FI67084B - DETERMINATION OF THERAPEUTIC ACID THERAPEUTIC CEFALOSPORINER ANVAENDBARA 7- (2- (2- (SKYDDAD-AMINO) -4-THIAZOLYL) -2-METHOXIMINOACETAMIDO) - Google Patents

Description

67084

7- / 2- (2- (Protected-amino) -4-thiazolyl) -2-methoxyiminoacetamido / cephalosporin derivatives useful in the preparation of therapeutically valuable cephalosporins 5 Divided by application 791703

The invention relates to novel 7- / 3- (2- (protected-amino) -

4-Thiazolyl) -2-methoxyiminoacetamide-cephalosporin derivatives of the formula 10 H H

CH3ON "C— CONH- ^ 11 fA 0J — N Y ^ CHr" x

15 RHN 2 S / COOH

wherein X is a 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl group or a corresponding tautomeric group 2,5-dihydro-6-hydroxy-2-methyl-5 -oxo-as-triazin-3-20 yl group, R is a cleavable protecting group and the carboxy group may be in protected form as a syn isomer, or as a mixture in which the syn isomer predominates.

The cephalosporin derivatives of formula II are valuable intermediates in the preparation of pharmacologically active cephalosporins. By cleaving off the protecting group R from the compound of formula II and, if desired, also the carboxy protecting group which may be present, the compound of formula II can be converted into a pharmacologically valuable cephalosporin compound of formula

H H

CH3QN = C-CONH-i_j ^ S \ ^ H2N S ^ COOR1 f 67084 wherein X1 is 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl or 2,5-dihydro-6-R-O-O-2-methyl-5-oxo-as-triazin-3-yl group and R1 is hydrogen or a readily hydrolysable ester or ether group, as a syn-isomer or a mixture, wherein the syn-isomer predominates, and salts of these compounds or hydrates of compounds of formula I wherein R 1 is hydrogen or hydrates of salts of compounds of formula I.

By readily hydrolysable esters of the compounds of the formula I are meant those compounds of the formula I in which the carboxy group is present as a readily hydrolysable ester group. Examples of such esters which may be conventional are lower alkanoyloxyalkyl esters, e.g. acetoxymethyl, pivaloyl-oxymethyl, 1-acetoxyethyl and 1-pivaloyloxyethyl esters; lower alkoxycarbonyloxyalkyl esters, e.g. methoxycarbonyloxymethyl, 1-ethoxycarbonyloxyethyl and 1-isopropoxycarbonyloxyethyl esters; lactonyl esters, e.g. phthalidyl and thiophthalidyl esters; lower alkoxymethyl esters, e.g. methoxymethyl ester; and lower alkanoylaminomethyl esters, e.g. acetamidomethyl ester. Other esters, e.g. benzyl and cyanomethyl esters, may also be useful.

By readily hydrolysable ethers of the compounds of the formula I are meant those compounds of the formula I in which X represents a 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl group whose enol OH- the group is in the form of an easily hydrolyzable ether group. Suitable ether groups are those already mentioned above for easily hydrolyzable ester groups. Representative of such ethers are thus, for example, lower alkanoyloxyalkyl ethers, e.g. acetoxymethyl, pivaloyloxymethyl, 1-acetoxyethyl and 1-p-valoyloxyethyl ethers; lower alkoxycarbonyloxy-35 alkyl ethers, e.g. methoxycarbonyloxymethyl, 1-ethoxycarbonyloxyethyl and 1-isopropoxycarbonyloxyethyl ethers; lactonyl ethers, e.g. phthalidyl and 67084 thiophthalidyl ether; lower alkoxymethyl ethers, e.g. methoxymethyl ethers; and lower alkanoylaminomethyl ethers, e.g. acetamidomethyl ether.

Examples of salts of the compounds of formula I include alkali metal salts such as sodium and potassium; ammonium salt; alkaline earth metal salts such as calcium salt; salts with organic bases, such as salts with amines, e.g. salts with N-ethylpiperidine, procaine, dibenzylamine, N, N'-dibenzylethylethylenediamine, alkylamines or dialkylamines, and salts with amino acids, e.g. salts with arginine or lysine with. The salts can be mono-salts or also di-salts. Another salt formation may occur in compounds with a hydroxy residue of 2,5-dihydro-6-hydroxy-2-methyl-5-oxa-triazin-3-yl.

