BE897719A - PROCESS FOR THE PREPARATION OF CEPHEM COMPOUNDS AND NEW PRODUCTS AS WELL AS THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM - Google Patents

Abstract

Cephem compounds having the formula (I), where R1 is an amino or acylamino group, R2 is a lower alkyl group and Y is CH or N, and their pharmaceutically acceptable salts, are products used as antibacterial agents.

Description

       

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   PATENT OF INVENTION in the name of: FUJISAWA PHARMACEUTICAL CO., LTD for: PROCESS FOR THE PREPARATION OF CEPHEM AND NEW COMPOUNDS
PRODUCTS AND PHARMACEUTICAL COMPOSITIONS
CONTAINING Priorities: Patent applications filed in Great Britain on September 10, 1982 under number 8225836 and on April 29, 1983 under number 8311815 Inventors: Takao TAKAYA-Hisashi TAKASUGI-Hideaki YAMANAKA
Kenji MIYAI-Yoshikazu INOUE

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The present invention relates to new cephem compounds and their pharmaceutically acceptable salts.

   More particularly, it relates to new cephem compounds and their pharmaceutically acceptable salts, which have antimicrobial activities, to processes for their preparation, to pharmaceutical compositions containing them, and to a process for using them in a manner therapy for the treatment of infectious diseases in humans and animals.



   Consequently, it is an object of this
 EMI2.1
 to provide for a new invention of cephem to provide for new compounds, their pharmaceutically acceptable salts, which are highly active against a number of pathogenic microorganisms.



   Another object of the present invention is to provide methods for the preparation of new cephem compounds and their pharmaceutically acceptable salts.



   Another object of the present invention is to provide pharmaceutical compositions comprising, as active ingredient, these new cephem compounds and their pharmaceutically acceptable salts.



   Yet another object of the present invention is to provide a method for the treatment of infectious diseases caused by pathogenic bacteria in humans and animals.



   The new cepphem compcs sought are new and can be represented by the following general formula (I):
 EMI2.2
 

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 EMI3.1
 where R1 is the amino group or an acylamino group, R2 is a lower alkyl group and Y is CH or N.



  According to the present invention, the new cephem compounds (I) can be prepared by various methods which are in the following schemes.



  Method 1
 EMI3.2
 S-AcylaJi 2 1 "Z tion.-R s H2N -CH = CH--" Tt 'H Y., L-L-CH = CH-- o' R2 COQ o coo-0; ,, 7 coo R- (la)
 EMI3.3
 or its derivative on the amino group or its salt
 EMI3.4
 or its salt
 EMI3.5
 Method 2 Elimination of R Z LJJ-CH. . ,,,, - o R -----------> 3 R2 carboxy R "
 EMI3.6
 (II) or its salt
 EMI3.7
 (I) or its salt
 EMI3.8
 Proceeds R1 1 Alkylation 0 Ifs LcH = CH- -CH = CH - J. cooH.



  % R, OOH OCP R
 EMI3.9
 (III) or its salt
 EMI3.10
 (I) or its salt 1

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 EMI4.1
 Process
 EMI4.2
 1 S S a, CH = CH-4, 0 -CH = CH-fi- 'acylation-N-. -CH = CH-) o \ a 0 OO (E) yl \ R2 coo (E) R2
 EMI4.3
 (Ib) or its salt
 EMI4.4
 (Ia) or its salt
 EMI4.5
 Method 5 Elimination of the group of p P. b / S Cil J-N CH = CH-0 CH = CH N 0
 EMI4.6
 (Ic) or its salt
 EMI4.7
 (Id) or its salt
 EMI4.8
 In these formulas, 1 2 and are each as defined above, 1 l. is an acylamino group, a i R is an acylamino group having a protected amino group, Re is an acylamino group having a c amino group, R3 is a protected carboxy group and Z is an acid residue.

   

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 Among the starting compounds of the present invention, the compounds (II) and (III) are new and can be prepared by the methods which are illustrated in the following schemes.



   Method A
 EMI5.1
 H2N =.



  J-N X PPh ,. ci ph-Z a 3 3 p R;
 EMI5.2
 (IV) or its reactive derivative amino group or scn salt
 EMI5.3
 (V) or its reactive derivative on the amino group or its salt
 EMI5.4
 i c Acylation Ri R3 o 0 R3 a (VI) or its salt -) S h- o - a 0 0. Pl 3 R a Ra (VII) (VIa) or its salt or its salt or its salt - -------->

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 EMI6.1
 Process B- H -P --- f '3 R 3 R3 R3
 EMI6.2
 (IV) or its reactive derivative on the amino group or its salt
 EMI6.3
 (IVa) or its salt
 EMI6.4
 pi s R -.- a 0 R.



  (IVb) Ri or its salt J <3 '0'R3 a 15/0 Ra or its salt 3 Ra
 EMI6.5
 (VIII) or its reactive derivative on the hydroxymethyl group or its salt
 EMI6.6
 cHo 1 (IX) R3 i, v or N-H 3 R a (III) or its salt or.

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 EMI7.1
 



  Method B-2) Rl oxidation Jf CHO; 7N 1 CHO 3 0 R a
 EMI7.2
 (VIII) or its reactive derivative on - hydroxymethyl group or its salt
 EMI7.3
 (IX) or its salt
 EMI7.4
 e Z. zen 1 c R --- f 0 QN-CHO "R a
 EMI7.5
 (X) or its salt
 EMI7.6
 o R R3 N il Ra a a
 EMI7.7
 (XII) or its salt
 EMI7.8
 (XIII) or its salt
 EMI7.9
 RS Reduction.-J-N'CHCH - fi-jL Reduction ': N j e (III) or its salt

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 EMI8.1
 Method B- (3) 1 die,; ; acYla- HZND (- le; R-j - j N-i - T "" 1 yN, a a a a
 EMI8.2
 (IIIb) or its salt
 EMI8.3
 (IIIc) or its reactive derivative on the amino group or its salt
 EMI8.4
 R1 s Acylation --------- "'' R 3 R3 a (IIIb)
 EMI8.5
 or its salt
 EMI8.6
 Elimination of the protection group n- * * L R -, -.



  ., .. 'NCH = CHit. Or 1 y carboxy o /; "y:: N R3 COOH
 EMI8.7
 (IIId) 'or its salt
 EMI8.8
 (III) or its salt

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 EMI9.1
 Method B- (5)
 EMI9.2
 Elimination of the Rbp protection 1 from the RCl group c N-CH = CH H = CH il .. p -. t 1 3 amino R (IIIe) (IIIf) or its salt or its salt In these formulas
 EMI9.3
 RI Z are each as defined above, Ra is the carboxy group or a protected carboxy group, protects,
X is a halogen, and
Ph is a phenyl group.



   With regard to the research compounds (I), (Ia) to (Id) and the starting compounds (II), (IIa), (III),
 EMI9.4
 (IIIa), (IIIb), (IIIc), (II (VI), (VIa), (XII) and (XIII), it should be understood that the compounds
Id), (Ille), (IIIi), sought and starting sés include the cis isomer, the trans isomer and their mixtures.

   For example, with regard to the desired compound (I), the cis isomer means a geometric isomer having the partial structure represented by the following formula. :

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 EMI10.1
    (where R2 and Y are each as defined above) and the trans isomer means the other geometric isomer having the
 EMI10.2
 partial structure represented by the following formula:

   
 EMI10.3
 
 EMI10.4
 (where are each
Suitable pharmaceutically acceptable salts of the desired compounds (I) are conventional non-toxic salts and include an organic acid salt (e.g. acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, trifluoroacetate, etc.), a mineral acid salt (for example hydrochloride, iodhydrate, sulfate, phosphate, etc.), a salt with an amino acid (for example arginine, aspartic acid, glutamic acid, etc.), and the like.



   In the preceding and subsequent descriptions of the present invention, suitable examples and illustrations of the various definitions which the present invention includes in its field of protection are explained in detail as follows.

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   The term "lower" is intended to mean 1 to 6 carbon atoms, unless otherwise indicated.



   The suitable "acyl" group and the suitable "acyl part" in the term "acylamin" as mentioned above may include the carbamoyl group, an aliphatic acyl group and an acyl group containing an aromatic ring, which is referred to as aromatic acyl group, or a heterocyclic ring, which is referred to as a heterocyclic acyl group.



   Suitable examples of this acyl group can be illustrated as follows: An aliphatic acyl group such as a lower or higher alkanoyl group (for example formyl, acetyl, succinyl, hexanoyl, heptanoyl, valeryl, stearoyie, etc. groups)
 EMI11.1
 a c an alkoxycarbonyl group, for example the methoxycarbonyl, ethoxycarbonyl, 1-Z butoxycarbonyl, t-pentyloxycarbonyl group, lower or upper (paretc); a higher or lower alkanesulfonyl group (for example the methanesulfonyl group, etanesulfonyl, etc.); or the like;
An aromatic acyl group such as an aroyl group (for example the benzoyl, toluoyl, naphthoyl group, etc.);

   a lower aralkanoyl group such as a lower phenylalkanoyl group (for example the phenylacetyl, phenylpropionyl group, etc.); an aryloxycarbonyl group (for example the phenoxycarbonyl group, naphthyloxycarbonyl, etc.) a lower aryloxyalkanoyl group (for example the phenoxyacetyl group, phenoxypropionyl, etc.); an arylglyoxyloyl group (for example the phenylglyoxyloyie group, naphthylgiyoxyloyie, etc.); an arenesulfonyl group (for example, benzenesulfonyl, p-toluenesulfonyl, etc.); or the like;

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 a heterocyclic acyl group such as a heterocyclic carbonyl group (for example thenoyl, furoyl, nicotincyl, etc.);

   a heterocyclic lower alkanoyl group (for example thienylacetyl, thiazclylacetyl, thiadiazolylacetyl, tetrazolylacetyl, etc. groups); a heterocyclic glyoxvloyl group (for example thiazolylglyoxyloyl, thienylglyoxyloyl groups, etc.); or the like; where the suitable heterocyclic part in the
 EMI12.1
 expressions "heterocyclic laughing carbonyl" and "heterocyclic glyoxyloyl", "inferred alkanoyl as mentioned above means, in more detail, a heterocyclic, monocyclic or polycyclic group, saturated or unsaturated, containing at least one heteroatom such as an atom oxygen, sulfur, nitrogen and the like.



   A particularly preferable heterocyclic group can be a heterocyclic group such as an unsaturated heterocyclic group triangular to octagonal, more preferably pentagonal or hexagonal, containing 1 to 4 nitrogen atoms, for example pyrrolyl, pyrrolinyl, imi -dazclyl, pyrazolyle, pyridyle and its N-oxide, dihydropyridyle, pyrimidyle, pyrazinyle, pyridazinyle, triazolyl, (for example 4H-1,2,4-triazolyle, IH-1, 2,3triazolyle, 2H-l, 2, 3 -triazolyl, etc), tetrazolyl (for example 1H-tetrazolyl, 2H-tetrazolyl, etc), etc;

   a saturated triangular to octagonal (preferably still pentagonal or hexagonal) heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, the pyrrolidinyl, imidazolidinyl, piperidine, piperazinyl group, etc; an unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atoms, for example, the indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, india group. zolyle, benzotriazolyle, etc;

   

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 a triangular to octagonal unsaturated heteromonocyclic group (preferably still pentagonal or hexagonal) containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, the oxazolyl, isoxazolyl, oxadiazolyl group (for example the group l, 2 , 4-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, etc) etc; a heterocyclic saturated triangular to octagonal (preferably still pentagonal or hexagonal) group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example the morpholinyl, sydnonyl group, etc;

   an unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, the benzoxazolyl, benzoxadiazolyl group, etc; a triangular to octagonal unsaturated heteromonocyclic group (preferably still pentagonal or hexagonal) containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms: for example, the thiazclyl, isothiazolyl, thiadiazolyl group (for example 1, 2, 3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1, 2,5thiadiazolyl, etc), dihydrothiazinyl, etc;

   a saturated triangular to octagonal (preferably still pentagonal to hexagonal) heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, the thiazolidinyl group, etc; a triangular to octagonal unsaturated heteromonocyclic group (preferably still pentagonal or hexagonal) containing 1 to 2 sulfur atoms, for example, thienyl, dihydrodithiinyl, dihydrodithiolyl group, etc; an unsaturated condensed heterocyclic group cor. - holding 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, the benzothiazolyl group, benzothiadiazolyle, etc;

   a triangular to octagonal unsaturated heteromonocyclic group (preferably still pentagonal to hexagonal) containing an oxygen atom, for example, the furyl group, etc;

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 a triangular to octagonal unsaturated heteromonocyclic group (preferably still pentagonal to hexagonal) containing an oxygen atom and 1 to 2 sulfur atoms, for example the dihydrooxathiinyl group, etc; an unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms, for example, benzothienyl, benzodithiinyl, etc .; an unsaturated condensed heterocyclic group containing one oxygen atom and 1 to 2 sulfur atoms, for example, the benzoxathiinyl group, etc., and the like.



   With regard to the heterocyclic group as mentioned above, the following points should be noted. Thus, in the case where the heterocyclic group is specifically a thiazolyl or thiadiazolyl group having an amino group or an amino group protected as a substituent in its molecule, this thiazolyl or thiadiazolyl group includes the tautomeric isomers, which are caused by the specific behavior of the thiazole or thiadiazole nucleus.

   Thus, for example, the thiazolyl or thiadiazolyl protected amino or amino group is represented by the formula:
 EMI14.1
 Q --- j amino group or a group R8 r \, R is R liL -'jr and Ya is CH or N), and 1 in the case where the group of formula (A) has the formula: p (A ') are each as jr-nis above), this group of R \ S can also be represented as a variant by its tautomer formula "-tL- Ya is as defined above and t'J H * - ,. k the protected imino or imino group).



  R8'-

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    (A) (or R is the Thus 1 the two groups of formula (A ') and (A ") are in a tautomeric equilibrium state which can be represented by the following equilibrium:
 EMI15.1
 (where RÖ, Ya and R are each as defined above).



   These types of tautomerism between the compounds of 2aminothiazole or thiadiazole and the compounds of 2-imino-thiazoline or thiadiazoline as indicated above are well known in the art, and it is obvious to a person skilled in the art that the two tautomeric isomers are in equilibrium and are in a reciprocal converting state, and therefore should be understood that these isomers are included in the same category of the compound per se. Consequently, the two tautomeric forms are clearly included in the scope of protection of the present invention.

   In the present description, the desired and starting compounds comprising the group of these tautomeric isomers are represented using one of the expressions, that is to say the 2-amino (or protected amino) thiazolyl or thiadiazolyl group and the formula:
 EMI15.2
 only for convenience.



   The acyl part as indicated above can have 1 to 10 suitable substituents, which are the same or different, such as a lower alkyl group (e.g. methyl, ethyl, etc.); lower alkoxy (e.g. methoxy, ethoxy, propoxy, etc.);

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   lower alkylthio (eg methylthio, ethylthio, etc.); lower alkylamino (e.g. methylamino group, etc.); lower cycloalkyl (e.g. cyclopentyl, cyclohexyl, etc.); lower cycloalkenyl (eg, cyclohexnyl, cyclchexadienyl, etc.); halogen; the amino group; an amino group protecting the hydroxy group; a protected hydroxy group; the cyano group; the nitro group;

   the carboxy group; a protected carboxy group; the sulfo group; the sulfamoyl group; the imino group; the oxo group; a lower aminoalkyl group (e.g., aminomethyl, aminoethyl, etc.); a carbamoyloxy group;
 EMI16.1
 9 3 a group of: where is hydrogen a lower alkyl group (for example the methyl, ethyl, propyl group, etc); a lower alkenyl group (for example vinyl, allyl, 2-butenyl, etc.); a lower alkynyl group (e.g., ethynyl, 2-propynyl, etc.); a lower cycloalkyl group (e.g., cyclopropyl, cyclohexyl, etc.); a lower aralkyl group such as a lower phenylalkyl group (for example benzyl, phenethyl, etc.);

   a lower carboxyalkyl group (eg, carboxymethyl, 1-carboxyethyl, etc.);
 EMI16.2
 an alkyl protected carboxy group or the like.



  In this report, when the one group part of R is above as one or more substituents, there are geometric isomers (syn and anti isomers) due to the presence of double bonds. For example, the syn isomer

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 means a geometric isomer having the group of formula:
 EMI17.1
   er. the corresponding anti-isomer signifies the other geometric isomer having the group of formula:
 EMI17.2
 The group "suitable thinner protects" can
 EMI17.3
 include an acylamino group where the "acyl" portion may be referred to as that mentioned above, a phosphonoamino, protected phosphonoamino, lower aralkyl amino group such as the group
 EMI17.4
 benzylamino, The group "phosphono phenethylamino, tritylamino;

   and the like. Including an esterified phosphono group in which the ester can be groups such as a lower alkyl ester (e.g. methyl ester, ethyl ester, propyl ester, iscpropyl ester, ester butyl, isobutyl ester, t-butyl ester, pentyl ester, t-pentyl ester, hexyl ester, etc.) or the like.



   The suitable "protected hydroxy group" may include an acyloxy group where the "acyl" part may be indicated as that mentioned above.
 EMI17.5
 



  The group "carboxy and suitable" protected lower protected "protected part" may include an esterified carboxy group where the "esterified carboxy group" may be designated as one of those as mentioned below.



   Suitable examples of the ester portion of an esterified carboxy group may be those such as an ester

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 lower alkyl (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, ester hexyl, l-cyclopropylethyl ester, etc.) which may have at least one suitable substituent, for example a lower alkanoyl ester oxy-
 EMI18.1
 lower alkoxy / lower acetoxymethyl alkyl,
Z for example the propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyioxymethyl ester, hexanoyioxymethyl ester, l (or 2) -acetoxyethyl ester,

   l (or 2 or 3) -acetoxypropyl ester, l (or 2 or 3 or 4) -acetoxybutyl ester, l (or 2) -propio-nyloxyethyl ester, ester l (or 2 or 3 ) -propionylcxypropylic, the l (or 2) -butyryloxyethyl ester, the l (or 2) -iso-butyryloxyethyl ester, the l (or 2) -pivaloyloxyethyl ester, the l (or 2) -hexanoyloxyethyl ester, '' isobutyryl-oxymethyl ester, 2-ethylbutyryloxymethyl ester, 3, 3-dimethylbutyryloxymethyl ester, l (or 2) -pentanol- oxyethyl ester, etc /, a lower alkane sulfonylalkyl ester (for example l '2-mesylethyl ester,

   
 EMI18.2
 etc), a lower mono (or di or tri) -haloalkyl ester (for example 2-iodoethyl ester, 2, 2, 2-trichloroethyl ester, etc.), a lower carbonyloxyalkyl lower alkoxy ester (for example methoxycarbonyl ester-
 EMI18.3
 oxymethyl, 2-methoxycarbonyloxyethyl ester, 1-ethoxycarbonyloxy ester - ethoxycarbonyloxymethyl, ethyl ester, l-isopropoxycarbonyloxyethyl ester, etc.), a lower phthalidylidenealkyl ester, or a lower 5-alkyl-2-oxo ester -1,3-dioxol-4-yl) lower alkyl / for example the (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl ester, the (5-ethyl-2- oxo-1,3-dioxol-4-yl) methyl, the (5-propyl-2-oxo-1,3-dioxol-4-yl) ethyl ester, and. ;

     a lower alkenyl ester (for example vinyl ester, allyl ester, etc.); a lower alkynyl ester (for example the ethynyl ester, the propynyl ester, etc.); a lower aralkyl ester which can have at least one

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 suitable substituent (e.g. benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis (methoxyphenyl) methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-dit-butylbenzyl ester, etc.); an aryl ester which may have at least one suitable substituent (e.g. phenyl ester, 4-chlorophenyl ester, tolyl ester, t-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.);

   phthalidyl ester; and the like.



