NO158344B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE 3-CEFEM COMPOUNDS. - Google Patents

Description

The present invention relates to a method for the production of hitherto unknown cephem compounds, namely hitherto unknown 7-substituted 3-cephem-4-carboxylic acids, or pharmaceutically acceptable salts and esters thereof, which compounds have antimicrobial action.

Examples of known compounds of the type here

in question are:

The above known compounds have antimicrobial properties

activity, but they are not satisfactory, and moreover their antimicrobial spectra are not so broad.

We have now discovered new compounds with the formula I below, which have far better antimicrobial activity and much broader antimicrobial spectra than the known compounds

bonds, in that i.a. the aminothiazole oxime group is introduced into the side chain in the 7-position, and hydrogen in the 3-position of the cephem ring.

Cefem compounds with the aminothiazole oxime group in the 7-position are known from application 75.4296, but these are also substituted in the 3-position in contrast to the above-mentioned compound of formula I. Comparison with these known compounds is shown below.

The cefem compounds produced by the method according to the present invention have the general formula I

where R<2>means C1-C6-alkyl, C2-C6-alkenyl, carboxy-C1-C6-alkyl or C1-C6-alkoxycarbonyl-C1-C6-alkyl, in the form of the syn isomer.

The terms and definitions used are explained below,

a) A substructure with the general formula

denotes both geometrical formulas

The geometry of formula (S) is designated as "syn" and of (A) as "anti".

One isomer of the compound with a partial structure as indicated by the above general formula (S) is designated as "syn-isomer", and the other isomer of the compound with the alternative formula (A) shown above is designated as "anti-isomer". .

Regarding the structure-activity relationship, it should be noted that the syn-isomer of the compound of the general formula I appears to have a much higher antimicrobial effect than the corresponding anti-isomer, and therefore it is the syn-isomer of the compound of the general formula I which are produced according to the invention.

b) The thiazolyl group with the general formula

exists as is known in tautomeric equilibrium with a thiazolinyl group of the general formula

The tautomerism between these thiazolyl and thiazolinyl groups can be illustrated by the following equilibrium:

It is clear that both of these groups are essentially the same, and the tautomers consisting of such groups are considered the same compounds, especially in synthetic chemistry. Both the tautomeric forms of the compound with such groups in the molecule are therefore covered by the present invention, and they are denoted by the single term "thiazolyl" and are indicated by the formula:

for the sake of overview.

The definitions used here are explained in more detail below.

"Ci-Ce alkyl" can be linear or branched alkyl groups with 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl, pentyl, neopentyl and hexyl, and groups with 1- 4 carbon atoms.

"C2-C6-alkenyl" can be linear or branched alkenyl groups of up to 6 carbon atoms, such as vinyl, allyl,

1-propenyl, isopropenyl, butenyl, isobutenyl, pentenyl and hexenyl, and such groups with up to 4 carbon atoms are particularly preferred.

Preferred examples of "carboxy-C 1 -C 6 alkyl" are carboxymethyl, 1-carboxyethyl, 2-carboxyethyl, 1-carboxypropyl, 3-carboxypropyl, 4-carboxybutyl, 5-carboxypentyl, 6-carboxyhexyl, 1-carboxyisopropyl , 1-ethyl-1-carboxyethyl and 2-methyl-2-carboxypropyl.

Preferred examples of "Ci-C6-Alkoxycarbonyl-Ci-Ce -

alkyl" is methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonylmethyl, tert-butoxycarbonylmethyl, 2-ethoxycarbonylethyl, 2-ethoxycarbonylpropyl, 4-ethoxycarbonylbutyl, 1-tert-butoxycarbonylisopropyl, 1-tert-butoxycarbonyl-1-methylpropyl, 4-tert-butoxycarbonylbutyl and 5-tert.butoxycarbonylpentyl, 6-butoxycarbonylhexyl.

According to the invention, the new compounds are produced

with formula I in that

1) a 7-amino-3-cephem compound of the general formula II

where

R<5> is carboxy or esterified carboxy, or a reactive

amino derivative or a salt thereof, is reacted with a syn-isomer of a carboxylic acid of the general formula III

where

R<2> has the above meaning, and R<6> is amino or protected amino, a reactive derivative thereof at the carboxyl group, or a salt thereof, or

2) a syn-isomer of a compound of the general formula V

where

R<5> and R<6> have the meaning stated above, or a salt thereof, is reacted with an etherifying agent which can introduce a C1-C8-alkyl-, C2-C6-alkenyl-, carboxy-C1-C6-alkyl- or C 1 -C 5 -Alkoxycarbonyl C 1 -C 5 -Alkyl group, or

3) a syn isomer of a compound of the general formula VI

where R<2> and R<9> have the meaning given above and R<1>b denotes haloacetyl, is reacted with a thiourea compound of the general formula VII

where R<6> has the above meaning,

4) a syn-isomer of a compound of the general formula Ig

where R2 , R<3> and R6 b have the above meaning, and R<7> is acyl, or a salt thereof, is treated with a base, then possible protective groups are removed and/or an obtained free acid is converted into pharmaceutically acceptable salts or esters, or pharmaceutically acceptable salts are converted to pharmaceutically acceptable esters, or pharmaceutically acceptable esters are converted to pharmaceutically acceptable salts.

"Protecting groups" in "protected amino" may mean common N-protecting groups, such as substituted or unsubstituted aryl-lower alkyl (eg, benzyl, benzhydryl, trityl, 4-methoxybenzyl or 3,4-dimethoxybenzyl), halogen-lower alkyl (eg trichloromethyl, trichloroethyl, trifluoromethyl), tetrahydropyranyl, substituted phenylthio, substituted alkylidene, substituted aralkylidene, substituted cycloalkylidene or acyl.

Suitable acyl protecting group may be substituted or unsubstituted lower alkanoyl (e.g. formyl, acetyl, chloroacetyl or trifluoroacetyl), substituted or unsubstituted lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl , tert-butoxycarbonyl, pentyloxycarbonyl, tert-pentyloxycarbonyl, hexyloxycarbonyl, trichloroethoxycarbonyl or 2-pyridylmethoxycarbonyl), substituted or unsubstituted aryl-lower alkoxycarbonyl (e.g. benzyloxycarbonyl, benzhydryloxycarbonyl or 4-nitrobenzyloxycarbonyl), lower cycloalkoxycarbonyl (eg cyclopentyloxycarbonyl or cyclohexyloxycarbonyl), 8-quinolyloxycarbonyl, succinyl or phthaloyl.

Furthermore, the protective group can be a reaction product between a silane, boron, aluminum or phosphorus compound and the amino group. Suitable examples of such compounds are trimethylsilyl chloride, trimethoxysilyl chloride, boron trichloride, butoxy boron dichloride, aluminum trichloride, diethoxyaluminum chloride, phosphorus dibromide and phenylphosphorus dibromide.

Suitable examples of pharmaceutically acceptable esters are alkyl esters (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, tert-pentyl ester, hexyl ester, heptyl ester, octyl ester or 1-cyclopropyl ethyl ester),

alkenyl esters (e.g. vinyl ester or allyl ester), alkynyl esters (e.g. ethynyl ester or propynyl ester), alkoxyalkyl esters (e.g. methoxymethyl ester, ethoxymethyl ester, isopropoxymethyl ester, 1-methoxyethyl ester or 1-ethoxyethyl ester),

alkylthioalkylesters (e.g. methylthiomethylester, ethylthiomethylester, ethylthioethylester or isopropylthiomethylester), haloalkylesters (e.g. 2-iodoethylester or 2,2,2-trichloroethylester),

alkanoyloxyalkyl esters (e.g. acetoxymethyl ester, propionyloxymethylester, butyryloxymethylester, valeryloxymethylester, pivaloyloxymethylester, hexanoyloxymethylester, 2-acetoxyethylester, 2-propionyloxyethylester or palmitoyloxymethylester), alkanesulfonylalkylesters (e.g. mesylmethylester or 2-mesylethylester),

substituted or unsubstituted aralkyl esters (e.g. benzyl ester), 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester or 4-hydroxy-3,5-di- tert.butylbenzyl ester),

substituted or unsubstituted aryl esters (e.g. phenyl ester, tolyl ester, tert.butyl phenyl ester, xylyl ester, mesity ester, cumenyl ester or salicylic ester), as well as

esters with a silyl compound such as trialkylsilyl compounds, dialkylalkyloxysilyl compounds or trialkoxysilyl compounds, e.g. trialkylsilyl esters (e.g. trimethylsilyl ester or triethylsilyl ester), dialkyl methoxysilyl esters (e.g. dimethylmethoxysilyl ester, dimethylethoxysilyl ester or diethyl methoxysilyl ester) or trimethoxysilyl esters (e.g. trimethoxysilyl ester, triethoxysilyl ester).

Suitable "pharmaceutically acceptable salts" of the compound of general formula I may be common non-toxic salts, including salts with inorganic bases or acids, e.g. metal salts such as alkali metal salts (eg sodium salt or potassium salt) or alkaline earth metal salts (eg the calcium salt or magnesium salt) or the ammonium salt, an inorganic acid addition salt (eg the hydrochloride, hydrobromide, sulphate, phosphate, carbonate or bicarbonate ), a salt with an organic base or acid, e.g. an amine salt (e.g. trimethylamine salt, triethylamine salt, pyridine salt, procaine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, N-methylglucamine salt, diethanolamine salt, triethanolamine salt, tris(hydroxymethylamino)methane salt or phenethylbenzylamine salt, an organic carboxylic acid or sulfonic acid salt (eg acetate, maleate, lactate, tartrate, mesylate, benzenesulfonate or tosylate) or a basic or acidic amino acid salt (eg arginine salt, aspartic acid salt, glutamic acid salt, lysine salt or serine salt).

The process according to the present invention for the preparation of the compounds of the general formula I can be explained by the reaction core below:

Method 1: N-acylation

Method 2: Priming

Method 3: Thiazole ring formation Method 4: 3-cephem formation Method a: Elimination of amino-protecting group

Method b: Esterification Method c: Carboxylation

R<2> is as stated above,

R<5> is carboxy or esterified carboxy,

R<1>'s

R<6>ber amino or protected amino, A is

R<1>ber haloacetyl

R6 a is protected amino

R<7>a is acyl

R<5>a is esterified carboxy

The methods specified above are described in more detail in the following:

Method 1: N-acylation

A compound of the general formula I or a salt thereof can be prepared by reacting a 7-amino-3-cephem compound of the general formula II or a reactive derivative thereof at the amino group or a salt thereof, with a carboxylic acid of the general formula III, a reactive derivative thereof at the carboxyl group or a salt thereof, in the usual way by so-called amidation reaction which is well known from (3-lactam chemistry.

The starting compounds with the general formula III are partly unknown, and the hitherto unknown compounds with the general formula III can be prepared by the methods described below.

Suitable reactive derivatives at the amino group of the compound of the general formula II can be common reactive derivatives used in a wide range of amidation reactions, e.g. isocyanate or isothiocyanate derivatives, a derivative formed by reacting a compound of the general formula II with a silyl compound (e.g. trimethylsilylacetamide or bis(tri-methylsilyl)acetamide), with an aldehyde compound (e.g. acetaldehyde, isopentaldehyde , benzaldehyde, salicylaldehyde, phenylacetaldehyde, p-nitrobenzaldehyde, m-chlorobenzaldehyde, p-chlorobenzaldehyde, hydroxynaphthoaldehyde, furfural or thiophene carboaldehyde, or the corresponding hydrate, acetal, hemiacetal or enolate thereof), with a ketone compound (e.g. acetone, methyl ethyl ketone, methyl isobutyl ketone, acetylacetone or ethyl acetoacetate or the corresponding ketal, hemiketal or enolate thereof), with a phosphorus compound (e.g. phosphorus oxychloride or phosphorus trichloride) or with a sulfur compound (e.g. thionyl chloride).

Suitable salts of compounds of general formula II may be the same as exemplified for compounds of general formula I.

Suitable reactive derivatives at the carboxyl group of the compound with the general formula III can e.g. be an acid halide, an acid anhydride, an activated amide or an activated ester, preferably an acid halide such as acid chloride or acid bromide, a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g. dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid or halogenated phosphoric acid), dialkylphosphoric acid, sulfuric acid, thiosulphuric acid, sulfuric acid, alkylcarboxylic acid, aliphatic carboxylic acid (eg pivalic acid, pentanoic acid, isopentanoic acid, 2-ethyl-butyric acid or trichloroacetic acid), or aromatic carboxylic acid (eg benzoic acid); a symmetrical acid anhydride, an activated acid amide or imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole or an activated ester (e.g. cyanomethyl ester, methoxymethyl ester, dimethylaminomethyl ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester . 1-hydroxy-2-(1H)-pyridone, N-hydroxy-succinimide, N-hydroxyphthalimide, 1-hydroxybenzotriazole or 1-hydroxy-6-chlorobenzotriazole).

Suitable reactive derivatives of the compounds of the general formulas II and III can be freely selected from those indicated above when consideration is given to which compounds of the general formulas II and III are to be used in practice, and to the reaction conditions.

Suitable salts of the compounds of the general formula III can be salts with inorganic bases, e.g. alkali metal salts (e.g. the sodium salt or the potassium salt) or an alkaline earth metal salt (e.g. the calcium salt or the magnesium salt), a salt with an organic base such as a tertiary amine (e.g. the tri-methylamine salt, the triethylamine salt, N,N- the dimethylaniline salt or the pyridine salt), or a salt with an inorganic acid (eg the hydrochloride or hydrobromide).

The reaction is usually carried out in a common solvent, e.g. water, acetone, dioxane, acetonitrile, chloroform, benzene, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide or pyridine or any other solvent which does not adversely affect the reaction, or optionally a mixture thereof.

When the acylating agent of the general formula III is used in the form of the free acid or a salt in this reaction, the reaction is preferably carried out in the presence of a condensing agent, e.g. a carbodiimide compound (e.g. N,N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide, N,N'-diethylcarbodiimide, N,N' -diisopropylcarbodiimide or N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide), a bis-imidazolide compound (e.g. N,N'-carbonyl-bis(2-methylimidazole), an imine compound (e.g. pentamethyleneketen- N-cyclohexyl imine or diphenylketene-N-cyclohexyl imine), an olefinic or acetylenic ether compound (e.g. acetoxyacetylene or p-chlorovinyl ethyl ether), 1-(4-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole, N-ethyl- benzisoxazolium salt, N-ethyl-5-phenylisoxazolium-3'-sulfonate, a phosphorus compound (e.g., polyphosphoric acid, trialkylphosphite, ethyl polyphosphate, isopropylpolyphosphate, phosphorus oxychloride, phosphorus trichloride, diethylchlorophosphite, or orthophenylenechlorophosphite), thionyl chloride, oxalyl chloride, or Vilsmeier's reagent prepared by reacting dimethylformamide with thionyl chloride, phosphorus oxychloride or phosgene.

Method 2: Priming

A compound of the general formula I or a salt thereof can be prepared by reacting a compound of the general formula V or a salt thereof with an etherifying agent which serves to introduce the group R<2>.

The output connection with the general formula V is new and

can be produced by the methods specified below.

Suitable examples of etherification agents can be common alkylating agents such as di-Ci-C6 alkyl sulfates (e.g. dimethyl sulfate or diethyl sulfate), diazo-Ci-Ce alkanes (e.g. diazomethane or diazoethane), Ci-Ce alkyl halides ( e.g. methyl iodide, ethyl iodide or ethyl bromide) or C 1 -C 6 alkyl sulfonates (e.g. methyl tosylate), the corresponding C 2 -C 6 alkenylating agents, where the C 1 -C 6 alkyl group may be substituted by carboxy or C 1 - C6-Alkoxycarbonyl, e.g. C 1 -C 6 alkenyl halides (e.g. allyl iodide), or C 1 -C 6 alkoxycarbonyl C 1 -C 6 alkyl halides (e.g. ethoxycarbonylmethyl iodide).

When diazoalkanes are used as etherification agents,

the reaction is usually carried out in a solvent such as diethyl ether or dioxane or another solvent which does not adversely affect the reaction, under cooling or at room temperature.

When another etherifying agent is used, the reaction is usually carried out in a solvent such as water,

acetone, ethanol, diethyl ether or dimethylformamide or another solvent which does not adversely affect the reaction, and the reaction can be carried out under cooling, at room temperature or under heating, preferably in the presence of a base, e.g. an inorganic or organic base, and suitable examples of such are the same as indicated below for use in the basic hydrolysis, method a).

Method 3: Thiazole ring formation

A compound of the general formula I or a salt thereof can be prepared by reacting a compound of the general formula VI or a salt thereof with a thiourea compound of the general formula VII.

The starting compound of the general formula VI is new and can be prepared as described below.

The reaction is usually carried out in a solvent such as water, alcohol (eg methanol or ethanol), benzene, dimethylformamide or tetrahydrofuran or another solvent which does not adversely affect the reaction, at room temperature or under heating.

