for

5.5 hours at 60 ° C. 20 ml of ethanol are then added to the reaction mixture and the mixture is maintained at 0-5 ° C overnight.

The separated crystals were collected by filtration, washed with ethanol and dried over silica gel under reduced pressure. 1.05 g of the sodium salt of the title compound is obtained. Mp 250-262 ° C.

Example 11

Preparation of 7- [DL - N- (4-hydroxypyridine-3-carboxamido) -α-p-hydroxymethylphenylacetamido

_From COOH CH ₃ OCOCH

To a solution of 7- [DL -? - p-hydroxymethylphenylacetamide orcephalosporanic acid (4.35 g) and triethylamine (2.02 g) in 80 mL of dichloromethane was added under stirring and ice cooling.

2.36 g of 4-hydroxypyridine-3-carboxylic acid ester and N-hydroxysuccinimide and 40 ml of dimethylformamide are added and the reaction mixture is stirred for 30 minutes at an ice bath temperature. After an additional two hours of keeping the reaction mixture at ambient temperature, 1.66 g of sodium 2-ethylhexanoate are added with stirring and after a further 10 minutes 100 ml of dichloromethane and 200 ml of diethyl ether are added to precipitate a crystalline product.

The crystals thus formed are isolated by filtration, washed with diethyl ether and dried over phosphorus pentoxide under reduced pressure.

Yield: 4 g of compound, m.p. 211-219 ° C.

Example 12

Preparation of 7- [DL - N - (4-hydroxy-1,5-naphthyridine-3-carboxamido) - N - p -hydroxymethylphenylacetamide orcephalosporanic acid

To a solution of 4.35 g of 7- [DL-os-p-hydroxymethylphenylacetamido] cep alosporanic acid and 2.02 g of triethylamine in 60 ml of dimethylformamide was added 2.87 g of 4-hydroxy-1,5-naphthyridine-3 ester. of the carboxylic acid and N-hydroxysuccinimide and the resulting reaction mixture is stirred for two hours at room temperature. The undissolved solid was filtered off and 100 ml of dichloromethane and 350 ml of diethyl ether were added to the filtrate to give a crystalline product. The crystals were collected by filtration, washed with diethyl ether and dried over phosphorus pentoxide under reduced pressure.

This procedure yields the triethylamine salt of the title compound in an amount

4.2 g. Melting point: 260-266 ° C.

The compound can be converted to the sodium salt by a known method.

Example 13

Preparation of 7- [DL - N- (4-hydroxypyridine-3-carboxamido) -α-p-hydroxymethylphenylacetamido] -3- (2-methyl-1,3,4-thiadiazol-6-yl) thiomethyl-3- cephem-4-carboxylic acid

OH

ΊΓ cqNH-CH-CONH-, 0.16x

COOH

N -— N

CH 2 OH

To a solution of 5.07 g of N- (DL-β-hydroxymethylphenylacetamido) -3- (2-methyl-1,3,4-thiadiazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid and 2.02 g of triethylamine in 80 ml of dimethylformamide was added 2.36 g of 4-hydroxypyridine-3-carboxylic acid ester and N-hydroxysuccinimide under stirring, then the reaction mixture was stirred at ambient temperature for 2 hours.

Subsequently, 1.66 g was added to the reaction mixture

Sodium 2-ethylhexanoate and after 10 minutes, 200 ml of acetone and 100 ml of diethyl ether are added to the mixture to precipitate a crystalline product.

The crystals obtained are collected by filtration, washed with diethyl ether and dried over phosphorus pentoxide under reduced pressure. In this way, 4.8 g of the sodium salt of the title compound having a melting point of 235-242 ° C is obtained.

Example 14

Preparation of 7- [DL-α- (4-hydroxy-1,5-naphthyridine-3-carboxamido) -α-hydroxymethylphenylacetamido] -3- (2-methyl-1,3,4-thiadiazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid

CH 2 OH

A mixture of 3.03 g of 7- [DL-α- (4-hydroxyl, 5-naphthyridine-3-carboxamido) -α-p-hydroxymethylphenylacetamido-cephalosporanic acid, 0.92 g of sodium bicarbonate, 0.90 g

Of 2-methyl-5-mercapto-1,3,4-thiadiazole and 60 ml of phosphate buffer (0.1 N ΚΗζΡΟι-Ο, Ι N NaHPOg 2: 1 by volume; pH 6.3) was stirred for 5.5 hours at 50 to 60 ° C. 40 ml of ethanol are then added to the mixture and the reaction mixture is maintained at 0-5 ° C overnight.

The separated crystals are then collected, isolated by filtration, washed with ethanol and dried over phosphorus pentoxide under reduced pressure. 2.5 g of the sodium salt of the title compound are thus obtained.

Mp 240-246 ° C.

