Cephalosporin derivatives

There is presented compounds of the formula ##STR1## in which R.sup.1 represents hydrogen or methyl, as well as readily hydrolyzable esters and salts of these compounds and the hydrates thereof. Also presented are various intermediates and a process to produce the novel derivatives. The acyl derivatives have pharmacological activity as antibacterial agents.

DESCRIPTION OF THE INVENTION 
The present invention is concerned with novel cephalosporin derivatives, 
namely cephalosporin derivatives of the general formula 
##STR2## 
in which R.sup.1 represents hydrogen or methyl, as well as readily 
hydrolysable esters and salts of these compounds and hydrates of the 
compounds of formula I or of their esters and salts. 
As readily hydrolysable esters of the compounds of formula I there are to 
be understood compounds of formula I, the carboxy group of which is 
present in the form of a readily hydrolysable ester group. Examples of 
such esters, which can be of the conventional type, are the lower 
alkanoyloxyalkyl esters, e.g. the acetoxymethyl, pivaloyloxymethyl, 
1-acetoxyethyl and 1-pivaloyloxyethyl ester; the lower 
alkoxycarbonyloxyalkyl esters, e.g. the methoxycarbonyloxymethyl, 
1-ethoxycarbonyloxyethyl and 1-isopropoxycarbonyloxyethyl ester; the 
lactonyl esters e.g. the phthalidyl and thiophthalidyl ester; the lower 
alkoxymethyl esters, e.g. the methoxymethyl ester; and the lower 
alkanoylaminomethyl esters, e.g. the acetamidomethyl ester. Other esters, 
e.g. the benzyl and cyanomethyl esters, can also be useful. 
Examples of salts of the compounds of formula I are 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, e.g. salts with N-ethyl-piperidine, procaine, dibenzylamine, 
N,N'-dibenzylethylenediamine, alkylamines or dialkylamines, as well as 
salts with amino acids such as e.g. salts with arginine or lysine. 
The compounds of formula I likewise form addition salts with organic or 
inorganic acids. Examples of such salts are hydrohalides, for example 
hydrochlorides, hydrobromides, hydroiodides, as well as other mineral acid 
salts such as sulphates, nitrates, phosphates and the like, alkyl- and 
monoaryl-sulphonates such as ethanesulphonates, toluenesulphonates, 
benzenesulphonates and the like and also other organic acid salts such as 
acetates, tartrates, maleates, citrates, benzoates, salicylates, 
ascorbates and the like. 
The compounds of formula I (including their salts and readily hydrolysable 
esters) can be hydrated. The hydration can be effected in the course of 
the manufacturing process or can occur gradually as a result of 
hygroscopic properties of an initially anhydrous product. 
The products in accordance with the invention can be present in the 
syn-isomeric form 
##STR3## 
or in the anti-isomeric form 
##STR4## 
or as mixtures of these two forms. The syn-isomeric form or mixtures in 
which the syn-isomeric form predominates is/are preferred. 
Preferred products are 
(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[(Z)-methoxyimino]acetamido]-3-[[(2,5- 
dihydro-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyc 
lo[4.2.0]oct-2-ene-2-carboxylic acid, 
(6R,7R)-7-[2-(2-amino-4-thiazolyl-2-[(Z)-methoxyimino]acetamido]-3-[[2,5-di 
hydro-2,6-dimethyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabic 
yclo[4.2.0]oct-2-ene-2-carboxylic acid and their salts as well as the 
corresponding hydrates. 
The above acyl derivatives are manufactured in accordance with the 
invention in that 
(a) the protecting group R, opt. also a carboxy protecting group possibly 
present, in a compound of the general formula 
##STR5## 
in which CH.sub.3 has the significance given above, R represents a 
cleavable protecting group and the carboxy group can be present in 
protected form, is cleaved off, or in that 
(b) for the manufacture of a readily hydrolysable ester of a compound of 
formula I, a carboxylic acid of formula I is subjected to a corresponding 
esterification, or in that 
(c) for the manufacture of salts or hydrates of a compound of formula I or 
hydrates of these salts, a compound of formula I is converted into a salt 
or hydrate or into a hydrate of this salt. 
