CS196372B2 - Method of preparing 2-lower alkyl-7-substituted-2-or 3-cephem-4-carboxylic acid - Google Patents

Description

Author of the invention KAMIYA TAKASHI, SUITA, TAKAYA TAKAO, SAKAI,

TERAJI TSUTOMU, HASHIMOTO MASASHI, TOYONAKA, NAKAGUTI OSAMU and OKU TERUO, OSAKA (Japan) (73) · ’

Owner of FUJISAWA PHARMACEUTICAL CO., LTD., OSAKA (Japan) (54) A process for preparing 2-lower alkyl-7-substituted-2 or 3-cephem-4-carboxylic acid

The invention relates to a process for preparing new ones

2-lower alkyl-7-substituted-2- or 3-cephem-4-carboxylic acids and pharmaceutically acceptable salts of these compounds.

Said 2-lower alkyl-7-substituted-2 or 3-cephem-4-carboxylic acid and the pharmaceutically acceptable salts thereof exhibit an antimicrobial activity. Also disclosed are pharmaceutical compositions comprising these compounds and a method for the therapeutic use of these compounds in the treatment of humans and animals suffering from infectious diseases.

It is a further object of the present invention to provide a pharmaceutical composition comprising as active ingredient said 2-lower alkyl-7-substituted-2- or 3-cephem-4-carboxylic acid and pharmaceutically acceptable salts thereof.

Another object is to provide a method of treating infectious diseases caused by pathogenic bacteria in humans and animals.

The aforementioned 2-lower alkyl-7-substituted 2- or 3-cephem-4-carboxylic acids which form the subject of the invention can be represented by the following general formula Ie,

(Ia.) In which.

R ¹ represents an alkyl group having 1 to 6 carbon atoms; R ² is a carboxy group, an alkoxycarbonylol group having 1 to 6 carbon atoms in the alkoxy moiety, which group may contain 1 to 3 halogen atoms, a (C 1 -C 6) alkanoyloxy- (C 1 -C 6) alkoxycarbonyl group or a phenyl (C 1 -C 6) alkoxycarbonyl group, which may contain a nitro group,

R ³ is an amino group or an alkanoylamino group having 1 to 6 carbon atoms in the alkanoyl moiety, wherein the group may contain 1 to 3 halogen atoms, and

R ⁴ is hydrogen or C 1 -C 6 alkyl.

The 2-lower alkyl-7-substituted-2- or 3-cephem-4-carboxylic acids of formula Ie or salts of these compounds may be at

4 are shown in various ways, which are illustrated in Procedure 1 by the following schemes.

Ύ-CH.CO-C-CO / VW ^λ II N oV> Z, f ^co ^ ^{w S} N

..... V '. STEED*

or it is a compound of this compound

In the formulas Ie, V and VI have axes P ¹ obec- tup 2 No Symbol defined above.

R * 4t- CONVV-4- 4-r ^<S \ *.

htrbo sut these «lou & frhÍhy π (lb) £ li.toi.híc.e, othha.hn &.

iKu / deaths AtniSCOUpLE

W-J-A-CONH

htbo sut these compounds

R ^z (la.)

Procedure 3 »

³ —-- XA-CONH

S ^ R ‘

Oa, bo aut ta-to Atthec ° (, /) • 4 »

4.Uhihi.te. cAt-Ahicu

Groups or *. Jr & nbexyGroupsX

R ³ '- (-); ^A - ^COH- J ( ^S ). 0 'X

S ¹ R ¹ or a salt thereof

COOH ( _lh )

S z;

/'and'..'

Procedure - 4 ' _VS C + ·;

R ³ '- ^^ - A-CONH-jrL

R ³ '·

Ά3- ⁴ X \ H '& HQ & l TFCT jloucArůny

COOH

CONH

COOR in which it means

R ¹ 'is a lower alkyl group,

R ² 'is carboxy or protected carboxy,' /

R ³ 'is an amino group or a protected amino group,

R ⁴ 'is hydrogen- or lower alkyl, A represents carbonyl, hydroxy (lower) alkylene, hydroxyimino (lower) alkylene or lower alkoxyimino (lower) alkylene, R ^2a is a protected carboxy group,

R ^3a is protected amino groups,

R ^4a is a lower alkyl group,

R ⁵ is the ester portion of the esterified carboxy group of the formula - COOR ⁵ , and

Y is an acid residue.

The preparation of the starting compounds can be illustrated by the following schemes.

One of the starting compounds of the general formula (II) is prepared according to the procedure described in DOS No. 2,412,513.

and

190372

Η, Ν

M1). Atni.no ikupi.hu do not be afraid Ajú díivíťíAktiuhL m A-tnihoikupihA htbo j a l AlaucAhihy & .JÍ (íll *)

R ^ - ^^ - ^{CO-S (lb ,,)} elůnCnax c echb «.hh« AkupÍnyjta. ka.fíioxyψ Group,

COCQQH

HfN-OR ^^^^

M, or 4, these, AlouAhiny

R ^U - ^ ~ ^ -C-COOH ^S II

Ůr ^ (IDa)

h ^ N-OR * 'na.bo Dissolve this sto-stin (IV)

S N i j (int)

OR ^ '' J.i.tnChA.c.t 'oc.hra.hhe. and a k.a.hboxy group.

(Hic.)

198372 t-cw ^ co-p-z

N οϋ '*'

N-y-N-y-C-COOH- ^SN

OR ^ (VIII) w ^ 3-,

N

OR * '<of li. me. on. ca, ¹ 'oc.hra.hni groups on. (4) - ^ - C-COOH II N 1

OR *. (IIU) -

S (lilo) reduction.

r * J ^ PhLchcooh χΝ-τΎΊΐi ^0H (II Id)

R ¹ '(II) has the activity of 3-t on. aJnunoSkupíhŠ. they are γ-cycloocyte-cooH (ix) ht-bo reactive. d »r £ nationalKa.rboxyskiAp £ * 4 ·

Ϊ9Β372

(Vh)

N / ¹ * ·

In these schemes, R 1 ', R ² ', R ^2a , R ^3a , R ⁴ ', R ^4a and Y represent the same substituents as mentioned above, and Z is a protected carboxy group.

With respect to the compounds of the invention and the starting compounds, it should be noted that all include tautomeric isomers. This means, for example, that if a group of the general formula is present in the molecule of the compounds of the present invention or in the starting compounds:

(wherein R ³ 'is as defined above), this means that the group represented by the general formula shown may also be present in a tau-day farm of the formula:

wherein R ³ 'and R ³ ' are as previously defined.

These tautomeric types between the amino compound and the corresponding amino compound, as mentioned above, are well known in the art, and it is well known to the person skilled in the art that both tautomeric isomers are readily convertible from each other and are also included in one general formula. contemplated compounds as such.

It follows from the foregoing that both tautomeric forms of all contemplated compounds of the present invention and of the starting compounds are of course within the scope of the present invention. In the description of the invention and in the definition of the subject compounds which are within the scope of the present invention and in the case of the starting compounds, the simplicity for both tautomeric forms will use only one general formula:

(wherein R ^{3 is an} imino group or a protected imino group).

It. it also means that both groups of the above formulas are in equilibrium with each other, this tautomerle can be represented by the following equilibrium:

196372 9

In addition, it should be noted that the compounds.

which are the subject of the invention, and the starting compounds include syn-isomers, anti-isomers and mixtures of these isomers in their general formulas. That is, when a hydroxyimino or lower alkoxyimino group is present in the molecule of the subject compound of the present invention and the parent compound, the parent compound and the parent compound may optionally be present as the syn-isomer or anti-. or a mixture of these isomers.

In view of the foregoing, it is understood that in this specification the symomer is a geometric isomer whose partial structure is illustrated by the following scheme:

—C — Z ¹¹ j ^: E - · '·

N — OR * or —C — COOH

ΊΙ

N — OR * ‘or, —0 — CONH— ...

. By N — OR * and anti-isomer is meant the second geometric isomer whose partial structure is illustrated by the following scheme:

—C — Z, —11 or R * O — N or —C — COOH ^: R * O — N or —C — CONH— '-ΊΙ. . · ^; . . R * O-N wherein R * and Z have been defined above.

. . A suitable pharmaceutically acceptable salt of the compound of formula (Ie) of the present invention is a conventional non-toxic salt, which includes a metal salt such as an alkali metal salt (e.g., sodium salt, potassium salt, etc.) and an alkaline earth metal salt (such as for example, calcium salt, magnesium salt, etc., ammonium salt, organic basic compound salt (such as trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, etc.), salt organic acids (such as acetate, maleate, tartrate, methanesulfonate, bezensulfonate, toluenesulfonate, etc.), an inorganic acid salt (such as hydrochloric, hydrobromic, sulfuric, phosphoric, etc.) or an amino acid salt (such as such as arginine, aspartic acid, glutamic acid, etc.) and the like. ’: · '· ·;

Hereinafter, various examples and embodiments of the present invention are included within the scope of the present invention, and the individual terms used for the above compounds are explained in more detail. .

The term "lower" refers to a structure having 1 to 6 carbon atoms, unless otherwise indicated. '·.

For the substituent R * 'lower alkyl is meant, which means methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl and the like.

R ² 'represents a carboxy group or a protected carboxy group, wherein a suitable protected carboxy group refers to an esterified carboxy group and the like, and a suitable ester component' v '. said esterified carboxy group may be, for example, lower alkyl esters (such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, perityl, hexyl, 1-cyclopropyl ether, etc.), which may contain at least one suitable substituent or substituents, e.g. alkanoyloxy- (lower alkyl ester) (such as acetoxymethyl ester, propiononyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, 2acetoxyethyl ester, 2-propionyloxy ester etc.), lower alkanesulfonyl (lower) alkyl ester such as tertiary or triethylethyl ester [or 2-mesylethyl ester] -halogen (lower)] alkyl ester (such as 2-iodoethyl ether, 2,2,2-trichloroethyl ester, etc.), lower alkenyl ester (such as vinyl ester, allyl ester, etc.), lower alkynyl ester (such as ethinyl ester, an aryl (lower) alkyl ester, which may contain at least one of the propionyl ester, etc .; a suitable substituent or substituents (such as a benzyl ester,

4-methoxybenzyl ester,.

4-nitro-benzyl ether, phenethyl ester, 'trityl ester, ...

diphenylmethyl ester, his (methoxyphenyl) methyl ester,

3,4-dimethoxybenzyl ester,

4-hydroxy-3,5-di-tert, butylhenzyl ester, etc.), an aryl ester, which may contain at least one suitable substituent or substituents (such as a phenyl ester,

4-chlorophenyl ester,.

tolyl ester, tert-butylphenyl ester,. .

xylylester,.

mesitylester, cumenylester, etc.) and the like.

