CH638220A5 - Cephalosporin compounds and pharmaceutical agents containing them - Google Patents

Abstract

The novel cephalosporin compounds correspond to the formula: <IMAGE> In the formula I, R<1>, R<2>, R<3>, R<4> and R<5> have the meanings given in Patent Claim 1. The compounds of the formula I, or their salts, can be processed, together with pharmaceutically harmless, non-toxic carrier substances, to give drugs possessing an antibacterial effect.

Description

       

  
 

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

 



   PATENT CLAIMS
1.  Cephalosporin compound, characterized by the general formula
EMI1. 1
 wherein: Rl is a group of the formula
EMI1. 2nd
 where X represents sulfur, oxygen or substituted or unsubstituted imino,
R2 is hydrogen or a saturated or unsaturated aliphatic hydrocarbon radical,
R3 is hydrogen or lower alkyl,
R4 is hydrogen, halogen, lower alkyl, acyloxymethyl or heterocyclic thicxmethyl, which may be substituted by lower alkyl, and
R5 carboxy or esterified carboxy, and a salt thereof. 



   2nd  Compound according to claim 1, characterized in that R3 is hydrogen. 



   3rd  Compound according to claim 1 or 2, characterized in that R4 is hydrogen. 



   4th  Connection according to claim.  1 or 2, characterized in that R4 is halogen. 



   5.  Compound according to claim 1 or 2, characterized in that R4 is lower alkyl. 



   6.  Compound according to claim 1 or 2, characterized in that R4 means acyloxymethyl. 



   7.  Compound according to Claim 1 or 2, characterized in that R4 denotes heterocyclic thiomethyl which can be substituted by lower alkyl. 



   8th.  Compound according to claim 1, characterized in that R3 is lower alkyl and R4 is hydrogen. 



   9.  Compound according to claim 1, characterized in that X is sulfur, oxygen or imino, R4 is hydrogen, halogen, lower alkyl, lower alkanoyloxymethyl, carbamoyloxymethyl or thiadiazolylthiomethyl or tetrazolylthiomethyl, which can each be substituted by lower alkyl, and R5 is carboxy. 



   10th  Compound according to Claim 1, characterized in that X denotes lower alkanimido and R4 and R5 have the meanings given in Claim 9. 



   11.  Syn isomer of the compound according to one of claims chelbisl0.    



   12.  Pharmaceutical composition, characterized in that it contains as active ingredient a compound of formula I specified in claim 1 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.    



   The invention relates to new cephalosporin compounds and their salts, in particular their pharmaceutically acceptable salts, which have antibacterial activity, i. H.  are highly effective against a number of pathogenic bacteria and can therefore be used for the treatment of infectious diseases in humans and animals. 



   Another object of the invention is a pharmaceutical agent which contains at least one of the new cephalosporin compounds or a pharmaceutically acceptable salt thereof as the active ingredient. 



   The new cephalosporin compounds are represented by the general formula:
EMI1. 3rd
 in which: R1 denotes a group of the formula:
EMI1. 4th
 wherein
X represents sulfur, oxygen or substituted or unsubstituted imino,
R2 is hydrogen or a saturated or unsaturated aliphatic hydrocarbon radical,
R3 is hydrogen or lower alkyl,
R4 is hydrogen, halogen, lower alkyl, acyloxymethyl or heterocyclic thiomethyl, which may be substituted by lower alkyl, and
R5 carboxy or esterified carboxy, and their salts, in particular their non-toxic, pharmaceutically acceptable salts. 



   In the formulas of the compounds (I) according to the invention and the corresponding starting compounds (III), the partial structure of the formula comprises
EMI1. 5
 also the syn and anti isomers, the structures of which can be represented by the following formulas
EMI1. 6
  (A) (A ') syn isomer anti isomer
For all compounds with the partial structure given above, the compounds with a geometric structure as represented by the formula (A) are referred to as syn isomeres and all compounds with the other structure as represented by the formula (A ') are referred to here as anti-isomer. 



   The various definitions given above and below are explained in more detail below and suitable examples are given. 



   Under the expression used here or  are low, unless otherwise stated, residues or  To understand groups that contain 1 to 6 carbon atoms. 



   The term saturated or unsaturated aliphatic hydrocarbon residue used for R2 may include lower alkyl, lower alkenyl and lower alkynyl, and may preferably include unbranched or branched lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl , Neopentyl, hexyl and the like. , preferred



  wise one with 1 to 4 carbon atoms; straight or branched lower alkenyl, such as vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl , 4-hexenyl, 5-hexenyl and the like. , preferably one having 2 to 4 carbon atoms; and straight or branched lower alkynyl, such as ethynyl, l-propynyl, propargyl, 1-butynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4- Hexinyl, 5-hexinyl and the like. , preferably one with 2 to 4 carbon atoms. 



   The term lower alkyl used here for R3 and R4 can include unbranched or branched alkyl as stated above, preferably one with 1 to 4 carbon atoms, particularly preferably methyl. 



   The term halogen used here for R4 can include chlorine, bromine, iodine and fluorine. 



   The acyl radical of acyloxymethyl, which stands for R4, can include lower alkanoyl and substituted or unsubstituted carbamoyl, a particularly suitable lower alkanoyl e.g. B.  can be formyl, acetyl, propionyl, butyryl, isobutyryl, isovaleryl, oxalyl, succinyl, pivaloyl and the like. , and a particularly suitable substituted or unsubstituted carbamoyl may include carbamoyl, N-lower alkyl carbamoyl (e.g. B.  N-methylcarbamoyl, N-ethylcarbamoyl and the like. ), N-arylcarbamoyl (e.g. B.  N-phenylcarbamoyl and the like. ), N- (substituted or unsubstituted lower alkanoyl) carbamoyl (such as. B.  N-acetylcarbamoyl, N-trichloroacetylcarbamoyl and the like. ) and the like  Particularly preferred examples of acyloxymethyl are carbamoyloxymethyl, acetyloxymethyl and the like. 



   Substituted imino for X in the definition of R 'is to be understood as an imino group which is substituted by a — preferably removable — substituent, which may comprise an acyl group and another conventional protective group.  The acyl group may be aliphatic acyl, acyl with an aromatic ring, and the like. 



   Suitable examples of aliphatic acyl can be its lower alkanoyl (such as formyl, acetyl, propionyl, butyryl, isobutyryl, isovaleryl, oxalyl, succinyl, pivaloyl and the like. ); lower alkoxycarbonyl (such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, t-pentyloxycarbonyl, hexyloxycarbonyl and the like. ); and lower alkoxyalkanoyl (such as methoxyacetyl, ethoxyacetyl, methoxypropionyl and the like. ), preferably alkanoyl with 1 to 4 carbon atoms. 



   Suitable examples of acyl having an aromatic ring may be ar (lower) alkanoyl (such as phenylacetyl, phenylpropionyl and the like. ); Ar (lower) alkoxycarbonyl (such as benzyloxycarbonyl, phenethyloxycarbonyl and the like. ); and aroyl (such as benzoyl, toluoyl, naphthoyl, phthaloyl, indancarbonyl and the like. ). 



   The above-mentioned acyl radical (in particular the alkane radical and the aromatic ring in acyl) can have at least one suitable substituent, such as. B.  Halogen (such as chlorine, bromine, iodine or fluorine), hydroxy, cyano, nitro, lower alkoxy, haloalkyl (such as trifluoromethyl and the like. ) and the like 



   Suitable examples of acyl having the substituent (s) may be: substituted alkanoyl such as mono (or di or tri) halogen (lower) alkanoyl (such as trifluoroacetyl, trichloroacetyl and the like. ),
Mono (or di or tri) halogen (low) alkanoylcarbamoyl (such as trichloroacetylcarbamoyl and the like. ), substituted Ar (lower) alkanoyl (such as 4-chlorophenylacetyl, 3-chloro-4-hydroxyphenylacetyl, 4-nitrophenylacetyl, 4-methoxyphenylacetyl, 4-fluorophenylacetyl, 4-trifluoromethylphenylacetyl and the like. );
Halogen (low) alkoxycarbonyl (such as chloroethoxycarbonyl,
Trichloroethoxycarbonyl and the like. ); substituted Ar (lower) alkoxycarbonyl, such as. B. 

  Halogenar (lower) alkoxycarbonyl (such as 4-chlorobenzyloxycarbonyl, 3.4
Dichlorobenzyloxycarbonyl, 4-trifluoromethylbenzyloxycarbonyl and the like ); lower alkoxyar (lower) alkoxycarbonyl (such as 4-methoxy benzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl and the like. ); substituted aroyl, such as. B.  Halogenaroyl (such as 4-chlorobenzoyl, 3, 4-dichlorobenzoyl, 3-trifluoromethylbenzoyl, 4-bromobenzoyl and the like. ); lower alkoxyaroyl (such as 4-methoxybenzoyl, 3,4,5-trimethoxybenzoyl and the like. ); 4-nitrobenzoyl,
4-methoxy-3-nitrobenzoyl, salicyloyl, 4-hydroxy-3-chlorobenzoyl, 5-hydroxy-2-naphthoyl and the like. 



   The heterocyclic residue of heterocyclic thiomethyl which may be substituted by lower alkyl which may represent R4 may comprise a saturated or unsaturated, monocyclic or condensed heterocyclic group, preferably a heterocyclic group such as e.g. B.  an unsaturated 3- to 6-membered heteromonocyclic group, the 1 to 4
Contains nitrogen atoms such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, the N-oxide thereof, pyrimidinyl, pyrazinyl, pyri dazinyl, triazolyl (e.g. B.    4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl,
2H-1,2,3-triazolyl and the like. ), Tetrazolyl (e.g. B.  1H-tetrazolyl,
2H-tetrazolyl and the like ) and the like ; a saturated 3- to 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms (such as pyrrolidinyl, imidazolinyl, piperidino, piperazinyl and the like. );

   an unsaturated condensed heterocyclic group which is 1 to
Contains 4 nitrogen atoms (such as indolyl, isoindolyl, indolizinyl,
Benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl and the like. ); an unsaturated 3- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as. B.  Oxazolyl, isoxazolyl, oxadiazolyl (such as 1,2,4
Oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl and the like. ) and the like ; a saturated 3- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g. B.  Morpholinyl and the like ); an unsaturated condensed heterocyclic group which is 1 to
Contains 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g. B. 



   Benzoxazolyl, benzoxadiazolyl and the like. ); an unsaturated 3- to 6-membered heteromonocyclic group that contains 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as B.  Thiazolyl, thiadiazolyl (such as 1,2,4-thiadiazolyl,
1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl and the like. ) and the like ; a saturated 3- to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g. B.  Thiazolidinyl and the like ); an unsaturated condensed heterocyclic group which is 1 to
Contains 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g. B. 



   Benzothiazolyl, benzothiadiazolyl and the like. ) and the like , and where the heterocyclic group can be substituted by lower alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
Pentyl, cyclopentyl, hexyl, cyclohexyl and the like. 

 

   If R5 is esterified carboxy, it may be
For example, esters are a lower alkyl ester (such as
Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, t-pentyl, hexyl, 1-cyclopropyl ethyl ester and the like. ); a lower alkenyl ester (such as a vinyl, allyl ester and the like. ); a lower alkyl ester (such as ethynyl, propynyl ester and the like. ); a lower alkoxyalkyl ester (such as methoxymethyl, ethoxymethyl, isopropoxymethyl, 1-methoxyethyl, 1-ethoxy ethyl ester and the like. ); a lower alkylthioalkyl ester (such as
Methylthiomethyl, ethylthiomethyl, ethylthioethyl, isopropylthiomethylester and the like. ); a mono (or di or tri) ha (low) alkyl ester (such as 2-iodoethyl, 2,2,2-trichloroethyl ester and the like. );

   a lower alkanoyloxy (lower) alkyl ester (such as acetoxymethyl, propionyloxymethyl, butyryloxymethyl, valeryloxymethyl, pivaloyloxymethyl, hexanoyloxymethyl, 2-acetoxyethyl, 2-propionyloxyethyl and the like. ); a lower alkanesulfonyl (lower) alkyl ester (such as mesylmethyl, 2-mesylethyl and the like. ); an Ar (lower) alkyl ester, e.g. B.  Phenyl (lower) alkyl ester, which may have one or more suitable substituents (such as. B.  a benzyl, 4-methoxybenzyl, 4-nitrobenzyI, phen ethyl, trityl, diphenylmethyl, bis (methoxyphenyl) methyl, 3,4-dimethoxybenzyl, 4-hydroxy-3,5-di-t- butylbenzyl ester and the like ); an aryl ester, which may have one or more suitable substituents (e.g. B.  a phenyl, tolyl, t-butylphenyl, xylyl, mesityl, cumenyl ester and the like. ); a tri (lower) alkylsilyl ester and the like. 



   Examples of suitable pharmaceutically acceptable salts of the compound (I) according to the invention are conventional non-toxic salts and these may include an inorganic salt such as e.g. B.  a metal salt, such as an alkali metal salt (e.g. B.  a sodium, potassium salt and the like. ), an alkaline earth metal salt (such as a calcium, magnesium salt and the like. ), an ammonium salt and the like. ; an organic salt, e.g. B.  an organic amine salt (such as a trimethylamine, triethylamine, pyridine, picoline, dicyclohexylamine, N, N'-dibenzylethylenediamine, N-methylglucamine, diethanolamine, triethanolamine, tris (hydroxymethylamino) methane salt and the like. ) and the like ; an amino acid salt (e.g. B. 



  an arginine, lysine salt and the like. ) and the like , the preferred pharmaceutically acceptable salts being the alkali metal and alkaline earth metal salts. 



   The compounds (I) according to the invention and their salts, in particular their pharmaceutically acceptable salts, can be prepared by processes which are explained in more detail below. 



  Procedure 1
EMI3. 1
 wherein Rl, R2, R3, R4 and R5 each have the meanings given above.  Procedure 2
EMI3. 2nd
 wherein Rt, R2, R3, R4, R5 and X each have the meanings given above, Y is an acid radical and Z is 2-mercaptoethyl, lower alkoxy- (thiocarbonyl) or 2-mercaptophenyl. 



  Procedure 3
EMI3. 3rd
 wherein Rl, R2, R3 and R5 each have the meanings given above, R4 acyloxymethyl and R6 mean a heterocyclic group which may be substituted by lower alkyl. 



  Procedure 4
EMI3. 4th
 wherein Rz, R2, R3 and R4 each have the meanings given above and R5, a derivative of the carboxy group.   



   The starting compounds (III) used in process 1 are new and they can be prepared by processes as represented by the following reaction scheme:
EMI4. 1
 wherein R2, X and Y each have the meanings given above. 



   In particular, for example, the 2- (2,3-dihydro-1,4oxathiin-6-yl) -2-methoxyiminoacetic acid (syn isomer) can be prepared by reacting 2-mercaptoethanol with ethyl 2-chloroacetyl-2-methoxyiminoacetate (syn -Isomeres) (also called ethyl 4-chloro-3-oxo-2-methoxyiminobutyrate (syn isomeres)) and subsequent hydrolysis of the product obtained.  The other starting compounds (III) can also be prepared in a similar manner to the above-described method, and a specific manufacturing method is explained below in the section Preparing the starting compound. 



   The processes for the preparation of the compounds (I) according to the invention are described in more detail below. 



   Procedure I
The compound (I) of the present invention and the salt thereof can be prepared by reacting a compound (II), a reactive derivative on the amino group or a salt thereof with a disubstituted acetic acid (III), a reactive derivative on the carboxy group or a salt thereof. 



   Suitable reactive derivatives on the amino group of compound (II) include a conventional reactive derivative as used in the amidation e.g. B.  a silyl derivative prepared by reacting the compound (II) with a silyl compound such as bis (trimethylsilyl) acetamide, trimethylsilylacetamide and the like. ; Isocyanato, isothiocyanato and the like ; a Schiff's base or its tautomeric enamine-type isomer prepared by reacting the compound (II) with an aldehyde compound (such as acetaldehyde, isopentaldehyde, benzaldehyde, salicylaldehyde, phenylacetaldehyde, p-mtrobenzaldehyde, m-chlorobenzaldehyde, p-chlorobenzaldehyde, hydroxynaphthuralaldehyde, fynynurfthoaldehyde, f , Thiophene carboaldehyde and the like. ), or a ketone compound (such as acetone, methyl ethyl ketone, methyl isobutyl ketone, acetylacetone, ethyl acetoacetate and the like. ) and the like 



   Suitable salts for the compound (II) are the same as those given above for the compound (I). 



