CH637965A5 - 2-Lower alkyl-7-substituted-2- or -3-cephem-4-carboxylic acid compounds and medicaments containing these compounds - Google Patents

Abstract

The compounds of the general formula: <IMAGE> in which R<1> represents lower alkyl, R<2> represents a carboxyl group or a protected carboxyl group, R<3> represents an amino group or a protected amino group, and A represents carbonyl, hydroxy(lower)alkylene, hydroxyimino(lower)alkylene or lower alkoxyimino(lower)alkylene, and their pharmaceutically acceptable salts have antimicrobial activities against a number of pathogenic microorganisms and can be used as active compound in medicaments for the treatment of infectious diseases of humans and animals.

Description

       

  
 

** WARNING ** beginning of DESC field could overlap end of CLMS **.

 



   PATENT CLAIMS
1. Therapeutically active 2-lower alkyl-7-substituted-2 or -3-cephem4-carboxylic acid compounds of the general formula:
EMI1.1
 where R 'is lower alkyl, R2 is a carboxy or an esterified carboxy group, R3 is an amino or an acylamino or arylalkylamino group, and A is carbonyl, hydroxy (lower) alkylene, hydroxyimino (lower) alkylene or lower alkoxyimino ( lower) -alkylene, the last two groups having the syn or the anti-configuration with respect to the group -CONH-, and the pharmaceutically acceptable salts thereof,
2nd

  Compounds according to claim 1, characterized in that R 'stands for lower alkyl, R2 stands for a carboxy or an esterified carboxy group, R3 stands for an amino or an acylamino or arylalkylamino group and A stands for carbonyl or hydroxy (lower) alkylene.



   3. Compounds according to claim 1, characterized in that R 'represents lower alkyl, R2 represents carboxy or an esterified carboxy group, R3 represents an amino or an acylamino or arylalkylamino group and A represents hydroxyimino- (lower) alkylene or lower alkoxyimino- (low) alkylene.



   4. Compounds according to claim 3, characterized in that it is the synisomers.



   5. Compounds according to claim 4, characterized in that R 'is lower alkyl, R2 is a carboxy or an esterified carboxy group, R3 is amino or acylamino and A is hydroxyimino (lower) alkylene or never.



  drigalkoxyimino (lower) alkylene.



   6. Compound according to claim, characterized in that Rl is lower alkyl, R2 is carboxy, lower alkoxycarbonyl, which can be substituted by 1 to 3 halogen atoms, or lower alkanoyloxy (lower) alkoxycarbonyl, R3 is amino or lower alkanoylamino, that by 1 to 3 Halogen atoms can be substituted, and A stands for hydroxyimino (lower) alkylene or lower alkoxyimino (lower) alkylene,
7. Compounds according to claim 6, characterized in that R 'is methyl, R2 is carboxy, 2,2,2-trichloroethoxycarbonyl or pivaloyloxymethoxycarbonyl, R3 is amino, formylamino or trifluoroacetylamino and A is hydroxyiminomethylene or methoxyiminomethylene.



   8. 2-Methyl-7- [2-methoxyimino-2- (2-aminothiazol-4-yl) -acet amido] -3-cephem-4-carboxylic acid (Synisomeres) and its hydrochloride, sodium salt and ammonium salt, as a compound Claim 7.



   9. Medicament, characterized in that it contains a compound according to claim 1 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.



   The invention relates to new 2-lower alkyl-7-substituted 2-or-3-cephem4-carboxylic acid compounds and their pharmaceutically acceptable salts. The invention relates in particular to new 2-lower alkyl-7-substituted-2- or -3-cephem-4-carboxylic acid compounds and their pharmaceutically acceptable salts which have antimicrobial activities. The invention further relates to a process for the preparation of these compounds, medicaments containing these compounds and a method for using these compounds for the treatment of infectious diseases in humans and animals.



   The object of the invention is therefore to provide 2-lower alkyl-7-substituted-2- or -3-cephem-4-carboxylic acid compounds and pharmaceutically acceptable salts which are active against a number of pathogenic microorganisms.



   The invention is also intended to provide a process for the preparation of 2-lower alkyl-7-substituted-2- or -3-cephem-4-carboxylic acid compounds and their pharmaceutically acceptable salts.



   The invention is also intended to provide a medicament which contains at least one 2-lower alkyl-7-substituted-2- or -3-cephem-4-carboxylic acid compound or a pharmaceutically acceptable salt thereof as active ingredient.



   The invention relates to new therapeutically active 2-lower alkyl-7-substituted-2- or -3-cephem4carbon- acid compound of the general formula:
EMI1.2
 wherein R1 is lower alkyl, R2 is a carboxy or an esterified carboxy group, R3 is an amino or an acylamino or arylalkylamino group, and A is carbonyl, hydroxy (lower) alkylene, hydroxyimino (lower) alkylene or lower alkoxyimino (low ) -alkylene, the last two groups with respect to the group -CONH- having the syn or the anti-configuration.



   The 2-lower alkyl-7-substituted-2- or -3-cephem-4-carboxylic acid compounds (I) can be prepared by various methods, which can be illustrated by the following reaction schemes.



  Procedure 1
EMI2.1




  or its reactive deri or a salt thereof vat on the amino group or a salt thereof Process 2
EMI2.2
 or a salt thereof or a salt thereof Method 3
EMI2.3
 or a salt thereof or a salt thereof Method 4
EMI3.1
  (Id) (Ic) or a salt thereof or a salt thereof Method 5
EMI3.2
  (V) (Ie) or a salt thereof or a salt thereof Method 6
EMI3.3
  (Ig) (If) or a salt thereof.

   or a salt thereof Method 7
EMI4.1
  (Ij) (Ih) or a salt thereof or a salt thereof method 8,
EMI4.2
  (Ih) Cij) or a salt thereof or a salt thereof in which R1, R2, R3 and A have the meanings given above, R2a stands for a protected carboxy group, R3 "stands for a protected amino group, R4 stands for hydrogen or lower alkyl, R4a represents lower alkyl, R5 represents an ester portion of an esterified carboxy group of the formula -COOR5 and Y represents the rest of an acid.



   The starting compounds (II) can be prepared by the methods according to DT-OS 2 412 513.



   Among the starting compounds (III) and (V), new compounds can be prepared by conventional methods, which can be represented by the following process schemes.
EMI4.3




  or its reactive derivative on the amino group or a salt thereof
EMI5.1
  
EMI6.1


 <tb> <SEP> or <SEP> its <SEP> reactive <SEP> derivative
 <tb> <SEP> on <SEP> the <SEP> amino group <SEP> or <SEP> on
 <tb> <SEP> salt <SEP> of it
 <tb> <SEP> Y-Cli2CoClI2COOII <SEP> (IX)
 <tb> <SEP> or <SEP> its <SEP> reactive <SEP> derivative
 <tb> <SEP> on <SEP> the <SEP> carboxy group
 <tb> Y-C1I2COCY \ 2CONH ( <SEP> StR1
 <tb> <SEP> '2
 <tb> <SEP> i2
 <tb> <SEP>)
 <tb> <SEP> t <SEP> nitrosating agent
 <tb> <SEP> Y-CE12CO- <SEP> COC-CON! I <SEP> R
 <tb> <SEP> 0NW
 <tb> <SEP> R2
 <tb> <SEP> (Va)
 <tb> <SEP> 1 <SEP> alkylating agent
 <tb> <SEP> Y-CH2CO- <SEP> I-CON <SEP> t
 <tb> <SEP> " <SEP> II <SEP> Ir
 <tb> <SEP> CVb)
 <tb> where R1, R2, R2a, R3a,

   R4, R4a and Y have the meanings given above and Z stands for a protected carboxy group. 



   With regard to the compounds (I) and (Ia) to (Ij) and the starting compounds (III), (IIIa) to (Ilih) and (VII), it is pointed out that these may contain tautomeric isomers.  If a group of the formula:
EMI6. 2nd
 (where R3 has the above meaning) is contained in the molecules of the compounds according to the invention and the starting compounds, then this group can alternatively by its tautomeric formula:
EMI6. 3rd
 (where R3 'represents an imino or protected imino group).  This means that both of these groups are in a state of equilibrium with one another.  This tautomerism can be represented by the following equation:
EMI7. 1
 wherein R3 and R3 'have the above definition. 



   These types of tautomerism between the amino compound and the corresponding imino compound, as indicated above, are well known in the literature.  It will be apparent to those skilled in the art that the tautomeric isomers are readily interchangeable and that they should be included in the same category of compound per se. 



   Accordingly, both tautomeric forms of the compounds (I) and (Ia) to (Ij) according to the invention and the starting compounds (III), (IIIa) to (IIIh) and (VII) clearly fall within the scope of the present invention.  Herein compounds according to the invention and starting compounds which contain the group of such tautomeric isomers are always only based on one form therefor, ie. H.  of the formula:
EMI7. 2nd
 specified, but what happens for the sake of simplicity. 



   With regard to the compounds (I), (la) to (Ib) and (Ie) to (Ij) and the starting compounds (III), (groove) to (IIIh), (V), (Va) to (Vb) and (VIII) it is further pointed out that the compounds according to the invention and the starting compounds include synisomers, antiisomers and mixtures thereof.  If a hydroxyimino or lower alkoxyimino group is contained in the molecules of the inventive and the starting compounds, then the inventive compounds and the starting compounds can optionally be obtained as synisomers or antiisomers or as mixtures thereof.  Herein, a synisomer means a geometric isomer, which is a partial structure of the following formula:
EMI7. 3rd
 Has. 

  The anti isomer is the other geometric isomer, which is a partial structure of the following formula:
EMI7. 4th
 in which R4 and Z each have the meanings given above. 



   Suitable pharmaceutically acceptable salts of the compounds (I) according to the invention are conventional non-toxic salts.  Examples include metal salts such as alkali metal salts (e.g. B.  the sodium salt, potassium salt, etc. ) and alkaline earth metal salts (e.g. B.  the calcium salt, magnesium salt, etc. ), the ammonium salts, the salts with organic bases (e.g. B.  the trimethylamine salt, triethylamine salt, pyridine salt, picolin salt, dicyclohexylamine salt, N, N '-dibenzylethylenediamine salt, etc. ), Salts with organic acids (e.g. B.  the acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc. ) and salts with inorganic acids (e.g. B.  the hydrochloride, hydrobromide, sulfate, phosphate, etc. ) or salts with an amino acid (e.g. B.  with arginine, aspartic acid, glutamic acid and the like) and the like. 



   The term low as used herein is intended to mean groups of 1 to 6 carbon atoms, unless otherwise specified. 



   Suitable lower alkyl groups are e.g. B.  Methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl and the like. 



   Suitable protected carboxy groups are e.g. B.  esterified
Carboxy groups and the like.  Suitable examples of the ester portion in the esterified carboxy group are e.g. B.  the lower alkyl ester (such as the methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, pentyl ester, hexyl ester, 1-cyclopropyl ethyl ester, etc. ), which can have at least one suitable substituent, such as. B. 

  Lower alkanoyloxy (lower) alkyl esters (such as acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, 2-acetoxyethyl ester, 2-propionyloxyethyl ester, etc. ), Lower alkanesulfonyl (lower) alkyl ester (such as the 2-mesyl ethyl ester etc. ) and mono (or di or tri) halogen (low) alkyl esters (e.g. B.  the 2-iodoethyl ester, 2,2,2
Trichloroethyl ester etc. ), Lower alkenyl esters (e.g. B.  the vinyl ester, allyl ester, etc. ), Lower alkynyl esters (e.g. B.  the ethyl ester, propinyl ester, etc. ), Ar (lower) alkyl esters, which may have at least one suitable substituent (e.g. B.  the benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, diphenylmethyl ester, bis (methoxyphenyl) methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-tert. 

   butyl benzyl ester, etc. ), Aryl esters, which may have at least one suitable substituent (e.g. B.  the phenyl ester, 4-chlorophenyl ester, tolyl ester, tert. -Butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester etc. ) and the same. 



   Suitable protected amino groups are e.g. B.  Aminogrup pen, which by conventional protective groups such. B.  Acyl, are substituted, Ar (lower) alkyl, which may have at least one suitable substituent (e.g. B.  Benzyl, 4-methoxybenzyl, phenethyl, trityl, 3,4-dimethoxybenzyl etc. ) or similar. 



   Suitable acyl groups are e.g. B.  Carbamoyl, aliphatic
Acyl groups and acyl groups containing an aromatic or heterocyclic ring.  Examples of such acyl groups are e.g. B.  Lower alkanoyl (e.g. B.  Formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl etc. ), Lower alkoxycarbonyl (e.g. B.  Methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, l-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert. -Butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl etc. ), Lower alkanesulfonyl (e.g. B.  Mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, etc. ), Arylsulfonyl (e.g. B.  Benzenesulfonyl, tosyl, etc. ), Atoyl (e.g. B.     Benzoyl, toluoyl, naphthoyl, phthaloyl, indancarbonyl etc. ), Ar (low) alkanoyl (e.g. B.  Phe nylacetyl, phenylpropionyl etc. ), Ar (low) alkoxycarbonyl (e.g. B. 

  Benzyloxycarbonyl etc. ) and the same. 



   The acyl part mentioned above may contain at least one suitable substituent, such as. B.  Halogen (e.g. B.  Chlorine, bromine, iodine or fluorine), cyano, lower alkyl (e.g. B.  Methyl, ethyl, propyl, isopropyl, butyl, etc. ).    Lower alkenyl (e.g. B.    



  Vinyl, allyl etc. ) or the like. 



   Individual examples of this are mono (or di or tri) halo (low) alkanoyl (e.g. B.  Trifluoroacetyl etc. ). 



   Suitable lower alkylene parts in the terms hydroxy (lower) alkylene, hydroxyimino (lower) alkylene and lower alkoxyimino (lower) alkylene are e.g. B.  Methylene, ethylene, trimethylene, propylene, tetramethylene and the like. 



   Suitable lower alkoxy parts in the designation lower alkoxyimino (lower) alkylene are e.g. B.  Methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy and the like. 



   Suitable ester parts of esterified carboxy groups are e.g. B.  the esters exemplified for the protected carboxy group. 



   Suitable residues of an acid are e.g. B.  Halogen (e.g. B.  Chlorine, bromine, iodine or fluorine) and the like. 



