CH643557A5 - Process for the preparation of syn isomers of 3,7-disubstituted 3-cephem-4-carboxylic acids - Google Patents

Abstract

The compounds correspond to the formula <IMAGE> in which R<1> denotes certain substituted phenyl, thiazolyl or thiazolinyl groups, R<2> denotes an aliphatic group, R<3> denotes carboxyl or protected carboxyl and R<4c> denotes a heterocyclic group. They are prepared by reacting a thiol R<4c>-SH or a metal salt thereof with a compound of the formula I, in which the group -SR<4c> is replaced by an acid radical, or with a salt thereof. Any amino or carboxyl protective groups can then be eliminated, and hydroxyphenyl compounds obtained can be O-acylated. The compounds and their salts have high antibacterial activity; they can be used for treating infectious diseases.

Description

       

  
 

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

 
EMI2. 1
 wherein R7 represents protected amino, or denotes a group of the formula:
EMI2. 2nd
 wherein R8 is lower alkyl and R9 represents protected imino, produces this compound or a salt thereof by an elimination reaction to remove the amino or imino protecting group and, if appropriate, the compound obtained is converted into a pharmaceutically acceptable salt. 



   8th.  Process for the preparation of a compound of the formula:
EMI2. 3rd
 wherein R5a is hydrogen, halogen, nitro, lower alkoxy or acyloxy and R6 "acyloxy and R2, R3 and R4" have the meanings given in claim 1, and their pharmaceutically acceptable salts, characterized in that a compound according to the process according to claim 1 of the formula:
EMI2. 4th
 wherein R2 to Rs have the meanings given in claim 1, produces the hydroxyl group of this compound or a salt thereof and optionally converts the compound obtained into a pharmaceutically acceptable salt. 



   9.  A process for the preparation of a compound of formula 1 in which R2 is carboxy (lower) alkyl, or its pharmaceutically acceptable salts, characterized in that a compound of formula I in which R2 is protected carboxy (lower) alkyl is used in the process according to claim 1, produces, this compound or a salt thereof is subjected to an elimination reaction to remove the carboxy protecting group and, if appropriate, the compound obtained is converted into a pharmaceutically acceptable salt. 



   The invention relates to processes for the preparation of new syn isomers of 3,7-disubstituted 3-cephem-4-carboxylic acids and their pharmaceutically acceptable salts which have antibacterial activity, in particular against pathogenic bacteria. 



   British Patent No.  1,399,086 3-cephem compounds were already known, the 7-position of which is substituted by an a- (hydroxyimino) -acetamido group etherified on the hydroxyimino group.  Also known from British Patent No.  1 389 194 3-cephem compounds, the 7-position of which bears an a- (hydroxyimino or acyloxyimino) acylamido group. 



   The new compounds of the cephemcarboxylic acid series obtainable according to the invention correspond to the following formula:
EMI2. 5
 in which: R1 denotes a group of the formula:
EMI2. 6
 wherein Rs are hydrogen, halogen, nitro, hydroxy, lower alkoxy or acyloxy and R6 is hydroxy, lower alkoxy, acyloxy, acylamino or di (lower) alkylamino; a group of the formula
EMI2. 7
 wherein R7 represents amino, protected amino, hydroxy or lower alkyl; or a group of the formula:
EMI2. 8th
 wherein R8 is lower alkyl and R9 is imino, protected imino or oxo;
R2 is an aliphatic hydrocarbon group that may have one or more substituents;
R3 carboxy or protected carboxy;

   and R4 "is an unsubstituted or one or more substituent heterocyclic group. 



   The process according to the invention is therefore directed to the preparation of the syn isomer of 3,7-disubstituted derivatives of ceph-3-em-4-carboxylic acid of the formula I, while the corresponding anti-isomer is due to the partial structure of the formula:
EMI2. 9
 can be represented.  When it is convenient for the explanation of the invention to express both the syn isomer and the anti isomer by a general formula, they are represented by the partial structure of the formula:
EMI3. 1




  reproduced. 



   The method according to the invention is defined in claim 1.  It can be illustrated by the following reaction scheme: Procedure
EMI3. 2nd
 or a salt thereof or its reactive derivative on the mercapto group or a salt thereof
The compounds obtained can be converted further by the method 2 defined in claims 7, 8 and 9. 

  These processes can be represented by the following reaction schemes:
EMI3. 3rd

Amino or imino
Protecting group (Ia) or a salt thereof. Method 3
Acylation of the hydroxy group
EMI3. 4th
    (Ib) or a salt thereof Method 4
Elimination of the carboxy protecting group
EMI3. 5
   In the above formulas, Rla means a group of the formula
EMI4. 1
 wherein R7a represents protected amino, or a group of the formula
EMI4. 2nd
 wherein R8 is as defined above and R9 represents "protected imino; Rib is a group of the formula Method 5
EMI4. 3rd
   Or a group of the formula
EMI4. 4th
 wherein R8 is as defined above;
R5a is hydrogen, halogen, nitro, lower alkoxy or acyloxy;

  ;
R6a acyloxy; R2a protected carboxy (lower) alkyl;
R2b carboxy (lower) alkyl. 



   The starting products of the formula (Vc) can be prepared by process 5 described below:
EMI4. 5
 or its reactive derivative on the amino group or a salt thereof or its reactive derivative on the carboxy group or a salt thereof (vc) or a salt thereof wherein R4b represents an acid residue. 



   Among the starting compounds, the starting compounds of the formula (III), including the corresponding anti-isomer, are new compounds and they can be prepared by processes which can be represented by the following reaction scheme:
EMI4. 6
  
EMI5. 1
  
EMI6. 1
  
EMI7. 1
  
EMI8. 1
 wherein R2, R5, R6, R5, R6a, R7a, R5 and R9a each have the meanings given above;
R5b halogen;
Y is an acid residue; wherein R8 and R9 each have the meanings given above;
R2d lower alkyl or lower alkenyl; and
Z, carboxy or protected carboxy. 



  R10 ar (lower) alkyl; RSC hydrogen, halogen or nitro; R6b lower alkoxy, Ar (lower) alkoxy or acylamino; R20 hydrogen, lower alkyl or lower alkenyl
The other starting compounds (IV), (V), (Va) to (V @ and (Ve) are also all new compounds. 



   Regarding the end products and the starting compounds, it should be noted.  that it also includes the tautomeric forms
R5d is hydrogen, halogen, nitro, hydroxy or lower alkoxy;
X halogen;
Z protected carboxy;
R7b lower alkyl, amino or lower alkoxy; R7c lower alkyl, amino or hydroxy;
R7d lower alkyl; R2 "lower alkyl; RlC include a group of the formula train on their thiazole groups.  

  That means if the group of the formula:
EMI8. 2nd
 wherein R7e represents amino, protected amino or hydroxy, in the formula of the compounds obtainable according to the invention and the starting compounds assumes the formula
EMI8. 3rd

EMI8. 4th
 wherein R7 has the meanings given above, or a group of the formula
EMI8. 5
 where R7e has the meanings given above, then this group of the formula
EMI8. 6
  can also be represented by their tautomeric formula
EMI9. 1
 wherein R7f represents imino, protected imino or oxo.  This means that both groups (A) and (B) exist in the equilibrium state as so-called tautomeric forms, which can be represented by the following equilibrium:
EMI9. 2nd
 wherein R7e and R7f each have the meanings given above. 



   These types of tautomerism between 2-amino and 2 hydroxy-thiazole compounds and 2-amino or 2-oxothiazoline compounds, as indicated above, are known in the literature and it will be readily apparent to those skilled in the art that both tautomeric isomers are in equilibrium with one another and are easily convertible into one another, and consequently the compounds obtainable according to the invention also comprise these isomers.  Accordingly, both tautomeric forms of the end products and the starting compounds fall within the scope of the present invention. 

  In the description as well as in the examples and in the claims, the compounds obtainable according to the invention and the starting compounds which comprise (contain) the group of these tautomeric isomers are, for the sake of simplicity, used by one of the terms therefor, i. H.  through the formula:
EMI9. 3rd
 shown. 



   Examples of suitable pharmaceutically acceptable salts of the syn isomers of 3,7-disubstituted 3-cephem-4-carboxylic acid compounds (I) 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. ) and an alkaline earth metal salt (e.g. B. 



  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, ethanolamine, diethanolamine, pyridine, picoline, dicyclohexylamine, N, N 'dibenzylethylenediamine salt and the like. ) and the like , a salt with an organic acid (e.g. B.  an acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate and the like. ), a salt with an inorganic acid (e.g. B.  a hydrochloride, hydrobromide, sulfate, phosphate and the like. ) or a salt with an amino acid (e.g. B.  Arginine, aspartic acid, glutamic acid and the like. ) and the like 



   Some suitable examples and explanations of the various definitions that are used are explained in more detail below. 



   Unless otherwise stated, the term low used here means that a group denoted by it contains 1 to 6 carbon atoms. 



   The term aliphatic hydrocarbon group as used herein means an unbranched (straight) or branched aliphatic hydrocarbon group, preferably having 1 to 6 carbon atoms, and this term may include lower alkyl, lower alkenyl and the like.  This aliphatic hydrocarbon group may have 1 to 2 suitable substituents, such as. B.  Carboxy, protected carboxy, arylthio, lower alkylthio, aryl, acyloxy, lower alkoxy, aryloxy, heterocyclic groups or the like. 



  exhibit. 



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



   A suitable lower alkoxy and a suitable lower alkoxy radical in the expression ar (lower) alkoxy can be one which can be branched, such as, for example, B.  Methoxy.  Ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert. -Butoxy, pentyloxy, hexyloxy and the like , and preferably it is one with 1 to 4 carbon atoms, in particular with 1 to 2 carbon atoms. 



   A suitable protected amino may include an acylamino and an amino group which may be substituted by a conventional protecting group other than the acyl group such as e.g. B. 



  Benzyl or the like , is substituted. 



   Suitable lower alkyl and lower alkyl in the terms lower alkylthio, carboxy (lower) alkyl, protected carboxy (lower) alkyl, ar (lower) alkyl and di (lower) alkylamino may include one which may be branched, e.g. B.  Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert. -Butyl, pentyl, hexyl and the like , preferably one with 1 to 4 carbon atoms, in particular one with 1 to 2 carbon atoms. 



   A suitable protected imino may include an acylimino and an imino group which are substituted by a conventional protecting group other than the acyl group such as e.g. B.  Benzyl and the like , is substituted. 



   A suitable protected carboxy and a suitable protected carboxy radical in the expression protected carboxy (lower) alkyl may include esterified carboxy, in which the ester may be one of the following: e.g. B.  a lower alkyl ester (such as methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, t-pentyl ester, hexyl ester, 1-cyclopropyl ethyl ester and the like. ), the lower alkyl radical preferably containing 1 to 4 carbon atoms; a lower alkenyl ester (e.g. B.  a vinyl ester, allyl ester and the like. ); a lower alkenyl ester (e.g. B. 



  an Athinylester, Propinylester and the like. ); a mono (or di or tri) halogen (low) alkyl ester (e.g. B.  a 2-iodoethyl ester, 2,2,2-trichloroethyl ester and the like. ); a lower alkanoyloxy (lower) alkyl ester (e.g. B.  an acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 2-acetoxyethyl ester, 2-propionyloxyethyl ester and the like. );

   a lower alkanesulfonyl (lower) alkyl ester (e.g. B.  a mesyl methyl ester, 2-mesyl ethyl ester and the like. ); an Ar (lower) alkyl ester, e.g. B.  a phenyl (lower) alkyl ester, which may have one or more suitable substituents (e.g. B.  a benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, diphenyl methyl ester, (bis (methoxyphenyl) methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-tert. -butylbenzyl ester and the like ); an aryl ester, which may have one or more suitable substituents (e.g. B.  a phenyl ester, tolyl ester, tert. -Butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester and the like ) and the like 



   A preferred example of protected carboxy may be lower alkoxycarbonyl (e.g. B.  Methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, hexyloxycarbonyl and the like. ) with 2 to 7 carbon atoms, preferably with 2 to 5 carbon atoms. 



   A suitable aryl and a suitable aryl radical in the terms ar (lower) alkyl, ar (lower) alkoxy, arylthio and aryloxy can e.g. B.  be phenyl, tolyl, xylyl, mesityl, cumenyl, naphthyl and the like. , wherein the aryl group may have 1 to 3 substituents, such as. B.  Halogen (such as chlorine, bromine, iodine or fluorine), hydroxy and the like. 



   A suitable heterocyclic group and a suitable heterocyclic radical in the expression heterocyclic thiomethyl group, which may have one or more substituents, is to be understood as a saturated or unsaturated, monocyclic or polycyclic heterocyclic group which contains at least one heteroatom, such as, for. B.  an oxygen, sulfur, nitrogen atom and the like.  A particularly preferred heterocyclic group is e.g. B.  one of the heterocyclic groups specified below: an unsaturated 3 to 8-membered (preferably 5 to 6-membered) heteromonocyclic group which contains 1 to 4 nitrogen atoms (such as, for. B. 

  Pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g. B.    4H-1 2,4-triazolyl, 1 H-1, 2,3-triazolyl, 2H 1,2,3-triazolyl and the like. ), Tetrazolyl (e.g. B.    1 H-tetrazolyl, 2H tetrazolyl and the like. ) and the like ; a saturated 3- to 8-membered (preferably 5- to 6-membered) hetermonocyclic group containing 1 to 4 nitrogen atoms, such as e.g. B.  Pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl and the like. ; an unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atoms, e.g. B. 

  Indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl and the like. ; an unsaturated 3- to 8-membered (preferably 5- to 6-membered) hetermonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as e.g. B.  Oxazolyl, isoxazolyl, oxadiazolyl (e.g. B.  1,2,4-oxadiazolyl, i, 3,4-oxydiazolyl, 1,2,5-oxadiazolyl and the like. ) and the like ; a saturated 3- to 8-membered (preferably 5- to 6-membered) hetermonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as e.g. B.  Morpholinyl and the like ; an unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, e.g. B. 

  Benzoxazolyl, benzoxadiazolyl and the like. ; an unsaturated 3 to 8-membered (preferably 5 to 6-membered) heteromonocyclic group containing 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 8-membered (preferably 5- to 6-membered) heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as e.g. B.  Thiazo lidinyl and the like ; an unsaturated 3- to 8-membered (preferably 5- to
6-membered) heteromonocyclic group containing a sulfur atom, such as. B.  Thienyl and the like ; an unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, e.g. B. 

  Benzothiazolyl, benzothiadiazolyl and the like.  and the like ; wherein the heterocyclic group may have 1 to 2 suitable substituents, such as. B.    Lower alkyl (such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, cyclopentyl, hexyl, isopropyl, butyl, isobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl and the like. ), preferably one with 1 to 4 carbon atoms; Lower alkenyl (such as vinyl, allyl, butenyl and the like. );
Aryl (e.g. B.  Phenyltolyl and the like ); Halogen (such as chlorine, bromine, iodine or fluorine); Amino; Di (lower) alkylamino (lower) alkyl (such as dimethylaminomethyl, dimethylaminoethyl, diethylaminopropyl, diethylaminobutyl and the like. ), preferably one having 3 to 6 carbon atoms or the like. 



   A suitable lower alkenyl includes one having 2 to 6 carbon atoms and this can be, for example, vinyl, allyl, isopropenyl, 1-propenyl, 2-butenyl, 3-pentenyl and the like. , preferably one with 2 to 4 carbon atoms. 



   Suitable acyl radicals in the terms acylamino, acylimino, acyloxy and acyloxymethyl, as mentioned above, include e.g. B.  Carbamoyl, an aliphatic acyl group and an acyl group containing an aromatic or heterocyclic ring.  Suitable examples of the acyl are lower alkanoyl (such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl and the like. ), preferably one with 1 to 4 carbon atoms, in particular one with 1 to 2 carbon atoms;

  ; Lower alkoxycarbonyl having 2 to 7 carbon atoms (such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, I-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, t-pentyloxycarbonyl, hexyloxycarbonyl and the like. ), preferably one with 3 to 6 carbon atoms; Lower alkanesulfonyl (such as mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl and the like. ), preferably one with 1 to 4 carbon atoms, in particular one with 1 to 2 carbon atoms; Arenesulfonyl (such as benzenesulfonyl, tosyl and the like. ); Aroyl (such as benzoyl, toluoyl, naphthoyl, phthaloyl, indancarbonyl and the like. ); Ar (lower) alkanoyl (such as phenylacetyl, phenylpropionyl and the like. );

  Ar (lower) alkoxycarbonyl (such as benzyloxycarbonyl, phenethyloxycarbonyl and the like. ) and the like 



   The acyl radical mentioned above can have 1 to 3 suitable substituents, such as. B.  Halogen (such as chlorine, bromine, iodine or fluorine): hydroxy, cyano, nitro, lower alkoxy (such as methoxy, ethoxy, propoxy, isopropoxy and the like. ), Lower alkyl (such as methyl, ethyl, propyl, isopropyl, butyl and the like. ), Lower alkenyl (such as vinyl, allyl and the like. ), Acyl, such as. B.  Halogen (lower alkanoyl (such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl and the like. ), Aryl (such as phenyl, tolyl and the like. ) and the like  Suitable examples of the acyl with the substituent (s) may be mono (or di or tri) halogen (lower) alkanoyl (e.g. B.  Trifluoroacetyl, trichloroacetyl and the like. ), preferably one with 2 to 4 carbon atoms; Mono (or di or tri) halogen (low) alkanoylcarbamoyl (such as e.g. B.  

  Trichloroacetylcarbamoyl and the like ), preferably one having 3 to 4 carbon atoms or the like. 



   Suitable amino protecting groups for R4 "include e.g. B. 



  Acyl, such as halogen (low) alkanoyl (e.g. B.  Chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl and the like. ), preferably one having 2 to 3 carbon atoms or the like. 



   Suitable acid residues include e.g. B.  the rest of an inorganic acid (such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and the like. ) or an organic acid (such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like. ). 



   A suitable example of an acid residue R4 "is e.g. B.  Halogen, azido or acyloxy, wherein the halogen and the acyl group of the acyloxy may be the same as stated above.   



   Among the suitable examples for each of the groups of the compounds obtainable according to the invention, as explained and explained above, some preferred examples are given below:
Preferred examples of R5 may be hydrogen, halogen (preferably chlorine) or nitro; preferred examples of R6 can be hydroxy, lower alkoxy (preferably one with 1 to 4, in particular 1 to 2 carbon atoms), acyloxy [preferably lower alkanoyloxy (preferably one with 1 to 4, in particular 1 to 2 carbon atoms) or carbamoyloxyl], acylamino [ preferably lower alkanesulfonylamino (preferably one having 1 to 4, in particular 1 to 2, carbon atoms) or di (lower) alkylamino (in which the alkyl radical preferably contains 1 to 4, in particular 1 to 2, carbon atoms);

   preferred examples of such with 1 to 4, in particular 1 to 2 carbon atoms), acyloxy [preferably lower alkanoyloxy (preferably one with 1 to 4, in particular 1 to 2 carbon atoms) or carbamoyloxyl], acylamino [preferably lower alkanesulfonylamino (preferably one with 1 to 4, in particular 1 to 2 carbon atoms] or di (lower) alkylamino (in which the alkyl radical preferably contains 1 to 4, in particular 1 to 2, carbon atoms);

   preferred examples of R7 can be amino, protected amino, such as acylamino (] [preferably lower alkanesulfonylamino (preferably one having 1 to 4, in particular 1 to 2 carbon atoms), trihalogen (lower) alkanoylamino (preferably one with 1 to 4, especially 1 to 2 carbon atoms), lower alkoxycarbonylamino (preferably one with 2 to 7, in particular 3 to 6 carbon atoms) or lower alkanoylamino (preferably one with 1 to 4, in particular 1 to 2 carbon atoms), hydroxy or lower alkyl (preferably one with 1 to 4, in particular 1 to 2 carbon atoms);

   preferred examples of R8 are C1-C4-lower alkyl, in particular C1-C2-lower alkyl; preferred examples of R9 can be protected imino, such as acylimino [preferably lower alkanesulfonylimino (preferably one having 1 to 4, in particular 1 to 2, carbon atoms)];

   preferred examples of R2 can be lower alkyl (preferably one with 1 to 4, in particular 1 to 2, particularly preferably with 1 carbon atom), lower alkenyl, Ar (lower) alkenyl [particularly preferably phenyl (lower) alkenyl], carboxy (low) alkyl, protected carboxy (lower) alkyl [particularly preferably lower alkoxycarbonyl (preferably one having 3 to 6 carbon atoms) - (lower) alkyl], arylthio (lower) alkyl [particularly preferably phenylthio (lower) alkyl], ar (low) alkyl [ particularly preferably phenyl (lower) alkyl], which may contain halogen (preferably bromine) and hydroxy, thienyl (lower) alkyl or aryloxy (lower) alkyl [particularly preferably phenoxy (lower) alkyl], which may have hydroxy, in which alkenyl and the Alkenyl radical contains 2 to 6, preferably 2 to 4, carbon atoms, and the alkyl radical preferably contains 1 to 4, in particular 1 to 2, carbon atoms;

   a preferred example of R3 can be carboxy; preferred examples of R4 "can be tetrazolyl, which is substituted by lower alkyl (preferably having 1 to 4, in particular 1 to 2 carbon atoms) or di (lower) alkylamino (lower rig) alkyl (in which the alkyl radical is preferably 1 to 4, in particular 1 to 2 Contains carbon atoms) may be substituted,
Triazolyl or thiadiazolyl, both of which can be substituted by lower alkyl (preferably having 1 to 4, in particular 1 or 2, carbon atoms). 



   The various processes are explained in more detail below. 



  Procedure 1
Suitable salts of the compound of formula (Vc) are a metal salt, an ammonium salt, an organic amine salt, especially a salt with an inorganic base, such as. B. 



  an alkali metal salt (such as a sodium salt, potassium salt and the like. ), an alkaline earth metal salt (such as a calcium salt, magnesium salt and the like. ) or an ammonium salt; a salt with an organic base (e.g. B.  a triethylamine salt, pyridine salt and the like. ) and the like 



   Suitable reactive derivatives on the mercapto group of compound (Vd) may include a metal salt, such as. B.  an alkali metal salt (such as a sodium salt, potassium salt and the like. ) or the like 



   The reaction according to the invention can be carried out in a solvent such as water, acetone, chloroform, nitrobenzene, methylene chloride, ethylene chloride, dimethylformamide, methanol, ethanol, ether, tetrahydrofuran, dimethyl sulfoxide or any other solvent which does not adversely affect the reaction, preferably in those with strong polarities, be performed.  Among these solvents, the hydrophilic solvents can be used mixed with water.  The reaction is preferably carried out under weakly basic or approximately neutral conditions. 

  When the compound (Vc) and / or the thiol compound (Vd) is used in free form, the reaction is preferably carried out in the presence of a base, e.g. B.  an inorganic base such as an alkali metal hydroxide, an alkali metal carbonate, an alkali metal bicarbonate, an organic base such as a trialkylamine, pyridine and the like. , carried out.  The reaction temperature is not critical and the reaction is usually carried out at ambient temperature or with heating.  The reaction product can be isolated from the reaction mixture using conventional methods. 



   The reaction of the compound (Vc) with the compound (Vd) also includes cases in which the protected carboxy group or the salts in the compound (Vc) can be converted into the free carboxy group in the course of the reaction or in the aftertreatment; in which the protected amino and / or imino group can be converted into the free amino and / or imino group or  where the acyloxy group can be converted to the hydroxy group. 



  Procedure 5
The compound (Vc) or a salt thereof can be prepared by reacting the compound (II) or a reactive derivative on the amino group or a salt thereof with the compound (III) or a reactive derivative on the carboxy group or a salt thereof, thereby this process is a basic process for the preparation of the compound (Vc). 

 

   A suitable reactive derivative on the amino group of compound (II) can e.g. B.  be a conventional reactive derivative as used in amidation e.g. B.  a silyl derivative, which is formed in the reaction of the compound (II) with a silyl compound, such as. B. 



  Bis (trimethylsilyl) acetamide, trimethylsilylacetamide or the like. 



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



   A suitable reactive derivative on the carboxy group of compound (III) can e.g. B.  be a conventional derivative as used in amidation. 



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



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



   The reaction is preferably carried out in the presence of a condensing agent such as. B.  a so-called Vilsmeier reagent, such as. B.  (Chloromethylene) dimethyl-ammonium chloride, which is formed in the reaction of dimethylformamide with thionyl chloride or phosgene, a compound which is formed by the reaction of dimethylformamide with phosphorus oxychloride, and the like. , or the like  carried out. 



   The reaction can also be carried out in the presence of an inorganic or an organic base such as e.g. B.  an alkali metal hydroxide, an alkali metal bicarbonate, an alkali metal carbonate, an alkali metal acetate, tri (low) alkylamine, pyridine, N- (low) alkylmorpholine, N, N-di- (low) alkylbenzylamine, N, N-di- (low) alkylaniline, as exemplified below, or the like.  be performed. 



  If the base or condensing agent is liquid, it can also be used as a solvent.  The reaction temperature is not critical and the reaction is usually carried out under cooling or at ambient temperature. 



   It should be noted that in the reaction, when the starting compound (III) with the compound (II) or a reactive derivative on the amino group or a salt thereof in the presence of, for example, phosphorus pentachloride, thionyl chloride and the like.  is implemented, only the corresponding anti-isomer to the compound (Ve) or a mixture of the corresponding anti-isomer and the syn isomer is given as the compound, even if the compound (III), i. H.  the syn isomer is used as the starting compound.  It goes without saying that the compound (Ve), that is to say the syn isomer, can never be formed in the preparation of the corresponding anti-isomer from the starting compound (III) and the compound (II). 

  It is believed that this tendency and uniqueness of the above-mentioned reaction is due to the fact that the less stable synisomer has a tendency to partially or completely become in the course of the reaction, for example in a so-called activation step of the compound (III) to isomerize more stable anti-isomers, so that as the compound the isomerized compound, i. H.  that anti-isomers corresponding to compound (Ve) can be formed. 



   For the selective preparation of the compound (Ve), d. H.  of the syn isomer, the starting compound (III), i.e. H.  the syn isomer can be used and suitable reaction conditions must be selected. 



  That is, the compound (Ve), that is, the syn isomer, can be obtained selectively and in a high yield by, for example, the reaction in the presence of a Vilsmeier reagent as mentioned above and the like. , and performs at approximately neutral conditions.  Especially when the starting compound (III), i.e. H.  such a compound is used in which R 'represents a group of the formula
EMI12. 1
 the compound (each), that is the syn isomer, can be obtained in a selective manner and in high yield if the reaction according to the invention of the corresponding starting compound (III), i.e. H. 

   of the syn isomer, with the compound (II), for example in the presence of a Vilsmeier reagent which has been prepared by reacting dimethylformamide with phosphorus oxychloride, and under approximately neutral conditions.  In this case it should be noted that particularly good results can be achieved by carrying out the reaction in the presence of more than two molar equivalents of phosphorus oxychloride, in each case based on the amount of the starting compound (III), i.e. H.  of the syn isomer, and dimethylformamide, as described in the exemplary embodiments.  In addition, good results can be achieved in this case if the starting compound (III), i. H.  the syn isomer, in the presence of a silyl compound (e.g. B.  Bis (trimethylsilyl) acetamide, trimethylsilylacetamide and the like. ) and the like  subject to activation. 



  Procedure 2
The compound (Ia) or a salt thereof is prepared by subjecting the compound (IV) or a salt thereof to an eliminating reaction to remove the amino or imino protecting group.  Examples of suitable salts of the compound (IV) are a metal salt, an ammonium salt, an organic amine salt and the like. , as you can read above. 



   The elimination reaction according to the invention is carried out by a customary process, for example by hydrolysis, reduction, by a process by reacting the compound (IV) in which the protective group is an acyl group, with an imino halogenating agent and then with an imino etherifying agent and, if necessary, the compound obtained is the Subjected to hydrolysis or the like 



   The hydrolysis can be a method in which an acid or a base or hydrazine and the like.  is used.  These methods can be selected depending on the type of protecting groups to be eliminated.  Among these methods, hydrolysis using an acid is one of the common and preferred methods for eliminating protecting groups, such as. B.  substituted or unsubstituted alkoxycarbonyl (such as t-pentyloxycarbonyl and the like. ), Alkanoyl (such as formyl and the like. ), Cycloalkoxycarbonyl, substituted or unsubstituted aralkoxycarbonyl (such as benzyloxycarbonyl, substituted benzyloxycarbonyl and the like. ), substituted phenylthio, substituted aralkylidene, substituted alkylidene, substituted cycloalkylidene or the like. 

 

  Examples of suitable acids are an organic or an inorganic acid, such as formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid and the like. , and a preferred acid is an acid 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 acid suitable for the reaction can be selected depending on the type of protective group to be eliminated.  If the elimination reaction is carried out with the acid, it can be carried out in the presence or in the absence of a solvent. 



  Suitable solvents include an organic solvent, water, or a mixture thereof.  If trifluoroacetic acid is used, the elimination reaction can preferably be carried out in the presence of anisole. 



   Hydrolysis using hydrazine is typically used to eliminate a protecting group, such as. B.  Succinyl or phthaloyl.  Hydrolysis with a base is preferably used to eliminate an acyl group, e.g. B.  of haloalkanoyl (such as trifluoroacetyl and the like. ) and the like  applied.  Suitable bases include e.g. B. 



  an inorganic base such as 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 dgI. ), an alkali metal acetate (such as sodium acetate, potassium acetate 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, e.g. B. 

   a trialkylamine (such as trimethylamine, triethylamine and the like. ), Picoline, N-methylpyrrolidine, N methylmorpholine, 1,5-diazabicyclo [4,3,0] non-5-ene, 1,4-diazabicyclo [2,2,2] octane, 2,5-diazabicyclo [ 5,4,0] undecen-5 or the like.  Hydrolysis using a base is often carried out in water or in a hydrophilic organic solvent or in a mixture thereof. 



   Among the protecting groups, the acyl group can generally be eliminated by hydrolysis as indicated above or by another conventional hydrolysis.  If the acyl group is halogen-substituted alkoxycarbonyl or 8-quinolyloxycarbonyl, it can be treated with a heavy metal such as copper, zinc or the like. , are eliminated.  Reductive elimination is generally used for the elimination of a protecting group such as e.g. B.    Haloalkoxycarbonyl (such as trichloroethoxycarbonyl and the like. ), substituted or unsubstituted aralkoxycarbonyl (such as benzyloxycarbonyl, substituted benzyloxycarbonyl and the like. ), 2-pyridylmethoxycarbonyl and the like.  applied.  A suitable reduction can e.g. B.  be the reduction with an alkali metal borohydride (such as sodium borohydride and the like. ) and the like 



   Suitable iminohalogenating agents that can be used in a process such as the one mentioned above include phosphorus pentabromide, phosphorus oxychloride, thionyl chloride, phosgene and the like.  The reaction temperature is not critical and the reaction is usually carried out at ambient temperature or with cooling.  Suitable imino etherification agents which are reacted with the reaction product thereby obtained may include an alcohol, a metal alkylate (metal alkoxide) and the like. 



  Suitable alcohols can include an alkanol (such as methanol, ethanol, propanol, isopropanol, butanol, t-butanol and the like. ) which may be substituted by alkoxy (such as methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like. ). 



  Suitable metal alkylates (metal alkoxides) may include an alkali metal alkylate (such as sodium alkylate, potassium alkylate and the like. ), an alkaline earth metal alkylate (such as calcium alkylate, barium alkylate and the like. ) and the like  The reaction temperature is not critical and the reaction is carried out in the
Usually performed with cooling or at ambient temperature. 



   The product obtained is subjected to hydrolysis if necessary.  The hydrolysis can easily be done in the
Be carried out by pouring the reaction mixture obtained above in water, but beforehand a hydrophilic solvent (such as methanol, ethanol and the like. ), a base (such as alkali metal bicarbonate, trialkylamine and the like. ) or an acid (such as dilute hydrochloric acid, acetic acid and the like. ) be added to the water. 



   The reaction temperature is not critical and may be more appropriate depending on the nature of the protecting group for the amino group and the elimination method mentioned above
Be selected and the reaction according to the invention is preferably carried out under mild conditions, for example under cooling, at ambient temperature or at a slightly elevated temperature. 



   The present invention also includes cases where the protected carboxy group is converted to the free carboxy group. 



   Procedure 3
The compound (Ib) or a salt thereof is prepared by acylating the hydroxy group of the compound (V) or a salt thereof.  As a suitable salt of the compound (V), there can be used one as exemplified for the compound (IV). 



   Acylating agents which can be used for the reaction according to the invention can include an aliphatic, aromatic and heterocyclic carboxylic acid and the corresponding sulfonic acid and thioic acid, which as
Acyl radicals have the abovementioned acyl group, and the reactive derivatives of the abovementioned acids.  Suitable reactive derivatives of the above acids include an acid halide, an acid anhydride, an activated amide, an activated ester and the like.  Suitable examples are an acid chloride, an acid azide, a mixed
Acid anhydride with an acid such as substituted phosphoric acid (e.g. B. 

  Dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated
Phosphoric acid and the like ), Dialkylphosphorous acid,
Sulphurous acid, thiosulphuric acid, sulfuric acid, alkyl carbonic acid, an aliphatic carboxylic acid (such as pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid or
Trichloroacetic acid and the like ) or an aromatic carboxylic acid (such as benzoic acid and the like. ); a symmetrical acid anhydride; an activated amide with imidazole, 4-substituted
Imidazole, dimethylpyrazole, triazole or tetrazole;

   or an activated ester (such as cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl (CH3) 2Nt = CH -) ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitro phenyl ester, trichlorophenyl ester, pentachlorophenyl ester,
Mesylphenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinol yl thioester] or an ester with N, N-dimethylhydroxylamine, 1-hydroxy-2- (lH) N-hydroxysuccinimide, N-hydr oxyphthalimide or l-hydroxy-6-chloro-lH-benzotriazole and the like.  These reactive derivatives can be selected if desired depending on the type of acylating agent to be used. 

 

   Suitable acylating agents may also include an aliphatic, aromatic or heterocyclic isocyanate or isothiocyanate (e.g. B.  Methyl isocyanate, phenyl isocyanate, trichloroacetyl isocyanate, methyl isothiocyanate and the like. ) and a halogen formate (such as ethyl chloroformate, benzyl chloroformate and the like. ).  In this case, for example, when the trichloroacetyl isocyanate is used as the acylating agent, the trichloroacetylcarbamoyl group is introduced as the acyl group, and this group can be converted to the carbamoyl group by treatment with a base, and when ethyl chloroformate is used as the acylating agent, the ethoxycarbonyl group can be introduced as the acyl group . 



   The reaction according to the invention is carried out under reaction conditions similar to those used for the above-mentioned reaction of the compound (II) with the compound (III), and it is preferably carried out in the presence of a base.  In the reaction of the compound (V) with an acylating agent, the protected carboxy group or the salts in the compound (V) can be converted into the free carboxy group in the course of the reaction or during an aftertreatment. 



  Procedure 4
The compound (Ic) or a salt thereof is prepared by subjecting the compound (Va) or a salt thereof to an elimination reaction to remove the carboxy protecting group.  Examples of suitable salts of the compound (via) are the same as those exemplified above for the compound (IV). 



   The elimination reaction according to the invention is carried out by a conventional method, for example by hydrolysis or the like. , carried out.  The hydrolysis can be a method using an acid or a base and the like.  is carried out.  These methods can be selected depending on the type of protecting groups to be eliminated. 



   Hydrolysis using an acid is one of the most common and most preferred methods for eliminating protecting groups, such as. B.  Phenyl (lower) alkyl, substituted phenyl (lower) alkyl, lower alkyl, substituted lower alkyl or the like.  Suitable acids can include inorganic or organic acids, such as. B. 



  Formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid and the like.  The reaction according to the invention can be carried out in the presence of anisole.  The acid suitable for the reaction can be selected depending on the protective group to be eliminated and on other factors.  Hydrolysis using an acid can be carried out in the presence of a solvent such as e.g. B.  an organic solvent, in the presence of water or a mixture thereof. 



   The reaction temperature is not critical and can be selected appropriately depending on the nature of the protecting group and the elimination process used, and the reaction according to the invention is preferably carried out under mild conditions, for example under cooling, at ambient temperature or under slight heating. 



   The present invention also includes the cases in which the protected carboxy group for R3 is converted into the free carboxy group during the reaction or during the aftertreatment in the course of the reaction according to the invention; in which the protected amino group is converted into the free amino group; in which the protected imino group is converted into the free imino group; in which the acyloxy group is converted into the hydroxy group. 



   The following describes the processes for the preparation of the starting compound (III), i.e. H.  of the syn isomer and the anti isomer thereof, which are used as reference examples, explained in more detail. 



  A) Process (VI) + (VII) <(VIII) [Reaction scheme (1) (i)]
The compound (VIII) can be prepared by reacting the compound (VI) with the compound (VII).



   The reaction is usually carried out in a solvent such as water, ethanol, acetone, ether, dimethylformamide or in any other solvent which does not adversely affect the reaction. The reaction is preferably carried out in the presence of a base, e.g.



  an inorganic base or an organic base as mentioned above. The reaction temperature is not critical and the reaction is usually carried out with cooling to heating to the boiling point of the solvent.



  B) Procedure (IX) <(X) [Reaction Scheme (1) (ii)] and (XXXII) <(XXXIII) [Reaction scheme (6) (ii)]
The compounds (X) and (XXXIII) can be prepared by oxidation of the compounds (IX) and (XXXII).



   The oxidation reaction is carried out using a conventional method which is used to convert the so-called activated methylene group to a carbonyl group. That is, the reaction is carried out using a conventional method, for example, by oxidation using a conventional oxidizing agent such as selenium dioxide, potassium permanganate or the like. The oxidation is usually carried out in a solvent which does not adversely affect the reaction, e.g. in water, dioxane, pyridine, tetrahydrofuran and the like. The reaction temperature is not critical and the reaction is preferably carried out with heating.



  C) Procedure (XI) <(XII [Reaction Scheme (1) (iii)]
The compound (XII) can be prepared by subjecting the compound (XI) to an elimination reaction to remove the Ar (lower) alkyl group.



   The elimination process includes all of the conventional processes used for the elimination of the Ar (lower) alkyl group, e.g. hydrolysis, reduction and the like.



