DD201683A5 - METHOD FOR THE PRODUCTION OF ESTERS OF CEPHALOSPORIN DERIVATIVES - Google Patents

Abstract

The invention relates to a process for the preparation of easily hydrolyzable esters of cephalosporin derivatives for use as medicaments, for example for the treatment and prophylaxis of infectious diseases. The aim of the invention is the provision of new cephalosporins with increased antimicrobial activity after oral administration. According to the invention readily hydrolysable esters of cephalosporin derivatives of the general formula I are prepared in which X is one of the groups a) and b), wherein R is high 1 lower alkyl.

Description

OOQ ⁰ X A 7 V Berlin, the 12 _# 2.1982

2 OO O O / 3. AP C 07 C / 233 367/3

Process for the preparation of esters of cephalosporin - '* ...' derivatives ^: v ::. ...... _: ',.: .. * * ... .. *. * ·.., .. . *: -. *., : * / * ·. · .-. ".-

ⁱ '""':' ^: ".. ' .r ."'' * * '. ·: *. ''. '''.' : ''''.""''':'''""'' -. ''''"

Field of application of the invention

: '.'. '.. "w -.'';,' -. ';•' ....: '· ·' .- ';''-': ·. .. · -. . ^'. · .-.'^.;:;.'·..'... / The invention relates to a method for the manufacture of readily hydrolyzable esters of cephalosporin derivatives having valuable pharmacological properties, the compounds according to the invention are antibiotic, especially bactericidal, activity · They are used as drugs, for example. for the treatment and prophylaxis of infectious diseases «

Characteristic of the known technical solutions

Cephalosporins with antimicrobial activity are known from DE-OS 2 922 036. For example, cephalexin is a previously known orally recognized cephalosporin,

Zi el the invention

, '' · ''. ' . ' :. -. -. '''''":' .. ';' : - ' ^: · ·', ':' ^: -; , , ·:.-Λ ^':',: · - '.-', object of the invention is to provide voji neuenCephalosporinen with increased antimicrobial activity after oral administration ·

Explanation of the essence of the invention

The invention has for its object to find new cephalosporins with the desired properties and processes for their preparation «

1 & FEE 19 82 * 9.1104 85

2333673

-JUr-

12,2,1982

AP C 07 C / 233 367/3

59 766/18

According to the invention, new cephalosporin derivatives, namely readily hydrolyzable esters of compounds of the general formula

H H

s = C CONH

CH ₂ - SX

COOH

made, in the X one of the groups

N / A)

N 'COOH (b)

- v>'- y - .. 2:. ^{·: -; ^'} · ν-;;;; -....... ".. .: ' ^: ' _: - '^' -: - ^ r ^ Λ ... ', ^: ; V; :.: ..;:; v; /: 'V _; ^:

in which R represents lower alkyl, as well as acid addition salts of these esters and hydrates of these esters or acid addition salts.

V "·, 5 is the lower alkyl group R in the group (a)

preferably a straight-chain or branched alkyl group having 1-7 carbon atoms, such as ethyl, ri-propyl, isopropyl, η-butyl, isobutyl, sec-butyl, t-butyl, n-perityl or, in particular, methyl. '

; ^: As readily hydrolyzable esters of the compounds of the formula I y ^ compounds of formula I are to be understood, wherein at least one carboxyl group in the form of a readily hydrolyzable Estergruppe present. Examples of such esters are the lower alkanoyloxyalkyl esters, for example the acetoxymethyl, pivaloyloxymethyl, 1-acetoxyethyl and 1-pivaloyloxyethyl esters; the lower alkoxycarbonyloxy- • alkyl esters, eg the methoxycarbonyl-oxymethyl, 1-ethoxy-

carbonyloxyethyl and 1-iso-propoxycarbpyloxy ethyl diesters; the lactonyl esters, e.g. the phthalidyl and thiophthalic: dyl ester; the lower alkoxymethyl esters, e.g. the methoxy

methylester; and the lower alkanoylaminomethyl esters,;:; ; ' z. B. the Acetamidomethylester. Other esters, for example the benzyl and cyanomethyl esters, may be useful. The esters can be monoesters or diesters. The second esterification can occur in conjunction with the carboxy radical of the 3-carboxy-1-methyl-1H-1,2,4-triazol-5-yl group X (group (b)). V /. _:: ; v. ' ^: '.;;^{; >:;}; . ''.·',. ·:. ';;: '-.;"'''' : ..: ..;.:.; , :, _: ''-;-;'.', .. ';'

The readily hydrolyzable esters of the compounds of the formula I form addition salts with organic or

, inorganic acids. Examples of such salts are hydrohalides, for example, hydrochlorides, hydrobromides, hydroiodides, and other mineral acid salts, such as sulfates, nitrates, phosphates and the like, alkyl and monoaryl sulfonates, such as ethane sulfonates, toluenesulfonates, benzenesulfonates, and the like other organic acid salts, such as acetates, tartrates, maleates, citrates, benzoates, salicylates, ascorbic acid,

2333673 Λ-

bate and the like.

The readily hydrolyzable esters of the compounds of formula I and their acid addition salts may be hydrati Siert. The hydration can take place in the course of the production process or occur gradually as a result of hygroscopic properties of an initially anhydrous product. , , ·

The products according to the invention can be in the synisomeric form

CONH S

or in the anti-isomeric form N-τ C CONH S

, !

or as mixtures of these two forms. Prej

zugt is the syn-isomeric form or mixtures in which

the syn-isomeric form predominates. , I

Particularly preferred products are cephalosporin

€

ester of the general formula

2333673

CH ₃ ON = C-CONH

I i

5 '

COOR *

H ₃ C

N-N

COOR

in the R, the pivaloyloxymethyl or acetoxymethyl

group represents,.

and acid addition salts of these esters and hydrates of these esters or acid addition salts.

Of these compounds are

Methylene (6R, 7R) -7- [2- (2-amino-4-thiazolyl) -2 - [(Z) -methoxyimino] acetamido] -3 - [[[2-methyl-5 - [[(pivaloyloxy ) methoxy] carbonyl3-2H-1,2,4-triazol-3-yl] thio] -methyl] -8, -oxo-S-thia-1-azabicycloC 4.2. 0] oct-2-ene-2-carboxylate pivalate

and its acid addition salts and the corresponding hydrates are particularly preferred.

