FI67385C - PROCEDURE FOR FRAMSTATION OF AV (6R 7R) -7- (2- (2-AMINO-4-THIAZOLYL) -2- (Z-METHOXYIMINO) ACETAMIDO) -3-CEFEM-4-CARBOXYL SYRATER DERIVATIVES - Google Patents

Abstract

For the Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE 1. A process for the manufacture of acyl derivatives of general formula I see diagramm : EP0030294,P12,F1 in which R represents hydrogen or a readily hydrolyzable ester group, as well as of salts of these compounds and hydrates of these compounds or of their salts by reating a halide of general formula II see diagramm : EP0030294,P12,F2 in which R has the significance given above and Y represents a halogen atom, or a salt of this compound with thiourea and, if desired, converting a compound of formula I obtained into a salt or hydrate or into a hydrate of this salt, characterized in that X signifies one of the groups see diagramm : EP0030294,P13,F3 in which R' represents hydrogen or a readily hydrolysable ether group.

Description

ΚΞ5 ^ * 1 Γ * 1 μ «\ ANNOUNCEMENT

VBj W ^ utläccnincssicrift 673 8 5 ^ (51) K * jii / tata.3 C 07 D 501/36 FINLAND — FINLAND pi) ν »·» * «- ν« -ιιλ, 793768 (Π) HakimhpSht — AiwBkjMngtdu 30.11. 79 '' (23) ANcuptM — GHdglMCtdaf 30.11.79 (41) TttMut (alklMksI —Blhrlt offmtNg 22.05.81

Patent and Registration Board

****** * «* retiatenkynlMii i0 '" M

(32) (33) (31) Pjr »4 *** jr Miwikwi — B ^« rd prior * · * 21.11.79

Switzerland-Schweiz (CH) 10384/79 Proven-Styrkt (71) F. Hoffmann-La Roche & Co. Aktiengesel1schaft, Grenzacherstrasse 12 ^ -184, Basel, Switzerland-Switzerland (CH) (72) Marc Montavon, Basel, Roland Reiner, Basel, Switzerland-Switzerland (CH) (7¾) Oy Kolster Ab (5¾) Method (6R, 7R) For the preparation of -7- [2- (2-amino-4-thiazolyl) -2- (2-methoxyimino) acetamido] -3-cephem-4-carboxylic acid derivatives -Furfarande för f rams full lning av ( 6R, 7R) -7- [2- (2-Amino-4-thiazolyl) -2- (Z-methoxyimino) acetamido] -7-cephem-4-carboxy] syrader

The invention relates to a process for the preparation of (6R, 7R) -7- [2- (2-amino-4-thiazolyl) -2- (z-methoxyimino) acetamido] -3-cephem-4-carboxylic acid derivatives of the formula I

H0N

N h h 1 T T s M _r-CONH ä_i / '\

Il I

N A-N J CH - S-X

\ rr 1 och3

COOR

wherein X is a group (a) or (b) 67385

B

H-C 2 -NO

J H C N OR

| 3 '"ν'" S /

^ N - ^% 0 __ I

(a) (b) R is a hydrogen atom or a readily hydrolyzable ester or ether group and the group = N-OCH 3 is in syn form, and for the preparation of salts of these compounds and hydrates of these compounds or hydrates of the salts.

When R in group (b) is hydrogen, this group is in tautomeric equilibrium with group (a).

The readily hydrolysable ester groups R of the compounds of the formula I mean the R groups in the carboxyl function which are in the form of a readily hydrolysable ester group. Examples of common ester groups are lower alkanoyloxyalkyl, e.g. acetoxymethyl, pivaloyloxymethyl, 1-acetoxyethyl and 1-pivaloyloxyethyl, lower alkoxycarbonyloxyalkyl, e.g. methoxycarbonyloxymethyl, 1-ethoxycarbonyloxyethyl and 1-ethoxycarbonyloxyethyl and e.g. phthalidyl and thiophthalidyl, lower alkoxymethyl, e.g. methoxymethyl, and lower alkanoylaminomethyl, e.g. acetamidomethyl.

