DE2707565C2 - - Google Patents

Description

The invention relates to the new syn isomer of [7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carb-one acid] including the usual protecting groups and salts, preferably the pharmaceutically acceptable salts, the antibacterial activity (Efficacy) has, processes for their preparation and containing them pharmaceutical agents and their therapeutic use in the treatment of infectious diseases in humans and animals.

The aim of the present invention is to develop this new syn isomer and its salts, preferably its pharmaceutically acceptable salts, to provide the opposite a number of pathogenic bacteria are highly active.

The aim of the invention is also to produce processes of this syn isomer and its salts, preferably of its pharmaceutically acceptable salts.

The aim of the invention is also pharmaceutical agents specify the active ingredient (active ingredient) of this Syn isomers and pharmaceutically acceptable salts thereof contain.

Finally, the aim of the invention is the use of these compounds in the treatment of injection diseases caused by pathogenic Bacteria are caused in humans and animals.  

The syn isomer of [7- [2-methoxyimino- 2- (2-aminothiazol-4-yl) acetamido] -3-carbamoyloxymethyl-3-cephem- 4-carboxylic acid] is new and can be represented by the general formula will:

including the usual protecting groups and salts, in particular the pharmaceutically acceptable salts.

It should be noted that the subject of the invention is the syn isomer of [7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-carbamoyloxym-ethyl- 3-cephem-4-carboxylic acid] is represented by the above formula (I) is and also by the substructure of the formula

can be represented in their molecules while the corresponding anti Isomers due to the partial structure of the formula

can be represented.

Accordingly, the following detailed explanations apply to the Invention both in the description and in the claims the syn- Isomers of the compounds according to the invention and those used according to the invention Starting compounds through the partial structure of the formula

are represented in their molecules, with the proviso that when it is  for the explanation of the invention is expedient both the syn Expressing isomers as well as anti-isomers by a general formula them through the substructure of the formula

can be displayed.

The compounds of formula I according to the invention are new connections and can be described below Method 1 to 3 are prepared.

Procedure 1

Procedure 2

Procedure 3

wherein

R¹ represents a common amino protecting group and also R represents a common amino protecting group.

Place the output connections under the output connections of formula (III) including the corresponding Anti-isomers are new compounds and they can be used Processes are prepared by the following reaction scheme can be represented:

wherein

XHalogen; Zprotected carboxy; R⁷Amino or protected amino; R ^7a protected amino; R ^7b amino; R ⁷ amino; R ^{1c is} a group of the formula wherein R⁷ has the meanings given above; and Z _{a is} carboxy or protected carboxy.

The other starting compounds (IV) and (V) are also new compounds and can be prepared by methods 1 to 3 above will.

With regard to the compounds of the formulas (I) according to the invention and the starting compounds of the formulas (III), (III _e ), (III _f ), (IV), (V), (XXIII) - (XXIII _b ), (XXIX) to ( XXXVI) and (XXXIX) it should be noted that the compounds according to the invention and the starting compounds also include the tautomeric isomers with respect to their thiazole groups. That is, the group of the formula

wherein R ^{7e represents} amino or protected amino, in the formula of the compounds according to the invention and the starting compounds can also be represented by their tautomeric formula

wherein R ^{7f represents} imino or protected imino. This means that both groups (A) and (B) exist in the equilibrium state as so-called tautomeric forms, which can be represented by the following equilibrium:

wherein R ^7e and R ^7f each have the meanings given above.

These types of tautomerism between 2-amino and 2-imino compounds, as stated above, are known in the literature and it is readily apparent to those skilled in the art that both tautomeric isomers are in equilibrium with one another and are easily convertible into one another and consequently the compounds according to the invention also include these isomers. Accordingly, both tautomeric forms of the compounds (I) according to the invention and of the starting compounds (III), (III _e ), (III _f ), (IV), (V), (XXIII) to (XXIII _b ), (XXIX) to ( XXXVI) and (XXXIX) clearly within the scope of the present invention. In the description as well as in the examples and in the claims, the compounds according to the invention and the starting compounds which comprise (contain) the group of these tautomeric isomers are described for the sake of simplicity by using one of the terms therefor, ie by the formula

represents.  

Examples of suitable pharmaceutically acceptable salts of the syn isomer of the invention (I) are conventional non-toxic salts and these can include an inorganic one Salt such as B. a metal salt such as an alkali metal salt (e.g. a sodium, potassium salt) and an alkaline earth metal salt (e.g. a calcium, magnesium salt), an ammonium salt, an organic salt (e.g. a organic amine salt, such as a trimethylamine, triethylamine, Ethanolamine, diethanolamine, pyridine, picoline, dicyclohexylamine, N, N′-dibenzylethylenediamine salt, an organic acid salt (e.g. an acetate, maleate, Tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, an inorganic acid salt (e.g. a hydrochloride, Hydrobromide, sulfate, phosphate or a salt with an amino acid (such as arginine, aspartic acid, Glutamic acid).

Below are some suitable examples and explanations of the various definitions according to the invention are applied and fall within the scope of the invention, explained in more detail.

Under the term "low" here is if nothing other is indicated to understand that a designated Group contains 1 to 6 carbon atoms.  

A suitable halogen is e.g. B. chlorine, bromine, fluorine and iodine.

A suitable protected amino may include an acylamino and an amino group replaced by another conventional one Protecting group as the acyl group, such as. B. benzyl, is substituted.

A suitable protected carboxy and a suitable protected carboxy radical in the expression "protected carboxy (lower) alkyl" may include esterified carboxy, in which the ester may be one of the following:
e.g. B. a lower alkyl ester (such as methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, t-pentyl ester, hexyl ester, 2-cyclopropylethyl ester), where the lower alkyl radical may preferably contain 1 to 4 carbon atoms; a lower alkenyl ester (e.g. a vinyl ester, allyl ester); a lower alkynyl ester (e.g. an ethynyl ester, propynyl ester); a mono (or di or tri) halogen (lower) alkyl ester (e.g. a 2-iodoethyl ester, 2,2,2-trichloroethyl ester);
a lower alkanoyloxy (lower) alkyl ester (e.g. an acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 2-acetoxyethyl ester, 2-propionyloxyethyl ester);
a lower alkanesulfonyl (lower) alkyl ester (e.g. a mesyl methyl ester, 2-mesyl ethyl ester);
an Ar (lower) alkyl ester, e.g. B. a phenyl (lower) alkyl ester, which may have one or more suitable substituents (such as a benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, diphenyl methyl ester, bis (methoxyphenyl) methyl ester, 3,4 -Dimethoxybenzyl ester, 4-hydroxy-3,5-di-tert-butylbenzyl ester); an aryl ester which may have one or more suitable substituents (such as, for example, a phenyl ester, tolyl ester, tert-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester).

A preferred example of protected carboxy can be Lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, Propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, Hexyloxycarbonyl) having 2 to 7 carbon atoms, preferably with 2 to 5 carbon atoms.

To suitable acyl residues, like them above have been mentioned include e.g. B. carbamoyl, an aliphatic Acyl group and an acyl group which has an aromatic or heterocyclic ring contains. Suitable examples of the acyl are lower alkanoyl (such as formyl, acetyl, propionyl, Butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, Pivaloyl), preferably one with 1 to 4 Carbon atoms, especially one with 1 to 2 carbon atoms; Lower alkoxycarbonyl with 2 to 7 carbon atoms (such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, t-pentyloxycarbonyl, Hexyloxycarbonyl), preferably a those with 3 to 6 carbon atoms; Lower alkanesulfonyl (such as mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, Butanesulfonyl), preferably one with 1 to 4 Carbon atoms, especially one with 1 to 2 Carbon atoms; Arenesulfonyl (such as benzenesulfonyl, tosyl); Aroyl (such as benzoyl, toluoyl, naphthoyl, phthaloyl, Indancarbonyl); Ar (lower) alkanoyl (such as phenylacetyl, Phenylpropionyl); Ar (low) alkoxycarbonyl (such as benzyloxycarbonyl, phenethyloxycarbonyl).

The acyl radical mentioned above can have 1 to 3 suitable substituents have such. B. halogen (such as chlorine, bromine, Iodine or fluorine), hydroxy, cyano, nitro, lower alkoxy (such as methoxy, ethoxy, propoxy, isopropoxy), Lower alkyl (such as methyl, ethyl, propyl, isopropyl, butyl), Lower alkenyl (such as vinyl, allyl), Acyl such as B. halogen (low) alkanoyl (such as chloroacetyl, Dichloroacetyl, trichloroacetyl, trifluoroacetyl), Aryl (such as phenyl, tolyl). Suitable examples for the acyl with the substituent (s) may be  Mono (or di- or tri) halogen (low) alkanoyl (e.g. trifluoroacetyl, Trichloroacetyl), preferably a those with 2 to 4 carbon atoms; Mono (or Di or Tri) halogen (low) alkanoylcarbamoyl (such as trichloroacetylcarbamoyl), preferably one with 3 up to 4 carbon atoms.

Suitable amino protecting groups for R⁴ include z. B. acyl, such as halogen (low) alkanoyl (e.g. chloroacetyl, dichloroacetyl, Trichloroacetyl, trifluoroacetyl), preferably a those with 2 to 3 carbon atoms.

Suitable acid residues include e.g. B. a residue of an acid, such as B. an inorganic acid (such as hydrochloric acid, Hydrobromic acid, hydroiodic acid, sulfuric acid) or an organic acid (such as methanesulfonic acid, Benzenesulfonic acid, p-toluenesulfonic acid).

Below are the different manufacturing processes of the compounds according to the invention in detail explained in more detail.