The above cephalosporin derivatives can be prepared according to the invention by subjecting a carboxylic acid of the formula I or a salt of this compound to a corresponding esterification and, if desired, converting the product obtained into an acid addition salt or hydrate or a hydrate of this acid addition salt.

The carboxylic acid of the formula I used in the above process can be prepared starting from 7-aminocephalosporanic acid as follows:

The 7-aminocephalosporanic acid is dissolved in aqueous solution with a thiol of the general formula

2333.6

HS-X

II

where X has the above meaning,

reacted, for example at a temperature between about 40 and 80 ⁰ C, suitably at about 60 ⁰ C. The solution is preferably buffered at a pH of about 6 to 7, preferably 6.5, buffered.

The compound of the general formula thus obtained

H H

III

COOH

in which X has the above meaning, is then 'with a carboxylic acid of the general formula

CH ₃ ON = C-

RHN

• COOH

IV

wherein R represents a cleavable group or with a reactive functional derivative of this carboxylic acid to a compound of the general formula

2333 * 73

RHN

COOH

where R has the above meaning, implements.

Possible R-protecting groups are, for example, acid-hydrolysable cleavable protecting groups, e.g. t-butoxycarbonyl or trityl, or also basic hydrolytically removable protecting groups, such as. Trifluoroacetyl. Preferred R-protecting groups are chloro, bromo and iodoacetyl, especially chloroacetyl. The latter protecting groups can be cleaved by treatment with thiourea.

As reactive functional derivatives of carboxylic acids of formula IV are e.g. Halides, i. Chlorides, bromides and fluorides; azides; Anhydrides, in particular mixed anhydrides with stronger acids; reactive esters, e.g. N-hydroxysuccinimide ester, and amides, e.g. Imidazolides, into consideration.

The reaction of the 7-amino compound of the formula III with the carboxylic 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 halide, preferably the chloride of a carboxylic acid of formula IV with the Ämin of formula III implement. The environmental ^J reduction is preferably carried out in the presence of an acid-binding agent, for example in the presence of aqueous alkali, preferably sodium hydroxide, or in the presence of alkali metal carbonates such as potassium carbonate or in the presence of a low-alkylated amine such as triethylamine. As a

2333673 · * ·

Water is preferably used, if appropriate in admixture with an inert organic solvent, such as tetrahydrofuran or dioxane. It can also be carried out in an aprotic organic solvent, such as dimethylformamide, dimethyl sulfoxide or hexamethylphosphoric triamide. The reaction may conveniently be carried out at temperatures between about -4O ⁰ C and room temperature / for example at about 0-10 "C, take place.

Subsequently, in the resulting compound of the formula V, the amino-protecting group R is split off, the desired starting carboxylic acid of the formula I being obtained. Protective agents which can be split off by acid hydrolysis are preferably removed with the aid of a lower alkanecarboxylic acid which, if appropriate, may be halogenated. In particular, formic acid or trifluoroacetic acid are used. The temperature is usually room temperature, although slightly elevated or slightly reduced temperatures can be used, for example in the range of about 0 ° C to +40 ⁰ C.

Alkaline cleavable protecting groups are "hydrolyzed to 30 ⁰ C. The chloroacetyl, bromoacetyl and iodoacetyl protecting groups can be by means of thiourea in acidic, neutral or alkaline medium at about 0-30" generally with dilute aqueous alkali at 0 ° C are cleaved C ,

Hydrogenolytic cleavage (e.g., cleavage of benzyl) is unsuitable herein because upon hydrogenolysis, the oxime function would be reduced to the amino group.

The resulting carboxylic acid of the formula I can then be converted into a salt, for example in an acid addition salt as described above, or else in salts with bases, for example alkali metal salts, such as the sodium and potassium salt; the ammonium salt; Alkaline earth metal salts, such as the calcium salt; Salts with organic bases, such as salts with amines, for example salts with N-ethyl-piperidine, procaine, dibenzylamine, N, N- ^1- dibenzylathylenediamine, alkylamines or dialkylamines, and salts with amino acids, such as salts with arginine or lysine. The salts may be monosalts or else disalts

23336 73

- or -

his. The salts are prepared in a known manner, e.g. by reacting the carboxylic acid of formula I with an equivalent amount of the desired acid or base, conveniently in a solvent such as water or in one

5 organic solvents such as ethanol, methanol, acetone and more. When a second equivalent of base is used, salt formation also takes place on the carboxy function of any group (b) which may be present to form a disalt. The temperature of salt formation is not critical.

It is generally at room temperature, but may also be slightly above or below it, for example in the range from 0 ^e C to + 50 ⁰ C.

The thiols of the formula II are in tautomeric equilibrium with the corresponding thiones in the sense of the following formulas

II a '

25 in which R has the above meaning or

H ₃ C,

N-N

II b

'COOH 1

N-N

COOH

II b

2333 $ 73

The preparation of these compounds is described in Examples A and B below. For the preparation of 6-position etherified thiols (thipnene) corresponding to group (a), the R group is generally introduced by reacting an S-protected thiol (eg, benzhydryl) with the halide containing the R group. preferably the iodide, in an inert organic solvent in the presence of an acid-binding agent, 'eg potassium carbonate, reacted, preferably at about 10 ° -50 ^e C, and the protective group cleaves off (benzhydryl can be cleaved with anisole and trifluoroacetic acid at room temperature who the).

For the production according to the invention of the readily hydrolyzable esters of the carboxylic acids of the formula I, the carboxylic acid is preferably reacted with the corresponding halide containing the ester group, preferably with the iodide. The reaction can be carried out with the aid of a base, e.g. an alkali metal hydroxide or carbonate, or an organic amine such as triethylamine.

In the presence of the group (b), its carboxy function is also esterified to give a readily hydrolyzable diester. Preferably, an excess of the corresponding halide is used. The esterification reaction is preferably carried out in an inert organic solvent, if appropriate in admixture with water, such as dimethylacetamide, hexamethylphosphoric triamide, dimethyl sulfoxide or, preferably, dimethylformamide. The temperature is preferably in the range of about 0-40 "C.

The preparation of the acid addition salts and hydrates of the compounds of the formula I or the hydrates of these acid addition salts can be carried out in a manner known per se, the acid addition salts, e.g. by reacting the carboxylic acid of formula I with an equivalent amount of the desired acid, conveniently in a solvent such as water or in an organic solvent such as ethanol, methanol, acetone and more. The tempera

' 2333673 - "-

door of salt formation is not critical. It is generally at room temperature, but may also be slightly above or below, for example in the range of O ⁴ G to + 50 ⁰ C.