The readily hydrolysable ether groups R of the compounds of the formula I mean the R groups in the enol function of the (b) 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-a-triazin-3-yl group, which are the easily hydrolysable ether groups. in terms of. Suitable ether groups are those already mentioned above in connection with easily hydrolyzable ester groups. Representative such ethers are, for example, lower alkanoyloxyalkyl ethers, e.g. acetoxymethyl, pivaloyloxymethyl, 1-acetoxyethyl and 1-pivaloyloxyether, lower alkoxycarbonyloxyalkyloxyethyloxyethyloxyethyloxyethyloxyethyl, 1-ethoxy. , lactonyl ethers, e.g. phthalidyl and thio-phthalidyl ether, lower alkoxymethyl ethers, e.g. methoxymethyl ether, and lower alkanoylaminomethyl ethers, e.g. acetamidomethyl ether.

3 67385

Examples of salts of the compounds of formula I include alkali metal salts such as sodium and potassium salts and alkaline earth metal salts such as calcium salt * salts with organic bases such as salts with amines, e.g. salts of N-ethylpiperidine, procaine, dibenzylamine, N, N ' -dibenzylethyl-ethylenediamine, alkylamines or dialkylamines, as well as salts with amino acids, such as salts with arginine or lysine. The salts can be mono-salts or also di-salts. A second salt of the compounds may be formed with the hydroxy residue of the 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl group.

The compounds of formula I also form addition salts with organic or inorganic acids. Examples of such salts are hydrohalides, for example hydrochlorides, hydrobromides, hydroiodides, as well as other salts of inorganic acids such as sulphates, nitrates, phosphates and the like, alkyl and monoaryl sulphonates such as ethanesulphonates and sulphonates, toluenesulphonates, toluenes salts, and other organic acid salts 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) can be hydrated. Hydration may occur during the manufacturing process or may occur gradually as a result of the initially hygroscopic properties of the anhydrous product.

The products according to the invention are in the form of the syn-isomer (Z-form) N-r-C-CCNH- \ OCH3 67385

Preferred products are (6R, 7R) -7- [2- (2-amino-4-thiazolyl) -2- (Z-methoxyimino) acetamido] -3-5-dihydro-6-hydroxy-2-methyl -5-Oxo-as-triazin-3-yl) thio-methyl '- 8-oxo-5-thia-1-azabicyclo [4.2.07] oct-2-ene-2-carboxylic acid and its salts and corresponding hydrates.

The invention is characterized in that the halide of formula II

H H

Ξ IS

YCH - CO-OCONH --- Y '\

2 II I 1 II

N J-N A— CH -S-X

\ 0 2 OCH- |

COOR

wherein X and R are as defined above, Y is a halogen atom and the group sN-OCH 2 is in syn form, or a salt of compound II is reacted with a thiourea, and that the compound of formula I obtained is optionally converted into a salt of this compound or a hydrate of this compound or a hydrate of the salt of the compound.

The halide of the formula II used according to the invention can be prepared, for example, by reacting a primary amine of the general formula 67385 5 H H f:

H2N III

-Nxx ^ i - CH 2 - S - X

COC R

wherein X and R are as defined above, reacting a halogenated carboxylic acid having the general formula

Choo = C-COOH

C/O

I IV

CH2V

wherein Y is a halogen atom, or with a reactive derivative of this compound. The halogenated carboxylic acid of formula IV is used either in free form with a condensing agent, e.g.

In the presence of an N, N'-disubstituted carbodiimide such as N, N'-dicyclohexylcarbodiimide or an azolide compound such as Ν, Ν'-carbonyldiimidazole or N, N'-thionyldiimidazole or also in the form of an acid halide, such as acid chloride or bromide, in the form of an acid anhydride, such as in the form of an acid anhydride, formed with a carbonic acid monoester, e.g. monomethyl or monoisopropyl carbonate, or an activated ester, such as p-nitrophenyl ester, 2,4- in the form of dinitrophenyl ester, N-hydroxysuccinimide ester or N-hydroxyphthalimide ester. The reaction generally takes place in a neutral organic solvent, e.g. a halogenated hydrocarbon such as chloroform, dichloromethane, tetrachloromethane, ether, e.g. tetrahydrofuran, dioxane, dimethylformamide, diraethylacetamide, water or mixtures thereof. The reaction temperature is preferably between about -50 and + 40 ° C, most preferably between -10 and + 10 ° C.