Procedure 1

The compound (I) according to the invention or a salt thereof can be prepared by reacting compound (II) or a reactive derivative on the amino group or a salt thereof with the compound (III) or a reactive one Derivative on the carboxy group or a salt of which, this is a basic procedure for the preparation of the compound according to the invention (I) acts.

A suitable reactive derivative on the amino group the compound (II) z. B. be a conventional reactive Derivative as used in amidation e.g. B. a silyl derivative, which in the implementation of the compound (II) is formed with a silyl compound, such as. B. bis (trimethylsilyl) acetamide, Trimethylsilylacetamide.  

A suitable salt for the compound (II) z. B. be an acid addition salt, e.g. B. an organic acid salt (like an acetate, maleate, tartrate, benzenesulfonate, toluenesulfonate) or an inorganic acid salt (such as a hydrochloride, hydrobromide, sulfate, phosphate); a salt with an inorganic base, such as. B. an alkali metal salt (such as a sodium salt, potassium salt) Alkaline earth metal salt (such as a calcium salt, magnesium salt) or an ammonium salt; a salt with an organic Base (e.g. a triethylamine salt, pyridine salt).

A suitable reactive derivative on the carboxy group the compound (III) z. B. a conventional derivative as used in amidation.

The salts of compound (III) can be salts with an inorganic base, such as. B. an alkali metal salt (such as a sodium or potassium salt) or an alkaline earth metal salt (such as a calcium or magnesium salt) Salt with an organic base such as trimethylamine, triethylamine, Pyridine, a salt with an acid (such as hydrochloric acid or hydrobromic acid).

The implementation is usually in a conventional Solvents such as water, acetone, dioxane, acetonitrile, Chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, Ethyl acetate, N, N-dimethylformamide, pyridine or any other organic solvents which the Reaction not adversely affected. Under These solvents can be the hydrophilic solvents in the form of a mixture with water.

The reaction according to the invention is preferably carried out in the presence a condensing agent, such as. B. a so-called Vilsmeier Reagent such as B. (chloromethylene) dimethyl-ammonium chloride, that with the implementation of dimethylformamide Thionyl chloride or phosgene is formed, a compound by the reaction of dimethylformamide with phosphorus oxychloride is formed.

The reaction can also take place in the presence of an inorganic or an organic base, such as. B. an alkali metal hydroxide, an alkali metal bicarbonate, an alkali metal carbonate,  an alkali metal acetate, tri (lower) alkylamine, Pyridine, N- (Low) alkylmorpholine, N, N-Di- (lower) alkylbenzylamine, N, N-di- (lower) alkylaniline, as exemplified below will. If the base or the condensing agent is liquid, it can also be used as a solvent will. The reaction temperature is not critical and that The reaction is usually under cooling or at ambient temperature carried out.

It should be noted that in the invention Reaction when the starting compound (III) with the Compound (II) or a reactive derivative on the Amino group or a salt thereof in the presence, for example of phosphorus pentachloride, thionyl chloride is, only the corresponding anti-isomer to that of the invention Compound (I) or a mixture of the corresponding anti-isomers and the syn isomer as the invention Connection is specified even if the Compound (III), d. H. the syn isomer, as the starting compound is used. It goes without saying that at the preparation of the corresponding anti-isomer from the Starting compound (III) and compound (II) never the compound (I) according to the invention, d. H. the syn isomer, can be formed. It is believed that this tendency and uniqueness of the above response to the The fact is that the less stable syn Isomer has a tendency to change in the course of the reaction, for example in a so-called activation stage of Compound (III) partially or completely to the corresponding to isomerize more stable anti-isomers, so that as the compound according to the invention the isomerized compound, d. H. that of the compound (I) according to the invention appropriate anti-isomers can be formed.

For the selective preparation of the compound according to the invention (I), i. H. of the syn isomer, in high yield, the starting compound (III), d. H. the syn isomer can be used and suitable reaction conditions must be chosen. That is, the compound (I) of the invention, i. H. the  Syn isomers can be selectively and in high yield can be obtained if, for example, the reaction in Presence of a Vilsmeier reagent, as mentioned above, and performs at roughly neutral conditions. If the starting compound (III) is used in which R 1 is a group of the formula means

Compound (I), i. H. the syn isomer, obtained in a selective manner and in high yield be, if one the implementation of the corresponding Starting compound (III), d. H. of the syn isomer, with the compound (II) for example in the presence of a Vilsmeier reagent by the reaction of dimethylformamide has been prepared with phosphorus oxychloride, and under about neutral conditions. In this case notes that particularly good results are achieved can that the implementation in the presence of more than two Molecular equivalents of phosphorus oxychloride, based in each case on the Amount of starting compound (III), d. H. of the syn isomer, and dimethylformamide, as in the working examples specified. It can also give good results in this case can be achieved if the starting compound (III), d. H. the syn isomer, in the presence of a silyl compound (e.g. bis (trimethylsilyl) acetamide, trimethylsilylacetamide) subject to activation.

Regarding the reaction of the compound (II) with the compound (III) the following should be noted:

If the compound (II) wherein the carbamoyloxymethyl group is protected with an acyl group, used as the starting compound  depending on the reaction conditions the compound (I) according to the invention, in which the carbamoyloxymethyl group is protected with an acyl group or is free, be preserved; furthermore the protected carboxy group or the salts in compound (II) in the course of the reaction or in a Aftertreatment can be converted into the free carboxy group. These cases also fall within the scope of the present one Invention.

As can be seen from the explanation given above the method 1 a fundamental and the most advantageous Process for the preparation of the compound according to the invention (I), i. H. of the syn isomer.

Procedure 2

The compound (I) according to the invention or a salt thereof can be made in such a way that the connection (IV) or a salt thereof for an elimination reaction Subject removal of the amino protecting group. Examples of suitable salts of compound (IV) are Metal salt, an ammonium salt, an organic amine salt and Like. As stated above.

The elimination reaction according to the invention is carried out according to a carried out customary processes, for example by hydrolysis, Reduction, according to a procedure by implementing the Compound (IV) in which the protecting group is an acyl group,  with an imino halogenating agent and then with a Imino etherifying agent and, if necessary, the subject compound obtained to hydrolysis or the like

Hydrolysis can be a process in which an acid or a base or hydrazine is used. These procedures can vary depending on the type of eliminating protective groups can be selected. Under these The process is hydrolysis using an acid one of the common and preferred methods of elimination of protecting groups, such as B. substituted or unsubstituted Alkoxycarbonyl such as t-pentyloxycarbonyl, Alkanoyl such as formyl, cycloalkoxycarbonyl, substituted or unsubstituted aralkoxycarbonyl (such as benzyloxycarbonyl, substituted benzyloxycarbonyl), substituted phenylthio, substituted aralkylidene, substituted alkylidene, substituted cycloalkylidene. Examples of suitable acids are organic or an inorganic acid, such as formic acid, trifluoroacetic acid, Benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid and a preferred acid is an acid the usual way, for example by distillation under reduced pressure, easily from the reaction mixture can be removed, e.g. B. formic acid, trifluoroacetic acid, Hydrochloric acid. The one for implementation Suitable acid can vary depending on the type of protecting group to be eliminated to be chosen. If the elimination reaction is carried out with the acid, it can be in the presence or be carried out in the absence of a solvent. To suitable solvents include an organic solvent, Water or a mixture thereof. If trifluoroacetic acid the elimination reaction may preferably be used be carried out in the presence of anisole.  

The hydrolysis using hydrazine is used in the Rule for eliminating a protecting group, such as B. succinyl or phthaloyl. Hydrolysis with a base is preferably used for the elimination of an acyl group, e.g. B. of haloalkanoyl (such as trifluoroacetyl) applied. Suitable bases include e.g. B. an inorganic Base, such as an alkali metal hydroxide (such as sodium hydroxide, Potassium hydroxide), an alkaline earth metal hydroxide (like magnesium hydroxide, calcium hydroxide), an alkali metal carbonate (such as sodium carbonate, potassium carbonate), an alkaline earth metal carbonate (such as magnesium carbonate, Calcium carbonate), an alkali metal bicarbonate (like sodium bicarbonate, potassium bicarbonate), an alkali metal acetate (such as sodium acetate, potassium acetate), an alkaline earth metal phosphate (such as magnesium phosphate, Calcium phosphate), an alkali metal hydrogen phosphate (such as disodium hydrogen phosphate, dipotassium hydrogen phosphate), and an organic base, e.g. B. a trialkylamine (such as trimethylamine, triethylamine), Picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo [4,3,0] non-5-ene, 1,4-diazabicyclo- [2,2,2] octane, 2,5- Diazabicyclo [5,4,0] undecene-5. The hydrolysis under Use of a base is often in water or in a hydrophilic organic solvents or in a mixture carried out of it.

The acyl group in general can be among the protective groups by hydrolysis as indicated above or by other conventional hydrolysis can be eliminated. If it the acyl group is halogen-substituted alkoxycarbonyl or 8-quinolyloxycarbonyl, this can be done by Treatment with a heavy metal such as copper, zinc, be eliminated. The reductive elimination will generally for the elimination of a protecting group, such as B. haloalkoxycarbonyl (such as trichloroethoxycarbonyl),  substituted or unsubstituted aralkoxycarbonyl (such as benzyloxycarbonyl, substituted benzyloxycarbonyl), 2-pyridylmethoxycarbonyl applied. A suitable reduction can e.g. B. be the reduction with an alkali metal borohydride such as sodium borohydride.