Method 4: 3-cephem formation

A compound of the general formula I or a salt thereof can be prepared by treating a compound of the general formula Ig or a salt thereof with a base.

Preferred bases are inorganic bases such as metal hydroxides (eg sodium hydroxide or potassium hydroxide), metal carbonates (eg sodium carbonate, potassium carbonate or magnesium carbonate) or metal bicarbonates (eg sodium bicarbonate or potassium bicarbonate) or organic bases such as tertiary amines (eg trimethylamine, triethylamine or pyridine) or alkali metal alkoxides (eg sodium methoxide or sodium ethoxide).

The reaction is usually carried out in a common solvent such as an alcohol, dimethylformamide, chloroform, methylene chloride or another solvent which does not have a harmful effect on the reaction, and the reaction can be carried out under cooling, at room temperature or under slight heating.

Method a): Elimination of an amino protecting group.

A compound of the general formula I or a salt thereof can be prepared by subjecting a corresponding compound having a protected amino group on the thiazole ring or a salt thereof to a reaction to eliminate the protecting group. The elimination reaction can be carried out in a manner known per se, e.g. by hydrolysis. The method is chosen in accordance with the type of protecting group to be eliminated.

The hydrolysis can be carried out using an acid (acidic hydrolysis) or a base (basic hydrolysis).

Among these methods, the acid hydrolysis is one of the common and preferred ways for the elimination of protecting groups such as acyl groups, e.g. substituted or unsubstituted lower alkanoyl.

A suitable acid for use in this acid hydrolysis can be an organic or inorganic acid, e.g. formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid or cation exchange resin. Preferred acids are those which can be easily separated from the reaction product in the usual way, e.g. by neutralization or distillation under reduced pressure, e.g. formic acid, trifluoroacetic acid or hydrochloric acid. A suitable acid for the reaction is chosen taking into account the chemical properties of the starting compound and the product, as well as the type of protecting group to be eliminated. The acid hydrolysis can be carried out in the presence or absence of a solvent. Suitable solvents can be ordinary organic solvents, water or mixtures thereof, which do not adversely affect the reaction. Especially when the hydrolysis is carried out with trifluoroacetic acid, the reaction can be accelerated by the addition of anisole.

A suitable base can e.g. be an inorganic base such as an alkali metal hydroxide (e.g. sodium hydroxide or potassium hydroxide), an alkaline earth metal hydroxide (e.g. magnesium hydroxide or calcium hydroxide), an alkali metal carbonate (e.g. sodium carbonate or potassium carbonate), an alkaline earth metal carbonate (e.g. magnesium carbonate or calcium carbonate), an alkali metal bicarbonate (eg sodium bicarbonate or potassium bicarbonate), an alkaline earth metal phosphate (eg magnesium phosphate or calcium phosphate), or an alkali metal hydrogen phosphate

(e.g. disodium hydrogen phosphate or dipotassium hydrogen phosphate)

or an organic base such as an alkali metal acetate (eg sodium acetate or potassium acetate), a trialkylamine (eg trimethylamine or triethylamine), picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo[4,3, 0]-5-nonene, 1,4-diazabicyclo-

[2,2,2]octane, 1,5-diazabicyclo[5,4,0]-7-undecene or an anion exchange resin. Hydrolysis using a base is often carried out in water or a common organic solvent, or a mixture thereof.

The reaction temperature is not critical and can be chosen freely when taking into account the chemical properties of the starting and reaction products as well as the type of N-protecting group and the method used, and the reaction is preferably carried out under mild conditions, e.g. during cooling, at room temperature or at a slightly elevated temperature.

It falls within the scope of the present method

that the esterified carboxyl group Rs is simultaneously converted into a free carboxyl group during the above-mentioned reaction or during the post-treatment.

Method b): Esterification

This method is used for the production of a pharmaceutically acceptable ester of the compound with the general formula I or a salt thereof to improve the chemical, physiological and/or pharmaceutical properties of the corresponding free carboxyl compound with the general formula I.

The esterification is carried out by reacting a free carboxyl compound of the general formula I, a reactive derivative thereof at the carboxyl group or a salt thereof with an esterification agent.

The esterification agent can be a hydroxy compound or a corresponding reactive agent.

Suitable examples of hydroxy compounds are an alkanoyloxy-lower alkanol (e.g. acetoxymethanol, propionyloxymethanol, butyryloxymethanol, pentanoyloxymethanol, hexanoyloxymethanol, acetoxyethanol, propionyloxyethanol, butyryloxyethanol, pentanoyloxyethanol, hexanoyloxyethanol, acetoxypropanol, propionyloxypropanol, hexanoyloxypropanol, hexanoyloxyhexanol or palmitoyloxymethanol).

A suitable reactive equivalent of the hydroxy compound may be a common compound, e.g. a halide.

A preferred halide of the hydroxy compound is

chloride, bromide or iodide.

The reaction can be carried out in the presence or absence of a solvent, e.g. N,N-dimethylformamide, dimethylsulfoxide or another solution that does not adversely affect the reaction, and it can be carried out under cooling, at room temperature or under heating. The liquid hydroxy compound can also be used as a solvent in this reaction.

The reaction can preferably be carried out in the presence of an inorganic or organic base, which is described in more detail in connection with method a).

The compounds produced by the methods described above can be isolated and purified in the usual way.

The prepared compound of the general formula I can be converted into a pharmaceutically acceptable salt in a manner known per se.

The compounds of the general formula I and pharmaceutically acceptable salts and esters thereof exhibit a high antimicrobial effect and inhibit the growth of a wide variety of pathogenic micro-organisms, including gram-positive and gram-negative bacteria, and are useful as antimicrobial agents.

The compounds of the general formula VI are the subject of divisional application 79.3077.

In order to demonstrate the utility of the active compounds of general formula I, experimental data for some representative compounds of general formula I are set forth below.

1. In vitro antibacterial activity:

1) Test method.

The antibacterial activity in vitro is determined by the double agar plate dilution method described below.

The content of a pinhole of a 100-fold dilution of an overnight culture of each test strain in trypticase-soy substrate is plated on heart infusion agar (HI agar) containing graded concentrations of the test compound, and incubated at 37°C in 20 hours. The minimum inhibitory concentration (MIC) is expressed in ug/ml.

2) Test compounds:

No.

1. 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer), 2. 7-[2-(2-amino-4-thiazolyl) )-2-ethoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer), 3. 7-[2-(2-amino-4-thiazolyl)-2-n-propoxyiminoacetamido]-3-cephem-4- carboxylic acid (syn isomer), 4. 7-[2-(2-amino-4-thiazolyl)-2-n-butoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer), 5. 7-[2 -(2-amino-4-thiazolyl)-2-allyloxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer), 6. 7-[2-(2-amino-4-thiazolyl)-2-n- pentyloxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer), 7. 7-[2-(2-amino-4-thiazolyl)-2-n-hexyloxyiminoacetamido]-3-cephem-4-carboxylic acid (syn- isomer), 8. 7-[2-(2-amino-4-thiazolyl)-2-carboxymethoxyiminoacetamido)-3-cephem-4-carboxylic acid (syn isomer).

Reference compound: 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-desacetoxycephalosporanic acid (syn isomer).

(NO-A-754296, ex. 62)

The above four known compounds A-D were examined in the same way with regard to antimicrobial activity (MIC ug/ml) and the results are reproduced in the following table.

When comparing the above MIC values with the corresponding values for the compounds produced according to the invention, it will be seen that the new compounds produced according to the invention are far better than the previously known compounds. 2. Protective effect against experimental infections in mice:

1) Test method.

4-week-old male mice from strain ICR, each weighing 18.5-21.5 g, are used in groups of 10 mice. The test bacteria are grown overnight at 37°C on trypticase soy agar and then suspended in 5% mucin to form a suspension of cells of each strain to be used for infection. The mice are inoculated intraperitoneally with 0.5 ml of the suspension. A solution containing each test compound is administered subcutaneously to the mice in different doses 1 hour after the infection.

The EDao values are calculated from the number of surviving mice for each dose after 4 days of observation.

2) Trial connections.

1. 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer)

reference: 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-cephalosporanic acid (syn isomer).

3) Test results:

3. Acute toxicity

1) Test method:

Each group comprises 10 6-week-old male rats and 10 6-week-old female rats (JCL-SD strain). The trial connection dissolved in distilled water and administered subcutaneously and intravenously to the animals. These animals are observed for 7 days after dosing. The LDso values are calculated from the number of dead animals by the Litchfield-Wilcoxon method. 2) Test compound: 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer). 3) Test result:

4. Absorbable

1) Test method:

The test compounds are administered orally to a group of 5 fasted rats (JCL-SD strain, 6-week-old male rats). Bile and urine samples are collected 0~6 and 6~24 hours. The concentration of the test compound in the samples is determined by bioassay (plate method) using Bacillus subtilis ATCC-6633 as test organism, and the recovery in bile and urine is calculated. 2) Trial connection: 7-[2-(2-amino-4-thiazolyl)-2-n-pentyloxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer).

3) Test result:

Total recovery from bile and urine in 24 hours is 22.8%. The starting compounds of the general formula III can be prepared as shown below:

where R<2> is as above, R<6> means protected amino, Y means lower alkoxycarbonyl and Z means lower alkyl.

Each of the above methods is described in more detail below.

Procedure (i): Preferred.

Compounds of the general formula Illb or Uld can be prepared by reacting a compound of the general formula Illa or Ille with an etherifying agent.

This reaction can be carried out in essentially the same way as the above-mentioned method 2.

Method (ii): Thiazole ring formation

A compound of the general formula Ille or Uld can be prepared by reacting a compound of the general formula Illa or Illb with a thiourea compound of the general formula Vila, and furthermore the compounds of the general formula Ille can be prepared by reacting a compound with the general formula IIIb with thiourea.

This reaction can be carried out in essentially the same way as the above-mentioned method 3.

Method (iii): Elimination of the amino protecting group.

A compound of the general formula Ille or Hig can be prepared by eliminating the protecting group in the protected amino group R<6>a in a compound of the general formula Uld or Ulf.

This reaction can be carried out in essentially the same way as the above-mentioned method a).

Method (iv): Carboxylation

A compound of the general formula Ulf or Hig can be prepared by converting an esterified carboxyl group in a compound of the general formula Uld or Ille into a free carboxyl group.

Method (v): Oximation

A compound of the general formula If can also be prepared by reacting a compound of the general formula Illh with a hydroxylamine derivative of the general formula XIV or a salt thereof.

The hydroxylamine derivative of the general formula XIV may be hydroxylamine substituted with R<2>; and reference is made in this connection to the above detailed description. A suitable salt of the hydroxylamine derivative of general formula XIV may be the hydrochloride, hydrobromide or sulfate.

The reaction is usually carried out in a common solvent such as water, alcohol, tetrahydrofuran, acetonitrile, dimethylsulfoxide or pyridine or another solvent that does not adversely affect the reaction, or mixtures thereof, and the reaction temperature is not critical. When a salt of the hydroxylamine derivative of the general formula XIV is used as reagent, the reaction is preferably carried out in the presence of a common base.

Among the starting compounds of the general formula III are compounds of the general formula III'

where R<2> and R<6> are as indicated above, and R" means hydrogen or lower alkyl, provided that R<6>b means amino which may be protected with formyl and R° means hydrogen, when R<2> means ethyl, isopropyl or allyl, hitherto unknown, and they are useful as starting materials in the above-mentioned method 1.

Detailed description of the above definitions

is indicated earlier.

The starting compounds V, VI and 1g can be prepared by the methods described below.

Preparation of output compounds V and VI Preparation of output compound lg

R<1>b, R<2>, R<3> and R<6> are as indicated above, and R<7>a is acyl.

The method according to the present invention is illustrated in more detail by the following examples:

Making Output Connections:

Example A

1) 160 g of powdered potassium carbonate is added to a solution of 152 g of ethyl 2-hydroxyiminoacetoacetate (a mixture of syn-

and anti-isomers) in 500 ml of acetone. 130 g of dimethylsulphate are added dropwise with stirring over the course of 1 hour at 45-50°C, and the mixture is stirred for 2 hours. Insoluble material is filtered off, and the filtrate is evaporated under reduced pressure. The filtered insoluble material is dissolved in 500 ml of water, and this solution is added to the residue. The mixture is extracted twice with 300 ml of ethyl acetate. The extract is washed twice with 200 ml of water and with 200 ml of saturated aqueous sodium chloride solution and dried over magnesium sulphate. The solvent is distilled off under reduced pressure, and the residue is distilled under reduced pressure, whereby 145.3 g of ethyl 2-methoxyiminoacetoacetate is obtained in the form of a colorless oil (a mixture of syn and anti isomers), boiling point 55-64° C/0.5 mm Hg.

IR spectrum (film): -Omax = 1745, 1695 and 1600 cm"<1>. NMR spectrum (CDC13): 5 ppm = 4.33 (4H, q, J=8Hz), 4.08

(3H, s), 3.95 (3H, s), 2.40 (3H, s), 1.63 (3H, s), 1.33

(6H, t, J=8Hz) .

2) 235 ml of sulfuryl chloride is added dropwise over 20 minutes with stirring and ice-cooling to a solution of 500 g of ethyl-2-methoxyiminoacetoacetate (syn isomer) in 500 ml of acetic acid, and the mixture is stirred overnight while cooling with water. Nitrogen gas is bubbled through the reaction mixture for 2 hours, and the resulting mixture is poured into 2.5 liters of water. After extraction with 500 ml of methylene chloride and twice with 200 ml of methylene chloride, the extracts are collected. The combined extracts are washed with a saturated aqueous sodium chloride solution, and the pH value is adjusted to 6.5 by adding 800 ml of water and sodium bicarbonate. The methylene chloride phase is separated, washed with an aqueous sodium chloride solution and dried over magnesium sulphate. The solvent is distilled off, whereby 559 g of ethyl 2-methoxyimino-4-chloroacetoacetate (syn isomer) is obtained.

IR spectrum (film): Oiak>= 1735 and 1705 cm"<1>.

3) 50 g of ethyl-2-methoxyimino-4-chloroacetoacetate (syn isomer) is added during 3 minutes with stirring at room temperature to a solution of 18.4 g of thiourea and 19.8 g of sodium acetate in a mixture of 250 ml of methanol and 250 ml of water. After stirring for 35 minutes at 40-45°C, the reaction mixture is cooled with ice, and the pH is adjusted to 6.3 with a saturated aqueous sodium bicarbonate solution. After stirring for 30 minutes at this temperature, the precipitate is collected by filtration, washed with 200 ml of water and then with 100 ml of diisopropyl ether and dried, whereby 37.8 g of ethyl-2-methoxyimino-2-(2-amino-1,3 -thiazol-4-yl)acetate (syn isomer) in the form of colorless crystals with a melting point of 161-162°C.

IR spectrum (nujol): vi.aks = 3400, 3300, 3150, 1725, 1630 and 1559 cm -1 .

NMR spectrum (CDCl 2 ): 5 ppm = 6.72 (1H, s), 5.91 (2H, broad s), 4.38 (2H, q, J=7Hz), 4.03 (3H, s) , 1.38 (3H, t, J=7Hz). 4) 10 ml of ethanol is added to a suspension of 2.2 g of ethyl-2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate (syn isomer) in 12 ml of IN aqueous sodium hydroxide solution, and the mixture is stirred for 15 hours at room temperature. The reaction mixture is adjusted to pH 7.0 with 10% hydrochloric acid, and the ethanol is distilled off under reduced pressure. The aqueous solution obtained as a residue is washed with ethyl acetate and adjusted to pH 2.8 with 10% hydrochloric acid, and it is stirred under ice cooling to precipitate crystals. The crystals are collected by filtration, washed with acetone and recrystallized from ethanol, whereby 1.1 g of 2-methoxyimino-2-(2-amino-1,3-thiazol-4-yacetic acid) (syn-isomer) is obtained in the form of colorless needles IR spectrum (nujol):Omax = 3150, 1670, 1610 and 1585 cnr<1>NMR spectrum (de-DMSO): 5 ppm = 7.20 (2H, broad s), 6.85

(1H, s), 3.83 (3H, s).

Example B

1) 35.2 g of sulfuryl chloride are added at once to a stirred solution of 48.9 g of ethyl 2-ethoxyimino-3-oxobutyrate (syn isomer) in 49 ml of acetic acid at room temperature and stirred at the same temperature for 1 hour. The resulting solution is poured into 200 ml of water, and the solution is extracted with methylene chloride. The extract is washed with saturated aqueous sodium chloride solution, neutralized with an aqueous sodium bicarbonate solution and washed with water. The solution is dried over magnesium sulfate and evaporated under reduced pressure, whereby 53.8 g of ethyl 2-ethoxyimino-3-oxo-4-chlorobutyrate (syn isomer) is obtained in the form of a pale yellow oil.