   Suitable salts of compound (III) include a salt with an inorganic base, such as. B.  an alkali metal salt (such as a sodium, potassium salt and the like. ), an alkaline earth metal salt (such as a calcium, magnesium salt and the like. ), a salt with an organic base such as trimethylamine, triethylamine and the like. 



   Suitable reactive derivatives on the carboxy group of compound (III) include e.g. B.  an acid halide, an acid anhydride, an activated amide, an activated ester and the like. , and preferably an acid chloride, acid bromide; 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 and the like. ), Dialkylphosphoric acid, sulfurous acid, thiosulfuric acid, sulfuric acid, alkyl carbonic acid, an aliphatic carboxylic acid (such as pivalic acid, pentanoic acid, isopentanoic acid, 2-ethyl butyric acid, trichloroacetic acid and the like. ), an aromatic carboxylic acid (such as benzoic acid and the like. ); a symmetrical acid anhydride; an activated acid amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; an activated ester (e.g. B. 



  a cyanomethyl, methoxymethyl, dimethylaminomethyl, vinyl, propargyl, p-nitrophenyl, 2,4-dinitrophenyl, trichlorophenyl, pentachlorophenyl, mesylphenyl, phenylazophenyl, phenylthio, p-nitrophenylthio, p- Kresylthio, carboxymethylthio, pyranyl, pyridyl, piperidyl, 8-quinolylthioesters, an ester with N, N-dimethylhydroxylamine, 1-hydroxy-2 (1H) pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxybenzotriazole, 1-hydroxy-6-chlorobenzotriazole and the like. ) and the like  The suitable reactive derivative can be selected in any manner from the above-mentioned derivatives depending on the kind of the compound (III) to be used. 



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



   When the disubstituted acetic acid (III) is used in the free acid form or in the form of a salt in this reaction, the reaction is preferably carried out in the presence of a conventional condensing agent such as N, N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-cyclohexyl-N '- (4-diethylaminocyclohexyl) carbodiimide, N, N'-diethylcarbodiimide, N, N' -disopropylcarbodiimide, N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide, N, N' carbonylbis (2 -methylimidazole), pentamethylene ketene-N-cy clohexylimine, diphenyl ketene-N-cyclohexylimine, ethoxyacetylene, P-chlorovinylethyl ether, 1 - (4-chlorobenzenesulfonyloxy) -6- chloro-lH-benzotriazole, trialkyl phosphite,

   Ethyl polyphosphate, isopropyl polyphosphate, phosphorus oxychloride, phosphorus trichloride, thionyl chloride, oxalyl chloride, triphenylphosphine, N-ethyl-benzis-oxazolium salt, N-ethyl-5-phenylisoxazolium 3, -sulfonate, a Vilsmeier reagent, with dimethyl chloride, made by phosphoramide chloride, dimethylchloride, from dimethylsulfonyl chloride, produced by by Phosgene or the like , carried out. 

 

   Regarding the reaction explained above, it should be noted that when the starting compound (III) with the compound (II) or its reactive derivative on the amino group or a salt thereof in the presence of, for example, phosphorus pentachloride, thionyl chloride and the like.  is generally reacted, an anti-isomer of the compound (I) according to the invention or a mixture of the anti-isomer and the syn isomer is isolated and that hardly a syn isomer of the compound (I) according to the invention can be isolated as the only product, even if a syn isomer of the starting compound (III) is used. 

  Of course, the tendency for such isomerization in the reaction, which is carried out according to the method explained above, is due to the fact that the less stable syn isomer has a tendency to change in the course of such a reaction, e.g. B.  in a so-called activation step of the compound (III), to completely or partially isomerize to the corresponding more stable anti-isomer, so that the more stable isomer, i. H.  the anti-isomer, the compound (I) according to the invention is isolated from the reaction product. 



   To selectively produce a syn isomer of the compound (I) according to the invention in high yield, a syn isomer of the starting compound (III) must therefore be used and the reaction carried out under selected reaction conditions.  That is, a syn isomer of the compound (I) according to the invention can be obtained more selectively and in higher yield by reacting the compound (II) preferably with a syn isomer of the starting compound (III), for example in the presence of a Vilsmeier reagent , as mentioned above, under approximately neutral conditions. 



  procedure 2
The compound (1) of the present invention and a salt thereof can also be prepared by reacting a compound (IV) or a salt thereof with a compound (V) or a salt thereof. 



   An acid residue for Y of the starting compound (IV) may be halogen (such as chlorine, bromine, iodine or fluorine), tosylate, mesylate or the like. , preferably halogen. 



   Suitable salts of the compound (IV) may be the same as those of the compound (11).    



   Suitable salts of compound (V) include an alkali metal salt (e.g. B.  a sodium, potassium salt and the like. ), an inorganic acid salt (e.g. B.  a hydrochloride and the like ) and the like 



   Suitable examples of lower alkoxy (thiocarbonyl) for Z include methoxy (thiocarbonyl), ethoxy (thiocarbonyl), propoxy (thiocarbonyl), isopropoxy (thiocarbonyl), butoxy (thiocarbonyl), t-butoxy (thiocarbonyl), pentyloxy (thiocarbonyl), hexyloxy (thiocarbonyl) and the like , preferably methoxy (thiocarbonyl) or ethoxy (thiocarbonyl). 



   The reaction is usually carried out in a solvent such as water, an alcohol (such as methanol, ethanol, propanol, butanol and the like. ), N, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dioxane, acetonitrile or in any other solvent which does not adversely affect the reaction.  The reaction temperature is not irritant and the reaction is preferably carried out within the range from heating to ambient temperature. 



   For the selective production of a syn isomer of the compound (I) according to the invention, it may be preferred to carry out the reaction using a syn isomer of the starting compound (IV) under mild conditions.  It should also be noted that the reaction is preferably carried out in the presence of a dehydrating agent. 



   Procedure 3
The compound (Ia) of the present invention and the salt thereof can be prepared by reacting a compound (VI) or its salt thereof with a compound (VII) or its reactive derivative on the mercapto group. 



   The starting compound (VI) used can be prepared by reacting the compound (II) in which R4 is acyloxymethyl, its reactive derivative on the amino group or its salt with the compound (III), its reactive derivative on the carboxy group or its salt under practically that same conditions as those given above for the preparation of compound (I) in the explanation of method 1. 



   Suitable reactive derivatives on the mercapto group of compound (VII) include a metal salt, such as. B. 



  an alkali metal salt (such as a sodium, potassium salt and the like. ), an alkaline earth metal salt (such as a magnesium salt and the like. ) and the like 



   The reaction is preferably carried out in a solvent such as water, acetone, chloroform, nitrobenzene, N, N-dimethylformamide, methanol, ethanol, dimethyl sulfoxide or any other organic solvent which does not adversely affect the reaction, or any mixture thereof, preferably in one rather highly polar solvent.  The reaction is preferably carried out under approximately neutral conditions.  When the compound (VI) or the compound (VII) is used in free form, the reaction is preferably carried out in the presence of a base such as e.g. B. 



  an alkali metal hydroxide, an alkali metal carbonate, an alkali metal bicarbonate, a trialkylamine or the like.  carried out.  The reaction is usually carried out at ambient temperature or at a slightly elevated temperature. 



   Procedure 4
The compound (Ib) of the present invention can be produced by subjecting the compound (Ic) to a reaction for converting a derivative of the carboxy group into the carboxy group. 



   Suitable examples of the derivative on the carboxy group for R5 include those as given above for R5 of the compound (I). 



   The above-mentioned reaction is carried out using a conventional method, for example by hydrolysis, by reduction or the like. , carried out. 



   Suitable acids for hydrolysis include an organic or an inorganic acid such as formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid and the like.  A preferred acid is one which can be easily removed from the reaction mixture in a conventional manner, for example by distillation under reduced pressure, e.g. B.  Formic acid, trifluoroacetic acid, hydrochloric acid and the like.  The acidic hydrolysis is preferably carried out in the presence of a solvent.  Suitable solvents include a conventional organic solvent, water, or a mixture thereof. 



   The basic hydrolysis is carried out in the presence of a base.  Suitable bases include e.g. B.  an inorganic base, such as. B.  an alkali metal hydroxide (such as sodium hydroxide, potassium hydroxide and the like. ), an alkaline earth metal hydroxide (such as magnesium hydroxide, calcium hydroxide and the like. ), an alkali metal carbonate (such as sodium carbonate, potassium carbonate and the like. ), an alkaline earth metal carbonate (such as magnesium carbonate, calcium carbonate and the like. ), an alkali metal bicarbonate (such as sodium bicarbonate, potassium bicarbonate and the like. ), an alkaline earth metal phosphate (such as magnesium phosphate, calcium phosphate and the like. ), an alkali metal hydrogen phosphate (such as disodium hydrogen phosphate, dipotassium hydrogen phosphate and the like. ) or the like , and an organic base, such as. B.  

   an alkali metal acetate (such as sodium acetate, potassium acetate and the like. ), an alkali metal alkylate (such as sodium methylate, sodium ethylate, sodium propylate and the like. ), a trialkylamine (such as trimethylamine, triethylamine and the like. ), Picoline, N-methylpyrrolidine, N-methylmorpholine, 1.5 diazabicyclo [4th 3rd 0] -5-nonen, 1,4-diazabicyclo [2nd 2nd 2] octane, 1,5-diazabicyclol5. 4th 0] -7-undecene or the like.  The basic hydrolysis is frequently and preferably carried out in water or in a hydrophilic or water-containing organic solvent or a mixture thereof. 



   The reduction can be carried out with a conventional reducing agent as used for the conversion of the derivative of the carboxy group into a carboxy group, e.g. B.  with an alkali metal borohydride (such as sodium borohydride and the like. ), Palladium-carbon, palladium oxide, platinum oxide and the like. 



   The reaction temperature is not critical and it can be selected appropriately depending on the nature of the derivative of the carboxy group and the method used, and the reaction according to the invention is preferably carried out under mild conditions, e.g. B.  with cooling, at ambient temperature or at a slightly elevated temperature. 



   With regard to the compound (I) according to the invention which has been prepared by the processes described above, it applies that if the compound (I) is a compound in which X denotes a substituted imino group, this compound is subjected to an elimination reaction Removal of a substituent from its substituted imino group X using a conventional method such as e.g. B.  by hydrolysis, by reduction or the like , can be obtained to obtain a compound (I) in which X represents an imino group.  The procedures for performing the hydrolysis and reduction and the reaction conditions (e.g. B.  the reaction temperature, the solvent and the like. ) are practically the same as those given for Method 4 above. 



   If the compound (I) according to the invention has a free carboxy group in the 4-position and / or a free imino group for X, it can be converted into its pharmaceutically acceptable salt using a conventional method.  If the compound (I) is a free carboxylic acid or a salt thereof, it can be converted into its corresponding ester.  The esterification reaction is carried out using a conventional method in a solvent which does not adversely affect the reaction, e.g. B.  in N, N-dimethylformamide, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate or the like. , carried out.  The reaction temperature is not critical, but the reaction is preferably carried out within the range from cooling to ambient temperature. 



   It should also be pointed out that the present invention also includes the cases in which the substituted imino and / or the derivative on the carboxy group is converted into the corresponding free imino group and / or carboxy group during the reaction or during the aftertreatment in the processes explained above (will). 



   The compound (I) according to the invention produced by the processes explained above can be isolated and purified in a conventional manner. 



   As indicated above, the compounds (I) and the starting compound (III) according to the invention are isomerized between the syn isomer and the anti isomer and the equilibrium is more on the side of the more stable anti isomer.  Therefore, in the course of the processes for the preparation of the compound (I) according to the invention, including the isolation and purification steps, an isomerization can occur and an anti-isomer of the compound (I) according to the invention can occasionally be isolated as the main end product, even if a syn -Isomer of the compound (III), (IV), (VI) or (Ic) is used.  Therefore, in the preparation of a syn isomer of the compound (I) according to the 1st 

  Process the reaction of the compound (II) with a syn-isomer of the compound (III) are preferably carried out in the presence of the above-mentioned Vilsmeier reagent, which is a particularly preferred condensing agent for preventing the above-mentioned undesirable geometric isomerization. 



   Furthermore, it should be pointed out that the above-mentioned reaction and / or aftertreatment of the reaction mixture can occasionally convert the above-mentioned tautomeric isomer into the other tautomeric isomer and that this case is also within the scope of the present invention. 



   When a mixture of the syn isomer and the anti isomer of the compound (I) of the present invention is obtained, they can be prepared using a conventional method, e.g. B.  by column chromatography on silica gel, by high pressure liquid chromatography, by fractional recrystallization, by selective hydrolysis or the like. , be separated from each other. 



   The compound (I) according to the invention or the salt, in particular the pharmaceutically acceptable salt thereof, is a new compound which has a high antibacterial activity, inhibits the growth of a wide variety of pathogenic microorganisms, including gram-positive and gram-negative bacteria, and can be used as an antibacterial agent.  In particular, it should be pointed out that a syn isomer of the compound (I) according to the invention has a much higher antibacterial activity than the corresponding anti-isomer of the compound (I) and that therefore a syn isomer of the compound (I) according to the invention is therapeutic Value is far superior to the corresponding anti-isomer. 



   In order to demonstrate the usefulness of the compound (I) according to the invention, tests were carried out with representative representatives of the compounds (I), the results of which are described below. 



  Antibacterial in vitro activity 1.  Test procedure
The in vitro antibacterial activity was determined by the agar plate double dilution method described below. 



   An eyelet fill of an overnight culture of each test strain in a trypticase soy broth (approximately 106 viable cells per ml) was streaked on cardiac infusion agar (HI agar) containing graded concentrations of antibiotics and after 20 hours incubation at 37 " C the minimum inhibitory concentration (MIC) expressed in Fg / ml was determined. 

 

  2nd  Tested connections no.  1) 7- [2- (2,3-dihydro-1,4-oxathiin-6-yl) -2-methoxyiminoacetamido] cephalosporanic acid (syn-isomer) No.  2) 7-C2- (2,3-dihydro-1,4-oxathiin-6-yl) -2-methoxyimino-acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3- cephem-4-carboxylic acid (syn isomer) no.  3) 7- [2- (2,3-Dihydro-1,4-oxathiin-6-yl) -2-methoxyiminoacetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn-isomer) No.  4) 7- [2- (2,3-dihydro-1,4-dithiin-5-yl) -2-methoxyiminoacetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3 -cephem-4-carboxylic acid (syn isomer) no.  5) 7- [2- (2,3-dihydro-1,4-dithiin-5-yl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid (syn isomer) 3. 

  Test results
MIC (Stg / ml)
Connection no.  1 2 3 4 5 Staphylococcus strain 3. 13 3. 13 6. 25 0. 39 6. 25 aureus 209-P JC-1 Proteus 12. 5 25 100 6. 25 3. 13 vulgaris LAM-1025 Pseudomonas 25 12. 5 50 50 400 aeruginose NCTC-10490 Esherichia coli 327 0. 78 0. 2 0. 78 0. 78 Proteus 0. 78 0. 78 0. 78 3. 13 mirabilis 525
For therapeutic use, the compound (I) according to the invention is used in the form of a conventional pharmaceutical preparation (medicament) which contains the compound as an active ingredient (active component), if appropriate in a mixture with one or more pharmaceutically acceptable carriers, such as, for. B.     an organic or inorganic acid or a liquid excipient suitable for oral, parenteral or external administration. 

  The pharmaceutical preparations can be in solid form, e.g. B.  in the form of capsules, tablets, dragees, ointments or suppositories, or in liquid form, e.g. B.  in the form of solutions, suspensions or emulsions.  If necessary, the above-mentioned preparations can be auxiliary substances, such as. B. 



  Stabilizers, wetting agents or emulsifiers, buffers and other commonly used additives. 



   The dosage of the compounds can vary and is dependent on the age, the condition of the patient, the type of disease, the type of compound (I) administered and the like. However, an average single dose of the compound (I) according to the invention of approximately 50 mg, approximately 100 mg, approximately 250 mg and approximately 500 mg has proven to be effective in the treatment of infectious diseases caused by pathogenic bacteria.  In general, amounts between 1 mg and about 1000 mg or even larger amounts can be administered to a patient. 



