BE853545A - NEW CEPHALOSPORIN DERIVATIVES WITH A NEW 7-ACYL GROUP AND THEIR MANUFACTURING PROCESS - Google Patents

Description

       

    <EMI ID = 1.1>

  
7-acyl and their manufacturing process.

  
  <EMI ID = 2.1>

  
sporin having a novel 7-acyl group and their preparation process. More particularly the present invention relates to

  
  <EMI ID = 3.1>

  

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  <EMI ID = 5.1>

  
of this derivative and also relates to the process for preparing these derivatives,

  
So far, studies on synthetic cephalosporin derivatives have been directed towards the conversion of 7-aminocephalosporanic acid into various acylated derivatives at the 7-position or into derivatives at the 3-position in order to synthesize compounds having a broad anti- spectrum. bacterial or a particular spectrum

  
  <EMI ID = 6.1>

  
Under these circumstances, the Applicant has found the cephalosporin derivatives represented by the following formula:

  

  <EMI ID = 7.1>


  
  <EMI ID = 8.1> further found that compounds of formula (I) are strongly active against a broad spectrum of gram-positive and gram-negative bacteria including Serratia marcescens, Proteus morganii, and also that compounds (I) are effective against β-lactamase-producing bacteria. the present invention is therefore carried out on the basis of these findings.

  
  <EMI ID = 9.1>

  
drogen or a residue of a nucleophilic compound. As examples of

  
  <EMI ID = 10.1>

  
there may be mentioned hydroxyl groups; mercapto; acyloxy derivative of a lower aliphatic carboxylic acid having 2 to 4 carbon atoms, which may optionally be substituted by oxo, carboxyl or ethoxycarbamoyl radicals (e.g. acetyloxy, propionyloxy, 3-oxobutyryloxy, 3-carboxypropionyloxy, 3ethoxycarbamoylpropionyloxy, 4-carboxy) ; an acyloxy group derived from aromatic carboxylic acid, which may optionally be substituted by hydroxyl, carboxyl, carbethoxycarbamoyl or carbethoxysulfamoyl radicals, (for example man-

  
  <EMI ID = 11.1>

  
2- (carboethoxysulfamoyl) benzoyloxy); a carbamoyloxy group; cyano; azido; aminogen; carbamoyithio; thiocarbamoyloxy; carbamoyloxy, the aminogenic group of which is protected by a conventional protective group for the aminogenic function (for example

  
  <EMI ID = 12.1>

  
chloracetylcarbamoyloxy, N-chlorosulfonylcarbamoyloxy, N-trimethylsilylcarbamoyloxy, etc.); a phenylglycyloxy group; etc. These residues of a nucleophilic compound may be substituted, the number of substituents normally being 1 or 2. Thus, the substituents on these residues which have been mentioned above may for example be alkyl groups (such as lower alkyl groups from 1 to 3 carbon atoms, e.g. methyl, ethyl, propyl, etc.) and acyl groups (such as acyl groups derived from lower aliphatic carboxylic acid having 2 to 4 carbon atoms, e.g. acetyl, propionyl, butyryl, etc .; acyl groups derived from acid

  
  <EMI ID = 13.1>

  
le, para-methylbenzoyl, mandeloyl, etc.). The rest of a compo-

  
  <EMI ID = 14.1> a heterocyclic ring bonded through a sulfur atom, i.e., a heterocyclic ringed thio group represented by the formula -S-heterocyclic ring. The heterocyclic ring mentioned above is five or six membered comprising 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen atoms, and the atom or atoms of nitrogen may be in the oxide form . It follows therefore-

  
  <EMI ID = 15.1>

  
derivative of a heterocyclic compound corresponding to the heterocyclic ring) can usually be one of the following groups:
pyridyl; N-oxydopyridyl; pyrimidyl, pyridazinyl, N-oxydopyridazinyl; pyrazolyl; diazolyl such as pyrazolyl; imidazolyl; thiazolyl such as 1,2-thiazolyl, 1,3-thiazolyl; thiadiazolyl such as 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4thiadiazolyl, 1,2,5-thiadiazolyl; oxadiazolyl such as 1,2,3oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl; triazolyl such as 1,2,3-triazolyl, 1,2,4-triazolyl; tetrazolyl such as 1H-tetrazolyl, 2H-tetrazolyl, etc. These heterocyclic groups may each have substituents such as lower alkyl groups of 1 to 3 carbon atoms.

  
  <EMI ID = 16.1>

  
lower trihaloalkyl groups (eg trifluoromethyl, trichlorethyl), hydroxyl, msrcapto, amino, carboxyl, carbamoyl, di-lower alkyl groups (having 1 to 3 carbon atoms) - lower aminoalkyl of 1 to 3 carbon atoms (eg dimethylaminoethyl , dimethylaminomethyl), carboxymethyl, carbamoylmethyl, carboxymethylthio, sulfomethyl, methoxycarbonylamino groups.

  
The number of such substituents which may be present on the heterocyclic group is normally 1 or 2. The ammo group

  
  <EMI ID = 17.1>

  
eg pyridinium which may optionally be substituted by a

  
  <EMI ID = 18.1>

  
moyle, carbomethoxycarbamoyl, cyanocarbamoyl, carboxymethyl,

  
  <EMI ID = 19.1> <EMI ID = 20.1>

  
With reference to the compounds of formula (I), the group,

  
  <EMI ID = 21.1>

  
  <EMI ID = 22.1>

  
lower having 2 to 4 carbon atoms such as acetyloxy, or the thio-heterocyclic group in which the heterocyclic ring is non-substituted or substituted.

  
The preferred substituents of the heterocyclic ring of the thio-heterocyclic group are one or two lower alkyl radicals.

  
  <EMI ID = 23.1>

  
thio, 1,2-dimethyl-1,3,4-triazol-5-yl-thio, etc.

  
If R is a carbamoyioxy group whose amino group has been protected, for example N-chloroacetylcarbamoyloxy, N-dichloroacetylcarbamoyloxy or N-trichloroacetylcarbamoyloxy, this protecting group for the aminogenic group can be removed by a pro

  
  <EMI ID = 24.1>

  
  <EMI ID = 25.1>

  
which is described later. Generally compound (I) is used

  
  <EMI ID = 26.1>

  
eg carbamoyloxymethyl) free and unprotected, as compound

  
  <EMI ID = 27.1>

  
  <EMI ID = 28.1>

  
or a protecting group for the amine function, the latter being any one of the known protecting groups generally used for the protection of amines, that is to say a conventional protecting group for the amine function. Thus, these protective groups include inter alia aromatic acyl groups such as phthaloyl, benzoyl, benzoyl substituted with halogen, a nitro or lower alkyl radical of 1 to 4 carbon atoms (for example chlorobenzoyl, para-nitrobenzoyl, para-

  
  <EMI ID = 29.1>

  
noxyacetyl; benzenesulfonyl; benzenesulfonyl substituted with

  
a lower alkyl radical of 1 to 4 carbon atoms (for example

  
  <EMI ID = 30.1> acyl group derived from aliphatic or halogenated aliphatic carboxylic acids such as acetyl, valeryl, caprylyl, ndecanoyl, acryloyl, pivaloyl, haloacetyl (e.g. monochloroacetyl, monobromacetyl, dichloroacetyl, trichloroacetyl, dichloroacetyl); a camphosulfonyl group; methanesulfonyl; esterified carboxyl groups such as ethoxycarbonyl, tert-butyloxycarbonyl, isobornyloxycarbonyl, phenyloxycarbonyl, trichlorethoxycarbonyl, benzyloxycarbonyl, etc .; carbamoyl groups such as methylcarbamoyl, phenylcarbamoyl, naphthylcarbamoyl, etc .; and corresponding thiocarbamoyl groups.

  
The cephalosporin derivative of formula (I) is believed to have a tautomeric form, i.e. a 2-minothiazole- compound and a 2-iminothiazoline compound as shown below, although it is described as a compound. thiazole throughout this brief.

  

  <EMI ID = 31.1>


  
Although the carboxyl group at position 4 of the foraul compound (I) may be free, it may form a salt, for example.

  
  <EMI ID = 32.1>

  
ple sodium or potassium; a basic amino acid, for example

  
  <EMI ID = 33.1>

  
can form acidic salt with mineral acid such as hydrochloric acid, sulfuric acid, etc. or with an organic acid such as toluenesulfonic acid, benzenesulfonic acid, etc.

  
also

  
The 4-carboxyl group can be one of those biologically active ester forms which results in eg increased blood concentrations and prolonged efficacy. These remains

  
  <EMI ID = 34.1>

  
ethyl, isopropoxyethyl), etc .; lower alkylthiomethyl groups of 1 to 3 carbon atoms, for example methylthio-

  
  <EMI ID = 35.1>

  
(I) are also within the scope of the present invention.