   The various production processes for the compounds according to the invention are explained in more detail below. 



  Procedure 1
The compounds (I) according to the invention and the salts thereof can be prepared in such a way that the compound (II) or its reactive derivative on the amino group or a salt thereof with the compound (III) or its reactive derivative on the carboxy group or a Salt from it. 



   Suitable reactive derivatives on the amino group of compound (II) are e.g. B.  the Schiff base type imino isomer or its enamine type tautomeric isomer formed by reacting the compound (II) with a carbonyl compound such as acetoacetic acid or the like; the silyl derivative obtained by reacting the compound (II) with a silyl compound such as Bis (trimethylsilyl) acetamide or the like, and the derivative formed by reacting the compound (II) with phosphorus trichloride or phosgene and the like. 



   Suitable salts of the compounds (II) and (III) are e.g. B. 



  Acid addition salts, for example salts with organic acids (e.g. B.  the acetate, maleate, tartrate, benzenesulfonate, toluenesulfonate, etc. ) or salts with inorganic acids (e.g. B.  the hydrochloride, hydrobromide, sulfate, phosphate, etc. ), Metal salts (e.g. B.  the sodium salt, potassium salt, calcium salt, magnesium salt, etc. ), the ammonium salt, organic amine salts (e.g. B. 



  the triethylamine salt, dicyclohexylamine salt, etc. ) and the same. 



   Suitable reactive derivatives on the carboxy group of compound (III) are e.g. B.  the acid halide, the acid anhydride, the activated amide, the activated ester and the like.  Examples include an acid chloride, such as. B.  an acid azide, a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g. B.  Dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, etc. ), dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, alkyl carboxylic acid, aliphatic carboxylic acid (e.g. B.  Pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid or trichloroacetic acid etc. ) or aromatic carboxylic acids (e.g. B. 

  Benzoic acid etc. ), symmetric acid anhydrides, amides activated with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole, and activated esters (e.g. B. 



  Cyanomethyl esters, methoxymethyl esters, dimethylimino methyl [(CH3) 2N + = CH -] esters, vinyl esters, propargyl esters, p-nitrophenyl esters, 2,4-dinitrophenyl esters, trichlorophenyl esters, pentachlorophenyl esters, mesylphenyl esters, phenylazophenyl esters, phenylthioenes, p-nitylthioenes, p-nitylthioester, p- Carboxymethyl thioesters, pyranyl esters, pyridyl esters, piperidyl esters, 8-quinolyl thioesters etc. ) or ester with an N-hydroxy compound (e.g. B.  N, N-dimethylhydroxylamine, l-hydroxy-2- (1 H) -pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, l-l-hydroxy-6-chloro-1H-benzotriazole, etc. ) and the same.  These reactive derivatives can be selected as desired depending on the type of compound (III) used. 



   The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine or any other organic solvent which does not adversely affect the reaction .  These conventional solvents can also be used in a mixture with water. 



   If the compound (III) is used in the free acid form or in salt form in the reaction, then the reaction is preferably carried out in the presence of a conventional condensing agent, e.g. B.  of N, N '-dicyclohexylcarbodimide, N-cyclohexyl-N' -morpholinoethylcarbodiimide, N-cyclohexyl-N '- (4-diethylaminocyclohexyl) -carbodiimide, N, N'-di-ethylcarbodiimide, N, N'-diisopropylcarbodiimide N-ethyl-N'- (3-dimethylaminopropyl) carbodiimide, N, N-carbonylbis- (2-methylimidazole), pentamethylene ketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine, ethoxyacetylene, l-alkoxy-l-chloroethylene, Trialkyl phosphite, ethyl polyphosphate, isopropyl polyphosphate, phosphorus oxychloride, phosphorus trichloride, thionyl chloride, oxalyl chloride, triphenylphosphine, 2-ethyl-7-hydroxybenzisoxazolium salt,

   2-ethyl-5- (m-sulfophenyl) isoxazolium hydroxide intramolecular salt (chloromethylene) dimethyl ammonium chloride, 1 - (p-chlorobenzenesulfonyloxy) -6-chloro-1 H -benzotriazole or the like. 



   The reaction can also be carried out in the presence of an inorganic or organic base, such as. B.  of alkali metal bicarbonate, tri (lower) alkylamine, pyridine, N- (lower) alkylmorphorin, N, N-di (lower) alkylbenzylamine or the like.  The reaction temperature is not critical and the reaction can usually be carried out under cooling or at ambient temperature. 



   It should be pointed out that for the preparation of a synisomer of the compounds (I) according to the invention it is expedient to select suitable conditions in a selective manner and in high yield.  So z. B.  a synisomer of the desired compounds (I) can be obtained selectively and in high yield by carrying out the reaction of the compound (II) with the corresponding synisomer of the starting compound (III) in the presence of a Vilsmeier reagent, for example one such as that obtained from dimethylformamide and producing phosphorus oxychloride or the like. 

  In particular, a synisomer of the compounds (I) according to the invention in which R3 is amino can be obtained well if the reaction is carried out in the presence of more than two molar equivalents of phosphorus oxychloride with respect to any amount of the corresponding synisomer of the starting compound (III), in which R3 is Amino and dimethylformamide is available.  Particularly good results can be obtained if an activation step of the synisomer of the starting compound (III), in which R3 is amino, in the presence of a silyl compound, e.g. B.  of bis (trimethylsilyl) acetamide, trimethylsilylacetamide or the like. 

 

  Procedure 2
The compounds (Ia) according to the invention or the salts thereof can be prepared by subjecting the compound (Ib) or a salt thereof to an elimination reaction of the amino protecting group. 



     Suitable salts of compound (Ib) are e.g. B.  Metal salts, ammonium salts and organic amine salts, as exemplified for the compound (II). 



   The elimination reaction takes place according to conventional methods, e.g. B.  by hydrolysis, reduction or the like. 



  The hydrolysis can also be carried out using an acid or base or hydrazine and the like. 



  These methods can be selected depending on the type of protecting groups to be eliminated. 



   Among these methods, acid hydrolysis is the most common and preferred method for eliminating the protecting groups, e.g. B.  of substituted or unsubstituted alkoxycarbonyl, cycloalkoxycarbonyl, substituted or unsubstituted aralkoxycarbonyl, aralkyl (e.g. B.  Trityl), substituted phenylthio, substituted aralkylidene, substituted alkylidene, substituted cycloalkylidene or the like. 



  Suitable acids are e.g. B.  organic or inorganic acids such as formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid and the like.  Best suited is an acid that can be easily removed from the reaction mixture by conventional means, such as by distillation under reduced pressure, such as. B.  Formic acid, trifluoroacetic acid etc.  The acids can be selected according to the type of protective group to be eliminated. 



  If the elimination reaction is carried out with an acid, it can be carried out in the presence or in the absence of a solvent.  Suitable solvents are e.g. B.  Water, conventional organic solvents or mixtures thereof.  Hydrazine hydrolysis is commonly used to eliminate phthaloyl type amino protecting groups. 



   Reductive elimination is generally used to remove the protecting group, e.g. B.  Haloalkoxycarbonyl (e.g. B.  Trichloroethoxycarbonyl etc. ), substituted or unsubstituted aralkoxycarbonyl (e.g. B.  Benzyloxycarbonyl etc. ), 2-pyridylmethoxycarbonyl etc.  Suitable reduction processes are e.g. B.  reduction with an alkali metal borohydride (two sodium borohydride, etc. ), the reduction with a combination of a metal (e.g. B.  Tin, zinc, iron etc. ) or the metal and a metal salt compound (e.g. B. 



  Chromium (II) chloride, chromium (II) acetate, etc. ) and an organic or inorganic acid (e.g. B.  Acetic acid, propionic acid, hydrochloric acid, etc. ) and the catalytic reduction.  Suitable catalysts are e.g. B.  the conventional catalysts such as Raney nickel, platinum oxide, palladium-on-charcoal and the like. 



   Among the protecting groups, the acyl group can generally be eliminated by hydrolysis.  In particular, the trifluoroacetyl group can be easily eliminated by treating with water at approximately neutral conditions.  Halogen substituted alkoxycarbonyl and 8-quinolyloxycarbonyl groups are usually eliminated by treatment with a heavy metal such as copper, zinc or the like. 



   Among the protecting groups, the acyl group can also be treated with an iminohalogenating agent (e.g. B.  Phosphorus oxychloride etc. ) and an imino etherifying agent, e.g. B. 



  a low alkanol (such as methanol, ethanol, etc. ) are treated, if necessary followed by hydrolysis. 



   The reaction temperature is not critical.  It can be selected according to the type of the protecting group for the amino group and the above-mentioned elimination method.  The reaction is preferably carried out under mild conditions, for example with cooling or at a slightly elevated temperature. 



   The invention also includes those cases in which a protected carboxy group is converted into the free carboxy group during the reaction or the aftertreatment step of the process according to the invention. 



  Procedure 3
The compounds (Ic) or salts thereof according to the invention can be prepared by reducing the compound (Id) or a salt thereof. 



   Suitable salts of the compounds (Id) are e.g. B.  those as exemplified for the compound (II). 



   The reduction is carried out according to conventional methods, for example using an alkali metal borohydride (e.g. B.  Sodium borohydride, potassium borohydride, etc. ) or similar. 



   The reduction is usually carried out in a solvent which does not adversely affect the reaction, such as e.g. B.  in water, methanol, ethanol, tetrahydrofuran, dioxane and the like.  The reduction can also be carried out in the presence of an inorganic or organic base, e.g. B.  an alkali metal (such as sodium, potassium, etc. ), an alkaline earth metal (such as magnesium, calcium, etc. ), a hydroxide or carbonate or bicarbonate thereof, a tri (lower) alkylamine (e.g. B. 



  of trimethylamine, triethylamine, etc. ), from picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo- [4,3,0] - non-5-ene, 1, diazabicydo- [2,2,2] -octane, 1, 8 -Diazabicyclo- [5,4,0] -undecen-7 or the like. 



   The reaction temperature is not critical and the reaction is preferably carried out under mild conditions, for example with cooling or slight warming. 



  Procedure 4
The compounds (Ie) according to the invention or the salts thereof can be prepared by reacting the compound (Id) or a salt thereof with a compound (IV) or a salt thereof. 



   Suitable salts of the compounds (Id) are e.g. B.  those as given as examples of the compounds (II). 



  Suitable salts of compound (IV) are e.g. B.  Salts with inorganic acids (e.g. B.  the hydrochloride, hydrobromide, sulfate, etc. ), Salts with organic acids (e.g. B.  the acetate, maleate, p-toluenesulfonate, etc. ) and the same. 



   The reaction is usually carried out in a solvent such as water, an alcohol (e.g. B.  Methanol, ethanol, etc. ) or any other solvent that does not adversely affect the reaction. 



   The reaction is preferably carried out in the presence of a base, e.g. an inorganic base such as an alkali metal (e.g. B.  Sodium, potassium, etc. ), Alkaline earth metal (e.g. B.  Magnesium, calcium etc. ), the hydroxide or carbonate or bicarbonate thereof or the like or an organic base, e.g. B. 



  an alkali metal alkoxide (e.g. B.  Sodium methoxide, sodium ethoxide, etc. ), a trialkylamine (e.g. B.  Trimethylamine, triethylamine etc. ), N, N-dialkylaniline (e.g. B.  N, N-dimethylaniline, etc. ), Pyridine or the like. 

 

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



  Procedure 5
The compounds (Ic) according to the invention or salts thereof can be prepared by reacting the compound (V) or a salt thereof with the compound (VI). 



   Suitable salts of the compounds (V) are e.g. B.  those as exemplified for the compounds (II). 



   The reaction is usually carried out in a solvent such as water, an alcohol (e.g. B.  Methanol, ethanol, etc. ), Benzene, dimethylformamide, tetrahydrofuran or any other solvent that does not adversely affect the reaction. 



   The reaction temperature is not critical and the reaction is usually carried out from ambient to elevated temperature.   



  Procedure 6
The compounds (If) according to the invention or salts thereof can be prepared by reacting the compound (Ig) or a salt thereof with an alkylating agent. 



   Suitable salts of the compounds (Ig) are those which have been given as examples of the compounds (II). 



   Suitable alkylating agents that can be used in this reaction are e.g. B.  Di (lower) alkyl sulfate (e.g. B. 



  Dimethyl sulfate, diethyl sulfate, etc. ), Diazo (low) alkane (e.g. B. 



  Diazomethane, diazoethane, etc. ), Lower alkyl halide (e.g. B. 



  Methyl iodide, ethyl iodide, ethyl bromide, etc. ), Lower alkyl sulfonate (e.g. B.  Methyl p-toluenesulfonate, etc. ) and the same. 



   The reaction using diazo (lower) alkane is usually carried out in a solvent such as diethyl ether, dioxane or any other solvent which does not adversely affect the reaction.  The reaction is usually carried out with cooling or at ambient temperature. 



   The reaction using other alkylating agents is usually carried out in a solvent such as water, acetone, ethanol, diethyl ether, dimethylformamide or any other solvent which does not adversely affect the reaction.  The reaction is carried out with cooling or heating.  The reaction is preferably carried out in the presence of a base, e.g. B.  an inorganic base or an organic base as mentioned above. 



  Procedure 7
The compounds (Ih) or salts thereof according to the invention can be prepared by subjecting the compound (Ii) or a salt thereof to an elimination reaction of the carboxyl protecting group. 



   Suitable salts of the compounds (Ii) are e.g. B.  the acid addition salts as they were called with regard to compound (II). 



   In this elimination reaction all conventional methods are applicable, which are common for the elimination reactions of carboxy protecting groups, e.g. B.  hydrolysis, reduction and the like. 



   If the carboxy protecting group is an ester group, then it can be eliminated by hydrolysis.  The hydrolysis is preferably carried out in the presence of a base or an acid.  Suitable bases are e.g. B.  inorganic bases and organic bases, as they were called in connection with method 2. 