2) A mixture of 38.7 g of ethyl 2-ethoxyimino-3-oxo-4-chloro-butyrate (syn isomer), 13.2 g of thiourea, 14.3 g of sodium acetate, 95 ml of methanol and 95 ml of water is stirred for 40 minutes at 48°C. After the resulting solution is adjusted to pH 6.5 with an aqueous sodium bicarbonate solution, the precipitated material is collected by filtration and washed with diisopropyl ether to obtain 14.7 g of ethyl 2-(2-amino-4-thiazolyl)-2 -ethoxy-iminoacetate (syn-isomer) with melting point 130-131°C. IR spectrum (nujol): Oiau = 3450, 3275, 3125, 1715 and

1620 cm-<1>. 3) 5 g of ethyl 2-(2-amino-4-thiazolyl)-2-ethoxyiminoacetate (syn isomer) is added to a mixture of 45.9 ml IN sodium hydroxide solution and 30 ml ethanol and stirred at room temperature for 5 hours . After evaporation of the ethanol from the resulting solution under reduced pressure, the residue is dissolved in 60 ml of water, and the pH is adjusted to 2.0 with 10% hydrochloric acid. The solution is desalted, and the precipitate is collected by filtration and dried, whereby 2.9 g of 2-(2-amino-4-thiazolyl)-2-ethoxyimino-acetic acid (syn isomer) is obtained.

IR spectrum (nujol): v max = 3625, 3225 (shoulder), 3100, 1650 and 1615 cm-<1>.

NMR spectrum (d6-DMSO): 5 ppm = 1.20 (3H, t, J=7Hz), 4.09 (2H, q, J=7Hz), 6.82 (1H, s), 7.24 (2H, wide s). 4) 100 g of 2-(2-aminothiazol-4-yl)-2-ethoxyiminoacetic acid (syn isomer), 85.5 g of formic acid and 190.1 g of acetic anhydride are treated in an analogous manner as in example F (5) to form 99.1 g 2-(2- formamidothiazol-4-yl)-2-ethoxyiminoacetic acid (syn isomer).

IR spectrum (nujol): ^max = 3200, 3140, 3050 and 1700 cirr1 NMR spectrum (de-DMSO): 5 ppm = 1.18 (3H, t, J=6Hz), 4.22

(2H, q, J=6Hz), 7.56 (1H, s), 8.56 (1H, s), 12.62 (1H, wide s).

Example C

1) To a suspension of 15 g of ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer) and 19.8 g of potassium carbonate in 75 ml of acetone, 16.2 g of propyl iodide are added dropwise while stirring, and the mixture is stirred at room temperature for 1 1 /2 hours. The insoluble substance is filtered off and washed with acetone. The washing liquids and the filtrate are collected and evaporated to dryness under reduced pressure. Water is added to the residue, and the aqueous solution is extracted twice with chloroform. The extract is washed with an aqueous sodium chloride solution, dried over magnesium sulfate and then evaporated to dryness under reduced pressure, whereby 15.4 g of ethyl 3-oxo-2-propoxyiminobutyrate (syn isomer) is obtained in the form of an oil. 2) 15.4 g of ethyl 3-oxo-2-propoxyiminobutyrate (syn isomer) and 10.6 g of sulfuryl chloride are dissolved in 15.4 ml of acetic acid, heated to 35-40°C for 10 minutes with stirring, and then stirred at room temperature for a further 6 hours. The reaction mixture is poured into 200 ml of ice water, and the resulting mixture is extracted twice with chloroform. The extract is washed with an aqueous sodium chloride solution, twice with a saturated aqueous sodium bicarbonate solution and once with water in the order mentioned, dried over magnesium sulfate and then evaporated to dryness under reduced pressure to obtain 15.4 g of ethyl-4-chloro-3 -oxo-2-propoxyiminobutyrate (syn isomer) in the form of an oil.

IR spectrum (film): Vmax = 1740, 1710, 1695 and 1455 cm"<1>.

3) 15.4 g of ethyl-4-chloro-3-oxo-2-propoxyiminobutyrate (syn isomer), 4.97 g of thiourea and 8.89 g of sodium acetate hydrate are dissolved in a mixture of 40 ml of water and 50 ml of ethanol and stirred at 40°C for 1 hour.

The reaction mixture is adjusted to pH 6.5 with a saturated aqueous potassium carbonate solution while cooling and stirred at the same temperature for 1/2 hour. The precipitated crystals are filtered off, washed with water and diisopropyl ether and then dried, thereby obtaining 10.55 g of ethyl 2-(2-amino-4-thiazolyl)-2-propoxyiminoacetate (syn isomer) in the form of crystals, melting point 142 -144°C. IR spectrum (nujol): 0mak3= 3460, 3260, 3120, 1720, 1620 and 1540 cm-<1>.

NMR spectrum (d6-DMSO): 5 ppm =0.88 (3H, t, J=7Hz), 1.27 (3H, t, J=6Hz), 1.60 (2H, sextet, J=7Hz) , 4.04 (2H, t, J=7Hz),

4.28 (2H, q, J=6Hz), 6.86 (1H, s), 7.23 (2H, s). 4) A solution of 10 g of ethyl 2-(2-amino-4-thiazolyl)-2-propoxyiminoacetate (syn isomer) in a mixture of 39 ml of tetrahydrofuran, 39 ml of methanol and 75.8 ml of IN sodium hydroxide is stirred at 35 -40°C for 5 hours.

After evaporation of the resulting solution under reduced pressure, the pH of the aqueous residue is adjusted to 2.5 with 10% hydrochloric acid. The precipitated material is filtered off and dried, whereby 6.2 g of 2-(2-amino-4-thiazolyl)-2-propoxyimino-acetic acid (syn-isomer) with melting point 161°C (decomposition) is obtained. IR spectrum (nujol):max = 3380, 3120 (broad), 1630, 1610 and 1460 cm-1.

NMR spectrum (d6-DMSO): 5 ppm =0.89 (3H, t, J=7Hz), 1.63 (2H, sextet, J=7Hz), 4.05 (2H, t, J=7Hz) , 6.83 (1H, s), 6.9-8.8

(3H, wide).

5) 21.8 g of 2-(2-aminothiazol-4-yl)-2-n-propoxyiminoacetic acid (syn isomer), 38.8 g of acetic anhydride and 17.15 g of formic acid are treated analogously to example E-(5), and the oil thus obtained is triturated with diisopropyl ether, whereby 19.2 g of 2-(2-formamidothiazol-4-yl)-2-n-propoxyiminoacetic acid (syn-isomer), melting point 164°C (decomposition) is obtained.

IR spectrum (nujol): Omax = 3200, 3120, 3050, 1700 and

1550 cm-<1>.

NMR spectrum (d6-DMSO): 5 ppm = 0.92 (3H, t, J=7Hz), 1.67 (2H, sextet, J=7Hz), 4.12 (2H, t, J=7Hz) , 7.53 (1H, p), 8.54

(1H, p).

Example D

1) 30 g of ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer), 32.5 g of isopropyl iodide, 39.5 g of potassium carbonate and 150 ml of acetone are treated analogously to example C (1), whereby 35.4 g are obtained ethyl 2-isopropoxyimino-3-oxobutyrate (syn isomer) in the form of an oil.

IR spectrum (film): Vmax = 1745, 1690 and 1600 cm"<1>. NMR spectrum (CCl*): 5 ppm = 1.33 (3H, t, J=7Hz), 1.35 (6H, d, J=6Hz), 2.32 (3H, s), 4.1~4.7 (3H, m). 2) 35.4 g ethyl 2-isopropoxyimino-3-oxobutyrate (syn isomer), 24.5 g of sulfuryl chloride and 35.4 g of acetic acid are treated analogously to example C (2), whereby 41.5 g of ethyl-4-chloro-3-oxo-2-isopropoxyiminobutyrate (syn isomer) is obtained in the form of an oil . IR spectrum (film): -Omax = 1745, 1715 and 1375 cm-<1>. 3) 41.5 g ethyl 4-chloro-3-oxo-2-isopropoxyiminobutyrate (syn-isomer), 13.4 g of thiourea, 14.4 g of sodium acetate, 110 ml of water and 110 ml of ethanol are treated analogously to example C (3), whereby 27.3 g of ethyl-2-(2-aminothiazol-4-yl)-2-isopropoxyimino- acetate (syn isomer), melting point 162-164°C.

IR spectrum (nujol): Omax = 3460, 3430, 3260, 3150, 1725,

1615 and 1540 are1 .

NMR spectrum (d6-DMSO): 5 ppm = 1.17 (6H, d, J=6Hz), 1.24 (3H, t, J=7Hz), 4~4.7 (3H, m), 6 .86 (1H, s), 7.24 (2H, s). 4) 26.8 g ethyl 2-(2-aminothiazol-4-yl)-2-isopropoxyimino-acetate (syn isomer), 156 ml IN aqueous sodium hydroxide solution, 156 ml methanol and 100 ml tetrahydrofuran are treated analogously to example C ( 4), whereby 15.3 g of 2-(2-aminothiazol-4-yl)-2-isopropoxyiminoacetic acid (syn isomer) is obtained, melting point 151°C (decomposition).

IR spectrum (nujol):\)agks= 3610, 3580, 3080, 1650 and

1610 cm-1.

NMR spectrum (d6-DMSO): 5 ppm = 1.22 (6H, d, J=6Hz), 4.33 (1H, quintet, J=6Hz), 6.80 (1H, s), 7.22 (2H, wide s). 5) 4 g of 2-(2-aminothiazol-4-yl)-2-isopropoxyiminoacetic acid (syn isomer), 7.6 g of acetic anhydride and 3.4 g of formic acid are treated analogously to example E (5), thereby obtaining 3, 75 g of 2-(2-formamidothiazol-4-yl)-2-isopropoxyiminoacetic acid (syn isomer), melting point 168-169°C (decomposition).

IR spectrum (nujol): v<>>mUks = 3200, 3130, 1710, 1600 and

1560 cm-1.

NMR spectrum (d6-DMSO): 5 ppm = 1.26 (6H, d), 4.4 (1H, m), 7.54 (1H, s), 8.52 (1H, s), 12, 56 (1H, wide p).

Example E

1) 46.9 g of n-butyl iodide is added dropwise over the course of 5 minutes to a stirred suspension of 40 g of ethyl 2-hydroxyimino-3-oxo-butyrate (syn isomer), 52.7 g of potassium carbonate and 200 ml of acetone under ice-cooling, and it is stirred for 4 hours at room temperature. The resulting solution is filtered and washed with acetone. The filtrate and washing solution are collected and evaporated in vacuo. 300 ml of water is added to the residue, and the solution is extracted three times with methylene chloride. The solution is washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo, whereby 48.8 g of ethyl 2-n-butoxyimino-3-oxobutyrate (syn isomer) is obtained in the form of an oil. IR spectrum (film): Omax = 1750, 1700, 1470, 1370 and

1320 cm-1. 2) A solution of 48.8 g of ethyl 2-n-butoxyimino-3-oxo-butyrate (syn isomer), 31.5 g of sulfuryl chloride and 48.8 ml of acetic acid is stirred for 10 minutes at 40° C and then at room temperature for 5 1/2 hours. To the resulting solution is added 300 ml of water under ice-cooling, and the solution is extracted three times with methylene chloride. The extracts are washed with water, aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution in the aforementioned order and dried over magnesium sulfate. The solution is evaporated in vacuo, whereby 52.1 g of ethyl 2-n-butoxyimino-4-chloro-3-oxobutyrate (syn isomer) is obtained in the form of an oil.

IR spectrum (film): Omax = 1740, 1710, 1470 and 1370 cm"<1>.

3) A solution of 52.1 g ethyl 2-n-butoxyimino-4-chloro-3-oxo-butyrate (syn isomer), 15.9 g thiourea, 28.4 g sodium acetate trihydrate, 130 ml water and 180 ml of ethanol are stirred at 40°C for 1 1/4 hours. The resulting solution is adjusted to pH 6.5 with an aqueous sodium carbonate solution under ice cooling and

stirred for 20 minutes under ice cooling. The precipitated material is filtered off and washed with water and then with diisopropyl ether, whereby 36.1 g of ethyl 2-(2-aminothiazol-4-yl)-2-n-butoxy-iminoacetate (syn isomer), melting point 126- 128°C.

IR spectrum (nujol): v.<g>ks = 3460, 3370, 3230, 1720, 1620 and 1550 cm-1.

NMR spectrum (de-DMSO): 6 ppm = 0.6-2.0 (6H, m), 1.28 (3H, t, J=7Hz), 4.12 (3H, t, J=6Hz) , 4.31 (2H, q, J=7Hz), 6.89 (1H, s), 7.24 (2H, s) . 4) A solution of 36 g of ethyl 2-(2-aminothiazol-4-yl)-2-n-butoxyiminoacetate (syn isomer), 133 ml of methanol, 133 ml of tetrahydrofuran and 133 ml of aqueous 2N sodium hydroxide solution is stirred at 30°C for 5 hours. The resulting solution is then evaporated in vacuo, and the residue is dissolved in water. The solution is adjusted to pH 7 with 10% hydrochloric acid and treated with activated charcoal. The solution is adjusted to pH 2.0 with 10% hydrochloric acid and stirred for 20 minutes under ice cooling. The precipitated material is filtered off, washed with water and acetone in the aforementioned order and dried, whereby 25.4 g of 2-(aminothiazol-4-yl)-2-n-butoxyiminoacetic acid (syn isomer) is obtained.

IR spectrum (nujol): Vmaus = 3325, 3190, 1660 and 1620 cm"<1>NMR spectrum (de-DMSO): 5 ppm = 0.88 (3H, t, J=7Hz), 1.0- 1.9 (4H, m), 4.06 (2H, t, J=7Hz), 6.81 (1H, s), 7.21 (2H, wide s).

5) 18.95 g of formic acid is added dropwise over 5 minutes with stirring to 42.0 g of acetic anhydride at room temperature, and it is stirred at 50°C for 1 hour. 25 g of 2-(2-aminothiazol-4-yl)-2-n-butoxyimino-acetic acid (syn-isomer) is added to the solution under ice-cooling, and it is stirred at room temperature for 3 hours and at 30°C for a further 1 hour. The resulting solution is evaporated in vacuo, and the residue is dissolved in diethyl ether. The solution is washed with water and saturated aqueous sodium chloride solution in the order mentioned, dried over magnesium sulfate and evaporated in vacuo. The oil obtained is triturated with a solution of n-hexane (1 part) and diisopropyl ether (1 part) and filtered, whereby 20.1 g of 2-(2-formamidothiazol-4-yl)-2-n-butoxyiminoacetic acid is obtained (syn isomer).

IR spectrum (nujol): v max = 3350, 3160, 3050, 1700, 1680 and 1570 cm-1.

NMR spectrum (de-DMSO): 6 ppm = 0.91 (3H, t, J=6Hz), 1.0-2.2 (4H, m), 4.18 (2H, t, J=6Hz) , 7.57 (1H, s), 8.59 (1H, s), 12.66 (1H, broad s).

Example F

1) 40 g of ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer),

200 ml of N,N-dimethylformamide, 52.7 g of potassium carbonate and 34.94 g of isobutyl bromide are treated in an analogous manner as in example E (1), whereby 42 g of ethyl 2-isobutoxyimino-3-oxobutyrate (syn isomer) is obtained .

IR spectrum (nujol): v>max = 1740 and 1670 (broad) cm-<1>.

2) 42 g of ethyl 2-isobutoxyimino-3-oxobutyrate (syn isomer),

42 ml of acetic acid and 27.1 g of sulfuryl chloride are treated analogously to example E (2), whereby 31.9 g of ethyl 2-isobutoxyimino-4-chloro-3-oxobutyrate (syn isomer) is obtained.

IR spectrum (film): Vmax = 1750, 1720 and 1680 cm"<1>.

3) 31.9 g of ethyl 2-isobutoxyimino-4-chloro-3-oxobutyrate (syn isomer), 9.72 g of thiourea, 17.4 g of sodium acetate trihydrate, 120 ml of ethanol and 80 ml of water are treated analogously to example E (3), whereby 17.6 g of ethyl 2-(2-aminothiazol-4-yl)-2-isobutoxyiminoacetate (syn isomer) is obtained, melting point 122-124°C. IR spectrum (nujol): v» max = 3470, 3260, 3120, 1730, 1620 and 1545 cm-1.