   Hydrolysis using an acid is one of the most preferred methods, and acids that can be used include an inorganic acid (such as hydrochloric acid, hydrobromic acid and the like), an organic acid (such as formic acid, acetic acid, trifluoroacetic acid and the like). ) and a mixture of them. The reaction can be carried out in a solvent such as water, in an organic solvent or in a mixture thereof or without a solvent. The reaction temperature is not critical and the reaction is preferably carried out with heating to heating.



  D) Process (XIII) + (XIV) e (IIIa) [Reaction Scheme (1) (iv)], (XXXIII) + (XIV) o (XXXV) [Reaction Scheme (6) (ii)] and (XXXIV) + ( XIV) o (IIIf) [Reaction scheme (6) (ii)]
The compounds (IIIa), (XXXV) and (IIIf) can be prepared by reacting the compounds (XIII), (XXXIII) and (XXXIV) each with the compound (XIV) or a salt thereof. Suitable salts for the compound (XIV) include an inorganic acid salt (such as a hydrochloride, hydrobromide, sulfate, and the like) or an organic acid salt (such as an acetate, p-toluenesulfonate and the like) and the like.

 

   The reaction is usually carried out in a solvent such as water, an alcohol (such as methanol, ethanol, and the like) or in a mixture thereof or in any other solvent which does not adversely affect the reaction.



   In the event that the compound (XIV) is used in the form of its salt, the reaction is preferably carried out in the presence of a base, e.g. an inorganic base, e.g.



  an alkali metal (such as sodium, potassium and the like), an alkaline earth metal (such as magnesium, calcium and the like), a hydroxide or carbonate or bicarbonate thereof or the like.



  and in the presence of an organic base, e.g. an alkali metal alkylate (such as sodium methylate, sodium ethylate and the like), a trialkylamine (such as trimethylamine, triethylamine and the like), N, N-dialkylamine (such as N, N-dimethylaniline and the like), N, N-dialkylbenzylamine (such as N , N-dimethylbenzylamine and the like), pyridine or the like.



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



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



   For the selective preparation of the syn isomer of the compound (IIIa), (XXXV) or (IIIf) in high yield, the reaction is preferably carried out under approximately neutral conditions.



  E) Process (XV) e (XVI) [Reaction Scheme (2) (i)] and (XXXIV) to (XXXVI) [Reaction Scheme (6) (ii)]
The compounds (XVI) and (XXXVI) can be prepared by reacting the compounds (XV) and (XXXIV) with hydroxylamine or a salt thereof, respectively.



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



   The reaction conditions of the reaction can also be the same as those for processes (XIII) + (XIV) e (IIIa), (XXX) + (XIV) (XXXV) and (XXXIV) + (XIV) e (IIIn) in section (d) above has been given as an example.



  F) Process (XVII) -, (XVIII) [Reaction Scheme (2) (ii)], (XXIV) to (XXV) [Reaction Scheme (4) (ii)], (XXVI) (XXVII) [Reaction Scheme (5)] and (XXXVII) (XXXVIII) [Reaction Scheme (6) (iii)]
Compounds (XVIII), (XXV), (XXVII) and (XXXVIII) can be prepared by alkylating compounds (XVII), (XXIV), (XXVI) and (XXXVII), respectively.



   Examples of alkylating agents that can be used in the alkylation reaction are di (lower) alkyl sulfate (such as dimethyl sulfate, diethyl sulfate and the like), diazo (lower) alkane (such as diazomethane, diazoethane and the like), a lower alkyl halide (such as methyl iodide, ethyl iodide) and the like), a lower alkyl sulfonate (such as methyl p-toluenesulfonate and the like) and the like.



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



   The reaction is preferably carried out in the presence of a base, e.g. an inorganic base or an organic base as mentioned above. The reaction temperature is not critical and the reaction is usually carried out with cooling to heating to about the boiling point of the solvent.



   The reaction, which is carried out using diazoalkane, is usually carried out in a solvent such as ether, tetrahydrofuran or the like. The reaction temperature is not critical and the reaction is usually carried out under cooling or at ambient temperature.



  G) Process (XVIII) e (IIIb) [Reaction Scheme (2) (ii)] and (XXXVIII) <(III [Reaction scheme (6) (iii)]
Compounds (IIIb) and (III can be prepared by subjecting compounds (XVIII) and (XXXVIII) to hydrolysis, respectively.



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



   Suitable acids may include an organic acid (e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid and the like) and an inorganic acid (e.g.



  Hydrochloric acid, hydrobromic acid, sulfuric acid and the like.).



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



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



  H) Procedure (XIX) <(IIIC) [reaction scheme (3)]
Compound (IIIC) can be prepared by subjecting compound (XIX) to acylation. Examples of acylating agents that can be used for the reaction and the reaction conditions that can be used in the reaction are e.g. those as exemplified above for Method 3.



  I) Process (XX) e (XXI) [Reaction Scheme (4) (i)]
Compound (XXI) can be prepared by subjecting compound (XX) to nitrosation.

 

   Examples of nitrosating agents that can be used in the reaction are conventional agents that give C nitroso compounds when reacted with an activated methylene group, e.g. Nitrous acid, an alkali metal nitrite (such as sodium nitrite and the like), a lower alkyl nitrite (such as isopentyl nitrite, t-butyl nitrite and the like) or the like.



   When a nitrous acid salt is used as the nitrosating agent, the reaction is usually carried out in the presence of an acid, e.g. an inorganic acid or an organic acid (such as hydrochloric acid, acetic acid and the like). If an ester of nitrous acid is used, the reaction is preferably carried out in the presence of a strong base, e.g. an alkali metal alkylate or the like.



   The reaction is usually carried out in a solvent such as water, acetic acid, benzene, an alcohol (such as methanol, methanol and the like) or in any other solvent which does not adversely affect the reaction. The reaction temperature is not critical and the reaction is usually carried out under cooling or at ambient temperature.



  J) Process (XXI) + (XXII) to (XXIII) [Reaction Scheme (4) (i)] and (XXVIII) + (XXII) <(XXIX [reaction scheme (5)]
The compounds (XXIII) and (XXIX) can be prepared by reacting the compounds (XXI) and (XXVIII) with the compound (XXII), respectively.



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



   To selectively prepare the syn isomer of the compound (XXIII) or (XXIX) in high yield, the syn isomer of the starting compound (XXI) or (XXVIII) must be used, and the reaction is preferably carried out about under neutral conditions in the presence of a base as above mentioned, carried out. Preferred examples of usable bases are a weak base such as an alkali metal acetate (e.g. sodium acetate, potassium acetate and the like), an alkali metal bicarbonate (such as sodium bicarbonate, potassium bicarbonate and the like), an alkali metal carbonate (such as sodium carbonate, potassium carbonate and the like) or the like.



  K) Method (XXIII) o (XXIIIa) [Reaction Scheme (4) (i)], (XXV <(111d) [Reaction scheme (4) (ii)], (XXIX) to (IIIe) [Reaction scheme (5)], (XXXIII) <(XXXIV) [Reaction Scheme (6) (ii)] and (XXXV) (IIIf) [Reaction Scheme (6) (ii)]
Compounds (XXIIIa), (IIId), (IIIe), (XXXIV) and (IIIf) can be prepared by combining compounds (XXIII), (XXV), (XXIX), (XXXIII) and (XXXV) each Elimination reaction to remove the carboxy protecting group.



   In the elimination reaction, conventional methods such as those used for the elimination of the protecting group, such as hydrolysis and the like, can be used. If the protecting group is an ester, it can be eliminated by hydrolysis. The hydrolysis is carried out in a similar manner to processes (XVIII) o (yellow) and (XXXVIII) o (IIIg), as described in the above
Section (G) have been described.



   L) Process (XXVII) e (XXVIII) [Reaction Scheme (5)]
The compound (XXVIII) can be produced by
Halogenation of the compound (XXVII).



   Examples of halogenating agents which can be used in the reaction are a conventional halogenating agent as used in the halogenation of the so-called activated methylene group, e.g. Halogen (such as bromine, chlorine and the like), sulfuryl halide (such as sulfuryl chloride and the like), a hypohalite (such as hypochlorous acid,
Sub-bromine acid, sodium hypochlorite and the like), a nhalogenated imide (such as N-bromosuccinimide, N-bromophthalimide, N-chlorosuccinimide and the like) and the like.



   The reaction is usually carried out in a solvent such as e.g. in an organic solvent (such as formic acid, acetic acid, propionic acid and the like), in carbon tetrachloride or in any other solvent which does not adversely affect the reaction. The reaction temperature is not critical and the reaction is usually carried out with cooling, at ambient temperature, with heating or with heating.



  M) Process (XXX) (XXXI) [Reaction Scheme (6) (i)] and (XXXIX) e (IIIh) [Reaction Scheme (7)]
The compound (XXXI) can be prepared by reacting the compound (XXX) or a reactive derivative thereof on the amino group or a salt thereof with an amino protective agent, and the compound (IIIh) can be prepared by reacting the compound (XXXIX) or a reactive derivative thereof on the amino group or a salt thereof with an amino protective agent.



   Examples of suitable reactive derivatives on the amino group of the compound (XXX) or (XXXIX) and suitable salts of the compound (XXX) or (XXXIX) may be the same as those in the explanations of the reactive derivative on the amino group of the compound (II) or the salt of the compound (11) have been given by way of example. Suitable amino protection agents include an acylating agent such as e.g. an aliphatic, aromatic and heterocyclic carboxylic acid and the corresponding sulfonic acid, a halogen formic acid ester, an isocyanic acid ester and the carbamic acid as well as the corresponding thio acid thereof and the reactive derivatives of the acids specified above.



   Suitable reactive derivatives of the acids given above may include the same ones as exemplified above in the explanation of method 3. An example of the protecting group (e.g. the acyl group) to be introduced into the amino group in the compound (XXX) or (XXXIX) by the above-mentioned amino protecting agent (e.g. the acylating agent) may be the same protecting group (e.g. acyl group), as stated in the description of the protective group residue (eg the acyl residue) in the expression acylamino.



   The amino protection reaction is carried out in a similar manner to that described in the reaction of the compound (II) with the compound (III) (Method 5).



  N) method (XXIIIb) <(XXXIII) [Reaction scheme (6) (ii)]
The compound (XXXIII) can be prepared by hydrolysis of the compound (XXIIlb).

 

   The hydrolysis is carried out in the presence of an alkali metal bisulfite (such as sodium bisulfite and the like), titanium trichloride, an inorganic or organic acid such as a hydrohalic acid (e.g. hydrochloric acid, hydrobromic acid and the like), formic acid, nitrous acid or the like. A hydrohalic acid is preferably used in combination with an aldehyde (such as formaldehyde and the like).



   The reaction is usually carried out in a solvent such as water, an aqueous alcohol (e.g. in aqueous methanol, aqueous ethanol and the like), in water / acetic acid or in any other solvent which does not adversely affect the reaction. The reaction temperature is not critical and the reaction is usually carried out at ambient temperature, with heating or with heating.



   In the reaction, the protected carboxy group can occasionally be converted into the free carboxy group.



  This case is also within the scope of the present invention. In the above-mentioned reactions and / or in the after-treatment, the above-mentioned tautomeric isomers can occasionally be converted into the other tautomeric isomers.



   When the compound (I) is obtained in the free acid form at the 4-position and / or when the compound (I) has a free amino group, it can be converted into its pharmaceutically acceptable salt as mentioned above by a conventional method will.



   The compound (I) and its pharmaceutically acceptable salts are all new compounds which have high antibacterial activity, inhibit the growth of a large number of pathogenic microorganisms, including gram-positive and gram-negative bacteria, and are suitable as antibacterial agents.



   In particular, it should be noted that compound (I), i.e. the syn isomer has much higher antibacterial activities than the corresponding anti isomer to the compound (I) and accordingly the compound (I), i.e. the syn isomer, is characterized in that it is related to the corresponding anti isomer is far superior to its therapeutic values.



   In order to demonstrate the usefulness of the compound (I) on the basis of some representative representatives, test results regarding the antibacterial activity in vitro as well as the test results in vivo, i.e. the protective effect against experimental infections, as well as the acute toxicity. In addition, some comparative test data of the antibacterial activities in vitro for the corresponding anti-isomer of the compound (I) are also given below for comparison.



  Compounds Tested (1) 7- [2-Methoxyimino-2- (3-hydroxyphenyl) acetamido] - 3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid, syn isomer (2) 7- [2-methoxyimino-2- (3-hydroxyphenyl) acetamido] - 3- (l-methyl-l H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid, anti Isomer (3) 7- [2-methoxyimino-2- (3-hydroxyphenyl) acetamido] - 3- (1,3, 4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid, syn isomer ( 4) 7- [2-methoxyimino-2- (3-acetoxyphenyl) acetamidoj-3- (1, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid, syn isomer (5) 7 - [2-Methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid ,

   Syn isomer (6) 7- [2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamidoj-3- (1-methyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid, anti-isomer (7) 7- [2-methoxyimino-2- (2-formamido-l, 3-thiazol-4 yl) acetamido] -3- (1,3,4-thiadiazole -2-yl) thiomethyl-3-cephem-4-carboxylic acid, syn isomer (8) 7- [2-methoxyimino-2- (2-formamido-1,3-thiazol-4-yl) acetamido] 3- ( 1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid, anti-isomer (9) 7- [2-methoxyimino-2- (2-amino-1,3-thiazol-4- yl) acetamido] -3- (1, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carbonic acid,

   Syn isomer (10) 7- [2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamidoj-3- (5-methyl-1,4-thiadiazol-2-yl ) thiomethyl-3-cephem-4-carboxylic acid, syn isomer (11) 7- [2-methoxyimino-2- (2-amino-1, 3-thiazol-4-yl) acetamido] -3- (4th -methyl-4H-1, 2,4-triazol-3-yl) thiomethyl-3-cephem-4-carboxylic acid, syn isomer 1.) Antibacterial activity in vitro
Test method: The antibacterial activity in vitro was determined according to the two-fold agar plate dilution method described below.



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



  Test results test M I C (, ug / ml) bacteria test compounds
1 2 3 4 5 6 7 8 9 10 11 Escherichia coli NIHJ JC-2 1.56 50 3.13 12.5 0.20 12.5 0.78 12.5 0.10 0.39 0.20 Klebsiella pneumoniae 417 0.39 6.25 0.78 0.78 0.10 6.25 1.56 3.13 0.20 0.10 0.20 Proteus mirabilis 525 0.78 25 0.78 1.56 0.10 3.13 0.39 3.13 0.10 0.39 0.39
As is clear from the test results given above, the compounds of formula (I), i.e. the syn isomers, have a much higher antibacterial activity than their corresponding anti isomers.



  2.) Protection against experimental infections in mice
Test Procedure: 4 week old ICR strain male mice each weighing 20 to 23 g were used in groups of 8 mice. The test bacteria were cultivated overnight at 37 ° C. on a HI agar and then suspended in a 2.5 to 5% strength mucin solution, the suspension corresponding to the respective vaccine cells being obtained. The mice were inoculated intraperitoneally with 0.5 ml of the suspension. A solution containing each test compound was administered subcutaneously in various doses to the mice 1 hour after vaccination. The ED50 values were calculated from the number of surviving mice at each dose after observation for weeks.



  Test results SchuL-t'irkwzg against experimental parts eections in mice Test bacteria Vaccine cells / MIC of the strain EDso (S. C.) used (mg / mouse)
Mouse (g / ml) viable test compounds test compounds hige cells / ml 9 4 3 CET * 9 4 3 CET Escherichia 6 x 106 108 <0.03 0.78 0.78 12.5 coli29 106 10.03 0.39 0.78 3.13 0.005 0.081 0.111 1.402 * CET: 7- (2-thienyl) acetamidocephalosporanic acid
Test results
Test bacteria vaccine cells / MIC of the strain EDso used (S. 

  C. ) (mg / mouse)
Mouse µg / ml life test compounds capable of test compounds
Cells / ml 5 cefuroximes 5 cefuroximes Escherichiacoli 3.5x 104 108 1.56 12.5
100 106 0.2 12.5 0.023 1.158
Test bacteria vaccine cells / MIC of the strain ED50 used (p. C. ) (mg / mouse)
Mouse µg / ml) viable test compounds test compounds ge cells / ml 1 CEZ Na * 1 CEZ Na Escherichia coli 5.5 x 105 108 0.78 3.13
29 106 10.1 0.78 0.386 0.182 * CEZ Na: sodium 7- [2- (1H-tetrazol-1-yl) acetamido] - 3- (5-methyl-l, 3,4-thiadiazol-2- yl) thiomethyl-3-cephem carboxylate 3. ) Acute toxicity in mice
The same strain of mice was used as in the above protection test against experimental infections in groups of 10 mice.  2 g of the text compound was administered intravenously to the mice. 

  After weeks of observation, all mice survived without showing any disturbance. 



   For therapeutic administration, the compound (I) is preferably used in the form of a conventional pharmaceutical preparation which contains this compound as an active ingredient, optionally in a mixture with pharmaceutically acceptable carriers, such as, for. B.  an organic or inorganic solid, or with a liquid excipient suitable for oral, parenteral or external administration.  The pharmaceutical preparations can be in solid form, for example in the form of capsules, tablets, dragées, ointments or suppositories, or in liquid form, for example in the form of solutions, suspensions or emulsions.  If necessary, auxiliary substances, stabilizers, wetting agents or emulsifying agents, buffers and other commonly used additives can also be incorporated into the preparations mentioned above. 



   The dosage of the compounds may vary and also depend 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 about 50 mg, about 100 mg, about 250 mg and about 500 mg of the compound (I) according to the invention has proven to be effective for the treatment of diseases caused by pathogenic bacteria.  In general, amounts between about 1 mg and about 1000 mg or even larger amounts can be administered to a patient. 



   The invention is illustrated by the following examples. 



  Production of the starting products example
0.89 g of phosphorus oxychloride and 0.44 g of dry dimethylformamide were mixed together under ice cooling and then heated to 40 ° C for 30 minutes.  20 ml of dry methylene chloride was added and then was distilled off.  10 ml of dry ethyl acetate and then 1.8 g of 2-methoxyimino-2- [2- (2,2,2-trifluoroacetamido) -1,3-thiazol-4-yl] acetic acid (syn-isomer ) while stirring and cooling with ice.  The mixture was stirred at the same temperature for 40 minutes to obtain a clear solution. 

  On the other hand, 6.36 g of trimethylsilylacetamide was added to a suspension of 1.65 g of 7-aminocephalosporanic acid in 25 ml of dry ethyl acetate with stirring at ambient temperature, after which the mixture was stirred for 1 hour to obtain a clear solution.  To this solution, the ethyl acetate solution obtained above was added all at once with stirring at -20 to -25 ° C, and the resulting mixture was stirred at the same temperature for 2 hours.  30 ml of water was added to the reaction mixture at the same temperature, and then the mixture was stirred at ambient temperature for 5 minutes.  The ethyl acetate layer was separated and the aqueous layer was further extracted with ethyl acetate.  The ethyl acetate layers were combined and 50 ml of water was added.  

  The mixture was adjusted to pH 7.5 with sodium bicarbonate and the aqueous layer was separated.  40 ml of ethyl acetate was added to the aqueous layer, and the mixture was adjusted to pH 2.5 with 10% hydrochloric acid with stirring and ice-cooling.  The ethyl acetate layer was separated, and the aqueous layer was further extracted twice with 50 ml of ethyl acetate.  The ethyl acetate layers were combined, washed with an aqueous sodium chloride solution and treated with activated carbon.  The solvent was distilled off, 3.05 g of 7- [2-methoxyimino-2- {> - (2,2,2-trifluoroacetamido) - 1,3-thiazol-4-ylacetamido] - cephalosporanic acid (Syn-Isomeres) , F.  2U5 (dec. ), received. 



   IR spectrum (Nujol) 3250.1790.1735.1680, 1650cm- '
N. M. R. Spectrum (d6-DMSO, 6) ppm 9.8 (1H, d, J = 8Hz)
7.55 (1H, s)
5.88 (1H, dd, J = 5.8Hz)
5.25 (1H, d, J = 5Hz)
4.8 (2H, ABq, J = 13Hz)
3.95 (3H, s)
3.59 (2H, broad s)
2.03 (3H, s)
Example 2
2.0 g of phosphorus oxychloride were added at 5 to
10 C to a suspension of 2 g of 2-methoxyimino-2- (2 amino-1,3-thiazol-4-yl) acetic acid (Syn-Isomeres) in 20 ml of dry ethyl acetate.  After stirring at 7 to 10 C for 20 minutes, 0.4 g of bis (trimethylsilyl) acetamide was added at the same temperature. 

  After stirring for 10 minutes at 7 to 10 C, 2.0 g of phosphorus oxychloride were added dropwise at the same temperature.  The resulting mixture was stirred at 7 to 10 C for 10 minutes and 0.8 g of dry dimethylformamide was added dropwise at the same temperature.  The mixture was stirred at 7 to 10 C for 30 minutes to give a clear solution.  On the other hand, 7.35 g of trimethylsilylacetamide was added to a suspension of 2.45 g of 7-aminocephalosporanic acid in 8 ml of dry ethyl acetate, after which the mixture was stirred at 40 ° C to form a clear solution. 



  To this solution, the ethyl acetate solution obtained above was added all at once at -15 C, and the resulting mixture was stirred at -10 to -15 C for 1 hour. 



  The reaction mixture was cooled to -30 ° C and 80 ml of water was added.  The aqueous layer was separated off, adjusted to pH 4.5 with sodium bicarbonate and subjected to column chromatography on a Diaion HP20 resin (trademark for a product from Mitsubishi Chemical Industries Ltd. ) using a 25% aqueous isopropyl alcohol solution as the eluent.  The eluate was lyophilized, 1.8 g of 7- [2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamidoj-cephalosporanic acid (Syn-Isomeres), F.  227 C (dec. ), received. 



   IR spectrum (Nujol) 3300-3350, 1780, 1740, 1670 cm- '
N. M. R. Spectrum (d6-DMSO, 6) ppm 9.6 (1H, d, J = 8Hz)
6.8 (1H, s)
5.8 (1H, dd, J = 5.8Hz)
5.2 (1H, d, J = 5Hz)
4.87 (2H, ABq, J = 13Hz)
3.89 (3H, s)
3.6 (2H, broad s)
2.08 (3H, s)
Example 3
3.8 g of phosphorus oxychloride were at 5 to 8 C to a suspension of 4.0 g of 2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetic acid (Syn-Isomeres) in 40 ml of dry Ethyl acetate added dropwise.  After stirring at about 5 C for 30 minutes, 0.86 g of bis (trimethylsilyl) acetamide was added at the same temperature.  After stirring at the same temperature for 10 minutes, 3.8 g of phosphorus oxychloride was added dropwise at 5 to 8 ° C, after which the mixture was stirred at the same temperature for 30 minutes. 

  1.6 g of dry dimethylformamide were added dropwise at 5 to 7 ° C, after which the resulting mixture was stirred at the same temperature for 30 minutes to obtain a clear solution.  On the other hand, 3.3 g of sodium acetate was added to a solution of 2.7 g of 7-aminocephalosporanic acid in an aqueous solution (20 ml) of 1.7 g of sodium bicarbonate, and then 20 ml of acetone was added.  The ethyl acetate solution obtained above was added dropwise to this solution with stirring at 0 to 5 ° C., the pH of this solution being kept at 7.0 to 7.5 with a 20% strength aqueous sodium carbonate solution.  The mixture was stirred at the same temperature for 1 hour.  An insoluble material was filtered off and the aqueous layer in the filtrate was separated. 

  The aqueous layer was concentrated under reduced pressure to remove the organic solvents, adjusted to pH 4.5 with sodium bicarbonate, and column chromatography on a Diaion HP-20 resin (trademark for a product of Mitsubishi Chemical Industries Ltd. ) using a 25% aqueous isopropyl alcohol solution as the eluent.  The eluate was lyophilized to give 2.8 g of 7- [2-methoxyimino-2- (2-amino-1,3-thiazol4-yl) acetamido] cephalosporanic acid (Syn-Isomeres). 



  This compound was identified with the compound obtained in Example 2 by IR and NMR spectra. 



   Example 4
0.26 g of disodium hydrogenphosphate were added to a suspension of 1 g of 7- [2-methoxyimino-2-t2- (2,2,2-trifluoroacetamido) -1,3-thiazol-4-yl acetamido] cephalosporanic acid (Syn-Isomeres ) to 15 m of water.  In addition, a saturated aqueous disodium hydrogen phosphate solution was added to adjust the pH of the mixture to 6.  The resulting mixture was stirred at ambient temperature for 23 hours.  The reaction mixture was adjusted to pH 4 with ice-cooling with 10% hydrochloric acid, washed with ethyl acetate and adjusted to pH 2.5 with 10% hydrochloric acid.  

  The precipitated crystals were collected by filtration, washed with cold water and dried, giving 0.18 g of 7- [2-methoxyimino-2- (2-amino-1, 3-thiazol-4-yl) acetamido] cephalosporanic acid (Syn -Isomeres), F.  227 C (dec. ), received. 



   IR spectrum (Nujol) 3300-3350,1780,1740,1670cm- '
N. M. R. Spectrum (d6-DMSO, 6) ppm 9.6 (1H, d, J = 8Hz)
6.8 (1H, s)
5.8 (1H, dd, J = 5, 8Hz)
5.2 (1H, d, J = 5Hz)
4.87 (2H, 6.8 (1H, s) 5.8 (1H, dd, J = 5, 5.8Hz)
5.2 (1H, d, J = 5Hz)
4.87 (2H, ABq, J = 13Hz)
3.89 (3H, s)
3.6 (2H, broad s)
2.08 (3H, s)
Example 5
10.4 ml of concentrated hydrochloric acid with stirring at ambient temperature to a suspension of 48.35 g of 7- [2-methoxyimino-2- (2-formamido-1, 3-thiazol-4-yl) acetamido] cephalosporanic acid (Syn-Isomeres ) in 725 ml of methanol. 

  After stirring for 3 hours at ambient temperature, the reaction mixture was adjusted to pH 4.5 with an aqueous ammonia solution and the methanol was distilled off.  100 ml of water were added to the residue.  The mixture was adjusted to pH 6.5 with an aqueous sodium bicarbonate solution and the insoluble material was collected by filtration, whereby 6.5 g of 6- [2-methoxyimlno-2- (2-amino-1,3-thiazole-4- yl) - acetamido] -5a, 6-dihydro-3H, 7H-aceto [2, 1-b] furo [3,4-d] - [1,3] thiazine-1,7 (4H) dione (syn- Isomeres).  The filtrate was adjusted to pH 4.5 with acetic acid, on Diaion HP20 resin (trademark for a product of Mitsubishi Chemical Industries Ltd. ) (600 ml), washed with 2 l of water, and then eluted with a 25% aqueous solution of isopropyl alcohol. 

  The eluates containing the desired compounds were collected and cooled after the addition of isopropyl alcohol (one third the volume of the eluates).  The precipitates were collected by filtration, washed with isopropyl alcohol and dried to give 10.4 g of 7- [2-methoxyimino-2- (2-amino-1, 3-thiazol-4-yl) acetamido] cephalosporanic acid (Syn-Isomeres ) received.  The mother liquor was concentrated under reduced pressure until crystals started to precipitate.  Isopropyl alcohol was added to the residue (2/3 of the volume of the residue).  The mixture was cooled and the precipitates were collected by filtration to give 5.8 g of the desired compound.  The overall yield was 16.2 g. 

  This compound was identified with the compound obtained in the above examples by IR and NMR spectra. 



   Example 6
0.51 g of phosphorus oxychloride was added dropwise over a period of 5 minutes at 5 C to a solution of 0.24 g of dimethylformamide in 1 ml of dry ethyl acetate.  After crystal precipitation, the mixture was stirred at 10 oC for 30 minutes, then 9 ml of dry ethyl acetate and 0.89 g of 2-methoxyimino-2- [2 (2,2,2-trifluoroacetamido) -1,3 -thiazol-4-yl] acetic acid (syn isomer) added at -10 ° C.  The resulting mixture was stirred at -10 to -5 C for 30 minutes. 

  The solution obtained was added dropwise over a period of 5 minutes at −15 ° C. to a solution of 1.0 g of 7-amino-3-benzoyloxymethyl-3-cephem-4-carboxylic acid and 3.2 g of trimethylsilylacetamide in 10 ml of dry ethyl acetate, the mixture obtained was then stirred at -10 to -15 ° C. for 1 hour.  10 ml of water was added to the reaction mixture, and the ethyl acetate layer was separated.  The aqueous layer was extracted with a further 10 ml of ethyl acetate.  The ethyl acetate layers were combined and 20 ml of water was added.  The resulting mixture was adjusted to about pH 6 with sodium bicarbonate.  The aqueous layer was separated and 25 ml of ethyl acetate was added. 

  The mixture was adjusted to pH 2.5 with ice cooling and with stirring with 10% hydrochloric acid.  The ethyl acetate layer was separated and the aqueous layer was further extracted with 15 ml and 10 ml of ethyl acetate.  The ethyl acetate layers were combined, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, treated with activated carbon and evaporated under reduced pressure to give crystals which were dried under reduced pressure to give 1.15 g of 7- [2-methoxyimino -2-i2- (2,2,2-trifluoroacetamido) - 1,3-thiazol-4-yb acetamido] -3-benzoyloxymethyl-3 cephem-4-carboxylic acid (syn isomer).    



   IR (Nujol) 3250.1790.1730.1650cm- '
NMR (d6-DMSO, I) 9.95 (in, d, J = 8Hz), 7.92-8.16 (2H, m), 7.4-7.84 (3H, m), 7.6 (1H, s), 5.92 (1H, dd, J = 5.8Hz), 5.26 (1H, d, J = 5Hz), 5.18 (2H, ABq, J = 13Hz), 3.96 (3H, s), 3.76 (2H, broad s)
Example 7
0.56 g of phosphorus oxychloride was suddenly added below 5 C to a mixture of 0.6 g of 2-methoxyimino-2- (2-amino-1, 3-thiazol-4-yl) acetic acid (syn isomer) and 6 ml of dry ethyl acetate was added and the mixture was stirred at 4 to 6 C for 20 minutes. 

  At the same temperature, 0.3 g of bis (trimethylsilyl) acetamide was added all at once, and the mixture was stirred at the same temperature for 10 minutes.  To the obtained mixture, 0.56 g of phosphorus oxychloride was added all at once, and the mixture was stirred at the same temperature for 30 minutes, then 0.24 g of dimethylformamide was added dropwise, and the obtained mixture was stirred at 4 to 6 ° C for 30 minutes .  The solution obtained was suddenly stirred at −15 ° C. to a solution of 1.1 g of 7-amino-3- (4-nitrobenzoyl) oxymethyl-3-cephem-4-carboxylic acid and 3.5 g of trimethylsilylacetamide in 20 ml of dry ethyl acetate was added and the resulting mixture was stirred at -5 to -10 ° C for 2 hours. 

  The reaction mixture was adjusted to pH 7 to 7.5 under 0 C with a saturated aqueous sodium bicarbonate solution, stirred for 1 hour at pH 7 below 5 C, adjusted to pH 2.5 and filtered.  The organic layer in the filtrate was separated and 20 ml of water was added. 



  The mixture was adjusted to pH 6.5 with sodium bicarbonate.  The aqueous layer was separated and washed with diethyl ether.  The solvent remaining in the aqueous layer was removed by introducing nitrogen gas, and the aqueous layer was adjusted to pH 2.5 with 10% hydrochloric acid with ice cooling.  The precipitates were collected by filtration, washed with water and dried, giving 0.7 g of 7- [2 methoxyimino-2- (2-amino-1, 3-thiazol-4-yl) acetamido] -3- (4- nitrobenzoyl) oxymethyl-3-cephem-4-carboxylic acid (syn isomer), F.  151 to 163 C (dec. ), in the form of a pale yellow powder. 

 

   IR (Nujol) 3250-3350, 2500-2600, 1780, 1725, 1680, 1650, 1600, 1535, 1350 cm- '
NMR (d6-DMSO, 6) 9.68 (1H, d, J = 8Hz), 8.5 (4H, m), 7.28 (2H, s), 6.80 (1H, s), 5, 88 (1H, dd, J = 5.8Hz), 5.24 (1H, d, J = 5Hz), 5.20 (2H, ABq, J = 13Hz), 3.82 (3H, s), 3, 72 (2H, ABq, J = 18Hz). 



   The following compounds can also be obtained by the same method: (1) 7- [2-methoxyimino-2- (3-hydroxyphenyl) acetamidoj-cephalosporanic acid (Syn-Isomeres). 



   I. R. -Spectrum (Nujol) 3250, 1785, 1740, 1720cm '
N. M. R.  Spectrum (d6-DMSO, b) ppm 9.78 (1H, d, J = 8Hz)
6.86-7.36 (4H, m)
5.86 (1H, dd, J = 5.8Hz)
5.18 (1H, d, J = 5Hz)
4.84 (2H, ABq, J = 13Hz)
3.98 (3H, s)
3.54 (2H, ABq, J = 17Hz)
2.00 (3H, s) (2) sodium 7- [2-methoxyimino-2- (3-hydroxyphenyl) acetamido] cephalosporanate (Syn-Isomeres)
I. R. Spectrum (Nujol) 3250, 1765, 1730, 1665 mc-1
N. M. R. - spectrum (D2O, 8) ppm 6.83-7.13 (4H, m)
5.83 (1H, d, J, = 5Hz)
5.17 (1H, d, J = 5Hz)
4.82 (2H, ABq, J = 13Hz)
4.03 (3H, s)
3.50 (2H, ABq, J = 17Hz)
2.1 (3H, s) (3) 7- [2-methoxymino-2- {2- (2, 2, 2-trifluoroacetamido) 1,3-thiazole-4-} acetamido] cephalosporanic acid (Syn-Isomeres), F.  205 C (dec. ).    



   I. R.  Spectrum (Nujol) 3250, 1790, 1735, 1680, 1650 cm-1
N. M. R. Spectrum (d6-DMSO, 6) ppm 9.8 (1H, d, J = 8Hz)
7.55 (1H, s)
5.88 (1H, dd, J = 5.8Hz)
5.25 (1H, d, J = 5Hz)
4.8 (2H, ABq, J = 13Hz)
3.95 (3H, s)
3.59 (2H, broad s)
2.03 (3H, s) (4) 7- [2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] cephalosporanoic acid (Syn-Isomeres), F.  227 C (dec. )
I. R. Spectrum (Nujol) 3300-3350, 1780, 1740 1670 cm-1
N. M. R. Spectrum (d6-DMSO, µ) ppm 9.6 (1H, d, J = 8Hz)
6.8 (1H s)
5.8 (1H, dd, J = 5.8Hz)
5.2 (1H, d, J = 5Hz)
4.87 (2H, ABq, J = 13Hz)
3.89 (3H, s)
3.6 (2H, broad s)
2.08 (3H, s) (5) 7- [2-methoxyimino-2- (2-formamido-1,3-thiazol-4yl) acetamido] cephalosporanic acid (Syn-Isomeres). 



   I. R. - Spectrum (Nujol) 3280, 1785, 1740, 1700, 1650 cm-1
N. M. R. -Spectrum (d6-DMSO, 6) ppm 12.68 (1H, broad s)
9.68 (1H, d, J = 8Hz)
8.54 (1H, s)
7.45 (1H, s)
5.86 (1H, dd, J = 5.8Hz)
5.20 (1H, d, J = 5Hz) 4.90 (2H, ABq, J = 8Hz)
3.61 (3H, broad s)
2.06 (3H, s) (6) benzhydryl-7- [2-methoxymino-2- (2-aminothiazol-4yl) acetamido] -3-pivaloyloxymethyl-3-cephem-4-carboxylate (Syn-Isomeres)
I. R. Spectrum (Nujol):

   3300, 1780, 1725, 1680, 1530 cm-1
N. M. R. -Spectrum (d6-DMSO, µ) ppm 1.13 (9H, s)
3.62 (2H, broad s)
3.88 (3H, s) 4.86 (2H, ABq, J = 14Hz)
5.26 (1H, d, J = 5Hz)
5.96 (1H, d, d, J = 5 and 8Hz)
6.80 (1H, s)
6.98 (1H, s) 7.127.68 (10H, m)
9.73 (1H, d, J = 8Hz) (7) 7- [2-methoxymino-2- (2-aminothiazol-4-yl) acetamido] -3-pivaloyloxymethyl-3-cephem-4-carboxylic acid (Syn Isomeres ). 



   I. R.  (Nujol): 3300, 1780, 1720, 1670, 1540 cm-1. 



   (8) Benzhydryl 7- [2-methoxyimino-2- (2-aminothiazol-4 yl) acetamido] -3- (4-nitrobenzoyloxymethyl) -3 cephem-4-carboxylate (syn-isomer). 



   I. R.  (Nujol): 3300, 1780, 1720, 1670, 1600, 1520 cm-1. 



   N. M. R.  (d6-DMSO, 6): 3.43 (2H, broad s) 3.92 (3H, s) 5.08 (2H, ABq, J = 13Hz) 5.2 (1H, d, J = 5Hz) 6 , 00 (1H, dd, J = 5 and 8Hz) 6.83 (1H, s) 7.00 (1H, s) 7.10 # 7.80 (10H, m) 8.15 (2H, d, J = 9Hz) 8.38 (2H, d, J = 9Hz) 9.73 (1H, d, J = 8Hz) (9) 7- [2-isobutoxyimino-2- (2-amino-1, 3-thiazole- 4-yl) acetamido] cephalosporanic acid (Syn-Isomeres. 



   I. R.  (Nujol) 3400-3200, 1780, 1740, 1660, 1630, 1540 cm- ')
N. M. R.    (d6-DMSO, 8) 9.56 (1H, d, J = 8Hz, 6.72 (1H, s), 5.78 (1H, dd, J = 5.8Hz), 5.14 (1H, d , J = 5Hz) 4.83 (2H, ABq, J = 14Hz), 3.82 (2H, d, J = 7Hz), 3.54 (2H, ABq, J = 17Hz), 2.02 (3H, s), 1.98 (1H, m), 0.88 (6H, d, J = 7Hz) (10) 7- [2-methoxyimino-2- {2- (2, 2, 2-trifluoroacetamido) 1, 3-thiazol-4-yjacetamido] -3- (4-nitrobenzoyl) oxymethyl-3-cephem-4-carboxylic acid (Syn-Isomeres), pale yellow powder. 



