BE852427A - PROCESS FOR PREPARATION OF SYN ISOMERS OF 3,7-CEPHEM-4-CARBOXYLIC 3,7-DISUBSTITUTED ACID COMPOUNDS AND NEW PRODUCTS THUS OBTAINED - Google Patents

Description

       

    <EMI ID = 1.1>
 

PROCESS FOR PREPARING SYN ISOMERS OF 3,7- ACID COMPOUNDS

  
  <EMI ID = 2.1>

OBTAINED, WITH ANTIBACTERIAL ACTIVITY.

  
(Invention: Takao TAKAYA, Takashi MASUGI, Hisashi TAKASUGI and Hiromu KOCHI) The present invention relates to novel syn isomers of compounds of 3,7-disubstituted 3-cephem-4-carboxylic acids

  
and their pharmaceutically acceptable salts: More particularly, it relates to new syn isomers of compounds of 3,7-disubstituted 3-cephem-4-carboxylic acids and to their pharmaceutical salts.

  
  <EMI ID = 3.1>

  
as well as to processes for their preparation, to pharmaceutical compositions comprising them and to a process for using them from

  
  <EMI ID = 4.1>

  
humans and animals.

  
Accordingly, it is an object of the present invention to provide syn isomers of 3,7-disubstituted 3-cephem-4-carboxylic acid compounds and their pharmaceutically acceptable salts, which are strongly active against a number of pathogenic bacteria.

  
Another object of the present invention is to provide methods for the preparation of syn isomers of 3,7-disubstituted 3cephem-4-carboxylic acid compounds and their pharmaceutically acceptable salts.

  
Another object of the present invention is to provide a pharmaceutical composition comprising, as active ingredients, the syn isomer of 3-cephem-4-carboxylic acid 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 in humans.

  
animals.

  
The desired syn isomers of 3,7-disubstituted 3-cephem4-carboxylic acid compounds are novel and can be presented by the following formula (I):

  

  <EMI ID = 5.1>


  
in which R is a group having the formula:

  

  <EMI ID = 6.1>
 

  
  <EMI ID = 7.1>

  
lower alkoxy or acyloxy and R is hydroxyl, lower alkoxy, acyloxy, acylamino or dialkyl (lower) amino; a group having the formula:

  

  <EMI ID = 8.1>


  
  <EMI ID = 9.1>

  
laughing; or a group having the formula:

  

  <EMI ID = 10.1>


  
where R 8 is lower alkyl and R9 is imino, protected imino or oxo; R <2> is an aliphatic hydrocarbon group which may have one or more suitable substituents; R <3> is a carboxy group

  
  <EMI ID = 11.1>

  
formyl or a heterocyclic thiomethyl group which may have one or more suitable substituents; or R <3> and R4 are linked together to form -COOÇH2-.

  
With regard to the present invention, it should be noted that it is characterized by the fact that it provides the syn isomer of compounds of 3,7-disubstituted 3-cephem-4-carboxylic acids, which is represented by the formula I, and this syn isomer can be represented by the partial structure of formula:

  

  <EMI ID = 12.1>


  
in their molecules, while the corresponding anti isomer is represented by the partial structure of formula:

  

  <EMI ID = 13.1>


  
Accordingly, in the following detailed explanations of the present invention in this description and in the claims, it should be understood that the syn isomers of the desired compounds as well as of the starting compounds are represented by the partial structure of the formula:

  

  <EMI ID = 14.1>


  
in their molecules, provided that, in the event that it is suitable.

  
for the explanation of the present invention to express both the syn isomer and the anti isomer by a single general formula, they are represented by the partial structure of formula:

  

  <EMI ID = 15.1>


  
The desired compounds of the present invention (I) are novel compounds and can be prepared by methods 1 to 8 as mentioned below:

  
Process 1

  

  <EMI ID = 16.1>


  
or its reactive derivative or its reactive derivative or its salt on the amino group on the carboxy group

  
or its salt or its salt

  
Process 2
  <EMI ID = 17.1>
 Process 4

  
Removal of the protecting group of the carboxy radical
  <EMI ID = 18.1>
-Process 5

  
Removal of the protecting group of the amino radical

  

  <EMI ID = 19.1>


  
  <EMI ID = 20.1>

  
or-its salt or its reactive derivative or its salt

  
about the mercapto group

  
Process 7
  <EMI ID = 21.1>
 Process 8

  

  <EMI ID = 22.1>


  
  <EMI ID = 23.1>

  

  <EMI ID = 24.1>


  
where R 7A is a protected amino group; or a group having the formula:

  

  <EMI ID = 25.1>


  
where R is as defined above and R is a pro imino group

  
  <EMI ID = 26.1>

  

  <EMI ID = 27.1>


  
or a group of formula:

  

  <EMI ID = 28.1>


  
  <EMI ID = 29.1>

  
a lower carboxyalkyl group; R 4a is an amino protecting group; R 4b is a group which may be substituted with a group

  
  <EMI ID = 30.1>

  
above..

  
Among the starting compounds, the starting compounds (III),

  
  <EMI ID = 31.1>

  
be prepared by the methods which are illustrated by the following schemes:

  

  <EMI ID = 32.1>


  

  <EMI ID = 33.1>
 

  

  <EMI ID = 34.1>


  

  <EMI ID = 35.1>
 

  

  <EMI ID = 36.1>
 

  

  <EMI ID = 37.1>


  

  <EMI ID = 38.1>


  

  <EMI ID = 39.1>


  
  <EMI ID = 40.1>

  

  <EMI ID = 41.1>
 

  
  <EMI ID = 42.1>

  

  <EMI ID = 43.1>


  
  <EMI ID = 44.1>

  
carboxy group or a protected carboxy group.

  
The other starting compounds (IV), (V), (Va), (Vc) and
(Ve) are all new compounds and can be prepared by Methods 1-8 mentioned above.

  
With regard to the desired compounds of formulas

  
  <EMI ID = 45.1>

  
(XXIX) - (XXXVII) and (XXXIX), it should be understood that these desired compounds and the starting compounds include tautomeric isomers referring to their thiazole groups. Thus, in the case where the group represented by the formula:

  

  <EMI ID = 46.1>


  
  <EMI ID = 47.1>

  
of these starting compounds or of these desired compounds takes the form:

  

  <EMI ID = 48.1>


  
(R 7e is as defined above), this group having the formula:

  

  <EMI ID = 49.1>


  
may alternatively be represented by its tautomeric form
  <EMI ID = 50.1>
   <EMI ID = 51.1>

  
two groups (A) and (B) are in a state of equilibrium of what are called tautomeric forms and which can be represented by the following equilibrium:

  

  <EMI ID = 52.1>


  
(where R 7e and R 7f are each as defined above).

  
These types of tautomerism between 2-amino and 2-hydroxythiazole compounds and 2-imino- or 2-oxo-thiazoline compounds, as indicated above, are well known in the literature, and are evident to those skilled in the art. the technique that

  
two tautomeric isomers are in equilibrium and readily convertible to each other, therefore, it should be understood that case isomers are included in the same category of the compound per se. Consequently,

  
  <EMI ID = 53.1>

  
clearly included within the scope of the present invention. In the present description, the claims and the examples, the desired compounds and the starting compounds, including the group of these tautomeric isomers, are represented by using one of the expressions, that is to say the formula:
  <EMI ID = 54.1>
 .only for convenience. (AT)

  
In addition, as regards the desired compounds (I),

  
  <EMI ID = 55.1>

  
can also be considered to be substantially the same.

  
  <EMI ID = 56.1>

  
intramolecular tal; therefore, it should be understood that both are included in the same class of compounds per se and, therefore, are included within the scope of protection of the present invention.

  
Suitable salts, acceptable from a pharma point of view

  
  <EMI ID = 57.1>

  
3,7-disubstituted 4-carboxylic acids (I) are conventional non-toxic salts and may include an inorganic salt, e.g. a metal salt, such as an alkali metal salt (e.g. sodium salt, potassium salt , etc ...) and an alkaline earth metal salt (for example calcium salt, magnesium salt, etc ...) an ammonium salt, etc ..., an organic salt, for example a salt of organic amine (eg, a trimethylamine salt, a tziethylamine salt, an ethanolamine salt, a diethanolamine salt, a pyridine salt, a picoline salt, a dicyclohexylamine salt,

  
  <EMI ID = 58.1>

  
of organic (eg acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.), a mineral acid salt (eg hydrochloride, hydrobromide, l

  
  <EMI ID = 59.1>

  
example arginine, aspartic acid, glutamic acid, etc.), and the like.

  
In the description given above and in the subsequent description of the present invention suitable examples and illustrations of the various definitions which the present invention intends to include within its scope of protection are explained as follows:

  
The term "lower" is intended to include 1 to 6 carbon atoms, unless otherwise specified.

  
The term "hydrocarbon aliphatic group" is intended to mean straight or branched chain aliphatic hydrocarbons having 1 to 6 carbon atoms and may include lower alkyl, lower alkenyl, and the like. This aliphatic hydrocarbon group may have one to two suitable substituents such as carboxy, protected carboxy, arylthio, lower alkylthio, aryl, acyloxy, lower alkoxy, aryloxy, heterocyclic group or the like.

  
A suitable halogen can include chlorine, bromine, fluorine and iodine.

  
A suitable lower alkoxy group and a suitable lower alkoxy moiety in the term "lower aralkoxy" may include a group which may be branched, for example a

  
  <EMI ID = 60.1>

  
t-butoxy, pentyloxy, hexyloxy and the like, and preferably a group having 1 to 4 carbon atoms and more preferably having

  
1 to 2 carbon atoms.

  
A suitable protected amino group may include an acylamino group and an amino group substituted with a conventional protecting group other than the acyl group such as benzyl or the like.

  
A suitable lower alkyl group and the lower alkyl portion of the terms "lower alkylthio", "lower carboxyalkyl", "protected lower carboxyalkyl", "lower aralkyl" and "lower dialkylamino" may include a group which may be branched, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl and the like, and preferably a group having 1 to 4 carbon atoms, and more preferably a group having 1 to 2 carbon atoms.

  
A suitable protected imino group may include an acylimino and imino group substituted with a conventional protecting group other than the acyl group, such as benzyl and the like.

  
The suitable protected carboxy group and the protected carboxy moiety in the term "protected carboxyalkyl" may include an esterified carboxy group in which the ester may be a compound such as a lower alkyl ester (eg, methyl ester,

  
  <EMI ID = 61.1>

  
butyl, isobutyl ester, t-butyl ester, pentyl ester, t-pentyl ester, hexyl ester, 1-cyclopropylethyl ester, etc.), where the part "lower alkyl "may preferably be a part having 1 to 4 carbon atoms, a lower alkenyl ester (eg vinyl ester, allylic ester, etc.); a lower alkynyl ester (for example ethynyl ester, propynyl ester, etc.); a lower mono (or di or tri) -haloalkyl ester (for example 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.); a lower alkanoyl oxyalkyl ester

  
  <EMI ID = 62.1> <EMI ID = 63.1>

  
"arylthio" and "aryloxy" may include phenyl, toly

  
  <EMI ID = 64.1>

  
(eg, chlorine, bromine, iodine, water, fluorine), a hydroxy group and the like.

  
A suitable heterocyclic group and a heterocyclic moiety

  
  <EMI ID = 65.1>

  
which may have one or more suitable substituents = s "means a saturated or unsaturated, monocyclic or: polycyclic, heterocyclic group, containing at least one heteroatom such as an atom of oxygen, sulfur, nitrogen and the like.

  
An especially preferable heterocyclic group may be a heterocyclic group such as a heteromonocyclic group.

  
  <EMI ID = 66.1> tetrazolyl (eg 1H-tetrazolyl, 2H-tetrazolyl, etc.); a triangular to octagonal saturated heteromonocyclic group (from

  
  <EMI ID = 67.1>

  
for example, pyrrolidinyl, imidaz lidinyl, piperidino, piperazinyl, etc ...; an unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atoms, for example indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, etc ...; a triangular to octagonal (preferably five-membered to hexagonal) unsaturated heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, eg oxazolyl, isoxazolyl, oxadiazolyl, (eg 1,2,4- oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc ...); a heteromonocyclic group.

  
  <EMI ID = 68.1>

  
gonal (preferably pentagonal to hexagonal) containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example the morpholinyl group, etc ...; a condensed unsaturated heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example the benzoxazolyl, benzoxadiazolyl, etc ... groups; an unsaturated, triangular to octagonal (preferably five-membered to hexagonal) heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example a thiazolyl or thiadiazolyl group (for example 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl), etc ...; a saturated, triangular to octagonal (preferably five-membered to hexagonal) heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example thiazolidinyl, etc ...;

   an unsaturated, triangular to octagonal (preferably five-membered to hexagonal) heteromonocyclic group containing 1 sulfur atom, for example thienyl group, etc ...; an unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example benzothiazolyl, benzothiadiazolyl, etc., and the like, where the heterocyclic group may have 1 to 2 suitable substituents such as a lower alkyl group (for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, etc.), preferably a group having 1 to 4 carbon atoms; a lower alkenyl group (for example vinyl, allyl, butenyl, etc.); an aryl group (for example phenyl, tolyl, etc.); a halogen (eg, chlorine, bromine, iodine or fluorine); the amino group;

   a dialkyl (lower) amino-loweralkyl group

  
  <EMI ID = 69.1>

  
propyl, diethylaminobutyl, etc.), preferably a group having

  
3 to 6 carbon atoms; or analogies.

  
A suitable lower alkenyl group is a group having 2 to 6 carbon atoms and may include, for example, vinyl group, allyl, isopropenyl, 1-propenyl, 2-butenyl, 3-pentenyl and the like, and preferably a group having 2 to 4 carbon atoms.

  
An acyl moiety suitable in the terms "acylamino", "acylimino", "acyloxy" and "acyloxymethyl", as mentioned above, may include a carbamoyl group, an aliphatic acyl group and an acyl group containing an aromatic or heterocyclic ring. Suitable examples of this acyl group may be a lower alkanoyl group (e.g. formyl, acetyl, propionyl butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc.), preferably a group having 1 to 4 carbon atoms, more preferably a group having 1 to 2 carbon atoms; a lower alkoxycarbonyl group having 2 to 7 carbon atoms

  
(for example methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, t-pentyloxycarbonyl, hexyloxycarbonyl, etc ...), preferably a group having 3 to 6 carbon atoms; a lower alkanesulfonyl group (for example mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, etc.), preferably a group having 1 to 4 carbon atoms, of pre-

  
  <EMI ID = 70.1>

  
arenesulfonyl (for example benzenesulfonyl, tosyl, etc.); an aroyl group (for example benzoyl, toluoyl, naphthoyl, phthaloyl, indanecarbonyl, etc.); a lower aralkanoyl group (for example phenylacetyl, phenylpropionyl, etc.): an aralkoxy (lower) carbonyl group (for example benzyloxycarbonyl, phenethyloxycarbonyl, etc.); and the like.

  
The acyl part, as shown above, can have 1

  
with 3 suitable substituents such as halogen (eg chlorine, bromine, iodine or fluorine), hydroxy, cyano, nitro, lower alkoxy (eg methoxy, ethoxy, propoxy, isoproxy, etc. .); lower alkyl (for example methyl, ethyl, propyl, isopropyl, butyl, etc.); lower alkenyl (eg vinyl, allyl etc.), acyl such as lower haloalkanoyl group (eg chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, etc.), aryl (eg phenyl, tolyl, etc. .), or the like.

  
Suitable examples of the acyl group having its substituents may be a mono (or di or tri) lower haloalkanoyl group (eg trifluoroacetyl, trichloroacetyl, etc.), preferably a group having 2 to 4 carbon atoms; a mono group (or di or

  
  <EMI ID = 71.1>

  
carbamoyl, etc.), preferably a group having 3 to 4 carbon atoms, or the like.

  
A suitable protecting group for the amino radical for

  
  <EMI ID = 72.1>

  
lower (eg chloroacetyl, dichloroacetyl, trichloroacetyl trifluoroacetyl, etc.), preferably a group having 2 to 3 carbon atoms, or the like.

  
A suitable acid residue can include a residue of an acid such as a mineral acid (eg hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, etc.) or an organic acid. (for example methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.).

  
A suitable example of a group which may be substituted by an R 4c -S- group may include an acidic residue such as halogen, an azido or acyloxy group where the halogen and the acid part of the acyloxy group are the same as those mentioned previously.

  
Among suitable examples of each of the groups

  
of the desired compounds, as explained and illustrated above, the preferred embodiments are illustrated as follows:

  
A preferable example of R may be hydrogen, halogen (preferably chlorine) or the nitro group; a preferable example of R is hydroxy, lower alkoxy (preferably

  
  <EMI ID = 73.1>

  
a preferable example for R may be an amino, protected amino group, such as an acylamino group [preferably alkane (inferior <EMI ID = 74.1>

  
a preferable example of R may be a protected imino group, such as an acylimino group [preferably an alka-

  
  <EMI ID = 75.1>

  
again (C1), lower alkenyl, lower aralkenyl [preferably lower phenylalkenyl], lower carboxyalkyl, protected lower carboxyalkyl [preferably (lower) alkoxy

  
  <EMI ID = 76.1>

  
lower [preferably lower phenylthioalkyl], lower aralkyl [preferably lower phenylalkyl] which may have halogen (preferably bromine) and hydroxy group, lower thienylalkyl or aryloxyalkyl group [preferably lower phenyloxyalkyl] which may have a hydroxy group, where

  
the alkenyl group and the alkenyl part are preferably C2-C6, preferably C2-C4, and the alkyl part is preferably

  
  <EMI ID = 77.1>

  
the preferable example of R may be the carboxy group;

  
the preferable example of R may be an acyloxymethyl group [preferably a (lower) alkanoyl oxymethyl group

  
  <EMI ID = 78.1>

  
eg acetyl) or carbamoyloxymethyl which may have a lower trihaloalkanoyl group (where the trihalo part is preferably a par-

  
  <EMI ID = 79.1> <EMI ID = 80.1>

  
together to form -COOCH2-.

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

  
Method 1:

  
The desired compound (I). or its salt can be prepared by reacting the compound (II), or its reactive derivative on the amino group or its salt, with the compound (III) or its reactive derivative on

  
the carboxy group or its salt, which is a fundamental process for preparing the desired compound (I).

  
A suitable reactive derivative on the amino group of compound (II) may include a conventional reactive derivative used in amidation, for example a silyl derivative formed by the reaction.

  
  <EMI ID = 81.1>

  
A suitable salt of the compound (II) may include an addition salt with acids, such as an organic acid salt (eg acetate, maleate, tartrate, benzenesulfonate, toluenesulfonate, etc.). .) or a mineral acid salt (for example

  
hydrochloride, hydrobromide, sulfate, phosphate, etc.); a salt with an inorganic base such as an alkali metal salt (e.g. sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g. calcium salt, salt magnesium, etc.) or an ammonium salt; a salt with an organic base (for example the triethylamine salt, the pyridine salt, etc.); and the like.

  
A suitable reactive derivative on the carboxy group of compound (III) can include a conventional group used in amidation.

  
The salts of the compound (III) can be salts with an inorganic base, such as an: alkali metal salt (for example sodium or potassium salt), or an alkaline earth metal salt (for example calcium salt or magnesium), a salt with an organic base <EMI ID = 82.1>

  
The present reaction is preferably carried out in the presence of a condensing agent such as a so-called reactant.

  
  <EMI ID = 83.1>

  
analogues.

  
The reaction can also be carried out in the presence of a

  
  <EMI ID = 84.1>

  
mine, N, N-dialkyl (lower) aniline, as set forth below, or the like. When the base or the condensing agent is in liquid form, it can also be used.

  
  <EMI ID = 85.1>

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

  
In the present reaction, it should be noted that in the case

  
  <EMI ID = 86.1> the desired compound (I) of the present invention, that is to say the syn isomer. It can be understood that these tendencies and this singularity of the reaction as mentioned above is due to the fact that the less stable syn isomer tends to partially or totally isomerize into the corresponding more stable anti isomer during the reaction, for example in the so-called stage of activation of the compound (III) so that the isomerized compound, that is to say the anti-isomer corres-

  
  <EMI ID = 87.1>

  
sought.

  
Accordingly, to obtain the desired compound (I), that is to say the syn isomer, selectively and in a yield

  
high, it is necessary to use the starting compound (III), i.e. the syn isomer and to choose suitable reaction conditions. Thus, the desired compound (I), i.e. the syn isomer, can be obtained selectively and with a high yield.

  
by carrying out the reaction, for example in the presence of a Vilsmeier reactant as mentioned above, etc ... and under approximately neutral conditions.

  
  <EMI ID = 88.1>

  
where R is a group of the formula:

  

  <EMI ID = 89.1>


  
is used, the desired compound (I), i.e. the syn isomer can be obtained selectively and in a high yield by carrying out the present reaction of the starting compound (III), i.e. the syn isomer, with compound (II), for example in the presence of a Vilsmeier reactant produced by the reaction of dimethylformamide with phosphorus oxychloride and under conditions

  
almost neutral. In this case, it should be noted that particularly good results can be obtained by carrying out the reaction in the presence of more than two molar equivalents of phosphorus oxychloride for each amount of the starting compound (III), i.e. say the syn isomer and dimethylformamide as presented in the exemplary embodiments. In addition, in this case, it should also be noted that good results can be obtained by carrying out a step of activating the starting compound (III), that is to say the syn isomer,

  
  <EMI ID = 90.1> <EMI ID = 91.1>

  
Regarding the reaction of compound (II) with compound (III), it should be noted that when compound (II) where R

  
is a carbamoyloxymethyl group having an acyl group is used as the starting compound, occasionally there can be obtained either the desired compound (I) where R is a carbamoyloxymethyl group having an acyl group or a free carbamoyloxymethyl group, depending on the reaction conditions; when the compound (II) where R is a hydroxymethyl group is used as the starting compound, occasionally the desired compound (I) can be obtained where R <3> and R4 are linked to form -COOCH &#65533;-; and further the protected carboxy group or salts in the compound (II) can be transformed into the free carboxy group during the reaction or during a post-treatment. These cases are also included within the scope of protection of the present invention.

  
As is clear from the explanations given above, it should be understood that process 1 is a fundamental process and it is the most advantageous process for preparation.

  
  <EMI ID = 92.1>

  
subjecting the compound (IV) or its salt to an elimination reaction

  
of the protecting group on the amino or imino group.

  
A suitable salt of compound (IV) can include a metal salt, an ammonium salt, an organic amine salt and the like, as mentioned above.

  
The present elimination reaction is carried out according to

  
a conventional process, such as hydrolysis, reduction, a process by reacting compound (IV) (where the protecting group is an acyl group) with an iminohalogenating agent and then with an iminoetherifying agent and, if this is necessary, subjecting the resulting compound to hydrolysis; or the like. Hydrolysis can include

  
a process using an acid or a base or hydrazine or the like. These methods can be chosen depending on the kind of protecting groups to be removed.