The substituent R ³ 'is an amino group or a protected amino group, with a suitable protected amino group. the amino group may be substituted by a commonly used protecting group, such as an acyloxy group which will still be ^; mentioned below, an aryl (lower ') alkyl group, which may contain at least one suitable substituent or substituents - (such as benzyl, 4-methoxybenzyl, phenethyl, trityl,

3,4-dimethoxybenzyl, etc.) or the like.

Suitable acyl groups include carbamoyl, an aliphatic acyl group containing an aromatic or heterocyclic ring. a suitable example of said acyl group may be a lower alkanoyl group (such as a formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc.), lower alkoxycarbonyl group (such as a methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl,

Isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc. J, a lower alkanesulfonyl group (such as mesyl, ethanesulfonyl, propanesulfonyl,

Isopropanesulfonyl, butanesulfonyl, etc.), an arensulfonyl group (such as benzenesulfonyl, tosyl, etc.), an aroyl group (such as benzoyl, toluoyl, naphthoyl, phthaloyl, indancarbonyl, etc.), ar (lower Jalkanoyl group (such as is, for example, phenylacetyl, phenylpropionyl, etc.), aryl (lower) alkoxycarbonyl (such as benzyloxycarbonyl, etc.) and the like.

The above acyl component may contain at least one suitable substituent or substituents such as halogen (such as chlorine, bromine, iodine, or fluorine), cyano, lower alkyl (such as methyl, ethyl, propyl, isopropyl, butyl, etc.) J, a lower alkenyl group (such as vinyl, allyl, etc.), or the like, and a suitable example of such groups is mono (or dl or triJalo (lower alkanoyl group (such as trifluoroacetyl, etc.)).

For substituent A, suitable lower alkylene moieties in the above groups may be "hydroxy (lower jalkylene", "hydroxyimino (lower j alkylene") and "lower alkoxyimino-lower jalkylene" such as methylene, ethylene, trimethylene, propylene, tetramethylene and the like.

. A suitable lower alkoxy moiety in the aforementioned "loweralkoxyimino" group may be methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy and the like.

A suitable ester moiety in the aforementioned esterified carboxy group may be an ester exemplified in the case of a carboxy protecting group.

A suitable acid residue may be halogen (such as chlorine, bromine, iodine or fluorine) and the like.

Several different methods for preparing the compounds of the invention will be described in the following description, and the steps will be described in detail.

P o st u p 1

The compound of formula (Ie), or a salt thereof, of the present invention is prepared by reaction of a compound of formula (Ie). In or her sol! with a compound of formula VI.

As a suitable salt of the compound of formula (V) there may be mentioned the salt already cited as an example of the compound of formula (II), i.e., acid addition salts such as salts of organic acids (such as acetate, maleic, tartrate, benzenesulfonate etc.); inorganic acid salts (such as hydrochloric, hydrobromic, sulfuric, phosphoric, etc.), metal salts (such as sodium, potassium, calcium, magnesium, etc.), ammonium salts, organic amine salts (such as triethylamine salt, dlcyclohexylamine salt etc.J and the like ,,

The above reaction is conveniently carried out in the presence of a solvent such as water, an alcohol (such as methanol, ethanol, etc.) as well as benzene, dimethylformamide, tetrahydrofuran or any other solvent that does not adversely affect the reaction.

The reaction temperature is not a critical factor, and the above reaction is usually carried out at temperatures ranging from ambient temperature to heating.

Procedure 2

The compound of formula (Ia) or a salt of the compound of the present invention is prepared by an elimination reaction of the amino protecting group of a compound of formula (Ib) or a salt thereof.

A suitable example of a salt of a compound of formula (b) is a metal salt, an ammonium salt, and an organic amine salt exemplified by the compound of formula (II). ’

The above elimination reaction is carried out in a conventional manner, such as hydrolysis, reduction or the like. Hydrolysis may also include such procedures using acids or bases or hydrazine and the like other other methods. The choice of these methods depends on the type of protecting group to be eliminated.

Of these methods, is; acid hydrolysis, one of the most common and most preferred methods of deprotection, such as substituted or unsubstituted alkoxycarbonyl, cycloalkoxycarbonyl, substituted or unsubstituted. aralkoxycarbonyl, aralkyl (such as trityl), substituted phenylthio, substituted aralkylidene, substituted alkylidene, substituted cycloalkylidene or the like.

As the above acids, preferably organic or inorganic acids such as formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid and the like are used. it should be noted that the most preferred acid is an acid which can be readily removed from the reaction mixture by conventional means, such as distillation under reduced pressure, such as formic acid, trifluoroacetic acid, etc. The acids are selected according to the nature of the deprotected group. If the elimination reaction is carried out with an acid, this step may be carried out in the presence or absence of a solvent. Suitable solvents in this case are water and conventional organic solvents or mixtures thereof. Hydrolysis using hydrazine is generally used in the elimination of the amino-protecting group of the phthaloyl type. Elimination by reduction is generally used.

for the elimination of a protecting group such as a haloalkoxycarbonyl group (such as a trichloroethoxycarbonyl group, etc.), a substituted or unsubstituted aralkoxycarbonyl group (such as a benzyloxycarbonyl group, e.g., 2-pyridylmethoxycarbonyl group etc. In such cases, a suitable reduction step is alkali metal borohydride reduction (such as sodium borohydride, etc.), metal combination reduction (such as tin, zinc, iron, etc.); or said metal together with a metal salt (such as chromium chloride) , chromium acetate, etc.) and with the aid of an organic and inorganic acid (such as acetic acid, propionic acid, hydrochloric acid, etc.), and finally a catalytic reduction can be used, for this catalytic reduction a commonly used catalyst, such as Raney's nickel, oxide p lath, palladium on charcoal and the like.

Of these protecting groups, the acyl group can be easily eliminated by conventional hydrolysis. In particular, it should be noted that the trifluoroacetyl group can be readily eliminated by treatment with water under approximately neutral conditions, and the alkoxycarbonyl groups and ^{: the} halogen-substituted 8-quinolyloxycarbonyl groups can be eliminated in a conventional manner by treatment with heavy metals such as copper, zinc or the like .

Of these protecting groups, the acyloy group can also be eliminated by treatment with an iminohalogenating agent (such as phosphorous oxychloride, etc.) and an imino etherifying agent such as a lower alkanol (such as methanol, ethanol, etc.) and, if necessary, followed by hydrolysis. .

The reaction temperature is not critical in carrying out the above reaction and may be selected according to the type of amino protecting group used and the elimination method as mentioned above, wherein the reaction is preferably carried out under mild conditions such as cooling or slightly elevated. temperature.

The subject process of the invention also encompasses, in essence, cases where a protected carboxy group is converted to a free carboxy group during the reaction or in a subsequent step thereafter.

P o s t p 3

The compound of formula (Ih) or a salt of the compound of the present invention is prepared by subjecting a compound of formula (Ii) or a salt of the compound by eliminating a carboxy-protecting group reaction.

7 3 7 2

As a suitable salt of a compound of formula (II), said acid addition salt may be, for example, organic acid salts (such as acetate, maleate, tartrate, benzene sulphonate, toluenesulphonate, etc.) or inorganic acid salts (such as hydrochloric, hydrobromic, sulfuric With respect to the actual carrying out of the above-mentioned elimination reaction, it is to be understood that all conventional methods used to eliminate a carboxy protecting group, such as hydrolysis, reduction, etc., may be used.

In the case where the carboxy protecting group is an ester, hydrolysis may be used to eliminate it. The hydrolysis is preferably carried out in the presence of a basic compound or acid. A preferred basic compound may be. the inorganic basic compound and the organic basic compound as previously described in process 2.

Suitable acids include organic acid (such as formic, acetic, propionic, etc.) and inorganic acid (such as hydrochloric, hydrobromic, sulfuric, etc.). The above reduction can be used to eliminate a protecting group, such as 2-iodoethyl ester, 2,2,2-trichloroethyl ester or the like. In the elimination reaction according to the invention, a reduction can be used, which reduction can be carried out as a reduction using a combination of metals (such as zinc, zinc amalgam, etc.) or with chromium compounds (such as chromium chloride, chromium acetate etc.). ) and in the presence of an organic or inorganic acid (such as acetic acid, propionic acid, hydrochloric acid, etc.), and reductions in the presence of a metal catalyst may be used. The above metal catalyst for performing the above reduction may be, for example, a platinum catalyst (such as platinum wire, platinum sponge, platinum, black, colloidal platinum, etc.), a palladium catalyst (such as palladium sponge, palladium black, palladium oxide, palladium on barium sulfate, palladium on barium carbonate / palladium on charcoal, palladium on silica gel, colloidal palladium, etc.), a nickel catalyst (such as reduced nickel, nickel oxide, Raney nickel, Urushibara nickel, etc.) and the like.

The reaction temperature is not a critical criterion for this reaction, and it is therefore appropriate to take this temperature according to the type of carboxy protecting group and the elimination method used.

P o s tup 4

The compound of formula (Ij) or a salt thereof, which are part of the present invention, is prepared by subjecting a compound of formula (Ih) or a salt thereof to an esterification reaction.

a suitable salt of the compound of formula (Ih) includes acid addition salts such as salts of organic acids (such as acetate, maleate, tartrate, benzenesulfonate, toluenesulfonate, etc.) or salts of inorganic acids (such as hydrochloric, hydrobromic, sulfur, phosphorus, etc.), metal salts (such as sodium, potassium, calcium, magnesium, etc.), ammonium salts, organic amine salts (such as triethylamine salt, dicyclohexylamine salt etc.) and the like.

An esterifying agent, which may be a compound of formula XI,

XR ⁵ (XI) v

in which

R ⁵ has the same meaning as described above and

X is a hydroxy group or a reactive derivative thereof.

A suitable example of a reactive hydroxy derivative is, for example, an acid residue as mentioned above.

The above reaction is conveniently carried out in the presence of a solvent such as dimethylformamide, pyridine, tri (dimethylamine). phosphoric acid, dioxane and other solvents that do not adversely affect the reaction.

When a compound of formula (Ih) is used in the free acid form, the reaction is preferably carried out in the presence of a basic compound such as the inorganic basic compound or the organic basic compound mentioned above in process 2.

The reaction temperature is not critical, and the reaction is preferably carried out with cooling, at ambient temperature or with heating.