Suitable iminohalogenating agents, which in a Methods like the one mentioned above can be used include phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, Phosphorus pentabromide, phosphorus oxychloride, thionyl chloride, Phosgene. The reaction temperature is not critical and implementation is usually at ambient temperature or carried out with cooling. To suitable Imino etherification agents with the reaction product obtained can be implemented include an alcohol, a metal alkylate (metal alkoxide). To suitable Alcohols can include an alkanol (such as methanol, ethanol, Propanol, isopropanol, butanol, t-butanol), the can be substituted by alkoxy (such as methoxy, ethoxy, Propoxy, isopropoxy, butoxy). Suitable metal alkylates (Metal alkoxides) can include an alkali metal alkylate (such as sodium alkylate, potassium alkylate) Alkaline earth metal alkylate (such as calcium alkylate, barium alkylate). The reaction temperature is not critical and the implementation is usually under cooling or at Ambient temperature.

The product thus obtained becomes one if necessary Subjected to hydrolysis. The hydrolysis can easily be done in this way be carried out by reacting the reaction mixture obtained above pouring in water, but before that, a hydrophilic one Solvent (such as methanol, ethanol), a base (such as alkali metal bicarbonate, trialkylamine) or one  Acid (such as dilute hydrochloric acid, acetic acid) be added to the water.

The reaction temperature is not critical and it can depending on the type of protective group for the amino group and according to the elimination method mentioned above Be selected and the reaction of the invention is preferably under mild conditions, for example under cooling, at ambient temperature or at slightly elevated Temperature.

The present invention also includes the cases where the protected carboxy group into the free carboxy group is converted; where when in connection (IV) the carbamoyloxymethyl group with an acyl group is provided depending on the Reaction conditions occasionally the compound of the invention (I), wherein the carbamoyloxymethyl group with an acyl group is protected or is free, can be obtained while the course of the implementation or post-treatment.

Procedure 3

The compound (I) according to the invention or a salt thereof can be made by connecting (V) or a salt thereof of an elimination reaction for removal subject to the amino protecting group. Suitable salts for the compound (V) z. B. the same as above have been exemplified for the compound (IV).  

The elimination reaction according to the invention can be is an elimination process that is being carried out using a base such as e.g. B. an inorganic Base, such as an alkali metal hydroxide (e.g. sodium hydroxide, Potassium hydroxide), an alkali metal bicarbonate (such as sodium bicarbonate, potassium bicarbonate) or one Alkali metal carbonate (such as sodium carbonate, potassium carbonate), an organic base, such as. B. an alkali metal alkylate (-alkoxide) (such as sodium methylate, sodium ethylate), a trialkylamine (such as trimethylamine, Triethylamine), of triethanolamine, N, N-dimethylaniline, N, N-dimethylbenzylamine, N-methylmorpholine or Pyridine, or an elimination reaction that occurs under Use of basic alumina, a basic one Ion exchange resin, an acid (such as trifluoroacetic acid, Trifluoroacetic acid, anisole) is carried out. The elimination reaction according to the invention is in the Usually in water, in a hydrophilic solvent or in a mixture of them. The reaction temperature is not critical and implementation is preferred at Ambient temperature or under cooling.

The present invention also includes the cases where during the course of the reaction or during post-treatment the protected carboxy group or salts in the compound (V) can be converted into the free carboxy group, and the cases where the protected amino group each in the free amino group is converted.

A) Process (XXXII) → (XXXIII) [Reaction Scheme (3) (ii)]

The compounds (XXXIII) can be obtained by oxidation of the compounds (XXXII).

The oxidation reaction according to the invention is used of a conventional process carried out for the Conversion of the so-called activated methylene group to a carbonyl group is used. That is, the invention Reaction is done using a conventional Process, for example by using oxidation a conventional oxidizing agent, such as selenium dioxide, Potassium permanganate. The invention  Oxidation is usually in a solvent performed, which does not adversely affect the reaction influenced, e.g. B. in water, dioxane, pyridine, tetrahydrofuran. The reaction temperature is not critical and the reaction is preferably carried out with heating to below Heating done.

B) Process (XXXIII) + (XIV) → (XXXV) [Reaction Scheme (3) (ii)] and (XXXIV) + (XIV) → (III _f ) [Reaction Scheme (3) (ii)]

The compounds (XXXV) and (III _f ) can be prepared by reacting the compounds (XXXIII) and (XXXIV) with the compound (XIV) or a salt thereof. Suitable salts for the compound (XIV) include an inorganic acid salt (such as a hydrochloride, hydrobromide, sulfate) or an organic acid salt (such as an acetate, p-toluenesulfonate).

The reaction according to the invention is usually carried out in one Solvents such as water, an alcohol (such as methanol, Ethanol) or in a mixture thereof or in any other solvent which the invention Reaction not adversely affected.

The reaction of the invention is in the event that the Compound (XIV) is used in the form of its salt, preferably in the presence of a base, e.g. B. an inorganic Base such as An alkali metal (such as sodium, potassium), an alkaline earth metal (such as magnesium, calcium), a hydroxide or carbonate or bicarbonate thereof and in the presence of an organic base, such as An alkali metal alkylate (such as sodium methylate, Sodium ethylate), a trialkylamine (such as trimethylamine, Triethylamine), of N, N-dialkylamine (such as N, N-dimethylaniline), N, N-dialkylbenzylamine (as N, N-dimethylbenzylamine), pyridine.

The reaction temperature is not critical and the implementation is usually carried out with cooling to heating.  

In the reaction of the present invention, a mixture of the syn and anti isomers of the compound (XXXV) or (III _f ) can be obtained depending on the reaction conditions used, and in such a case, both isomers can be separated from the mixture in a conventional manner . For example, the mixture is first esterified and the esters obtained are broken down, for example by chromatography into each isomer. Each isomer of the esters obtained is hydrolyzed by a conventional method to give the corresponding syn or anti-carboxylic acid.

For the selective preparation of the syn isomer of the compound (XXXV) or (III _f ) in high yield, the reaction according to the invention is preferably carried out under approximately neutral conditions.

C) Process (XXXIV) → (XXXVI) [Reaction Scheme (3) (ii)]

The connections (XXXVI) can be made by implementing the compounds (XXXIV) in each case with hydroxylamine or a salt thereof.

Suitable salts for hydroxylamine are, for example, those as exemplified above for compound (XIV) have been specified.

The reaction conditions of the reaction according to the invention can also be the same as those exemplified above for processes (XXXIII) + (XIV) → (XXXV) and (XXXIV) + (XIV) → (III _f ) in section (B) above are.

D) Process (XXVI) → (XXVII) [Reaction Scheme (2)]

The compounds (XXVII) can be prepared by methylation of connections (XXVI).

Examples of methylating agents used in the methylation reaction according to the invention can be used are dimethyl sulfate, diazomethane, a methyl halide (such as methyl iodide), methyl sulfonate (such as methyl p-toluene) sulfonate).

The reaction, using dimethyl sulfate, a methyl halide or a methyl sulfonate is usually carried out in a solvent such as water, acetone, ethanol, ether, dimethylformamide or in any other solvent which does not adversely affect the reaction influenced, performed.

The reaction according to the invention is preferably carried out in the presence a base such as B. an inorganic base or an organic Base, as mentioned above. The reaction temperature is not critical and implementation is in usually with cooling to heating until about Boiling point of the solvent carried out.

The reaction carried out using diazomethane is usually in a solvent such as Ether, tetrahydrofuran. The reaction temperature is not critical and implementation is in usually carried out under cooling or at ambient temperature.

E) Process (XX) → (XXI) [Reaction scheme (1) (i)]

The compound (XXI) can be prepared by using the Compound (XX) is subjected to nitrosation.

Examples of nitrosating agents used in the invention Reaction that can be used are conventional Agents that give C-nitroso compounds in the implementation  with an activated methylene group, such as. B. Nitrous Acid, an alkali metal nitrite (such as sodium nitrite), a lower alkyl nitrite (such as isopentyl nitrite, t-butyl nitrite).

If the nitrosating agent is a salt of nitrous acid is used, the reaction according to the invention is usually in the presence of an acid, such as. B. an inorganic Acid or an organic acid (such as hydrochloric acid, Acetic acid). If an ester the nitrous acid is used, the invention Reaction preferably in the presence of a strong base, such as B. an alkali metal alkylate.

The implementation of the invention is usually in one Solvents such as water, acetic acid, benzene, an alcohol (such as ethanol, methanol) or in any other solvent, which does not adversely affect the reaction influenced, performed. The reaction temperature is not critical and the implementation is usually under cooling or carried out at ambient temperature.

F) Process (XXI) + (XXII) → (XXIII) [Reaction scheme (1) (i)] and (XXVIII) + (XXII) → (XXIX) [Reaction scheme (2)]

Compounds (XXIII) and (XXIX) can be prepared by reacting compounds (XXI) and (XXVIII) each with compound (XXII).

The reaction according to the invention is generally carried out in a solvent, like water, in an alcohol (like methanol, ethanol), in benzene, dimethylacetamide, dimethylformamide, tetrahydrofuran, a mixture of these or in any other Solvent which does not adversely affect the reaction, carried out. The reaction temperature is not critical and the reaction is usually up to ambient temperature carried out with heating to about the boiling point of the solvent.

For the selective preparation of the syn isomer of the compound (XXIII) or (XXIX) in high yield must be the syn isomer of the starting compound  (XXI) or (XXVIII) are used and the invention Reaction is preferably about neutral Conditions in the presence of a base as mentioned above carried out. Preferred examples of bases that can be used are a weak base, such as an alkali metal acetate (e.g. Sodium acetate, potassium acetate), an alkali metal bicarbonate (like sodium bicarbonate, potassium bicarbonate), an alkali metal carbonate (such as sodium carbonate, potassium carbonate).