   The invention is explained in more detail by the following examples, but without being restricted thereto. 



  Preparation of the starting compounds
Example A 2- (2,3-dihydro-1,4-oxythiin-6-yl) -2-methoxyiminoacetic acid (syn isomer) (i) A solution of 65 g of ethyl 2-chloroacetyl-2-methoxyiminoacetate in 130 ml Dry chloroform was added to a stirred mixture of 25 g of 2-mercaptoethanol, 35 g of triethylamine and 70 ml of dry chloroform at 20 "C over a period of 30 minutes and stirred at the same temperature for 2.5 hours.  After the solution was adjusted to pH 1.0 with 10% of the hydrochloric acid under ice-cooling, the chloroform layer was separated, washed twice with water and dried over magnesium sulfate.  The solution was concentrated in vacuo at 40 C to give a yellow oil. 

  The oil was dissolved in 600 ml of toluene and then 5.5 g of p-toluenesulfonic acid was added to the toluene solution.  The solution was heated under reflux for 2 hours while the water formed was removed.  The resulting solution was allowed to cool to room temperature and filtered.  The filtrate was washed three times with water (100 ml), twice with a saturated aqueous sodium bicarbonate solution (100 ml) and twice with water (100 ml) and then dried over magnesium sulfate.  The solution was concentrated under reduced pressure. 



  The residue was subjected to column chromatography on silica gel silica gel 60 (trademark of a product from E. 



  Merck) (1 kg) and eluted with benzene.  After the eluate was concentrated under reduced pressure, the residue was washed with diisopropyl ether and dried to give 21 g of ethyl 2- (2,3-dihydro-1,4-oxathiin-6yl) -2-methoxyiminoacetate (syn-isomer ) in the form of pale yellow crystals, F.  64 to 66 "C.    



      v Nujol
IR v max: 1715.1650.1620cm1
NMR Ï (DMSON6, ppm): 1.25 (3H, t, J = 7Hz), 3.13 (2H, t, J = 4Hz), 3.83 (3H, s), 4.15-4.40 (4H, m), 5.88 (1H, s) (ii) 24 ml of a 1N aqueous sodium hydroxide solution became a solution of 4.6 g of ethyl 2- (2,3-dihydro-1,4-oxathiine) -6-yl) -2-methoxyiminoacetate (syn isomer) in 50 ml of methanol was added and the mixture was stirred at room temperature for 16 hours.  After the solution obtained was concentrated in vacuo, the residue was dissolved in water.  The solution was washed with ethyl acetate and adjusted to pH 1.0 with 10% hydrochloric acid. 

  The solution was extracted with ethyl acetate and the extract was washed with water and dried over magnesium sulfate.  The solution was concentrated at 40 ° C. under reduced pressure and the residue was washed with diisopropyl ether and then dried, giving 3.8 g of 2- (2,3-dihydro-1,4-oxathiin-6-yl) 2-methoxyiminoacetic acid (syn-isomer) in the form of white crystals, F.  129 to 131 "C (decomposition). 



   IR v Nujol: 2550-2600, 1725, 1650, 1620 cm - max
NMR 8 (DMSO-d6, ppm): 3.06 (2H, t, J = 4Hz), 3.80 (3H, s), 4.18 (2H, t, J = 4Hz), 5.80 (1H , s)
Example B 2- (2,3-Dihyd'o-1,4-oxathiin-6-yt) -2-methoxyiminoacetic acid (anti-isomer) (i) To a stirred solution of 7.8 g of 2-mercaptoethanol and 2, 08 g of ethyl 2- (2-chloroacetyl) -2-methoxyiminoacetate in 200 ml of dry chloroform, a solution of 11 g of triethylamine in 30 ml of dry chloroform was added at 20 ° C. and the mixture was stirred at the same temperature for 3 hours. 



  The resulting solution was washed twice with 10% hydrochloric acid, twice with a saturated aqueous sodium hydroxide solution and then twice with water and dried over magnesium sulfate.  The solution was concentrated in vacuo at 40 C and the residue was dissolved in 200 ml of dry toluene.  After adding 3 g of p-toluenesulfonic acid to the solution, the solution was heated under reflux for 30 minutes, whereby the water formed was removed.  The resulting solution was allowed to cool to room temperature and treated with activated carbon, and then 150 ml of ethyl acetate was added.  

  The solution was washed with a saturated aqueous sodium bicarbonate solution and then twice with water, dried over magnesium sulfate and then concentrated in vacuo at 40 ° C., giving 18.5 g of ethyl 2- (2,3-dihydro-1,4-oxate). 6-yl) -2-methoxyiminoacetate (mixture of syn and anti isomers) in the form of a yellow oil. 



      v y Nujol
IR v max: 2800-2900.1715.1620 cm- l (ii) A mixture of 16 g of ethyl 2- (2,3-dihydro-1,4-oxathiin-6-yl) -2-methoxyiminoacetate, 160 ml of methanol and 85 ml of a 1N aqueous sodium hydroxide solution were stirred at room temperature for 25 minutes.  The solution obtained was adjusted to pH 4.5 with 10% hydrochloric acid and concentrated at 40 ° C. in vacuo.  Ethyl acetate was added to the residue, and the solution was adjusted to pH 7.5 with a saturated aqueous sodium bicarbonate solution and then shaken sufficiently.  The organic layer was separated and extracted with a saturated aqueous sodium bicarbonate solution. 

  The extract and the aqueous layer were combined and adjusted to pH 1.0 with 10% hydrochloric acid.  The solution was extracted with ethyl acetate and the extract was washed with water and then dried over magnesium sulfate.  After the solution was concentrated in vacuo, the residue was washed with diisopropyl ether, giving 3.5 g of 2- (2,3 dihydro-1,4-oxathiin-6-yl) -2-methoxyiminoacetic acid (anti isomer) in the form received from yellow crystals, F.  108 to 110 C (dec. ). 



   IR #maxNujol: 2550-2650, 1965, 1620, 1600 cm-1
NMR v (DMSOd6, ppm): 3.06 (2H, t, J = 5Hz), 4.20 4.20 (2H, t, J = 5Hz), 4.89 (3H, s), 6.43 ( 1H, s)
Example C 2- (2,3-Dihydro-1,4-dithiin-6-yl) -2-methoxyimimoacetic acid (syn-isomer) (i) 20.6 g of ethane-1,2-dithiol were mixed with 41.4 g Ethyl-2-chloroacetyl-2-methoxyiminoacetate was reacted in a manner similar to Example A- (i), giving 11 g of ethyl-2 (2,3-dihydro-1,4-dithiin-6-yl) -2- methoxyiminoacetate (syn isomer) in the form of white crystals, F.  65 to 67 C. 



      IR v Nujol 1725.1670 cm¯ l max
NMR ö (DMSOd6, ppm): 1.25 (3H, t, J = 7Hz), 3.25 (4H, s), 3.80 (3H, s), 4.30 (2H, q, J = 7Hz) ), 6.78 (1H, s) (ii) 2.47 g of the ethyl 2- (2,3-dihydro-1,4-dithiin-6-yl) -2-methoxyiminoacetate (syn isomer) obtained were obtained similarly hydrolyzed as in Example A- (ii), 2.0 g of 2- (2,3-dihydro-1,4-dithiin-6-yl) -2-methoxyiminoacetic acid (syn isomer) in the form received from white crystals, F.  120 to 122 C (dec. ). 



   IR #maxNujol: 2500-2600, 1720, 1670, 1620 cm-1
NMR Ï (DMSO-d6, ppm): 3.20 (4H, s), 3.80 (3H, s), 6.61 (lH, s)
Example D 2- (4-Formyl-2,3-dEhydro-4H-1,4-thiazin-5-yl) -2-methoxy-iminoacetic acid (syn-isomer) (i) To a stirred solution of 10.0 g 2-mercaptoethylamine hydrochloride in 100 ml of chloroform, 18.7 g of triethylamine and 26.2 g of ethyl 2-chloroacetyl-2-methoxyiminoacetate (purity 70%) were added with ice cooling and stirred for 1.5 hours at room temperature.  After the resulting solution was concentrated in vacuo, water was added to the residue and extracted four times with diethyl ether. 

  The extract was washed with a saturated aqueous sodium chloride solution and extracted four times with 10 t hydrochloric acid.  The hydrochloric acid extract was washed twice with diethyl ether and adjusted to pH 6.5 with a saturated aqueous sodium bicarbonate solution and extracted a further four times with diethyl ether.  The extract was dried over magnesium sulfate and concentrated in vacuo to give 5.2 g of ethyl 2- (2,3-dihydro-4H-1,4thiazin-5-yl) -2-methoxyiminoacetate (syn isomer) in the form of a Got oil. 



   IR #maxNujol: 3400 (shoulder), 1740, 1635 cm-
NMR ö (CCl4, ppm): 1.36 (3H, t, J = 7Hz), 2.9-3.2 (2H, m), 3.5-3.8 (2H, m), 3.89 (3H, s), 4.30 (2H, q, J = 7Hz), 5.00 (1H, s) (ii) 5.8 g of ethyl 2- (2,3-dihydro-4H-1,4) -thiazin-5-yl) -2-methoxyiminoacetate (syn-isomer) were added to a mixture of 7.7 g of acetic anhydride and 3.48 g of formic acid, which had previously been heated to 50 ° C. for 2 hours, with ice cooling and over Stirred at room temperature overnight.  After adding 100 ml of chilled water to the resulting solution, the solution was extracted three times with ethyl acetate. 

  The extract was washed once with a saturated aqueous solution of sodium chloride, four times with an aqueous solution of sodium bicarbonate and once with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate.  The solution was concentrated in vacuo and the residue was treated (triturated) with 15 ml of diisopropyl ether.  The crystals were collected by filtration and washed with diisopropyl ether, whereby 5.0 g of ethyl 2 (4-formyl-2,3-dihydro-4H-1,4-thiazin-5-yl) -2-methoxyiminoacetate ( syn-Isomeres), F.  94 to 96 C. 



   IR v Nujol: 1735, 1725, 1675 cm-l max
NMR Ï (CDCl3, ppm): 3.16 (3H, t, J = 7Hz), 3.95 (3H, s), 2.96-3.28 (2H, m), 3.78M, 20 (2H , m), 4.38 (2H, q, J = 7Hz), 6.15 (1H, s), 8.62 (1H, s) (iii) To a suspension of 4.8 g of the ethyl 2- (4-formyl-2,3-dihydro-4H-1,4-thiazin-5-yl) -2-meth-oxyiminoacetate (syn isomer) in 48 ml of ethanol was added to 22.3 ml of a 1N aqueous potassium hydroxide solution and the mixture was stirred at room temperature for 1.25 hours. 

  After removing ethanol from the resulting solution under reduced pressure, water was added to the residue to a total volume of 100 ml, and it was washed with diethyl ether.  The solution was adjusted to pH 1 with 10% hydrochloric acid and salted out.  After the solution was extracted with ethyl acetate, the extract was washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate, and concentrated in vacuo.  The residue was treated (triturated) with 15 ml of diethyl ether and the crystals were collected by filtration and washed with diethyl ether, giving 3.51 g of 2- (4-formyl-2,3-dihydro-4H-1,4-thiazine 5-yl) -2-methoxyiminoacetic acid (syn isomer) was obtained. 



     
IR v Nujol: 1710, 1610 cm- l max
NMR Ï (DMSO-d6, ppm): 3.08 (2H, m), 3.80 (2H, m), 3.83 (3H, s), 6.40 (1H, s), 8.47 ( 1H, s). 

 

   Example E 2- (2-Oxo-1,3-dithiol-4-yl) -2-methoxyiminoacetic acid (syn isomer and anti-isomer) (i) 31.2 g of ethyl 2-chloroacetyl-2-methoxyiminoacetate were added added dropwise to a solution of 31 g of sodium o-ethyl xanthate in 150 ml of water and stirred at 15 ° C. for 1 hour. 



  After removal of methanol from the resulting solution in vacuo, the residue was extracted with benzene to give ethyl 2-ethoxy- (thiocarbonyl) thioacetyl-2-methoxyiminoacetate. 



     
Film max 1735.1700.1593 cm¯ l
NMR Ï (CCl4, ppm): 1.30 (3H, t, J = 7Hz), 1.40 (3H, t, J = 7Hz), 4.12 (3H, s), 4.25 (2H, q , J = 7Hz), 4.32 (2H, s), 4.58 (2H, q, J = 7Hz)
A mixture of 41 g of the ethyl 2-ethoxy (thiocarbonyl) thioacetyl-2-methoxyiminoacetate obtained, 8 ml of concentrated sulfuric acid and 300 ml of benzene was heated under reflux for 2 hours while the water formed was removed.  The resulting solution was washed successively with water, an aqueous sodium bicarbonate solution and water, and then dried over magnesium sulfate. 



  The solution was treated with activated carbon and the solvent was removed in vacuo to give 34.3 g of ethyl 2 (2-oxo-1,3-dithiol-4-yl) -2-methoxyiminoacetate.  This product was subjected to column chromatography on silica gel (eluent: benzene), whereby 13.5 g of the syn isomer and 8.5 g of the anti isomer were obtained separately. 



  syn-isomeric IR #maxFilm: 1735, 1710, 1650 cm-1
NMR # (DMSO-d6, ppm): 1.35 (3H, t, J = 7Hz), 3.95 (3H, s), 4.34 (2H, q, J = 7Hz), 7.63 (1H , s) anti-isomer
IR #maxFilm: 1740, 1720, 1640 cm-1
NMR 8 (DMSOd6, ppm): 1.30 (3H, t, J = 7Hz), 4.08 (3H, s), 4.33 (2H, q, J = 7Hz), 8.00 (1H, s ) (ii) To a solution of 1.7 g of the ethyl2- (2-oxo-1,3-dithiol-4-yl) -2-methoxyiminoacetate (anti-isomer) obtained in 20 ml of ethanol was a solution of 2 , 2 g of sodium carbonate decahydrate in 10 ml of water was added dropwise and the mixture was stirred at room temperature for 3 hours. 

  After removal of ethanol from the solution obtained in vacuo, the residue was acidified with hydrochloric acid and extracted with diethyl ether.  The extract was washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate and concentrated in vacuo to give an oily product.  The oil was left in a refrigerator to give 0.75 g of 2- (2-oxo-1,3dithiol-4-yl) -2-methoxyiminoacetic acid (anti-isomer). 



   IR #maxNujol: 3270, 1730, 1625 cm-1
NMR 6 (DMSO-d6, ppm): 4.02 (3H, s), 8.0 (1H, s) (iii) To a solution of 1 g of ethyl 2- (2-oxo-1,3-dithiol) -4yl) -2-methoxyiminoacetate (syn isomer) in 10 ml of tetrahydrofuran and 20 ml of ethanol, a solution of 1.3 g of sodium carbonate decahydrate in 20 ml of water was added and the mixture was stirred for 3 hours at room temperature. 



  After the solvent was removed in vacuo, the residue was washed with diethyl ether, adjusted to pH 2 and extracted with diethyl ether.  The extract was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo to give 0.2 g of 2- (2-oxo-1,3-dithiol-4-yl) -2-methoxyiminoacetic acid (syn isomer) received. 



   IR #maxFilm: 1725, 1625 cm-1
NMR # (DMSO-d6, ppm): 3.93 (3H, s)
Example F 2- (1,4-Benzoxathiin-2-yl) -2-methoxyiminoacetic acid (syn-isomer) (i) 3.5 g of 2-mercaptophenol were added in a similar manner to Example A- (i) with 6.2 g of ethyl 2-chloroacetyl-2-methoxyiminoacetate is allowed to react, giving 1.2 g of ethyl 2- (1,4-benzoxathiin-2-yl) -2-methoxyiminoacetate (syn isomer) in the form of pale yellow crystals received, F.  78 to 80 C.    