NMR spectrum (de-DMSO): 5 ppm = 0.86 (6H, d, J=7Hz), 1.28 (3H, t, J=7Hz), 1.6-2.2 (1H, m) , 3.86 (2H, d, J=7Hz), 4.28 (2H, q, J=7Hz), 6.86 (1H, s), 7.22 (2H, s). 4) 19.6 g of ethyl 2-(2-aminothiazol-4-yl)-2-isobutoxyiminoacetate, 72.2 ml of aqueous 2N sodium hydroxide solution, 72.2 ml of methanol and 72.2 ml of tetrahydrofuran are treated analogously to example E (4 ), whereby 16.1 g of 2-(2-aminothiazol-4-yl)-2-isobutoxyiminoacetic acid (syn isomer) is obtained, melting point 180°C (decomposition). IR spectrum (nujol): -Omax = 3375, 3300, 3130, 3050 and 1640 cm-1.

NMR spectrum (d6-DMSO): 6 ppm = 0.91 (6H, d, J=7Hz), 1.5-2.3 (1H, m), 3.90 (2H, d, J=7Hz) , 6.87 (1H, s), 7.26 (2H, wide s). 5) 11.5 g of 2-(2-aminothiazol-4-yl)-2-isobutoxyiminoacetic acid (syn isomer), 19.3 g of acetic anhydride and 8.7 g of formic acid are treated analogously to example E (5), which gives 11.15 g of 2-(2-formamidothiazol-4-yl)-2-isobutoxyiminoacetic acid (syn isomer), melting point 163°C (decomposition).

IR spectrum (nujol): Vmax = 3175, 3110, 3050, 1695 and 1550 cm-1.

NMR spectrum (d6-DMSO): 5 ppm = 0.91 (6H, d, J=7Hz), 1.7-2.3 (1H, m), 3.92 (2H, d, J=7Hz) , 7.52 (1H, s), 8.52 (1H, s), 12.58 (1H, wide s).

Example G

1) 40 g of ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer),

200 ml of N,N-dimethylformamide, 52 g of potassium carbonate and 41.4 g of n-hexyl bromide are treated analogously to example E (1), whereby 60.7 g of ethyl 2-n-hexyloxyimino-3-oxobutyrate (syn-isomer )

in the form of an oil.

IR spectrum (film): Vmax = 1740, 1705 and 1700 cm"<1>. NMR spectrum (CC14): 5 ppm = 0.6-2.1 (14H, m), 2.37 (3H, s ), 4.1^4.6 (4H, m). 2) 60.7 g of ethyl 2-n-hexyloxyimino-3-oxobutyrate (syn isomer), 61 ml of acetic acid and 34.7 g of sulfuryl chloride are treated analogously with example E (2), whereby 55.6 g of ethyl 2-n-hexyloxyimino-4-chloro-3-oscobutyrate (syn isomer) is obtained.

IR spectrum (film): V max = 1740, 1720 and 1470 cm"<1.>NMR spectrum (CC14): 5 ppm = 0.6~2.2 (14H, m), 4.1~4, 6

(4H, m), 4.47 (2H, s).

IN

3) 55.6 g ethyl 2-n-hexyloxyimino-4-chloro-3-oxobutyrate (syn isomer), 15.2 g thiourea, 27.2 g sodium acetate trihydrate,

280 ml of ethanol and 140 ml of water are treated analogously to example E

(3), thereby obtaining 29.3 g of ethyl 2-(2-aminothiazol-4-yl)-2-n-hexyloxyiminoacetate (syn isomer), melting point 77-78°C. IR spectrum (nujol): Vmax = 3460, 3250, 3140, 1720 and

1535 cm"<1>.

NMR spectrum (ds-DMSO): 5 ppm = 0.85 (3H, t, J=6Hz), 1.0-1.9 (11H, m), 2.07 (2H, t, J=6Hz) , 2.26 (2H, q, J=7Hz), 6.85 (1H,

s), 7.22 (2H, s), 4) 29.1 g ethyl 2-(2-aminothiazol-4-yl)-2-n-hexyloxyimino-acetate (syn isomer), 97.2 ml methanol , 97.2 ml of aqueous 2N sodium hydroxide solution and 50 ml of tetrahydrofuran are treated analogously to example E (4), whereby 24.0 g of 2-(2-aminothiazol-4-tl)-2-n-hexyloxyiminoacetic acid (syn isomer) is obtained , melting point 174°C (decomposition).

IR spectrum (nujol): -Omax = 1660, 1625 and 1425 cm-<1>NMR spectrum (d6-DMSO): 5 ppm = 0.6~2.1 (11H, m), 4.07 (2H , t, J=6Hz), 6.83 (1H, s), 7.19 (2H, s).

Example H

1) 40 g of ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer), 200 ml of N,N-dimethylformamide, 52 g of potassium carbonate and 37.9 g of pentyl bromide are treated analogously to example E (1), whereby 57, 5 g of ethyl 2-pentyloxyimino-3-oxobutyrate (syn isomer) in the form of an oil.

IR spectrum (film): Vmax = 1745, 1680 and 1470 cm"<1>. NMR spectrum (CC1<): 5 ppm = 0.7-2.2 (12H, m), 2.36 (3H, s), 4.1-4.6 (4H, m). 2) 57.5 g of ethyl 2-pentyloxyimino-3-oxobutyrate (syn isomer), 58.5 ml of acetic acid and 20.9 ml of sulfuryl chloride are treated analogously with example E (2), whereby 51.1 g of ethyl 2-pentyloxy-imino-4-chloro-3-oxobutyrate (syn isomer) is obtained in the form of an oil IR spectrum (film): Umax = 1750 , 1715 and 1470 cm"<1>. NMR spectrum (CC14): 5 ppm = 0.7-2.1 (11H, m), 4.1-4.6 (4H, m), 4.48 (2H, s). 3) 51.1 g ethyl 2-pentyloxyimino-4-chloro-3-oxobutyrate (syn isomer), 14.7 g thiourea, 26.4 g sodium acetate trihydrate, 175 ml ethanol and 125 ml water are treated analogously to example E (3), whereby 28.7 g of ethyl 2-(2-aminothiazol-4-yl)-2-pentyloxyiminoacetate (syn isomer) is obtained, melting point 86-88°C. IR spectrum (nujol): Omax = 3450, 3250, 3130, 1715 and 1535 cm-1.

NMR spectrum (d6-DMSO): 5 ppm = 0.6-2.0 (12H, m), 4.11 (2H, t, J=6Hz), 4.32 (2H, q, J=7Hz) , 6.90 (1H, s), 7.25 (2H, s). 4) 28.6 g of ethyl 2-(2-aminothiazol-4-yl)-2-pentyloxyiminoacetate (syn isomer), 100.2 ml of aqueous 2N sodium hydroxide solution, 100 ml of methanol and 100 ml of tetrahydrofuran are treated analogously to example E ( 4), whereby 22.4 g of 2-(2-aminothiazol-4-yl)-2-pentyloxyiminoacetic acid (syn isomer) is obtained, melting point 176°C (decomposition).

IR spectrum (nujol): Umax = 3160, 1655, 1620 and 1460 cm"<1>. NMR spectrum (de-DMSO): 5 ppm = 0.6-2.2 (9H, m), 4.07 (2H, t, J=6Hz), 6.82 (1H, s), 7.20 (2H, s). 5) 15 g of 2-(2-aminothiazol-4-yl)-2-pentyloxyiminoacetic acid (syn- isomer), 23.8 g of acetic anhydride and 10.7 g of formic acid are treated analogously to example E (5), whereby 14.7 g of 2-(2-formamidothiazol-4-yl)-2-pentyloxyiminoacetic acid (syn isomer) is obtained , melting point 125°C (decomposition).

IR spectrum (nujol): Vmax = 3200, 3140, 1700 and 1565 cm"<1>. NMR spectrum (d6-DMS0): 5 ppm = 0.6-2.0 (9H, m), 4.13 (2H, t, J=6Hz), 7.53 (1H, s), 7.54 (1H, s), 12.66 (1H, s).

Example I

1) 2.91 g of allyl bromide is added dropwise under ice-cooling over the course of 5 minutes to a stirred suspension of 10 g of ethyl 2-(2-tritylamino-thiazol-4-yl)-2-hydroxyiminoacetate (syn isomer), 100 ml N,N-dimethylformamide and 4.54 g of potassium carbonate, and it is stirred at this temperature for 4 hours. To the resulting solution is added 200 ml of water, and the solution is extracted twice with diethyl ether. The extract is washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solution is evaporated in a vacuum, and the residue is triturated with a solution of n-hexane and diethyl ether. The precipitated material is filtered off, whereby 9.4 g of ethyl-2-(2-tritylaminothiazol-4-yl)-2-allyloxyiminoacetate (syn-isomer) is obtained, melting point 130-132°C. IR spectrum (nujol): 1),lks= 3380, 1735, 1520 and 1500 cm"<1>. NMR spectrum (ds-DMSO): 5 ppm = 1.08 (3H, t, J=7Hz), 3.96 (2H, q, J=7Hz), 4.54 (2H, wide d, J=5Hz), 5.0-5.5 (2H, m), 5.6-6.3 (1H, m), 6.90 (15H, broad s), 7.74 (1H, s). 2) A solution of 8.7 g of ethyl 2-(2-tritylaminothiazol-4-yl)-2-allyloxyiminoacetate (syn -isomer), 42.5 ml of 50% formic acid and 42.5 ml of tetrahydrofuran are stirred at 60°C for 40 minutes. After evaporation of the resulting solution in vacuo, the residue is dissolved in ethyl acetate, washed with an aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution in the aforementioned order, and dried over magnesium sulfate. After evaporation of the resulting solution in vacuum, the residue is column chromatographed on silica gel with benzene and ethyl acetate in the aforementioned order, whereby 3.7 g of ethyl-2-(2-aminothiazole-4) is obtained -yl)-2-allyloxyiminoacetate (syn isomer), melting point 102-104° C. IR spectrum (nujol): Vmax = 3460, 3260, 3130, 1725, 1620, 1540 and 1460 cm-<1>.

NMR spectrum (ds-DMSO): 5 ppm = 1.25 (3H, t, J=7Hz), 4.30 (2H, q, J=7Hz), 4.61 (2H, dd, J=5Hz, 1Hz), 5.0-5.5 (2H, m), 5.6-6.5 (1H, m), 6.95 (1H, s), 7.28 (2H, s). 3) A solution of 3.6 g of ethyl 2-(2-aminothiazol-4-yl)-2-allyloxyiminoacetate (syn isomer), 14.1 ml of aqueous 2N sodium hydroxide solution, 14.1 ml of tetrahydrofuran and 15 ml methanol is stirred at 40°C for 1 1/2 hours. The resulting solution is evaporated in vacuo and the residue is dissolved in water. The solution is adjusted to pH 2.8 with 10% hydrochloric acid under ice-cooling, and the precipitated material is filtered off, washed with water and acetone in the order mentioned and dried, thereby obtaining 1.91 g of 2-(2-aminothiazol-4-yl) -2-allyloxyiminoacetic acid (syn isomer), melting point 187° C (decomposition).

IR spectrum (nujol): - Omax = 3350, 1630, 1580 and 1460 cm-<1>.

NMR spectrum (cU -DMSO) : 5 ppm = 4.61 (2H, d, J=6Hz) , 5.1-5.5 (2H, m) , 5.7-v6.2 (1H, m) , 6.84 (1H, s), 7.25 (2H, wide s).

Example J

0.84 g of sodium bicarbonate is added to a suspension of 2 g of 2-(2-formamidothiazol-4-yl)oxalic acid in 120 ml of water to prepare a solution. 4.56 g of ethyl 2-aminooxyacetate hydrochloride is added to the solution, and it is stirred at room temperature for 3 hours while the pH is adjusted to 6 with sodium bicarbonate. The resulting solution is adjusted to pH 1.5 with hydrochloric acid, desalted and extracted three times with ethyl acetate. The extract is dried over magnesium sulphate and evaporated in vacuo. The residue is pulverized with diethyl ether, and the precipitated material is filtered off and dried, thereby obtaining 1.44 g of 2-(2-formamido-thiazol-4-yl)-2-ethoxycarbonylmethoxyiminoacetic acid (syn isomer), melting point 112°C (decomposition) .

IR spectrum (nujol):max3 = 3150, 1740, 1670 and 1550 cm"<1>. NMR spectrum (d6-DMSO): 5 ppm = 1.23 (3H, t, J=7Hz), 4 .16 (2H, q, J=7Hz), 4.77 (2H, s), 7.56 (1H, s), 8.54 (1H, s).

Example K

10 g of 2-(2-formamidothiazol-4-yl)oxalic acid, 4.2 g of sodium bicarbonate and 8.1 g of tert.butyl-2-aminooxyacetate are treated analogously to example J, whereby an oil is obtained. The oil is triturated with n-hexane, and the precipitated material is filtered off and dried, thereby obtaining 11.3 g of 2-(2-formamidothiazol-4-yl)-2-tert.-butoxycarbonylmethoxyiminoacetic acid (syn isomer), melting point 117° C (fission).

IR spectrum (nujol): Umax = 3180, 3140, 1750, 1690 and 1630 cm-1.

NMR spectrum (d 6 -DMSO): 5 ppm = 1.46 (9H, s), 4.66 (2H, s), 7.56 (1H, s), 8.56 (1H, s), 12, 67 (1H, wide p).

Example L

1) 2.37 g of triethylamine, 7.12 g of dimethylaniline and 3.93 g of trimethylsilyl chloride are added in the aforementioned order to a stirred suspension of 10 g of 4-nitrobenzyl-7-(2-phenylacetamido)-3-hydroxy-3-cephem- 4-carboxylate in 200 ml of methylene chloride, and the solution is stirred at room temperature for 1 hour. 4.88 g of phosphorus pentachloride are added to the solution at -30 to -25°C, and it is stirred at -25 to -20°C for 3 hours. 42 ml of methanol at -25 to -20°C are added to the solution, and it is stirred for 1 hour. 35 ml of water at -25 to -20°C is added to the solution, and the solution is stirred at room temperature. The precipitated material is filtered off and washed with methylene chloride and diethyl ether in the order mentioned and dried, thereby obtaining 5.2 g of 4-nitrobenzy1-7-amino-3-hydroxy-3-cephem-4-carboxylate, melting point 148°C (decomposition) .

IR spectrum (nujol): "Omax = 3440, 3300, 1760 and 1740 cm"<1>. NMR spectrum (de-DMSO): 5 ppm = 2.8-3.7 (2H, m), 4.90 (1H, t, J=4Hz), 5.29 (1H, d, J=4Hz) , 5.38 (2H, s), 7.71 (2H, d, J=8Hz), 8.26 (2H, d, J=8Hz). 2) To a solution of 1.37 g of N,N-dimethylformamide in 10 ml of ethyl acetate, add 2.87 g of phosphoryl chloride dropwise at 5-10°C. 40 ml of ethyl acetate are added to the solution, and it is stirred under ice cooling for 40 minutes. 3.58 g of 2-(2-formamido-4-thiazolyl)-2-methoxyiminoacetic acid (syn isomer) is added, and the solution is stirred at 0-5°C for 40 minutes. The resulting solution is added at once at -15°C to a mixture of 5 g of 4-nitrobenzyl-7-amino-3-hydroxy-3-cephem-4-carboxylate, 50 ml of ethyl acetate,

14.3 g of trimethylsilyl acetamide and 5.8 g of bis(trimethylsilyl)acetamide, and it is stirred at -20 to -15°C for 1.2 hours.

50 ml of water is added to the resulting solution at -25 to

-20°C, and it is stirred until the temperature has risen to +5°C. The aqueous phase is separated and extracted with ethyl acetate. The ethyl acetate phase and the extract are combined, washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solution is then evaporated to a volume of 50 ml under reduced pressure, and the precipitated material is filtered off and washed with ethyl acetate, whereby 3.5 g of 4-nitrobenzyl-7-[2-(2-

formamido-4-thiazolyl)-2-methoxyiminoacetamido]-3-hydroxy-3-cephem-4-carboxylate (syn isomer), melting point 163°C (decomposition). IR spectrum (nujol): max = 3210, 3160, 3050, 1780 and

1665 cm-1.

NMR spectrum (de-DMSO): 5 ppm = 3.0-4.2 (2H, m), 3.95 (3H, s), 5.28 (1H, d, J=4Hz), 5.41 (2H, s), 5.64 (1H, dd, J=4Hz, 9Hz), 7.49 (1H, s), 7.67 (2H, d, J=8Hz), 8.21 (2H, d , J=8Hz), 8.50 (1H, t, J=9Hz). 3) A solution of 1 g of the compound obtained above in 15 ml of methanol, 5 ml of tetrahydrofuran and 0.72 g of concentrated hydrochloric acid is stirred at room temperature for 1 hour. 100 ml of diethyl ether is added to the resulting solution and triturated. The formed crystals are filtered off, whereby 0.65 g of 4-nitrobenzyl-7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-hydroxy-3-cephem-4-carboxylate hydrochloride ( syn isomer).

IR spectrum (nujol): Omax = 3180, 1780, 1680, 1670 and

1640 cm-1.