  
As known cephalosporins or penicillins, the compounds
(I) according to the present invention can be administered under

  
  <EMI ID = 36.1>

  
granules. Thus, compounds (I) are new compounds which show excellent activity against a broad spectrum of bacteria including gram-negative bacteria such as

  
  <EMI ID = 37.1>

  
with p-lactamase. The compound (I) can be used for example as a disinfectant to eliminate the above microorganisms

  
  <EMI ID = 38.1>

  
If the compound (I) is used as an anti-infective agent, for example for the treatment of intraperitoneal infectionsa,

  
infections of the respiratory organs, urinary tract infections and other infectious diseases produced by the microorganisms mentioned above, it can be safely administered to mammals including humans, mice and rats to daily doses of 0.5 to 80 mg per kilogram of body weight, preferably 1 to 20 mg on the same basis in 3 or 4 daily portions. The compounds (I) can

  
  <EMI ID = 39.1>

  
granules and tablets which can be made by known techniques. If the compound (I) is used by injection, the carrier can for example be distilled water or physiological solution. In the case where the compound (I) is used in capsule, powder, granule or tablet, the compound (I) is used for example in admixture with known pharmacologically acceptable excipients, for example starch, lactose, sucrose, calcium carbonate, calcium phosphate).,. binders

  
  <EMI ID = 40.1>

  
cellulose, crystallized cellulose, etc.), lubricants (stearate, magnesium, talc, etc.), and disintegrating agents
(eg carboxymethyl-calcium, talc, etc.).

  
The compound (I) of the present invention can be prepared by a process known per se.

  
(1) Thus, the cephalosporin derivative of formula (I) is prepared by acylation of the 7-aminogenic group of the 7-aminocephalosporin compound of formula (II):

  

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formula (III)

  

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then removing, if necessary, the protecting group of the aminogenic group (Method I).

  
  <EMI ID = 46.1>

  
is used

  
free, or in the form of a reactive derivative / as an acylating agent to acylate the aminogenic group located in position 7 on the compound (II). Thus, the free acid (III), a metal salt

  
  <EMI ID = 47.1>

  
(eg sodium, potassium or calcium) an organic amine salt of the free acid (III) (eg trimethylamine salt or pyridine salt), or a reactive derivative thereof

  
  <EMI ID = 48.1> or acid bromide), anhydride, mixed anhydride, active amide, active ester etc. is subjected to the acylation reaction mentioned above. As examples of this active ester, there may be mentioned the para-nitrophenyl ester, 2,4-dinitro-

  
  <EMI ID = 49.1>

  
mide ester and N-hydroxyphthalimide ester. As examples of mixed anhydrides, there may be mentioned the mixed anhydride with a carbonic acid monoester (for example ethyl hydrogen carbonate or isobutyl hydrogen carbonate) and a mixed anhydride with a lower alkanoic acid which can be substituted by a halogen group (eg pivalic acid or trichloroacetic acid). If the carboxylic acid (III) is used as the free acid or as a salt, a suitable condensing agent can be used. As examples of this condensing agent, mention may be made of the N, N'- carbodi-imides.

  
  <EMI ID = 50.1>

  
azolides, for example N, N'-carbonylimidazole and N, N'-thionyldi.-imidazole; dehydrating agents, for example Nethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, oxychloride, phosphorus and alkoxyacetylene; 2-halopyridinium salts (for example methyl-2-chloropyridinium iodide, methyl-2-fluoropyridinium iodide) etc. if such a condensing agent is used, it is believed that the reaction takes place via the reactive carboxylic acid derivative (III).

  
  <EMI ID = 51.1>

  
The reaction is usually carried out in a suitable solvent. As examples of solvents, there may be mentioned halogenated hydrocarbons such as chloroform, methylene dichloride, etc., ethers, for example tetrahydrofuran, dioxane, etc .; dimethylformamide; dimethylacetamide; acetone,

  
water and mixtures of these solvents. The proportion of said acylating agent is normally 1 to 5, and preferably

  
&#65533; ur

  
  <EMI ID = 52.1>

  
reaction is generally carried out at temperatures comprising

  
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protective group of the amine function can be removed if necessary. The elimination of the protective group of the amine function can generally be carried out by known methods (for example by the method described in Japanese patent application N [deg.] 52083/1975 and in the book: Pure and Applied Chemistry, Z 335 (1963)) or a similar process.

  
  <EMI ID = 54.1>

  
preferably 1 to 3 hours.

  
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a carbamoyloxy group whose aminogenic group has been protected, such as an N-monohaloacetylcarbamoyloxy group (e.g.

  
  <EMI ID = 56.1>

  
genoacetyl (eg monochloracetyl) can be simultaneously removed. In this case, the protecting group of the aminogenic group represented by R2 is preferably a monohaloacetyl group. The elimination reaction of the monohaloacetyl group from the amino group is carried out by reacting a compound of formula (I) whose amino group or amino groups have been protected by a monohaloacetyl group, with thiourea and a basic substance . Normally, this reaction is carried out in a solvent at a temperature around room temperature, and in a large number of cases, this reaction becomes complete in a time varying from 1 to 10 hours and more. The solvent can be any solvent which will not interfere with the present reaction.

   Thus, there may be mentioned ethers, for example ethyl ether, tetrahydrofuran, dioxane, etc .; lower alcohols, for example methanol, ethanol, etc .; halogenated hydrocarbons, for example chloroform, methylene dichloride, etc .; esters, for example ethyl acetate, butyl acetate; ketones, for example acetone, methyl ethyl ketone, etc .; water and various mixtures of these solvents.

  
This reaction to remove the N-haloacetyl group

  
  <EMI ID = 57.1>

  
Sition 3 of compound (I) does not continue for long when thiourea alone acts on compound (I). However, if the compound (I) reacts with thiourea and a basic substance, the desired reaction to remove the monohaloacetyl group takes place selectively and slowly to give the compound -carbamoyloxymethyl (I). As the basic substance, there can be used for this purpose an alkali metal or alkaline earth metal salt of a lower aliphatic carboxylic acid or

  
  <EMI ID = 58.1>

  
greater than 9.5 and preferably between 9.8 and 12. As examples of this salt of lower aliphatic carboxylic acid, there may be mentioned the salts of aliphatic carboxylic acids

  
  <EMI ID = 59.1> sodium, potassium, calcium, barium, sodium formate, sodium propionate, potassium hexanoate, etc. As examples of said mineral base, there may be mentioned the alkali metal salts of carbonic acid) such as sodium potassium carbonates, etc. The organic base can for example be one of the amines mono-, di- or tri-substituted by lower alkyl groups, the lower alkyl group having from 1 to 4 carbon atoms, for example trimethylamine, triethylamine, ethylamine, methylamine, diethylamine, dimethylamine, tributylamine, dibutylamine, butylamine, etc .; and 5- or 6-membered cyclic amines substituted on nitrogen with lower alkyl groups of 1 or 2 carbon atoms) such as N-methylpyrrolidine, N-ethylpyrrolidine, N-methylpiperazine, Nethylpiperazine, etc.

   Although, as said above, thiourea is used in this reaction, this can also be carried out successfully with N- or N, N-substituted thioureas.

  
  <EMI ID = 60.1>

  
noacetamidolcephalosporin of formula (V)

  

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  <EMI ID = 62.1>

  
is a residue of a nucleophilic compound, is prepared by reacting a compound of formula (IV)

  

  <EMI ID = 63.1>


  
  <EMI ID = 64.1>

  
an acyloxy, carbamoyloxy or halogen group, with a nucleophilic compound, then removing if necessary the protecting group of the aminogenic group (Method 2).

  
  <EMI ID = 65.1>

  
(IV), for example, mention may be made of acyloxy groups derived from a lower aliphatic carboxylic acid having 2 to 4 carbon atoms which may optionally be substituted by oxo, carboxyl or ethoxycarbamoyl groups, for example acetyloxy, propionyloxy, 3- radicals. oxobutyryloxy, 3-carboxypropionyloxy, 3-ethoxy-carbamoylpropionyloxy, 4-carboxybutyryloxy, etc .; and groups, acyloxy derived from aromatic carboxylic acid, which may optionally be substituted by hydroxyl, carboxyl, carboethoxy-carbamoyl or carboethoxy-carbamoyl or carboethoxysulfamoyl groups, for example the mandelyloxy, 2carboxybenzoyloxy, 2- (carboethoxycarbamoyl) benzoyloxy and 2-

  
  <EMI ID = 66.1>

  
may for example be chlorine, bromine or iodine. The rest of a

  
  <EMI ID = 67.1>

  
  <EMI ID = 68.1>

  
However, it is generally advantageous to use a compound (IV) having an acyloxy group derived from a lower aliphatic carboxylic acid such as acetyloxy. The nucleophilic compound used in this reaction is a compound corresponding to the residue of a nucleophilic compound designated by the symbol R5 in the formula (V). Most preferred are heterocyclic thiol compounds, for example mercapto compounds, which may contain a substituent. Among the nucleophilic compounds correspond-

  
  <EMI ID = 69.1>

  
can be used in their free form, although it is preferable to use them in the form of alkali metal salts, for example sodium or potassium salts. This reaction is preferably carried out in a solvent. For example, one can use water, heavy water or an organic solvent which is easily miscible with water and does not react with the reagents, for example dimethylformamide, dimethylacetamide, dioxane, acetone, alcohol, acetonitrile , dimethylsulfoxide and tetrahydrofuran. Although the temperature of the reaction and the duration thereof vary; with these factors such as the special starting materials and the solvent used, the temperature is generally 0 to 100 [deg.] C, preferably 30 to
70 [deg.] C, and the duration of 2 to 48 hours, preferably 3 to 15 hours.

   The reaction is preferably carried out in the vicinity of neutrality and takes place at a pH of between about 2 and 8, preferably at pH 5 to 8. The course of this reaction can sometimes be made slow by adding a salt of. Quaternary ammonium having a surface tension such as trimethylbenzylammonium bromide or triethylbenzylammonium bromide or triethylbenzylammonium hydroxide. In addition, more satisfactory results are obtained when the reaction is carried out in an atmosphere of an inert gas, such as nitrogen. to prevent oxidation by atmospheric air of mercapto compounds.