The compounds of the formula I likewise form addition salts with organic or inorganic acids. Examples of such salts include hydrohalides, e.g. hydrochlorides, hydrobromides, hydroiodides, and other mineral acid salts such as sulfates, nitrates, phosphates and the like, alkyl and monoaryl sulfonates such as ethanesulfonates and other titanium sulfonates, toluenesulfonates, acid phenols such as acetates, tartrates, maleates, citrates, benzoates, salicylates, ascorbates and the like.

The compounds of formula I (including their salts, readily hydrolysable esters and ethers) may be hydrated. Hydration can occur during the manufacturing process or gradually as a result of the hygroscopic properties of the nearly anhydrous product.

The products of the invention may exist in syn-isomeric form, NrC-CONH- (AT i-RHN \ och3 4 67084 or in anti-isomeric form, N t -C CONH- \ 5 / n RHN ^ / ch3o, or mixtures of both. a syn-isomeric form or mixtures in which the syn-isomeric form predominates is considered.

Preferred end products of formula I are: (6R, 7R) -1- [2- (2-amino-4-thiazolyl) -2- (Z-methoxyimino) acetamide] -3- (2,5-dihydro- 6-hydroxy-2-methyl-5-oxo-az-15-triazin-3-yl) thiomethyl-e-oxo-5-thia-1-azabicyclo [4. 2.07-Oct-2-ene-2-carboxylic acid and its salts and corresponding hydrates.

The preferred intermediate is: (6R, 7R) -Ί- [2-Cl- (2-chloroacetarido) -4-thiazolyl] -2- (Z-20-methoxyimino) acetamido7-2- [1S, 5-dihydro -6-Hydroxy-2-methyl-5-oxo-as-triazin-3-yl) -thiomethyl-7,8-oxo-5-thia-1-aza-bicyclo [4.2.07] oct-2-ene-2-carboxylic acid.

The cephalosporin compounds of formula I and their esters / ethers, salts and hydrates are prepared in such a way that a) a compound of formula

H H

CH30N-C CONH-4-Y

30 I I II

J ~ \

RHIT ^ S ^ COOH

Wherein X is as defined above, the protecting group R and, if desired, also the carboxy protecting group optionally present are cleaved, or b) to prepare a readily hydrolysable ester or ether of a compound of formula I, the compound I is esterified or etherified or

c) for the preparation of salts or hydrates of a compound of formula I or hydrates of salts of compound I

converted to a salt or hydrate or a salt hydrate.

The carboxy group present in the compound of formula II may be protected, e.g. esterified to a readily cleavable ester such as silyl ester, trimethylsilyl silyl ester. The easily hydrolysable esters described above are also possible. The carboxy group can be protected by salt formation with an inorganic or tertiary organic base such as triethylamine. Possible R-protecting groups are, for example, acid-hydrolytically cleavable protecting groups, such as, for example, t-butoxycarbonyl or trityl, or also base-hydrolytically cleavable protecting groups, such as, for example, trifluoroacetyl. Preferred R protecting groups are chloro, bromo and iodoacetyl, especially chloro-acetyl. The latter protecting groups can be cleaved by treatment with thiourea.

Compounds of formula II may be prepared, for example, by N-acylation of the corresponding 7-amino compound, namely by administering a compound of general formula

H H

h2n--

-I J_CH2-S-X III

0 I

30 1

COOH

wherein X is as defined above and the carboxy group and / or amino group may be in protected form, reacting with an acid of general formula 35, i! i 6 67084

CH ON = C COOH

, / ΓΛ 5 RHN "'Nk"' wherein R is as defined above, or with a reactive derivative of this acid, and any carboxy protecting group present is cleaved off in certain cases.