     
IR v Nujol 3050.1725.1600 cm- l max
NMR 8 (DMSO-d6, ppm): 1.25 (3H, t, J = 7Hz), 3.92 (3H, s), 4.33 (2H, q, J = 7Hz), 6.25 (1H , s), 7.24 (4H, m) (ii) 1.2 g of the ethyl 2- (1,4-benzoxathiin-2 yl) -2-methoxyiminoacetate (syn isomer) thus obtained were prepared in a manner similar to in Example A- (ii) hydrolyzed to give 0.9 g of 2- (1,4-benzoxathiin-2-yl) -2-methoxyiminoacetic acid (syn isomer), F.  143 to 145 C (dec. ). 



   IR #maxNujol: 2600-2500, 1735, 1600 cm-1
NMR 8 (DMSO-d6, ppm): 3.90 (3H, s), 6.15 (1H, s), 6.8-7.2 (4H, m)
Example G 2- (1, 4-Benzodithiin-2-yl) -2-methoxyiminoacetic acid (syn-isomeres) (i) 7.1 g of o-benzenedithiol were treated with 11 in a manner similar to Example A- (i) , 4 g of ethyl 2-chloroacetyl-2-methoxyiminoacetate reacted, giving 1.0 g of ethyl 2- (1,4-ben zodithiin-2-yl) -2-methoxyiminoacetate (syn isomer) in the form of yellow Received crystals, F.  78 to 81 C. 



      IR #maxNujol: 1725, 1620, 1600 cm-1
NMR 8 (DMSOd6, ppm): 1.20 (3H, t, J = 7Hz), 3.90 (3H, s), 4.20 (2H, q, J = 7Hz), 7.03 (1H, s ), 7.2-7.5 (4H, m) (ii) 1.0 g of the ethyl 2- (1,4-benzodithiin-2yl) -2-methoxyiminoacetate (syn isomer) obtained in a similar manner hydrolyzed as in Example A- (ii) to give 0.8 g of 2- (1,4-benzodithiin-2-yl) -2-methoxyiminoacetic acid (syn isomer). 



   Movie
IR #max: 2550-2600,1735,1650,1650,1625,1600cm-1
NMR # (DMSO-d6, ppm): 3.9 (3H, s), 7.00 (1H, s), 7.2-7.5 (4H, m)
Example H (i) 5 g of 4-nitrobenzyl-7-amino-3-cephem-4-carboxylate were dissolved in a solution of 13.8 g of trimethylsilylacetamide and 10 ml of bis (trimethylsilyl) acetamide in 50 ml of dry ethyl acetate and 1. Stirred at 45 C for 5 hours.  A solution of 2.88 bromine in 7 ml of methylene chloride was added dropwise to a solution of 1.5 g of diketene in 7 ml of methylene chloride at -40 C over a period of 20 minutes and stirred at -30 C for 1 hour. 

  The resulting solution was added dropwise to the above solution of 4-nitrobenzyl-7-amino-3-cephem-4-carboxylate while cooling to -15 ° C and then stirred at the same temperature for 30 minutes.  50 ml of water were added to the solution obtained, and the mixture was extracted with ethyl acetate.  The ethyl acetate extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to obtain 6.15 g of oily 4-nitrobenzyl-7- [2- (2-bromoacetyl) acetamido] -3-cephem-4-carboxylate. 

 

     
IR v Nujol: 178Q1740,1630cm1 max
NMR 6 (DMSOHl6, ppm): 3.62 (2H, broad s), 4.37 (2H, s), 5.08 (1H, d, J = 5Hz), 5.40 (2H, s), 5 , 77-6.05 (m), 6.67 (1H, t, J = 5Hz), 7.68, 8.04 (4H, m, J = 9Hz), 9.07 (1H, d, J = 8 Hz) (ii) 8.40 g of 4-nitrobenzyl-7- [2- (bromoacetyl) acetamido] -3-cephem-4-carboxylate were suspended in a mixture of 150 ml of tetrahydrofuran and 30 ml of water.  50 ml of acetic acid and a solution of 1.20 g of sodium nitrite in 15 ml of water were added to the suspension while cooling with ice, and the mixture was stirred at 20 to 22 ° C. for 1.5 hours.  The resulting solution was poured into 300 ml of ice water and stirred for 20 minutes. 

  The precipitated substance was collected by filtration, washed with water, dried and then recrystallized from ethyl acetate, whereby 3.1 g of 4-mtrobenzyl-7- [2- (2-bromoacetyl) -2-hydroxyiminoacetamido] -3-cephem -4-carboxylate (syn isomer), F.  153 to 162 C. 



   Nujol IR v: 3250, 1780, 1720, 1705, 1650, 1610, 1600 (shoulder), 1550, 1520 cm -
NMR 8 (DMSOHi6, ppm): 3.67 (2H, d, J = 4Hz), 4.63 (1.5H, s), 4.88 (0.5H, s), 5.18 (1H, d , J = 5Hz), 5.45 (2H, s), 5.93 (1H, dd, J = 5Hz), 6.72 (1H, t, J = 4Hz), 7.73 (2H, d, J = 9Hz), 8.28 (2H, d, J = 9Hz), 9.38 (1H, d, J = 8Hz), 11.27 (1H,

   s)
Example I (i) 180.0 g of 4-chloro-3-oxo-2-n-propoxyiminovaleric acid ethyl ester are added to a stirred solution of 71.6 g of 2-mercaptoethanol in 1.8 liters of chloroform, and this solution is then added to a solution Solution of 93.1 g of triethylamine in 200 ml of chloroform was added over a period of 5 minutes.  The solution is stirred at 20 C for 80 minutes.  The resulting mixture is washed twice with 10% hydrochloric acid, twice with a saturated aqueous sodium hydrogen carbonate solution and finally with water, dried over magnesium sulfate and concentrated in vacuo.  178.7 g of ethyl 4- (2-hydroxyethylthio) -3-oxo2-n-propoxyiminovalerate are obtained. 



   Movie
IR spectrum: v max: 2980.1740.1685 cm
Nuclear Magnetic Resonance Spectrum: 8 (CDCl3), ppm): 0.99 (3H, t, J = 8.0Hz), 1.39 (3H, t, J = 7.0Hz), 1.50 to 2.10 ( 2H, m), 2.80 (2H, t, J = 6.0Hz), 3.74 (2H, s), 4.31 (2H, t, J = 8.0Hz), 4.34 (2H, q, J = 7.0 Hz) (ii) A solution of 178.0 g of 4- (2-hydroxyethylthio) -3oxo-2-n-propoxyiminoacetic acid ethyl ester and 25.0 g of p-toluenesulfonic acid in 1.6 liters of toluene is stirred for 30 Stirred minutes at 150 C with separation of the water generated. 



  The resulting solution is treated with activated carbon and 1 liter of ethyl acetate is added.  The solution is washed twice with a saturated aqueous sodium hydrogen carbonate solution and twice with water, dried over magnesium sulfate and concentrated in vacuo.  153.4 g of mixture of the syn isomer and the anti isomer of 2- (2,3-dihydro-1,4-oxathiin-6-yl) -2-n-propoxyiminoacetic acid ethyl ester are obtained. 



   IR spectrum: #maxFilm: 2970, 2940, 2880, 1735,
1665 cm-1
Nuclear Magnetic Resonance Spectrum: 8 (CDCl3, ppm): 0.92 (3H, t, J = 7.0Hz), 1.35 (3H, t, J = 7.8Hz), 1.27 to 1.9 (2H , m), 3.06 (2H, m), 4.0 to 4.6 (6H, m), 5.67, 6.49 (1H, s, s) (iii) 1 g mixture of the syn isomer and the anti-isomer of 2- (2,3-dihydro-1,4-oxathiin-6-yl) -2-n-propoxyiminoacetic acid ethyl ester is added to a mixture of 10 ml of methanol and 6 ml of 1 normal aqueous sodium hydroxide solution and the solution is stirred for 18 hours at room temperature. 



  The methanol is distilled off from the resulting solution in vacuo, 15 ml of saturated aqueous sodium hydrogen carbonate solution and 15 ml of ethyl acetate are added to the residue and the mixture is shaken vigorously.  The watery
Layer is separated, adjusted to a pH of 1.0 with 10% hydrochloric acid and extracted with 20 ml of ethyl acetate.  The
The extract is washed with water, dried over magnesium sulfate and concentrated in vacuo.  The residue is triturated with a mixture (1: 1) of n-hexane and diethyl ether. 



   The crystallized material which has separated out is separated off by filtration and washed with the same mixture of n-hexane and diethyl ether.  0.30 g of syn isomer of 2- (2,3-dihydro-1,4-oxathiin-6-yl) -2-n-propoxyiminoacetic acid is obtained. 



   IR spectrum: # film / max: 1740 cm-1
NMR spectrum: 8 (DMSO-d6, ppm): 0.86 (3H, t, J = 7.5Hz), 1.59 (2H, m),
3.07 (2H, t, J = 4.0Hz), 3.98 (2H, t, J = 7.0Hz), 4.28 (2H, t, J = 4.0Hz), 5.80 (1H , s)
Example J (i) 255.0 g of 4-chloro-3-oxo2-n-hexyloxyiminovaleric acid ethyl ester, 86.1 g of 2-mercaptoethanol, 11.13 g of triethylamine and
2.8 liters of chloroform are treated as described in Example I (i), and stirred for 3¸ hours at room temperature.  The resulting solution is treated in the same manner as in Example I (i) and is obtained
290.5 g of 4- (2-hydroxyethylthio) -3-oxo-2-n-hexyloxyiminovale ethyl rianate. 



   Movie
IR spectrum: v max: 2930, 1740, 1680 cm-t
Nuclear Magnetic Resonance Spectrum: 8 (CDCl3, ppm): 0.70 to 2.07 (14H, m), 2.53 to 3.07 (4H, m), 3.70 (2H, m), 4.22 ( 2H, t, J = 8Hz), 4.38 (2H, q, J = 7Hz) (ii) 300 g of 4- (2-hydroxyethylthio) -3-oxo-2-n-hexyloxyimi novaleriansäureäthylester, 42.0 g p -Toluenesulfonic acid and 2.5
Liters of toluene are treated in the same way as in example I (ii) and heated to boiling under reflux for 1¸ hours.  The resulting solution is treated in the same way as in Example I (ü) and is obtained
186.8 g of a mixture of the syn and anti isomers of 2- (2.3
Dihydro-1,4-oxathiin-6-yl) -2-n-hexyloxyiminoacetic acid ethyl ester. 



   Movie
IR spectrum: v max: 2930, 1735, 1665 cm-
Nuclear Magnetic Resonance Spectrum: 8 (CDCl3, ppm): 0.67 to 2.00 (14H, m), 3.10 (2H, m),
3.93 to 4.63 (6H, m), 5.63.6.47 (1H, s, s) (iii) 186.8 g of 2- (2,3-dihydro-1,4-oxathiin-6 -yl) -2-n-hexyl oxyiminoacetic acid ethyl ester (mixture of syn and anti-Iso mere), 472 ml 1-normal aqueous sodium hydroxide solution and 1.8 liters of methanol are stirred for 35 minutes at room temperature and the insoluble material is removed by filtration .  

  The filtrate is stirred for 43 hours at room temperature and then treated according to the same procedure as in example I (iü); 43 g of syn isomer of 2- (2,3
Dihydro-1,4-oxathiin-6-yl) -2-n-hexyloxyiminoacetic acid. 



   IR spectrum: X max: 1735 cm-
NMR spectrum: 8 (DMSO-d6, ppm): 0.67 to 2.13 (liH, m), 3.10 (2H, m), 4.00 to 4.60 (4H, m), 5, 80 (1H, s)
Example K (i) A solution of 50 g of ethyl 4-bromo-2-hydroxyimino-3-oxova lerianate in 100 ml of chloroform is added dropwise to a solution of 20.5 g of 2-mercaptoethanol and 26.6 g of triethylamine in 100, which is kept under stirring ml of chloroform is added at room temperature and over a 1 1/2 hour period and the mixture is stirred at the same temperature for 2 hours. 

  The chloroform is removed from the resulting solution in vacuo, 600 ml of water and 600 ml of ethyl acetate are added to the residue, and the mixture is adjusted to pH 1.0 using concentrated hydrochloric acid. 



  The ethyl acetate layer is separated off, washed with 200 ml of water, dried over magnesium sulfate and finally concentrated in vacuo; 38.8 g of ethyl 4- (2-hydroxyethylthio) 2-hydroxyimino-3-oxovalerate are obtained. 



   Film IR spectrum: #max: 3450, 2980, 2930, 1730 cm-1.    



   NMR spectrum: Ï (CDCl3, ppm): 1.37 (3H, t), 2.83 (2H, m), 3.67 to 4.0 (4H, m), 4.42 (2H, q) (ii) 3.98 g of potassium iodide are added to a solution of 2.90 g of allyl bromide in 45 ml of acetone and the solution is stirred for 1 hour at room temperature and then the insoluble material is removed by filtration. 



   The filtrate is added to a suspension of 4.70 g of 4- (2-hydroxyethylthio) -2-hydroxyimino-3-oxovaleric acid ethyl ester and 4.15 g of potassium carbonate in 40 ml of acetone, and the suspension is stirred for 2 hours at room temperature. 



  The insoluble material is removed by filtration and the filtrate is concentrated in vacuo.  35 ml of diethyl ether and 50 ml of water are added to the residue and the mixture is shaken vigorously.  The organic layer is separated off, washed with 20 ml of water, dried over magnesium sulfate and concentrated in vacuo.  4.30 g of ethyl 2-allyloxyimino-4- (2-hydroxyethylthio) -3-oxovalerate are obtained in the form of an oil. 



   IR spectrum: #maxFilm: 3460, 2980, 2860, 1730,
1680 cm-1 NMR spectrum: Ï (CDCl3, ppm): 1.36 (3H, t), 2.76 (2H, m), 3.68 (2H, m), 4.10 to 4.67 ( 4H, m), 4.75 (2H, m), 5.32 (2H, m), 5.96 (1H, m) (iii) 0.40 g of p-toluenesulfonic acid are added to a solution of 4.30 g of 2 -Allyloxyimino-4- (2-hydroxyethylthio) -3 -oxovaleriansäureäthylester added in 43 ml of toluene and the mixture is heated to reflux for 20 minutes with separation of the water generated to boiling.  After cooling, 10 ml of ethyl acetate are added to the resulting solution and the mixture is washed twice with 40 ml of water. 



  The solution is dried over magnesium sulfate and concentrated in vacuo; 3.3 g of oily residue are obtained.  The residue is chromatographed on a column of silica gel while eluting with chloroform.  The eluate is concentrated in vacuo; 2.92 g of 2- (2,3-dihydro-1,4-oxathiin-6-yl) -2-allyloxyiminoacetic acid ethyl ester are obtained. 



     
Movie
IR spectrum: v max: 3060, 2980, 2940, 2880,
1730cm1
NMR spectrum: Ï (CDCl3, ppm): 1.33 (3H, t), 3.07 (2H, m), 4.17 to 4.50 (4H, m), 4.67 (2H, m) , 5.30 (2H, m), 5.67 (1H, s), 6.60 (1H, m). 



   (iv) 1.22 ml of 1 normal aqueous sodium hydroxide solution are added to a solution of 0.90 g of 2- (2,3-dihydro-1,4-oxathiin-6-yl) -2-allyl-oxyiminoacetic acid ethyl ester in 9 ml of methanol and the mixture is stirred at room temperature for 22 hours.  The methanol is distilled off from the solution and the residue is dissolved in 20 ml of water.  The solution is adjusted to pH 7.0 with concentrated hydrochloric acid, washed with 20 ml of ethyl acetate, adjusted to pH 1.5 with concentrated hydrochloric acid and extracted with 50 ml of ethyl acetate.  The extract is washed with 50 ml of water, dried over magnesium sulfate and concentrated in vacuo. 

  The residue is recrystallized from a mixture (1: 1: 1) of diisopropyl ether, diethyl ether and n-hexane; 0.50 g of syn isomer of 2- (2,3-dihydro-1,4-oxathiin-6-yl) -2-allyloxyiminoacetic acid are obtained in the form of colorless crystals of mp. 



  119 to 121 C.    



     
IR spectrum: v Nujol: 3060.1730 cm - max
Nuclear Magnetic Resonance Spectrum: (CDCl3, ppm): 3.05 (2H, m), 4.40 (2H, m), 4.68 (2H, m), 5.30 (2H, m), 5.83 ( 1H, s), 6.02 (1H, m). 