  
Among these methods, hydrolysis using an acid is one of the most common and preferable methods for removing protecting groups, such as a substituted or unsubstituted alkoxycarbonyl group (eg, t-pentyloxycarbonyl, etc.), an alkanoyl group (for example formyl, etc ...), a cycloalkoxycarbonyl group, a substituted or unsubstituted aralkoxycarbonyl group (for example benzyloxycarbonyl, substituted benzyloxycarbonyl, etc ...),

  
a substituted phenylthio group, a substituted aralkylidene, a substituted alkylidene, a substituted cycloalkylidene group, or the like. A suitable acid may include an organic or inorganic acid, for example, formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid and the like, and a preferable acid is an acid which can be easily removed from the reaction mixture in a conventional manner, such as distillation under reduced pressure, for example formic acid, trifluoroacetic acid, hydrochloric acid, etc. The acid suitable for the reaction can be chosen according to the kind of group

  
protection to be removed. When the elimination reaction is carried out with the acid, it can be carried out in the presence or absence of a solvent. A suitable solvent can include an organic solvent, water or a mixed solvent. When trifluoroacetic acid is used, the elimination reaction can preferably be used in the presence of ahisole.

  
Hydrolysis using hydrazine is commonly applied to remove the protecting group, for example, the succinyl or phthaloyl group.

  
Hydrolysis with a base is preferably applied to remove an acyl group, e.g. a haloalkanoyl group (e.g. trifluoroacetyl, etc.), etc. A suitable base may include, for example, an inorganic base such as '' an alkali metal hydroxide (for example soda, potash, etc.), an alkaline earth metal hydroxide (for example 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 (for example example sodium bicarbonate, potassium bicarbonate, etc ...), an alkali metal acetate (for example sodium acetate, potassium acetate, etc ...),

   an alkaline earth metal phosphate (for example magnesium phosphate, calcium phosphate, etc.), a phosphate

  
  <EMI ID = 93.1> dipotassium acid phosphate, etc.), or the like, and a base

  
  <EMI ID = 94.1>

  
gues. Hydrolysis using a base is often carried out in water or in a hydrophilic organic solvent or a mixed solvent.

  
Among the protecting groups, the acyl group can

  
generally be removed by hydrolysis, as mentioned above, or by other conventional hydrolysis. In the case where the acyl group is a halogen-substituted alkoxycarbonyl group or an 8-quinolyloxycarbonyl group, these groups are removed by treatment with a heavy metal, such as copper, zinc or the like.

  
Reduction elimination is generally applied to remove the protecting group, for example a haloalkoxycarbonyl group (for example trichloroethoxycarbonyl, etc ...), substituted or unsubstituted aralkoxycarbonyl (for example benzyloxycarbonyl, substituted henzyloxycarbonyl, etc ...), 2-Pyridylmethoxycarbonyl, etc. Suitable reduction can include, for example, reduction with an alkali metal borohydride (eg, sodium borohydride, etc.) and the like.

  
A suitable iminohalogenating agent used in a process as mentioned above can include phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide, phosphorus oxychloride, thionyl chloride, phosgene and the like. Reaction temperature

  
  <EMI ID = 95.1>

  
room temperature or while cooling. A suitable iminoetherifying agent reacted with the reaction product thus obtained may include an alcohol, a metal alkylate and the like.

  
A suitable alcohol can include an alkanol (eg methanol, propanol, isopropanol, butanol, t-butanol, etc.)

  
which may be substituted by an alkoxy group (for example methoxy, ethoxy, propoxy, isopropoxy, butoxy, etc.). A suitable metal alkylate may include an alkali metal alkylate (eg sodium alkylate, potassium alkylate, etc.), an alkaline earth metal alkylate (eg calcium alkylate, barium alkylate, etc.) etc ...) and the like. The reaction temperature is not critical and the reaction is ordinarily carried out under cooling or at room temperature.

  
The product thus obtained is subjected, if necessary, to hydrolysis. Hydrolysis can be easily carried out by pouring the above reaction mixture obtained into water, but one

  
can add beforehand a hydrophilic solvent (for example rethanol, ethanol, etc.), a base (for example an alkali metal bicarbonate, a trialkylamine, etc.) or an acid (for example

  
dilute hydrochloric acid, acetic acid, etc.) to ;; 'water.

  
The reaction temperature is not critical and can be suitably selected according to the kind of the protecting group of the amino group and the removal method as mentioned above, and

  
the present reaction is preferably carried out under mild conditions such as cooling, at room temperature or at a slightly elevated temperature.

  
The present invention includes within its scope of protection the case where the protected carboxy group is transformed into a free carboxy group; the case where the compound (IV), where R is a carbamoyoxymethyl group having an acyl group, is used as a compound of

  
  <EMI ID = 96.1>

  
or R is a carbamoyloxymethyl group having an acyl group, or

  
the free carbamoyloxymethyl group according to the reaction conditions; and the case where, when the compound (IV) where R is an acyloxymethyl group is employed as the starting compound, there can be obtained occasionally

  
  <EMI ID = 97.1>
-COOCH2- depending on the reaction conditions; during the reaction or during a post-treatment.

  
Process 3

  
  <EMI ID = 98.1>

  
acylating the hydroxy group of compound (V) or its salt.

  
A suitable salt of compound (V) can be referred to as exemplified for compound (IV).

  
The acylating agent to be used for the present reaction can comprise an aliphatic, aromatic and heterocyclic carboxylic acid and the corresponding sulfonic acid and thioacid which have the aforementioned acyl group as an acyl part, and. reactive derivatives of the acids mentioned above. A suitable reactive derivative of the acids mentioned above may comprise a

  
  <EMI ID = 99.1> enabled, and the like. A suitable example can be an acid chloride; an acid azothhydride; a mixed acid anhydride with

  
an acid such as a substituted phosphoric acid (for example a dialkylphosphoric acid, a diphenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, a halogenated phosphoric acid, etc.), a dialkylphosphoric acid, sulfurous acid, thiosulfuric acid, sulfuric acid, an alkylcarbonic acid, an aliphatic carboxylic acid (eg pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid or 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 [for example a cyanomethyl ester, a methoxymethyl ester

  
  <EMI ID = 100.1>

  
that, a propargyl ester, a p-nitrophenyl ester, a 2,4-dinitrophenyl ester, a trichlorophenyl ester, a pentachlorophenyl ester, a mesylphenyl ester, a phenylazophenyl ester, a phenyl thioester, a thioester p-nitrophenyl

  
  <EMI ID = 101.1>

  
limide or 1-hydroxy-6-chloro-1H-benzotriazole, and the like. These reactive derivatives can be optionally chosen depending on the kind of acylation to be used.

  
The acylating agent may further include an aliphatic, aromatic, or heterocyclic isocyanate or isothiocyanate (eg, methyl isocyanate, phenyl isocyanate, trichloroacetyl isocyanate, methyl isothiocyanate, etc. ...) and a haloformate (for example ethyl chloroformate, benzyl chloroformate, etc.). In this case, for example, when trichloroacetyl isocyanate is employed as an acylating agent, the

  
trichloroacetylcarbamoyl group is introduced as acyl group and this group can be transformed into carbamoyl group by treating with a base and, when ethyl chloroformate is used as an acylating agent, the ethoxycarbonyl group is introduced as an acyl group.

  
the.

  
The present reaction is carried out under reaction conditions similar to those of the above-mentioned reaction of compound (II) with compound (III), and is preferably carried out in the presence of a base. In the reaction of the compound (V) with an acylating agent, the protected carboxy group or its salts in the compound (V) can be transformed into the free carboxy group during the reaction or in the post-treatment; and when the compound
(V), where R is a carbamoyloxymethyl group having an acyl group, is employed as the starting compound, occasionally one can obtain

  
  <EMI ID = 102.1>

  
thyl having an acyl group, or the free carbamoyloxymethyl group depending on the reaction conditions during the reaction or in the post-treatment. These cases are also included within the scope of the present invention.

  
Process 4

  
  <EMI ID = 103.1>

  
subjecting the compound (V) or its salt to a reaction of elimination of the protecting group on the carboxy radical.

  
  <EMI ID = 104.1>

  
being that indicated by way of example for the compound (IV).

  
The present elimination reaction is carried out according to a conventional method such as hydrolysis or the like. Hydrolysis can include a process using an acid or a base or the like. These methods can be chosen depending on the kind of protecting groups to be removed.

  
Hydrolysis using an acid is one of the most common and preferable methods for removing protecting groups such as phenyl lower alkyl, phenyl (substituted) lower alkyl, lower alkyl, substituted lower alkyl or the like. Suitable acids can include organic or inorganic acids, for example formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, and the like. The present reaction can be carried out in the presence of anisol. The acid suitable for the reaction can be selected depending on the protecting group to be removed and other factors. Hydrolysis using an acid can be carried out in the presence of a solvent, such as an organic solvent, water or a solvent.

  
mixed.

  
  <EMI ID = 105.1>

  
  <EMI ID = 106.1>

  
me in a free carboxy group; the case where the protected amino group is

  
  <EMI ID = 107.1>

  
your reaction-

  
Process 5

  
  <EMI ID = 108.1>

  
- The present elimination reaction may include an elimination process using a base, for example, an inorganic base, such as an alkali metal hydroxide (e.g. soda, potash , et. = ...), an alkali metal bicarbonate (for example sodium bicarbonate, potassium bicarbonate, etc ...) or a <EMI ID = 109.1>

  
born; and an elimination reaction using basic alumina, a basic ion exchange resin, an acid (e.g. acid

  
  <EMI ID = 110.1>

  
reaction temperature is not critical and the reaction is preferably carried out at room temperature or with cooling.

  
The present invention includes, within its scope of protection, cases where the protected carboxy group or its salts in the compound

  
  <EMI ID = 111.1>

  
wherein the protected amino group and / or the protected imino group may be transformed into a free amino group and / or a free imino group, respectively, during the reaction or during a post-treatment. Process 6

  
The desired compound (I) or its salt can be prepared by

  
  <EMI ID = 112.1>

  
its reactive derivative on the mercapto group.

  
A suitable salt of compound (V) may be designated as in that exemplified for compound (IV).

  
The suitable reactive derivative on the mercapto group of

  
  <EMI ID = 113.1>

  
alkali metal (eg sodium salt, potassium salt, etc.) or the like.

  
  <EMI ID = 114.1>

  
such as water, acetone, chloroform, nitrobenzene, methylene chloride, ethylene chloride, dimethylformamide, methanol, ethanol, ether, tetrahydrofuran, dimethyl sulfoxide, or any other solvent which does not adversely affect the reaction, preferably in solvents having strong polarities. Among the solvents, hydrophilic solvents can be used in a mixture with water. The reaction is preferably carried out in a weakly basic state or around neutrali-

  
  <EMI ID = 115.1>

  
sés in free form, the reaction is preferably carried out in the presence of a base, for example an inorganic base such as a hydroxide

  
  <EMI ID = 116.1>

  
alkali metal, an organic base such as a trialkylamine, pyridine, and the like. The reaction temperature is not critical, and the reaction is ordinarily carried out at room temperature or with heating. The reaction product can be isolated from the reaction mixture by conventional methods.

  
  <EMI ID = 117.1>

  
  <EMI ID = 118.1>

  
  <EMI ID = 119.1>

  
protected imino can be transformed into a free amino group and / or a free imino group; and the case where the acyloxy group can be transformed into a hydroxy group; respectively during the reaction or during a post-treatment.

  
Process 7

  
The desired compound (If) or its salt can be prepared by treating the compound (V) or its salt with an acid.

  
A suitable salt of compound (V) may be referred to as an exemplary salt for compound (IV).

  
A suitable acid for use in the present reaction may include a mineral acid (eg hydrochloric acid, hydrobromic acid, sulfuric acid, etc.) or an organic acid (eg formic acid, l. acetic acid, etc ...).

  
The present reaction is ordinarily carried out in a solvent such as water, acetone, acetic acid or any other solvent which does not adversely affect the reaction. Of these solvents, hydrophilic solvents can be used mixed with water.

  
The reaction temperature is not critical and the reaction is preferably carried out by cooling or heating. Process 8

  
  <EMI ID = 120.1>

  
by oxidizing the compound (V) or its salt.

  
A suitable oxidant used in the present invention may include Jones's reactant, obtained by a combination of sulfuric acid and chromium trioxide, manganese dioxide, a reactant used by a combination of dimethyl sulfoxide and N, N ' -dicyclohexylcarbodiimide etc ..., and the like.

  
The present reaction is ordinarily carried out in a solvent such as water, acetone, dimethylformamide, or any other solvent which does not adversely affect the reaction. These solvents can be used in the form of mixtures.

  
The reaction temperature is not critical and the reaction is preferably carried out with cooling or at approximately

  
Room temperature.

  
Methods for preparing the starting compound (III) i.e. the syn-isomer and the anti-isomer used for references are explained in detail as follows.

  

  <EMI ID = 121.1>


  
Compound (VIII) can be prepared by reacting compound (VI) with compound (VII).

  
The present reaction is ordinarily carried out in a solvent such as water, ethanol, acetone, ether, dimethylfor-

  
  <EMI ID = 122.1>

  
the present reaction. The 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 ordinarily carried out by cooling or heating to the boiling point of the solvent.

  

  <EMI ID = 123.1>


  
Compounds (X) and (XXXIII) can be prepared by oxidizing compounds (IX) and (XXXII), respectively.

  
The present oxidation reaction is carried out by a conventional method which is applied to the conversion of the activated dimethylene group to the carbonyl group. Thus, the present oxidation is carried out by a conventional method, such as oxidation using a conventional oxidant such as selenium dioxide, permanganate

  
potassium, or the like. The present oxidation is ordinarily carried out in a solvent which does not adversely affect the reaction, for example water, dioxane, pyridine, tetrahydrofuran, and the like.

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

  

  <EMI ID = 124.1>


  
Compound (XII) can be prepared by subjecting the compound
(XI) to a reaction for eliminating the lower aralkyl group.

  
The present removal process can include all of the conventional processes used in the lower aralkyl group removal reaction, e.g. hydrolysis, reduction, etc.

  
Hydrolysis using an acid is one of the very

  
  <EMI ID = 125.1>

  
(eg hydrochloric acid, hydrobromic acid, etc.) an organic acid (eg formic acid, acetic acid, trifluoroacetic acid, etc.) and a mixture. The present reaction can be carried out in a solvent such as water, a solvent

  
  <EMI ID = 126.1>

  
The reaction is not critical and the reaction is preferably carried out using moderate to strong heating.

  

  <EMI ID = 127.1>


  
Compounds (IIIa), (XXXV) and (IIIf) can be prepared by reacting compounds (XIII), (XXXIII) and (XXXIV)

  
with the compound (XIV) or a salt, respectively.

  
A suitable salt of the compound (XIV) may include a mineral acid salt (eg hydrochloride, hydrobromide, sulfate, etc.), an organic acid salt (eg acetate, p- toluenesulfonate, etc.) and the like.

  
The present reaction is usually carried out in a solvent such as water, an alcohol (for example methanol, ethanol, etc.), a mixture of these products or any other solvent which does not adversely affect the present. reaction.

  
The present reaction, in the case where the compound (XIV) is used in its salt form, is preferably carried out in the presence of a base, for example an inorganic base such as an alkali metal (for example sodium, potassium, etc ...), an alkaline earth metal (e.g. magnesium, calcium, etc.), a hydroxide or a carbonate or a bicarbonate of these metals or the like, and an organic base such as alkali metal alkylate
(eg sodium methoxide, sodium ethoxide, etc.), a trialkylamine (eg trimethylamine, triethylamine, etc.), an N, N-dialkylamine (eg N, N -dimethylaniline, etc.), an N, N-dialkylbenzylamine (for example N, N-dimethylbenzylamine, etc.), pyridine or the like.

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

  
In the present reaction, the mixture of syn and anti isomers of the compound (IIIa), (XXXV) or (IIIf) can be obtained according to the reaction conditions, etc., and, in such a case, both

  
  <EMI ID = 128.1> ge. For example, the mixture is first esterified and the resulting esters are resolved, for example by chromatography, into the individual isomer. Each resolved isomer of the esters is hydrolyzed by a conventional method to give the corresponding syn or anti carboxylic acid.

  
To obtain the syn isomer of compound (IIIa), (XXXV) or
(IIIf) selectively and in high yield, the present reaction is preferably carried out under substantially neutral conditions.

  

  <EMI ID = 129.1>


  
Compounds (XVI) and (XXXVI) can be prepared by reacting compounds (XV) and (XXXIV) with hydroxylamine and a salt, respectively.

  
A suitable hydroxylamine salt may be referred to as that exemplified for compound (XIV).

  
The reaction conditions of the present reaction can also be referred to as being those given by way of examples.

  
  <EMI ID = 130.1>

  
  <EMI ID = 131.1>

  

  <EMI ID = 132.1>


  
Compounds (XVIII), (XXV), (XXVII) and (XXXVIII) can be prepared by alkylating compounds (XVII), (XXIV), (XXVI) and
(XXXVII), respectively.

  
The alkylating agent to be used in the present alkylation reaction may include a lower dialkyl sulfate (eg, dimethyl sulfate, diethyl sulfate, etc.), a lower diazoalkane (eg, diazomethane, diazoethane, etc.), lower alkyl halide (eg methyl iodide, ethyl iodide, etc.), lower alkyl sulfonate
(eg, methyl p-toluenesulfonate, etc.) and the like.

  
The reaction using a lower dialkyl sulfate, lower alkyl halide or lower alkyl sulfonate is ordinarily carried out in a solvent such as water, acetone, eth anol, ether, dimethylformamide or any other solvent which does not adversely affect the reaction.

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

  
The reaction temperature is not critical and the reaction is ordinarily carried out by cooling or heating to around the boiling point of the solvent.

  
The reaction using a diazoalkane is ordinarily carried out in a solvent, such as ether, tetrahydrofuran or the like.

  
The reaction temperature is not critical and the reaction is ordinarily carried out under cooling or at room temperature.

  

  <EMI ID = 133.1>


  
Compounds (IIIb) and (IIIg) can be prepared by subjecting compounds (XVIII) and (XXXVIII) to hydrolysis, respectively.

  
The hydrolysis is preferably carried out in the presence of a base or an acid. A suitable base can include an inorganic base and an organic base, such as an alkali metal (eg sodium, potassium, etc.), an alkaline earth metal.
(for example magnesium, calcium, etc ...), hydroxide or carbonate or bicarbonate of these metals, a trialkylamine (for example trimethylamine, triethylamine, etc ...), picoline,

  
  <EMI ID = 134.1>

  
A suitable acid includes an organic acid (eg formic acid, acetic acid, propionic acid, trifluoroacetic acid, etc.) and a mineral acid (eg hydrochloric acid, acid hydrobromic, sulfuric acid, etc ...).

  
The reaction is usually carried out in a solvent.

  
  <EMI ID = 135.1>

  
a mixture of these products or any other solvent which does not adversely affect the reaction. A base or a liquid acid can be used as a solvent.

  
The reaction temperature is not critical and the reaction is usually carried out by cooling or heating -
  <EMI ID = 136.1>
 Compound (III) can be prepared by subjecting compound (XIX) to acylation.

  
The acylating agent to be used for the present reaction and the reaction conditions for the present reaction can be given as being those exemplified for Process 3.

  

  <EMI ID = 137.1>


  
Compound (XXI) can be prepared by subjecting compound (XX) to nitrosation.

  
The nitrosating agent to be used for the present reaction may include a conventional agent which yields a C-nitroso compound upon reaction with the activated methylene group, such as nitrous acid, alkali metal nitrites (e.g. sodium, etc.), lower alkyl nitrite (eg isopentyl nitrite, t-butyl nitrite, etc.) or the like.

  
In case the nitrous acid salt is used as a nitrosating agent, the present reaction is ordinarily carried out in the presence of an acid such as a mineral acid or an organic acid.
(eg hydrochloric acid, acetic acid, etc.). In the case where a nitrous acid ester is used, the present reaction is preferably carried out in the presence of a strong base such as alkali metal alkylate or the like.

  
The present reaction is usually carried out in a solvent such as water, acetic acid, benzene, an alcohol (for example ethanol, methanol, etc.) or any other solvent which does not adversely affect the reaction.

  
The reaction temperature is not critical and the reaction is ordinarily carried out under cooling or at room temperature.

  

  <EMI ID = 138.1>


  
Compounds (XXIII) and (XXIX) can be prepared by reacting compounds (XXI) and (XXVIII) with compound (XXII), respectively.

  
The present reaction is ordinarily carried out in a solvent such as water, alcohol (e.g. methanol, ethanol,

  
  <EMI ID = 139.1> tetrahydrofuran, a mixture of these products or any other solvent which does not adversely influence the reaction.

  
The reaction temperature is not critical and the reaction is ordinarily carried out between room temperature and the temperature of heating around the boiling point of the solvent.

  
To obtain the syn isomer of the compound (XXIII) or (XXIX), selectively, and with a high yield, it is necessary to use the syn isomer of the starting compound (XXI) or (XXVIII) and the present reaction is preferably carried out around neutrality, in the presence of a base as mentioned above.

  
A preferable example of a base may be a weak base such as an alkali metal acetate (eg sodium acetate, potassium acetate, etc.), an alkali metal bicarbonate (eg sodium bicarbonate. sodium, potassium bicarbonate, etc.), an alkali metal carbonate (eg sodium carbonate, potassium carbonate, etc.) or the like.

  

  <EMI ID = 140.1>


  
  <EMI ID = 141.1>

  
can be prepared by subjecting compounds (XXIII), (XXV), (XXI
(XXXIII) and (XXXV) to a reaction to eliminate the protecting group of the carboxy radical, respectively.

  
In the present elimination reaction, conventional methods used in the reaction to eliminate the protected carboxy group, eg hydrolysis, etc., may be applicable. When the protecting group is an ester, it can be removed by hydrolysis.

  
The present hydrolysis is carried out in a similar manner

  
  <EMI ID = 142.1>

  
mentioned in (G) above.

  

  <EMI ID = 143.1>


  
Compound (XXVIII) can be prepared by halogenating compound (XXVII).

  
The halogenating agent to be used in the present reaction may include a conventional halogenating agent used in the halogenation of the so-called activated methylene group, with a halogen (e.g. chlorine, bromine, etc.), a sulfuryl halide (e.g. sulfuryl chloride, etc.), a hypôhalite (e.g. hypochlorous acid, hypobromous acid, sodium hypochlorite, etc.), an N-halogenated imide ( for example N-bromosuccinimide, N-bromophthalimide, N-chlorosuccinimide, etc.) and the like.