G) Process (XXIII) → (XXIII _a ) [Reaction Scheme (1) (i)], (XXIX) → (III _e ) [Reaction Scheme (2)], (XXXIII) → (XXXIV) [Reaction Scheme (3) (ii )] and (XXXV) → (III _f ) [Reaction scheme (3) (ii)]

Compounds (XXIII _a ), (III _e ), (XXXIV) and (III _f ) can be prepared by subjecting Compounds (XXIII), (XXIX), (XXXIII) and (XXXV) to an elimination reaction to remove the carboxy protecting group submits.

Conventional can be used in the elimination reaction according to the invention Procedures for protecting group elimination be used, for example hydrolysis, be applied. If the protecting group is an ester, so it can be eliminated by hydrolysis.

The hydrolysis is preferably carried out in the presence of a base or an acid. Suitable bases can include an inorganic base and an organic base, such as. B. an alkali metal (such as sodium, potassium), an alkaline earth metal (like magnesium, calcium), the hydroxide or carbonate or bicarbonate thereof, a trialkylamine (such as Trimethylamine, triethylamine), picoline, 1,5-diazabicyclo [4,3,0] non-5-ene, 1,4-diazabicyclo [2,2,2] octane, 1,5-diazabicyclo [5,4,0] undecene-5.  

Suitable acids can include an organic acid (e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid) and an inorganic acid (such as hydrochloric acid, Hydrobromic acid, sulfuric acid).

The reaction is usually carried out in a solvent such as Water, an alcohol (such as methanol, ethanol), a mixture thereof or in any other solvent, which does not adversely affect the reaction, carried out. A liquid solvent can also be used Base or a liquid acid can be used.

The reaction temperature is not critical and the implementation is usually carried out with cooling to heating.

H) Process (XXVII) → (XXVIII) [Reaction Scheme (2)]

The compound (XXVIII) can be produced by halogenation the connection (XXVII).

Examples of usable in the reaction of the invention Halogenating agents are a conventional halogenating agent as is the case with the halogenation of the so-called activated methylene group is used, such as. B. Halogen (such as bromine, chlorine), sulfuryl halide (such as sulfuryl chloride), a hypohalite (like hypochlorite Acid, sub-bromine acid, sodium hypochlorite), an N-halogenated imide (such as N-bromosuccinimide, N-bromophthalimide, N-chlorosuccinimide).

The reaction according to the invention is usually carried out in one Solvents such as B. in an organic solvent (such as formic acid, acetic acid, propionic acid), in Carbon tetrachloride or in any other solvent, which does not adversely affect the reaction, carried out. The reaction temperature is not critical and the reaction is usually done under cooling, at ambient temperature, performed with heating or with heating.  

I) Process (XXX) → (XXXI) [Reaction Scheme (3) (i)] and (XXXIX) → (III _h ) [Reaction Scheme (4)]

The compound (XXXI) can be prepared by reacting the compound (XXX) or a reactive derivative thereof on the amino group or a salt thereof with an amino protective agent, and the compound (III _h ) can be prepared by reacting the compound (XXXIX) or a reactive one Derivative thereof on the amino group or a salt thereof with an amino protective agent.

Examples of suitable reactive derivatives on the amino group compound (XXX) or (XXXIX) and suitable salts connection (XXX) or (XXXIX) can be the same as in the explanations of the reactive derivative the amino group of compound (II) or the salt of Compound (II) have been given by way of example. To suitable Amino protection agents include an acylating agent, such as B. an aliphatic, aromatic and heterocyclic Carboxylic acid and the corresponding sulfonic acid, a halogen formate, an isocyanic acid ester and the carbamic acid as well as the corresponding thioacid thereof and the reactive ones Derivatives of the acids listed above.

Suitable reactive derivatives of the above acids include an acid halide, an acid anhydride, an activated amide, an activated ester. Suitable examples are Acid chloride, an acid azide, a mixed acid anhydride with an acid, such as substituted phosphoric acid (e.g. dialkyl phosphoric acid, Phenylphosphoric acid, diphenylphosphoric acid, Dibenzylphosphoric acid, halogenated phosphoric acid), Dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, Sulfuric acid, alkyl carbonic acid, an aliphatic Carboxylic acid (such as pivalic acid, pentanoic acid, isopentanoic acid, 2-ethyl butyric acid or trichloroacetic acid) or one aromatic carboxylic acid such as benzoic acid; a symmetric acid anhydride; an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or Tetrazole; or an activated ester (such as cyanomethyl ester, Methoxymethyl ester, dimethyliminomethyl (CH₃) ₂N⁺ = CH -) - ester, Vinyl esters, propargyl esters, p-nitrophenyl esters, 2,4-dinitrophenyl esters,  Trichlorophenyl ester, pentachlorophenyl ester, Mesylphenyl ester, phenylazophenyl ester, phenylthioester, p-nitrophenylthioester, p-cresylthioester, carboxymethylthioester, Pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolylthioester) or an ester with N, N-dimethylhydroxylamine, 1- Hydroxy-2- (1H) pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide or 1-hydroxy-6-chloro-1H-benzotriazole. These reactive derivatives can, if desired selected depending on the type of acylating agent to be used will.

An example of the protecting group (e.g. the acyl group), into the amino group in compound (XXX) or (XXXIX) by the amino protection agent specified above (e.g. the acylating agent) the same can be introduced Protecting group (z. B. acyl group), as in the explanation the protective group residue (e.g. the acyl residue) in the Expression "acylamino" has been given.

The amino protection reaction according to the invention is similar As in the reaction of the compound (II) with the compound (III) (Process 1) indicated performed.

K) Process (XXIII _b ) → (XXXIII) [Reaction scheme (3) (ii)]

The compound (XXXIII) can be prepared by hydrolysis of the compound (XXIII _b ).

The hydrolysis according to the invention is carried out in the presence of an alkali metal bisulfite, like sodium bisulfite, from titanium trichloride, an inorganic or organic acid, such as a hydrohalic acid (e.g. hydrochloric acid, Hydrobromic acid), formic acid, nitrous acid carried out. A hydrohalic acid is preferred  in combination with an aldehyde such as formaldehyde applied.

The reaction according to the invention is usually carried out in one Solvents such as water, an aqueous alcohol (e.g. in aqueous methanol, aqueous ethanol), in water, Acetic acid or in any other solvent which does not adversely affect the reaction. The Reaction temperature is not critical and the implementation is usually at ambient temperature, with warming or carried out with heating.

In the reaction according to the invention, the protected carboxy group occasionally converted to the free carboxy group will. This case is also within the scope of the present one Invention. In the above reactions and / or at the aftertreatment of the reactions according to the invention the above-mentioned tautomeric isomers occasionally into the other tautomeric isomers are converted and this Case is also within the scope of the present invention.

If the compound (I) according to the invention in the form of the free Acid is obtained in the 4-position, and / or when the invention Compound (I) has a free amino group, it can be pharmaceutical in it by a conventional method compatible salt, as indicated above, converted will.

The compound (I) according to the invention and its salts, in particular their pharmaceutically acceptable salts all new compounds that are high antibacterial Have activity (effectiveness), the growth of a large Number of pathogenic microorganisms including gram positive ones and inhibit or prevent gram-negative bacteria (inhibit) and they are suitable as antibacterial agents.  

In particular, it should be noted that the invention Compound (I), i.e. H. the syn isomer, much higher antibacterial Activities (efficacies) has as that corresponding anti-isomers to the compound (I) and accordingly is the compound (I) according to the invention, i. H. the syn isomer, characterized in that it is the corresponding anti-isomers with respect to their therapeutic Value is far superior.

The usefulness of the compound (I) according to the invention to demonstrate with the help of some representative representatives, Below are test results regarding the antibacterial Activity (effectiveness) in vitro as well as the test results in vivo, d. H. the protective effect against experimental Infections, as well as the acute toxicity indicated.

Tested connections

• (1) 7- [2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] - 3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (Syn-Isomeres)
• (2) 7- [2-methoxyimino-2- {2- (2,2,2-trifluoroacetamido) -1,3- thiazol-4-yl} acetamido] -3-carbamoyloxymethyl-3-cephem-4- carboxylic acid (Syn-Isomeres)

1.) Antibacterial activity in vitro Test procedure

Antibacterial activity in vitro was determined according to the two-fold Agar plate dilution method.

A platinum loop from an overnight culture of each test strain in a trypticase soy broth (10⁸ viable cells per ml) was graduated onto a cardiac infusion agar (HI agar) Concentrations of antibiotics contained, streaked and the minimum inhibitory concentration (MIC), expressed in µg / ml, was after 20 hours of incubation determined at 37 ° C.  

Test results

2.) Protection against experimental infections in mice Test procedure

4 week old male ICR strain mice, each weighing 20 to 23 g were grown in Groups of 8 mice used. The test bacteria were over Cultivated at 37 ° C on a HI agar overnight and then in a 2.5 to 5% mucin solution suspended, the suspension corresponding to the respective vaccine cells was obtained. The mice became intraperitoneal with 0.5 ml of the suspension inoculated. Any containing any test compound Solution was subcutaneously in various doses Administered to mice 1 hour after vaccination. The ED₅₀ Values were taken from the number of surviving mice in each Dosage calculated after 1 week observation.  

For therapeutic administration, the invention Compound (I) in the form of a conventional pharmaceutical The preparation uses this compound as an active ingredient (Active ingredient) optionally in a mixture with pharmaceutical compatible carriers, such as B. an organic or inorganic solid, or with a liquid auxiliary, which is for oral, parenteral or external Administration is suitable, used. The pharmaceutical preparations (pharmaceutical agents) can be in solid form, for example in the form of capsules, tablets, dragees, ointments or suppositories, or in liquid form, for example in Forms of solutions, suspensions or emulsions. If necessary, you can use the preparations listed above also auxiliary substances, stabilizers, wetting agents or emulsifiers, Buffers and other commonly used additives be incorporated.