   I. R.  (Nujol) 3200, 2500-2600, 1785, 1720, 1680, 1650, 1600, 1525, 1355 cm-l
N. M. R.    (d6-DMSO, 6) 9.80 (1H, d, J = 8Hz), 8.4 (4H, m), 7.60 (1H, s), 5.78 (1H, dd, J = 5, 8Hz) 5.25 (1H, d, J = 5Hz), 5.15 (2H, ABq, J = 13Hz), 3.94 (3H, s), 3.75 (2H, ABq, J = 18Hz) ( 11) 7- [2-Methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3-benzoyloxymethyl-3-cephem-4-carboxylic acid (Syn Isomeres). 



   I. R.  (Nujol) 3300, 1780, 1720, 1680 cm-1
9.63 (1H, d, J = 8Hz), 7.87-8.1 (2H, m), 7.48-7.75 (3H, m), 6.75 (1H, s), 5, 83 (1H, dd, J = 5.8Hz), 5.19 (1H, d, J = 5Hz), 5.15 (2H, ABq, J = 13Hz), 3.83 (3H, s), 3, 72 (2H, broad s) (12) 7- [2-methoxymino-2- (2-amino-1, 3-thiazol-4-yl) acetamido] -3-phenylacetoxymethyl-3-cephem-4-carboxylic acid (syn -Isomeres). 



   I. R.  (Nujol) 3350,3300, 1780, 1710, 1660, 1542, 1535, 1460, 1400, 1380, 1320,1280,1260,1240,1130,1115, 1065,1042,965,720 cm- '
N. M. R.  (d6-DMSO, µ) 7.33 (5H, s), 7.23 (2H, broad s), 6.78 (1H, s), 5.81 (1H, dd, J = 4.8Hz), 5.16 (1H, d, J = 4Hz), 4.78 and 5.06 (2H, ABq, J = 8Hz), 3.9 (3H, s), 3.73 (2H, s), 3, 5 (2H, broad s) (13) 7- [2-methoxymino-2- (2-amino-1, 3-thiazol-4-yl) acetamido] -3-hexanoyloxymethyl-3-cephem-4-carboxylic acid isomer)) . 



     IR (Nujol) 3350, 3300, 1780, 1700, 1660, 1535, 1460, 1400, 1375, 1340 1315, 1280, 1255, 1045 cm-1 NMR (d6-DMSO, µ) 9.63 (1 H, d, J = 8Hz), 7.24 (2H, broad s), 6.76 (1H.  s), 5.81 (111, dd, J = 4.8Hz), 5.17 (1H, d, J = 4Hz), 4.75 and 5.03 (2H, ABq, J = 12Hz), 3, 84 (3H, s), 3.45 and 3.67 (2H, ABq, J = 18Hz), 2.32 (2H, t, J = 8Hz, 1-1.7 (6H, m), 0.85 (3H, t, J = 3Hz) (14) 7- [2-methoxymino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (4-nitrobenzoyl) oxymethyl-3- cephem-4-carboxylic acid (syn-isomeres), pale yellow powder, F.  151-163 çC (dec. ). 



     IR (Nujol) 32503350,25002600, 1780, 1725, 1680, 1650, 1600, 1535, 1350 cm-1
NMR (d6-DMSO, µ) 9.68 (111, d, 3 = 8Hz), 8.5 (411, m), 7.28 (2H, s), 6.80 (1H, s), 5, 86 (1H, dd, J = 5.8Hz), 5.24 (1H, d, J = 5Hz, 5.20 (2H, ABq, J = 13Hz), 3.82 (3H, s), 3.72 (2H, ABq, J = 18Hz) (15) 7- [2-methoxymino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3-phenylacetoxymethyl-3-cephem-4-carboxylic acid (syn-isomeres).    



   IR (Nujol) 3350,3300,1780,1710,1660,1542,1535,1460,1400,1380, 1320, 1280, 1260, 1240, 1130, 1115, 1065, 1042, 965, 720 cm-1
NMR (d6-DMSO, 6) 7.33 (5H, s), 7.23 (2H, broad s), 6.78 (1H, s), 5.81 (1H, dd, J = 4.8Hz) , 5.16 (1H, d, J = 4Hz), 4.78 and 5.06 (2H, ABq, J = 8Hz), 3.9 (3H, s), 3.73 (2H, s), 3rd , 5 (2H, broad s) (16) 7- [2-methoxymino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3-hexanoyloxymethyl-3-cephem-4-carboxylic acid ( syn isomeres). 



   IR (Nujol) 3350.3300, 1780, 1700, 1660, 1535, 1460, 1400, 1375, 1340, 1315, 1280, 1255, 1045cm- '
NMR (d6-DMSO, b) 9.63 (1H, d, J = 8Hz), 7.24 (2H, broad s), 6.76 (1H, s), 5.81 (1H, dd, J = 4.8Hz), 5.17 (1H, d, J = 4Hz), 4.75 and 5.03 (2H, ABq, J = 12Hz), 3.84 (3H, s), 3.45 and 3, 67 (2H, ABq, J = 18Hz), 2.32 (2H, t, J = 8Hz), 1-1.7 (6H, m), 0.85 (3H, t, J = 3Hz) (16) 7- [2- (4-Fluorobenzolyoxymino) -2- (2-aminothiazol-4yl) -acetamido] -cephalosporanoic acid (syn isomer), melting point 185 to 192 C (decomposition). 



   I. R.  (Nujol): 3380, 3250, 1780, 1700, 1650 cm-1. 



   N. M. R.    (DMSO-d6, 8): 2.02 (3H, s), 3.53 (2H, m), 4.84 (2H, ABq, J = 13Hz), 5.13 (2H, s), 5, 40 (1H, d, J = 4Hz), 5.79 (1H, dd, J = 4 and 8Hz), 6.73 (1H, s), 6.96-7.63 (4H, m), 9, 62 (1H, d, j = 8Hz). 



   (18) 7- [2- (3,4-dichlorobenzyloxymino) -2- (2-aminothi azol-4-yl) acetamido] cephalosporanic acid (syn isomer), melting point 200 to 205 C (decomposition). 



   I. R.  (Nujol): 1730, 1640, 1600, 1230, 1020 cm-1
N. M. R.  (DMSO-d6, µ): 2.00 (3H, s), 3.30 (2H, ABq, J = 18Hz), 4.68-5.12 (5H, m), 5.60 (1H, dd , J = 6 and 8Hz), 6.72 (1H, s,), 7.32-7.64 (3H, m), 9.60 (1H, d, J = 8Hz). 



  Examples according to the invention
Example 8
A suspension of 2.76 g of 7- [2-methoxyimino-2- ± 2- (2,2,2-trifluoroacetamido) -1,3-thiazol-4-yl] -acetamido] cephalosporanoic acid (Syn-Isomeres) and 0 , 63 g of 4-methyl-4H-1,2,4-triazole-3-thiol in 50 ml of a pH 6.4 phosphate buffer solution was adjusted to pH 6.4 with sodium bicarbonate and stirred at 65 to 70 C for 6 hours.  The reaction mixture was cooled and ethyl acetate was added.  The mixture was adjusted to pH 5 with 10% hydrochloric acid and washed with ethyl acetate. 



  The aqueous layer was treated with activated carbon and adjusted to pH 2.7 with 10% hydrochloric acid with stirring and with ice cooling.  The precipitated crystals were collected by filtration, washed with cold water and dried, whereby 0.7 g of 7- [2-methoxyimino-2 (2-amino-1,3-thiazol-4-yl) acetamido] -3- ( 4-methyl-4H-1,2,4-triazol-3-yl) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres), F.  185 C (dec. ), received. 

 

   IR spectrum (Nujol) 3150-3350, 1770, 1710, 1660, 1630 cm- '
N. M. R. Spectrum (d6-DMSO, #) ppm 9.61 (1H, d, J = 8Hz)
8.69 (1H, s)
6.73 (1H, s)
5.72 (1H, dd, J = 4.8Hz)
5.1 (1H, d, J = 4Hz)
4.1 (2H, ABq, J = 13Hz)
3.87 (3H, s)
3.59 (3H, s)
3.65 (2H, broad s)
Example 9
The compounds shown below were obtained in a similar manner as in Example 8. 



   (1) 7- [2-Methoxyimino-2- (2-methyl-, 3-thiazol-4-yl) acet amidoj-3- (1-methyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem -4- carboxylic acid (syn isomer)
I. R. - Spectrum (Nujol) 1780, 1710, 1675 cm-1
N. M. R. Spectrum (d6-DMSO, â) ppm 9.65 (1H, d, J = 10Hz)
7.66 (1H, s)
5.81 (1H, dd, J = 5, 10Hz)
5.15 (1H, d, J = 5Hz) 4.31 (2H, ABq, J = 13Hz)
3.93 (3H, s)
3.90 (3H, s) 3.70 (2H, ABq, J = 16Hz)
2.65 (3H, s) (2) 7- [2-methoxyimino-2- (2-mesylimino-3-methyl-2,3-dihydro-1,3-thiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer). 



   I. R. Spectrum (Nujol) 3250, 1780, 1718, 1675 cm-1
N. M. R. Spectrum (d6-DMSO, #) ppm 9.80 (1H, d, J = 8Hz)
7.08 (1H, s)
5.80 (1H, dd, J = 5.8 Hz)
5.18 (1H, d, J = 5 Hz) 4.34 (2H, ABq, J = 13Hz)
3.99 (3H, s)
3.96 (3H, s) 3.72 (2H, ABq, J = 17Hz)
3.66 (3H, s)
2.98 (3H, s) (3) 7- [2-methoxyimino-2- (2-mesylamino-1,3-thiazol-4- yl) -acetamidoj-3- (1-methyl-1 H-tetrazole- 5-yl) thiomethyl-3-cephem-4-carboxylic acid, (Syn-Isomeres)
I. R. 

  Spectrum (Nujol) 3300-3150, 1780, 1670 cm-1
N. M. R. Spectrum (D6-DMSO, # = ppm 9.84 (1H, d, J = 8Hz)
6.97 (1H, s)
5.76 (1H, dd, J = 5, 8Hz)
5.12 (1H, d, J = 5Hz)
4.33 (2H, ABq, J = 13Hz)
3.93 (6H, s) 3.74 (2H, ABq, J = 17Hz)
2.96 (3H, s) (4) 7- [2-methoxyimino-2- (2-oxo-2,3-dihydro-1,3-thiazol 4-yl) acetamido] -3- (1-methyl- 1 H-tetrazol-5-yl) thiomethyl-3cephem-4-carboxylic acid (syn isomer). 



   I. R. Spectrum (Nujol)
1780, 1665 cm-1
N. M. R. Spectrum (d6-DMSO, a) ppm 11.67 (1H, s)
9.83 (1H, d, J = 8Hz)
6.61 (1H, s)
5.80 (1H, dd, J = 5.5, 8 Hz)
5.17 (1H, d, J = 5.5 Hz)
4.37 (2H, broad s)
4.00 (3H, s)
3.96 (3H, s)
3.75 (2H, broad) (5) 7- [2-Alloyloxyimino-2- (2-mesylamino-1,3-thiazol-4-yl) acetamido] 3- (1-methyl-1 H-tetrazole-5 -yl) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres). 



   I. R. -Spectrum (Nujol) 3100-3300, 1780, 1720, 1675 cm-1
N. M. R. Spectrum (d6-DMSO, â) ppm 9.90 (1H, d, J = 8Hz)
7.00 (1H, s)
6.07 - 5.63 (2H, m)
5.43 (2H, d, J = 8Hz)
5.18 (1H, d, J = 8.5 Hz)
4.70 (2H, d, J = 5Hz)
4.37 (2H, broad s)
3.98 (3H, s)
3.75 (2H, broad s)
3.00 (3H, s) (6) 7- [2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazole-5 -yl) thiomethyl) -3-cephem-4carboxylic acid (Syn-Isomeres)
I. R. - Spectrum (Nujol) 3200, 1765, 1600 cm-1
N. M. R. Spectrum (d6-DMSO, â) ppm 9.51 (1H, d, J = 8.5Hz)
7.22 (2H, broad)
6.72 (1H, s)
5.59 (1H, dd, J = 8.5 Hz)
5.00 (1H, d, J = 5 Hz) 4.35 (2H, ABq, J = 12Hz)
3.90 (3H, s) 3.81 (311, s)
3.55 (2H, ABq,

   J = 18 Hz) (7) 7- [2-methoxyimino-2- [2-amino-1,3-thiazol-4-yl) acetamido] -3- (5-methyl-1,3,4-thiadialzol-2 -yl) thiomethyl-3cephem-4-carboxylic acid (Syn-Isomeres). 



   I. R. - Spectrum (Nujol) 3400-3150, 1770, 1670, 1625 cm-1
N. M. R. Spectrum (d6-DMSO, â) ppm 9.66 (1H, d, J = 8Hz)
7.34 (2H, broad s)
6.76 (1H, s)
5.78 (2H, dd, J = 5.8 Hz)
5.16 (1H, d, J = 5Hz) 4.40 (2H, ABq, J = 14Hz)
3.85 (3H, s)
3.70 (2H, ABq, J = 17Hz)
2.68 (3H, s) (8) 7- [2-allyloxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (1-methyl-1 H- tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres)
I. R. - Spectrum (Nujol) 3100-3400, 1775, 1660, 1625 cm-1
N. M. R. Spectrum (d6-DMSO, ô) ppm 9.70 (1H, d, J = 8Hz)
6.80 (1H, s)
6.30-5. 60 (2H, m)
5.24 (2H, dd, J = 8, 16Hz)
5.15 (1H, d, J = 5Hz)
4.63 (2H, d, J = 5Hz)
4.32 (2H, ABq, J = 12Hz)
3.94 (3H, s)
3.70 (2H, ABq,

   J = 17 Hz) (9) 7- [2-methoxyimino-2- (2-formamido-1,3-thiazol-4-yl) acetamido] -2- (1,3,4-thiadiazol-2-yl) thiomethyl -3-cephem4-carboxylic acid (Syn-Isomeres), F.  145-147 C (dec. ). 



   I. R. - Spectrum (Nujol) 3150-3400, 1780, 1725, 1690, 1640 cm-1
N. M. R. Spectrum (d6-DMSO, #) ppm 12.58 (1H, broad s)
9.70 (1H, d, J = 8Hz)
9.58 (1H, s)
8.50 (1H, s)
7.40 (1H, s)
5.82 (1H, dd, J = 5.8 Hz)
5.17 (1H, d, J = 5 Hz)
4.43 (2H, ABq, J = 13Hz) 3.88 (3H, s)
3.70 (2H, broad s) (10) 7- [2-methoxyimino-2- (2-acetamido-1,3-thiazol4-yl) acetamido] 3- (a-methyl-1H-tetrazole-5-xl ) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres), F. 

   171-173 C (dec. )
I. R. Spectrum (Nujol) 3500, 3250, 1780, 1670 cm-1
N. M. R. Spectrum (d6-DMSO, ô) ppm 9.65 (1H, d, J = 8Hz)
7.3 (1H, s)
5.8 (1H, dd, J = 5.8Hz)
5.15 (1H, d, J = 5 Hz)
4.35 (2H, broad s)
3.97 (3H, s) 3.9 (3H, s)
3.75 (2H, broad s)
2.15 (3H, s) (11) 7- [2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2 -yl) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres), F.  172-175 C.
I. R. - Spectrum (Nujol) 3300, 1770, 1665 cm-1
N. M. R. Spectrum (d6-DMSO, o) ppm 9.80 (1H, d, J = 8Hz)
9.63 (1H, s)
6.95 (1H, s)
6.8 (2H, m)
5.82 (1H, dd, J = 5.8 Hz)
5.22 (1H, d, J = 5 Hz)
4.48 (2H, ABq, J = 15 Hz)
3.97 (3H, s) 3.76 (2H, ABq, J = 18Hz) (12) 7- [2-methoxyimino-2- (2-amino-1, 3-thiazol-4-y1) acet.    



      amido] 3- [1 - (2-dimethylaminoethyl) -1 H-tetrazol-5-yl] thio-methyl-3-cephem-4-carboxylic acid (syn isomer). 



     I. R. -Spectrum (Nujol) 1765 cm- '
N, M, R, spectrum (d6-DMSO, #) ppm 9.56 (1H, d, J = 8Hz)
6.75 (1H, s)
5.75 (1H, m)
5.10 (1H, d, J = 4 Hz)
4.58 (2H, broad s)
4.32 (2H, broad s)
3.82 (3H, s)
3.68 (2H, broad s)
3.20 (2H, broad s) 2.50 (6H, s) (13) 7- [2-methoxyimino-2- (2-ethoxycarbonylamino-1,3 thiazol-4-yl) acetamido] -3- (1st , 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres)
I. R. -Spekrum (Nujol) 3200.1775.1720.1680.1660cm- '
N. M. R. - spectrum (d6-DMSO, ô) ppm 11.9 (111, m)
9. 70 (1H, d, J = 10Hz)
9.55 (1H, s)
7.31 (1H, s)
5.80 (1H, dd, J = 5.10Hz) 4.44 (2H, ABq, J = 1 6Hz)
4.22 (2H, q, J = 7Hz)
3.89 (3H,

   s) 3.72 (2H, ABq, J = 16Hz)
1.23 (3H, t, J = 7HZ) (14) 7- [2-methoxyimino-2- (2-formamido-1,3-thiazol-4 y1) acetamidoj-3- (1-methyl-1 H- tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres)
I. R. - Spectrum (Nujol) 3200-3300, 2600, 1780, 1720, 1690, 1675 cm-1
N. M. R. Spectrum (d6-DMSO, ô) ppm 12.60 (1H wide s)
9.70 (1H, d, J = 8Hz)
8.50 (1H, s)
7.44 (1H, s)
5.88 (1H, dd, J = 5.8Hz)
5.19 (1H, d, J = 5 Hz)
4.25 (2H, ABq, J = 13Hz)
3.95 (3H, s)
3.85 (3H, s) 3.65 (2H, ABq, J = 18Hz) (15) 7- [2-methoxyimino-2- (3-hydroxyphenyl) acetamido] 3- (1-methyl-1 H-tetrazole -5-yl) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres). 



   I. R. Spectrum (Nujol) 3250, 1770, 1725, 1670 cm-1
N. M. R. Spectrum (d6-DMSO, o) ppm 9.76 (1H, d, J = 8Hz)
6.70-7.40 (4H, m)
5.86 (1H, dd, J = 5, 8Hz)
5.18 (1H, d, J = 5 Hz) 4.34 (2H, ABq, J = 13Hz)
3.92 (6H, s) 3.72 (2H, ABq, J = 17Hz) (16) 7- [2-t-Butoxycarbonylmethoxyimino-2- (3-chloro4-hydroxyphenyl) acetamido] -3 (1 -methyl- 1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres), powder. 



   (17) 7- [2-Carboxy-methoxyimino-2- (3-chloro-4-hydroxyphenyl) acetamido-3- (1-methyl-1H-tetrazol-5-yxl) thiomethyl3-cephem-4-carboxylic acid (syn- Isomeres), F.  145-148 C (dec. )
I. R. - Spectrum (Nujol) 3400, 3200-3300, 2500-2600, 1780, 1720, 1670, 1600 cm
N. M. R. Spectrum (d6-DMSO, ô) ppm 9.70 (1H, d, J = 8Hz)
7.50 (1H, d, J = 2Hz)
7.45 (1H, dd, J = 2.8Hz)
7.10 (1H, d, J = 8Hz)
5.90 (1H, q, J = 5Hz)
5.22 (1H, d, J = 5Hz)
4.70 (2H, s) 4.35 (2H, ABq, J = 13Hz)
3.95 (3H, s) 3.75 (2H, ABq, J = 18Hz) (18) 7- [2- (1-t-butoxycarbonylethoxyimino) -2- (3-chloro4-hydroxyphenyl) acetamido] -3 - (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres), powder. 

 

   (19) 7- [2- (1-Carboxyethoxyimino) -2- (3-chloro-4-hydroxyphenyl) acetamido] -3 - (1-methyl-1-tetrazol-5-yl) thiomethyl-3-cephem-4 -carboxylic acid (Syn-Isomeres) 147-151 C (dec. )
I. R. - Spectrum (Nujol) 3500, 3250, 2500-2600, 1780, 1730, 1660, 1630, 1600 cm- 'N. M. R. Spectrum (d6-DMSO, ô) ppm 9.62 (1H, d, J = 8Hz)
7.46 (1H, d, J = 2Hz)
7.34 (1H, dd, J = 2.8 Hz)
7.04 (1H, d, J = 8Hz)
5.90 (1H, q, J = 5Hz)
5.22 (1H, d, J = 5Hz)
4.73 (1H, q, J = 6, Hz) 4.33 (2H, ABq, J = 13Hz)
4.00 (3H, s) 3.73 (2H, ABq, J = 18Hz)
1.37 (3H, d, J = 6Hz) (20) 7- [2-methoxyimino-2- (3-hydroxyphenyl) acetamido] 3- (4H-1,2,4-triazol-3-yl) thiomethyl- 3-cephem-4-carboxylic acid (Syn-Isomeres). 



   I. R. -Spectrum (Nujol) 3250, 1775, 1710, 1665cm '
N. M. R. Spectrum (d6-DMSO, ô) ppm 9.67 (1H, d, J = 8Hz)
8.40 (1H, s)
6.70 - 7.43 (4H, m)
5.82 (1H, dd, J = 5, 8Hz)
5.13 (1H, d, J = 5Hz) 4.18 (2H, ABq, J = 13Hz)
3.90 (3H, s)
3.67 (2H, broad s) (21) 7- [2-methoxyimino-2- (3-hydroxyphenyl) acetamido] 3- (1-, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem -4-carboxylic acid (syn isomer). 



   I. R. Spectrum (Nujol) 3250, 1780, 1720, 1670 cm-1. 



   N. M. R. Spectrum (d6-DMSO, ô) ppm 9.78 (1H, d, J = 8Hz)
9.55 (1H, s)
6.70-7.40 (4H, m)
5.89 (1H, dd, J = 5, 8Hz)
5.22 (1H, d, J = 5Hz) 4.46 (2H, ABq, J = 13Hz)
3.92 (3H, s) 3.76 (2H, ABq, J = 18Hz) (22) 7- [2-methoxyimino-2- (3-hydroxyphenyl) acetamido] 3- (5-methyl-1,3, 4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer). 



   I. R. Spectrum (Nujol) 3250, 1780, 1670 cm-1
N. M. R. Spectrum (d6-DMSO, 8 ppm 9.72 (1H, d, J = 8Hz)
6.62-7.40 (4H, m)
5.94 (1H, dd, J = 5, 8Hz)
5.18 (1H, d, J = 5Hz)
4.18 (2H, ABq, J = 13Hz)
3.89 (3H, s) 3.70 (2H, ABq, J = 17Hz)
2.65 (3H, s) (23) 7- [2-methoxyimino-2- (3-methoxyphenyl) acetamido] 3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4- carboxylic acid (syn isomer). 



   I. R. Spectrum (Nujol) 3250, 1780, 1720, 1670 cm-1. 



   N. M. R. Spectrum (d6-DMSO, ô) ppm 9.78 (1H, d, J = 8Hz)
6.95-7.54 (4H, m)
5.94 (1H, dd, J = 5, 8Hz)
5.18 (1H, d, J = 5Hz)
4.12 (2H, ABq, J = 13Hz)
3.92 (6H, s)
3.76 (3H, s) 3.72 (2H, ABq, J = 18Hz) (24) 7- [2-methoxyimino-2- (4-hydroxyphenyl) acetamido] -3- (1-methyl-1H-tetrazole -5-yl) -thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres). 



   I. R. - Spectrum (Nujol) 3250.1780, 1720, 1670 cm-1
N. M. R. Spectrum (d6-DMSO, ô) ppm 9.70 (1H, d, J = 8Hz)
7.44 (2H, d, J = 8Hz)
6.48 (2H, d, J = 8Hz), 5.86 (1H, dd, J = 5, 8Hz)
5.18 (1H, d, J = 5Hz) 4.34 (2H, ABq, J = 13Hz)
3.93 (3H, s)
3.87 (3H, s) 3.74 (2H, ABq, J = 18Hz) (25) 7-] 2-methoxyimino-2- (3-chloro-4-hydroxyphenyl) acetamido] -3- (1-methyl -1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres), F.  145-148 C (dec. ). 



   I. R. - Spectrum (Nujol) 3500, 3250, 2500-2600, 1780, 1720, 1655,, 1625, 1600 cm-1
N. M. R. Spectrum (d6-DMSO, ô) ppm 10.80 (1H, broad s)
9.68 (1H, d, J = 2 Hz)
7.46 (1H, d, J = 2Hz)
7.32 (1H, q, J = 2.8 Hz)
7.00 (1H, d, J = 8Hz)
5.80 (1H, q, J = 5Hz)
5.16 (1H, d, J = 5Hz) 4.28 (2H, ABq, J = 13Hz)
3.92 (3H, s)
3.87 (3H, s)
3.72 (2H, ABq, J = 18Hz) (26) 7- [2-methoxyimino-2- [3-chloro-4methoxyphenyl) acetamido] -3- (1-methyl-lH-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres), F. 

   143-145 C (dec. )
I. R. -Spectrum (Nujol) 3300, 2500-2600, 1785, 1730, 1670, 1630, 1600cm- '
N. M. R. Spectrum (d6-DMSO, ô) ppm 9.76 (1H, d, J = 8Hz)
7.56 (1H, d, J = 2Hz)
7.48 (1H, dd, J = 2.8Hz)
7.22 (1H, d, J = 8Hz)
5.84 (1H, q, J = 5Hz)
5.18 (1H, d, J = 5Hz)
4.27 (2H, ABq, J = 13Hz)
3.90 (6H, s)
3.88 (3H, s)
3.70 (2H, ABq, J = 18Hz) (27) 7- [2-methoxyimino-2- (3-nitro-4-hydroxyphenyl) acetamido] -3- (l-methyl-1H-tetrazol-5-yl ) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres), F. 

   149-152 C (dec. )
I. R. -Spectrum (Nujol) 3400-3450, 3200, 2500-2600, 1780, 1720, 1660, 1620, I600, 1535, 1350 cm- '
N. M. R. Spectrum (D6-DMSO, ô) ppm 9.72 (1H, d, J = 8Hz)
7.97 (1H, d, J = 2H)
7.72 (1H, dd, J = 2.8 Hz)
7.21 (1H, d, J = 8Hz)
5.82 (1H, q, J = 5Hz)
5.16 (1H, d, J = 5Hz)
4.3 (2H, ABq, J = 13Hz)
3.92 (3H, s)
3.87 (3H, s) 3.72 (2H, ABq, J = 18Hz) ('8) 7- [2-allyloxyimino-2- (3-chloro-4-hydroxyphenyl) acetamido] -3- (1- methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres), F.  163-165 C (dec. )
I. R. 

  Spectrum (NUjol) 3200-3300, 2500-2600, 1780, 1720, 1670, 1600 cm-1
N. M. R. Spectrum (d6-DMSO, ô) ppm 9.70 (1H, d, J = 8Hz)
7.40 (1H, d, J = 2Hz)
7.30 (1H, dd, J = 2.8Hz)
6.95 (1H, d, J = 8Hz)
5.80 (2H, m)
5.30 (2H, d, J = 8Hz)
5.10 (1H, d, J = 5Hz)
4.60 (2H, d, J = 5Hz)
4.27 (2H, ABq, J = 13Hz)
3.85 (3H, s)
3.65 (2H, ABq, J = 18Hz) (29) 7- [2-allylloxyimino-2- (3-hydroxyphenyl) acetamido] 3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3- cephem-4-carboxylic acid (Syn-Isomeres. ) F. 

   149-152 C (dec. ) l. R. -Spectrum (Nujol) 3250-3350, 2500-2600, 1780, 1730, 1670, 1650, 1600 cm-1
N. M. R. Spectrum (d6-DMSO, ô) ppm 9.70 (1H, d, J = 8Hz)
7.2-6.8 (4H, m)
6.1-5.8 (2H, m)
5.35 (2H, d, J = 8Hz)
5.17 (1H, d, J = 5Hz)
4.7 (2H, d, J = 5Hz)
4.17 (2H, ABq, J = 13Hz)
3.93 (3H, s)
3.75 (2H, ABq, J = 18Hz) (30) 7- [2- (3-hydroxy-4-bromobenzyloxyimino) -2- (4hydroxyphenyl) acetamido] -3- (1-methyl-1 H-tetrazole- 5-yl) - thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres), powder
I. R. - Spectrum (Nujol) 3150.1780, 1720, 1670 cm-1
N. M. R. Spectrum (d6-DMSO, ô) ppm 9.60 (1H, d, = 8Hz)
6.72-7.52 (7H, m)
5.80 (1H, dd, J = 4.8Hz) 5.15 (111, d, J = 4Hz)
5.00 (2H, s)
4.28 (2H, ABq, J = 13Hz)
3.90 (3H, s)
3.65 (2H, ABq,

   J = 18Hz) (31) 7- [2- (2-thienylmethoxyimino) -2- (4-hydroxyphenyl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl9thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres), powder. 



   I. R. Spectrum (Nujol) 3200-3300, 1780, 1720, 1660 cm-1
N. M. R. - spectrum (d6-DMSO, 8) ppm 9.77 (1H, d, J = 8Hz)
6.7-7.7 (7H, m)
5.83 (1H, dd, J = 5, 8Hz)
5.29 (2H, s)
5.15 (1H, d, J = 5Hz)
4.3 (2H, ABq, J = 13Hz)
3.92 (3H, s)
3.72 (2H, ABq, J = 18 Hz) (32) 7- [2-ethoxyimino-2- (3-chloro-4-hydroxyphenyl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl ) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres), colorless powder, F. 



  153-156 C (dec. ). 



   I. R. - Spectrum (Nujol) 3450, 3250, 2500-2600, 1780, 1725, 1665, 1630, 1600 cm-1
N. M. R.  Spectrum (d1-DMSO, ô) ppm9.71 (1H, d, J = 8Hz)
7.50 (1H, d, J = 2Hz)
7.36 (1H, dd, J = 2.8Hz)
7.03 (1H, d, J = 8Hz)
5.83 (1H, q, J = 5Hz)
5.17 (1H, d, J = 5Hz) 4.33 (2H, ABq, J = 13Hz)
4.17 (2H, q, J = 7Hz)
3.97 (3H, s)
3.73 (2H, ABq, J = 18Hz)
1.25 (3H, t, J = 7Hz) (33) 7- [2-allyloxyimino-2- (3-methoxyphenyl) acetamido] 3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3- cephem-4-carboxylic acid (Syn-Isomeres), powder, F. 

   135-138 C (dec. )
I. R. -Spectrum (Nujol) 3300.2600.1785.1730.1670.1645.1600cm- '
N. M. R. Spectrum (d6-DMSO, ô) ppm 9.82 (1H, d, J = 8Hz)
7.0-7.45 (4H, m)
5.8-6.2 (2H, m)
5.36 (2H, t, J = 10Hz)
5.21 (1H, d, J = 5Hz)
4.72 (2H, d, J = 5Hz) 4.36 (2H, ABq, J = 13Hz)
3.95 (3H, s) 3.91 (311, s)
3.87 (2H, ABq, J = 18 Hz) (34) 7- [2-ethoxyimino-2- (3-hydroxyphenyl) acetamido] -3 (1-methyl-1 H-tetrazol-5-y1) thiomethyl-3 -cephem-4-carbon acid (Syn-Isomeres), yellow powder, F. 

   145-148 C (dec. )
I. R. - Spectrum (Nujol) 3450, 3250, 2500-2600, 1775, 1720, 1665, 1600 cm-1
N. M. R. Spectrum (d6-DMSO, o) ppm 9.70 (1H, d, J = 8Hz)
6.8-7.4 (4H, m)
5.90 (1H, q, J = 5Hz)
5.20 (1H, d, J = 5 Hz) 4.36 (2H, ABq, J = I3Hz)
4.20 (2H, q, J = 7Hz)
4.00 (3H, s) 3.76 (2H, ABq, J = 18Hz)
1.33 (3H, t, J = 7Hz) (35) 7- [2-ethoxyimino-2- (3-methoxyphenyl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3 -cephem-4-carboxylic acid (Syn-Isomeres), pale yellow powder, F.  140-143 C (dec. ). 

 

   I. R. - Spectrum (Nujol) 3300, 2500-2600, 1785, 1730, 1670, 1630, 1600 cm-1
N. M. R. Spectrum (d6-DMSO, ô) ppm 9.71 (1H, d, J = 8Hz)
6.9-7.5 (4H, m)
5.90 (1H, q, J = 5Hz) 5, 17 (1H, d, J = 5Hz) 433 (2H, ABq, J = 13Hz)
4.20 (2H, q, J = 7Hz)
3.95 (3H, s)
3.85 (3H, s) 3.75 (2H, ABq, J = 18Hz)
1.30 (3H, t, J = 7Hz) (36) 7- [2-allyloxyimino-2- (3-chloro-4-methoxyphenyl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl ) thiomethyl-3-ce phem-4-carboxylic acid (Syn-Isomeres), pale yellow powder, F. 



  153-156 C (dec. )
I. R. - Spectrum (Nujol) 3250, 2600, 1780, 1720, 1670, 1645, 1630, 1600 cm-1
N. M. R. Spectrum (d6-DMSO, ô) ppm 9.65 (1H, d, J = 8Hz)
7.27 (1H, d, J = 2Hz)
7.20 (1H, dd, J = 2.8Hz)
7.09 (1H, d, J = 8Hz)
5.85-6.15 (2H, m)
5.15 (2H, t, 9Hz)
5.05 (1H, d, J = 5Hz)
4.60 (2H, d, J = 5Hz)
41.5 (2H, ABq, J = 13Hz)
3.95 (3H, s)
3.90 (3H, s) 3.47 (2H, ABq, J = 18 Hz) (37) 7- [2-phenylthiomethoxyimino-2- (3-hydroxyphenyl) acetamido] 3- (l-methyl-l H-tetrazole -5-yl) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres). 



   I. R. -Spectrum (Nujol) 3300, 1760, 1660 1600, 1580, 1520, cm- '
N. M. R. Spectrum (d6-DMSO, oo) ppm 9.7 (1H, d, J = 8Hz)
7.7-6.7 (9H, m)
5.8-5.4 (3H, broad s)
5.06 (1H, d, J = 5Hz)
4.33 (2H, broad s)
3.9 (3H, s)
3.56 (2H, broad s) (38) 7- [2-methoxyimino-2- (3-mesylaminophenyl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem- 4-carboxylic acid (syn isomer), F. 

   155 C (dec. )
I. R. -Spectrum (Nujol) 3300.1780, 1730, 1670cm- '
N. M. R. Spectrum (d6-DMSO, ô) ppm 9.98 (1H, s)
9.81 (1H, d, J = 9Hz)
9.62 (1H, s)
5.90 (1H, dd, J = 5.9Hz)
5.24 (1H, d, J = 5Hz) 4.49 (2H, ABq, J = 14Hz)
3.98 (311, s)
3.77 (2H, broad s)
2.96 (3H, s) (39) 7- [2-methoxyimino-2- [3-carbamoyloxyphenyl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem -4-carboxylic acid (syn isomer). 



   I. R. - Spectrum (Nujol) 3450, 3300, 3200, 1780, 1725, 1670, 1620, 1590, 1520 cm-1
N. M. R. Spectrum (d6-DMSO, ô) ppm 9.77 (1H, d, J = 7Hz)
7.6-6.8 (6H, m)
5.83 (1H, dd, J = 4.7Hz)
5.17 (1H, d, J = 4Hz) 4.31 (2H, ABq, J = 14Hz) 3.96 (611, s)
3.72 (2H, broad s) (40) 7- [2-methoxyimino-2- (3-carbamoyloxyphenyl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem- 4-carboxylic acid (Syn-Isomeres)
I. R. Spectrum (Nujol) 3250, 1780, 1735, 1675 cm-1
N. M. R. Spectrum (d6-DMSO, ô) ppm 9.81 (1H, d, J = 8Hz)
9.62 (1H, s)
6.7-7.58 (4H, m)
5.8 (1H, dd, J = 5.8Hz)
5.2 (1H, d, J = 5Hz)
4,25,4,63 (2H, ABq, J = 14Hz)
3.9 (3H, s)
3.7 (2H, broad s) (41) 7- [2-methoxyimino-2- (3-acetoxyphenyl) acetamido] 3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4 -carboxylic acid (Syn-Isomeres). 



   I. R. - Spectrum (Nujol) 3250, 1780, 1740, 1720, 1680 cm-1
N. M. R. Spectrum (d6-DMSO, ô) ppm 9.86 (1H, d, J = 8Hz)
9.61 (1H, s)
7.00-7.65 (4H, m)
5.84 (1H, dd, J = 5.8Hz)
5.2 (1H, d, J = 5Hz) 4,254.63 (2H, ABq, J = 14Hz)
3.92 (3H, s)
3.53, 3.86 (2H, ABq, J = 19Hz)
2,3 (3H, s) (42) 7- [2- (3-phenylallyloxyimino) -2- (3-hydroxyphenyl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3 -cephem-4-carboxylic acid (Syn-Isomeres) F. 

   138-142 C (dec. )
I. R. -Spectrum (Nujol) 3300-3400, 2600, 1780, 1720, 1665, 1600 cm- '
N. M. R. Spectrum (d6-DMSO, ô) ppm 9.80 (1H, d, J = 8Hz)
6.4-7.4 (11H, m)
5.85 (1H, dd, J = 5.8 Hz
5.20 (1H, d, J = 5Hz)
4.83 (2H, d, J = 5Hz)
4.32 (2H, ABq, J = 15Hz)
3.95 (3H, s) 3.68 (2H, ABq, J = 18Hz) (43) 7- [2-methoxyimino-2- (4-dimethylaminophenyl) acet amidoj-3- (1-methyl- 1 H- tetrazol-5-yl) thiomethyl-3-cephem-4carboxylic acid (Syn-Isomeres), F. 