67385

The halide of formula II used according to the invention can also be prepared by halogenating a compound of general formula

H H

CH3ON = C — CONH-- co

I ö T

ch3 I v

COOR

where R is as defined above. The starting material of formula V used in this case can in turn be prepared by reacting a primary amine of formula III as defined above with 3-oxo-2-methoxyiminobutyric acid or a reactive derivative of this compound. This reaction proceeds in substantially the same manner as the acylation of the primary amine described above with the halogenated carboxyl pole of formula IV or a reactive derivative thereof. Halogenation of the resulting acylation product of formula V results in the formation of halides of formula II as defined above and is preferably by treatment with the corresponding halogen or thionyl halide, e.g. chlorine, bromine or sulfuryl chloride, preferably in a neutral solvent such as halogenated hydrocarbon, e.g. in dichloroethylene, tetrachloromethane, or in a low molecular weight alkanecarboxylic acid such as acetic acid, in an aromatic solvent such as benzene or toluene. The reaction temperature is generally about 0 to 60 ° C.

7 67385

The reaction of a halide of formula II or a salt thereof according to the invention with a thiourea preferably takes place in a neutral solvent such as a lower alkanol, e.g. ethanol, a low ketone such as acetone, an ether such as tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, in mixtures. The reaction temperature is generally about 0 to 60 ° C, preferably room temperature. As the halide of the formula II, chloride, bromide, fluoride or iodide can be used, mainly chloride or bromide. The free acid of the formula II can be used, but alternatively its salt, in which case the same salts as the salts of the compounds of the formula I described above can be used.

Salts and hydrates of the compounds of formula I or hydrates of these salts can be prepared in a known manner, e.g. by reacting a carboxylic acid of formula I with an equivalent amount of the desired base, preferably in a solvent such as water or an organic solvent such as ethanol, methanol, acetone and other solvents. When a second equivalent of base is used, salt formation occurs with the tautomeric enol form (2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl group X) that may be present to give the di-salt. When forming a salt, temperature is not critical. It is usually room temperature but can still be slightly higher or lower, approx. 0-50 ° C.

Hydrates are usually prepared automatically during the manufacturing process or initially as a result of the hygroscopic properties of the anhydrous product. To prepare the hydrate, the intentionally completely or partially anhydrous product (carboxylic acid of formula I or an ester, ether or salt thereof) may be maintained in a humid atmosphere at a temperature of, for example, about 10-40 ° C.

67385

The compounds of the formula I, as well as the corresponding salts or hydrates of these products, have an antibiotic, antibacterial effect. They have a broad spectrum of activity against gram-negative microorganisms, including β-lactamase-forming staphylococci and various β-lactamase-forming gram-negative bacteria such as, for example, Pseudomonas aeruginosa, Haemophilus influenzae, Escherichia coli, Serratia marcescens, and Klebsiella species.

The compounds of the formula I as well as the corresponding easily hydrolysable esters, ethers and salts or hydrates of these products can be used for the treatment and prevention of infectious diseases. For adults, a suitable daily dose is from about 0.1 to about 2 g. Parenteral administration of the compounds of the invention is particularly preferred.

To demonstrate the antimicrobial activity of said products, the in vitro activity (minimum inhibitory concentration in μg / ml) was determined for the compound (6R, 7R) -7- [2- (2-amino-4-thiazolyl) -2- (Z-methoxy- ) 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 (hereinafter referred to as A), as a representative of the process products obtained according to the invention. The results are summarized in the following table: 67385

Test organisms A

Haemophilus influenzae Strain 1 0.08

Stock 2 0.005

Stock 3 0.005

Stock 4 0.005

Stock 5 0.0025

Stock 6 0.0025

Stock 7 0.0025

Klebsiella pneumoniae 1,2

Escherichia coli Strain 1 0.02

Stock 2 0.6

Proteus mirabilis Strain 1 <0.01

Stock 2 ¢ 0.01

Proteus vulgaris <0.01

Proteus rettgeri <0.01

Staphylococcus aureus Strain ATCC 6538 2.5

Penicillin resistance strain 2.5

Pseudomonas aeruginosa Strain 1 0.3

Stock 2 10

Stock 3 2.5

Stock 4 5

Stock 5 5

Position 6 10

Stock 7 5

Serratia marcescens 0.08

The antibacterial effect in vivo was determined as follows: Groups of five mice are infected intraperitoneally subcutaneously as physiological saline three times, i. one hour, 2 1/2 hours, and four hours after infection. On the fourth day, the number of surviving animals is determined. Different dosages are used for application, and interpolation determines the dose at which 50% of the experimental animals are alive (CD1, mg / kg).

