DK150600B - Cephalosporin derivatives - Google Patents

Description

150600

The present invention relates to novel cephalosporin derivatives which are characterized in that they have the general formula II

Η H

f ϊ, sx

CH3ON- = C— CONH — i-J I

// Λ S-X "RHN ^ \ g /

COOH

wherein X represents a 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-5-yl group or a 2,5-dihydro-6-hydroxy-2-methyl-5- oxo-as-triazin-3-yl group, R represents a leaving protecting group which may be tert-butoxycarbonyl, trityl, trifluoroacetyl or chloro, bromo or iodoacetyl, and the carboxy group may be as silyl ester or _-alkyl-COO-C - alkyl ester or protected by salt formation with an inorganic or tertiary organic base.

The cephalosporin derivatives of formula II are valuable intermediates for the preparation of pharmacologically valuable cephalosporin derivatives.

They can be converted into the pharmacologically valuable cephalosporin derivative of the general formula I by cleavage of the protecting group R and optionally also the carboxy protecting group present if present.

Η H

! } s CH3ON = tC- conh -: - ^^ r \ 'Η2ΝΛδ /.

COOH

Wherein X is as defined above, or C 1-6 alkyl-COO-C 1-4 alkyl esters / ethers or salts of this compound or hydrates of the compound of formula I or of said esters / ethers or salts.

Esters of the compound of formula I are understood to be compounds similar to formula I whose carboxy group is in the form of an ester group as defined above. Examples of such esters are aceto-xymethyl, pivaloyloxymethyl, 1-acetoxyethyl and 1-pivaloyloxyethyl esters.

Ethers of the compound of formula I are understood to be compounds similar to formula I wherein X represents a 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl group whose enolic OH group is in the form of an ether group as indicated above. As ether groups can be used the same groups referred to above as ester groups.

Examples of such ethers are, for example, acetoxymethyl, pivaloyloxymethyl, 1-acetoxyethyl and 1-pivaloyloxyethyl ether.

Esters / ethers (dider derivatives) are formed for both meanings of X; these are similar, tautomeric forms of X that are in equilibrium with each other.

Examples of salts of the compound of formula I are the alkali metal salts, for example the sodium and potassium salt; the ammonium salt; alkaline earth metal salts, e.g., the calcium salt; salts with organic bases, for example salts with amines such as salts with N-ethylpiperidine, procaine, dibenzylamine, Ν, Ν'-dibenzylethylethylenediamine, alkylamines or dialkylamines and salts with 25 amino acids, for example salts with arginine or lysine.

The salts may be monosaltic or disaltic. The second salt formation can occur in compounds with the hydroxy group of the 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl group.

The compound of formula I also forms addition salts with organic or inorganic acids. Examples of such salts are hydrohalogenides, e.g. hydrochlorides, hydrobromides and hydroiodides, as well as 3,150,600 other mineral acid salts such as sulfates, nitrates and phosphates, alkyl and mono-aryl sulfonates such as ethane sulfonates, toluene sulfonates and benzenesulfonates, and other organic acid salts such as acetates, , citrates, benzoates, salicylates and ascorbates.

The compound of formula I and its salts and esters / ethers can. be hydrated. The hydration can be carried out during the preparation process or gradually due to hygroscopic properties of an initially anhydrous product.

'*

Compounds I and II may be in the syn-isomeric form N - C-CONH-? jTii. * H2N \ S / och3 10 or in the anti-isomeric form 'Μ} Λ ch30 or as mixtures of these two forms. The syn-isomeric form or mixtures in which the syn-isomeric form is predominant are preferred.

Preferred end products of formula I are 15 (6R, 7R) -7- [2- (2-amino-4-thiazolyl) -2- (Z-methoxyimino) -acetamido] -3 - ([C2,5-dihydro-6 -hydroxy-2-methyl-5-oxo-az-triazin-3-yl) thio] -methyl) -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid and salts thereof as well as the corresponding hydrates.