  
The present reaction is ordinarily carried out in a solvent such as an organic acid (eg formic acid, acetic acid, propionic acid, etc.), carbon tetrachloride or any other solvent which is not not adversely influence the reaction.

  
The reaction temperature is not critical and the reaction is ordinarily carried out with cooling, to room temperature, with moderate or strong heating.

  

  <EMI ID = 144.1>


  
  <EMI ID = 145.1> compound (XXX), or its derivative reactive with the amino group or its

  
salt, with an agent for protecting the amino radical and the compound

  
(IIIh) can be prepared by reacting the compound (XXXIX),

  
or its derivative reactive with the amino group or its salt, with an agent

  
protection of the amino radical.

  
A suitable derivative reactive with the amino group of compound (XXX) or (XXXIX) and a suitable salt of the compound (XXX) or (XXXIX), may include the same products as those illustrated in the explanations of the derivative reactive with the amino group of compound (II)

  
and the salt of compound (II), respectively.

  
A suitable amino radical protecting agent may include an acylating agent which may include an aliphatic, aromatic and heterocyclic carboxylic acid, and the corresponding sulfonic acid, the haloformic acid ester, an isocyanic acid ester and the corresponding sulfonic acid. 'carbamic acid, and the corresponding thioacid, and the reactive derivative of the acids indicated above.

  
A suitable reactive derivative of the acids indicated above may include the same as illustrated in the explanation of method 3. Example of protecting group (eg acyl group.

  
to be introduced into the amino group in the compound (XXX) or (XXXIX) by the agent for protecting the amino radical indicated above (for example acylating agent) can be the same protecting group
(eg acyl group) than that illustrated in the explanation of the part of the protecting group (eg acyl part) in the term "acylamino".

  
The present reaction for protecting the amino group is carried out in a manner similar to that illustrated in the reaction of compound (II) with compound (III) (Method 1).

  

  <EMI ID = 146.1>


  
Compound (XXXIII) can be prepared by subjecting compound (XXIIIb) to hydrolysis.

  
The present hydrolysis is carried out in the presence of alkali metal bisulfite (for example sodium bisulfite, etc.),

  
titanium trichloride, an inorganic or organic acid such as a hydrohalic acid (eg hydrochloric acid, hydrobromic acid, etc.), formic acid, nitrous acid or the like An acid hydrogen halide is preferably used in a combination

  
  <EMI ID = 147.1>

  
The present reaction is ordinarily carried out in a solvent such as water, an aqueous alcohol solution (eg, an aqueous solution of methanol, an aqueous solution of ethanol, etc.), a water-acetic acid mixture or all other solvent which does not adversely affect the reaction.

  
The reaction temperature is not critical and the reaction is ordinarily carried out at room temperature, with gentle to strong heating.

  
In the present reaction, the protected carboxy group may occasionally be transformed into the free carboxy group. This case is also included within the scope of protection of the present invention.

  
In the reactions mentioned above and / or in the post-processing of the reactions of the present invention, the tautomeric isomers mentioned above may occasionally be transformed into other tautomeric isomers, and this case is also included within the scope. protection of the present invention.

  
In the case where the desired compound (I) is obtained under

  
  <EMI ID = 148.1> wanted (I) has a free amino group, it can be transformed into

  
  <EMI ID = 149.1>

  
by a conventional process.

  
The desired compound (T) and its pharmaceutically acceptable salt according to the present invention are all new compounds which exhibit a strong antibacterial activity, inhibiting the growth of a large number of pathogenic microorganisms, including gram-positive and gram-negative bacteria, and they are useful as antibacterial agents. Particularly, it should be noted that the desired compound (I), that is to say the syn isomer, has antibacterial activities much superior to the corresponding anti isomer of the compound (I), and that consequently, the compound sought
(I), i.e. the syn isomer, is characterized by having a very great superiority over the corresponding anti isomer from the point of view of therapeutic heat.

  
In order to present the utility of the desired compound (I), in

  
As regards certain representative compounds of the present invention, the experimental results on the antibacterial activity in vitro, the experimental results on experiments carried out in vivo, that is to say the test for protection against experimental infections, are presented. , and acute toxicity in what follows. In addition, comparative experimental data on the antibacterial activities in vitro with respect to the corresponding anti isomer of the desired compound (I) is also presented for reference in what follows.

  
Experimental compounds

  
  <EMI ID = 150.1>

  
(anti isomer)

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

  
  <EMI ID = 151.1> <EMI ID = 152.1>

  
cephalosporanic (syn isomer)

  
(9) 7- [2-methoxyimino-2- (2-amino-1,3-thiazol.-4-yl) acetamido] cephalosporanic acid (anti isomer)

  
  <EMI ID = 153.1>

  
mido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic
(syn isomer)

  
  <EMI ID = 154.1>

  
(syn isomer).

  
1. Antibacterial activity in vitro

  
Experimental process

  
Antibacterial activity in vitro was determined by the double dilution method on agar-agar plate as described.

  
below.

  
The contents of a loop of a culture (carried out overnight) of each experimental strain in sojatrypticase broth (18 viable cells per ml) were allowed to develop, in a strip on agar-agar (HI -agar-agar) containing these concentrates:
gradual doses of antibiotics, and the minimum inhibitic concentration (MIC) was expressed in ug / ml after incubation at 37 [deg.] C penc
20 hours.

  

  <EMI ID = 155.1>


  

  <EMI ID = 156.1>
 

  
As can be seen clearly from the experimental results shown above, the desired compounds (I) of the present invention, i.e. the syn isomer, have much higher antibacterial activities as compared to the isomers. anti correspondents.

  
2. Protective effect against experimental infections in

  
mouse:

  
Experimental process

  
Male mice of the so-called ICR strain, 4 weeks old, each weighing 20-23 g, were used in groups of eight
-mouse. The experimental bacteria were grown overnight at 37 [deg.] C on HI-agar-agar and suspended in a 2.5-5% mucin solution to obtain the corresponding suspension for each cell. challenge. The mice were inoculated intraperitoneally with 0.5 ml of the suspension. A solution containing each test compound was administered subcutaneously to the mice at various doses one hour after the challenge. ED 50 values were calculated from the number of mice that survived for each dose, after one week

  
observation.

  

  <EMI ID = 157.1>


  

  <EMI ID = 158.1>
 

  

  <EMI ID = 159.1>
 

  
3. Acute toxicity in mice

  
The mice of the same strain as in the mentioned protection test against experimental infections were used in groups of 10. The experimental compound (8) (2 g) was administered intravenously to these mice. All the mice survived without showing any disturbances after one week of observation.

For therapeutic administration, the desired compound

  
(I) of the present invention is used in the form of conventional pharmaceutical preparations which contain the compound, as an active ingredient, in admixture - with pharmaceutically acceptable carriers such as liquid or solid, organic or inorganic excipients, which are suitable for administration. oral, parenteral or external.

  
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 necessary, auxiliary substances, stabilizers, wetting or emulsifying agents, buffers and other additives commonly used can be included in the above preparations.

  
While the dosc of the compounds may vary and also depend on the age, the condition of the patient, the kind of disease, the kind

  
of compound (I) to be applied etc ..., an average single dose of approximately

  
50 mg, 100 mg, 250 mg and 500 mg of the desired compound (I) of the present invention has been found to be effective in treating diseases caused by pathogenic bacteria.

  
Usually amounts between 1 mg and about. 1,000 mg

  
or even more can be administered to a patient.

  
The following examples are given for the purpose of illustrating

  
the present invention.

EXAMPLE 1

  
A mixture of dimethylformamide (2.81 g) and oxychloride

  
of phosphorus (5.36 g) was heated to 40 [deg.] C for 1 hour. After cooling, methylene chloride (60 ml) was added thereto and removed by distillation. To the residue was added dry ethyl acetate (50 mL). Then, 2-methoxyimino-2- (3-hydroxyphenyl) acetic acid (syn isomer) (6.83 g) was added thereto at 5 [deg.] C with stirring under ice-cooling. The resulting mixture was then stirred for 50 minutes at the same temperature. On the other hand, acid <EMI ID = 160.1>

  
that (11.5 g) and bis (trimethylsilyl) acetamide (28.4 g) were dissolved in dry ethyl acetate (150 ml) and stirred with cooling; at some point, the solution obtained above was added thereto at -40 [deg.] C. After stirring for two hours at -30 to -20 [deg.] C a saturated aqueous solution of sodium chloride (100 ml) was added at -20 [deg.] C to the reaction mixture. The mixture was stirred for 5 minutes. The precipitates were separated by filtration and the ethyl acetate layer in the filtrate was separated. The aqueous layer was extracted twice with ethyl acetate (50ml). The ethyl acetate layer separated from the filtrates and the extracts were combined. The combined ethyl acetate solution was

  
was washed with a saturated aqueous solution of sodium chloride (50 ml). In the ethyl acetate layer, activated charcoal was added and the mixture was stirred for 5 minutes and filtered. Water (100ml) was added to the filtrate and the resulting mixture was adjusted to

  
a pH of 7 with an aqueous solution of sodium bicarbonate. The aqueous layer was separated and washed with methylene chloride. After the aqueous layer has been prepared, the methylene chloride

  
was removed from the aqueous layer by bubbling nitrogen gas while cooling with ice. After filtration, the aqueous layer was adjusted to pH 2 with 10% hydrochloric acid, with stirring and ice-cooling. The precipitated crystals were collected by filtration, washed with water and dried to give

  
  <EMI ID = 161.1>

  
(11.3 g).

  

  <EMI ID = 162.1>


  
he

  
EXAMPLE 2

  
  <EMI ID = 163.1> phosphorus (2.95g) was heated for one hour at 40 [deg.] C. After cooling, methylene chloride (30 ml) was added and removed by distillation. In the residue was added acetate

  
  <EMI ID = 164.1>

  
acetic (syn isomer) (3.4 g) was added with stirring and ice-cooling, and the mixture was stirred for thirty minutes while ice-cooling. On the other hand,

  
  <EMI ID = 165.1>

  
(27.5g) in dry ethyl acetate (70ml). In the solution,

  
at one point, the solution obtained above was added to -30 [deg.] C and

  
the mixture was stirred for an hour and a half at -30 to -10 [deg.] C. A saturated aqueous solution of sodium chloride was added

  
to the reaction mixture at -20 [deg.] C. The ethyl acetate layer was separated and the aqueous layer was extracted with ethyl acetate. Two layers of ethyl acetate were combined, washed with aqueous sodium chloride solution and treated with charcoal.

  
  <EMI ID = 166.1>

  
aqueous tion of sodium bicarbonate. The aqueous layer was separated and ethyl acetate was added to it. The mixture was

  
  <EMI ID = 167.1>

  
aqueous was separated. Ethyl acetate was added thereto and the mixture was adjusted to pH 2 with 10% hydrochloric acid The ethyl acetate layer was separated and the aqueous layer was further extracted ethyl acetate. The two ethyl acetate layers were combined, washed with aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed by distillation and the residue was sprayed with diisopropyl ether. The powder was collected by filtration and

  
  <EMI ID = 168.1>

  
acetamido] -3-carbamoyl-oxymethyl-3-cephem-4-carboxylic (syn isomer) (3.26 g).

  

  <EMI ID = 169.1>
 

  

  <EMI ID = 170.1>


  
1

  
7- [2-methoxyimino-2- (3-hydroxyphenyl) acetamido] - acid

  
  <EMI ID = 171.1>

  
was suspended in water (15ml) and dissolved by adding sodium bicarbonate (0.35g) with stirring at room temperature. The solution was lyophilized and dried to give 7-

  
  <EMI ID = 172.1>

  
Sodium 3-cephem-4-carboxylate (syn isomer) (1.9 g).

  

  <EMI ID = 173.1>


  
EXAMPLE 3

  
  <EMI ID = 174.1>

  
Dry methylene chloride (15ml) was added thereto and distilled off under reduced pressure, to the residue were added dry ethyl acetate (15ml) and 2-metthoxyimino-2 acid. - (3chloro-4-hydroxyphenyl) acetic (syn isomer) (0.53 g) was added thereto with stirring at -20 [deg.] C. The mixture was stirred for one hour below -10 [deg.] C. On the other hand, a mixture of 7-amino-3-

  
  <EMI ID = 175.1>

  
trimethylsilylacetamide (5g) and dry ethyl acetate (25ml) was stirred for one hour at room temperature. In this solution, the solution obtained above was added dropwise

  
  <EMI ID = 176.1>

  
Ethyl acetate (50ml) was added to the reaction mixture at -20 [deg.] C and the mixture was stirred. The organic layer containing <EMI ID = 177.1>

  
syn) was adjusted to pH 7.0 by adding water (50 mL) and sodium bicarbonate and the mixture was stirred for 2 hours

  
at room temperature. Ethyl acetate (50 mL) was added.

  
  <EMI ID = 178.1>

  
10% hydrochloric acid. The aqueous layer was separated, adjusted to pH 2.0 with 10% hydrochloric acid and extracted with ethyl acetate (50 mL). The extract was washed with water and ice and dried over magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was washed thoroughly with ether, collected by filtration and dried to

  
  <EMI ID = 179.1>

  
(0.3 g).

  

  <EMI ID = 180.1>

EXAMPLE 4

  
2-methoxyimino-2- (3-hydroxyphenyl) acetic acid
(syn isomer) (1.1 g) and 7-amino-3-trichloroacetylcar- acid

  
  <EMI ID = 181.1>

  
lic (syn isomer) (0.5 g). This compound is identified with the compound obtained in Example 2 by I.R. and R.M.N.

  
EXAMPLE 5
(a) 2-t-Butoxycarbonylmethoxyimino-2- (3-chloro- <EMI ID = 182.1>

  
5-yl) thiomethyl-3-cephem-4-carboxylic (syn isomer) (1.5 g).

  
(b) The powder obtained in Example 5 (a), (1.5 g) was added to a mixture of anisol (1.5 ml) and trifluoroacetic acid
(6 ml), and the resulting mixture was stirred for 30 minutes at room temperature. The reaction mixture was adjusted to pH 8 by adding aqueous sodium bicarbonate solution (50 ml), acetate d ethyl (50 mL) and sodium bicarbonate, cooling with ice. The aqueous layer was separated, adjusted to pH 5.0 with 10% hydrochloric acid and washed with ethyl acetate (50 mL). The aqueous layer was further adjusted to

  
  <EMI ID = 183.1>

  
  <EMI ID = 184.1>

  
tion under reduced pressure and the residue was dissolved in an acetate buffer at pH 5.0 and subjected to column chromatography on neutral alumina called Woelm (registered trademark manufactured by the so-called ICN Company) using a buffer with acetate at pH 5.0 as a developing solvent. The eluate was adjusted to pH 2.0 with 10% hydrochloric acid while cooling with ice. The precipitated material was collected by filtration, the-

  
  <EMI ID = 185.1>

  
145 to 148 [deg.] C (decomposition).

  

  <EMI ID = 186.1>
 

EXAMPLE 7

  
The following compounds were obtained in a manner similar to that of Examples 1 and 2.

  
  <EMI ID = 187.1>

  
(syn isomer).

  

  <EMI ID = 188.1>


  

  <EMI ID = 189.1>


  
  <EMI ID = 190.1>

  
(syn isomer).

  

  <EMI ID = 191.1>


  

  <EMI ID = 192.1>


  
  <EMI ID = 193.1>

  
mido] -3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4carboxylic (syn isomer).

  

  <EMI ID = 194.1>
 

  

  <EMI ID = 195.1>


  
(4) 7- [2-Methoxyimino-2- (3-hydroxyphenyl) acetamido] cephalosporanic acid (syn isomer).

  
Specter I.R. (Nujol)

  

  <EMI ID = 196.1>


  

  <EMI ID = 197.1>


  
  <EMI ID = 198.1>

  
(syn isomer).

  
Specter I.R. (Nujol)

  
  <EMI ID = 199.1>
  <EMI ID = 200.1>
 .1 <EMI ID = 201.1>

  
(syn isomer).

  

  <EMI ID = 202.1>
 

  

  <EMI ID = 203.1>


  
  <EMI ID = 204.1>

  
xylic (syn isomer) m.p. 145 to 148 [deg.] C (decomposition).

  
Specter I.R. (Nujol)

  

  <EMI ID = 205.1>


  
  <EMI ID = 206.1>

  
xylic (syn isomer) m.p. 143 to 145 [deg.] C (decomposition).

  
Specter I.R. (Nujol)
  <EMI ID = 207.1>
 
  <EMI ID = 208.1>
(9) 7- [2-Methoxyimino-2- (3-nitro-4-hydroxyphenyl) acid

  
  <EMI ID = 209.1>

  
xylic (syn isomer), m.p. 149 to 152 [deg.] C (decomposition).

  
Specter I.R. (Nujol)
  <EMI ID = 210.1>
 .1 <EMI ID = 211.1>

  
Specter I.R. (Nujol)
  <EMI ID = 212.1>
 
  <EMI ID = 213.1>
  <EMI ID = 214.1>

  
that (syn isomer), m.p. 149 to 152 [deg.] C (decomposition).

  
Specter I.R. (Nujol)

  

  <EMI ID = 215.1>


  
  <EMI ID = 216.1>

  

  <EMI ID = 217.1>


  
(13) 7- [2- (3-hydroxy-4-bromobenzyloxyimino) -2- (4- acid

  
  <EMI ID = 218.1>

  
3-cephem-4-carboxylic (syn isomer), powder.

  
Specter I.R. (Nujol)
  <EMI ID = 219.1>
 
  <EMI ID = 220.1>
 .1
(14) 7- [2- (2-thienylmethoxyimino) -2- (4-hydroxyphé acid)

  
  <EMI ID = 221.1>

  
4-carboxylic (syn isomer), powder.

  
Specter I.R. (Nujol)

  

  <EMI ID = 222.1>


  
  <EMI ID = 223.1>

  
xyl (syn isomer), colorless powder, m.p. 153 to 156 [deg.] C (decomposition).

  
Specter I.R. (Nujol)

  
  <EMI ID = 224.1>

  
R.M.N. (d &#65533; -DMSO, 5)
  <EMI ID = 225.1>
   <EMI ID = 226.1>

  
(syn isomer), powder m.p. 135 to 138 [deg.] C (decomposition).

  
Specter I.R. (Nujol)

  

  <EMI ID = 227.1>


  
  <EMI ID = 228.1>

  
Specter I.R. (Nujol)

  

  <EMI ID = 229.1>


  
(18) 7- [2-Ethoxyimino-2- (3-methoxyphenyl) acetamido] - acid

  
  <EMI ID = 230.1>

  
mother syn), pale yellow powder, m.p. 140 to 143 [deg.] C (decomposition).

  
Specter I.R. (Nujol)
  <EMI ID = 231.1>
 
  <EMI ID = 232.1>
  <EMI ID = 233.1>

  
carboxylic (syn isomer), pale yellow powder, m.p. 153 to 156 [deg.] C
(decomposition).

  
Specter I.R. (Nujol)

  
3250, 2600, 1780, 1720, 1670, 1645,

  
  <EMI ID = 234.1>

  
R.M.N. (d &#65533; -DMSO, 5)

  

  <EMI ID = 235.1>


  
(20) 7- [2-Methoxyimino-2- (3-acetoxyphenyl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer).

  
Specter I.R. (Nujol)

  
  <EMI ID = 236.1>
  <EMI ID = 237.1>
 
  <EMI ID = 238.1>
  <EMI ID = 239.1>

  
lic (syn isomer).

  
Specter I.R. (Nujol)

  
  <EMI ID = 240.1>

  

  <EMI ID = 241.1>


  
(22) 7- [2-Methoxyimino-2- (3-mesylaminophenyl) acetaminic acid

  
  <EMI ID = 242.1>

  
(syn isomer), m.p. 155 [deg.] C (decomposition).

  
Specter I.R. (Nujol)

  
  <EMI ID = 243.1>

  

  <EMI ID = 244.1>


  
  <EMI ID = 245.1>
  <EMI ID = 246.1>
 
  <EMI ID = 247.1>
  <EMI ID = 248.1>

  
(syn isomer).

  
Specter I.R. (Nujol)

  
  <EMI ID = 249.1>

  
  <EMI ID = 250.1>

  

  <EMI ID = 251.1>


  
  <EMI ID = 252.1>

  
(syn isomer).

  
Specter I.R. (Nuiol)
  <EMI ID = 253.1>
  <EMI ID = 254.1>
   <EMI ID = 255.1>

  
4-carboxylic (syn isomer), m.p. 138 to 142 [deg.] C (decomposition).

  
Specter I.R. (Nujol)

  
3300, 3400, 2600, 1780,

  
  <EMI ID = 256.1>

  

  <EMI ID = 257.1>


  
  <EMI ID = 258.1>

  
xylic (syn isomer), m.p. 88 [deg.] C (decomposition).

  

  <EMI ID = 259.1>


  
  <EMI ID = 260.1>

  
4-carboxylic (syn isomer).

  
Specter I.R. (Nujol)

  
1765 cm - <1>

  
  <EMI ID = 261.1>

  
  <EMI ID = 262.1>
  <EMI ID = 263.1>
  <EMI ID = 264.1>

  
3-cephem-4-carboxylic (syn isomer).

Specter I.R. (Nujol)

  

  <EMI ID = 265.1>


  
EXAMPLE 8

  
  <EMI ID = 266.1>

  
of phosphorus (1.6 g) was heated for 30 minutes at 40 [deg.] C. Benzene was added thereto and the mixture was concentrated. The residue has

  
was suspended in ethyl acetate (20 ml) and 2-methoxyimino-2- (3-hydroxyphenyl) acetic acid (isomer) was added thereto.

  
syn) (1.95'g) between -15 and -5 [deg.] C, after which the resulting mixture

  
was stirred for 30 minutes at the same temperature. On the other hand, a solution of soda (0.9 g) in water (5 ml) was added dropwise.

  
drop between 0 and 5 [deg.] C, for 25 minutes, to a suspension of 7-aminocephalosporanic acid (2.7 g) in water (12.5 ml) and the mixture was stirred for 5 minutes, after which acetone (20 ml) was added thereto. To the resulting mixture containing sodium 7-amino-3-hydroxymethyl-3-cephem-4-carboxylate, the acetate solution was added dropwise between 0 and 5 [deg.] C over 3 minutes. ethyl obtained

  
  <EMI ID = 267.1>

  
triethylamine. After stirring for 30 minutes, the organic solvents were removed by distillation. The aqueous layer was washed with ethyl acetate (20 mL), adjusted to pH.

  
2.0 with hydrochloric acid and extracted with ethyl acetate
(60 ml) between 0 and 3 [deg.] C. The aqueous layer was further extracted with ethyl acetate (30 mL). The combined ethyl acetate extracts were washed with saturated aqueous sodium chloride solution and dried. The solvent was removed by distillation and the residue was sprayed with diisopropyl ether.