   Example L 2- (2,3-dihydro-1,4-oxathiin-6-yl) -2-allyloxyiminoacetic acid (syn-isomer)
2.0 g of 2-mercaptoethanol and 5.8 g of ethyl 2- (2-chloroacetyl) 2-allyloxyiminoacetate were allowed to react with each other in a similar manner as in Example A (i) and A (ü), giving 0.6 g 2- (2,3-dihydro-1,4-oxathiin-6-yl) -2-allyloxyiminoacetic acid (syn isomer), IR: v max:

   1720 cm-1
Example I 7- [2- (2,3-Dihydro-1,4-oxathEin-6-yl) -2-methoxyiminoacetamido] cephalosporanic acid (syn isomer)
820 mg of phosphoryl chloride was added to a solution of 400 mg of dry N, N-dimethylformamide in 1.5 ml of dry ethyl acetate over a period of 10 minutes at 5 C and stirred at 5 to 10 C for 30 minutes to prepare a Vilsmeier reagent.  To the solution was added 1 g of 2- (2,3-dihydro-1,4-oxathiin-6-yl) -2-methoxyiminoacetic acid (syn isomer) and 8 ml of dry ethyl acetate at -10 C in one portion and the mixture was added Stirred at - C for 30 minutes to prepare the acid chloride solution. 



  On the other hand, a mixture of 1.4 g of 7-aminocephalosporanoic acid, 5.4 g of trimethylsilylacetamide and 50 ml of dry ethyl acetate was stirred to prepare a solution.  The above acid chloride solution was added to the solution all at once at -15 C and stirred at -10 C for 2 hours.  To the solution thus obtained, 30 ml of water was added and shaken sufficiently, and then the organic layer was separated.  After 30 ml of water was added to the organic layer, the solution was adjusted to pH 6.5 with sodium bicarbonate and the aqueous layer was separated.  The aqueous layer was washed with methylene chloride and the organic solvent was removed by introducing nitrogen gas. 

  The solution was adjusted to pH 2.0 with ice-cooling with 10% hydrochloric acid and the precipitates were collected by filtration, washed with water and dried, whereby 1.7 g of 7- [2 (2,3-dihydro-1,4 -oxathiin-6-yl) -2-methoxyiminoacetamido] - cephalosporanic acid (syn isomer) in the form of a pale yellow powder, F.  175 to 177 C (dec. ). 

 

     
IR #maxNujol # 3300, 2500-2600, 1775, 1740, 1720,
1645 cm-1
NMR # (DMSON6, ppm): 2.10 (3H, s), 3.10 (2H, broad s), 3.55 (2H, AB-q, J = 18Hz), 3.85 (3H, s) , 4.20 (2H, broad s), 4.85 (2H, AB-q, J = 13Hz), 5.15 (1H, d, J = 5Hz), 5.65-5.76 (2H, m ), 9.60 (1H, d, J = 8Hz)
Example 2 7- [2 (2,3-Dihydro-1,4-oxathiin-6-yl) -2-methoxyiminoacetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer)
0.508 g of 2- (2,3-dihydro-1,4-oxathiin-6-yl) -2-methoxyiminoacetic acid (syn isomer) was prepared in a similar manner as in Example 1 with 0.82 g of 7-amino-3-carbamoyloxymethyl -3-cephem-4-carboxylic acid reacted,

   to obtain 0.85 g of the above compound in the form of a pale yellow powder, F.  175 to 180 C (dec. ). 



     
IR # Nujol / max: 3450, 3350, 3300, 260, 1765, 1720,
1660 cm-1
NMR # (DMSOd6, ppm): 3.06 (2H, broad s), 3.62 (2H, AB-q, J = 18Hz), 3.80 (3H, s), 4.26 (2H, broad s ), 4.76 (2H, AB-q, J = 13Hz), 5.13 (1H, d, J = 5Hz), 5.68 (1H, dd, J = 5Hz, 8Hz), 5.76 (1H , s), 6.56 (2H, s), 9.60 (1H, d,

   J = 8Hz)
Example 3 7- [2- (2,3-dihydro-1,4-oxathiin-6-yl) -2-methoxyiminoacetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem -4-carboxylic acid (syn isomer)
I g of 2- (2,3-dihydro-1,4-oxathiin-6-yl) -2-methoxyiminoacetic acid (syn isomer) was treated in a similar manner as in Example 1 with 1.8 g of 7-amino-3- ( 1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid reacted to give 2.3 g of the above compound as a pale yellow powder, F. 



  160 to 165 C (dec. ). 



     
JR v Nujol
3300, 2600, 1785, 1730, 1670 cm-1
NMR # (DMSO-d6, ppm): 3.10 (2H, broad s), 3.78 (2H, ABq, J = 18Hz), 3.82 (3H, s), 4.15 (2H, broad s ), 4.48 (2H, AB-q, J = 13Hz), 5.17 (1H, d, J = 5Hz), 5.65-5.76 (2H, m). 



  9.53 (1H, s), 9.65 (1H, d, J = 8Hz)
Example 4
7- [2- (2,3-Dihydro-1,4-oxathiin-6-yl) -2-methoxyiminoacetamido] -3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3 -cephem-4-carboxylic acid (syn-isomer)
1 g of 2- (2,3-dihydro-1,4-oxathiin-6-yl) -2-methoxyiminoacetic acid (syn-isomer) was treated with 2 g of 7-amino-3- (5- methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid reacted to give 2.2 g of the above compound in the form of a pale yellow powder, F.  160 to 165 C (dec. ). 



      IR # Nujol / max: 3300, 2500-2600, 1780, 1720, 1675,
1620 cm-1
NMR # (DMSO-d6, ppm): 2.70 (3H, s), 3.05 (2H, broad s), 3.70 (2H, AB-q, J = 18 Hz), 3.85 (3H , s), 4.21 (2H, broad), 4.30 (2H, AB-q, J = 13Hz), 5.15 (1H, d, J = 5Hz), 5.68 (1H, dd, J = 5Hz, 8Hz), 5.75 (1H, s), 9.68 (1H, d, J = 8Hz)
Example S 7- [2- (2,3-Dihydro-1,4-oxathiin-6-yl) -2-methoxyiminoacetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem -4-carboxylic acid (syn-isomer)
1 g of 2- (2,3-dihydro-1,4-oxathiin-6-yl) -2-methoxyiminoacetic acid (syn isomer) was treated with 2 g of 7-amino-3- (1- methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid reacted to give 2.0 g of the above compound in the form of a pale yellow powder, F. 

   145 to 150 C (dec. ). 



      IR # Nujol / max: 3300, 2600-2550, 1785, 1730, 1680 cm-1
NMR # (DMSO-d6, ppm): 3.04 (2H, broad s), 3.68 (2H, ABq, J = 18Hz), 3.76 (3H, s), 3.90 (3H, s) , 4.28 (4H, m), 5.06 (1H, d, J = 4Hz), 5.6-5.75 (2H, m), 9.56 (1H, d, J = 8Hz)
Example 6 7- [2- (2,3-dihydro-l,

   4-oxathiin-6-yl) -2-methoxyiminoacetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (anti-isomer)
1 g of 2- (2,3-dihydro-1,4-oxathiin-6-yl) -2-methoxyiminoacetic acid (anti-isomer) was treated with 2 g of 7-amino-3- (1- methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid reacted to give 1.8 g of the above compound in the form of a pale yellow powder, F.  144 to 148 C (dec. ). 



   IR # Nujol / max: 3300, 2600, 1780, 1720, 1675, 1625 cm-1
NMR 8 (DMSOd6, ppm): 3.06 (2H, broad s), 3.70 (2H, AB-q, J = 18Hz), 3.90 (3H, s), 3.96 (3H, s) , 4.20 (2H, broad s), 4.32 (2H, AB-q, J = 13Hz), 5.10 (1H, d, J = 5Hz), 5.80 (1H, dd, J = 5Hz , 8Hz), 6.72 (1H, s), 9.28 (1H, d, J = 8Hz)
Example 7 7- [2- (2,3-Dihydro-1,4-dithEin-S-yl) -2-methoxyiminoacetam- do] -3- (i, 3, 4-thiadiazol-2-yl) thiomethyl- 3-cephem-4 carboxylic acid (syn-isomer)
1.1 g of 2- (2,3-dihydro-1,4-dithiin-5-yl) -2-methoxyiminoacetic acid were mixed with 1.7 g of 7-amino-3- (1,3 , 4-thiadiazol-2-yl) thiomethyl-3-cephem-4 carboxylic acid reacted,

   2 g of the above compound were obtained in the form of a pale yellow powder, F.  192 to 194 C (dec. ). 



     
IR v Nujol: 3300, 2600-2550, 1780, 1725, 1675 cm - max
NMR 8 (DMSO-d6, ppm): 3.22 (4H, broad s), 3.65 (2H, AB-q, J = 18Hz), 3.84 (3H, s), 4.48 (2H, AB-q, J = 13Hz), 5.16 (1H, d, J = 5Hz), 5.76 (1H, d, d, J = 5Hz), 8Hz), 6.62 (1H, s), 9 , 56 (1H, s), 9.76 (1H, d, J = 8Hz)
Example 8
7- [2- (4-Formyl-2,3-dihydro-4H-1,4-thiazin-4-yl) -2-methoxyiminoacetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl -3cephem-4-carboxylic acid (syn-isomer)
2.3 g of 2- (4-formyl- (2,3-dihydro-4H-1,4-thiazin-5-yl) -2-methoxyiminoacetic acid) (syn isomer) were added in a similar manner to Example 1 with 3.3 g of 7-amino-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid was reacted to give 2.5 g of the above compound in the form of a pale yellow powder, F . 

   150 to 155 C (dec. ). 



     
IR #maxNujol: 3300, 2600-2550, 1785, 1725, 1690,
1675 cm-1
NMR 8 (DMSOd6, ppm): 3.10 (2H, broad s), 3.70 (2H, AB-q, J = 18Hz), 3.78 (3H, s), 3.85 (2H, broad s ), 3.90 (3H, s), 4.30 (2H, AB-q, J = 13Hz), 5.10 (1H, d, J = 5Hz), 5.70 (1H, d, d, J = 5 Hz), 8 Hz), 6.25 (1H, s), 8.50 (1H, s), 9.63 (1H,

   d, J = 8Hz)
Example 9
7- [2- (2-Oxo-1,3-dithiol-4-yl) -2-methoxyiminoacetamido] -3 (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid ( syn-isomeres)
0.2 g of 2- (2-oxo-1, 3-dithiol-4-yl) -2-methoxyiminoacetic acid (syn isomer) were prepared in a similar manner as in Example 1
1.2 g of 7-amino-3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem4-carboxylic acid reacted and crystallized in diisopropyl ether to give 0.15 g of the above compound, F .  80 to 90 C (dec. ). 



   IR #maxNujol: 1780, 1710, 1640 cm-1
NMR # (acetone 6, ppm): 3.85 (2H, broad s), 3.98 (3H, s), 4.59 (2H, AB-q, J = 14Hz), 5.29 (1H, d, 3 = 5Hz), 5.97 (1H, d, J = 5Hz), 7.45 (1H, s), 9.42 (1H, s)
Example 10
7- [2- (2-oxo-1,3-dithiol-4-yl) -2-methoxyiminoacetamido] -3 (1,3,4-thiadiazol-4-yl) thiomethyl-3-cephem-4-carboxylic acid ( anti-isomer)
0.7 g of 2- (2-oxo-1,3-dithiol-4-yl) -2-methoxyiminoacetic acid (anti-isomer) was treated with 1.06 g of 7-amino-3- ( 1,3,4-thiadiazol-2-yl) thiomethyl-3-ce phem-4-carboxylic acid was allowed to react to obtain 0.85 g of the above compound. 



     IR v max: 1780, 1710, 1670, 1640 cm-1
NMR # (DMSO-d6, ppm): 3.72 (2H, broad s), 4.05 (3H, s), 4.46 (2H, AB-q, J = 14Hz), 5.17 (1H, d, J = 6Hz), 5.72 (1H, dd, J = 8Hz, 6Hz) 7.98 (1H, s), 9.50 (1H, d, J = 8Hz), 9.52 (1H, s )
Example 11 7- [2- (1,4-Benzoxathiin-2-yl) -2-methoxyiminoacetamido] -3 (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn- Isomeres)
0.85 g of 2- (1,4-benzoxathiin-2-yl) -2-methoxyiminoacetic acid (syn isomer) was treated with 1.09 g of 7-amino-3- (1,3, 4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid reacted to give 1.50 g of the above compound in the form of a yellow powder, F.  157 to 161 C (dec. ). 



     
IR #maxNujol: 3350, 2600-2500, 1780, 1720, 1670,
1625 cm-1
NMR # (DMSO-d6, ppm): 3.75 (2H, AB, J = 18Hz), 3.90 (3H, s), 4.55 (2H, AB-q, J = 13Hz), 5.17 (1H, d, J = 5Hz), 5.80 (1H, dd, J = 5Hz, 8Hz), 6.05 (1H, s), 6.8-7.15 (4H, m), 9.60 (1H, s), 9.78 (1H, d, J = 8Hz)
Example 12 7-J2- (1,4-Benzodithiin-2-yl) -2-yl) -2-methoxyiminoacetamidol- 3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4- carboxylic acid (syn-isomer)
0.75 g of 2- (1,4-benzodithiin-2-yl) -2-methoxyiminoacetic acid (syn isomer) was treated with 1 g of 7-amino-3- (1,3,4- thiadiazol-2-yl) thiomethyl-3-co-phem-4-carboxylic acid reacted to give 0.7 g of the above compound in the form of a yellow powder, F. 

   142 to 147 C (dec. ). 



     
IR v Nujol 3300.2600, 1775, 1720, 1665, 1620,
IR #max # 3300, 2000, 1775, 1720, 1000, 1020,
1600 cm-1
NMR # (DMSO-d6, ppm): 3.68 (2H, AB-q, J = 18Hz), 3.90 (3H, s), 5.40 (2H, AB-q, J = 13Hz), 5 , 16 (1H, d, J = 5Hz), 5.80 (1H, dd, J = 5Hz, 8Hz), 6.84 (1H, s), 7.2-7.4 (4H, m), 9 , 50 (1H, s), 9.76 (1H, d, J = 8Hz)
Example 13 7- [2- (2,3-Dihydro-I, 4-dithiin-5-yl) -2-methoxyiminoacetamido] -3- (1-methyl-l H-tetrazol-5-yl) thiomethyl -3-cephem-4-carboxylic acid (syn-isomer)
1.2 g of 2- (2,3-dihydro-1,4-dithiin-5-yl) -2-methoxyiminoacetic acid (syn isomer) were prepared in a similar manner as in Example 1 with 1.65 g of 7-amino-3 - (1-methyl-1H-tetrazol-5-yl) thio-methyl-3-cephem-4-carboxylic acid reacted,

   2.1 g of the above compound were obtained in the form of a pale yellowish-white powder. 



      IR #maxNujol # 3300, 2600-2500, 1790, 1730, 1680,
1630 cm-1
NMR ö (DMSO-d6, ppm): 3.25 (4H, s), 3.72 (2H, ABS, J = 18Hz), 3.85 (3H, s), 3.95 (3H, s), 4.38 (2H, AB-q, J = 13Hz), 5.17 (1H, d, J = 5Hz), 5.78 (1H, dd, J = 5Hz, 8Hz), 6.63 (1H, s ), 9.77 (1H, d, J = 9Hz)
Example 14 7- [2- (2,3-Dihydro-1,4-dithiin-5-yl) -2-methoxyiminoacetamido] -2-methyl-3-cephem-4-carboxylic acid (syn-isomer)
The Vilsmeier reagent was prepared in the usual way from 0.44 g of dry N, N dimethylformamide, 2 ml of ethyl acetate and 0.92 g of phosphoryl chloride. 

  To the Vilsmeier reagent, 10 ml of ethyl acetate and 1.2 g of 2- (2,3-dihydro-1,4-dithiin-5-yl) -2-methoxyiminoacetic acid (syn isomer) were added to prepare the acid chloride solution.  On the other hand, 1.07 g of 7-amino-2-methyl-3-cephem-4-carboxylic acid, 4.5 g of trimethylsilylacetamide and 20 ml of ethyl acetate were mixed together and stirred at room temperature for 1 hour.  The solution was cooled to -15 ° C, and the acid chloride solution obtained above was added all at once with stirring, and then the solution was stirred at -10 ° C for 1 hour. 