The hydrates are usually produced automatically in the course of the production process or as a consequence of hygroscopic properties of an initially anhydrous product. For the targeted production of a hydrate, a wholly or partially anhydrous product (carboxylic acid of the formula I or ester, ether or salt thereof) of a moist atmosphere, for example at about +10 ⁰ C to +40 ⁰ C, are exposed.

A possibly obtained syn / anti mixture can be separated into the corresponding syn- and anti-forms in a customary manner, for example by recrystallization or by chromatographic methods using a suitable solvent or solvent mixture. However, preference is given to obtaining the esters according to the invention in the syn-isomeric form by using a starting compound of the formula IV in syn form.

The esters according to the invention and the corresponding acid addition salts or the hydrates of these products are antibiotically active, in particular bactericidally active. They have a broad spectrum of activity against Gram-positive bacteria, e.g. Streptococci, and against gram-negative bacteria, e.g. Neisseria meningitidis, as well as against various β-lactamase-producing Gram-negative pathogens, such as Escherichia coli and Serratia marcescens.

The esters of the compounds of the formula I according to the invention and the corresponding acid addition salts or the hydrates of these products can be used for the treatment and prophylaxis of infectious diseases. For the adult, a daily dose of about 0.1 g to about 4 g, in particular about 0.25 g to about 2 g into consideration: enteric or parenteral administration is possible;

2333 6 73

a particular advantage lies in the usability of the he-V VV products according to the invention for enteral, eg oral, administration. "V -" - "- .-. V :; .VV --- V ¹ . ν ^Λ ν 'v.V'-V-. , , · -. V

The primary antimicrobial efficacy of the products according to the invention can be demonstrated by in vivo experiments on the mouse. In the following means the kura-. tive dose (CD ₅ Q, mg / kg) the dose at which 50% of the mice tested survive.

": '··· / · ·.'; ^..:. - Test ^{Compounds:: V;} i ^;.;; ''...::: ^, --.''-- ''-V'- ^v V / ^':' 'VV. '. - ^:

Product A:

Methylene (6R, 7R) -7- [2- (2-amino-4-thiazolyl) -2-C (Z) -methoxyiminol-acetamidol-SC [C2-methyl-5-C [(piyaloyloxy) methoxy] carbonyl] -2H-1,2,4-triazol-3-yl] thio] methyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate pivalate

- Cephalexin (previously known, orally recognized 20-active cephalosporin)

Result (CD ₅₀ , mg / kg)

pathogen Product A p. 0. s. c. Cephalexin p.0. S.C. Escherichia cpli Serratia marcescens Neisseria meningitidis SLuzjjIijuuulus p ^ dQenes 0.047 0.002 0.95; 0.044 ". 't. "" - - "''''. ^: "-:. '.''".''. ^; , ³ '²; ν-: ν ^ν ::,;':: ² - ¹ ; >so;:> so ': ·: .:, - ......

Product A is significantly more effective than cephalexin 35 after both oral and subcutaneous administration.

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12,2.1982

AP C 07 C / 233 367/3

59 766/18

The blood level values obtained after oral administration are obtained in the rat according to the following comparison *

oral dose antibiotic concentration 30 45 to in blood 150 mg / kg mg / kg in g / ml 12 12 60 minutes 5 15 12 14 10 90 5 Product A 20 6 18 8th Cephalexin 50 8th

Product A is at least as non-toxic as cephalexin (LD ₅₀ p "p" in mouse after 24 hours:> 4000 mg / kg for product AV 1600-4500 mg / kg for cephalexin) «

The products according to the invention can be used as medicaments in the form of pharmaceutical preparations containing them or their salts in admixture with one for enteral or parenteral, preferably enteral; Application of suitable pharmaceutical, organic or inorganic inert carrier material, such as, for example, water / gelatin; gum arabic; Lactose, starch, magnesium stearate, talc vegetable oils, polyalkylene glycols; Vaseline; etc. "The pharmaceutical preparations may be in solid formy zy B" as tablets; dragees; Suppository; capsules; or in liquid form ζ. Β «as solutions; Suspensions or emulsions are present. If necessary, they are sterilized and / or contain excipients, such as preservatives, stabilizers, wetting agents or emollients for altering the osmotic pressure; Anesthetic or buffer "They may also contain other therapeutically valuable substances" embodiment

The invention is .'nachstehe * nd illustrated by some examples, "* *" - ^{': *:} _·.' '''' · ': ^{^:'} - ^'-'. . ' .-:. ". '> ·.

2333673 -

Preparation of starting compounds

Example A

Preparation of the sodium salt of (6R, 7R) -7- [2- (2- *

Amino-4-thiazolyl) -2 - [(Z) -methoxyimino! Acetamido] -3- [C (2, 5-dihydro-6-methoxy-methyl-S-oxo-as-triazine-S- -,!

yl) thio] methyl] -8-OXO-5-thia-1-azabicyclo [4.2.O 3oct-2-ene-2-carboxylic acid

34.5 g of the sodium salt of (6R, 7R) -7- [2- [2- (2-chloroacetamido) -4-thiazolyl] -2-C (Z) -methoxyimino] acetamido] -3 - [[(2, 5-dihydro-6-methoxy-2-methyl-5-oxo-as-triazin-3-yl) -thioümethyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene 2-j

carboxylic acid are dissolved in 700 ml of water together with 20 g of thiourea and stirred overnight at 25 ⁰ C under nitrogen gassing, the pH of the reaction solution is maintained at 7 with the addition of 1N sodium hydroxide solution. With vigorous stirring, the pH is reset to 4 by addition of 1N hydrochloric acid. The failed material is sucked off and discarded. The yellow mother liquor is adjusted to pH 3 with 1N hydrochloric acid. The precipitated product is filtered off with suction, washed with water, ethanol and low-boiling petroleum ether and dried in vacuo at 40 ^e C ^N 25. This gives beige (6R, 7R) -7- [2- (2-amino-4-thiazolyl) -2 - [(Z) -methoxyimino] acetamido] -3 - [[(2,5-dihydro- _Λ 6-methoxy-2-methyl-5r-oxo-as-triazin-3-yl) thioumethyl] -8-oxo-5-thia-1-azabicyclo C4.2.0] oct-2-ene-2-carboxylic acid which, for conversion into the sodium salt, suspended in 350 ml of methanol and treated with 20 ml of a 2N solution of 2-Aethylcapronsäure sodium salt in ethyl acetate. After about 15 minutes, a solution is formed, which is diluted with 300 ml of ethanol. In this case, little amorphous material precipitates, which is sucked off and discarded. The FII entered is strongly concentrated in vacuum at 40 ⁰ C. The precipitated material is filtered off with suction, washed with ethanol and low-boiling petroleum ether, and over. Night ^; . In high vacuum at 40 ⁰ C dried. Pure sodium is obtained.