  
  <EMI ID = 268.1>

  
(syn isomer) (II) (2.64 g).

  
I.R. spectrum of (I) (Nujol)

  
  <EMI ID = 269.1>

  

  <EMI ID = 270.1>


  

  <EMI ID = 271.1>


  
EXAMPLE 9

  
7- [2-Methoxyimino-2- (3-hydroxyphenyl) acetaminic acid

  
  <EMI ID = 272.1>

  
(0.23 g) was dissolved in pyridine (1 ml) with stirring

  
and cooling with ice, and acetyl chloride (0.082 g was added. The mixture was stirred for 40 minutes while cooling with ice. The reaction mixture was poured into water and ice, acidified with hydrochloric acid

  
and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over sulfate.

  
magnesium. After treatment with activated charcoal, it was filtered and the filtrate was concentrated. The residue was sprayed with diisopropyl ether to give a mixture of 7- [2-metho-- acid.

  
  <EMI ID = 273.1>

  

  <EMI ID = 274.1>

EXAMPLE 10

  
The following compounds were obtained in a manner similar to that of Example 9.

  
(1) 7- [2-methoxyimino-2- (3-acetoxyphenyl) acetaminic acid

  
  <EMI ID = 275.1>

  
(syn isomer).

  

  <EMI ID = 276.1>
 

  

  <EMI ID = 277.1>


  
  <EMI ID = 278.1>

  
carboxylic (syn isomer).

  
Specter I.R. (Nujol)

  
3450, 3300, 3200, 1780, 1725, 1670, 1620,

  
  <EMI ID = 279.1>

  

  <EMI ID = 280.1>


  
  <EMI ID = 281.1>

  
lic (syn isomer).

  
Specter I.R. (Nujol)

  

  <EMI ID = 282.1>


  
EXAMPLE 11

  
  <EMI ID = 283.1> and the mixture was heated to 40 [deg.] C for 1 hour. Ethyl acetate (1.5 ml) was added thereto, and in the mixture to a certain

  
  <EMI ID = 284.1>

  
Zol-4-yl) acetic (syn isomer) (0.3g) with stirring and ice-cooling, after which the resulting mixture was stirred for 20 minutes at 0-5 [deg.] C. On the other hand, bis (trimethylsilyl) acetamide (1.2 g) was added to the 7-amino acid suspension.

  
  <EMI ID = 285.1>

  
(0.53g) in ethyl acetate (7ml), and the mixture was stirred at room temperature. To this solution was added dropwise the ethyl acetate solution obtained above at -20 [deg.] C,

  
and the mixture was stirred for 2 hours at -10 to -20 [deg.] C. Water (20 ml) was added to the reaction mixture below
-25 [deg.] C and ethyl acetate (20 mL) was added thereto, after which the mixture was stirred. Insoluble material was filtered off and the ethyl acetate layer was separated. Water (15ml) was added to the ethyl acetate layer and the mixture was adjusted to pH 7.5 with saturated aqueous podium bicarbonate solution. The aqueous clump was separated, washed with methylene chloride, and the methylene chloride in the aqueous layer was removed by bubbling nitrogen gas. The aqueous solution was adjusted to pH 2.2 with hydrochloric acid

  
to 10% and the precipitates were collected by filtration and dried.

  
  <EMI ID = 286.1>

  
xyl (syn isomer) (0.28 g).

  
Specter I.R. (Nujol)
  <EMI ID = 287.1>
  <EMI ID = 288.1>
 EXAMPLE 12

  
Phosphorus oxychloride (0.89 g) and dimethyl-

  
  <EMI ID = 289.1>

  
ice and then heated for 30 minutes at 40 [deg.] C. Chloride

  
of dry methylene (20 ml) was added thereto and then removed by distillation. To the residue was added dry ethyl acetate (10 mL) followed by 2-methoxyimino-2- [2- (2,2,2-trifluoroacetami-

  
  <EMI ID = 290.1>

  
tion and cooling by ice. The mixture was stirred for 40 minutes at the same temperature to give a clear solution. On the other hand, trimethylsilylacetamide (6.36 g) was added as a suspension of 7-aminocephalosporanic acid.
(1.65g) in dry ethyl acetate (25ml) with stirring at room temperature, after which the mixture was stirred for

  
1 hour to give a clear solution. In this solution, we

  
The ethyl acetate solution obtained above was added all at once while stirring at -20 to -25 [deg.] C, and the resulting mixture was stirred for 2 hours at the same temperature. Some water

  
  <EMI ID = 291.1>

  
ture, and then the mixture was stirred for 5 minutes at room temperature. The ethyl acetate layer was separated, and the aqueous layer was further extracted with ethyl acetate. The ethyl acetate layers were combined and water was added thereto (50ml). The mixture was adjusted to pH 7.5 with sodium bicarbonate, and the aqueous layer was separated. Ethyl acetate (40ml) was added to the aqueous layer, and

  
  <EMI ID = 292.1>

  
at 10%, with stirring and ice cooling. The ethyl acetate layer was separated, and the aqueous layer was extracted twice more with ethyl acetate (30 ml). The ethyl acetate layers were combined, washed with soap.

  
  <EMI ID = 293.1>
  <EMI ID = 294.1>
 
  <EMI ID = 295.1>
 EXAMPLE 13

  
Phosphorus oxychloride (2.0 g) was added in one

  
  <EMI ID = 296.1>

  
Dry ethyl tate (20 mL). After stirring for 20 minutes at 7-
10 [deg.] C, bis (trimethylsilyl) acetamide (0.4 g) was added at the same temperature. After stirring for 10 minutes at 7-10 [deg.] C, to this was added dropwise phosphorus oxychloride (2.0 g) at the same temperature. The resulting mixture was stirred for 10 minutes.

  
  <EMI ID = 297.1>

  
On the other hand, trimethylsilylacetamide (7.35g) was added to a suspension of 7-aminocephalosporanic acid (2.45g) in dry ethyl acetate (8ml), after which the mixture was stirred at 40 [deg.] C to give a clear solution. To this solution, the ethyl acetate solution obtained above was added all at once to <EMI ID = 298.1> and water (80ml) was added to it. The aqueous layer was separated, adjusted to pH 4.5 with sodium bicarbonate and subjected to column chromatography on the so-called Diaion HP-20 resin.
(registered trademark of the company known as Mitsubishi Chemical Industries Ltd.) using a 25% aqueous solution of isopropyl alcohol

  
  <EMI ID = 299.1>

  
that (syn isomer) (1.8 g), m.p. 227 [deg.] C (decomposition).

  

  <EMI ID = 300.1>
 

  

  <EMI ID = 301.1>

EXAMPLE 14

  
Phosphorus oxychloride (3.8 g) was added dropwise, at 5 to 8 [deg.] C, to a suspension of 2-methoxyimino- acid.

  
  <EMI ID = 302.1>

  
dry ethyl acetate (40 mL). After stirring for 30 minutes at around S [deg.] C, bis (trimethylsilyl) acetamide (0.86 g) was added thereto at the same temperature. After stirring for
At the same temperature for 10 minutes, phosphorus oxychloride (3.8 g) at 5-8 [deg.] C was added dropwise thereto, after which the mixture

  
  <EMI ID = 303.1>

  
On the other hand, sodium acetate (3.3g) was added to a solution of 7-aminocephalosporanic acid (2.7g) in aqueous solution
(20 ml) sodium bicarbonate (1.7 g), then acetone

  
(20 ml) was added thereto. To this solution was added dropwise the ethyl acetate solution obtained above with stirring.

  
  <EMI ID = 304.1>

  
ble was separated by filtration, and the aqueous layer in the filtrate was separated. The aqueous layer was concentrated under pressure:
reduced to remove organic solvents, adjusted to pH 4.5 with sodium bicarbonate and subjected to column chromatography on the so-called Diaion DP-20 resin (registered trademark of the company known as Mitsubishi Chemical Industries Ltd.) using a 25% aqueous solution of isopropyl alcohol as eluent. The eluate

  
  <EMI ID = 305.1> 1,3-thiazol-4-yl) acetamido] cephalosporanic (syn isomer) (2.8 g). This compound was identified with the compound obtained in Example 13 by I.R. and R.M.N.

EXAMPLE 15

  
The following compounds were obtained by methods similar to those of Examples 11 to 14.

  
  <EMI ID = 306.1>

  
yl) thiomethyl-3-cephem-4-carboxylic (syn isomer)

  
Specter I.R. (Nujol)

  

  <EMI ID = 307.1>


  
  <EMI ID = 308.1>

  
carboxylic (syn isomer).

  

  <EMI ID = 309.1>


  
  <EMI ID = 310.1> phem-4-carboxylic (syn isomer).

  
Specter I.R. (Nujol)

  
  <EMI ID = 311.1>

  

  <EMI ID = 312.1>


  
  <EMI ID = 313.1>

  
thiomethyl-3-cephem-4-carboxylic (syn isomer).

  
Specter I.R. (Nujol)

  
  <EMI ID = 314.1>

  

  <EMI ID = 315.1>


  
  <EMI ID = 316.1>

  
R.M.N. (d6-DMSO, 5)

  
ppm 9.65 (1H, d, J = 8Hz)
  <EMI ID = 317.1>
 
  <EMI ID = 318.1>
  <EMI ID = 319.1>

  
3-cephem-4-carboxylic (syn isomer).

  
Specter I.R. (Nujol)

  
  <EMI ID = 320.1>

  

  <EMI ID = 321.1>


  
  <EMI ID = 322.1>

  
R.M.N. (d, -DMSO, 5)
  <EMI ID = 323.1>
  <EMI ID = 324.1>
 (8) 7- [2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acid

  
  <EMI ID = 325.1>

  
lylic (syn isomer)

  

  <EMI ID = 326.1>


  
  <EMI ID = 327.1>

  
4-carboxylic (syn isomer).

  

  <EMI ID = 328.1>


  
(10) 7- [2-allyloxyimino-2- (2-amino-1,3-thiazol- acid

  
  <EMI ID = 329.1>

  
4-carboxylic (syn isomer).

  
Specter I.R. (Nujol)
  <EMI ID = 330.1>
 
  <EMI ID = 331.1>
  <EMI ID = 332.1>

  
carboxylic (syn isomer), m.p. 145 to 147 [deg.] C (decomposition).

  
Specter I.R. (Nujol)

  

  <EMI ID = 333.1>


  
  <EMI ID = 334.1>

  
cephem-4-carboxylic (syn isomer) m.p. 171 to 173 [deg.] C (decomposition).

  

  <EMI ID = 335.1>


  
  <EMI ID = 336.1> <EMI ID = 337.1>

  

  <EMI ID = 338.1>


  
  <EMI ID = 339.1>

  
4 - carboxylic (syn isomer).

  

  <EMI ID = 340.1>


  
  <EMI ID = 341.1>

  
thyl-3-cephem-4-carboxylic (syn isomer).

  
Specter I.R. (Nujol)
  <EMI ID = 342.1>
 
  <EMI ID = 343.1>
  <EMI ID = 344.1>

  
m.p. 260 to 270 [deg.] C (decomposition).

  
Specter I.R. (Nujol)

  
  <EMI ID = 345.1>

  

  <EMI ID = 346.1>


  
  <EMI ID = 347.1>

  
position).

  

  <EMI ID = 348.1>


  
  <EMI ID = 349.1>

  
(syn isomer) m.p. 210 to 220 [deg.] C (decomposition).

  

  <EMI ID = 350.1>
 

  

  <EMI ID = 351.1>


  
  <EMI ID = 352.1>

  
lic (syn isomer) m.p. 172 to 175 [deg.] C (decomposition).

  
Specter I.R. (Nujol)

  
3300, 1770, 1665 cm -1

  
  <EMI ID = 353.1>

  

  <EMI ID = 354.1>


  
  <EMI ID = 355.1>

  
4-carboxylic (syn isomer), m.p. 185 [deg.] C (decomposition).

  
Specter I.R. (Nujol)

  
  <EMI ID = 356.1>

  
R.M.N. (d &#65533; -DMSO, 5)
  <EMI ID = 357.1>
  <EMI ID = 358.1>
   <EMI ID = 359.1>

  
carboxylic (syn isomer) m.p. 155 to 160 [deg.] C (decomposition).

  
Specter I.R. (Nujol)

  

  <EMI ID = 360.1>


  
  <EMI ID = 361.1>

  
Specter I.R. (Nujol)

  
  <EMI ID = 362.1>

  

  <EMI ID = 363.1>


  
(23) 7- [2-methoxyimino-2- (2-amino-1,3-thiazol-4- acid

  
  <EMI ID = 364.1>

  
3-cephem-4-carboxylic (syn isomer).

  
Specter I.R. (Nujol)

  
  <EMI ID = 365.1>
  <EMI ID = 366.1>
 
  <EMI ID = 367.1>
  <EMI ID = 368.1>

  
4-yl) -acetamido] cephalosporanic, (syn isomer)

  
Specter I.R. (Nujol)

  

  <EMI ID = 369.1>


  
  <EMI ID = 370.1>

  
4-carboxylic (syn isomer).

  
Specter I.R. (Nujol)

  

  <EMI ID = 371.1>


  
  <EMI ID = 372.1>

  
(syn isomer) [or this compound may be represented by 3-

  
  <EMI ID = 373.1>

  

  <EMI ID = 374.1>


  
  <EMI ID = 375.1>

  
4-carboxylic (syn isomer).

  

  <EMI ID = 376.1>


  
q-

  
  <EMI ID = 377.1>

  
syn).

  

  <EMI ID = 378.1>
 

  

  <EMI ID = 379.1>


  
EXAMPLE 16

  
  <EMI ID = 380.1>

  
heated to 45 [deg.] C for 6 hours. Water (15ml) and ethyl acetate (30ml) were added to the reaction mixture and the resulting mixture was adjusted to pH 3.5 with 10% hydrochloric acid. The aqueous layer was separated, washed with ethyl acetate.

  
  <EMI ID = 381.1>

  
on a column on the product called Amberlite XAD-2 (20 ml) (prepared

  
by the company known as Rohm & Haas Co.) using 10% ethanol as a developing solvent. The eluate containing the desired compound was combined and lyophilized to give the acid 7- [2-methoxy-

  
  <EMI ID = 382.1>

  
5-yl) thiomethyl-3-cephem-4-carboxylic (syn isomer) (0.12 g).

  
Specter I.R. (Nujol)

  

  <EMI ID = 383.1>
 

EXAMPLE 17

  
Trifluoroacetic acid (3 mL) was added, while cooling with ice, to 7- [2-metthoxyimino-2- (2-

  
  <EMI ID = 384.1>

  
1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic (syn isomer)
(0.5 g), and the mixture was stirred for 30 minutes at room temperature. In the mixture, ether was added, the precipitated powder was collected by filtration and dissolved in a mixture.

  
  <EMI ID = 385.1>

  
pH 12 to 13. The solution was adjusted to pH 4.6 with 10% hydrochloric acid, washed with ethyl acetate and chloride.

  
methylene. The excess of methylene chloride in the aqueous layer was completely removed by bubbling nitrogen gas. The aqueous layer was adjusted to pH 2 with stirring and ice-cooling to precipitate a powder. The powder was gathered

  
  <EMI ID = 386.1>

  
2-yl) thiomethyl-3-cephem-4-carboxylic (syn isomer) (0.128 g).

  

  <EMI ID = 387.1>

EXAMPLE 18

  
Trifluoroacetic acid (4 ml) and anisol (2 ml) were added, while cooling with ice, to acid 7-

  
  <EMI ID = 388.1>

  
xyl (syn isomer) (0.9 g), and the mixture was stirred for 40 minutes at room temperature. The reaction mixture was post-treated in a manner similar to that of Example 17 to give <EMI ID = 389.1>

  
syn) (0.425 g).

  

  <EMI ID = 390.1>


  
EXAMPLE 19

  
Disodium acid phosphate (0.26 g) was added to a

  
  <EMI ID = 391.1>

  
water (15 ml). A saturated aqueous solution of disodium acid phosphate was further added to adjust the pH value of the mixture to

  
6. The resulting mixture was stirred for 23 hours at room temperature. The reaction mixture was adjusted to pH 4, ice-cooling with 10% hydrochloric acid, washed.

  
with ethyl acetate and adjusted to pH 2.5 with 10% hydrochloric acid. The precipitated crystals were collected by filtration, washed with cold water and dried to give acid 7 - [2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] cephalosporanic (syn isomer) (0.18 g), mp 227 [deg.] C (decomposition).

  

  <EMI ID = 392.1>


  

  <EMI ID = 393.1>
 

  
3.6 (2H, broad)

  
2.08 (3H, s)

  
EXAMPLE 20

  
  <EMI ID = 394.1>

  
in a solution of sodium acetate trihydrate (74.8 g) in

  
water (230 ml), and the suspension was stirred for 15 hours

  
at room temperature. The reaction mixture was adjusted to pH 5.0 with concentrated hydrochloric acid and the insoluble material was filtered off. The filtrate was adjusted to pH 2.5 and the precipitated crystals were collected by filtration and dried.

  
  <EMI ID = 395.1>

  
lic (syn isomer) (14 g), m.p. 172 to 175 [deg.] C (decomposition).

  

  <EMI ID = 396.1>


  
EXAMPLE 21

  
  <EMI ID = 397.1>

  
carboxylic acid (syn isomer) (3.5 g) was suspended in a solution of sodium acetate trihydrate (12.2 g) in water (30

  
ml). The mixture was stirred for 15 hours at room temperature. The reaction mixture was saturated with sodium chloride and adjusted to pH 5.0 with concentrated hydrochloric acid, with stirring and ice-cooling. The insoluble matter precipitated

  
was prepared by filtration. The filtrate was adjusted to pH 3.0 with concentrated hydrochloric acid and further adjusted to pH 1.5 with 10% hydrochloric acid. The precipitates were collected by filtration and dried to give 7- [2-me- acid.

  
  <EMI ID = 398.1>

  
(decomposition). ;

  

  <EMI ID = 399.1>

EXAMPLE 22

  
Concentrated hydrochloric acid (10.4 ml) was added with stirring at room temperature, to an acid suspension.

  
  <EMI ID = 400.1>

  
poranic (syn isomer) (48.35 g) in methanol (725 ml). After stirring for 3 hours at room temperature, the reaction mixture was adjusted to pH 4.5 with ammonia and the mixture.

  
  <EMI ID = 401.1>

  
water (100 ml). The mixture was adjusted to pH 6.5 with aqueous sodium bicarbonate solution, and insoluble material was collected by filtration to give 6- [2-methoxyimino-2-

  
  <EMI ID = 402.1>

  
trat was adjusted to a pH of 4.5 with acetic acid, adsorbed by the so-called Diaion HP-20 (registered trademark of the so-called Mitsubishi Chemical Industries Ltd.) resin (600 ml), washed with water (2 1)

  
and then eluted with a 25% aqueous solution of isopropyl alcohol. The eluates containing the desired compounds were combined and cooled after addition of isopropyl alcohol (1/3 of the volume of the eluates) The precipitates were collected by filtration, washed with isopropyl alcohol.

  
  <EMI ID = 403.1> <EMI ID = 404.1>

  
The mother liquor was concentrated under reduced pressure until

  
as the crystals begin to precipitate. To the residue was added isopropyl alcohol (2/3 of the residue volume). The mixture

  
was cooled and the precipitates were collected by filtration to give the same desired compound (5.8 g). Total yield 16.2 g. This compound was identified as being identical to the compound obtained in the preceding examples by I.R. and R.M.N.

  
EXAMPLE 23

  
  <EMI ID = 405.1>

  
yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic (syn isomer) (10.8 g) was added to methanol (200 ml),

  
and phosphorus oxychloride (7.2 g) was added thereto dropwise, with stirring and ice-cooling to 2-9 [deg.] C. After stirring for 1 1/2 hours at the same temperature, the reaction mixture was concentrated under reduced pressure on a water bath at
25-28 [deg.] C up to a volume of 100 ml. To the residue was added ether (300 ml) with stirring and ice-cooling. The precipitates were collected by filtration and dried to give

  
  <EMI ID = 406.1>

  
lic (syn isomer) (12.3 g). This powder (12.3 g) was suspended in water (100 ml) and dissolved by adjusting the pH of the suspension to 7.5 with a saturated aqueous solution of sodium bicarbonate. In the solution was added ethyl acetate (100 ml),

  
and the mixture was adjusted to pH 2.5 with 10% hydrochloric acid. The precipitates were collected by filtration, washed with cold water and dried to give 7- [2 acid -methoxyimi-

  
  <EMI ID = 407.1>

  
thiomethyl-3-cephem-4-carboxylic (syn isomer) (6.1 g). The aqueous layer in the mother liquor was separated and stirred with cooling after addition of sodium chloride. The precipitates were collected by filtration to give the same desired compound (3.8 g) Total yield: 9.9 g. This compound was identified as being identical to the compound obtained in the preceding examples by spectra

  
I.R. and R.M.N.

  
EXAMPLE 24

  
The following compounds were obtained in a similar manner

  
to that of Examples 16 to 23.

  
  <EMI ID = 408.1>

  
m.p. 260 to 270 [deg.] C (decomposition).

  
Specter I.R. (Nujol)

  

  <EMI ID = 409.1>


  
  <EMI ID = 410.1>

  
syn), m.p. 210 to 220 [deg.] C (decomposition).

  

  <EMI ID = 411.1>


  
  <EMI ID = 412.1>

  
carboxylic (syn isomer) m.p. 185 [deg.] C (decomposition).

  
Specter I.R. (Nujol)
  <EMI ID = 413.1>
 
  <EMI ID = 414.1>
  <EMI ID = 415.1>

  
(4H) -dione (syn isomer), m.p. 210 to 215 [deg.] C (decomposition).

  
Specter I.R. (Nujol)

  
  <EMI ID = 416.1>

  

  <EMI ID = 417.1>


  
  <EMI ID = 418.1>

  
thyl-3-cephem-4-carboxylic (syn isomer).

  

  <EMI ID = 419.1>


  
EXAMPLE 25

  
  <EMI ID = 420.1> <EMI ID = 421.1>

  
in phosphate buffered solution at pH 6.4 (50 ml) was adjusted to pH 6.4 with sodium bicarbonate and stirred for 6

  
  <EMI ID = 422.1>

  
Ethyl tate was added thereto. The mixture was adjusted to pH 5 with 10% hydrochloric acid and washed with ethyl acetate.

  
The aqueous layer was treated with activated charcoal and set

  
to pH 2.7 with 10% hydrochloric acid with stirring and ice cooling. The precipitated crystals were collected by filtration, washed with cold water and dried to give.

  
  <EMI ID = 423.1> that (syn isomer) (0.7 g), m.p. 185 [deg.] C (decomposition).