  After adding 60 ml of water to the resulting solution, the organic layer was separated.  150 ml of water was added to the organic layer, and then it was adjusted to pH 6.5 with sodium bicarbonate.  The aqueous layer was separated, washed with diethyl ether and the organic layer was removed by introducing nitrogen gas.  The aqueous solution was adjusted to pH 2.2 with 10% hydrochloric acid with ice cooling.  The precipitates were removed by filtration, washed with water and dried over magnesium sulfate, giving 1.45 g of 7- [2 (2,3-dihydro-1,4-dithiin-5-yl) -2-methoxyiminoacetarnido] -2methyl 3-cephem-4-carboxylic acid (syn isomer) in the form of a pale yellow powder. 



      IR #maxNujol # 3300, 2500-2600, 1790, 1735, 1670,
1635 cm-1
NMR 8 (DMSO-d6, ppm): 1.43 (3H, d, J = 7Hz), 3.18 (4H, s), 3.7-3.8 (4H, m), 5.10 (1H , d, J = 5Hz), 5.79 (1H, dd, J = 5Hz, 8Hz), 6.50 (1H, d, J = 6Hz), 6.55 (1H, s), 9.65 (1H , d, J = 8Hz)
Example 15 7- [2- (2,3-Dihydro-1,4-dithiin-5-yl) -2-methoxyiminoacetami do] -3-cephem-4-carboxylic acid (syn isomer) (i) The Vilsmeier reagent was prepared in the usual way from 440 mg of dry N, N-dimethylformamide, 2.0 ml of dry ethyl acetate and 920 mg of phosphoryl chloride. 

   10 ml of dry ethyl acetate and 1.2 g of 2- (2,3-dihydro-1,4-dithiln-5-yl) -2-methoxyiminoacetic acid (syn isomer) were added to the Vilsmeier reagent to prepare an acid chloride solution.     On the other hand, 1.68 g of 4-nitrobenzyl-7-amino3-cephem-4-carboxylic acid, 4.6 mg of trimethylsilylacetamide and 20 ml of dry ethyl acetate were mixed together and stirred at 40 to 50 ° C. for 1.5 hours.  After the solution was cooled to -15 ° C, the acid chloride solution obtained above was added to the solution all at once with stirring and stirred at -10 ° C for 1 hour.  60 ml of water were added to the solution thus obtained and the solution was stirred below 10 ° C. for 1.5 hours.  

  The precipitates were collected by filtration, washed with water and dried, giving 2.1 g of 4-nitrobenzyl-7- [2 (2,3-dihydro-l, 4-dithiin-5-yl) -2-methoxyiminoacetamido] - 3-cephem-4-carboxylic acid (syn isomer) in the form of a yellow powder.   



      IR v Nujol 3350, 1785, 1700, 1690, 1635, 1610, 1530, max 1350 cm
NMR # (DMSO-d6, ppm): 3.20 (4H, s), 3.53 (2H, d, J = 4Hz), 3.90 (3H, s), 5.16 (1H, d, J = 5Hz), 5.35 5.35 (2H, s), 5.68 (1H, dd, J = 5Hz, 8Hz), 6.48 (1H, s), 6.58 (1H, d, J = 5Hz), 7.58 (2H, d, J = 9Hz), 8.23 (2H, d, J = 9Hz),

   9.60 (1H, d, J = 8Hz) (ii) 0.8 g of palladium-carbon was added to a mixture of 2.0 g of 4-nitrobenzyl-7- [2- (2,3-dihydro-1,4 -dithiin-5-yl) -2- methoxyiminoacetamido] -3-cephem-4-carboxylate (syn-isome res), 20 ml of methanol, 40 ml of tetrahydrofuran, 0.3 ml of acetic acid and 3 ml of water and added under normal pressure at room temperature Subjected to catalytic reduction for 4 hours.  After filtering off the catalyst from the resulting mixture, the filtrate was concentrated at 40 ° C. in vacuo.  To the residue was added 20 ml of ethyl acetate, and the solution was adjusted to pH 6.5 to 7.0 with a saturated aqueous sodium bicarbonate solution, stirred for 30 minutes, and then filtered. 

  The insoluble product was washed with 10 ml of water.  The filtrate and the washings were combined and the aqueous layer was separated and washed with ethyl acetate and adjusted to pH 5.0 with 10% hydrochloric acid.  The solution was treated with 0.1 g activated carbon for 5 minutes and that filtered in vacuo.  The filtrate was washed with diethyl ether and the organic solvent was removed by introducing nitrogen gas.  The aqueous layer was adjusted to pH 2.0 with 10% hydrochloric acid under ice-cooling and extracted twice with 50 ml of ethyl acetate. 



  The extract was washed with ice water, dried over magnesium sulfate and filtered.  The filtrate was concentrated in vacuo to 40 C and the residue was crystallized in 30 ml of ether.  The crystals were collected by filtration, washed with diethyl ether and dried, giving 0.9 g of 7- [2- (2,3-dihydro-1,4-dithiin-5-yl) -2-methoxyiminoacetamido] -3 -cephem-4-carboxylic acid (syn isomer) in the form of a pale yellow powder. 



     
IR #maxNujol: 3300, 2500-2600, 1790, 1735, 1660,
1640 cm-1
NMR # (DMSOd6, ppm): 3.16 (4H, s), 3.58 (2H, d, J = 4Hz), 3.77 (3H, s), 5.09 (1H, d, J = 5Hz) ), 5.78 (1H, dd, J = 5Hz, 8Hz), 6.43 (1H, d, 1 = 5Hz), 6.54 (1H, s), 9.60 (1H, d, J = 8Hz )
Example 16 7- [2- (2,3-Dihydro-4H-1,4-thiazin-5-yl) -2-hydroxyiminoacet amido] -3-cephem-4-carboxylic acid (syn-isomer) (i) A suspension 0.25 g of 2-aminoethanethiol hydrochloride in 1 ml of water and 2 ml of tetrahydrofuran was adjusted to pH 7.5 with a saturated aqueous sodium bicarbonate solution. 

  The solution was added to a suspension of 1.05 g of 4-nitrobenzyl-7- (2-hydroxyimino-3-oxo-4-bromobutyramido) -3-cephem-4-carboxylate (syn isomer) in 30 ml of tetrahydrofuran and stirred for 4 hours at room temperature.  The solution obtained was concentrated in vacuo and water and ethyl acetate were added to the residue.  The ethyl acetate layer was separated, washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and that concentrated in vacuo. 



  Diethyl ether was added to the residue and the precipitates were collected by filtration, whereby 0.5 g of 4-nitrobenzyl-7- [2- (2,3-dihydro-4H-thiazin-5-yl) -2-hydroxy-iminoacetamido ] -3-cephem-4-carboxylate (syn isomer). 



     
IR #maxNujol: 3350-3200, 1780, 1730, 1670, 1630, 1605,
1520 cm-1
NMR # (DMSO = 16, ppm): 2.93 (2H, m), 3.83-3.30 (4H, m), 5.03 (1H, s), 5.18 (1H, d, J = 5Hz), 5.47 (2H, broad s), 5.88 (1H, d, J = 5Hz), 6.70 (1H, t, J = 5Hz), 7.75 (1H, d, J = 9Hz), 8.30 (1H, d, J = 9Hz) (ii) 0.5 g of the 4-nitrobenzyl-7- [2- (2,3-dihydro-4H-thiazin-5 -yl) - 2-hydroxyiminoacetamido] -3-cephem4-carboxylate (syn isomer) were dissolved in a mixture of 15 ml of tetrahydrofuran and 15 ml of methanol.  0.3 g of 10% palladium-carbon was added to the solution and subjected to a catalytic reduction under normal pressure at room temperature. 

  The catalyst was filtered off from the resulting mixture and the filtrate was concentrated in vacuo.  After water and ethyl acetate were added to the residue, the solution was adjusted to pH 8.0 with an aqueous sodium bicarnate solution.  The insoluble substance was filtered off and the aqueous solution was separated.  The aqueous solution was adjusted to pH 5.5 and washed with ethyl acetate and methylene chloride and the organic solvent was removed by introducing nitrogen gas.  The solution was adjusted to pH 3.3 and a column chromatography on a non-ionic adsorption resin Diaion HP-20 (trademark for a product of Mitsubishi Chemical Industries Ltd.  (30 ml)).  The column was washed with water and eluted with 40% aqueous acetone. 

  The eluate was concentrated in vacuo and lyophilized, 90 mg of 7- [2- (2,3-dihydro-4H-1,4-thiazine-5-yl) -2-hydroxyiminoacetamido] -3-cephem-4 -carboxylic acid (syn isomer) received. 



     
IR v Nujol: 3400-3200.1750, 1650, 1590 cm max
NMR # (DMSO-d6, ppm): 2.90 (2H, m), 3.80-3.30 (4H, m), 5.00 (2H, m), 5.63 (1H, m), 6.3 (1H, m)
Example 17 7- [2- (2,3-Dihydro-1,4-dithiin-5-yl) -2-methoxyiminoacetamido] -3-methyl-3-cephem-4-carboxylic acid (syn-isomer)
1.15 g of 2- (2,3-dihydro-1,4-dithiin-5-yl) -2-methoxyiminoacetic acid (syn isomer) was prepared in a similar manner as in Example 1 with 1.07 g of 7-amino-3 -methyl-3-cephem-4-carboxylic acid reacted to obtain 0.8 g of the above compound in the form of a pale yellow powder. 



     
IR #maxNujol # 3300, 2500-2600, 1785, 1720, 1660, 1640,
1620 cm-1
NMR # (DMSO-d6, ppm): 2.00 (3H, s), 3.17 (4H, s), 3.43 (2H, ABffl, J = 12Hz), 3.75 (3H, s), 5.10 (1H, d, J = 5Hz), 5.65 (1H, dd, 1 = 5Hz, 8Hz), 6.62 (1H, s), 9.70 (1H, d, J = 8Hz)
Example 18
7- [2- (2,3-Dihydro-1,4-oxathiin-6-yl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid (syn isomer) (i) From 1.25 g dry N , N-dimethylformamide, 2.61 g of phosphoryl chloride and 6 ml of dry ethyl acetate, the Vilsmeier reagent was prepared in the usual way.  

  20 ml of ethyl acetate were added to the solution and then 3.0 g of 2- (2,3-dihydro-1,4-oxathiin-6-yl) -2-methoxyiminoacetic acid (syn isomer) were added all at once at -10 ° C. added to the solution and stirred at the same temperature for 30 minutes to prepare an acid chloride solution.  On the other hand, a mixture of 4.51 g of 4-nitrobenzyl-7-amino-3-cephem-4-carboxylate, 14.2 g of trimethylsilylacetamide and 180 ml of ethyl acetate was stirred at 45 ° C for 1 hour.  The acid chloride solution obtained above was added to the solution all at once at -15 ° C. and stirred at the same temperature for 1 hour.  100 ml of water were added to the resulting solution and the organic layer was separated. 

  The organic solution was washed with 60 ml of a saturated aqueous sodium bicarbonate solution and then with 100 ml of a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo.  The residue was washed with diethyl ether and the precipitates were collected by filtration, giving 4.8 g of 4-nitrobenzyl-7- [2, (2,3-dihydro-1,4-oxathiin-6-yl) -2-methoxyiminoacetamido ] -3-cephem-4-carboxylate (syn isomer). 



   IR #maxNujol: 3280, 1770, 1730, 1650 cm-1
NMR ö (DMSO-d6, ppm): 3.08 (2H, broad s), 3.64 (2H, AB-q, J = 18Hz), 3.80 (3H, s), 4.27 (2H, wide s), 5.12 (1H, d, J = 8Hz), 5.40 (2H, s), 5.76 (1H, s), 5.80 (1H, dd, J = 5Hz, 8Hz), 6.65 (1H, t, J = 4Hz), 7.70 (2H, d, J = 9Hz), 8.22 (2H, d, J = 9Hz). 

   9.40 (1H, d, J = 8Hz) (ii) 3.30 g of the 4-nitrobenzyl-7-2- (2,3-dihydro-1,4-oxathiin-6-yl) obtained above - 2-methoxyiminoacetamido] -3-cephem-4-carboxylate (syn isomer) were suspended in a mixture of 150 ml of tetrahydrofuran, 70 ml of methanol, 10 ml of water and 1 ml of acetic acid.  2.3 g of 10% palladium-carbon were added to the solution and catalytically hydrogenated at room temperature for 45 minutes.  After filtering off the catalyst from the solution obtained, the filtrate was concentrated in vacuo.  Water and a saturated aqueous sodium bicarbonate solution were added to the residue and the pH was adjusted to 7.0.  After filtering, the filtrate was washed with 60 ml of ethyl acetate and 20 ml of methylene chloride, and then the organic solvent was removed by bubbling with nitrogen gas. 

  The solution was adjusted to pH 2.0 with 10% hydrochloric acid with ice cooling.  The precipitates were collected by filtration, washed with water and dried, giving 1.55 g of 7- [2- (2,3-dihydro-1,4-oxathiin-6-yl) -2-methoxyiminoacetamole-3-cephem -4-carboxylic acid (syn isomer) was obtained. 



   IR #maxNujol: 3225, 1770, 1660 cm-1
NMR # (DMSO-d6, ppm): 3.07 (2H, broad s), 3.57 (2H, AB-q, J = 18Hz), 3.78 (3H, s), 4.27 (2H, broad), 5.06 (1H, d, 1 = 5Hz), 5.71 (1H, s), 5.72 (iM, dd, J = 5Hz, 8Hz), 6.45 (1H, t, J = 4Hz), 9.58 (1H, d, J = 8Hz)
Example 19 7- [2- (2,3-Dihydro-1,4-oxathiin-6-yl) -2-methoxyiminoacetami do] -3-chloro-3-cephem-4-carboxylic acid (syn-isomer) (i) The Vilsmeier reagent was prepared in the usual way from 0.4 g of N, N-dimethylformamide and 0.86 g of phosphoryl chloride and suspended in 20 ml of dry ethyl acetate. 

  1.0 g of 2- (2,3-dihydro-1,4-oxathiin-6-yl) -2-methoxyiminoacetic acid (syn isomer) was added to the suspension at -5 ° C. and the mixture was stirred at the same temperature for 30 minutes for the preparation of an acid chloride solution.  On the other hand, 2.0 g of 4-nitrobenzyl-7-amino-3-chloro-3-cephem-4-carboxylate hydrochloride was dissolved in a solution of 5.2 g of trimethylsilylacetamide in 40 ml of ethyl acetate.  The acid chloride solution obtained above was added to the solution at -30 ° C. and stirred at -20 to -10 ° C. for 2 hours.  Water was added to the resulting solution at -20 C and it was extracted with 160 ml of ethyl acetate. 

  The extract was washed with a saturated aqueous sodium bicarbonate solution and then with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and then concentrated in vacuo.  The residue was treated (triturated) in diisopropyl ether and the precipitates were collected by filtration and dried to give 2.6 g of 4-nitrobenzyl-7- [2- (2,3dihydro-1,4-oxathiin-6-yl) - 2-methoxyiminoacetymido] -3chlor-3-cephem-4-carboxylate (syn isomer). 



      IR v Nujol 3250.1775.1730.1655, 1610.1590, max 1525 cm1
NMR 6 (DMSO-d6, ppm): 3.10 (2H, broad 3.83 (3H, s), 3.93 (2H, broad s), 4.28 (2H, broad s), 5.32 ( 1H, d, J = 5Hz), 5.48 (2H, s), 5.75 (1H, s), 5.85 (1H, dd, J = 5Hz, 8Hz), 7.73 (1H, d, J = 9Hz), 8.27 d, d, 1 = 9Hz), 9.73 (1H, d,

   J = 8Hz) (ii) 2.5 g of the 4-nitrobenzyl-7- [2- (2,3-dihydro-1,4-oxathiin-6-yl) -2-methoxyiminoacetamido] -3-chloro-3 thus prepared. cephem-4-carboxylate (syn isomer) was dissolved in a mixture of 40 ml of tetrahydrofuran and 40 ml of methanol. 