   Preferable examples of the esterified carboxy groups, as mentioned above, may include a lower carbonyl alkoxy group (for example the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl group). t-pentyloxycarbonyl, hexyloxycarbonyl, l-cyclopropylethoxycarbonyl, etc.) and a phenylalkoxy (lower) carbonyl group (for example the benzyloxycarbonyl group, benzhydryloxycarbonyl group, etc.) which may have a nitro group.



   A suitable "lower alkyl" group may include a straight or branched chain group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl or the like .



     Suitable "halogen" can include chlorine, bromine, fluorine and iodine.
 EMI19.1
 



  The may include an acyloxy group, azido, halogen and the like, where the acyl part in the expression "acyloxy" and the halogen can be designated as one of those as set forth above by way of examples.



   The suitable "acylamino" group and the parts "protected amino" in the expressions "acylamino having a protected amino group" and "acylamino having an amino group" may be designated as one of those as shown above by way of examples .

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   The methods for preparing the desired compounds of the present invention are explained in detail in the following.



   PROCESS 1
The desired compound (Ib) or its salt can be prepared by reacting the compound (Ia) or its reactive derivative on the amino group or its salt with an acylating agent.



   A suitable reactive derivative on the amino group of the compound (la) may comprise an amino group of the Schiff base type or its tautomeric isomer of the enamine type formed by the reaction of the compound (Ia) with a carbonyl compound such as an aldehyde, a ketone or the like; a silyl derivative formed by the reaction of the compound (Ia) with a silyllic compound such as bis (trimethylsilyl) acetamide, mono (trimethylsilyl) acctamide or the like; a derivative formed by reaction of the compound (Ia) with phosphorus trichloride or phosgene and the like.



   A suitable acylating agent may include
 EMI20.1
 a conventional agent and can be represented by formula 4 R'-OH (XIV) (in which R 'is the acyl rump) or its: reactive derivative or its salt.



   A suitable salt of compounds (Ia) and (XIV) can comprise an acid addition salt such as an organic acid salt (for example acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.) or a mineral acid salt (e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.); a metal salt (for example the sodium salt, the potassium salt, the calcium salt, the magnesium salt, etc.); an ammonium salt; an organic amine salt (for example a triethylamine salt, a dicyclohexylamine salt, etc.) and the like.



     A suitable reactive derivative of the compound (XIV) can include an acid halide, an acid anhydride, an activated amide, an activated ester and the like. A suitable example can be an acid chloride, an azothydride

  <Desc / Clms Page number 21>

 acid;

   an acid anhydride mixed with an acid such as a substituted phosphoric acid (for example a dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, a halogenated phosphoric acid, etc.), a dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, an alkylcarbonic acid, an aliphatic carboxylic acid (e.g. pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, or l trichloroacetic acid, etc.) or an aromatic carboxylic acid (for example benzoic acid, etc.); a symmetrical acid anhydride;

   an amide activated with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; or an activated ester (e.g. cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl ester
 EMI21.1
 -qter S = CH /, vinyl ester, propargyl ester, (CH-) p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, the phenylazophenyl ester, the phenyl thioester, the p-nitrophenyl thioester, the p-cresyl thioester, the carboxymethyl thioester, the pyranyl ester, the pyridyl ester, the piperidyl ester,
 EMI21.2
 8-quinolylic thioester, etc.),

   or an ester with an N-hydroxylated compound (for example N, N-dimethylhydroxylamine, l-hydroxy-2- (1H) -pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, l-hydroxy-6-chloro -H-benzotriazole, etc.), and the like. These reactive derivatives can optionally be chosen from among them according to the type of compound (XIV) to be used.



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

  <Desc / Clms Page number 22>

 used in a mixture with water.



   When the compound (XIV) is used in the form of free acid or in the form of its salt in the reaction, the reaction is preferably carried out in the presence of a conventional condensing agent such as N, N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, -cyclohexyl-N'- (4-diethylaminocyclohexyl) carbodiimide, N, N'-diethylcarbodiimide, N, N'-diiso-
 EMI22.1
 propylcarbodiimide, N-ethyl-N'- carbodiimide, N, N-carbonylbis- pentamethylene ketene-N-cyclohexylimine, diphenyl ketene N-cyclohexylimine, ethoxyacetylene, l-alkoxy-1-chloro ethylene, trialkyl phosphite, poly (3-dimethylaminopropyl) ethyl, isopropyl polyphosphate, phosphorus oxychloride (phosphoryl chloride), phosphorus trichloride, thionyl chloride, oxalyl chloride,

   triphenylphosphine, a 2-ethyl-7-hydroxybenzisoxazolium salt, an intra-molecular salt of 2-ethyl-5- (m-sulfophenyl) isoxazolium hydroxide, l- (p-chlorobenzenesulfonyloxy) 6-chloro- 1H-benzotriazole, a so-called Vilsmeir reagent prepared by the reaction of dimethylformamide with thionyl chloride, phosgene, phosphorus oxychloride, etc; or the like.



   The reaction can also be carried out in the presence of a mineral or organic base such as an alkali metal bicarbonate, a trialkyl (lower) amine, pyridine, an N- (lower alkyl) morpholine, an N, N-di ( lower alkyl) benzylamine or the like. The reaction temperature is not critical and the reaction is usually carried out with cooling or at room temperature.



   In the present reaction, a syn isomer of the desired compound (Ib) can preferably be obtained by carrying out the present reaction of the compound (Ia) with the corresponding syn isomer of the starting compound (XIV).



   PROCESS 2
The desired compound (I) or its salt can be prepared by subjecting the compound (II) or its salt to a

  <Desc / Clms Page number 23>

 carboxy group protective group removal reaction.



   A suitable salt of the compound (II) can be indicated as being the acid addition salt indicated by way of example for the compound (Ia).



   In the present elimination reaction, all the conventional methods used in the reaction for eliminating the carboxy protecting group, for example hydrolysis, reduction, elimination using Lewis acid, etc. are applicable. When the protecting group of the carboxy radical is an ester, it can be eliminated by hydrolysis or elimination using a Lewis acid. The hydrolysis is preferably carried out in the presence of a base or an acid. A suitable base may include a mineral base and an organic base as mentioned above.



   A suitable acid can comprise an organic acid (for example formic acid, acetic acid, propionic acid, etc.) and a mineral acid (for example hydrochloric acid, hydrobromic acid, sulfuric acid, etc).



   The present hydrolysis is ordinarily carried out in an organic solvent, in water or in a mixed solvent.



   The reaction temperature is not critical and can be suitably selected depending on the kind of carboxy protecting group and the removal process.



   Removal using a Lewis acid is preferable for removing a substituted or unsubstituted lower aralkyl ester and carried out by reacting the compound (II) or its salt with a Lewis acid such as a boron trihalide (e.g. boron trichloride, boron trifluoride, etc.), a titanium tetrahalide (for example titanium tetrachloride, titanium tetrabromide, etc.), a tin tetrahalide (for example tin tetrachloride, tetrabromide) tin, etc.),

  <Desc / Clms Page number 24>

 aluminum halide (e.g. aluminum chloride, aluminum bromide, etc.), trihaloacetic acid (e.g. trichloroacetic acid, trifluoroacetic acid, etc.) or the like.

   This elimination reaction is preferably carried out in the presence of cation-trapping agents (for example anisol, phenol, etc.) and is usually carried out in a solvent such as a nitroalkane (for example nitromethane, nitroethane, etc.), an alkylene halide (for example methylene chloride, ethylene chloride, etc.), diethyl ether, carbon sulfide, or any other solvent which does not adversely affect the reaction. These solvents can be used in the form of a mixture.



   Reduction removal can preferably be applied to remove the protecting group such as a lower haloalkyl ester (e.g. 2-iodoethyl ester, 2,2, 2-trichloroethyl ester, etc.), an aralkyl ester lower (e.g. benzyl ester, etc.) or the like.

   A reduction process applied to the elimination reaction may include, for example, reduction using a combination of a metal (e.g. zinc, zinc amalgam, etc.) or a salt of chromium compound (e.g. chromous chloride, chromous acetate, etc.) and an organic acid or a minor acid (for example acetic acid, propionic acid, hydrochloric acid, etc.) and a conventional catalytic reduction in the presence of a conventional metallic catalyst (for example palladium-carbon, Raney nickel, etc.).



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



   The present carboxy group protecting group removal reaction includes, within its protection domain, in cases where one or more other protected and / or protected amino carboxy groups are converted into corresponding free and / or free amino carboxy groups during the reaction or

  <Desc / Clms Page number 25>

 the post-processing stage of the present process.



   PROCESS 3
The desired compound (I) or its salt can be prepared by reacting the compound (III) or its salt with a lower alkylating agent.



   A suitable salt of the compound (I) or (III) can be indicated as being one of those as indicated above by way of examples for the compound (Ia).



   The lower alkylating agent to be used in the present alkylation reaction may comprise a conventional agent such as a mono (or di) lower alkyl sulphate (for example dimethyl sulphate, etc.), an alkane (lower ) lower alkyl sulfonate (e.g. methyl methanesulfonate, etc.), lower haloalkane (e.g. bromomethane, iodomethane, iodoethane, etc.) or the like.



   When a lower alkyl ester of an acid is used as a lower alkylating agent, the reaction is entirely carried out in a solvent such as water, acetone, tetrahydrofuran, ethanol, ether, dimethylformamide, or any other solvent which does not adversely influence the reaction.



   The present reaction is preferably carried out in the presence of a base such as an inorganic base or an organic base as mentioned above.



   The reaction temperature is not critical, and the reaction is usually carried out at a temperature from cooling to heating around the boiling point of the solvent.



   PROCESS 4
The desired compound (Ia) or its salt can be prepared by subjecting the compound (Ib) or its salt to a deacylation reaction.



   The present deacylation reaction is carried out according to a conventional process such as hydrolysis, reduction, deacylation using a Lewis acid, a

  <Desc / Clms Page number 26>

 deacylation process by reacting the compound (Ib) with an iminohalogenating agent and then with an iminoetherification agent and, if necessary, subjecting the resulting compound to hydrolysis, or the like.



   Among these methods, "the deacylation process by reacting the compound (Ib) with an iminohalogenation agent and with an iminoetherification agent and, if necessary, subjecting the resulting compound to hydrolysis" is a preferable method .



   A suitable iminohalogenating agent can include a phosphorus halide (e.g. phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide, etc.), phosphorus oxychloride, thionyl chloride, phosgene and the like. The reaction temperature is not critical and the reaction is usually carried out with cooling or at room temperature.



   In the case where the compound (Ib) has a free carboxy group in position 4, this reaction is preferably carried out by protecting the free carboxy group with a silylating agent (for example trimethylsilyl chloride, trimethylsilylacetamide, bis ( trimethylsilyl) acetamide, etc.) before this reaction.



   A suitable iminoetherification agent reacted with the reaction product thus obtained may include an alcohol, a metal alkylate and the like.



  A suitable alcohol may include an alkanol (e.g. methanol, ethanol, propanol, isopropanol, butanol, t-butanol, 1,3-butandiol, etc.) which may be substituted by an alkoxy group ( for example methoxy, ethoxy, propoxy, isopropoxy, butoxy, etc.). A suitable metal alkylate can comprise an alkali metal alkylate (for example a sodium alkylate, a potassium alkylate, etc.), an alkaline earth metal alkylate (for example a calcium alkylate, a barium alkylate, etc.) and analogues. The reaction temperature is not

  <Desc / Clms Page number 27>

 critical and the reaction is usually carried out with cooling or at room temperature.



   The product thus obtained is, if necessary, subjected to hydrolysis. Hydrolysis can easily be carried out by pouring the reaction mixture obtained above into water, but it is possible beforehand to add a hydrophilic solvent (for example methanol, ethanol, etc.), a base (for example bicarbonate alkali metal, trialkylamine, etc.) or an acid (eg dilute hydrochloric acid, acetic acid, etc.) to water.



   The reaction temperature is not critical and can be suitably selected depending on the kind of amino group protecting group and the removal method as mentioned above, and the present reaction is preferably carried out under moderate conditions such as '' while cooling, at room temperature or at a slightly high temperature.



   The present invention includes, in its field of protection, the case where the protected carboxy group is transformed into a free carboxy group according to the reaction conditions and the kinds of protection groups during the reaction or in the post-treatment. The hydrolysis can include a process using an acid or a base and the like. These methods can be chosen according to the kind of acyl groups to be eliminated.



   A suitable acid can include an organic acid or a mineral acid, for example, formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid and the like.



  The acid suitable for the reaction can be chosen according to the kind of acyl group to be eliminated. When the deacylation reaction is carried out with the acid, it can be carried out in the presence or in the absence of a solvent. A suitable solvent can include an organic solvent, water or a mixed solvent. When trifluoroacctic acid,

  <Desc / Clms Page number 28>

 is used, the deacylation reaction can preferably be carried out in the presence of anisol.



   A suitable base may include, for example, an inorganic base such as an alkali metal hydroxide (eg soda, potash, etc.), an alkaline earth metal hydroxide (eg magnesia, lime, etc.) , an alkali metal carbonate (for example sodium carbonate, potassium carbonate, etc.), an alkaline earth metal carbonate (for example magnesium carbonate, calcium carbonate, etc.), an alkali metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate, etc.), an alkali metal acetate (e.g. sodium acetate, potassium acetate, etc), an alkaline earth metal phosphate (e.g. magnesium phosphate, calcium phosphate, etc.), an alkali metal acid phosphate (for example disodium acid phosphate, dipotassium acid phosphate, etc.), or the like,

   an organic base such as a trialkylamine (for example trimethylamine, triethylamine, etc.), picoline, N-methylpyrrolidine, N-methylmorpholine, 1, S-diazabicycloL 4, 3/0 / non-5-ene , the
 EMI28.1
 1, 4-diazabicyclo / 2, 2, 1, 5-diazabicycloL5, 4, P / undecene-5, or the like. Hydrolysis using a base is often carried out in water or in a hydrophilic organic solvent or in a mixed solvent.



   The reduction can include, for example, reduction with an alkali metal borohydride (e.g. sodium borohydride, etc.), catalytic reduction and the like.



   The reaction temperature is not critical, and the reaction is normally carried out at a temperature from cooling to heating.



   The present invention includes, in its field of protection, the cases where one type of tautomeric isomer is transformed into another type of tautomeric isomer during the reaction and / or the post-treatment stage of each process.

  <Desc / Clms Page number 29>

 



   PROCESS 5
The desired compound (Id) or its salt can be prepared by subjecting the compound (Ic) or its salt to a reaction for removing the protecting group from the amino group.



   The present elimination reaction can be carried out in a manner similar to that of method 4.



   The desired compound (I) can be transformed into its pharmaceutically acceptable salt as mentioned previously by a conventional method.



   The methods for preparing the starting compounds of the present invention are explained in detail in the following.



   PROCESS A i): (IV) - (V)
Compound (V) or its reactive derivative on the amino group or its salt can be prepared by reacting the compound (IV) or its reactive derivative on the amino group or its salt with triphenylphosphine-
The present reaction can be carried out in a solvent such as water, a phosphate buffer, acetone, chloroform, acetonitrile, nitrobenzene, methylene chloride, ethylene chloride, formamide, dimethylformamide, methanol, ethanol, ether, tetrahydrofuran, dimethyl sulfoxide, or any other organic solvent which does not adversely influence the reaction, preferably in organic solvents having strong polarities. Among the solvents, the hydrophilic solvents can be used in the form of a mixture with water.

   The present reaction is preferably carried out in the presence of an alkali metal halide (for example sodium iodide, potassium iodide, etc.), an alkali metal thiocyanate (for example sodium thiocyanate, potassium thiocyanate, etc., etc. The reaction temperature is not critical and the reaction is usually carried out at room temperature, heating slightly or strongly.

  <Desc / Clms Page number 30>

   ii): (V) (VI)
The compound (VI) or its salt can be prepared by reacting the compound (V) or its reactive derivative on the amino group or its salt with an acylating agent.

   The reaction can be carried out in a similar manner to that of method 1. iii): (VIa) + (VII) --7 (lIa)
The compound (IIa) or its salt can be prepared by reacting the compound (VIa) or its salt with the compound (VII) or its salt.



   The present reaction is usually carried out in a solvent such as acetone, dioxane, acetonitrile, chloroform, methylene chloride, dimethylformamide, tetrahydrofuran, ethyl acetate, or any other solvent which does not not adversely affect the reaction. The reaction temperature is not critical and the reaction is usually carried out by cooling, at room temperature or by heating.



   PROCESS B i): (IV) -7 (IVa)
The compound (IVa) or its salt can be prepared by reacting the compound (IV) or its reactive derivative on the amino group or its salt with an acylating agent.



   The present reaction can be carried out in a similar manner to that of process 1 mentioned above. ii): (IVb) -7 (Va)
The compound (Va) or its salt can be prepared by reacting the compound (IVb) or its salt with triphenylphosphine.



   The present reaction can be carried out in a similar manner to that of process A-i mentioned above. iii): (VIII) -> (Va)
The compound (Va) or its salt can be prepared by reacting the compound (VIII) or its reactive derivative on the hydroxymethyl group or its salt with triphenylphosphine.

  <Desc / Clms Page number 31>

 



   The present reaction can be carried out in a similar manner to that of the process A-i mentioned above. iv): (Va) + (IX) -> (IIIa)
The compound (IIIa) or its salt can be prepared by reacting the compound (Va) or its salt with the compound (IX) or its salt.



   The present reaction is usually carried out in a solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, tetrahydrofuran, dimethylformamide, ethyl acetate or any other solvent which does not adversely affect the reaction.



   The reaction is preferably carried out in the presence of a base such as an alkali metal hydroxide, an alkali metal carbonate, an alkali metal bicarbonate, a trialkylamine, pyridine or the like and preferably it is carried out under conditions roughly alkaline or neutral. The reaction temperature is not critical and the reaction is usually carried out by cooling, at room temperature or by heating.



   PROCESS B- (2) i): (VIII) - (IX)
The compound (IX) or its salt can be prepared by oxidizing the compound (VIII) or its reactive derivative on the hydroxymethyl group or its salt.



   A suitable reactive derivative on the hydroxymethyl group of the compound (VIII) can comprise the compound where the hydroxymethyl group of the compound (VIII) is converted into a methyl group having an acid residue such as a halogen (for example chlorine, bromine, etc. ), an arenesulfonyloxy group (for example the p-toluenesulfonyloxy group, p-nitrobenzenesulfonyloxy, etc.), a haloformyloxy group (for example the chloroformyloxy group, etc.) or the like.



   An oxidant suitable for use in this oxidation reaction can include conventional oxidants which can oxidize the hydroxymethyl group or its reactive derivatives on the hydroxymethyl group to formyl group.

  <Desc / Clms Page number 32>

 



   The oxidant can comprise (1) an activated dimethylsulfoxide formed by a reaction of dimethylsulfoxide and dicyclohexylcarbodiimide, dimethylsulfoxide and acetic anhydride, dimethylsulfoxide and phosphorus pentoxide, dimethylsulfoxide and sulfuric anhydride-pyridine, dimethyl sulfoxide and keteneimine, dimethyl sulfoxide and chlorine, dimethyl sulfoxide and mercuric acetate, dimethyl sulfide and N-chlorosuccinimide, dimethyl sulfide or methyl and phenyl sulfide) and chlorine, etc;

   (2) a chromium compound such as chromium trioxide-pyridine, chromium trioxide-sulfuric acid, an alkali metal dichromate (for example sodium dichromate, potassium dichromate, etc.), a chromate of lower alkyl (e.g., t-butyl chromate, etc.) and the like.