10 67385

Tested substance

CD50, mg / kg 0.005

Toxicity

Tested substance

LD50 q, mg / kg i.v. 250-500 s.c. 4,000 p.o. 5,000

The formulations according to the invention may have use as medicaments, e.g. as pharmaceutical preparations containing them or their salts in admixture with pharmaceutical, organic or inorganic neutral carriers suitable for enteral or parenteral administration, e.g. water, gelatin, acacia, lactose, starch, magnesium stearate , with vegetable oils, polyalkylene glycols, petrolatum, etc. The pharmaceutical preparations may be in solid form, e.g. tablets, dragees, suppositories, capsules; or in liquid form, e.g. as solutions, suspensions or emulsions. In this case, they are sterilized and / or contain adjuvants, such as preservatives, stabilizers, wetting or emulsifiers, salts for varying the osmotic pressure, analgesics or buffers. In addition, they may contain other therapeutically valuable substances. The compounds of the formula I and their salts or hydrates are mainly for parenteral administration and, for this purpose, they are mainly used to prepare lyophilisates for dilution with customary substances, such as water or isotonic saline. The readily hydrolysable esters or ethers of the compounds of the formula I and their salts or hydrates are also suitable as enterally administrable substances.

11 67385

Pharmacological comparative tests

Compound A = the final product of Example 1 prepared according to the invention.

Compound Z = carboxylic acid monosodium salt known from FI application 783846 and Example 151 of FI application 780966.

The in vitro antimicrobial activity of Compound A against the microorganism Pseudomonas aeruginosa was compared with that of Compound Z. 17 different strains of this human pathogenic species were studied. The results are shown in the following table as minimum inhibitory concentration (MIC) in μg / ml.

Pseudomonas Compound A Compound Z

aeruginosa (new) (known) strain No 1 80> 80 2 10 80 3 5 40 4 10 80 5 5 40 6 2,5 20 7 1,2 10 8 5 20 9 20 80 10 1,2 20 11 1 , 2 5 12 10 80 13 10 80 14 10 80 15 2,5 5 16 20> 80 17 20 80 12 67385

The results show that the compound A prepared according to the invention is generally more active against Pseudomonas aeruginosa than the closely related known compound Z, with in most cases an advantage of 8 times or more.

From this, it can be concluded that Compound A is significantly more effective than Compound Z in the treatment of infections caused by Pseudomonas aerugi-nosa.

The effects of compounds A and Z on plasma elimination half-life were compared to provide information on the relative time that the antibiotic remains in the circulation. Rats (intravenous administration) and rabbits (intramuscular administration) were used as experimental animals.

a) Rotat

Male rats weighing 200 g were administered test substance in physiological saline into the tail blood vessel. The dose was 200 mg / kg calculated as free acid. After a specified time, 2 rats for each antibiotic were sacrificed and blood was drawn from the heart by puncturing. The blood of the two rats was pooled and placed in a tube containing potassium oxalate, the plasma fraction was separated and kept deep-frozen until microbiological analysis was performed.

b) Rabbits

The test substance was administered to male rabbits by intramuscular injection into the hind leg. Blood samples were taken from the peripheral vein of the ear, first immediately before injection and then at specified intervals after injection. Plasma was prepared and stored as described for rat experiments.

(c) Biological research

Antibiotic concentrations in plasma samples were determined by agar assay using Bacillus subtilis strain ATCC-6622 as the test organism. Standards for test compounds were prepared from pure plasma of rat and rabbit and unknown concentrations were read from the corresponding standard curve. The approximate plasma elimination half-lives were determined graphically from a plot of time as a function of the logarithm of the concentration and represent the time required to halve the concentration of the test compound in plasma after the semi-logarithmic time / concentration curve has reached linearity. Linearity is reached immediately after intravenous drug administration (rats), allowing the entire curve to be used for half-life determinations. Following intramuscular drug administration (rabbits), the plasma mirror requires 1 1/2 hours to reach equilibrium, so that only the portion of the curve that is 1 1/2 hours ahead can be used for half-life determinations.