If desired, the carboxy group present in the starting compound of formula 
II can be protected, e.g. by esterification to give a readily cleavable 
ester such as a silyl ester, e.g. the trimethylsilyl ester. The readily 
hydrolysable esters elucidated above also come into consideration. The 
carboxy group can also 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 
e.g. t-butoxycarbonyl or trityl, or also basic-hydrolytically cleavable 
protecting groups such as e.g. trifluoroacetyl. Preferred R-protecting 
groups are chloro-, bromo- and iodoacetyl, especially chloroacetyl. The 
latter protecting groups can be cleaved off by treatment with thiourea. 
The starting compounds of formula II can be manufactured e.g. by 
N-acylation of the corresponding 7-amino compound, namely by reacting a 
compound of the general formula 
##STR6## 
in which R.sup.1 has the significance given above and the carboxy group 
and/or the amino group can be present in protected form, with an acid of 
the general formula 
##STR7## 
in which R has the significance given above, or with a reactive functional 
derivative of this acid and, if desired, cleaving off a carboxy protecting 
group possibly present. 
If desired, the carboxy group present in the 7-amino compound of formula 
III can be protected, namely in the manner elucidated above for the 
starting compound of formula II to be manufactured. The amino group of the 
compound of formula III can be protected e.g. by a silyl protecting group 
such as trimethylsilyl. 
As reactive functional derivatives of acids of formula IV there come into 
consideration e.g. halides, i.e. chlorides, bromides and fluorides; 
azides; anhydrides, especially mixed anhydrides with strong acids; 
reactive esters, e.g. N-hydroxysuccinimide esters, and amides, e.g. 
imidazolides. 
The reaction of the 7-amino compound of formula III with the acid of 
formula IV or a reactive functional derivative thereof can be carried out 
in a manner known per se. Thus, e.g. a free acid of formula IV can be 
condensed with one of the mentioned esters corresponding to formula III by 
means of a carbodiimide such as dicyclohexylcarbodiimide in an inert 
solvent such as ethyl acetate, acetonitrile, dioxan, chloroform, methylene 
chloride, benzene or dimethylformamide and subsequently the ester group 
can be cleaved off. In place of carbodiimides there can also be used as 
the condensation agent oxazolium salts, e.g. 
N-ethyl-5-phenyl-isoxazolium-3'-sulphonate. 
According to another embodiment, a salt of an acid of formula III, e.g. a 
trialkylammonium salt such as the triethylammonium salt, is reacted with a 
reactive functional derivative of an acid of formula IV as mentioned above 
in an inert solvent, e.g. one of the above-named. 
According to a further embodiment, an acid halide, preferably the chloride, 
of an acid of formula IV is reacted with the amine of formula III. The 
reaction is preferably effected in the presence of an acid-binding agent, 
e.g. in the presence of aqueous alkali, preferably sodium hydroxide, or 
also in the presence of an alkali metal carbonate such as potassium 
carbonate or in the presence of a lower-alkylated amine such as 
triethylamine. As the solvent there is preferably used water, opt. in 
mixture with an inert organic solvent such as tetrahydrofuran or dioxan. 
The reaction can also be performed in an aprotic organic solvent such as 
e.g. dimethylformamide, dimethyl sulphoxide or hexamethylphosphoric acid 
triamide. With the use of silylated starting compounds of formula III the 
reaction is performed in anhydrous medium. 
The reaction of the 7-amino compound of formula III with the acid of 
formula IV or a reactive functional derivative thereof can conveniently be 
effected at temperatures between about -40.degree. C. and room 
temperature, for example at about 0.degree.-10.degree. C. 
The starting compounds of formula II can also be manufactured by 
thiolation, namely by reacting a compound of the general formula 
##STR8## 
in which R has the significance given above, Y represents a leaving group 
and the carboxy group can be present in protected form, with a thiol of 
the general formula 
##STR9## 
in which R.sup.1 has the significance given above, and, if desired, 
cleaving off a carboxy protecting group possibly present. 
As the leaving group Y of a compound of formula V there come into 
consideration, for example, halogens, e.g. chlorine, bromine or iodine, 
acyloxy residues, e.g. lower alkanoyloxy residues such as acetoxy, lower 
alkyl- or arylsulphonyloxy residues such as mesyloxy or tosyloxy, or the 
azido residue. The compound V can be protected at the carboxy group in the 
manner elucidated for the starting compound of formula II. 
The reaction of the compound of formula V with the thiol of formula VI can 
be carried out in a manner known per se, e.g. at a temperature between 
about 40.degree. and 80.degree. C., conveniently at about 60.degree. C., 
in a polar solvent, for example in an alcohol such as e.g. in a lower 
alkanol such as ethanol, propanol and the like, in dimethylformamide or 
dimethyl sulphoxide, preferably in water or in a buffer solution with a pH 
of about 6 to 7, preferably 6.5. 