NMR spectrum (de-DMSO): 5 ppm = 3.2-4.0 (2H, m), 3.97 (3H, s), 5.27 (1H, d, J=4Hz), 5.41 (2H, s), 5.60 (1H, dd, J=4Hz, 8Hz), 7.10 (1H, s), 7.66 (2H, d, J=9Hz), 8.25 (2H, d , J=9Hz), 9.73 (1H, d, J=8Hz).

Example M

2.14 g of dry pyridine are added to a suspension of 10.50 g of p-nitrobenzyl-7-phenylacetamido-3-cephem-4-carboxylate in 100 ml of dry dichloromethane. 5.50 and phosphorus pentachloride are added to the solution at -10°C, and the mixture is stirred at -5°C for 45 minutes and then at 10°C for 1 hour. To the resulting mixture is added 520 g of methanol, and the mixture is then stirred for 1 1/2 hours at -20°C. The precipitated material is filtered off, washed with 120 ml of dichloromethane and 130 ml of diethyl ether in the aforementioned order and then dried, whereby 7.90 g of p-nitrobenzyl-7-amino-3-cephem-4-carboxylate, melting point 182°C ( cleavage).

IR spectrum (nujol): vJmax = 1790, 1730, 1638 and 1600 cm"<1>. NMR spectrum (de-DMSO): 5 ppm = 3.7 8 (2H, d, J=4Hz), 5, 27 (2H, dd, J=5Hz), 5.44 (2H, s), 6.78 (1H, t, J=4Hz), 7.72 (2H, d, J=9Hz), 8.26 ( 2H, d, J=9Hz),

Example N

1) 5 g of 4-nitrobenzyl-7-amino-3-cephem-4-carboxylate is dissolved in a solution of 13.8 g of trimethylsilyl acetamide and 10 ml of bis(tri-methylsilyl)acetamide in 50 ml of dry ethyl acetate, and it is stirred at 45 °C for 1 1/2 hours. A solution of 2.88 g of bromine in 7 ml of methylene chloride is added dropwise at -40°C over the course of 20 minutes to a solution of 1.5 g of diketene in 7 ml of methylene chloride, and it is stirred at -30°C for 1 hour. The resulting solution is added dropwise while cooling to -15°C to the solution of 4-nitrobenzyl-7-amino-3-cephem-4-carboxylate obtained above, and it is stirred at the same temperature for 30 minutes. To the resulting solution is added 50 ml of water, and it is extracted with ethyl acetate. The ethyl acetate extract is washed with water, dried over magnesium sulfate and evaporated under reduced pressure, whereby 6.15 g of 4-nitrobenzyl-7-[2-(2-bromoacetyl)acetamido]-3-cephem-4-carboxylate are obtained in the form of an oil.

IR spectrum (nujol): Omax = 1780, 1740 and 1630 cm"<1>. NMR spectrum (d6-DMS0): 5 ppm = 3.62 (2H, broad s), 4.37 (2H, s) , 5.08 (1H, d, J=5Hz), 5.40 (2H, s), 5.77-6.05 (m), 6.67 (1H, t, J=5Hz), 7.68 , 8.04 (4H, m, J=9Hz), 9.07 (1H, d, J=8Hz). 2) 8.40 g 4-nitrobenzyl-7-[2-(2-bromoacetyl)acetamido]- 3-cephem-4-carboxylate is suspended in a mixture of 150 ml of tetrahydrofuran and 30 ml of water. To the suspension is added 50 ml of acetic acid and a solution of 1.20 g of sodium nitrite in 15 ml of water under ice-cooling, and it is stirred at 20- 22°C for 1 1/2 hours. The resulting solution is poured into 300 ml of ice water and stirred for 20 minutes. The precipitated material is filtered off, washed with water, dried and then recrystallized from ethyl acetate to give 3.1 g of 4-nitrobenzyl -7-[2-(2-bromoacetyl)-2-hydroxyimino-acetamido]-3-cephem-4-carboxylate (syn isomer), melting point 153-162°C.

IR spectrum (nujol): Vmax = 3250, 1780, 1720, 1705, 1650, 1610, 1600 (shoulder), 1550 and 1520 cm"<1>.

NMR spectrum (d6-DMSO): 5 ppm = 3.67 (2H, d, J=4Hz), 4.63 (1.5H, s), 4.88 (0.5H, s), 5.18 (1H, d, J=5Hz), 5.45 (2H, s), 5.93 (1H, dd, J=5Hz, 8Hz), 6.72 (1H, t, J=4Hz), 7.73 (2H, d, J=9Hz), 8.28 (2H, d, J=9Hz) , 9.38 (1H, d, J=8Hz), 11.27 (1H, s) . 3) A solution of diazomethane in diethyl ether is added in small portions to a solution of 0.9 g of 4-nitrobenzyl-7-[2-(2-bromo-acetyl )-2-hydroxyiminoacetamido)-3-cephem-4-carboxylate in 30 ml of tetrahydrofuran under ice-cooling until the reaction is complete, and then acetic acid is added to the resulting solution to decompose excess diazomethane. The resulting solution is evaporated under reduced pressure, whereby 0.9 g of 4-nitrobenzyl-7-[2-(2-bromoacetyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer) is obtained in the form of a foam.

IR spectrum (nujol): Omax = 3250, 1780, 1730, 1712, 1650, 1630 (shoulder), 1600, 1520, 1295, 1230, 1050 cm"<1>.

Example O

0.18 g of thiourea is added to a suspension of 1.05 g of 4-nitrobenzyl-7-[2-(2-bromoacetyl)-2-hydroxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer) in 25 ml of ethanol , 25 ml of tetrahydrofuran and 5 ml of water, and it is stirred at room temperature for 4 hours. The resulting solution is evaporated under reduced pressure and cooled. The residue is crystallized by treatment with a mixture of tetrahydrofuran and ethyl acetate and isolated by filtration, whereby 0.95 g of 4-nitrobenzyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-cephem is obtained -4-carboxylate (syn isomer) in the form of colorless crystals, melting point 172-175°C (decomposition).

IR spectrum (nujol): Omax = 3350-3200, 1770, 1725, 1670, 1625 and 1520 cm-<1>.

NMR spectrum (de-DMSO): 5 ppm = 3.68 (2H, d, J=4Hz), 5.20 (1H, d, J=5Hz), 5.43 (2H, s), 5.90 (1H, dd, J=8Hz, 5Hz), 6.70 (1H, t, J=4Hz), 6.88 (1H, s), 7.70 (2H, d, J=9Hz), 8.23 (2H, d, J=9Hz), 9.68 (1H, d, J=8Hz).

Example P

160 mg of sodium borohydride are added at 0° C. during 10 minutes to a suspension of 1 g of 4-nitrobenzyl-7-[2-(2-form-amido-4-thiazolyl)-2-methoxyiminoacetamido]-3-hydroxy-3 -cephem-4-carboxylate (syn isomer) in 10 ml of tetrahydrofuran, 3 ml of acetic acid and 1 ml of water, and it is stirred at 0-3°C for 55 minutes. Water is added to the resulting solution and the solution extra-

here with ethyl acetate. The extract is washed with a saturated aqueous sodium chloride solution, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution in that order, and dried over magnesium sulfate. The solution is evaporated under reduced pressure, and the residue is pulverized with diethyl ether, whereby 0.77 g of 4-nitrobenzyl-7-[2-(2-formamido-4-thiazolyl)-2-methoxyiminoacetamido]-3-hydroxycephem-4-carboxylate is obtained (syn-isomer), melting point 172-175° C. (decomposition). IR spectrum (nujol): Vmax = 3250, 1775, 1745 and 1660 cm"<1>. NMR spectrum (d6-DMSO): 5 ppm = 2.76 (1H, dd, J=14Hz, 3Hz), 3 .17 (1H, dd, J=14Hz, 13Hz), 3.92 (3H, s), 4.03 (1H, m), 4.72 (1H, d, J=6Hz), 5.24 (1H , d, J=4Hz), 5.37 (2H, s), 5.56 (1H, dd, J=9Hz, 4Hz), 6.07 (1H, d, J=4Hz), 7.44 (1H , s), 7.72 (2H, d, J=8Hz), 8.27 (2H, d, J=8Hz), 8.54 (1H, s), 9.67 (1H, d, J=9Hz ).

Production of end products

Example 1

1) A Vilsmeier reagent prepared from 0.43 g of dimethylformamide and 0.92 g of phosphorus oxychloride is suspended in 10 ml of dry ethyl acetate. 1.15 g of 2-(2-formamido-4-thiazolyl)-2-methoxyiminoacetic acid (syn-isomer) is added to the suspension under ice-cooling and stirring, and the mixture is stirred at this temperature for 30 minutes to prepare the activated acid solution. 1.79 g of p-nitrobenzyl-7-amino-3-cephem-4-carboxylate hydrochloride and 5.0 g of trimethylsilylacetamide are dissolved in 40 ml of ethyl acetate. To this solution, the activated acid solution is added all at once at -20°C, and the mixture is stirred at this temperature for 2 1/2 hours. To the resulting solution are added 60 ml of water and 200 ml of ethyl acetate, and the ethyl acetate phase is separated, washed with 60 ml of 10% hydrochloric acid, 60 ml of saturated aqueous sodium bicarbonate solution and 50 ml of aqueous sodium chloride solution in the order mentioned, dried over magnesium sulfate, treated with activated charcoal and evaporated then under reduced pressure. Diethyl ether is added to the residue, and the precipitated material is filtered off, whereby 1.30 g of p-nitrobenzyl-7-[2-(2-formamido-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate is obtained ( syn isomer), melting point 210-212°C (decomposition).

IR spectrum (nujol):-Omax = 3240, 1780, 1730, 1690, 1655, 1605, 1550 and 1520 cm"<1>.

NMR spectrum (ds-DMSO): 5 ppm = 3.65 (2H, broad s), 3.90 (3H, s), 5.20 (1H, d, J=5Hz), 5.43 (2H, s), 5.95 (1H, q, J=5.8Hz), 6.68 (1H, t, J=4Hz), 7.42 (1H, s), 7.72 (2H, d, J= 9Hz), 8.28 (2H, d, J=9Hz), 8.46 (1H, s), 9.72 (1H, d, J=8Hz).

2) To a solution of 1.25 g of p-nitrobenzyl-7-[2-(2-formamido-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer) in 40 ml of methanol and 50 ml of tetrahydrofuran, 0.65 g of 10% palladium/charcoal is added, and the mixture is subjected to catalytic reduction at room temperature under atmospheric pressure for 3 1/2 hours. The catalyst is removed from the reaction mixture, and the filtrate is evaporated under reduced pressure. 80 ml of water is added to the residue, and the mixture is adjusted to pH 7.5 with an aqueous sodium bicarbonate solution, and then insoluble material is filtered off. The filtrate is washed with 50 ml of ethyl acetate, and then set

100 ml ethyl acetate to the solution. After adjusting the pH to 1.5 with 10% hydrochloric acid, the ethyl acetate phase is separated. The aqueous phase obtained as a residue is extracted twice with 80 ml of ethyl acetate, and the extracts and the ethyl acetate phase obtained above are combined, washed with an aqueous sodium chloride solution, dried over magnesium sulfate and then evaporated under reduced pressure, whereby 0.60 g of 7-[2 -(2-formamido-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer), melting point 176-183°C (decomposition).

IR spectrum (nujol): Omax = 3250, 1780, 1690, 1660 and

1550 cm"<1>.

NMR spectrum (d6-DMSO): 6 ppm = 3.63 (2H, d, J=4Hz), 3.93 (3H, s), 5.10 (1H, d, J=5Hz), 5.90 (1H, q, J=5.8Hz), 6.53 (1H, t, J=4Hz), 7.47 (1H, s), 8.57 (1H, s), 9.70 (1H, d , J=8Hz), 12.63 (1H, s). 3) 95 mg of 7-[2-(2-formamido-4-triazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer) is suspended in 4 ml of methanol. 110 mg of concentrated hydrochloric acid is added to the suspension,

and the solution is stirred at room temperature for 4 hours. The methanol is distilled off under reduced pressure, and then dissolved

the residue in 30 ml of water, and the aqueous solution is washed with 10 ml of ethyl acetate and 15 ml of dichloromethane in the aforementioned order. Nitrogen gas is passed down into the aqueous solution to drive

out remaining organic solvent, and the aqueous solution is lyophilized, whereby 83 mg of 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid hydrochloride (syn isomer) is obtained , melting point 180-190°C (decomposition). IR spectrum (nujol):\)max = 3300, 1770, 1710, 1660 and

1630 cm-1.

NMR spectrum (d6-DMSO): 5 ppm =3.64 (2H, broad s), 3.95 (3H, s), 5.14 (1H, d, J=5Hz), 5.82 (1H, t, J=4Hz), 6.95 (1H, s), 9.80 (1H, d, J=8Hz). 4) A solution of 10.8 g of 7-[2-(2-formamido-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer), 11 g of concentrated hydrochloric acid and 350 ml of methanol stirred at room temperature for 4 hours. The resulting solution is evaporated under reduced pressure, and ethyl acetate is added to the residue. The solution is adjusted to pH 8.0 with saturated aqueous sodium bicarbonate solution, and the aqueous phase is separated and washed with diethyl ether. Nitrogen gas is then bubbled through the aqueous solution, and the aqueous solution is adjusted to pH 4.0 with 10% hydrochloric acid. The precipitated substance is filtered off and washed with water, thereby obtaining 8.2 g of 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer), melting point > 290°C.

IR spectrum (nujol): Omax = 3470, 3280, 3200, 1780, 1695, 1655 and 1622 cm-<1>.

NMR spectrum (d6-DMSO): 5 ppm = 3.60 (2H, broad s), 3.84 (3H, s), 5.12 (1H, dd, J=5Hz), 5.84 (1H, dd, J=5.8Hz), 6.52 (1H, wide t), 6.76 (1H, s), 7.26 (2H, wide s), 9.65 (1H, d, J=8Hz) . 5) 1.04 g of sodium bicarbonate is added under ice cooling to a solution of 2.6 g of 7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-3-cef em-4-carboxylic acid hydrochloride (syn isomer) in 100 ml of water, and it is stirred at room temperature. The resulting solution is lyophilized, whereby sodium 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer) is obtained.

IR spectrum (nujol): Omax = 3100, 1760, 1650, 1590 and

1530 cm-1.

NMR spectrum (D2O): 5 ppm = 3.60 (2H, broad q), 4.00 (3H, s), 5.22 (1H, d), 5.88 (1H, d), 6.35 (1H, q), 7.03 (1H, s). 6) The product obtained above is dissolved in 20 ml of dry N,N-dimethylformamide. A solution of 1.33 g of iodomethyl-n-hexanoate and 5 ml of dry N,N-dimethylformamide is added dropwise at -40°C over the course of 5 minutes to the solution, and it is then stirred at this temperature for 40 minutes and then ice-cooled in 45 minutes. The resulting solution is added to a mixture of 60 ml of ethyl acetate and 125 ml of water. The ethyl acetate phase is separated, washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution in the order mentioned, dried over magnesium sulfate and then treated with activated charcoal. The ethyl acetate is evaporated from the solution, and the residue is triturated with diethyl ether, whereby 750 mg of n-hexanoyloxymethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn- isomer).

IR spectrum (nujol): Omax = 3170, 1780, 1750 (shoulder), 1670, 1630 and 1530 cm-<1>.

NMR spectrum (CDCl 2 ): 5 ppm = 0.68-1.84 (9H, m), 2.20-2.48 (2H, t), 3.20-3.80 (2H, m), 4 .02 (3H, s), 5.04 (1H, d), 5.60-6.20 (3H, m), 6.62 (1H, q), 6.80 (1H, s), 7, 72 (1H, d). 7) 1.1 g of p-nitrobenzyl-7-[2-(2-formamido-4-thiazolyl)-2-methoxy-iminoacetamido]-3-cephem-4-carboxylate (syn isomer) is suspended in a mixture of 10 ml of ethanol and 15 ml of water. 6 ml IN aqueous potassium hydroxide solution is added dropwise at 5-7°C over 10 minutes to the suspension, and it is stirred for 10 minutes. The resulting solution is adjusted to pH 7.5 with 10% hydrochloric acid, washed with ethyl acetate and adjusted to pH 2.5 with 10% hydrochloric acid. hydrochloric acid. The precipitated crystals are filtered off, whereby a mixture of 0.32 g of 7-[2-(2-formamido-4-thiazolyl)-2-methoxy-iminoacetamido]-3-cephem-4-carboxylic acid (syn isomer) is obtained and 0.035 g of 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer). These compounds were identified with authentic samples. 8) 5 g of 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer) is slowly added to a solution of 1.04 g of sodium bicarbonate in 30 ml of water at 35-40°C, and it is stirred at 50-53°C for 30 minutes. Insoluble material is filtered from the resulting solution, and the filtrate is treated with 0.3 g of activated carbon and filtered. The filtrate is lyophilized, whereby 4.2 g of sodium 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer) is obtained. IR spectrum (nujol): Omax = 3300-3100, 1760, 1670, 1595 and 1530 cm-1.