   88 C (dec. )
I. R. -Spectrum (Nujol) 3250.1780.1730.1680, 1610cm-1
N. M. R. Spectrum (d6-DMSO, o) ppm 9.63 (1H, d, J = 8Hz)
7.40 (2H, d, J = 8Hz)
6.73 (2H, d, J = 8Hz)
5.83 (1H, dd, J = 5.8Hz)
5.17 (1H, d, J = 5Hz)
4.33 (2H, ABq, J = 13Hz)
3.97 (3H, s)
3.87 (3H, s)
3.73 (2H, broad s)
3.00 (6H, s) (44) 7- [2-methoxyimino-2- (3-hydroxyphenyl) acetamido] 3- [1- (2-dimethylaminoethyl) -1 H-tetrazol-5-yl] thiomethyl-3cephem -4-carboxylic acid (Syn-Isomeres)
I. R. - Spectrum (Nujol) 1765 cm-1
N. M. R. Spectrum (d6-DMSO, ô) ppm 9.67 (1H, d, J = 9Hz)
6.72-7.36 (4H, m)
5.78 (1H, dd, J = 5.9 Hz)
5.12 (1H, d, J = 5 Hz)
4.55 (2H, broad s)
4.30 (2H, broad s)
3.90 (3H, s)
3.40-3.80 (2H, m)
3.14 (2H, broad s)
2.48 (6H,

   s) (45) -7- [2- [2- (2-hydroxyphenoxy) ethoxyimino] -2- (3hydroxyphenyl) acetamido] -3- (1-methyl 1H-tetrazol-5-yl) thiomethyl-3-cephem -4-carboxylic acid (Syn-Isomeres)
I. R. - Spectrum (Nujol) 3270, 1780, 1725, 1670, 1560 cm-1
N. M. R. - spectrum (d6-DMSO, ô) ppm 6.5-7.4 (8H, m)
5.86 (1H, dd, J = 5.8Hz)
5.14 (1H, d, J = 5Hz)
4.0-4.6 (6H, m)
3.92 (3H, s) 3.52, 3.70 (2H, ABq, J = 7Hz)
Example 10
The following compounds were prepared in a manner similar to Examples 8 and 9: (1) 7- [2-isopropoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1,3,4- thiadiazol-2-yl) thiomethyl-3-cephem-4carboxylic acid (Syn-Isomeres). 



   I. R. (Nujol): 3300, 3050, 1777, 1727, 1672cm-1 N. M. R. (d6-DMSO, #): 1.28 (6H, d, J = 6Hz), 3.75 (2H, broad s), 4.43 (3H, m), 4.8 ¯ 5.6 5.6 (1H), 5.90 (1H, d, d, J = 5 and 8Hz), 7.45 (1H, s), 8.58 (1H, broad s), 9.60 (111, s), 9 , 77 (1H, d, J = 8Hz), 12.80 (1H, broad s) (2) 7- [2-pentyloxyimino-2- (2-formamidothiazol-4-yl) acet amido] -3- (1st , 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer). 



   I. R. (Nujol): 3300, 3250, 1785cm-1
N. M. R.  (d6-DMSO, ô): 0.6 # 1.9 (9H, m), 3.72 (2H, broad s), 4.11 (2H, t, J = 6Hz), 4.47 (2H, ABq, J = 13Hz), 5.18 (1H, d, J = 5Hz), 5.82 (111, d, d, J = 5 and 8Hz), 7.41 (111, s), 8.53 ( 1H, s), 9.57 (111, s), S), 9.64 (1H, d, J = 8Hz), 12.65 (111, s) (3) 7- [2-butoxyimino-2- (2-formamidothiazol-4-yl) acetamidoj-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres). 



   I. R.  (Nujol): 3300, 2500 - 2600, 1775, 1710, 1690, 1670, 1645 cm- '
N. M. R.  (d6-DMSO, ô): 0.90 (3H, m), 1.2 1.8 (4H, m), 3.70 (2H, AB1, J = 18Hz), 3.94 (3H, s) , 4.12 (2H, m), 4.32 (2H, ABq, J = 13Hz), 5.16 (1H, d, J = 5Hz), 5.80 (1H, d, d, J = 5 and 8Hz), 7.37 (111, s), s), 8.50 (1H, s), 9.62 (1H, d, J = 8Hz), 12.6 (1H, s) (4) 7- [2-methoxyimino-2- (2-formamidothiazol-4-yl) acet amido] -3- (1-propyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer). 



   I. R. (Nujol): 3180, 1775, 1665 cm-1. 



   N. M. R. (d6-DMSO, #): 0.85 (3H, t, J = 8.0Hz), 1.82 (2H, m), 3.69 (2H, m) 3.88 (3H, s), 4 .0 # 4.66 (4H, m), 5.13 (1H, d, J = 5.0Hz), 5.81 (1H, d, d, J = 5.0Hz), 5.81 (1H, d, d, J = 5.0 and 8.0Hz), 7.42 (1H, s), 8.52 (1H, s), 9.65 (1H, d, J = 8.0Hz). 



   (5) 7- [2-Allyloxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1-propyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid ( Syn-Isomeres). 



   I. R. (Nujol): 3180, 1775, 1670cm-1
N. M. R.  (d6-DMSO, ô): 0.87 (3H, t, J = 8.0Hz), 1.65 (2H, m), 3.73 (2H, ABq, J = 16.0Hz), 4.00 # 4.53 (4H, m), 4.69 (2H, d, J = 5.0Hz), 5.00 # 5.68 (3H, m), 5.68 # 6.36 (2H, m) , 7.45 (1H, s,), 8.56 (1H, s), 9.72 (1H, d, J = 8.0Hz) (1H, s,) L, 8.56 (1H, s) , 9.72 (1H, d, J = 8.0 Hz) (6) 7- [2-isopropoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1-hexyl-1H-tetrazole- 5-yl) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres). 



   I. R. (Nujol): 3175, 1780, 1670cm-1. 



   N. M. R.  (d6-DMSO, ô): 0.66 (3H, t, J = 5.0Hz), 1.05 # 1.57 (6H, m), 1.92 (2H, m), 3.77 (2H , m), 4.10 # 4.72 (5H, m), 5.24 (1H, d, J = 5.0Hz), 5.90 (1H, d, d, J = 5.0 and 8, 4Hz), 7.43 (1H, s), 8.56 (1H, s), 9.64 (1H, d, J = 8.4Hz) (7) 7- [2-hexyloxyimino-2- (2- formamidothiazol-4-yl) acetamido] -3- (1-hexyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (Syn-Isomeres)
I. R. (Nujol): 3175, 1785, 1642 cm-1. 



   N. M. R.  (d6-DMSO, ô): 0.86 (6H, m), 1.00 # 1.57 (12H, m), 1.57 # 2.07 (4H, m), 3.75 (2H, m ), 3.97 # 4.60 (8H, m), 5.18 (1H, d, J = 5.2Hz), 5.85 (1H, d, d, J = 5.2 and 8.4Hz) , 7.41 (1H, s), 8.56 (111, s), 9.65 (1H, d, J = 8.4Hz) (8) 7- [2-allyloxyimino-2- (2-formamidothiazole- 4-yl) acet amido] -3 (1-hexyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer). 



   I. R.  (Nujol): 3180.1780, 1680 cm-1 N. M. R. (d6-DMSO, #: 0.64'1.97 (11H, m), 3.68 (2H, ABq, J = 18Hz), 4.30 (4H, m), 4.64 (2h, m) , 5.00 # 546 (3H, m), 5.56 # 6.24 (2H, m), 7.37 (1H, s), 8.48 (1H, s), 9.67 (1H, d , J = 8Hz), 5.92 (1H, d, d, J = 5 and 8Hz), 6.78 (1H, s), 6.88 (4H, s), 6.95 (1H, s), 7.04 # 7.64 (10H, m), H = 8Hz) (9) 7- [2-ethyloxyimino-2- (2-aminothiazol-4-yl) acetamido] 3- (1,3,4-thiazole -2-yl) thiomethylo-3-cephem-4-carboxylic acid (syn isomer). 



   I. R. (Nujol), 3300, 1775, 1660cm-1 (10) 7- [2-isopropoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1, -3,4-thiadiazol-2-yl ) thiomethyl-3-cephem-4-carboxylic acid (syn isomer). 



   I. R.  (Nujol): 3325, 1774, 1656cm '.    



   (11) 7- [2-Pentyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer). 



   I. R.  (Nujol): 3350,3200, 1775, 1675cm-1. 



   (12) 7- [2-Butoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -Isomeres). 



   I. R.  (Nujol): 3350, 3250.2550 # 2600, 1780, 1700, 1670, 1630cm-1 (13) 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1- propyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer). 



   I. R. (Nujol): 3350, 1780, 1670, 1630cm-1 (14) 7 [2-allyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-propyl-1H-tetrazol-5-yl ) thiomethyl-3-cephem-4-carboxylic acid (syn isomer). 



   I. R.  (Nujol): 3340, 3230, 1780, 1680, 1630 cm- '. 



   (15) 7- [2-Methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-hexyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -Isomeres). 

 

   I. R. (Nujol): 3350, 3230, 1777, 1675, 1627cm-. 



   (16) 7- [2-Isopropoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-hexyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4 carboxylic acid (syn isomer )
I. R. (Nujol): 3320, 1780, 1675, 1630cm-1 (17) 7- [2-hexyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-hexyl-1H-tetrazole-5 -yl) thiomethyl-3-cephem-4carboxylic acid (syn isomer)
I. R. (Nujol): 3350 3230, 1765, 1670 1615cm-1 (18) 7- [2-allyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-hexyl-1H-tetrazole-5 -yl) thiomethyl-3-cephem-4carboxylic acid hydrochloride (syn isomer)
I. R.  (Nujol): 3240, 1780, 1720, 1675 cm-1 (19) 7- [2-propoxyoxy-2- (2-amino-1,3-thiazol-4-yl) -ace tamido] 3- (l- methyl 1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer)
I. R. (Nujol):

   3400-3200, 1780, 1670, 1630 1535cm-1
N. M. R.  (d6-DMSO, ô): 9.57 (1H, d, J = 8Hz), 6.72 (1H, s), 5.77 (1H, dd, J = 5.8Hz), 5.13 (1H , d, J = 5Hz), 4.30 (2H, ABq, J = 14Hz), 4.02 (2H, t, J = 7Hz), 3.93 (3H, s), 3.69 (2H, Abq , J = 18Hz), 1.64 (2H, m), 0.90 (3H, t, J = 7Hz) (20) 7- [2-pentyloxyimino-2- (2-amino-1,3-thiazole- 4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem4-carboxylic acid (syn isomer)
I. R.  (Nujol):

   3300, 1770, 1660, 1630 cm-1
N. M. R.    (d6-DMSO, ô): 9.52 (1H, d, J = 8Hz), 7.20 (2H, m), 6.68 (1H, s), 5.74 (1H, dd, J = 4 , 8Hz), 5.10 (1H, d, J = 4Hz), 4.30 (2H, ABq, J = 13Hz), 4.02 (2H, t, J = 6Hz), 3.90 (3H, s ), 3.66 (2H, ABq, J = 18Hz), 1.60 (2H, m), 1.30 (4H, m), 0.82 (3H, t, J = 6Hz) (21) 7- [Hexyloxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid, (syn -Isomeres). 



   I. R.  (Nujol) 3350, 3250, 1780, 1630 cm-1
N. M. R (d6-DMSO, ô) 10.25 (1H, d, J = 5Hz), 7.25 (2H, m), 6.73 (1H, s), 5.77 (1H, dd, J = 5 , 8Hz), 5.13 (1H, d, J = 5Hz), 4.17 (2H, m), 3.91 (3H, s), 3.67 (2H, m), 1.33 (8H, m), 0.83 (3H, m) (22) 7- [2-propoxyimino-2- (2-amino-1,3-thiazol-4-yl) amido] -3- (1,3,4- thiadiazol-2-yl) thiomethyl-3-cephem-4bonic acid (syn-isomer)
I. R. 

   (Nujol) 3400-3200, 1780, 1670, 1540 cm-1
N. M. R.    (d6-DMSO, ô) 9.50 (1H, s), 9.50 (1H, d, J = 8Hz), 6.68 (1H, s), 5.74 (1H, dd, J = 5, 8Hz), 5.12 (1H, d, J = 5Hz), 4.40 (2H, ABq, J = 14Hz), 3.98 (2H, t, J = 7Hz), 3.66 (2H, ABq, J = 17Hz), 1.62 (2H, m), 0.87 (3H, t, J = 7Hz) (23) 7- [2-ethoxyimino-2- (2-formamido-1,3-thiazole-4 -yl acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4 carboxylic acid (syn isomer). 



   I. R.  (Nujol) 3500, 3200, 1780, 1670, 1620 cm-1
N. M. R.    (d6-DMSO, ô) 9.64 (1H, d, J = 8Hz), 8.5 (1H, s), 7.9 (1H, s), 7.4 (1H, s), 5.76 (1H, dd, J = 4.8Hz), 5.14 (1H, d, J = 4Hz), 4.1 (2H, q, J = 7Hz), 3.92 (2H, ABq, J = 13Hz) , 3.58 (2H, ABq, J = 18Hz), 1.26 (6H, t, J = 7Hz) (24) 7- [2-ethoxyimino-2- (2-amino-1,3-thiazole-4 -yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer). 



   I. R.  (Nujol) 3350, 3150, 1770, 1670 cm-1
N. M. R.  (d6-DMSO, #) 9.56 (1H, d, J = 9Hz), 7.92 (1H, s), 7.28 (1H, m), 6.75 (1H, s), 5.75 (1H, dd, J = 9.5Hz), 5.06 (1H, d, J = 5Hz), 4.05 (2H, q, J = 7Hz), 3.9 (2H, m), 3.64 (2H, ABq, J = 17Hz), 1.24 (3H, t, J = 7Hz) (25) 7- [2-propoxyimino-2- (2-formamido-1,3-thiazol-4yl) acetamido] - 3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem 4-carboxylic acid (syn isomer). 



   I. R.  (Nujol) 3300-3100, 1780, 1680, 1650, 1550 cm-1
N. M. R.    (d6-DMSO, ô)
9.62 (1H, d, J = 8Hz), 8.50 (1H, s), 7.92 (1H, s), 7.38 (1H, s), 5.78 (1H, dd, J = 5.8Hz), 5.15 (1H, d, J = 5Hz), 4.20-3.70 (4H, m), 3.65 (2H, ABq, J = 17Hz), 1.66 (1H, m), 0.90 (3H, t, J = 7Hz) (26) 7- [2-propoxyimino-2- (2-amino-1,3-thiazol-1-yl) acet amido] -3- (1H -1,2,3-triazol-5-yl) thiomethyl-3-cephem-4-car bonic acid (syn isomer). 



   I. R.  (Nujol) 3400-3100, 1770, 1670, 1630, 1530 cm-1
N. M. R.    (d6-DMSO, ô) 9.58 (1H, d, J = 8Hz), 8.97 (1H, s), 6.77 (1H, s), 5.78 (1H, dd, J = 5, 8Hz), 5.18 (1H, d, J = 5Hz), 4.23-3.76 (4H, m), 3.67 (2H, broad s), 1.67 (2H, m), 0, 93 (3H, t, J = 7Hz) (27) 7- [2-pIsoropoxyimino-2- (2-amino-1,3-thiazol-1-yl) acetamido] -3- (1H-1,2,3 -triazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer). 



   I. R.  (Nujol): 3300, 3150, 1780, 1670, 1640 cm-1
N. M. R.  (d6-DMSO, #): 9.50 (1H, d, J = 9Hz), 7.97 (1H, s), 6.73 (1H, s), 5.77 (1H, dd, J = 5 , 9Hz), 5.17 (1H, d, J = 5Hz), 4.33 (1H, m), 4.0 (2H, ABq, J = 13Hz), 3.67 (2H, ABq, J = 18Hz ), 1.23 (6H, d, J = 6Hz) (28) 7- [2-isobutoxyimino-2- (2-amino-1,3-thiazol-1-yl) acetamido] -3- (1H-1 , 2,3-triazol-5-yl) thiomethyl-3-cephem-4carboxylic acid (syn isomer)
I. R.  (Nujol):

   3470, 3320, 3200, 3160, 1770, 1660 cm-1
N. M. R.  (d6-DMSO, ô): 9.57 (1H, d, J = 9Hz), 7.97 (1H, s), 7.22 (2H, broad), 6.75 (1H, s), 5, 77 (1H, dd, J = 5.9Hz), 5.18 (1H, d, J = 5Hz), 4.03 (2H, ABq, J = 12Hz), 3.88 (2H, d, J = 6Hz) ), 3.70 (2H, ABq, J = 18Hz), 2.0 (1H, m), 0.92 (6H, d, J = 6Hz) (29) 7- [2-isopropoxyimino-2- (2nd -2-aminothiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephemcarboxylic acid (syn-isomer). 



   I. R.  (Nujol): 3330, 3250, 1780, 1680 cm-1 (30) 7- [2-methoxyimino-2- (2-formamido-1,3-thiazol-4yl) acetamido] -3- (benzothiazolyl) thiomethyl-3 -cephem-4-carboxylic acid (syn-insomeres). 



   I. R.  (Nujol): 3200, 1780, 1680, 1620, 1545, 1460, 1435, 1385, 1040, 1000 cm-1
N. M. R.  (d6-DMSO, #): 9.7 (1H, d, J = 8Hz), 8.53 (1H, s), 7.66-8.16 (2H, m), 7.16-7.66 (3H, m), 5.83 (1H dd, J = 5, 8Hz), 5.18 (1H, d, J = 5Hz), 4.23 and 4.81 (2H, ABq, J = 15Hz), 3.93 (3H, s), 3.73 (2H, broad s)
Example 11
Working in a similar manner as in Examples 8-10, the following compounds can be prepared: (1) 7- [2-isopropoxyimino-2- (2-foramidothiaz acetamido] -3- (1 -allyl-1 H-tetrazole 5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer). 



   I. R.  (Nujol): 3220, 1780, 1670 cm-1. 



   N. M. R.  (d6-DMSO, #): 1.20 (3H, s 1.32 (3H, s), 3.70 (2H, broad s), 4.07-4.87 (3H, m), 4.93 -5.50 (4H, m). 



  5.67-6.23 (2H, m) 7.40 (1H, s), 8.50 (1H, s), 9.58 (1H, d, J = 8Hz). 



   (2) 7- [2-Butoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1-allyl-tetrazol-5-yl) thiomethyl-3-cephem-4 carboxylic acid (syn isomer). 



   I. R.  (Nujol): 3200, 1780, 1695, 1675, 1655 cm-1. 

 

   N. M. R.  (d6-DMSO, #): 0.88 (3H, m), 1.10-2.01 (4H, m), 3.71 (2H, m), 4.14 (2H, t, J = 7 , 0Hz), 4.38 (2H, ABq, J = 14.0Hz), 4.83-5.51 (5H, m), 5.63-6.40 (2H, m), 7.42 (1H , s), 8.56 (1H, s), 9.65 (1H, d, J = 9.0Hz). 



   (3) 7- [2-Hexyloxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1-allyl-tetrazol-5-yl) thiomethyl-3-cephem-4 carboxylic acid (syn isomer). 



   I. R.  (Nujol): 3175, 1780, 1757, 1684 1640 cm-1. 



   N. M. R.  (d6-DMSO, ô): 0.84 (3H, m), 1.06-2.03 (8H, m), 3.73 (2H, m), 4.14 (2H, t, J = 6 , 0Hz), 4.40 (2H, ABq, J = 14.0Hz), 4.85-5.52 (5H, m), 5.75-6.45 (2H, m), 6.97 (1H , broad s), 7.41 (1H, s), 8.54 (1H, s) 9.63 (1H, d, J = 8.0Hz). 



   (4) 7- [2- (2-formyloxyethoxy) imino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1-allyl-tetrazol-5-yl) thiomethyl-3-cephem- 4-carboxylic acid (syn isomer).   



   I. R.  (Nujol): 3265, 1780, 1720, 1680 cm-1. 



   N. M. R.    (d6-DMSO, 6): 3.74 (2H, m), 4.13-4.70 (6H, m), 4.85-5.53 (5H, m) 5.70-6.42 ( 2H, m), 7.48 (1H, s), 8.26 (1H, s), 8.56 (1H, s), 9.69 (1H, d, J = 9.0Hz). 



   (5) 7- [2-ethoxycarbonylmethoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1-allyl-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer ). 



   I. R.  (Nujol): 3500.3280, 1780, 1735, 1690 cm-1. 



   N. M. R.    (d6-DMSO, ô): 1.24 (3H, t, J = 7Hz), 3.74 (2H, s) 4.90 (2H, q, J = 7Hz), 4.42 (2H, s) , 4.77 (2H, s), 4.5-5.6 (5H, m), 5.7-6.4 (3H, m), 7.50 (1H, s), 8.57 (1H , s), 9.68 (1H, d, J = 8Hz), 12.69 (1H, broad s).    



   (6) 7- [2-tert. -Butoxycarbonylmethoxyimino-2- (2-formamido-thiazol-4-yl) acetamido] -3- (1-allyl-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer). 



   I. R.  (Nujol): 3250.1780.1720.1680.1540 cm-1. 



   N. M. R.  (d6-DMSO, #): 1.44 (9H, s), 3.71 (2H, ABq, J = 18Hz), 4.37 (2H, ABq, J = 14Hz), 4.62 (2H, s ), 4.8-5.4 (5H, m), 5.5-6.4 (2H, m), 7.46 (1H, s), 8.52 (1H, s), 9.58 ( 1H, d, J = 8Hz), 12.60 (1H, broad s). 



   (7) 7- [2-ethoxyimino-2- (2-aminothiazol-4-yl) acetamido] 3- (1-allyl-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer ).    



   I. R.  (Nujol): 3350.1780.1675.1635 cm-1. 



   (8) 7- [2-isopropoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-allyl-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer) .    



   I. R.  (Nujol): 3350, 3250, 1780, 1675, 1630 cm-1. 



   (9) 7- [2-Butoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-allyl-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn- isomer). 



   I. R.  (Nujol): 3360.1780.1672 cm-1. 



   (10) 7- [2-Hexyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-allyl-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) . 



   I. R.  (Nujol): 3350, 3240, 1780, 1675, 1630 cm-1. 



      (11) 7- [2-Allyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-allyl- I H-tetrazol-5-yl) thiomethyl-3-cephem- 4-carboxylic acid (syn-isomer). 



   I. R.  (Nujol): 3350, 3210, 1778, 1675 cm-1. 



   (12) 7- [2-Etchoxycarbonylmethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-allyl-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn- Isomer). 



   I. R.  (Nujol): 3360, 3230, 1780, 1680, 1630 cm-1. 



   (13) 7- [2-tert. -Butoxycarbonylmethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-allyl-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid (syn-isomer). 



   I. R.  (Nujol): 3330, 1780, 1730, 1680, 1630 cm-1. 



   (14) 7- [2-Methylthiomethoxyimino-2- (2-aminothiazol-4 yl) acetamido] -3- (1-allyl-tetrazol-5-yl) thiomethyl-3-ce phem-4-carboxylic acid (syn- Isomer). 



   I. R.  (Nujol): 3270, 1760, 1650 1520 cm-1. 



   (13) 7- [2- (3-isoxazolyl) methoxyimino-2- (2-aminothi azol-4-yl) acetamido] -3- (1-allyl-tetrazol-5-yl) thio methyl-3- cephem-4-carboxylic acid (syn isomer). 



   I. R.  (Nujol): 3300, 1770, 1660, 1530 cm-1. 



   (16) 7- [2-Carbomethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-allyl-tetrazol-5-yl) thiomethyl-3-ce phem-4-carboxylic acid (syn -Isomer). 



   I. R.  (Nujol): 3360, 1780, 1680, 1630 cm-1. 



   (17) 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetam do] -3- (1-allyl-tetrazol-3-yl) thiomethyl-3-cephem-4 carboxylic acid (syn- Isomer). 



   I. R.  (Nujol): 3350, 1775, 1670, 1530 cm-1. 



   (18) 7- [2- (4-Fluorobenzyloxyimino-2- {2- (2,2,2-trifluoroacetamido) thiazol-4-yl) acetamido] -3- (1-allyl-tetrazole
5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer). 



   I. R.  (Nujol): 3250.3170.1780.1720.1650 cm-1. 



   N. M. R.  (DMSO-d6, ô): 3.64 (2H, m), 4.34 (2H, ABq, J = 14 Hz), 4.79-5.44 (7H, m), 5.65-6, 27 (2H, m), 6.95-7.61 (4H, m), 7.51 (1H, s), 9.83 (1H, d, J = 8Hz).    



   (19) 7- [2-Fluorobenzyloxyimino-2- (2-aminothi acetamido] -3- (1-ally-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid, (syn- Isomeres), melting point 157 to 161 C (decomposition).    



   I. R.  (Nujol): 3500, 1770, 1660, 1630, 1600 cm-1. 



      (20) 7- [2- (3,4-dichlorobenzyloxyimino) -2- {2- (2,2,2-trifluoroacetamido] thiazol-4-yl} acetamido] -3- (1-allyl-1H- tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer). 



   I. R.  (Nujol): 1770.1650 cm-1. 



   N. M. R.  (DMSO-d6, ô): 3.72 (2H, m), 4.40 (2H, m), 5.00 5.43 (7H, m), 5.73-6.60 (2H, m) , 7.30-7.77 (4H, m), 9.90 (1H, d, J = 8Hz).    



   (21) 7- [2- (3,4-dichlorobenzyloxyimino) -2- (2-aminothi azol-4-yl) acetamido] -3- (1-allyl-lH-tetrazol-5-yl) thio- methyl-3-cephem-4-carboxylic acid (syn isomer), melting point 155 to 175 C (decomposition).    



   I. R.  (Nujol): 1770.1660.1620.1450 cm-1. 



   Example 12
A solution of 4.8 g of 7- [2-allyloxyimino-2- (2-aminothiazol-4-yl) acetamido] cephalosporanic acid (syn isomer) in 100 ml of a phosphate buffer solution (pH 6.4) was mixed with 2.1 g of 1-allyl-1H-tetrazole-5-thiol were added and the mixture was stirred at 55 to 60 ° C. for 2 hours.     The reaction mixture was then cooled and the pH was adjusted to 3.0 by adding 10% hydrochloric acid.  The precipitate was collected by filtration, washed with water and dried to give 2.0 g of 7- [2-allyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-allyl-1H- tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer). 



   I. R.  (Nujol): 3350, 3210, 1778, 1675 cm-1. 



   N. M. R.  (DMSO-d6, ô): 3.68 (2H, ABq, J = 18Hz), 4.40-4.71 (4H, m), 4.80-5.45 (7H, m), 5.64 -6.24 (3H, m), 6.74 (1H, s), 7.35 (2H, broad s), 9.62 (1H, d, J = 8Hz).    



   Example 13
The following compounds could be made if the procedure was similar to that in Example 12. 



   (1) 7- [2-Allyloxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid ( syn isomer). 



   I. R.  (Nujol): 3180, 1775, 1665, cm-1. 



   (2) 7- [2-ethoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -Isomer). 



   I. R.  (Nujol): 3200.1765.1665 cm-1. 



   (3) 7- [2-methylthiomethoxyimino-2- (2-formamido azol-4-yl) acetamido] -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4- carboxylic acid (syn isomer). 

 

   I. R.  (Nujol): 3250,3200,1780,1670, 1540 cm-1. 



   (4) 7- [2- (3-isoxazolyl) methoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl- 3-cephem-4-carboxylic acid (syn isomer). 



   I. R.  (Nujol): 3250, 1780, 1670, 1550 cm-1. 



   (5) 7- [2-Benzyloxyimino-2- (2-aminothiazol-4-yl) aceta do] -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4- ca bonic acid (syn isomer). 



   I. R.  (Nujol): 3350.3230, 1780, 1675, 1635 cm-1. 



   (6) 7- [2-methoxyimino-2- (2-formamidothiazol-4-yl) amido] -3- (4-allyl-4H-1,2,4-triazol-3-yl) thiomethyl-3- cephem-4-carboxylic acid (syn isomer). 



   I. R.  (Nujol): 3200.1780.1680.1550 cm-1.   



   (7) 7- [2-Isopropoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1-allyl- 1 H-tetrazol-5-yl) thiomethyl-3-cephem-4 -carboxylic acid (syn isomer). 



   I. R.  (Nujol): 3220, 1780, 1670cm '.    



   (8) 7- [2-butoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1-allyl-lH-tetrazol-5-yl) thiomethyl-3-cephem-4- carboxylic acid (syn isomer). 



   I. R.    (Nujol): 3200, 1780, 1695, 1675, 1655 cm-1. 



   (9) 7- [2-Hexyloxyimino-2- (2-formamidothiazol-4-yl) acetamido] 3- (l-ally-l H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid, ( syn isomer). 



   I. R.  (Nujol): 3175, 1780, 1757, 1684, 1640 cm-1. 



   (10) 7- [2-ethoxycarbonylmethoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer). 



   I. R.  (Nujol): 3500, 3280, 1780, 1735, 1690 cm- '. 



   (11) 7- [2-tert. -Butoxycarbonylmethoxyimino-2- (2-form-amidothiazol-4-yl) -acetamido] -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer)
I. R. (Nujol): 3250, 1780, 1720, 1680, 1540 cm-1. 



   (12) 7- [2-ethoxyimino-2- (2-aminothiazol-4-yl) acetamido-3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid ( syn isomer). 



   I. R.  (Nujol): 3350, 1780, 1675, 1635 cm- '. 



   (13) 7- [2-Isopropoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-allyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4 - carboxylic acid (syn isomer). 



   I, R.  (Nujol): 3350, 3250, 1780, 1675, 1630 cm- (14) 7- [2-butoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-allyl-1H-tetrazole -5-yl) -thiomethyl-3-cephem-4-carboxylic acid (syn isomer). 



   I. R.  (Nujol): 3360, 1780, 1672 cm-1. 



   (15) 7- [2-Hexyloxyimino-2- (2-aminothiazol-4-yl) acetamido-3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn- Isomer). 



   I. R.  (Nujol): 3350, 3240, 1780, 1675, 1630 cm-1. 



   (16) 7- [2-ethoxycarbonylmethoxyimino-2- (2-aminothiazol-4-yl) acetamido] - 3- (1-allyl-lH-tetrazol-5-yl) thiomethyl-3-cephem-4- carboxylic acid (syn isomer). 



   I. R.  (Nujol): 3360, 3230, 1780, 1680, 1630 cm-1. 



   (17) 7- [2-tert. -Butoxycarbonylmethoxyimino-2- (2-ami nothiazol-4-yl) -acetamido] -3- (1-allyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid (syn-isomer). 



   I. R.  (Nujol): 3330, 1780, 1730, 1680, 1630 cm- '. 



   (18) 7- [2-Methylthiomethoxyimino-2- (2-aminothiazol-4yl) acetamido] -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl3-cephem-4-carboxylic acid (syn isomer ). 



   I. R.  (Nujol): 3270, 1760, 1650, 1520 cm-1. 



   (19) 7- [2- (3-Isoxazolyl) methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-allyl-1 H-tetrazol-5-yl) thiomethyl -3-cephem-4-carboxylic acid (syn isomer). 



   I. R.  (Nujol): 3300, 1770, 1660, 1530 cm-1. 



   (20) 7- [2-Carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (l-allyl-l H-tetrazol-5-yl) thiomethyl-3-cephem-4 -carboxylic acid (syn isomer). 



   I. R.  (Nujol): 3360, 1780, 1680, 1630 cm-1. 



   (21) 7- [2-Methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (4-allyl-4H-1,2,4-triazol-3-yl) thiomethyl-3 -cephem-4-carboxylic acid (syn isomer). 



   I. R.  (Nujol): 3350, 1775, 1670, 1530 cm- '. 



   (22) 7- [2- (4-Fluorobenzyloxyimino) -2- (2-aminothiazol-4yl) acetamido] -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-ccphem-4 -carboxylic acid (syn isomer), melting point 157 to 161 C (decomposition).    



   I. R.  (Nujol): 3500, 1770, 1660, 1630, 1600 cm- '.    



   (23) 7- [2- (3,4-dichlorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- (1-allyl-IH-tetrazol-5-yl) thiomethyl-3 -cephem-4-carboxylic acid (syn isomer), melting point 155 to 175 C (decomposition). 



   I. R.  (Nujol): 1770, 1660, 1620, 1450 cm- '.    



   Example 14
1.1g 7- [2- (4-fluorobenzyloxyimino) -2- (2-aminothiazol-4yl) acetamido] cephalosporanic acid (syn isomer) and 0.23 g 1,3,4-thiadiazol-2-thiol were added in a solution of 0.34 g of sodium bicarbonate is stirred into 30 ml of a phosphate buffer solution (pH 5.8) and the mixture is stirred at 60 ris 65 C for 3 hours.  The reaction mixture was then paid for and the pH was adjusted to 3 by adding 10% strength hydrochloric acid.  The precipitate was collected by filtration, washed with water and dried, yielding 0.45 g of 7- [2- (4-fluorobenzyloxyimino) -2- (2-aminothiazol-4yl) -acetamido] -3- (1,3, 4-thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylic acid (syn isomer), melting point 145 to 149 C (decomposition). 



   I. R.  (Nujol): 3250, 1765, 1650 cm¯ 1.    



   N. M. R.    (DMSO-d6, 8): 3.73 (2H, ABq, J = 18Hz), 4.48 (2H, ABq, J = 14Hz), 5.01-5.39 (3H, m), 5.85 (111, dd, J = 4 and 8Hz), 6.83 (1H, s), 7.02-7.75 (4H, m), 9.63 (1H, s), 9.75 1H, d, J = 8Hz).    



   Example 15
The following compounds were obtained by working in a similar manner to that in Example 14. 



   (1) 7- [2-Methylthiomethoxyimino-2- (2-formamidothi zol-4-yl) acetamido] -3- (l, 3,4-thiadiazol-2-yl) thiomethyl-3-: ephem-4 -carboxylic acid (syn isomer). 



   I. R.  (Nujol): 3230, 1780, 1680, 1550 cm- '. 



   (2) 7- [2-Benzyloxyimino-2- (2-aminothiazol-4-yl) acetami- 10] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4- carboxylic acid (syn isomer). 



   I. R.  (Nujol): 3320.3200, 1770, 1670, 1610cm- '.    



   (3) 7- [2-tert. -Butoxycarbonylmethoxyimino-2- (2-formamidothiazol-4-yl) -acetamido] -3- (1,3,4-thiadiazol-2-yl) -thioethyl-3-cephem-4-carboxylic acid (syn-isomer). 



   I. R.  (Nujol): 3225, 1780, 1725, 1685, 1550 cm-1. 



   (4) 7- [2-Methylthiomethoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thionethyl-3-cephem-4-carboxylic acid (syn isomer). 



   I. R.  (Nujol): 3250, 1780, 1675, 1550 cm- '. 



   (5) 7- [2- (2-ethoxyethoxy) imino-2- (2-formamidothiazol1-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-ce ;, hem-4-carboxylic acid (syn isomer). 



   I. R.  (Nujol): 3500, 3200, 1780, 1720, 1680 cm-1. 



   (6) 7- [2-ethoxycarbonylmethoxyimino-2- (2-formamido dhiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4- carboxylic acid (syn isomer). 



   I. R.  (Nujol): 3250, 1775, 1720, 1680, 1540 cm-1. 

 

   (7) 7- [2-Ethoxycarbonylmethoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thionethyl-3-cephem-4-carboxylic acid (syn isomer). 



   I. R.  (Nujol): 3250, 1780, 1725, 1680, 1540 cm-1. 



   (8) 7 - [- 2-tert. -Butoxycarbonylmethoxyimino-2- (2-formamido-thiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5yl) -thiomethyl-3-cephem-4-carboxylic acid (syn-isomer). 



   I. R.  (Nujol): 3180, 1785, 1725, 1690, 1550 cm-1. 



   (9) 7- [2-Benzyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-hexyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4 -carboxylic acid (syn isomer). 



   I. R.  (Nujol): 3350, 3250, 1780, 1680, 1633 cm- '. 



   (10) 7- [2- (3-isoxazolyl) methoxyimino-2- (2-formamido thiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl 3-cephem-4-carboxylic acid (syn isomer). 



   I. R.  (Nujol): 3200, 1775, 1675, 1540 cm-1.   



   (11) 7- [2-Methylthiomethoxyimino-2- (2-aminothiazol-4 yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid ( syn isomer). 



   I. R.  (Nujol): 3340, 3200, 1775, 1670 cm-1. 



   (12) 7- [2-Methylthiomethoxyimino-2- (2-aminothiazol-4 yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3 cephem-4-carboxylic acid (syn -Isomer). 



   I. R.  (Nujol): 3300, 1770, 1670, 1530 cm-1. 



   (13) 7- [2- (2-Ethoxyethoxy) imino-2- (2-aminothiazol-4yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem -4-carboxylic acid (syn isomer). 



   I. R.  (Nujol): 3160, 3100, 1780, 1670, 1630 cm-1. 



   (14) 7- [2-ethoxycarbonylmethoxyimino-2- (2-aminoth azol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4- carboxylic acid (syn isomer). 



      I. R.  (Nujol): 3350, 3220, 1780, 1680, 1630 cm-1. 



   (15) 7- [2-ethoxycarbonylmethoxyimino-2- (2-aminoth azol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl cephem-4-carboxylic acid (syn -Isomer). 



   I. R.  (Nujol): 3350, 3230, 3100, 1780, 1680, 1630 cm-1. 



     (16) 7- [2-tert. -Butoxycarbonylmethoxyimino-2- (2-aminothiazol-4-yl) -acetamido] -3- (1,3,4-thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylic acid (syn-isomer). 



   I. R.  (Nujol): 3300, 1775, 1730, 1675, 1630 cm-1. 



   (17) Carboxymethoxyimino-2- (2-aminothiazol-4-yl) ace amido] -3 - (1-methyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem 4-carboxylic acid (syn isomer ). 



   I. R.  (Nujol): 3340.3200.1775.1675.1630 cm-1. 



   (18) 7- [2- (3-Isoxazolyl) methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3cephem -4-carboxylic acid (syn isomer). 



   I. R.  (Nujol): 3350, 3230, 3110, 1775, 1675 cm-1. 



   (19) 7- [2-Carboxymethoxyimino-2- (2-formamidothiazol4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3cephem-4-carboxylic acid (syn isomer) . 



   I. R.  (Nujol): 3200, 1780, 1720, 1680, 1545 cm-1. 



   (20) 7- [2-Carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4carboxylic acid (syn- Isomer). 