The thiols of formula VI stand in tautomeric equilibrium with the 
corresponding thiones. Their manufacture is described in Examples 1 and 2. 
In accordance with process variant (a) of the process in accordance with 
the invention, the amino protecting group R of a starting compound of 
formula II is cleaved off. Protecting groups cleavable by acid hydrolysis 
are preferably removed with the aid of a lower alkanecarboxylic acid which 
opt. can be halogenated. In particular, formic acid or trifluoroacetic 
acid is used. The temperature is as a rule room temperature, although 
slightly higher or slightly lower temperature can be used, e.g. in the 
range of about 0.degree. C. to +40.degree. C. Protecting groups cleavable 
alkalinically are generally hydrolysed with dilute aqueous caustic alkali 
at 0.degree. C. to 30.degree. C. The chloroacetyl, bromoacetyl and 
iodoacetyl protecting groups can be cleaved off by means of thiourea in 
acidic, neutral or alkaline medium at about 0.degree.-30.degree. C. 
Hydrogenolytic cleavage (e.g. cleavage of benzyl) is unsuitable in this 
case, since the oxime function is reduced to the amino group during the 
hydrogenolysis. 
After carrying our process variant (a), a carboxy protecting group possibly 
present in the reaction product can be cleaved off if desired. When the 
protecting group represents a silyl group (silyl ester), this group can be 
cleaved off especially readily by treatment of the reaction product with 
water. Lower alkanoyloxyalkyl, alkoxycarbonyloxyalkyl, lactonyl, 
alkoxymethyl and alkanoylaminomethyl esters are preferably cleaved 
enzymatically with the aid of a suitable esterase (at about 
20.degree.-40.degree. C.). When the carboxy group is protected by salt 
formation (e.g. with triethylamine), then the cleavage of this 
salt-forming protecting group can be effected by treatment with acid. As 
the acid there can hereby be used e.g. hydrochloric acid, sulphuric acid, 
phosphoric acid or citric acid. 
The carboxy protecting group can be cleaved off in the same manner as just 
described also before the cleavage of the protecting group R. 
For the manufacture of the readily hydrolysable esters of the carboxylic 
acids of formula I in accordance with variant (b), the carboxylic acid is 
preferably reacted with the corresponding halide containing the ester 
group, preferably with the iodide. The reaction can be accelerated with 
the aid of a base, e.g. an alkali metal hydroxide or carbonate or an 
organic amine such as triethylamine. The esterification reaction is 
preferably carried out in an inert organic solvent such as 
dimethylacetamide, hexamethylphosphoric acid triamide, dimethyl sulphoxide 
or preferably, dimethylformamide. The temperature preferably lies in the 
range of about 0.degree.-40.degree. C. 
The manufacture of the salts and hydrates of the compounds of formula I or 
the hydrates of these salts can be effected in a manner known per se, e.g. 
by reaction of the carboxylic acid of formula I with an equivalent amount 
of the desired base, conveniently in a solvent such as water or in an 
organic solvent such as ethanol, methanol, acetone and many others. The 
temperature of the salt formation is not critical. It lies in general at 
room temperature, but can also be slightly thereover or thereunder, about 
in the range of 0.degree. C. to +50.degree. C. 
The manufacture of the hydrates for the most part takes place automatically 
in the course of the manufacturing process or as a result of hygroscopic 
properties of an initially anhydrous product. For the controlled 
manufacture of a hydrate, a completely or partially anhydrous product 
(carboxylic acid of formula I or ester, ether or salt thereof) can be 
exposed to a moist atmosphere, e.g. at about +10.degree. C. to +40.degree. 
C. 
The 7-amino compounds of formula III used above can be manufactured 
starting from a compound of the formula 
##STR10## 
in which Y represents a leaving group and the carboxy group can be present 
in protected form, with a thiol of formula VI. The reaction can be 
effected under the same conditions as those which have been described for 
the reaction of the starting compounds V with VI. On the other hand, the 
compounds of formula V can be manufactured starting from a compound of 
formula VII and an acid of formula IV or a reactive functional derivative 
thereof under the same conditions as have been described for the reaction 
of the compounds of formulae III and IV. 