   Suitable acids are e.g. B.  organic acids (e.g. B.  Formic acid, acetic acid, propionic acid etc. ) and inorganic acids (e.g. B.  Hydrochloric acid, hydrobromic acid, sulfuric acid etc. ).  The reduction can be due to the elimination of the protective group, e.g. B.  of 2-iodoethyl ester, 2,2,2-trichloroethyl ester or the like may be applicable.  Reductions which can be applicable for the elimination reaction according to the invention are e.g. B.  a reduction with a combination of a metal (e.g. B.  Zinc, zinc amalgam, etc. ) or a chromium salt compound (e.g. B.  Chromium (II) chloride, chromium (II) acetate etc. ) and an organic or inorganic acid (e.g. B.  Acetic acid, propionic acid, hydrochloric acid, etc. ) and the reduction in the presence of a metal catalyst.  Metal catalysts for catalytic reduction are e.g. B.  Platinum catalysts (e.g. B. 

  Platinum wire, sponge platinum, platinum black, platinum colloid, etc. ), Palladium catalysts (e.g. B. 



  spongy palladium, palladium black, palladium oxide, palladium on barium sulfate, palladium on barium carbonate, palladium on charcoal, palladium on silica gel, palladium colloid, etc. ), Nickel catalysts (e.g. B.  reduced nickel, nickel oxide, Raney nickel, Urushibara nickel, etc. ) and the same. 



   The reaction temperature is not critical.  It can be selected according to the kind of the protective group of the carboxy group and the elimination method. 



  Procedure 8
The compounds (Ij) or salts thereof according to the invention can be prepared by subjecting the compound (Ih) or a salt thereof to an esterification reaction. 



   Suitable salts of the compound (Ih) are e.g. B.  those as they were called in connection with the compound (II). 



   The esterification agent used in the reaction can be a compound of the general formula:
X-R5 (XI) where R5 has the above meaning and X is hydroxy or a reactive derivative thereof. 



   Suitable examples of reactive derivatives of hydroxy groups are e.g. B.  Residues of acids as mentioned above. 



   The reaction is usually carried out in a solvent such as dimethylformamide, pyridine, hexamethylphosphoric triamide, dioxane or another solvent which does not adversely affect the reaction. 



   If the compound (Ih) is used in the form of the free acid, then the reaction is preferably carried out in the presence of a base, e.g. B.  an inorganic base or an organic base, as mentioned above in connection with process 2, carried out. 



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



   In the above reactions. , nd / or post-treatment stages of the process according to the invention can occasionally be converted into other tautomeric isomers.  These cases are also intended to be included in the scope of the present invention. 



   In the aforementioned reactions and / or post-treatment stages of the processes according to the invention, the aforementioned syn- or anti-isomers can occasionally be partially or completely converted into other isomers.  These cases are also intended to be encompassed by the scope of the present invention. 



   If the compound (I) according to the invention is obtained in the free acid form and / or if the compound (I) according to the invention has a free amino group, then it can be converted into its pharmaceutically acceptable salt by conventional methods. 



   Processes for the preparation of the starting compounds are explained in more detail below. 



   The starting compounds (IIIa) can be prepared by reacting a compound (VII) or a reactive derivative on the amino group or a salt thereof with an amino protective agent.  The starting compounds (III) can be prepared by reacting the compounds (IIIh) or their reactive derivatives on the amino group or salts thereof with an amino protective agent. 

 

   Suitable reactive derivatives on the amino group of the compounds (VII) and (IIIh) and suitable salts of the compounds (VII) and (IIIh) are, for. B.  those as described above with regard to the reactive derivatives on the amino group of the compounds (II) and salts of the compounds (II). 



   Suitable amino protecting groups are e.g. B.  Alkylating agents and the like. 



   Suitable acylating agents are e.g. B.  aliphatic, aromatic and heterocyclic isocyanates and the corresponding isothiocyanates and aliphatic, aromatic and heterocyclic carboxylic acids and the corresponding sulfonic acids, carboxylic esters and carbamic acids and the corresponding thioacids and the reactive derivatives of the abovementioned acids. 



   Suitable reactive derivatives of the above acids may include the same as those discussed above with respect to the reactive derivatives on the carboxy group of the compounds (III).  The examples of protecting groups which can be introduced into the amino group of the compounds (VII) and (IIIh) with the above-mentioned amino protecting group agents may be the same as those mentioned above in the explanation of the protecting groups for protected amino groups. 



   The reaction is carried out in a manner similar to the reaction of the compound (II) or its reactive derivative on the amino group or its salt with a compound (III) or its reactive derivative on the carboxy group. 



   The starting compounds (IIIb) can be prepared by oxidizing the compounds (IIIa). 



   The oxidation reaction takes place according to conventional methods which are used to convert the so-called activated methylene group into a carbonyl group. 



  Thus, the oxidation can be carried out, for example, using conventional oxidizing agents, e.g. B.  of selenium dioxide, trivalent manganese compounds (e.g. B.  Manganese (III) acetate and potassium permanganate, etc. ) or the like.  The oxidation is usually carried out in a solvent which does not adversely affect the reaction, e.g. B.     of water, dioxane, tetrahydrofuran and the like. 



   The reaction temperature is not critical and the reaction is preferably carried out with heating to heating. 



   The starting compounds (IIIc) can be prepared by subjecting the compounds (IIIb) to an elimination reaction of the carboxy protecting group.  The starting compounds (IIIe) can be prepared by subjecting the compounds (IIIf) to an elimination reaction of the carboxy protecting group.  The starting compounds (IIIh) can be prepared by subjecting the compounds (IIIg) to an elimination reaction of the carboxy protecting group. 



   The elimination reaction is carried out in a manner similar to that described in the process 7 elimination reaction. 



   The starting compounds (imide) can be prepared by reducing the compounds (IIIc).  The reduction is carried out in a manner similar to the reduction in method 3. 



   The starting compounds (IIIe) can be prepared by reacting compounds (IIIc) with compounds (IV) or a salt thereof.  The starting compounds (IIIf) can be prepared by reacting the compounds (IIIb) with compounds (IV) or a salt thereof. 



   The reaction is carried out in a manner similar to that of Method 4. 



   The starting compounds (IIIg) can be prepared by reacting the compounds (VIII) with thiourea.  The reaction is carried out in a manner similar to that of Method 5. 



   The compounds (X) can be prepared by reacting the compounds (II) or their reactive derivatives on the amino group or salts thereof with compounds (IX) or their reactive derivatives on the carboxy group. 



   Suitable reactive derivatives on the carboxy group of the compounds (IX) are e.g. B.  those as described with regard to the reactive derivatives on the carboxy group of compounds (III).  The reaction is carried out in a similar manner to the reaction in Method 1. 



   The starting compounds (Va) can be prepared by reacting compounds (X) with a nitrosating agent. 



   Suitable nitrosating agents are e.g. B.  nitrous acid, alkali metal nitrites (e.g. B.  Sodium nitrite etc. ), Lower alkyl nitrites (e.g. B.  Amyl nitrite etc. ) and the same. 



   The reaction is usually carried out in a solvent such as water, acetic acid, benzene, methanol, ethanol or any other solvent which does not adversely affect the reaction. 



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



   The starting compounds (Vb) can be prepared by reacting the compound (Va) with an alkylating agent. 



   The reaction is carried out in a manner similar to the reaction in Method 6. 



   The compounds (I) according to the invention and their pharmaceutically acceptable salts have a high antibacterial activity and they inhibit the growth of a number of microorganisms, including gram-positive and gram-negative bacteria.  In particular, the synisomers of the compounds (I) according to the invention and their pharmaceutically acceptable salts generally have a considerably higher antibacterial activity than the corresponding antiisomers of the compounds (I) according to the invention and the pharmaceutically acceptable salts thereof. 

  For therapeutic purposes, the compounds according to the invention can be used in the form of medicaments which contain the compounds as active ingredients in a mixture with pharmaceutically acceptable carriers, e.g. B.  contain organic or inorganic solids or liquid excipients suitable for oral, parenteral or external administration. 



  The drugs can e.g. B.  Capsules, tablets, dragees, ointments or suppositories, solutions, suspensions, emulsions and the like.  If desired, the preparations can also contain auxiliary substances, stabilizing agents, wetting or emulsifying agents, buffers and other customary additives. 



   The dosage of the compounds varies according to the age and condition of the patient.  An average single dose of about 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the compounds according to the invention has proven to be effective for the treatment of infectious diseases which have been caused by pathogenic bacteria. 

 

   The antimicrobial activities of some representative compounds according to the invention against some test strains of pathogenic bacteria are shown below on the basis of their minimal inhibitory concentrations. 



  Test method
In vitro antibacterial activity was determined by the two-fold agar plate dilution method described below. 



   The loop content of an overnight culture of the individual test strains in trypticase soy broth (108 viable cells per ml) was spread on cardiac infusion agar (HI agar) which contained graded concentrations of the representative test compounds.  The minimum inhibitory concentration (MIC) was expressed as 11 g / ml after 20 hours of incubation at 37 ° C.   



     Test compounds: (1) 2-methyl-7- [2- (2-aminothiazol-4-yl) glyoxylamido] -3- cephem4-carboxylic acid (test compound (1)) (2) 2-methyl-7- [2- hydroxy-2- (2-aminothiazol 1 yl) acetamido] -3-cephem4-carboxylic acid (test compound (2)) (3) 2-methyl-7- [2-methoxyimino-2- (2-aminothiazole) - 4-yl) - acetamido] -3-cephem-4-carboxylic acid (synisomeres) (test compound (3)) (4) pivaloyloxymethyl-2-methyl-7- [2-methoxyimino-2- (2 aminothiazol-4-yl) -acetamido] -3-cephem-4-carboxylate (Synisomeres) (test compound (4)). 



  Test results: Organism Testver- Testver- Testver- Testververbindung binding binding binding (1) (2) (3) (4) E.  Coli No.  324 0.78 0.78 0.05 0.2 E.  Coli No.  341 0.2 0.39 0.2 0.78 cl.  Aerogenes No.  417 0.39 0.39 0.2 0.2 cl.  Aerogenes No.  418 0.39 0.78 0.1 0.78 Kl.  Aerogenes No.  427 0.1 0.39 0.05 0.2 cl.  Aerogenes No.  428 0.78 1.56 0.2 1.56 Pr.  Minabilis No.  501 0.78 1.56 0.05 0.2 Pr.  Minabilis No.  520 0.39 1.56 0.05 0.1 Pr.  Minabilis No.  525 6.25 1.56 0.05 0.2
The invention is illustrated in the examples. 



  Preparation of the starting compounds: Preparation Example 1 (a) A mixture of 2,2,2-trichloroethyl-2-methyl-7-amino-3-cephem-4-carboxylate hydrochloride (0.38 g), trimethylsilylacetamide (1.1 g ) and methylene chloride (10 ml) was stirred at room temperature for 30 min.  The solution thus obtained was cooled to -15 ° C.  To the solution was added dropwise 3-oxo-4-bromobutyryl bromide (1.0 mmol) in carbon tetrachloride (13 ml) while cooling to -15 ° C.  The mixture was stirred at the same temperature for 1.5 hours and without external cooling for 30 minutes.  The mixture was poured into cold water.  The organic layer was then separated. 

  The organic layer was washed with 2N hydrochloric acid (8 ml x 3) and water (10 ml x 2) in order, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure.  The residue was pulverized in diisopropyl ether, collected by filtration and then dried, yielding a light brown powder of 2,2,2-trichloroethyl-2-methyl-7- (3-oxo-4-bromobutyramido) -3-cephem-4-carboxylate (0.31 g), mp.  78 to 83 C (dec. ) was obtained. 



  IR spectrum (Nujol):
3320, 1785, 1735, 1675, 1284, 1210 cm- '. 



  NMR spectrum (CDCb, 6): 1.54 (3H, d, J = 7Hz)
3.65 (1H, m)
3.76 (4 / 5H, s) 4.11 (6/511, s) 4.90 (2H, s) 5.00 (1H, d, J = 6Hz)
5.95 (1H, m)
6.72 (IH, d, J = 6.8Hz) 7.05 (2 / 5H, d, J = 9Hz)
7.73 (3 / 5H, d, J = 9Hz). 



   In a similar procedure, the p-nitrobenzyl-2-methyl-7- (3-oxoXbromobutyramido) -3-cephem-4-carboxylate was obtained in the form of a powder. 



  IR spectrum (Nujol): 3270, 1780, 1725, 1655, 1625, 1600 cm¯1.    



  NMR spectrum (Ds-dimethyl sulfoxide, o): ppm 1.79 (3H, d, J = 6.5 Hz)
3.67 (2H, s) 3.7-4.2 (1H, m)
4.43 (2H, s)
5.13 (1H, d, J = 4.5Hz)
5.43 (2H, s)
5.87 (1H, dd, J = 4.5 and 8Hz) 6.76 (1H, d, J = 6.5Hz)
7.73 (2H, d, J = 9Hz) 8.26 (2H, d, J = 9Hz) 9.13 (1H, d, J = 8Hz) (b) To a solution of 2,2,2-trichloroethyl -2-methyl-7- (3oxo-4-bromobutyramido) -3-cephem-4-carboxylate (2.54 g) in glacial acetic acid (25 ml) was added dropwise to a solution of sodium nitrite hydrate (0.33 g) in water (1 ml) in the course of 3 min with stirring at 10 to 15 C.  The mixture was stirred at the same temperature for 1 hour. 

  After pouring the reaction mixture into cold water (70 ml), the precipitate formed was collected by filtration and then dried, whereby a brown powder of 2,2,2-trichloroethyl-2-methyl-7- (2-hydroxyimino-3-oxoXbrom - butyramido) -3-cephemXcarboxylate (a mixture of syn and anti isomers) (2.0 g), mp.  76 to 80 C (dec. ) was obtained. 



  IR spectrum (Nujol):
1670 to 1710, 1540, 1280, 1215, 715 cm-1. 



  Nuclear Magnetic Resonance Spectrum (d6-dimethyl sulfoxide, 6): 1.44 (3H, d, J = 7Hz)
3.2 to 3.8 (2H, broad)
3.91 (1H, m)
4.57 (1H, s) 5.02 (2H, s)
5.16 (1H, d, J = SHz) 5.91 (1H, dd, J = 5 and 9Hz)
6.74 (1H, d, J = 6.5Hz)
9.32 (1H, d, J = 9Hz). 



   The p-nitrobenzyl-2-methyl-7- (2-hydroxyimino-3-oxo-4-bromobutyramido) -3-cephem-4-carboxylate (syn-isomer) was obtained in a similar manner. 



  IR spectrum (Nujol):
3260, 1775, 1725, 1700, 1660, 1630, 1600cm-1. 