The carboxy group present in the 7-amino compound of formula III may be protected, namely in the manner clarified for the compound of formula II to be prepared above. The amino group of the compound of formula III may be protected, e.g., by a silyl protecting group such as tri-methylsilyl.

Suitable reactive derivatives of the acids of the formula IV are, for example, halides, i.e. chloride, bromide and fluoride; azides; anhydrides, especially mixed anhydrides with stronger acids; reactive esters, e.g. N-hydroxysuccinimide esters, and amides, e.g. imidazolides.

The reaction of a 7-amino compound of the formula III with an acid of the formula IV or a reactive functional derivative thereof can be carried out in a manner known per se. Thus, for example, an acid of formula IV may be condensed with one of said esters of formula III with carbodiimide, dicyclohexylcarbodiimide in an inert solvent such as acetic acid ester, acetonitrile, dioxane, chloroform, dimethylformamide and methylene chloride, benzene, benzene the ester group can be cleaved off. Instead of carbodiimides, oxazolium salts, e.g. N-ethyl-5-phenylisoxazolium 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 such as a triethylammonium salt, is reacted with a reactive functional derivative of an acid of formula IV 67084 as mentioned above in an inert solvent, e.g. in one of the above solvents.

In another embodiment, an acid halide genide, preferably an acid chloride of formula IV, is reacted with an amine of formula III. The reaction preferably takes place in the presence of an acid scavenger, e.g. in the presence of an aqueous alkali, preferably sodium hydroxide, or also in the presence of an alkali metal carbonate, such as potassium carbonate, or a lower alkylated amine, such as triethylamine. The solvent used is preferably water, optionally in admixture with an inert organic solvent such as tetrahydrofuran or dioxane. It is also possible to work in an aprotic organic solvent, such as, for example, dimethylformamide, dimethylsulfoxide or hexamethylphosphoric triamide. When using silylated starting compounds of formula III, the work is carried out in an anhydrous medium.

The reaction of a 7-amino compound of formula III with an acid of formula IV or a reactive functional derivative thereof may conveniently take place at a temperature between about -40 ° C and room temperature, e.g. at about 0-10 ° C.

According to embodiment a) above, the amino protecting group R is cleaved off from the starting material of the formula II. The protecting groups which can be cleaved by acid hydrolysis are preferably removed by means of lower alkanecarboxylic acids, which carboxylic acids can be halogenated. In particular, formic acid and trifluoro-30-acetic acid are used. The temperature is generally room temperature, although a slightly higher or slightly lower temperature may be used, for example a temperature in the range 0-40 ° C. The alkali-cleavable protecting groups are hydrolyzed with dilute aqueous sodium hydroxide solution at 0-30 ° C. The chloroacetyl and iodoacetyl protecting groups can be cleaved off with thiourea in an acidic, neutral or alkaline medium at about 0-30 ° C. Hydrogenolytic cleavage is not appropriate here (e.g., benzyl cleavage) because hydrogenolysis reduces the oxime function of the amino-5 group.

After the completion of embodiment a), any carboxyl protecting group present in the reaction product can be cleaved off, if desired. If the protecting group is silyl (silyl ester), this loh-10 band can be removed very easily by treating the reaction product with water.

The lower alkanoyloxyalkyl, lower alkoxycarbonyloxyalkyl, lactonyl, lower alkoxymethyl and alkanoylaminomethyl esters are preferably cleaved off enzymatically by a suitable esterase at about 20-40 ° C. If the carboxyl group is protected by salt formation (for example with triethylamine), the removal of this salt-forming protecting group can be performed by treatment with an acid. As the acid, for example, hydrochloric acid, sulfuric acid, phosphoric acid or citric acid can be used.

The carboxyl protecting group can also be removed as described above before removing the protecting group R. To prepare a readily hydrolyzable carboxylic acid ester of formula I according to embodiment b) (-COOR 4 = readily hydrolyzable ester group), the carboxylic acid is preferably reacted with a corresponding ester group-containing halide, preferably iodide. The reaction may be accelerated by a base such as an alkali metal hydroxide or carbonate or by an organic amine such as triethylamine. When X is a 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl group having an enol function, it etherifies to form the corresponding readily hydrolyzable ether.