A possibly obtained syn/anti mixture of a compound of formula I can be 
separated into the corresponding syn- and anti-forms in the customary 
manner, for example by recrystallisation or by chromatographical methods 
with the use of a suitable solvent or solvent mixture. 
The compounds of formula I and II as well as the corresponding readily 
hydrolysable esters and salts or the hydrates of these products are 
antibiotically, especially bactericidally, active. They possess a broad 
spectrum of action against gram-positive bacteria, e.g. Staphylococci, and 
against gram-negative bacteria such as e.g. Haemophilus influenzae, 
Neisseria gonorrhoeae, as well as against various .beta.-lactamase-forming 
gram-negative germs such as Escherichia coli, Serratia marcescens, 
Pseudomonas aeruginosa, Proteus mirabilis, Proteus vulgaris. 
The compounds of formula I and II as well as the corresponding readily 
hydrolysable esters and salts or the hydrates of these products can be 
used for the treatment and prophylaxis of infectious diseases. A daily 
dosage of about 0.1 g to about 2 g comes into consideration for adults. 
The parenteral administration of the compounds in accordance with the 
invention is especially preferred. 
For the demonstration of the antimicrobial activity of the mentioned 
products, the following representative representatives were tested: 
Product A: 
(6R,7R)-7-[2-(2-amino-5-thiazolyl)-2-[(Z)-methoxyimino]acetamido]-3-[[(2,5- 
dihydro-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyc 
lo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt 
Product B: 
(6R,7R)-7-[2-(2-amino-4-thiazolyl-2-[(Z)-methoxyimino]acetamido]-3-[[(2,5-d 
ihydro-2,6-dimethyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabi 
cyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt. 
______________________________________ 
Activity in vitro: Minimum inhibitory concentration 
(.mu.g/ml) 
Pathogenic agent A B 
______________________________________ 
Escherichia coli* 0.04 0.08 
Serratia marcescens* 0.16 0.32 
Enterobacter cloacae* 
2.5 2.5 
Proteus mirabilis* 0.04 0.08 
Proteus vulgaris* 0.02 0.02 
Pseudomonas aeruginosa 
strain 1* 40 80 
strain 2* 40 80 
Haemophilus influenzae 
0.02 0.02 
Neisseria gonorrhoeae 
0.02 0.02 
Staphylococcus aureus 
2.5 2.5 
______________________________________ 
*lactamase forming strain 
______________________________________ 
Toxicity 
Test substance A B 
______________________________________ 
LD.sub.100, mg/kg i.v. 
1000 500 
s.c. &gt;5000 &gt;4000 
p.o. &gt;5000 &gt;5000 
______________________________________ 
The products in accordance with the invention can find use as medicaments 
e.g. in the form of pharmaceutical preparations which contain them or 
their salts in mixture with a pharmaceutical, organic or inorganic inert 
carrier material suitable for enteral or parenteral application, such as 
e.g. water, gelatin, gum arabic, lactose, starch, magnesium stearate, 
talc, vegetable oils, polyalkylene glycols, Vaseline, etc. The 
pharmaceutical preparations can be present in solid form, e.g. as tablets, 
dragees, suppositories, capsules; or in liquid form, e.g. as solutions, 
suspensions or emulsions. If necessary, they are sterilised and/or contain 
adjuvants such as preserving, stabilising, wetting or emulsifying agents, 
salts for the variation of the osmotic pressure, anaesthetics or buffers. 
The can also contain still other therapeutically valuable substances. The 
compounds of formula I and their salts or hydrates come into consideration 
preferably for parenteral application and for this purpose are preferably 
prepared as lyophilisates or dry powders for dilution with customary 
agents such as water or isotonic sodium chloride solution. The readily 
hydrolysable esters of the compounds of formula I and their salts or 
hydrates also come into consideration for enteral administration.

In the following working Examples all temperatures are given in 
.degree.Centigrade. 
EXAMPLE 1 
(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[(Z)-methoxyimino]-acetamido]-3-[[(2,5 
-dihydro-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicy 
clo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt 
61 g of 
(6R,7R)-7-[2-(chloroacetamido-4-thiazolyl)-2-[(Z)-methoxyimino]-acetamido] 
-3-[[(2,5-dihydro-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 are treated in 1.5 l of 
water with 30.4 g of thiourea and, with nitrogen gasification and 
stirring, held for 20 hours at a pH-value of 7.0 with 1N sodium hydroxide 
via autotitrator. The pH-value is adjusted to 3.75 by dropwise addition of 
1N HCl while stirring. The separated precipitate is filtered off under 
suction and rejected. Now, the filtrate is adjusted to a pH-value of 3.0 
with 1N hydrochloric acid while stirring, the precipitate is filtered off 
under suction, washed with water, ethanol and petroleum ether and dried. 