  NMR spectrum (D6-dimethyl sulfoxide, o): ppm 1.45 (3H, d, J = 7Hz)
3.6-4.2 (1H, m) 4.6 (2H, s)
5.17 (1H, d, J = 5Hz)
5.43 (2H, s)
5.98 (1H, dd, J = 5 and 9Hz)
6.77 (1H, d, J = 7Hz)
7.73 (2H, d, J = 9Hz)
8.27 (2H, d, J = 9Hz) 9.37 (1H, d, J = 9Hz) 13.32 (1H, s) Preparation Example 2
To a solution of 2,2,2-trichloroethyl-2-methyl-7- (2-hydroxyimino-3-oxoffibromobutyramido) -3-cephem4carboxy-lat (a mixture of syn and anti isomers) (1.2 g) in ethanol (20 ml) was added dropwise a solution of diazomethane (0.1 mol) in diethyl ether with stirring and ice-cooling to complete the reaction. 

  After concentrating the reaction mixture under reduced pressure, the residue was pulverized in diisopropyl ether, collected by filtration, and dried to give a brown powder of 2,2,2-trichloroethyl-2-methyl-7- (2-methoxyimino-3-oxo-4bromo - butyramido) -3-cephem-4-carboxylate (a mixture of syn and anti isomers) (1.1 g), mp.  80 to 83 "C (dec. ) was obtained. 



  IR spectrum (Nujol):
3300, 1785, 1737, 1650 to 1710, 1535, 1280, 1210, 1160, 1045, 715cm- '.    



  NMR spectrum (ds-dimethyl sulfoxide, o): 1.46 (3H, d, J = 7Hz) 4.0 (1H, m)
4.04 (3H, s) 4.62 (1H, s)
5.05 (2H, s)
5.29 (in, d, J = 5Hz) 5.95 (1H, m)
6.74 (1H, m)
9.48 (1H, d, J = 9Hz) t Preparation Example 3 (a) Formic acid (169.2 ml) was added dropwise to acetic anhydride (384 ml) over the course of 15 to 20 minutes and while cooling to 35 ° C.  The mixture was stirred at 55 to 60 ° C. for 1 h. 

  To the mixture became ethyl 2- (2-aminothhiazol4yl) acetate, which can also be called ethyl 2- (2-imino-2,3-dihydrothiazol4-yl) acetate, (506 g) in the course given from 15 to 20 min with ice cooling and stirring. 



  The mixture was stirred at room temperature for 1 hour.  After the reaction, the solvents were distilled off.  To the residue was added isopropyl ether (2500 ml) and the mixture was stirred at room temperature for 1 h.  The precipitates were collected by filtration, washed with diisopropyl ether and then dried to give ethyl 2- (2-formylaminothiazol-4-yl) acetate, also known as ethyl 2- (2-formylimino-2,3-dihydrothiazole) .    



     4-yl) acetate (451.6 g), mp.  125 to
126 "C.     The remaining filtrate was concentrated and the residue was washed with diisopropyl ether (500 ml) and dried to give an additional amount of the same compound (78.5 g). 



  IR spectrum (Nujol):
1737, 1700 cm- '. 



  NMR spectrum (CDCl3, o): 1.25 (3H, t, J = 8Hz)
3.7 (2H, s)
4.18 (2H, q, J = 8Hz) 6.9 (1H, s)
8.7 (1H, s). 



   (b) A mixture of manganese (III) acetate tetrahydrate (120 g), acetic acid (1000 ml) and acetic anhydride (100 ml) was stirred for 2C min in an oil bath from 130 to 135 "C.  Potassium permanganate (20 g) was added to the mixture over 5 minutes at 105 to 110 ° C. with stirring.  The mixture was then stirred at 130 to 135 ° C. for a further 30 min.  The mixture was cooled to room temperature and the mixture was treated with ethyl 2- (2-formylaminothiazol-4-yl) acetate, which is also called ethyl 2- (2-formylimino-2,3-dihydrothiazol-4-yl) - acetate can be designated, (53.5 g) added.  The mixture was then stirred at 38 to 40 ° C. for 15 hours while introducing air at a rate of 6000 ml per min. 



  After the reaction, the precipitates were collected by filtration.  The precipitates were washed successively with acetic acid and water and then dried to give ethyl 2- (2-formylaminothiazol-4-yl) glyoxylate, which was also called ethyl 2- (2-formylimino-2,3-dihydro thiazoleXyl ) -glyoxylate can be called (41.5 g), mp.  232 to 233 "C (dec. ). 



   (c) To a suspension of ethyl 2- (2-formylaminothia zolXyl) glyoxylate, which can also be called ethyl 2- (2-formylimino-2,3-dihydrothiazol4-yl) glyoxylate, (281 g) in water (1100 ml) was added an aqueous 1N sodium hydroxide solution (2.23 l) with stirring and ice cooling.  The mixture was then stirred at 10 to 15 ° C. for 5 minutes.  After filtering the reaction mixture, the filtrate was adjusted to a pH of 1 with concentrated hydrochloric acid with stirring.  The precipitates were collected by filtration, washed with water and then dried to give 2-2- (formylaminothiazol-4-yl) glyoxylic acid, which was also called 2- (2-formylimino-2,3-dihydrothiazol-4-yl) -glyoxylic acid can be called (234 g), mp. - 133 to 136 C (dec. ). 



     NMR spectrum (NaDCO3, b):
8.27 (1H, s) 8.6 (1H, s). 



  Production Example 4
To a suspension of 2- (2-formylaminothiazol-4-yl) glyoxylic acid, which can also be called 2- (2-formylimino-2,3-dihydrothiazol4-yl) glyoxylic acid, (20 g) in water (400 ml ) sodium bicarbonate (8.4 g) was added with ice cooling and stirring.  The mixture was stirred at the same temperature for 10 minutes and then ethanol (10 ml) was added. 



  To the mixture was added sodium borohydride (1.52 g) over 10 minutes with stirring at the same temperature, and the mixture was stirred at the same temperature for 1 hour and 50 minutes.  After the reaction, the reaction mixture was filtered.  The filtrate was adjusted to pH 4.0 with 10% hydrochloric acid and then concentrated under reduced pressure until the volume was 100 ml.  The concentrated filtrate was brought to a pH of
1 adjusted with 10% hydrochloric acid and the crystallization was started by scratching.  The concentrated filtrate was stirred at room temperature for 1 hour and then left in a refrigerator overnight.  

  The precipitates were collected by filtration, washed twice with ice water and then dried under suction to give 2-hydroxy-2- (2-formylaminothiazoleXyl) acetic acid, also known as 2-hydroxy-2- (2-formylimino-2,3- dihydrothiazolX yl) -acetic acid (14.8 g), mp.  188 to 189 C (dec. ) was obtained. 



  IR spectrum (Nujol):
1730, 1635cm- '.    



  NMR spectrum (NaDCO3, b): 5.07 (1H, s) 7.15 (1H, s)
8.5 (1H, s). 



  Preparation 5 (a) A solution of ethyl 2-methoxyiminoXbromacetoacetate (a mixture of syn and anti isomers) (17.4 g) and thiourea (5.4 g) in ethanol (100 ml) was heated under reflux for 4 h .  The reaction mixture was left in a refrigerator, whereby crystals were precipitated. 



  The crystals were 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 under reduced pressure. 



  Water (100 ml) was added to the residue and the mixture was washed with ether.  The aqueous layer was made alkaline with a 28% aqueous ammonia solution and extracted with ethyl acetate.  The extract was washed with water and a saturated aqueous sodium chloride solution and dried over magnesium sulfate.  The solvent was distilled off under reduced pressure to give crystalline ethyl 2-methoxyimino-2- (2-aminothiazol4-yl) acetate (Synisomeres), which is also called ethyl 2-methoxyimino 2- (2-imino-2,3- dihydrothiazol-4-yl) acetate (Synisomeres), (5.2 g) was obtained. 



  IR spectrum (Nujol): 3400.3300.3150, 1725.1630, 1559cm '.    



  NMR spectrum (CDCb, o):
1.38 (3H, t, J = 7Hz)
4.03 (3H, s)
4.38 (2H, q, J = 7Hz)
5.91 (2H, broad s) 6.72 (1H, s). 



   (b) Ethanol (10 ml) was converted into a suspension of ethyl 2-methoxyimino-2- (2-aminothiazol-4-yl) acetate (Synisomeres), also known as ethyl 2-methoxyimino-2- (2-imino- 2,3-dihydrothia zolXyl) acetate (Synisomeres) can be referred to (2.2 g) in an IN aqueous sodium hydroxide solution (12 ml). 



  The mixture was stirred at ambient temperature for 15 h. 



  The reaction mixture was adjusted to pH 7.0 with 10% hydrochloric acid.  Ethanol was distilled off under reduced pressure.  The remaining aqueous solution was washed with ethyl acetate, adjusted to pH 2.8 with 10% hydrochloric acid, and stirred under ice cooling, whereby crystals were precipitated.  The crystals were collected by filtration, washed with acetone and recrystallized from ethanol, whereby colorless needles of 2-methoxyimino-2- (2-aminothiazol4-yl) -acetic acid (Synisomeres), also known as 2-methoxyimino-2- (2 -imino-2,3-dihydrothiazole-4.    



  yl) -acetic acid (Synisomeres) can be called (1.1 g) were obtained. 



  IR spectrum (Nujol): 3150.1670.1610, 1585cm¯1. 



  NMR spectrum (d6-dimethyl sulfoxide, o):
3.83 (3H, s) 6.85 (1H, s)
7.20 (2H, broad s). 



  Production Example 6
Pyridine (5 ml) was converted into a suspension of 2-methoxyimino-2- (2-aminothiazol4-yl) acetic acid (Synisomeres), also known as 2-methoxyimino-2- (2-imino-2,3. dihydrothiazol-4-yl) - acetic acid (Synisomeres) can be referred to (2.0 g) in ethyl acetate (20 ml).  A solution of bis (2,2,2-trifluoroacetic acid) anhydride (2.5 g) in ethyl acetate (3 ml) was added dropwise with stirring at 5 to 7 "C and the mixture was stirred at 3 to 5" for 30 min C stirred.  Water (30 ml) was added to the reaction mixture and the ethyl acetate layer was separated.  The aqueous layer was further extracted with ethyl acetate.  The two layers of ethyl acetate were combined, washed with water and a saturated aqueous sodium chloride solution and dried over magnesium sulfate. 

  The solvent was distilled off under reduced pressure, whereby 2-methoxyimino-2- [2- (2,2,2-trifluoroacetylamino) thiazol-4-yl] acetic acid (Synisomeres), also known as 2-methoxyimino-2 - [2- (2,2,2-trifluoroacetylimino) -2,3-dihydro-thiazol-4-yl] acetic acid (Synisomeres) (0.72 g) was obtained. 



  IR spectrum (Nujol):
1725, 1590 cm- '. 



  Nuclear Magnetic Resonance Spectrum (ds-dimethyl sulfoxide, o): 3.91 (311, s) 7.68 (1H, s). 



   The following compounds were prepared in a similar manner: i) 2-methoxyimino-2- (2-formylaminothiazol-4-yl) acetic acid (Synisomeres), which is also known as 2-methoxyimino-2- (2-formyl imino-2 , 3-dihydrothiazol-4-yl) acetic acid (Synisomeres), mp.  152 "C (dec. ). 



  IR spectrum (Nujol): 3200.2l00 to 2800, 1950.1600cm- '.    



  NMR spectrum (ds-dimethyl sulfoxide, o): 3.98 (1H, s:
7.62 (1H, s) 8.60 (1H, s). 



  example 1
To dimethylformamide (0.54 g) was added dropwise phosphorus oxychloride (1.13 g) with stirring and ice cooling, and the mixture was stirred at 40 ° C for 30 min.  Then dried ethyl acetate (13 ml) was added.  The mixture gradually became 2- (methoxyimino-2- (2-trifluoroacetylaminothiazol-4-yl) acetic acid (Synisomeres), also known as 2-methoxyimino-2- (2-trifluoroacetylimino-2,3-dihydrothiazolffi yl) acetic acid (Synisomeres) can be given (2.0 g) with cooling to 3 to 5 "C.  The mixture was stirred at the same temperature for 40 minutes. 

  The solution thus obtained was added while cooling to -25 "to -20" C with stirring to a solution which was prepared by mixing a mixture of 2-methyl-7-amino-3-cephem-4-carboxylic acid ( 1.44 g) and trimethylsilylacetamide (9.78 g) in dried ethyl acetate (30 ml) was stirred at 35 to 40 ° C. for 5 to 10 min.  The mixture was stirred at the same temperature for 1 h.  Cold water was added under ice cooling. 



  The mixture was then stirred at the same temperature for about 5 minutes.  The ethyl acetate layer was separated from the reaction mixture and the remaining aqueous layer was extracted with ethyl acetate (20 ml x 2).  The ethyl acetate layers were combined, washed with water and then water (50 ml) was added.  The mixture was adjusted to pH 7.5 with a saturated aqueous sodium bicarbonate solution with ice cooling and stirring. 

 

  The aqueous layer was separated.  After washing the aqueous layer with ethyl acetate, ethyl acetate (70 ml) was added.  The mixture was adjusted to pH 2.5 with 10% hydrochloric acid with ice cooling and stirring.  The ethyl acetate layer was separated from the mixture and the remaining aqueous layer was extracted with ethyl acetate (30 ml).  The ethyl acetate layers were combined, washed with an aqueous sodium chloride solution, dried and then concentrated to a total volume of about 10 ml.  To the residue was added diethyl ether (20 ml) and the mixture was stirred for 1 hour. 

  The precipitates were collected by filtration, washed with diethyl ether and then dried to give 2-methyl-7- [2-methoxyimino-2- (2-trifluoroacetylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (Synisomeres ), which can also be called 2-methyl-7 [2-methoxyimino-2- (2-trifluoroacetylimino-2,3-dihydrothiazol4-yl) -acetamido] -3-cephem4-carboxylic acid (Synisomeres), (2.2 g), mp.  197 to 198 C (dec. ) was obtained.  The remaining filtrate was concentrated.  The residue was washed with diethyl ether and then dried, whereby the same compound (0.3 g) was obtained. 



  IR spectrum (Nujol): 3270.1788, 1730, 1660 cm- '. 