  1.2 g of 10% palladium-carbon were added to the solution and catalytically hydrogenated for 4 hours at normal pressure and room temperature.  After filtering off the catalyst from the solution obtained, the filtrate was concentrated in vacuo.  Water and ethyl acetate were added to the residue and the pH was adjusted to 7.5 with a saturated aqueous sodium bicarbonate solution.  The insoluble substance was filtered off and the aqueous solution was separated.  After ethyl acetate was added to the aqueous solution, the solution was adjusted to pH 1.5 with 10% hydrochloric acid and extracted with ethyl acetate.  The extract was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and then concentrated in vacuo. 

  The residue was treated (triturated) with diisopropyl ether and the precipitates were filtered off, giving 1.3 g of 7- [2- (2,3-dihydro-1,4-oxathiin-6-yl) -2-methoxyiminoacetamido] -3-chloro-3-cephem-4-carboxylic acid (syn isomer) was obtained. 



      IR #maxNujol: 3260, 1760, 1720, 1655, 1620, 1580,
1530 cm-1
NMR 8 (DMSO-d6, ppm): 3.10 (2H, broad s), 3.85 (3H, broad), 3.87 (2H, broad broad), 4.33 (2H, broad broad), 5 , 27 (1H, d, J = 5Hz), 5.77 1H, s), 5.78 (1H, dd, J = 5Hz, 8Hz),

   9.7 (1H, d, J = 8Hz)
Example 20 7- [2- (2,3-Dihydro-1,4-oxathiin-6-yl) -2-methoxyiminoacetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem -4-carboxylic acid (syn-isomer)
2.29 g of 7- [2- (2,3-dihydro-1,4-oxathiin-6-yl) -2-methoxyiminoacetamido] cephalosporanic acid (syn isomer) and 0.84 g of sodium bicarbonate were mixed together 30 ml acetone and 38 ml water dissolved.  0.65 g of 1,3,4 thiadiazole-2-thiol was added to the solution and it was stirred for 4 hours at 60 to 65 ° C, during which time the pH value at 6.5 to with a saturated aqueous sodium bicarbonate solution 7.5 was held.  The solution obtained was concentrated in vacuo and water was added to the residue with cooling. 

  The solution was adjusted to pH 2 with 10% hydrochloric acid and extracted with ethyl acetate.  Water was added to the extract and the pH was adjusted to 6.5 with a saturated aqueous sodium bicarbonate solution.  The aqueous layer was separated, washed with methylene chloride and the organic solvent was removed by introducing nitrogen gas.  The solution was adjusted to pH 2 with 10% hydrochloric acid and the precipitates were collected by filtration, washed with water and dried, whereby 0.88 g of 7- [2 (2,3-dihydro-1,4-oxathiin-6 -yl) -2-methoxyiminoacetamido] 3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).  The IR and NMR spectra of the compound were identical to that of the compound obtained in Example 3. 

 

   Example 21 7- [2- (2,3-Dihydro-1,4-oxathiin-6-yl) -2-methoxyiminoacetamido] -3- (1H-1,2,3-triazol-5-yl) - thiomethyl-3-cephem-4-carboxylic acid (syn-isomer)
0.92 g of phosphoryl chloride are added to a solution of 0.44 g of N, N-dimethylformamide in 2 ml of ethyl acetate, which is kept under stirring and at a temperature of -5 to 10 ° C., over a period of 2 minutes.  The solution are 20 ml of ethyl acetate and 1.0 g of syn isomer of 2- (2,3-dihydro
1, 4-oxathiin-6-yl) -2-methoxyiminoacetic acid is added and the mixture is stirred for 20 minutes at the same temperature to form a solution of the activated acid. 



  On the other hand, 4.6 g of trimethylsilylacetamide are added to a solution of 1.57 g of 7-amino-3- (1H-1,2,3-triazol-5-yl) thiomethyl-3cephem-4-carboxylic acid in 20 ml of ethyl acetate and that Mixture is stirred at 40 C for 30 minutes.  The solution of the activated acid is added to this solution at −15 ° C. all at once and the mixture is stirred for 1 hour at the same temperature.  30 ml of water are added to the resulting solution, the mixture is stirred for 5 minutes and then the ethyl acetate layer is separated off.  The aqueous layer is extracted with 20 ml of ethyl acetate and this extract is combined with the ethyl acetate layer.  30 ml of water are added to the ethyl acetate solution and the pH is adjusted to below 7.0 C to a value of 7.0.  The aqueous layer is separated off and adjusted to a pH of 2.7 with concentrated hydrochloric acid. 

  The solid which has separated out is separated off by filtration, washed with water and dried over phosphorus pentoxide; 1.2 g of the compound mentioned in the title are obtained. 



     
IR spectrum: #maxNujol: 3300, 3150, 1780, 1710, max 1670 cm -1
Nuclear Magnetic Resonance Spectrum: # (DMSOHi6, ppm): 3.17 (2H, m), 3.75 (2H, broad s), 3.83 (3H, s), 4.0 (2H, q, J = 13Hz ), 4.33 (2H, m), 5.17 (1H, d, J = 5Hz), 5.67 (1H, dd, J = 9Hz, 5Hz), 5.80 (1H, s), 7, 99 (1H, s), 9.67 (1H, d,

   J = 9Hz) <
Example 22 7- [2- (2,3-Dihydro-1,4-oxathiin-6-yl) -2-n-propoxyiminoacetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3 -cephem-4-carboxylic acid (syn-isomer (syn-isomer)
1.55 g syn isomer of 2- (2,3-dihydro-1,4-oxathiin-6-yl) -2-n-propoxyiminoacetic acid, 0.56 ml dry N, N-dimethylformamide, 2.1 ml dry Ethyl acetate and 0.66 ml of phosphoryl chloride are treated in a known manner to form a solution of the activated acid. On the other hand, 2 g of 7-amino-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid and 5.6 g of trimethylsilylacetamide are added to 40 ml of dry ethyl acetate and for 1 hour stirred at 40 C.

  The solution of the activated acid is added to this solution at −15 ° C. and the mixture is stirred for 2 hours at a temperature of −10 to −20 ° C.



  50 ml of water are added to the resulting solution and the ethyl acetate layer is separated off. 30 ml of water are added to the ethyl acetate layer and the pH is adjusted to 7.5 using sodium bicarbonate. The aqueous layer is separated off, washed with ethyl acetate and adjusted to a pH of 2.0 with 10% hydrochloric acid. The solid substance which has separated out is separated off by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure; 2.75 g of the compound mentioned in the title are obtained.



      Nujol
IR spectrum: #max: 3300, 1783, 1730, 1680 cm-1
NMR spectrum:
6 (DMSO-d6, ppm): 0.86 (3H, t, J = 7.0Hz), 1.25 to 1.85 (2H, m), 3.08 (2H, m), 3.68 ( 2H, m), 3.95 (2H, t, J = 6.2Hz), 4.29 (4H, m), 5.09 (1H, d, J = 5Hz), 6.72 (1H, s) , 6.72 (1H, dd, J = 5.0Hz, 8.0Hz), 10.18 (1H, d, J = 8.0Hz)
Example 23 7- [2- (2,3-Dihydro-1,4-oxathiin-6-yl) -2-n-propoxyiminoacetamino] -3- (1H-1,2,3-triazol-5-yl ) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer)
1.6 g syn isomer of 2- (2,3-dihydro-1,4-oxathiin-6-yl) 2-n-propoxyiminoacetic acid,

   0.56 ml of dry N, N-dimethylformamide, 22.3 ml of dry ethyl acetate and 0.69 ml of phosphoryl chloride are treated in the same manner as in Example 14 to form a solution of the activated acid.



  On the other hand, 2.0 g of 7-amino-3- (1H-1,2,3-triazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid and 5.9 g of trimethylsilylacetamide are added to 40 ml of dry ethyl acetate and the Mixture is stirred at 40 C for 1 hour. The solution of the activated acid is added to this solution at −15 ° C. and the mixture is stirred for 50 minutes at −10 to −20 ° C. 30 ml of water are added to the resulting solution and the ethyl acetate layer is separated off. 30 ml of water are added to the ethyl acetate layer and the pH is adjusted to 7.0 with sodium hydrogen carbonate. The aqueous solution is separated off, washed with ethyl acetate and adjusted to pH 2.7 with 10% hydrochloric acid.

  The solid substance which has separated out is separated off by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure. The product is added to 100 ml of diethyl ether and stirred. The solid which has separated out is separated off by filtration and washed with diethyl ether; 2.33 g of the compound mentioned in the title are obtained.



   IR spectrum: #maxNujol: 3300, 1780, 1730, 1660 cm-1
NMR spectrum:
6 (DMSOHi6, ppm): 0.86 (3H, t, J = 7.4Hz), 1.60 to 1.80 (2H, m), 3.08 (2H, m), 3.67 (2H, ready s), 3.80 to 4.17 (2H, m), 5.13 (1H, d, J = 5.5Hz), 5.70 (1H, dd, J = 5.5Hz), 9.0Hz ), 7.99 (1H, s).



   Example 24 7- [2- (2,3-Dihydro-1,4-oxathiin-6-yl) -2-n-hexyloxyiminoacetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3 -cephem-4-carboxylic acid (syn-isomer)
1.214 g of phosphoryl chloride, 0.579 g of N, N-dimethylformamide and 3 ml of ethyl acetate are treated in a known manner to form the Vilsmeier reagent. 2.00 g of syn isomer of 2- (2,3-dihydro-1,4-oxathiin-6-yl) -2-n-hexyloxyiminoacetic acid at -10 ° C. are added to the reagent and the mixture is kept at the same for 20 minutes Temperature stirred.



  On the other hand, 6.93 g of trimethylsilylacetamide are added to a solution of 2.18 g of 7-amino-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid in 50 ml of ethyl acetate and the mixture is stirred at 40 C for 1 hour.



  The solution of the activated acid is added to this solution at −10 ° C. and the mixture is stirred for 1 hour at the same temperature. 20 ml of water are added to the resulting solution and the organic layer is separated off. The solution is washed twice with 20 ml of water and dried. After concentrating the solution in vacuo, the residue is triturated with 50 ml of diisopropyl ether. The solid substance which has separated out is separated off by filtration and dried; 3.4 g of the compound mentioned in the title are obtained.

 

   IR spectrum: v max: 3280, 1785, 1730, 1675 cm-1
NMR spectrum:
6 DMSO-d6, ppm): 1.00 (3H, t, J = 8Hz), 1.17 to 1.94 (8H, m), 3.10 (2H, m), 3.73 (2H, m ), 3.98 (3H, s), 4.00 to 4.33 (4H, m), 5.13 (1H, d, J = 5Hz), 5.73 (2H, m), 9.58 ( 1H, d, J = 8Hz).



   Example 25 7- [2- (2,3-Dihydro-1,4-oxathiin-6-yl) -2-n-hexyloxyiminoacetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl- 3-cephem-4-carboxylic acid (syn-isomer)
1.214 g of phosphoryl chloride, 0.579 g of N, N-dimethylformamide and 3 ml of ethyl acetate are treated in a known manner to form the Vilsmeier reagent. To this solution are added 7 ml of ethyl acetate and 2.18 g of syn isomer of 2- (2,3-dihydro-1,4oxathiin-6-yl) -2-n-hexyloxyiminoacetic acid, and the mixture is prepared in the same manner as in Example 24 treated to form a solution of the activated acid. This solution is added to a solution of 2.18 g of 7-amino-3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid and 6.93 g of trimethylsilylacetamide in 50 ml of ethyl acetate the mixture is treated in the same manner as in Example 24. 3.00 g of the compound mentioned in the title are obtained.



   IR spectrum: # Nujol / max: 3250, 1785, 1725, 1675 cm-1
NMR spectrum: # (DMSO-d6, ppm): 1.00 (3H, t, J = 8Hz), 1.17 to 1.90 (8H, m), 3.08 (2H, m), 3, 70 (2H, m), 3.90 to 4.67 (6H, m), 5.18 (1H, d, J = 5Hz), 5.71 (2H, m), 9.55 (1H, s) , 9.55 (1H, d, J = 8Hz).



   Example 26 7- [2- (2,3-Dihydro-1,4-dithiin-5-yl) -2-methoxyiminoacetamido] -3- (1H-1,2,3-triazol-5-yl) thiomethyl-3 -cephem-4-carboxylic acid (syn-isomer)
A solution of 1.57 g of 7-amino-3- (1H-1, 2,3-triazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid and 4.6 g of trimethylsilylacetamide in 20 ml of ethyl acetate and a mixture 1.1 g of syn isomer of 2- (2,3-dihydro-1,4-dithiin-5-yl) -2-methoxyiminoacetic acid, 0.44 g of N, N-dimethylformamide and 0.92 g of phosphoryl chloride are used treated in the same manner as in Example 21. 1.85 g of the compound mentioned in the title are obtained.



   IR spectrum: # Nujol / max: 3300, 1780, 1720, 1680 cm-1
Nuclear Magnetic Resonance Spectrum: 6 (DMSO-d6, ppm): 3.23 (4H, s), 3.70 (2H, broad s), 3.83 (3H, s), 4.03 (2H, q, J = 13Hz), 5.17 (1H, d, J = 4Hz), 5.70 (1H, dd, I = 8Hz, 4Hz), 6.63 (1H, s), 7.97 (1H, s), 9.73 (1H, d, J = 8Hz).



   Example 27 7- [2- (2,3-Dihydro-1,4-oxathEin-6-yl) -2-n-hexyloxyiminoacetamido'-3- (1 -n4iexyl-IH4etrazol-5-yOthiomethyl-3-cephem -4- carboxylic acid (syn-isomer)
A solution of 2.0 g of 7-amino-3- (1-n-hexyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid and 4.6 g of trimethylsilylacetamide in 40.0 ml of dry ethyl acetate and a solution of 1.5 g syn isomer of 2- (2,3-dihydro-1,4-oxathiin-6-yl) -2-n-hexyloxyiminoacetic acid, 0.44 g dry N, N-dimethylformamide and 0 , 92 g of phosphoryl chloride in 21.75 ml of ethyl acetate are treated according to the same procedure as in Example 22. 2.26 g of the compound mentioned in the title are obtained.



     
IR spectrum: # Nujol / max: 3300, 1790, 1730, 1680,
1630 cm-1
NMR spectrum:
6 (DMSOd6, ppm): 0.60 to 2.13 (22H, m), 3.11 (2H, m), 3.72 (2H, m), 3.88 to 4.60 (8H, m) , 5.13 (1H, d, J = 5.0 Hz), 5.73 (1H, s, 1H, dd, J = 5.0Hz, 8.0Hz), 9.59 (1H, d, J = 8.0 Hz).



   Example 28 7- [2- (2,3-Dihydro-1,4-oxathiin-6-yl) -2-methoxyiminoacetamido] -2-methyl-3-cephem-4-carboxylic acid (syn isomer)
A solution of 1.4 g syn isomer of 2- (2,3-dihydro1,4-oxathiin-6-yl) -2-methoxyiminoacetic acid, 0.59 ml dry N, N-dimethylformamide and 1.17 g phosphoryl chloride in 12.3 ml of dry ethyl acetate and a solution of 1.35 g of 7-amino-2-methyl-3-cephem-4-carboxylic acid and 5.75 g of trimethylsilylacetamide in 40 ml of ethyl acetate are treated according to the same procedure as in Example 14. 1.45 g of the compound mentioned in the title are obtained.



   IR spectrum: v Nujol: 3160, 1765, 1660, 1635 cm-1
NMR spectrum:
6 (DMSO-d6, ppm): 1.42 (3H, d, J = 7.0Hz), 3.07 (2H, m), 3.79 (3H, s), 4.27 (2H, m) , 5.03 (1H, d, J = 5.0Hz), 5.72 (2H, m), 6.40 (1H, d, J = 7.0Hz), 9.63 (1H, d, J = 8.0 Hz).