   I. R.  (Nujol): 3360, 3240, 3100, 1780, 1680, 1635 cm-1. 



   (21) 7- [2- (tert. -Butoxycarbonylmethoxyimino) -2- (2-form amido-thiazol-4-yl) -acetamido] -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid, (syn-isomer). 



   I. R.  (Nujol): 3170, 1770, 1720, 1670 cm-1. 



   (22) 7- [2-ethoxycarbonylmethoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1H-tetrazol-5-yl) thiomethy 3-cephem-4-carboxylic acid (syn isomer) , Melting point 112 to 125 C (decomposition). 



   I. R.  (Nujol): 3250, 1770, 1730, 1680 cm-1. 



   (23) 7- [2-Benzyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer ), Melting point 172 to 174 C (decomposition). 



   I. R.  (Nujol): 3250, 3150, 1770, 1620 cm-1. 



   (24) 7- [2-Cinnamyloxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4carboxylic acid (syn- Isomer). 



   I. R.  (Nujol): 3400-3100, 1780, 1680, 1540 cm-1. 



   (25) 7- [2- (3-Hydroxy-4-bromobenzyloxyimino) -2- (2-form amidothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) - thio methyl-3-cephem-4-carboxylic acid (syn isomer). 



   I. R.  (Nujol): 3400-3100, 1780, 1680, 1540 cm-1. 



   (26) 7- [2- (tert-Butoxycarbonylmethoxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- (1H-tetrazol-5-yl) thiomethyl3-cephem-4-carboxylic acid (syn -Isomer). 



   I. R.  (Nujol): 3280.3200.1770.1670.1630 cm-1. 



   (27) 7- [2- (4-Flurbenzyloxyimino) -2- (2-aminothiazol-4 yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3cephem-4- carboxylic acid (syn isomer). 



   I. R.  (Nujol): 3300, 3200, 1770, 1660, 1620, 1600 cm-1. 



   (28) 7- [2-ethoxycarbonylmethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1H-tetrazol-5-yl) thiomethyl-3-ce phem-4-carboxylic acid (syn- Isomer), melting point 168 to
185 C (decomposition).    



      I. R. (Nujol): 3250, 1765, 1670, 1625 cm-1.    



   (29) 7- [2-Cinnamyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephemcarboxylic acid (syn-isomer) . 



   I. R.  (Nujol): 3350-3100, 1760, 1650, 1620, 1520 cm-1. 



   (30) 7- [2- (4-Fluorobenzyloxyimino) -2- (2-aminothiazol-4yl) acetamido] -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer ). 



   I. R.  (Nujol): 3300, 3200, 1770, 1660, 1630, 1600 cm-1. 



   (31) 7- [2- (3-Hydroxy-4-bromobenzyloxyimino) -2- (2 aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3- cephem-4-carboxylic acid (syn isomer). 



   I. R.  (Nujol): 3400-3100, 1760, 1660, 1620, 1520 cm-1. 



   (32) 7- [2-carboxymethoimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) , Melting point 178 to 180 C (decomposition). 



   I. R.  (Nujol): 3300.3280.1770, 1670.1630 cm-1. 



   Example 16
A solution of 0.3 g of 7- [2- (methoxyimino-2- {2- (2,2,2trifluoroacetamido) -1,3-thiazol-4-yl} acetamidol] -3- (1-methyl
1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomeres) in 10.5 ml of an aqueous 0.1N sodium hydroxide solution was heated to 45 ° C. for 6 hours.  15 ml of water and 30 ml of ethyl acetate were added to the reaction mixture, and the resulting mixture was mixed with
10% hydrochloric acid adjusted to pH 3.5.  The aqueous layer was separated, washed with ethyl acetate and adjusted to pH 5.0 with an aqueous sodium carbonate solution.  The aqueous solution was subjected to column chromatography on Amberlite XAD-2 (20 ml) (a product of Rohm & Haas Co. ) using 10% ethanol as the developing solvent. 

  The eluate containing the desired compound was collected and lyophilized, 0.12 g of 7- [2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (1 -meth-yl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) was obtained. 



   IR spectrum (Nujol) 3200.1765.1600cm-l.    



   N. M. R. Spectrum 6d6-DMSO, #) ppm 9.51 (1H, d, J = 8.5Hz)
7.22 (2H, broad s)
6.72 (1H, s)
5.59 (1H, dd, J = 5.8, 5Hz)
5.00 (1H, d, J = 5Hz) 4.35 (2H, ABq, J = 12Hz)
3.90 (3H, s) 3.81 (3H, s)
3.55 (2H, ABq, J = 18 Hz)
Example 17
3 ml of trifluoroacetic acids were ice-cooled to 0.5 g of 7- [2-methoxyimino-2- (2-t-pentyloxycarbonylamino-1,3thiazol-4-yl) acetamido] -3- (5-methyl-1,3,4 -thiadiazol-2-yl-thiomethyl-3-cephem-4-carboxylic acid (syn isomer) added,

   and the mixture was stirred at ambient temperature for 30 minutes.  Ether was added to the mixture, and the precipitated powder was collected by filtration and dissolved in a mixture of 20 ml of water and an aqueous solution of sodium hydroxide to adjust to pH 12 to 13.  The solution was adjusted to pH 4.6 with 10% hydrochloric acid, washed with ethyl acetate and methylene chloride.  The excess methylene chloride in the aqueous layer was thoroughly removed by introducing nitrogen gas.  The aqueous layer was adjusted to pH 2 with stirring and with ice cooling, whereby a powder precipitated. 

  The powder was collected by filtration and dried to give 0.128 g of 7- [2-methoxyimino-2- (2 amino-1,3-thiazole-4-yl) acetamido] -3- (5-methyl-1,3,4 -thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) was obtained. 



   IR spectrum (Nujol) 3400-3150,1770,1670, 1625cm-l
N. M. R. - spectrum (d6-DMSO, o) ppm 9.66 (1H, d, J = 8Hz) 7.34 (2H, broad s) 6.76 (1H, s)
5.78 (2H, dd, J = 5, 8Hz) 5.16 (1H, d, J = 5Hz) 4.40 (2H, ABq, J = 14Hz)
3.85 (3H, s) 3.70 (2H, ABq, J = 17Hz)
2.68 (3H, s)
Example 18
4 ml of trifluoroacetic acid and 2 ml of anisole were added to 0.9 g of 7- [2-allyloxyimino-2- (2-t-pentyloxycarbonylamino-1, 3-thiazol-4-yl) acetamido] -3- (1-methyl) with ice cooling 111-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) added,

   and the mixture was stirred at ambient temperature for 40 minutes. The reaction mixture was post-treated in a manner similar to that in Example 17, whereby 0.425 g of 7- [2-allyloxyimino-2- (2-amino-1,3-thiazole-4- yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thio-methyl-3-cephem-4-carboxylic acid (syn-isomer). 



   I. R. -Spectrum (Nujol) 3100-3400, 1775, 1660, 1625 cm- '
N. M. R.  Spectrum (d6-DMSO, o) ppm 9.70 (1H, d, J = 8Hz) 6.80 (1H, s) 6.30-5.60 (2H, m) 5.24 (2H, dd, J = 8.16Hz)
5.15 (1H, d, J = 5Hz)
4.63 (2H, d, J = 5Hz) 4.32 (2H, ABq, J = 12Hz) 3.94 (3H, s) 3.70 (2H, ABq, J = 17Hz)
Example 19
23 g 7- [2-methoxyimino-2-t2- (2,2,2-trifluoroacetamido) -l, 3-thiazol-4-yl) acetamido] -3- (l, 3,4-thia iazol- 2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) were suspended in a solution of 74.8 g of sodium acetate trihydrate in 230 ml of water,

   and the suspension was stirred at ambient temperature for 15 hours.  The reaction mixture was adjusted to pH 5.0 with concentrated hydrochloric acid and the insoluble material was filtered off.  The filtrate was adjusted to pH 2.5, and the precipitated crystals were collected by filtration and dried, whereby 14 g of 7- [2-methoxyimino-2- (2-amino 1, 3-thiazol-4-yl) acetamido] -3- (1, 3,4-thiadiazol-2-yl) thio-methyl-3-cephem-4-carboxylic acid (syn isomer), F.  172 to
175 C (dec. ), received. 



   IR spectrum (Nujol) 3300, 1770, 1665 cm-1. 



   N. M. R spectrum (d6-DMSO, o) ppm 9.80 (1H, d, J = 8 Hz)
9.63 (1H, s)
6.95 (1H, s)
6.8 (2H, m)
5.82 (1H, dd, J = 5.8 Hz)
5.22 (1H, d, J = 5 Hz)
4.48 (2H, ABq, J = 15Hz)
3.97 (3H, s) 3.76 (2H, ABq, J = 18Hz)
Example 20
10.8 g 7- [2-methoxyimino-2- (2-formamido-1,3-thiazol-4yl) -acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3- cephem-4-carboxylic acid (syn isomer) was added to 200 ml of methanol and 7.2 g of phosphorus oxychloride were added dropwise with stirring and with ice cooling at 2 to 9 ° C.  To
Stirring at the same temperature for 1.5 hours, the reaction mixture was concentrated under reduced pressure on a water bath of 25 to 28 ° C to a volume of 100 ml. 

  300 ml of ether were added to the residue with stirring and with ice cooling.  The precipitates were collected by filtration and dried, giving 12.3 g of 7- [2-methoxyimino-2- (2-amino-1,3-thiazol4-yl) acetamido] -3- (1,3,4-thiadiazole -2-yl) -thiomethyl3-cephem-4-carboxylic acid hydrochloride (syn-isomer) was obtained. 



  12.3 g of this powder were suspended in 100 ml of water and dissolved by adjusting the pH of the suspension to 7.5 by adding a saturated aqueous sodium bicarbonate solution.  100 ml of ethyl acetate was added to the solution and the mixture was adjusted to pH 2.5 with 10% hydrochloric acid.  The precipitates were collected by filtration, washed with cold water and dried, giving 6.1 g of 7- [2-methoxyimino-2 (2-amino-1,3-thiazol-4-yl) acetamido] -3- (1 , 3,4-thiadiazol-2yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).  The aqueous layer in the mother liquor was separated and stirred with cooling after the addition of sodium chloride.  The precipitates were collected by filtration to give 3.8 g of the same desired compound.  The overall yield was 9.9 g. 

  This compound was identified with the compound obtained in the above examples by IR and NMR spectra. 



   Example 21
The compounds shown below were obtained in a similar manner as in Examples 16 to 20. 



   (1) 7- [2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (4-methyl-4-H-, 2,4-triazole- 3-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer), F.  185 C (dec. ).    



   I. R. -Spectrum (Nujol) 3150 3350.1770.1710.1660.1630cm- '
N. M. R. - spectrum (d6-DMSO, o) ppm 9.61 (1H, d, J = 8Hz) 8.69 (1H, s)
6.73 (1H, s) 5.72 (1H, dd, J = 4.8 Hz)
5.1 (1H, d, J = 4Hz) 4.1 (2H, ABq, J = 13Hz) 3.87 (3H, s)
3.65 (2H, broad s)
3.59 (3H, s) (2) 7- [2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- [1 - (2-dimethylaminoethyl) - 1 H-tetrazol-5-yl] thiomethyl-3-cephem-4-carboxylic acid (syn isomer). 



   I. R. -Spectrum (Nujol) 1765 cm- '
N. M. R. Spectrum (d6-DMSO, 6) ppm 9.56 (1H, d, J = 8Hz)
6.75 (1H, s)
5.75 (1H, m)
5.10 (1H, d, J = 4 Hz)
4.58 (2H, broad s)
4.32 (2H, broad s)
3.82 (3H, s)
3.68 (2H, wide s) 3.20 (2H, wide s) 2.50 (6H, s)
Example 22
0.85 g of concentrated hydrochloric acid was cooled with ice to a stirred solution of 2.3 g of 7- [2-ethoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol- 2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) was added in a mixture of 23 ml of methanol and 23 ml of tetrahydrofuran, and the mixture was stirred at ambient temperature for 2.5 hours.  The solvent was distilled off under reduced pressure and the residue was dissolved in a saturated aqueous sodium bicarbonate solution (pH 7.0). 

  The aqueous solution was washed with ethyl acetate and adjusted to pH 3.5 with concentrated hydrochloric acid.  The precipitates were collected by filtration, washed with water and dried, giving 1.865 g of 7- [2-ethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2 -yl) thiomethyl3-cephem-4-carboxylic acid (syn-isomer) was obtained in the form of a powder. 



   I. R.  (Nujol): 3300, 1775, 1660 cm-1
N. M. R.  (d6-DMSO, b): 1.67 (3H, t, J = 7.6Hz), 3.75 (2H, m), 4.16 (2H, q, J = 7.6Hz), 4.48 (2H, ABq, J = 13.6Hz), 5.18 (1H, d, J = 5.2Hz), 5.83 (1H, d, d, J = 5.2 and 8, OHz), 6, 79 (1H, s), 7.38 (2H, broad s), 9.63 (1H, s), 9.63 (1H, d, J = 8.0 Hz)
Example 23
2.1 g of concentrated hydrochloric acid were cooled to a solution of 6.0 g of 7- [2 methoxyimino-2- (2-formamidothiazol-4-yl) acetamidoj-3- (1 - hexyl-1H-tetrazole- 5-yl) -thiomethyl-3-cephem-4-carboxylic acid (syn-isomer) in 60 ml of methanol was added and the mixture was stirred at ambient temperature for 4 hours.  The solvent was removed from the reaction mixture and 50 g of ethyl acetate was added. 

  The mixture was adjusted to pH 7.0 with a saturated aqueous sodium bicarbonate solution.  The aqueous layer was separated, washed with ethyl acetate and adjusted to pH 3.5 with concentrated hydrochloric acid.  The precipitates were collected by filtration, washed with water and dried under reduced pressure, giving 4.62 g of 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-hexyl- 1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) was obtained. 



   I. R.  (Nujol): 3350, 3230, 1777, 1675, 1627 cm-1
N. M. R.  (d6-DMSO, 6): 0.82 (3H, t, J = 5.0Hz), 1.23 (6H, m), 1.80 (2H, m), 3.69 (2H, m), 3.85 (3H, s), 4.05 # 4.63 (4H, m), 5.12 (1H, d, J = 5.0 Hz), 5.75 (1H, d, d, J = 5.0, 8.6Hz), 6.76 (1H, s), 7.23 (2H, broad s), 9.59 (1H, d, J = 8.6Hz)
Example 24
1 ml of concentrated hydrochloric acid was added to a solution of 1.5 g of 7- [2-isopropoxyimino-2- (2-formamido-1,3-thiazol-4-yl) acetamido] -3- (1-methyl-1H- tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) added in a mixture of 12 ml of tetrahydrofuran and 12 ml of methanol.  The mixture was stirred at ambient temperature for 3.5 hours and then concentrated to dryness. 



  Water was added to the residue and sodium bicarbonate was added to the mixture to form a solution.  The solution was adjusted to pH 3.0 with concentrated hydrochloric acid with ice cooling.  The precipitates were collected by filtration, washed with water and dried, whereby 0.8 g of 7- [2-isopropoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (1 -meth yl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) was obtained. 



   I. R.  (Nujol): 3330.3250.1780.1680cm- '
N. M. R.    (d6-DMSO, 8) 9.50 (1H, d, J = 8 Hz), 6.70 (1H, s), 5.83 (1H, dd, J = 5.8 Hz), 5.17 ( 1H, d, J = 5Hz), 4.33 (2H, broad s), 3.97 (3H, s), 3.71 (2H, broad s), 1.25 (6H, d, 3 = 6Hz)
Example 25
The following compounds were prepared in a similar manner as in Examples 22 to 24: (1) 7- [2-isopropoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4 -thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer). 



   I. R.  (Nujol): 3325, 1774, 1656 cm-1
N. M. R.    (d6-DMSO, #): 1.22 (6H, d, J = 6 Hz), 3.70 (2H, broad s), 4.37 (3H, m), 5.15 (1H, d, J = 5Hz), 5.77 (111, d, d, J = 5 and 8Hz), 6.70 (1H, s), 7.20 (2H, m), 9.50 (111, d, 3 = 8Hz ), 9.55 (1H, s). 



   (2) 7- [2-Pentyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid ( syn isomer). 



   I. R.  (Nujol): 3350.3200.1775.1675cm- '
N. M. R.  (d6-DMSO, 6): 0.62 # 2.0 (9H, m), 3.72 (2H, broad s), 4.06 (2H, t, J = 6 Hz), 4.45 (2H , ABq, J = 13 Hz), 5.17 (1H, d, J = 5 Hz), 5.78 (1H, d, d J = 5 and 8 Hz), 6.73 (1H, s), 7 , 2 (2H, s), 9.5 (1H, d, J = 8 Hz), 9.55 (1H, s) (3) 7- [2-butoxyimino-2- (2-aminothiazol-4-yl ) acetamido] 3 1 -methyl-I H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer). 



   I. R.  (Nujol): 3350, 3250, 2500 # 2600, 1780, 1700, 1670, 1630 cm
N. M. R.    (d6-DMSO, 6): 1.0 (3H, m), 1.2 # 1.7 (4H, m), 3.77 (2H, ABq, J = 19 Hz), 3.95 (3H, s), 4.15 (2H, m), 4.33 (2H, ABq, J = 13 Hz), 5.20 (1H, d, J = 5Hz), 5.82 (111, d, d, J = 5.8Hz), 6.73 (1H, s), 9.56 (111, d, J = 8Hz) (4) 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetami- do] -3- (1-propyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer). 

 

   I. R.  (Nujol): 3350.1780.1670.1630cm- '
N. M. R.    (d6-DMSO, 8): 0.87 (3H, t, J = 7.0Hz), 1.84 (2H, m), 3.73 (2H, broad s), 3.89 (3H, s) , 4.06 # 4.72 (4H, m), 5.14 (1H, d, J = 5.0 Hz), 5.80 (1H, d, d, J = 5.0 and 8Hz), 6 , 78 (1H, s), 7.23 (2H, broad s), 9.59 (1H, d, J = 8.0 Hz) (5) 7- [2-allyloxyimino-2- (2-aminothiazole- 4-yl) acetami do] -3- (1-propyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer). 



   I. R.  (Nujol): 3340, 3230, 1780, 1680, 1630 cm-1
N. M. R.    (d6-DMSO, 6): 0.86 (3H, t, J = 7.0Hz), 1.83 (2H, m), 3.71 (2H, broad s) 4.05 # 4.80 (6H , m), 5.01 # 5.53 (3H, m), 5.63 # 6.42 (2H, m), 6.75 (1H, s), 7.20 (2H, broad s), 9 , 59 (1H, d, J = 8.2Hz) (6) 7- [2-isopropoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-hexyl-1H-tetrazole-5 -yl) thiomethyl-3-cephem-4 carboxylic acid (syn isomer). 



   I. R.  (Nujol): 3320.1780.1675.1630cm- '
N. M. R.    (d6-DMSO, 6): 0.84 (3H, t J = 6.0 Hz), 1.00 # 1.50 (12H, m), 1.80 (2H, m), 3.72 (2H , ABq, J = 17.0Hz) 4.10 # 4.60 (5H, m), 5.15 (111, d, J = 5.0Hz), 5.81 (111, d, d, J = 5 , 0, 8.0 Hz), 6.77 (1H, s), 9.59 (1H, d, J = 8.0Hz)
7- [2-Hexyloxyimino -2- (2-aminothiazol-4-yl) acetamido] 3- (1 -hexyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer ). 



   I. R.  (Nujol): 3350.3230, 1765, 1670, 1615 cm-
N. M. R.    (d6-DMSO, 6): 0.84 (6H, m), 1.26 (12H, m), 1.70 (4H, m), 3.20 # 4.60 (8H, m), 5, 40 (111, d, J = 5.0 Hz), 5.68 (111, d, d, J = 5.0 8.0 Hz), 6.72 (1H, s), 7.23 (2H, broad s), 9.49 (111, d, J = 8.0 Hz) (8) 7- [2-allyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-hexyl-lH- tetrazol-5-yl) thiomethyl-3-cepham-4-carboxylic acid hydrochloride (syn isomer). 



   I. R.  (Nujol): 3240, 1780, 1720, 1675 cm
N. M. R.    (d6-DMSO, #): 0.63 # 2.13 (11H, m), 3.73 (2H, ABq, J = 18 Hz), 4.04 # 4.90 (6H, m), 5, 10 # 6.30 (5H, m), 6.94 (1H, s), 7.93 (2H, broad s), 9.80 (1H, d, J = 8Hz)
Example 26 a) The 7- [2-tert. Butoxycarbonylmethoxyimino-2- (3-chloro-4-hydroxyphenyl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) in the form of a powder. 



   b) 1.5 g of the powder obtained in Example 5 (a) was added to a mixture of 1.5 ml of anisole and 6 ml of trifluoroacetic acid, and the resulting mixture was stirred at ambient temperature for 30 minutes.  The reaction mixture was adjusted to pH 8 by adding 50 ml of an aqueous sodium bicarbonate solution, 50 ml of ethyl acetate and sodium bicarbonate with ice cooling.  The aqueous layer was separated, adjusted to pH 5.0 with 10% hydrochloric acid and washed with 50 ml of ethyl acetate.  The aqueous layer was further adjusted to pH 2.0 with 10% hydrochloric acid and extracted with 100 ml of ethyl acetate.  The extract was washed with water and dried over magnesium sulfate. 

  The solvent was distilled off under reduced pressure and the residue was dissolved in a pH 5.0 acetate buffer and on Woelm neutral alumina (trademark for a product of ICN Company) using a pH 5.0 acetate buffer as a developing solvent Subject to column chromatography.  The eluate was adjusted to pH 2.0 with 10% hydrochloric acid with ice cooling.  The precipitating materials were collected by filtration, washed with water and dried, giving 0.5 g of 7- [2-carboxymethoxyimino-2- (3-chloro-4hydroxyphenyl) acetamido] -3- (1-methyl-1H tetrazole-5 -yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer), F.  145 to 148 C (dec. ), received. 



   I. R. -Spectrum (Nujol) 3400, 3200-3300, 2500-2600, 1780, 1720, 1670, 1600 cm- '
N. M. R.  Spectrum (d6-DMSO, 6) ppm 9.70 (1H, d, J = 8Hz) 7.50 (1H, d, J = 2Hz)
7.45 (1H, dd, J = 2.8Hz) 7.10 (1H, d, J = 8Hz) 5.90 (1H, q, J = 5Hz) 5.22 (1H, d, J = 5Hz)
4.70 (2H, s) 4.35 (2H, ABq, J = 13Hz)
3.95 (3H, s) 3.75 (2H, ABq, J = 18Hz)
Example 27 a) The 7- [2- (1-t-butoxycarbonylethoxyimino) -2- (3-chloro-4-hydroxyphenyl) acetamido] -3- (1-methyl-1H-tetrazole) is obtained in a similar procedure -5-yl) thiomethyl-3-cephem-4carboxylic acid (syn isomer in the form of a powder. 



   b) 3.6 g of the powder obtained in Example 6 (a), 4 ml of anisole and 16 ml of trifluoroacetic acid were reacted with one another in a similar manner as in Example 5 (b), giving 2.0 g of 7- [2- (1 -Carboxyethoxyimino) -2- (3-chloro-4-hydroxyphenyl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer), F.  147 to 151 C (dec. ), in the form of a yellow powder. 



   IR spectrum (Nujol) 3500, 3250, 2500-2600, 1780, 1730, 1660, 1630, 1600 cm
N. M. R. - Specktrum (d6-DMSO, #) ppm 9.62 (1H, d, J = 8 Hz) 7.46 (1H, d, J = 2 Hz) 7.34 (1H, dd, J = 2.8 Hz) 7 , 04 (1H, d, J = 8Hz) 5.90 (1H, q, J = 5Hz) 5.22 (1H, d, J = 5Hz)
4.73 (1H, q, J = 6Hz) 4.33 (2H, ABq, J = 13Hz)
4.00 (3H, s)
3.73 (2H, ABq, J = 18Hz)
1.37 (3H, d,

   J = 6 Hz)
Example 28
0.33 g of concentrated hydrochloric acid was dissolved in a solution of 1.30 g of 7- [2-allyloxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1-allyl-1H-tetrazol-5-yl ) -thiomethyl-3-ce phem-4-carboxylic acid (syn isomer) in 13 ml of methanol was added and the mixture was stirred at room temperature for 41/2 hours.  The solvent was then distilled off under reduced pressure and the residue was dissolved in 25 ml of a saturated aqueous sodium bicarbonate solution. 



  This aqueous solution was washed with 25 ml of ethyl acetate and its pH was adjusted to 2.0 by adding 10% hydrochloric acid.  The precipitate was collected by filtration, washed with water and dried, giving 0.95 g of a colorless powder consisting of allyloxyimino-2- (2-aminothiazol-4-yl) acetamidoj-3- (1-allyl-1H- tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer). 

 

   I. R.  (Nujol): 3350, 3210, 1778, 1675 cm-1. 



   N. M. R.    (d6-DMSO, #): 3.68 (2H, ABq, J = 18Hz), 4.40-4.71 (4H, m), 4.80-5.45 (7H, m), 5.64 -6.24 (3H, m), 6.74 (1H, s), 7.35 (2H, broad s), 9.62 (1H, d, J = 8Hz). 



   Example 29
0.9 g of concentrated hydrochloric acid was added at room temperature to a solution of 2.4 g of 7- [2-ethoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1 -allyl- 1 H-tetrazole- 5-yl) -thio methyl-3-cephem-4-carboxylic acid (syn isomer) was added in a mixture of 16.8 ml of methanol and 4.8 ml of tetrahydrofuran and the mixture was stirred at 30 ° C. for 3 hours.  Then the solvent was distilled off under reduced pressure and the residue was dissolved in a saturated aqueous sodium bicarbonate solution. 

  The aqueous solution was washed with ethyl acetate and the pH was adjusted to 2.8 by adding concentrated hydrochloric acid. The precipitate was collected by filtration, washed with water and dried, giving 1.72 g of 7- [2 ethoxyimino-2- ( 2-aminothiazol-4-yl) acetamido] -3- (1 allyl-H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer). 



   I. R.  (Nujol): 3350, 1780, 1675, 1635cm '.    



   N. M. R.  (d6-DMSO, 6): 1.24 (3H, t, J = 7.3Hz), 3.71 (2H, m), 4.13 (2H, q, J = 7.3Hz), 4.37 (2H, ABq, J = 13.5Hz), 4.80-5.53 (5H, m), 5.64-6.45 (2H, m), 6.77 (1H, s), 7.25 (2H, broad s), 9.62 (1H, d, J = 8.0Hz). 



   Example 30
A mixture of 0.95 g of 7- [2-methylthiomethoxyimino-2 (2-formamidothiazol-4-yl) acetamido] -3- (1-allyl-1H-tetrazol 5-yl) thiomethyl-3-cephem-4 -carboxylic acid (syn isomer), 0.324 g of concentrated hydrochloric acid, 9.5 ml of methanol and 2 ml of tetrahydrofuran was stirred at room temperature for 2 hours.  Then the solvent was distilled off under reduced pressure and the residue was dissolved in a saturated aqueous sodium bicarbonate solution.  The aqueous solution was washed with 25 ml of ethyl acetate and the pH was adjusted to 1.5 by adding 10% hydrochloric acid.  The precipitate was collected by filtration, washed with water and dried, giving 0.78 g of 7- [2-methylthiomethoxyimino -2- (2-aminothiazol-4-yl) acetamido] -3- (1-allyl-1H- tetrazol-5-yl) thiomethyl-3-ce phem-4-carboxylic acid (syn isomer) was obtained. 



   I. R.  (Nujol): 3270, 1760, 1650, l520, cm '.    



   N. M. R.  (d6-DMSO, 6): 2.21, (3H, s), 3.72 (2H, s), 4.38 (2H, ABq, J = 14Hz), 4.8 - 5.6 (7H, m), 5.7 - 6.4 (2H, m), 6.8 ((1H, s), 7.26 (2H, broad s) 9.66 (1H, d, J = 8Hz).    



   Example 31
A mixture of 1.5 g of 7- [2- (3-isoxazolyl) methoxyimino
2- (2-formamidothiazol-4-yl) acetamido] -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer),
0.497 g of concentrated hydrochloric acid, 15 ml of methanol and 3 ml of tetrahydrofuran was stirred at room temperature for 2 hours.  Then the solvent was distilled off under reduced pressure and the residue was dissolved in an aqueous saturated sodium bicarbonate solution.  The aqueous solution was washed with 25 ml of ethyl acetate and the pH was adjusted to 1.5 by adding 10% hydrochloric acid. 

  The precipitate was collected by filtration, washed with water and dried, giving 0.65 g of 7- [2- (3-isoxazolyl) methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-ce phem-4-carboxylic acid (syn isomer). 



   I. R.  (Nujol):
3300, 1770, 1660, 1530 cm-1. 



   N. M. R.  (d6-DMSO, 6): 3.71 (2H, s), 4.40 (2H, d,
J = 14Hz), 4.8 - 5.6 (7H, m), 5.6 - 6.5 (2H, m), 6.62 (1H, d,
J = 2Hz), 6.83 (1H, s), 7.29 (2H, broad s), 8.92 (1H, d, J = 2Hz), 9.73 (1H, d. , J = 8Hz).    



   Example 32
A mixture of 0.9 g of 7- [2-methoxyimino-2- (2-formamothothiazol-4-yl) acetamido] -3- (4-allyl-4H 1,2,4-triazol-3-yl) - Thiomethyl-3-cephem-4-carboxylic acid (syn isomer) and 0.3 ml of concentrated hydrochloric acid, 7 ml of methanol and 7 ml of tetrahydrofuran were stirred at room temperature for 41/2 hours.  The solvent was then distilled off under reduced pressure and the residue was dissolved in an aqueous saturated sodium bicarbonate solution.  The aqueous solution was washed with 25 ml of ethyl acetate and its pH was adjusted to 2.0 by adding 10% hydrochloric acid. 



  The precipitate was collected by filtration, washed with water and dried to give 0.5 g of 7- [2 methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (4-allyl-4H-1 , 2,4-triazol-3-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer). 



   I. R.  (Nujol): 3350, 1775, 1670, 1530 cm-1. 



   N. M. R.    (d6-DMSO, 6): 3.65 (2H, broad s), 3.83 (3H, s), 4.15 (2H, broad s), 4.58 (2H, m), 4.77 - 5.5 (3H, m), 5.58 - 6.33 (2H, m), 6.73 (1H, s), 8.60 (1H, s), 9.58 (1H, d, J = 8Hz). 



   Example 33
The following compounds were obtained by operating in a manner similar to that in Examples 28-32. 



   (1) 7- [Benzyloxyimino-2- (2-aminothiazol-4-yl) acetami do] -3- (1-allyl-lH-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid ( syn isomer). 



   I. R.  (Nujol): 3350, 3230, 1780, 1675, 1635 cm-1. 



   (2) 7- [2-Isopropoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -Isomer). 



   I. R.  (Nujol): 3350, 3250, 1780, 1675, 1630 cm-1. 



   N. M. R.    (d6-DMSO, 6): 1.20 (3H, s), 1.30 (3H s), 3.70 (2H, broad s), 4.30 (3H, m), 4.97 - 5, 40 (4H, m), 5.63 - 6.27 (2H, m), 6.70 (111, s), 9.55 (1H d, J = 8 Hz). 



   (3) 7- [2-Butoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3 - (1-allyl-1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -Isomer). 



   I. R.  (Nujol): 3360, 1780, 1672 cm-1. 



   N. M. R.    (d6-DMSO, 6): 0.91, (3H, t, J = 6.0Hz), 1.18 - 1.96 (4H, m), 3.73 (2H, m), 3.87 - 4.73 (4H, m), 4.83 - 5.57 (5H, m), 5.63 - 6.40 (2H, m), 6.74 (1H, s), 7.20 (2H, broad s), 9.55 (111, d, J = 8.0 Hz). 



   (4) 7- [2-Hexyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (l-allyi-1H-tetrazol-5- yl) thiomethyl-3-cephem-4- carboxylic acid (syn isomer). 



   I. R.  (Nujol): 3350, 3240, 1780, 1675, 1630 cm-1. 



   N. M. R.  (d6-DMSO,): 0.85 (3H, m), 1.00-2.00 (8H, m), 3.68 (2H, m), 4.05 (2H, m), 4.37 (2H, m), 4.80 - 5.47 (5H, m), 5.60 - 6.47 (2H, m), 6.69 (1H, s), 7.20 (2H, broad s) , 9.50 (1H, d, J = 8.0Hz). 

 

   (5) 7- [2-Athoxycarbonylmethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4 -carboxylic acid (syn isomer). 



   I. R.  (Nujol): 3360, 3230, 1780, 1680, 1630 cm-1. 



   N. M. R.    (d6-DMSO, 6): 1.21, (3H, t, J = 7Hz), 3.68 (2H, s), 4.14 (2H, q, J = 7Hz), 4.38 (2H, s), 4.66 (2H, s), 4.8 - 5.5 (5H, m), 5.6 - 6.4) (3H, m), 6.80 (1H, s), 7, 20 (2H, broad s), 9.48 (1H, d, J = 8Hz).   



   (6) 7- [2-tert.  Butoxycarbonylmethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer). 



   I. R.  (Nujol): 3330, 1780, 1730, 1680, 1630 cm-1. 



   N. M. R.  (d6-DMSO, #): 1.43, (9H, s, 3.67 (2H, s), 4.37 (2H, ABq, J = 14 Hz), 4.56 (2H, s), 4 , 8 - 5.5 (5H, m), 5.6 - 6.4 (2H, m), 6.78 (1H, s), 7.20 (2H, broad s), 9.43 (1H, d, J = 8Hz). 



   (7) 7- [2- (Carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido-3- (1-allyl-1H-tetrazol-5-yl) thiomethyl) -3-cephem-4-carboxylic acid (syn isomer). 



   I. R.  (Nujol): 3360, 1780, 1680, 1630 cm (8) 7- [2- (4-fluorobenzyloxyimino) -2- (2-aminothiazol-4 yl) acetamido] -3- (1-allyl-1 H-tetrazole -5-yl) -thiomethyl-3-cephem-4-carboxylic acid (syn isomer), melting point 157 to 161 C (decomposition). 



   I. R.  (Nujol): 3500, 1770, 1660, 1630, 1600 cm-1. 



   N. M. R.  (DMSO-d6, #): 3.69 (2H, m), 4.39 (2H, ABq, J = 14Hz), 4.75-5.48 (7H, m), 5.63-6.57 (2H, m), 6.76 (1H, s), 6.86-7.76 (4H, m), 9.67 (1H, d, J = 8Hz). 



   (9) 7- [2- (3,4-dichlorobenzyloxyimino) -2- (2-aminothiazol-4-yl) -acetamido] -3 - (1-allyl- 1 H-tetrazol-5-yl) -thiomethyl- 3-cephem-4-carboxylic acid (syn isomer), melting point 155 to 175 C (decomposition). 



   I. R.  (Nujol): 1770, 1660, 1620, 1450 cm- '.    



   N. M. R.  (DMSO-d6, #): 3.63 (2H, m), 4.33 (2H, m), 4.93-5.37 (7H, m), 5.67-6.40 (2H, m ), 6.73 (111, s), 7.10-7.70 (3H, m), 9.73 (111, d, J = 8Hz).    



   Example 34
20 ml of trifluoroacetic acid were cooled with ice in a suspension of 2.05 g of 7- [2-tert. -Butoxycarbonylmethoxyimi- no-2- (2-aminothiazol-4-yl) -acetamido] -3- (1-allyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid (syn-isomer) stirred in 2 ml of anisole and the resulting mixture was stirred at room temperature for 2 hours.  Then the reaction mixture was concentrated under reduced pressure and diethyl ether was added.  The precipitate was collected by filtration, washed with diethyl ether, dried and dissolved in an aqueous sodium bicarbonate solution. 



  The insoluble constituents were filtered off and the filtrate was adjusted to a pH of 3.2 by adding concentrated hydrochloric acid.  The precipitate was collected by filtration, washed with water and dried, yielding 0.8 g of 7- [2-carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-allyl-1H -tetrazol-5-yl) -thio-methyl-3-cephem-4-carboxylic acid (syn isomer) was obtained. 



   I. R.  (Nujol): 3360, 1780, 1680, 1630 cm-1. 



   N. M. R.  (D6-DMSO, #): 3.68 (2H, ABq, J = 19 Hz), 4.36 (2H, ABq, J = 14 Hz), 4.60 (2H, s), 4.60-6 , 2 (7H, m), 6.80 (1H, s), 7.24 (2H, broad s), 9.51 (111, d, J = 9Hz). 



   Example 35
A mixture of 0.58 g of 7- [2-methylthiomethoxyimino-2 (2-formamidothiazol-4-yl) acetamido] -3- (l, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem- 4-carboxylic acid (syn isomer), 0.405 g of concentrated hydrochloric acid, 8.7 ml of methanol and 5 ml of tetrahydrofuran were stirred at room temperature for 135 minutes.  Then the solvent was distilled off under reduced pressure and the residue was dissolved in a 10% aqueous sodium hydroxide solution (pH 7 to 8.5).  The insoluble constituents were filtered off and the filtrate was adjusted to a pH of 3.4 by adding 10% hydrochloric acid with ice cooling and stirring for 30 minutes. 

  The precipitate was collected by filtration, washed with water and dried, giving 0.4 g of 7- [2-methylthiomethoxyimino-2- (2-aminothhiazol-4-yl) acetamido] -3- (1, 3,4-thiadia ol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer). 



   I. R.  (Nujol): 3340, 3200, 1775, 1670, cm-1. 



   N. M. R.  (d6-DMSO,): 2.23 (3H, s), 3.74 (2H, s) 4.48 (2H, ABq, J = 13Hz), 5.20 (111, d, J = 5Hz), 5.24 (2H, s), 5.83 (1H, dd, J = 5 and 9Hz), 6.83 (1H, s), 7.28 (2H, broad s), 9.62 (111, s ), 9.68 (1H, d, J = 9Hz). 



   Example 36
A mixture of 2.3 g of 7- [2-tert. -Butoxycarbonylmethoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (I, 3,4thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer), 3.74 g Concentrated hydrochloric acid and 35 ml of methanol were stirred at room temperature for 160 minutes. 