  NMR spectrum (d6-dimethyl sulfoxide, o): 1.46 (3H, d, J = 8Hz, 2-CH3)
3.7 to 4.0 (1H, m, 2-H)
3.95 (3H, s, OCH3) 5.17 (1H, d, J = 6Hz, 6-H) 5.94 (1H, d, d, J = 6 and 7Hz, 7-H) 6.62 (1H, d, J = 6Hz, 3-H) 7.56 (1H, s, 5-H on the thiazole ring) 9.81 (1H, d, J = 7Hz, 7-CONH). 



  Example 2
To dimethylformamide (78 ml) was added dropwise phosphorus oxychloride (11.9 g) with stirring and ice cooling. 



  The mixture was stirred at 40 C for 30 min.  To the mixture was added 2- (2-formylaminothiazol4-yl) glyoxylic acid, which can also be called 2- (2-formylimino-2, 3-dihydrothiazol-4yl) glyoxylic acid, (7.8 g) while cooling to -20 C given.  The mixture was then stirred for 30 minutes while cooling to -20 to -15 ° C.  The mixture thus obtained was added, with stirring and with cooling to -50 to -45 C, to a solution which had been prepared in such a way that a mixture of 2-methyl-7-amino-3-cephem-4-carboxylic acid ( 8.35 g) and bis (trimethylsilyl) acetamide (19.5 ml) in dried methylene chloride (170 ml) was stirred at room temperature.  The mixture was stirred at -45 to -40 ° C for 1 hour and then the reaction mixture was poured into a solution of sodium bicarbonate (32 g) in water (1.5 l) with shaking. 

  The aqueous layer was separated and washed with ethyl acetate.  The aqueous layer was layered with ethyl acetate and then adjusted to pH 1-2 with concentrated hydrochloric acid.  The ethyl acetate layer was separated from the mixture and the remaining aqueous layer was extracted with ethyl acetate (200 ml x 2).  The ethyl acetate layers were combined, washed with water and then concentrated to a small volume. 

  The precipitates were collected by filtration, washed with a small amount of ethyl acetate and then dried to give 2-methyl-7- [2- (2-formylaminothiazolffiyl) glyoxylamido] -3-cephemic carboxylic acid, also known as 2-methyl 7- [2- (2-formylimino-2,3-dihydro-thiazol-4-yl) -glyoxylamido] -3-cephem-4-carboxylic acid (7.9 g), mp.  210 to 215 C (dec. ) was obtained. 



  IR spectrum (Nujol).    



   3300.3150, 1780, 1713, 1660, 1625, 1533 cm¯l.    



  NMR spectrum (d6-dimethyl sulfoxide, o): 1.45 (3H, d, J = 7Hz, 2-CH3)
3.7 to 4.1 (IHm, 2-H) 5.17 (1H, d, J = 5Hz, 6-H) 5.91 (1H, dd, J = 5 and 8Hz, 7-H) 6, 59 (1H, d, J = 6Hz, 3-H) 8.40 (1H, s, 5-H on the thiazole ring)
8.57 (1H, s, OHC-N =)
9.83 (1H, d, J = 8Hz, 7-CONH).    



  Example 3
To a solution of thionyl chloride (3.01 g) in methylene chloride (45 ml) was added dimethylformamide (0.928 g) and 2- (2 formylaminothiazol-4-yl) glyoxylic acid, also known as 2- (2-formylimino-2,3- dihydrothiazol-4-yl) glyoxylic acid can be given (3.71 g).  The mixture was stirred at room temperature for 4 hours.  The mixture thus obtained was added, with stirring and with cooling to -25 to -20 ° C., to a solution which had been prepared by adding a mixture of 2-methyl-7-amino-3-cephem4-carboxylic acid (3rd , 3 g) and trimethylsilylacetamide (16.2 g) in methylene chloride (60 ml) had been stirred for 40 min at room temperature.  The mixture was stirred at -25 to -20 ° C. for 30 minutes, at -10 to 0 ° C. for 30 minutes and then at room temperature for 30 minutes. 

  Water (30 ml) was added to the reaction mixture and the mixture was stirred for 10 minutes.  After a saturated aqueous sodium bicarbonate solution was added to the mixture to dissolve the precipitates, the aqueous layer was separated.  Ethyl acetate was added to the aqueous layer and the mixture was adjusted to pH 2 with 2N hydrochloric acid.  The ethyl acetate layer was then separated off; the remaining aqueous layer was further extracted with ethyl acetate. 



  The ethyl acetate layers were combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then concentrated.  The crystalline residue thus obtained was pulverized in diethyl ether, collected by filtration, and then dried, whereby yellow crystalline powder of 2-methyl-7- [2- (2-formylaminothiazol-4-yl) glyoxylamido] -3-cephem-4- carboxylic acid, which can also be referred to as 2-methyl-7- [2- (2-formylimino-2,3-dihydrothiazoleXyl) glyoxylamido] -3-cephem4-carboxylic acid, was obtained (3.81 g). 



  IR spectrum (Nujol):
3475.3315.3200.1788, 1655.1620.1530.1293, 1240.1185 cm-l.    



  NMR spectrum (d6-dimethyl sulfoxide, o):
1.48 (3H, d, J = 7Hz)
3.70 to 4.17 (111, m) 5.21 (1H, d, J = 5Hz) 5.96 (1H, d, J = 5Hz)
6.63 (1H, d, J = 6Hz)
8.44 (1H, s) 8.62 (1H, s). 



  Example 4
Phosphorus oxychloride (12.5 g) was added dropwise to dimethylformamide (6.42 g) over the course of 20 min with stirring and cooling to 5 to 10 ° C.  The mixture was stirred at 40 ° C for 30 min and then ethyl acetate (200 ml) was added with vigorous stirring.  After the mixture had cooled to 3 C, 2-methoxyimino-2- (2-formyl aminothiazolffiyl) acetic acid (synisomer), which was also called 2-methoxyimino-2- (2-formylimino-2,3-dihydrothiazolffiyl) acetic acid ( Synisomeres), (18.34 g) was added and the mixture was then stirred at 3 to 5 C for 40 min.  

  The solution thus obtained was added with vigorous stirring and cooling to -25 C to a solution which had been prepared by a mixture of 2-methyl-7-amino-3 cephem4. carboxylic acid (17.1 g) and trimethylsilylacetamide (84 g) in ethyl acetate (300 ml) were stirred at room temperature for 1 h.  The mixture was stirred at -20 to -15 C for 1 h and at -10 to -5 C for 30 min.  Water (200 ml) at room temperature was added to the mixture, and the mixture was stirred at the same temperature for an additional 30 minutes. 



  After adding a saturated aqueous sodium bicarbonate solution to the mixture to dissolve the precipitates, the aqueous layer was separated.  Ethyl acetate was added to the aqueous layer and the mixture was adjusted to pH 2 with 2N hydrochloric acid.  The ethyl acetate layer was then separated.  The remaining aqueous layer was further extracted with ethyl acetate.  The ethyl acetate layers were combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, treated with activated carbon, and then concentrated. 

  The crystalline residue thus obtained was pulverized in diethyl ether, collected by filtration and then dried, whereby white crystals of 2-methyl-7- [2-methoxyimino-2- (2-formylaminothiazol-4-yl) -acetamido] -3-cephemXcarboxylic acid (Synisomeres), which are also referred to as 2-methyl-7 [2-methoxyimino-2- (2-formylimino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (Synisomeres) can, (32.2 g) were obtained. This compound was recrystallized from methanol, whereby white crystals of the pure compound, mp. 174 to 204 C (dec. ) were obtained. 



  IR spectrum (Nujol): 3270.1780.1655.1285.1040 cm-1. 



  NMR spectrum (d6-dimethyl sulfoxide, o): 1.44 (3H, d, J = 7Hz) 3.68 to 4.12 (1H, m)
3.90 (3H, s) 5.14 (1H, d, J = 5Hz)
5.90 (1H, d, J = 5Hz) 6.56 (1H, d, J = 6Hz)
7.40 (1H, s)
8.50 (1H, s).    



   Similarly, the following compounds were made:
1) 2-Methyl-7- [2-hydroxy-2- (2-aminothiazole-amido] -3-cephem-4-carboxylic acid hydrochloride, which is also known as 2-methyl-7- [2-hydroxy-2- ( 2-imino-2,3-dihydrothiazol-4-yl) -acetamido] -3-cephem-4-carboxylic acid hydrochloride, mp.     > 250 C.    



   2) 2-Methyl-7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (Synisomeres), also known as 2-methyl-7- [2-methoxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) acetamido] 3-cephem-4-carboxylic acid (Synisomeres), Zp.     > 241 C.    



   3) 2-methyl-7- [2- (2-aminothiazol-4-yl) -glyo cephem-4-carboxylic acid hydrochloride, which is also known as 2-methyl-7- [2- (2-imino-2,3 -dihydrothiazol-4-yl) -glyoxylamino] -3- cephem4carboxylic acid hydrochloride, mp.     > 270 C.    



     4) 2,2,2-Trichloroethyl-2-methyl-7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate (Synisomeres), which is also known as 2,2,2-trichloroethyl-2-methyl-7- [2-methoxy-imino-2- (2-imino-2,3-dihydrothiazolffiyl) acetamido] -3- cephem 4 carboxylate (Synisomeres) can be designated, Mp 128 to 149 C (dec. ). 



     5) Pivaloyloxymethyl-2-methyl-7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate (Syniso- (Synisomeres), also known as pivaloyloxymethyl-2 -methyl-7- [2-metho-Ajimino-2- (2-imino-2,3-dihydrothiazol-4-yl) -acetamido] -3- cephem-4-carboxylate (Synisomeres), mp. 165 to 170 C (dec. ). 



     6) p-nitrobenzyl-2-methyl-7- [2-hydroxyimino-2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate (syn isomer), which is also known as p-nitrobenzyl 2-methyl-2- [2-hydroxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylate (syn isomer) can be prepared; powder product. 



     7) 2-methyl-7- [2-hydroxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn isomer), which is also known as 2-methyl 7 {2-hydroxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn isomer) can be prepared. 



     8) 2-methyl-7- [2-ethoxyimino-2- (2-formylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn isomer), which is also known as 2-methyl-7- [2-ethoxyimino-2- (2-formylimi drothiazollyl) acetamido] -3-cephem-4-carboxylic acid (syn-isomer) can be prepared. 



  IR spectrum (Nujol): 3350.3240.3190.1775.1700.1650.1620cm¯ 'NMR spectrum (D6-dimethyl sulfoxide, o): 1.28 (3H, t, J = 7Hz)
1.47 (3H, d, J = 8Hz)
3.68-4.2 (I H, m)
4.18 (2H, q, J = 7Hz)
5.15 (IH, d, J = 5Hz) 5.94 (IH, d, d, J = 5 and 8Hz)
6.58 (IH, d, J = 6Hz)
7.40 (1H, s)
8.52 (1H, s)
9.65 (1H, d, J = 8Hz)
11.64 (1H, broad s)
9) 2-methyl-7- [2-isopropoxyimino-2- (2-formylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn-isomer),

   which also as 2-methyl-7- [2-isopropoxyimino-2- (2-formylimino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn-isomer) can be represented. 



  IR spectrum (Nujol): 3480,3300,3180,1780,1740,1700,1660cm¯ NMR spectrum (D6-dimethylsulfoxide, o): 1.14 (6H, d, J = 7Hz)
1.4 (3H, d, J = 6Hz) 3.8 (1H, m)
4.35 (1H, m) 5.1 (1H, d, J = 5Hz)
5.87 (1H, d, d, J = 5 and 8Hz)
6.5 (1H, d, J = 6Hz)
7.35 (1H, s)
8.45 (I H, s)
9.55 (1H, d, J = 8Hz)
10) 2-Methyl-7- [2-äthotyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid hydrochloride (syn-isomer), which is also known as 2-methyl -7- [2-ethoxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid hydrochloride (syn isomer) can be prepared. 

 

  IR spectrum (Nujol):
3350.1790.1730.1670.1630cm-1
11) 2-methyl-7- [2-isopropoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn isomer), which is also known as 2-methyl-7- [2-isopropoxyimino-2- (2-imino-2,3-dihydrothiazole) acetamido] -3-cephem-4-carboxylic acid (syn-isomer) can be prepared. 



  IR spectrum (Nujol): 3350, 1780, 1670, 1600 cm-1
12) 2-Methyl-7- [2-propoxyimino-2- (2-formylaminothiazol-4-yl) acetamidol-3-cephem-4-carboxylic acid (syn isomer), which is also known as 2-methyl-7- [2 -propoxyimino-2- (2-formyl-imino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephemcarboxylic acid (synisomeres) can be prepared. 



  IR spectrum (Nujol):
3450,3300,3050,1780,1730,1690,1660cm-1 NMR spectrum (D6-dimethyl sulfoxide, o): 0.96 (3H, t, J = 6Hz) 1.48 (3H, d, J = 6Hz)
1.68 (2H, m)
3.85 (1H, m)
4.02 (2H, t, H = 6Hz) 5.14 (111, d, J = SHz)
5.96 (1H, d, d, J = 5.9Hz) 6.6 (1H, d, J = 6Hz)
7.42 (1H, s)
8.56 (lH, -s)
9.70 (1H, d, J = 9Hz)
13) 2-Methyl-7- [2-propoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem4-carboxylic acid (syn isomer), which is also known as 2-methyl-7- [2 -propoxyimino-2- (2-imino-2,3-dihydro-thiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn-isomer) can be prepared. 



  IR spectrum (Nujol):
3330,3080,1780,1670 cm-l
14) 2-Methyl-7- [2-hexyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem4-carboxylic acid (syn isomer), which is also known as 2-methyl-7 [2-hexyloxyimino -2- (2-imino-2,3-dihydrothiazo-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn isomer) can be prepared. 



  IR spectrum (Nujol):
3300,3200,1780,1670, l630cm-1
15) 2-methyl-7- [2-hexyloxyimino-2- (2-formylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn isomer), which is also known as 2-methyl-7- [2-hexyloxyimino-2- (2-formylimino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn isomer) can be prepared. 