  
(3) The. Cephalosporin derivative of formula (I) can also be prepared by subjecting a 7- [2- (2-amino-thiazol-

  
  <EMI ID = 70.1>

(VI)

  

  <EMI ID = 71.1>


  
  <EMI ID = 72.1>

  
lation) is carried out by reacting the compound (VI) with a methylating agent (Method 3).

  
This 0-methylation reaction is normally carried out in a solvent while cooling with ice or ice.

  
(0 [deg.] To 40 [deg.] C, preferably 5 [deg.] To 30 [deg.] C)

  
neighborhood of ordinary temperature / and, in many

  
, this 5 minutes at <2> hours-. solvent

  
  <EMI ID = 73.1>

  
can be any solvent which does not interfere with the reagents, such as ethers, for example tetrahydrofuran, dioxane, etc .; lower alcohols, eg methanol, ethan, etc .; halogenated hydrocarbons, for example chloroform, methylene chloride, etc .; esters, for example ethyl acetate, butyl acetate, etc .; amides, for example

  
  <EMI ID = 74.1>

  
organic chemistry, such as a methyl halide (eg methyl iodide, methyl bromide), dimethyl sulfate, diazomethane, etc.

  
This reaction can take place slowly in the presence of a suitable base) except in the case of diazomethane. As such a base, normally an inorganic base such as an alkali metal salt of carbonic acid (eg sodium carbonate, potassium carbonate), hydroxides is used.

  
alkali metals (eg sodium hydroxide, potassium hydroxide). If the stability of the compound (VI) is to be taken into consideration, however, sodium carbonate, potassium carbonate or the like is preferably used. This reaction can also be used in a buffer of pH about 7.5-8.5.

  
The cephalosporin (I) compounds which are prepared by the various manufacturing methods described above can each

  
  <EMI ID = 75.1>

  
column chromatography, extraction, precipitation, recrystallization, etc. If necessary, each of these compounds can be treated by methods known per se to obtain the desired salts, esters.

  
One of the starting materials for the present invention,

  
  <EMI ID = 76.1>

  
ple according to several different methods described in more detail below.

  
(I) First, a derivative of 4-halo-3-oxo-2oxyiminobutyric acid of formula (VII)

  

  <EMI ID = 77.1>


  
in which X is halogen, for example chlorine or

  
  <EMI ID = 78.1>

  
lower alkyl group (the 1 to 3 carbon atoms, for example methyl, ethyl or propyl, is reacted with thiourea

  
  <EMI ID = 79.1>

  
noacetic of formula (VIII):

  

  <EMI ID = 80.1>


  
  <EMI ID = 81.1>

  
  <EMI ID = 82.1> respectively, compound (VIII) is normally prepared as a mixture of these syn and anti isomers. This reaction is normally carried out by reacting a compound of formula (VII) with a thiourea in an organic solvent) such as ethanol, methanol or tetrahydrofuran at temperature

  
  <EMI ID = 83.1>

  
derived from the obtained mixture of syn- and anti- isomers of the compound
(VIII), one of the following methods can be used successfully. Thus, these processes include the fractional crystallization process, which is based on the advantage due to the difference in crystallization ability or solubility of isomers of compound (VIII) itself of a salt of compound (VIII) halohydrate. , (for example hydrobromide or hydrochloride) or of a derivative of the compound (VIII) with; a protective group on its 2-aminogenic group, the protective group (for example monochloroacetyl or dichloroacetyl) having been introduced by a method known per se; isolation by chromatography and / a method such as when the compound (VIII) or the compound (VIII) with protecting group on the 2-aminogen group is hydrolyzed, on its posi-

  
  <EMI ID = 84.1>

  
In the last mentioned process, because of the higher rate of hydrolysis for the anti-isomer than for the isomer-

  
  <EMI ID = 85.1>

  
mine. The hydrolysis reaction of the ester bond of the compound
(VIII) with or without a substituent on its 2-aminogen group,

  
  <EMI ID = 86.1>

  
molar values of an alkali metal hydroxide, for example potassium hydroxide or sodium hydroxide at a

  
  <EMI ID = 87.1>

  
in water or in a mixture of water with an organic solvent miscible with water, for example methanol, ethanol, acetone,

  
  <EMI ID = 88.1>

  
acetamide. If R6 in compound (VIII) is hydrogen,

  
  <EMI ID = 89.1>

  
posed (VIII) in which R6 is a methyl group, subjecting the first compound (VIII) to methylation. This methylation reaction is normally carried out in a solvent while * (0 [deg.] To 100 [deg.] C, preferably 10 [deg.] To 50 [deg.] C). The duration of the reaction

  
is of the order of 1 to 30 hours, and preferably 1 to 5 hours.

  
cooling by ice or at similar temperatures

  
room temperature and, in many cases

  
is finished after a few minutes to several hours. For this purpose, the solvent used can be any type

  
solvent, only if it does not interfere with the reaction. For example, tetrahydrofuran, dioxane, methanol, ethanol, chloroform, methylene dichloride, ethyl acetate, butyl, N, N-dimethylformamide, N, N-dimethylacetamide and water can be used, as well as mixtures of these solvents. As the methylating agent, there may be mentioned methyl halides, for example methyl iodide and methyl bromide; dimethyl sulphate and diazomethane; to name a few. In all cases unless diazomethane is used,

  
  <EMI ID = 90.1>

  
react with said methylating agent in the presence of a base such as an alkali metal carbonate (eg sodium carbonate, potassium carbonate, etc.) or an alkali metal hydroxide (eg sodium hydroxide, hydroxide potassium, etc.). Some of the physical constants of the syn isomers of compounds (III) and (VIII) thus obtained are shown below compared to the physical constants of the corresponding anti isomers (see Table 1).

  
Table 1
  <EMI ID = 91.1>
 
  <EMI ID = 92.1>
 
  <EMI ID = 93.1>
 Notes: s: singlet

  
The methoxyimino (hydroxyimino) group in the "syn" isomer is cis with respect to the carboxyl function, and in the "anti" isomer is trans with respect to the carboxyl function.

  
(II) Process for the selective manufacture of compound (III)
(syn isomer) is described below. While the above-mentioned reaction of compound (VII) with thiourea gives a mixture of syn and anti isomers of compound (VIII), in many cases the anti isomer of compound (VIII) predominates. The Applicant's study of the conditions of the cyclization reaction gives an idea of the conditions to lead to

  
  <EMI ID = 94.1>

  
reaction of the compound (VII) with the thiourea to produce the compound (VIII) is carried out under the conditions described below.

  
  <EMI ID = 95.1> a ratio between 2: 98 and 50:50.

  
The Applicant has discovered, however, that if this cyclization reaction is carried out in water or in a mixture of water and a solvent miscible with water, such as methanol,

  
  <EMI ID = 96.1>

  
mide, N, N-dimethylacetamide or N-methylpiperidone and in the presence of a basic substance the syn isomer of compound (VIII) is made selectively (normally in a ratio of about
85:15 to 100: 0). As the basic substance usable for this reaction, there may be mentioned the alkali or alkaline earth metal salts of lower aliphatic carboxylic acids, and mineral or organic bases having a pKa value not less than 9.5, of preferably between 9.8 and 12.0.

   As examples of lower aliphatic carboxylic acid salts, there may be mentioned the salts of lower aliphatic carboxylic acids having 1 to 6 carbon atoms, such as sodium, potassium, calcium, barium acetate, sodium formate. , sodium propionate, potassium hexanoate, etc .; while the mineral bases mentioned above include the alkali metal salts of carbonic acid such as sodium carbonate, potassium carbonate, etc.

   As organic bases, there may be mentioned tri-(lower) alkyl amines in which the lower alkyl group has 1 to 4 carbon atoms such as trimethylamine, triethylamine, tributylamine, etc., and substituted 5 or 6 membered cyclic amines. on nitrogen by lower alkyl groups of 1 or 2 carbon atoms, such as N-methylpyrrolidine, N-ethylpyrrolidine, N-methyl-

  
  <EMI ID = 97.1>

  
N, N-dimethylacetamide or N-methylpyrrolidone is used as a solvent, it is not always necessary to add said basic substance. *

  
(III) Compound (VIII) (syn isomer) can also be selectively prepared by the following method. Thus, in a subsequent search for a process for the selective manufacture of the syn isomer, the Applicant has discovered that by reacting a 2-aminothiazol-4-ylglyoxyl acid derivative of formula

  
  <EMI ID = 98.1>

  
hours (preferably 1 to 5 hours).

  

  <EMI ID = 99.1>


  
  <EMI ID = 100.1>

  
Normally this reaction can be carried out slowly in a suitable solvent at pH of about 4.0 to 9.0. The mentioned solvent can be any type of solvent unless it is included.

  
  <EMI ID = 101.1>

  
ethers such as ethyl ether, tetrahydrofuran, dioxane, etc .; lower alcohols such as methanol, ethanol, etc .; halogenated hydrocarbons such as chloroform, methylene dichloride, etc .; esters such as ethyl acetate, butyl acetate, etc .; some water; and mixtures of these solvents.

  
  <EMI ID = 102.1>

  
ordinary, it can be accelerated by heating. The temperature and duration of the reaction are generally of the order of 0 [deg.] To
100 [deg.] C (preferably 0 [deg.] To 50 [deg.] C) and 1 to 10 hours (preferably 1 to 5 hours).