NMR spectrum (d6-DMSO): 5 ppm = 3.50 (2H, broad s), 3.83 (3H, s), 5.00 (1H, d, J=5Hz), 5.68 (1H, dd, J=5Hz, 8Hz), 6.13 (1H, wide s), 6.73 (1H, s), 7.3 (2H, wide s), 9.60 (1H, d, J=8Hz) . 9) 1.15 g of 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer) is added to an aqueous solution of 0.111 g of calcium hydroxide in 100 ml water, and the solution is stirred at room temperature for 10 minutes. The solution is then filtered, and the filtrate is lyophilized, whereby 1.2 g of calcium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer ).

IR spectrum (nujol): Omax = 3350, 1760, 1670, 1590, 1535 and 1465 cm-1.

NMR spectrum (D 2 O): 6 ppm = 3.51 (1H, d, J=5Hz), 3.59 (1H, d, J=3Hz), 3.97 (3H, s), 5.15 (1H , d, J=5Hz), 5.82 (1H, d, J=5Hz), 6.33 (1H, dd, J=5Hz, 3Hz), 6.95 (1H, s). 10) 1.15 g of 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer) is added to a suspension of 0.088 g of magnesium hydroxide in 100 ml water, and the mixture is stirred at 70°C for 30 minutes to form a solution. The resulting solution is filtered, and the filtrate is lyophilized,

whereby 1.1 g of magnesium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer) is obtained. IR spectrum (nujol): Omax = 3350, 1760, 1660, 1610, 1530 and 1460 cm-1.

NMR spectrum (D2O): 5 ppm = 3.53 (1H, d, J=5Hz), 3.59 (1H, d,

J=3Hz), 3.96 (3H, s), 5.16 (1H, d, J=5Hz), 5.84 (1H, d, J=5Hz), 6.32 (1H, dd, J=5Hz, 3Hz), 7.98 (1H, s). 11) 1.15 g of 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer) is added to a solution of 0.523 g of arginine in 50 ml of water , and the solution is stirred at room temperature for 10 minutes. The resulting mixture is filtered, and the filtrate is lyophilized, whereby 1.35 g of arginine salt of 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer) is obtained .

IR spectrum (nujol): Vmax = 3350, 3150, 1770, 1650 (broad), 1580, 1530 and 1460 cm"1 .

NMR spectrum (D 2 O): 5 ppm = 1.4-2.1 (4H, m), 3.22 (2H, t, J=6Hz), 3.55 (1H, d, J=6Hz), 3 .65 (1H, d, J=3Hz), 3.82 (1H, d, J=6Hz), 3.97 (3H, s), 5.18 (1H, d, J=5Hz), 5.85 ((1H, d, J=5Hz), 6.33 (1H, dd, J=6Hz, 3Hz), 7.00 (1H, s). 12) 1.21 g sodium 7-[2-(2-aminothiazole) -4-yl)-2-methoxyimino-acetamido]-3-cef em-4-carboxylate (syn isomer) is added to a solution of 0.55 g of lysine hydrochloride in 12 ml of water. The solution is lyophilized, whereby 1.6 g of the lysine salt of 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer) is obtained.

IR spectrum (nujol): Vmax = 3350, 3150, 1770, 1600 (broad), 1530 and 1460 cm-<1>.

NMR spectrum (D 2 O): 5 ppm = 1.3-2.1 (6H, m), 3.03 (2H, t, J=7Hz), 3.54 (1H, d, J=5Hz), 3 .64 (1H, d, J=3Hz), 3.80 (1H, d, J=6Hz), 3.97 (3H, s), 5.17 (1H, d, J=5Hz), 5.84 (1H, d, J=5Hz), 6.32 (1H, dd, J=5Hz, 3Hz), 6.99 (1H, s).

13) To a suspension of 15 g of 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cef em-4-carboxylic acid (syn isomer) in a mixture of 8 ml of ethanol and 8 ml of water are added at room temperature to a 20% aqueous sodium hydroxide solution until a solution with a pH value of 7.5 is obtained. It is filtered and washed, and the filtrate and washing liquids are collected (18.3 ml of water in total) and added dropwise to 46 ml of ethanol at 20-25°C with stirring, and it is stirred at this temperature for 30 minutes. For the mixture

28 ml of ethanol are added dropwise over the course of 30 minutes, and it is stirred at the same temperature for 2 hours. The precipitated material is filtered off, washed with 20 ml of ethanol and dried in vacuum at room temperature, whereby 13.5 g of plates of sodium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3- cephem-4-carboxylate dihydrate (syn isomer), melting point 260°C (decomposition). IR spectrum (nujol): Umax = 3430, 3250, 1760 (shoulder), 1745, 1650, 1630 (shoulder), 1590 and 1540 er'. 14) Dissolve 15 g of sodium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacet-amido]-3-cef em-4-carboxylate (syn isomer) in 13 ml of water while stirring at 35 -45°C. 52 ml of ethanol, heated to 30°C, is added dropwise to the stirred solution, and it is stirred at this temperature for 5 minutes, and then at room temperature for 2 hours. The precipitated material is filtered off, washed with ethanol and dried under reduced pressure, whereby 13.45 g of plates of sodium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4 are obtained -carboxylate dihydrate (syn isomer). 15) To a stirred suspension of 52 g of 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer) in 100 ml of water is carefully added at a temperature below 5°C, dropwise 4N aqueous sodium hydroxide solution until a solution with pH 7.0-7.5 is obtained. This is filtered and washed, and the filtrate and washings (200 ml) are collected and added dropwise with stirring over 30 minutes to 2 liters of ethanol, and it is stirred at room temperature for 15 minutes and then at 5-10°C

for 1 hour.. The precipitated material is filtered off, washed with 200 ml of ethanol and dried in vacuum at 30°C, whereby 46.3 g of amorphous sodium-7-[2-(2-aminothiazol-4-yl)-2 are obtained -methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer).

IR spectrum (nujol): Vmax = 3400, 3300, 3170, 1750, 1650 and 1580 cm-<1>.

16) A suspension of 10 g of sodium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer) in 250 ml of methanol is treated in an ultrasonic apparatus for to form a clear solution. The solution is allowed to stand at room temperature, and is then stirred at the same temperature for 3 hours. The precipitated material is filtered off and washed with methanol, whereby amorphous sodium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cef em-4-carboxylate (syn isomer) is obtained . 17) The crystals obtained in example 1 (13) are dried over P2 0a in vacuum for 1 day at room temperature, whereby other plates of sodium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacet- amido]-3-cef em-4-carboxylate (syn isomer).

Example 2

1.7 g of 7-amino-3-cephem-4-carboxylic acid and 2.84 g of sodium bicarbonate are dissolved in a mixture of 35 ml of water and 35 ml of acetone. 1.95 ml of phosphorus oxychloride is added dropwise over 10 minutes at 0-6°C to a suspension of 3.42 g of 2-(2-amino-4-thiazolyl)-2-methoxyiminoacetic acid (syn-isomer) in 34 ml of dry ethyl acetate, and the mixture is stirred at the same temperature for 30 minutes. A solution of 2.39 g of trimethylsilylacetamide in 5 ml of ethyl acetate is added dropwise at 0-6°C over the course of 20 minutes to the solution, and the mixture is stirred for 20 minutes. To the mixture, 1.95 ml of phosphorus oxychloride is added dropwise over 10 minutes and at the temperature indicated above, and the resulting mixture is stirred for 30 minutes. Then 1.29 ml of dimethylformamide is added dropwise to the mixture over 10 minutes at the same temperature, and it is stirred for 1 hour, whereby a clear solution is obtained. This is added dropwise at -5 to +5°C over the course of 30 minutes to the solution of 7-amino-3-cephem-4-carboxylic acid at a pH value in the range 6.5-7.5, and the reaction mixture is stirred for 1 hour at the same temperature. 200 ml of ethyl acetate are added to the resulting solution, and the aqueous phase is separated and washed with methylene chloride, nitrogen gas is bubbled through, and the pH value is adjusted to 4 with acetic acid. The solution is column chromatographed on a macroporous, nonionic adsorption resin "Diaion" HP-20 (trademark, manufactured by Mitsubishi Chemical Industries Ltd.) and eluted with 20% aqueous isopropyl alcohol solution. The eluate is evaporated under reduced pressure and lyophilized, whereby 2.0 g of 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-

carboxylic acid (syn isomer). The product is identified with the authentic sample by IR and NMR spectrum.

Example 3 1) 1.2 g of phosphorus oxychloride is added all at once at 5°C to a suspension of 1.23 g of 2-(2-amino-4-thiazolyl)-2-methoxyimino-acetic acid (syn isomer) in 12 ml ethyl acetate, and it is stirred at 4-6°C for 30 minutes. 1.0 g of trimethylsilylacetamide is added to the solution, and it is stirred at 4-6°C for 30 minutes. 1.2 g of phosphorus oxychloride is added to the solution, and it is stirred for 15 minutes. To the solution, put at once at 4-6°C, 0.5

g of dimethylformamide, and it is stirred for 40 minutes, whereby a clear solution is obtained. 1.9 g of p-nitrobenzyl-7-amino-3-cephem-4-carboxylate hydrochloride is added to a mixture of 30 ml of tetrahydrofuran and 10 ml of acetone, and to the mixture is added 20 ml of an aqueous solution of 0.6 g of sodium bicarbonate. To this solution, the solution obtained above is added dropwise at 0-5°C, pH value 8.0. The mixture is stirred at -2 to +2°C and at pH 8.0 for 30 minutes, and then insoluble material is filtered off. The filtrate is extracted with ethyl acetate, and the extract is washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and then evaporated under reduced pressure. The residue is pulverized with diisopropyl ether, whereby 1.6 g of p-nitrobenzyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-3-cef em-4-carboxylate (syn isomer ).

IR spectrum (nujol): Omax = 3300, 1780, 1730, 1670 and

1520 cm-1.

NMR spectrum (de-DMSO): 6 ppm = 3.60 (2H, m), 3.81 (3H, s), 5.12 (1H, d, J=5Hz), 5.85 (1H, dd , J=5Hz, 10Hz), 6.64 (1H, m), 6.70

(1H, s), 7.20 (2H, s), 7.65 (2H, d, J=10Hz), 8.19 (2H, d,

J=10Hz), 9.60 (1H, d, J=10Hz).

2) 7.8 g of p-nitrobenzyl-7-[2-(2-amino-4-thiazolyl)-2-methoxy-iminoacetamido]-3-cef em-4-carboxylate (syn isomer) is suspended in a mixture of 60 ml of ethanol and 60 ml of water. 45 ml IN aqueous potassium hydroxide solution is added dropwise over 10 minutes under ice cooling to the stirred suspension, and it is stirred at 5°C for 15 minutes. The resulting solution is adjusted to pH 7.0 with concentrated hydrochloric acid, washed with ethyl acetate and evaporated under reduced pressure to half the original volume. The evaporated solution is adjusted to pH 5.0 and column chromatographed on 80 ml of macroporous nonionic adsorption resin "Diaion" HP-20 (trademark, manufactured by Mitsubishi Chemical Industries Ltd.), and it is eluted with 5% aqueous isopropyl alcohol solution. The fractions containing the compound produced are collected and adjusted to pH 3.2 with 10% hydrochloric acid. The precipitated crystals are filtered off and dried, whereby 2.3 g of 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer) is obtained. This compound was identified with the authentic sample.

Example 4

3.4 g of p-nitrobenzyl-7-amino-3-cephem-4-carboxylate are suspended in 60 ml of tetrahydrofuran, and 20 ml of an aqueous solution of 1.2 g of sodium bicarbonate are added to the suspension. 30 ml IN aqueous sodium hydroxide solution is added dropwise at 3-4° C to the solution, and it is stirred for 20 minutes. The resulting solution is adjusted to pH 7.0 with 10% hydrochloric acid and evaporated under reduced pressure. The insoluble material is filtered off, and the filtrate is washed with ethyl acetate. 30 ml of acetone is added to the filtrate, and it is cooled to -5°C. To the solution obtained above, at -5 to 0°C and pH 7.5-8.5, a solution of phosphorus oxychloride, dimethylformamide, trimethylsilylacetamide and 2.2 g of 2-(2-amino-4-thiazolyl)-2- methoxyiminoacetic acid (syn isomer), which is prepared analogously to example 2. The mixture is stirred at 3-7°C and a pH value in the range 7.5-8.5 for 2 hours, and the insoluble material is filtered off. The aqueous phase is separated from the filtrate, washed with ethyl acetate and adjusted to pH 3.0, whereby 1.1 g of 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4 is obtained -carboxylic acid (syn isomer). This compound was identified with the authentic sample.

Example 5

1) 1.764 g of phosphoryl chloride is added to a suspension of 1.0 g of 2-(2-amino-4-thiazolyl)-2-ethoxyiminoacetic acid (syn isomer) in 10 ml of tetrahydrofuran at a temperature below 5°C, and it is stirred at same temperature for 20 minutes. 0.4 g of trimethylsilylacetamide and 0.4 g of N,N-dimethylformamide are added to the solution, and the solution is stirred at a temperature below 5° C. for 40 minutes (solution A). 3.5 g of trimethylsilylacetamide is added to a suspension of 1.5 g of 4-nitrobenzyl-7-amino-3-cephem-4-carboxylate in 15 ml of tetrahydrofuran, and it is stirred at room temperature for 1 1/2 hours. To this solution is added all of solution A at once at -20°C, and the solution is stirred at -5 to 0°C for 1 hour. 20 ml of water is added to the resulting -20°C solution, and the solution is adjusted to pH 7.5 with an aqueous sodium bicarbonate solution.

70 ml of tetrahydrofuran and 50 ml of saturated aqueous sodium chloride solution are added to the solution, and the solution is shaken sufficiently. The aqueous phase is separated and extracted with tetrahydrofuran. The tetrahydrofuran phase and the extract are combined and washed with saturated aqueous sodium chloride solution. The solution is dried over magnesium sulfate and evaporated under reduced pressure. The residue is triturated with diisopropyl ether, whereby 2.5 g of 4-nitrobenzyl-7-[2-(2-amino-4-thiazolyl)-2-ethoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer) is obtained.

IR spectrum (nujol): Umax = 3330, 1780, 1730, 1680, 1640 and 1610 cm-1.

NMR spectrum (d6-DMSO): 5 ppm = 1.17 (3H, t, 7Hz), 3.50 (2H, m), 4.05 (2H, q, J=7Hz), 5.10 (1H , d, J=5Hz), 5.85 (1H, dd, J=5Hz, 8Hz), 6.67 (1H, s), 7.17 (2H, m), 7.63 (2H, d, J =8Hz), 8.18 (2H, d, J=8Hz), 10.13 (1H, d, J=8Hz).

2) 1.0 g of palladium/charcoal moistened with 3 ml of water is added to a solution of 2.3 g of 4-nitrobenzyl-7-[2-(2-amino-4-thiazolyl)-2-ethoxyiminoacetamido]-3-cephem -4-carboxylate (syn isomer) in a mixture of 30 ml of tetrahydrofuran, 15 ml of methanol and 0.3 ml of acetic acid, and the suspension is subjected to catalytic reduction at room temperature under atmospheric pressure for 2 hours. The catalyst is filtered from the resulting mixture, and the filtrate is evaporated under reduced pressure. Ethyl acetate is added to the residue, and the solution is adjusted to pH 7.5 with an aqueous sodium bicarbonate solution. Insoluble material is filtered off, the aqueous phase is separated, washed with ethyl acetate, adjusted to pH 5.5 and then treated with activated charcoal. The aqueous solution is adjusted to pH 3.2, and the precipitated material is filtered off and dried, whereby 0.6 g of 7-[2-(2-amino-4-thiazolyl)-2-ethoxyiminoacetamido]-3-cephem-4 is obtained -carboxylic acid (syn isomer). IR spectrum (nujol): max = 3500, 3300, 3200, 1785, 1625 and 1600 cm-<1>.

NMR spectrum (de-DMSO): 5 ppm = 1.20 (3H, t, J=7Hz) ,, 3.57 (2H, m) , 4.08 (2H, q, J=7Hz) , 5, 08 (1H, d, J=5Hz) , 5.83 (1H, dd, J=5Hz, 8Hz), 6.47 (1H, m), 6.73 (1H, s), 7.20 (2H, m), 9.58 (1H, d, J=8Hz).