   The oxidation using dimethyl sulfoxide and dicyclohexylcarbodiimide is preferably carried out in the presence of a proton donor such as an acid (for example phosphoric acid, trifluoroacetic acid, dichloroacetic acid, etc.), of a mixture of acid and a base (eg trifluoroacetic acid-pyridine, phosphoric acid-pyridine, etc.) or the like.



   The present oxidation reaction is carried out without acid or without base or in the presence of an acid or a base and it is optionally chosen according to the kind of oxidant to be used.



   The present oxidation is carried out without solvent or with solvent such as benzene, toluene, chloroform, methylene chloride, carbon tetrachloride, diethyl ether, dimethylformamide, or any other solvent which does not adversely affect the reaction, solvent is optionally chosen according to the kind of oxidant to be used.



   In the case where the starting compound for the present oxidation reaction is in the form of a reactive derivative on the hydroxymethyl group, a suitable oxidant can

  <Desc / Clms Page number 33>

 include dimethyl sulfoxide and the like. The present oxidation is preferably carried out in the presence of a base (for example sodium bicarbonate, triethylamine, etc.).



   The oxidation reaction temperature of this process is not critical and the reaction is carried out by cooling, to room temperature, under slight or strong heating. The reaction temperature is so
 EMI33.1
 optional chosen according to the type of oxidant to be used. ii): (IX) -
The compound (X) or its salt can be prepared by subjecting the compound (IX) or its salt to an isomerization reaction.



   The present reaction is usually carried out in a solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, tetrahydrofurans, dimethylsulfoxide, ethyl acetate or any other solvent which does not adversely affect the reaction.



   The reaction is preferably carried out in the presence of a base such as an alkali metal hydroxide, an alkali metal carbonate, an alkali metal bicarbonate, a trialkylamine, pyridine or the like.



   The reaction temperature is not critical and the reaction is preferably carried out with cooling or at room temperature. iii): (X) + (XI) -> (XII)
The compound (XII) or its salt can be prepared by reacting the compound (X) or its salt with the compound (XI) or its salt. The present reaction can be carried out in a similar manner to that of process B- (l) -iv),
 EMI33.2
 previously mentioned. iv): (XII) -> The compound (XIII) or its salt can be prepared by oxidizing the compound (XII) or its salt.



   The present oxidation reaction can be carried out by a conventional method which is applied for the trans-

  <Desc / Clms Page number 34>

 
 EMI34.1
 u formation of-S-en¯ + ¯, using an oxidant, such as JI acid- peracetic acid, ozone, hydrogen peroxide, periodic acid or the like.



   The present reaction is ordinarily carried out in a solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, tetrahydrofuran, ethyl acetate or any other solvent which does not not adversely affect the reaction.



   The reaction temperature is not critical and the reaction is preferably carried out with cooling or at room temperature. v): (XIII) -7 '(IIIa)
The compound (IIIa) or its salt can be prepared by reducing the compound (XIII) or its salt.



   The present reduction can be carried out by a conventional method which is applied to the transformation of into-S-, for example using - Sphosphorus trichloride, a combination of stannous chloride and acetyl chloride, a combination of iodide of an alkali metal (eg sodium iodide, etc.) and a trihaloacetic anhydride (eg trifluoroacetic anhydride, etc.) and the like.



   The present reduction is usually carried out in a solvent such as acetone, dioxane, acetonitrile, dimethylformamide, benzene, hexane, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, or 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 or at room temperature.



   PROCESS B- (3) i): (IIIb) ---- 7 (IIIc)
The compound (IIIc) or its derivative reactive on the amino group or its salt can be prepared by subjecting the compound (IIIb) or its salt to a deacylation reaction.

  <Desc / Clms Page number 35>

 



   The present reaction can be carried out in a similar manner to that of process 4 mentioned above. ii): (IIIc) -> (IIIb)
The compound (IIIb) or its salt can be prepared by reacting the compound (IIIc) or its reactive derivative on the amino group or its salt with an acylating agent.



   The present reaction can be carried out in a similar manner to that of process 1 mentioned above.



   PROCESS B- (4) i): (IIId) (III)
The compound (III) or its salt can be prepared by subjecting the compound (IIId) or its salt to the reaction for removing the protecting group from the carboxy group.



   The present reaction can be carried out in a similar manner to that of process 2 mentioned above.



   PROCESS B- (5)
The desired compound (IIIf) or its salt can be prepared by subjecting the compound (III) or its salt to a reaction for removing the protecting group from the amino group.



   A suitable salt of the compound (Ille) can be indicated as being one of those given as examples for the compound (I).



   The elimination reaction is carried out according to a conventional process such as hydrolysis, reduction, a process treating the compound (IIIe), where the protected amino part is an acylamino group, with an iminohalogenating agent, an iminoetherification and then, if necessary, hydrolyzing the resulting product; or the like. The hydrolysis may include a process using an acid or a base or hydrazine and the like. These methods can be chosen according to the kind of protection groups to be eliminated.



   Among these methods, hydrolysis using an acid is one of the most common and preferable methods for removing protective groups such as a substituted or unsubstituted alkoxycarbonyl group, for example

  <Desc / Clms Page number 36>

 t-pentyloxycarbonyl, lower alkanoyl group (e.g. formyl, acetyl group, etc.), cycloalkoxycarbonyl group, substituted or unsubstituted aralkoxycarbonyl group, aralkyl group (e.g. trityl group), substituted phenylthio group, group substituted aralkylidene, substituted alkylidene group, substituted cycloalkylidene group or the like.

   A suitable acid includes an organic or inorganic acid such as formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid and the like, and the very suitable acid is an acid which can easily be removed from the reaction mixture in a conventional manner such as distillation under reduced pressure, for example formic acid, trirluoroacetic acid, hydrochloric acid, etc. The acids can be chosen according to the kind of protection to be eliminated. When the elimination reaction is carried out with an acid, it can be carried out in the presence or in the absence of a solvent. A suitable solvent includes water, a conventional organic solvent or mixtures thereof.



   The elimination reaction using tri acid: luoroac6tique can be carried out in the presence of anisol.



  Hydrolysis using hydrazine is commonly applied to remove a protective group from the amino group, of the phthaloyl or succinyl type.



   Elimination using a base is used to remove an acyl group such as the trifluoroacetyl group. A suitable base can include a mineral base and an organic base.



   Reduction removal is generally applied to remove the protecting group, for example a haloalkoxycarbonyl group (for example the trichloroethoxycarbonyl group, etc.), a substituted or unsubstituted aralkoxycarbonyl group (for example the benzyloxycarbonyl group, etc.), group 2 -pyridylmethoxycarbonyl, etc.



  A suitable reduction may include, for example, a reduction with an alkali metal borohydride (for example

  <Desc / Clms Page number 37>

 sodium borohydride, etc.), reduction with a combination of a metal (e.g. tin, zinc, iron, etc.) or that metal with a metal salt compound (e.g. chromium chloride, l chromate acetate, etc.) and an organic or mineral acid (for example acetic acid, propionic acid, hydrochloric acid, etc.); and catalytic reduction. A suitable catalyst includes a conventional catalyst, for example Raney nickel, platinum oxide, palladium-carbon and the like.



   Among the protecting groups, the acyl group can generally be removed by hydrolysis. Especially, the halogen-substituted alkoxycarbonyl and 8quinolyloxycarbonyl groups are usually removed by treating with a heavy metal such as copper, zinc or the like.



   Among the protecting groups, the acyl group can also be eliminated by treating with an imirohalogenation agent (for example phosphorus oxychloride, etc.) and an iminoetherification agent such as a lower alkanol (for example methanol, ethanol, etc.) if necessary, followed by hydrolysis.



   The reaction temperature is not critical and can conveniently be selected depending on the kind of amino group protecting group and the removal method as mentioned above, and the reaction is preferably carried out in a moderate state such as while cooling or at a slightly elevated temperature.



   The present invention includes, in its field of protection, the cases where another or more other protected amino groups and / or protected carboxy groups are transformed into free amino groups and / or into corresponding free carboxy groups during the reaction or the step of post-processing of the present process.



   The desired compounds (I) and their pharmaceutically acceptable salts of the present invention are new compounds which exhibit strong antibacterial activity and inhibit the growth of a large number of

  <Desc / Clms Page number 38>

 pathogenic microorganisms including Gram-positive and Gram-negative bacteria and are useful as antimicrobial agents. For therapeutic purposes, the compounds according to the present invention can be used in the form of conventional pharmaceutical preparations which contain these compounds, as active ingredients, mixed with a pharmaceutically acceptable carrier such as a solid or organic or inorganic liquid suitable. for oral, parenteral or external administration.

   The pharmaceutical preparations can be in solid form such as capsules, tablets, dragees, ointments or suppositories, or in liquid form such as solutions, suspensions or emulsions. If desired, auxiliary preparations, stabilizers, wetting or emulsifying agents, buffers and other commonly used additives may be included in the above preparations.



   While the dose of the compounds varies according to the age or condition of the patient, an average single dose of approximately 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the compounds according to the present invention has been shown to be effective in treating infectious diseases caused by pathogenic bacteria. In general, amounts between 1 mg / organism and about 6000 mg / organism or even more can be administered per day.



   To illustrate the usefulness of the desired compound, the antimicrobial activities of a representative compound of the present invention are presented below.



  Minimum inhibition concentration (A) Experimental procedure
The in vitro antibacterial activity was determined by the double dilution method on an agaragar plate as described below.



   The content of a culture loop, performed
 EMI38.1
 overnight, from each experimental strain in a 0 trypticase-soy broth (10 viable cells per ml)

  <Desc / Clms Page number 39>

 was caused to develop in streaks or bands on agar-agar-infusion of heart (agar-agar-HI) containing gradual concentrations of the representative experimental compound, and the minimum inhibition concentration (MIC) was expressed in ug / ml after incubation at 370C for 20 hours.



  (B) Experimental compounds (1) A 7- / 2- (5-amino-1,2,4,4-thiadiazol-3-yl) -2- ethoxyiminoacetamido] -3- [2- (1-methyl-3-pyridinio ) vinyl] - 3-cephem-4-carboxylate (syn-isomer) (cis, trans mixture).



   (2) A 7- / 2- (5-amino-1,2,4,4-thiadiazol-3-yl) -2-
 EMI39.1
 ethoxyiminoacetamido / -3-2- cephem-4-carboxylate (syn isomer) (trans isomer).



  (C) Results
 EMI39.2
 
 <tb>
 <tb> (1-methyl-3-pyridinio) <SEP> vinyl / -3-C, <SEP> M. <SEP> (jugf / ml) <SEP>
 <tb> Strains <SEP> experiments
 <tb> (1) <SEP> (2)
 <tb> Escherichia <SEP> coli <SEP> 35 <SEP> < <SEP> 0.025 <SEP> < <SEP> 0.025
 <tb> Proteus <SEP> vulgaris <SEP> 2 <SEP> 0.050 <SEP> 0.50
 <tb> Citrobacter <SEP> freundii <SEP> 75 <SEP> 0.780 <SEP> 1.56
 <tb> Enterobacter <SEP> cloacae <SEP> 60 <SEP> 0.050 <SEP> 0.050
 <tb>
 
The following preparations and examples are given to illustrate the present invention in more detail.



   Preparation of the starting compounds of the present invention Preparation 1
1) Jones' reagent (14.5 ml) was added dropwise to a suspension of 7- [2- (2-formamidothiazol-4-yl) -2-methoxyiminoacetamidc / -3-hydroxymethyl-3- benzhydryl cephem-4-carboxylate (syn isomer) (19.5 g)

  <Desc / Clms Page number 40>

 in acetone (300 ml) between 0 and 30C with stirring and the mixture was stirred for 20 minutes at the same temperature. The reaction mixture was filtered and the filtrate was washed with acetone.



   To the mixture of the filtrate and the washings was added ethyl acetate (300 ml), washed with brine and dried with magnesium sulfate.



   The solution was evaporated and the residue was sprayed into diethyl ether to give 7- / 2- (2-formamidothiazol-4-yl) -2-methoxyiminoacetamidj0 / -3- formyl-3-cephem-4- benzhydryl carboxylate (syn isomer) (13.7 g).



  IR (Nujol): 3250.1780, 1720.1670, 1600.1540 cm-1
 EMI40.1
 NMR (DMSO-d-): 3.67 (2H, s), 3.95 (3H, s), 5.45 (1H, d, o J = 5Hz), 6.15 dd, J = 5.8Hz ), 7, 30 (1H, s), 7, 23-7, 77 (11H, m), 8, 57 (1H, s), 9, 53 (1H, s), 9, 83 (1H, d, J = 8Hz), 12.70 (1H, s).



  2) A solution of benzhydryl 7-L2- 2-methoxyiminoacetamidQ / -3-formyl-3-cephem-4-carboxylate (syn isomer) (3 g) and triethylamine (0.45 g) in tetrahydrofuran (30 ml) ) was stirred at room temperature for 40 minutes. To the reaction mixture was added ethyl acetate (50 ml) and washed with 3% hydrochloric acid and brine. The organic solution was dried over magnesium sulfate and evaporated. The residue was sprayed on diisopropyl ether to give 7-L2- (2-formamidothiazol-4-yl) -2-methoxyiminoacetamido] -3-formyl- 2-cephem-4-carboxylate (syn isomer) (2.48 g).



  IR (Nujol): 1780.1730, 1665 cm NMR (DMSO-d): 3.93 (3H, s), 5.3 (1H, d, J = 4Hz), 5.43 (1H, s), 5 , 73 (1H, d. D, J = 4.8Hz), 6.83 (1H, s), 7.13-
7.72 (10H, m), 7.53 (1H, s), 8.3 (1H, s), 8.57 (1H, s),
9.40 (1H, s), 9.80 (1H, d, J = 8Hz), 12.63 (1H, large s).
 EMI40.2
 



  3) To a solution of 7-L2-methoxyimino-2- formamidothiazol-4-yl) o boxylate

  <Desc / Clms Page number 41>

 
 EMI41.1
 3-pyridazinylmethy1triph2ny1phosphonium osphonium (1.15 g) in methylene chloride (40 ml) and in water (40 ml) was added tetra-n-butylammonium acid sulfate (25 mg).



  The solution was adjusted to pH 8.5 with 20% aqueous potassium carbonate solution and stirred at room temperature for 3 hours. The resulting solution was adjusted to pH 2.0 with 10% hydrochloric acid. The separated organic layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to chromatography on
 EMI41.2
 column on silica gel to give 7- / 2-methoxyimino-2-pyridazinyl) vinyl / -2-cephem-4-carboxylate yrL p (syn isomer) (trans isomer) (0.2 g).



  IR (Nujol): 3170, 1778.1740, 1670.1620 cm-1 J NMR (DMSO-d.): 3.90 (3H, s), 5.30 (IH, d, J = 4Hz),
5.67 (1H, dd, J = 4Hz, 8Hz), 5.80 (1H, s), 6.83 (1H, s),
6.9-7.7 (16H, m), 8.47 (1H, s), 9.0 (1H, m), 9.68 (1H, d, J = 8Hz), 12.6 (1H, large s).
 EMI41.3
 



  4) a solution of benzhydryl 7-L2-methoxyimino-2formamidothiazol 2-cephem-4-carboxylate (syn isomer) (trans isomer) (2.1 g) in methylene chloride (40 ml), a solution was added 70% m-chloroperbenzoic acid (0.87 g) in methylene chloride (20 ml) at -35 ° C with stirring. The reaction mixture was stirred at the same temperature for 20 minutes. The resulting solution was washed with a 5% aqueous sodium bicarbonate solution. The separated organic layer was concentrated under reduced pressure and the residue was triturated in liisopropyl ether to give 7- [2-methoxyimido-2- (2-forma-midothiazole-4-yl) acetamido l-oxide ] -3- [2- (3-pyridazinyl) vinyl] -3 cephem-4-benzhydryl carboxylate (syn-isomer) (trans-isomer) (1.85 g).

  <Desc / Clms Page number 42>

 



  IR (Nujol): 3200.1786, 1710 (shoulder), 1665 in NMR (DMSO-d.): 3.91 (2H, m), 3.97 (3H, s), 5, 17 (1H, d,
J = 5Hz), 6.13 (1H, dd, J = 5Hz, 8Hz), 7.12 (1H, s),
7.2-7.8 (14H, m), 8.10 (1H, d, J = 16Hz), 8.58 (1H, s),
9.17 (1H, m), 9.33 (1H, d, J = 8Hz), 12.4 (1H, large s).



   5) To a solution of 7-L2-methoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- [2- (3-pyridazinyl) vinyl / -3-cephem-4-carboxylate oxide benzhydryl (syn isomer) (trans isomer) (1.8 g) in N, N-dimethylformamide (18 ml), phosphorus trichloride (0.45 ml) was added at -30 ° C with stirring. The reaction mixture was stirred at -15 to -10 ° C for 30 minutes and added dropwise to ice-water (100 ml). The suspension was adjusted to pH 7.5 with a saturated aqueous solution of sodium bicarbonate.

   The precipitate was collected by filtration, washed with water, dried under reduced pressure and subjected to column chromatography on gel.
 EMI42.1
 silica to give benzhydryl 7-L2-methoxyimino-2-thiazol cephem-4-carboxylate (syn-isomer) (trans-isomer) (0.9 g).



  IR (Nujol): 1780.1710, 1671 cm '
 EMI42.2
 NMR (DMSO-d.): 3.93 (3H, s), 4.0 (2H, m), 5.35 (1H, d, b J = 5Hz), 6.02 (1H, dd, J = 5Hz, 8Hz), 7.06 (1H, s), 7.2 (1H, d, J = 16Hz), 7.2-7, 8 (1H, m), 7.88 (1H, d, J = 16Hz), 8.55 (1H, s), 9.13 (1H, m), 9.82 (1H, d, J = 8Hz), 12.6 (1H, large s).
 EMI42.3
 



  6. In a solution of 7-L (2-formamidothiazol-4-yl) 2- 2-methoxyimino-2-vinyl / -3-cephem-4-carboxylate (benz isomer syn) (trans isomer) (0.85 g) in methanol (45 ml) and tetrahydrofuran (9 ml), concentrated hydrochloric acid (0.56 ml) was added and the mixture was stirred at room temperature for 1.5 hours. The resulting solution was adjusted to pH 7.0 with 5% aqueous sodium bicarbonate solution and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (150 ml).

   The organic layer has been washed

  <Desc / Clms Page number 43>

 with saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo
 EMI43.1
 to give 7-2-methoxyimino-2- -4-yl) acetamidQ / -3-L2- of benzhydryl (syn isomer) (trans isomer) (0.68 g).



  IR (Nujol): 3300, NMR 6 (DMSO-d): 3.87 (3H, s), 3, 9 (2H, m), 5.33 (1H, d, (2-aminothiazoJ = 5Hz), 5 , 93 (1H, dd, J = 5Hz, 8Hz), 6.78 (1H, s), 7.03 (1H, s), 7.12 (1H, d, J = 16Hz), 7.1-7 , 8 (14H, m), 7.84 (1H, d, J = 16Hz), 9.10 (li, m), 9.67 (1H, d, J = 8Hz).



     7) To a solution of 7-L2-methoxyimino-2- (2-
 EMI43.2
 aminothiazol / - benzhydryl 3-cephem-4-carboxylate (isomer (trans isomer) (0.65 g) in methylene chloride (6.5 ml) and in anisol (1.5 ml), we have added trifluoroacetic acid (3.0 ml) while cooling with ice with stirring The reaction mixture was stirred at room temperature for 30 minutes The resulting solution was added dropwise to diisopropyl ether (100 ml) and the precipitate was collected by filtration and dissolved in an aqueous sodium bicarbonate solution The aqueous layer (100 ml) was washed with ethyl acetate (50 ml) twice, concentrated to '' to 30 ml under reduced pressure and adjusted to a pH of 3.0 with 10% hydrochloric acid.