In this case, an excess of the corresponding halo- 9 67084 genid is preferably used. The esterification / etherification reaction is preferably carried out in an inert organic solvent such as dimethylacetamide, hexamethylphosphoric acid triamide, dimethylsulfoxide or preferably dimethylformamide. The temperature-5 state is preferably about 0-40 ° C.

Salts and hydrates of the compounds of formula I as well as hydrates of the salts can be prepared in a manner known per se, for example by reacting a carboxylic acid of formula I with an equivalent amount of the desired base, suitably in a solvent such as water or an organic solvent such as ethanol, methanol, acetone, etc. equivalent base salt formation also occurs in the tautomeric enol form (2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl group X) to give the salt. The salt formation temperature is not critical. It is usually room temperature, but it can also be slightly higher or slightly lower, about 0-50 ° C.

Hydrates of the carboxylic acid of formula I are usually formed automatically during the manufacturing process due to the initially hygroscopic properties of the anhydrous product. When intentionally preparing a hydrate, the completely or partially anhydrous product may be placed in a humid atmosphere at, for example, about 10-40 ° C.

7-Amino compounds of formula III can be prepared by reacting a compound of formula: H H s

H2 «4 — f N

J-N J — CH, -Y

30 0 ^ 2

COOH

wherein Y is a leaving group to react with a compound of formula

35 HS - X VI

where X is as defined above.

10 67084

Suitable leaving groups in the formula V are, for example, halogen, such as chlorine, bromine or iodine, an acyloxy group, for example alkanoyloxy groups such as acetoxy, lower alkyl or arylsulfonyloxy groups, such as mesyloxy or tosyloxy, or an azido group.

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

The compounds of the formula I and the corresponding easily hydrolysable esters, ethers and salts or hydrates of these products have an antibiotic, in particular bactericidal, effect. They have a broad spectrum of activity, including gram-positive and gram-negative microorganisms, including β-lactamase-forming staphylococci and various β-lactamase-forming gram-negative bacteria such as Pseudomonas aeruginosa, Haemophilus influenzae, Eschrichia coli, Serratia 20 marcescens, Proteus and Klebsiella species.

Example (6R, 7R) -7- [2- (2-Amino-4-thiazolyl) -2- (Z-methoxyiminoacetamide] -3- [2,5-dihydro-6-hydroxy-2- Preparation of methyl 5-oxo-as-triazin-3-yl) thio] methyl-7-25-25 oxo-5-thia-1-azabicyclo [4.2.t] oct-2-ene-2-carboxylic acid disodium salt 15.3 g (6R (7R) -7- [2-Z- (2-chloroacetamido) -4-thiazolyl] -2- (Z-methoxyimino) -acetamide p7-3- [2,5-dihydro-6-hydroxy- 2-Methyl-5-oxo-as-triazin-3-yl) thio-methyl-7,7-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (fraction I, see below) suspended together with 5 g of thiourea in 150 ml of water. Under good nitrogen gasification and with stirring, the pH is adjusted to 6.7-7.0 with saturated sodium bicarbonate solution to give an orange solution. Using an autotitrator, the pH of the reaction solution is kept constant by adding sodium hydrogen carbonate solution 11,67084 at 6.8 for 6 hours. An additional 2.5 g of thiourea is then added and the solution is stirred for a further 3 hours, keeping the pH constant at 6.8 by adding saturated sodium hydrogen carbonate solution. After that-5, the red solution is stored overnight in the refrigerator, making it darker. The pH of this solution is adjusted to 2.0-2.5 by the addition of 100% formic acid, whereupon the substance precipitates. This is filtered off with suction and washed with 100 ml of 10% formic acid. The mother liquor is discarded. The brown cake is suspended in 200 ml of water and the pH is adjusted to 7 with triethylamine to give a brown solution. This solution is mixed with 2 g of activated carbon for 30 min. time, separated from the carbon and the pH of the still brown filtrate is adjusted to 3.5 with 100% formic acid with good stirring. The precipitate is then filtered off with suction, washed with 50 ml of 10% formic acid and discarded. The pH of the dark yellow filtrate is adjusted to 2-2.5 with 100% formic acid, whereupon the substance precipitates. This is filtered off with suction, washed with ice water and dried. The cephalosporinic acid 20 obtained is suspended - for conversion to the disodium salt - into a mixture of 40 ml of acetone and 40 ml of water and 20 ml of a solution of 2-ethylcaproic acid sodium salt in 2-ethyl acetate are added. To the resulting orange solution is added 50 ml of acetone, whereupon brown hart-25 si precipitates, and it is separated by filtration. The yellow filtrate is stirred for 30 min. the time when the disodium salt crystallizes. An additional 50 mL of acetone is added portionwise to the mixture and stored in the refrigerator overnight. The crystals are filtered off with suction, washed successively with acetone-water (85:15), with pure acetone and low-boiling petroleum ether, 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 Magnetic Resonance Spectrum: (D 2 O) δ (ppm): about 3.58 (2-CH 2 Cl 2) (AB-q, 2), δ 3.62 (NCH 3) (s, 3) 3.98 (OCH 3) (s , 3, 4, 22) (3-CH 2) (AB-q, 2), 5.20 (H-6) (d, 1), 5.77 (H-7) (d, 1), 6, 99 (thiazole-H) (s, 1).