  
The starting compound (IX) for this reaction can be prepared according to the reaction described below. For example, hydrolysis of the compound ni throne of formula (X)

  

  <EMI ID = 103.1>


  
in which R2 and R7 have already been defined give the compound
(IX). This hydrolysis reaction takes place slowly in the presence of mineral acid and is normally carried out in a solvent. As examples of mineral acid, there may be mentioned hydrochloric acid, sulfuric acid, phosphoric acid, etc. The solvent can be any of the desired types which does not interfere with the reaction. Thus there may be mentioned, for example, tetrahydrofuran, dioxane, etc .; alcohols, for example methanol, ethanol, etc .; ketones, for example acetone, methyl ethyl ketone; water and mixtures of these solvents. Normally, this reaction can be carried out while cooling with ice or at room temperature. The starting compound (X) can be prepared by subjecting a

  
  <EMI ID = 104.1>

  
whose amino group in position 2 has been protected, at the same time

  
i <EMI ID = 105.1>

  
thylation. The conditions of this methylation reaction are essentially the same as the conditions under which the above mentioned compound (VIII) in which R6 is hydrogen is methylated. (see process N [deg.] (I) above).

  
Under the methylation conditions thus described, the methylation

  
  <EMI ID = 106.1>

  
  <EMI ID = 107.1>

  
as the dominant product.

  
The compound of formula (VII) can be prepared for example by the method described in Journal of Medicinal Chemistry, 16,

  
  <EMI ID = 108.1>

  
RFA to the public inspectorate N [deg.] 2 556 736 or else by procedures identical to these. The compound of formula (II) used in the present invention can be prepared, for example, by a pro

  
  <EMI ID = 109.1>

  
RFA patent application N [deg.] 2,607,064 (Dutch patent application N [deg.] 7,601,902), RFA patent application N [deg.] 2,619,243, Japanese patent application n [deg. .] 52083/1975, the RFA patent applications N [deg.] 2 460 331 and 2 460 332 or by processes similar to these.

  
  <EMI ID = 110.1>

  
  <EMI ID = 111.1>

  
prepared for example by the process described below:
(see further reactions on page 21)
  <EMI ID = 112.1>
   <EMI ID = 113.1>

  
  <EMI ID = 114.1>

  
has been defined previously.

  
The reaction of the derivative, 3-deacetyl-cephalosporanic acid of formula (A) with a monohaloacetyl-isocyanate (B) is normally carried out slowly by contacting the two reactants in an appropriate solvent, either by cooling with ice. , or at a temperature close to ordinary temperature. The solvent used for this purpose can be any solvent which does not interfere with this reaction. For example ethers such as ethyl ether, tetrahydrofuran, dioxane, etc .; ketones such as acetone, methyl ethyl ketone, etc .;

  
halogenated hydrocarbons such as chloroform, dichloride

  
methylene, trichloroethane, etc .; esters such as ethyl acetate, butyl acetate, etc .; and mixtures of these sol-

  
  <EMI ID = 115.1>

  
starting compound (A). The monohaloacetyl-isocyanate (B) can be prepared, for example, by the process described in Journal of

  
  <EMI ID = 116.1>

  
The reaction to remove the 7-acyl group from the compound of formula (C) [or (g)] can be any of the reactions generally used for the deacylation of penicillins.

  
and cephalosporins. Thus, for example, the process described in RFA patent applications N [deg.] 2,460,331 and 2,460,332, Japanese patent applications Na 13862/1966, 40899/1970 and N [deg.]
34387/1972 and U.S. Patent No. [deg.] / ', Etc. may *. be used-successfully. By way of illustration, the compound (C) [or (g)] is treated with an agent forming an imide halide to obtain the corresponding imide halide first and then the latter compound is then treated with an alcohol. to have the corresponding ether imide. This imide-ether is hydrolyzed to the corresponding 7-amino derivative (d) [or (h)].

  
As the imide halide-forming agent, it is possible to use

  
  <EMI ID = 117.1>

  
fre and acid halides derived from leuis oxy acids

  
(eg phosphorus oxychloride, phosphorus pentachloride phosphorus trichloride, thionyl chloride, phosgene,

  
  <EMI ID = 118.1>

  
para-toluenesulfonyl chloride, etc.), for example. This reaction forming the imide halide is normally advantageously carried out in a solvent. Solvents used for this purpose include not only conventional inert solvents

  
  <EMI ID = 119.1>

  
tertiary amines (such as triethylamine, pyridine, dimethylaniline, etc.) and other solvents as well as mixtures of these solvents. The reaction forming imide-ethers is carried out by contacting the reaction mixture of halide-imide with an alcohol. Alcohols which can normally be used include lower alkanols containing

  
1 to 4 carbon atoms, such as methanol, ethanol and n-butanol. The hydrolysis mentioned above is carried out by contacting the reaction mixture containing the imidoether product with water. In order to avoid side reactions, the reactions mentioned above are preferably carried out under cooling.

  
The reaction to remove the monohaloacetyl group

  
of compound (c) (or (e)] is substantially the same reaction as that used to remove the same group from compound (I) which is described above.

  
Referring to formulas (A) and (B) above, the groups

  
  <EMI ID = 120.1>

  
the following: such as acyl groups derived from carboxy- acid

  
  <EMI ID = 121.1>

  
ne, and acyl groups derived from cycloaliphatic carboxylic acid containing up to 6 carbon atoms, for example formyl, acetyl, propionyl, hexanoyl, butanoyl, heptanoyl, octanoyl, cyclopentanoyl, etc .; acyl groups derived from lower aliphatic carboxylic acid (up to 4 carbon atoms) substituted by phenyl or phenoxy groups,

  
  <EMI ID = 122.1>

  
propionyl, α-phenoxybutyryl, para-nitrophenylacetyl, etc .; acetyl or thioacetyl groups substituted with a 5- or 6-membered heterocyclic group comprising a heteroatom

  
  <EMI ID = 123.1>

  
comprising said hetero atom and 1 or 3 additional hetero atoms selected from the class consisting of N, S and 0, which latter heterocyclic group may in turn be optionally substituted by an aminogen or hydroxyl group, or by the group

  
  <EMI ID = 124.1> acetyl, tetrazplylacetyl, tetrazolylthioacetyl, a- (2-pyridyloxy)

  
  <EMI ID = 125.1>

  
hydroxythiazol-4-yl) -acetyl, 2- (2-aminothiazol-4-yl) -acetyl, 4-pyridylthioacetyl, 1-pyrazolylacetyl, 2-furylacetyl, 6-

  
  <EMI ID = 126.1>

  
thio-3-oxobutyryl, 4-carbamoylmethylthio-3-oxo-butyryl, etc .; α-substituted phenylacetyl groups, for example man- groups

  
  <EMI ID = 127.1>

  
glycyl substituted in position a by a 5 or 6-membered ring comprising an oxygen or sulfur atom as heteroatom,

  
  <EMI ID = 128.1>

  
a nitrogen atom as additional hetero-atom, the latter ring is substituted by an aminogen or hydroxyl radical, by

  
  <EMI ID = 129.1>

  
dienyl glycyl, thienylglycyl, para-hydroxyphenylglycyl, furylglycyl, 2-aminothiazol-4-ylglycyl, 2-hydroxythiazol-4-ylglycyl, etc .; acyl groups derived from diaubstituted aliphatic carboxylic acid such as 5-amino-5-carboxyvaleryl groups, etc .; and heterocyclic acyl groups, for example 5-methyl-3-

  
  <EMI ID = 130.1>

  
Compound (A) can be prepared generally (1) by acylating 7-aminocephalosporanic acid (7-ACA) with an acylating agent corresponding to the acyl group, represented by 5., according to known methods for acylation of an aminogenic group at position 7 of a cephalosporin mentioned above, and removing the 3-acetyl group by enzymes from the same cephalosporin having a 3-acetoxymethyl group: (Biochemical Journal _81, 591 (1961 )); or (2) by preparing by fermentation

  
  <EMI ID = 131.1>

  
carboxylic (cephalosporadesic acid, deacetylcephalosporin 0, DCPC) [Nature 246, 154 (1973); Japanese patent application

  
  <EMI ID = 132.1>

  
  <EMI ID = 133.1>

  
  <EMI ID = 134.1>

  
posed nucleophile according to the present invention can be synthesized <EMI ID = 135.1>

  
  <EMI ID = 136.1>

  
read

  
  <EMI ID = 137.1>

  
  <EMI ID = 138.1>

  
this one. Alternatively, this compound can be prepared by applying the above-mentioned method (1) to the compound (III)

  
  <EMI ID = 139.1>

  
can be obtained by one of the processes mentioned above as processes for the preparation of the compound / or processes analogous thereto. The compound (VI) can be prepared for example according to a process analogous to that described in the patent application

  
  <EMI ID = 140.1>

  
mother syn of compound (VIII) in which R6 is hydrogen.

  
The present invention is illustrated in more detail by the descriptive and non-limiting examples below, to which any variant can be made without departing from the scope of the present invention. In these examples, "g", "mg", "kg", "ml",

  
  <EMI ID = 141.1>

  
"part per million", "Herz", "mega Herz", "Mole", "milliMole", "microgram", "Calculated", "dimethyl sulfoxide," Nanometer ", and" decomposed ", respectively. The resins known as" Amberlite "are products manufactured by Rohm & Haas Co. in USA All temperatures are / corrected and percentages are all expressed by weight unless otherwise indicated. NMR spectra given here are measured using a model spectrometer

  
  <EMI ID = 142.1>

  
lane as internal or external reference and all values 6 are expressed in ppm. The symbol s means singlet, d

  
  <EMI ID = 143.1>

  
coupling aunt.