The results are shown in the following tables.

a) rat, 20 mg / kg i.v.

Plasma concentration,

Time kg / ml

Compound A Compound Z

i> T 10 min 80 25 ΎAll of these 20 64 9.8 usable 30 54 2.65 plasma 45 41 1.2 elimination half 1 h 28 1.0 dwell time li 16 <1.0 as determined 2 \ 5.3 0.0 4 <2.0 0.0

Approximate plasma elimination half-life 35 10, min.

14 67385 b) rabbits, 20 mg / kg i.m.

Plasma concentration,

Time _mg / ml___

Compound A Compound Z

___ 10 min 10 13.5 20 27 16 30 32 15 45 36 13.5 1 h 32 12 w 1 $ 32 8.0 w Plasma elimination half-life * 14.5 1.0 can be define _ n j. only b b '' of these values

Approximate plasma elimination half-life 110 50, min.

15 67385

The tables show that the new compound A remains in the circulation for a significantly longer time than the known compound Z in its close structure and is expected to have a higher antibiotic activity than the compound Z. In addition, a significantly lower amount of compound A than compound Z is needed to control the corresponding in vivo infection. When Compound A is used, longer times may be allowed between administrations than when Compound Z is used to maintain a certain concentration of the active ingredient in the plasma.

Example 1 28.8 g of (6R, 7R) -7- {4-bromo-2- [S (Z) -methoxyimino] acetoacetamide) -3 - [[(2,5-dihydro-6- hydroxy-2-methyl-5-oxo-as-triazin-3-yl) thiomethyl-3-8-oxo-5-thia-1-azabicyclo [4.2.0] octa-2-ene-2-carboxylic acid is dissolved To 400 ml of absolute ethanol, 7.6 g of thiourea are added to the solution, after stirring for 15-20 minutes at 25 [deg.] C., the reaction product begins to crystallize as an hydrobromide from the orange solution. ml of alcohol and 200 ml of low boiling petroleum ether and dried under high vacuum at 35-40 ° C overnight to give 22 g of practically colorless hydrobromide, which is dissolved together with 15.7 g of sodium acetate titrate. to a mixture of 110 ml of water and 110 ml of acetone, 140 ml of acetone are added to this solution until the solution is slightly cloudy, shortly after which the reaction product begins to crystallize. n 30 minutes, after which 180 ml of acetone are added dropwise over the next 30 minutes, whereby crystallization is complete. The reaction product is filtered off, washed successively with 250 ml of 85% aqueous acetone solution, 250 ml of acetone and 250 ml of low-boiling petroleum ether and finally dried in vacuo at 25 ° C. 19.6 g (59.3% of theory) of practically colorless (6R, 7R) -7- [2- (2-amino-4-thiazolyl) -2- (Z-methoxyimino) -acetamide] are obtained. -3- {[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) thio] methyl} -8-oxo-5-thia-1-azabicyclo [4 , 2.07 oct-2-ene-2-carboxylic acid disodium salt, which is recrystallized from 16,678,385 water-acetone mixture. 17.3 g (52.3% of theory) of pure material are obtained, with = -150.8 ° (c = 1 in water). 1 H-NMR spectrum in DMSO-d 2 (<5 values in ppm, s = singlet, d = doublet, q =

O

quartet, b = wide; J = switching constants in Hz; percentage in brackets): 3.47 (N-CH3) (s) (3), 3.49 (2-CH2) (AB-q / centering value; Jgem = 18 Hz) (2), 3.85 C = N'OCH 3, (Z) 7 (s) (3), 4.37 (3-CH 2 "-S) (AB-q / centering value; Jgem = 12.5 Hz) (2), 5.04 (H- 6) (d, JH_6fH_7 = 4.5 Hz) (1), 5.59 (H-7) (q, JH_7> NR = 8 Hz), JH-7 h-6 '= 4.5 Hz) (1 ) 6.75 (thiazolyl-11-O) <s) (1), 7.29 (-NH 2) (b) (2), 9.52 (-CO-NH-) (d, = 8 Hz) (1 ).