Example 6

1) 4.6 g of phosphoryl chloride, 0.95 g of trimethylsilylacetamide and 1.2 g of N,N-dimethylformamide are added at a temperature below 5°C during 30 minutes to a stirred suspension of 2.8 g of 2-(2- amino-4-thiazolyl)-2-isopropoxyiminoacetic acid (syn isomer) in 25 ml of tetrahydrofuran (solution A). 10.5 g of trimethylsilylacetamide is added to a suspension of 3.9 g of 4-nitrobenzyl-7-amino-3-cephem-4-carboxylate in 50 ml of tetrahydrofuran, and it is stirred at room temperature for 1 1/2 hours. To this solution, the solution A obtained above at -20°C is added at once, and the solution is stirred at -5 to 0°C for 40 minutes. 70 ml of water and 100 ml of tetrahydrofuran are added to the resulting solution at -20°C. The solution is adjusted to pH 7.5 with an aqueous sodium bicarbonate solution and stirred for 1 hour.

200 ml of saturated aqueous sodium chloride solution are then added, and the organic phase is separated. The aqueous phase obtained as a residue is extracted with tetrahydrofuran, and the extract and the organic phase obtained above are collected, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and then evaporated under reduced pressure. The residue is triturated with diisopropyl ether, and the precipitated substance is filtered off, whereby 6.0 g of 4-nitrobenzyl-7-[2-(2-amino-4-thiazolyl)-2-isopropoxy-iminoacetamido]-3-cephem-4- carboxylate (syn isomer).

IR spectrum (nujol): Omax = 3320, 3270, 1775, 1730, 1670 and 1630 cm-1.

NMR spectrum (d6-DMSO): 5 ppm = 1.17 (6H, d, J=6Hz), 3.63 (2H, m), 4.33 (1H, q, J=6Hz), 5.17 (1H, d, J=5Hz), 5.42 (2H, s), 5.92

(1H, dd, J=5Hz, 8Hz), 6.67 (1H, m), 6.70 (1H, s), 7.22 (2H, m), 7.70 (2H, d, J=8Hz ), 8.25 (2H, d, J=8Hz), 10.13 (1H, d, J=8Hz). 2) 1 ml of acetic acid and a suspension of 2.0 g of 10% palladium/charcoal in 8 ml of water are added to a solution of 5.0 g of 4-nitrobenzyl-7-[2-(2-amino-4-thiazolyl) )-2-isopropoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer) in 150 ml of tetrahydrofuran, and the suspension is subjected to catalytic reduction at room temperature and atmospheric pressure. The catalyst is filtered off, and the filtrate is evaporated under reduced pressure. 80 ml of ethyl acetate is added to the residue, and it is adjusted to pH 7.5 with an aqueous sodium bicarbonate solution. The organic phase is separated and extracted with an aqueous sodium bicarbonate solution. The extract and the aqueous phase obtained above are combined, adjusted to pH 3.0 with concentrated hydrochloric acid and extracted with tetrahydrofuran. The extract is washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The precipitated crystals are filtered off and dried, whereby 0.8 g of 7-[2-(2-amino-4-thiazolyl)-2-isopropoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer) is obtained.

IR spectrum (nujol): Vmax = 3320, 1780, 1670 and 1635 cm"<1>. NMR spectrum (d6-DMSO): 6 ppm = 1.20 (6H, d, J=6Hz), 3.55 (2H, m), 4.30 (1H, q, J=6Hz), 5.08 (1H, d, J=5Hz), 5.82 (1H, dd, J=5Hz, 8Hz), 6.45 (1H, m), 6.68 (1H, s), 7.10 (2H, m), 10.08 (1H, d, J=8Hz).

Example 7

1) 4.6 g of phosphoryl chloride, 0.95 g of trimethylsilylacetamide and 1.2 g of N,N-dimethylformamide are added at a temperature below 5°C to a stirred suspension of 2.8 g of 2-(2-amino-4-thiazolyl )-2-propoxyiminoacetic acid (syn isomer) in 25 ml of tetrahydrofuran, and it is stirred for 20 minutes. The solution is added dropwise at -5 to +5°C to a suspension of 3.9 g of 4-nitrobenzyl-7-amino-3-cephem-4-carboxylate in a mixture of 20 ml of tetrahydrofuran, 20 ml of water and 20 ml of acetone, with the pH value being kept in the range 6.9-7.1 with a 20% aqueous sodium carbonate solution. The solution is stirred at -5 to +5°C for 30 minutes and then at 10°C for 1 hour and adjusted to pH 7.5. 100 ml of tetrahydrofuran and 200 ml of saturated aqueous sodium chloride solution are added to the resulting solution, and the insoluble substance is filtered off. The organic phase is separated from the filtrate, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and then evaporated under reduced pressure. The residue is triturated with diisopropyl ether, and the precipitated substance is filtered off, thereby obtaining 5.8 g of 4-nitrobenzyl-7-[2-(2-amino-4-thiazolyl)-2-propoxyiminoacet-amido]-3-cephem-4 -carboxylate (syn isomer).

IR spectrum (nujol): V max = 3300, 1780, 1730, 1670 and

1640 cm-<1>.

NMR spectrum (de-DMSO): 5 ppm = 0.93 (3H, t, J=6Hz), 1.70 (2H, m), 3.70 (2H, m), 4.08 (2H, t , J=6Hz), 4.5 (2H, m), 5.23 (1H, d, J=5Hz), 5.50 (2H, s), 5.97 (1H, dd, J=5Hz, 8Hz ), 6.73 (1H, m), 6.80 (1H, s), 7.75 (2H, d, J=9Hz), 8.30 (2H, d, J=9Hz), 9.65 ( 1H, d, J=8Hz). 2) 5.0 g of 4-nitrobenzyl-7-[2-(2-amino-4-thiazolyl)-2-propoxy-iminoacetamido]-3-cephem-4-carboxylate (syn isomer) is treated analogously to example 6 ( 2), whereby 0.9 g of 7-[2-(2-amino-4-thiazolyl)-2-propoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer) is obtained.

IR spectrum (nujol): Vmax = 3250, 1770, 1650, 1660 and

1620 cm-<1>.

NMR spectrum (d6-DMSO): 5 ppm = 0.93 (3H, t, J=7Hz), 1.67 (2H, sextet, J=7Hz), 3.60 (2H, m), 4.03 (2H, t, J=7Hz), 5.13 (1H,

d, J=5Hz), 5.83 (1H, dd, J=5Hz, 8Hz), 6.48 (2H, t, J=4Hz), 6.70 (1H, s), 7.18 (2H, m), 9.53 (1H, d, J=8Hz).

Example 8

1) 13.2 g of phosphoryl chloride is added dropwise at -5°C to a stirred solution of 6.3 g of N,N-dimethylformamide and 24.7 ml of tetrahydrofuran, and it is stirred at the same temperature for 30 minutes. 120 ml of tetrahydrofuran and 19.5 g of 2-(2-formamidothiazol-4-yl)-2-n-butoxyiminoacetic acid (syn-isomer) are added to the solution at -5°C, and it is stirred at the same temperature for 30 minutes. This solution is added dropwise at a temperature between -5 and +5°C over the course of 15 minutes to a stirred suspension of 24.7 g of 4-nitrobenzyl-7-amino-3-cephem-4-carboxylate, 120 ml of tetrahydrofuran, 60 ml of acetone and 60 ml of water, the pH being adjusted to 7-7.5 with a 20% aqueous sodium carbonate solution, and then the solution is stirred for 30 minutes. The insoluble material is filtered off, and a saturated aqueous sodium chloride solution is added to the filtrate. The solution is extracted twice with tetrahydrofuran. The extract is washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and evaporated in vacuo. The residue is triturated with diisopropyl ether, whereby 34.6 g of 4-nitrobenzyl-7-[2-(2-formamidothiazol-4-yl)-2-n-butoxy-iminoacetamido]-3-cephem-4-carboxylate (syn- isomer).

IR spectrum (nujol): Vmax = 3240, 3050, 1780, 1730, 1695 and 1660 cm-1.

NMR spectrum (d6-DMSO): 5 ppm = 0.92 (3H, t, J=7Hz), 0.8~2.2 (4H, m), 3.67 (2H, d, J=4Hz) , 4.16 (2H, t, J=7Hz), 5.23 (1H, d, J=5Hz), 5.46 (2H, s), 5.99 (1H, dd, J=5Hz, 8Hz) , 6.71 (1H, t, J=5Hz), 7.43 (1H, s), 7.76 (2H, d, J=9Hz), 8.30 (2H, d, J=9Hz), 8 .58 (1H, s), 9.72 (1H, d, J=8Hz), 12.66 (1H, s). 2) A mixture of 34.5 g of 4-nitrobenzyl-7-[2-(2-formamidothiazol-4-yl)-2-n-butoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer), 345 ml tetrahydrofuran, 14 g 10% palladium/charcoal,

140 ml of methanol, 2.5 ml of acetic acid and 50 ml of water are subjected to catalytic reduction at atmospheric pressure and at room temperature for 3 hours. The resulting mixture is filtered and washed with tetrahydrofuran. The filtrate is evaporated in vacuo, and the residue is dissolved in a mixture of ethyl acetate and aqueous sodium bicarbonate solution. The insoluble substance is filtered off. The ethyl acetate phase is separated and extracted with an aqueous sodium bicarbonate solution, the aqueous phase and the aqueous extract are collected.

The aqueous solution is washed with ethyl acetate and diethyl ether in the order mentioned, and the solution is adjusted to pH 2.0 with 10% hydrochloric acid and stirred for 30 minutes. The precipitated substance is filtered off, washed with water and dried over magnesium sulfate, whereby 18.3 g of 7-[2-(2-formamidothiazol-4-yl)-2-butoxy-iminoacetamido]-3-cephem-4-carboxylic acid ( syn isomer). IR spectrum (nujol): Vmax = 3330, 3040, 1780, 1725, 1695 and 1655 cm-1.

NMR spectrum (de-DMSO): 5 ppm = 0.90 (3H, t, J=7Hz), 1.1^1.9 (4H, m), 3.58 (2H, d, J=5Hz) , 4.12 (2H, t, J=7Hz), 5.13 (1H, d, J=5Hz), 5.86 (1H, dd, J=5Hz, 8Hz), 6.46 (1H, t, J=4Hz), 7.40 (1H, s), 8.50 (1H, s), 9.63 (1H, d, J=8Hz), 12.57 (1H, wide s). 3) A mixture of 12.7 g of 7-[2-(2-formamidothiazol-4-yl)-2-n-butoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer),

9.6 ml of concentrated hydrochloric acid, 9.5 ml of methanol and 9.5 ml of tetrahydrofuran are stirred at room temperature for 3 hours. The resulting solution is evaporated in vacuo and the residue is suspended in water. The suspension is adjusted to pH 3.5 with sodium bicarbonate under ice cooling, and stirred at the same temperature for 30 minutes. The precipitated substance is filtered off and dried over magnesium sulphate, whereby 10 g of a powder is obtained. The powder is suspended in 300 ml of water and the pH is adjusted to 7.0 with sodium bicarbonate. The solution is adjusted to pH 6.0 with 10% hydrochloric acid and column chromatographed on 300 ml of nonionic adsorption resin ("Diaion" HP-20, trade mark, manufactured by Mitsubishi Chemical Industries Ltd.) with 10% aqueous isopropyl alcohol solution. The eluate is adjusted to pH 3.5 with 10% hydrochloric acid under ice-cooling, and the precipitated substance is filtered off, washed with water and dried, thereby obtaining 7.2 g of 7-[2-(2-aminothiazol-4-yl)-2 -n-butoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer).

IR spectrum (nujol): Umax = 3320, 1775 and 1660 cm"<1.>NMR spectrum (d6-DMSO): 5 ppm = 0.88 (3H, t, J=7Hz), 1.1^1 .9 (4H, m), 3.58 (2H, wide s), 4.05 (2H, t, J=7Hz), 5.08 (1H, d), J=5Hz), 5.80 (1H , dd, J=5Hz, 8Hz) 6.44 (1H, wide s), 7.18 (2H, s), 9.51 (1H, d, J=8Hz).

Example 9

1) 6.48 g 2-(2-formamidothiazol-4-yl)-2-isobutoxyimino-acetic acid (syn isomer), 2.10 g N,N-dimethylformamide, 4.40 g phosphoryl chloride, 110 ml tetrahydrofuran, 8 .23 g of 4-nitrobenzyl-7-amino-3-cephem-4-carboxylate, 16 ml of acetone and 16 ml of water are treated analogously to example 8 (1), whereby 12.8 g of 4-nitrobenzyl-7-[2 -(2-Formamidothiazol-4-yl)-2-isobutoxyimino-acetamido]-3-cephem-4-carboxylate (syn isomer).

IR spectrum (nujol): Vmax = 3240, 3050, 1780, 1720, 1700 and 1655 cm-1.

NMR spectrum (d6-DMS0): 5 ppm = 0.92 (6H, d, J=7Hz) , 1.7/v2.2 (1H, m), 3.67 (2H, broad s), 3, 91 (2H, d, J=7Hz), 5.21 (1H, d, J=5Hz), 5.95 (1H, dd, J=5Hz, 9Hz), 6.67 (1H, t, J=4Hz ), 7.37 (1H, s), 7.72 (2H, d, J=8Hz), 8.24 (2H, d, J=8Hz), 8.52 (1H, s), 9.68 ( 1H, d, J=9Hz), 12.58 (1H, wide s). 2) 14.2 g 4-nitrobenzyl-7-[2-(2-formamidothiazol-4-yl)-2-isobutoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer), 5.7 g 10% palladium/charcoal, 57 ml of methanol, 142 ml of tetrahydrofuran, 1 ml of acetic acid and 10 ml of water are treated analogously to example 8 (2), whereby 4.25 g of 7-[2-(2-formamidothiazol-4- yl)-2-isobutoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer).

IR spectrum (nujol): v max = 3260, 1790, 1725 and 1670 cm"<1>. NMR spectrum (ds-DMSO): 5 ppm = 0.92 (6H, d, J=6Hz), 1, 6^2.3 (1H, m), 3.61 (2H, d, J=4Hz), 3.91 (2H, d, J=6Hz), 5.14 (1H, d, J=5Hz), 5.88 (1H, dd, J=5Hz, 8Hz), 6.50 (1H, t, J=5Hz), 7.40 (1H, s), 8.56 (1H, s), 9.64 ( 1H, d, J=8Hz). 3) 4.1 g 7-[2-(2-formamidothiazol-4-yl)-2-isobutoxyimino-acetamido]-3-cef em-4-carboxylic acid (syn isomer) , 3.65 g of concentrated hydrochloric acid and 61.5 ml of methanol are treated analogously to example 8 (3), whereby 2.4 g of 7-[2-(2-aminothiazol-4-yl)-2-isobutoxyiminoacetamido]-3 is obtained -cephem-4-carboxylic acid (syn isomer) .

IR spectrum (nujol): Vmax = 3330, 1780, 1665, 1630 and

1545 cm-1.

NMR spectrum (de-DMSO): 5 ppm = 0.89 (6H, d, J=7Hz), 1.6^2.2 (1H, m) 3.58 (2H, broad s), 3.84 <2H, d, J=7Hz) 5.10 (1H, d, J=5Hz), 5.82 (1H, dd, J=5Hz, 9Hz), 6.46 (1H, wide s), 6.68 (1H, s) , 7.20 (2H, s) , 9.53 (1H, d, J=9Hz).

Example 10

0.84 g of phosphoryl chloride is added dropwise at 5°C to a stirred suspension of 1.0 g of 2-(2-aminothiazol-4-yl)-2-allyl-oxyiminoacetic acid (syn isomer), 10 ml of tetrahydrofuran and

0.05 ml of water, and it is stirred at the same temperature for 20 minutes. 0.66 g of trimethylsilylacetamide, 0.84 g of phosphoryl chloride and 0.45 g of N,N-dimethylformamide are added to the solution, and it is stirred at 5°C for 1 hour to produce an activated acid solution. 4.0 g of trimethylsilylacetamide is added at 40°C to a suspension of 0.88 g of 7-amino-3-cephem-4-carboxylic acid in 10 ml of tetrahydrofuran, and it is stirred for 30 minutes. To this solution, the activated acid solution prepared above is added all at once at -20°C, and it is stirred at 0°C for 1 hour. 20 ml of water are added to the resulting solution at -20°C, and the solution is adjusted to pH 7.5 with an aqueous sodium bicarbonate solution. Ethyl acetate is added to the solution, and the aqueous phase is separated. The solution is washed with ethyl acetate and diisopropyl ether in the order mentioned, the pH is adjusted to 5.0 and it is treated with activated charcoal. The pH is adjusted to 3.0, and the precipitated material is filtered off, washed with water and dried over phosphorus pentoxide, whereby 0.8 g of 7-[2-(2-aminothiazol-4-yl)-2-allyloxyiminoacetamido]-3- cephem-4-carboxylic acid (syn isomer).

IR spectrum (nujol): Vmax = 3300, 1780, 1660 and 1630 cm"<1>. NMR spectrum (ds-DMSO): 5 ppm = 3.67 (2H, d, J=4Hz), 4.67 (2H, m), 5.17 (1H, d, J=5Hz), 5.25 (1H, m), 5.50 (1H, m), 5.90 (1H, dd, J=5Hz, 8Hz ), 6.03 (1H, m), 6.55 (1H, m), 6.80 (1H, s), 7.50 (2H, m), 9.68 (1H, d, J=8Hz) .