  Then the solvent was distilled off under reduced pressure and the residue was dissolved in a 10% aqueous sodium hydroxide solution (pH 7 to 8).  The aqueous solution was adjusted to a pH of 3.0 by adding 10% hydrochloric acid with ice cooling and stirring and stirred for 30 minutes.  The precipitate was collected by filtration, washed with water and dried, giving 1.1 g of 7- [2-tert-butoxycarbonylmethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1, 3.4 thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) was obtained. 



   I. R.  (Nujol): 3300, 1775, 1730, 1675, 1630 cm-1. 



   N. M. R.  (d6-DMSO, #): 1.46 (9H, s), 3.67 (2H, s), 4.42 (2H, ABq, J = 14 Hz), 4.55 (2H, s), 5 , 16 (111, d, J = 5Hz), 5.78 (111, dd, J = 5 and 9Hz), 6.77 (1H, s), 7.21 (2H, s), 9.43 (111 , d, J = 9Hz), 9.52 9.52 (111, s).    



   Example 37
With stirring, a solution of 2.7 g of sodium acetate in 46 ml of water was mixed with 2.3 g of 7- [2- (4-fluorobenzyloxyimino) 2- {2- (2,2,2-trifluoroacetamido) thiazol-4-yl } -acetamido] -3 (1,3,4-thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylic acid (syn isomer) was added and the mixture was stirred at room temperature for 20 1/2 hours.  Ethyl acetate was then added to the reaction mixture, and the pH was then adjusted to 5.0 by adding 10% hydrochloric acid. 



  The mixture was shaken.  The aqueous layer was separated, washed twice with ethyl acetate and its pH was adjusted to 3.0 using 10% hydrochloric acid.  The precipitate was collected by filtration, washed with water and dried, giving 1.82 g of 7- [2- (4-fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamidoj-3- (1, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer), melting point 145 to 149 C (decomposition). 

 

   I. R.  (Nujol): 3250, 1765, 1650 cm-1. 



   N. M. R.  (DMSO-d6, #): 3.73 (2H, ABq, J = 18 Hz), 4.48 (2H, ABq, J = 14 Hz), 5.01-5.39 (3H, m), 5 , 85 (1H, dd, J = 4 and 8Hz), 6.83 (1H, s), 7.02-7.75 (4H, m), 9.63 (1H, s), 9.75 (1H , d, J = 8 Hz). 



   Example 38
Working in a similar manner as in Examples 35 to 37, the following compounds were obtained.   



   (1) 7- [2-Benzoyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).    



   I. R.  (Nujol): 3320, 3200, 1770, 1670, 1610 cm-1. 



   (2) 7- [2-Benzyloxyimino-2- (2-aminothiazol-4-yl) acetami do] -3- (1-hexyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4- carboxylic acid (syn isomer).    



   I. R.  (Nujol): 3350, 3250, 1780, 1680, 1633 cm-1. 



   (3) 7- [2-Methylthiomethoxyimino-2- (2-aminothiazol-4yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3cephem-4-carboxylic acid (syn isomer ). 



   I. R.  (Nujol): 3300, 1770, 1670, 1530 cm-1. 



   N. M. R.  (d6-DMSO, #): 2.20 (3H, s), 3.72 (2H, s), 3.97 (3H, s), 4.36 (2H, s), 5.17 (1H, d, J = 5Hz), 5.22 (2H, s), 5.82 (1H, dd, J = 5 and 8Hz), 6.82 (1H, s), 7.28 (2H, br s), 9.60 (1H, d, J = 8Hz). 



   (4) 7- [2- (2-ethoxyethoxy) imino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3 -eephem-4-carboxylic acid (syn-isomer). 



   1. R.  (Nujol): 3160, 3100, 1780, 1670, 1630 cm-1. 



   N. M. R.  (d6-DMSO, â): 1.08 (3H, t, J = 7Hz), 3.45 (2H, q, J = 7Hz), 3.5 # 3.90 (4H, m).  4th 20 (2H, t, J = 4Hz), 4.47 (2H, ABq, J = 13Hz), 5.17 (1H, d, J = 5Hz), 5.80 (1H, dd, J = 5 and 8Hz ), 6.77 (1H, s), 9.55 (1H, s), 9.55 (1H, d, J = 8 Hz). 



   (5) 7- [2-ethoxycarbonylmethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer). 



   I. R.  (Nujol): 3350, 3220, 1780, 1680, 1630 cm-1. 



   N. M. R.  (d6-DMSO, â): 1.23 (3H, t, J = 7Hz), 3.70 (2H, s), 3.97 (3H, s), 4.16 (2H, q, J = 7Hz ), 4.35 (2H, s), 4.69 (2H, s), 5.15 (1H, d, J = 5Hz), 5.80 (1H, dd, J = 5 and 9Hz), 6, 81 (1H, s), 7.24 (2H, broad s), 9.54 (1H, d, J = 9 Hz). 



   (6) 7- [2-ethoxycarbonylmethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3cephem-4-carboxylic acid (syn -Isomer).    



   I. R.  (Nujol): 3350, 3230, 3100, 1780, 1680, 1630 cm-1. 



   N. M. R.  (d6-DMSO, â): 1.21 (3H, t, J = 7Hz), 3.72 (2H, ABq, J = 18Hz), 4.18 (2H, q, J = 7Hz), 4.70 (2H, s), 5.20 (1H, d, J = 5Hz), 5.84 (1H, dd, J = 5 and 8Hz), 6.84 (1H, s), 7.26 (2H, broad s), 9.56 (1H, d, J = 8HZ), 9.60 (1H, s). 



   (7) 7- [2-Carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid ( syn isomer). 



   I. R.  (Nujol): 3340, 3200, 1775, 1675, 1630 cm-1. 



   N. M. R.  (d6-DMSO, â): 3.68 (2H, s), 3.94 (3H, s), 4.32 (2H, ABq, J = 14 Hz), 4.70 (2H, s), 5 , 14 (1H, d, J = 5 Hz), 5.78 (1H, dd, J = 5 and 9 Hz), 6.81 (1H, s), 7.1 (2H, broad s), 9, 59 (1H, d, J = 9Hz). 



   (8) 7- [2- (3-Isoxazolyl) methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3 -cephem-4-carboxylic acid (syn isomer). 



   I. R.  (Nujol): 3350, 3230, 3110, 1775, 1675 cm-1. 



   N. M. R.  (d6-DMSO, â): 3.71 (2H, ABq, J = 18 Hz), 4.46 (2H, ABq, J = 14 Hz), 5.17 (1H, d, J = 5 Hz), 5.27 (2H, s), 5.82 (1H, dd, J = 5 and 8 Hz), 6.66 (1H, s), 6.83 (1H, s), 7.30 (2H, broad s), 8.87 (1H, s), 9. 57 (1H, s), 9.75 (1H, d, J = 8Hz).    



   (9) 7- [2-Carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4carboxylic acid (syn- Isomer). 



   I. R.  (Nujol): 3360, 3240, 3100, 1780, 1680, 1635 cm-1. 



   (10) 7- [2-Benzyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer ), Melting point 172 to 174 C (decomposition). 



   I. R.  (Nujol): 3250, 3150, 1770, 1620 cm-1. 



   (11) 7- [2- (tert. -Butoxycarbonylmethoxyimino) -2- (2-aminothiazol-4-yl) -acetamido] -3- (1H-tetrazol-5-yl) -thiomethyl3-cephem-4-carboxylic acid (syn-isomer). 



   I. R.  (Nujol): 3280.3200.1770.1670.1630 cm¯ '.    



   (12) 7- [2- (4-Fluorobenzyloxyimino) -2- (2-aminothiazol-4yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3cephem-4-carboxylic acid (syn isomer). 



   I. R.  (Nujol): 3300, 3200, 1770, 1660, 1620, 1600 cm-1. 



   N. M. R.  (DMSO-d6, #): 3.67 (2H, m), 3.94 (3H, s), 4.32 (2H, m), 4.98-5.36 (3H, m), 5, 78 (1H, dd, J = 5 and 8Hz), 6.72 (111, s), 6.95-7.65 (4H, m), 9.65 (1H, d, J = 8 Hz). 



   (13) 7- [2-Ethoxycarbonylmethoxyimino-2- (2-aminothi azol-4-yl) acetamido] -3 - (1 H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer), melting point 168 to 185 C (decomposition). 



   I. R.  (Nujol): 3250, 1765, 1670, 1620 cm-1. 



   N. M. R.  (DMSO-d6, #): 1.21 (3H, t, J = 7Hz), 3.70 (2H, broad s), 4.18 (2H, q, J = 7Hz), 4.31 (2H , m), 4.72 (2H, broad s), 5.17 (1H, d, J = 4 Hz), 5.82 (1H, dd, J = 4 and 7 Hz), 6.83 (1H, s), 7.17 (2H, broad s), 9.57 (1H, d, J = 7Hz). 



   (17) 7- [2- (4-Fluorobenzyloxyimino) -2- (2-aminothiazol-4yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4 -carboxylic acid (syn isomer), melting point 145 to 149 C (decomposition). 



   I. R.  (Nujol): 3250, 1765, 1650 cm-1. 



   (15) 7- [2-Cinnamyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4carboxylic acid (syn- Isomer). 



   (I. R.  (Nujol): 3350-3100, 1760, 1650, 1620, 1520 cm- '.    



   N. M. R.  (DMSO-d6, â): 3.47-3.97 (2H, m), 4.47 (2H, AB, q, J = 14 Hz), 4.8 (2H, d, J = 5 Hz) , 5.18 (1H, d, J = 5 Hz), 5.83 (1H, dd, J = 5 and 8 Hz), 6.83 (1H, s), 6.1-7.0 (2H, m), 7.08-7.72 (5H, m), 9.6 (1H, s), 9.72 (1H, d, J = 8Hz). 

 

   (16) 7- [2- (4-Fluorobenzyloxyimino) -2- (2-aminothiazol-4yl) acetamido] -3- (1H, tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer ). 



   I. R.  (Nujol): 3300, 3200, 1770, 1660, 1630, 1600 cm-1. 



   N. M. R.  (DMSO-d6, â): 3.69 (2H, ABq, J = 18Hz), 4.35 (2H, ABq, J = 15 Hz), 4.93-5.43 (3H, m), 5, 81 (1H, dd, J = 5 and 8Hz), 6.80 (1H, s), 6.96-7.70 (4H, m), 9.73 (1H, d, J = 8Hz). 



   (17) 7- [2- (3-Hydroxy-4-bromebenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl -3-cephem-4-carboxylic acid (syn isomer). 



   I. R.  (Nujol): 3400-3100, 1760, 1660, 1620, 1520 cm-1.   



   N. M. R.  (DMSO-d6, â): 3.72 (2H, broad s), 4.47 (2H, ABq, J = 14 Hz), 5.1 (1H, d, J = 5 Hz), 5.22 ( 2H, s), 5.83 (1H, dd, J = 5 and 8 Hz), 6.85 (1H, s), 6.87 (1H, dd, J = 2 and 8 Hz), 7.08 ( 1H, d, J = 2 Hz), 7.52 (1H, d, J = 8 Hz), 9.67 (1H, s), 9.77 (1H, d, J = 8Hz).    



   (18) 7- [2-Carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) , Melting point 178 to 180 C (decomposition). 



   I. R.  (Nujol): 3300, 3280, 1770, 1670, 1630 cm-1. 



   Example 39
4 ml of trifluoroacetic acid were cooled with ice in a suspension of 1.0 g of 7- [2-tert. -Butoxycarbonyl] methoxyimino-2- (2-aminothiazol-4-yl) -acetamido] -3- (1,3,4-thi yl) -thiomethyl-3-cephem-4-carboxylic acid (syn-isomer) in 1 ml of anisole was stirred in and the mixture obtained was stirred at room temperature for 70 minutes.  Then the reaction mixture was concentrated under reduced pressure and diethyl ether was added.  The precipitate was collected by filtration, washed with diethyl ether, dried, suspended in 10 ml of water and then dissolved in a 10% aqueous sodium hydroxide solution (pH 7 to 7.5).  The solution was adjusted to a pH of 3.0 using 10% hydrochloric acid with ice cooling and stirring and stirred for 30 minutes with ice cooling. 

  The precipitate was collected by filtration, washed with water and dried, giving 0.75 g of 7- [2-carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3, 4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) was obtained. 



      I. R.  (Nujol): 3360.3240.3100.1780.1680.1635 cm- '.    



   N. M. R.    (d6-DMSO, â): 3.68 (2H, s), 4.46 (2H, ABq, J = 15 Hz), 4.61 (2H, s) 5.17 (1H, d, J = 5 Hz), 5.28 (1H, dd, J = 5 and 9 Hz), 6.83 (1H, s), 7.23 (2H, broad s), 9.50 (1H, d, J = 9 Hz ), 9.53 (1H, s). 



   Example 40
When working according to Example 39 above, the following compounds could be prepared: (1) 7- [2-carboxymethoxyimino-2- (2-formamidothiazolyl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) -thiomethyl-3 cephem-4-carboxylic acid (syn isomer). 



   I. R.    (Nujol): 3200.1780.1720.1680.1545cm- '.    



   N. M. R.  (D6-DMSO, a): 3.72 (2H, ABq, J = 16 Hz), 3.96 (3H, s), 4.33 (2H, ABq, J = 14 Hz), 4.67 (2H , s), 5.17 (1H, d, J = 5Hz), 5.86 (1H, dd, J = 5 and 9 Hz), 7.47 (1H, s), 8.52 (1H, s) , 9.64 (1H, d, J = 9 Hz), 12.64 (1H, broad s).    



   (2) 7- [2-Carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-ce phem-4-carboxylic acid (syn isomer). 



   I. R.  (Nujol): 3340, 3200, 1775, 1675, 1630 cm-1. 



   (3) 7- [2-carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) , Melting point 178 to 180 C (decomposition). 



   I. R.  (Nujol): 3300.3280.1770.1670.1630cm- '.    



   N. M. R.  (DMSO-d6, a): 3.69 (2H, m), 4.32 (2H, ABq, J = 14 Hz), 4.60 (2H, m), 5.14 (1H, d, J = 5 Hz), 5.79 (1H, dd, J = 5 and 8Hz), 6.79 (1H, s), 9.47 (1H, d, J = 8Hz),
In the following preparation examples, the preparation of the starting compounds used in the above examples and reference examples is explained in more detail.    



   Production Example I
A mixture of 11.9 g 3-chloro-4-hydroxyacetophenone, 9.35 g benzyl chloride, 14.5 potassium carbonate and 60 ml dimethylformamide was stirred at 100 for 1 hour.    



  The reaction mixture was poured into 150 ml of water and extracted with ethyl acetate.  The extract was washed with an aqueous sodium chloride solution and dried over magnesium sulfate.  After the solvent had been distilled off, the residue (18 g) was recrystallized from 160 ml of ethanol, 13.2 g of 3-chloro-4-benzyloxyaceto-phenone, F. 110 to 112 C, received.    



   Production Example 2
1. ) 12.6 g of selenium dioxide powder were added over a period of 10 minutes to a solution of 19.7 g of 3-chloro-4-benzyl-oxyacetophenone in 100 ml of dry pyridine with stirring at 100 ° C. and the mixture was stirred for 3 hours stirred at the same temperature.  The precipitated selenium was filtered off and the filtrate was concentrated.  The residue was dissolved in 150 ml of water and the solution was washed with ether.  The aqueous solution was acidified while cooling with concentrated hydrochloric acid and extracted with ether. 

  The extract was washed with an aqueous sodium chloride solution, dried over magnesium sulfate and concentrated, giving 15.9 g of 2- (3 chloro-4-benzyloxyphenyl) glyoxylic acid, F. 134 to 135 C, received. 



     2nd ) The following compounds were obtained in a similar manner as in Preparation 2- (1): (1) 2- (3-nitro-4-benzyloxyphenyl) glyoxylic acid, F. 



  61-164 C. 



   (2) 2- (3-chloro-4-methoxyphenyl) glyoxylic acid, F. 



  81-82 C. 



   I. R. -Spectrum (Nujol) 2500-2600, 1715, 1670, 1600 cm-1 (3) 2- (3-mesylaminophenyl) glyoxylic acid, F. 66-68 C. 



   I. R. Spectrum (Nujol) 1560, 3250, 1720, 1670 cm-1
Production Example 3
1. A mixture of 30 g of 2- (3-nitro-4-benzyloxyphenyl) glyoxylic acid, 90 ml of concentrated hydrochloric acid and 120 ml of acetic acid were stirred at 100 ° C. for 3 hours.    600 @ nl of ice water was added to the reaction mixture with cooling, and the mixture was extracted with ethyl acetate.  The extract was washed with ice water, dried over magnesium sulfate and concentrated to dryness under reduced pressure.  

  The residue was recrystallized from a benzene / ether / petroleum ether (2/1/4) mixture.     The crystals were collected by filtration, washed with benzene and dried under reduced pressure, giving 19.0 g of 2- (3-nitro-4-hydroxyphenyl) glyoxylic acid, F.  139 to 140.4 C. 



     2nd ) The following compound was obtained in a similar manner as in Production Example 3 (1): 2- (3-chloro-4-hydroxyphenyl) glyoxylic acid, F.  114 to 116 C. 



   Production Example 4
3.32 g of 2- (3-hydroxyphenyl) glyoxylic acid and 45 ml of a 1N methanol solution of hydroxylamine were refluxed with stirring for 25 minutes.  The reaction mixture was concentrated under reduced pressure.  The residue was dissolved in 70 ml of a 1N aqueous sodium hydroxide solution.  The aqueous solution was washed with ether, acidified with dilute hydrochloric acid and then extracted with ethyl acetate.  The extract was washed, dried and treated with activated carbon.  The solvent was distilled off to obtain 2.9 g of 2-hydroxy imino-2- (3-hydroxyphenyl) acetic acid (a mixture of the syn and anti isomers). 



   I. R. Spectrum (Nujol) 3200.1700, cm-1
Production Example 5
1. ) a) 3 drops of phenolphthalein indicator were added to a solution of 5.5 g of O-methylhydroxylamine hydrochloride in 60 ml of dry methanol.  65 ml of a 1N methanol solution of sodium methylate were added dropwise to the solution with stirring at ambient temperature until the color of the solution turned purple.  O-Methylhydroxylamine hydrochloride was added in small portions until the solution became colorless.  The mixture was stirred at ambient temperature for 30 minutes.  After filtering off the precipitated sodium chloride, 9.85 g of 2- (3 hydroxyphenyl) glyoxylic acid was added to the filtrate and the mixture was refluxed for 30 minutes. 



  After the methanol was distilled off at a low temperature, a saturated aqueous sodium chloride solution was added to the residue.  The mixture was adjusted to pH 1 with 10% hydrochloric acid and extracted with 300 ml of ether.  The extract was dried over magnesium sulfate.  The ether was distilled off at low temperature to give 2-methoxyimino-2- (3-hydroxyphenyl) acetic acid (in the form of a mixture of the syn and anti isomers). 



   b) This material was dissolved in 60 ml of ether and a solution of diazomethane in ether was slowly added while cooling with ice until the color of the mixture turned yellow. 



  Immediately thereafter, acetic acid was added and the mixture was washed with an aqueous sodium bicarbonate solution and an aqueous saturated sodium chloride solution and dried over magnesium sulfate.  The ether was distilled off to obtain 10.8 g of an oily residue.  The oily residue was subjected to column chromatography on silica gel (165 g) using a benzene / ethyl acetate (9/1) mixture as a developing solvent.  First, the eluate containing the syn isomer was eluted, and the eluate was collected and concentrated to obtain 7.9 g of an oily methyl 2-methoxyimino-2- (3-hydroxyphenyl) acetate (syn isomer).  The oil was left standing to give crystals, F.  39.5 to 40.5 C.    



     I. R. -Spectrum (Nujol): 3450.1730cm- '
N. M. R. -Spectrum (CDC13.6) ppm 6.7-7.42 (4H, m)
3.98 (3H, s)
3.92 (3H, s)
After the eluate containing the syn isomer was eluted, the eluate containing the anti-isomer was eluted.  The eluate was collected and concentrated to give 1.5 g of methyl 2-methoxyimino-2- (3-hydroxyphenyl) acetate (anti-isomer).  This material was recrystallized from a benzene / petroleum ether mixture to give crystals, F.  96 to 98 C.    



     I. R. -Spectrum (Nujol) 3350.1715cm- '
N. M. R. - spectrum (CDC13.6) ppm 7.12-7.40 (1H, m)
6.96-7.02 (3H, m)
3.99 (3H, s) 3.84 (3H, s) c) 40 ml of a 2N aqueous sodium hydroxide solution became a suspension of 7.55 g of methyl-2-methoxyimino-2- (2-hydroxyphenyl) with stirring at ambient temperature ) acetate (Syn-Isomeres) in 70 ml of water was added and the mixture was stirred at ambient temperature for 1 hour.  The reaction mixture was adjusted to pH 6.5 with 10% hydrochloric acid, salted out and washed with 60 ml of ether. 

  The aqueous layer was adjusted to pH 1 with concentrated hydrochloric acid and extracted once with 100 ml and twice with 60 ml of ether. 



  The extract was washed twice with 60 ml of a saturated aqueous sodium chloride solution and dried over magnesium sulfate.  The ether was distilled off to obtain an oil.  Benzene was added and removed again (twice), giving 6.44 g of crystals of 2-methoxyimino-2- (3-hydroxyphenyl) acetic acid (Syn-Isomeres), F. 



  98 to 101 C (dec. ), received. 



   IR spectrum (Nujol) 3370.1720cm¯ '.    



   8 ml of an aqueous 2N sodium hydroxide solution were added with stirring at ambient temperature to a solution of 1.56 g of methyl 2-methoxyimino-2- (3-hydroxyphenyl) acetate (anti-isomer) in 30 ml of methanol.  After stirring for 3 hours at the same temperature, the methanol was distilled off.  Water was added to the residue and the mixture was washed with ether.  The aqueous layer was adjusted to pH 1 with 10% hydrochloric acid, salted out and extracted with ether. 



  The extract was washed with an aqueous sodium chloride solution and dried over magnesium sulfate.  The ether was distilled off to obtain 1.07 g of crystals of 2-methoxyimino-2- (3-hydroxyphenyl) acetic acid (anti-isomer).  The crystals were recrystallized from a petroleum ether / ether mixture to give 0.7 g of crystals, F.  99 to 101 C (dec. ).    



   - IR spectrum (Nujol) 3350, 1690 cm- '
2nd ) a) 3 drops of phenolphthalein indicator were added to a solution of 3.7 g of O-methylhydroxylamine hydrochloride in 45 ml of dry methanol.  39 ml of a 1N methanol solution of sodium methylate was added dropwise to the solution with stirring at ambient temperature until the color of the solution turned purple.  O-Methylhydroxylamine hydrochloride was added in small portions until the solution became colorless.  The mixture was stirred at ambient temperature for 30 minutes.  After filtering off the precipitated sodium chloride, 6.56 g of 2- (4 hydroxyphenyl) glyoxylic acid was added to the filtrate and the mixture was stirred at ambient temperature for 1 hour.  After the methanol was distilled off at a low temperature, a saturated sodium chloride aqueous solution was added to the residue. 

 

   The mixture was adjusted to pH 1 with 10% hydrochloric acid, salted out and extracted with ether. 



  The extract was dried over magnesium sulfate.  The ether was distilled off at low temperature to give 2-methoxyimino-2- (4-hydroxyphenyl) acetic acid (Syn Isomeres). 



   b) This material was dissolved in 50 ml of ether and a solution of diazomethane in ether was slowly added while cooling with ice until the color of the mixture turned yellow.   



  Immediately thereafter, acetic acid was added, and the mixture was washed with an aqueous sodium bicarbonate solution under a saturated aqueous sodium chloride solution and dried over magnesium sulfate.  The ether was distilled off to obtain 8 g of an oily residue.  The oily residue was subjected to silica gel column chromatography using a benzene / ethyl acetate (9/1) mixture as a developing solvent to obtain 6.39 g of methyl 2-methoxyimino-2- (4hydroxyphenyl) acetate (syn isomer). 



   IR spectrum (Nujol): 3350, 1720cm-1
N. M. R. -Spectrum (CDCl3, 6) ppm 7.40 (2H, d, J = 8Hz) 6.80 (2H, d, J = 8Hz)
3.96 (3H, s)
3.92 (3H, s) c) 11 ml of a 2N aqueous sodium hydroxide solution were stirred with ambient temperature to a solution of 2.1 g of methyl 2-methoxyimino-2- (4-hydroxyphenyl) acetate (Syn-Isomeres) in 30 ml of methanol was added and the mixture was stirred at ambient temperature for 18 hours.  The reaction mixture was adjusted to pH 7 with 10% chlorohydric acid and the methanol was removed.  Water was added to the residue and the mixture was washed with ether. 

  The aqueous layer was adjusted to pH 1 with 10% hydrochloric acid, salted out and extracted with ethyl acetate.  The extract was washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. 



  The ethyl acetate was distilled off to obtain 1.5 g of crystals of 2-methoxyimino-2- (4-hydroxyphenyl) acetic acid (Syn-Isomeres). 



   IR spectrum (Nujol) 3150.1700 cm-1
3rd 7 a) 2 drops of phenolphthalein indicator were added to a solution of 2.74 g of O-methylhydroxylamine hydrochloride in 30 ml of dry methanol.  A 1N methanol solution of sodium methylate was added dropwise to the solution with stirring at ambient temperature until the color of the solution turned purple.  O-Methylhydroxylamine hydrochloride was added in small portions until the solution became colorless.  The mixture was stirred at ambient temperature for 1 hour.  After the precipitated sodium chloride was filtered off, 6.75 g of 2- (3-nitro-4-hydroxyphenyl) glyoxylic acid was added to the filtrate and the mixture was stirred at ambient temperature for 1 hour. 

  After distilling off the methanol
A saturated sodium chloride aqueous solution was added to the residue at 35 ° C.  The mixture was adjusted to pH 1 with 10% hydrochloric acid and extracted with ether.  The extract was dried over magnesium sulfate.  The ether was added under reduced pressure
Distilled at 35 C, 7 g of yellow crystals of 2 methoxyimino-2- (3-nitro-4-hydroxyphenyl) acetic acid (a mixture of the syn and anti isomers). 



   b) This material was dissolved in a mixture of 15 ml of tetrahydrofuran and 100 ml of ether and a solution of diazomethane in ether was slowly added at ambient temperature until the color of the mixture turned yellow. 



  Immediately afterwards, acetic acid was added, and the
The mixture was evaporated to dryness at 35 ° C. under reduced pressure.  The residue was dissolved in an ethyl acetate / benzene (1/9) mixed solvent, using the same mixed solvent as the developing solvent, subjected to silica gel column chromatography.  The eluate containing the syn isomer was collected and concentrated to give 3.7 g of methyl 2-methoxyimino-2- (3-nitro-4-hydroxyphenyl) acetate (Syn-Isomeres), F. 



  93 to 95 "C, received
IR spectrum (Nujol) 3300.1745.1630, 1535, 1350cm-
N. M. R. -Spectrum (CDCl3, 6) ppm 10.87 (1H, s) 8.22 (1H, d, J = 2Hz) 7.86 (1H, dd, J = 2.8Hz) 7.20 (1H, d, J = 8Hz)
4.03 (3H, s)
3.95 (3H, s) c) 14 ml of a 2 N aqueous sodium hydroxide solution were stirred with ambient temperature to a solution of 3.5 g of methyl 2-methoxyimino-2- (3-nitro-4-hydroxyphenyl) acetate (Syn -Isomeres) in 70 ml of methanol and the mixture was stirred at ambient temperature for 60 hours.  The reaction mixture was evaporated to dryness under reduced pressure at 40 C and the residue was dissolved in water. 

  The solution was washed with ethyl acetate, adjusted to pH 1 with 10% hydrochloric acid with ice-cooling and extracted with ethyl acetate.  The extract was back extracted with a saturated aqueous sodium bicarbonate solution.  The aqueous extract was adjusted to pH 1 with concentrated hydrochloric acid with ice cooling and extracted with ethyl acetate.  The extract was washed with ice water and dried over magnesium sulfate.  The solvent was evaporated to dryness under reduced pressure at 40 ° C., 3.2 g of yellow crystals of 2-methoxyimino-2- (3 nitro-4-hydroxyphenyl) acetic acid (Syn-Isomeres), F.  142 to 143 C (dec. ), received. 



   IR spectrum (Nujol) 3300.2502600, 1710.1630.1600.1535, 1375 cm- '
N. M. R. - spectrum (CDCl3, 6) ppm 10.67 (2H, s)
8.33 (1H, d, J = 2Hz) 7.95 (1H, dd, J = 2.8Hz) 7.22 (1H, d, J = 8Hz)
4.13 (3H, s)
4th ) a) 6.45 g of 2- (3-chloro-4-hydroxyphenyl) glyoxylic acid and 2.74 g of O-methylhydroxylamine hydrochloride were reacted with each other in a similar manner to Production Example 5 (3) (a) to form 7 g 2 -Methoxyimino2- (3-chloro-4-hydroxyphenyl) acetic acid (mixture of syn and anti-isomers) in the form of an oil. 



   b) 7 g of 2-methoxyimino-2- (3-chloro-4-hydroxyphenyl) acetic acid (mixture of the syn and anti isomers) and 1.5 g of diazomethane were reacted with each other and the product was prepared in a manner similar to that in the Production Example 5 (3) (b) purified by column chromatography to obtain 3.0 g of crystals of methyl 2-methoxyimino-2- (3-chloro-4-hydroxyphenyl) acetate (Syn-Isomeres). 

 

   IR spectrum (film) 3450.1735, 1605, 1600cm- '
N. M. R. - Spectrum (CDCl3, 6) ppm 7.55 (1H, d, J = 2Hz) 7.37 (1H, dd, J = 2.8Hz) 6.95 (1H, d, J = 8Hz) 6.12 ( 1H, s)
3.97 (3H, s) 3.91 (311, s) c) 2.6 g of methyl 2-methoxyimino-2- (3-chloro-4-hydroxyphenyl) acetate (Syn-Isomeres) and 10.6 ml a 2N aqueous sodium hydroxide solution was treated in a similar manner as in Production Example 5 (3) (c), whereby 2.4 g of 2-methoxyimino-2- (3-chloro-4-hydroxyphenyl) acetic acid (Syn-Isomeres), F. 

   147 to 150 C (dec. ), received
IR spectrum (Nujol) 3500,2500-2600, 1745, 1610, 1600cm '
N. M. R. - spectrum (CDCI3, b) ppm 8.40 (2H, broad s)
7.65 (1H, d, J = 2 Hz)
7.40 (1H, d d, J = 2.8 Hz)
7.00 (1H, d, J = 8Hz)
4.07 (3H, s)
5. ) 2.0 g of 2- (3-hydroxyphenyl) glyoxylic acid and 1.7 g of O-allylhydroxylamine hydrochloride were reacted with each other in a similar manner as in Production Example 5 (2) (a) to give 2.7 g of 2-allyloxyimino-2 - (3-hydroxyphenyl) acetic acid (syn-isomer) in the form of an oil. 



   IR spectrum (film) 3350.25502600, 1720.1645, 1600 cm- '
6. ) 2 g of (2- (3-chloro-4-hydroxyphenyl) glyoxylic acid and 1.1 g of O-allylhydroxylamine hydrochloride were reacted with each other in a similar manner to Production Example 5 (2) (a) to form 2.5 g of 2- Allyloxyimino-2- (3 chloro-4-hydroxyphenyl) acetic acid (Syn-Isomeres) in the form of an oil. 



   IR spectrum (film) 3450.2600, 1730, 1700, 1650, 1610, 1600 cm- 'N. M. R. -Spectrum (d6-DMSO, 8) ppm 9.5-10.5 (2H, broad s) 7.52 (1H, d, J = 2Hz) 7.42 (1H, dd, J = 2.8Hz ) 7.12 (1H, d, J = 8Hz)
6.0 (1H, m)
5.40 (2H, t, J = 8Hz)
4.70 (2H, d, J = 5Hz)
7. ) A mixture of 2.0 g of 2- (3-chloro-4-hydroxyphenyl) glyoxylic acid, 1.62 g of ot-butoxycarbonylmethylhydroxylamine and 20 ml of methanol was adjusted to pH 5 to 6 with the addition of a 1N methanol solution of sodium methylate and Stirred at ambient temperature for 3 hours. 



  The reaction mixture was evaporated to dryness under reduced pressure and the residue was dissolved in a 1N aqueous sodium hydroxide solution to adjust to pH 7.0.  The aqueous solution was washed with ether, adjusted to pH 2.0 with 10% hydrochloric acid with ice-cooling and extracted with ether.  The extract was washed with water and dried over magnesium sulfate. 



  The solution was evaporated to dryness under reduced pressure, giving 2.6 g of crystals of 2-t-butoxycarbonylmethoxyimino-2- (3-chloro-4-hydroxyphenyl) acetic acid (Syn-Isomeres), F.  116 to 118 C (dec. ) received. 



   IR spectrum (Nujol) 3250.2600.1735.1690.1670.1610.1590cm- '
N. M. R. - spectrum (d6-DMSO, 6) ppm 11.00 (2H, broad s) 7.50 (1H, d, J = 2Hz) 7.40 (1H, dd, J = 2.8Hz)
7.08 (1H, d, J = 8 Hz)
4.68 (2H, s)
1.45 (9H, s). 



   8th. ) (a) 49.7 g of potassium carbonate and 45.4 g of dimethyl sulfate were added to a solution of 18.1 g of 2-hydroxyimino-2- (3-hydroxyphenyl) acetic acid (a mixture of the syn and anti-isomers) in 250 ml of dry acetone was added and the mixture was refluxed with stirring for 8.5 hours.  After the acetone was distilled off, the residue was dissolved in water and extracted with ethyl acetate.  The extract was washed with an aqueous sodium chloride solution and dried over magnesium sulfate.  The solvent was distilled off to obtain 24 g of oil.  The oil was subjected to column chromatography on silica gel using benzene as a developing solvent. 

  First, the eluate containing the syn isomer was eluted, and the eluate was collected and concentrated to obtain 9.2 g of methyl 2-methoxyimino-2 (3-methoxyphenyl) acetate (syn isomer) as an oil. 



   IR spectrum (film) 1738cm- '
N. M. R. - Spectrum (CDCI3.6) ppm 7.47-6.77 (4H, m) 4.00 (3H, s) 3.92 (3H, s)
3.82 (3H, s)
After the eluate containing the syn isomer was eluted, the eluate containing the anti-isomer was eluted.  The eluate was collected and concentrated to give 3.9 g of methyl 2-methoxyimino-2- (3-methoxyphenyl) acetate (anti-isomer), F.  66 to 68 C, received.  This substance was recrystallized from petroleum ether to give prisms, F.  65 to 65.5 C.    



   IR spectrum (Nujol) 1720 cm- '
N. M. R. - spectrum (CDCl3, 8) ppm 7.14-7.44 (1H, m)
6.80-7.04 (3H, m) 4.02 (3H, s) 3.84 (3H, s)
3.76 (3H, s) b) 1.6 g of methyl 2-methoxyimino-2- (3-methoxyphenyl) acetate (Syn-Isomeres) and 4 ml of an aqueous 2N sodium hydroxide solution were prepared in a similar manner to that in Preparation Example 5 (3) (c) treated to obtain 1.23 g of 2-methoxyimino-2- (3-methoxyphenyl) acetic acid (syn isomer) in the form of an oil. 



   IR spectrum (film) 1735 cm- '
1.6 g of methyl 2-methoxyimino-2- (3-methoxyphenyl) acetate (anti-isomer) and 4 ml of a 2N aqueous solution of sodium hydroxide were treated in a similar manner to that in Preparation 5 (3) (c) 1.3 g of 2-methoxyimino-2- (3-methoxyphenyl) acetic acid (anti-isomer), F.  97 to 98 C, in the form of colorless prisms. 



   IR spectrum (Nujol) 1695cm
9. ) (a) A solution of diazomethane in ether was added at ambient temperature to a solution of 7 g of 2-methoxy imino-2- (3-chloro-4-h, ydroxyphenyl) acetic acid (Syn-Isomeres) in 50 ml of dry ether until the The color of the mixture turned yellow.  Immediately afterwards, acetic acid was added and the reaction mixture was concentrated to dryness at 35 ° C. under reduced pressure.  The residue was subjected to column chromatography on silica gel (120 g) using a benzene / ethyl acetate (9/1) mixture as a developing solvent.  

  The first eluate was collected and concentrated under reduced pressure at 40 oC to give 3.1 g of methyl 2-methoxyimino-2- (3 chloro-4-methoxyphenyl) acetate (syn isomer) in the form of an oil. 



   IR spectrum (film) 2850, 1735, 1610, 1600, 1250 cm-1
N. M. R. - spectrum (CDCI3.6) ppm 7.57 (1H, d, J = 2Hz)
7.37 (1H, dd, J = 2.8Hz) 6.87 (1H, d, J = 8Hz)
3.97 (3H, s) 3.91 (311, s)
3.88 (3H, s) b) 2.7 g of methyl 2-methoxyimino-2- (3-chloro-4-methoxyphenyl) acetate (Syn-Isomeres) and 10.6 ml of an aqueous 2N sodium hydroxide solution treated in a similar manner as in Preparation Example (5 (3) (c), whereby 2.6 g of crystals of 2-methoxyimino-2- (3-chloro-4-methoxyphenyl) acetic acid (Syn-Isomeres), F.  133 to 135 C (dec. ), received. 



   IR spectrum (Nujol) 2500-2600, 1745, 1610.1600cm-
N. M. R. - Spectrum (CDCI3.6) ppm 9.95 (1H, broad s) 7.72 (1H, d, J = 2Hz) 7.50 (1H, dd, J = 2.8Hz) 6.92 (1H, d , J = 8Hz)
4.08 (3H, s)
3.95 (3H, s)
10th ) (a) A solution of 25 g of 2-bromopropionyl bromide in 50 ml of dry chloroform was added dropwise to a solution of 24 g of N, N-dimethylaniline in 11 g of t-butanol while stirring and with ice-cooling, and the mixture was added under 2 hours Reflux heated.  After cooling, the reaction mixture was poured into 150 ml of 6N sulfuric acid and extracted with ether. 