4 150600

A preferred intermediate II is (6R, 7R) -7- (2- [2- (2-chloroacetamido) -4-triazolyl] -2- (Z-methoxyimino) acetamido) -3- ([(2.5 -dihydro-6-hydroxy-2-methyl-5-oxo-az-triazin-3-yl) -thio] methyl) -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2 -en-2-carboxylic acid.

The above-mentioned cephalosporin derivative of formula I or β-alkyl-COO-C ^ _ alkyl esters / ethers or salts of this compound or hydrates of the compound of formula I or of said esters / ethers or salts is prepared by that a) the protecting group R as defined above and optionally also a silyl group optionally present or -alkyl-COO-C

salt group or carboxy protecting group in salt form as defined above is cleaved from compounds of general formula II

Η H

! I g CH-, ΟΝ ~ = C- CONH --- \ N-1 i ΐΓ \ 0 ^ ~ S ~ X "

RHN - ^ \ g / J

COOH

wherein X and R have the meaning set forth above and the carboxy group 15 may be as defined above, wherein the latter protecting group, if necessary or desired, is also cleaved and optionally to prepare a C 1-6 alkyl-COO-C 1-4 alkyl ester / ether of the compound of formula I therein is reacted with a C 1-6 alkyl-COO-C 1-4 alkyl halide, and optionally to prepare salts or hydrates or hydrates of these salts, the compound obtained is converted to a salt or hydrate or a hydrate of the salt, or b) to prepare a C 1-6 alkyl-COO-C 1- alkyl ester / ether of the compound of formula I which is reacted with a C 1-6 alkyl-COO-C 1-4 alkyl halide, or ) for the preparation of salts or hydrates of the compound of formula I or hydrates of these salts the compound of formula I is converted into a salt or hydrate or hydrate of this salt.

The carboxy group present in the compound of formula II may, if desired, be present as the cilyl ester, for example, the trimethylsilyl ester, or as a C 1-4 alkyl-COO-C 1-4 alkyl ester. The carboxy group may also be protected by salt formation with an inorganic or tertiary organic base such as triethylamine. Protective groups R are, for example, by acid hydrolysis-deprotected protecting groups, for example tert-butoxycarbonyl or trityl, or by basic hydrolysis-deprotected protecting groups, eg trifluoroacetyl. Preferred protecting groups R are chloro, bromo and iodoacetyl, especially chloroacetyl. The last protecting groups can be split off by treatment with thiourea.

For example, the compounds of formula II may be prepared by N-acylation of the corresponding 7-amino compound, a compound of general formula 111

H H

»- M

H2N— ^ f X

o '^ \ ^ · ~ ° Η2_3-Χ

COOH

wherein X is as defined above and the carboxy group and / or amino group may be in protected form, reacted with an acid of the general formula IV

CH2 N - C-COOH

ri

RHN ^ \ s X

Wherein R is as defined above or with a reactive functional derivative of this acid and optionally a carboxy protecting group present is optionally cleaved.

The carboxy-5 group present in the 7-amino compound of formula III may be protected if desired, which may be provided in the manner described above in connection with the starting compound of formula II to be prepared. For example, the amino group of the compound of formula III may be protected by a silyl protecting group such as trimethylsilyl.

For example, as reactive functional derivatives of acids of formula IV, halides, i.e. chlorides, bromides and fluorides; azides; anhydrides, especially mixed anhydrides with strong acids; reactive esters such as N-hydroxysuccinimide ester; and amides such as imidazolides.

The reaction between the 7-amino compound of formula III and the acid of formula IV or a reactive functional derivative thereof can be carried out in a manner known per se. Thus, for example, a free acid of formula IV can be condensed with a derivative corresponding to the ester of formula III by means of a carbodiimide, for example dicyclohexylcarbodiimide, in an inert solvent, for example ethyl acetate, acetonitrile, dioxane, chloroform, methylene chloride, benzene or benzene chloride. , after which the ester group is cleaved. Instead of carbodiimides, oxazolium salts such as N-ethyl-5-phenyl-isoxazolium-3'-sulfonate can also be used as condensing agents.