  IR spectrum (Nujol): 3270.3180, 1790, 1700, 1655 cm-1 NMR spectrum (D6-dimethyl sulfoxide, o) 0.6 to 2.1 (14H, m)
3.6 to 4.4 (3H, m) 5.15 (1H, d, J = 5) 5.93 (1H, d, d, J = 5.8Hz) 6.57 (1H, d, J = 6)
7.40 (1H, s)
8.54 (1H, s) 9.62 (1H, d, J = 8Hz)
12.7 (1H, s)
16) 2-Methyl-7- [2-hexyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid hexanoyloxymethyl ester (syn isomer), which is also known as 2- Methyl-7- [2-hexyloxyimino 2- (2-imino-2,3-dihydrothiazol-4-yl) -acetamidoj-3-cephem-4-carboxylic acid hexanoyloxymethyl ester (syn-isomer) can be prepared. 



  IR spectrum (Nujol):
3340.3200, (wide), 3150 (wide, 1790 (wide), 1750 to 1790,
1680.1630cm-1 Example 5
A suspension of 2-methoxyimino-2- (2-aminothiazol4-yl) acetic acid (Synisomeres), also known as 2-methoxyimino-2- (2imino-2,3-dihydrothiazol-4-yl) acetic acid (Synisomeres) (26 g) in ethyl acetate (250 ml) was cooled to 5 C and phosphorus oxychloride (25 g) was added dropwise with stirring and ice-cooling.  The mixture was then stirred at 4 to 6 C for 30 min.  To the mixture was added dropwise a solution of trimethylsilylacetamide (22 g) in ethyl acetate (20 ml) with stirring and under ice cooling.  The mixture was stirred at 4 to 6 C for 30 min.  Then.  additional phosphorus oxychloride (25 g) was added with stirring and under ice cooling. 

  The mixture was stirred at the same temperature for 15 minutes and dimethylformamide (10.6 g) was added dropwise at the same temperature.     The mixture was stirred at the same temperature for 40 minutes.  The resulting clear solution was cooled to -10 ° C.  On the other hand, to a solution of 2-methyl-7-amino-3-cephem4-carboxylic acid (23.9 g) in a solution of sodium bicarbonate (25 g) and water (400 ml), acetone (300 ml) was added and the mixture was cooled to -5 C.  To the mixture was dropwise added the clear solution of -5 to 0 ° C prepared above, and then the mixture was stirred for 2 hours.  The pH of the mixture was maintained at 6 throughout with a 15% aqueous sodium bicarbonate solution.  Insoluble materials were filtered off and the aqueous layer was separated. 

  The aqueous layer was adjusted to pH 3 with 20% hydrochloric acid, and precipitated crystals were collected by filtration, washed with water and acetone in order, and then dried under reduced pressure.  In this way, 2-methyl-7- [2-methoxyimino-2- (2-aminothiazol4-yl) acetamido] -3-cephem4-carboxylic acid (Synisomeres), which is also known as 2-methyl-7- [2-methoxyimino 2- (2-imino-2,3-dihydrothiazol-4yl) -acetamidoj-3-cephem4-carboxylic acid (Synisomeres) can be called (39.4 g).  The compound was identified by IR and NMR analysis with the compound of Example 6. 



   The sodium or ammonium salt of this compound is said to be obtained in a conventional manner.  The physical properties of these compounds are as follows: 1) sodium salt, powder: IR spectrum (Nujol):
1770, 1660, 1560, 1500 cm- '. 



  Nuclear Magnetic Resonance Spectrum (d6-dimethyl sulfoxide, o): 1.37 (3H, d, J = 7, OHz) 3.64 (1H, m) 3.84 (3H, s) 4.97 (1H, d, J = 5.OHz) 5.74 (1H, m)
6.21 (1H, d, J = 6, OHz) 6.70 (1H, s) 7.30 (2H, m)
9.63 (1H, m). 



  2) Ammonium salt, powder: IR spectrum (Nujol): 1775, 1660, 1580, 1530 cm- '. 



  NMR spectrum (d6-dimethyl sulfoxide, b):
1.37 (3H, d, J = 7, OHz)
3.64 (1H, m)
3.83 (3H, s) 4.99 (1H, d, J = 5, OHz)
5.8 (5H, m) 6.17 (1H, d, J = 6, OHz)
6.87 (1H, s)
7.27 (2H, m)
9.55 (1H, m).   



  Example 6
To a solution of sodium acetate (11.6 g) in water (43 ml) was added 2-methyl-7- [2-methoxyimino-2- (2-trifluoroacetylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (Synisomeres), which is also known as 2-methyl-7- [2-methoxyimino-2- (2-trifluoroacetylimino-2,3-dihydrothiazol4-yl) acetamido] -3-cephem-4-carboxylic acid (Synisomeres ) (2.1 g) was added with stirring and the mixture was adjusted to a pH of 6 with 5% aqueous sodium bicarbonate solution. 



  The mixture was stirred at room temperature overnight. 



  After the reaction, the reaction mixture was adjusted to pH 2.8 to 3 with 10% hydrochloric acid and then cooled.  The precipitates were collected by filtration and then dried to give 2-methyl-7- [2-methoxyimino-2- (2-aminothiazol-4yl) -acetamido] -3-cephem4-carboxylic acid (Synisomeres), also known as 2- Methyl-7- [2-methoxyimino-2 (2-imino-2,3-dihydrothiazol-yl-acetamido] -3-cephem-4-carboxylic acid (Synisomeres) can be called (1.1 g), mp .   > 241 C.  The same compound (0.25 g) was obtained from the filtrate in a conventional manner. 



  IR spectrum (Nujol):
3470, 3320,3190, 2380, 1783, 1690, 1655, 1622, 1530 cm-l.    



  NMR spectrum (D6-dimethyl sulfoxide, o): 1.44 (3H, d, J = 8Hz, 2-CH3)
3.7 to 4.0 (1H, m, 2-H) 3.84 (3H, s, OCH3) 5.12 (1H, d, J = 6Hz, 6-H) 5.89 (1H, dd, 5 = 6 and 8Hz, 7-H)
6.57 (1H, d, J = 7Hz, 3-H) 6.77 (1H, s, 5-H on the thiazole ring) 9.62 (1H, d, J = 8Hz, 7-CONH). 



  Example 7
To a suspension of 2-methyl-7- [2- (2-formylaminothiazol-4-yl) glyoxylamido] -3-cephem-carboxylic acid, which is also known as 2-methyl-7- [2- (2-formylimino-2, 3-dihydrothiazol-4-yl) -glyoxyl-amido] -3-cephem-4-carboxylic acid (3.0 g) in methanol (60 ml) was added dropwise to phosphorus oxychloride (2.55 g) with ice cooling and stirring given.  The mixture was stirred at the same temperature for 3.5 hours and then at room temperature for 30 minutes.  After the reaction, the reaction mixture was poured into diethyl ether (400 ml). 

  The precipitates were collected by filtration, washed with diethyl ether and then dried, whereby 2-methyl-7 [2- (2-aminothiazoleXyl) -glyoxylamido] -3-cephem-4-carboxylic acid hydrochloride, which compound also as 2nd -Methyl-7- [2 (2-imino-2,3-dihydrothiazol-4-yl) -glyoxylamido] -3-cephem-4-carboxylic acid hydrochloride, (2.2 g), mp. 



   > 270 C was obtained. 



  IR spectrum (Nujol): 1770, 1700 (shoulder), 1665, 1624, 1515 cm- '.    



  NMR spectrum (d6-dimethyl sulfoxide, o): 1.44 (3H, d, J = 7Hz, 2-CH3)
3.6 to 4.1 (1H, m, 2-11) 5.15 (1H, d, 3 = 511z, 6-11) 5.82 (1H, dd, J = 5 and 8Hz, 7-H)
6.58 (1H, d, J = 6Hz, 3-H) 8.17 (1H, s, 5-H on the thiazole ring) 9.87 (1H, d, J = 8Hz, 7-CONH). 



  Example 8
To a suspension of 2-methyl-7 {2-methoxyimino-2- (2-formylaminothiazolffiyl) acetamido] -3-cephemXcarboxylic acid (Synisomeres), also known as 2-methyl-7- [2-methoxyimino-2- (2formylimino -2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (Synisomeres), (9.0 g) in methanol (90 ml) was concentrated hydrochloric acid (2.12 ml) added with stirring at room temperature and the mixture was stirred at the same temperature for 7 hours.  Diethyl ether was gradually added to the reaction mixture until crystals began to precipitate.  The mixture was left to stand for 30 minutes. 

  Then, the precipitated crystals were collected by filtration, washed with diethyl ether and then dried, whereby white crystals of 2-methyl-7- [2-methoxyimino-2- (2-aminothiazol4yl) -acetamidoj-3-cephem carboxylic acid hydrochloride (Synisomeres) which compound can also be referred to as 2-methyl-7- [2-methoxyimino-2- (2-imino-2,3-dihydro-thiazolyl) acetamidoj-3-cephem-4-carboxylic acid hydrochloride (Synisomeres), (7.9 g) were obtained. 



   The remaining filtrate was concentrated until the total volume was reduced by half.  Diethyl ether was gradually added to the concentrated filtrate until crystals began to precipitate.  The mixture was left to stand for 1 hour.  The precipitated crystals were collected by filtration, washed with diethyl ether and then dried, whereby an additional amount of the same compound (0.5 g) was obtained. 



  IR spectrum (Nujol):
3300, 3295, 1780, 1720, 1660, 1630, 1300cm-1. 



  NMR spectrum (d6-dimethyl sulfoxide, o): 1.44 (3H, d, J = 7Hz) 3.70 to 4.14 (1H, m) 3.94 (3H, s)
5.10 (1H, d, J = 5Hz)
5.84 (1H, d, J = 5Hz) 6.59 (1H, d, J = 6Hz)
6.94 (1H, s). 



   To a suspension of 2-methyl-7- [2-methoxyimino-2- (2 aminothiazoleXyl) acetamido] -3-cephem iI carboxylic acid hydrochloride (synisomer), which compound also as 2-methyl-7- [2-methoxyimino -242-imino-2,3-dihydrothiazol'I yl) -acetamido] -3-cephem-4-carboxylic acid hydrochloride (Synisomeres) can be called (7.7 g) in water (77 ml) was a saturated aqueous Sodium bicarbonate solution (44 ml) added.  The solution thus obtained was adjusted to pH 3 by 1N hydrochloric acid, and then left to stand in a cool place for 1 hour. 

  The precipitated crystals were collected by filtration, washed with water and then dried, whereby a white powder of 2-methyl-7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- cephem-4carboxylic acid (Synisomeres), which can also be referred to as 2-methyl-7- [2-methoxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) acetamido] -3 cephemXcarboxylic acid (Synisomeres) , (6.67 g), mp.  196 to 240 C (dec. ) was obtained. 

 

  IR spectrum (Nujol): 3470.3310.3200.1790, 1655.1620.1530.1295, 1055 cm- '.    



  Nuclear Magnetic Resonance Spectrum (d6-dimethyl sulfoxide, 8):
1.48 (3H, d, J = 8Hz)
3.65 to 4.08 (1H, m) 3.84 (3H, s)
5.10 (1H, d, J = 5Hz) 5.84 (1H, d, J = 5Hz) 6.54 (1H, d, J = 6Hz)
6.72 (1H, s). 



   Similarly, the following compounds were obtained 1) 2-methyl-7- [2-hydroxy-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid hydrochloride, which compound can also be referred to as 2-methyl-7- [2-hydroxy-2- (2-imino-2,3-dihydro-thiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid hydrochloride, mp .     > 250 C.    



   2) 2,2,2-Trichloroethyl-2-methyl-7-12-methox aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate (Synisomeres), which is also called 2,2,2-trichloroethyl -2-methyl-7- [2-methoxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) -acetamido] -3-cephemXcarboxylate (Synisomeres), mp. 128 to 149 C (dec. ). 



      3) 2,2,2-trichloroethyl-2-methyl-7- [2-hydroxyimino-2- (2-aminothhiazol-4-yl) acetamido] -3-cephem-4-carboxylate (Synisomeres), the also as 2,2,2-trichloroethyl-2-methyl-7- [2-hydroxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephemic carboxylate (Synisomeres) can be designated, Mp. 175 to 178 C (dec. ).    



     4) p-Nitrobenzyl-2-methyl-7- [2-hydroxyimino-2- (2-aminothiazoleXyl) acetamido] -3-cephem-4-carboxylate (syn isomer), which is also known as p-nitrobenzyl-2 -methyl-7- [2-hydroxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylate (syn-isomer) can be prepared; powder product. 



     5) 2-methyl-7- [2-hydroxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn isomer), which is also known as 2-methyl-7- [2-hydroxyimino-2- (2-imino-2,3-dihydrot-hiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn isomer) can be prepared. 



     6) 2-Methyl-7- [2-ethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid hydrochloride (syn-isomer), which is also known as 2-methyl -7- [2-ethoxyimino-2- (2-imino-2,3-drothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid hydrochloride (syn-isomer) can be prepared. 



  IR spectrum (Nujol): 3350.1790,1730,1670,1630cm¯i NMR spectrum (D6-dimethyl sulfoxide, o): 1.30 (3H, t) J = 6Hz)
1.47 (3H, d, J = 6Hz)
3.6-4.5 (1H, m)
4.25 (2H, q, J = 6Hz) 5.17 (1H, d, J = 5Hz) 5.92 (1H, d, d, J = 5 and 8Hz) 6.60 (1H, d, J = 6Hz)
6.97 (1H, s)
9.82 (1H, d, J = 8Hz)
7) 2-methyl-7- [2-isopropoxyimino-2- (2-aminothiazol-4-yl) acetamido] 3-cephem4-carboxylic acid (syn-isomer),

   which can also be represented as 2-methyl-7- [2-isopropoxyimino-2- (2-imino-2,3-dihydrothiazol-yl) acetamido] -3-cephem-4-carboxylic acid (syn-isomer). 



  IR spectrum (Nujol): 3350.1780, 1670, 1600 cm-1 NMR spectrum (D6-dimethyl sulfoxide, o): 1.20 (6H, d, J = 6Hz)
1.43 (lH, d, J = 6Hz)
3.83 (lH, m)
4.27 (1H, m)
5.12 (1H, d, J = 5Hz)
5.87 (1H, d, d, J = 5 and 9Hz)
6.55 (lH, d, J = 6Hz)
6.72 (1H, s)
7.23 (2H, broad s) 9.49 (lH, d, J = 9Hz)
8) 2-methyl-7- [2-propoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn-isomer),

   which can also be represented as 2-methyl-7- [2-propoxyimino-2- (2-imino-2, 4-yl) acetamido] -3-cephem- $ carboxylic acid (syn-isomer). 