The crude product obtained is suspended in 90 ml of acetone/water (1:1), 
treated with 45 ml of a 2N solution of sodium 2-ethylcaproate in ethyl 
acetate, stirred up to complete solution and thereafter precipitated with 
dropwise addition into 800 ml of acetone while stirring. The sodium salt 
is filtered off under suction, washed with acetone, ether and petroleum 
ether and dried. For further purification, the substance is dissolved in 
800 ml of methanol while stirring and filtered off from a little 
undissolved substance. The filtrate is treated with active charcoal, 
filtered, evaporated to ca 400 ml in vacuo and filtered off from a little 
precipitated substance. The filtrate is precipitated with dropwise 
addition of 1.6 l of ethyl acetate, filtered off under suction, washed 
with ethyl acetate, ether and petroleum ether and dried. There is obtained 
(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[(Z)-methoxyimino]acetamido]-3-[[(2,5 
-dihydro-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicy 
clo[4.2.0]oct-2-ene-carboxylic acid sodium salt; m.p.=from 192.degree. slow 
dec. [.alpha.].sub.D.sup.25 =-135.degree. (c=1 in water). 
The 
(6R,7R)-7-[2-(chloroacetamido-4-thiazolyl)-2-[(Z)-methoxyimino]acetamido]- 
3-[[(2,5-dihydro-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 used as the starting 
substance can be manufactured as follows: 
2-Methyl-5-oxo-3-thioxo-2,3,4,5-as-triazine 
84 g of 2-methyl-thiosemicarbazide are introduced portionwise into a 
solution of 80.8 g of glyoxylic acid hydrate in 450 ml of 
dimethylformamide. The suspension is stirred at 80.degree. for 45 minutes. 
The reaction mixture is cooled, treated with 2.5 l of water and the 
suspension is stirred at 0.degree. for 1 hour. After filtration under 
suction, washing with water and drying, there is obtained the 
2-methyl-thiosemicarbazone of glyoxylic acid, m.p. 204.degree.-205.degree. 
(dec.). This substance is introduced while stirring into a solution of 74 
g of sodium carbonate in 700 ml of water and thereafter heated at 
95.degree.-98.degree. for 3 hours while stirring. The solution is cooled 
to 5.degree. and adjusted to a pH-value of 2 with stirring and dropwise 
addition of conc. hydrochloric acid. After suction filtration, washing 
with ice/water and drying, there is obtained 
2-methyl-5-oxo-3-thioxo-2,3,4,5-as-triazine, m.p. 221.degree.-222.degree.. 
(6R,7R)-7-amino-3-[[(2,5-dihydro-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 
27.2 g of 7-amino-cephalosporanic acid are treated in 200 ml of water while 
stirring first of all portionwise with 23.1 g of sodium hydrogen carbonate 
and thereafter with 21.5 g of 2-methyl-5-oxo-3-thioxo-2,3,4,5-as-triazine. 
Subsequently, the mixture is heated at 60.degree. for 5 hours with 
nitrogen gasification. The solution is cooled to 5.degree., adjusted to a 
pH-value of 3.5 with conc. hydrochloric acid, the precipitated substance 
is filtered off, washed with water and stirred twice with 230 ml of 
methanol each time, filtered off, washed with methanol and ether and dried 
in vacuo. There is obtained 
(6R,7R)-7-amino-3-[[(2,5-dihydro-2-methyl-5-oxo-as-triazin-3-yl)thio]methy 
l]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, m.p. from 
195.degree. dec., which is further reacted without further purification. 
(6R,7R)-7-[2-(chloroacetamido-4-thiazolyl)-2-[(Z)-methoxyimino]acetamido]-3 
-[[(2,5-dihydro-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 
63 ml of N,N'-dimethylformamide are added dropwise to a -20.degree. cold 
suspension of 34.5 g of phosphorus pentachloride in 500 ml of 
dichloromethane, the mixture is stirred at -15.degree. for 10 minutes, 
thereafter cooled to -25.degree., treated with 46 g of 
2-(2-chloroacetamido-4-thiazolyl)-2-methoxyimino-acetic acid (syn-form) 
and stirred at -15.degree. for 45 minutes. The solution is cooled to 
-30.degree., mixed with 50 g of ice, whereby the temperature rises to 
-15.degree.. 