The dosage of the compounds can vary and also depend on the age, the condition of the patient, the type the disease, the type of compound administered (I) and the like, an average single dose of about 50 mg, about 100 mg, about 250 mg and about 500 mg of the invention However, compound (I) has been found to be effective for Treatment of pathogenic bacteria Diseases proven. In general, amounts can vary between about 1 mg and about 1000 mg or even larger amounts Patients are administered.

The invention is illustrated by the following examples.

example 1

The compounds (1) to (3) given below were similar Obtained as in the working example below.

3.8 g of phosphorus oxychloride became one at 5 to 8 ° C Suspension of 4.0 g of 2-methoxyimino-2- (2-amino-1,3- thiazol-4-yl) acetic acid (Syn-Isomeres) in 40 ml dry Ethyl acetate added dropwise. After stirring for 30 minutes at about 5 ° C were 0.86 g of bis (trimethylsilyl) acetamide at the same temperature added. After stirring for 10 minutes at the same temperature were 3.8 g of phosphorus oxychloride added dropwise at 5 to 8 ° C., after which the mixture became 30 Stirred at the same temperature for minutes. There were 1.6 g of dry dimethylformamide added dropwise at 5 to 7 ° C, thereafter the mixture obtained was kept at the stirred at the same temperature, leaving a clear solution received. On the other hand, 3.3 g of sodium acetate became one Solution of 2.7 g of 7-aminocephalosporanic acid in an aqueous Solution (20 ml) of 1.7 g sodium bicarbonate added and then 20 ml of acetone were added. This was the solution Ethyl acetate solution obtained above with stirring at 0 to 5 ° C. added dropwise, the pH of this solution with a 20% aqueous sodium carbonate solution kept at 7.0 to 7.5 has been. The mixture was kept at the same for 1 hour Temperature stirred. An insoluble material was filtered off and the aqueous layer in the filtrate was separated. The aqueous layer became under reduced pressure concentrated to remove the organic solvents, adjusted to pH 4.5 with sodium bicarbonate and one Column chromatography on a Diaion HP-20 resin (trademark for a product from Mitsubishi Chemical Industries Ltd.) using a 25% aqueous Subjected to isopropyl alcohol solution as eluent. The eluate was lyophilized, 2.8 g of 7- [2-methoxyimino- 2- (2-amino-1,3-thiazol-4-yl) acetamido] cephalosporanic acid (Syn-Isomeres) received.  

IR spectrum (Nujol): 3300-3350, 1780, 1740, 1670 cm ^-1
NMR spectrum (d₆-DMSO, δ ):

ppm: 9.6 (1H, d, J = 8 Hz), 6.8 (1H, s), 5.8 (1H, dd, J = 5.8 Hz), 5.2 (1H, d, J = 5 Hz),
4.87 (2H, AB _q , J = 13 Hz), 3.89 (3H, s), 3.6 (2H, broad s), 2.08 (3H, s)

• (1) 7- [2-methoxyimino-2- {2- (2,2,2-trifluoroacetamido) -1,3-thiazol-4-yl} acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid ( Syn-Isomeres). IR spectrum (Nujol): 3500, 3200, 1785, 1700, 1660 cm ^-1
  NMR spectrum (d6-DMSO, δ ): ppm: 9.5 (1H, d, J = 8 Hz), 8.4 (2H, m), 7.53 (1H, s),
  6.3 (1H, m), 6.20 (1H, d, J = 5 Hz), 5.83 (1H, m),
  4.77 (2H, AB _q , J = 14 Hz), 3.91 (3H, s), 3.55 (2H, m)
• (2) 7- [2-Methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] - 3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (Syn-Isomeres), mp 210 -220 ° C (dec.). IR spectrum (Nujol): 3250, 1765, 1650 cm ^-1
  NMR spectrum (d6-DMSO), δ ): ppm: 9.64 (1H, d, J = 8 Hz), 7.4 (2H, m), 6.79 (1H, s),
  6.60 (2H, m), 5.77 (1H, dd, J = 5.8 Hz), 5.16 (1H, d, J = 5 Hz),
  4.75 (2H, AB _q , J = 12 Hz), 3.87 (3H, s), 3.53 (2H, AB _q , J = 18 Hz)
• (3) 7- [2-methoxyimino-2- (2-formamido-1,3-thiazol-4-yl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer). IR spectrum (Nujol): 3300, 1780, 1705, 1680 cm ^-1
  NMR spectrum (d₆-DMSO, δ ): ppm: 12.50 (1H, broad s), 9.67 (1H, d, J = 8 Hz), 8.50 (1H, s), 7.43 (1H, s),
  6.58 (2H, broad s), 5.80 (1H, dd, J = 5.8 Hz), 5.16 (1H, d, J = 5 Hz),
  4.78 (2H, AB _q , J = 14 Hz), 3.95 (3H, s), 3.57 (2H, AB _q , J = 18 Hz)

Example 2

3.5 g 7- [2-methoxyimino-2- {2- (2,2,2-trifluoroacetamido) - 1,3-thiazol-4-yl} acetamido] -3-carbamoyloxymethyl-3-cephem- 4-carboxylic acid (Syn-Isomeres) were in a solution of 12.2 g of sodium acetate trihydrate suspended in 30 ml of water. The mixture was left at ambient temperature for 15 hours touched. The reaction mixture was washed with sodium chloride saturated and under with concentrated hydrochloric acid  Stir and adjust to pH 5.0 with ice cooling. The failing insoluble material was filtered off. The filtrate was adjusted to pH 3.0 with concentrated hydrochloric acid adjusted and further with 10% hydrochloric acid pH 1.5 adjusted. The precipitates were filtered collected and dried, giving 2.1 g of 7- [2-methoxyimino 2- (2-amino-1,3-thiazol-4-yl) acetamido] -3-carbamoyloxymethyl- 3-cephem-4-carboxylic acid (Syn-Isomeres), mp 210 to 220 ° C (Dec.).

IR spectrum (Nujol): 3250, 1765, 1650 cm ^-1
NMR spectrum (d₆-DMSO, δ ):

ppm: 9.64 (1H, d, J = 8Hz), 7.4 (2H, m), 6.79 (1H, s),
6.60 (2H, m), 5.77 (1H, dd, J = 5.8 Hz), 5.16 (1H, d, J = 5 Hz),
4.75 (2H, AB _q , J = 12 Hz), 3.87 (3H, s), 3.53 (2H, AB _q , J = 18 Hz)

Example 3

The compounds shown below were obtained by carrying out an elimination reaction for the amino protecting group on the Carbamoyl group in a similar manner as in the working example below.

A mixture of 0.18 g dry dimethylformamide and 0.38 g of phosphorus oxychloride was at 40 ° C for 30 minutes touched. 15 ml of dry methylene chloride were added and distilled off under reduced pressure. To that 15 ml of dry ethyl acetate were added to the residue and 0.53 g of 2-methoxyimino-2- (3-chloro-4-hydroxyphenyl) acetic acid (Syn-Isomeres) added. The mixture was below -10 ° C for 1 hour touched. On the other hand, a mixture of 1 g of 7-amino 3-trichloroacetylcarbamoyloxymethyl-3-cephem-4-carboxylic acid, 5 g of trimethylsilylacetamide and 25 ml of dry ethyl acetate Stirred at ambient temperature for 1 hour. To this Solution became the solution obtained above with stirring below -10 ° C was added dropwise and the mixture obtained was 2 hours long stirred at the same temperature. To the reaction mixture were 50 ml of water and 50 ml of ethyl acetate at -20 ° C. added and the mixture was shaken. The 7- [2-methoxyimino-2- (3-chloro-4-hydroxyphenyl) acetamido] - 3-trichloroacetylcarbamoyloxymethyl-3-cephem-4-carboxylic acid Organic layer containing (Syn-Isomeres) was by  Add 50 ml of water and sodium bicarbonate to pH 7.0 and the mixture was left at ambient temperature for 2 hours touched. 50 ml was added to the aqueous layer Ethyl acetate was added and the mixture was washed with 10% Hydrochloric acid adjusted to pH 5.0. The watery Layer was separated with 10% hydrochloric acid adjusted to pH 2.0 and extracted with 50 ml of ethyl acetate. The extract was washed with ice water and over magnesium sulfate dried. The solvent was reduced Pressure distilled off. The residue was carefully washed with ether washed, collected by filtration and dried, whereby 0.3 g of 7- [2-methoxyimino-2- (3-chloro-4-hydroxyphenyl) - acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (Syn-Isomeres) received.