2333673 - »-

salt of (6R, 7R) -7- [2- (2-amino-4-thiazolyl) -2- [(Z) -methoxyimino] acetamido] -3- [E (2,5-dihydro-6- methoxy-2-methyl-5-oxo-α-triazin-3-yl) thio] methyl] -8-OXO-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid as yellowish Powder with CcO ^ ⁵ - -140.9 ° (c> 1 in water).

The compound used as the starting material in the above process can be prepared as follows.

a) Preparation of tetrahydro-2-methyl-5,6-dioxo-3-thioxo-as-triazine-1 (2H) -carboxylic acid benzyl ester;

39.79 g of l, 2,5,6-tetrahydro-5,6-dioxo-3-mercapto-2-methyl-as-triazine are dissolved in 500 ml of dimethylformamide.

 J5 and with 35 ml of triethylamine. added. During 15 minutes 39 ml of benzyloxycarbonyl chloride are added dropwise, the temperature of the reaction mixture rises to 45 ° C, j triethylamine hydrochloride precipitates and the suspension yellow! is colored. The mixture is stirred for 2 .1 / 2 hours at 25'C and then evaporated in vacuo at 70 ° C. ,

The oily evaporation residue is washed with "500 ml of water during j

Stirred for 1 hour, this becomes solid. The solid I is filtered off with suction and washed with 50 ml of water. , The yellow filter cake is stirred well with 250 ml of ethanol, drained off

Nutscht, washed with ethanol and in vacuo at 40 ⁰ C j

dried. This gives a colorless crude crystals, .the / is recrystallized from methanol and colorless tetrahydro-2-methyl-5,6-dioxp-3-thioxo-as-triaziri-l (2H) -carboxylic acid, benzyl ester of melting point 150-153 ⁹ C supplies.

> _: b) Preparation of 3-C (Diphylmethyl) thio] -5,6-dihydro- ^

2-methyl-5,6-dioxo-as-triazine-1 (2H) -carboxylic acid ^: benzyl ester | - ^:. ; ': '..'-.^; , ^:; · '' _^V:; ·;; y '/. ['^; : ' ^_: · '' · Y ^{"^} -'.-- ^'. R' ^{r ':.} .. ..".:' .. '. '' /: ':

-J35 13, 2 g of tetrahydro-2-methyl-5, 6-dio'xp-3-thiöxb -;. As- "V triazin-1 (2H) -carboxylic acid, benzyl ester in 500 _ml; / ethyl acetate and treated with a solution of Diphenyldiazb-: i methane in 90 ml of low-boiling petroleum ether

2333673

initially violet reaction solution is allowed to stand for 40 hours at 25 ⁰ C, the color becomes biass red. 3 ml of glacial acetic acid are added, and the mixture is evaporated at 40 ^° C. after ¹ hour in vacuo. A yellow OeI is obtained as evaporation residue. This is separated by column chromatography on silica gel with the eluents benzene, benzpl / ethyl acetate 95: 5 and benzene / ethyl acetate 90:10. The substance containing the desired substance. Fractions are collected and evaporated in vacuo at 40 ° C. Are obtained after recrystallization from ethanol colorless 3-C / (Diphenylmethyr) thiö '] - 5 _{r 6-dihydro-2-methyl-::':;:} · · -.. 5,6-dioxo-as-triazine-1 (2H) -carboxylic acid benzyl ester of

; '.. Melting point 90-92 ⁰ C. T'",':-v" - ^ ;;' - V -; -.- ": '_ t'. '^ ./-U^ ·; / \ ^ V '

c) Preparation of 3 - [(diphenylmethyl) thio] -1,2-dihydro- '';^;; \. '2-methyl-as-triazine-5,6-dione; v :: · '-.':. '';. '';^;'· -. ";' - ..""; ^.: · '·' ^ ^\::: -;.

6.9 g of benzyl 3-C (diphenylmethyl) thio] -5,6-dihydro-2-methyl-5,6-dioxo-as-triazine-l (2H) -carboxylate are dissolved in 100 ml of ethyl acetate and washed with 30 ml of an aqueous, 7% strength ammonia solution at 25 ° C. for 15 minutes.The ethyl acetate phase is separated off and discarded.The aqueous phase is mixed with 7 ml of concentrated hydrochloric acid and stirred for 30 minutes in an ice bath.The precipitated substance is filtered with suction, washed with water and immediately recrystallized from ethanol to give colorless. 3 - [(diphenylmethyl) thio] -l, 2-dihydro-2 ^{J-methyl-as-triazine-5,6-dione} of melting point 180-182 ⁰ C. ,

d) Preparation of 3 - [(diphenylmethyl) thio] -6-methoxy-2-methyl-as-triazine-5 (2H) -one;

3.9 g of 3-C (diphenylmethyl) thio] -1,2-dihydro-2-methylas-triazine-5,6-dione are dissolved in 40 ml of dimethylformamide. dissolved and treated with 1.68 ml of triethylamine and 4 ml of methyl iodide. After 2 hours of stirring at 25 ° C, the mixture is added to 1.38 g of potassium carbonate to accelerate the reaction. After stirring for a further 2 hours

23336 73 "*"

at 25 ° C, the starting material is completely reacted. The resulting red suspension is poured onto water and extracted three times with ethyl acetate. The combined ethyl acetate extracts are washed with water, dried over sodium sulfate and evaporated in vacuo at 40 ^e C. The red evaporation residue is purified by column chromatography on silica gel with ethyl acetate as eluent. Recrystallization from ethyl acetate /: Adther / petroleum ether provides yellowish 3 - [(diphenylmethyl) thio] -6-methoxy-2-methyl-as-triazine-5 (2H) -one of melting point 135-1 38 ⁰ C.