The mixture is stirred at -15.degree. for 10 minutes and then the 
dichloromethane solution is separated off. It is cooled to -15.degree. and 
employed immediately for the following acylation. 
Meanwhile, 61 g of 
(6R,7R)-7-amino-3-[[2,5-dihydro-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 are dissolved 
in 800 ml of water at a pH-value of 7.8 via autotitrator by dropwise 
addition of 2N sodium hydroxide while stirring and cooled to 0.degree.. At 
this temperature there is added dropwise within 45 minutes the above 
-15.degree. cold dichloromethane solution of the acid chloride and a 
pH-value of 7.8-8.0 is maintained by simultaneous dropwise addition of 2N 
sodium hydroxide via autotitrator. The mixture is subsequently stirred for 
a further 30 minutes at 5.degree. and for 1 hour at 20.degree.. The 
solution is treated with 500 ml of n-butanol and 500 ml of 
dichloromethane, whereafter it is adjusted to a pH-value of 7 with citric 
acid, stirred for 5 minutes at this pH-value and subsequently filtered in 
vacuo. The organic phase is separated, washed 3 times with 200 ml of water 
each time, treated with active charcoal, filtered off and evaporated in 
vacuo at 55.degree. to ca 200 ml. The suspension obtained is cooled to 
20.degree. and filtered in vacuo. There is obtained a 1st fraction of 
solid (6R,7R)-7-[2-(chloroacetamido-4-thiazolyl)-2-[(Z)-methoxyimino]-acet 
amido]-3-[[(2,5-dihydro-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. The mother liquor is 
evaporated to 100 ml in vacuo, mixed with 100 ml of ether and yields, 
after suction filtration, a 2nd fraction of the mentioned acid. Both 
fractions are dissolved together in 2 l of acetone while stirring within 
15 minutes and filtered off from insolubles. 300 ml of butyl acetate are 
added to the filtrate and the acetone is distilled off in vacuo until the 
substance crystallises. There is obtained 
(6R,7R)-7-[2-(chloroacetamido-4-thiazolyl)-2-[(Z)-methoxyimino]-acetamido] 
-3-[[(2,5-dihydro-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, m.p. from 173.degree. dec., 
[.alpha.].sub.D.sup.25 =-238.7.degree. (c=1 in dimethylformamide). The 
product is uniform in accordance with thin-layer chromatography in the 
system n-propanol/acetic acid/water 55/15/30 and is further reacted 
without further purification. 
EXAMPLE 2 
(6R,7R)-7-[2-(2-amino-4-thiazolyl-2-[(Z)-methoxyimino]acetamido]-3-[[(2,5-d 
ihydro-2,6-dimethyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabi 
cyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt 
37 g of 
(6R,7R)-7-[2-(chloroacetamido-4-thiazoly)-2-[(Z)-methoxyimino]-acetamido]- 
3-[[2,5-dihydro-2,6-dimethyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thi 
a-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and 18 g of thiourea are 
suspended in 800 ml of water and held at a pH-value of 7.0 for 20 hours 
with 1N sodium hydroxide via autotitrator with nitrogen gasification and 
stirring. The pH-value is adjusted to 4.0 by dropwise addition of 1N HCl 
while stirring and separated sludge is filtered off. Further 1N 
hydrochloric acid is added dropwise to the filtrate up to a pH-value of 
2.8. The precipitate is filtered off under suction, washed with water, 
ethanol, ether and petroleum ether and dried. The substance is suspended 
in 30 ml of water, brought into solution by addition of 30 ml of a 2N 
solution of sodium 2-ethylcaproate and the solution is precipitated in 500 
ml of acetone with dropwise addition and stirring. The sodium salt is 
filtered off under suction, washed with acetone, ether and petroleum ether 
and re-precipitated a further twice from water/acetone. This product is 
dissolved with 80 percent aqueous ethanol, filtered, concentrated in 
vacuo, evaporated several times with ethanol/butyl acetate, filtered off 
under suction and finally re-precipitated further from methanol/butyl 
acetate. There is obtained 
(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[(Z)-methoxyimino]acetamido]-3-[[(2,5 
-dihydro-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicy 
clo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt, m.p. from 180.degree. 
dec., [.alpha.].sub.D.sup.25 =-164.degree. (c=1 in water). 