In carrying out the above reactions and / or following the procedures of the present invention, the aforementioned tautomeric isomers may optionally be converted to other tautomeric isomers, it being noted that all such forms are included in the spirit of the invention.

. In carrying out the above reactions and / or following the process of the invention, the above-mentioned syn isomers or anti-isomers may optionally be converted to other isomers partially or completely, at which point it should again be noted that also all

These forms are within the scope of the present invention.

When the process of the invention yields a compound of formula Ie, which is the subject of the invention, as the free acid at the fourth position, and / or wherein the compound of formula Ie contains a free amino group, it can be converted to a pharmaceutically acceptable salt. an acceptable salt according to the methods commonly used above.

Methods for preparing the starting compounds will be described in more detail below.

The starting compound of formula (IIIa) is prepared by reacting a compound of formula (VII) or a reactive derivative thereof with an amino group or a salt thereof, with an amino-protecting agent, and the starting compound of formula (IIIa) can be prepared by reacting a compound of formula IIIh or a reactive derivative thereof. or a salt of this compound with an amino protecting agent.

Suitable reactive derivatives of compounds of formulas VII and IIIb on the amino, and suitable salts of compounds of formulas VII and IIIb are, for example: Schiff's base of the Imine type or its tautomeric enamine isomeric form prepared by reacting a compound of formula II with a carbonyl compound such as acetoacetic acid or acetoacetic acid. similar compounds, a silyl derivative prepared by reacting a compound of formula VII and IIIb with a silyl compound such as, for example, bis-trimethylsilyl-acetamide or the like, a derivative prepared by reacting a compound of formula VII. or Illb with phosphorus trichloride or phosgene and the like. '

Suitable salts of the compounds of formulas VII and IIIh are, for example, acid addition salts such as salts of organic acids (such as acetate, maleate, tartrate, benzenesulfonate, toluenesulfonate, etc.) or salts of inorganic acids (such as hydrochloric, hydrobromic, sulfuric , phosphate, etc.), metal salts (such as sodium, potassium, calcium, magnesium, etc.), ammonium salts, organic amine salts (such as triethylamine salt, dicyclohexylamine salt, etc.), and the like.

A suitable amino protecting agent is the acylating agent and the like.

A suitable acylating agent is an aliphatic, aromatic and heterocyclic isocyanate and the corresponding isocyanate, and an aliphatic aromatic and heterocyclic carboxylic acid, and the corresponding sulfonic acid, carbonic acid ester and reactive derivatives of the above acids.

Suitable reactive derivatives of the abovementioned acids may be the same compounds as exemplified in explaining the term "reactive derivative at the carboxy group of a compound of formula III". As an example of a protecting group that is introduced into the. The amino groups in the compounds of formulas VII and IIIh together with the above-mentioned amino protecting agent may be mentioned as exemplified in the explanation of the protecting group in relation to the "protected amino group".

The starting compound of formula IIIb is prepared by oxidizing a compound of formula IIIa.

This oxidation reaction is carried out in a conventional manner, which is used to convert a so-called activated methylene group into a carbonyl group. That is, the oxidation can be carried out, for example, using a conventional oxidizing agent such as selenium dioxide, a trivalent manganese compound (such as manganese acetate and potassium permanganate, etc.) or the like. The above oxide. c is usually carried out in the presence of a solvent which does not adversely affect the reaction; such as water, dioxane, tetrahydrofuran and the like.

The reaction temperature is not critical, at which point the reaction is preferably carried out under heating.

The starting compound of formula (IIIc) is prepared by subjecting a compound of formula (IIIb) to an elimination reaction of a carboxy-protecting group. The starting compound of formula IIIe is prepared by subjecting the compound of formula IIIf to a carboxy-protecting group elimination reaction and the starting compound of formula IIIh is prepared by subjecting a compound of formula IIIh to a carboxy-protecting group elimination reaction.

The elimination reaction is carried out in a manner similar to that described for the elimination reaction according to the procedure

3.

The starting compound of formula IIId is prepared by reducing the compound of formula IIIc.

The starting compound of formula (Tile) is prepared by reacting a compound of formula (IIIc) with a compound of formula (IV) or a salt thereof, and a starting compound of formula (IIIf) is prepared by reacting a compound of formula (IIIb) with a compound of formula (IV) or a salt thereof.

The starting compound of formula IIIg is prepared by reacting a compound of formula III with thiourea.

This reaction was carried out in a similar manner to that described for Procedure 1.

198372

The compound of formula (X) is prepared by reacting a compound of formula (II) or a reactive derivative thereof on the amino group or a salt thereof with a compound of formula (IX) or a reactive derivative thereof on the carboxy group.

Suitable reactive derivatives of the compound of formula (IX) on the carboxy group are the following compounds: acid halide, acid anhydride, activated amide, activated ester and the like. Suitable examples include acid chloride, acid azide, mixed acid anhydride with acid such as substituted phosphoric acid (such as dlalkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid etc.), dialkylphosphoric acid, sulfuric acid, thiosulphuric acid. sulfuric, alkylcarbonic, aliphatic carboxylic acids (such as pivalic acid, valeric, isovaleric,

2-ethylbutyric or trichloroacetic acid, etc., or aromatic carboxylic acid (such as benzoic acid, etc.), symmetrical acid anhydride, imidazole-activated,

4-substituted imidazole, dimethylpyrazole, triazole or tetrazole, or an activated ester (such as cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [(CH 3) 2 N ⁺ = CH-] ester, vinyl ester, propargyl ester, p-nitrophenyl ester,

2,4-dinitrophenyl ester, trichlorophenyl ester;

pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenylthioester, p-nitrophenylthioester, p-cresylthioester, carboxymethylthioester, pyranyl ester, pyridyl ester, piperidyl ester,

An 8-quinolylthioester, etc., or an ester with an N-hydroxy compound (such as e.g.

N, N-dimethylhydroxylamine, 1-hydroxy-2- (1H) -pyridone,

N-hydroxy hydroxysuccinimide,

N-hydroxyphthalimide, 1-hydroxy-6-chloro-1H-benzotriazole, etc., and the like. These reactive derivatives may optionally be selected according to the type of compound of formula IX used.

The starting compound of formula (Va) is prepared by reacting a compound of formula (X) with a nitrosating agent.

As an example of a suitable nitrosating agent, nitrous acid, an alkali metal nitrite (such as sodium nitrite, etc.), a lower alkyl nitrite (such as amyldusite, etc.) and the like can be mentioned.

The above reaction is conveniently carried out in the presence of a solvent such as water, acetic acid, benzene, methanol, ethanol or any other solvent that does not adversely affect the reaction.

The reaction temperature is not critical, and the reaction may be carried out under cooling or at ambient temperature.

The starting compound of formula (Vb) is prepared by reacting a compound of formula (Va) with an alkylating agent.

The compounds of formula (Ie) of the present invention and the pharmaceutically acceptable salts thereof exhibit high anti-bacterial activity and inhibit the growth of a large number of microorganisms, including Gram-positive and Gram-negative bacteria. In particular, it should be noted that the syn-isomers of the subject compounds of Formula Ie and the pharmaceutically acceptable salts thereof exhibit generally much higher antihacterial activity than the corresponding anti-isomers of the present compounds and the pharmaceutically acceptable salts thereof. For pharmaceutical use, it should be noted that the compounds of the invention may be used in the form of pharmaceutical preparations containing the compounds as active ingredient in admixture with pharmaceutically acceptable carriers, such as inorganic and organic solid or liquid additives suitable for oral, parenteral or external administration. Said pharmaceutical preparations are intended to be in the form of capsules, tablets, dragees, ointments or suppositories, furthermore suspensions, solutions, emulsions and the like. If necessary, additives, stabilizers, wetting or emulsifying agents, buffers and other commonly used additives can be added to the above compositions.

The dose of the compounds of the invention used may vary depending on the age and condition of the patient, and it has been found that the effective average dose of the compounds of the invention in the treatment of infectious diseases caused by pathogenic bacteria may be about 10, 50, 100, 250, 500. and 1000 milligrams.

In order to illustrate the usefulness of the compounds of the present invention, the antimicrobial activity of the multi-preszeintive compounds of the present invention with respect to

several selected pathogenic bacterial species tested, the results being expressed as minimum inhibitory concentrations.

Testing Method a

The in vitro antibacterial activity was determined by a two-fold dilution method on an agar plate which will be explained below.

The culture urine of the individual test species was selected with a seed needle and grown overnight in trypicase soybean (10 ⁸ viable cells per milliliter) and then the culture was spread on HI-agar (heart infusion agar) in which it was present. The minimum inhibitory concentration (MIC) was expressed as gg / ml after incubation at 37 ° C for 20 hours.

. · /. i · '

2-methyl-7- [2- (2-amino-thiazol-4-yl) glyoxylamido] -3-cephem-4-carboxylic acid, test compound (1),

2.

2-methyl-7- [2-hydroxy-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid, test compound (2), -3.

2-methyl-7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid, syn-isomer, test compound (3);

pivaloyloxymethyl-2-methyl-7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate, syn-isomer, test compound (4).

Organism

Test Compound (1s) (ICs) (g / ml)

Test compound (2 j

Test compound (3j

Test compound (4)

E coli 324 0.78 0.78 0.05 0.2 No. 341 0.2 0.39 0.2 0.78 Kl. aerogenes No. 417 0.39 0.39 0.2 .0,2 No. 418 0,39 - 0.78 0.1 0.78 C. 427 0.1 0.39 0.05 0.2 No. 428 0.78 1.56 0.2 1.56 Ex. Minabilis No. 501 0.78 1.56 0.05 0.2 No. 520 0.39 1.56 0.05 .0,1 ' No. 525 6.25 1.56 0.05 0.2

The invention will be further illustrated by the following examples.

Preparation of starting ivory

Preparation 1 * aj In a mixture of 2,2,2-trichloroethyl-2-methyl-7-amino-3-C3-β-4-carboxylate hydrochloride (0.38 g), trimethylsilylacetamide (1.1 g) and methylene chloride (10 ml) was stirred at room temperature for 30 minutes and the solution was cooled to -15 DEG C. 3-oxo-4-bromobutyryl bromide (1.0 ml) was added dropwise. in carbon tetrachloride (13 mL), while cooling to -15 ° C, and the mixture is stirred for

1.5 hours at the same temperature and then an additional 30 minutes without performing an external cooling. zení. The mixture was then poured into cold water and the organic layer formed was separated. The resulting organic layer was then washed with 2N hydrochloric acid (8 mL X 3) and water (10 mL X 2), then dried using magnesium sulfate and the mixture was filtered. The filtrate was concentrated under reduced pressure. The residue obtained is triturated in diisopropyl ether, separated by filtration, and then dried to give a light brown powder of 2,2,2-trichloroethyl-2-methyl-7- (3-oxo-4-bromobutyramide). -3-cep-4-carboxylate (0.31 g), m.p. 78-83 ° C (dec.).