• (1) 7- [2-Methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] - 3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (Syn-Isomeres), mp 210 -220 ° C (dec.). IR spectrum (Nujol): 3250, 1765, 1650 cm ^-1
  NMR spectrum (d₆-DMSO, δ ): ppm: 9.64 (1H, d, J = 8 Hz), 7.4 (2H, m), 6.79 (1H, s),
  6.60 (2H, m), 5.77 (1H, dd, J = 5.8 Hz), 5.16 (1H, d, J = 5 Hz),
  4.75 (2H, AB _q , J = 12 Hz), 3.87 (3H, s), 3.53 (2H, AB _q , J = 18 Hz)
• (2) 7- [2-Methoxyimino-2- (2-formamido-1,3-thiazol-4-yl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer). IR spectrum (Nujol): 3300, 1780, 1705, 1680 cm ^-1
  NMR spectrum (d₆-DMSO, δ ): ppm: 12.50 (1H, broad s), 9.67 (1H, d, J = 8 Hz), 8.50 (1H, s), 7.43 (1H, s),
  6.58 (2H, broad s), 5.80 (1H, dd, J = 5.8 Hz), 5.16 (1H, d, J = 5 Hz),
  4.78 (2H, AB _q , J = 14 Hz), 3.95 (3H, s), 3.57 (2H, AB _q , J = 18 Hz)

Reference Example 1

A suspension of 1.7 g phosphorus pentachloride in 20 ml Methylene chloride was obtained by stirring at ambient temperature for 2 hours converted into a solution. There were 0.8 g 2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetic acid (syn- Isomeres) added all at once at ambient temperature and the mixture was stirred. Under reduced pressure  Distilled methylene chloride and the residue was in 20 ml of acetone dissolved. On the other hand, 1.0 g of 7-amino-3- carbamoyloxymethyl-3-cephem-4-carboxylic acid in a solution of 0.59 g of sodium bicarbonate suspended in 20 ml of water and dissolved by adding 10 ml of acetone. About this solution the solution obtained above containing the acid chloride was added dropwise with stirring and with ice cooling, the Solution with a 20% aqueous sodium carbonate solution pH 7.5 to 8.5 was maintained. After stirring for 1 hour An insoluble material was filtered off at pH 8 with ice cooling. The acetone was removed from the The filtrate was distilled off and an insoluble material was filtered off. The filtrate was treated with 10% hydrochloric acid adjusted to pH 2.5. The rainfall was through Filter collected and dried, giving 0.4 g of 7- [2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- carbamoyloxymethyl-3-cephem-4-carboxylic acid (a mixture of the Syn and anti isomers) was obtained. The filtrate was washed with sodium chloride saturated and stirred under ice cooling, whereby precipitation was obtained. The rainfall was through Filter collected and dried, giving 0.3 g of same desired compound received, the overall yield was 0.7 g.

IR spectrum (Nujol): 3400, 1775, 1705 cm ^-1
NMR spectrum (d₆-DMSO, δ ):

ppm: 9.71 (1H, d, J = 8 Hz), 9.42 (1H, d, J = 8 Hz), 7.70 (1H, s), 7.40 (4H, broad s),
7.00 (1H, s), 6.61 (4H, s), 5.76 (2H, m), 5.16 (2H, d, J = 4.5 Hz),
4.76 (4H, AB _q , J = 12 Hz), 3.98 (3H, s), 3.89 (3H, s), 3.53 (4H, AB _q , J = 18 Hz)

In the following manufacturing examples, the manufacturing that in the above examples and reference examples used starting compounds explained in more detail.

Production Example 1

1.) A solution of 12.4 g sodium nitrite in 150 ml water became with stirring at 5 to 7 ° C to a solution of 30 g Ethyl 4-bromoacetoacetate was added dropwise in 200 ml of acetic acid and the mixture was stirred at 10 ° C for 2 hours. To the 200 ml of water were added to the reaction mixture and the the mixture obtained was extracted with 500 ml of ether. The extract was washed twice with 200 ml of water and with 200 ml an aqueous sodium chloride solution and washed over magnesium sulfate dried. The solvent was reduced Distilled off pressure, 32.6 g of yellowish brown crystals of ethyl 2-hydroxyimino-4-bromoacetoacetate (a mixture of the syn and anti isomers).

IR spectrum (film): 3350, 1740, 1710, 1620 cm ^-1
NMR spectrum (CDCl₃, δ ):

ppm: 8.75 (2H, broad s), 4.35 (8H, m), 1.35 (6H, m)

2.) 160 g of powdered potassium carbonate became one Solution of 152 g of ethyl 2-hydroxyiminoacetoacetate (a Mixture of the syn and anti isomers) added in 500 ml of acetone. With stirring over a period of 1 hour 130 g of dimethyl sulfate were added dropwise at 45 to 50 ° C. and the Mixture was stirred for 2 hours. An insoluble one Material was filtered off and the filtrate was reduced under reduced pressure Pressure reduced. The insoluble filtered off Material was dissolved in 500 ml of water and this solution was added to the residue. The mixture was made twice extracted with 300 ml of ethyl acetate. The extract was twice with 200 ml of water and with 200 ml of a saturated aqueous sodium chloride solution and washed over magnesium sulfate  dried. The solvent was reduced The pressure was distilled off and the residue was reduced Distilled pressure, 145.3 g of a colorless Oil of ethyl 2-methoxyiminoacetoacetate (a mixture of the syn and anti isomers), bp. 55 to 64 ° C / 0.5 mm Hg

IR spectrum (film): 1745, 1695, 1600 cm ^-1
NMR spectrum (CDCl₃, δ ):

ppm: 4.33 (4H, q, J = 8 Hz), 4.08 (3H, s), 3.95 (3H, s),
2.40 (3H, s), 1.63 (3H, s), 1.33 (6H, t, J = 8 Hz)

3.) 100 g of bromine were added over a period of 40 minutes under reflux to a solution of 100 g of ethyl 2-methoxyiminoacetoacetate (a mixture of the syn and anti isomers) in a mixture of 300 ml carbon tetrachloride and 300 ml Acetic acid added dropwise. The mixture was at 70 to 80 ° C stirred until the hydrogen bromide evolution stopped. The reaction mixture was washed twice with 300 ml of water, an aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution and washed over magnesium sulfate dried. The solution was treated with 2 g activated carbon and concentrated under reduced pressure, wherein 120.8 g of ethyl 2-methoxyimino-4-bromoacetoacetate (a mixture of the syn and anti isomers).

IR spectrum (film): 1740, 1705, 1600 cm ^-1
NMR spectrum (CDCl₃, δ ):

ppm: 4.17-4.54 (8H, m), 4.15 (3H, s), 4.13 (3H, s), 1.33 (6H, t, J = 8 Hz)

4.) A mixture of 11.1 g of selenium dioxide, 250 ml of dioxane and 5 ml of water were stirred at 110 to 115 ° C. for 15 minutes, giving a yellow solution. While stirring at the same temperature 26.4 g of ethyl 2- (2-mesylamino 1,3-thiazol-4-yl) acetate added. After stirring for 1 hour the reaction mixture was decanted with heating and cooled, whereby yellow crystals precipitated. The crystals were collected by filtration, with dioxane and ether washed and dried, 23.5 g of ethyl 2- (2- mesylamino-1,3-thiazol-4-yl) glyoxylate.  

IR spectrum (Nujol): 3300, 1718, 1682 cm ^-1

5.) 13.9 g of ethyl 2- (2-mesylamino-1,3-thiazol-4-yl) glyoxylate became a solution with stirring at ambient temperature of 5.0 g sodium hydroxide in 150 ml water. The Mixture was stirred at ambient temperature for 1 hour, with concentrated hydrochloric acid to pH 7 adjusted and washed with ethyl acetate. The aqueous layer was adjusted to pH 0.5 with concentrated hydrochloric acid adjusted, whereby yellow crystals failed. The crystals were collected by filtration, washed with water and dried, 10.16 g of 2- (2-mesylamino-1,5-thiazole- 4-yl) glyoxylic acid was obtained.

IR spectrum (Nujol): 3350, 1725, 1650 cm ^-1

6.) To a solution of 14 g of ethyl 2- (2-amino-1,3-thiazole) 4-yl) acetate in a mixture of 40 g pyridine and 300 ml Methylene chloride slowly became 70 ml of a diethyl ether solution of t-pentyl chloroformate, the 0.35 mole of t-pentyl chloroformate contained, over a period of 10 minutes at -20 ° C below Stir was added and the mixture was stirred for 2 hours stirred at the same temperature and for a further 0.5 hours stirred at 0 ° C. After the reaction, the reaction mixture poured into 200 ml of water and then the organic layer separated. The organic layer was successively treated with 2 n Hydrochloric acid, water, a 5% aqueous sodium bicarbonate solution and washed with water and then over magnesium sulfate dried. The solvent was removed from the organic Layer distilled off, giving 12 g of a dark brown oil of ethyl 2- (2-t-pentyloxycarbonylamino-1,3-thiazol-4-yl) acetate received.  

IR spectrum (liquid): 1667, 1660 (CO) cm ^-1
NMR spectrum (CDCl₃, δ ):

ppm: 3.75 (2H, s), 6.75 (1H, s)

7.) 0.3 g of ethyl 2- (2-t-pentyloxycarbonylamino-1,3-thiazole- 4-yl) acetate and 0.11 g of selenium dioxide were prepared in a similar manner as in Production Example 1 (4) treated to form 0.22 g of ethyl 2- (2-t-pentyloxycarbonylamino-1,3-thiazole- 4-yl) glyoxylate in the form of a brown oil.

IR spectrum (liquid): 1720, 1690 (CO) cm ^-1
NMR spectrum (CDCl₃, δ ):

ppm: 8.3 (1H, s)

8.) 2.8 g of ethyl 2- (2-t-pentyloxycarbonylamino-1,3-thiazole- 4-yl) glyoxylate and a solution of 0.54 g sodium hydroxide in 20 ml of water in a manner similar to that in the preparation example 1 (5) treated to form 1.75 g 2- (2-t-pentyloxycarbonylamino-1,3-thiazol-4-yl) glyoxylic acid in the form of a brown powder.