In another embodiment, a salt of an acid of formula III, e.g., a trialkylammonium salt, e.g., triethylammonium salt, is reacted with a reactive functional derivative of an acid of formula IV as mentioned above in an inert solvent, e.g., one of the above.

In a further embodiment, an acid halide, preferably the chloride, of an acid of formula IV is reacted with the amine of formula 30 III. The reaction is preferably carried out in the presence of an acid-binding agent, for example, in the presence of aqueous base, preferably sodium hydroxide solution, or in the presence of an alkali metal carbonate, e.g., potassium carbonate, or in the presence of a lower alkylated amine, e.g., triethylamine. The solvent is preferably used as water, optionally in admixture with an inert organic solvent such as tetrahydrofuran or dioxane. An aprotic organic solvent, for example, dimethylformamide, dimethylsulfoxide or hexamethylphosphoric triamide, may also be employed. Using silylated starting compounds of formula III, it is worked in anhydrous medium.

The reaction between the 7-amino compound of formula III and the acid of formula IV or a reactive functional derivative thereof can conveniently be carried out at temperatures between ca. -40 ° C and room temperature, e.g. 0-10 ° C.

In preparing compound I of process variant a), the amino protecting group R as defined above is cleaved from a compound of formula II. The tert.butoxycarbonyl group and a trityl group R 15 are preferably removed by a lower alkane carboxylic acid which may be optionally halogenated. In particular, formic acid or trifluoroacetic acid is used. The temperature is usually room temperature, although slightly higher or slightly lower temperatures can be used, for example in the range between approx. 0 and + 40 ° C. When R represents trifluoroacetyl, this protecting group can generally be hydrolyzed with dilute aqueous bases at 0-30 ° C. Chloroacetyl, bromoacetyl and iodoacety (protecting groups R can be cleaved by thiourea in an acidic, neutral or alkaline environment at about 0-30 ° C.

Following the preparation of Compound I using process variant a), if desired, a carboxy protecting group present in the reaction product may be cleaved. When the carboxy group is present as a silyl group (silyl ester), this group can be split off particularly easily by treating the reaction product with water. C ^ _ Al Alkyl-COO-C ^ alk alkyl esters are preferably enzymatically cleaved off by a suitable esterase (at about 20-40 ° C). When the carboxyl group is protected By salt formation (e.g. with triethylamine), the cleavage of this salt-forming protecting group can be effected by treatment with acid. As an acid, for example, hydrochloric acid, sulfuric acid, phosphoric acid or citric acid may be used.

8 150600

The carboxy protecting group can be cleaved in a similar manner as described above before cleaving the protecting group R.

In the optional step of process variant a) and in process variant b) to prepare β-alkyl-COO-C ^ alkyl esters of the compound I, the carboxylic acid is reacted with the corresponding halide, preferably with the iodide. The reaction may be accelerated by a base, for example, an alkali metal hydroxide or carbonate or an organic amine such as triethylamine. The 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl group X with its enolic function is etherified to give a corresponding, easily hydrolyzable ether. (The products thus obtained, esterified and etherified, are referred to above and below as "esters / ethers"). An excess of the corresponding halide is preferably used for this. The esterification / etherification reaction is preferably carried out in an inert organic solvent, e.g., dimethylacetamide, hexamethylphosphoric triamide, dimethylsulfoxide or, preferably, dimethylformamide. The temperature is preferably in the range of between approx. 0 and 40 ° C.

The preparation of the salts and hydrates of the compound of formula I or the hydrates of these salts can be carried out in a manner known per se, for example by reacting the carboxylic acid of formula I with an equivalent amount of the desired base, suitably in a solvent such as water or in an organic solvent such as ethanol, methanol or acetone. Using one additional equivalent base, salt formation is also carried out on the tautomeric enol form (2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl group X), thereby forming a disalt. The temperature of the salt formation is not critical. It is usually at room temperature, but may also lie slightly above or below, for example, in the range of 0 to + 50 ° C.

The preparation of the hydrates is often carried out automatically during the preparation process or on the basis of the hygroscopic properties of an initially anhydrous product. A hydrate can be prepared from a completely or partially anhydrous product (carboxylic acid of formula I or ester, ether or salt thereof) by exposing it to a moist atmosphere, e.g. 10-40 ° C.