Example 15

Preparation of 7- [D - N- (4-hydroxypyridine-3-carboxamido) -α-p-hydroxyphenylacetamido] cep alosporanic acid

OH

CONH-CH-CQNH-

CH _from OCOCH ₃

COOH

OH t * A

2.34 g of 4-hydroxypyridine-3-carboxylic acid ester and N-hydroxysuccinimide are added to a mixture of 4.21 g of 7- [D - N-p-hydroxyphenylacetamide orcephalosporanic acid, 60 ml of dichloromethane and 2.02 g of triethylamine. 30 ml of dimethylformamide, with cooling, is then stirred at this temperature for 30 minutes. After stirring the reaction mixture at ambient temperature for 2 hours, 1.66 g was added to the mixture

Sodium 2-ethylhexanoate and after 10 minutes 200 ml of dichloromethane and 100 ml of diethyl ether to give a crystalline product.

The precipitated crystals were collected by filtration and washed with diethyl ether and then dissolved in water and the resulting solution was cooled with ice with stirring, then the pH of this solution was adjusted to 2 by addition of aqueous 3N hydrochloric acid.

The crystals obtained are collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure. 2.1 g of the title compound are obtained. Mp 190-201 ° C.

The free acid thus obtained was added to 13 ml of dimethylformamide and 1.1 molar equivalent of sodium 2-ethylhexanoate was added to the reaction mixture. Subsequent addition of dichloromethane and acetone to give a crystalline product yields 1.9 g of the sodium salt as crystals.

Example 16

Preparation of 7- (D-α- (4-hydroxy-1,5-naphthyridine-3-carboxamido) -α-β-hydroxyphenylacetamido) cep alosporanic acid

2.87 g of 4-hydroxy-1,5-naphthyridine-3-carboxylic acid ester and N-hydroxysuccinimide are added to a solution of 4.21 g of 7- [D - N-p-hydroxyphenylacetamide orcephalosporanic acid and 1.975 g of triethylamine in 80 ml of dimethylformamide. and the mixture thus obtained is stirred for two hours at ambient temperature.

The insoluble solid is then collected by filtration and to the filtrate is added 80 ml of dichloromethane and 350 ml of diethyl ether. The precipitated crystals were collected by filtration, washed with diethyl ether and dried over phosphorus pentoxide under reduced pressure.

4.4 g of the triethylamine salt of the title compound of melting point 258 DEG-261 DEG C. are obtained.

The salt obtained is converted into the corresponding sodium salt in a manner known per se. Example 17

Preparation of 7- [D-a- (4-hydroxy-1,5-naphthyridine-3-carboxamido) -c-p-hydroxyphenylacetamido] cephaosporic acid

To an ice-cooled solution of 4.21 g of 7- [Dwp-hydroxyphenylacetamido] cep alosporanic acid and 2.02 g of triethylamine in 100 ml of dichloromethane was added 2.45 g of 4-hydroxy-1,5-naphthyridine-3 hydrochloride with stirring. -carboxylic acid, followed by stirring for 20 minutes. To the mixture was then added 1.01 g of triethylamine and the mixture was allowed to react at the same temperature for 3 hours.

Subsequently, the insoluble solid was filtered off and the filtrate was extracted three times with 20 ml of aqueous sodium bicarbonate solution. The aqueous extract was cooled with ice and acidified to pH 2 with stirring by addition of a 1N aqueous hydrochloric acid solution.

The separated crystals are collected by filtration, washed with water, methanol and diethyl ether and dried over phosphorus pentoxide under reduced pressure.

2.2 g of the title compound of melting point 258 DEG-261 DEG C. are obtained.

The compound obtained is then converted by treatment with sodium 2-ethylhexanoate into the corresponding sodium salt.

Example 18

Preparation of 7- [D - N - (4-hydroxycinnoline-3-carboxamido) -α-p-hydroxyphenylacetamido] cep alosporanic acid

1.90 g of 4-hydroxy-3-carboxylic acid are dissolved in 60 ml of anhydrous dimethylformamide with stirring at ambient temperature, and 1.78 g of carbonyldiimidazole are added to the reaction mixture, followed by stirring for 30 minutes. Then, 4.21 g of 7- [D-α-p-hydroxyphenylacetamido] cep alosporanic acid and 1.8 g of triethylamine were added to the reaction mixture, and the resulting mixture was stirred for 3 hours at ambient temperature.

Subsequently, 2.64 g of a 50% solution of sodium 2-ethylhexanoate in n-butanol are added and the reaction mixture is stirred for a further 10 minutes. The reaction solution is then poured into acetone and the precipitated crystals are collected by filtration.

The separated crystals were dissolved in water and the resulting solution was cooled and the pH was adjusted to 2 by addition of 1N aqueous solution

CONH-CH-CONH - hydrochloric acid to a stirred solution.

The separated crystals are collected by filtration and dried over phosphorus pentoxide under reduced pressure.

3.2 g of the title compound of melting point 215 DEG-227 DEG C. are obtained. The compound is further converted into the sodium salt of the corresponding compound with 2-ethylhexanoate.

Example 19

Preparation of 7- [D-α- (4-hydroxypyridine-3-carboxamido) -α-p-hydroxyphenylacetamido] -3- (2-methyl-1,3,4-thiadiazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid

COOH

OH

To a mixture of 4.93 g of 7- (Dap-hydroxyphenylacetamido) -3- (2-methyl-1,3,4-thladiazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid, 2.02 g of triethylamine and 2.00 g of dimethylformamide are added under ice-cooling, 2.36 g of 4-hydroxypyridine-3-carboxylic acid ester and N-hydroxysuccinimide are added while stirring the resulting mixture, followed by stirring at the same temperature for 30 minutes.