  The extract was washed successively with 6N sulfuric acid, water, a 10% aqueous potassium carbonate solution and water and dried over magnesium sulfate.  The solvent was distilled off to obtain 21 g of t-butyl 2-bromopropionate in the form of an oil. 



   b) 21 g of this oil were added with stirring at ambient temperature to a mixture of 16.3 N-hydroxyphthalimide, 24 g of triethylamine, 20 ml of dimethylformamide and 20 ml of dimethyl sulfoxide, and the resulting mixture was stirred at ambient temperature for 4 hours. 



  The reaction mixture was poured into 800 ml of water, and the precipitating materials were collected by filtration, washed with water and dried to obtain 22.7 g of t-butyl-2-phthalimidopropionate. 



   c) 22.7 g of this compound were dissolved in 200 ml of methylene chloride.  A solution of 9 ml of 10% hydrazine hydrate in 20 ml of methanol was added and the mixture was stirred at ambient temperature for 2 hours.  The precipitated materials were dissolved by adding an aqueous 5N ammonia solution and the aqueous layer was extracted with methylene chloride.  Two layers of methylene chloride were combined and dried over magnesium sulfate.  The solvent was distilled off under reduced pressure to obtain 13.5 g of O- (1-t-butoxycarbonylethyl) hydroxylamine in the form of an oil. 



   IR spectrum (film) 3350, 3250, 1745 cm-1 d) 2.0 g of 2- (3-chloro-4-hydroxyphenyl) glyoxylic acid and 3.2 g of O- (1-t-butoxycarbonylethyl) hydroxylamine were similar Reacted as in Preparation Example 5 (7) with one another, 3.3 g of 2- (1-t-butoxycarbonyl ethoxyimino) -2- (3-chloro-4-hydroxyphenyl) acetic acid (Syn Isomeres), F.  148 to 151 "C, received. 



   IR spectrum (Nujol) 3450.2500-2600.1725.1690.1620.1600 1600 cm- '
N. M. R. - spectrum (d6-DMSO, 6) ppm 7.46 (1H, d, J = 2Hz) 7.33 (1H, dd, J = 2.8Hz) 7.07 (1H, d, J = 8Hz) 4, 67 (1H, q, J = 6Hz) 1.50 (12H, s). 



   11. ) 3 drops of phenolphthalein indicator were added to a solution of 8.8 g of O-methylhydroxylamine hydrochloride in 60 ml of dry methanol.  105 ml of a 1N methanol solution of sodium methylate was added dropwise to the solution with stirring at ambient temperature until the color of the solution became pale pink.  O-Methylhydroxylamine hydrochloride was added in small portions until the solution became colorless.  The pH of the solution was 8.0 to 8.5.  The mixture was stirred at ambient temperature for 30 minutes.  After filtering off the precipitated sodium chloride, 16.6 g of 2- (3-hydroxyphenyl) glyoxylic acid was added to the filtrate and the mixture was stirred at ambient temperature for 1 hour. 



  After the methanol was distilled off at a low temperature, water was added to the residue.  The mixture was adjusted to pH 7 with an aqueous sodium bicarbonate solution, washed with ether, adjusted to pH 1 with 10% hydrochloric acid, salted out and extracted with ether.  The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The ether was distilled off, and the procedure in which benzene was added to the residue and distilled off was repeated twice to obtain 14.8 g of crystals of 2-methoxyimino-2- (3-hydroxyphenyl) acetic acid (Syn-Isomeres).  This compound was identified with the compound obtained in Production Example 5 (1) (c) by the IR spectrum. 



   12. ) A solution of 1.8 g of 2- (3-methoxyphenyl) glyoxylic acid in an aqueous sodium bicarbonate solution was adjusted to pH 7.0.  On the other hand, a solution of 1.4 g of O-ethylhydroxylamine hydrochloride in 20 ml of water was adjusted to pH 7.0 with sodium bicarbonate.  Both solutions were combined, adjusted to pH 5.5 with 10% hydrochloric acid and stirred overnight at ambient temperature.  The reaction mixture was adjusted to pH 7.5 with sodium bicarbonate and washed with ethyl acetate.  The aqueous layer was adjusted to pH 1.0 with concentrated hydrochloric acid under ice cooling and extracted with ethyl acetate.  The extract was washed with ice water and dried over magnesium sulfate. 

 

  The solvent was distilled off under reduced pressure to obtain 2.2 g of 2-ethoxyimino-2- (3-methoxyphenyl) acetic acid (syn isomer) in the form of an oil. 



   IR spectrum (film) 2600, 1735, 1700, 1610, 1600 cm-1
13. ) The following compounds were obtained in a similar manner as in Preparation Examples 5 (5) to 5 (7) and 5 (10) to 5 (12): (1) 2-ethoxyimino-2- (3-chloro-4- hydroxyphenyl) acetic acid (Syn-Isomeres), oil
I. R. -Spectrum (film) 3450, 2250-2600, 1700-1720, 1610, 1600 cm-1 (2) 2-ethoxyimino-2- (3-hydroxyphenyl) acetic acid (Syn Isomeres), oil
I. R. -Spectrum (film) 3400.2600, 1700-1730, 1605, 1600 cm- '(3) 2- (3-hydroxy-4-bromobenzyloxyimino) -2- (4-hydroxyphenyl) acetic acid (Syn-Isomeres), colorless powder .   



   I. R. Spectrum (Nujol) 3500, 3200, 1700 cm-1
N. M. R. - Spectrum (d6-acetone, 6) ppm 6.68-8.05 (7H, m) 5.15 (2H, s) (4) 2- (2-thienylmethoxyimino) -2- (4-hydroxyphenyl) acetic acid ( Syn-Isomeres), powder. 



   I. R. -Spectrum (Nujol) 1705 cm- '
N. M. R. - spectrum (d6-DMSO, 6) ppm 6.7-7.7 (7H, m)
5.28 (2H, s) (5) 2-allyloxyimino-2- (3-methoxyphenyl) acetic acid (Syn Isomeres), 01. 



   I. R. - Spectrum (film) 3050-3100, 2600, 1730, 1645, 1610, 1600 cm-1
N. M. R. - spectrum (d6-DMSO, 6) ppm 7.00-7.50 (4H, m)
5.80-6.30 (1H, m)
5.33 (2H, t, J = 9Hz) 4.70 (2H, d, J = 5Hz) 3.82 (3H, s) (6) 2-allyloxyimino-2- (3-chloro-4-methoxyphenyl) acetic acid (Syn-Isomeres), pale yellow oil
I. R. -Spectrum (film) 3100, 2600, 1710-1730, 1645, 1610, 1600 cm- '
N. M. R. - spectrum (d6-DMSO, 8) ppm 7.63 (1H, d, J = 2Hz) 7.50 (1H, dd, J = 2.8Hz)
7.22 (1H, d, J = 8Hz)
5.9-6.3 (1H, m)
5.33 (2H, t, J = 9Hz)
4.73 (2H, d,

   J = 5Hz) 3.91 (311, s) (7) 2-phenylthiomethoxyimino-2- (3-hydroxyphenyl) acetic acid (Syn-Isomeres) I. R. -Spectrum (film) 3300.1730cm- '
N. M. R. -Spectrum (CDCl3, #) ppm 6.8-7.7 (9H, m) 5.54 (2H, s) (8) 2-methoxyimino-2- (3-mesylaminophenyl) acetic acid (Syn-Isomeres), F .  128 C (dec. ).    



   I. R. -Spectrum (Nujol) 3300.1740cm-1 (9) 2- (3-phenylallyloxyimino) -2- (3-hydroxyphenyl) acetic acid (Syn-Isomeres), F.  115-116 C.    



     I. R. -Spectrum (Nujol) 3400, 1725 cm-1 (10) 2-methoxyimino-2- (4-dimethylamino-phenyl) acetic acid (Syn-Isomeres), F.  88-89 C (dec. ).    



   I. R. - Spectrum (Nujol) 2700-2100, 1720, 1660, 1612, 1590 cm-1
14. ) 4.1 g of acetyl chloride was added to a solution of 5 g of 2-methoxyimino-2- (3-hydroxyphenyl) acetic acid (Syn-Isomeres) in 20 ml of pyridine with stirring and ice-cooling, and the mixture was stirred for 50 minutes
Ambient temperature stirred.  The reaction mixture was poured into ice water, adjusted to pH 2.1 and extracted 3 times with ether.  The extract was washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate.  The solvent was removed thoroughly under reduced pressure to obtain 6.1 g of 2-methoxyimino-2- (3-acetoxyphenyl) acetic acid (Syn-Isomeres). 



   IR spectrum (film) 3500, 2950, 1760, 1735, 1605, 1575, 1485, 1440, 1425, 1370 cm-1
N. M. R. - spectrum (CDCl3, #) ppm 7.94 (1H, s)
7.6-7.0 (4H, m)
4.05 (3H, s)
2.30 (3H, s)
15. ) 70 ml of trichloroacetyl isocyanate was added dropwise over a period of 6 minutes at ambient temperature to a solution of 40 g of 2-methoxyimino-2- (3-hydroxyphenyl) acetic acid (Syn-Isomeres) in 200 ml of dry dioxane, and the resulting mixture was 5 hours long stirred at ambient temperature.  The dioxane was distilled off, and to the residue were added 200 ml of ethyl acetate and 200 ml of water in small portions while cooling with ice. 



  The mixture containing trichloroacetylcarbamoyl-2-methoxyimino-2- (3-trichloroacetylcarbamoyloxyphenyl) acetate was stirred at ambient temperature for 5 hours while maintaining the pH of the mixture at 6.0 to 6.4 by adding an aqueous sodium bicarbonate solution . 



  The resulting mixture was washed twice with ethyl acetate.  The aqueous layer was adjusted to pH 2 with a 10% hydrochloric acid and extracted three times with ethyl acetate.  The combined ethyl acetate extracts were washed twice with an aqueous sodium chloride solution and dried over magnesium sulfate.  The solvent was distilled off and the precipitated crystals were collected by filtration, whereby 15 g of colorless crystals of 2-methoxyimino-2- (3-carbamoyloxyphenyl) acetic acid (Syn-Isomeres), F.  163 C (dec. ), received. 



   5.4 g of the same compound were obtained from the mother liquor. 



   I. R. - Spectrum (Nujol) 3480, 3360, 1730, 1660 cm-1
N. M. R. - spectrum (d6-DMSO, 6) ppm 3.97 (3H, s) 7.16 (211, broad s) 7.1-7.7 (4H, m)
9.7 (1H, broad, s)
Production Example 6
1. A solution of 12.4 g of sodium nitrite in 150 ml of water was added dropwise with stirring at 5 to 7 C to a solution of 30 g of ethyl 4-bromoacetoacetate in 200 ml of acetic acid, and the mixture was stirred at 10 C for 2 hours.  200 ml of water was added to the reaction mixture, and the resulting mixture was extracted with 500 ml of ether. 

  The extract was washed twice with 200 ml of water and with 200 ml of an aqueous sodium chloride solution and dried over magnesium sulfate.  The solvent was distilled off under reduced pressure to obtain 32.6 g of yellowish brown crystals of ethyl 2-hydroxyimino-4-bromoacetoacetate (a mixture of the syn and anti isomers). 



   IR spectrum (film) 3350, 1740, 1710, 1620 cm-1
N. M. R. - spectrum (CDCl3, 6) ppm 8.75 (2H, broad s)
4.35 (8H, m) 1.35 (6H, m)
2nd ) 160 g of powdered potassium carbonate were added to a solution of 152 g of ethyl 2-hydroxyiminoacetoacetate (a mixture of the syn and anti isomers) in 500 ml of acetone.  With stirring, 130 g of dimethyl sulfate was added dropwise at 45 to 50 ° C. over a period of 1 hour, and the mixture was stirred for 2 hours.  An insoluble material was filtered off and the filtrate was concentrated under reduced pressure.  The insoluble matter filtered off was dissolved in 500 ml of water and this solution was added to the residue.  The mixture was extracted twice with 300 ml of ethyl acetate. 

  The extract was washed twice with 200 ml of water and with 200 ml of a saturated aqueous sodium chloride solution and dried over magnesium sulfate.  The solvent was distilled off under reduced pressure and the residue was distilled under reduced pressure, giving 145.3 g of a colorless oil of ethyl 2-methoxyiminoacetoacetate (a mixture of the syn and anti isomers), b.p.  55 to 64 "C / 0.5 mmHg. 



   IR spectrum (film) 1745.1695.1600cm-1
N. M. R. - spectrum (CDC13.6) ppm 4.33 (4H, q, J = 8Hz)
4.08 (3H, s)
3.95 (3H, s) 2.40 (3H, s)
1.63 (3H, s) 1.33 (6H, t, J = 8Hz)
3rd 100 g of bromine were added dropwise over a period of 40 minutes under reflux to a solution of 100 g of ethyl 2-methoxyiminoacetoacetate (a mixture of the syn and anti-isomers) in a mixture of 300 ml of carbon tetrachloride and 300 ml of acetic acid.  The mixture was stirred at 70 to 80 C until the evolution of hydrogen bromide stopped.  The reaction mixture was washed twice with 300 ml of water, an aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution and dried over magnesium sulfate. 

  The solution was treated with 2 g of activated carbon and concentrated under reduced pressure to give 120.8 g of ethyl 2-methoxyimino-4-bromoacetoacetate (a mixture of the syn and anti isomers). 



   IR spectrum (film) 1740.1705.1600cm-1
N. M. R. - Spectrum (CDC13, Ï) ppm4.17-4.54 (8H, m) 4.15 (3H, s)
4.13 (3H, s) 1.33 (6H, t, J = 8Hz)
4th ) A mixture of 11.1 g of selenium dioxide, 250 ml of dioxane and 5 ml of water was stirred at 110 to 115 ° C for 15 minutes to obtain a yellow solution.  26.4 g of ethyl 2- (2-mesylamino-1,3-thiazol-4-yl) acetate were added with stirring at the same temperature.  After stirring for 1 hour, the reaction mixture was decanted with heating and cooled, whereby yellow crystals precipitated out. 

  The crystals were collected by filtration, washed with dioxane and ether and dried to obtain 23.5 g of ethyl 2 (2-mesylamino-1, 3-thiazol-4-yl) glyoxylate. 



   IR spectrum (Nujol) 3300, 1718.1682cm¯ '
5. ) 13.9 g of ethyl 2- (2-mesylamino-1, 3-thiazol-4-yl) glyoxylate were added with stirring at ambient temperature to a solution of 5.0 g of sodium hydroxide in 150 ml of water.  The mixture was stirred at ambient temperature for 1 hour, adjusted to pH 7 with concentrated hydrochloric acid and washed with ethyl acetate.  The aqueous layer was adjusted to pH 0.5 with concentrated hydrochloric acid, whereby yellow crystals precipitated.  The crystals were collected by filtration, washed with water and dried, giving 10.16 g of 2- (2-mesylamino
1,3-thiazol-4-yl) glyoxylic acid was obtained. 



   IR spectrum (Nujol) 3350.1725.1650cm- '
6. ) To a solution of 14 gÄthyl-2- (2-amino-1,3-thiazol-4-yl) acetate in a mixture of 40 g pyridine and 300 ml methylene chloride were slowly added 70 ml of a diethyl ether solution of t-pentylchloroformate , which contained 0.35 mol of t-pentylchloroformate, was added over a period of 10 minutes at -20 C with stirring, and the mixture was stirred at the same temperature for 2 hours and stirred at 0 C for a further 0.5 hour.  After the reaction, the reaction mixture was poured into 200 ml of water, and then the organic layer was separated. 



  The organic layer was washed successively with 2N hydrochloric acid, water, a 5% aqueous sodium bicarbonate solution and water, and then dried over magnesium sulfate.  The solvent was distilled off from the organic layer to obtain 12 g of a dark brown oil of ethyl 2- (2-t-pentyloxycarbonylamino 1,3-thiazol-4-yl) acetate. 



   IR spectrum (liquid) 1667, 1660 (CO) cm- '
N. M. R. - spectrum (CDCl3, ô) ppm 3.75 (2H, s) 6.75 (1H, s)
7. ) 0.3 g of ethyl 2- (2-t-pentyloxycarbonylamino-1, 3-thiazol-4-yl) acetate and 0.11 g of selenium dioxide were treated in a similar manner as in Production Example 6 (4) to give 0.22 g of ethyl 2- (2-t-pentyloxycarbonylamino-1,3-thiazol-4-yl) glyoxylate in the form of a brown oil. 



   IR spectrum (liquid) 1720.1690 (CO) cm- '
NMR spectrum (CDCl3, Ï) ppm 8.3 (1H, s)
8th. ) 2.8 g of ethyl 2- (2-t-pentyloxycarbonylamino-1,3-thiazol-4-yl) glyoxylate and a solution of 0.54 g of sodium hydroxide in 20 ml of water were prepared in a similar manner to that in the preparation example 6 (5) treated to give 1.75 g of 2- (2-t-pentyloxycarbonylamino-1, 3-thiazol-4-yl) glyoxylic acid in the form of a brown powder. 



   IR spectrum (Nujol) 1730, 1680 (CO) cm- '
NMR spectrum (d6-dimethyl sulfoxide, ô) ppm 8.4 (1H, s)
9. ) A mixture of 0.37 g of ethyl 2-hydroxyimino-2- (2 amino-1,3-thiazol-4-yl) acetate (a mixture of the syn and anti-isomers), 5 ml of ethanol, 5 ml of water and 0.72 g of sodium bisulfite was stirred at 65 to 70 C for 12 hours.  The reaction mixture was concentrated and 10 ml of water was added to the residue.  The resulting mixture was salted out and extracted with ethyl acetate. 

 

  The extract was dried over magnesium sulfate and concentrated to give 0.18 g of yellow crystals of ethyl 2- (2 amino-1,3-thiazol-4-yl) glyoxylate, F.  115 to 120 C, received. 



   IR spectrum (Nujol) 3420.3250.3120.1730.1665.1612cm-1
10th ) 235 ml of sulfuryl chloride were added dropwise over a period of 20 minutes with stirring and with ice cooling to a solution of 500 g of ethyl 2-methoxyiminoacetoacetate (Syn Isomeres) in 500 ml of acetic acid.  and the mixture was stirred with water cooling overnight.  Nitrogen gas was bubbled into the reaction mixture for 2 hours, and the resulting mixture was poured into 2.5 liters of water.  After extracting with 500 ml of methylene chloride and extracting twice with 200 ml of methylene chloride, the extracts were combined.  The combined extracts were washed with a saturated aqueous sodium chloride solution and adjusted to pH 6.5 by adding 800 ml of water and sodium bicarbonate. 

  The methylene chloride layer was separated, washed with an aqueous sodium chloride solution and dried over magnesium sulfate.  The solvent was distilled off to obtain 559 g of ethyl 2-methoxyimino-4-chloroacetoacetate (syn-isomer).    



   IR spectrum (film) 1735, 1705 cm - production example 7
1. ) A mixture of 22.0 g of ethyl 2-hydroxyimino-4bromoacetoacetate (a mixture of the syn and anti isomers), 7.5 g of thioacetamide and 100 ml of benzene was heated under reflux for 3 hours.  After cooling, 10 g of triethylamine was added and the mixture was stirred for 1 hour.  An insoluble material was filtered off and the filtrate was concentrated under reduced pressure to give 8.6 g of ethyl 2-hydroxyimino-2- (2-methyl-1,3-thiazol4-yl) acetate (a mixture of Syn and Anti -Isomers) was obtained. 



  This substance was subjected to silica gel column chromatography (80 g) using benzene as a developing solvent.  First, the eluate containing the anti-isomer was eluted, collected and concentrated, whereby 2.5 g of ethyl 2-hydroxyimino-2- (2-methyl-1,3-thiazol4-yl) acetate (anti-isomer), F .  90 to 92 "C, received. 



   IR spectrum (Nujol): 1720cm- '.    



   N. M. R. Spectrum (d6-DMSO, ô) ppm 12.55 (1H, s) 8.25 (1H, s)
4.27 (2H, q, J = 7Hz)
2.63 (3H, s) 1.25 (3H, t, J = 7Hz)
After the eluate containing the anti-isomer was eluted, the eluate containing the syn-isomer was eluted, collected and concentrated to give 0.5 g of ethyl-2-hydroxyimino-2- (2-methyl-1,3-thiazole- 4-yl) acetate (Syn-Isomeres), F.  134 to 136 "C. 



     I. R. -Spectrum (Nujol): 1720 cm- '
N. M. R. - Spectrum (d6-DMSO, 6) ppm 11.81 s) 7.81 (in, s) 4.35 (2H, q, J = 7Hz) 2.70 (3H, s) 1.30 (3H, t , J = 7Hz)
2nd 3 drops of phenolphthalein indicator was added to a solution of 4.2 g of hydroxylaminohydrochloride in 60 ml of dry methanol.  60 ml of a 1N methanol solution of sodium ethylate was added dropwise to the solution with stirring at ambient temperature until the color of the solution turned purple.  Hydroxylamine hydrochloride was added in small portions until the solution became colorless. 



  The mixture was stirred at ambient temperature for 30 minutes.  After filtering off the precipitated sodium chloride, 12.5 g of 2- (2-mesylamino-1,3-thiazol4yl) glyoxylic acid was added to the filtrate, and the mixture was heated under reflux with stirring for 1.5 hours. 



  The reaction mixture was cooled, whereby crystals precipitated.  The crystals were collected by filtration and dried to give 5.5 g of crude 2-hydroxyimino-2- (2mesylamino-l, 3-thiazol-4-yl) acetic acid (a mixture of the syn and anti-isomers).  The filtrate was concentrated to a quarter of its volume and ether was added. 



   The precipitated crystals were collected by filtration, washed with ether and dried to obtain 8.78 g of the same compound.  The overall yield was
14.3 g. 



   3rd ) A mixture of 2.4 g of ethyl 2-hydroxyimino-4 bromoacetoacetate (a mixture of the syn and anti isomers) and 0.76 g of thiourea in 15 ml of ethanol was stirred at 60 C for 1 hour.  Ethanol was distilled off under reduced pressure, and water was added to the residue.  The resulting mixture was adjusted to pH 1.0 and washed with ethyl acetate.  The aqueous layer was adjusted to pH 4.5 with tritahylamine and extracted with ethyl acetate.  The extract was washed with water and a saturated aqueous sodium chloride solution and dried over magnesium sulfate.  The solvent was distilled off under reduced pressure and the residue was subjected to column chromatography on silica gel using an ethyl acetate / benzene (1/3) mixture as a developing solvent. 

  The eluates containing the syn isomer were collected and concentrated to give 0.3 g of ethyl 2-hydroxyimino-2- (2-amino-1, 3-thiazol-4-yl) acetate (syn isomer). 



   IR spectrum (Nujol) 3450, 3300, 3200, 1725, 1620 cm-
N. M. R. - spectrum (CDC13, Ï) ppm 7.65 (1H, s)
5.33 (2H, broad s) 4.40 (2H, q, J = 7.5Hz)
1.38 (3H, t, J = 7.5 Hz)
After the eluates containing the syn isomer were collected, they became a mixture of the syn and
Eluates containing anti-isomers were collected and concentrated, giving 0.3 g of ethyl 2-hydroxyimino-2- (2-amino
1,3-thiazol-4-yl) acetate (a mixture of the syn and anti-isomers) was obtained. 



   IR spectrum (Nujol) 3400.3300, 3200, 1715.1620 cm¯l
N. M. R. Spectrum (d6-DMSO, Ï) ppm 12.42 (in, broad s) 11.55 (1H, s) 7.52 (1H, s)
7.12 (4H, broad s)
6.83 (1H, s) 4.23 (4H, m) 1.26 (6H, m)
4th ) A solution of 1.1 g of ethyl 2-hydroxyimino-2- (2 amino-1,3-thiazol-4-yl) acetate (a mixture of the syn and anti isomers) in 15 ml of an aqueous 1N Sodium hydroxide solution was left at ambient temperature for 2 hours. 

  The reaction mixture was adjusted to pH 3.5 with 10% of the hydrochloric acid and the precipitating
Crystals were collected by filtration, washed with acetone and dried to give 0.52 g of 2-hydroxyimino
2- (2-amino-1,3-thiazol-4-yl) acetic acid (a mixture of the syn and anti-isomers), F.  184 to 186 C (dec. ), received. 

 

   IR spectrum (Nujol) 3200, 1670, 1530cm¯1
Production Example 8
1. ) 3.8 g of thioacetamide was added to a solution of 12.6 g of ethyl 2-methoxyimino-4-bromoacetoacetate (a mixture of the syn and anti isomers) in 50 ml of ethanol and the mixture was stirred at 50 for 5 hours C stirred. 



   The ethanol was distilled off under reduced pressure and water was added to the residue.  The obtained mixture was extracted with ethyl acetate.  The extract was washed successively with water, an aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution and dried over magnesium sulfate. 



  The solvent was distilled off under reduced pressure to obtain 9.0 g of ethyl 2-methoxyimino-2- (2-methyl1,3-thiazol-4-yl) acetate (a mixture of the syn and anti isomers). 



   2nd ) A mixture of 7.6 g of ethyl 2-methoxyimino-4-bromoacetoacetate (a mixture of the syn and anti-isomers), 3.0 g of O-ethylthiocarbamate and 5 ml of dimethylacetamide was stirred at 50 ° C. for 3 hours. The reaction mixture was added 50 ml of ethyl acetate was added, and the resulting mixture was washed with water and with a saturated aqueous sodium chloride solution and dried over magnesium sulfate.  The ethyl acetate was distilled off to obtain a crystalline residue.  The residue was washed with diisopropyl ether to give 2.35 g of ethyl 2-methoxyimino-2- (2-oxo-2,3-dihydro-1,3-thiazol-4-yl) acetate (Syn-Isomeres). 



   IR spectrum (Nujol) 3200, 1735, 1680, 1650 cm-1
N. M. R. -Spectrum (CDC13.6) ppm9.13 (1H, broad s)
6.37 (1H, s) 4.40 (2H, q, J = 6Hz) 4.01 (3H, s) 1.38 (3H, t, J = 6Hz)
The diisopropyl ether mother liquor was concentrated and the residue was subjected to column chromatography on silica gel (70 g) using a benzene / ethyl acetate (9/1) mixture as a developing solvent.  The eluate containing the syn isomer was collected and concentrated to give an additional 0.65 g of the syn isomer obtained above.  The overall yield was 3.0 g.  A benzene / ethyl acetate (5/1) mixture was then used as the developing solvent. 

  The eluate containing the anti-isomer was collected and concentrated to give 0.26 g of ethyl 2-methoxyimino-2- (2-oxo-2,3-dihydro-1,3-thiazol-4-yl) acetate (anti -Isomeres) received. 



   IR spectrum (Nujol) 3250,3200,1720, 1690 cm- '
N. M. R. -Spectrum (CDCl3, o) ppm 9.90 (1H, broad s) 7.30 (1H, s) 4.40 (2H, q, J = 6Hz)
4.03 (3H, s) 1.38 (3H, t, J = 6Hz)
3rd A solution of 17.4 g of ethyl 2-methoxyimino-4-bromoacetoacetate (a mixture of the syn and anti isomers) and 5.4 g of thiourea in 100 ml of ethanol was heated under reflux for 4 hours.  The reaction mixture was left to stand and cooled in a refrigerator, whereby crystals precipitated. 

  The crystals were collected by filtration, washed with ethanol and dried to obtain 9.5 g of ethyl 2-methoxyimino-2- (2-amino-1, 3-thiazol-4-yl) ace tathydrobromide (anti-isomer) .  The filtrate and the washings were combined and concentrated under reduced pressure.  100 ml of water was added to the residue and the mixture was washed with ether. 



  The aqueous layer was made alkaline with a 20% aqueous ammonia solution and extracted with ethyl acetate.  The extract was washed with water and a saturated aqueous sodium chloride solution and dried over magnesium sulfate.  The solvent was distilled off under reduced pressure to obtain 5.2 g of ethyl 2-methoxyimino-2- (2-amino-1, 3-thiazol-4-yl) acetate (syn isomer) in the form of a crystalline substance. 



   IR spectrum (Nujol) 3400.3300.3150.1725, 1630, 1559, cm- '
N. M. R. - spectrum (CDCl3, #) ppm 6.72 (1H, s) 5.91 (2H, broad s)
4.38 (2H, q, J = 7Hz)
4.03 (3H, s) 1.38 (3H, t, J = 7Hz)
9.5 g of the ethyl 2-methoxyimino-2- (2 amino-1,3-thiazole-4-yl) acetate hydrobromide (anti-isomer) obtained above was suspended in 200 ml of ethyl acetate and 4.0 g of triethylamine was added .  After stirring for 1 hour at ambient temperature, an insoluble material was filtered off and the filtrate was concentrated under reduced pressure, whereby 6.15 g of ethyl 2-methoxyimino-2- (2-amino1,3-thiazol-4-yl) acetate (anti Isomeres) was obtained in the form of a crystalline substance. 



   IR spectrum (Nujol) 3450.3250.3150.1730.1620cm- '.    



   N. M. R. - spectrum (CDCl3, 6) ppm 7.50 (1H, s)
5.60 (2H, broad s)
4.35 (2H, q, J = 7Hz)
4.08 (3H, s) 1.33 (3H, t, J = 7Hz)
4th ) 3 drops of phenolphthalein indicator were added to a solution of 1.25 g of O-methylhydroxylamine hydrochloride in 15 ml of dry methanol.  13 ml of a 1N methanol solution of sodium methylate was added dropwise to the solution with stirring at ambient temperature until the color of the solution turned purple.  O-Methylhydroxylamine hydrochloride was added in small portions until the solution became colorless.  The mixture was stirred at ambient temperature for 30 minutes. 

  After the precipitated sodium chloride was filtered off, 3.8 g of ethyl 2 (2-methylamino-1,3-thiazol-4-yl) glyoxylate was added to the filtrate, and the mixture was refluxed with stirring for 2 hours.  After the methanol was distilled off, the residue was dissolved in ethyl acetate.  An insoluble material was filtered off and the filtrate was concentrated.     The residue was subjected to column chromatography on silica gel using a benzene / ethyl acetate (9/1) mixture as a developing solvent.  The eluate containing the syn isomer was collected and concentrated to give 2.8 g of ethyl 2-methoxyimino-2- (2-mesylamino-1, 3-thiazol-4-yl) acetate (syn isomer) . 



   IR spectrum (Nujol) 1725 cm- '
N. M. R. - Spectrum (CDCI3.6) ppm 6.76 (1H, s) 4.44 (2H, q, J 7Hz) 4.04 (3H, s) 3.04 (3H, s) 1.37 (3H, t , J = 7Hz)
5. ) 0.33 g of powdered potassium carbonate was suspended in a solution of 0.5 g of ethyl 2-hydroxyimino-2- (2-methyl-1,3thiazol-4-yl) acetate (Syn-Isomeres) in 20 ml of acetone. 

 

   A solution of 0.3 g of dimethyl sulfate in 5 ml of acetone was added dropwise at 40 to 45 ° C. with stirring.  After stirring at the same temperature for 2 hours, an insoluble material was filtered off.  The filtrate was concentrated and water was added to the residue.  The resulting mixture was extracted with ethyl acetate.  The extract was washed successively with water, an aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution and dried over magnesium sulfate. 



  The solvent was distilled off under reduced pressure to obtain 0.5 g of ethyl 2-methoxyimino-2- (2-methyl1,3-thiazol-4-yl) acetate (syn isomer) in the form of a pale yellow oil. 



   IR spectrum (film) 1740, 1710, 1595 cm-1
N. M. R. - spectrum (CDCl3, ô) ppm 7.40 (111, s)
4.25 (2H, q, J = 7Hz) 4.03 (311, s)
2.73 (311, s)
1.38 (3H, t, J = 7 Hz)
6. ) 14.3 g of the 2-hydroxyimino-2- (2-mesylamino-1,3-thiazol-4-yl) acetic acid (a mixture of the syn and anti isomers) obtained in Preparation Example 7 (2) was dissolved in 300 ml of dry acetone suspended.  22.8 g of potassium carbonate and 20.8 g of dimethyl sulfate were added to the suspension. 



  The mixture was refluxed with stirring for 9 hours.  The acetone was distilled off from the reaction mixture, and water was added to the residue.  The resulting mixture was extracted with ethyl acetate.  The extract was washed with an aqueous sodium chloride solution and dried over magnesium sulfate.  The solvent was distilled off to obtain 13 g of an oil.  The oil was subjected to column chromatography on silica gel using a benzene / ethyl acetate (9/1) mixture as a developing solvent.  First, the eluate containing the anti-isomer was eluted, collected and concentrated.  The remaining oil (2.4 g) was ground with cooling to crystallize. 



  The crystals were collected by filtration, by adding petroleum ether to give 2.1 g of methyl 2-methoxyimino-2- (2-mesylimino-3-methyl-2,3-dihydro-1,3-thiazol-4yl) acetate (Anti-isomer). 



   IR spectrum (Nujol) 1740 cm-1
N. M. R. - spectrum (CDCl3, 6) ppm 7.90 (111, s)
4.10 (3H, s)
3.90 (3H, s)
3.47 (311, s)
3.07 (311, s)
After the eluate containing the anti-isomer was eluted, the eluate containing the syn-isomer was eluted, collected, and concentrated to give 5.5 g of crystals of methyl 2-methoxyimino-2- (2-mesylimino-3-methyl) -2,3-dihydro-1,3-thiazol-4-yl) acetate (Syn-Isomeres) was obtained. 



   IR spectrum (Nujol) 1740 cm-1
N. M. R. - spectrum (CDCl3, 6) ppm 6.72 (111, s)
4.05 (311, s)
3.92 (311, s)
3.72 (311, s)
3.01 (3H, s)
7. ) The compound shown below was obtained in a similar manner as in Production Example 8 (4):

  : Ethyl-2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetate (Syn-Isomeres)
IR spectrum (Nujol) 3400,3300,3150, 1725, 1630, 1559, cm- '
N. M. R. - spectrum (CDCl3, 6) ppm 6.72 (1H, s)
5.91 (2H, broad s)
4.38 (211, q, J = 7Hz)
4.03 (311, s)
1.38 (3H, t, J = 7 Hz)
8th. ) A mixture of 6.1 g of acetic anhydride and 2.8 g of formic acid was stirred at 50 C for 2 hours.  The resulting mixture was cooled and 4.6 g of ethyl 2-methoxyimino-2- (2-amino-1,3-thiazole-4-acetate (Syn-Isomeres) were added at 15 ° C.  After the mixture was stirred at ambient temperature for 3.5 hours, 100 ml of chilled water was added.  The resulting mixture was extracted with 200 ml of ethyl acetate. 



  The extract was washed with water and then with a saturated aqueous sodium bicarbonate solution until the wash water was slightly alkaline.  The extract was further washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate.  The solvent was distilled off and the residue was washed with diisopropyl ether, collected by filtration, and dried to give 4.22 g of ethyl 2-methoxyimino-2 (2-formamido-1,3-thiazol-4-yl) acetate (syn- Isomeres) F. 122 to 124 C (dec. ), received. 



   IR spectrum (Nujol) 3150.1728.1700cm-1
N. M. R. -Spectrum (CDCl3, o) ppm 12.58 (111, broad s)
8.95 (1H, s)
7.17 (1H, s)
4.42 (2H, q, J = 8Hz)
4.00 (3H, s)
1.37 (3H, t, J = 8 Hz)
9. ) 3 g of pyridine were added to a solution of 6.5 ethyl 2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetate (Syn-Isomeres) in a mixture of 60 ml of ethyl acetate and 20 ml of dimethylformamide admitted.  8 g of ethyl chloroformate were added dropwise to the solution with stirring at 4 C.  After adding 50 ml of water to the reaction mixture, the organic layer was separated, washed with water and then with a saturated aqueous sodium chloride solution and dried over magnesium sulfate.  The solvent was distilled off under reduced pressure. 

  The residue was subjected to column chromatography on silica gel (120 g) using an ether / petroleum ether (5/2) mixture as the eluent to give 5.4 g of ethyl 2-methoxyimino-2- (2-ethoxycarbonylamino-1, 3- thiazol-4-yl) acetate (Syn-Isomeres). 



   NMR spectrum (CDCl3, o) ppm 9.36 (1H, broad s)
7.10 (1H, s) 4.004.66 (411, m)
4.00 (3H, s) 1.20-1.60 (611, m)
10th ) 50 g of ethyl 2-methoxyimino-4-chloroacetoacetate (Syn Isomeres) were added over a period of 3 minutes with stirring at ambient temperature to a solution of 18.4 g of thiourea and 19.8 g of sodium acetate in a mixture of 250 ml of methanol and 250 ml of water added. 



  After stirring for 35 minutes at 40 to 45 C, the reaction mixture was cooled with ice and adjusted to pH 6.3 with a saturated sodium bicarbonate solution.  After stirring at the same temperature for 30 minutes, the precipitates were collected by filtration, washed with 200 ml of water and then with 100 ml of diisopropyl ether and dried to give 37.8 g of ethyl 2-methoxyimino-2- (2-amino-1, 3-thiazol-4-yl) acetate (Syn-Isomeres), F.  161 to 162 C, obtained in the form of colorless crystals. 



   IR spectrum (Nujol) 3400.3300, 3150, 1725, 1630, 1559 cm-1
N. M. R. - spectrum (CDCl3, o) ppm 6.72 (1H, s) 5.91 (2H, broad s)
4.38 (2H, q, J = 7Hz)
4.03 (3H, s) 1.38 (3H, t, J = 7Hz)
11. ) 0.3 g of ethyl 2-hydroxyimino-2- (2-methyl-1,3-thiazol-4-yl) acetate (anti-isomer) and 0.18 g of dimethyl sulfate were prepared in a similar manner to that in Preparation Example 8 ( 5) reacted with one another, giving 0.27 g of ethyl 2-methoxy imino-2- (2-methyl-1,3-thiazol-4-yl) acetate (anti-isomer) in the form of a pale yellow oil. 



   IR spectrum (film) 1750.1605cm- '
N. M. R. - spectrum (CDCl3, o) ppm 8.07 (1H, s)
4.41 (2H, q, J = 7Hz)
4.13 (3H, s) 2.75 (3H, s) 1.40 (3H, t.    J = 7Hz)
12. ) The following compound was obtained in a similar manner as in Preparation Example 8 (8): ethyl 2-methoxyimino-2- (2-formamido-1, 3-thiazol-4-yl) acetate (anti-isomer), F .  96 to 99 C (dec. ).    