The 
(6R,7R)-6-[2-(chloroacetamido-4-thiazolyl)-2-[(Z)-methoxyimino]-acetamido] 
-3-[[2,5-dihydro-2,6-dimethyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-th 
ia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid used as the starting 
compound can be manufactured as follows: 
2,6-Dimethyl-5-oxo-3-thioxo-2,3,4,5-as-triazine 
30 ml of pyruvic acid are dissolved in a solution of 42.4 g of sodium 
bicarbonate and 500 ml of water, treated with 42 g of 
2-methyl-thiosemicarbazide and stirred at 95.degree. for 2 hours. Conc. 
hydrochloric acid is slowly added dropwise to the cooled solution while 
stirring until a pH-value of 3.8 is reached. The precipitated substance is 
filtered off under suction, washed with water and recrystallised from 
methanol/water. There is obtained 
2,6-dimethyl-5-oxo-3-thioxo-2,3,4,5-as-triazine, 
m.p.=162.degree.-164.degree.. 
(6R,7R)-7-amino-3-[[(2,5-dihydro-2,6-dimethyl-5-oxo-as-triazin-3-yl)thio]me 
thyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 
27.2 g of 7 -amino-cephalosporanic acid are dissolved in 200 ml of water at 
pH 7.0 by addition of 1N sodium hydroxide via autotitrator while stirring. 
Thereto there are added 18.9 g of 
2,6-dimethyl-5-oxo-3-thioxo-2,3,4,5-as-triazine and the mixture is 
adjusted to a pH-value of 6.75 with 1N sodium hydroxide. Thereafter, the 
mixture is heated at 55.degree. for 5 hours under nitrogen gasification. 
The solution, cooled to 5.degree., is adjusted to a pH-value of 3.8 with 
3N hydrochloric acid while stirring, the precipitated substance is 
filtered off under suction, washed with water and acetone and dried. For 
the purification, the powdered substance is suspended several times in 
methane, filtered off, washed with methanol and ether and dried. There is 
obtained 
(6R,7R)-7-amino-3-[[(2,5-dihydro-2,6-dimethyl-5-oxo-as-triazin-3-yl)thio]m 
ethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid; m.p. 
from 190.degree. slow dec. The substance is further reacted without 
further purification. 
(6R,7R)-7-[2-(chloroacetamido-4-thiazolyl)-2-[(Z)-methoxyimino]-acetamido]- 
3-[[2,5-dihydro-2,6-dimethyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thi 
a-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 
41.8 ml of N,N'-dimethylacetamide are added dropwise to a -20.degree. cold 
suspension of 22.7 g of phosphorus pentachloride in 400 ml of 
dichloromethane, the mixture is stirred at -15.degree. for 10 minutes, 
thereafter cooled to -25.degree., treated with 30.4 g of 
2-(2-chloroacetamido-4-thiazolyl)-2-methoxyimino-acetic acid (syn-form) 
and stirred at -15.degree. for 45 minutes. Thereafter, the solution is 
cooled to -30.degree., mixed with 40 g of ice, whereby the temperature 
rises to -15.degree.. The mixture is further stirred at -15.degree. for 10 
minutes, then the dichloromethane solution is separated off, it is cooled 
to -15.degree. and it is used immediately for the following acylation. 
Meanwhile, 41.8 g of 
(6R,7R)-7-amino-3-[[2,5-dihydro-2,6-dimethyl-5-oxo-as-triazin-3-yl)thio]me 
thyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid are 
dissolved in 600 ml of water at a pH-value of 7.8 via autotitrator by 
dropwise addition of 2N sodium hydroxide while stirring and cooled to 
0.degree.. At this temperature there is added dropwise within 45 minutes 
the above -15.degree. cold dichloromethane solution of the acid chloride 
and the mixture is maintained at a pH-value of 7.8-8.0 by simultaneous 
dropwise addition of 2N sodium hydroxide via autotitrator. The mixture is 
subsequently stirred for a further 30 minutes at 5.degree. and for 1 hour 
at 20.degree.. 500 ml of n-butanol and 500 ml of under suction. The 
substance is dissolved in ca 800 ml of acetone while stirring, filtered, 
treated with 200 ml of butyl acetate and evaporated in vacuo to ca 300 ml, 
whereby the substance precipitates. It is filtered off under suction, 
washed with butyl acetate, hexane and petroleum ether and dried. There is 
obtained 
(6R,7R)-7-[2-(chloroacetamido-4-thiazolyl)-2-[(Z)-methoxyimino]acetamido]- 
3-[[2,5-dihydro-2,6-dimethyl-5-oxo-as-triazin-3-yl)-thio]methyl]-8-oxo-5-th 
ia-1-azabicyclo[4.2.0]oct- 2-ene-2-carboxylic acid, m.p. 