  
REFERENCE EXAMPLE 1

  
In a solution of 13.3 g of sodium carbonate in 120 ml of water, 10 g of ethyl 3-oxo-2-hydroxyimino-butyrate are dissolved, then 30 ml of methanol are added. The mixture is cooled with ice, and while stirring is added dropwise
15.8 g of dimethylsulfate over 3 minutes. After the dropwise addition is complete, the ice bath is removed and the mixture is stirred at room temperature for
40 minutes. The reaction mixture (pH 8 or greater than 8)

  
is extracted twice with ethyl acetate and the extracts are combined, washed with water and dried. The solvent is then removed by evaporation under reduced pressure and the residue is distilled off under reduced pressure. By this process we obtain

  
  <EMI ID = 144.1>

  

  <EMI ID = 145.1>


  
  <EMI ID = 146.1>

  
Reference example 2

  
(1) In 120 ml of chloroform, 27.3 g of ethyl3oxo-2-methoxyiminobutyrate was dissolved, and the solution was heated to 4000. Then, a solution of 25.3 g of bromine in 30 ml of chloroform was added dropwise. drop within 30 minutes. The mixture is stirred and allowed to react at room temperature for one hour. The reaction mixture is washed successively with a 5% aqueous solution of sodium bicarbonate and then with water, and the organic layer is dried. The solvent is then removed by distillation under pressure.

  
  <EMI ID = 147.1>

  
iminobutyrate as an oily product. NMR spectrum (60 MHz, in CDCl3):

  
  <EMI ID = 148.1>

  
BrCH2C0)

  
(2) In 20 ml of ethanol, 5 g of the above product is dissolved, then 1.8 g of thiourea is added. The mixture is heated at reflux for 3 hours. After cooling, the precipitate is collected by filtration and dissolved in 20 ml of water,

  
  <EMI ID = 149.1>

  
separated is extracted with ethyl acetate. The ethyl acetate layer is washed and dried. Then the ethyl acetate is evaporated off to obtain white crystals. Recrystallization from ethanol gives 2.6 g (57.2% ', ethyl 2- (2-aminothiazol-4-yl) -2- (anti) -methoxyiminoacetate

  
  <EMI ID = 150.1>

  

  <EMI ID = 151.1>


  
  <EMI ID = 152.1>

  
(3) the. filtrate. obtained, collecting the first crop of precipitated crystals is concentrated under reduced pressure and sodium bicarbonate is added to the precipitate. The mixture is extracted with ethyl acetate and the oil obtained from the ethyl acetate layer is purified by chromatography on a silica gel column. By this process we obtain 59 mg

  
  <EMI ID = 153.1>

  

  <EMI ID = 154.1>


  
  <EMI ID = 155.1>

  
6.74 ppm (1H, s., Thiazole 5H)

  
Reference example 3

  
  <EMI ID = 156.1>

  
and the mixture is stirred at room temperature for 3 hours. The ethanol is then removed by evaporation under reduced pressure and 350 ml of water are added. The aqueous layer is washed with ether, neutralized with sodium bicarbonate (pH 7.5) and extracted with a mixture of ethyletetrahydrofuran acetate (1: 1). The organic layer is washed with water and dried. The solvent is then distilled off to obtain 45 g of crystalline product.

  
A portion of 1 g of the above product is taken and purified by chromatography on a silica gel column (elution solvent: ethyl acetate-n-hexane). The first fraction gives 650 mg of anti-ethyl -2- (2-amino-thiazol4-yl) -2-hydroxyiminoacetate isomer and 150 mg of syn isomer are obtained from the second fraction. Anti-crystal isomer <EMI ID = 157.1>

  

  <EMI ID = 158.1>


  
  <EMI ID = 159.1>

  
Reference example 4

  
In 150 ml of water, 10.6 g of sodium carbonate are dissolved.

  
  <EMI ID = 160.1>

  
150 ml of tetrahydrofuran and 50 ml of methanol. While cooling with ice, 12.6 g of dimethyl sulfate is added dropwise over 5 minutes. After the drip addition is complete, the ice bath is removed and

  
the mixture is stirred at room temperature. During agitation, white crystals begin to separate. At the end of

  
3 hours, most of the organic solvent is distilled off under reduced pressure and the residue is cooled with ice. The resulting precipitate is collected by filtration, washed with water and dried. By the above process

  
  <EMI ID = 161.1>

  
methoxyiminoacetate in the form of white crystals. By its NMR spectrum and other properties, this product is

  
  <EMI ID = 162.1>

  
Reference example 5

  
2.15 g are dissolved in 10 ml of N, N-dimethylacetamide

  
  <EMI ID = 163.1>

  
from ice, 1.27 g of chloroacetyl chloride are added dropwise. The mixture is stirred while cooling with ice for 30 minutes, then at room temperature for 30 minutes. The reaction mixture is diluted with 50 μl of water and extracted twice with 100 ml each time of ethyl acetate. The extracts are combined, washed successively with a 5% aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, then dried.

  
The solvent is then removed by evaporation, which makes it possible to obtain 2.04 g of ethyl 2- (2-chloracetamidothiazol-4-yl) -2-

  
  <EMI ID = 164.1>

  

  <EMI ID = 165.1>


  
  <EMI ID = 166.1>

  
7.15 ppm (1H, s., Thiazole 5-H)

  
Reference example 6

  
To a solution of 9 g of potassium hydroxide in a mixture of 85 ml of water and 452 ml of ethanol was added 9.62 g

  
  <EMI ID = 167.1>

  
acetate and the mixture is stirred at room temperature for 2 hours. The ethanol is removed by distillation under reduced pressure and, after adding 85 ml of water, the mixture is washed.

  
the residue with 100 ml of ethyl acetate. The aqueous layer is adjusted to pH 2 with 10% hydrochloric acid and extracted

  
twice with 200 ml portions of ethyl acetate. The extracts are combined, washed with a saturated aqueous solution of sodium chloride and dried. The solvent is then removed

  
  <EMI ID = 168.1>

  

  <EMI ID = 169.1>


  
NMR spectrum (60 MHz, in d6-DMSO): 3.95 ppm (3H, singlet,

  
  <EMI ID = 170.1>

  
(1H, singlet, 5-H thiazole).

  
Reference example 7

  
  <EMI ID = 171.1>

  
2- (2-aminothiazol-4-yl) -2-methoxyiminoacetate are chloroacetylated with chloroacetyl chloride as in Reference Example 5, and 30 ml of ether is added to the resulting mixture of the syn and anti-ethyl forms 2- (2-Chloracetamidothiazol-4-yl) -2methoxyiminoacetate. The crystals which: have separated. are <EMI ID = 172.1>

  
  <EMI ID = 173.1>

  
Yield 600 mg.

  
The oil obtained by concentrating the filtrate (2.42 g of a

  
  <EMI ID = 174.1>

  
879 mg of potassium hydroxide in a mixture of 5 ml of water and 80 ml of ethanol, while cooling with ice and the whole is stirred at this temperature for 15 minutes. The ethanol is distilled off under reduced pressure and the residue is diluted with 50 ml of water and extracted twice with 100 ml of ethyl acetate each time. The ethyl acetate layer is washed with water and dried. The ethyl acetate is removed by distillation, which makes it possible to obtain 577 mg

  
  <EMI ID = 175.1>

  
tate [Product (B)]. By its NMR spectrum and other properties, this product is identical to the syn isomer prepared in

  
  <EMI ID = 176.1>

  
give a total yield of 1,076 g, ie a recovery rate of 96.8%.

  
Reference example 8

  
In 600 ml of 50% aqueous tetrahydrofuran, are dissolved

  
  <EMI ID = 177.1>

  
add 155 g of sodium acetate trihydrate and 53.2 g of thio-

  
  <EMI ID = 178.1>

  
4 hours. The reaction mixture is adjusted to pH 7.0 with sodium bicarbonate and, after adding sodium chloride

  
  <EMI ID = 179.1>

  
The extracts are combined, washed with water and dried.

  
The tetrahydrofuran is then removed by distillation to

  
  <EMI ID = 180.1>

  
results, this product was found to be an 82:18 mixture of syn and anti isomers.

  
An identical reaction is carried out without using sodium acetate. Based on the same criteria, the resulting product was found to be a 25:75 mixture of isomers.

  
  <EMI ID = 181.1>

  
Reference example 9

  
The reaction of Reference Example 8 was repeated except that 50% aqueous ethanol was used instead of 50% aqueous tetrahydrofuran. Also in this case, if sodium acetate is used, an 83:17 mixture of the syn and anti isomers is obtained.

  
  <EMI ID = 182.1>

  
conversely, if sodium acetate is not used, the reaction

  
  <EMI ID = 183.1>

  
proportions of syn and anti isomers is determined by the spectrum

  
  <EMI ID = 184.1>

  
Reference example 10

  
The reaction of Reference Example 9 is repeated except

  
that N, N-dimethylacetamide is used in place of the 50% aqueous mixture of tetrahydrofuran-sodium acetate. This method gives an 85:15 mixture of the syn and anti-ethyl isomers. 2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetate.