IR spectrum (Nujol): 1730, 1680 (CO) cm ^-1
NMR spectrum (d₆-dimethyl sulfoxide, δ ):

ppm: 8.4 (1H, s)

9.) A mixture of 0.37 g of ethyl 2-hydroxyimino-2- (2-amino- 1,3-thiazol-4-yl) acetate (a mixture of the syn and anti Isomers), 5 ml of ethanol, 5 ml of water and 0.72 g of sodium bisulfite was stirred at 65 to 70 ° C for 12 hours. The  The reaction mixture was concentrated and 10 ml of water added to the residue. The mixture obtained was salted out and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated, with 0.18 g of yellow crystals of ethyl 2- (2-amino-1,3-thiazole- 4-yl) glycolate, mp 115 to 120 ° C, was obtained.

IR spectrum (Nujol): 3420, 3250, 3120, 1730, 1665, 1612 cm ^-1

10.) 235 ml of sulfuryl chloride were added over a period of 20 minutes with stirring and cooling with ice to a solution 500 g of ethyl 2-methoxyiminoacetoacetate (Syn-Isomeres) added dropwise in 500 ml of acetic acid and the mixture was added under Cool with water stirred overnight. Was in for 2 hours the reaction mixture introduced nitrogen gas and the obtained mixture was poured into 2.5 l of water. After this Extract with 500 ml of methylene chloride and twice The extracts were extracted with 200 ml of methylene chloride united with each other. The combined extracts were with a saturated aqueous sodium chloride solution and by adding 800 ml of water and sodium bicarbonate to pH 6.5 set. The methylene chloride layer was separated washed with an aqueous sodium chloride solution and over Magnesium sulfate dried. The solvent was distilled off and 559 g of ethyl 2-methoxyimino-4- were obtained chloroacetoacetate (Syn-Isomeres).

IR spectrum (film): 1735, 1705 cm ^-1

Production Example 2

1.) 3 drops of phenolphthalein indicator became one Solution of 4.2 g of hydroxylaminohydrochloride in 60 ml of dry Methanol added. The solution was added with stirring Ambient temperature 60 ml of a 1N methanol solution of Sodium methylate was added dropwise until the color of the solution turned purple has been. In small portions, hydroxylamine hydrochloride added until the solution became colorless. The mixture was stirred at ambient temperature for 30 minutes. To filtering off the precipitated sodium chloride 12.5 g of 2- (2-mesylamino-1,3-thiazol-4-yl) glyoxylic acid added to the filtrate and the mixture was 1.5 hours heated under reflux with stirring. The reaction mixture was cooled, whereby crystals precipitated. The Crystals were collected by filtration and dried, 5.5 g of crude 2-hydroxyimino-2- (2-mesylamino-1,3- thiazol-4-yl) acetic acid (a mixture of syn and anti Isomers) was obtained. The filtrate was reduced to a quarter of his Volume was concentrated and ether was added. The failing Crystals were collected by filtration using Washed ether and dried, taking 8.78 g of the same Connection received. The overall yield was 14.3 g.

2.) A mixture of 2.4 g of ethyl 2-hydroxyimino-4-bromoacetoacetate (a mixture of the syn and anti isomers) and 0.76 g Thiourea in 15 ml of ethanol was at 60 ° C for 1 hour touched. Ethanol was distilled off under reduced pressure and water was added to the residue. The received Mixture was adjusted to pH 1.0 and with ethyl acetate washed. The aqueous layer was adjusted to pH with triethylamine 4.5 adjusted and extracted with ethyl acetate. The extract was washed with water and a saturated aqueous sodium chloride solution washed and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was washed using an ethyl acetate /  Benzene (1/3) mixture as a developing solvent Subject to column chromatography on silica gel. Which the syn- Eluates containing isomers were collected and concentrated, where 0.3 g of ethyl 2-hydroxyimino-2- (2-amino-1,3-thiazole- 4-yl) acetate (Syn-Isomeres) was obtained.

IR spectrum (Nujol): 3450, 3300, 3200, 1725, 1620 cm ^-1
NMR spectrum (CDCl₃, δ ):

ppm: 7.65 (1H, s), 5.33 (2H, broad s), 4.40 (2H, q, J = 7.5 Hz), 1.38 (3H, t, J = 7.5 Hz)

After the eluates containing the syn isomer are collected a mixture of syn and anti Eluates containing isomers are collected and concentrated, where 0.3 g of ethyl 2-hydroxyimino-2- (2-amino-1,3-thiazol-4-yl) acetate (a mixture of the syn and anti isomers).

IR spectrum (Nujol): 3400, 3300, 3200, 1715, 1620 cm ^-1
NMR spectrum (d6-DMSO, δ ):

ppm: 12.42 (1H, broad s), 11.55 (1H, s), 7.52 (1H, s), 7.12 (4H, broad s),
6.83 (1H, s), 4.23 (4H, m), 1.26 (6H, m)

3.) A solution of 1.1 g of ethyl 2-hydroxyimino-2- (2-amino- 1,3-thiazol-4-yl) acetate (a mixture of the syn and anti Isomers) in 15 ml of an aqueous 1N sodium hydroxide solution was left at ambient temperature for 2 hours. The reaction mixture was treated with 10% hydrochloric acid adjusted to pH 3.5 and the precipitated crystals were collected by filtration, washed with acetone and dried, whereby 0.52 g of 2-hydroxyimino-2- (2-amino-1,3- thiazol-4-yl) acetic acid (a mixture of syn and anti Isomers), mp 184 to 186 ° C (dec.).

IR spectrum (Nujol): 3200, 1670, 1530 cm ^-1

Production Example 3

1.) A solution of 17.4 g of ethyl 2-methoxyimino-4-bromoacetoacetate (a mixture of the syn and anti isomers) and 5.4 g of thiourea in 100 ml of ethanol was added for 4 hours heated under reflux. The reaction mixture was left to stand and cooled in a refrigerator, taking crystals failed. The crystals were collected by filtration, washed with ethanol and dried, 9.5 g of ethyl 2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetate hydrobromide (Anti-isomer). The filtrate and the wash water were combined and concentrated under reduced pressure. 100 ml of water were added to the residue and the mixture was washed with ether. The aqueous layer became made alkaline with a 20% aqueous ammonia solution and extracted with ethyl acetate. The extract was made with water and a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, 5.2 g Ethyl 2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetate (Syn isomer) in the form of a crystalline substance.  

IR spectrum (Nujol): 3400, 3300, 3150, 1725, 1630, 1559 cm ^-1
NMR spectrum (CDCl₃, δ ):

ppm: 6.72 (1H, s), 5.91 (2H, broad s), 4.38 (2H, q, J = 7 Hz),
4.03 (3H, s), 1.38 (3H, t, J = 7 Hz)

9.5 g of the ethyl 2-methoxyimino-2- (2-amino- 1,3-thiazol-4-yl) acetate hydrobromide (anti-isomer) suspended in 200 ml of ethyl acetate and there were 4.0 g of triethylamine admitted. After stirring for 1 hour at ambient temperature an insoluble material was filtered off and the filtrate was concentrated under reduced pressure, whereby 6.15 g of ethyl 2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetate (Anti-isomer) in the form of a crystalline substance received.

IR spectrum (Nujol): 3450, 3250, 3150, 1730, 1620 cm ^-1
NMR spectrum (CDCl₃, δ ):

ppm: 7.50 (1H, s), 5.60 (2H, broad s), 4.35 (2H, q, J = 7 Hz),
4.08 (3H, s), 1.33 (3H, t, J = 7 Hz)

2.) 3 drops of phenolphthalein indicator became one Solution of 1.25 g of O-methylhydroxylamine hydrochloride in 15 ml dry methanol added. The solution was below Stir at ambient temperature 13 ml of a 1N methanol solution of sodium methylate added dropwise until the color of the solution turned purple. O-Methylhydroxylamine hydrochloride was added in small portions added until the solution became colorless. The mixture was at ambient temperature for 30 minutes touched. After filtering off the precipitated sodium chloride 3.8 g of ethyl 2- (2-mesylamino-1,3-thiazole- 4-yl) glyoxylate added to the filtrate and the mixture was refluxed with stirring for 2 hours. After the methanol was distilled off, the residue dissolved in ethyl acetate. An insoluble material was filtered off and the filtrate was concentrated. The residue was using a benzene / ethyl acetate (9/1) mixture as a development solvent for column chromatography Subjected to silica gel. The eluate containing the syn isomer was collected and concentrated, giving 2.8 g of ethyl 2-methoxyimino 2- (2-mesylamino-1,3-thiazol-4-yl) acetate (Syn-Isomeres) received.

IR spectrum (Nujol): 1725 cm ^-1
NMR spectrum (CDCl₃, δ ):

ppm: 6.76 (1H, s), 4.44 (2H, q, J = 7 Hz), 4.04 (3H, s),
3.04 (3H, s), 1.37 (3H, t, J = 7 Hz)

3.) The connection given below was similar Obtained as in Production Example 3 (2): Ethyl 2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetate (Syn isomer).

IR spectrum (Nujol): 3400, 3300, 3150, 1725, 1630, 1559 cm ^-1
NMR spectrum (CDCl₃, δ ):

ppm: 6.72 (1H, s), 5.91 (2H, broad s), 4.38 (2H, q, J = 7 Hz),
4.03 (3H, s), 1.38 (3H, t, J = 7 Hz)

4.) A mixture of 6.1 g of acetic anhydride and 2.8 g Formic acid was stirred at 50 ° C for 2 hours. The the resulting mixture was cooled and at 15 ° C 4.6 g of ethyl 2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetate (Syn isomer) added. After the mixture is 3.5 Had been stirred for hours at ambient temperature 100 ml of chilled water was added. The one received Mixture was extracted with 200 ml of ethyl acetate. The Extract was saturated with water and then with a aqueous sodium bicarbonate solution washed until the wash water was weakly alkaline. The extract was made with a saturated aqueous sodium chloride solution further washed and dried over magnesium sulfate. The solvent was distilled off and the residue was treated with diisopropyl ether washed, collected by filtration and dried, where 4.22 g of ethyl 2-methoxyimino-2- (2- formamido-1,3-thiazol-4-yl) acetate (Syn-Isomeres), mp 122 bis 124 ° C (dec.).  