IR spectrum (nujol):

3320, 1785, 1735, 1675, 1284, 1210 cm ' ¹ '

NMR Spectrum (CDCl3, d)

1.54 (3H, d, J = 7Hz),

65 [1 H, m),

76 (4 / 5H, s), 4.11 (6 / 5H, s),

4.90 (2 H, s),

5.00 (1 H, d, J = 6 Hz),

5.95 (1 H, m),

J

19β372

6.72 (b, d, J = 6.8 Hz),.

7.05 (2 / 5H, d, J = 9 Hz),

7.73 (3/5H, d, J = 9Hz). :

In a similar manner as described above, the following compound was prepared: p-nitrobenzyl 2-methyl-7- (3-oxo-4-bromobutyramide) -3-cephem-4-carboxylate as a powder.

IR spectrum (nujol)

3270, 1780, 1725, 1655, 1625 cm‘l

NMR Spectrum. (de-dimethylsulfoxide, d) ^; ppm 1.79 (3H, d, J = 6.5Hz),

3.67 (2 H, s),

3.7-4.2 (1H, m),

4.43 (2 H, s),

5.13 (1 H, d, J = 4.5 Hz),

5.43 (2 H, s),

5.87 (1H, dd, J = 4.5 and 8 Hz),

6.76 (1H, d, J = 6.5Hz),

7.73 (2H, d, J = 9Hz);

8.26 (2H, d, J = 9Hz),

9.13 (1 H, d, J = 8 Hz).

According to this embodiment, to a solution of 2,2,2-trichloroethyl 2-methyl-7- (3-oxo-4-bromotyramido) -3-cephem-4-carboxylate (2.54 g) in glacial acetic acid (25 mL) ) is added dropwise a solution of sodium nitrite hydrate (0.33 grams) in water (1 ml) over 3 minutes with stirring at a temperature ranging from 10 to 15 ° C, and then the mixture is stirred for 1 hour at at the same temperature. After this work-up, the reaction mixture is poured into cold water (70 ml), the precipitate is collected by filtration and then dried to give a brown powder which is 2,2,2-trichloroethyl 2-methyl-7- (2-hydroxyimino-3). oxo-4-bromobutyramido) -3-cephem-4-carboxylate (a mixture of the syn- and anti-isomer 2.0 g), the melting point of the product thus obtained being from 76 to 80 ° C (with decomposition) ).

IR spectrum (nujol)

1670 - 1710, 1540, 1280, 1215, 715 cm'1 NMR Spectrum (d6-dimethylsulfoxide, d)

1.44 (3H, d, J = 7Hz),

3.2 - 3.8 (2H, band),

3.91 (1 H, m),

4.57 (1 H, s),

5.02 (2 H, s),

5.16 (1H, d, J = 5 Hz),

5.91 (1 H, dd, J = 5 and 9 Hz),

6.74 (1H, d, J 6.5Hz),

9.32 (1H, d, J = 9Hz).

In a similar manner, the following compound can be prepared: p-nitrobenzyl 2-methyl-7- (2-hydroxyimino-3-oxo-4-bromobutyramido) -3-cephem-4-carboxylate (syn-isomer).

IR spectrum (nujol)

3260, 1775, 1725, 1700, 1660, 1630, 1600 cmH NMR spectrum (d 6 -dimethylsulfoxide, d) ppm 1.45 (3H, d, J = 7 Hz),

6-4.2 (1H, m),

4.6 (2H, s),

5.17 (1H, d, J = 5Hz),

5.43 (2 H, s),.

5.98 (1H, dd, J = 5 and 9 Hz),

77 (1H, d, J = 7Hz),

7.73 (2H, d, J = 9Hz);

8.27 (2H, d, J = 9Hz)

9.37 (1 H, d, I = 9 Hz),

13.32 (1 H, s).

C ons 2

According to this embodiment, to the solution of 2,2,2-trichloroethyl 2-methyl-7- (2-hydroxyimino-3-oxo-4-bromobutyramido) -3-cephem 4-carboxylate (a mixture of syn- and anti- isomer (1.2 g) in ethanol (20 ml) was added dropwise a solution of diazomethane (0.1 mol) in diethyl ether, with stirring, while cooling with ice was complete to complete the reaction. The reaction mixture was concentrated under reduced pressure, the residue was triturated in dilsopropyl ether, the solid collected by filtration and then dried to give a brown powder of 2,2,2-trichloroethyl-2-methyl-7- (2). -methoxyimino-3-oxo-4-bromobutyramido) -3-cefenl-4-carboxylate (son of an anti-isomer, 1.1 g), the melting point of the product thus obtained being in the range of 80 to * 83 ° C ( decomposition).

IR spectrum (nujol)

3300, 1785, 1737, 1650-1710, 1535, 1280, 1210, 1160, 1045, 715 cm ^-1 .

NMR Spectrum (d6-dimethylsulfoxide, d)

1.46 (3H, d, J = 7Hz),

4.0 (1 H, m),

4.04 (3 H, s),

4.62 (1 H, s),

5.05 (2 H, s),

5.29 (1H, d, J = 5Hz); 5.95 (1H, m);

6.74 (1 H, m),

9.48 (1H, -d, J = 9Hz).

Preparation 3

a] Formic acid (169.2 ml) was added dropwise to acetic anhydride (384 ml) over a period of 15 to 20 minutes, while cooling below 35 ° C, and the resulting mixture was then stirred for 1 hour at a temperature ranging from 55 to 60 ° C.

196372 25

Ethyl 2- (2-aminothiazol-4-yl) acetate, which can also be expressed as ethyl 2- (2-amino-2,3-dihydrothiazo) -4-, is then added to this mixture. yl) acetate (506 g) over 15 to 20 minutes while cooling with ice and stirring. The mixture was then stirred for 1 hour at room temperature. After the reaction, the solvents were distilled off. To the residue so prepared, diisopropyl ether (2500 ml) was added and then the mixture was stirred for 1 hour at room temperature. The precipitated particles are collected by filtration, washed with diisopropyl ether and then dried to give ethyl 2- (2-formyl-aminothiazol-4-yl) -acetate, which may also be referred to as ethyl 2- (2-formylimino-2). 3-dihydro-thiazol-4-yl) acetate (451 grams), the melting point of the product thus obtained is from 125 to 126 ° C. The filtrate obtained above was concentrated and the residue was washed with diisopropyl ether (500 mL) and then dried to give the title compound (78.5 g).

IR spectrum (nujol)

1737, 1700 cm @ -1

NMR Spectrum (CDCl 3, δ)

1.25 (3H, t, J = 8Hz),

3.7 (2H, s,

Claims (9)