   Example 29 7- [2- (2,3-Dihydro-1,4-oxathiin-6-yl) -2-n-propoxyiminoacetamido] -3-cephem-4-carboxylic acid (4-nitrobenzyl) ester (syn -Isomeres) (1) 1.26 ml dry N, N-dimethylformamide, 1.48 ml phosphoryl chloride, 3.48 g syn isomer of 2- (2,3-dihydro-1,4-oxathiin-6-yl) -2-n-propoxyiminoacetic acid and 5 ml dry ethyl acetate are treated in a known manner to form a solution of the activated acid. On the other hand, a solution of 5.0 g of 7-amino-3-cephem-4-carboxylic acid (4-nitrobenzyl) ester, 6 g of trimethylsilylacetamide and 8.3 g of bis (trimethylsilyl) acetamide in 700 ml of ethyl acetate for 1 hour at 40 ° C. touched.

  The solution of the activated acid is added to this solution at -30 C all at once and the solution is stirred at -10 to -30 C for 2 hours. 50 ml of water are added to the resulting solution, the ethyl acetate layer is separated off, washed with a saturated aqueous sodium hydrogen carbonate solution and then with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue is triturated with diisopropyl ether and the solid substance which has separated out is separated off by filtration and washed with diisopropyl ether. 6.80 g of the compound known in the title are obtained.



   IR spectrum: # Nujol / max: 3250, 1780, 1730, 1660 cm-1
NMR spectrum:
6 (DMSO-d6, ppm): 0.79 (3H, t, J = 7.0Hz), 1.52 (2H, m), 3.00 (2H, m), 3.55 (2H, m) , 3.89 (2H, t, J = 6Hz), 4.20 (2H, m), 5.06 (1H, d, J = 4Hz), 5.33 (2H, s), 5.62 (1H , s), 5.75 (1H, dd, J = 4.0Hz, 8.0Hz), 6.58 (1H, m), 7.62 (2H, d, J = 8Hz), 8.15 (2H , d, J = 8.0Hz), 9.54 (1H, d, J = 8.0Hz) (2) 6.7 g syn isomer of 7- [2- (2,3-dihydro-1,4 -oxathiin- 6-yl) -2-n-propoxyiminoacetamido] -3-cephem-4-carboxylic acid (4-nitrobenzyl) ester, 200 ml of tetrahydrofuran, 67 ml of methanol,

   2 ml of acetic acid, 6 ml of water and 3.3 g of 10% palladium-on-carbon are treated according to the same procedure as in Example 18 (2). 2.59 g of syn isomer of 7- [2- (2,3-dihydro-1,4-oxathiin-6-yl) -2-n-propoxyiminoacetamido] -3-cephem-4-carboxylic acid are obtained.



      IR spectrum: v max:: 3300, 1790, 1776, 1660 cm-1
NMR spectrum:
6 (DMSO-d6, ppm): 0.87 (3H, t, J = 7.6Hz), 1.30 to 1.96 (2H, m), 3.10 (2H, m), 3.60 ( 2H, d, J = 4.0 Hz), 4.00 (2H, t, J = 6.4Hz), 4.31 (2H, m), 5.10 (1H, d, J = 5.0Hz) , 5.72 (1H, s), 5.79 (1H, dd, J = 5Hz), 6.48 (1H, m), 9.58 (1H, d, J = 8.0 Hz)
Example 30 7- [2- (2,3-Dihydro-1,4-oxathiin-6-yl) -2-n-hexyloxyiminoacetamido] -3-cephem-4-carboxylic acid (syn-isomer)
0.579 g of N, N-dimethylformamide, 1.214 g of phosphoryl chloride and 3 ml of ethyl acetate are treated in a known manner to form the Vilsmeier reagent, and the reagent is added to 7 ml of ethyl acetate.

  The solution is mixed with 2.00 g of syn isomer of 2- (2,3-dihydro-1,4-oxathiin-6-yl) -2-n-hexyloxyiminoacetic acid with stirring, a solution of the activated acid being formed. On the other hand, 1.46 g of 7-amino-3cephem-4-carboxylic acid, 3.84 g of trimethylsilylacetamide, 4.40 ml of bis (trimethylsilyl) acetamide and 24 ml of ethyl acetate are stirred together to prepare a solution. This solution, the solution of the activated acid is added at -10 C at a time and the mixture is stirred for 1¸ hours at the same temperature. 30 ml of water and 15 ml of ethyl acetate are added to the resulting solution, the solution is shaken vigorously and the organic layer is separated off.



  30 ml of aqueous sodium hydrogen carbonate solution are added to the organic solution and it is shaken vigorously and the aqueous layer is separated off. The solution is adjusted to a pH of 2.0 with concentrated hydrochloric acid and extracted with 60 ml of ethyl acetate. The extract is washed twice with 20 ml of water, dried over magnesium sulfate and concentrated in vacuo. The residue is triturated with 50 ml of diisopropyl ether and the solid substance which has separated out is separated off by filtration. 2.40 g of the compound mentioned in the title are obtained.



     
IR spectrum: #maxNujol: 3280, 1785, 1730, 1660 cm-1 max
NMR spectrum: # (DMSO-d6, ppm): 0.67 to 1.83 (1 iM, m), 3.07 (2H, m), 3.60 (2H, c, J = 14Hz), 3 , 99 t, t, 3 = 6Hz), 4.37 (2H, m), 5.06 (1H, d, J = 5Hz), 5.86 (1H, s), 5.74 (1H, dd, J = 5Hz, 8Hz), 6.46 (1H, t, J = 5Hz), 9.55 (1H, dd, J = 8Hz)
Example 31
7- [2- (2,3-Dihydro-1,4-oxathiin-6-yl) -2-allyloxyiminoacetamido] -3-cephem-4-carboxylic acid (syn-isomer)
0.175 g N, N-dimethylformamide,

   0.367 g of phosphoryl chloride and 0.5 ml of ethyl acetate are treated in a known manner to prepare the Vilsmeier reagent and the reagent is added to 5 ml of ethyl acetate. To this solution is added 0.500 g of syn isomer of 2- (2,3-dihydro-1,4-oxathiin-6-yl) -2-allyloxyiminoacetic acid at - 15 ° C and the mixture is stirred for 20 minutes at the same temperature to form a solution the activated acid stirred. The solution is added to a solution of 0.524 g of 7-amino-3-cephem-4-carboxylic acid, 1.4 g of trimethylsilylacetamide and 1.5 ml of bis (trimethylsilyl) acetamide in 7.5 ml of ethyl acetate at - 15 ° C. at a time and the mixture is stirred at the same temperature for 2 hours.

  10 ml of water are added to the resulting solution, the mixture is adjusted to a pH of 7.0 with an aqueous sodium hydrogen carbonate solution and the aqueous layer is separated off. The aqueous solution is adjusted to a pH of 3 with 10% hydrochloric acid. The solid substance which has separated out is separated off by filtration and washed with water; 0.73 g of the compound mentioned in the title is obtained.



   IR spectrum: #maxNujol: 3225, 1770, 1708, 1660 cm-1
NMR spectrum: # (DMSOHi6, ppm): 3.07 (2H, m), 3.55 (2H, d, J = 4Hz), 4.27 (2H, m), 4.53 (2H, m) , 5.07 to 5.40 (3H, m), 5.67 to 6.27 (3H, m), 6.45 (1H, t, J = 4Hz), 9.60 (1H, d,

   J = 8Hz)
Example 32 7- [2- (2,3-Dihydro-1,4-oxathiin-6-yl) -2-n-propoxyininoacetamido] -3-chloro-3-cephem-4-carboxylic acid (syn isomer) (1 ) A solution of 5.0 g of 7-amino-3-chloro-3-cephem-4-carboxylic acid (4-nitrobenzyl) ester hydrochloride and 11.3 g of trimethylsilylacetamide in 100 ml of dry ethyl acetate and a solution of 3.13 g of syn -Isomer of 2- (2,3-dihydro-1,4-oxathiin-6-yl) -2-n-propoxyiminoacetic acid, 1.13 ml dry N, N-dimethylformamide and 1.33 ml phosphoryl chloride in 54.4 ml Ethyl acetate is treated in the same manner as in Example 19 (1). 7.10 g of syn isomer of 7- [2 (2,3-dihydro-1,4-oxathiin-6-yl) -2-n-propoxyiminoacetamido] 3-chloro-3-cephem-4-carboxylic acid are obtained. (4-nitrobenzyl) esters.



   IR spectrum: #maxNujol: 1780, 1730, 1675, 1607 cm-1
NMR spectrum: # (DMSOd6, ppm): 0.87 (3H, t, J = 7.0Hz), 1.30 to 1.90 (2H, m), 3.10 (2H, m), 3, 98 (2H, t, J = 6.4Hz), 4.28 (2H, m), 5.32 (1H, d, J = 5.0Hz), 5.48 (2H, s), 5.73 ( 1H, s), 6.87 (1H, dd, J = 5.0Hz, 8.2Hz), 7.74 (2H, d, J = 9.0Hz), 8.29 (2H, d, J = 9 , 0Hz) (2) 7.0 g of the compound obtained previously, 2 ml of acetic acid, 10 ml of water, 3.5 g of 10% palladium-on-carbon, 100 ml of tetrahydrofuran and 100 ml of methanol are prepared in the same manner as in Example 19 (2) treated. The crystals obtained are recrystallized from 20 ml of methylene chloride; 2.31 g of the compound mentioned in the title of the example are obtained.



   IR spectrum: #maxNujol: 3300, 1784, 1740, 1665 cm-1
NMR spectrum: # (DMSO-d6, ppm): 0.87 (3H, t, J = 8.0Hz), 1.61 (2H, m), 3.08 (2H, m), 3.83 ( 2H, q, J = 16.8Hz), 3.97 (2H, t, 3 = 8.0Hz), 4.28 (2H, m), 5.23 (1H, d, J = 5, OHz), 5.68 (1H, s), 5.74 (1H, dd, J = 5.0Hz, 9.0Hz), 9.64 (1H, d,

   J = 9.0Hz)
Example 33 7- [2- (2,3-Dihydro-1,4-dithEin-5-yl) -2-methoxyiminoacetamido] -3-chloro-3-cephem-4-carboxylic acid (syn isomer) (1 ) A solution of 4.06 g of 7-amino-3-chloro-3-cephem-4-carboxylic acid (4-nitrobenzyl) ester hydrochloride and 9.19 g of trimethylsilylacetamide in 40 ml of ethyl acetate and a solution of 2.2 g of syn- Isomeres of 2- (2,3-dihydro-1,4-dithiin-5-yl) -2-methoxyiminoacetic acid, 0.8 g of N, N-dimethylformamide and 1.67 g of phosphoryl chloride in 24 ml of ethyl acetate are prepared in the same way as treated in Example 19 (1). 5.1 g of syn isomer of 7- [2- (2,3-dihydro-1,4-dithiin-5yl) -2-methoxyiminoacetamido] -3-chloro-3-cephem-4-carboxylic acid (4th -nitrobenzyl) esters.



     
IR spectrum: v Nujol: 3280, 1790, 1740, 1680 cm - max
Nuclear Magnetic Resonance Spectrum: # (DMSO-d6, ppm): 3.20 (4H, s), 3.80 (3H, s), 3.93 (2H, AB-q, J = 18Hz), 5.30 d , d, 3 = 5Hz), 5.48 (2H, s), 5.87 (1H, dd, J = 8Hz, 5Hz), 6.6 (1H, s), 7.73 (2H, d, J = 9Hz), 8.30 (2H, d, J = 9Hz), 9.63 d, d, 3 = 8Hz) (2) 5.0 g syn isomer of the compound obtained previously, 50 ml tetrahydrofuran, 30 ml methanol .2 g 10% palladium on carbon,

   7 ml of water and 0.7 ml of acetic acid are treated according to the same procedure as in Example 19 (2); 1.6 g of the compound mentioned in the title of the example are obtained.

 

   IR spectrum: #maxNujol: 3300, 1780, 1730, 1660 cm-1
NMR spectrum: # (DMSO-d6, ppm): 3.20 (4H, s), 3.81 (2H, AB-q, J = 18Hz), 3.80 (3H, s), 5.72 ( 1H, dd, J = 8Hz, 5Hz), 6.55 (1H, s), 9.77 (1H, d, J = 8Hz).



   Example 34 7- [2- (2,3-Dihydro-1,4-oxathiin-6-yl) -2-allyloxyiminoacetami dof-3-cephem-4-carboxylic acid (syn-isomer)
0.23 g of 2- (2,3-dihydro-1,4-oxathiin-6-yl) -2-allyloximinoacetic acid (syn isomer) was treated with 0.2 g of 7-amino-3-cephem4-carboxylic acid in a similar manner left to react as in Example 15 (i), 0.11 g of 7- [2- (2,3-dihydro-1,4-oxathi-in-6-yl) -2-allyloxyiminoacetamido] -3-cephem- 4-carboxylic acid (syn isomer) was obtained.



   IR v Nujol: 3225, 1770, 1660 cm-1.


    

Claims (12)

 PATENT CLAIMS 1. Cephalosporin compound, characterized by the general formula EMI1.1  wherein: Rl is a group of the formula EMI1.2  where X represents sulfur, oxygen or substituted or unsubstituted imino, R2 is hydrogen or a saturated or unsaturated aliphatic hydrocarbon radical, R3 is hydrogen or lower alkyl, R4 is hydrogen, halogen, lower alkyl, acyloxymethyl or heterocyclic thicxmethyl, which may be substituted by lower alkyl, and R5 carboxy or esterified carboxy, and a salt thereof.  2. A compound according to claim 1, characterized in that R3 is hydrogen.  3. A compound according to claim 1 or 2, characterized in that R4 is hydrogen.  4. Connection according to claim. 1 or 2, characterized in that R4 is halogen.  5. A compound according to claim 1 or 2, characterized in that R4 is lower alkyl.  6. A compound according to claim 1 or 2, characterized in that R4 means acyloxymethyl.  7. A compound according to claim 1 or 2, characterized in that R4 is heterocyclic thiomethyl, which may be substituted by lower alkyl.  8. A compound according to claim 1, characterized in that R3 is lower alkyl and R4 is hydrogen.  9. A compound according to claim 1, characterized in that X is sulfur, oxygen or imino, R4 is hydrogen, halogen, lower alkyl, lower alkanoyloxymethyl, carbamoyloxymethyl or thiadiazolylthiomethyl or tetrazolylthiomethyl, which can each be substituted by lower alkyl, and R5 is carboxy.  10. A compound according to claim 1, characterized in that X is lower alkanimido and R4 and R5 have the meanings given in claim 9.  11. Syn isomer of the compound according to one of claims chelbisl0.  12. Pharmaceutical composition, characterized in that it contained as active ingredient a compound of formula I specified in claim 1 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.  The invention relates to new cephalosporin compounds and their salts, particularly their pharmaceutically acceptable salts, which have antibacterial activity, i.e. are highly effective against a number of pathogenic bacteria and can therefore be used for the treatment of infectious diseases in humans and animals.  Another object of the invention is a pharmaceutical agent which contains at least one of the new cephalosporin compounds or a pharmaceutically acceptable salt thereof as the active ingredient.  The new cephalosporin compounds are represented by the general formula: EMI1.3  in which: R1 denotes a group of the formula: EMI1.4  wherein X represents sulfur, oxygen or substituted or unsubstituted imino, R2 is hydrogen or a saturated or unsaturated aliphatic hydrocarbon radical, R3 is hydrogen or lower alkyl, R4 is hydrogen, halogen, lower alkyl, acyloxymethyl or heterocyclic thiomethyl, which may be substituted by lower alkyl, and R5 carboxy or esterified carboxy, and their salts, in particular their non-toxic, pharmaceutically acceptable salts.  In the formulas of the compounds (I) according to the invention and the corresponding starting compounds (III), the partial structure of the formula comprises EMI1.5  also the syn and anti isomers, the structures of which can be represented by the following formulas EMI1.6   (A) (A ') syn isomer anti isomer For all compounds with the partial structure given above, the compounds with a geometric structure as represented by the formula (A) are referred to as syn isomeres and all compounds with the other structure as represented by the formula (A ') are referred to here as anti-isomer.    The various definitions given above and below are explained in more detail below and suitable examples are given.  The term low or low, unless stated otherwise, is to be understood as meaning residues or groups which contain 1 to 6 carbon atoms.  The term saturated or unsaturated aliphatic hydrocarbon residue used for R2 may include lower alkyl, lower alkenyl and lower alkynyl, and may preferably include unbranched or branched lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl , Neopentyl, hexyl and the like, preferred ** WARNING ** End of CLMS field could overlap beginning of DESC **.