The starting compound (6R, 7R) -7- [4-bromo-2 - [(Z) -methoxyimino] acetoacetamido] -3- [N- (2,5-dihydro-6-hydroxy-2-methyl-5- oxo-as-triazin-3-yl) thiomethyl) -8-oxo-5-thia-1-azabicyclo [4.2.07] oct-2-ene-2-carboxylic acid can be prepared as follows: 592.1 g of acetic acid The tert-butyl ester is dissolved in 560 ml of glacial acetic acid. A solution of 290.6 g of sodium nitrite in 655 ml of water is added dropwise to this solution at 5-10 ° C over a period of 2 1/2 hours. The resulting yellow suspension is stirred for 30 minutes at 20 ° C, 940 ml of water are added and the mixture is stirred for a further two hours. 900 ml of water and 900 g of ice are added to the mixture and the mixture is extracted three times with one liter of ethyl acetate in a mixing vessel. the combined ethyl acetate extracts are washed three times with one liter of water, then 5 l of water are added and the pH is adjusted to 6.8 with sodium hydrogen carbonate. After separation of the aqueous phase, it is washed once more with water. The ethyl acetate solution is then dried over sodium sulfate and evaporated to dryness in vacuo at 40 ° C. (Z) -2-Hydroxyimino-3-oxo-butyric acid tert-butyl ester is obtained in the form of a yellow oil, which is dried for a further nine hours under high vacuum at 40 ° C. Yield 626.65 g (89.2% of theory).

626.65 g of (Z) -2-hydroxyimino-3-oxo-butyric acid tert-butyl ester are dissolved in 2.86 liters of acetone. The solution is cooled to 5 ° C and 703.5 g of potassium carbonate are added portionwise. 322 ml of dimethyl sulphate are then added dropwise to the yellow suspension without cooling over a period of one hour, so that the temperature of the mixture does not rise above 25 ° C.

17 67385

The light beige suspension is stirred for about four hours at 20-25 ° C until no starting material is detectable by thin layer chromatography. The mixture is then poured into seven liters of water and extracted three times with one liter of ethyl acetate. The combined ethyl acetate extracts are washed three times with one liter of water, dried over sodium sulfate and evaporated to dryness in vacuo at 40 ° C. The residual yellow oil is dried for a further six hours under high vacuum at 40 ° C and then distilled. 577 g of (Z) -2-methoxyimino-3-oxo-butyric acid tert-butyl ester (85.6% of theory) are obtained in the form of a yellow oil with a boiling point of 57 ° C under a vacuum of 0.02 mmHg. 1 H-NMR spectrum in CDCl 3 (S values in pp, s = singlet, number of protons in parentheses): 1.55 / -C (CH 3) 37 (s) (9), 2.36 (CH 2 -CO) (s) (3), 4.01 Z: = N-OCH 3, (Z) 7 (s) (3).

86 g of (Z) -2-methoxyimino-3-oxo-butyric acid tert-butyl ester are dissolved in 400 ml of trifluoroacetic acid. The solution is allowed to stand for one hour at 25 ° C, then evaporated to dryness in vacuo at 35 ° C. the oily residue is crystallized from an ether / petroleum ether mixture. 50 g (80.6% of theory) of yellowish, water-soluble (z) -2-methoxyimino-3-oxobutyric acid are obtained, m.p. is 80-85 ° C. 1 H-NMR spectrum in CDCl 3 (d values in ppm, s = singlet, number of protons in parentheses): 2.43 (CH 3 -CO) (3), 4.14 / = N OCH3, (Z17 (s) (3), 10.47 (OH) (s) (1).