1.47 (3H, d, J = 7 Hz), 1.18 (9H, s). 1.44 g], melting point 196372 The product ranges from 165 to 170 ° C (with decomposition); IR spectrum (nuijol): 3340, 1787, 1757, 1678, 1637, 1834, 1283, H218, 1158, 1132, 1098, 1034, 996 µm. NMR Spectrum (ds-dimethylisulfoxide, δ): 1.42 (3H, 'd, J = 6.8Hz), 1. 2-Methyl-7- [2-methoximino-2- (2-formyl-aminothiazol-4-yl) -acetamido] -3-cephem-4-carboxylic acid, syn-isomer, the structure of which may also be expressed as acid 2 methyl-7- [2-methoxyimino-2 '- (2-formylimino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid syn-isomer, m.p. the compound ranges from 174 to 204 ° C (decomposed), 1.47 (3Ή, d, J = 6 Hz), 1.30 (3H, t, J = 6 Hz), CLAIMS 1. 2-Methyl-7- [2-hydroxy-2-i [2-amino-thiazol-4-yl) -acetamido] -3-cyclohexyl-4-carboxylic acid hydrochloride; this compound can also be expressed as 2-methyl-7- [2-hydroxy-2- (2-methyl) -hydrochloride] hydrochloride ^. (2-imino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid, m.p. &gt; 250 DEG C., 1.43 (3H, d, J = 8 Hz), 1.44 (3H, d, J = 7 Hz), 1.44 (3H, d, J = 8 Hz, 2-C'Hs), The first 2-methyl-7- [2-methoxyimino-2- (2-fluoro-4 ormylaminot ^hiažoi: J yl acetamido] ^{-3-cephem-4-kar'bO'xylo.vá,:} syn-isomer, the the structure may also be expressed as 2-methyl-7- [2-ethoxyimino-2- (2-formylimino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid syn-isomer the melting point of the compound being in the range of 174 to 204 ° C (with decomposition). 1.45 (3H, d, J = 7Hz). · '. -Λ ' 1.68 (2 H, m),. 1.48 (3H, d, J = 6 Hz), 1.43 (1H, d, J = 6 Hz). 3.83 (1 H, m), 1.20, (6H, d, J = BHz) 1.47 (3H, d, J = 6H); 1.30 (3H, t, J = 6 Hz), 1.4 (3H, d, J = 6 Hz) 1.14 (6H, d, J = 7 Hz), 1.28 (bH, t = JHz), I, 47 (3H, d, J = 8Hz), 1. p-nitrobenzyl 2-methyl-7- [2-hydroxyimino-2- (2-aminothiazol-4-yl) acetamide] -3-cephem-4-carboxylate in the form of the syn-isomer, also referred to as p -nitrobenzyl 2-methyl-7- [2-hydroxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylate, syn-isomer, as a powder. IR spectrum (nujol) 3400, 3280, 3200, 1770, 1710, 1700, 1650, 1620 cm ¹ . NMR spectrum (d 6 -dimethylsulf oxide, δ) ppm 1.44 (3H, d, J = 7Hz), 1.38 (3H, t, J = 7Hz), 2. 2-methyl-7- [2-hydroxy-2-i (2-aminothlazol-4-yl) acetamido] -3-cephem-4-carboxylic acid hydrochloride, the structure of which may also be expressed as acid hydrochloride 2 methyl-7- [2-hydroxy-2- (2-imino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid, the melting point of which is greater than 250 ° C, -2,3-di ^; hydrothiazol ^and -4-yl) acetamido] -3 · cephem-4-carboxylate, syn-isomer. IR spectrum (nujol): 3340, 3) 200 (pals), 3150 [band], 1790 band) · 1750—1790, 1680, 1630 cm ” ¹ . Example 5 In this example, to the solution of 2,2,2-trichloroethyl 2-methyl-7- [2-methoxy-amino-2- (12-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate as the syn-isomer , the structure of which may also be expressed as 2,2,2-trichloroethyl-2-methyl-7- [2-methoxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem -4-carboxylate (syn-Isomer, 0.1 g), in tetrahydrofuran (2'ml) and glacial acetic acid (0.25 ml) add zinc powder (0.1 g) while stirring the resulting mixture continuously while keeping the mixture below 25 ° C under an ice bath and then stirring the mixture for 1 hour at ambient temperature. The reaction mixture was then filtered and the insoluble material was washed with a small amount of tetrahydrofuran, then the filtrate and washings were combined. The solvent is distilled off from this mixture and 5% aqueous sodium bicarbonate solution and ethyl acetate are added to the residue, and then monitored until the pH of the aqueous layer is between 7 and 8. The final mixture it is then filtered and the resulting aqueous layer is separated. The pH of the separated aqueous layer was adjusted to 2-3 with 2N hydrochloric acid solution and then slightly concentrated. The defective layer obtained above is subjected to separation in a chromatographic column (which is filled with Dion HP 20 nonionic adsorption resin material, prepared by Mitsubishi Chemical Industries), firstly washing the column with water and then eluting with 201% methanol and then 40% The eluates containing the compound of the present invention are then separated and lyophilized to give a white powder, i.e. 2-methyl-7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acid. Acetamido-3-cephem-4-carboxylic acid In the form of the syn-isomer, which compound can also be expressed as 2-methyl-7- [2-methoxy-xyimi-2- (2-imino-2,3-) - dihydrothiazol-4-yl] acetamido] -3-carboxylic acid syn-isomer, yield 0.015 g, mp 230 DEG -235 DEG C. (dec.). The following compounds can be prepared in a similar manner: 2,2,2-trichloroethyl second '2-methyr-7- [2-methoxyimino ^J 2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-.karboxylát, syn-isomer, which may be also expressed as 2,2,2-trichloroethyl 2-methyl-7- [2-methoxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylate, syn -isomer, the melting point of this compound being in the range of from 128 to 149 ° C (decomposition), 2. 2-Methyl-7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid, the isomer, the structure of which may be: also expressed as 2-methyl-7- [2-methyl-ximino-2- (2-imino-2,3-dihydro-thiazol-4-yl) -acetamido] -3-cephem-4-carboxylic acid, syn the isomer, the melting point of which is greater than 241 ° C. The second acid ^- 2-methyl-7- [2-hydroxyimino-Z- (2-aminothiazol-4-yl j acetamido] -3 • .cefem-4-carboxylic acid, syn isomer, which may also be represented as 2 methyl-7- [2-hydroxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid syn-isomer, 3.6-4 · 1 (3H, s), 3.54-3.94 (1 H, m), 3. 2-methyl-7- [2-hydroxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid, syn-isomer, which may also be expressed as 2-methyl-acid 7- [2-hydroxyimino-2- ^{(2-imirio-2,3-dihydro-4-yl)} acetamido] -3; -cephem-4-carbonyl, syn-isomer, IR spectrum (nujol): 3250, 1765.1625 ^cm-1. ' NMR Spectrum (d-dimethylsulfoxide, < S): ppm 3.83 (1 H, m),. 3.6-4.5 (1Ή, m), 3. 2,2,2-Trichloroethyl 2-methyl-7- [2-hydroxyimino-2- [2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate in the form of the syn-isomer, wherein: this compound can also be expressed as 2,2,2-trichloro-2-methyl-7- (2-hydroxyimino-2- (2-amino-2,3-dihydro-thiazol-4-yl)) acetamido-3-cephem-carboxylate, syn-isomer, and melting point: 175-178X3 (decomp.), 4'-p-nitrobenzyl 2-methyl-7- [2-hydroxy] lmino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate, in the form of the syn isomer, which compound can also be expressed as p-nitrobenzyl 2-methyl-7- [2] Hydroxyimino-2- (2-amino-2,3-dihydrothlazol-4-yl) aceitamido] -3-cephem-4-carboxylate, syn-isomer, as a powder, 5,2-Methyl-7- [2-hydroxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid syn-isomer, which can also be expressed as 2-methyl-7- ^2-L hydro'xyim.i amino-2- (2-imino-2,3-dlhydrot hiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid syn-isomer, 3.84 (3H, s). 3.65-4.08 (1 H, m), 3.94 (3 H, s) ^; 3.70-4.14 (1H, m) 3.84 (3H, s, OCH 3), 3.7-4.0 (1 H, m, 2-H), 3. pivaloyl-oxymethyl-2-methyl ^: 7- [2-methoxyimino-2- (2-aminothiaaol-4-yl) acetamido] -3-cephem-4-carboxylate, syn-isomer, - the structure of which may be expressed also as pivaloyloxymethyl-2-methyl-7- [2-methoxyimino-2- ('2-imino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylate, syn-isomer, the melting point of this compound ranges from 165 to 170 ° 170 (with decomposition). 198372 Example 3 To a solution of sodium acetate (11.6 g) in water (43 mL) was added 2-methyl 1-7- (2-methoxyimino-2- (2-trifluoroacetylaminothiazol-4-yl) acetamido] -3 -cephem-4-carboxylic acid in the form of the syn-isomer, which can also be expressed as 2-methyl-7- [2-methoxyimino-2- (2-trifluoroacetylimino-2,3-dihydrothiazol-4-yl)] 3-acetyl-4-carboxylic acid (syn-isomer, 2.1 g], with stirring, and the pH of the mixture is then adjusted to pH 6 with 5% aqueous sodium bicarbonate. After stirring overnight at room temperature, the reaction mixture was adjusted to pH 2.8-3 with 10% hydrochloric acid solution and then cooled, and the precipitated solid was collected by filtration and dried. to give 2-methyl-7- [2-methoxyimino-2- ^(2-aminoth, iazoh4-yl) acetamido] -3-cephem-4-carboxylic acid syn isomer, which may b t also expressed as 2-methyl-7- [2-methoxyimino-2- (2-imino-2,3-dlhydrothiazol-4-yl) acetamido] -3-cephem-4-yl -carbonyl, syn-isomer (1.1 g), the melting point of the compound thus obtained being higher than 24 ° C. The same compound, but in an amount of 0.25 g, can be obtained further from the above. filtrate in the usual manner. IR spectrum (nujol): 3470, 3320, 3190, 2380, 1783, 1690, 1606, 16.62, 1530 cm ¹ . NMR spectrum (d 6 -dimethylsulfoxide, δ): 3.92 (1H, mj, -). 3.82 (3H, s, J); 3.6-4.4 (3H, m), 3.85 (1 H, m), 3.6-4.5 (1 H, m),. ··. ·. 3.8 (1 H, m), 3.68-4.2 (1H, m), 4.18 (2H, q, J = 7Hz), 3. 2-Methyl-7- [2-ethoxyimino-2- (2-formyl-aminothiazol-4-yl) -acetamido] -3-cephem-4-carboxylic acid, syn-isomer, which compound may also be represented as 2-methyl-7- [2-ethoxyimino-2- (2-formylimino-2,3-dihydrobenzol-4-yl) acetamido] -3-cephem-4-carbo-. xyl, syn-isomer, IR spectrum (nujol). 3350, 3240, 3190, 1775, 1700, 1650, 1620 cm ^{@ -1} . NMR Spectrum (d 6 -dimethylsulfoxide, δ) 3.6-4.2 (1 H, m), 3.94 (1H, mj, 3.98 (1 H, s), 3.91 (3 H, s), 3.83 (3H, sj, 3.7 (2H, s, 4. 