9 150600

The above 7-amino compounds of formula III can be prepared from compounds of general formula V

Η H

1 I

H 2 ί-ν '

o 'ϊ V

COOH

wherein Y represents a leaving group and the carboxy group may be in protected form by reaction with a thiol of general formula VI

HS - X VI

where X has the meaning given above.

As leaving group Y in a compound of formula V, there may be mentioned, for example, halogens, for example chlorine, bromine or iodine, acyloxy groups, e.g. lower alkanoyloxy groups such as acetoxy, lower alkyl or arylsulfonyloxy groups such as mesyloxy or tosyloxy or azido.

The reaction of the compound of formula V with the thiol of formula VI can be carried out in a manner known per se, for example at a temperature between 40 and 80 ° C, conveniently at approx. 60 ° C, in water or in a buffer solution with a pH of approx. 6-7, preferably 6.5.

An optionally obtained syn / anti-mixture of the compound of formula I may be resolved in the usual manner into the corresponding syn and anti-forms, for example, by recrystallization or by chromatographic methods 20 using a suitable solvent or solvent mixture.

The compounds of formula I as well as the correspondingly easily hydrolyzable esters / ethers and salts or hydrates of these products are antibiocetic, especially bactericidal. They have a broad spectrum of action against gram-positive and gram-negative microorganisms, including (5-lac-tamase-forming staphylococci and various β-lactamase-forming gram-negative bacteria, e.g., Pseudomonas aeruginosa, Haemophilus 5. influenzae, Escherichia coli, Serratia marcescens, Proteus and Klebsi species.

The compounds of formula I as well as the corresponding esters / ethers and salts or hydrates of these products can be used for the treatment and prophylaxis of infectious diseases. For adults, a 10 daily dose of approx. 0.1 - approx. The parenteral administration of the subject compounds is particularly preferred.

To detect the antimicrobial activity of the compounds of formula I, the following representative compound was tested: C6R, 7R) -7- [2- (2-amino-4-thiazolyl) -2- (Z-methoxyimino) acet-15-amido] - 3- C [(2,5-Dihydro-6-hydroxy-2-methyl-5-oxo-az-triazine-3-yl) thio] -methyl) -8-oxo-5-thia-1- azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid.

In vitro activity: Minimum inhibitory concentration (vg / ml).

in 11 150600

Haemophilus influenzae Strain 1 0.08

Strain 2 0.005

Strain 3 0.005

Strain 4 0.005

Strain 5 0.0025

Strain 6 0.0025 _Store 7__0.0025

Klebsiella pneumoniae 1,2

Escherichia coli Strain 1 0.02

Strain 2 0.6

Proteus mirabilis Strain 1 ^ 0.01

Strain 2 ~ 0.01

Proteus vulgaris - 0.01

Proteus straightener Ξ = 0.01

Staphylococcus aureus Strain ATCC 6538 2.5

Penicillin resistant strain 2.5

Pseudomonas aeruginosa Strain 1 0.3

Strain 2 10

Strain 3 2.5

Tribe 4 5

Tribe 5 5

Tribe 6 10

Tribe 7 5

Serratia marcescens 0.08! , _ I_i

In vivo activity

Groups of every 5 mice are infected intraperitoneally with an aqueous suspension of Escherichia coli. Three times, ie At 1 hour, 2 1/2 hours and 4,112,600 hours after infection, the drug is administered subcutaneously in physiological saline. The number of surviving animals is determined on the 4th day. Different dosages are administered and by interpolation the dose is determined at which 50% of the test animals survive 5 (CD50, mg / kg).