   9) 2-methyl-7- [2-butoxyimino-2- (2-aminothiazol-4-yl) -acetamido] -3-cephem-4-carboxylic acid (syn isomer), which is also known as 2- Methyl-7- {2-butoxyimino-2- (2-imino-2,3-dihydrothiazol-s yl) acetamido] -3-cephemic carboxylic acid (syn isomer) can be prepared. 



   10) 2-methyl-7- [2-isobutoxyimino-2- (2-aminot acetamido-3-cephem-4-carboxylic acid (syn isomer)), which is also known as 2-methyl-7- [2-isobutoxyimino-2- (2-imino-2,3-dihydro-thiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn isomer) can be prepared. 



     1 1) 2-Methyl-7- [2-hexyloxyimino-2- (2-aminothiazol-syl) acetamido] -3-cephem-4-carboxylic acid (syn isomer), which is also known as 2-methyl-7- [ 2-hexyloxyimino-2- (2-imino-2,3-dihydro-thiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn isomer) can be prepared. 



  IR spectrum (Nujol): 3300.3200, 1780.1670, 1630 cm-1
12) 2-methyl-7- [2-hexyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid hexanoyloxymethyl ester (syn isomer), which is also known as 2-methyl 7- [2-hexyloxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid hexanoyloxymethyl ester (syn isomer) can be prepared. 



  IR spectrum (Nujol):
3340.3200 (wide), 3150 (wide), 1790 (wide), 1750 to 1790,
1680.1630 cm¯ Example 9
To a suspension of 2-methyl-7- [2- (2-aminothiazol-4-yl) -glyoxylamido] -3-cephem-4-carboxylic acid - which compound also as 2-methyl-7- [2- (2- imino-2,3-dihydrothiazol-yl) -glyoxylamido] -3-cephem-4-carboxylic acid hydrochloride, (3.80 g) in methanol (70 ml), IN aqueous sodium hydroxide solution (18.8 ml) with ice cooling and stirring.  Sodium borohydride (0.13 g) was added to the mixture over 2Q min with cooling with ice and stirring.  The mixture was stirred at the same temperature for 30 minutes.  After the reaction, the methanol was distilled off from the reaction mixture. 

  Cold water (60 ml) was added to the residue, and the mixture was washed with ethyl acetate, adjusted to pH 2 with 10% hydrochloric acid, and then filtered. 



  The filtrate was subjected to column chromatography (non-ionic adsorbent Diaion HP 20 manufactured by Mitsubishi (Chemical Industries), and the column was washed with water and then eluted with 10% aqueous isopropyl alcohol solution.  The eluates containing the aimed compound were collected and then lyophilized to give a light yellow powder (1.80 g).  To the powder was added methanol (10 ml) and 35% hydrochloric acid (0.5 g) in order.  The solution thus obtained was subjected to column chromatography using activated carbon (2.0 g).    The column was then eluted with methanol.  

  The eluates containing the aimed compound were collected, and then the solvent was distilled off under reduced pressure.  The residue was washed with ethyl acetate and then dried, yielding-2-methyl-7- [2-hydroxy-2- (2-aminothiazol-4-yl) acetamido] 3-cephem-4-carboxylic acid hydrochloride, which compound as well can be referred to as 2-methyl-7- [2-hydroxy-2- (2-imino-2,3-dihydro-thiazol4-yl) acetamido] -3-cephem-4-carboxylic acid hydrochloride, (1.10 g) was obtained, mp.   > 250 C. 



  IR spectrum (Nujol): 3000 to 3400, 1775, 1690, 1630, 1523 cm- '.    



  NMR spectrum (d6-dimethyl sulfoxide, o):
1.48 (3H, d, J = 8Hz, 2-CH3) 3.5 to 4.1 (lH, m, 2-H)
5.09 (1H, d, J = 5Hz, m, 2-H) 5.17 (s) and 5.19 (s) (-CHCO-N =) (total: 1H) |
O
5.78 (1H, dd, J = 5 and 9Hz, 7-H) 6.54 (1H, d, J = 6Hz, 3-H)
6.76 (1H, s, 5-H on the thiazole ring)
8.73 (d, J = 9Hz) and 8.81 (d, J = 9Hz) (7-CONH) (total: 1H). 



  Example 10
To a suspension of 2-methyl-7- [2- (21-formylamino thiazol4-yl) -glyoxylamido] -3-cephem4-carboxylic acid, which is also known as 2-methyl-7- [2- (2-formylimino-2, 3-dihydrothiazol-4-yl) -gly-oxylamido] -3-cephem-4-carboxylic acid (792 mg) in water (20 ml), sodium bicarbonate (168 mg) was added with stirring.  Sodium acetate trihydrate (272.2 mg) and O-methylhydroxylamine hydrochloride (334 mg) were added to the solution thus obtained and the mixture was stirred at 48 to 50 ° C. for 2 hours.  After the reaction mixture was cooled, a saturated aqueous sodium bicarbonate solution (10 ml) and ethyl acetate (15 ml) were added to dissolve the precipitated insoluble material. 

  The aqueous layer was separated, washed with ethyl acetate, adjusted to pH 1 with 2N hydrochloric acid, and then extracted with ethyl acetate.  The ethyl acetate extract was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then concentrated. 



  The residue was pulverized in diethyl ether, collected by filtration, and then dried to give 2-methyl-7 [2-methoxyimino-2- (2-formylaminothiazol-4-yl) acetamido] -3-cephem4-carboxylic acid (Synisomeres) can also be called 2-methyl-7 [2-methoxyimino-2- (2-formylimino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (Synisomeres), (505 mg ) was obtained.  This compound was recrystallized from methanol, whereby pure crystals of the desired pure compound were obtained. 



  IR spectrum (Nujol):
3270.3200, 1775, 1650, 1530, 1280 cm-1. 



  NMR spectrum (D6-dimethyl sulfoxide, o): 1.44 (3H, d, J = 7Hz)
3.50 to 4.00 (1H, m) 3.90 (3H, s) 5.12 (1H, d, J = 5Hz) 5.92 (1H, d, J = SHz)
6.57 (1H, d, J = 6Hz)
7.41 (1H, s)
8.51 (1H, s). 



   The following compounds were obtained in a similar manner:
1) 2-methyl-7- [2-methoxyimino-2- (2-aminothiazol-4-yl) -acet amido] -3-cephem4-carboxylic acid (Synisomeres), which is also known as 2-methyl-7- [2- methoxyimino-2- (2-imino-2,3-dihydrothiazol-4yl) -acetamido] -3-cephem-4-carboxylic acid (Synisomeres), Zp.   > 241 C. 



   2), 2-Trichloroethyl-2-methyl-7- [2-methoxyimino-2- (2aminothiazol4yl) acetamido] -3-cephemcarboxylate (Synisomeres), which is also called 2,2,2-trichloroethyl-2-methyl-7 - [2-methoxyimino-242-imino-2,3-dihydrothiazol-4-yl) acetamido] -3- cephem-4-carboxylate (Synisomeres), mp.  128 to 149 C (dec. ). 



  Example 11
To a solution of 2,2,2-trichloroethyl-2-methyl-7- [2hydroxyimino-3-oxo4-bromobutyramido) -3-cephem-4-carboxylate (a mixture of syn and anti isomers) (0.51 g) in ethanol (10 ml) was added thiourea (0.068 g) and the mixture was stirred at room temperature for 1 h.  The reaction mixture was concentrated under reduced pressure.  To the residue was added ethyl acetate and water with stirring, and the ethyl acetate layer was separated. 



  The remaining aqueous layer was adjusted to pH 7 and ethyl acetate was extracted.  The ethyl acetate layer and the extract were combined, washed with water, dried over magnesium sulfate, and then concentrated.  The residue was pulverized in diethyl ether, collected by filtration and then dried, yielding a light brown powder of 2,2,2-trichloroethyl-2-methyl-7- [2-hydroxyimino-2- (2-aminothiazol-4-yl ) -acet-amido] -3-cephem-4-carboxylate (Synisomeres), also known as 2,2,2-trichloroethyl-2-methyl-7- [2-hydroxyimino-2- (2-imino-2,3 - dihydrothiazol-4-yl) -acetamido] -3-cephem-4-carboxylate (Synisomeres), mp.  175 to 178 C (dec. ) was obtained. 



  IR spectrum (Nujol): 3300, 1785, 1740, 1710 to 1670, 1540, 1280, 1215, 1045.715 cm-1. 



  Nuclear Magnetic Resonance Spectrum (d6-dimethyl sulfoxide, o): 1.45 (3H, d, J = 7Hz) 3.94 (1H, m) 5.06 (2H, s).    



     5.20 (1H, d, J = 5Hz) 5.94 (1H, dd, J = 5 and 9Hz) 6.64 (1H, s)
7.08 (2H, broad s) 9.47 (1H, d, J = 9Hz) 11.28 (111, s).    



   The following connections were obtained in a similar manner:
1) p-nitrobenzyl-2-methyl-7- [2-hydroxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate (syn isomer), which is also known as p -Nitrobenzyl-2-methyl-7- [2-hydroxyimino-2 (2-imino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylate (syn isomer) can be prepared; powder product. 

 

  IR spectrum (Nujol):
3400.3280.3200, 1770, 1710, 1700, 1650, 1620cm-1 NMR spectrum (D6-dimethyl sulfoxide, o): ppm 1.44 (3H, d, J = 7Hz)
3.6-4.2 (1H, m) 5.25 (1H, d, J = 4.5Hz)
5.43 (2H, s)
5.97 (1H, dd, 5 = 4.5 and 9Hz)
6.73 (1H, s)
6.76 (1H, d, J = 7Hz) 7.74 (2H, d, J = 9Hz) 8.29 (2H, d, J = 9Hz)
9.59 (1H, d, J = 9Hz)
2) 2-methyl-7 [2-hydroxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem4-carboxylic acid (syn isomer), which is also known as 2-methyl-7- [ 2-hydroxyimino-2- (2-imino-2,3-dihydrothiazol-yl) -acetamido] -3-cephem-4-carboxylic acid (syn-isomer) can be prepared. 



  Example 12
To a mixture of 2,2,2-trichloroethyl-2-methyl-7- (2 methoxyimino-3-oxo4brnmbutyramido) -3-cephem4carboxylate (mixture of syn and anti isomers) (0.94 g) and ethanol (10 ml) of thiourea (0.12 g) was added.  The mixture was stirred at room temperature for 40 minutes.  The reaction mixture was concentrated under reduced pressure and the residue was shaken with ethyl acetate and water.  The ethyl acetate layer was separated, and the remaining aqueous layer was neutralized with sodium bicarbonate and then extracted with ethyl acetate.  The ethyl acetate layers thus obtained were combined, washed with water, dried over magnesium sulfate, treated with activated carbon, and then concentrated under reduced pressure. 

  The residue was pulverized in diethyl ether, collected by filtration, and then dried to give 2,2,2-trichloroethyl-2-methyl-7- [2-methoxyimino-2- (2-aminothiazolffiyl) acetamido] -3-cephem-3 carboxylate (synisomeres), which is also called 2,2,2-trichloroethyl-2-methyl-7- [2-methoxyimino-2- (24mino-2,3-dihydrothiazol4y1) -acetamidoj-3-cephem-4- carboxylate (Synisomeres) can be called (0.6 g) was obtained.  This compound was subjected to column chromatography on silica gel using mixed solvent of benzene, ethyl acetate and acetic acid (10: 10: 1) as a developer.  The eluates containing the aimed compound were collected, washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. 

  The residue was pulverized in diethyl ether, collected by filtration and then dried, whereby a light brown powder of the desired pure compound (Synisomeres) was obtained (0.16 g), mp. 



   128 to 149 C (dec. ).    



  IR spectrum (Nujol): 3100 to 3500, 1785, 1735, 1675, 1620, 1530, 1280, 1218, 710 cm-1. 



  NMR spectrum (ds-dimethyl sulfoxide, o): 1.45 (3H, d, J = 7Hz) 3.82 (3H, s) 3.92 (1H, m)
5.05 (2H, s) 5.20 (1H, d, J = 5Hz) 5.97 (1H, dd, J = 5 and 9Hz) 6.73 (1H, s) 6.77 (1H, d, J = 6Hz)
7.10 (2H, broad s)
9.65 (1H, d, J = 9Hz). 



   The following compounds were obtained in a similar manner:
1) 2-Methyl-7- [2-methoxyimino-2- (2-formylamino-thiazol-4 yl) -acetamido] -3-cephem4-carboxylic acid (Synisomeres), also known as 2-methyl-7- [2- methoxyimino-2- (2-formylimino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (Synisomeres), mp.  174 to 204 "C (dec. ). 



   2) 2-Methyl-7- [2-methoxyimino-2- (2-aminothiazol-4-yl) -acet amido] -3-cephem-4-carboxylic acid (Synisomeres), also known as 2-methyl-7- [ 2-methoxyimino-2- (2-imino-2,3-dihydrothiazolX yl) acetamido] -3-cephem4-carboxylic acid (Synisomeres), Zp.   > 241 C. 



   3) Pivaloyloxymethyl-2-methyl-7- [2-methoxyimino-2- (2 aminothiazolffiyl) acetamido] -3-cephem-4-carboxylate (synisomer), which is also known as pivaloyloxymethyl-2-methyl-7- [2- methoximino-2- (2-imino-2,3-dihydrothiazolyl) acetamidoj-3 cephemXcarboxylate (Synisomeres), mp.  165 to 1700C (dec. ).    



  Example 13
To a solution of 2,2,2-trichloroethyl-2-methyl-7- [2hydroxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4 carboxylate (Synisomeres), which is also known as 2, 2,2-trichloroethyl-2-methyl-7- [2-hydroxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylate (Synisomeres) can be designated , (125 mg) in dioxane (5 ml) was added dropwise a 0.1 N-diazomethane solution in diethyl ether until the starting compound disappeared. 

  After concentrating the reaction mixture, the residue was pulverized in diethyl ether, collected by filtration, and then dried, whereby a brown powder of 2,2,2-trichloroethyl-2-methyl-7- [2-methoxyimino-2- (2-aminothiazole -4-yl) -acetamido} 3-cephem-4-carboxylate (Synisomeres), also known as 2,2,2-trichloroethyl-2-methyl-7- [2-methoxyimino-2- (2-imino-2 , 3-dihydrothiazol-4-yl) -acetamido] -3-cephem-carboxylate (Synisomeres), (110 mg), mp.  128 to 149 "C (dec. ) was obtained. 