  
Specter I.R. (Nujol)

  

  <EMI ID = 424.1>

EXAMPLE 26

  
The following compounds were obtained in a manner similar to that of Example 25.

  
  <EMI ID = 425.1>

  
xylic (syn isomer).

  

  <EMI ID = 426.1>
 

  

  <EMI ID = 427.1>


  
  <EMI ID = 428.1>

  
thyl-3-cephem-4-carboxylic (syn isomer).

  
Specter I.R. (Nujol)

  

  <EMI ID = 429.1>


  
  <EMI ID = 430.1>

  
carboxylic (syn isomer).

  
Specter I.R. (Nujol)

  

  <EMI ID = 431.1>


  
(4) 7- [2-methoxyimino- 2- (2-oxo-2, 3-cihydro- acid

  
  <EMI ID = 432.1>

  
3-cephem-4-carboxylic (syn isomer).

  

  <EMI ID = 433.1>


  
  <EMI ID = 434.1>

  
4-carboxylic (syn isomer).

  
SDectre I.R. (Nuiol)

  

  <EMI ID = 435.1>


  
  <EMI ID = 436.1>

  
xylic (syn isomer).

  
Spectrum I.R. (NUjol)
  <EMI ID = 437.1>
 
  <EMI ID = 438.1>
  <EMI ID = 439.1>

  
4-carboxylic (syn isomer).

  
Spectrum I.R. (Nuuol)

  

  <EMI ID = 440.1>


  
(8) 7- [2-allyloxyimino-2- (2-amino-1,3-thiazol-4- acid

  
  <EMI ID = 441.1>

  
carboxylic (syn isomer).

  
Specter I.R. (Nujol)

  

  <EMI ID = 442.1>


  
  <EMI ID = 443.1>

  

  <EMI ID = 444.1>


  
  <EMI ID = 445.1>

  
4-carboxylic (syn isomer), m.p. 171 to 173 [deg.] C (decomposition).

  
Specter I.R. (Nujol)

  

  <EMI ID = 446.1>


  
  <EMI ID = 447.1>

  
xylic (syn isomer), m.p. 172 to 175 [deg.] C (decomposition).

  
Specter I.R. (Nujol)

  
  <EMI ID = 448.1>
  <EMI ID = 449.1>
 
  <EMI ID = 450.1>
  <EMI ID = 451.1>

  
cephem-4-carboxylic (syn isomer).

  
Specter I.R. (Nujol)

  
  <EMI ID = 452.1>

  
  <EMI ID = 453.1>

  

  <EMI ID = 454.1>


  
  <EMI ID = 455.1>

  

  <EMI ID = 456.1>


  
  <EMI ID = 457.1> <EMI ID = 458.1>

  
carboxylic (syn isomer).

  

  <EMI ID = 459.1>


  
q

  
  <EMI ID = 460.1>
(syn isomer).

  
Specter I.R. (Nujol)

  
  <EMI ID = 461.1>

  

  <EMI ID = 462.1>


  
  <EMI ID = 463.1>

  
3-cephem-4-carboxylic (syn isomer), powder.

  
(17) 7- [2-Carboxy-methoxyimino-2- (3-chloro-4-hydro- acid

  
  <EMI ID = 464.1>

  
4-carboxylic (syn isomer), m.p. 145 to 148 [deg.] C (decomposition).

  
Specter I.R. (Nujol)
  <EMI ID = 465.1>
 
  <EMI ID = 466.1>
(18) 7- [2- (1-t-butoxycarbonylethoxyimino) -2- (3-chlo- acid

  
  <EMI ID = 467.1>

  
3-cephem - 4-carboxylic (syn isomer), m.p. 147 to 151 [deg.] C (decomposition).

  
Specter I.R. (Nujol)

  
3500, 3250, 2500 = 2600, 1780, 1730, 1660, 1630,

  
1600 cm -1

  
R.M.N. (d, -DMSO, 5)

  

  <EMI ID = 468.1>


  
  <EMI ID = 469.1>

  
mother syn).

  

  <EMI ID = 470.1>
 

  

  <EMI ID = 471.1>


  
  <EMI ID = 472.1>

  
(syn isomer).

  
Specter I.R. (Nujol)

  
  <EMI ID = 473.1>

  
R.M.N. (d, -DMSO, 5)

  

  <EMI ID = 474.1>


  
  <EMI ID = 475.1>

  
dol-3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic (syn isomer).

  
Specter I.R. (Nujol)

  

  <EMI ID = 476.1>


  
  <EMI ID = 477.1> <EMI ID = 478.1>

  
R.M.N. (d &#65533; -DMSO, 5)

  

  <EMI ID = 479.1>


  
  <EMI ID = 480.1>

  
(syn isomer).

  
Specter I.R. (Nujol)

  
  <EMI ID = 481.1>

  
R.M.N. (d6-DMSO, 5)

  

  <EMI ID = 482.1>


  
  <EMI ID = 483.1>

  
carboxylic (syn isomer), m.p. 145 to 148 [deg.] C (decomposition).

  
Specter I.R. (Nujol)

  
3500, 3250, 2500-2600, 1780, 1720,

  
  <EMI ID = 484.1>
  <EMI ID = 485.1>
 
  <EMI ID = 486.1>
(26) 7- [2-Methoxyimino-2- (3-chloro-4-methoxyphé) acid

  
  <EMI ID = 487.1>

  
carboxylic (syn isomer) m.p. 143 to 145 [deg.] C (decomposition).

  

  <EMI ID = 488.1>


  
(27) 7- [2-methoxyimino-2- (3-nitro-4-hydroxyphenyl) acid

  
  <EMI ID = 489.1>

  
xylic (syn isomer), m.p. 149 to 152 [deg.] C (decomposition).

  
Specter I.R. (Nujol)

  
3400 - 3450, 3200, 2500 - 2600, 1780,.

  
  <EMI ID = 490.1>

  
  <EMI ID = 491.1>

  

  <EMI ID = 492.1>
 

  

  <EMI ID = 493.1>


  
  <EMI ID = 494.1>

  
lic (syn isomer), m.p. 163 to 165 [deg.] C (decomposition).

  

  <EMI ID = 495.1>


  
(29) 7- [2-allyloxyimino-2- (3-hydroxyphenyl) aceta-

  
  <EMI ID = 496.1>

  
that (syn isomer), m.p. 149 to 152 [deg.] C (decomposition).

  

  <EMI ID = 497.1>


  
  <EMI ID = 498.1> <EMI ID = 499.1>

  
cephem-4-carboxylic (syn isomer), powder.

  

  <EMI ID = 500.1>


  
  <EMI ID = 501.1>

  
carboxylic (syn isomer), powder.

  

  <EMI ID = 502.1>


  
  <EMI ID = 503.1>

  
lic (syn isomer), colorless powder, m.p. 153 to 156 [deg.] C (decomposition).

  
Specter I.R. (Nujol)
  <EMI ID = 504.1>
 
  <EMI ID = 505.1>
(33) 7- [2-allyloxyimino-2- (3-methoxyphenyl) aceta- acid

  
  <EMI ID = 506.1>

  
as (syn isomer), powder, m.p. 135 to 138 [deg.] C (decomposition).

  

  <EMI ID = 507.1>


  
(34) 7- [2-ethoxyimino-2- (3-hydroxyphenyl) acetaminic acid

  
  <EMI ID = 508.1>

  
(syn isomer), yellow powder, m.p. 145 to 148 [deg.] C (decomposition).

  

  <EMI ID = 509.1>
 

  
  <EMI ID = 510.1>

  
(syn isomer), pale yellow powder, m.p. 140 to 143 [deg.] C (decomposition).

  

  <EMI ID = 511.1>


  
  <EMI ID = 512.1>

  
xylic (syn isomer), pale yellow powder, m.p. 153 to 156 [deg.] C (decomposition).

  

  <EMI ID = 513.1>


  
  <EMI ID = 514.1> <EMI ID = 515.1>

  
4-carboxylic (syn isomer).

  

  <EMI ID = 516.1>


  
  <EMI ID = 517.1>

  
(syn isomer), m.p. 155 [deg.] C (decomposition).

  

  <EMI ID = 518.1>


  
(39) 7- [2-methoxyimino-2- (3-carbamoyloxyphenyl) acid

  
  <EMI ID = 519.1>

  
xylic (syn isomer).

  

  <EMI ID = 520.1>
 

  

  <EMI ID = 521.1>


  
  <EMI ID = 522.1>

  
(syn isomer).

  

  <EMI ID = 523.1>


  
  <EMI ID = 524.1>

  
(syn isomer).

  

  <EMI ID = 525.1>


  
  <EMI ID = 526.1>

  
carboxylic (syn isomer), m.p. 138 to 142 [deg.] C (decomposition).

  

  <EMI ID = 527.1>
 

  

  <EMI ID = 528.1>


  
(43) 7- [2-methoxyimino-2- (4-dimethylaminophenyl) acE acid

  
  <EMI ID = 529.1>

  
that (syn isomer), m.p. 88 [deg.] C (decomposition).

  

  <EMI ID = 530.1>


  
(44) 7- [2-methoxyimino-2- (3-hydroxyphenyl) acetaminic acid

  
  <EMI ID = 531.1>

  
4-carboxylic, (syn isomer).

  
Specter I.R. (Nujol)

  
  <EMI ID = 532.1>

  
  <EMI ID = 533.1>

  
ppm 9.67 (1H, d, J = 9Hz)
  <EMI ID = 534.1>
 
  <EMI ID = 535.1>
  <EMI ID = 536.1>

  
cephem-4-carboxylic (syn isomer).

  

  <EMI ID = 537.1>


  
q ..

  
EXAMPLE 27

  
  <EMI ID = 538.1>

  
thiazol-4-yl) acetamido] -3-hydroxymethyl-3-cephem-4-carboxylic
(syn isomer) (0.3 g) in a mixture of acetone (3 ml) and water (1.5 ml) was adjusted to pH 2 with 6N hydrochloric acid and stirred for 4 hours at room temperature. After that acetone

  
was removed by distillation, to the residue was added water

  
(1 ml). The mixture was adjusted to pH 7 with a saturated aqueous solution of sodium bicarbonate and cooled with ice for 1 hour. The precipitated crystals were collected by filtration.

  
  <EMI ID = 539.1>

  
m.p. 210 to 215 [deg.] C (decomposition),
  <EMI ID = 540.1>
 
  <EMI ID = 541.1>
 EXAMPLE 28

  
The following compound was obtained by a similar process

  
  <EMI ID = 542.1>

  

  <EMI ID = 543.1>


  
EXAMPLE 29

  
  <EMI ID = 544.1>

  
xyl (syn isomer) (1.0g) was dissolved in a mixture of dimethylformamide (6ml) and acetone (30ml). Jones's reagent (1.25 ml), which was prepared from concentrated sulfuric acid (0.28 ml), chromium trioxide (0.33 g) and water (0.9 ml) , was added dropwise over 2 minutes with stirring and cooling to 0-2 [deg.] C. After stirring for 20 minutes at the same temperature, the reaction mixture was poured into ice and water.
(50 ml). After the acetone was removed by distillation, the residue was extracted twice with ethyl acetate (50ml). The extracts were washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was removed by distillation and the residue was sprayed with ether.

  
  <EMI ID = 545.1>

  

  <EMI ID = 546.1>

EXAMPLE 30

  
The following compounds were obtained by carrying out the reaction to remove the protecting group of the amino radical

  
on the carbamoyl group, in a manner similar to that of Example 3.

  
  <EMI ID = 547.1>

  
syn), m.p. 210 to 220 [deg.] C (decomposition).

  

  <EMI ID = 548.1>


  
the

  
  <EMI ID = 549.1>

  
re syn).

  

  <EMI ID = 550.1>
 

  

  <EMI ID = 551.1>

REFERENCE EXAMPLE 1

  
Phosphorus pentachloride (3.3 g) was added, while cooling with ice, to a suspension of 2-methoxyimino- acid.

  
  <EMI ID = 552.1>

  
Methylene chloride (30 ml) and the mixture was stirred for 30 minutes at room temperature. Methylene chloride was removed by distillation under reduced pressure and acetone was added to the residue to give a suspension. On the other hand, a suspension of acid 7-

  
  <EMI ID = 553.1>

  
(2.2 g) in aqueous sodium bicarbonate solution (0.76 g in 50 ml of water) was stirred for 10 minutes, and acetone

  
(50 ml) was added thereto to give a solution. In the solution, the suspension obtained above containing the acid chloride was added dropwise, with stirring and cooling with ice, and maintaining the solution at a pH of 7.5 to 8.5 with a 20% aqueous solution of sodium carbonate. The mixture was stirred for 1 hour at 3-5 [deg.] C and pH 8.0. Acetone was removed by distillation under reduced pressure and the residue was adjusted to

  
pH 7.4 with saturated aqueous sodium bicarbonate solution and further adjusted to pH 4.5 with hydrochloric acid

  
at 10%, with stirring and ice cooling. The precipitates were separated by filtration and the filtrate was saturated with sodium chloride, adjusted to pH 2.5 with 10% hydrochloric acid and stirred for 1 hour. The precipitates were collected by filtration, washed with water and dried to give 7- [2- acid.

  
  <EMI ID = 554.1>

  
syn and anti) (0.95 g).

  

  <EMI ID = 555.1>
 

  

  <EMI ID = 556.1>


  
REFERENCE EXAMPLE 2

  
A suspension of phosphorus pentachloride (1.7 g)

  
in methylene chloride (20 ml) was brought to solution by stirring for 2 hours at room temperature. Aci-

  
  <EMI ID = 557.1>

  
(0.8 g) was added thereto all at once at room temperature, and the mixture was stirred. Methylene chloride was removed by distillation under reduced pressure and the residue was dissolved in acetone (20ml). On the other hand, 7-amino-3-carbamoyloxymé acid

  
  <EMI ID = 558.1>

  
solution of sodium bicarbonate (0.59 g) in water (20 ml) and dissolve by adding acetone (10 ml). To this solution, the solution obtained above containing the acid chloride was added dropwise, with stirring and cooling with ice, and maintaining the solution at a pH of 7.5 to 8.5 with a 20% aqueous solution of sodium carbonate. After stirring for 1 hour at

  
pH 8 on cooling with ice, insoluble material was removed by filtration. Acetone was removed by distillation under reduced pressure from the filtrate and insoluble material was removed by filtration. The filtrate was adjusted to pH 2.5 with 10% hydrochloric acid. The precipitates were collected by

  
  <EMI ID = 559.1>

  
carboxylic (mixture of syn and anti isomers) (0.4 g). The filtrate

  
was saturated with sodium chloride and stirred while cooling with ice, to give precipitates. The precipitates were filtered off and dried to give the same desired compounds (0.3 g). Total yield: 0.7 g.

  

  <EMI ID = 560.1>


  
REFERENCE EXAMPLE 3

  
A mixture of dimethylformamide (0.22 g) and phosphorus oxychloride (0.46 g) was heated for 1 hour at 40 [deg.] C. The mixture was dissolved in dry methylene chloride (20 mL) and 2-methoxyimino-2- (2-mesylimino-3-methyl- acid was added thereto.

  
  <EMI ID = 561.1>

  
stirring and cooling with ice, after which the resulting mixture was stirred for 1 1/2 hours while cooling with water.

  
  <EMI ID = 562.1>

  
of dry methylene (20 ml). To this solution, the methylene chloride solution obtained above was added at -30 [deg.] C, after which the mixture was stirred for 2 hours at -5 to -20 [deg.] C. After removing the methylene chloride by low temperature distillation, water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and water (50ml) was added thereto. The mixture

  
  <EMI ID = 563.1>

  
sodium bonate and the aqueous layer was separated. The aqueous layer

  
was adjusted to pH 1.5, saturated with sodium chloride. and extracted with ethyl acetate. The extract was washed with aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed by distillation and the residue was sprayed with a mixture of diisopropyl ester and ether. The powder has

  
  <EMI ID = 564.1>

  
(anti isomer) (1.0 g). This powder (1.0 g) was suspended in water (30 ml) and dissolved by adjusting to a pH of 6 with an aqueous solution of sodium bicarbonate. After removing the solvent by bubbling nitrogen gas through, the aqueous solution was lyophilized.

  
  <EMI ID = 565.1>

  
Sodium thiomethyl-3-cephem-4-carboxylate (anti isomer) (0.98 g).

  

  <EMI ID = 566.1>

REFERENCE EXAMPLE 4

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

  
  <EMI ID = 567.1>

  
4-carboxylic (anti isomer)
  <EMI ID = 568.1>
 
  <EMI ID = 569.1>
  <EMI ID = 570.1>

  
carboxylic (anti isomer).

  

  <EMI ID = 571.1>


  
  <EMI ID = 572.1>

  
acetamido] -cephalosporanic (anti isomer)

  

  <EMI ID = 573.1>


  
  <EMI ID = 574.1>
  <EMI ID = 575.1>
  <EMI ID = 576.1>

  
anti mother).

  

  <EMI ID = 577.1>


  
q

  
Preparation of the starting compounds to be used for the examples and

  
the reference examples mentioned above.

  
Preparation 1

  
A mixture of 3-chloro-4-hydroxyacetophenone (11.9 g),

  
benzyl chloride (9.35 g), potassium carbonate (14.5 g)

  
and dimethylformamide (60 mL) was stirred for 1 hour at 100 [deg.] C. The reaction mixture was poured into water (150 ml) and extracted.

  
with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over magnesium sulfate. After removing the solvent by distillation, the residue (18 g) was recrystallized from ethanol (160 ml) to give 3-chloro-4-benzyloxy-

  
  <EMI ID = 578.1>

  
Preparation 2

  
1) Selenium dioxide powder (12.6g) was added over 10 minutes to a solution of 3-chloro-4-benzyloxyacetophenone (19.7g) in dry pyridine (100ml) with stirring

  
at 100 [deg.] C, and the mixture was stirred for 3 hours at the same temperature. Precipitated selenium was removed by filtration and the filtrate was concentrated. The residue was dissolved in water (150 ml)

  
and the solution was washed with ether. The aqueous solution was acidified while cooling with concentrated hydrochloric acid and extracted with ether. The extract was washed with an aqueous solution

  
of sodium chloride, dried over magnesium sulfate and concentrated to give 2- (3-chloro-4-benzyloxyphenyl) glyoxylic acid (15.9 g) m.p. 134 to 135 [deg.] C.

  
  <EMI ID = 579.1>

  
m.p. 81 to 82 [deg.] C. -

  
Specter I.R. (Nujol)

  
  <EMI ID = 580.1>

  
66 to 68 [deg.] C.

  
Specter I.R. (Nujol)

  
  <EMI ID = 581.1>

  
Preparation 3

  
1) A mixture of 2- (3-nitro-4-benzyloxyphenyl) glyoxylic acid (30 g), concentrated hydrochloric acid (90 ml) and acetic acid (120 ml) was stirred for 3 hours at 100 [deg.] C. To the reaction mixture were added, with cooling, water and ice.
(600 mL) and the mixture was extracted with ethyl acetate. The extract was washed with ice and water, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was recrystallized from a mixture of benzene: ether: petroleum ether
(2: 1: 4). The crystals were collected by filtration, washed with benzene and dried under reduced pressure to give acid.

  
  <EMI ID = 582.1>

  
2) The following compound was obtained in a similar manner

  
to that of preparation 3-1).

  
  <EMI ID = 583.1>

  
m.p. 114 to 116 [deg.] C.

  
Preparation 4

  
2- (3-hydroxyphenyl) glyoxylic acid (3.32 g) and a

  
  <EMI ID = 584.1>

  
reflux with stirring for 25 minutes. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in a solution.

  
  <EMI ID = 585.1>

  
ether, acidified with dilute hydrochloric acid and then extracted with ethyl acetate. The extract was washed, dried and treated with activated charcoal. The solvent was removed by distillation to give

  
  <EMI ID = 586.1>

  
syn and anti) (2.9 g).

  
Specter I.R. (Nujol)

  
  <EMI ID = 587.1>

  
Preparation 5

  
1) (a) An indicator formed from phenolphthalein (3 drops) was added to a solution of O-methylhydroxylamine hydrochloride
(5.5g) in dry methanol (60ml). To the solution was added dropwise, with stirring at room temperature, a solution.

  
  <EMI ID = 588.1>

  
the color of the solution changes to violet red. Omethylhydroxylamine hydrochloride was added to it in small portions until the solution turned to a colorless solution. The mixture was stirred for 30 minutes at room temperature. After precipitation, sodium chloride was filtered off, 2- (3-hydroxyphenyl) glyoxylic acid (9.85g) was added to the filtrate, and the mixture was heated under reflux for 30 minutes. After the methanol was removed by low temperature distillation, a saturated aqueous solution of sodium chloride was added to the residue. The mixture was adjusted to pH 1 with 10% hydrochloric acid and extracted with ether (300 mL). The extract was dried over magnesium sulfate. The ether was removed by low temperature distillation to give

  
  <EMI ID = 589.1>

  
syn and anti mothers).

  
(b) This material was dissolved in ether (60 µl), and a solution of diazomethane in ether was gradually added thereto.

  
  <EMI ID = 590.1> ge turns yellow. Acetic acid was immediately added thereto, and the mixture was washed with an aqueous solution of sodium bicarbonate and an aqueous solution saturated with sodium chloride, and dried over magnesium sulfate. The ether was removed by distillation to give an oily residue (10.8 g). The oily residue was subjected to column chromatography on silica gel (165 g &#65533; using a mixture of benzene and ethyl acetate (9: 1) as the developing solvent. the eluate containing the syn isomer was eluted and the eluate was pooled and concentrated to give oily methyl 2-methoxyimino-2- (3-hydroxyphenyl) acetate (syn isomer) (7.9 g). allowed the oil to stand to give crystals, mp 39.5 to 40.5 [deg.] C.

  

  <EMI ID = 591.1>


  
After the eluate containing the syn isomer was eluted, the eluate containing the anti isomer was eluted. The eluate was combined and concentrated to give methyl 2-methoxyimino-2- (3-hydroxyphenyl) acetate (anti-isomer) (1.5 g). This material was recrystallized from a mixture of benzene and petroleum ether to give crystals, m.p. 96 to 98 [deg.] C.

  

  <EMI ID = 592.1>


  
(c) A 2N aqueous sodium hydroxide solution (40 ml) was added, with stirring at room temperature, to a suspension of methyl 2-methoxyimino-2 - (3-hydroxyphenyl) acetate (syn isomer) (7.55 g) in water (70 ml) and the mixture was stirred for 1 hour at room temperature. The reaction mixture was adjusted to a pH of 6.5 with 10% hydrochloric acid, subjected to salting out and washed with ether (60 ml). The aqueous layer was adjusted to pH 1 with <EMI ID = 593.1>

  
of ether and twice with 60 ml of ether. The extract was washed twice with saturated aqueous sodium chloride solution (60 mL) and dried over magnesium sulfate. The ether was removed by distillation to give an oil. Benzene was added and removed
(2 times) to give crystals of 2-methoxyimino-2- (3-hydroxyphenyl) acetic acid (syn isomer) (6.44 g) m.p. 98 to 101 [deg.] C (decomposition).