145 g of (Z) -2-methoxyimino-3-oxobutyric acid are dissolved in 1000 ml of non-alcoholic and anhydrous dichloromethane. To this solution is added 10 ml of 30% hydrobromic acid-glacial acetic acid solution. A solution of 37.5 ml of bromine in 112.5 ml of dichloromethane is then added dropwise over a period of about two hours, keeping the temperature of the reaction mixture at 20-25 ° C with slight cooling. To remove HBr from the reaction mixture, a strong stream of nitrogen is then blown through it. Then 250 g of ice, 250 ml of water and 2 l of ether are added successively. The aqueous phase is separated and discarded. The organic phase is washed with 250 ml of water and 250 ml of saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness in vacuo. 170 g of a brown oil remain, which is crystallized from tetrachloromethane. 100 g (44.6% of theory) of 6 7 3 8 5 18 are obtained, practically colorless (Z) -4-bromo-2-methoxyimino-3-oxobutyric acid. 1 H-NMR spectrum in CDCl 3 (ε values in ppm,

^ OCH

s = singlet, number of protons in parentheses): 4.24 / = N '3, (Z \ J, (s), 4.41 (-CH2-) (s) (2) (2), 11.0 (OH) , (s) (1).

37.1 g of (7R) -7-amino-3-deacetoxy-3- (2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) -thig7-cephalosporan The acid is suspended in 800 ml of ethyl acetate and 100 ml of Ν, Ο-bis- (trimethylsilyl) acetamide are added. The mixture is stirred under protection from moisture for 30 minutes at 25 ° C to give a pale yellow solution. To this solution cooled to -10 ° C is added dropwise over 30 minutes at -10 to 0 ° C a solution of (Z) -4-bromo-2-methoxyimino-3-butyric acid chloride prepared in 22.4 g: from (Z) -4-bromo-2-methoxyimino-3-oxobutyric acid in 300 ml of non-alcoholic and anhydrous dichloromethane and 20.8 g of phosphorus pentachloride at 8-10 ° C. The reaction mixture is stirred for 30 minutes at 0-5 ° C and for one hour at 25 ° C. Add 1 L of ethyl acetate and 500 mL of water with stirring. The aqueous phase and the resinous interlayer are discarded. The organic phase is washed six times with 500 ml portions of water, dried over sodium sulfate and evaporated in vacuo at 40 ° C to a volume of 200 ml. This orange concentrate is added dropwise with stirring to 1.8 liters of ether, whereupon the reaction product precipitates amorphous. This is filtered off, washed successively with a liter of ether and a liter of low-boiling petroleum ether and dried overnight in vacuo at 35 ° C. 37.2 g (64.4% of theory) of (6R, 7R) -7- (4-bromo-2- [((Z) -methoxyimino) acetoacetamido) -3-, 5-dihydro-6 -hydroxy-2-methyl-5-oxo-as-triazin-3-yl) tig-methyl-38-oxo-5-thia-1-azabicyclo [4.2.07] oct-2-ene-2-carboxylic acid beige as a colored, amorphous product, m.p. = -223.1 ° (c = 1 in methanol).

1 ° H-NMR spectrum in DMSO-d 6 (ε values in ppm, s = singlet, d = doublet, q = quartet, b - broad; J - coupling constants in Hz; number of protons in parentheses): 3.60 (N -CH 2) (s) (3), 3.63 (2-CH 2) (AE-q / centering value; Jgem - 18 Hz) (2), 4.07 / j = N "0CH 3, (Z) 7 ( s) (3), 4.25 (3-CH 2 -S) (AB-q / centering value; J m = 13 Hz) (2), 4.62 (Br-CH 2 -) (s) (2), 5 , 15 (H-6) (d, JR_6 H_? = 5 Hz) (1), 5.78 (H-7) (q = JR_7fNH = 8 Hz, JH_7 / H_6 = 5 Hz) (1), 9, 47 (NH) (d, JNHfH_7 = 8 Hz) / 11.12 (-COOH and -OH) (b) (2).

Claims (3)

A process for the preparation of (6R, 7R) -7- [2- (2-amino-4-thiazolyl) -2- (Z-methoxyimino) acetamido7-3-cephem-4-carboxylic acid derivative of formula I H-N S 2. HHT for II IIN -Nv 2 -CH 2 -SX and 3 ϋ J COOR where X is the group (a) or (b) H D 3 CX / V ° H ^ C 2 X / OR 1 LJ (a) a hydrogen atom or a readily hydrolyzable ester or ether group and the group = N-OCH3 is present in the syn form, and salts of these compounds and hydrates of these compounds or hydrates of salts, characterized in that a halide of formula II ffs YCH CO-C-CONH-IN, 2. ii 11 nn OCH3 j COOR where X and R are as defined above, Y is a halogen atom and the group = N-OCH3 is in the syn form, or a site