After stirring the reaction mixture at ambient temperature for 2 hours, 1.66 g of sodium 2-ethylhexanoate is added, and after a further 10 minutes 200 ml of acetone and 100 ml of diethyl ether are added to precipitate crystals.

The separated crystals were collected by filtration and washed with diethyl ether. These crystals were dissolved in water and the resulting solution was cooled with ice and acidified to pH 2 by the addition of aqueous hydrochloric acid. The precipitated crystals were collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure.

2.6 g of the title compound are obtained.

A mixture of 4.93 g of 7- (Dap-hydroxyphenylacetamido) -3- (2-methyl-1,3,4-thiadiazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid, 2.02 grams of triethylamine and 80 g of ethyl acetate. ml of dimethylsulfoxide was stirred at ambient temperature and 2.36 g of 4-hydroxypyridine-3-carboxylic acid and N-hydroxysuccinimide were added thereto. After stirring the reaction mixture for 30 minutes, 1.66 g of sodium 2-ethylhexanoate was added and after a further 10 minutes, acetone was added in an amount of two liters to precipitate a crystalline product.

The separated crystals were collected by filtration, washed with acetone and dried with diethyl ether over phosphorus pentoxide under reduced pressure;

ku. 5.2 g of the sodium salt of the title compound are obtained.

Mp 225-235 ° C.

Example 20

Preparation of 7- [D-α- (4-hydroxypyridine-3-carboxamido-α-p-hydroxyphenylacetamido] -3- (1-methyltetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid

The compound was obtained in the same manner as in Example 19 using 7- (D-α-p-hydroxyphenylacetamido) -3- (1-methyltetrazol-5-yl) thlomethyl-3-cephem-4-carboxylic acid.

Mp 204-213 ° C.

Claims (4)

SUBJECT YNAtEZU A process for the preparation of N-acylamino-α-arylacetamidocephalosporin of the general formula I ho-a-conh-ch-conhCOOH ^from which: A is a divalent heteroaromatic ring selected from the group consisting of quinoline, isoquinoline, cinnoline, naphthyridine, quinoxaline, pyrazolopyridine, pyridopyrazine, pyridazinopyrimidine, thienopyridine, thiazolopyridine, thiazolopyrimidine, pyridopyrimidine, pyridine, pyrimidine, pyridazine, pyridazine, pyridazine, pyridazine, pyridazine, or more substituents selected from the group consisting of alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, alkanoyl having 2 to 5 carbon atoms, alkoxycarbonyl having 2 to 5 carbon atoms 5, an alkylthio group having a total carbon number of 1 to 4, a mercapto group, a hydroxyl group, an alkoxymethyl group having a total carbon number of 2 to 6, a halogen atom, a cyano group, a nitro group, an alkylsulfonyl group having a total carbon number of 1 to 4, a phenyl group, a pyridylsulfonyl group, a sulfamoyl group, a carbamoyl group, a phenoxycarbonylamino group, an acetoacetylamino group, an alkylamino group having a total carbon number of 1 to 4, a dialkylamino group in which each alkyl has 1 to 4 carbon atoms, a haloalkyl group having a total carbon number (t) atoms of 1 to 4, alkenyl of 2 to 6, phenyl, pyridyl and cycloalkyl of 3 to 6; R is a phenyl group substituted with a substituent selected from the group consisting of hydroxyl, amino, hydroxymethyl, and ureide, and X is -OCOCH 3 or -S-Het wherein Het is a member of the group consisting of tetrazol-5-yl, 1,3,4-thiadiazol-5-yl, 1,2,3-triazole-5- yl, 1,2,4-triazol-3-yl, 1,3,4-oxadiazol-5-yl, pyridazin-6-yl, each of which may be substituted with a substituent from the group consisting of an alkyl group of 1 to 2 (C 4 -C 4), mercapto, hydroxymethyl, (C 1 -C 4) alkylamino and hydroxyl, characterized in that the carboxylic acid (II) is reacted HO-A-COOH (II), wherein A is as defined above, or a reactive carboxylic acid derivative selected from the group consisting of an acid halide, acid anhydride, acid azolid, active ester or acid azide, with a compound of formula III wherein R and X is as defined above, or a salt or derivative thereof, wherein the reaction is carried out at a temperature ranging from -20 ° C to +50 ° C and optionally converting the compound obtained to a compound of formula I with a free carboxylic acid. group in position 4. 2. Process according to claim 1, characterized in that the reaction is carried out in the presence of a polar solvent or a non-polar solvent, or in the presence of mixtures thereof. 3. A process according to claim 1, wherein the reactive derivative of the compound of formula (II) is an acid halide, acid anhydride, acid azolid, reactive acid ester or acid azide. 4. The process of claim 1 wherein the derivative of the compound of formula (III) is a compound in which the carboxyl group is protected by an easily cleavable group.