  

  <EMI ID = 594.1>


  
A 2N aqueous sodium hydroxide solution (8 ml) was added, with stirring at room temperature, to a solution of 2methoxyimino-2- (3-hydroxyphenyl) methyl acetate (anti-isomer).
(1.56g) in methanol (30ml). After stirring for 3 hours

  
at the same temperature, methanol was removed by distillation. To the residue, water was added and the mixture was washed with ether. The aqueous layer was adjusted to pH 1 with hydrochloric acid.

  
  <EMI ID = 595.1>

  
as (anti isomer) (1.07 g). The crystals were recrystallized from a mixture of petroleum ether and ether to give crystals.
(0.7 g), m.p. 99 to 10l [deg.] C (decomposition).

  

  <EMI ID = 596.1>


  
  <EMI ID = 597.1>

  
(3.7g) in dry methanol (45ml). Into the solution was added dropwise, with stirring at room temperature, a solution.

  
  <EMI ID = 598.1>

  
color of the solution changes to violet red. Omethylhydroxylamine hydrochloride was added to it in small portions until the solution turned to a colorless solution. The mixture was

  
  <EMI ID = 599.1>

  
The sodium chloride was removed by filtration, 2- (4-hydroxyphenyl) glyoxylic acid (6.56g) was added to the filtrate and the mixture was stirred for 1 hour at room temperature.

  
After the methanol was removed by low temperature distillation, a saturated aqueous solution of sodium chloride was added to the residue. The mixture was adjusted to a pH of 1 with 10% hydrochloric acid, subjected to salting out and extracted with ether. The extract was dried over magnesium sulfate. The ether was removed by low temperature distillation to give 2-methoxyimino-2- (4-hydroxyphenyl) acetic acid (syn isomer).

  
b) This material was dissolved in ether (50 ml) and a solution of diazomethane in ether was gradually added to it while cooling with ice, until the color of the mixture turned yellow. . Acetic acid was immediately added and the mixture was washed with aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The ether was removed by distillation to give an oily residue (8 g).

   The oily residue was subjected to column chromatography on silica gel, using a mixture of benzene and ethyl acetate (9: 1) as a developing solvent, to give 2-methoxyimino-2- ( Methyl 4-hydroxyphenyl) acetate (syn isomer) (6.39 g).
  <EMI ID = 600.1>
(c) A 2N aqueous sodium hydroxide solution (11 ml) was added, with stirring at room temperature, to a solution of 2-me- <EMI ID = 601.1>

  
(2.1g) in methanol (30ml), and the mixture was stirred for
18 hours at room temperature. The reaction mixture was

  
  <EMI ID = 602.1>

  
nol has been removed. To the residue was added water and the mixture

  
was washed with ether. The aqueous layer was adjusted to a pH of 1

  
with 10% hydrochloric acid, subjected to salting-out and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The ethyl acetate was removed by distillation to provide crystals. <EMI ID = 603.1>

  
(1.5 g).

  

  <EMI ID = 604.1>


  
3) (a) An indicator formed from phenolphthalein (2 drops).

  
  <EMI ID = 605.1>

  
(2.74g) in dry methanol (30ml). To the solution was added dropwise while stirring at room temperature, a solution.

  
  <EMI ID = 606.1>

  
of the solution turns violet red. O-methylhydroxylamine hydrochloride was added to it in small portions until the solution turned to a colorless solution. The mixture was stirred for one hour at room temperature. After precipitation, sodium chloride

  
was removed by filtration, 2- (3-nitro-4-hydroxyphenyl) glyc xylic acid (6.75 g) was added to the filtrate, and the mixture was stirred for 1 hour at room temperature. After the methanol was removed by distillation at 35 [deg.] C, a saturated aqueous solution of sodium chloride was added to the residue. The mixture was set at a

  
pH of 1 with 10% hydrochloric acid and extract with ether. The extract was dried over magnesium sulfate. The ether was removed by distillation at 35 [deg.] C under reduced pressure to give yellow crystals of 2-methoxyimino-2- (3-nitro-4-hydroxyphenyl) acetic acid (mixture of syn isomers and anti) (7 g).

  
(b) This material was dissolved in a mixture of tetrahydrofuran (15ml) and ether (100ml), and a solution of diazomethane in ether was added thereto little by little at room temperature until that the color of the mixture changes to yellow. Acetic acid was immediately added thereto and the mixture was concentrated to dryness at 35 [deg.] C under reduced pressure. The residue was dissolved in a. mixed solvent consisting of ethyl acetate and benzene (1: 9) ,. and subjected to column chromatography on silica gel,

  
using the same mixed solvent as developing solvent. The eluate containing the syn isomer was pooled and concentrated to give.

  
  <EMI ID = 607.1>

  
  <EMI ID = 608.1>

  

  <EMI ID = 609.1>
 

  

  <EMI ID = 610.1>


  
(c) 2N aqueous sodium hydroxide solution (14 ml) was added, with stirring at room temperature,! a solution of methyl 2methoxyimino-2 (3-nitro-4-hydroxyphenyl) acetate (syn isomer) (3.5 g) in ethanol (70 ml), and the mixture was stirred for 60 hours at room temperature. The reaction mixture was concentrated to dryness at 40 [deg.] C under reduced pressure and the residue was dissolved in water. The solution was washed with ethyl acetate, adjusted to pH 1 with 10% hydrochloric acid while cooling with ice, and extracted with ethyl acetate. The extract was back extracted with a saturated aqueous solution of sodium bicarbonate.

   The aqueous extract was adjusted to pH 1 with conc. Hydrochloric acid, cooling with ice, and extracted with ethyl acetate. The extract was washed with ice and water. water and dried over magnesium sulfate. The solvent was concentrated to dryness at 40 [deg.] C under reduced pressure to give crystals.

  
  <EMI ID = 611.1>

  
re syn) (3.2 g), m.p. 142 to 143 [deg.] C (decomposition).

  

  <EMI ID = 612.1>


  
4) (a) 2- (3-chloro-4-hydroxyphenyl) glyoxylic acid

  
  <EMI ID = 613.1>

  
reacted in a similar manner to Preparation 5-3) (a) to give an oil of 2-methoxyimino - 2- (3-chloro-4hydroxyphenyl) acetic acid (mixture of syn and anti isomers ) (7 g).

  
  <EMI ID = 614.1> phenyl) acetic (mixture of syn and anti isomers) (7 g) and diazo-methane (1.5 g) were reacted .. and the product was purified by column chromatography , in a manner similar to that of the

  
  <EMI ID = 615.1>

  

  <EMI ID = 616.1>


  
(c) Methyl 2-methoxyimino-2- (3-chloro-4-hydroxyphenyl) acetate (isomer.syn) (2.6 g) and 2N aqueous sodium hydroxide solution (10.6 ml) were treated with 'in a similar manner to Preparation 5-3) (c) to give 2-methoxyimino-2- (3-chloro- <EMI ID = 617.1>

  
(decomposition) .

  

  <EMI ID = 618.1>


  
(5) 2- (3-Hydroxyphenyl) glyoxylic acid (2.0g) and O-allylhydroxylamine hydrochloride (1.7g) were reacted in a similar manner to the preparation 5-2) (a) to give an oil of 2-allyloxyimino-2- (3-hydroxyphenyl) acetic acid
(syn isomer) (2.7 g).

  

  <EMI ID = 619.1>


  
(6) 2- (3-chloro-4-hydroxyphenyl) glyoxylic acid

  
(2 g) and O-allylhydroxylamine hydrochloride (1.1 g) were

  
reacted in a manner similar to that of Preparation 5-2) (a) to give an oil of 2-allyloxyimino-2- (3-chloro-4-hydroxyphë-
  <EMI ID = 620.1>
  <EMI ID = 621.1>

  
lique (2.0 g, O-t-butoxycarbonylmethylhydroxylamine (1.62 g) and methanol (20 ml) was adjusted to pH 5-6 by adding a

  
  <EMI ID = 622.1>

  
hours at room temperature. The reaction mixture was concentrated to dryness under reduced pressure and the residue was dissolved in

  
  <EMI ID = 623.1>

  
The aqueous solution was washed with ether, adjusted to pH 2.0 with 10% hydrochloric acid while cooling with ice and extracted with ether. The extract was washed with water and dried over magnesium tallow. The solution was concentrated to dryness under reduced pressure.

  
  <EMI ID = 624.1>

  
no-2- (3-chloro-4-hydroxyphenyl) acetic (syn isomer) (2.6 g), m.p.
116 to 118 [deg.] C (decomposition).

  

  <EMI ID = 625.1>


  
8) (a) Potassium carbonate (49.7g) and dimethyl sulfate. (45.4g) were added to a solution of 2hydroxyimino-2 - &#65533; 3-hydroxyphenyl) acetic acid ( mixture of syn and anti isomers (18.1 g) in dry acetone (250 ml), and the mixture has <EMI ID = 626.1>

  
After the acetone was removed by distillation, the residue had

  
was dissolved in water and extracted with ethyl acetate. The extract

  
was washed with aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed by distillation to give an oil (24 g). The oil was subjected to chromatography

  
  <EMI ID = 627.1>

  
vant of development. First, the eluate containing the syn isomer was eluted and the eluate was pooled and concentrated to give an oil of methyl 2-methoxyimino-2- (3-methoxyphenyl) acetate (syn isomer)
(9.2 g).

  

  <EMI ID = 628.1>


  
After the eluate containing the syn isomer was eluted, the eluate containing the anti isomer was eluted. The eluate was combined and concentrated to give methyl 2-methoxyimino-2- (3-methoxyphenyl) acetate (anti isomer) (3.9 g), m.p. 66 to 68 [deg.] C. This material was recrystallized from petroleum ether to give prisms, m.p. 65 to 65.5 [deg.] C.

  

  <EMI ID = 629.1>


  
  <EMI ID = 630.1> methyl (syn isomer) (1.6 g) and 2N aqueous sodium hydroxide solution

  
(4ml) was treated in a similar manner to Preparation 5-3) (c) to give 2-methoxyimino-2- (3methoxyphenyl) acetic acid (syn isomer) oil (1.23 g ).

  

  <EMI ID = 631.1>
 

  
  <EMI ID = 632.1>

  
(anti isomer) (1.6g) and 2N aqueous sodium hydroxide solution (4ml) were treated in a similar manner to preparation 5-3) (c) to give colorless prisms of acid 2 -methoxyimino2- (3-methoxyphenyl) acetic (anti isomer) (1.3 g), mp 97 to 98 [deg.] C.

  

  <EMI ID = 633.1>


  
9) (a) A solution of diazomethane in ether was

  
  <EMI ID = 634.1>

  
2- (3-Chloro-4-hydroxyphenyl) acetic (syn isomer) (7 g) in dry ether (50 ml), until the color of the mixture turns yellow. Acetic acid was immediately added and the reaction mixture was concentrated to dryness at 35 [deg.] C under reduced pressure. The residue

  
was subjected to column chromatography on silica gel
(120 g), using a mixture of benzene and ethyl acetate

  
(9: 1) as a developing solvent. The first eluate was gathered

  
  <EMI ID = 635.1>

  
re syn) (3.1 g).

  

  <EMI ID = 636.1>


  
  <EMI ID = 637.1> methyl (syn isomer) (2.7 g) and 2N aqueous sodium hydroxide solution (10.6 ml) were treated in a similar manner to that of

  
  <EMI ID = 638.1>

  
135 [deg.] C (decomposition).

  

  <EMI ID = 639.1>
 

  

  <EMI ID = 640.1>


  
10 (a) A solution of 2-bromopropionyl bromide (25

  
g) in dry chloroform (50 ml) was added dropwise with stirring and ice-cooling to a solution of N, N-dimethylaniline (24 g) in t-butanol (11 g), and the mixture was heated at reflux for 2 hours. After cooling, the reaction mixture was poured into 6N sulfuric acid (150 mL) and extracted with ether. For its part, the extract was washed with 6N sulfuric acid, water, a 10% aqueous solution of potassium carbonate and water and dried over magnesium sulfate. The solvent was removed by distillation to give a butyl 2-bromopropionate oil (21 g).

  
(b) This oil (21 g) was added, with stirring at room temperature, a mixture of N-hydroxyphthalimide (16.3 g), <EMI ID = 641.1>

  
foxide (20 ml), and the resulting mixture was stirred for 4 hours at

  
Room temperature. The reaction mixture was poured into water (800 ml) and the precipitated materials were collected by filtration, washed with water and dried to give t-butyl 2-phthalimidoxypropionate (22.7 g).

  
(c) This compound (22.7g) was dissolved in methylene chloride (200ml). A 10% hydrazine hydrate solution (9

  
ml) in methanol (20 ml) was added thereto and the mixture was stirred for 2 hours at room temperature. The precipitated materials were dissolved by adding 5N ammonia solution and the aqueous layer was extracted with methylene chloride. Two layers of methylene chloride were combined and dried over magnesium sulfate. The solvent was removed by distillation under reduced pressure.

  
  <EMI ID = 642.1>

  
g).

  

  <EMI ID = 643.1>


  
  <EMI ID = 644.1> <EMI ID = 645.1> 5-7), to give 2- (1-t-butoxycarbonylethoxyimino) -2- acid

  
  <EMI ID = 646.1>

  
at 151 [deg.] C.

  

  <EMI ID = 647.1>


  
11) An indicator formed from phenolphthalein (3 drops) was added to a solution of O-methylhydroxylamine hydrochloride (8.8 g) in dry methanol (60 ml). To the solution was added dropwise, with stirring at room temperature,

  
  <EMI ID = 648.1>

  
parts until the solution turns to a colorless solution.

  
The pH value of the solution was 8.0-8.5. The mixture was stirred for 30 minutes at room temperature. After precipitation, sodium chloride was filtered off, 2- (3-hydroxyphenyl) glyoxylic acid (16.6g) was added to the filtrate, and the mixture was stirred for 1 hour at room temperature. After the methanol was removed by low temperature distillation, water was added to the residue. The mixture was adjusted to a pH of 7 with an aqueous solution of sodium bicarbonate, washed with ether, adjusted to a pH of 1 with 10% hydrochloric acid, subjected to salting out and extracted with ether. . The extract was washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate.

   The ether was removed by distillation, and the operation in which benzene was added to the residue and removed by distillation was repeated twice to give crystals of 2-methoxyimino-2- (3-hydroxyphenyl) acetic acid. (syn isomer) (14.8-g), This compound was identified as being identical to the compound obtained in preparation 5-1 (c) by IR spectrum

  
12) A solution of 2- (3-methoxyphenyl) glyoxylic acid
(1.8 g) in aqueous sodium bicarbonate solution was adjusted to pH 7.0, On the other hand, hydrochloride solution

  
  <EMI ID = 649.1>

  
at 10% and stirred overnight at room temperature. The melar. The reaction was adjusted to pH 7.5 with sodium bicarbonate and washed with ethyl acetate. The aqueous layer was adjusted to pH 1.0 with conc. Hydrochloric acid while cooling with ice and extracted with ethyl acetate. The extract was washed with water and ice and dried over sulfate.

  
magnesium. The solvent was removed by distillation under reduced pressure to give 2-ethoxyimino-2- (3-methoxyphenyl) acetic acid (syn isomer) oil (2.2 g).

  
Specter I.R. (Film)

  
  <EMI ID = 650.1>

  
13) The following compounds were obtained in a similar manner to that of Preparations 5-5) to 5-7) and 5-10) to 5-12).

  
(1) 2-ethoxyimino-2- (3-chloro-4-hydroxyphenyl) acid

  
  <EMI ID = 651.1>

  

  <EMI ID = 652.1>


  
(2) 2-ethoxyimino-2- (3-hydroxyphenyl) acetic acid
(syn isomer) oil

  

  <EMI ID = 653.1>


  
(3) 2- (3-hydroxy-4-bromobenzyloxyimino) -2- (4- acid

  
  <EMI ID = 654.1>

  

  <EMI ID = 655.1>


  
  <EMI ID = 656.1>

  
acetic (syn isomer), powder,
  <EMI ID = 657.1>
   <EMI ID = 658.1>

  
(syn isomer), oil

  

  <EMI ID = 659.1>


  
  <EMI ID = 660.1>

  
acetic (syn isomer), pale yellow oil.

  

  <EMI ID = 661.1>


  
(7) 2-Phenylthiomethoxyimino- (2- (3-hydroxyphenyl) acetic acid (syn isomer), oil.

  

  <EMI ID = 662.1>


  
(8) 2-Methoxyimino-2- (3-mesylaminophenyl) acetic acid (syn isomer), m.p. 128 [deg.] C (decomposition).

  

  <EMI ID = 663.1>


  
(9) 2- (3-Phenylallyloxyimino) -2- (3-hydroxyphenyl) acetic acid (syn isomer), m.p. 115 to 116 [deg.] C

  

  <EMI ID = 664.1>


  
  <EMI ID = 665.1>
  <EMI ID = 666.1>
 tation and cooling with ice, with an acid solution

  
  <EMI ID = 667.1>

  
in pyridine (20 mL), and the mixture was stirred for 50 minutes at room temperature. The reaction mixture was poured into ice and water, adjusted to pH 2.1 and extracted three times with ether. The extract was washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was completely removed under reduced pressure to give

  
2-methoxyimino-2- (3-acetoxyphenyl) acetic acid (syn isomer)
(6.1 g).

  

  <EMI ID = 668.1>


  
15) Trichloroacetyl isocyanate (70 mL) was added dropwise over 6 minutes at room temperature,

  
  <EMI ID = 669.1>

  
(syn isomer) (40g) in dry dioxane (200ml), and the resulting mixture was stirred for 5 hours at room temperature.

  
Dioxane was removed by distillation and to the residue was added ethyl acetate (200 mL) and, in small portions,

  
water (-200 ml) while cooling with ice. The mixture containing trichloroacetylcarbamoyl 2-methoxyimino-2- (3-trichloroacetylcarbamoyloxyphenyl) acetate was stirred for 5 hours at room temperature, maintaining the pH value of the mixture at 6.0-6.4 in adding an aqueous solution of sodium bicarbonate. The resulting mixture was washed twice with ethyl acetate. The aqueous layer was adjusted to pH 2 with 10% hydrochloric acid and extracted three times with ethyl acetate. The combined ethyl acetate extracts were washed twice with aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed by distillation and the precipitated crystals were collected by filtration to give crystals.

  
  <EMI ID = 670.1>

  
mother syn) (15 g), m.p. 163 [deg.] C (decomposition). The same compound (5.4 g) was obtained from the mother liquor.

  

  <EMI ID = 671.1>


  
Preparation 6

  
1) A solution of sodium nitrite (12.4 g) in water
(150 ml) was added dropwise, with stirring at 5-7 [deg.] C, 5 "a solution of ethyl 4-bromoacetoacetate (30 g), in acetic acid (200 ml), and the mixture was stirred for 2 hours at 10 [deg.] C. Water (200ml) was added to the reaction mixture and the resulting mixture was extracted with ether (500ml). was washed twice with water (200ml) and with aqueous sodium chloride solution (200ml), and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give crystals Yellowish chestnuts of ethyl 2-hydrpxyimino-4-bromoacetoacetate (mixture of syn and anti isomers) (32.6 g).

  

  <EMI ID = 672.1>


  
2) Powdered potassium carbonate (160 g) was added to --- a solution of ethyl 2-hydroxyiminoacetoacetate (mixture of syn and anti isomers) (152 g) in acetone (500 ml). Dimethyl sulfate (130 g) was added thereto dropwise with stirring, over 1 hour at 45-50 [deg.] C, and the mixture was stirred for 2 hours. Insoluble material was removed by filtration and the filtrate was concentrated under reduced pressure. The insoluble filtered material was dissolved in water (500ml) and this solution was added to the residue. The mixture was extracted twice with ethyl acetate (300ml).

  
  <EMI ID = 673.1>

  
saturated aqueous sodium chloride solution (200 ml), and dried over magnesium sulfate. The solvent was removed by distillation under reduced pressure and the residue was distilled off under reduced pressure to give a colorless ethyl 2-methoxyiminoacetoacetate oil (mixture of syn and anti isomers) (145.3 g), m.p. 55 to 64 [deg.] C / 0.5 mm Hg.

  

  <EMI ID = 674.1>


  
40 minutes at reflux, in a solution of ethyl 2-methoxyiminoacetoacetate (mixture of syn and anti isomers) (100 g) in a mixture of carbon tetrachloride (300 ml) and acetic acid (300 ml), The The mixture was stirred at 70 ° C [deg.] C until evolution of hydrobromic acid ceased. The reaction mixture was washed twice with water (300 ml), an aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. The solution was treated with activated charcoal
(2 g) and concentrated under reduced pressure to give ethyl 2-methoxyiminc 4-bromoacetoacetate (mixture of syn and anti isomers) (120.8 g)

  

  <EMI ID = 675.1>


  
dioxane (250 ml) and water (5 ml) was stirred for 15 minutes at

  
  <EMI ID = 676.1>

  
Ethyl thiazol-4-yl) acetate (26.4 g) was added thereto with stirring

  
at the same temperature. After stirring for 1 hour, the reaction mixture was decanted with heating and cooled to precipitate the yellow crystals. The crystals were collected by filtration, washed with dioxane and ether, and dried to give

  
  <EMI ID = 677.1>

  

  <EMI ID = 678.1>


  
5) Ethyl 2- (2-mesylamino-1,3-thiazol-4-yl) glyoxylate (13.9g) was added, with stirring at room temperature,

  
to a solution of sodium hydroxide (5.0 g) in water (150 ml). The mixture has

  
was stirred for 1 hour at room temperature, adjusted to pH

  
of 7 with concentrated hydrochloric acid and washed with ethyl acetate. The aqueous layer was adjusted to pH 0.5 with concentrated hydrochloric acid to precipitate the yellow crystals = The crystals were collected by filtration, washed with water and dried:
to provide 2- (2-mesylamino-1,3-thiazol-4-yl) glyoxylic acid
(10.16 g).