2-Methyl-7- [2-ethoxyimino-2- (2-formylrainothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid syn-isomer, which compound can also be expressed as an acid 2-methyl-7- [2-ethoxyimino-2- (2-formyl-amino-2,3-dihydro-thiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid syn-isomer, IR spectrum (nujol): 3350, 3240, 3190 ', 1775, 1700, 1650, 1620 cm ^-1 , 4.27 (1 H, m), 4.25 (2H, q, J = 6 Hz), -4-yl) acetamido] -3-cephem-4-carboxylic acid in the form of the syn-isomer, which may also be referred to as 2-methyl-7- [2-methoxyimino-2- (2-imino) -acetic acid hydrochloride. 2,3-dihydrothiazol-4-yl acetamido] -3-cephem-4-carboxylic acid (syn-isomer, 7.7 g) in water (77 ml) was added saturated aqueous sodium bicarbonate solution (44 ml), the pH of the solution was adjusted to 3 with 1N hydrochloric acid, and the solution was allowed to stand for 1 hour in a cool place. the crystals which are collected by filtration are further washed with water and then dried to give 2-methyl-7- [2-methoxyimino-2- (2-aminoitlhlazol-4-yl) acetamido] -3-cephem-4- carboxylic acids in the form of the syn-isomer, which compound can also be expressed as 2-methyl-7- [2-methoxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) acetamido] -3 -cef em-4- carbonyl, syn-isomer, yield 8.67 g, m.p. 196-250 ° C (dec.). 9 9 37 IR spectrum (nujol): m.p. 3470, 3310, 3280, 1790, 1655, 1620, 1530, 1295, 105.5. . NMR Spectrum (d-dimethylsulfoxide): -4-yl-acetamido] -3-cephem-4-carboxylate, syn-isomer, IR spectrum (nujol) 3340, 3200 (band), 3150 (band), 1790 .. (band), 1750—1790, 1680; 1630 cm ¹ .. 12th acid @ ^2: methyl-7- (2-butoxyimlno-2- (2-aminothiazol-4-yl Jacetamido] -3-cephem-4-carboxylic acid, syn isomer, which may also be represented as 2-methyl-7 - 2-butoxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid syn-isomer, Ϊ3. 2-methyl-7- [2-isobutoxy] acid. 2- (2-Aminothiazol-4-yl) acetamido-3-cephem-4-carboxylic acid syn isomer, which compound can also be expressed as 2-methyl acid. 7- [2-Isobutoxyimino-2- (2-imino-2,3-dihydro-4-thiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid syn-isomer. Example 2 In this example, to the mixture consisting of 24-chloromethyl-2-methyl-7-12-methoxyimino-3-oxo-4-bromo-3-oxo-3-cephem-4-carboxylate as a syn-isomer mixture a) anti-isomer (0.94 g) and ethanol (10 mL) were added thiourea (0.12 g) and the mixture was then stirred for 40 minutes at room temperature. The reaction mixture is then concentrated under reduced pressure and. The resulting residue was shaken with ethyl acetate and water. The ethyl acetate layer obtained is separated and the remaining aqueous layer is neutralized with sodium bicarbonate and then subjected to extraction with ethyl acetate. '; The ethyl acetate layers obtained above were combined / washed with water, dried over magnesium sulfate, treated with activated charcoal, and then the final solution was concentrated under reduced pressure. The resulting residue was triturated in diethyl ether, the solid was collected by filtration and then dried to give 2,2,2-trichloroethyl-2-methyl-7- [2-methoxyimino-2- (2-amino-thiazol-4-one). -yl) acetamido] -3-cephem-4-carboxylate in the form of the sine isomer, which compound can also be expressed as 2,2,2-trichtorethyl-2-methyl-7- [2-methoxyimino] -2- (2-Imino-2,3-dihydro-thiazol-4-yl) acetamido] -3-cephem-4-carboxylate (syn-isomer, 0.6 g) This compound is subjected to a further procedure. The residue was chromatographed on silica gel using a solvent mixture consisting of benzene, ethyl ester, acetic acid and acetic acid (10: 10: 1) as the eluent to give the eluates containing the title compound. water, dried over magnesium sulphate and then concentrated under reduced pressure. The resulting residue is triturated in diethyl ether, the solid phase separated. The mixture is filtered and then dried to give the light brown powder of the title compound in pure form as an isomer. The yield is 0.16 g, the melting point of the product thus obtained is in the range of 128 to 149 ° C (decomposition). IR spectrum (nujol): 3100-300, 1785, 1735 // 1675, 1620, 1530, 1280, 1218, 710 cm. ¹ . · NMR spectrum (ds-dimethylsulfoxide, d '): 4.02 (2H, t, J = 6 Hz), 4.27 (1 H, m), 4.25 (2H, q, J = 6 Hz), 4.35 (1 H, m), -4-yl) acetamido] 3-cephem-4-carboxy, syn-isomer, IR spectrum (nujol) 3480, 3300, 3180, 1780, 1740, 1700, 1660 cm ^-1 NMR Spectrum (ds-dimethylsulfoxide, d) 4. 2-methyl-7- [2-isopropoxyimino-2- (2-formyl-aminothiazol-4-yl) -acetamido] -3-cephem-4-carboxylic acid, syn-isomer, which may also be expressed as 2- methyl 7- [2-isopropoxyimino-2- (2-formylimino-2,3-dihydrothiazole) 196372 4.38 (2H, q, J = 7Hz) 4.03 (3 H, s), 4.18 (2H, q, J = 8Hz); 5.78—5.96 (3Ή, m), 5.18 (1 H, d, J = 6 Hz), 5. 2-Methyl-7- [2-isopropoxyimino-2- (2-formyl-aminothiazol-4-yl) -acetamido] -3-cephem-4-carboxylic acid syn-isomer, which compound may be expressed also as 2-methyl-7- [2-isopropoxyimino-2-i (2-formylimino-2,3-dihydric acid) R6372 41. . • rothiazol-1-ylacetamido] -3-cef-em- +; . -carboxylic, syn-isomer,. IR spectrum (nujol): -; 3480, 3.300, 3180, 1780, 1740, 1700, 1060; Tin ^-1 / '. . ./· '' · '. ··''' 6. hydrochloride. acid. 2-methyl-7- [2'-etíwxyiininó-Si-FJI ajninotUiázol-yl ·) · · ^1st acetamido] -3-cephem-4-carbonyl; isomer, wherein the compound may also be expressed as 2-Meithyl-7- [2-ethyl-amino] - (2-iroino-2,3-dihydro-thiazol-4-yl) -acetamido] -3- 4-carboxy-4-carbonyl, syn-isomer, IR spectrum (, Nujol): • 3350, 1790, 1730, 1670, 1630 ^cm-1 5.82 (1H, dd, J = 6 and 8Hz), 5.23 (1 H, d, J = 6 Hz), 5.07 · (1H, d, d, J = 5 and 9.Hz), 5.12 (1H, d, J = 5'Hz), 5.92 (1H, d, d, J = 5 and 8'H); 5.17 (1H, d, J = 5 Hz), 5.84 (1 H, d, J = 5 Hz), 5.10 (1H, d, J = 5'Z), 5.84 (1 H, d, J = 5 Hz), 5.10 (1 H, d, J = 5 Hz), 5.8Θ (1H, dd, J = 6 and 8Hz, 7-H), 5.12 '(1H, d, J = 6Hz, 6-H), 5.20 (1H, d, J-5Hz); 5.97 (1H, dd, J-5 and 9Hz). 5,05. (2H, s). 5.93 (1H, d, d, J = 5.8Hz), 5.15 (lH, d, J = 5) 5.96 (1Ή, d, d, J = 5.9Hz), 5.14 (1 H, d, J = 5 Hz), 5.87 (1H, d, d, J = 5 and 9Hz), 5.12 (1 H, d, J = 5 Hz), 5.92 (1H, d, d, J = 5 and 8Hz), 5.17 (2H, d, J = 6H2), 5. 2-methyl-7- [2-ethoxyimino-2- (2-amiriothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid hydrochloride, syn-isomer, which may also be expressed as hydrochloride 2-methyl-7- ['2-ethoxyimino-2- (2-amino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid syn-isomer, IR spectrum (nujol) 3350 ,. 1790, 1730, 1670, 1630 cm ¹ NMR Spectrum (d-dimethylsulfoxide, d) 5.87 (1H, d, d, J = 5 and 8Hz), 5.1 (1H, d, J = 5 Hz), 5.94 (1H, d, d, J-5 and 8Hz '), 5.15 (1H, d, J = 5Hz), 5.97 (1H, dd, J = 4.5 and 9Hz), 5.43 (2 H, s), 5.25 (1H, d, J = 4.5Hz), 5.94 (1H, dd, J = 5 and 9Hz) 5.20 (1H, d, J = 5 Hz), 5.06 (2H, s); 5.91 (2H, sj band, 5.07 (1 H, s), 6.76-6.88 (1H, ^s); 6.70 (1H, d, J = 6Hz); 6.64 (1 H, s), 9.44 (1H, d, J = 8Hz), 6.40 (1Ή, d, j = 6.8Hz), 6.72 (1 H, s), 6.55. JIH, d, J-6Hz) 6.97 (1H, s), 9.82 (1 H, d, J = 8. Hz), 6.60 (1H, d, J = 6Hz); 6th acid ¹ 2-Methyl-7- [2-ethoxyimlno-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid in form of its hydrochloride, syn-isomer, this compound can be also expressed as 2-methyl-7- [2-ethoxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) acetamido] -3-methyl-4-carboxylic acid hydrochloride, syn- isomer, IR spectrum (nujol): 3350, 1790, 1730, 1870, 1630 cm @ -1 NMR spectrum (de-dimethylsulfoxide, <S): 6.54 (1H, d, J = 0 < Hz),. 6.72 (1 H, s). In a similar manner, they can be prepared as follows: compounds: 6.94 (1H, s). To the suspension of 2-methyl-7- [2-methoxy-amino-2- {2-aminothiazole hydrochloride · 6.59 (1H, d, J = 6Hz), 6.77 (TH, s, 5-H on thiazole ring), 9.6-2 (1H, d, J = 8Hz, 7-CONH). Example 4 (According to this example, a suspension of 2-methyl-7- [2-methoxyimino-2- (2-formylthiazol-4-yl) acetamido] -3-methyl-4-carboxylic acid in the the form of the sine-isomer, which can be expressed as 2-methyl 1-7- [2-methoxyimino'-2- (2-formylimino'-2,3-dlhydrothlazol-4-yl) acetamido] -cephem-4- carboxylic acid (syn-isomer, 9.0 g) in methanol (90 mL) was added concentrated hydrochloric acid (2.12 mL) with stirring at room temperature, and the mixture was then stirred at the same temperature for 7 hours. the reaction mixture was then added gradually changing ether until crystals begin to form. the mixture was allowed to stand for 30 minutes and the resulting crystals were collected by ^filtration,! then washed with diethyl ether and finally dried, white přičemž'vzniknou kryfetalký acid hydrochloride 2-methyl-7 - [- 2-methoxyimido-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid, in the form of the syn-isomer, this compound can also be expressed as 2-methyl-7- [2-methoxyimi-2- (2-imino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid hydrochloride, syn-isomer, 7.9 g. The residual filtrate was concentrated to half volume. To this ^one the concentrated filtrate was then gradually added diethyl ether until the solution starts to separate from the first crystals, and the mixture was allowed to stand for 1 hour. The precipitated crystals are then collected by filtration, then washed with diethyl ether and finally dried to give the same compound as above but in a yield of 0.5 g. IR spectrum (nujol): 3300, 3295, 1780, 1720, 166¾. 1630, 1300 cm ^-1 . Nuclear Magnetic Resonance Spectrum (ds-dimethylalfuxide): 6.57 (1H, d, J = 7Hz, 3-H), 6.77 (1H, d, J-6Hz); 6.73. (1 H, s), 6.57 (1H, d, J = 6), 6.6 (1H, d, J = 6Hz); 6.72 (1H, s), 6.55 (1 H, d, J = 6 Hz), 6. 