  
Reference example 11

  
In 10 ml of 50% aqueous ethanol, 200 mg are dissolved

  
  <EMI ID = 185.1>

  
under reduced pressure and the residue is diluted with 10 ml of water and extracted with ethyl acetate. The ethyl acetate layer is washed with water and dried. Ethyl acetate is in-

  
  <EMI ID = 186.1>

  
83:17 mixture of syn and anti isomers.

  
Reference example 12

  
In 70 ml of ethanol containing 10% HCl, the

  
  <EMI ID = 187.1>

  
for 16 hours. The reaction mixture is concentrated under reduced pressure and then, after adding 10 ml of water, the residue is adjusted to pH 7.5 with a 5% aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate layer is washed with water and dried. The ethyl acetate is then removed by distillation and the residue is

  
  <EMI ID = 188.1>

  

  <EMI ID = 189.1>


  
Reference example 13

  
In 50 ml of 1N hydrochloric acid, 1 g of the same N- (2-aminothiazol-4-yl-ethoxycarbonyl) methylenemethylamine Noxyde, used in Reference Example 12, is dissolved and the solution is stirred at room temperature for 5 hours. The reaction mixture is neutralized with sodium carbonate and extracted with ethyl acetate. Then, the process of Reference Example 12 is repeated to have 0.5 g of ethyl 2-aminothiazol-4-ylglyoxylate. Based on NMR and other results this product was found to be that obtained in Reference Example 12.

  
Reference Example 14

  
In 20 ml of ethanol containing 10% HCl, 1.2 g of methylnitronedu 2- (2-aminothiazol-4-yl) -2- are suspended.
(syn) -hydroxyiminoacetate, i.e. N- (2-aminothiazol4-yl-ethoxycarbonyl) methylenemethylamine-N-oxide, melting at
111.6 [deg.] C and the suspension is stirred at room temperature for 16 hours. Then the process of the example is repeated

  
  <EMI ID = 190.1>

  
glyoxylate as yellow crystals. By the NMR spectrum and the other properties, it is found that this product is identical to that obtained in Reference Example 12.

  
Reference example 15

  
Has a mixture of 10 ml of tetrahydrofuran and 5 ml of ac-

  
  <EMI ID = 191.1>

  
an excess of a diazomethane-ether solution is added. The mixture is left to stand at room temperature for 2 days. Then, the residual diazomethane is decomposed with acetic acid, the reaction mixture is concentrated under reduced pressure and the residue is recrystallized from ethyl acetate. By this process, 0.8 g of the compound methyl-nitrôn e, that is to say N- (2-aminothiazol-4-yl-ethoxycarbonyl) methylene- is obtained. <EMI ID = 192.1>

  

  <EMI ID = 193.1>


  
  <EMI ID = 194.1>

  
(1H, singlet, 5-H thiazole).

  
Reference example 16

  
Has a solution of 23 mg of sodium in 8 ml of methanol,

  
  <EMI ID = 195.1>

  
xyiminoacetate (melting point 145.3 [deg.] C) and, at room temperature, 280 mg of methyl iodide. The mixture is stirred for 45 minutes, after which it is concentrated under reduced pressure. The residue is diluted with water (pH 7 or greater than 7) and extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried and concentrated. The residue is recrystallized from an ethyl tetrahydrofuraneacetate mixture. By this process, 160 mg of the methylnitrone compound are obtained in the form of yellow crystals. This product is absolutely identical to that obtained in the reference example.

  
  <EMI ID = 196.1>

  
Reference Example 17

  
The filtrate obtained after collecting the precipitate of ethyl =

  
  <EMI ID = 197.1>

  
of the reaction mixture concentrated in the method of Reference Example 4, is extracted with an ethyl tetrahydrofuraneacetate mixture (1: 1) and the extract is washed with water, dried and concentrated. To the brown oily residue is added 20 ml

  
of tetrahydrofuran and the mixture is left to stand in a refrigerator overnight. The crystals obtained are collected by filtration and recrystallized from ethyl acetate. By this process, 1.3 g of ethyl methyl nitrone are obtained.

  
  <EMI ID = 198.1>
  <EMI ID = 199.1>
   <EMI ID = 200.1>

  
+

  
N-CH3), 5.34 ppm (2H, broad, singlet, NH2), 6.62 ppm

  
  <EMI ID = 201.1>

  
Reference Example 18

  
In 10 ml of tetrahydrofuran is dissolved 1.5 g of ethyl 4-bromo-3-oxo-2-methoxyiminobutyrate and then added

  
7 ml of water, 2.4 g of sodium acetate trihydrate and 0.9 g of thiourea. The mixture is stirred at room temperature for
17 hours, after which it is concentrated under reduced pressure. The concentrate is adjusted to pH about 1.5 with dilute hydrochloric acid and washed with ethyl acetate. The aqueous layer is neutralized with sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried and concentrated under reduced pressure to obtain 0.8 g of yellowish crystals. This product

  
  <EMI ID = 202.1>

  
you. Based on NMR and other results, this pro-

  
  <EMI ID = 203.1>

  
reference 2.

  
Reference Example 19

  
In 10 ml of dimethylformamide are dissolved 2 g of ethyl 4-bromo-3-oxo-2-methoxyiminobutyrate, then 1.2 g of thiourea are added. The mixture is left to react at room temperature for 5 hours. To the reaction mixture is added 20 ml of a saturated aqueous solution of sodium chloride, then the pH of the mixture is adjusted to about 1.5 with dilute hydrochloric acid. Then, the process of Reference Example 18 is repeated to obtain 1.1 g of pale yellow crystals. Based on NMR and other data, this product is found to be an 87:13 mixture of the syn and anti isomers.

  
  <EMI ID = 204.1>

  
Washing the product with small amounts of ether gives

  
  <EMI ID = 205.1>

  
Reference example 20

  
1) In 80 ml of anhydrous acetone are dissolved 20 g of 7- (5-carboxy-5-benzamidovalerylamido) deacetylcephalosporanic acid, then 7 g of chloroacetyl isocyanate are added. The mixture is stirred at 20 [deg.] C for 40 minutes, after which 200 ml of ether are added. The precipitate is collected by filtration and washed with 50 ml of ether. By this process we obtain <EMI ID = 206.1>

  
cetyl) -carbamoyloxymethyl-3-cephem-4-carboxylic acid in the form of a white powder.

  
  <EMI ID = 207.1>

  
0

  
not

  
  <EMI ID = 208.1>

  
5.77 ppm (1H, doublet, 7-H)

  
(2) In 80 ml of methylene dichloride containing 7.6 ml of

  
  <EMI ID = 209.1>

  
for 2 1/2 hours, after which it is cooled to -40 [deg.] C and 37 ml of cold methanol are quickly added. The mixture is then stirred at -5 [deg.] C for 25 minutes and after adding 22 ml

  
  <EMI ID = 210.1>

  
The reaction mixture is left to stand at 5 [deg.] C for 1 hour and then the precipitate is collected by filtration. By this process we

  
  <EMI ID = 211.1>

  

  <EMI ID = 212.1>


  
  <EMI ID = 213.1>

  
Reference example 21

  
While a mixture of sodium azide, ethanol and water is stirred under reflux, an ethanolic solution of N, Ndimethylaminoethyl-isothiocyanate is added dropwise. The mixture is then heated under reflux for 45 minutes, after which the ethanol is removed by distillation under reduced pressure. The residual solution is acidified with acid

  
  <EMI ID = 214.1> with n-hexane, collected by filtration and recrystallized from toluene. By this process, 1- (2-N, N-dimethylaminoethyl) -1H-tetrazol-5-thiol is obtained.

  
  <EMI ID = 215.1>

  
Reference example 22

  
(1) While a mixture of glycine-N, N-dimethylamide, triethylamine and methylene chloride is stirred. carbon disulphide and methyl iodide are added successively. The mixture is stirred at room temperature for one hour, after which it is shaken vigorously with an aqueous solution.

  
5% phosphoric acid. We remove the organic layer, we

  
  <EMI ID = 216.1>

  
under reduced pressure. The crystallized residue is stirred with n-hexane, collected by filtration and dried. By the above process

  
  <EMI ID = 217.1>

  
methyl carbamate.

  
IR (KBr, cm "): 1626, 1543

  
  <EMI ID = 218.1>

  
dithiocarbamate, sodium azide and ethanol is stirred while heating at 80 [deg.] C for 6.5 hours. The reaction mixture is adjusted to pH 2.5 with 10% hydrochloric acid and then concentrated to dryness under reduced pressure. The residue is extracted with 100 ml of methanol and the methanolic extract is treated with activated charcoal and then dried. The residual powder is recrystallized from water. By this process we obtain the

  
  <EMI ID = 219.1>

  
5.21 (s, CH2C0)

  
(3) Using sodium hydroxide solution, 1-N, N-

  
  <EMI ID = 220.1>

  
have 1-carboxymethyl-1H-tetrazole-5-thiol. Melting point: 156 [deg.] - 160 [deg.] C (decomposed).

  
  <EMI ID = 221.1>

  
  <EMI ID = 222.1> Reference example 23

  
To 200 ml of water, 38 g of sodium nitrite are added and
53 g of methyl acetoacetate, and, while cooling with

  
ice and with stirring, 200 ml of 4N sulfuric acid are added dropwise over a period of approximately one hour. During this dropwise addition, the temperature of the reaction mixture is maintained at 50-8 ° Ci. The mixture is then stirred in this temperature range for 2 1/2 hours, after which it is extracted twice with 300 ml each time. 'ethyl acetate. The extracts are combined and washed twice with a saturated aqueous solution of sodium chloride. Then, a solution of 96.7 g of sodium carbonate in 11 water is divided into three equal portions, with which the 3-oxo-2-hydroxyiminobutyrate is extracted from the above ethyl acetate layer.