   The precipitate was collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure to
 EMI43.3
 give 7-L2-methoxyimino-2-yl) acetamidQ / -3-L2- carboxylic acid (syn isomer) (trans isomer) (0.37 IR (Nujol): 3250, 1775, 1660, NMR ($ ( DMSO-d.): 3.87 (3H, s), 3, 9 (2H, m), 5.28 d, J = 5Hz), 5.85 (1H, dd, J = 5Hz, 8Hz), 6 , 77 (1H, s), 7.12 (1H, d, J = 16Hz), 7.67 (2H, m), 8.00 (1H, d, J = 16Hz), 9.07 (1H, m ), 9.63 (1H, d, J = 8Hz).

  <Desc / Clms Page number 44>

 



  Preparation 2
1) Benzhydryl 7-phenylacetamido-3-formyl-2-cephem-4-carboxylate (5.1 g) was added to the mixture of 2-pyridylmethylenetriphenylphosphonium chloride (4.7 g), water ( 25 ml) and dichloromethane (50 ml) and the solution was stirred at room temperature for 2 hours keeping the pH between 8.8 and 9.0 with a 20% aqueous solution of sodium carbonate.



   The separated organic layer was washed with brine, and dried over magnesium sulfate and evaporated to give a crude product. The crude product was added to ethyl acetate (300 ml). The precipitate was filtered, washed with ethyl acetate and diisopropyl ether, and dried to give 7-phenylacetamido-3- L2- (2-pyridyl) viny1 / -2-cephem-4-carboxylate benzhydryl (trans isomer) (2.8 g).



  IR (Nujol): 3150, 1770, 1730, 1670, 1620, 1535 cm 'NMR (DMSO-d.): 3.60 (2H, s), 5.28 (1H, d, J = 5Hz),
5.50 (1H, dd, J = 5Hz, 8Hz), 5.72 (1H, s), 7.02 (1H, d, J = 17Hz), 7.13-7, 67 (16H, m), 7.90 (1H, d, J = 17Hz),
7.7-8.50 (3H, m), 8.72 (1H, d, J = 4Hz), 9.30 (1H, d,
J = 8Hz).



   2) A solution of m-chloroperbenzoic acid (9.73 g) in dichloromethane (60 ml) was added dropwise to a solution of 7-phenylacetamido-3- [2- (2-pyridyl) vinyl] - Benzhydryl 2-cephem-4-carboxylate (trans isomer) (27.6 g) in dichloromethane (280 ml) between -25 and -30 C and the solution was stirred for 10 minutes at the same temperature. The reaction mixture was poured into water (100 ml). The separated organic layer was washed with a 2% aqueous solution of sodium bicarbonate and brine, dried over magnesium sulfate and evaporated to give 1-oxide. Benzhydryl benzhydryl 7-phenylacetamido-3- [2- (2-pyridyl) vinyl] -3-cephem-4carboxylate (trans isomer) (24.5 g).

  <Desc / Clms Page number 45>

 



  IR (Nujol): 3270.1780, 1700.1640, 1580.1560, 1530 cm NMR (DMSO-d): 3.67 (2H, s), 3.72 and 4.55 (2H, ABq, J = 18Hz ),
5.05 (1H, d, J = 5Hz), 5.93 (1H, dd, J = 5Hz, 8Hz), 7.02 (1H, s), 7.05 (1H, d, J = 17Hz), 8.12 (1H, d, J = 17Hz),
7.05-8.67 (19H, m).



   3) Phosphorus trichloride (15.2 g) was
 EMI45.1
 added to the solution of benzhydryl (2-pyridyl) vinyll-3-cephem-4-carboxylate 1-oxide of 7-phenylacetamido-3L2- (trans isomer) (22.2 g) in dimethylformamide (220 ml) at- 30 C and the solution is stirred at -30 to -25 C for 10 minutes. The reaction mixture was poured into cold water (1 L) and the resulting precipitates were collected by filtration. The filtrate was dissolved in ethyl acetate (300 ml) and the ethyl acetate layer was washed with brine, dried over magnesium sulfate and evaporated to give 7-phenylacetamido -3- / 2- (2-pyridyl) vinyl / -3-cephem-4-carboxylate
 EMI45.2
 benzhydryl (trans isomer) (15.9 g).



  IR (Nujol): 3300, 1770, 1695, 1645, 1575, 1555, 1520 cm, RMN S: 3.60 (2H, s), 3.95 (2H, ABq, J = 18Hz), 5.27 (1H , d, J = 5Hz), 5, 83 (1H, dd, J = 5Hz, 8Hz),
7.07 (1H, s), 7.15 (1H, d, J = 17Hz), 7.92 (1H, d,
J = 17Hz), 7.17-8.0 (18H, m), 8.60 (1H, d, J = 5Hz),
9, 20 (1H, d, J = 8Hz).



   4) To a suspension of phosphorus pyridinepentachloride complex prepared from pyridine (48 g) and phosphorus pentachloride (12.7 g) in methylene chloride (120 ml), 7-phenylacetamido-3 was added - Benzhydryl [2- (2-pyridyl) vinyl] -3-cephem-4-carboxylate (trans isomer) (12 g) while cooling in ice with stirring. The mixture was stirred at the same temperature for 30 minutes and poured into methanol (90 ml) at -25 C. The mixed solution was further stirred at -5 to -15 C for 10 minutes, then it was evaporated under reduced pressure.

   To the residue was added a mixture of tetrahydrofuran (200 ml), ethyl acetate (200 ml) and water (200 ml) and the mixture was adjusted to pH 6.5 with a solution saturated aqueous

  <Desc / Clms Page number 46>

   sodium bicarbonate.

   The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated to give benzhydryl 7-amino-3- [2-92-pyridinyl) vinyl] -3-cephem-4carboxylate (trans isomer) (6, 6 g).
 EMI46.1
 IR (Nujol): 3300, 1770, 1720, 1615, 1580 cm R N6 (DMSO-d6): 3.93 (2H, ABq, J = 18Hz), 4.92 (lH, d, J = 5Hz), 5 , 20 (1H, d, J = 5Hz), 7.05 (1H, s), 7.15 (1H, d, J = 17Hz),
7.92 (leu, d, J = 17Hz), 7, 17-8, 10 (15H, m), 8.50-8, 75 (1H, m).



   5) A Vilsmeier reagent was prepared from 1 of phosphorus oxychloride (1.29 g) and dimethylformamide (0.62 g) in ethyl acetate (30 ml) in the usual way . 2- (2-formamidothiazol-4-yl) -2-methoxyiminoacetic acid (syn isomer) (1.6 g) was added to the stirred suspension of Vilsmeier's reagent in acetate of ethyl (2 ml) and tetrahydrofuran (10 ml) while cooling with ice and stirred at the same temperature for 1/2 hour to produce an activated acid solution. N- (tri-methylsilyl) acetamide (5.0 g) was added to the stirred solution of benzhydryl 7-amino-3- [2- (2-pyridyl) vinyl] -3-cephem-4-carboxylate (isomer trans) (3 g) in ethyl acetate (30 ml) and stirred at 40 to 43 C for 30 minutes.

   To the clear solution was added the activated acid solution prepared above at -20 ° C and stirred at the same temperature for 30 minutes, Water (30 ml) was added to the resulting solution and the separated organic layer was washed with 5% aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated to give 7- [2-methoxyimino-2- (2-for - mamidothiazol-4-yl) acetamido] -3- [2- (2-pyridyl) vinyl] -3-benzhydryl cephem 4-carboxylate (syn isomer) (trans isomer) (4,1 g).



   IR (Nujol): 3150, 1770,1710, 1670, 1610,1540 cm-
NMR 6 (DMSO-d6): 3.58 (2H, m), 3.92 (3H, s),
5.38 (hui, d, J = 5Hz), 6.0 (IH, dd, J = 5Hz, 8Hz),
7.07 (1H, s), 7, 13-8, 28 (2H, m), 8.55 (1H, s), 8.50-8, 77 (1H, m),
9.82 (1H, d, J = 8Hz).



   6) A mixture of benzhydryl 7-amino-3- [2- (2-pyridyl) vinyl] - 3-cephem-4-carboxylate (trans isomer) (25 g)

  <Desc / Clms Page number 47>

 and N- (trimethylsilyl) acetamide (4.2 g) in ethyl acetate (20 ml) and tetrahydrofuran (10 ml) was stirred at room temperature for 20 minutes to give a clear solution. To the solution was added 2-ethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetyl chloride (syn isomer) (1.4 g) between -15 and -20 C and stirred at the same temperature for 30 minutes.

   Water (20 ml) was added to the resulting solution and the separated organic layer was washed with 5% aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated to give 7- / 2-
 EMI47.1
 ethoxyimino-2- 2,4-thiadiazol-3-yl) 3-L2- benzhydryl (syn-isomer) (trans-isomer) (3.6 g).



  IR (Nujol) r NMR t, J = 7Hz), 3.83 (2H, m), 15b (2H, q, J = 7Hz), 5.28 (1H, d, J = 5Hz), 5.92 (1H, dd,
J = 5Hz, 8Hz) 6.98 (1H, s), 7.08 (1H, d, J = 17Hz),
7.60 (1H, d, J = 17Hz), 7.10-8, 33 (1H, m), 8.55 (1H, d,
J = 5Hz), 9.58 (1H, d, J = 8Hz).



  Preparation 3
1) The following compounds were obtained in a manner similar to that of preparation 2-1).



   (1) Benzhydryl 7-phenylacetamido-3- [2- (4-pyridyl) vinyl] - 2-cephem-4-carboxylate (trans isomer).



  IR (Nujol): 3770.1767, 1725.1645 cm-1
 EMI47.2
 NMR: 3.57 (2H, s), 5.23 (1H, d, J = 4Hz), b
5.50 (1H, dd, J = 4Hz, 8Hz), 5.83 (1H, s), 6.85 (1H, s),
7.53 (1H, s), 6.6-7.8 (19H, m), 8.52 (2H, d, J = 6Hz),
9.16 (1H, d, J = 8Hz) (2) Benzhydryl 7-phenylacetamido-3- [2-93-pyridyl) vinyl] - 2-cephem-4-carboxylate (cis isomer)
 EMI47.3
 IR (Nujol): 3250, 1760, 1720 (s), 1650, 1520 cm-1 NMR- (DMSO-d): 3, (2H, s), 5, 20 (1H, d, J = 5Hz), 5 , 43
60 (1H, m), 5.80 (1H, s), 6.53 (2H, s), 6.80-8, 50 (19H, m), 8.68 (2H, m), 9.27 (1H, d, J = 8Hz).

  <Desc / Clms Page number 48>

 



   2) The following compounds were obtained in a manner similar to that of preparation 2-2).



   (1) Benzhydryl 7-phenylacetamido-3- / 2- (4-pyridyl) vinyl] -3-cephem-4-carboxylate 1-oxide (trans isomer).



  IR (Nujol): 1770.1718, 1698.1647 cm NMR (DMSO-d.): 3.66 (2H, s), 3.8 (2H, m), 5.07 (1H, d,
J = 4Hz), 5.97 (1H, dd, J = 4Hz, 8Hz), 6.9-8, 2 (20H, m),
8.53 (2H, large s), 8.60 (1H, d, J = 8Hz)
 EMI48.1
 (2) Benzhydryl 7-phenylacetamido-3-2-pyridyl) vinylf-3-cephem-4-carboxylate 1-oxide (cis isomer).



  IR (Nujol) 3200, 1780, 1720, 1670 cm NMR J '(DMSO-d6): 3.50 (2H, m), 3.67 (2H, s), 5.03 (1H, bd, J = 5Hz ), 5.92 (1H, dd, J = 5Hz, 8Hz), 6.52 (2H, s),
6.85 (1H, s), 7.0-8.0 (17H, m), 8.47 (3H, m).



   3) The following compounds were obtained in a manner similar to that of preparation 2-3).



   (1) benzhydryl 7-phenylacetamido-3- [2- (4-pyridyl) vinyl] - 3-cephem-4-carboxylate (trans isomer) IR (Nujol): 3270-3170, 1772,1710, 1670 cm NMR ô "(DMSO-d.): 3.60 (2H, s), 3.70, 4.13 (2H, ABq, J = 17Hz), 5.23 (1H, d, J = 5Hz), 5, 82 (1H, dd, J = 5Hz, 8Hz), 6.9-7, 7 (20H, m), 8.50 (2H, large s), 9.23 (1H, d, J = 8Hz).
 EMI48.2
 



  (2) benzhydryl 7-phenylacetamido-3-2- 3-cephem-4-carboxylate (cis isomer).



  IR (Nujol): 3150, 1770, NMR c (DMSO-d6): 3.47 (2H, ABq, J = 18Hz), 3.57 (2H, s), 5.27 (1H, d, J = 5Hz ), 5, 83 (1H, dd, J = 5Hz, 8Hz), 6, 52 (2H, s), 6, 85 (1H, s), 7, 17-8, 0 (17H, m), 8, 57 (1H, d, J = 8Hz).



  4) The following compounds were obtained in a manner similar to that of preparation 2-4).



   (1) Benzhydryl 7-amino-3- [2- (4-pyridyl) vinyl] -3-cephem-4-carboxylate (trans isomer).



  IR (Nujol): 1770.1719, 1583 cm
 EMI48.3
 NMR (DMSO-d6): 3, 83 (2H, m), 4, 87, 5, 13 (2H, ABq, J = 5Hz), J

  <Desc / Clms Page number 49>

 
 EMI49.1
 6, 9-7, 6 (17H, m), 8, 45 (2K, d, J = 5Hz).



  (2) benzhydryl 7-amino-3-2- 4-carboxylate (cis isomer).



  IR (Nujol): 3300, 1760.1720 cm NMR # (DMSO-d6): 3.42 (2H, ABq, J = 18Hz), 4.87 (1H, d, J = 5Hz), 5.12 (1H , d, J = 5Hz), 6.45 (2H, s), 6.77 (1H, s), 7.05-7, 67 (12H, m), 8.38 (2H, m).



   (3) benzhydryl 7-amino-3- [2- (3-pyridyl) vinyl] -3-cephem-4-carboxylate (cis, trans mixture).



  IR (Nujol): 3300.1760, 1710 cm
 EMI49.2
 NMR: 3.87 (2H, m), 4.90 (1H, d, J = 5Hz), b
5.15 (1H, d, J = 5Hz), 7.0-7, 80 (15H, m), 8.43 (2H, m).



   5) The following compound was obtained in a manner similar to that of preparation 2-5).
 EMI49.3
 



  Benzhydryl 7-L2-formamidothiazol 3-cephem-4-carboxylate (syn-isomer) (trans-isomer).



  IR (Nujol): 3250.1780, 1720.1680, 1540 cm-1 NMR # (DMSO-d6): 1.43 (9H, s), 3.95 (2H, ABq, J = 18Hz),
4.67 (2H, s), 5.38 (1H, d, J = 5Hz), 6.0 (1H, dd,
J = 5Hz, 8Hz), 7.05 (1H, s), 7.18 (1H, d, J = 17Hz),
7.68 (1H, d, J = 17Hz), 7.19-8, 15 (13H, m), 8.57 (1H, s), 8.50-8, 75 (1H, m), 9, 75 (1H, d, J = 8Hz).



   6) The following compounds were obtained in a manner similar to that of preparation 1-6).
 EMI49.4
 



  (1) Benzhydryl 7-L2-methoxyimino-2-yl) acetamidQ / -3-L2- / -3-cephem-4-carboxylate (syn isomer) (trans isomer).



   IR (Nujol): 3250,1780, 1720, 1680, 1610, 1580,
1530 cm '
 EMI49.5
 NMR J (DMSO-d): 3.63 (2H, m), 3.88 (3H, s), 5.30 (1H, d, J = 5Hz), 5.92 (1H, dd, J = 5Hz , 8Hz), 6.97 (1H, d, J = 17Hz), 7.03 (1H, s), 7.97 (1H, d, J = 17Hz), 7.08-7, 70 (14H, m ), 8.45-8, 67 (1H, m), 9.67 (1H, d, J = 8Hz).

  <Desc / Clms Page number 50>

 
 EMI50.1
 



  (2) methoxyimino) -2-pyridyl) benzhydryl dihydrochloride (syn isomer) (trans isomer).



  IR (Nujol): 3200,1780, 1720,1680, 1610, 1570 cm
 EMI50.2
 RIM,: 1, 47 (9H, s), 3, 93 (2H, large s), b
4.72 (2H, s), 5.42 (1H, d, J = 5Hz), 6.05 (1H, dd, J = 5Hz, 8Hz), 7.05 (1H, s), 7.18 ( 1H, d, J = 17Hz),
7.80 (1H, J = 17Hz), 7.17-8.50 (13H, m), 8.72 (1H, d, J = 5Hz), 9.92 (1H, d, J = 8Hz).



   7) The following compounds were obtained in a manner similar to that of preparation 2-6).
 EMI50.3
 



  (1) Benzhydryl 7-L2-ethoxyimino-2- 2, 4thiadiazol ido / -3-L2- (5-amino-1, cephem-4-carboxylate (syn isomer) (trans isomer).



  IR (Nujol): 3260, 1777, 1710, 1672, 1610 cm-1
 EMI50.4
 Ef NMR: 1.20 (3H, t, J = 7Hz), 3.85 (2H, m), b 4.15 (2H, q, J = 7Hz), 5.25 (1H, d, J = 5Hz ), 5.92 (1H, dd, J = 5Hz, 8Hz), 6.99 (1H, s), 6.9-7, 8 (16H, m), 8.70 (2H, d, J = 5Hz ), 9.60 (1H, d, J = 8Hz).
 EMI50.5
 



  (2) Benzhydryl 7-L2-ethoxyimino-2- 2, 4thiadiazol / -3- (5-amino-1, cephe-4-carboxylate (syn isomer) (cis isomer).



  IR (Nujol): 3250.1770, 1720.1670, 1610, 1520 cm-1 NMR # (DMSO-d6): 1.10 (3H, t, J = 7Hz), 3.47 (2H, ABq,
J = 18Hz), 4.22 (2H, q, J = 7Hz), 5.33 (1H, d, J = 5Hz),
5.97 (1H, dd, J = 5Hz, 8Hz), 6.50 (2H, s), 6.83 (1H, s), 7.10-7.88 (12H, m), 8.40 ( 1H, m), 9.67 (1H, d, J = 8Hz).



   8) The following compounds were obtained in a manner similar to that of preparation 1-7).



   (1) 7- [2-methoxyimino-2- (2-amino-
 EMI50.6
 t-hi-azol-4-yl) acetamid-3thiazol-4-yl) 2- 4-carboxylic (syn isomer) (trans isomer). t

  <Desc / Clms Page number 51>

 
 EMI51.1
 IR (Nujol): 3300, 1570, 1520 NMR D (DMSO-d6): 3.62 (2H, m), 3.88 (3H, s), 28 (1H, d, b acetamido / -3-J = 5Hz), 4.83 (1H, dd, J = 5Hz, 8Hz), 6.78 (1H, s), 7.05 (1H, d, J = 17Hz), 7.95 (1H, d, J = 17Hz), 7.0-8, 18 (5H, m), 8.57 (1H, d, J = 5Hz), 9.65 (1H, d, J = 8Hz).
 EMI51.2
 



  (2) 2, 4thiadiazol 4-carboxylic acid (syn isomer) (trans isomer).