Example 11

3 g 2-(2-aminothiazol-4-yl)-2-n-hexyloxyiminoacetic acid (syn isomer), 0.15 g water, 3.8 g phosphoryl chloride, 10.7 g trimethylsilylacetamide, 1.0 g N,N-dimethylformamide, 50 ml tetrahydrofuran and 2.0 g of 7-amino-3-cephem-4-carboxylic acid are treated analogously to example 10, whereby 1.1 g of 7-[2-(2-aminothiazol-4-yl)-2-n-hexyloxyiminoacetamido is obtained ]-3-cephem-4-carboxylic acid (syn isomer).

IR spectrum (nujol): V»a"s = 3250, 1760, 1640 and 1600 cm"<1>. NMR spectrum (d 6 -DMSO): 5 ppm = 1.88 (3H, m), 1.1^1.9 (8H, m), 3.60 (2H, m), 4.06 (2H, t , J=6Hz), 5.10 (1H, d, J=5Hz), 5.82 (1H, dd, J=5Hz, 8Hz), 6.46 (1H, m), 6.70 (1H, s ), 7.26 (2H, m), 9.56 (1H, d, J=8Hz).

Example 12

1) 4.14 g 2-(2-formamidothiazol-4-yl)-2-pentyloxyimino-acetic acid (syn isomer), 4.5 g 4-nitrobenzyl-7-amino-3-cephem-4-carboxylate, 1 .41 g of N,N-dimethylformamide, 2.96 g of phosphoryl chloride, 72 ml of tetrahydrofuran, 15 ml of acetone and 15 ml of water are treated analogously to example 8 (1), whereby 8.1 g of 4-nitro-benzyl-7- [2-(2-Formamidothiazol-4-yl)-2-pentyloxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer).

IR spectrum (nujol): \) >ik> = 3240, 3050, 1780, 1730 and

1655 cm-<1>.

NMR spectrum (ds-DMSO): 5 ppm = 0.6-2.0 (9H, m), 3.66 (2H, s), 4.10 (2H, t, J=6Hz), 5.19 (1H, d, J=5Hz), 5.42 (2H, s), 5.95

(1H, dd, J=5Hz, 8Hz), 6.16 (1H, wide s), 7.38 (1H, s), 7.72

(2H, d, J=9Hz), 8.26 (2H, d, J=9Hz), 8.54 (1H, s), 9.69 (1H, d, J=8Hz), 12.69 (1H , wide s).

2) 8 g 4-nitrobenzyl-7-[2-(2-formamidothiazol-4-yl)-2-pentyl-oxyiminoacetamido]-3-cef em-4-carboxylate (syn isomer), 3.6 g 10% ig palladium/charcoal, 36 ml of methanol, 90 ml of tetrahydrofuran, 0.63 g of acetic acid and 6.3 ml of water are treated analogously to example 8 (2), whereby 3.4 g of 7-[2-(2-formamidothiazol- 4-yl)-2-pentyloxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer). IR spectrum (nujol): Vmax = 3275, 3075, 1795, 1700, 1660 and 1630 cm-<1>.

NMR spectrum (ds-DMSO): 5 ppm = 0.6-2.0 (9H, m), 3.60 (2H, d, J=4Hz), 4.12 (2H, t, J=6Hz) , 5.14 (1H, d, J=5Hz), 5.87 (1H, dd, J=5Hz, 9Hz), 6.49 (1H, t, J=3Hz), 7.40 (1H, s) , 8.53 (1H, s), 9.64 (1H, d, J=9Hz), 12.68 (1H, s) . 3) 3.3 g 7-[2-(2-formamidothiazol-4-yl)-2-pentyloxyimino-acetamido]-3-cef em-4-carboxylic acid (syn isomer), 2.80 g concentrated hydrochloric acid, 20 ml of tetrahydrofuran and 50 ml of methanol are treated analogously to example 8 (3), whereby 2.3 g of 7-[2-(2-aminothiazol-4-yl)-2-pentyloxyiminoacetamido]-3-cephem-4-carboxylic acid is obtained ( syn isomer).

IR spectrum (nujol): Vmax = 3300, 1775, 1650 and 1540 cm"<1>. NMR spectrum (ds-DMSO): 5 ppm = 0.6-2.0 (9H, m), 3.56 (2H, d, J=2Hz), 4.03 (2H, t, J=6Hz), 5.08 (1H, d, J=5Hz), 5.81 (1H, dd, J=5Hz, 8Hz) , 6.46 (1H, t, J=4Hz), 6.69 (1H, s), 7.20 (2H, s), 9.15 (1H, d, J=8Hz).

Example 13

1) 1.35 g 2-(2-formamidothiazol-4-yl)-2-ethoxycarbonyl-methoxyiminoacetic acid (syn isomer), 1.54 g 4~nitrobenzyl-7-amino-3-cephem-4-carboxylate, 393 mg of N,N-dimethylformamide, 825 mg of phosphoryl chloride, 21.2 ml of tetrahydrofuran, 3.9 ml of acetone and 3.9 ml of water are treated analogously to example 8 (1), whereby 2.52 g of 4-nitrobenzyl-7- [2-(2-Formamidothiazol-4-yl)-2-ethoxycarbonylmethoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer).

IR spectrum (nujol): Umax = 3250, 1790, 1730, 1690 and

1640 cm-<1>.

NMR spectrum (de-DMSO): 5 ppm = 1.23 (3H, t, J=7Hz), 3.66 (2H, s), 4.13 (2H, q, J=7Hz), 4.74 (2H, s), 5.22 (1H, d, J=5Hz), 5.42 (2H, s), 5.98 (1H, dd, J=5Hz, 9Hz), 6.49 (1H, wide s) , 7.43 (1H, s), 7.71 (2H, d, J=9Hz), 8.23 (2H, d, J=9Hz), 8.52 (1H, s), 9.68 (1H, d , J=9Hz), 12.66 (1H, s), 2) 2.52 g 4-nitrobenzyl-7-[2-(2-formamidothiazol-4-yl)-2-ethoxycarbonylmethoxyiminoacetamido]-3-cephem-4 -carboxylate (syn isomer), 1.3 g of 10% palladium/charcoal, 13 ml of ethanol, 25 ml of tetrahydrofuran, 0.22 ml of acetic acid and 2.2 ml of water are treated analogously to example 8 (2), whereby one obtains 0.4 g of 7-[2-(2-formamidothiazol-4-yl)-2-ethoxycarbonylmethoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer).

IR spectrum (nujol): Vmax = 3250, 3060, 1780, 1750, 1690 and 1660 cm-<1>.

NMR spectrum (de-DMSO): 5 ppm = 1.23 (3H, t, J=7Hz), 3.61 (2H, broad s), 4.15 (2H, q, J=7Hz), 4, 73 (2H, s), 5.13 (1H, d, J=5Hz), 5.87 (1H, dd, J=5Hz, 9Hz), 6.48 (1H, wide s), 7.43 (1H , s), 8.50 (1H, s), 9.62 (1H, d, J=9Hz), 12.58 (1H, s). 3) A solution of 0.35 g of 7-[2-(2-formamidothiazol-4-yl)-2-ethoxycarbonylmethoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer), 0.39 g of concentrated hydrochloric acid, 5 .3 ml of ethanol and 8 ml of tetrahydrofuran are stirred at room temperature for 4.5 hours. The resulting solution is evaporated in vacuo, the residue is dissolved in an aqueous solution of sodium bicarbonate, treated with activated carbon and filtered. The filtrate is adjusted to pH 3.5 with 10% hydrochloric acid under ice cooling. The precipitated material is filtered off, washed with water and dried, whereby 0.1 g of 7-[2-(2-aminothiazol-4-yl)-2-ethoxycarbonylmethoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn- isomer).

IR spectrum (nujol): Vmax = 3250, 3050, 1775, 1720, 1660, 1630 and 1550 cm-<1>.

NMR spectrum (ds-DMSO): 5 ppm = 1.21 (3H, t, J=7Hz), 3.59 (2H, s), 4.14 (2H, q, J=7Hz), 4.66 (2H, s), 5.10 (1H, d, J=5Hz), 5.83 (1H, dd, J=5Hz, 8Hz), 6.47 (1H, wide s), 6.78 (1H, s), 7.23 (2H, s), 9.52 (1H, d, J=8Hz).

Example 14

1) A solution of 3.2 g of 2-(2-formamidothiazol-4-yl)-2-(tert.butoxycarbonylmethoxyimino)acetic acid (syn isomer), 0.852 g of N,N-dimethylformamide and 1.79 g of phosphoryl chloride in 34 ml of ethyl acetate and a solution of 1.95 g of 7-amino-3-cephem-4-carboxylic acid and 9.9 g of bis(trimethylsilyl)acetamide in 19.5 ml of ethyl acetate are treated analogously to example 8 (1), thereby obtaining 2 .9 g of 7-[2-(2-formamidothiazol-4-yl)-2-(tert-butoxy-carbonylmethoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer).

IR spectrum (nujol): \Jmax = 3260, 3180, 3060, 1785, 1730, 1690 and 1640 cm"<1>.

NMR spectrum (ds-DMSO): 5 ppm = 1.44 (9H, s), 3.63 (2H, s), 4.62 (2H, s), 5.12 (1H, d, J=5Hz ), 5.87 (1H, dd, J=5Hz, 9Hz), 6.48 (1H, wide s), 7.42 (1H, s), 8.50 (1H, s), 9.57 (1H , d, J=9Hz), 12.62 (1H, wide s).

2). A mixture of 2.8 g of 7-[2-(2-formamidothiazol-4-yl)-2-(tert-butoxycarbonylmethoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer), 2.8 ml of anisole and 11.2 ml of trifluoroacetic acid are stirred at room temperature for 1 hour. To the resulting solution are added ethyl acetate and water, and the pH is adjusted to 7.0 with sodium bicarbonate. The aqueous phase is separated and the ethyl acetate phase is extracted with water. The aqueous extracts are collected, washed with ethyl acetate and diethyl ether in the order mentioned, and the pH is adjusted to 2.0 with 10% hydrochloric acid under ice cooling. The precipitated material is filtered off, washed with water and dried, whereby 1.43 g of 7-[2-(2-formamidothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer) is obtained .

IR spectrum (nujol): Omax = 3270, 3130, 3070, 1760,, 1720, 1690, 1660 and 1620 cm"<1>.

NMR spectrum (de-DMSO): 5 ppm = 3.60 (2H, s), 4.63 (2H, s), 5.11 (1H, d, J=5Hz), 5.88 (1H, dd , J=5Hz, 9Hz), 6.48 (1H, t, J=4Hz), 7.44 (1H, s), 8.52 (1H, s), 9.59 (1H, d, J=9Hz ), 12.64 (1H, wide s). 3) A mixture of 1.35 g 7-[2-(2-formamidothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer), 3.926 g concentrated hydrochloric acid, 20 ml methanol , 10 ml of water and 40 ml of tetrahydrofuran are stirred at 30°C for 6 hours. The resulting solution is evaporated in vacuo to evaporate the methanol, and the resulting aqueous solution is adjusted to pH 4.2 with 10% aqueous sodium hydroxide solution. The solution is adjusted to pH 3.0 with 10% hydrochloric acid. The precipitated material is filtered off and dried, whereby 0.8 g of 7-[2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer) is obtained.

IR spectrum (nujol): iJmax = 3300 (broad), 3200 (broad), 1775, 1670 and 1635 cm-<1>.

NMR spectrum (de-DMSO): 5 ppm = 3.64 (2H, s), 4.64 (2H, s), 5.13 (1H, d, J=5Hz), 5.86 (1H, dd , J=5Hz, 7Hz), 6.49 (1H, t, J=4Hz), 6.82 (1H, s), 7.33 (2H, s), 9.57 (1H, d, J=9Hz ).

Example 15

0.14 g of thiourea is added to a solution of 0.8 g of 4-nitrobenzyl-7-[2-(2-bromoacetyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer) in 20 ml of ethanol and 5 ml of water,

and it is stirred at room temperature for 3.5 hours. The resulting solution is evaporated under reduced pressure, and water and ethyl acetate are added to the residue. The ethyl acetate phase is separated, washed with water, dried over magnesium sulphate and evaporated under reduced pressure

pressure, whereby 0.6 g of crude product is obtained. This product is purified by column chromatography on silica gel (eluent: benzene and ethyl acetate 8:2), which gives 0.21 g of 4-nitro-benzyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido] -3-cephem-4-carboxylate (syn isomer), melting point 165-170°C (decomposition).

IR spectrum (nujol): \)max = 3350-3200, 1770, 1720, 1665,

1615 and 1515 cm"<1>.

NMR spectrum (ds-DMSO): 5 ppm =3.60 (2H, broad s), 3.81 (3H,

s), 5.12 (1H, d, J=5Hz), 5.36 (2H, s), 5.83 (1H, dd, J=5Hz,

8Hz), 6.64 (1H, t, J=4Hz), 6.70 (1H, s), 7.20 (2H, s), 7.65

(2H, d, J=9Hz), 8.19 (2H, d, J=9Hz), 9.60 (1H, d, J=8Hz).

Example 16

A solution of diazomethane in diethyl ether is added in small portions to a solution of 0.3 g of 4-nitrobenzyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-cephem-4-carboxylate ( syn-isomer) in 30 ml of methanol until the reaction ended. The resulting solution is evaporated under reduced pressure,

the residue is pulverized with diethyl ether, and by filtration and drying, 0.26 g of 4-nitrobenzyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn- isomer). This product is identical to an authentic sample.

Example 17

0.406 g of mesyl chloride is added dropwise at 0-5°C over the course of 2 minutes to a stirred mixture of 1 g of 4-nitrobenzyl-7-[2-(2-formamido-4-thiazolyl)-2-methoxyiminoacetamido]-3-hydroxy -cephem-4-carboxylate (syn isomer), 10 ml of N,N-dimethylformamide and 0.7 32 g of potassium carbonate, and the solution is stirred at room temperature for 2.5 hours. To the resulting solution are added ethyl acetate and water, and the solution is extracted with ethyl acetate.

The remaining aqueous phase is extracted again with ethyl acetate. The ethyl acetate extract solution is washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue is column chromatographed on 30 g of silica gel, and it is eluted with a mixture of chloroform and ethyl acetate. The eluate is evaporated under reduced pressure, whereby 0.12 g of 4-nitrobenzyl-7-[2-(2-formamido-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer) is obtained, melting point 224° (decomposition).

Example 18

11 mg of thiourea and a solution of 30 mg of 7-[2-(2-bromoacetyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer) in 2 ml of ethanol are treated analogously to example 15, whereby one obtains 7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-3-cephem-4-carboxylic acid (syn isomer). The product is shown by thin-layer chromatography to be identical to an authentic sample.

Claims (2)

1. Analogy method for the preparation of the syn isomer of a therapeutically active 3-cephem compound with the general formula I where R<2>means C 1 -C 8 -alkyl, C 2 -C 8 -alkenyl, carboxy-C 1 -C 8 -alkyl or C1-C6-Alkoxycarbonyl-C1-C6-Alkyl, or pharmaceutically acceptable salts and esters thereof, characterized in that 1) a 7-amino-3-cephem compound of the general formula II where R<3> is carboxy or esterified carboxy, or a reactive amino derivative or a salt thereof, is reacted with a syn-isomer of a carboxylic acid of the general formula III where R<2> has the meaning given above, and R6 b is amino or protected amino, a reactive derivative thereof at the carboxyl group, or a salt thereof, or 2) a syn isomer of a compound with the general formula V where R s and R 6 b have the above meaning, or a salt thereof, is reacted with an etherifying agent which can introduce a C 1 -C 6 -alkyl-, C 2 -C 8 -alkenyl-, carboxy-C 1 -C 8 -alkyl- or C 1 -C 8 - alkoxycarbonyl-Ci-Cs-alkyl group, or 3) a syn isomer of a compound with the general formula VI where R<2> and R<5> have the meaning given above and R1 b means haloacetyl, is reacted with a thiourea compound of the general formula VIII where R<6> has the meaning given above, 4) a syn-isomer of a compound of the general formula lg where R<2>, R<5> and R<6> have the meaning given above, and R<7> is acyl, or a salt thereof, is treated with a base, then possible protective groups and/or an obtained free acid are removed are converted into pharmaceutically acceptable salts or esters, or pharmaceutically acceptable salts are converted into pharmaceutically acceptable esters, or pharmaceutically acceptable esters are converted into pharmaceutically acceptable salts. 2. Process as stated in claim 1, for the preparation of 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn-isomer) and pharmaceutically acceptable salts and esters thereof, characterized in that starting materials are used where R<2> is methyl.