   Similarly, the following compound was obtained: 1) Pivaloyloxymethyl-2-methyl-7- [2-methoxyimino-2- (2 aminothiazol-yD-acetamido] -3-cephem-4carboxylate (Synisqmeres), also known as pivaloyloxymethyl-2 -methyl-7- [2-methoxyimino-2- (2-imino-2,3-dihydrothiazolyl) acetamido] -3- cephem-4-carboxylate (Synisomeres), mp.  165 to 170 "C (dec. ). 



  Example 14
To a solution of 2,2,2-trichloroethyl-2-methyl-7- [2-methoxyimino-2- (2-aminothiazol-4y1) -acetamido] -3-cephem4-carboxylate (Synisomeres), also known as 2,2,2-trichloroethyl-2-methyl-7- [2-methoxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephemXcarboxylate (Synisomeres) can be designated , (0.1 g) in tetrahydrofuran (2 ml) and glacial acetic acid (0.25 ml), zinc powder (0.1 g) was added all at once with stirring, the temperature being kept below 25 ° C. in an ice bath.  The mixture was stirred at room temperature for 1 hour.  Zinc powder (0.1 g) was further added to the reaction mixture, and the mixture was stirred at the same temperature for 1 hour. 

  The reaction mixture was filtered and the insoluble material was washed with a small amount of tetrahydrofuran.  After the filtrate was combined with the washing water, the solvents were distilled off.  A 5% aqueous sodium bicarbonate solution and ethyl acetate were added to the residue, so that the aqueous layer had a pH of 7-8.  The resulting mixture was filtered, and then the aqueous layer was separated.  The aqueous layer was adjusted to a pH of 2 to 3 with 2N hydrochloric acid and then slightly concentrated.  The aqueous layer thus obtained was subjected to column chromatography (Diaion HP 20 non-ionic adsorbent resin manufactured by Mitsubishi Chemical Industries).  The column was washed with water and then successively eluted with 20% methanol and 40% methanol.  

  The eluates containing the aimed compound were collected and then lyophilized, whereby a white powder of 2-methyl 7- [2-methoxyimino-2- (2-aminothiazole vI yl) -acetamido] -3-cephem-4-carboxylic acid (Synisomeres), also known as 2-methyl-7- [2-methoxyimino-2- (2-imino-2,3-dihydro-thiazol-4-yl) -acetamido] -3-cephem-4-carboxylic acid (Synisomeres ), (0.015 g), mp.  230 to 235 "C (dec. ) was obtained. 



   Similarly, the following compounds were made:
1) 2-methyl-7- [2-methoxyimino-2- (2-formylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (synisomer), which is also known as 2-methyl-7 {2- methoxyimino-2- (2-formylimino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (Synisomeres), mp.  174 to 204 "C (dec. ). 



   2) 2-methyl-7- [2-hydroxy-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid hydrochloride, which compound also as 2-methyl-7- [2-hyxdroxy-2- (2-imino-2,3-dihydro-thiazolXyl) -acetamido] -3-cephem-4-carboxylic acid hydrochloride, mp.   > 250 C. 



   3) 2-methyl-7- [2-hydrynximino-2- (2-aminothiazol-4yl) -acetamido] -3-cephem-4-carboxylic acid (syn isomer), which is also known as 2-methyl-7- [2-hydroxyimino-2- (2-imino-2,3-dihydrothiazol4-yl) acetamido] -3-cephem-4-carboxylic acid (syn isomer) can be prepared. 



  IR spectrum (Nujol):
3250.1765.1625cm- 'NMR spectrum (Ds-dimethyl sulfoxide, o): ppm 1.42 (3H, d, J = 6.8Hz)
3.54-3.94 (1H, m)
5.23 (1H, d, J = 6Hz) 5.82 (1H, dd, 5 = 6 and 8Hz) 6.40 (1H, d, J = 6.8Hz) 6.64 (1H, s)
9.44 (1H, d, J = 8Hz)
4) 2-methyl-7- [2-ethoxyimino-2- (2-formylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn isomer), which is also known as 2-methyl-7- [2-ethoxyimino-2- (2-formylimino-2,3-dihydrothiazol4-yl) acetamido] -3-cephem-4-carboxylic acid (syn-isomer) can be prepared. 



  IR spectrum (Nujol): 3350.3240.3190.1775, 1700.1650.1620cm- '
5) 2-Methyl-7- [2-isopropoxyimino-2- (2-formylaminothiazol-4-yl) acetamido] -3-cephem4-carboxylic acid (syn isomer), which is also known as 2-methyl-7- [2 -isopropoxyimino-2- (2-formylimino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn isomer) can be prepared. 



  IR spectrum (Nujol): 3480,3300,3180,1780, 1740, 1700, 1660cm¯ '
6) 2-methyl-7- [2-ethoxyimino-2 - (- aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid hydrochloride (syn-isomer), which is also known as 2-methyl-7- [ 2-ethoxyimino-2- (2-imino-2,3-dihydrothiazol4-yl) acetamido] -3-cephem-4-carboxylic acid hydrochloride (syn-isomer) can be prepared. 



  IR spectrum (Nujol):
3350, 1790, 1730, 1670, 1630 cm- '
7) 2-Methyl-7- [2-isopropoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem4-carboxylic acid (syn isomer), which is also known as 2-methyl-7- [2 -sopropoxyimino-2- (2-imino-2,3-dihy drothiazol4yl) acetamido] -3-cephem-4-carboxylic acid (syn-isomer) can be prepared. 



  IR spectrum (Nujol): 3350, 1780, 1670, 1600 cm¯ '
8) 2-methyl-7- [2-propoxyimino-242-formylaminothiazol-4-yl) -acetamido] -3-cephem4carboxylic acid (syn isomer), which is also known as 2-methyl-7- [2-propoxyimino-2- (2-formylimino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn isomer) can be prepared. 



  IR spectrum (Nujol):
3450, 3300,3050, 1780, 1730, 1690, 1660 cm-
9) 2-methyl-7- [2-propoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn isomer), which is also known as 2-methyl-7- [2-propoxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn isomer) can be prepared. 



  IR spectrum (Nujol): 3330.3080, 1780, 1670cm¯ '
1 0) 2-Methyl-7- [2-hexyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem4-carboxylic acid (syn-isomer), which is also known as 2-methyl-7 {2 -hexyloxyimino-2- (2-imino-2,3-dihydro-thiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn-isomer) can be represented. 



  IR spectrum (Nujol):
3300, 3200, 1780, 1670, 1630 cm- '
11) 2-Methyl-742-hexyloxyimino-2- (24ormylaminotb iazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn isomer), which is also known as 2-methyl-7- [2-hexyloxyimino -2- (2-formylimino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn isomer) can be prepared. 



  IR spectrum (Nujol): 3270.3180, 1790, 1700, 1655cm¯ Example 15
To a suspension of 2-methyl-7- [2-methoxyimino-2- (2 aminothiazol-4-yl) acetamido] -3-cephemic carboxylic acid (syn isomer), also known as 2-methyl-7- [2-methoxyimino -2- (2 imino-2,3-dihydrothiazol-4-yl) acetamido] -3 cephem-4-carboxylic acid (Synisomeres), (4.8 g) in water (48 ml) was added dropwise a 1N aqueous solution of sodium hydroxide was given at such a rate that the pH of the mixture was not more than 7. 

  The mixture was filtered and then lyophilized to give sodium 2methyl-7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate (Synisomeres), also known as sodium -2 methyl-7- [2-methoxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem4-carbonxylate (Synisomeres) (4.8 g) , Fp.   > 250 OC was obtained.  This compound was suspended in dry dimethylformamide (20 ml).  Iodomethyl pivalate (2.30 g) was added to the suspension with vigorous stirring and cooling to 3 to 5 ° C.  The mixture was stirred at the same temperature for 20 minutes.  The reaction mixture was poured into a mixture of ethyl acetate (60 ml) and ice water (10 ml) and the mixture was shaken well. 

  The ethyl acetate layer was separated and washed successively with a saturated aqueous solution of sodium bicarbonate, water and a saturated aqueous solution of sodium chloride.  After the ethyl acetate layer was dried over magnesium sulfate, the ethyl acetate was distilled off under reduced pressure.  The remaining oil was pulverized in diethyl ether (25 ml), collected by filtration, and then dried to give pivaloyloxymethyl-2-methyl-7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamide]] -3-cephem4-carboxylate (Synisomeres), also known as piva loyloxymethyl-2-methyl-7- [2-methoxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) acetamido] -3- cephem-4-carboxylate (Synisomeres) can be called (1.44 g), mp.  165 to 170 C (dec. ) was obtained. 

 

     IR spectrum (Nujol):
3340, 1787, 1757, 1678, 1637, 1634, 1283, 1218, 1158, 1132, 1098, 1034.996cm¯ '.    



  NMR spectrum (ds-dimethyl sulfoxide, o): 1.18 (9H, s) 1.47 (3EI, d, J = 7Hz)
3.6 to 4.1 (3H, s)
5.18 (1H, d, J = 6Hz)
5.78 to 5.96 (3H, m) 6.70 (1H, d, J = 6Hz)
6.76 to 6.88 (1H, s)
9.65 (1H, broad d, J = 8Hz).    

 

   In a similar procedure, the 2-methyl-7- [2-hexyl oxyimino-2- (2-aminothiazol-4-yl) acetamido | -3-cephem-scarbonic acid hexanoyloxymethyl ester (syn-isomer) was obtained, which also as 2-Methyl-7- [2-hexyloxyimino-2- (2-imino-2,3-dihydrothiazol-4yl) acetamido] -3-cephem-4-carboxylic acid hexanoylxymethyl ester (syn-isomer) can be prepared. 



  IR spectrum (Nujol):
3340.3200, (wide), 3150 (wide), 1790 (wide), 1750 to 1790,
1680, 1630 cm- '


    

Claims (9)

 PATENT CLAIMS 1. Therapeutically effective 2-lower alkyl-7-substituted- 2 or -3-cephem4-carboxylic acid compounds of the general formula: EMI1.1  where R 'is lower alkyl, R2 is a carboxy or an esterified carboxy group, R3 is an amino or an acylamino or arylalkylamino group, and A is carbonyl, hydroxy (lower) alkylene, hydroxyimino (lower) alkylene or lower alkoxyimino ( lower) -alkylene, the last two groups having the syn or the anti-configuration with respect to the group -CONH-, and the pharmaceutically acceptable salts thereof, 2nd Compounds according to claim 1, characterized in that R 'stands for lower alkyl, R2 stands for a carboxy or an esterified carboxy group, R3 stands for an amino or an acylamino or arylalkylamino group and A stands for carbonyl or hydroxy (lower) alkylene.  3. Compounds according to claim 1, characterized in that R 'represents lower alkyl, R2 represents carboxy or an esterified carboxy group, R3 represents an amino or an acylamino or arylalkylamino group and A represents hydroxyimino (lower) alkylene or lower alkoxyimino (low) alkylene.  4. Compounds according to claim 3, characterized in that it is the synisomers.  5. Compounds according to claim 4, characterized in that R 'is lower alkyl, R2 is a carboxy or an esterified carboxy group, R3 is amino or acylamino and A is hydroxyimino (lower) alkylene or never. drigalkoxyimino (lower) alkylene.  6. Compound according to claim, characterized in that Rl is lower alkyl, R2 is carboxy, lower alkoxycarbonyl, which can be substituted by 1 to 3 halogen atoms, or lower alkanoyloxy (lower) alkoxycarbonyl, R3 is amino or lower alkanoylamino, that by 1 to 3 Halogen atoms can be substituted, and A stands for hydroxyimino (lower) alkylene or lower alkoxyimino (lower) alkylene, 7. Compounds according to claim 6, characterized in that R 'is methyl, R2 is carboxy, 2,2,2-trichloroethoxycarbonyl or pivaloyloxymethoxycarbonyl, R3 is amino, formylamino or trifluoroacetylamino and A is hydroxyiminomethylene or methoxyiminomethylene.  8. 2-Methyl-7- [2-methoxyimino-2- (2-aminothiazol-4-yl) -acet amido] -3-cephem-4-carboxylic acid (Synisomeres) and its hydrochloride, sodium salt and ammonium salt, as a compound Claim 7.  9. Medicament, characterized in that it contains a compound according to claim 1 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.  The invention relates to new 2-lower alkyl-7-substituted 2-or-3-cephem4-carboxylic acid compounds and their pharmaceutically acceptable salts. The invention relates in particular to new 2-lower alkyl-7-substituted-2- or -3-cephem-4-carboxylic acid compounds and their pharmaceutically acceptable salts which have antimicrobial activities. The invention further relates to a process for the preparation of these compounds, medicaments containing these compounds and a method for using these compounds for the treatment of infectious diseases in humans and animals.  The object of the invention is therefore to provide 2-lower alkyl-7-substituted-2- or -3-cephem-4-carboxylic acid compounds and pharmaceutically acceptable salts which are active against a number of pathogenic microorganisms.  The invention is also intended to provide a process for the preparation of 2-lower alkyl-7-substituted-2- or -3-cephem-4-carboxylic acid compounds and their pharmaceutically acceptable salts.  The invention is also intended to provide a medicament which contains at least one 2-lower alkyl-7-substituted-2- or -3-cephem-4-carboxylic acid compound or a pharmaceutically acceptable salt thereof as active ingredient.  The invention relates to new therapeutically active 2-lower alkyl-7-substituted-2- or -3-cephem4carbon- acid compound of the general formula: EMI1.2  wherein R1 is lower alkyl, R2 is a carboxy or an esterified carboxy group, R3 is an amino or an acylamino or arylalkylamino group, and A is carbonyl, hydroxy (lower) alkylene, hydroxyimino (lower) alkylene or lower alkoxyimino (low ) -alkylene, the last two groups with respect to the group -CONH- having the syn or the anti-configuration.    The 2-lower alkyl-7-substituted-2- or -3-cephem-4-carboxylic acid compounds (I) can be prepared by various methods, which can be illustrated by the following reaction schemes. ** WARNING ** End of CLMS field could overlap beginning of DESC **.