  
  <EMI ID = 223.1>

  
of methanol and, after cooling with ice, 150 g of dimethyl sulfate is added dropwise while stirring for about 10 minutes. After the dropwise addition, the mixture is stirred at room temperature for 1 1/2 hours and extracted twice with 300 ml each time, of ethyl acetate. The extracts are combined, washed with water and dried. The ethyl acetate is then removed by distillation and the residue is cooled with ice, which produces its solidification. The solid residue is collected by filtration and washed with a small amount of water. By this process, 52.3 g is obtained

  
  <EMI ID = 224.1>

  

  <EMI ID = 225.1>


  
  <EMI ID = 226.1>

  
Then a solution of 40 g of bromine in 50 ml of chloroform is added dropwise over one hour. After, the reaction

  
  <EMI ID = 227.1> one hour. The reaction mixture is washed successively with
-a 5% aqueous solution of sodium bicarbonate and water and the organic layer is dried. The solvent is then removed by distillation to obtain 52.1 g of methyl 3-4-bromo-3-oxo-2methoxyiminobutyrate in the form of an oily product.

  
  <EMI ID = 228.1>

  
  <EMI ID = 229.1>

  
4-bromo-3-oxo-2-methoxyiminobutyrate, then add 250 ml of water and then add 89.1 g of sodium acetate trihydrate

  
  <EMI ID = 230.1>

  
ordinary for 18 hours. To the reaction mixture is added

  
  <EMI ID = 231.1>

  
then extracted with ethyl acetate. The organic layer is washed with water, dried and concentrated under reduced pressure to remove the solvent. To the concentrate, 200 ml of ether is added and the resulting precipitate is collected by filtration. By the pro-

  
  <EMI ID = 232.1>

  

  <EMI ID = 233.1>


  
  <EMI ID = 234.1>

  
COOCH3), 4.02 ppm (3H, singlet, = NOCH3), 5.74 ppm
(2H, broad, singlet, NH2), 6.74 ppm (1H, 5-H thiazole singlet)

  
Reference Example 25

  
, pans 90 ml of N, N-dimethylacetamide are dissolved 21.5 g of

  
  <EMI ID = 235.1>

  
While cooling with ice, 13.6 g of chloroacetyl chloride are added dropwise. The mixture is stirred while cooling with ice for 30 minutes, then at room temperature for 30 minutes. After adding 500 ml of water, the reaction mixture is extracted twice with ethyl acetate. The extracts are combined, washed successively with a 5% aqueous solution of sodium bicarbonate and water and dried. The solvent is then driven off

  
  <EMI ID = 236.1> <EMI ID = 237.1>

  

  <EMI ID = 238.1>


  
  <EMI ID = 239.1>

  
thiazole-5-H)

  
Reference example 26

  
To a solution of 19.2 g of potassium hydroxide in a mixture of 170 ml of water and 900 ml of ethanol is added 20 g

  
  <EMI ID = 240.1>

  
noacetate and the solution is stirred at room temperature for 2 hours. The ethanol is removed by distillation under reduced pressure and, after adding 170 ml of water, the residue is washed with 200 ml of ethyl acetate. The aqueous layer is adjusted to pH 2 with 10% hydrochloric acid and extracted twice with 300 ml of ethyl acetate each time.

  
The extracts are combined, washed with a saturated aqueous solution of sodium chloride and dried. The solvent is removed by distillation to obtain 16.8 g of 2- (2-chloro-acetamidothiazol-4-yl) -2- (syn) -methoxyiminoacetic acid in the form of crystals. By the NMR spectrum and the other properties, it is found that this product is identical to that obtained in Reference Example 6.

  
Reference Example 27

  
(1) Six grams of 7- (5-carboxy-5-benzamidovalerylamido) 3- (N-chloroacetyl) carbamoyloxymethyl-3-cephem-4-carboxylic acid are suspended in 80 ml of methylene dichloride

  
  <EMI ID = 241.1>

  
Sant at -50 [deg.] C, 2.25 ml of phosphorus trichloride are added. The mixture is stirred at -30 [deg.] C for 1 1/2 hours until a clear solution is obtained. To this solution, 4.17 g of phosphorus pentachloride is added and the mixture is stirred at -25 ° C for 2 1/2 hours. Then it is cooled to -40 [deg.] C and 37 ml of cold methanol are quickly added. The mixture -

  
  <EMI ID = 242.1>

  
with 22 ml of water and adjusted to pH 3.5 with dilute ammonia.

  
  <EMI ID = 243.1> <EMI ID = 244.1>

  
and the precipitate obtained is collected by filtration. By the above process, 1.76 g of 7-amino-3- (N-

  
  <EMI ID = 245.1>

  

  <EMI ID = 246.1>


  
NMR spectrum (60 MHz, in CF3COOH).

  
3.78 ppm (2H, broad singlet, 2-CH2), 4.35 ppm (2H,

  
  <EMI ID = 247.1>

  
(2) In N, N-dimethylacetamide is dissolved 1.05 g of 7-amino-3- (N-chloroacetyl) carbamoyloxymethyl-3-cephem-4-carboxylic acid obtained above in (1) and while cooling

  
Dealing with ice, 998 mg of 2-chloroacetamidothiazol-4-yl-oc- (anti) -methoxyiminoacetyl chloride hydrochloride is added. The mixture is stirred while cooling with ice for 15 minutes, then at room temperature for 2 hours. Then, after adding 50 ml of water, the reaction mixture is extracted twice with each time

  
100 ml of ethyl acetate. The organic layers are combined, washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The ethyl acetate is then distilled off. By the above process, 2.2 g of 7 - [(2-chloroacetamidothiazol-4-yl) -oc- acid are obtained
(anti) -methoxyimino] -acetamido-3- (N-chloroacetyl) carbamoyloxymethyl-3-cephem-4-carboxylic acid in the form of a white powder.

  
Note: Manufacture of 2-chloroacetamidothiazol-4-yl- chloride.

  
  <EMI ID = 248.1>

  
and, while cooling with ice, 5.91 g of chloroacetyl chloride is added dropwise. The mixture is stirred at room temperature for one hour, after which time it is poured into ice water. The mixture is extracted with ethyl acetate and the organic layer is washed, dried and distilled to remove the solvent. By this process,

  
  <EMI ID = 249.1>

  
tamido) thiazol-4-yl] acetate in the form of crystals melting at 81 [deg.] - 82 [deg.] C.

  
  <EMI ID = 250.1>

  

  <EMI ID = 251.1>


  
The nuclear magnetic resonance spectrum (60 MHz in

  
  <EMI ID = 252.1>

  
attributable to methoxy protons, at 4.24 ppm it is attributable to chloroacetyl protons and at 7.94 ppm it is attributable to hydrogen at position 5 of the thiazole ring.

  
  <EMI ID = 253.1>

  
mido) thiazol-4-yl] acetate are added to a solution of 11.74 g of potassium hydroxide in a mixture of 25 ml of water and
500 ml of ethanol. The mixture is stirred at room temperature for 20 minutes and the ethanol is distilled off under reduced pressure and the residue is diluted with water. The mixture is acidified with 1N hydrochloric acid

  
and the precipitate obtained is collected by filtration. By

  
  <EMI ID = 254.1>

  
[2- (chloracetamido) thiazol-4-yl] acetic, melting point:
182 [deg.] - 183 [deg.] C.

  
  <EMI ID = 255.1>

  

  <EMI ID = 256.1>


  
The nuclear magnetic resonance spectrum (60 MHz,

  
  <EMI ID = 257.1>

  
ppm, respectively.

  
(iii) In 5 ml of methylene chloride, suspend

  
  <EMI ID = 258.1>

  
mido) thiazol-4-yl] acetic and, while cooling with ice, 416.3 mg of phosphorus pentachloride are added. The mixture is allowed to react while stirring for 30 minutes. To the reaction mixture is added n-hexane and the resulting precipitate is collected by filtration. By the process

  
  <EMI ID = 259.1>
  <EMI ID = 260.1>
 (3) In 50 ml of tetrahydrofuran are dissolved 2.2 g of acid

  
  <EMI ID = 261.1>

  
3- (N-chloroacetyl) carbamoyloxymethyl-3-cephem-4-carboxylic prepared in (2) above, then 913 mg of finely powdered thiourea and 1.63 g of sodium acetate trihydrate are added. The mixture is stirred at room temperature for 17 hours. The precipitate is collected by filtration, washed with ethyl ether and dissolved in 10 ml of water. The solution is brought to pH 7 with sodium bicarbonate and passed through an Amberlite XAD-2 column. By the above process, 360 mg of

  
  <EMI ID = 262.1>

  
sodium bamoyloxymethyl-3-cephem-4-carboxylate in the form of a white powder,

  
  <EMI ID = 263.1>

  

  <EMI ID = 264.1>


  
  <EMI ID = 265.1>

  

  <EMI ID = 266.1>


  
  <EMI ID = 267.1>

  
Sodium oephem-4-oarboxylate prepared in this example is shown below
  <EMI ID = 268.1>
 Reference Example 28

  
(1) In 20 ml of N, N-dimethylacetamide is dissolved 1.05 g

  
  <EMI ID = 269.1>

  
thiazol-4-ylacetyl. The mixture is stirred while cooling with ice for 15 minutes, then at room temperature for 2 hours. Once this reaction is complete, the mixture is diluted with 50 ml of water and extracted twice with 100 ml of ethyl acetate each time. The organic layers are combined, washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The ethyl acetate is then removed by distillation to obtain a

  
  <EMI ID = 270.1>

  
3- (N-chloroacetyl) carbamoyloxymethyl-3-cephem-4-carboxylic acid. Yield: 1.6 g.