CD = q: <0.005 mg / kg

Toxicity l_D50, mg / kg intravenously 250-500 10 subcutaneously> 4000 perorally> 5000 2-amino-4-thiazolyl) -2- (Z-methoxy-imino) -acetamido] group. However, the cephalosporins of formula I are distinctively different from the known compounds in the configuration of the substituent at the 3-position, thus providing novel compounds with surprising efficacy benefits. Thus, a comparison with a structurally adjacent, comparable compound of the prior art (the only compound which, at the 3-position, similar to the cephalosporins of formula I, contains a 6-membered N-heterocyclic thiol methyl group, namely a (6- methyl-1-oxido-pyridazin-3-yl) -thiomethyl group) has shown that a representative compound for the cephalosporins of formula I wherein X 25 is a 1,2,5,6-tetrahydro-2-methyl-5,6- dioxo-as-triazin-3-yl group or its corresponding tautomeric form, a 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl group, has a massive (over 50 times more potent) ) efficacy superiority in a prophylactic in vivo test on mice against the pathogenic microorganisms Serratia marcescens, Klebsiella 30 pneumoniae, Proteus mirabilis and Proteus vulgaris.

The invention is further illustrated by the following Examples, wherein Example 1 illustrates the preparation of a subject compound of Formula II and Example 2 illustrates the conversion of II to a pharmacologically valuable compound of Formula I.

EXAMPLE 1

Preparation of (6R, 7R) -7- (2- [2- (2-chloroacetamido) -4-thiazolyl] -2- (Z-methoxyimino) acetamido) -3- ([(2,5-dihydro-6- hydroxy-2-methyl-5-oxo-as-triazin-3-yl-thio] methyl) -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-5 en-2 -carboxylic acid: 22.24 g of 2- (2-chloroacetamido-thiazol-4-yl) -2- (Z-methoxyimino) acetic acid is suspended in 240 ml of methylene chloride. To this suspension is added 13.39 ml of triethylamine to form a light brown solution.

This solution is cooled to 0-5 ° C, 16.72 g of phosphorus penta-chloride is added and stirred for 5 minutes at 0-5 ° C and for 20 minutes without cooling. The yellow solution is evaporated in vacuo at 35 ° C. The evaporation residue is shaken twice with n-heptane which is decanted off.

The resinous residue is treated with 240 ml of tetrahydrofuran and the undissolved triethylamine hydrochloride is filtered off. The yellow filtrate 15 contains the acid chloride.

22 g of (7R) -7-amino-3-desacetoxy-3 - [(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-az-triazin-3-yl) thio] cephalosporanoic acid are suspended in a mixture of 300 ml of water and 150 ml of tetrahydrofuran. To the suspension, drop under a good cover of nitrogen gas 2N sodium hydroxide solution by means of an autotitrator until a tan solution of pH 8 is formed. It is cooled to 0-5 ° C and added dropwise over 15 minutes. solution of the acid chloride in tetrahydrofuran. Then stir for 2 1/2 hours at 25 ° C. The pH of the acylation mixture is kept constant at 8 by the addition of 2N sodium hydroxide solution. The practically black solution is frozen for tetrahydrofuran in vacuo at 40 ° C. 100 ml of 2N sulfuric acid solution is then added. The thus precipitated substance is isolated by suction filtration, washed with water and suctioned thoroughly.

The moist brown filtration product is dissolved in 1.5 liters of acetone. The 30 dark solution is filtered off a small amount of dark undissolved material over "Hyflo" ®, added to charcoal, stirred for 30 minutes and filtered again over "Hyflo" ®. The orange-red filtrate is dried over sodium sulfate, evaporated in vacuo and evaporated with ethyl acetate. Thereby a black resin is precipitated which is filtered off and discarded. The 2-phase, still 14, 150,600 aqueous filtrate is subjected to azeotropic distillation 3 times with -benzene in vacuo at 40 ° C. The thus precipitated substance is isolated by suction filtration and dried in vacuo at 40 ° C. The substance is stirred twice with 1 liter of acetone each time, giving as a residue a 5 brown resin which is discarded. The combined orange colored acetone extracts are evaporated in vacuo to 150 ml at 40 ° C, whereupon a brown resin is filtered off and discarded. To the filtrate is added 1 liter of ethyl acetate and evaporated in vacuo at 40 ° C. The precipitate thus obtained is isolated by suction filtration, washed with ethyl acetate and then with 10 ether [(6R, 7R) -7- (2- [2- (2-chloroacetamido) -4-thiazolyl] -2- (Z-methoxy-imino) ) acetamido) -3 - ([(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-tri-azine-3-yl) thio] methyl-8-oxo-5-thia-1 -azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, fraction I: a beige colored, amorphous acid] This fraction I can be used directly to prepare the desired final product, as in Example 2.