  

  <EMI ID = 679.1>


  
  <EMI ID = 680.1>

  
te of ethyl (14 g) in a mixture of pyridine (40 g) and methylene chloride (300 ml), a solution of t-pentyl chloroformate (70 ml) in diethyl ether was added little by little containing 0.35 mol of t-pentyl chloroformate in 10 minutes, at -20 [deg.] C

  
with stirring, and the mixture was stirred for 2 hours at the same temperature and further stirred for half an hour at 0 [deg.] C. After the reaction, the reaction mixture was poured into water (200 ml)

  
and then the organic layer was separated. The organic layer has

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

  
  <EMI ID = 681.1>

  
ppm 3.75 (2H, s)

  
6.75 (1H, s) <EMI ID = 682.1>

  
ethyl tate (0.3 g) and selenium dioxide (0.11 g) were treated in a similar manner to preparation 6-4) to give a brown oil of 2- (2-t Ethyl pentyloxycarbonylamino-1,3-thiazol4-yl) glyoxylate (0.22 g).

  

  <EMI ID = 683.1>


  
8) ethyl 2- (2-t-pentyloxycarbonylamino-1,3-thiazol-4-yl) glyoxylate (2.8 g) and a solution of soda (0.54 g) in water (20 ml ) were treated in a similar manner to Preparation 6-5) to give a brown powder of 2- (2-t-pentyloxy-

  
  <EMI ID = 684.1>

  

  <EMI ID = 685.1>


  
9) A mixture of ethyl 2-hydroxyimino-2- (2-amino-1,3-thiazol-4yl) acetate (mixture of syn and anti isomers) (0.37 g), ethanol (5 ml ), water (5 ml) and sodium bisulfite (0.72 g),

  
was stirred for 12 hours at 65-70 [deg.] C. The reaction mixture was concentrated and water (10ml) was added to the residue. The resulting mixture was subjected to salting out and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated to give yellow crystals of ethyl 2- (2-amino-1,3-thiazol-4-yl) -glyoxylate (0.18 g), m.p. 115 to 120 [deg.] C.

  

  <EMI ID = 686.1>


  
10) Sulfuryl chloride (235 ml) was added dropwise

  
dropwise over 20 minutes, with stirring and ice-cooling, to a solution of ethyl 2-methoxyiminoacetoacetate (syn isomer) (500 g) in acetic acid (500 ml), and the mixture was stirred overnight while cooling with water. Nitrogen gas was introduced into the reaction mixture for 2 hours, and the resulting mixture was poured into water (2.5 L). After extraction with methyl chloride (500 ml) and twice with methylene chloride (200 ml), the extracts were combined. The extracts:

  
  <EMI ID = 687.1>

  
of sodium, and adjusted to a pH of 6.5 by adding water (800 r.il) and sodium bicarbonate. A layer of methylene chloride was

  
  <EMI ID = 688.1>

  
cured on magnesium sulfate. The solvent was removed by distillation to give ethyl 2-methoxyimino-4-chloroacetoacetate
(syn isomer) (559 g).

  
Specter I.R. (Film)

  
  <EMI ID = 689.1>

  
Preparation 7

  
1) A mixture of ethyl 2-hydroxyimino-4-bromoacetoacetate
(mixture of sy n and anti isomers) (22.0 g), thioacetamide (7.5 g)

  
  <EMI ID = 690.1>

  
After cooling, triethylamine (10 g) was added thereto and the mixture was stirred for 1 hour. Insoluble material was filtered off and the filtrate was concentrated under pressure.

  
  <EMI ID = 691.1>

  
Ethyl tate (mixture of syn and anti isomers) (8.6 g). This material was subjected to column chromatography on silica gel (80 g), using benzene as a developing solvent. First, the eluate containing the anti isomer was eluted, pooled and

  
  <EMI ID = 692.1>

  
Ethyl acetate (anti isomer) (2.5 g), m.p. 90 to 92 [deg.] C.

  

  <EMI ID = 693.1>


  
After the eluate containing the anti isomer was eluted, the eluate containing the syn isomer was eluted, pooled and concentrated.

  
  <EMI ID = 694.1>

  
ethyl (syn isomer) (0.5 g), m.p. 134 to 136 [deg.] C.

  

  <EMI ID = 695.1>
 

  

  <EMI ID = 696.1>


  
2) An indicator formed from phenolphthalein (3 drops) has

  
was added to a solution of hydroxylamine hydrochloride (4.2

  
g) in dry methanol (60 ml). Into the solution was added dropwise, with stirring at room temperature, a solution.

  
  <EMI ID = 697.1>

  
their of the solution turns purple red. Hydroxylamine hydrochloride was added in small portions until the solution changed to a colorless solution. The mixture was stirred for 30 minutes

  
at room temperature. After precipitation, the sodium chloride

  
  <EMI ID = 698.1>

  
Thiazol-4-yl) glyoxylic acid (12.5g) was added to the filtrate and the mixture was refluxed with stirring for 1.5 hours. The reaction mixture was cooled to precipitate the crystals. The crystals were collected by filtration and dried to

  
  <EMI ID = 699.1>

  
crude tick (mixture of syn and anti isomers) (5.5 g). The filtrate was concentrated to 1/4 volume and ether was added to it. The precipitated crystals were collected by filtration, washed with ether and dried to give the same compound (8.78 g). Total yield:

  
14.3 g.

  
3) A mixture of ethyl 2-hydroxyimino-4-bromoacetoacetate (mixture of syn and anti isomers) (2.4 g) and thiourea (0.76 g)

  
  <EMI ID = 700.1>

  
the ethanol was removed by distillation under reduced pressure and water was added to the residue. The resulting mixture was adjusted to pH 1.0 and washed with ethyl acetate. The aqueous layer was adjusted to pH 4.5 with triethylamine and extracted with ethyl acetate. The extract was washed with water and with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. The solvent was removed by distillation under reduced pressure and the residue was subjected to column chromatography on

  
silica gel, using a mixture of ethyl acetate and benzene (1: 3) as the developing solvent. The eluates containing the syn isomer were pooled and. concentrates to give 2-hydro- <EMI ID = 701.1>

  
(0.3 g).

  

  <EMI ID = 702.1>


  
After the eluates containing the syn isomers were pooled, the eluates containing a mixture of syn and anti isomers were pooled and concentrated to give 2-hydroxyimino-2- (2-amino-1,3 &#65533; hiazol- Ethyl 4-yl acetate (mixture of syn and anti isomers) (0.3 g).

  

  <EMI ID = 703.1>


  
4) A solution of 2-hydroxyimino-2- (2-amino-1,3-thiazol-4-

  
  <EMI ID = 704.1>

  
for 2 hours at room temperature. The reaction mixture was adjusted to pH 3.5 with 10% hydrochloric acid and the precipitated crystals were collected by filtration, washed with acetone and dried to give 2-hydroxyimino-2 acid. - (2-amino-1,3-thiazol-4-yl) acetic (mixture of syn and anti isomers) (0.52 g), mp 184 to 186 [deg.] C (decomposition).

  
Specter I.R. (Nujol)

  
  <EMI ID = 705.1>

  
of ethyl 2-methoxyimino-4-bromoacetoacetate (mixture of syn and anti isomers) (12.6 g) in ethanol (50 ml), and the mixture was stirred for 5 hours at 50 [deg. ]VS. Ethanol. was removed by distillation under reduced pressure and water was added to the residue. The resulting mixture was extracted with ethyl acetate. For its part, the extract

  
was washed with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent was removed by distillation under reduced pressure to give ethyl 2-methoxyimino-2- (2methyl-1,3-thiazol-4-yl) acetate (mixture of syn and anti isomers) (9.0 g).

  
2) A mixture of ethyl 2-methoxyimino-4-bromoacetoacetate (mixture of syn and anti isomers) (7.6 g), Oethyl thiocarbamate (3.0 g) and dimethylacetamide (5 ml) has was stirred for 3 hours at 50 [deg.] C. Ethyl acetate (50 ml) was added to the reaction mixture and the resulting mixture was washed with water and with a saturated aqueous solution of sodium chloride, then dried over magnesium sulfate. The ethyl acetate was removed by distillation to give a crystalline residue. The residue was washed with ether

  
  <EMI ID = 706.1>

  
Ethyl thiazol-4-yl) acetate (syn isomer) (2.35 g).

  

  <EMI ID = 707.1>


  
The mother liquor of diisopropyl ether was concentrated

  
and the residue was subjected to column chromatography on silica gel (70 g) using a mixture of benzene and ethyl acetate (9: 1) as a developing solvent. The eluate containing the syn isomer was combined and concentrated to further give the syn isomer obtained above (0.65 g). Total yield: 3.0 g. Then, a mixture of benzene and ethyl acetate (5: 1) was used as the developing solvent. The eluate containing the anti isomer was pooled and

  
  <EMI ID = 708.1>

  
Ethyl thiazol-4-yl) acetate (anti-isomer) (0.26 g).

  

  <EMI ID = 709.1>
 

  

  <EMI ID = 710.1>


  
3) A solution of ethyl 2-methoxyimino-4-bromoacetoacetate (mixture of syn and anti isomers) (17.4 g) and thiourea (5.4 g) in ethanol (100 ml) was heated at reflux for 4 hours.

  
The reaction mixture was allowed to stand and cooled in ur. refrigerator to precipitate crystals. The crystals were collected by filtration, washed with ethanol and dried to give

  
  <EMI ID = 711.1>

  
ethyl (anti isomer) (9.5 g). The filtrate and washings were rinsed and concentrated under reduced pressure. Water (100ml) was added to the residue and the mixture was washed with ether. The aqueous layer was basified with 28% ammonia and extracted with

  
  <EMI ID = 712.1>

  
aqueous saturated with sodium chloride, then dried over sodium sulfate

  
  <EMI ID = 713.1>

  
(5.2 g).

  

  <EMI ID = 714.1>


  
  <EMI ID = 715.1>

  
Thus obtained ethyl 4-yl) acetate (anti-isomer) '(9.5 g) was suspended in ethyl acetate (200 ml) and triethylamine (4.0 g) was added thereto. ). After stirring for 1 hour at room temperature, insoluble material was removed by filtration and the filtrate was concentrated under reduced pressure to give a

  
  <EMI ID = 716.1>
  <EMI ID = 717.1>
 4) An indicator formed from phenolphthalein (3 drops) has

  
  <EMI ID = 718.1>

  
(1.25 g) in dry methanol (15 mL). To the solution was added dropwise, with stirring at room temperature, a solution.

  
  <EMI ID = 719.1>

  
the color of the solution changes to violet red. Omethylhydroxylamine hydrochloride was added thereto in small portions until

  
that the solution changes to a colorless solution. The mixture was &gi-; tee for 30 minutes at room temperature. After rushing

  
  <EMI ID = 720.1>

  
The mixture was filtered off and the mixture heated to reflux with stirring for 2 hours. After the methanol was removed by distillation, the residue was dissolved in ethyl acetate. Insoluble material was removed by filtration, and the filtrate was concentrated. The residue was subjected to column chromatography on silica gel using a mixture of benzene and ethyl acetate (9: 1) as a developing solvent. The eluate containing the isome-

  
  <EMI ID = 721.1>

  

  <EMI ID = 722.1>


  
5) Pulverized potassium carbonate (0.33 g) was suspended in a solution of 2-hydroxyimino-2- (2-methyl-1,3-thiazol-4-yl) ethyl acetate (isomer syn ) (0.5 g) in acetone (20 ml). A solution of dimethyl sulfate (0.3 g)

  
in acetone (5 ml) was added thereto dropwise with stirring, at 40-45 [deg.] C. After stirring for 2 hours at the same temperature, insoluble material was removed by filtration. The filtrate was concentrated and water was added to the residue. The resulting mixture was extracted with ethyl acetate. For its part, the extract

  
was washed with water, with an aqueous solution of sodium bicarbonate, then dried over magnesium sulfate. The solvan.t was removed by distillation under reduced pressure to give an oil.

  
  <EMI ID = 723.1>

  
ethyl (syn isomer) (0.5 g).

  

  <EMI ID = 724.1>


  
  <EMI ID = 725.1>

  
yl) acetic (mixture of syn and anti isomers) (14.3 g), obtained in preparation 7-2), was suspended in dry acetone
(300 ml). In the suspension was added potassium carbonate
(22.8 g) and dimethyl sulfate (20.8 g). The mixture was heated to reflux with stirring for 9 hours. Acetone was removed by distillation from the reaction mixture and water was added to the residue. The resulting mixture was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was removed by distillation to give an oil (13 g). The oil was subjected to column chromatography on silica gel, using a mixture of benzene and ethyl acetate (9: 1) as a developing solvent.

   First, the eluate containing the anti isomer was eluted, pooled and concentrated. The residual oil (2.4 g) was triturated while cooling to crystallize. The crystals were collected by filtration adding petroleum ether <EMI ID = 726.1>

  
Methyl 1,3-thiazol-4-yl) acetate (anti-isomer) (2.1 g).

  

  <EMI ID = 727.1>


  
After the eluate containing the anti isomer was eluted, the eluate containing the syn isomer was eluted, pooled and concentrated.

  
  <EMI ID = 728.1>

  
g).

  

  <EMI ID = 729.1>


  
7) The following compound was obtained in a manner similar to that of Preparation 8-4):

  
  <EMI ID = 730.1>

  
mother syn).

  

  <EMI ID = 731.1>


  
  <EMI ID = 732.1>

  
8) A mixture of acetic anhydride (6.1 g) and formic acid (2.8 g) was stirred for 2 hours at 50 [deg.] C. The resulting mixture was cooled and ethyl 2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetate (syn isomer) (4.6 g) was added thereto at 15 [ deg.] C.

  
  <EMI ID = 733.1>

  
At room temperature, cooled water (100 mL) was added thereto. The resulting mixture was extracted with ethyl acetate (200 mL). The extract was washed with water and with a saturated aqueous solution of sodium bicarbonate, until the washing changed to a weakly alkaline solution. The extract was further washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was removed by distillation and the residue was washed with diisopropyl ether, combined by filtration and drying.

  
  <EMI ID = 734.1>

  
Ethyl acetate (syn isomer) (4.22 g), m.p. 122 to 124 [deg.] C (decomposition).

  

  <EMI ID = 735.1>


  
9) Pyridine (3 g) was added to a solution of

  
  <EMI ID = 736.1>

  
syn) (6.5 g) in a mixture of ethyl acetate (60 ml) and dimethylformamide (20 ml). Into the solution was added dropwise, with stirring at 4 [deg.] C, ethyl chloroformate (8 g). After adding water (50 ml) to the reaction mixture, the organic layer was separated, washed with water and then with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was subjected to column chromatography on silica gel (120 g) in

  
  <EMI ID = 737.1>

  
yl) ethyl acetate (syn isomer) (5.4 g).

  

  <EMI ID = 738.1>
 

  
10) Ethyl 2-methoxyimino-4-chloroacetoacetate

  
(syn isomer) (50 g) was added over 3 minutes, with stirring at room temperature, to a solution of thiourea (18.4 g) and sodium acetate (19.8 g) in a mixture of methanol (250 ml) and water

  
(250 ml). After stirring for 35 minutes at 40-45 [deg.] C, the reaction mixture was cooled with ice and adjusted to pH 6.3 ave. a saturated aqueous solution of sodium bicarbonate. After stirring for 30 minutes at the same temperature, the precipitates have

  
was combined by filtration, washed with water (200 ml) then with diisopropyl ether (100 ml), and dried to give colorless crystals of 2-methoxyimino-2- (2-amino-1,3-thiazol -4-yl) acetate

  
  <EMI ID = 739.1>

  

  <EMI ID = 740.1>


  
  <EMI ID = 741.1>

  
ethyl (anti-isomer) (0.3 g) and dimethyl sulfate (0.18 g) were reacted in a manner, similar to that of the preparation

  
  <EMI ID = 742.1>

  

  <EMI ID = 743.1>


  
12) The following compound was obtained in a similar manner

  
  <EMI ID = 744.1>
  <EMI ID = 745.1>
 
  <EMI ID = 746.1>
 Preparation 9

  
1) Ethanol (10 ml) was added to a suspension of

  
  <EMI ID = 747.1>

  
  <EMI ID = 748.1>

  
mixture was stirred for 15 hours at room temperature. The reaction mixture was adjusted to pH 7.0 with 10% hydrochloric acid and ethanol was removed by distillation under reduced pressure. The residual aqueous solution was washed with ethyl acetate, adjusted to pH 2.8 with hydrochloric acid at
10% and stirred while cooling with ice to precipitate the crystals. The crystals were collected by filtration, washed with

  
  <EMI ID = 749.1>

  
(syn isomer) (1.1 g).

  

  <EMI ID = 750.1>


  
  <EMI ID = 751.1>

  
  <EMI ID = 752.1>

  
The resulting ge was stirred for 2 hours at 40 [deg.] C. The reaction mixture was adjusted to pH 7.0 with 10% hydrochloric acid, concentrated under reduced pressure, adjusted to pH 1.5 with 10% hydrochloric acid and extracted with water. ethyl acetate. The extract was. washed with water and with a saturated aqueous solution of sodium chloride, then dried over magnesium sulfate. The solvent was removed by distillation to give a crystalline substance of 2-metho- acid.

  
  <EMI ID = 753.1>

  

  <EMI ID = 754.1>
 

  

  <EMI ID = 755.1>


  
3) The following compounds were obtained in a similar manner to that of Preparations 9-1) to 9-2).

  
  <EMI ID = 756.1>

  
zol-4-yl) acetic (syn isomer,

  

  <EMI ID = 757.1>


  
(2) 2-methoxyimino-2- (2-mesylamino-1,3-thiazol4-yl) acetic acid (syn isomer)

  

  <EMI ID = 758.1>


  
(3) 2-methoxyimino-2- (2-mesylimino-3-methyl-2,3dihydro-1,3-thiazol-4-yl) acetic acid (syn isomer)

  

  <EMI ID = 759.1>


  
  <EMI ID = 760.1>

  
yl) acetic (syn isomer), m.p. 152 [deg.] C (decomposition)

  

  <EMI ID = 761.1>


  
(5) 2-Methoxyimino-2- (2-ethoxycarbonylamino-1,3thiazol-4-yl) acetic acid (syn isomer)
  <EMI ID = 762.1>
 
  <EMI ID = 763.1>
 4) Pyridine (5ml) was added to a suspension of 2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetic acid (syn isomer) (2.0g) in ethyl acetate (20 mL). A solution of anhy-

  
  <EMI ID = 764.1>

  
the (3ml) was added dropwise, with stirring at 5-7 [deg.] C and the mixture was stirred for 30 minutes at 3-5 [deg.] C. Water (30 ml)

  
was added to the reaction mixture and the ethyl acetate layer was separated. The aqueous layer was further extracted with ethyl acetate and two ethyl acetate layers were combined, washed with water and with saturated aqueous sodium chloride solution, and dried over sodium chloride sulfate. magnesium. The solvent was removed by distillation under reduced pressure to give acid.

  
  <EMI ID = 765.1>

  
tick (syn isomer) (0.72 g):

  

  <EMI ID = 766.1>


  
5) The following compound was obtained in a similar manner

  
to that of preparation 9-4): 2-methoxyimino-2- (2-acetamido-1,3-thiazol-4-yl) acetic acid (syn isomer), m.p. 184 to 185 [deg.] C (decomposition).

  

  <EMI ID = 767.1>


  
6) An indicator formed from phenolphthalein (3 drops) was added to a solution of O-allylhydroxylamine hydrochloride (0.84 g) in dry methanol (10 ml). To the solution was added dropwise, with stirring at room temperature, a methane solution.

  
  <EMI ID = 768.1>

  
the solution turned to a pale rosé. O-allylhydroxylamine hydrochloride was added thereto in small portions until the solution turned to a colorless solution. The mixture was stirred for 30 minutes at room temperature After precipitation, the sodium chloride was removed by filtration, 2- (2-t-per.tyloxy- acid

  
  <EMI ID = 769.1>

  
filtrate and the mixture was stirred for 1 hour at room temperature. After the methanol was removed by distillation at low temperature, the residue was dissolved in IN aqueous solution.

  
of soda. The solution was washed with ether and ethyl acetate was added to it. The mixture was adjusted to pH 1.5 with phosphoric acid and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over magnesium sulfate. Ethyl acetate was removed by distillation and the residue was washed with diisopropyl ether, combined by filtration and dried to give 2-allyloxyimino-2- (2-t-penty- acid.

  
  <EMI ID = 770.1>

  

  <EMI ID = 771.1>


  
7) The following compounds were obtained in a similar manner to that of Preparation 9-6).

  
(1) 2-methoxyimino-2- (2-t-pentyloxycarbonylamino- acid

  
  <EMI ID = 772.1>

  

  <EMI ID = 773.1>


  
  <EMI ID = 774.1>

  
4-yl) acetic (syn isomer)
  <EMI ID = 775.1>
   <EMI ID = 776.1>

  
acetic (syn isomer)

  

  <EMI ID = 777.1>


  
8) Ethyl 2-methoxyimino-2- (2-amino-1,3thiazol-4-yl) hydrobromide (anti isomer) (15.5 g) was dissolved in sodium hydroxide solution (4.4 g) in water (150 ml) and the solution

  
  <EMI ID = 778.1>

  
you. Insoluble material was removed by filtration and the filtrate

  
was adjusted to pH 5.0 to precipitate crystals. The crystals were collected by filtration and dried to give acid.

  
  <EMI ID = 779.1>

  
(8.0 g).

  

  <EMI ID = 780.1>


  
9) The following compounds were obtained in a manner similar to that of Preparation 9-8)

  
  <EMI ID = 781.1>

  
acetic (anti isomer)

  

  <EMI ID = 782.1>


  
(2) 2-methoxyimino-2- (2-mesylimino-3-methyl-2,3dihydro-1,3-thiazol-4-yl) acetic acid (anti isomer)

  
Specter I.R. (Nujol)

  
  <EMI ID = 783.1>

  
(3) 2-methoxyimino-2- (2-formamido-1,3-thiazol4-yl) acetic acid (anti-isomer), m.p. 156 to 158 [deg.] C (decomposition).

  

  <EMI ID = 784.1>


  
The present invention is not limited to the exemplary embodiments which have just been described; on the contrary, it is susceptible of variants and modifications which will appear to those skilled in the art.

CLAIMS

  
1 - As new industrial products, syn isomers of compounds of 3,7-disubstituted 3-cephem-4-carboxylic acid having the formula:

  

  <EMI ID = 785.1>


  
  <EMI ID = 786.1>

  

  <EMI ID = 787.1>


  
  <EMI ID = 788.1>

  
lower or acyloxy and R6 is hydroxy, lower alkoxy, acyloxy, acylamino or dialkyl (lower) amino; a group having the formula:

  

  <EMI ID = 789.1>


  
  <EMI ID = 790.1>

  
or a group having the formula:

  

  <EMI ID = 791.1>


  
where R8 is a lower alkyl group and R9 is an imino, protected imino or oxo group; R <2> is an aliphatic hydrocarbon group which can

  
have one or more suitable substituents; R is a carboxy or protected carboxy group; and R4 is an acyloxymethyl, hydroxymethyl, formyl or heterocyclic thiomethyl group which may have

  
  <EMI ID = 792.1>

  
form -COOCH2-, and their pharmaceutically acceptable salts.