  IR (Nujol): 3250.1770, 1670.1620, 1575.1520 cm-1 NMR J (DMSO-d): 1.12 (3H, t, J = 7Hz), 3.90 (2H, ABq,
J = 18Hz), 4.22 (2H, q, J = 7Hz), 5.27 (1H, d, J = 5Hz),
5.87 (1H, dd, J = 5Hz, 8Hz), 7.03 (1H, d, J = 17Hz),
7.93 (1H, d, J = 17Hz), 7.17-8.38 (3H, m), 8.58 (1H, d,
J = 5Hz), 9.62 (1H, d, J = 8Hz) (3) 7- [2-ethoxyimino-2- (5-amino-1,2,4-) acid
 EMI51.3
 - - thiadiazol-3-yl) 4-carboxylic (syn isomer) (trans isomer).



  IR (Nujol) 3200, 1770, 1665, 1630, 1608 cm-1 RMN ra (DMSO-d6): 1, 28 (3H, 3, 93 (2H, m), 4, 22 b acetamido / -3- / 2 - (4-pyridyl) vinyl / -3-cephem- (2H, q, J = 7Hz), 5.28 (1H, d, J = 5Hz), 5.87 (1H, dd, J = 5Hz, 8Hz) , 7.07 (1H, d, J = 16Hz), 7.62 (2H, d, J = 5Hz), 7.73 (1H, d, J = 16Hz), 8.17 (2H, wide s), 8.65 (2H, d, J = 5Hz), 9.60 (1H, d, J = 8Hz).
 EMI51.4
 



  (4) 2, 4thiadiazol 7 -L2-ethoxyimino-2- (5-amino-1,4-carboxylic acid (syn isomer) (cis isomer) acid.



  IR (Nujol): 3250, 17770, 1680, 1610, 1520 cm-1 NMR cf (DMSO-d6): 1.18 (3H, t, J = 7Hz), 3.67 (2H, m), 4.17 (2H, q, J = 7Hz), 5.22 (1H, d, J = 5Hz), 5.82 (1H, dd,
J = 5Hz, 8Hz), 6.57 (2H, s), 7.10-7.88 (2H, m), 8.47 (2H, m), 9.58 (1H, d, J = 8Hz)
 EMI51.5
 (5) 7 aminothiazol cephem-4-carboxylic acid (syn isomer) (trans isomer). IR (Nujol): 3250.1770, 1670.1620, 1565.1530 cm

  <Desc / Clms Page number 52>

 
 EMI52.1
 v 0 5.33 (1H, d, J = 5Hz), 5.90 (1H, dd, J = 5Hz, 8Hz),
6.87 (1H, s), 7.05 (1H, d, J = 17Hz), 8.0 (1H, d,
J = 17Hz), 7.0-8.08 (3H, m), 8.62 (1H, d, J = 5Hz),
9.62 (1H, d, J = 8Hz).



  Preparation 4
1) Sodium iodide (1.8 g) was added to a solution of benzhydryl benzhydryl 7-amino-3-chloromethyl-3-cephem-4carboxylate (5.0 g) and triphenylphosphine (3.2 g ) in dimethylformamide (15 ml) while cooling with ice and stirred for 3 hours at room temperature. The resulting solution was added dropwise to ethyl acetate (250 ml) with vigorous stirring. The precipitate, collected by filtration, was washed with ethyl acetate to give [4-benzhydryloxycarbonyl-7-amino-3-cephem-3-ylmethylltriphenylphosphonium iodide hydrochloride (9,6 g) .



  IR (Nujol): 3330.1780, 1700.1645 cm.



   2) (4-Benzhydryloxycarbonyl-7-amino-3-cephem-3-ylmethyl) triphenylphosphonium iodide hydrochloride (5 g) was dissolved in a mixed solution of tetrahydrofuran (35 ml) aqueous sodium bicarbonate solution (1.6 g). To the solution was added a 2- (5 amino- 1,2,4-thiadiazol-3-yl) -2-ethoxyiminocetyl chloride hydrochloride solution
 EMI52.2
 (syn isomer) (2.6 g) in tetrahydrofuran between -3 ° C. and 3 ° C., and the solution was stirred for 30 minutes while maintaining the pH between 6.5 and 7.5 with a 20% aqueous solution of potassium carbonate. Ethyl acetate was added to the reaction mixture and the mixture was adjusted to pH 10.0 with 20% aqueous potassium carbonate solution.

   The separated organic layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated to give 7-L2- (5-amino-1,2,4,4-thiadiazol-3-yl) - 2-ethoxyiminoaceta-
 EMI52.3
 benzhydryl mido / -3- late (syn isomer) (4.5 g). ((

  <Desc / Clms Page number 53>

 
 EMI53.1
 IR (Nujol): 1740, 1640 (wide) NMR 25 (3H, t, J = 7, OHz), 3, 11-3, 77 (2H, m, b H20 4, 10 (2H, q, J = 7 , OHz), 5, 19 20 in recovery.



   (triphenylphosphoranediylmethyl) -3-cephem-4-carboxy- (1H, d, J = 4, OHz), 5.63 (1H, m), 6.70-8, 27 (26H, m),
9.20 (1H, d, J = 8, OHz).



   3) The following compound was obtained in a manner similar to that of preparation 8-2).
 EMI53.2
 



  Benzodryl 7-L2-2,4-thiadiazol-3yl) -2-ethoxyiminoacetamido / -3-2-vinyll-3-cephem-4-carboxylate iodide (syn isomer) (cis, trans mixture).



  IR (Nujol): 1780, 1720, 1660, 1610 cm-1 NMR J (DMSO-d6) 27 (3H, t, J = 7, 0Hz), 3.53 (2H, m), b 4, 20 (2H , q, J = 7, OHz), 4.31 (2H, s), 5.37 (1H, d, J = 4.0Hz), 5.90 (1H, m), 6.58-8, 30 (15E, m), 8, 73 (5-amino-1, (1H, m), 9.54 (1H, d, J = 8, OHz).



   Preparation 5
1) 2- (5-amino-1, 2, 4-thiadiazol-3-yl) - 2-ethoxyiminoacetic acid (syn isomer) (14.4 g) was added to the stirred suspension of phosphorus pentachloride (13.8 g) in dichloromethane (150 ml) at -5 ° C. and stirred for 20 minutes at -10 ° C. to 0 ° C. Isopropyl ether was added to the reaction mixture at the same temperature and stirred for 10 minutes at Room temperature.



  * The precipitate was removed by filtration and washed with isopropyl ether. N- (trimethylsilyl) acetamide
 EMI53.3
 (43.6 g) was added to the stirred suspension of benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate hydrochloride (25 g) in ethyl acetate (250 ml) - In the solution as obtained, the above precipitate was added at -10 ° C and stirred for 30 minutes at -10 ° C to -5 ° C. Water was added to the reaction mixture. The separated organic layer was washed with a saturated aqueous solution of sodium bicarbonate and water.

   The organic layer was dried over magnesium sulfate and evaporated to give 7-L2- (5-amino-1. 2. 4-

  <Desc / Clms Page number 54>

 
 EMI54.1
 thiadiazol-3-yl) -2-ethoxyiminoacetamido / -3-chloromethyl-3-cephalem-4-benzhydryl carboxylate (syn isomer) (36.8g).



  IR (Nujol): 3270, 1670, 1620 cm 'RMN J: 1, 25 (3H, t, J = 7, OHz), 3, 61 (2H, m), b 4, 19 (2H, q, J = 7, OHz), 4.43 (2H, s), 5.24 (1H, d, J = 5.0Hz), 5.95 (1H, dd, J = 5, OHz, 8, OHz), 6, 95 (1H, s), 7.36 (10H, m), 8.12 (2H, broad s), 9.59 (1H, d, J = 8, OHz).
 EMI54.2
 



  2) A mixture of 7- / 2- (5-amino-1, 2, 4-thiadiazol-3-yl) -2-ethoxyiminoacetamido / -3-chloromethyl-3-cephem- 4-carboxylate benzhydryl (syn isomer) (36.7 g) in ethyl acetate (600 ml), triphenylphosphine (18.8 g) and sodium iodide (1 g) was boiled with reflux for 100 minutes. The precipitates were combined by filtration and washed with ethyl acetate to give / 4-benzhydryloxycarbonyl-7- / 2- (5-amino-1,2,4-thiadiazol -3-yl chloride ) -2-ethoxy-
 EMI54.3
 iminoacetamido iminoacetamidQ / -3-cephem-3-ylmethyl / triphenylphosphonium (syn isomer) (31.1 g).



  IR (Nujol): 1770, 1670, 1600 cm-1
 EMI54.4
 NMR: 1.23 (3H, t, J = 7, OHz), 3.62 (2H, m), 4.19b (2H, q, J = 7, OHz), 5.03-5, 56 ( 2H, m), 5.38 (1H, d,
J = 5.0Hz), 5.95 (1H, dd, J = 5, OHz, 8, OHz), 6.30 (1H, s),
7, 10-8, 07 (25H, m), 8.36 (2H, large s), 9.64 (1H, d,
J = 8, OHz).



   3) Nicotinaldehyde (1.1 g) was added to a solution of {4-benzhydryloxycarbonyl-7 [-2- (3-amino-1,2,4-thiadiazol-3-yl) -2-ethoxyiminoacetamido chloride ] -3 cephem-3-ylmethyl} triphenylphosphonium (syn isomer) (3.0 g) in tetrahydrofuran (30 ml) and water (15 ml) and the solution was adjusted to pH 9.0 with a 20% aqueous sodium carbonate solution. The solution was stirred at room temperature for 2 hours while maintaining the pH between 8, 8 and 9.2 with a 20% aqueous solution of potassium carbonate. Ethyl acetate and water were added to the solution.

  <Desc / Clms Page number 55>

 resulting tion. The separated organic layer was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate.



   The crude product obtained by concentration was purified by chromatography on a column of silica gel using a mixture of acetone and dichloromethane (ratio 1: 1) as eluent. The eluted fractions were evaporated to give 7- / 2- (5-amino-1, 2, 4-thiadiazol-3-yl) -2-ethoxyiminoacetamido / -3- / 2- (3-pyridyl) vinyl / - 3- benzhydryl cephem-4-carboxylate (syn isomer) (cis-trans mixture) (1.1 g).



  IR (Nujol): 1770,1710, 1670, 1610 cm-1
 EMI55.1
 Cl NMR (DMSO-d): 1, 26 and 1, 30, 3H total, each t, J = 7, OHz), 3.48 (2H, q, J = 18, OHz), 4.21 (2H, q, J = 7.0 Hz), 5.33 (1H, d, J = 5, OHz), 5.77 (1H, dd, J = 5, OHz, 8, OHz), 6.51 (1H, s), 6, 83 (1H, s), 7, 07-7, 76 (13H, m), 8, 17 (2H, s), 8, 35-8,
9.74 (1H, d, J = 8, OHz).



   4) Trifluoroacetic acid (1.2 ml) was added to a suspension of 7-L2- (5-amino-1, 2, 4-thiadiazol- 3-yl) -2-ethoxyiminoacetamido] -3- [ Benzhydryl (2- (3-pyridyl) vinyl] -3 cephem-4-carboxylate (syn-isomer) (cis-trans mixture) (1.0 g) in dichloromethane (10 ml) and anisol (0.65 ml) at room temperature and stirred for 2 hours at the same temperature. To the resulting solution wasopropyl ether (50 ml) was added and stirred. The precipitates, collected by filtration, were washed with diisopropyl ether The precipitates were added to a mixture of ethyl acetate and water and adjusted to pH 7.5 with a 20% aqueous solution of potassium carbonate.

   The separated aqueous layer was adjusted to pH 3.5 with 10% hydrochloric acid while cooling with ice. The resulting precipitates were separated by filtration, washed with ice-water and dried over phosphorus pentoxide in vacuo to give 7-L2- (5-amino-1,2,4-thiadiazol-

  <Desc / Clms Page number 56>

 
 EMI56.1
 3-yl) -2-ethoxyiminoacetamido / -3- / 2- cephem-4-carboxylic (syn-isomer) (cis-trans mixture) (0.4 g).



   IR (Nujol): 3240, 3140, 1765, 1665.1610 cm
 EMI56.2
 NMR (DMSO-d): 1, 25 and 1, 29 (3H total, each t, J = 7, OHz), 3.40 (2H, q, J = 18, OHz), 4, 18 and 4.22 (2H total, each q, J = 7, OHz),
5, 26 (1H, d, J = 5, OHz), 5.85 (1H, d-d,
J = 5, OHz, 8, OHz), 6.58 (1H, s), 7.04 (0.5H, d, J = 17, OHz), 7.23-8, 24 (3.5H, m ),
8.28 (2H, large s), 8.39-8.72 (2H, m),
9.58 (1H, d, J = 8, OHz).



  Preparation 6
1) The following compound was obtained in a similar manner to that of preparation 5-3).
 EMI56.3
 



  Benzhydryl 7-L2-iminoacetamid / -3- / 2-late (syn-isomer) (cis-trans mixture).



  IR (Nujol): 1765, 1670, 1640 cm-1 NMR # (DMSO-d6): 3.48 (2H, m), 3.91 (3H, s),
5.35 (1H, d, J = 5, OHz),
5.98 (1H, d-d, J = 5, OHz, 8.0 Hz),
6.52 (1H, s), 6.83 (1H, s),
6.85-7.71 (14H, m),
8.37-8.66 (3H, m), 9.80 (1H, d, J = 8, OHz)
2) The following compound was obtained in a manner similar to that of preparation 5-4).
 EMI56.4
 



  7-L2-methoxyiminoacetamido-3-L2-carboxylic acid (syn-isomer) (cis-trans mixture).



  IR (Nujol): 1760.1665 cm
 EMI56.5
 NMR 3, 43 (2H, q, J = 18, OHz), b 3.92 (3H, s), 5.29 (1H, d, J = 5, OHz), 5.87 (1H, dd, J = 5, OHz, 8, OHz), 6.61 (1H, s), 6.85-8, 31 (3H, m),

  <Desc / Clms Page number 57>

 
7.43 and 7.46 (total HI, each s),
8.38-8.77 (3H, m),
9.74 (IH, d, J = 8, OHz)
3) A mixture of 7-L2- (2-formamidothiazol-4-yl) -2-methoxyiminoacetamido] -3- [2- (3-pyridyl) vinyl] -3 cephem-4-carboxylic acid (syn isomer) (mixture cis-trans) (0.8 g) in methanol (6 ml), tetrahydrofuran (3 ml) and concentrated hydrochloric acid (0.5 g) was stirred for 3 hours at room temperature.

   The resulting solution was added to a mixture of ethyl acetate and water and adjusted to pH 7.5 with a 20% aqueous solution of potassium carbonate. The separated aqueous layer was adjusted to pH 3.5 with 10% hydrochloric acid while cooling with ice. The precipitate was separated by filtration, washed with ice-water and dried over phosphorus pentoxide under vacuum to give 7] -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido / - acid. 3-2- (3-pyridyl) vinyl / -3-cephem- 4-carboxylic (syn isomer) (cis-trans mixture) (0.3 g).
 EMI57.1
 



  IR (Nujol): 3280, NMR d: 3.39 (2H, q, J = 18, OHz),
3.85 (3H, s), 5.23 (IH, d, J = 5, OHz),
5.80 (IH, d-d, J = 5, OHz, 8, OHz),
6.56 (1H, s), 6.77 (1H, s),
6.80-8.00 (3H, m), 8.35-8.68 (2H, m),
9.65 (IH, d, J = 8, OHz) Preparation 7
1) A solution of phosphorus tribromide (5.0 g) in tetrahydrofuran (10 ml) was added dropwise to a mixture of benzhydryl 7-phenylacetamido-3-hydroxymethyl-3-cephem-4-carboxylate (25 , 7 g) in tetrahydrofuran (200 ml) at -10 to -5 ° C and the mixture was stirred at the same temperature for 15 minutes. The resulting mixture was poured into a mixture of water (250 ml) and ethyl acetate (300 ml).

   The separated organic layer was washed with brine and dried over magnesium sulfate. The
 EMI57.2
 j

  <Desc / Clms Page number 58>

 solvent was evaporated to give an oily product. The crude oily product was dissolved in ethyl acetate (250 ml) and triphenylphosphine (21 g) was added. The mixture was stirred at room temperature for 3 hours. The precipitate was collected by filtration and washed with ethyl acetate to give (4-benzhydryloxycarbonyl-7- bromide
 EMI58.1
 phenylacetamido-3-cephem-3-ylmethyl) triphenylphosphonium (22.8 g).



  IR (Nujol): 1780.1710, 1665 cm-1
2) Nicotinaldehyde (32.1 g) was added to a solution of / 4-benzhydryloxycarbonyl-7- (2-phenylacetamido) -3-cephem-3-ylmethyJL / triphenylphosphonium (84.0 g) bromide a mixture of tetrahydrofuran (800 ml) and water (400 ml) and the solution was adjusted to pH 9.0 with 20% aqueous sodium carbonate solution. The solution was stirred at room temperature for 2 hours keeping the pH between 8.8 and 9.2 with a 20% aqueous solution of potassium carbonate.



  Ethyl acetate (800 ml) and water (800 ml) were added to the resulting solution. The separated organic layer was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The crude product obtained by concentration was purified by chromatography on a column of silica gel using a mixture of acetone and dichloromethane
 EMI58.2
 (1: 1 The eluted fraction was evaporated to give benzhydryl 7-vinyl / -3-cephem-4-carboxylate (cis-trans mixture) (28.5 g).



  IR (Nujol): 3250.1770, 1710.1660, 1530 cm
 EMI58.3
 NMR 50 (2H, ABq, J = 18Hz), 6 3.58 (2H, s), 5.27 (1R, d, J = 5Hz), 5.80 (1H, dd, J = 5Hz, 8Hz), 6.55 (1.5H, s) 6.82 (1H, s), 7, 17-7, 93 (17.5H, m), 8.50 (2H, m), 9, 22 (1H, d , J = 8Hz).
 EMI58.4
 r

  <Desc / Clms Page number 59>

 
 EMI59.1
 3) A mixture of benzhydryl 7-phenylacetamido-3-L2-pyridyl) viny1 / -3-cephem-4-carboxylate (3- (cis-trans mixture) (5.9 g), anisol (6 ml) and trifluoroacetic acid (20 ml) was stirred at room temperature for 30 minutes The reaction mixture was added to diisopropyl ether (300 ml).

   The precipitate was collected by filtration, washed with diisopropyl ether to give 7-phenylacetamido-3-2- (3-pyridyl) vinyl] -3-cephem-4-carboxylic acid trifluoroacetate (cistrans mixture) ( 2.5 g).



  IR (Nujol): 3200, 1760,1660, 1520 cm-1
 EMI59.2
 NMR S (DMSO-d,): 3.58 (2H, s), 3.45 (2H, ABq, J = 18Hz), 5, d, J = 5Hz), 5.70 (1H, dd, J = 5Hz, 8Hz), 6, 65 (1H, s), 7, 17-8, 33 (8H, m), 8, 65 (2H, m),
9.15 (1H, d, J = 8Hz) Preoaration 8
1) A solution of (4-benzhydryloxycarbonyl-7-phenylacetamido-3-cephem-3-ylmethyl) triphenylphosphonium bromide (8.4 g) in tetrahydrofuran (50 ml) and in water (50 ml) was adjusted at pH 11.0 with aqueous sodium hydroxide solution and the resulting solution was extracted with ethyl acetate and tetrahydrofuran. The organic layer was washed with brine and dried over magnesium sulfate.

   The solvent was evaporated and the residue was washed with ether to give benzhydryl 7-phenylacetamido-3- (triphenylphosphoranediylmethyl) -3-cephem-4-carboxylate (4.5 g).