67084

Microanalysis (C 18 H 28 N 2 O 2 • S 2 Na 2.3.5 H 2 O) (MG = 661.59) Calculated: C 32.68, H 3.50, N 16.94 S 14.54, H 2 O 9.53% Found: C 32.89, H 3.46, N 16.96 S 14.54, H 2 O 9.50% (6R, 7R) -7- [2- / 2- (2-chloro-5-acetamido) -4 -thiazolyl] -2- (Z-methoxyimino) acetamido-3- (N-) (2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) thio] methyl -6-oxo-5-thia-1-azabicyclo [12.2] oct-2-ene-2-carboxylic acid can be prepared as follows: 22.24 g of 2- (2-chloroacetamido-thiazol-4-yl) - 2- (Z-10 methoxyimino) acetic acid is suspended in 240 ml of methylene chloride. To this suspension is added 13.39 ml of triethylamine to give a pale yellow solution. This solution is cooled to 0-5 ° C and 16.72 g of phosphorus pentachloride are added, stirred for 5 min. at 0-5 ° C and 20 min.

15 without cooling. The yellow solution is evaporated in vacuo at 35 ° C. The evaporation residue is shaken twice with n-heptane and the latter is decanted. The resinous residue is treated with 240 ml of tetrahydrofuran and the insoluble triethylamine hydrochloride is filtered off.

20 The yellow filtrate contains acid chloride.

22 g of (7R, 7R) -7-amino-3-deacetoxy-3- [2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) thio] cephalosporanic acid suspended in a mixture of 300 ml of water and 150 ml of tetrahydrofuran. Under good nitrogen gasification, 2-N sodium hydroxide solution is added dropwise to the suspension using an autotitrator until a brown-red solution with a pH of 8 is formed. This is cooled to 0-5 ° C and 15 min. a solution of the acid chloride in tetrahydrofuran prepared above is added dropwise. It is then stirred 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. Practically the tetrahydrofuran is removed from the black solution in vacuo at 40 ° C. Now add 100 ml of 2N sulfuric acid. In this case, the precipitated substance is filtered off with suction, washed with water and filtered well. Dissolve the moist brown filter cake in 1.5 liters of acetone. The dark solution is filtered through a small amount of dark insoluble material through Hyflo, carbon is added, stirred for 30 minutes, and filtered again through Hyflo. The orange-red filtrate is dried over sodium sulfate, concentrated in vacuo and evaporated with acetic acid ester. This precipitates a black resin which is filtered and discarded. The 2-phase filtrate, still containing water, is azeotroped three times with benzene under vacuum at 40 ° C. The precipitate is then filtered off with suction and dried in vacuo at 40 ° C. The latter is mixed twice with 1 liter of acetone each time, leaving 10 brown resins which are discarded. The combined orange acetone extracts are concentrated in vacuo at 40 ° C to about 150 ml, whereupon the brown resin is filtered off and discarded. To the filtrate is added 1 liter of acetic acid ester and concentrated in vacuo at 40 ° C. The precipitated substance is then filtered off with suction, washed with ethyl acetate and then with ether (_ (6R, 7R) -7- [2-Tj-2- (2-chloroacetamido) -4-thiazol-yl] -2- (Z-methoxyimino)). acetamido-3- [7- (2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) n-methyl-7-8-oxo-5-thia-1 -azabicyclo / 3.2.07 oct-2-ene carboxylic acid, fraction I: beige amorphous acid 7. This fraction I can be used directly to prepare the desired final product.