2-methyl-7- [2-isopropoxyimino-2- (2-aminothiazol-4-yl lacetamido) -3-cephem-4-carboxylic acid syn-isomer, which compound may also be expressed as acid 2-methyl-7- [2-isopropoxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) acetamido] -3-methyl-4-carboxylic acid syn-isomer), IR spectrum (nujol) 3350, 1780, 1670, 1,600 cm ¹ NMR Spectrum (d-dimethylsulfoxide, d) 6.97 (1H, s), 9.82 (1H, d, J = 8Hz). ' 6.60 (1H, d, 16Hz),. 6.5 (III, d, J = 6 Hz) 6.58 (7H, d, J = 6 Hz); 7.4O (1H, s), 6.76 (1 H, d, J = 7 Hz), 6.73 (1 H, s), 6.64 (1 H, s), 6.85 (1 H, s), 6.72 (1H, s). b) In this embodiment, ethanol (10 ml) is added to a suspension consisting of ethyl 2-methoxyimino-2- (2-aminothiazol-4-yl) acetate (syn-isomer j; which can also be expressed as ethyl-2). -methoxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) acetate (syn-isomer, 2.2 g) in 1 N aqueous sodium hydroxide solution (12 mL) and the resulting mixture was stirred for 15 hours The reaction mixture is then adjusted to pH 7.0 with 10% hydrochloric acid solution and then ethanol is distilled off under reduced pressure to give an aqueous solution, which is washed with ethyl acetate, the pH of the solution. The solution was adjusted to 2.8 with a 10% hydrochloric acid solution and stirred while cooling with ice until crystals began to form. colorless needles are formed, which is the end product of 2-meth oixyiroino-2- (2-aminothiazol-4-yl) acetic acid (syn-isomer), which may also be expressed as 2-methoxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) acetic (syn-isomer, 1.1 g). IR spectrum, (nujol) 3150, 1670, 1610, 1585 cm ¹ NMR Spectrum (d-dimethylsulfoxide, δ) 6.9 (1H, s); 7. 2-Methyl-1- [2- (2-isoxyphoxyimino-2- (2-aminophthiazol-4-yl) acetamido] -3- [3- (iso-propyl) amino] -3-methyl-4-carboxylic acid -carboxylic, syn-isomer,. ..whereas . this compound can also be expressed as 2-methyl-7- [2-iso-proipoxyimino-2- (2-imino-2,3-dihydro-thiazole-1 + 1) acetamido] -3-cephem-4-carbonyl, syn-isomer, IR (Nujol): · '· .3350, 1780, 1670, 1660 cm ^1. 7.23 (2H, band), 9.49 (1Ή, d, J = 9Hz) 7. 2-Methyl-7- [2-isopropyloxyimino-2- (2-aminothiazol-1-yl-1-acetamido) -3-cephem-4-carboxylic acid, syn-isomer, which compound may be also expressed as 2-methyl-7- [2-isopropoxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid, syn- isomer, IR spectrum (nujol.): 3350, 1780, 167.0, 1600 cm ¹ . NMR Spectrum (d-dimethylsulfoxide, d): I, 20 (6H, d, J = ZHz), II, 43 (1 H, d, J = 6 Hz), 7.10 (2H, sj band, 9.65 (1H, d, J = 9 Hz). • In a similar way, the following compounds are prepared with mitha: 7.40 (1 H, S), 7.42 (1H, s). 7. 2-Methyl-7- [2-propoxyimino-2- (2-fluorinylaminothiazol-4-yl) acet32-amido] -3-cephem-4-carboxylic acid syn-isomer, which compound may also be expressed as 2-methyl-7- [2-propoxyimino-2- (2-formylimino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid, syn-isomer, IR spectrum (nujol) 3450, 3300, .3050, 1780, 1730, 1690, 1660 cm ^-1 NMR spectrum (d-dimethylsulfoxide, d) 0.96 (3H, t, J = 6Hz) 7.23 (2H, band), 9. 49 (1H, d, J = 9 Hz). 7.35 (1H, d); 7.74 (2H, d, J = 9 Hz), 7.08 (2H, s-band), 9.47 (1 H, d, J = 9 Hz), H, 28 (1H, s). In a similar manner as described above, the following compounds were prepared: 7.62 (1 H, s), 7.68 (1 H, s). 198372 2β In a similar manner, the following compound can be obtained: i) 2-methoxyimino-2- (2-formylathinothiazol-4-yl) acetic acid, syn-isomer, which can also be expressed as 2-methoxyimino-2- (2-formylimino-2,3-dihydrothiazole-4) (yl) acetic acid, syi-isomer; mp 152 ° C (dec.). IR spectrum (nujol) 3200, 2100—2800, 1950, 1600 cifl-1 NMR Spectrum (d6-dimethylsulfoxide, δ) 7.20 (2H, s-band). Preparation 6 According to this embodiment, pyridine (5 mL) is added to a suspension consisting of 2-methoxyimino-2- (2-aminothiazol-4-yl) acetic acid (syn-isomer j, which can also be expressed otherwise as 2-methoxyimino- 2- (2-Imino-2,3-dihydro-thiazol-4-yl) -acetic acid (syn-isomer, 2.0 g) in 20 ml of ethyl acetate. (2,2,2-trifluoroacetate) anhydride (2.5 g) in 3 ml of ethyl acetate with stirring at a temperature ranging from 5 to 7 ° C and the resulting mixture is then stirred for 30 minutes at a temperature of Water (30 ml) was added to the reaction mixture, and the resulting ethyl acetate layer was separated, the aqueous layer was extracted with ethyl acetate, and the two ethyl acetate layers were combined, washed with water. and a saturated aqueous solution of sodium chloride and finally dried over magnesium sulfate the solid is distilled off under reduced pressure to give the final product 2-methoxyimino-2- [2- (2,2,2-trifluoroacetylamino-1 H -thiazol-4-yl) acetic acid, which can also be expressed as 2-methoxyimino- 2- [2- (2,2,2-trifluoroacetylimino) -2,3-dihydrothiazol-4-yl] acetic acid (syn-Isomer, 0.72 g); IR spectrum (nujol) 1725, 1590 cm ^-1 NMR Spectrum (d 6-dimethylsulfoxide, δ) 7.15 (1 H, s), 8. 2-Methyl-7- [2'-propoxyimino, -2- (2-formyl-aminothlazol-4-yl-acetamido); 3-isepe, m-4-carboxylic acid, syn-isomer wherein the compound may also be expressed as 2-methyl-7- [2-propoxylmino-2- (2-bromylimino-2,3-dihydro-thiazol-4-yl) acetamido] - 3-cef em-4-carboxylic acid, isomer, IR spectrum (nujol): • 3450, 3300, 3050, 178.0, 1730, 1690, - 1660 cm ^-1 ,. ·, ··. · 9i acid. 2-methyl-7- [2-propoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-fluoro-4-carboxy] syn-isomer, which compound can also be expressed as 2-methyl acid -7- [2-propoxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid syn-isomer, IR spectrum (nujol): 3330, 3080, 1780, 1670 cm ¹ ,, • the tenth 2-methyl-7- ^[2-hexynyl yIoxyimino-2- (2-aminothiazol-4-y l) acetamido] -3-cephem-4-ka.rhoxylová, syn-isomer, <. which can also be expressed as 2-methyl-7- [2-oxoxyloxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid , syn-isomer, IR spectrum (nujol): 3300, 3200, 1780, 1670, 1630 cm ' ¹ , 11. 2-methyl-7- [2-hexyloxy] -4-imino-2- (2H-methylaminoiminothiazol-4-yl) acetic acid; .; · _· Amide] -'3-cefe.m árbóxylo.vá-4 +, -; synomeromer, which compound can also be expressed as 2-methyl-7-methyl-2- [2- (2-methyl-methyl) -7- (2 H) -pyridine] -2- methyl- [2- (2-methyl-methyl) -7- (2 H) -pyridine] -1- ^J hexyloxylamino-2- (2-formylimino-2,3-). - dihydrolizol-4-yl Jacetamido] -3-cephem-; -4-carboxylic acids, syn-isomer,. IR (nujol): m.p. , 3270, 3180, 1790, 1700, 1055 cm ¹ . Example 6 ..... '., <+ In this example, to the suspension of 2-methyl-7- [2-methoxyimido-2- (2-aminothiazol-4-yl) acetamido] -3-ceifem-4-carboxylic acid as the syn-isomer wherein the compound may also be expressed as 2-methyl-7- [2-methoxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4- carboxylic acid (syn-isomer, 4.8 g); in water (48 ml) was added dropwise a 1N solution of sodium hydroxide in water in an amount such that the pH of the mixture was not greater than 7. The mixture was then filtered and lyophilized to give 2-methyl-7- [2]. sodium methoxy-2 '- (2,2'-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate in the form of the syn-*-isomer, the structure of which may also be expressed as 2-methyl Sodium 7- [2-methoxy-amino-2- (2-amino-2,3-dihydrothiazol-4-yl) -acetamido] -3-cephem-4-carboxylate (syn-isomer, 4.8 g), at a temperature of this compound The compound thus obtained is then suspended in dry dimethylformamide (20 ml) and iodomethyl pivalate (2.30 g) is then added under vigorous stirring, and the resulting suspension is stirred at room temperature for 2 hours. Cooling to the temperature · moving. in the range of 3 to 5 ° C, whereupon the mixture is stirred for 20 minutes at the same temperature. Then; The mixture thus obtained is poured into a mixture of ethyl acetate. (6.0 mL) and ice water (10 mL), and shake vigorously; The ethyl acetate layer formed, which was separated, washed with a saturated aqueous solution of sodium bicarbonate, then with water, and again with a saturated aqueous solution of sodium bicarbonate. Next, the ethyl acetate layer is dried over magnesium sulfate and then the ethyl acetate is distilled off from the solution under reduced pressure. The residual oil is triturated in diethyl ether (25 ml), the solid is collected by filtration and then dried to give the final product, i.e. pivaloyloxymethyl-2-methyl-7R- [2-methoxyethoxy-2- ( 2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate in the form of the syn-isomer, which compound may also be expressed as pivaloyloxymethyl-2-methyl-7- [2-methoxyimino, -2 - (2-imino-2,3-dihydrothiazol-4-yl) aicetamido) -3-cephem-4-carboxylate (syn-isomer, 8. 2-methyl-7- [2-propoxyimino-2- (2-aminothiazol-4-yl) acetamido] -2-cephem-4-carboxylic acid syn-isomer, which compound can also be expressed as acid 2 -me.thyl-7- [2-propoxyimiino ^J 2- ^(2-imino, amino-2,3-dihydro-4-yl jacetamido] -3-cephem-4-carboxylic acid, syn isomer, 9. 2-Methyl-7- [2-butoxy-amino] -2- (2-amino-thiazol-4-yl) -acetamido] -3-methyl-4-carboxylic acid, syn-isomer, which may also be expressed as acid 2-methyl-7- [2-butoxyimiino-2- (2-imino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid syn-isomer, 10. 2-Methyl-7- [2-isobutoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid, syn-isomer, which compound may be also expressed as 2-methyl-7- [2-isobutexylimino-2- (2-imino-2,3-dihydrothiothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid syn-isomer; . ·. · ' 11. 