  IR (Nujol): 3370, 1760, 1680.1650 cm
 EMI59.3
 2) A solution of benzhydryl 7-phenylacetamido-3- (triphenylphosphoranediylmethyl) -3-cephem-4-carboxylate (3.8 g) and 1-methyl-3formylpyridinium iodide (3.74 g) in dimethylformamide (50 ml) was stirred at room temperature for 5 hours. The mixture was poured into a mixture of diethyl ether-ethyl acetate (2: 1) and decanted.



  Water was added to the residue and the mixture was

  <Desc / Clms Page number 60>

 adjusted to a pH of 8.0 with a 20% aqueous solution of potassium carbonate. The solution was extracted with a mixture of ethyl acetate-tetrahydrofuran and the solution was dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was sprayed into
 EMI60.1
 diethyl ether to give benzhydryl 7-phenylacetamido-3- / 2- carboxylate iodide (cis-trans mixture) (2.1 g).



  IR (Nujol) 1770, 1720, 1660 cm RMNc): 3, 6 (2H, s), 3, 6 (2H, m), b
4.33 (3H, s), 5.28 (1H, m),
5.78 (1H, m), 6.57-8, 23 (19H, m),
8.6-9.4 (3H, m).



  Preparation 9
The mixture of trans isomer and cis isomer of 7-L2- (5-amino-1, 2, 4-thiadiazol-3-yl) -2-ethoxyimino-
 EMI60.2
 benzhydryl acetamido / -3- / 2- (syn isomer) (8 g) was subjected to column chromatography under medium pressure on silica gel called Merck, Kieselgel 60.



  (dimension passing through a sieve with an opening of m, range of 0.063-0.0337 160 g) -L mesh / using chloroform-ethyl acetate (rate 20: 1-10: 1) as eluent . The fraction containing the cis-form isomer was washed with saturated sodium bicarbonate solution and brine and dried over magnesium sulfate. The solution was evaporated and the residue was sprayed with ether
 EMI60.3
 diethyl to give the cis-isomer form of benzhydryl 7-L2-- amino-1,2,2 L2- (syn isomer) (4.1 g). Then the second fraction containing the trans-form isomer was washed with saturated sodium bicarbonate solution and brine and dried over magnesium sulfate.

   The solution was evaporated and the residue was sprayed with diethyl ether to
 EMI60.4
 give the trans-isomer of 7-L2-2, 4thiadiazol-3-yl) -2-ethoxyiminoacetamido / -3- / 2- 1

  <Desc / Clms Page number 61>

    (5-amino-1, vinyl / -3-cephem-4-carboxylate, benzhydryl (syn isomer) (1.72 g). Trans isomer IR (Nujol): 1765, 1670 cm - 1
 EMI61.1
 CS NMR (DHSO-d) 1, 29 (3H, t, J = 7, OHz), 3, 93 (2H, q, J = 18, OHz), 4, 20 (2H, q, J = 7, 0Hz ),: 5.29 (1R, d, J = 5.0Hz), 5.92 (1H, dd, J = 5.0Hz, 8, OHz),
6, 98 (1H, d, J = 17, OHz), 7.00-7.58 (13H, m), 7.03 (1H, s), 8.33-8, 51 (2H, m), 9.51 (1H, d, J = 8Hz) cis IR isomer (Nujol): 1765, 1670 cm
 EMI61.2
 NMR S (DMSO-d):

   1, 24 (3H, t, J = 7, OHz), 3.45 (2H, q, J = 18, OHz), 4, 19 (2H, q, J = 7, OHz), 5.32 (1H , d, 3 = 5.0Hz), 5.97 (1H, dd, J = 5, OHz, 8, OHz), 6.50 D (2H, s), 6.81 (1H, s), 7, 14-7, 70 (12H, m), 8.34-8, 53 (2E, m), 9, 66 (1H, d, J = 8, OHz). ' Preparation 10
The following compound was obtained in a manner similar to that of Preparation 1-7).
 EMI61.3
 



  7-L2-2,4-thiadiazol-3-yl) - 2-ethoxyiminoacetarnido / -3-2- carboxylic acid (syn isomer) (trans isomer).



  IR (Nujol): 3400, 3250, 1760, 1670, 1655, 1620 RMN r5 (DMSO-d6) 28 (3H, t, J = 7, OHz), 3, 88 (2H, q, o J = 18, OHz ), 4.20 (2H, q, J = 7, OHz), 5.25 (1H, d, J = 4, OHz), 5.83 i, dd, J = 4, OHz, 8, OHz), 7, 01 (Li, d, J = 17, OHz), 7, 21-8, 24 (3H,), 8, 32-8, 75 (2H, m), 9, 57 (1H, d, J = 8, OHz).



   (5-amPreparation11
1) Nicotinaldehyde (1.28 g) was added to a solution of {4-benzhydryloxycarbonyl-7 - [(5-
 EMI61.4
 benzhycryloxycarbonyl-5-benzamido) ylmethyl} (4.8 g) in a mixture of valeramido / -3-cephem-3-N, N-dimethylformamide (48 ml) and ethanol (4.8 ml). The mixture was stirred at room temperature for 3.5 hours. To the reaction mixture, water (300 ml) and ethyl acetate (300 ml) were added. Layer
 EMI61.5
 

  <Desc / Clms Page number 62>

 separated organic was washed with brine and dried over magnesium sulfate. The crude product obtained by concentration was purified by chromatography on a column of silica gel using a mixture of acetone and dichloromethane (1: 1 by volume / volume) as eluent.



  The fraction containing the desired compound was evaporated to give the benzhydryl 7- (5-benzhydryloxycarbonyl-5-benzamidovaleramido) -3- [2- (3-pyridyl) vinyl] -3-cephem-4-carboxylate (mixture cis-trans) (1.25 g).



  NMR (DMSO-d, () 1.83 (4H, m), 2.33 (2H, m), 4.63 (1H, m),
5.25 (1H, d, J = 5Hz), 5.83 (1H, dd, J = 5Hz, 8Hz), 6.33-
8.17 (36H, m), 8.45 (2H, m), 8.82 (1H, d, J = 8Hz),
8.95 (1H, d, J = 8Hz).



   2) To a suspension of the phosphidine pyridinepentachloride complex, prepared from pyridine (4.7 g) and phosphorus pentachloride (12.5 g), in
 EMI62.1
 dichloromethane (90 ml), 7-dryloxycarbonyl-5-benzamidovaleramido) benzyllryl vinyll-3-cephem-4-carboxylate (viny mixture (5-benzhy-cis-trans) (17.7 g) was added while cooling with ice and stirring. The mixture was stirred at the same temperature for 30 minutes. Methanol (5.7 ml) was added to the resulting solution at -15 to -10 ° C and poured into water ( 300 ml) The separated aqueous layer was washed successively with methylene chloride and diisopropyl ether, and the aqueous layer was adjusted to pH 5.5 with a 20% aqueous sodium hydroxide solution.

   The precipitate was collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure to give 7-amino-3- / 2- (3-pyridyl) vinyl / -
 EMI62.2
 Benzhydryl 3-cephem-4-carboxylate (cis-trans mixture) (6.9g).



  IR (Nujol): 3300, 1760, 1710 cmRMN (DMSO-d, (): 3.87 (2H, m), 4, 90 (1H, d, J = 5Hz),
5.15 (1H, d, J = 5Hz), 7.0-7, 80 (15H, m), 8.43 (2H, m)

  <Desc / Clms Page number 63>

 
 EMI63.1
 Preparation 12 The following compounds were obtained in a manner similar to that of Preparation 1-7).



  1) 2-methoxyimino-2- 2, 4-thiadiazol-3-yl) acetamidQ / -3-L2-lique (syn-isomer) (cis-trans mixture).



  IR (Nujol): 3270, 1670, 1610, NMR (DMSO-d,) 3.37 (2H, ABq, J = 18Hz), 3.90 (3H, s), 5, 22 (ID, 5, 83 ( 1H, dd, J = 5Hz, 8Hz), 6.35-7.85 (4H, m), 8.47 (2H, m), 57 (1H, d, J = 8Hz).



  2) 7- / 2-ethoxyimino-2-acetamidQ / -3-L2- acid (syn isomer) (cis-trans mixture).



  IR (Nujol) 1770, 1670, 1610, 1530 NMR,): 1, 20 (3H, t, J = 7Hz), 3.37 (2H, ABq, o J = 18Hz), 10 (2H, q, J = 7Hz), 5.23 (1H, d, J = 8Hz), 5.80 (1H, dd, J = 5Hz, 8Hz), 6.37-7.87 (4H, m), 6.70 (1H, s), 8, 43 (2H, m), 9, 60 (1H, d, J = 8Hz).



  3) Acid yl) vl) acetani (o / -3- L carboxylic (isomer (cis-trans mixture).



  IR (Nujol): 3250, 1765, 1670, 1610, 1330 cm-1 NMR: 3, (2H, ABq, J = 18Hz), 3, 35 (1H, m), b 4, 70 (2H, m), 5, 23 (1H, d, J = 5Hz), 5.80 (1H, dd, J = 5H2), 5.80 (1H, dd, J = 5Hz, 8Hz), 6, 50-7, 80 (5H , m), 8, 47 (2H, m), 9, 67 (1H, d, J = 8Hz).



  4) 7-formamido-3-2- 4-cerboxylic acid (cis-trans mixture).



  IR (Nujol) 1665, 1600 cm-1 Rm: 3, 41} 6-Q} 3, 93 5, 22 (1H, d, J = 5, 5, 82 dd, J = 5, 6, 61 (0, 5H, s), 7.02 (0.75H, d, J = 17, OHz), 7.27-7, 60 (hui, m), 7.60 (0.75H, d, J = 17, OHz ), 7, 68-8, 07 (1H, m), n 8, 37-8, 80 (2H, m), 9, 11 (1H, d, J = 8, OHz).



  5) Acid 7- 3-L2- (cis-trans mixture).

  <Desc / Clms Page number 64>

 
 EMI64.1
 



  U IR (Nujol): 3150, 1770, 1678 cm
7-NMR acid DMSO-d6, #): 3.8 (2H, m), 4.0 (3H, s), 5.26 (1H, d, J = 4Hz), 5.90 (1H, dd, J = 4Hz, 8Hz), 6.7-8.0 (8H, m), 8.50 (2H, m), 9.77 (1H, d, J = 8Hz).



   6) 7-Z2- (5-amino-1, 2, 4-thiadiazol-3-yl) - 2-carboxymethoxyiminoacetamido] -3- [2- (3-pyridinyl) vinyl] - 3-cephem-4 acid -carboxylic (syn isomer) (cis-trans mixture).



  IR (Nujol): 3300.1770, 1674.1620 cm-1 NMR (D2O-NaHCO3, #): 3.70 (2H, m), 4.75 (2H, s), 5.30 (1H, d, J = 5Hz), 5.90 (1H, d, J = 5Hz), 6.5-7.8 (4H, m),
8.40 (2H, m).



  Preparation 13
The following compounds were obtained in a manner similar to that of Preparation 1-6).



   1) The 7] -2-propargyloxyimino-2- (2-aminothiazol-4-yl) acetamido / -3- / 2- (3-pyridyl) vinyl / -3-cephem-4-carboxy-late benzhydryl (isomer syn) (cis-trans mixture).



  IR (Nujol): 3250.1780, 1710.1670, 1610.1540 cm NMR (DMSO-d6, #): 3.50 (2H, ABq, J = 18Hz), 3.50 (1H, m),
4.73 (2H, m), 5.35 (1H, d, J = 5Hz), 5.87 (1H, dd,
J = 5Hz, 8Hz), 6.40-7.73 (15H, m), 8.43 (2H, m), 9.77 (1H, d, J = 8Hz).
 EMI64.2
 



  2) Benzhydryl 7-L2-ethoxyimino-2-yl) acetamido / -3- / 2-late (syn-isomer) (cis-trans mixture).



  IR (Nujol): 3200, 1770, 1720, 1670, 1610, 1520 cm-1 NMR (DMSO-d6, #): 1.23 (3H, s), 3.43 (2H, ABq, J = 18Hz),
4.13 (2H, q, J = 7Hz), 5.33 (1H, d, J = 5Hz), 5.88 (1H, dd, J = 5Hz, 8Hz), 6.37-7.87 (5H , m), 8.38 (1H, m),
9.62 (1H, d, J = 8Hz).



  Preparation 14
The following compounds were obtained in a manner similar to that of Preparation 2-5).
 EMI64.3
 



  1) 7-L2-allyloxyimino-2- 2, 4thiadiazol-3-yl) / -3-L-7- (3-pyridyl) vinyl7 benzhydryl cephem-4-carboxylate (syn-isomer) (cis-trans mixture) .

  <Desc / Clms Page number 65>

 
 EMI65.1
 



  IR: 1770, 1720, 1670 2) 7-L2-propargyloxyimino-2-thiazol-4-yl) 2- -3-cephem- (5-amino-1,4-benzhydryl carboxylate (syn isomer) (cistrans mixture) ).



  IR (Nujol): 3200.1770, 1710, 1670.1535 cm
 EMI65.2
 NMR (DMSO-d.): 3, 17-4, 17 (3H, m), 5.08 (2H, m), b 5, 13 and 5.32 (1H, d, J = 5Hz), 5 , 80 and 6.0 (1H, dd, J = 5Hz, 8Hz), 6.4-7.77 (15H, m), 8.37 (1H, s), 8.47 (2H, m), 9 , 80 (1H, d, J = 8Hz).
 EMI65.3
 



  3) 7-L2-methoxyimino-2- 2,4-thiadiazol-3-yl) 2- (5-amino-1,4-carboxylic acid benzhydryl (syn isomer) (cistrans mixture).



    IR (Nujol): 3150.1760, 1720.1660, 1520 cm- NMR (DMSO-d,): 3.90 (2H, ABq, J = 18Hz), 5.28 (1H, d, J = 5Hz), 5.92 (1H, dd, J = 5Hz, 8Hz), 6.37-7.90 (15H, m),
8.37 (2H, m), 9.62 (1H, d, J = 8Hz).
 EMI65.4
 



  4) 7-L2-ethoxyimino-2-4 - il) acetamido / -3- / 2- benzhydryl carboxylate (syn isomer) (cistrans mixture).



  IR (Nujol): 3150, 1780.1720, 1660.1550 cm
 EMI65.5
 NMR (DMSO-d.,): 1, 2 (3H, t, J = 7Hz), 3.40 (2H, ABq, DJ = 18Hz), 4.12 (2H, q, J = 7Hz), 5, 30 (1H, d, J = 5Hz), 5.92 (1H, dd, J = 5Hz, 8Hz), 6.37-7.87 (17H, m), 8.40 (2H, m), 9, 70 (1H, d, J = 8Hz).
 EMI65.6
 



  5) Benzhydryl 7-acetamido} (syn isomer) (cis-trans mixture).



  IR (Nujol): 1780.1720, 1670 cm-1
 EMI65.7
 NMR (DMSO-d.): 3.7 (2H, m), 3.95 (3H, s), 5.03b (1H, d, J = 5Hz), 6.0 (1H, dd, J = 5Hz, 8Hz), 6, 6-7.6 (19H, m), 8.45 (2H, m), 9.80 (1H, d, J = 8Hz)
 EMI65.8
 6) Benz-7-L2- 2,4-thiadiazoJ-3-yl) -2-tbutoxycarbonylmethoxyiminoacetamidQ / -3-L2- (5-amino-l, vinyl] -3-cephem-4-carboxylate (syn isomer) .



  (cis-trans mixture).

  <Desc / Clms Page number 66>

 
 EMI66.1
 



  IR (Nujol): 3350, NMR (DMSO-d6,): 1.43 (9H, s), 3.67 (2H, m), 4.70b (2H, s), 5.37 (1H, d , J = 5Hz), 6.00 (lul, dd, J = 5Hz,
8Hz), 6.6-7.6 (7H, m), 8.45 (2H, m), 9.70 (1H, d,
J = 8Hz).



  Preparation 15
Trifluoroacetic acid (2.6 ml) was added to a suspension of 7-L2-allyloxyimino-2- (5-
 EMI66.2
 Y-3 - / - 2- (3-pyridyl) amino-1, 2, 4-thiadiazol -3-yl) acetarnidQ / -3-L2- (3-pyridyl) vinyl / -3-cephem-4-carboxylate benzhydryl (syn isomer) (cis-trans mixture) (2.3 g) and anisol (1.5 ml) in dichloromethane (11 ml) at room temperature and stirred for 1.5 hours at the same temperature. To the resulting solution was added diisopropyl ether (50 ml) and stirred. The precipitate was collected by filtration, washed with diisopropyl ether, then added to a mixture of ethyl acetate and water. The mixture was adjusted to pH 8 with 20% potassium carbonate.

   The separated aqueous layer was adjusted to pH 3.5 with 10% hydrochloric acid while cooling with ice. The precipitate was filtered and washed with water.



  To the precipitate was added water and the mixture was adjusted to pH 5.0 with an aqueous solution of saturated sodium bicarbonate. The insoluble substance was removed by filtration. The filtrate was subjected to column chromatography on a macroporous non-ionic adsorption resin called "Diaion HP-20" (registered trademark: product prepared by the company called Mitsubishi Chemical Industries) and eluted with an aqueous solution at 15% d 'Isopropylic alcohol. The fraction containing the desired compound was concentrated and lyophilized to give 7-L2-allyloxyimino-2- (5 amino-l, 2,4-thiadiazol-3-yl) acetamido] -3- [2- (3-pyridyl) - sodium vinyl / -3-cephem-4-carboxylate (syn isomer)
 EMI66.3
 (trans isomer) (0.5 g).



  IR (Nujol): 3250, 1760, 1660, 1610 cm

  <Desc / Clms Page number 67>

 
 EMI67.1
 66 NMR,) 73 (2H, large s), 4, 66 (4H, m), a 5, 06-5, 56 (3H, m), 5, 63-6, 60 (2H, m), 7, 06 (1H, d, J = 17, OHz), 7.29-8, 06 (3H, m), 8.40-8, 79 (2H, m),
9.61 (1H, d, J = 8, OHz).



  Preparation 16
 EMI67.2
 From the 2. (15.2 ml) was added to a suspension of 7-amino-3-L2-vin-,> T viny1 / -3-cephem-4-benzhydryl carboxylate (cis-trans mixture) (8.0 g) and anisol (7.4 ml) in dichloromethane (40 ml) at room temperature, then the mixture was stirred for 1.5 hours at the same temperature. To the resulting solution, diisopropyl ether (200 ml) was added and stirred. The precipitate was collected by filtration and washed with diisopropyl ether. The precipitate was added to a mixture of ezu and ethyl acetate and the mixture was adjusted to pH 7 with 20% potassium carbonate. The separated aqueous layer was adjusted to pH 4.5 with 10% hydrochloric acid while cooling with ice.

   The precipitate, the main component of which was the desired trans isomer, was separated by filtration and added to water. The mixture was adjusted to pH 7.0 with a saturated aqueous solution of sodium bicarbonate. After removal of an insoluble substance, the aqueous filtrate was adjusted to pH 4.5 with 10% hydrochloric acid while cooling with ice. The resulting precipitate was filtered, washed with water, cooled with ice and dried over phosphorus pentoxide in vacuo to give 7-amino-3- [2- (3-pyridyl) vinyl acid] -3-cephem-4-carboxylic (trans isomer) (1.9 g).



  IR (Nujol): 3150.1790, 1670.1610 cm-1 NMR (D20 + DCl, #): 4.03 (2H, s), 5.28 (1H, d, J = 5jOHz),
5.45 (1H, d, J = 5, OHz), 7.17 (1H, d, J = 17, OHz),
7, 85 (1H, d, J = 17, OHz), 7, 94-8, 25 (1H, m), 8, 65-
9.00 (3H, m).