   IR spectrum (Nujol) 3150.1740.1650.1600cm- '. 



   N. M. R. -Spectrum (CDCl3, #) ppm 11.20 (1H, broad s) 8.60 (1H, s)
7.90 (1H, s) 4.32 (2H, q, J = 8Hz) 4.13 (3H, s) 1.32 (3H, t, J = 8Hz)
Production Example 9
1. ) 10 ml of ethanol were added to a suspension of 2.2 g of ethyl 2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetate (Syn-Isomeres) in 12 ml of an aqueous 1N sodium hydro Oxide solution was added and the mixture was stirred at ambient temperature for 15 hours.  The reaction mixture was adjusted to pH 7.0 with 10% hydrochloric acid, and the ethanol was distilled off under reduced pressure. 

  The remaining aqueous solution was washed with ethyl acetate, adjusted to pH 2.8 with 10% hydrochloric acid and stirred with ice-cooling, whereby crystals precipitated.  The crystals were collected by filtration, washed with acetone and recrystallized from Athano, giving 1.1 g of 2-methoxyimino-2- (2 amino-1,3-thiazol-4-yl) acetic acid (Syn-Isomeres) in the form of colorless Received needles. 



   IR spectrum (Nujol) 3150, 1670, 1610, 1585 cm-1. 



   N. M. R. Spectrum (d6-DMSO, o) ppm 7.20 (2H, broad s)
6.85 (1H, s)
3.83 (3H, s)
2nd ) 1.5 ml of an aqueous 1N sodium hydroxide solution became a solution of 0.3 g of ethyl 2-methoxyimino-2 (2-methyl-1,3-thiazol-4-yl) acetate (Syn-Isomeres) in 5 ml Ethanol was added and the resulting mixture was stirred at 40 ° C for 2 hours.  The reaction mixture was adjusted to pH 7.0 with 10% hydrochloric acid, concentrated under reduced pressure, adjusted to pH 1.5 with 10% hydrochloric acid and extracted with ethyl acetate.  The extract was washed with water and a saturated aqueous sodium chloride solution and dried over magnesium sulfate. 

  The solvent was distilled off, whereby 0.14 g of a crystalline substance of 2-methoxyimino-2- (2-methyl-1, 3-thiazol-4-yl) acetic acid (Syn-Isomeres) was obtained. 



   IR spectrum (Nujol) 1730 cm-1
N. M. R. - spectrum (d6-DMSO, o) ppm 7.80 (1H, s) 3.85 (3H, s) 2.62 (3H, s)
3rd ) The compounds shown below were obtained in a similar manner as in Production Example 9 (1) to 9 (2): (1) 2-methoxyimino-2- (2-oxo-2,3-dihydro-1,3-thiazole- 4- yl) acetic acid (Syn-Isomeres)
I. R. Spectrum (Nujol) 3250, 1710, 1650 cm-1
N. M. R. Spectrum (d6-DMSO, o) ppm 10.61 (1H, broad s)
6.73 (1H, s)
3.95 (311, s) (2) 2-methoxyimino-2- (2-mesylamino-1,3-thiazol-4-yl) acetic acid (syn isomer)
I. R. Spectrum (Nujol):

  : 3150.1720cm- '
N. M. R. Spectrum (d6-DMSO, o) ppm 7.17 (1H, s)
3.93 (3H, s)
3.02 (3H, s) (3) 2-methoxyimino-2- (2-mesylimino-3-methyl-2,3-dihydro-1,3-thiazol-4-yl) acetic acid (syn isomer)
I. R. - Spectrum (Nujol): 1730 cm- '. 



   (4) 2-methoxyimino-2- (2-formamido-1,3-thiazol-4-yl) acetic acid (syn isomer), m.p.  152 C (dec. )
I. R. - Spectrum (Nujol): 3200, 2800-2100, 1950, 1600, 1600 cm-1
N. M. R. Spectrum (d6-DMSO, o) ppm 8.60 (1H, s) 7.62 (1H, s) 3.98 (1H, s) (5) 2-methoxyimino-2- (2-ethoxycarbonylamino-1, 3-thi-azol-4-yl) acetic acid (syn isomer)
I. R. - Spectrum (Nujol): 3200, 1730, 1710, 1690, 1570 cm-1. 

 

   N. M. R. - spectrum (d6-DMSO, o) ppm 12.16 (1H, broad s) 7.50 (1H, s)
7.20 (1H, broad s)
4.25 (2H, q, J = 7Hz)
3.93 (3H, s)
1.25 (3H, t, J = 7Hz)
4th ) 5 ml of pyridine were added to a suspension of 2.0 g of 2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetic acid (Syn-Isomeres) in 20 ml of ethyl acetate.  A solution of 2.5 g of bis- (2,2,2-trifluoroacetic acid) anhydride in 3 ml of ethyl acetate was added dropwise at 5 to 7 ° C. with stirring, and the mixture was stirred at 3 to 5 ° C. for 30 minutes. 



  30 ml of water was added to the reaction mixture and the ethyl acetate layer was separated.  The aqueous layer was further extracted with ethyl acetate and two layers of ethyl acetate were combined, washed with water and a saturated aqueous sodium chloride solution and dried over magnesium sulfate.  The solvent was distilled off under reduced pressure, 0.72 g of 2-methoxyimino-2- [2- (2,2,2-trifluoroacetamido) -1,3-thiazol-4-yl] acetic acid (syn isomer ) received. 



   IR spectrum (Nujol)
1725, 1590 cm-1
N. M. R. - spectrum (d6-DMSO, 6) ppm 7.68 (1H, s) 3.91 (311, s)
5. ) The following compound was obtained in a similar manner as in Production Example 9 (4): 2-methoxyimino-2- (2-acetamido-1, 3-thiazol-4-yl) acetic acid (Syn-Isomeres), F.  184 to 185 C (dec. ).    



   IR spectrum (Nujol) 3200, 3050, 1695, 1600cm-l
6. ) 3 drops of phenolphthalein indicator were added to a solution of 0.84 g of O-allylhydroxylamine hydrochloride in 10 ml of dry methanol.  6 ml of a 1N methanol solution of sodium methylate was added dropwise to the solution with stirring at ambient temperature until the color of the solution became pale pink.  0 allyl hydroxylamine hydrochloride was added in small portions until the solution became colorless.  The mixture was stirred at ambient temperature for 30 minutes.  After the precipitated sodium chloride was filtered off, 2.0 g of 2- (2-c-pentyloxycarbonylamino-1,3-thiazol-4-yl) glyoxylic acid was added to the filtrate and the mixture was stirred at ambient temperature for 1 hour. 

  After the methanol was distilled off at a low temperature, the residue was dissolved in an aqueous 1N sodium hydroxide solution. 



  The solution was washed with ether and ethyl acetate was added.  The mixture was adjusted to pH 1.5 with phosphoric acid and extracted with ethyl acetate.  The extract was washed with an aqueous sodium chloride solution and dried over magnesium sulfate.  The ethyl acetate was distilled off and the residue was washed with diisopropyl ether, collected by filtration and dried to give 1.62 g of 2-allyloxyimino-2- (2-t-pentyl oxycarbonylamino-1, 3-thiazol-4-yl) acetic acid ( Syn-Isomeres received. 



   IR spectrum (Nujol) 3200, 1712 cm-1
N. M. R. Spectrum (d6-DMSO, b) ppm 7.40 (1H, s)
6.24-5.76 (1H, m)
5.26 (2H, d d, J = 9.1OHz)
4.65 (2H, d, J = 5Hz) 1.78 (2H, q, J = 8Hz) 1.44 (6H, s)
0.88 (3H, t, J = 8Hz)
7. ) The compounds shown below were obtained in a similar manner as in Production Example 9 (6):

  : (1) 2-methoxyimino-2- (2-t-pentyloxycarbonylamino-1,3thiazol-4-yl) acetic acid (Syn-Isomeres)
IR spectrum (Nujol) 3200, 1712cm-l
N. M. R. - spectrum (d6-DMSO, 6) ppm 7.40 (1H, s) 3.88 (311, s)
1.77 (2H, q, J = 8Hz) 1.44 (6H, s)
0.88 (3H, t, J = 8Hz) (2) 2-allyloxyimino-2- (2-mesylamino-1, 3-thiazol-4-yl) -acetic acid (syn isomer). 



   I. R. -Spectrum (Nujol) 3150, 1710, 1605cm-1 (3) 2-methoxyimino-2- (2-amino-1, 3-thiazol-4-yl) acetic acid (Syn-Isomeres)
I. R. Spectrum (Nujol) 3150, 1670, 1610, 1585 cm-1
N. M. R. - spectrum (d6-DMSO, 6) ppm 7.20 (2H, broad s)
6.85 (1H, s)
3.83 (3H, s)
8th. ) 15.5 g of ethyl 2-methoxyimino-2- (2-amlno-1,3-thiazol-4-yl) acetate hydrobromide (anti-isomer) were dissolved in a solution of 4.4 g of sodium hydroxide in 150 ml of water, and the resulting solution was stirred at ambient temperature for 1 hour.  An insoluble material was filtered off and the filtrate was adjusted to pH 5.0, whereby crystals precipitated. 

  The crystals were collected by filtration and dried to obtain 8.0 g of 2-methoxyimino 2- (2-amino-1, 3-thiazol-4-yl) acetic acid (anti-isomer). 



   IR spectrum (Nujol) 3150, 1655, 1595, 1550 cm- '
N. M. R. Spectrum (d6-DMSO, S) ppm 7.53 (1H, s)
7.23 (2H, broad s)
3.99 (3H, s)
9. ) The compounds shown below were obtained in a similar manner as in Production Example 9 (8):

  : (1) 2-methoxyimino-2- (2-methyl-1,3-thiazol-4-yl) acetic acid (anti-isomer)
I. R. Spectrum (Nujol) 1730, 1590 cm-1
N. M. R. Spectrum (d6-DMSO, ö) ppm 8.10 (1H, s) 4.00 (3H, s) 2.65 (3H, s) (2) 2-methoxyimino-2- (2-mesylimino-3- methyl-2,3-dihydro-1,3-thiazol-4-yl) acetic acid (anti-isomer)
I. R. -Spectrum (nujol) 1730 cm-l (3) 2-methoxyimino-2- (2-formamido-1, 3-thiazol-4-yl) acetic acid (anti-isomer), F.  156158 C (dec. )
I. R. Spectrum (Nujol):

  : 3200,2700-2100, 1690, 1590, 1560cm-
N. M. R. - spectrum (d6-DMSO, 6) ppm 8.05 (1H, s) 4.02 (3H, s)
Production Example 10
To a solution of 30 g of 2- (2-formamidothiazol-4yl) glyoxylic acid and 12.6 g of sodium bicarbonate in 1300 ml of water was added 19.8 g of allyloxyamine hydrochloride and the mixture was stirred at ambient temperature at pH 6 for 7 hours.  500 ml of ethyl acetate was added to the reaction mixture.  After the mixture was adjusted to pH 1.9 with 10% hydrochloric acid, the ethyl acetate layer was separated.  The ethyl acetate layer was washed with an aqueous sodium chloride solution, dried over magnesium sulfate, and then the solvent was distilled off. 

  The residue was pulverized in diisopropyl ether, collected by filtration, and then dried to obtain 25.3 g of 2-allyloxyimino-2 (2-formamidothiazol-4-yl) acetic acid (syn isomer). 



   I. R.  (Nujol): 3110, 1730, 1660, 1540 cm-1
N. M. R.  (d6-DMSO, o) 4.70 (2H, m), 5.13-5.60 (2H, m), 5.73-6.27 (1H, m), 7.57 (111, s) , 8.35 (111, s)
Production Example 11
1. ) 35.2 g of sulfuryl chloride were added all at once to a stirred solution of 48.9 g of ethyl 2-ethoxyimino-3-oxobutyrate (syn isomer) in 49 ml of acetic acid at room temperature, and stirring was carried out at the same temperature for 1 hour long continued.  After the solution thus obtained was added to 200 ml of water, the solution was extracted with methylene chloride.  The extract was washed with a saturated aqueous sodium chloride solution, neutralized with an aqueous sodium bicarbonate solution and washed with water. 

  The solution was dried over magnesium sulfate and concentrated under reduced pressure to obtain 53.8 g of ethyl 2-ethoxyimino-3-oxo-4-chlorobutyrate (syn isomer) in the form of a pale yellow oil. 



   2nd ) A mixture of 38.7 g of ethyl 2-ethoxyimino-3oxo-4-chlorobutyrate, 13.2 g of thiourea, 14.3 g of sodium acetate, 95 ml of methanol and 95 ml of water was stirred at 48 C for 40 minutes.  After the resulting solution was adjusted to pH 6.5 with an aqueous sodium bicarbonate solution, the precipitates which appeared were collected by filtration and washed with diisopropyl ether, whereby 14.7 g of ethyl 2-ethoxyimino-2- (2-aminothiazol-4 -yl) acetate (syn-isomeres), F.  130 to 131 C, received. 



   I. R.  (Nujol): 3450.3275.3125.1715.1620 cm-l
3rd ) 5 g of ethyl-2-ethoxyimino-2- (2-aminothiazol-4-yl) acetate (syn isomer) were added to a mixture of 45.9 ml of 1N sodium hydroxide and 30 ml of ethanol, and 5 Stirred at room temperature for hours.  After the ethanol had been removed from the resulting solution under reduced pressure, the residue was dissolved in 60 ml of water and adjusted to pH 2.0 with 10% hydrochloric acid.  The solution was subjected to salting out, and the precipitates were collected by filtration and dried to obtain 2.9 g of 2-ethoxyimino-2- (2 aminothiazol-4-yl) acetic acid (syn isomer). 



   I. R.  (Nujol): 3625 3225 (shoulder), 3100, 1650, 1615 cm- '
N. M. R.  (d6-DMSO, ô): 1.20 (3H, t, J = 7 Hz), 4.09 (2H, q, J = 7 Hz), 6.82 (1H, s), 7.24 (2H , wide s)
4th ) 100 g of 2-ethoxyimino-2- (2-aminothiazol-4-yl) acetic acid (syn isomer), 85.5 g of formic acid and 190.1 g of acetic anhydride were treated in the same manner as in Production Example 9 (4) , whereby 99.1 g of 2-ethoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer) was obtained. 



   I. R.  (Nujol): 3200, 3140, 3050, 1700 cm-1
N. M. R.  (d6-DMSO, o): 1.18 (3H, t, J = 6 Hz), 4.22 (2H, q, J = 6 Hz), 7.56 (1H, s), 8.56 (1H , s), 12.62 (1H, broad s)
Production Example 12
The following compounds were prepared in a similar manner as in Preparation Examples 10 and 11: (1) 2-isopropoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn-isomeres), F.  168 169 C (dec. ).    



   I. R.  (Nujol): 3200, 3130, 1710, 1600, 1560 cm-1 (2) 2-butoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn-isomer)
I. R.  (Nujol): 3350,3160,3050,1700,1680,1570cm- '(3) 2-hexyloxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer), F.  115-116 C (dec. )
I. R.  (Nujol): 3170, 3070, 1720, 1700, 1660, cm-1
N. M. R.  (d6-DMSO, o): 0.6-2.1 (11H, m), A15 (2H, t, J = 6Hz), 7.53 (1H, s), 8.56 (1H, s), 12.69 (1H, s) (4) 2-pentyloxyimino-2- (2-aminothiazol-4-yl) acetic acid (syn isomer), F.  176 C (dec. )
I. R.  (Nujol):

   3160.1655.1620.1460cm- '
N. M. R.  (d6-DMSO, o): 7.20 (2H, s), 6.82 (1H, s), 4.07 (2H, t, J = 6Hz), 0.6-2.2 (9H, m ) (5) 2-Propoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer), F.  164 C (dec. )
I. R.  (Nujol): 3200, 3120, 3050, 1700, 1550 cm-1 (6) 2-pentyloxyimino-2 (2-formamidothiazol-4-yl) acetic acid (syn isomer), F.  125 C (dec. )
I. R.  (Nujol): 3200, 3140, 1700, 1565 cm-1 (7) 2-allyloxyimino-2- (2-aminothiazol-4-yl) acetic acid (syn-isomeres), F.  187 C (dec. )
I. R.  (Nujol):

   3350, 1630, 1580, 1460 cm-1 (8) 2-hexyloxyimino-2- (2-aminothiazol-4-yl) acetic acid (syn isomer), F.  174 C (dec. )
I. R.  (Nujol): 1660, 1625, 1425cm '(9) 2-isopropoxyimino-2- (2-aminothiazol-4-yl) acetic acid (syn-isomeres), F.  151 C (dec. ) (10) 2-isobutoxyimino-2- (2-aminothiazol-4-yl) acetic acid (syn isomer), F.  122-124 C (11) 2-propoxyimino-2- (2-aminothiazol-4-yl) acetic acid (syn isomer), F.  161 C (dec. ) (12) 2-isobutoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer), F.  163 C (dec. ) (13) Benzhydryl-7-amino-3- (4-nitrobenzoyloxymethyl) -3cephem-4-carboxylate hydrochloride
I. R. Spectrum (Nujol):

  : 3400.3350.1770.1720.1630.1600.1540, cm- '
N. M. R. - Spectrum (d6-DMSO, o): ppm 3.74 (2H, broad s) 5.32 (4H, m)
6.92 (1H, s)
7.64 (10 H, m)
8.12 (2H, d, J = 9Hz) 8.32 (2H, d, J = 9Hz)
Production Example 13 (1) 126.4 g of 2-hydroxyimino-2- (2-aminothiazol-4-yl) -esacetic acid ethyl ester (syn-isomer), 81.3 g of formic acid and 180 g of acetic anhydride were prepared in a similar manner to that in Preparation Example 9-4 has been treated to give 109.6 g of 2-hydroxyimino-2- (2-formamidothiazol-4-yl) ethyl acetate (syn isomer). 



   I. R.  (Nujol): 3320, 3140, 3050, 1710, 1555 cm-1
N. M. R.  (d6-DMSO, o): 1.30 (3H, t, J = 7Hz), 4.33 (2H, q, J = 7Hz), 7.54 (1H, s), 8.54 (1H, s ), 11.98 (1H, s), 12.58 (1H, s). 



   (2) A mixture of 7.97 g of chloromethylthiomethane, 15.1 g of powdered potassium iodide and 79 ml of acetone was stirred at room temperature for 1 hour, and the resulting mixture was then filtered and washed with a little acetone.  Then the washing water and the filtrate were combined and stirred into a suspension of 17.5 g of 2-hydroxyimino-2 (2-formamidothiazol-4-yl) ethyl acetate (syn isomer) and 15.5 g of powdered potassium carbonate in 300 ml of acetone .  The mixture was then stirred at room temperature for 3 hours, filtered and washed with acetone.  Then the washing water and the filtrate were combined and concentrated in vacuo.  The residue was dissolved in ethyl acetate, washed twice with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. 

  The oily residue thus obtained was subjected to column chromatography over silica gel, eluting with chloroform.  In this way, 2.4 g of 2-methylthiomethoxyimino-2- (2formamidothiazol-4-yl) ethyl acetate (syn isomer) were obtained, melting point 130 to 131 C l. R.  (Nujol): 3160, 3125, 3050, 1740, 1695 cm-1
N. M. R.    (d6-DMSO. #): 1.32 (3H, t, J = 7Hz), 2.22 (3H, s), 4.38 (2H, q, J = 7Hz), 5.33 (2H, s), 7.67 (IH, s), 8.56 (1H, s). 



   (3) A mixture of 2.4 g of 2-methylthiomethoxyimino-2 (2-formamidothiazol-4-yl) ethyl acetate (syn isomer), 23.8 ml of aqueous sodium hydroxide solution and 19.8 ml of methanol was added during 2 ' / Stirred at 30 C for 2 hours. 



  The solution thus obtained was then adjusted to a pH of 7 by adding 10% hydrochloric acid and the methanol was then distilled off under vacuum.  The pH of the aqueous solution was adjusted to 10 by adding 10% hydrochloric acid while cooling with ice, and this solution was then extracted three times with ethyl acetate.  The extracts were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo, giving 1.13 g of 2-methylthiomethoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer), melting point 157 C ( Decomposition). 



   I. R.  (Nujol): 3'10.3160.3075, 1700, 1555cm¯
N. M. R.  (d6-DMSO, o): 2.24 (3H, s).       5.31 (2H, s), 7.61 (1H, s), 8.57 (1H, s), 12.73 (1H, s). 



   Production Example 14
The following compounds could be made by operating in a manner similar to that described in the previous preparation examples. 



   (1) 2-isopropoxyimino-2- (2-formamidothiazol-4-yl) acetic acid, m.p.  168 to 169 C (decomposition) (syn isomer). 



   I. R.  (Nujol): 3200, 3130, 1710, 1600, 1560cm-1 (2) 2-butoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer). 



   I. R.  (Nujol): 3350, 3160, 3050, 1700, 1680, 1570 cm-1. 



   (3) 2-Hexyloxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn-isomer), m.p.  115 to 116 C (decomposition). 



   I. R.  (Nujol): 3170,3070,1720,1700, 1660cm '.    



   N. M. R.  (d6-DMSO, o): 0.6-2.1 (11H, m), 4.15 (2H, t, J = 6 Hz), 7.53 (1H, s), 8.56 (1H, s), 12.69 (1H, s). 



   (4) 2- (2-Formyloxyethoxy) imino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer). 



   I. R.  (Nujol): 3200, 1710, 1690 cm-1. 



   (5) 2-Benzyloxyimino-2- (2-aminothiazol-4-yl) acetic acid (syn isomer). 



   I. R.  (Nujol): 3330, 3200, 3100, 1660, 1590 cm- '.    



   (6) 2-ethoxycarbonylmethoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn-isomer), m.p.  112 C (decomposition). 



   I. R.  (Nujol): 3150, 1740, 1670, 1550 cm-1. 



   (7) 2-tert. -Butoxycarbonylmethoxyimino-2- (2-formamido-4-yl) acetic acid (syn isomer), mp, 117 C (decomposition).    



   I. R.  (Nujol): 3180, 3140, 1750, 1690, 1630 cm- '.    



   (8) 2- (3-isoxazolyl) methoxyimino-2- (2-formamidothi azol-4-yl) acetic acid (syn isomer), m.p.  110 C (decomposition). 



   I. R.  (Nujol): 3270, 3130, 1680, 1540 cm-1. 



   (9) 2-Ethoxycarbonylmethoxyimino-2- (2-aminothiazol-4-yl) acetic acid (syn isomer). 



   I. R.  (Nujol): 3170, 1720, 1660, 1620 cm-1. 



   N. M. R.  (d6-DMSO, o): 1.27 (3H, t, J = 7Hz), 4.25 (2H, q, J = 7 Hz), 4.77 (2H, s), 6.96 (111, s). 



   (10) 2- (2-ethoxyethoxy) imino-2- (2-formamidothiazol-4yl) acetic acid (syn isomer). 



   I. R.  (Nujol): 3350, 3140, 1740, 1700 cm-1. 



   Production Example 15
A solution of 17.4 g of 4-bromo-3-hydroxybenzyloxyaminophosphate in 200 ml of water and 200 ml of ethanol was stirred at room temperature and its pH was adjusted to 7.0 using sodium bicarbonate.  Then 10.0 g of 2- (2-formamidothiazol-4-yl) glycolic acid were added to the solution, and the resulting suspension was adjusted to a pH of 4.0 to 4.5.  After stirring the solution for 2 hours at room temperature, the ethanol was removed from the solution obtained in vacuo. 



  Ethyl acetate was then added to the aqueous residue and the pH was adjusted to 2.5 using 10% hydrochloric acid.  The ethyl acetate layer was separated, washed with water and dried over magnesium sulfate.  The solution was finally concentrated in vacuo to give 14.8 g of 2- (2-formamidothiazol-4-yl) -2- (4-bromo-3-hydroxybenzyloxyimino) acetic acid (syn isomer). 

 

  I. R. max / Nujol 3350, 3150, 1720, 1680, 1570 cm-1. 



   M. R.    8 (DMSO-d6-ppm): 5.13 (2H, m), 6.8 (111, dd, J = 811z, 2Hz), 7.02 (1H, d, i = 2Hz), 7.5 ( 111, d, J = 8Hz), 7.58 (111, s), 8.58 (1H, s), 10.35 (1H, broad s), 12.7 (111, broad s). 



   Production Example 16 (1) 40.0 g of 2-hydroxyimino-3-oxobutyric acid ethyl ester (syn isomer), 43.6 g of 4-fluorobenzyl chloride, 60.0 g of N, N-dimethylformamide, 52.0 g of potassium carbonate and 60.0 ml Ethyl acetate was treated in the usual manner to obtain 64.4 g of ethyl 2- (4-fluorobenzyloxyimino) -3-oxobutyrate (syn isomer).   



   I. R.  (Film): 3000, 2940, 1730, 1690, 1600 cm-1. 



     N. M. R.     (DMSO-d6, o): 1.21 (3H, t, J = 7.0 Hz), 2.34 (3H, s), 4.26 (2H, q, J = 7.0 Hz), 5 , 32 (2H, s), 6.97-7.73 (4H, m). 



   (2) 64.0 g of ethyl 2- (4-fluorobenzyloxyimino) -3-oxobutyrate (syn isomer), 35.6 g of sulfuryl chloride and 70.0 ml of acetic acid were treated in a similar manner as in Preparation 11-1), to obtain 29.55 g of 2- (4-fluorobenzyloxyimino) -3-oxo-4-chlorobutyric acid ethyl ester (syn isomer). 



   I. R.  (Film): 1720, 1600 cm-1. 



   N. M. R.  (DMSO-d6, O): 1.20 (3H, t, J = 7.0 Hz), 4.28 (2H, q, J = 7.0 Hz), 4.87 (2H, s), 5 , 36 (2H, s), 7.00-7.75 (4H, m). 



   (3) 29.0 g of ethyl 2- (4-fluorobenzyloxyimino) -3-oxo-4-chlorobutyrate (syn isomer), 8.8 g of thiourea, 7.9 g of sodium acetate, 72.5 ml of water, 60 ml of tetrahydrofuran and 72.5 ml of ethanol were treated in a similar manner as in preparation example 11- (2), 28.0 g of 2- (4-fluoro-benzyloxyimino) -2- (2-aminothiazol-4-yl) ethyl acetate ( syn isomer). 



   I. R.  (Nujol): 3450, 3150, 3100, 1710, 1620 cm-1. 



   N. M. R.  (DMSO-d6, Ô): 1.23 (3H, t, J = 7.0 Hz), 4.30 (2H, q, J = 7 Hz), 5.15 (2H, s), 6.90 (1H, s), 6.95-7.60 (4H, m). 



   (4) 25.5 g of ethyl 2- (4-fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetate (syn isomer), 1.3 g of l-methylimidazole, 118.3 ml of a 1N Sodium hydroxide solution, 52 ml of methanol and 200 ml of tetrahydrofuran were treated in a similar manner to Preparation 11- (3), giving 22.11 g of 2- (4-fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetic acid (syn isomer). 



   I. R.  (Nujol): 3650, 3450, 3300, 3150, 1630 cm-1. 



   N. M. R.  (DMSO-d6, o): 5.16 (2H, s), 6.88 (1H, s), 7.04-7.66 (4H, m). 



   (5) 23.4 g of 2- (4-fluorobenzyloxyimino-2- (2-aminothiazol4-yl) acetic acid (syn isomer), 32.2 g of bis (trimethylsilyl) acetamide, 49.9 g of 2, 2,2-Trifluoroacetic anhydride and 234 ml of dry ethyl acetate were treated in a manner similar to Preparation 9- (4), 18.9 g of 2- (4-fluorobenzyloxyimino- (2- [2- (2,2,2-trifluoroacetamido ) -thiazol- 4-yl] -acetic acid (syn isomer), melting point 180 to 182 C. 



   I. R.  (Nujol): 3200.3150.1730cm- '. 



   N. M. R.  (DMSO-d6, o): 5.25 (2H, s), 7.02-7.60 (4H, m), 7.72 (1H, s). 



   Preparation Example 17 (1) By reacting ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer) with 3,4-dichlorobenzyl chloride in a manner which is conventional per se, ethyl 2- (3,4-dichlorobenzyloxyimino) -3-oxobutyrate ( syn isomer), Ö1. 



     I. R.     (Film): 1730, 1690, 1600, 1470, 1400, 1370, 1310, 1240, 1130, 1080, 1010 cm- '.    



   N. M. R.    (CC148): 1.30 (3H, t, J = 6Hz), 2.30 (3H, s), 4.30 (2H, q, J = 6 Hz), 4.47 (2H, s), 7 , 00-7.53 (3H, m). 



   (2) Working according to preparation example 11 - (1), ethyl-2- (3,4-dichlorobenzyloxyimino) -3-oxo 4-chlorobutyrate (syn isomer), 01 was obtained. 



     1. R.     (Film): 1740, 1710, 1590, 1470, 1400, 1370, 1320, 1260, 1200, 1130, 1010 cm- '. 



   N. M. R.  (CCl4, #): 1.37 (3H, t, J = 6 Hz), 4.23 (2H, q, J = 6 Hz), 4.43 (2H, s), 5.27 (2H, s ), 7.10-7.60 (3H, m). 



   (3) Working in a similar manner to Preparation 1 1- (2) gave ethyl 2- (3,4-dichlorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetate (syn-isomer) . 



   I. R.  (Nujol): 3460, 1720, 1600, 1540, 1460, 1390, 1260, 1180, 1020, 1010. 



  880, 810 cm-1. 



      N. M. R.  (DMSO-d6,): 1.25 (3H, t, J = 7 Hz), 4.30 (2H, q, J = 7 Hz), 5.17 (2H, s), 6.93 (1H, s), 7.27-7.73 (3H, m). 



   (4) Working in a similar manner to Preparation 11- (3) gave 2- (3,4-dichlorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetic acid (syn isomer). 



   I. R.  (Nujol): 3430, 1660, 1590, 1400, 1010 cm-1. 



   N. M. R.  (DMSO-d6, o): 5.23 (2H, s), 6.93 (1H, s), 7.30-7.77 (3H, m). 



   (5) Working in a similar manner to Preparation 9- (4) gave 2- (3,4-dichlorobenzyloxyimino) -2- [2- (2,2,2-trifluoroacetamido) thiazol-4-yl] acetic acid (syn isomer). 



   I. R.  (Nujol): 1720.1580,1300,1260,1200,1160,1150cm- '.    



   N. M. R.  (DMSO-d6, O): 5.40 (2H, s), 7.47-7.93 (4H, m). 



   Production Example 18
8.3 g of hydrazine hydrate at 60 ° C. were added to a suspension of 21.0 g of N- (cinnamyloxy) phthalimide in 200 ml of ethanol, and the mixture was stirred at this temperature for 11/2 hours.  The mixture was then mixed with 22 ml of concentrated hydrochloric acid and with 220 ml of water and then filtered.  The filtrate was concentrated to give a precipitate, which was filtered off. 



  The filtrate was then adjusted to pH 7.0 and the solution containing O-cinnamylhydroxylamine was mixed with 300 ml of ethanol and 10.0 g of 2- (2-formamidothiazol-4-yl) glyoxylic acid.  The mixture thus obtained was stirred at a pH of 4.0 to 4.5 for 2 hours.  The reaction mixture was then concentrated and its pH was adjusted to 2.0 after the addition of ethyl acetate.  The organic layer was washed with an aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to give 8.6 g of 2-cinnamyloxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer). 

 

   I. R.  (Nujol): 3400-3100, 1700, 1550 cm-1. 



   N. M. R.  (DMSO-d6, D): 4.85 (2H, d, J = 5Hz), 6.2-6.93 (3H, m),, 7.2-7.72 (5H, m), 7, 6 (1H, s), 8.57 (111, s), 12.7 (1H, broad s).  


    

Claims (9)

 PATENT CLAIMS 1. Process for the preparation of the syn isomers of 3,7-disubstituted 3-cephem-4-carboxylic acid compounds of the general formula: EMI1.1  in which Rl is a group of the formula: EMI1.2  wherein R5 is hydrogen, halogen, nitro, hydroxy, lower alkoxy or acyloxy and R6 is hydroxy, lower alkoxy, acyloxy, acylamino or di (lower) alkylamino; a group of the formula: EMI1.3  wherein R7 represents amino, protected amino, hydroxy or lower alkyl; or a group of the formula: EMI1.4  wherein R8 is lower alkyl and R9 is imino, protected imino or oxo; R2 is an aliphatic hydrocarbon group that may have one or more substituents; R3 carboxy or protected carboxy;  and R4 "is an unsubstituted or one or more substituent-containing heterocyclic group, and their pharmaceutically acceptable salts, characterized in that a compound of the formula: EMI1.5  wherein Rl, R2 and R3 each have the meanings given above and R4b represents an acid residue, or a salt thereof with a compound of the general formula: R4C-SH (Vd) wherein R4 "is as defined above, or its reactive derivative on the mercapto group reacted and the compound obtained optionally converted into a pharmaceutically acceptable salt.  2. The method according to claim 1, characterized in that R 'is a group of the formula: EMI1.6  wherein R7 represents amino, acylamino, hydroxy or lower alkyl, and R2 represents lower alkyl or lower alkenyl.  3. The method according to claim 2, characterized in that the heterocyclic group R4c has one or two substituents from the group lower alkyl and di (lower) alkylamino (lower) alkyl 4. The method according to claim 3, characterized in that R4C means an optionally substituted by a lower alkyl or di (lower) alkylamino (lower) alkyl tetrazolyl group, an optionally substituted by a lower alkyl triazolyl group or an optionally substituted by a lower alkyl thiadiazolyl group.  5. The method according to claim 1, characterized in that Rl is a group of the formula: EMI1.7  wherein R8 represents lower alkyl and R9 represents acylimino, R2 represents a lower alkyl and R4c represents a tetrazolyl group which is optionally substituted by a lower alkyl.  6. The method according to claim 1, characterized in that the following compound is prepared: 7- [2-methoxyimino-2- (3-hydroxyphenyl) acetamidoj-3- (1 methyl-1 H-tetrazol-5-yl) thiomethyl-3 -cephem-4-carboxylic acid, syn isomer, 7- [2-methoxyiinino-2- [3-hydroxyphenyl) acetamidoj-3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem- 4-carboxylic acid, syn isomer, 7- [2-methoxyimino-2- (3-acetoxyphenyl) acetamido] -3- (1,3, 4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid , syn isomer, 7- [2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl -3-cephem-4-carboxylic acid, syn isomer, 7- [2-methoxyimino-2- (2-formamido-1,3-thiazol-4y1) acetamido] -3- (1,3-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid,  syn isomer, 7- [2-Methoxyimino-2- (2-amino-1,3-thiazoI-4-yl) acetami do] -3- (5-methyl-1,3, 4-thiadiazol-2-yl) thiomethyl-3 -cephem-4-carboxylic acid, syn isomer, 7- [2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (4-methyl-4H-I , 2,4-triazol-3-yl) thiomethyl-3-cephem4-carboxylic acid, syn isomer.  7. A process for the preparation of a compound of formula I, wherein R1 is a group of the formula: EMI 1.8  means in which R8 represents lower alkyl, or a pharmaceutically acceptable salt thereof, characterized in that a compound of the formula I in which R is a group of the formula: EMI2.1  wherein R7 represents protected amino, or denotes a group of the formula: EMI2.2  wherein R8 is lower alkyl and R9 represents protected imino, produces this compound or a salt thereof by an elimination reaction to remove the amino or imino protecting group and, if appropriate, the compound obtained is converted into a pharmaceutically acceptable salt.  8. Process for the preparation of a compound of the formula: EMI2.3  wherein R5a is hydrogen, halogen, nitro, lower alkoxy or acyloxy and R6 "acyloxy and R2, R3 and R4" have the meanings given in claim 1, and their pharmaceutically acceptable salts, characterized in that a compound according to the process according to claim 1 of the formula: EMI2.4  wherein R2 to Rs have the meanings given in claim 1, produces the hydroxyl group of this compound or a salt thereof and optionally converts the compound obtained into a pharmaceutically acceptable salt.  9. A process for the preparation of a compound of formula 1, wherein R2 is carboxy (lower) alkyl, or its pharmaceutically acceptable salts, characterized in that, according to the process of claim 1, a compound of formula I wherein R2 is protected carboxy (lower) alkyl means, produces, this compound or a salt thereof is subjected to an elimination reaction to remove the carboxy protecting group and the compound obtained is optionally converted into a pharmaceutically acceptable salt.  The invention relates to processes for the preparation of new syn isomers of 3,7-disubstituted 3-cephem-4-carboxylic acids and their pharmaceutically acceptable salts which have antibacterial activity, in particular against pathogenic bacteria.  British Patent No. 1 399 086 has already disclosed 3-cephem compounds, the 7-position of which is substituted by an a- (hydroxyimino) acetamido group etherified on the hydroxyimino group. Also known from British Patent No. 1,389,194 3-cephem compounds, the 7-position of which bears an a- (hydroxyimino or acyloxyimino) acylamido group.  The new compounds of the cephemcarboxylic acid series obtainable according to the invention correspond to the following formula: EMI2.5  in which: R1 denotes a group of the formula: EMI2.6  wherein Rs are hydrogen, halogen, nitro, hydroxy, lower alkoxy or acyloxy and R6 is hydroxy, lower alkoxy, acyloxy, acylamino or di (lower) alkylamino; a group of the formula EMI2.7  wherein R7 represents amino, protected amino, hydroxy or lower alkyl; or a group of the formula: EMI 2.8  wherein R8 is lower alkyl and R9 is imino, protected imino or oxo; R2 is an aliphatic hydrocarbon group that may have one or more substituents; R3 carboxy or protected carboxy;  and R4 "is an unsubstituted or one or more substituent heterocyclic group.  The process according to the invention is therefore directed to the preparation of the syn isomer of 3,7-disubstituted derivatives of ceph-3-em-4-carboxylic acid of the formula I, while the corresponding anti-isomer is due to the partial structure of the formula: EMI2.9  can be represented. When it is convenient for the explanation of the invention to express both the syn isomer and the anti isomer by a general formula, they are represented by the partial structure of the formula: ** WARNING ** End of CLMS field could overlap beginning of DESC **.