2-Methyl-7- [2-hexyloxyimino-2- (2-amino-thiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid, syn-isomer, which compound may also be represented as 2-methyl-7- [2-hexyloxyimino-2- (2-im ⁱ i ^l amino-2,3-dihydro-4-yl J acetamido] -3-cephem-4-carboxylic acid, syn isomer . IR spectrum (nujol):. 3300, 3200, 1780, 1670, 1630 cm ^- /. 12. Hexanoyloxymethyl 2-methyl-7- [2-hexyloxyimino-2- (2-aminothiazol-4'-yl)] - 'Cetamido] -3-eephem-4-carboxylate, the syn isomer, which compound may also be expressed as hexanoyloxymethyl 2-methyl-7- [2-hexyloxyxyl] -2- (2-amino) - 8.54 (1H, s); 9.62 (1H, d, J = 8Hz), 12.7 (1 H, s). . 11. hexanoyloxymethyl 2-methyl 1-7- (2H-hexyloxyimino-2- (2-amino-thiazol-4-yl) acetamido] -3-cephem-4-carboxylate, a synomer, which can also be expressed as hexanoyl-oxymethyl-2- methyl-7- [2-hexyloxyimino-2- (2-imino-2,3-dihydrothiazole-2-yl) ... 8.56 (1H, s); 9.70 (1Ή, d, J = 9 '); 8) 2-methyl-7- (2-propoxyimino-2-) acid. [aminothlazol-4-yl] acetamido] -3-cephem-4-carboxylic acid syn-isomer, which compound may also be expressed as 2-methyl-7- [2-propoxyimino-2- (2-imino-2) -acid (3-dihydrothiazol-4-yl) -acetamido] -3-cephem-4-carboxylate, sisrisomer,. IR spectrum (nujol) ' 3300, 3080; 1780, 1670 cm ” ¹ / '''' 9. 2-Methyl-7- [2-hexyloxy] amino no-2- (2-aminothiazol-4-yl) acetamido] -; -3-cephem-4-carboxy, syn-isomer; the compound may also be expressed as 2-methyl-7- [2-hexyloxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid syn-isomer , IR spectrum (nujol) 3300, 3200, 1780, 1670, 1630 cm ' ¹ 10. 2-methyl-7- [2-hexyloxyimino-2- (2-formylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid syn-isomer, which compound may also be expressed as 2-methyl-7- [2-hexyloxyimino-2- (2-formylimino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid syn-isomer, IR spectrum (nujol) 3270, 3180, 1790, 1700, 1655 cm ^-1 NMR spectrum (d 6 -dimethylsulfoxide, d). 0.6-2.1 (14H, m), 8.45 (1Ή, s), 9.55 (1H, d, J = 8Hz). 8.52 (1H, s), 9.65 (1H, d, J = 8Hz); II, 64 (1H, band). 8.29 (2H, d, J = 9 Hz), 9.59 (1H, d, J = 9 Hz). 8.60 (1H, s). Example 1 According to this example, to the solution of 2,2,2-trichloroethyl 2-methyl-7- (2-hydroxyimino-3-oxo-4-bromobutyramido) -3-cephem-4-carboxylate as a mixture of the son of anti-isomers (0 51 g) in ethanol (10 ml) was added thiourea (0.068 g) and the mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure. Ethyl acetate and water were added to the residue with stirring, and then the ethyl acetate layer was separated. The pH of the remaining aqueous layer was adjusted to pH 7 and subjected to extraction with ethyl acetate. The ethyl acetate layer and extract were combined, washed with water, dried over magnesium sulfate, and then concentrated. The resulting residue is triturated in diethyl ether and the solid is collected by filtration. The solid is dried to give pale brown powder particles of the title compound, i.e. 2,2,2-trichloroethyl-2-methyl-7- [2-hydroxyimirio- 2- (2-aminothiazol-4-yl) acetamido-3-cephem-4-carboxylate, in the form of the syn-isomer, which compound may also be represented as 2,2,2-trichloroethyl-2-methyl-7 - [2-hydroxyimino-2- (2-imino-2,3-dihydrothlazol-4-yl) acetamido] -3-cephem-4-carboxylate (syn-isomer), m.p. mp 178 ° C (dec.). IR spectrum (nujol) 3300, 1785, 1740, 1710—1670, 1540, 1280, 1215, 1045, 715 cm ¹ NMR Spectrum- (d6-Dimethylsulfoxide, <5) 1.45 (3H, d, f = 7Hz) 8.5 (1 H, s). Preparation 5 aj In this embodiment, a solution consisting of ethyl 2-methoxyimino-4-bromoacetoacetate (a mixture of the syn- and anti-isomer, 17.4 g) and thiourea (5.4 g) in ethanol (100 ml) ref. vacuum for 4 hours. The reaction mixture is then allowed to stand in a cooling device where crystals precipitate. The formed crystals were then collected by filtration, washed with ethanol and dried to give ethyl 2-methoxyimino-2- (2-aminothiazol-4-yl) acetate hydrobromide (anti-isomer <9.5 g). The filtrate and washings were combined and concentrated. Water (100 mL) was added and the mixture was washed with ether, basified with 28% aqueous ammonia solution, then extracted with ethyl acetate, and the extract was washed with water and then with a saturated aqueous solution. The solvent was distilled off under reduced pressure to give a crystalline mass which is ethyl 2-methoxyimino-2- (2-aminothiazol-4-yl) acetate as the syn-isomer, which it can also be expressed as ethyl 2-methoxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) acetate (syn-isomer, 5.2 g). IR spectrum (nujol) 3400, 3300, 3150, 1725, 1630, 1559 cm ^-1 NMR spectrum (CDCl 3, Sj) 8.6 (1 H, s). Preparation 4 According to this embodiment, a suspension consisting of 2- (2-formylaminothiazol-4-yl) glyoxylic acid, which can also be expressed as 2- (2-formylimino-2,3-dihydrothiazol-4-yl) glyoxylic acid (20 g) in water (400 ml) sodium bicarbonate (8.4 g) is added, while cooling with ice and stirring, and the resulting mixture is then stirred for 10 minutes at the same temperature and finally ethanol (10 ml) is added. ). Sodium borohydride (1.52 g) was added over 10 minutes at the same temperature while stirring, and the mixture was further stirred for 1 hour and 50 minutes at the same temperature. After the reaction was completed, the reaction mixture was filtered. The filtrate obtained is adjusted to pH 4.0 with 10% hydrochloric acid and then concentrated under reduced pressure until the volume of the mixture is 100 ml. The concentrated filtrate was adjusted to pH 1 with hydrochloric acid, then crystallization was induced by scratching. The concentrated filtrate was stirred for 1 hour at room temperature and then allowed to stand overnight in a refrigerator. The resulting precipitate is collected by filtration, then washed twice with ice-water, and the precipitate is suction dried to give 2-hydroxy-2- (2-formylaminothiazol-4-yl) acetic acid, which can also be expressed as 2-hydroxy- 2- (2-formylimino-2,3-dihydrothiazol-4-yl) acetic acid, yield 14.8 g, the temperature 198372 melting at 188-189 ° C (dec.). IR spectrum (nujol) 1730, 1635 cm ¹ NMR Spectrum (NaDCCP, δ) 8.27 (1H, sj, ' 8.7 (1 H, s). b) According to this embodiment, the mixture consisting of manganese acetate tetrahydrate (120 g), acetic acid (1000 ml) and acetic anhydride (100 ml) is stirred for 20 minutes in an oil bath heated to a temperature in the from 130 to 135 ° C, and then potassium permanganate (20 g) is added to the mixture over a period of 5 minutes at a temperature ranging from 105 to -10 ° C with stirring, followed by stirring it is further stirred for 30 minutes at temperatures ranging from 130 to 135 ° C. The mixture is then cooled to ambient temperature and ethyl 2- (2-formylaminothiazol-4-yl) acetate, which can also be expressed as ethyl 2- (2-formyllmino-2,3-dihydrothiazole-4-), is added to the mixture. yl) acetate (53.5 g), and then the mixture is stirred for 15 hours at a temperature ranging from 38 to 40 ° C, while air is supplied at a rate of 6000 ml per minute while stirring. After reaction, the precipitate formed was collected by filtration. Then, the separated precipitate is washed with water and acetic acid, washing first with acid, and the product is then dried to give ethyl 2- (2-formyl-aminothlazol-4-yl) glyoxylate, which can also be expressed as ethyl 2- (2-formylimide ^, n-2,3-dihydrothiazol-4-yl) glyoxylate (41.5 g), m.p. 232 DEG-233 DEG C. (with decomposition). c) According to this embodiment, to a suspension consisting of ethyl 2- (2-formylimino-2,3-dihydrothiazol-4-yl) glyoxylate, which may also be expressed as ethyl 2- (2-formylimino-2,3- dihydrothiazol-4-yl] glyoxylate (281 grams) in water (10 mL) was added a 1N aqueous solution of sodium hydroxide (2.23 mL), stirred and cooled with ice, and then the mixture was stirred The mixture is stirred for 5 minutes at a temperature ranging from 10 to 15 [deg.] C. The reaction mixture is filtered, the filtrate is adjusted to pH 1 with concentrated hydrochloric acid and stirred. with water and then dried to give 2- (2-formylaminothiazol-4-yl) glycolic acid, which can also be expressed as 2- (2-formylimino-2,3-dihydrothiazol-4-yl) glyoxylic acid. (234 g), the melting point of the product thus obtained is in the range of 133 to 136 ° C (dec.) NMR spectrum (NaDCO 3, d) 9.65 {ifí; band s, J = 8Hz). · ' In a similar manner, the following compound can be prepared:. hexanoyioxymethy L-2-methyl-7 - [, 2-hexyÍpxyIxnino _1-2- (2-aminothiazol-4-y1) acetamido] -3-cephem-4-carboxylate, syn-izsomer at-structure thereof wherein can also be expressed as hexanoyloxymethyl 2-methyl-7- (2-hexyloxyimino-2- (2-amino-2,3-dihydro-thiazol-4-yl) -acetamido] -3-methyl-4-carboxylate, syn-isomer , IR spectrum (nujol): 3340, 3200 (band), 3150 (band), 1790 ./(band j, 1750—1790, '1880, 1Θ30 eíeqmEt AND; A process for preparing a 2-lower alkyl-7-hexafluoro-2 or 3-cephem-4-carboxylic acid of the formula Ie, (Ia,) in which: R ¹ represents an alkyl group having 1 to 6 carbon atoms; R ^a is a carboxy group, a (C 1 -C 6 alkoxycarbonyl group which may contain 1 to 3 halogens, a (C 1 -C 6 alkoxycarbonyl) group or a phenyl (C 1 -C 6 alkoxycarbonyl group which may contain -ntroscycline), R ^{3 is} amino or (C 1 -C 6 alkanoylamino) which may contain 1 to 3 halogen atoms, and R ⁴ is hydrogen or (C 1 -C 6 alkyl). or a salt of this compound, characterized by: se