  <Desc / Clms Page number 68>

 
 EMI68.1
 



  Preparation 17 Triflic acid.



  L (18.3 m. 1) was added to a suspension of 7- / 2- 2,4-thiadiazol-3-yl) -2-ethoxyiminoacetamido / -3- / 2- Droacétiqtle (18.3 ml) a benzhydryl ethephem-4-carboxylate (syn-isomer) (cis-trans mixture) (16.4 g) and anisol (10.7 ml) in dichloromethane (65 ml) at room temperature and stirred for 1.5 time at the same temperature. To the reaction mixture was added diisopropyl ether (300 ml) with stirring. The resulting precipitate was collected by filtration and washed with diisopropyl ether.



  The precipitate was added to a mixture of ethyl acetate (100 ml) and water (300 ml) and the mixture was adjusted to pH 8 with 20% potassium carbonate. The separated aqueous layer was adjusted to pH 3.5 with 10% hydrochloric acid while cooling with ice. The precipitate, the main component of which was the desired trans isomer, was separated by filtration and added to water (300 ml). The solution was adjusted to pH 7.5 with a saturated aqueous solution of sodium bicarbonate. After removal of the insoluble material by filtration, the filtrate was adjusted to pH 3.5 with 2N hydrochloric acid while cooling with ice.

   The precipitate was filtered, washed with water, cooled with ice and dried over phosphorus pentoxide in vacuo to give 7-L2- (5-amino-1, L, 4-thiadiazol-3- yl) -2-ethoxyiminoacetamido / -3-2- (3-pyridyl) vinyl] -3-cephem-4-carboxylic acid (syn isomer) (trans isomer) (5.2 g). The filtrate and the washings were combined and the resulting solution was subjected to column chromatography on a macroporous non-ionic adsorption resin called "Diaion HP-20" and eluted with a 30% aqueous solution of isopropyl alcohol.

   The fraction containing the desired compound was concentrated and lyophilized to obtain 7-L2- (5 amino- 1, 2, 4-thiadiazol-3-yl) -2-ethoxyiminoacetamido] -3- [2-

  <Desc / Clms Page number 69>

 (3-pyridyl) vinyl] -3-cephem-4-carboxylic (syn isomer) (cis isomer) (3.7 g). trans isomer
 EMI69.1
 IR (Nujol) NMR (DMSO-d ,,) 1, 28 (3H, t, J = 7, OHz), 3.88 (2H, q, b J = 18, 0Hz), 4.20 (2H, q , J = 7, OHz), 5.25 (1H, d, J = 4, OHz), 5.85 (1H, dd, J = 4, OHz, 8, OHz), 7.01 (1H, d, J = 17, OHz), 7, 21-8, 24 (3H, m), 8, 32-8, 75 (2H, m),
9.57 (1H, d, J = 8, OHz). cis IR isomer (Nujol):

   3250.1770, 1680.1610, 1520 cm-1
 EMI69.2
 NMR (DMSO-d ,,) 1, 18 (3H, t, J = 7, OHz), 3.67 (2H, m), o 4, (2H, q, J = 7, OHz), 5.22 (1H, d, J = 5, OHz),
5.82 (1H, dd, J = 5, OHz, 8, OHz), 6.57 (2H, s),
7.10-7.88 (2H, m), 8.47 (2H, m), 9.58 (1H, d,
J = 8Hz).



  Preparation 18
The following compounds were obtained in a manner similar to that of Preparation 5-2).



   1) (4-Benzhydryloxycarbonyl-7formaido-3-cephem-3-ylmethyl) triphenylphosphonium iodide.



  IR (Nujol): 1785.1680 (wide) cm-1.
 EMI69.3
 



  2) (4-Benzhydryloxycarbonyl-7- (p-nitrobenzamido) -3-cephem-4-ylmethy1 / triphenylphos-phonium iodide.



  IR (Nujol): 1780, 1715, 1670, 1605 cm.
 EMI69.4
 r NMR,) 1, 43 (9H, s), 3, 22-4, 30 (2H, m),
5.23 (1H, d, J = 5, OHz), 5.44-5.78 (1H, m), 6.54 (1H, s), 6.71 (0.5H, d, J = 0 , 5H), 7.04-7, 81 (13.5H, m), 8.53 (2H, m).



   3) Benzhydryl 7-acetamido-3- [2- (3-pyridyl) vinyl] - 3-cephem-4-carboxylate (cis-trans mixture) IR (Nujol): 1775, 1720, 1670 cm-1
 EMI69.5
 NMR (DMSO-d ,,) 1.95 (3H, s), b 'l 3.93 q, J = 17, OHz),

  <Desc / Clms Page number 70>

 
5.26 (1H, d, J = 4, OHz), 5.81 (1H, dd, J = 4, OHz,
8, OHz), 6.51 (0.5H, s), 6.77 (0.75H, d, J = 17, OHz),
6.87 (1H, s), 7.07-7, 90 (12, 75H, m), 8.36-8, 56 (2H, m), 8.94 (1H, d, J = 8.0Hz ).



   4) Benzhydryl 7- (p-nitrobezamido) -3- [2- (3-pyridyl) vinyl] -3-cephem-4-carboxylate (cis-trans mixture).



  IR (Nujol): 1780.1720, 1665.1600 cm
 EMI70.1
 NMR (DMSO-d.,: 3, 33-4, 20 (2H, m), 5.40 (1H, d, 6 6) J = 4, OHz), 6.02 (1H, dd, J = 4 , OHz, 8, OHz), 6.56 (0.5H, s), 6.76 (0.75H, d, J = 0.75), 7.09-7.77 (13.75H, m) , 8.14 (2H, d, J = 8, OHz), 8.37 (2H, d, J = 8, OHz), 8.46 (2H, m), 9.89 (1H, d, J = 8, OHz)
 EMI70.2
 5) (4-Benzhydryloxycarbonyl-7acetamido-3-cephem-3-ylmethyl) IR iodide (Nujol): 1770, 1710.1670 cm RrviN (DMSO-d6'6): 1.94 (3H, s), 3.58 (2H, m),
4.82-5.43 (3H, m), 5.73 (1H, dd, J = 5, OHz, 8, OHz),
6.31 (1H, s), 7.31 (10H, s), 7.52-8, 03 (15H, m),
8.86 (1H, d, J = 8, OHz).



  Preparation 19
The following compounds were obtained in a manner similar to that of Preparation 5-3).



   1) Benzhydryl 7-formamido-3- [2- (3-pyridyl) vinyl] - 3-cephem-4-carboxylate (cis-trans mixture), IR (Nujol): 1770.1670 cm NMR (DMSO-d6 , #): 3, 12-3, 86} 2H, m) 3, 96 q, J = 18, OHz),
5.30 (1H, d, J = 5, OHz), 5.90 (1H, dd, J = 5, OHz, 8, 0Hz).



   6.53 (0.7H, s), 6.83-7.94 (14.3H, m), 8.23 (1H, s),
8.47 (2H, m), 9.16 (1H, d, J = 8, OHz).
 EMI70.3
 



  2) Benzhydryl IR (Nujol) 7-formamido-3-L2- / -3 cephem-4-carboxylate IR (Nujol): 1770, 1670 cm-1 NMR)) 3, 12-3, 86 3, 96 (q, J = 18 , OHzJ

  <Desc / Clms Page number 71>

 
5.30 (1H, d, J = 5, OHz), 5.90 (1H, dd, J = 5, OHz, 8, OHz),
6.53 (0.5H, s), 6.83-7.94 (14.5H, m), 8.23 (1H, s),
8.47 (2H, m), 9.19 (1H, d, J = 8, OHz).



   3) Benzhydryl 7-t-butoxycarbonylamino-3- [2- (3-pyridyl) viny / -3-cephem-4-carboxylate (cistrans mixture).



  IR (Nujol): 1780.1710 cm.



  Preparation 20
The following compounds were obtained in a manner similar to that of Preparation 2-5).



   1) 7- / D (-) -2- (4-ethyl-2, 3-díoxo-1-pipérazinecarboxamido) -2- (phenyl) acetamido] -3- [2- (3-pyridyl) vinyl ] -3-cephem-4-benzhydryl carboxylate (cistrans mixture).



  IR (Nujol): 3270, 1780,1710, 1670,1500 cm '
 EMI71.1
 NMR 07 (3H, 3, 20-4, 17 (8H, m), u 5, d, J = 5Hz), 5.65 (1H, d, J = 7Hz), 5.82 (1H, 7 dd, J = 5Hz, 8Hz), 6.50 (1H, m), 6.82 (1H, s), 7.0-7.83 (16H, m), 8.45 (2H, m), 9.53 (1H, d, J = 7Hz), 9.83 (1H, d, J = 8Hz).



  2) 7-LD-piperazinecarboxamido) 3-L2- of benzhydryl (cis-trans mixture).



  IR (Nujol): 3250.1780, 1710, 1680, 1600.1500 cm
 EMI71.2
 NMR (DMSO-d6 ') 1.08 (3H, t, J = 7Hz), 3.17-4, 10 (8H, m), b 5.17 (1H, d, J = 5Hz), 5.52 (1H, d, J = 7Hz), 5.83 (1H, dd, J = 5Hz, 8Hz), 6.57 (1H, d, J = 13Hz), 6.82 (1H, s),
7.0-7, 67 (17H, m), 8.45 (2H, m), 9.42 (1H, d, J = 7Hz),
9.73 (1H, d, J = 8Hz).



  Preparation 21
The following compounds were obtained in a similar manner to that of Preparation 1-7).
 EMI71.3
 



  1) 7- / D- piperazinecarboxamido) vinyl / -3-cephem-4-carboxylic acid (cis-trans mixture)

  <Desc / Clms Page number 72>

 
 EMI72.1
 IR (Nujol): 3270, 1770, 1710, 1670, 1510 NMR) 10 (3H, t, J = 7Hz), 3, 42 (2H, q, J = 7Hz), b 3, 32-4, 10 (6H , m), 5.15 (1H, d, J = 5Hz), 5.67 (1H, d, J = 7Hz), 5.68 (1H, dd, J = 5Hz, 8Hz), 6.58 (1H , s), 7.10-8, 10 (8H, m), 8.58 (2H, m), 9.55 (1H, d, J = 7Hz), 9.90 (1H, d, J = 8Hz ).



   2) Acid 7- / D (-) - 2- (4-ethyl-2,3-dioxo-1-
 EMI72.2
 piperazinecarboxamido) -2- L2- cis- trans).



  IR (Nujol): 3250.1770, 1710.1670, 1610.1510 cm-1
 EMI72.3
 NMR (DMSO-d.,) 1, 10 (3H, J = 7Hz), 3.40 (2H, q, 6
J = 7Hz), 3.17-4, 17 (6H, m), 5.13 (1H, d, J = 5Hz),
5.52 (1H, d, J = 7Hz), 5.77 (1H, dd. J = 5Hz, 8Hz),
7.0 (4H, ABq, J = 7Hz), 6.5-8, 1 (4H, m), 8.55 (2H, m),
9.40 (1H, d, J = 7Hz), 9.75 (1H, d, J = 8Hz).



     Preparation of the desired compounds of the present invention
Example 1
A mixture of 7-amino-3- [2- (1-methyl-3-pyridinio) vinyl] -3-cephem-4-carboxylate dihydrochloride (cis-trans isomer) (0.39 g) and N- ( trimethylsilyl) acetamide (0.92 g) in tetrahyrofurar2 (10 ml) was stirred at room temperature for 20 minutes to give a clear solution. To the solution was added 2-ethoxyimino-2- (5-amino-1,2,4,4-thiadiazol-3-yl) acetyl chloride (syn isomer) (0.41 g) between -15 and -10 C and stirred at the same temperature for 30 minutes.

   Water (10 ml) was added to the resulting solution, and the separated aqueous layer was adjusted to pH 3.5 with 5% aqueous sodium bicarbonate solution. The solution was subjected to column chromatography on a macroporous non-ionic adsorption resin called "Diaion HP-20" / registered trademark: product prepared by the company called Mitsubishi Chemical Industrial and eluted with an aqueous solution at 10% of Isopropylic alcohol. The fraction containing the desired compound was concentrated and lyophilized to give 7-L2- (5-amino-
 EMI72.4
 /

  <Desc / Clms Page number 73>

 
 EMI73.1
 1,2,4-thiadiazo-3-yl) -2-ethoxyiminoacetamido / -3- /.



   : (syn isomer) (cis-trans mixture) (0.15 g).



  IR (Nujol): 1765, 1660, 1610 cm NMR (D 0, cf): 1.33 (3H, t, J = 7, OHz), 3, 42 and 3.77 (2H total, each q, J = 18, OHz and large s), 4.30 (2H, q, J = 7, OHz), 4.31 (3H, s), 5.26 (1H, d, J = 4, OHz),
5.80 (1H, d, J = 4, OHz), 6.55 (1H, s), 6.66 (0.5H, d,
J = 17, OHz), 7.43 (0.5H, d, J = 17Hz), 7.64-8, 73 (4H, m).



   Example 2
The following compounds have been obtained from a
 EMI73.2
 similar to that of Example 1. anL i-m
1) 7-Phenylacetamido-3- [2- (1-methyl-3-pyridinio) vinyl] -3-cephem-4-carboxylate methanesulfonate (cis-trans mixture).



  IR (Nujol): 3200, 1750.1650, 1510 cm-1
 EMI73.3
 2) 7-phenylacetamido-3-L2-pyridinio) (cis-trans mixture) IR (Nujol): 3200, 1770, 1660.1600, 154 0 cm
Example 3
A mixture of benzhydryl 7-phenylacetamido-3- [2- (1-methyl-3-pyridinio) vinyl] -3-cephem-4-carboxylate iodide (cis-trans mixture) (1.8 g) and d The trifluoroacetic acid (2.8 g) and anisole (1.06 g) in dichloromethane (8 ml) was stirred at room temperature for one hour. The reaction mixture was added dropwise to diisopropyl ether and the resulting precipitate was filtered. The precipitate was suspended in water and adjusted to pH 7.0 with a 20% aqueous solution of potassium carbonate.

   The insoluble material was removed by filtration and the filtrate was acidified to a pH of 2.0 with 10% hydrochloric acid. The solution was subjected to column chromatography on a macroporous non-ionic adsorption resin called "Diaion HP-20" and eluted with a 20% aqueous solution of isopropyl alcohol. The fraction containing

  <Desc / Clms Page number 74>

 the desired compound was concentrated and lyophilized to give 7-phenylacetamido-3- [2- (1-methyl-3-pyridinio) vinyl] -3-cephem-4-carboxylate (cis-trans mixture) (0.3 g ).
 EMI74.1
 



  IR (Nujol): 3200, 1770, 1600, 1540 NMR: 3.47 (2H, q, J = 18Hz), 3.55 (2H, s), o
4.35 (3H, s), 5.18 (1H, d, J = 5Hz), 5.60 (1H, dd,
J = 5.8Hz), 6.25 (0.5H, d, J = 7Hz), 6.30 (1H, s),
7, 0-7, 6 (0.5H, m), 7.27 (5H, s), 7.77-8, 67 (2H, m),
8.90 (2H, m), 9.13 (1H, d, J = 8Hz).



   Example 4
The following compounds were obtained in a manner similar to that of Example 3.



   1) 7-Phenylacetamido-3- [2- (1-methyl-3-pyridinio) vinyl] -3-cephem-4-carboxylate methanesulfonate (cis-trans mixture).



  IR (Nujol): 3200, 1750, 1650, 1510 cm
2) 7-L2- (5-amino-1, 2, 4-thiadiazol-3-yl) -
 EMI74.2
 2-ethoxyiminoacetamidQ / -3-L2- 3-cephem-4-carboxylate (cis-trans mixture).



  IR (Nujol): 1765, 1660, 1610 cm
3) 7-amino-3- / 2- (1-methyl-3-pyridinio) vinyl] -3-cephem-4-carboxylate dihydrochloride (cis-trans mixture).



  IR (Nujoi): 1780, 1700 cm ".



   Example 5
1) A mixture of 7-phenylacetamido-3- [2- (3-pyridyl) vinyl] -3-cephem-4carboxylic acid trifluoroacetate (cis-trans mixture) (0.5 g) and methyl methanesulfonate (0 , 13 g) in tetrahydrofuran (60 ml) was stirred at room temperature for 48 hours. The precipitate was collected by filtration and washed with tetrahydrofuran to give 7-phenylacetamido-3- [2- (1-methyl-3-pyridinio) methanesulfonate
 EMI74.3
 vinyl / -3-cephem-4-carboxylate (cis-trans mixture) (0.2 g). viny IR (Nujol): 3200, 1750, 1650, 1510 cm -1 RMN J (DMSO-d6):

   2.37 (3H, s), 3.53 (2H, s), 3.53 (2H, m),
4.33 (3H, s), 5.20 (1H, dd, J = 5Hz), 5.68 (IH, dd,

  <Desc / Clms Page number 75>

 J = 5Hz, 8Hz), 7.23 (5H, s), 6.72 (1H, s), 7.10 (0.5H, d, J = 17Bz), 7.50 (0.5H, d, J = 17Hz), 8.0-8, 7 (2H, m), 8.83 (2H, m), 9.07 (1H, d, J = 8Hz).
 EMI75.1
 



  2) 7-Phenylacetamido-3-2- methanesulfonate (cis-trans mixture) (0.8 g) was added to water (14 ml).



  The solution was acidified to pH 2.0 with 10% hydrochloric acid. The solution was subjected to column chromatography on a macroporous non-ionic adsorption resin called "Diaion HP-20" and eluted with a 30% aqueous solution of isopropyl alcohol. The fraction containing the sought-after compound was concentrated and lyophilized to give 7-phenylacetamido-3- [2- (1-methyl-3-pyridinio) vinyl] -3-cephem-4-carboxylate (cistrans mixture) (0.41 g).



  IR (Nujol): 3200.1770, 1660.1600, 1540 cm NMR # (DMSO-d6): 3.47 (2H, q, J = 18Hz), 3.55 (2H, s), 4.35 (3H , s), 5.18 (1H, d, J = 5Hz), 5.60 (1H, dd, J = 5, 8Hz),
6.25 (0.5H, d, J = 17Hz), 6.30 (1H, s), 7.0-7.6 (0.5H, m),
 EMI75.2
 7, 27 s), 7, m), 8, 90 (2H, m), 9, 13 (1H, d, J = 8Hz).



   Example 6
The following compounds were obtained in a manner similar to that of Example 5.
 EMI75.3
 



  1) 7-L2-2,4-thiadiazol-3-yl) - 2-ethoxyiminoacetamido / -3-L2- 3-cephem-4-carboxylate (syn isomer) (cis-trans mixture).



  IR (Nujol): 2) The du de 7-amino-3- / 2- z 1-3-cepheiii7-4-carboc? cis-trans).



    (5-amino-1, i IR (Nujol): 1780.1700 cm ".



   Example 7
To a suspension of methanesulfonate
 EMI75.4
 7-phenylacetamido-3- / 2- 1 phen (1-methyl-3-pyridinio) vinyl / -3-cephe-4-carboxylate (cis-trans mixture) (0.8 g) and dimethylaniline (0.7 g ) in dichloromethane (10 ml), trimethylsilyl chloride (0.33 g) was added between

  <Desc / Clms Page number 76>

 22 and 250C and the mixture was stirred between 30 and 350C for 2 hours. To the mixture was added phosphorus pentachloride (0.63 g) at -30 to -28 ° C and the solution was stirred at -33 to -25 ° C for 1.5 hours. 1,3-Butanediol (1.6 ml) was added to the above solution at -28 to -5 ° C and stirred at 0-50 ° C for 30 minutes.