e) Preparation of 3,4-dihydro-6-methoxy-2-methyl-3-

thioxo-as-triazin-5 (2H) -one;

2.6 g of 3- [(diphenylmethyldithiol-S-methoxy-1-methyl-as-V '/ -. Triazine-S ^ HJ-one) are dissolved in 26 ml of anisole and 50 ml of trifluoroacetic acid and stirred for 3 hours at 25 stirred "C. The reaction solution is evaporated in vacuo at 40 ^e C. The evaporation residue is stirred with a little ethyl acetate and much low-boiling petroleum ether, filtered off with suction and recrystallized from methanol. This gives 3,4-dihydro-6-methoxy-2-methyl-3 -thioxo-as-triazine-5 (2H) -one as colorless, shiny crystals of melting point 215-220 ⁰ C.

i2S / -:. :: . -.; ; '"._

f) Preparation of (6R, 7R) -7-amino-3-C [(2,5-dihydro-6 ^: - '

methoxy-2-methyl-5-oxo-as-triazin-3-yl) thiQ] methyl] - ^ · 8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid ·

'...'

13.6 g of 7-aminocephalosporanic acid and 9.53 g of 3,4-dihydro-6-methoxy-2-methyl-3-thioxo-as-triazine-5 (2H) -one are suspended in 250 ml of water. The pH of the suspension is adjusted to 6.5 with 25N sodium hydroxide solution at 25 ° C. The suspension is heated to 60 ^° C. and stirred at 60 ^° C. for 4 hours while gassing with nitrogen, the pH being adjusted to 6 with 1N sodium hydroxide solution, After 1 hour, a solution is formed, after 2 hours, some material begins to precipitate, and no caustic soda is added.

2333673

needs. The mixture is cooled to 25 ° C and separated from a little undissolved by filtration. The orange FiI-trat is with conc. Hydrochloric acid at 25 ° C to pH 3.5. The precipitated substance is sucked off, after

each with 100 ml water, 300 ml of acetone and 300 ml subscript ^r

washed with boiling petroleum ether and in vacuo overnight

dried at 40 ⁰ C. This gives a beige-colored substance which is suspended for purification in '150 ml of water / methanol 1: 1 and treated dropwise with 3.6 ml of triethylamine during, 1 hour, wherein at pH 8.5, a dark solution is formed, which is still little Contains unresolved. After addition of 3 g of decolorizing carbon, the mixture is stirred for 15 minutes at 25 ° C., filtered off from the decolorizing carbon through a hard filter and washed with 50 ml of water / methanol 1: 1. The orange filtrate is adjusted to pH 3 with about 2 ml of concentrated hydrochloric acid . The thereby precipitated substance is filtered with suction, washed successively with 50 ml of water / methanol 1: 1, 100 mL methanol, 50 mL of ether and 50 ml of low-boiling petroleum ether and dried overnight in vacuo at 40 ⁰ C dried to give pure, beige-colored. (6R, 7R) -7-amino-S- [C (2, S-dihydro-S-methoxy ^ -methyl-S-oxo-

Ε-triazin-3-yl) thio] methyl] -8-oxo-5-thia-1-azabicyclo-j

[4.2.0] oct-2-ene-2-carboxylic acid. I

I g) Preparation of the sodium salt of (6R, 7R) -7- [2- [2- (2-

Chloroacetamido) -4-thiazolyl] -2 - [(Z) -methoxyimino] -, j

acetamido] -3-C [(2, 5-dihydro-e-methoxy-methyl-S-oxo-As-triazin-S-yl) thio] methyl] -8-oxo-5-thia-1-azabicyclo [ 4.2.0] oct-2-ene-2-carboxylic acid · ^s J

^ "!

To 2 00 ml of methylene chloride dried over calcium chloride

Chloride are added 25 g of phosphorus pentachloride. The i

Suspension is cooled with stirring to -10 ⁰ C, and about 5 minutes, 46 ml of N, N-dimethylacetamide are added dropwise, the temperature rises to -5 ⁰ C. The suspension is cooled to -15 ⁰ C and stirred for 15 minutes. After cooling to -2 0 ⁰ C, 33.3 g of 2- (2-chloroacetamido-4-thiazolyl) -2- (Z) -methoxyimino-acetic acid z'ugegeben

and stirred at -15 ° C for 45 minutes to give a yellow-orange solution. This solution is cooled to -30 ^e C, mixed with 50 g of ice · and stirred for 10 minutes at -5 ° C. The methylene chloride phase containing the acid chloride formed is separated and initially stored at about -15 ° C. This acid chloride solution is cooled to 0-5 ⁰ C solution prepared by adding the (6R, 7R) -7-amino-3 - [[(2, S-dihydro-e-methoxy) -methyl -S-oxoas-triazin-3-yl) thio] methyl] -8-0x0-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid with 3N sodium hydroxide solution until pH 8.2 in 500 ml of water, while added dropwise with vigorous stirring for 30 minutes, the pH of the

'' '. ". ' : '·' '' '' '· · .. ·' .- · .:. '.' .:.. .-.

Is kept at 8.0-8.2 with 3N sodium hydroxide solution using an autotitrator. The mixture is stirred for 2 hours at 25 ° C. Thereafter, 300 ml of methylene chloride and 2 1 n-butane oil are added. With vigorous stirring, the pH is returned to 2 with 3N hydrochloric acid. The organic phase is'abgetrennt, washed three times with 1 1 of water, stirred with 20 g of decolorizing carbon for 15 minutes and filtered. The light yellow filtrate is concentrated strongly in vacuo at 60 ° C, the reaction product precipitates. The latter is filtered off with suction and washed successively with n-butanol, ethers and low-boiling petroleum ether and dried overnight in vacuo at 40 ⁰ C. This gives crude, beige (6R, 7R) -7-C2- [2- (2-chloroacetamido) -4-thiazolyl] -2 - [(Z) -methoxyimino] acetamido] -3-C [(2,5-) dihydro-6-methoxy-2-methyl-5-oxo-as-triazin-3-yl) thio] methyl] -8-oxo-5-Thial-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid , For conversion into the sodium salt and purification, the latter is dissolved in a mixture of 300 ml of acetone and 50 ml of methanol and treated with 35 ml of a 2N solution of 2-Aethylcapronsäure sodium salt in ethyl acetate. The precipitated sodium salt is filtered off with suction, washed successively with acetone and low-boiling petroleum ether »and dried in vacuo at 25 ° C. This gives beige-colored sodium salt oil (6R, 7R) -7- [2- [2- (2-chloroacetamido) -4-thiazolyl] -2-C (Z) -methoxyimino] acetamido] -3- [C (2 , 5-dihydro-6-methoxy-2-methyl-5-oxo-as-tfiazin-3-yl) thio] methyl] -8-oxo-5-thia-1-

a?