162.degree.-164.degree. dec. [.alpha.].sub.D.sup.25 =-272.2.degree. (c=1 
in dimethylformamide). dichloromethane are added to the solution, the 
mixture is adjusted to a pH-value of 3 with citric acid, stirred at this 
pH-value for 5 minutes and the whole is filtered in vacuo. The organic 
phase is separated, washed 3 times with 200 ml of water each time, treated 
with active charcoal, filtered and evaporated at 55.degree. in vacuo to a 
volume of 100 ml. It is mixed with 300 ml of ether and the precipitate is 
filtered off under suction. 
EXAMPLE 3 
Methylene 
(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[(Z)-methoxyimino]acetamido]-3-[[(2,5 
-dihydro-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicy 
clo[4.2.0]oct-2-ene-2-carboxylate pivalate 
8 g of 
(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[(Z)-methoxyimino]acetamido]-3-[[(2,5 
-dihydro-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicy 
clo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt are dissolved in 80 ml of 
dimethylformamide, cooled to 0.degree., treated with 6 g of 
pivaloyloxymethyl iodide and stirred at 0.degree. for 30 minutes. The 
solution is precipitated in ice/water, the precipitate is filtered off in 
vacuo, dissolved in ethyl acetate with addition of some methanol, washed 
with sodium hydrogen carbonate solution and sodium chloride solution, 
dried with magnesium sulphate and evaporated in vacuo up to the beginning 
of crystallisation. The crystallisation is completed by addition of a 
mixture of ether-petroleum ether 1:1. The substance is filtered off and 
subsequently chromatographed over silica gel with benzene/methanol 4:1. 
The uniform fractions are combined, evaporated in vacuo and finally 
crystallised from chloroform/ether. There is obtained methylene 
(6R,7R)-7-[2-(2-amino-4-thiazolyl)- 
2-[(Z)-methoxyimino]acetamido]-3-[[(2,5-dihydro-2-methyl-5-oxo-as-triazin- 
3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 
pivalate. M.p.=149.degree. dec., [.alpha.].sub.D.sup.25 =-173.degree. (c=1 
in dimethylformamide). 
EXAMPLE 4 
Methylene 
(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[(Z)-methoxyimino]acetamido]-3-[[(2,5 
-dihydro-2,6-dimethyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-1-aza 
bicyclo[4.2.0]oct-2-ene-2-carboxylate pivalate 
5.7 g of 
(6R,7R)-7-[2-(2-amino-4-thiazolyl-2-[(Z)-methoxyimino]acetamido]-3-[[2,5-d 
ihydro-2,6-dimethyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabi 
cyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt are treated in 30 ml of 
dimethylformamide at 0.degree. with 4 g of pivaloyloxymethyl iodide and 
stirred at 0.degree. for 30 minutes. The solution is precipitated in 
ice/water and the precipitate is filtered off in vacuo. The substance is 
dissolved in ethyl acetate, washed with sodium hydrogen carbonate solution 
and sodium chloride solution, dried over magnesium sulphate, evaporated in 
vacuo and mixed with ether. The solid substance is chromatographed over 
silica gel with benzene/methanol 85:15. The uniform fractions are 
combined, evaporated up to the beginning of crystallisation, mixed with 
ether and filtered off under suction. There is obtained methylene 
(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[(Z)-methoxyimino]acetamido]-3-[[2,5- 
dihydro-2,6-dimethyl-5-oxo-as-triazin-3-yl)thio] 
methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate pivalate, 
m.p. from 146.degree. dec., [.alpha.].sub.D.sup.25 =-214.degree. (c=1 in 
dimethylformamide). 
EXAMPLE 5 
Manufacture of dry ampoules for intramuscular administration: 
A lyophilisate of 1 g of the active substance is manufactured in the 
customary manner and filled into an ampoule. Prior to the administration, 
the lyophilisate is treated with 2.5 ml of a 2% aqueous lidocaine 
hydrochloride solution.