   The resulting mixture was decanted and the residue was washed with dichloromethane. The residue, dissolved in methanol (5 ml) was added dropwise 3 of dichloromethane (40 ml). The resulting precipitate was collected by filtration and washed with dichloromethane
 EMI76.1
 to give 7-amino-3-L2-3-pyridinio dihydrochloride) vinyll-3-cephem-4-carboxylate cistrans) (0.32 g).



  IR (Nujol) NMR <f O) 3.56 (2H, m), 4.38 (3H, 6.67-9.00 (6H, m).



   Example 8
The following compounds have been obtained from a
 EMI76.2
 similar to that of Example 1, 3 and 5.



  (1) 7- / 2- 2, 4-thiadiazol-3-) 2-ethoxyiminoacetamido / -3- / 2- 3-cephem-4-carboxylate (syn isomer) (trans isomer).



  IR (Nujol): 3300, 1765, 1660.1610 cm NMR t (DO): 1.33 (3H, t, J = 7, OHz), 3.79 (2H, large s),
4.33 (2H, q, J = 7, OHz), 4.37 (3H, s), 5.30 (1H, d,
J = 5, OHz), 5.85 (1H, d, J = 5, OHz), 6.74 (1H, d,
J = 17, OHz), 7.53 (1H, d, J = 17, OHz), 7.75-8, 10 (1H, m),
8.33-8.83 (3H, m).



   (2) 7- [2- (5-amino-1, 2, 4-thiadiazol-3-yl) - 2-ethoxyiminoacetamido] -3- [2- (1-methyl-3-pyridinio) vinyl] - 3 -céphem-4-carboxylate (syn isomer) (cis isomer).



  IR (Nujol): 1765, 1665, 1600 cm-1 NMR # (D2O): 1.33 (3H, t, J = 7, OHz), 3.48 (2H, q, J- = 18, 0hz),
4.33 (2H, q, J = 7.0Hz), 4.34 (3H, s), 5.30 (1H, d,

  <Desc / Clms Page number 77>

 J = 5, OHz), 5.81 (1H, d, J = 5, OHz), 6.60 (2H, s), 7.76-8.08 (1H, m), 8.26-8, 79 (3H, m).



   (3) 7-L2- (5-amino-1, 2, 4-thiadiazol-3-yl) -
 EMI77.1
 2-ethoxyiminoacetamidQ / -3-L2- 3-cephem-4-carboxylate (syn isomer) (trans isomer).



  IR (Nujol): 3300, 1770, 1670, 1630, 1510 cm.



  NMR (DMSO-d ,,): 1, 28 (3H, t, J = 7Hz), 3.32-4, 17 (2H, m), b 4.10 (2H, q, J = 7Hz), 4 , 27 (3H, s), 5.22 (1H, d, J = 5Hz), 5.80 (1H, dd, J = 5Hz, 8Hz), 6.85 (1H, d, J = 17Hz), 7 , 93- 8.67 (4H, m), 8.80 (1H, m), 9.58 (1H, d, J = 8Hz).



   (4) 7-L2- (5-amino-1, 2, 4-thiadiazol-3-yl) -
 EMI77.2
 2-ethoxyiminoacetamido / -3- / 2- vinyl / - 3-cepheIT. (syn isomer) (trans isomer).



  IR (Nujol) 3250, 1765, 1660, 1610 cm-1 RL t, J = 7, OHz), 3.78 (2H, large 5), 4.35 (2H, q, J = 7, OHz), 4 , 30-5, with 5.32 (LU, d, J = 5.0Hz), 5.87 (1H, d, J = 5, OHz), 6.73 (1H, d, J = 16, OHz) , 7, 53 (1H, d, J = 16, OHz), 7, 77-8, 10 (1H, m), 8, 33-8, 94 (3H, (5) On 7- / 2- 2, 4-thiadiazol-3-yl) - 2-ethoxyiminoacetamido / -3-2- (1-ethyl-3-pyridinio) 3-cephem-4-carboxylate (syn isomer) (cis isomer).



  IR (Nujol): 3250, 1760.1660, 1600 cm 'NMR (D2O, #): 1.34 (3H, t, J = 7, OHz),
1.64 (3H, t, J = 7, OHz), 3.51 (2H, q, J = 18, OHz),
4.38 (2H, q, J = 7, OHz), 4.68 (2H, q, J = 7, OHz),
5.33 (1H, d, J = 5, OHz), 5.85 (1H, d, J = 5, OHz),
6.67 (2H, s), 7.83-8, 14 (1H, m),
9.30-8.93 (3H, m).
 EMI77.3
 



  (6) 7-L2-methoxyimino-2- 4-yl) acetamido / -3- / 2- (2-aminothiazoJ-ceph2m-4-carboxylate (syn isomer) (trans isomer).



  IR (Nujol): 3280, 1760, 1655.1610 cm-1 NMR DD20-DCl,): 3.97 (2H, s), 4.11 (3H, s), 4.43 (3H, s),
5.36 (1H, d, J = 5, OHz), 5.86 (1H, d, J = 5, OHz), 7.07

  <Desc / Clms Page number 78>

 
 EMI78.1
 (1H, d, J = 17, OHz), 7.19 (1H, s), 7.77 (1H, d, J = 17, OHz), 7.19 (1H, s), 7.77 (1H , d, J = 17, OHz), 7, 99-8, 20 (1H, m), 8, 48-9, 01 (3H, m).



  (7) 7-L2-propargyloxyimino-2- 4-yl) acetamidQ / -3-L2- 4-carboxylate (syn-isomer) (cis-trans mixture).



  IR (Nujol): 3250, 2100, 1765, 1660, 1 605 cm-l NMR (D2O-DCl, #): 3.12 (1H, m), 3.58 (q, J = 18.0Hz)} 2H total, 3.98 (m), 4.44 (3H, s), 4.96 (2H, m), 5, 36 and 5.41 (1R total, each d, J = 5, OHz), 5, 81 and 5.87 (1H total, each d, J = 5, OHz), 6.86 (1H, s), 7.09 (0.5H, d, J = 17, OHz), 7.27 (1H , s), 7.80 (0.5H, d, J = 17, OHz),
 EMI78.2
 8, 00-8, 23 (1H, m), 8, 34-9, 02 (3H, (8) Le 7- [2-allyoxyimino-2- (5-amino-1, 2, 4thiadiazol-3-yl ) acetamido] -3- [2- (1-methyl-3-pyridinio) vinyl] -3-cephem-4-carboxylate (syn isomer) (trans isomer).



  IR (Nujol): 3280, 1765, 1660, 1610 cm-1 NMR (D2O-DCl, #): 3.92 (2H, m),
4.32 (3H, s), 4.93 (2H, d, J = 5, OHz),
5.17-5.63 (3H, m), 5.75-6.14 (2H, m),
7.06 (1H, d, J = 17, OHz), 7.71 (1H, d, J = 17, OHz),
7, 95-8, 17 (1H, m), 8.44-8, 94 (3H, m),
 EMI78.3
 (9) 7-L2-methoxyimino-2-acetamido / -3-2-carboxylate (syn-isomer) (cis-trans mixture).



  IR (Kujol) NMR): 3, 8-4, 1 (2H, m), b
3.93 (3H, s), 4.40 (3H, s), 5.36 (1H, d, J = 5Hz),
5.90 (1H, d, J = 5Hz), 6.7-7.6 (6H, m),
7.9-9.2 (4H, m).



   (10) 7- [2-carboxymethoxyimino-2- (5-amino- 1, 2, 4-thiadiazol -3-yl) acetamido] -3- [2- (1-methyl-3-pyridinio) vinyl] - 3-cephem-4-carboxylate (syn isomer) (cis-trans mixture).

  <Desc / Clms Page number 79>

 
 EMI79.1
 



  IR: 3300, 1616 NMR (D, 76 (2H, broad s), 4.35 (3H, s), 4, broad s), 5.33 (1H, d, J = 5Hz), 5.86 (1H , d, J = 5Hz), 6, 65-7, 8 (2H, 7, 8-8, 83 (4H, m).



  (11) 7-formamido-3- / 2- (1-methyl-3-pyridinio) vinYll-3-cephem-4-carboxylate iodhydrate (cis-trans mixture).



  IR (Nujol): 1770, 1670 (wide) cm NMR (DM50-d., ..-. O} 4, 35 (3H, s), 5, 25 (1H, d, J = 4, OHz),
5.63-5, 98 (1H, m), 6.61 (0.75H, d, J = 16, OHz),
6.70 (0.5H, s), 7.35 (0.75H, d, J = 16, OHz),
7, 87-8, 08 (1H, m), 8.12 (1H, s),
8, 22-9, 20 (3H, m).



   Example 9
A mixture of 7-formamido-3-L2- (1-methyl-3-pyridinio) vinyl] -3-cephem-4-carboxylate iodhydrate (cis-trans mixture) (0.3 g) in methanol ( 5 ml) and concentrated hydrochloric acid (0.2 g) was stirred for 2 hours at room temperature. The insoluble material was collected by filtration, washed with methanol to give 7-amino-3- -2- (1-methyl-3-pyridinic) vinyl] -3-cephem-4-carboxylate hydrochloride ( trans isomer) (0.17 g). To the above filtrate, isopropyl ether was added and stirred.

   The precipitate was collected by filtration to give 7-amino-3] -2- (1-methyl-3-pyridinio) vinyl] - hydroiodide hydrochloride.
 EMI79.2
 3-cephe-4-carboxylate cis, containing small amounts of trans isomer IR (Nujol): 1705 cm-1 NMR O, 3.99 (2H, s), 4.41 (3H,
5.25 (1H, d, J = 5, OHz), 5.43 (1H, d, J = 5, OHz),
7.05 (1H, d, J = 17, OHz), 7.75 (1H, d, J = 17, OHz),
7.96-8, 32 (1H, m), 8.49-8, 80 (2H, m), 8.90 (1H, s). cis IR isomer (Nujol): 1775, 1705 cm-1

  <Desc / Clms Page number 80>

 
 EMI80.1
 r NMR 3.93 m), 4.41 (3H, s), 5.20 (1H, d, J = 5, OHz), 5.46 (18, d, J = 5, OHz), 6.86 (2H, s),
7.91-8.18 (1H, m), 8.25-8.98 (3H, m).



   Example 10
Vilsmeier's reagent was prepared from phosphorus oxychloride (0.3 ml) and dimethylformamide (0.3 g) in ethyl acetate (1.2 ml) in an ordinary manner. 2-methoxyimino-2- (2-trifluoroacetamidothiazol-4-yl) acetic acid (syn isomer) (1.0 g) was added to the stirred suspension of Vilsmeier reagent in tetrahydrofura. 15 ml) while cooling with ice and stirred for 30 minutes at the same temperature to produce an active acid solution.



   7-amino-3- / 2- (1- methyl-3-pyridinio) vinyl / -3-cephem-4-carboxylate (trans isomer) hydroiodide (1.2 g) was dissolved in the solution of sodium bicarbonate (0.7 g) in water (10 ml) and acetone (20 ml). To the solution, the above activated acid solution was added between -3 and 30C and the solution was stirred for 30 minutes maintaining the pH between 6.5 and 7.5 with a 20% aqueous solution of potassium carbonate. Water and ethyl acetate were added to the mixture
 EMI80.2
 containing 7-L2-thiazol-4-yl) -2-methoxyiminoacetamido / -3- / 2-pyridinio) viYll-3-cephem-4-carboxylate (syn isomer) (trans isomer) and the separated aqueous layer was adjusted to a pH of S, 0 with 10% hydrochloric acid.

   Sodium acetate (2.2 g) was added to the aqueous layer and a solution was stirred for 18 hours at room temperature. The resulting solution was adjusted to a pH of 4.0 with 10% hydrochloric acid and a solution was subjected to column chromatography on a macroporous non-ionic adsorption resin called "Diaion HP-20" and eluted with a 10% aqueous solution of isopropyl alcohol. The fractions of the desired compound were concentrated and dried by freezing to give 7] -2- (2-aminothiazol -4-yl) -2-methoxyiminoacetamindo] -3-

  <Desc / Clms Page number 81>

 -2- (1-methyl-3-pyridinio) vinyl] -3-cephem-4-carboxylate (syn isomer) (trans isomer) (0.81 g).



  IR (Nujol): 3280.1760, 1655.1610 cm NMR (D20-DCl, 6): 3.97 (2H, s),
4.11 (3H, s), 4.43 (3H, s), 5.36 (1H, d, J = 5, OHz),
5.86 (1H, d, J = 5, OHz), 7.07 (1H, d, J = 17, OHz),
7, 19 (1H, s), 7.77 (1H, d, J = 17, OHz), 7.99-8, 20 (1H, m), 8.48-9, 01 (3H, m).


    

Claims (1)

 CLAIMS 1. New cephem compounds, characterized in that they have the formula:  EMI82.1    EMI82.2  where R is the amino group or an acylamino group, 2 R is a lower alkyl group, and Y is CH or N, and their pharmaceutically acceptable salts. 2. Compound according to claim l, characterized 1 in that is the amino group, an amino lower alkanoyl group, amino lower aralcanoyl, aralkanoyl laughing alkoxy group aur The lower imino, amino or acylaminothiazolylalkanoyl lower amino having a lower alkoxy group imino, amino or acylaminothiazolylalkanoyl lower amino having a lower alkynyl group oxyimino, aminothiadiazolylalcanoyl lower amino having a lower alkoxy group imino, aminothiadiazolylalkyloyl aminoalkylinoylinoalkylinoylinoalkylinoyl lower alkyl amino lower aminothiadiazolylalkanoyl having an imino lower carboxyalkoxy group.  3. Syn isomer of a compound of claim 2, characterized in that is e 2-methoxyimino group  EMI82.3  2- aminothiazol-4-yl) ino-1,2, 4thiadiazol-3-yl) acetamido, 2,4- thiadiazol-3-yl) acetamido, 2-carboxymethoxyimino-2- (5-amino- 1, 2, 4 -thiadiazol-3-yl) acetamido, or 2-methoxyimino-2- (m- h. ydroxyphenyl) aceta! "tido, and R2 is methyl or ethyl.  4-Compound according to Claim 2, characterized in that it is formed by 7-amino-3- / 2- (methyl-3-pyridinio) vinyl] -3-cephem-4-carboxylate (cis isomer, trans isomer or cis-trans mixture) or its dichlorhy-  <Desc / Clms Page number 83>  drate or its hydrochloride iodhydrate.  5. Compound according to claim 3, characterized in that it is formed by 7-L2-methoxy-  EMI83.1  3-pyridinio) vinyl / -3-cephem-4-carboxylate (syn isomer) (trans isomer).  6. Compound according to claim 3, characterized in that it is formed by 7- / 2-propargyl-  EMI83.2  oxyimino-2-methyl-3-pyridinio) vinyl / -3-cephem-4-carboxylate (syn-isomer) (cis-trans mixture).  7. Compound according to claim 3, characterized in that it is chosen from the group consisting of:  EMI83.3  7- / 2-ethoxyimino-2- acetamido / -3- / 2- (5-amino-1,2,4-thiadiazol-3-yl) -carboxylate (syn isomer) (cis isomer, trans isomer or cis mixture -trans),  EMI83.4  7-L2-ethoxyimino-2- 2, 4-thiadiazoJ acetamido, / - 3- /. Trans 4-carboxylate) and 7- / 2-ethoxyimino-2- 2,4-thiadiazoJ-3-yl) acetamido / -3- / 2- 4-carboxylate (syn isomer) (cis isomer or trans isomer).  8. Compound according to claim 3, characterized in that it is formed by 7- / 2-allyloxy-  EMI83.5  imino-2- 2,4-thiadiazol L2- (5-amino-l, (syn-isomer) (trans-isomer).  9. Compound according to claim 3, characterized in that it is formed by 7- / 2-carboxy-  EMI83.6  methoxyimino-2- 2,4-thiadiazol 3- /. (syn isomer) (cis-trans mixture).  <Desc / Clms Page number 84>    EMI84.1   10. Process for the preparation of new co-formulas:  EMI84.2    EMI84.3  where is the amino group or an acylamino group, 2 R is a lower alkyl group, and (5-amino-1, Y is CH or N, or their pharmaceutically acceptable salts, characterized in that it consists in reacting a  EMI84.4  composed:  EMI84.5    EMI84.6  where R Y are each as or its reactive derivative on the amino group or its salt, with an acylating agent, to give a compound having the  EMI84.7  formula  EMI84.8    EMI84.9  2 where 8 are each: R is an acylamino group, or its salt. at 11.  Process for the preparation of new cephem compounds having the formula indicated in claim 10 or their pharmaceutically acceptable salts, characterized in that it consists in subjecting a compound having the formula;  <Desc / Clms Page number 85>    EMI85.1    1 2 or R, R and Y are each as defined in claim 10, R is a protected carboxy group, and Z is an acid residue, or its salt, in a reaction for eliminating the protecting group from the carbo v group, to give a compound having the formula:  EMI85.2    EMI85.3  . L 2 ùRR, Claim 10, or its salt.  12. Process for the preparation of new cep1: em compounds, or their pharmaceutically acceptable salts, having the formula as indicated in claim 10, characterized in that it consists in reacting a compound having the formula:  EMI85.4  where R and Y are each as defined in claim 10, or its salt, with a lower alkylating agent, to give a compound of formula:  <Desc / Clms Page number 86>    EMI86.1    EMI86.2  1 2 where R ", and Y are each as defined in claim 10, or its salt.  13. Process for the preparation of new cephem compounds, having the formula indicated in claim 10 or their pharmaceutically acceptable salts, characterized in that it consists in reacting a compound having the formula:  EMI86.3    EMI86.4  1 2 where R, estungroupeacylaminoetR and Y are each a. as in claim 10, or its salt, in a deacylation reaction, to give a compound having:  EMI86.5    EMI86.6  ? WHERE P in claim 10, or its salt.  14. Method for preparing new cephem compounds having the formula as defined in claim 10. or their pharmaceutically acceptable salts, characterized in that it consists in subjecting a compound having the formula:  EMI86.7    <Desc / Clms Page number 87>    EMI87.1  2 in which and Y are each as defined in claim 10 and R, an acylamino group having b a protected amino group, or its salt, in an amino group protecting group removal reaction, to give a compound having the formula :  EMI87.2    EMI87.3  2. or R tion 10 an acylamino group having a c amino group, or its salt.  15. Pharmaceutical composition characterized in that it comprises a compound of claim 1 or its pharmaceutically acceptable salt, in association with a pharmaceutically acceptable carrier or excipient, substantially non-toxic.    16. A method of producing a pharmaceutical composition, characterized in that it consists in mixing a compound of claim 1 or its pharmaceutically acceptable salt, as active ingredient, with an inert support.  17. Use of the compound of claim 1 or its pharmaceutically acceptable salt, characterized in that this product is used for the treatment of infectious diseases in humans and animals.  18. Composed of cephem, characterized in that it formulates it:  EMI87.4    <Desc / Clms Page number 88>    EMI88.1  Where R is an amino group or an acylamino group, 2 is a lower alkyl group, R is a carboxy group or a protected carboxy group, Y is CH or N, and Z is an acid residue, and its salt.  19. Process for the preparation of a cephem compound having the formula:  EMI88.2    EMI88.3  where the amino group or an acylamino group, 2 R is an alkyl group 3 is the carboxy group or a carboxy group R- estY is CH or N, and Z is an acid residue, or its salt, characterized in that it consists in reacting a compound of formula:  EMI88.4  where R1 and R8 are each as defined above, and a Ph is the phenyl group, or its salt, with a compound having the formula:  EMI88.5    EMI88.6  '. or R, Y and Z are inis or  EMI88.7  its salt.