The ethyl acetate mother liquor is vaporized vigorously in vacuo at 40 ° C and diluted with ether, and the precipitate is isolated by suction filtration [(6R, 7R) -7- (2- [2- (2-chloroacetamido) -4-thiazolyl] -2- ( Z-methoxyimino) -acetamido) -3- ([(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) thio] methyl) -8-oxo-5 -thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, fraction II: an ice-beige, amorphous acid, thin-layer chromatography somewhat purer than fraction I].

To prepare the disodium salt, 3.5 g of acid (fraction II) is dissolved in a mixture of 20 ml of acetone and 11 ml of water. To this solution is added 7 25 ml of a 2N solution of 2-ethylcaproic acid sodium salt in ethyl acetate, thereby crystallizing the disodium salt. Then 25 ml of acetone is added portionwise and the mixture is stored in the freezer for 2 hours.

Then the crystallate is isolated by suction filtration, washed with 25 ml of an ice-cold acetone-water mixture (80:20), pure acetone and low-boiling petroleum ether in the order indicated and dried overnight in high vacuum at 40 ° C. There is obtained the disodium salt of (6R, 7R) -7- (2- [2- (2-chloroacetamido) -4-thiazolyl] -2- (Z-methoxyimino) -acetamido) -3 - ([(2,5-dihydro) -6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) thio] methacrylate-yl) -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene -2-carboxylic acid in the form of 35 light yellow crystals.

2 0 150600 15

Oq - -142.7 (c - 1 in water). Nuclear resonance spectrum and microanalysis correspond to the structure indicated.

NMR Spectrum (D 2 O): δ (ppm) = 3.6 (2-CH 2), 3.63 (NCH 3), 4.05 (OCH 3), 4.27 (3-CH 2), 4.43 (-CH 2 Cl) ), 5.23 (H-6), 5.83 (H-7), 7.47 (5-thiazolyl-H).

EXAMPLE 2

Preparation of the disodium salt of (6R, 7R) -7- [2- (2-amino-4-thiazolyl) -2- (Z-methoxyimino) acetamido] -3 - ([(2,5-dihydro-6-hydroxy) 2-methyl-5-oxo-az-triazin-3-yl] thio] -methyl) -8-oxo-5-thia-1-azabicyclo [4.2.0] -10-oct-2-en-2-carboxylic acid.

15.3 g (6R, 7R) -7- (2- [2- (2-chloroacetamido) -4-thiazolyl] -2- (Z-methoxy-imino) acetamido) -3 - ([(2.5 dihydro-6-hydroxy-2-methyl-5-oxo-as-tri-azin-3-yl) thio] methyl) -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene -2-Carboxylic acid (Fraction I, see above) is suspended together with 5 g of thiourea in 150 ml of water. Under good nitrogen gasification and stirring, the pH is adjusted to 6.8-7.0 with saturated sodium bicarbonate solution to form an orange solution. Using autotitrates, the pH of the reaction solution is kept constant at 6.8 for 6 hours with the addition of sodium hydrogen carbonate solution. Then an additional 2.5 g of thiourea is added and the solution is stirred for an additional 3 hours while maintaining the pH of 6.8 with the addition of saturated sodium bicarbonate solution.

The red solution is then stored in the refrigerator overnight, thereby darkening. The pH of this solution is adjusted to 2.0-2.5 by the addition of 100% formic acid, whereby the substance precipitates.