2333673 '** "

25 azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid with [α] _ - -131.5 ° (c = 1 in water).

Example B

Preparation of the disodium salt of (6R, 7R) -7- [2- (2-amino-4-thiazolyl) -2-C (Z) -methoxyimino] acetamido] -3- [C (3-carboxy-1-methyl) IH-I, 2/4-triazol-5-yl) thio] methyl] -8-oxo-5-thia-1-azabicyclo [4,2'0] oct-2-ene-2-carboxylic acid;

53 g (6R, 7R) -3 - [[(3-carboxy-1-methyl-1H-1,2,4-triazol-5-yl) thio] methyl] -7- [2- [2- (2 -chloroacetamido) -4-thiazolyl 3-2-C (Z) -methoxyimino-2-acetamido] -8-oxo-5-thiα-1-azabicyclo [4.2.O] oct-2-ene-2-carboxylic acid are suspended in 1 liter of water along with 34 g of thiourea. The pH is adjusted to 7 by dropwise addition of 1N sodium hydroxide solution, whereby a dark brown solution is formed. This is stirred overnight with nitrogen gassing at pH 7, wherein the pH is kept constant with IN sodium hydroxide solution using an autotitrator. The pH of the reaction solution is returned to 3.5 with 1N hydrochloric acid with stirring. The precipitated substance (fraction I) is filtered off, washed with 250 ml of water and dried in vacuo at 40 ° C. Fraction I is brown in color and heavily contaminated; she is rejected. The orange mother liquor is returned to pH 2.65 with 1N hydrochloric acid while stirring. The precipitated material is filtered off with suction and washed with 250 ml of water. The beige-colored filter cake is azeotroped under reduced pressure with ethanol, filtered off with suction, washed with ethanol and low-boiling petroleum ether and dried in vacuo at 40 ° C. This gives a beige-brown fraction II, which is purified in the disodium salt in 2 l of a 2N solution of the sodium salt of 2-Aethylcapronsäure in ethyl acetate and then stirred with 200 ml of water for 30 minutes.A little undissolved, brown material is filtered off and discarded.From the orange-colored FiI-occurs in vacuo evaporated at 40 ⁰ C about 1 1, then 1 1

Ethanol added and concentrated in vacuo to a volume of about 500 ml. From thereby precipitated, greasy brown resin, which is a strong mixture, is decanted off. The decanted yellow-orange solution is treated with 1 l of ethanol and concentrated in vacuo at 40 ° C., whereby some of the substance precipitates. After addition of 2.5 l of methanol, a yellow solution is formed which is strongly concentrated in vacuo at 40 ^° C. the disodium salt which precipitated is suction filtered, washed with methanol and low-boiling petroleum ether and a high vacuum at 35 ^e C dried. this gives pure, beige-colored disodium salt of (6R, 7R) -7- [2- (2-amino-4-thiazolyl ) -2 - [(Z) -methoxyimino] acetamido] -3-CC (3-carboxy-1-methyl-1H-1,2,4-triazip-5-yl) thio] methyl] -8-oxo-5 -thia-1-azabicycloC4.2.0] oct-2-ene-2-carboxylic acid with Ta] = -38.7 ° (c = 1 in water).

The compound used as the starting material in the above process can be prepared as follows:

a) Preparation of methyl 4,5-dihydro-1-methyl-5-thioxo-1H-1,2-triazole-β-carboxylate;

12.9 g of 1-methoxyoxalyl-2-methylthiosemicarbazide are added to a solution of 1.6 g of sodium in 200 ml of methanol. The mixture is refluxed for 4 hours. The precipitated after a 1/2 hour substance is separated. The mother liquor is evaporated in vacuo at 40 ⁰ C. The evaporation residue is dissolved in 100 ml of water and acidified with conc. Hydrochloric acid acidified. The thereby precipitated crystals gives after recrystallization from water pure, colorless 4,5-dihydro-l-methyl-5-thioxo-IH-I, 2, ^ - thiazol-S-carboxylic acid methylester of melting point 188-190 ⁰ C ( dec.).

2333673

b) Preparation of 4-S-dihydro-1-methyl-S-thioxo-1H-1,2,4-triazole-3-carboxylic acid:

3.46 g of methyl S-dihydro-1-methyl-S-thioxo-1H-l, 2,4-triazole-3-carboxylate are dissolved in 50 ml of 1N sodium hydroxide solution. After half an hour stirring at 25 ° C the reaction is'"provided tion solution with 25 ml of 2N hydrochloric acid and dried in vacuo at 40" C and concentrated to give the desired acid crystallized. This is filtered off, washed with ice water and dried under high vacuum, at 45 ° C. This gives colorless 4,5-dihydro-l-methyl-5-thioxo-lH-l, 2,4-triazole-3-carboxylic acid of melting point 177-178 ° C (dec.).

c) Preparation of (6R, 7R) -7-amino-3 - [[(3-carboxy-l

methyl-1,2,4-triazol-5-yl) thio] methyl 3-8-oxo-5-thia-1-azabicycloC4.2.0] oct-2-ene-2-carboxylic acid

34 g of 7-aminocephalosporanic acids are used together with 25.5 g of 4, S-dihydro-1-methyl-S-thioxo-1H-1,2,4-triazole-3 _r ':

carboxylic acid suspended in 500 ml of water. The pH is adjusted to 6.5 with 3N sodium hydroxide solution. The mixture is stirred for 4 hours at 55 ⁰ C under nitrogen, the pH is adjusted with 3N sodium hydroxide solution by means of a 'Autoti.trators constant' at 6.5 is maintained. The dark solution is cooled to 25 ° C and treated with conc. Hydrochloric acid to pH 3.5. After 15 minutes, the precipitated Mat er dial is filtered off with suction, suspended in 500 ml of water and dissolved with 3N sodium hydroxide solution at pH 7 in solution. The orange-red solution is washed with conc. Hydrochloric acid adjusted to pH 3. The precipitated substance is filtered off with suction and washed successively with 250 ml of water, 500 ml of acetone, 500 ml of low-boiling petroleum ether "and dried overnight in vacuo at 40-45 ⁰ C. (6R, 7R) -7-AmInO-S-CC (3-carboxy-1-methyl-1, 2,4-triazol-5-yl) -thio-methyl] -8-pxo-5-thia-1-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid as beige-colored Powder. '