IR spectrum (Nujol): 3150, 1728, 1700 cm ^-1
NMR spectrum (CDCl₃, δ ):
ppm: 12.58 (1H, broad s), 8.95 (1H, s), 7.17 (1H, s),
4.42 (2H, q, J = 8 Hz), 4.00 (3H, s), 1.37 (3H, t, J = 8 Hz)

5.) 3 g of pyridine were added to a solution of 6.5 g of ethyl 2- methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetate (Syn-Isomeres) in a mixture of 60 ml of ethyl acetate and 20 ml Dimethylformamide added. The solution was added with stirring 8 g of ethyl chloroformate were added dropwise at 4 ° C. After adding 50 ml of water to the reaction mixture became the organic Layer separated, with water and then with a saturated aqueous sodium chloride solution and washed over magnesium sulfate dried. The solvent was reduced Pressure distilled off. The residue was used an ether / petroleum ether (5/2) mixture as eluent subjected to column chromatography on silica gel (120 g), 5.4 g of ethyl 2-methoxyimino-2- (2-ethoxycarbonylamino- 1,3-thiazol-4-yl) acetate (Syn-Isomeres) was obtained.

NMR spectrum (CDCl₃, δ ):

ppm: 9.36 (1H, broad s), 7.10 (1H, s), 4.00-4.66 (4H, m),
4.00 (3H, s), 1.20-1.60 (6H, m)

6.) 50 g of ethyl 2-methoxyimino-4-chloroacetoacetate (Syn-Isomeres) were stirred for 3 minutes at ambient temperature to a solution of 18.4 g thiourea  and 19.8 g sodium acetate in a mixture of 250 ml Methanol and 250 ml of water added. After 35 minutes The reaction mixture was stirred with ice at 40 to 45 ° C. cooled and with a saturated aqueous sodium bicarbonate solution adjusted to pH 6.3. After stirring for 30 minutes the same temperature, the rainfall was through Filter collected, with 200 ml of water and then with 100 ml Washed diisopropyl ether and dried, giving 37.8 g Ethyl 2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetate (Syn-Isomeres), mp 161 to 162 ° C, in the form of colorless Received crystals.

IR spectrum (Nujol): 3400, 3300, 3150, 1725, 1630, 1559 cm ^-1
NMR spectrum (CDCl₃, δ ):

ppm: 6.72 (1H, s), 5.91 (2H, broad s), 4.38 (2H, q, J = 7 Hz),
4.03 (3H, s), 1.38 (3H, t, J = 7 Hz)

Production Example 4

1.) 10 ml of ethanol were added to a suspension of 2.2 g Ethyl 2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetate (Syn isomer) in 12 ml of an aqueous 1N sodium hydroxide solution added and the mixture was stirred for 15 hours  Ambient temperature stirred. The reaction mixture was with 10% hydrochloric acid adjusted to pH 7.0 and the ethanol was distilled off under reduced pressure. The remaining aqueous solution was treated with ethyl acetate washed with 10% hydrochloric acid to pH 2.8 adjusted and stirred with ice cooling, whereby crystals failed. The crystals were collected by filtration, washed with acetone and recrystallized from ethanol, whereby 1.1 g of 2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetic acid (Syn-Isomeres) in the form of colorless needles.

IR spectrum (Nujol): 3150, 1670, 1610, 1585 cm ^-1
NMR spectrum (d₆-DMSO, δ ):

ppm: 7.20 (2H, broad s), 6.85 (1H, s), 3.83 (3H, s)

2.) The compounds given below were similar Obtained as in Production Example 4 (1):

• (1) 2-Methoxyimino-2- (2-mesylamino-1,3-thiazol-4-yl) acetic acid (Syn-Isomeres) IR spectrum (Nujol): 3150, 1720 cm ^-1
  NMR spectrum (d₆-DMSO, δ ): ppm: 7.17 (1H, s), 3.93 (3H, s), 3.02 (3H, s)
• (2) 2-Methoxyimino-2- (2-formamido-1,3-thiazol-4-yl) acetic acid (syn isomer), mp 152 ° C (dec.). IR spectrum (Nujol): 3200, 2800-2100, 1950, 1600 cm ^-1
  NMR spectrum (d₆-DMSO, δ ): ppm: 8.60 (1H, s), 7.62 (1H, s), 3.98 (1H, s)
• (3) 2-methoxyimino-2- (2-ethoxycarbonylamino-1,3-thiazol-4-yl) acetic acid (Syn-Isomeres) IR spectrum (Nujol): 3200, 1730, 1710, 1690, 1570 cm ^-1
  NMR spectrum (d₆-DMSO, δ ): ppm: 12.16 (1H, broad s), 7.50 (1H, broad), 7.20 (1H, broad broad),
  4.25 (2H, q, J = 7 Hz), 3.93 (3H, s), 1.25 (3H, t, J = 7 Hz)

3.) 5 ml of pyridine were added to a suspension of 2.0 g 2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetic acid (Syn-Isomeres) added in 20 ml of ethyl acetate. Under A solution of 2.5 g of bis- (2,2,2-trifluoroacetic acid) anhydride in 3 ml of ethyl acetate was added dropwise and the mixture was added for 30 minutes 3 to 5 ° C stirred. 30 ml were added to the reaction mixture Water was added and the ethyl acetate layer was separated. The aqueous layer was further treated with ethyl acetate extracted and two layers of ethyl acetate were joined together combined with water and a saturated aqueous sodium chloride solution washed and dried over magnesium sulfate. The solvent was removed under reduced pressure distilled off, 0.72 g of 2-methoxyimino-2- [2- (2,2,2- trifluoroacetamido) -1,3-thiazol-4-yl] acetic acid (Syn-Isomeres) received.

IR spectrum (Nujol): 1725, 1590 cm ^-1
NMR spectrum (d₆-DMSO, δ ):

ppm: 7.68 (1H, s), 3.91 (3H, s)

4.) The connection given below was similar Obtained as in Production Example 4 (3): 2-methoxyimino-2- (2-acetamido-1,3-thiazol-4-yl) acetic acid (Syn-Isomeres), mp 184 to 185 ° C (dec.).

IR spectrum (Nujol): 3200, 3050, 1695, 1600 cm ^-1

5.) The compounds given below were similar Obtained as in the following manufacturing example:

3 drops of phenolphthalein indicator became one of 0.84 g of O-allylhydroxylamine hydrochloride in 10 ml of dry Methanol added. The solution was added with stirring Ambient temperature 6 ml of a 1N methanol solution of sodium methylate added dropwise until the color of the solution was pale pink has been. O-Allylhydroxylamine hydrochloride was added in small portions added until the solution became colorless. The Mixture was at ambient temperature for 30 minutes touched. After the precipitated sodium chloride is filtered off 2.0 g of 2- (2-c-pentyloxycarbonylamino 1,3-thiazol-4-yl) glyoxylic acid was added to the filtrate and the mixture was left at ambient temperature for 1 hour touched. After the methanol at low temperature had been distilled off, the residue was in a aqueous 1 N sodium hydroxide solution. The solution was washed with ether and ethyl acetate was added. The Mixture was adjusted to pH 1.5 with phosphoric acid and extracted with ethyl acetate. The extract was made with a aqueous sodium chloride solution and washed over magnesium sulfate dried. The ethyl acetate was distilled off and the residue was washed with diisopropyl ether Filter and collect, drying 1.62 g 2- Allyloxyimino-2- (2-t-pentyloxycarbonylamio-1,3-thiazole- 4-yl) acetic acid (Syn-Isomeres) was obtained.  

• (1) 2-Methoxyimino-2- (2-t-pentyloxycarbonylamino-1,3-thiazol-4-yl) acetic acid (Syn-Isomeres) IR spectrum (Nujol): 3200, 1712 cm ^-1
  NMR spectrum (d₆-DMSO, δ ): ppm: 7.40 (1H, s), 3.88 (3H, s), 1.77 (2H, q, J = 8 Hz),
  1.44 (6H, s), 0.88 (3H, t, J = 8 Hz)
• (2) 2-Methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetic acid (Syn-Isomeres) IR spectrum (Nujol): 3150, 1670, 1610, 1585 cm ^-1
  NMR spectrum (d₆-DMSO, δ ): ppm: 7.20 (2H, broad s), 6.85 (1H, s), 3.83 (3H, s)

Claims (3)

1. 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-carbamoyloxy-methyl- 3-cephem-4-carboxylic acid (syn isomer), including the usual protecting groups and salts, especially the pharmaceutical tolerable salts. 2. A process for the preparation of the compound according to claim 1, including the usual protective groups and salts, in particular the pharmaceutically acceptable salts, by reaction of the compound of the formula which is known per se including conventional protecting groups or a reactive derivative thereof on the amino group or a salt thereof with the compound of the formula or a reactive derivative thereof on the carboxy group or a salt thereof; or
by eliminating the amino protecting group in a manner known per se from a compound of the formula wherein R¹ is a common protecting group, or a salt thereof; or
by eliminating the amino protecting group in a manner known per se from a compound of the formula including common protecting groups, wherein R⁴ represents a common amino protecting group, or a salt thereof. 3. Pharmaceutical composition containing the compound according to Claim 1 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable, essentially non-toxic Carriers or excipients.