The acetic acid ester solution is concentrated vigorously in vacuo at 40 ° C, diluted with ether and the precipitate is filtered off with suction Z36R, 7R) -1- [2- [2- (2-chloroacetamido) -4-thiazolyl] -2- (Z-methoxyimino) acetamido7 -3- [72,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) thio] methyl] -8-oxo-5-thia-1-azabicyclo74 .2.07oct-2-ene-2-carboxylic acid, fraction II; light beige amor-30 physical acid, slightly purer by thin layer chromatography than fraction I? ·

To prepare the disodium salt, 3.5 g of acid (fraction II) are dissolved in a mixture of 20 ml of acetone and II ml of water. To the solution is added 7 ml of a 2-n solution of sodium 2-ethylcaproic acid in acetic acid ester, whereupon the disodium salt crystallizes. 25 ml of acetone are now added portionwise and the mixture is kept in the freezer for 2 hours. The crystals are then filtered off with suction, washed successively with 25 ml of ice-cold acetone-water (80:20), with pure acetone and low-boiling petroleum ether and dried overnight under high vacuum at 40 ° C. There is obtained (6R, 7R) -7- [2- [2- (2-chloroacetamido) -4-thiazolyl] -2- (2-methoxyimino) acetamido] -3- [7- (2-dihydro-6- hydroxy-2-methyl-5-oxo-as-triazin-3-yl) thidylmethyl-S-oxo-S-thia-1-azabicyclo [2.0.0] oct-2-ene-2-carboxylic acid disodium-10 salt as pale yellow crystals. l & Öq = “142.7 ° (c = 1 in water).

NMR spectrum (D 2 O) δ (ppm): about 3.6 (2-CH 2), 3.63 (NCH-j), 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).

Claims (2)

1. Intermediates for use in the preparation of therapeutically valuable cephalosporin derivatives of the general formula I I i Sv CH3ON = C — CONH —- S '\ τ Wherein X1 is 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-astriazin-3-yl. a yl group or a 2,5-dihydro-6-R10-2-methyl-5-oxo-as-triazin-3-yl group and R1 is a hydrogen atom or -COOR4, respectively, R2- is a readily hydrolysable ester or ether group, as a synisomer or a mixture , in which the 20 syn-isomer predominates, and in the preparation of salts of these compounds or hydrates of compounds of formula I in which R 1 is hydrogen, or hydrates of salts of compounds of formula I, characterized in that they are 7- / 2- (2 - (protected-amino) -4-25-thiazolyl) -2-methoxyiminoacetamide-7-cephalosporin derivatives of the general formula II 30. SS ch3on = c-CONH-lf X. II 11 $ \ 2 RHN ^ ^ XS ^ COOH 35 67084 if 9a X is 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-α- a triazin-3-yl group or a 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl group, R is a cleavable protecting group and the carboxy group may be in a protected form, wherein the compound of formula II the compounds are in the form of a syn isomer or a mixture in which the syn isomer predominates. Cephalosporin derivative according to Claim 1, characterized in that it is (6R, 7R) -10 1- [2- [2- (2-chloroacetamido) -4-thiazolyl] -2- (Z-methoxyimino) acetamido] -3- // 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) -tio7metyyli7 "8-oxo-5-thia-l-aza-bicyclo / 4.2, Q7okt -2-ene-2-carboxylic acid. 67084