ά) Preparation of (6R, 7R) -3 - [[(3-carboxy-1-methyl-1H; 1 _/ 2,4-triazol-5-yl) thio] methyl] -7- [2-C2 - (2-chloro-i ^\: vi acetamido) -4-thiazolyl] -2-C (Z) -methoxyiminp] acetamido] -S-oxo-S-thia-l-azabicyclo [4.2.0] oct-2- ene-2-carboxylic acid:

This compound is prepared according to paragraph g) of Example 1 starting from 100 g of 2- (2-chloroacetamido-4-thiazolyl) -2- (Z-methoxyiminoacetic acid and 111.5 g (6R, 7R) -7-AmInO- S - [[(3-carboxy-1-methyl-1,2,4-triazol-5-yl) -thelimethyl] -8-10-oxo-S-thia-i-azabicycloC ^. a) oct-2-ene-2-carboxylic acid is obtained, giving beige-colored (6R 1R) -S-CC (3-carboxy-1-methyl-1H-i, 2,4-triazole-5 -yl) thio] methyl] -7- [2- (2-chloroacetamido) -4-thiazolyl] -2-C (Z) -methoxyimino] acetamido] -8-; oxo-5-thia-1-azabicyclo [ 4.2.0] oct-2-ene-2-carboxylic acid.

'- - ^: - ¹ S '. :: ..:. -. .. ':: - ^; ; - \: V, · 'r - ^ U V-: V

Production of end products:

ν: - '.. ·': -.... '"...;^.:;: - - · ·'';;::-.'': - ^; ': '¹;;' example 1

Preparation of methylene (6R, 7R) -7- [2- (2-amino-4-thiazolyl) -2 - [(Z) -methoxyimino-3-acetamido] -3 - [[[2-methyl-5-C] (pivaloyloxy) methoxy] carbonyl] -2H-1,2,4-triazol-3-yl] -thio] methyl] -8-pxo-5-thia-1-azabicyclo [4.2.0] oct-2- s-2. carboxylai> -pivalate · γ-s ^; - . · 25;.;:. '":"'. ; ..- .; ·: ':.'^{:; :} - '': ''^'.: ^ -'-.' ^_Y yy

3.9 g of the disodium salt of (6R, 7R) -7- [2- (2-amiho-4-thiazolyl) -2-C (Z) -methoxyimino] acetamido] -3 - [[3-carboxy- methyl-1H-1'-triazol-3-yl-thiolmethyl-D-e-oxo-S-thia-V 1-azabicycloC 1 -o-oocto-1-C5-carboxylic acid are dissolved in a mixture of 100 This solution is treated under nitrogen with 3.13 g of iodomethyl pivalate at ⁰ ° -5 ° C. The reaction mixture is stirred at 0-5 ° C. for 30 minutes, then poured onto 500 ml of water and taken three times The aqueous phase is discarded and the combined ethyl acetate phases are washed successively with water, dilute aqueous sodium bicarbonate solution and again with water, dried over sodium sulphate

2333673

and concentrated in vacuo at 40 ⁰ C greatly. After addition of low-boiling petroleum ether, the precipitated crude product is filtered off with suction, washed with low-boiling petroleum ether and dried under high vacuum at 40 ° C. This gives beige, amorphous crude product For purification, this product is chromatographed on a column with 100 g of silica gel (0.2-0, The pure, beige, amorphous title substance is obtained with Rf = 0.31 in thin-layer chromatography on silica gel 60F-254 precast plates with ethyl acetate as the eluent, the specific rotation being Cot. - = -121.6 ° C (as 0.4924 in acetone), the nuclear magnetic resonance spectrum and the microanalysis correspond to the structure indicated.

In an analogous manner are prepared from the product prepared according to Example 1, the sodium salt (6R, 7R) -7- [2- (2-amino-4-thiazolyl) -2 - [(Z) -methoxyimino] acetamido] -3-C 1 (2, 5-hydroxy-6-methoxy-2-methyl-5-oxo-a-triazine-3-yl) -thio] -methyl] -8-oxo-5-thia-1-azabicyclo [4.2. 0] oct-2-ene-2-carboxylic acid the corresponding methylene (6R, 7R) -C 2 - (2-amino-4-thiazolyl) -2 - [(Z) -methoxyimino] -acetamido] -3- [ [(2,5-dihydro-6-methoxy-2-methyl-5-oxo-as-triazin-3-yl) -thio] methyl] -8-oxo-5-thia-1-azabicyclo [4.2 3ct-2-ene-2-carboxylate-pivalate

^::; Γ "·. ';.''..'':'': _ \': - ^: I \ ^: r '..'}:.:. - "'' Example 2 '{.:'. :: - ''. ^/: '* - /' ^ .. .. ·· ',''';"·..

Preparation of methylene (6R, 7R) -7-C2- (2-amino-4-thiazolyl) -2-C (Z) -rmethoxyimino] -acetamido] -3- [[[2-methyl-5 - [[( acetoxy) methoxy! carbonyl] -2H-I, 2,4-triazol-3-yl] thio-methyl-a-oxo-S-thia-1-azabicycloC 1-10] oct-2-ene-2: '. ·. carboxyl at-ace t at: '; ^{':.: ::'.} - '.' yy: ^: '.. ^-:.;' '(': ^':'. ^ ''^{'l' c:} 'A.' ί · \ ν-. ""'V,''- ^. ^ y'"';

5.98 g of (6R, 7R) -7-amino-O-3- [C (3-carboxy-1-methyl-1,2,4-triazole-5-yl) -thio] -methyl] -8-OXO-5-. thia-1-azabicyclo C4.2.O] oct-2-0n-2-carboxylic acid dinetrium salt are dissolved in a mixture of 70 ml of dimethylformamide and 25 ml of water. The solution is treated under nitrogen gassing at 0-5 ⁰ C with 6.12 g of acetic acid bromomethyl ester and 3 hours

23336 73. The reaction mixture is poured into 500 ml of water and extracted twice with ethyl acetate with the addition of a little acetone The combined organic phases are washed successively with dilute aqueous sodium bicarbonate solution and water, dried over sodium sulfate and strongly concentrated in vacuo at 40 ⁰ C. After the addition of low-boiling petroleum ether, the amorphous precipitated substance is filtered off under suction, washed with low-boiling petroleum ether and dried overnight in the high

10 ~ vacuum dried at 25 ⁰ C. A beige crude product is obtained which, for purification, is placed on a column with 80 g of silica gel (0.2-0.5 mm diameter) and ethyl acetate

 , , · · '

is chromatographed as Elutiqnsmittel. You get

pure, beige, amorphous title substance (from ethyl acetate / lg low-boiling petroleum ether) with Ca] ^ ⁵ = -107.16 ° (c = 1.0358 in acetone). The nuclear magnetic resonance spectrum and the microanalysis correspond to the given structure.