This is isolated by suction filtration and washed with 100 ml of 10% formic acid solution. The mother liquor is discarded. The brownish suction filtration product is suspended in 200 ml of water and the pH is adjusted to 7 with triethylamine to form a brown solution. This solution 30 is stirred with 2 g of activated charcoal for 30 minutes, the charcoal is filtered off and the still brown filtrate is adjusted with vigorous stirring to pH 3.5 with 100% formic acid. The thus precipitated substance is isolated by suction filtration, washed with 50 ml of 10% formic acid solution and discarded. The dark yellow filtrate is adjusted to pH 2-2.5 with 100% formic acid, whereby the substance precipitates. This is isolated by suction filtration, washed with ice water and dried. The cephalosporic acid obtained is suspended for conversion to the disodium salt in a mixture of 40 ml of acetone and 40 ml of water and 20 ml of a 2-N solution of 2-ethyl-capric acid sodium salt in ethyl acetate is added. To the orange solution thus formed is added 50 ml of acetone, which precipitates a brown resin which is separated by filtration. The yellow filtrate is stirred for 10 minutes to crystallize the disodium salt. To the mixture is added 50 ml of acetone in portions and the mixture is stored in the refrigerator overnight. The crystallate is isolated by suction filtration, washed with an acetone-water mixture in the ratio of 85:15, pure acetone and low-boiling petroleum ether in the order indicated and dried overnight in vacuo at 40 ° C. The title compound is obtained in the form of beige crystals, = -144 ° (c = 0.5 in water). Nuclear resonance spectrum and microanalysis correspond to the structure indicated.

NMR Spectrum (D 2 O): δ (ppm) = ca. 3.58 (2-01 +) (AB-q, 2), 3.62 (NCH3) (s, 3), 3.98 (OCH3) (s, 3,4,22) (3-CH2) ( AB-q, 2), 5.20 (H-6) (d, 1) 5.77 (H-7), 6.99 (thiazole-H) (s, 1).

Microanalysis:

Calculated for C C ^H ^ gNNOyS3Na2.3.5H₂O: C 32.68 H 3.50 N 16.94 S 14.54 F₂O 9.53 Found: C 32.89 H 3.46 N 16.96 S 14 , 54 F ^ O 9.50 25 Calculated mole weight: 661.59.

Preparation of methylene- (6R, 7R) -7- [2- (2-amino-4-thiazolyl) -2- (Z-methoxy-amino) acetamido] -3 - [[[2,5-dihydro-2- methyl 5-oxo-6 - [(pivaloyl-oxy) methoxy3-as-triazin-3-yl] thio] methyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2 ene-2-carboxylate pivalate.

1.85 g of the cephalosporin disodium salt prepared in the manner described above is suspended in 50 ml of dimethylformamide and added under nitrogen atmosphere at 0-5 ° C 1.35 g pivaloyloxymethyl iodide. The reaction mixture is stirred for 30 minutes at 0-5 ° C and poured

Claims (3)

150600 then into 500 ml of ethyl acetate. The mixture is washed 3 times with water, 2 times with 5% sodium bicarbonate solution and then again with water. The solution is dried over sodium sulfate and evaporated vigorously in vacuo at 35 ° C. After the addition of ether, the title compound is precipitated in amorphous form. This compound is isolated by suction filtration, washed with ether and low-boiling petroleum ether and dried overnight in high vacuum at 25 ° C. The title compound is obtained in the form of a beige amorphous powder. Nuclear resonance spectrum and microanalysis are in accordance with the structure indicated. NMR Spectrum (DMSO-d 6): δ (ppm) = 1.17 (2x (CH2 CO-) (s, 18), about 3.6 (2-CH2) (AB , 64 (NCH 3) (s, 3), 3.83 (OC 2) (s, 3), 4.28 (3-CH 2) (AB , 1), about 5.8 (H-7) (q, 1), about 5.9 (2x-O-CH 2 -O-) (m, 4), 6.75 (thiazolyl-H) ( s, 1), 7.17, (NH 2) (b, 2), 9.70 (NH) (d, 1) Microanalysis: Calculated for C 31 Found: C 45.82 H 4.90 N 14.13 Calculated mole weight: 782.86. 20 PATENT REQUIREMENTS 1. Cephalosporin derivatives, characterized in that they have the general formula II Η H I Ϊ g ch3on = c— CO