    

Claims (1)

2 - Compounds according to claim 1, characterized in that <EMI ID = 793.1> <EMI ID = 794.1> where R5 is hydrogen, a halogen or a nitro group and .is a hydroxy, lower alkoxy, acyloxy, acylamino or dialkyl (lower) amino group; a group of the formula; , <EMI ID = 795.1> <EMI ID = 796.1> laughing; or a group of formula: <EMI ID = 797.1> <EMI ID = 798.1> ge; R2 is lower alkyl or lower alkenyl, each of which may have 1 to 2 substituents selected from the group consisting of carboxy, protected carboxy, arylthio, aryloxy group which may have hydroxy group, aryl which may have halogen and group hydroxy, thienyl; R3 is a carboxy group; and R 4 is an acyloxymethyl, hydroxymethyl, formyl, or a heterocyclic thiomethyl group which may have 1 to 2 substituents selected from the group consisting of lower alkyl and dialkyl (lower) aminoalkyl; or R and R are linked to form -COOCH-. 3 - Compounds according to claim 2, characterized in that R is a group of formula: <EMI ID = 799.1> <EMI ID = 800.1> zolylthiomethyl which may have a -substituent selected from the group consisting of lower alkyl and dialkyl (lower) aminoalkyl, thiadiazolylthiomethyl which may have lower alkyl or triazolylthiomethyl; or R <3> and R4 are connected <EMI ID = 801.1> 4 - Compounds according to claim 3, characterized in that R <2> is a lower alkyl group, which may have a substituent selected from the group consisting of carboxy, (lower) alkoxy carbonyl, phenylthio, phenoxy having a hydroxy group , phenyl having a halogen and a hydroxy group, and thienyl, or a lower alkenyl group which may have a phenyl group. 5 - Compounds according to claim 2, characterized in that <EMI ID = 802.1> <EMI ID = 803.1> <EMI ID = 804.1> R <2> is lower alkyl or lower alkenyl. 6 - Compounds according to claim 5, characterized in that <EMI ID = 805.1> laughing and R is an acyloxymethyl group. 7 - Compounds according to claim 6, characterized in that R4 is a (lower) alkanoyl oxymethyl orcarbamoyloxymethyl group. 8 - Compounds according to claim 7, characterized in that R4 is a (lower) alkanoyl oxymethyl group. 9 - Compounds according to claim 8, characterized in that <EMI ID = 806.1> 11 - Compounds according to claim 8, characterized in that <EMI ID = 807.1> <EMI ID = 808.1> amino. 13 - Compounds according to claim 12, characterized in that R7 is a (lower) alkanoyl amino group. 14 - Compounds according to claim 13, characterized in that R7 is the formamido group. 15 - A compound according to claim 14, characterized in that <EMI ID = 809.1> 17 - Compounds according to claim 16, characterized in that R7 is a trihaloalkanoyl (lower) amino group. 18 - Compounds according to claim 17, characterized in that R7 is the 2,2,2-trifluoroacetamido group. <EMI ID = 810.1> syn). 20 - Compounds according to claim 7, characterized in that <EMI ID = 811.1> 21 - Compounds according to claim 20, characterized in that R7 is the amino group. 22 - A compound according to claim 21, characterized in that it is formed by the acid 7- [2-methoxyimino-2- (2-amino-1,3-thia- <EMI ID = 812.1> (syn isomer). 23 - Compounds according to claim 20, characterized in that R7 is the acylamino group. <EMI ID = 813.1> that R7 is a (lower) alkanoyl amino or a haloalkanoyl (lower) amino group. 25 - Compounds according to claim 24, characterized in that R7 is a (lower) alkanoyl amino group. 26 - Compounds according to claim 25, characterized in <EMI ID = 814.1> 27 - A compound according to claim 26, characterized in that <EMI ID = 815.1> (syn isomer). 28 - Compounds according to claim 24, characterized in that <EMI ID = 816.1> 29 - Compounds according to claim 28, characterized in that R is a trihaloalkanoyl (lower) amino group. 30 - Compounds according to claim 29, characterized in <EMI ID = 817.1> 31 - A compound according to claim 30, characterized in that <EMI ID = 818.1> phem-4-carboxylic (syn isomer); 32 - Compounds according to claim 5, characterized in that R 7 is amino or acylamino, R2 is lower alkyl and R 4 is hydroxymethyl. 33 - Compounds according to claim 32, characterized in that R is the amino group. 34 - A compound according to claim 33, characterized in that it is formed by the acid 7- [2-methoxyimino-2- (2-amino-1,3-thiazol- <EMI ID = 819.1> syn &#65533;. 35 - Compounds according to claim 32, characterized in that R is an acylamino group. 36 - Compounds according to claim 35, characterized in that <EMI ID = 820.1> 37 - Compounds according to claim 36, characterized in that R is a trihaloalkanoyl (lower) amino group. 38 - Compounds according to claim 37, characterized in that R is the 2,2,2-trifluoroacetamido group. 39 - A compound according to claim 38, characterized in that it is formed by the acid 7- [2-methoxyimino-2- [2- (2,2,2-trifluoro- <EMI ID = 821.1> carboxylic (syn isomer). 40 - Compounds according to claim 5, characterized in that is an acylamino group, R2 is a lower alkyl group and R is the formyl group. 41 - Compounds according to claim 40, characterized in ' <EMI ID = 822.1> 42 - Compounds according to claim 41, characterized in <EMI ID = 823.1> 43 - Compounds according to claim 42, characterized in <EMI ID = 824.1> 44 - A compound according to claim 43, characterized in <EMI ID = 825.1> 45 - Compounds according to claim 5, characterized in that R4 is a heterocyclic thiomethyl group which may have 1 to 2 substituents selected from the group consisting of lower alkyl and dialkyl (lower) amino loweralkyl. 46 - Compounds according to claim 45, characterized in that R4 is an unsaturated pentagonal heteromonocyclic thiomethyl group, containing 3 or 4 nitrogen atoms, which may have a substituent selected from the group consisting of lower alkyl and dialkyl (lower). amino loweralkyl, or an unsaturated 5-membered heteromonocyclic thiomethyl group containing 1 sulfur atom and 2 nitrogen atoms, which may have a lower alkyl group. <EMI ID = 826.1> that R4 is tetrazolylthiomethyl group which may have a substituent selected from the group consisting of lower alkyl and dialkyl (lower) amino lower alkyl, triazolylthiomethy- <EMI ID = 827.1> thyl which may have a lower alkyl group. 48 - Compounds according to claim 47, characterized in <EMI ID = 828.1> selected from the group consisting of lower alkyl and dialkyl (lower) aminoalkyl.e lower. 49 - Compounds according to claim 48, characterized in that <EMI ID = 829.1> inferior. 50 - Compounds according to claim 49, characterized in that R7 is the amino group. 51 - Compounds according to claim 50, characterized in that R <2> is a lower alkyl group and R4 is the tetrazolylthiomethyl group having a methyl group. 52 - A compound according to claim 51, characterized in that <EMI ID = 830.1> <EMI ID = 831.1> 4-carboxylic (syn isomer). 53 - Compounds according to claim 50, characterized in that R <2> is a lower alkenyl group and R 4 is the tetrazolylthiomethyl group having a methyl group. 54 - Compose'selon claim 53, characterized in that it is formed by the acid 7- [2-allyloxyimino-2- (2-amino-1,3- <EMI ID = 832.1> cephem-4-carboxylic (syn isomer). 55 - Compounds according to claim 49, characterized in that R7 is an acylamino group. 56 - Compounds according to claim 55, characterized in <EMI ID = 833.1> mino. 57 - Compounds according to claim 56, characterized in that R7 is a (lower) alkane sulfonylamino group. 58 - Compounds according to claim 57, characterized in that R <2> is a lower alkyl group and R 4 is the tetrazolylthiomethyl group having a methyl group. 59 - A compound according to claim. 58, characterized in that <EMI ID = 834.1> cephem-4-carboxylic (syn isomer). 60 - Compounds according to claim 57, characterized in that R2 is a lower alkenyl group and R 4 is the tetrazolylthiomethyl group having a methyl group. 61 - A compound according to claim 60, characterized in which is formed by the acid 7- [2-allyloxyimino-2- (2-mesylamino-1,3- <EMI ID = 835.1> cephem-4-carboxylic (syn isomer). 62 - Compounds according to claim 56, characterized in that R7 is a (lower) alkanoyl amino group and R <2> is a lower alkyl group. 63 - Compounds according to claim 62, characterized in that R is the formamido or acetamido group, R is the methyl group and R is a tetrazolylthiomethyl group having a methyl group. 64 - Compounds according to claim 63, characterized in that <EMI ID = 836.1> cephem-4-carboxylic (syn isomer). 65 - A compound according to claim 63, characterized in that <EMI ID = 837.1> cephem-4-carboxylic (syn isomer). 66 - Compounds according to claim 56, characterized in that R 7 is a haloalkanoyl (lower) amino group and R <2> is a lower alkyl group. 67 - Compounds according to claim 66, characterized in that R is a trihaloalkanoyl (lower) amino group and R is the tetrazolylthiomethyl group having a methyl group. 68 - A compound according to claim 67, characterized in that <EMI ID = 838.1> yl) -thiomethyl-3-cephem-4-carboxylic (syn isomer). 69 - Compounds according to claim 56, characterized in that R 7 is an alkoxy (lower) carbonylamino group, R is a lower alkenyl group and R 4 is a tetrazolylthiomethyl group having a methyl group. 70 - A compound according to claim 69, characterized in that it is formed by the acid 7- [2-allyloxyimino-2- (t-pentyloxycarbo- <EMI ID = 839.1> 71 - A compound according to claim 49, characterized in that R 7 is the hydroxy group, R <2> is a lower alkyl group and R4 is the tetrazolylthiomethyl group having a methyl group. 72 - A compound according to claim 71, characterized in that <EMI ID = 840.1> 3-cephem-4-carboxylic (syn isomer). 73 - Compounds according to claim 49, characterized in that R 7 is a lower alkyl group, R <2> is a lower alkyl group and R is tetrazolylthiomethyl group having a methyl group. 74 - A compound according to claim 73, characterized in that <EMI ID = 841.1> <EMI ID = 842.1> 75 - Compounds according to claim 48, characterized in <EMI ID = 843.1> R4 is the tetrazolylthiomethyl group having a dimethylaminoethyl group. 76 - A compound according to claim 75, characterized in that <EMI ID = 844.1> methyl-3-cephem-4-carboxylic (syn isomer). 77 - Compounds according to claim 47, characterized in that R 7 is an amino group, R <2> is a lower alkyl group and R4 is the triazolylthiomethyl group having a lower alkyl group. 78 - Compounds according to claim 77, characterized in that R4 is the triazolylthiomethyl group having a methyl group. 79 - A compound according to claim 78, characterized in that <EMI ID = 845.1> 4-carboxylic (syn isomer). 80 - Compounds according to claim 47, characterized in that R 7 is the amino or acylamino group, R <2> is a lower alkyl group and R is the thiadiazolylthiomethyl group which may have a lower alkyl group. 81 - Compounds according to claim 80, characterized in that R is the amino group and R is the thiadiazolylthiomethyl group which may have a methyl group. 82 - A compound according to claim 81, characterized in <EMI ID = 846.1> cephem-4-carboxylic (syn isomer). 83 - A compound according to claim 81, characterized in that <EMI ID = 847.1> 4-carboxylic (syn isomer). 84 - Compounds according to claim 80, characterized in that R is an acylamino group. 85 - Compounds according to claim 84, characterized in <EMI ID = 848.1> <EMI ID = 849.1> 86 - Compounds according to claim 85, characterized in that R7 is a (lower) alkanoyl amino group and R 4 is a thiadiazolylthiomethyl group. 87 - A compound according to claim 86, characterized in <EMI ID = 850.1> cephem-4-carboxylic (syn isomer). 88 - Compounds according to claim 85, characterized in that R7 is a haloalkanoyl (lower) amino group and R 4 is the thiadiazolylthiomethyl group. 89 - Compounds according to claim 88, characterized in that is a trihaloalkanoyl (lower) amino group. 90 - A compound according to claim 89, characterized in <EMI ID = 851.1> thiomethyl-3-cephem-4-carboxylic (syn isomer). 91 - Compounds according to claim 85, characterized in <EMI ID = 852.1> 92 - Compounds according to claim 91, characterized in <EMI ID = 853.1> mino and R4 is the thiadiazolyothiomethyl group which may have a methyl group. 93 - A compound according to claim 92, characterized in that it is formed by the acid 7- [2-methoxyimino-2- (2-ethoxycarbonyl- <EMI ID = 854.1> thyl-3-cephem-4-carboxylic (syn isomer). 94 - A compound according to claim 92, characterized in that it is formed by the acid 7- [2-methoxyimino-2- (2-t-pentyloxycarbo- <EMI ID = 855.1> 2-yl) -thiomethyl-3-cephem-4-carboxylic (syn isomer). 95 - Compounds according to claim 5, characterized in that R7 is an amino group, R <2> is a lower alkyl group and 34 <EMI ID = 856.1> thiazine-1,7 (4H) -dione (syn isomer). 97 - A compound according to claim 2, characterized in that R is a group having the formula: <EMI ID = 857.1> where R8 is lower alkyl and R9 is acylimino, R <2> is lower alkyl and R4 is tetrazolylthio- group <EMI ID = 858.1> 98 - Compounds according to claim 97, characterized in that R9 is a (lower) alkane sulfonylimino group. 99 - Process for the preparation of syn isomers of compounds <EMI ID = 859.1> <EMI ID = 860.1> <EMI ID = 861.1> RS R6 where R is hydrogen, halogen, nitro, hydroxy, lower alkoxy or acyloxy and R is hydroxy, lower alkoxy, acyloxy, acylamino or dialkyl (lower) amino; a group having the formula: <EMI ID = 862.1> <EMI ID = 863.1> laughing; or a group having the formula: <EMI ID = 864.1> <EMI ID = 865.1> protected or oxo; R <2> is an aliphatic hydrocarbon group which may have one or more suitable substituents, R is the carboxy or protected carboxy group, and R is an acyloxymethyl, hydroxymethyl, formyl or heterocyclic thiomethyl group which may have one or more suitable substituents, or R4 and R4 are linked together to form - COOCH2-, or their pharmaceutically acceptable salts, characterized in that it consists in reacting a compound having the formula: <EMI ID = 866.1> 1 &#65533; where R <3> and R4 are each as defined above, or its derivative reactive with the amino group or its salt, with a substituted acetic acid having the formula: <EMI ID = 867.1> <EMI ID = 868.1> on the carboxy group or its salt. 100 - Method according to claim 99, characterized in that the reaction is carried out in the presence of a condensing agent. 101 - Method according to claim 100, characterized in what the condensing agent is a Vilsmeier reactant. 102 - Process according to claim 101, characterized in that the reaction is carried out in the presence of a Vilsmeier reactant produced by the reaction of phosphorus oxychloride with dimethylformamide, and under approximately neutral conditions. 103 - Method according to claim 102, characterized in what R1 is a group of formula: <EMI ID = 869.1> and the reaction is carried out in the presence of a reactant of Vilsmeier produced by the reaction of phosphorus oxychloride with dimethylformamide, and under approximately neutral conditions, where phosphorus oxychloride is used in an amount of more than two molar equivalents based on each amount of acetic acid substituted and dimethylformaiaide. 104 - Process for the preparation of a compound having the formula: <EMI ID = 870.1> not <EMI ID = 871.1> <EMI ID = 872.1> or a group of formula -: <EMI ID = 873.1> <EMI ID = 874.1> aliphatic which may have one or more suitable substituents; R <3> is the carboxy group or a protected carboxy group; and R 4 is an acyloxymethyl, hydroxymethyl, formyl or heterocyclic thiomethyl group which may have one or more suitable substituents; or R <3> and R4 are linked to form the group -COOCH2-, or their pharmaceutically acceptable salts, characterized in that it consists in submitting a compound having the formula: <EMI ID = 875.1> <EMI ID = 876.1> is a group of formula: <EMI ID = 877.1> <EMI ID = 878.1> <EMI ID = 879.1> where R is such that. defined above and R9a is the protected imino group or its salt, to a reaction of elimination of the protective group of the amino or imino radical. 105 - Process for preparing a compound having the formula: <EMI ID = 880.1> <EMI ID = 881.1> lower alkoxy or acyloxy, R6a is an acyloxy group; R is an aliphatic hydrocarbon group, which may have one or more suitable substituents; R <3> is a carboxy or carboxy group protected <EMI ID = 882.1> or a heterocyclic thiomethyl group which may have one or more suitable substituents; or R <3> and R4 are linked together to form- <EMI ID = 883.1> ized in that it consists in acylating the hydroxy group of the compound having the formula: <EMI ID = 884.1> <EMI ID = 885.1> laughing or acyloxy, or its salt. 106 - Process for preparing a compound having the formula: <EMI ID = 886.1> <EMI ID = 887.1> <EMI ID = 888.1> <EMI ID = 889.1> <EMI ID = 890.1> laughing, acyloxy, acylamino or dialkyl (lower) amino; a group of formula: <EMI ID = 891.1> <EMI ID = 892.1> laughing, or a group of the formula: <EMI ID = 893.1> where R8 is lower alkyl and R9 is imino, protected imino or oxo; R2b is a lower carboxyalkyl group; <EMI ID = 894.1> acyloxymethyl, hydroxymethyl, formyl or a heterocyclic thiomethyl group which may have one or more suitable substituents <EMI ID = 895.1> their pharmaceutically acceptable salts, characterized in that it consists in submitting a compound having the formula: <EMI ID = 896.1> where'R, R and R are each as defined above and R2a is a protected lower carboxyalkyl group or its salt, to a reaction of elimination of the protecting group of the carboxy radical. 107 - Process for the preparation of a compound having the formula <EMI ID = 897.1> <EMI ID = 898.1> <EMI ID = 899.1> where R5 is hydrogen, halogen, nitro, hydroxy, lower alkoxy or acyloxy and R is hydroxy, lower alkoxy, acyloxy, acylamino or dialkyl (lower) amino; a group of formula: <EMI ID = 900.1> <EMI ID = 901.1> laughing; or a group of formula: <EMI ID = 902.1> <EMI ID = 903.1> protected imino or oxo; R <2> is an aliphatic hydrocarbon group which may have one or more suitable substituents; and R is a carboxy or protected carboxy group; or of their pharmaceutically acceptable salts., characterized in that it consists in submitting a compound having the formula: <EMI ID = 904.1> <EMI ID = 905.1> an amino protecting group, or its salt, to a reaction for removing the amino protecting group. 108 - Process for the preparation of a compound having the formula <EMI ID = 906.1> where R is a group of the formula: <EMI ID = 907.1> <EMI ID = 908.1> lower alkoxy or acyloxy and R is hydroxy, lower alkoxy, acyloxy, acylamino or dialkyl (lower) amino; a group having the formula: <EMI ID = 909.1> <EMI ID = 910.1> laughing; or a group of formula: <EMI ID = 911.1> where R is lower alkyl and R is imino, protected imino or oxo; R2 is an aliphatic hydrocarbon group which may have one or more suitable substituents; R is the carboxy or protected carboxy group; and R4c is a heterocyclic group which may have one or more suitable substituents; or of their pharmaceutically acceptable salts, characterized in that it consists in reacting a compound having the formula: <EMI ID = 912.1> <EMI ID = 913.1> as defined above, or its salt, with a compound having the formula: <EMI ID = 914.1> where R4c is as defined above, or its derivative reactive with the mercapto group. 109 - Process for the preparation of a compound of formula: <EMI ID = 915.1> <EMI ID = 916.1> <EMI ID = 917.1> <EMI ID = 918.1> lower or acyloxy and R is hydroxy, lower alkoxy, acyloxy, acylamino or dialkyl (lower) amino; a group of formula: <EMI ID = 919.1> where R is amino, protected amino, hydroxy or lower alkyl; or a group of formula: <EMI ID = 920.1> <EMI ID = 921.1> protected imino or oxo; and R <2> is an aliphatic hydroxy carbon group which may have one or more suitable substituents; or its pharmaceutically acceptable salts, characterized in that it consists in treating a compound having the formula: <EMI ID = 922.1> where R and R are as defined above and R is a carboxy or protected carboxy group, or its salt with an acid. 110 - Process for preparing a compound having the formula: <EMI ID = 923.1> where R is a group of the formula: <EMI ID = 924.1> <EMI ID = 925.1> <EMI ID = 926.1> lower alkoxy, acyloxy, acylamino or dialkyl (lower) amino, <EMI ID = 927.1> <EMI ID = 928.1> laughing; or a group of formula: <EMI ID = 929.1> <EMI ID = 930.1> protected or oxo; R <2> is an aliphatic hydrocarbon group, which may have one or more suitable substituents; and R is a carboxy or pregegged carboxy group; or of its pharmaceutically acceptable salts, characterized in that it consists in oxidizing a compound having the formula: <EMI ID = 931.1> <EMI ID = 932.1> 111 - Antibacterial pharmaceutical composition, character <EMI ID = 933.1> association with a substantially non-toxic pharmaceutically acceptable carrier or excipient. 112 - Process for the production of a pharmaceutical composition, characterized in that it consists in mixing a compound of claim 1, as an active ingredient, with an inert carrier. 113 - As new industrial products, compounds having the formula: <EMI ID = 934.1> where R2e is lower alkyl and Za is a protected carboxy ocarboxy group, or their salts. 114 - Compounds according to claim 113, characterized in that they have the formula: <EMI ID = 935.1> <EMI ID = 936.1> or (lower) alkoxy carbonyl or their salts. 115 - Compounds according to claim 114, characterized in that Za is the carboxy group. 116 - A compound according to claim 115, characterized in that it is formed by 2-methoxyimino-2- (2-amino-1,3-thiazol4-yl) -acetic acid (syn isomer). 117 - Process for preparing a compound of formula: <EMI ID = 937.1> <EMI ID = 938.1> what it consists of submitting a compound having the formula: <EMI ID = 939.1> where R2e is as defined above and Z is a protected carboxy group <EMI ID = 940.1> carboxy. 118 - Process for preparing a compound having the formula: <EMI ID = 941.1> <EMI ID = 942.1> in that it consists in halogenating a compound having the formula: <EMI ID = 943.1> <EMI ID = 944.1> ge, reacting the resulting compound having the formula: <EMI ID = 945.1> where R2e and Z are each as defined above and X is halogen, with a compound of the formula: <EMI ID = 946.1> in the presence of a base, and then subjecting the resulting compound of formula: <EMI ID = 947.1> where R2e and Z are each as defined above, to a reaction for removing the protecting group from the carboxy radical.