The sodium salt prepared according to Example 1 is prepared in an analogous manner of (6R, 7R) -7- [2- (2-amino-4-thiazolyl) -2 - [(Z) -methoxyimino] acetamido] -3 - [[ (2,5-dihydro-6-methoxy-2-methyl-5-oxo-as-triazin-3-yl) thio] methyl] -8-oxo-.5-thia-l-azabicyclo [4.2. 0] oct-2-ene-2-carboxylic acid the corresponding methylene (6R, 7R) - [2- (2-amino-4-thiazolyl) -2 - [(Z) -methoxyimino] -acetamido] -3- [C (2,5-dihydro-6-methoxy-2-methyl-5-oxo-as-triazin-3-yl) -thio] -methylD-8-OXO-5-thia-1-azabicyclo [4.2.0] oct-2 -ene-2-carboxylate-acetate. . '; , : ·.

2333673

500 mg 20 mg 20 mg 15 mg 2 mq

Example 3

A gelatin plug-in capsule of the following composition is prepared in the usual way:

Methylene (6R, 7R) -7- [2- (2-amino-4-thiazolyl) -2-C (Z) -methoxyimino] acetamido] -3 - [[[2-methyl-5-C [(pivaloyloxy ) methoxy] carbonyl] -2H-l, 2,4-triazol-3-yl] thio] methyl] -8-oxo-5-thia-l-azabicyclo [4.2.0] oct-2-ene-2-carboxylatpivalat

Luviskol (water-soluble polyvinylpyrrolidone)

mannitol

talc

magnesium stearate

55 7 mg 15

Example 4

It is in the usual way a tablet following

, Composition: 20

Methylene (6R, 7R) -7- [2- (2-amino-4-thiazolyD-2 - [(Z) -methoxyimino] acetamido] -3-CCC 2-methyl-5-CC (pivaloyloxy) methoxy] carbonyl ] -2H-1,2,4-triazol-3-yl] thio] methyl] -8-oxo-5-thia-1-azabicycloC4.2.0] oct-2-ene-2-carboxylate

pivalate 250 mg

Lactose 70 mg

Corn starch Polyvinylpyrrolidone Magnesium stearate

^4C0

With the active ingredient, lactose, the polyvinylpyrrolidone and 40 parts by weight of corn starch granules are prepared in the usual way. This is mixed with the remaining 25 parts by weight of corn starch and 5 parts by weight of magnesium stearate and pressed into tablets. ,

65 mg 10 mg , 5 mg

Claims (1)

invention claim 1 «Process for the preparation of easily hydrolyzable esters of cephalosporin derivatives of the general formula CH ₃ ON = SC-CONH COOH in the X one of the groups ^H 3 ^C ^ N-N JLX N COOH and R represents lower alkyl, as well as acid addition salts of these esters and hydrates of these esters or acid addition salts, characterized in that a carboxylic acid of the formula i or a salt of this compound is subjected to a corresponding esterification and, if desired, the product obtained is converted into an acid addition salt or hydrate or hydrate * converts a hydrate of this acid addition salt * 2 # Method according to item 1 for the preparation of ethers in the syn-isomeric form or * of mixtures in which the syn-isomeric form is predominantly characterized in that a starting compound with appropriate configuration or a syn / anti mixture obtained is used 2333 (573 XB 12.2 «1982 AP C 07 C / 233 367/3 59 766/18 Process according to item 1 or 2 for the preparation of cephaloeporine derivatives of the general formula H H CH ₇ ONsC.- CONH-4 N '^ COOR COOR ' 2
in the R, the pivaloyloxymethyl or acetoxymethyl group represents, and of acid addition salts of these compounds and of hydrates of the compounds of the formula Ia or of their acid addition salts, characterized in that appropriately substituted starting compounds are used. 4 · Method according to item 3 for the preparation of cephalosporin derivatives in the syn-isomeric form or of mixtures in which the syn-isomeric form predominates, characterized by; that one uses a starting compound with appropriate configuration or separates a syn / anti mixture obtained » 5 · Process according to item 4 for the preparation of methylene (6R, 7R) -7-t 2 - (2-amino-4-thiazolyl) -2-C (Z) -methoxy-imino] -acetamido] · »S-ff / k-methyl-δ-ff (pivaloyloxy) methoxy-carbonyl-3-2H-l, 2,4-triazol-3-yl-thio] methyl] -8-oxo-5-thia-1'-azabicyclo-4,2 * 03oct- 2-en-2-carboxylate-pivalate and of acid addition salts of this compound and of hydrates of this compound or of acid addition salts, characterized in that correspondingly substituted starting compounds are used « 23336 73 - T ^& us AP C 07 C / 233 367/3 AP C 07 C / - -.- ν, ... ;; λ: ..V ;; \ - 28 ^-:; - .; Λ> ^ν : -A. ::.: 59 766/18 I ; - ^ r! A ^ r 6 · Method according to item 4 for the preparation of methylene (6R, 7R) -7 - ./: 2- (2-amino-4-thiazolyl) -2-f (Z) -methoxyimino3-acetamidol'-3-rff2-. methyl-5-fI (acetoxy) methoxy-2-yl-3-yl-thio] methyl] -8 - OXO-5-thia-1-azabicycloi4 # 2 _# 0joct-2 -en-2-carboxylate-acetate And acid addition salts of this compound and of hydrates of this compound or acid addition salts, characterized in that correspondingly substituted starting compounds are used » : 7V. Process according to one of the items 1 to 6, characterized in that the corresponding halide, in particular the Oodidy, is used as the esterifying agent.