  
Note: Manufacture of 2-chloroacetamidothiazol-4-yl- chloride

  
acetyl.

  
In 15 ml of dimethylacetamide are dissolved 4 g of ethyl 2-aminothiazol-4-ylacetate and, while cooling with

  
3.62 g of chloroacetyl chloride are added dropwise with ice. The mixture is stirred under cooling with ice for 30 minutes, then at room temperature for another 30 minutes. Then after the addition of 50 ml of water, the mixture is extracted twice with 100 ml of ethyl acetate-tetrahydrofuran each time. The extract is washed with 100 ml of a 5% aqueous solution of sodium bicarbonate, then with 100 ml of a saturated aqueous solution of sodium chloride, then dried. The solvent is then removed by distillation. By this process

  
  <EMI ID = 271.1>

  
as an oily product. All of this oil is suspended in 100 ml of methanol, and, while cooling with ice, 12 ml of water containing 761 mg of sodium hydroxide are added. The mixture is stirred at room temperature for 30 minutes, after which time most of the methanol is distilled off under reduced pressure. To the residue is added 10 ml of water. The aqueous layer is washed with 50 ml of ethyl acetate and after addition of 20 ml of ethyl acetate the pH is adjusted to 2 with hydrochloric acid.

  
well

  
10% drric. The mixture is / shaken and the organic layer is 1 saturated

  
taken, washed with aqueous / sodium chloride solution and dried. The solvent is then removed by distillation. By

  
  <EMI ID = 272.1>

  

  <EMI ID = 273.1>


  
In 20 ml of methylene dichloride, suspend
938 mg of the above product, and while cooling with ice, 1 g of phosphorus pentachloride is added. The mixture is stirred at room temperature for 30 minutes. After adding 50 ml of petroleum ether, the precipitate is collected.

  
  <EMI ID = 274.1>

  
By the above process, 1.06 g of 2-chloro-acetamidothiazol-4-yl-acetyl chloride hydrochloride is obtained as colorless crystals.

  
  <EMI ID = 275.1>

  

  <EMI ID = 276.1>


  
  <EMI ID = 277.1>

  
(2) In 40 ml of tetrahydrofuran is dissolved 1.6 g of acid

  
  <EMI ID = 278.1>

  
carbamoyloxymethyl-3-cephem-4-carboxylic obtained in (1) above. To this solution are added 860 mg of thiourea, then sodium acetate trihydrate. The mixture is stirred at room temperature overnight. The precipitate is collected by filtration, washed with ethyl ether and dissolved in
10 ml of water. The solution is brought to pH 7 with bicarbonate

  
sodium and purified by column chromotagrophy on "Amber-

  
  <EMI ID = 279.1>

  
Sodium (2-aminothiazol-4-yl) acetamido-3-carbamoyloxymethyl-3-cephem-4carboxylate as a white powder.

  
  <EMI ID = 280.1>

  

  <EMI ID = 281.1>


  
  <EMI ID = 282.1> <EMI ID = 283.1>

  
TEMPLE 1

  
(1) In 6 ml of N, N-dimethylacetamide are dissolved 290 mg

  
  <EMI ID = 284.1>

  
4-carboxylic acid and, while cooling with ice, 276 mg of 2- (2-chloroacetamidothiazol-4- chloride hydrochloride

  
  <EMI ID = 285.1>

  
stirred while cooling with ice for 15 minutes and at room temperature for 2 hours. Then the reaction mixture was diluted with 30 ml of water and extracted twice with 50 ml of ethyl acetate each time. The extracts are combined, washed with 50 ml of a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. Ethyl acetate is distilled off to obtain

  
  <EMI ID = 286.1>

  
cephem-4-carboxylic acid in the form of a viscous oil.

  
  <EMI ID = 287.1> 6-H), 5.73 ppm (1H, doublet, 7-H), 7.32 ppm (1H,

  
singlet, thiazole -5-H).

  
(2) All of the above product is dissolved in 9 ml of tetrahydrofuran, then 168 mg of thiourea and 300 mg of sodium acetate trihydrate are added. The mixture is stirred at room temperature for 4 hours. The precipitate is collected by filtration, washed with ether and dissolved in 5 ml of water. The solution is adjusted to a pH of about 7 with sodium bicarbonate and purified by column chromatography on "Amberlite.

  
  <EMI ID = 288.1>

  

  <EMI ID = 289.1>


  
  <EMI ID = 290.1> <EMI ID = 291.1>

  
iminoacetic prepared in Reference Example 6, and while cooling with ice, 208 mg of phosphorus pentachloride are added. The mixture is stirred at room temperature for 30 minutes, after which it is washed with petroleum ether. By the above process, 276 mg of the chloride is obtained.

  
  <EMI ID = 292.1>

  

  <EMI ID = 293.1>


  
EXAMPLE 2

  
In 22 ml of dry tetrahydrofuran are dissolved 500 mg

  
  <EMI ID = 294.1>

  
acetic and, while stirring, 182 mg of triethylamine are added. This mixture is cooled to -10 [deg.] C and added dropwise.
245 mg of isobutyl chloroformate. The mixture is stirred at this temperature for 2 hours. To the resulting solution of mixed acid anhydride are added 182 mg of triethylamine, together with a solution (ice-cooled) of
590 mg of 7-amino-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl3-cephem-4-carboxylic acid in 18 ml of aqueous tetrahydrofuran
50%. The mixture is stirred while cooling with ice for one hour and at room temperature for 2 hours. Subsequently, most of the tetrahydrofurans is distilled off under reduced pressure and the residue is diluted with 100 ml of water and with 40 ml of ethyl acetate.

   Then, while stirring, the aqueous layer is adjusted to pH about 2 with 1N hydrochloric acid. The layers are separated and the aqueous layer is extracted with 60 ml of ethyl acetate. The ethyl acetate layers are combined, washed with 50 ml of a saturated aqueous solution of sodium chloride and dried. The ethyl acetate is distilled off to obtain 700 mg

  
  <EMI ID = 295.1>

  
4-carboxylic in the form of a viscous oil.

  
(2) All of the above product is dissolved in 15 ml

  
of tetrahydrofuran, then 226 mg of thiourea and 406 mg of sodium acetate trihydrate are added. The mixture is stirred at room temperature for 4 hours. When the reaction is complete, the precipitate is collected by filtration, washed with ether and dissolved in 10 ml of water. The solution is adjusted to a pH of about 7 with sodium bicarbonate and purified by chroma-

  
  <EMI ID = 296.1>

  
sodium acetamido] -3- (1-methyl-1H-tetrazol-4-yl) thiomethyl-3-cephem-4carboxylate as a white powder.

  
  <EMI ID = 297.1>

  

  <EMI ID = 298.1>


  
  <EMI ID = 299.1>

  
singlet, h-CH3), 4.08 ppm (2H, quartet, 3-CH2) '5.12 ppm (1H, doublet, 6-H), 5.72 ppm (1H, doublet,

  
  <EMI ID = 300.1>

  
EXAMPLE 3

  
(1) 762 mg are dissolved in 15 ml of N, N-dimethylacetamide

  
  <EMI ID = 301.1>

  
From ice, 931 mg of 2- (2-Chloroacetamidothiazol-4-yl) -2-methoxy-iminoacetyl chloride hydrochloride (prepared from the syn isomer) is added. The mixture is stirred while cooling with ice for 15 minutes and at room temperature for 2 hours. The reaction mixture is diluted with

  
  <EMI ID = 302.1>

  
The extracts are combined, washed with 100 ml of a saturated aqueous solution of sodium chloride and dried. The ethyl acetate is removed by distillation to obtain 1.4 g of 7- [2- (2-

  
  <EMI ID = 303.1>

  
losporanic as an oil.

  
(2) In 30 ml of tetrahydrofuran, all of the above product is dissolved, then 500 mg of thiourea and 895 mg of sodium acetate trihydrate are added. The mixture is stirred at room temperature for 4 hours. The precipitate obtained is collected by filtration, washed with ether and dissolved in 6 μl of water. The solution is adjusted to pH about 7.0 with sodium bicarbonate and purified by means of chromatography on <EMI ID = 304.1>

  
sodium acetamido] cephalosporanate as a white powder.

  
  <EMI ID = 305.1>

  

  <EMI ID = 306.1>


  
  <EMI ID = 307.1>

  
5.21 ppm (1H, doublet, 6-H), 5.81 (1H, doublet, 7-H), 7.01 ppm (1H, singlet, thiazole-5-H).

  
EXAMPLE 4

  
To 10 ml of water are added g of 7- [2- (2-aminothiazol-4-yl) -

  
  <EMI ID = 308.1>

  
naked in Example 3, 270 mg of. potassium salt of 2-methyl-1,3,4oxadiazole-5-thiol and 7 mg of triethylbenzylammonium bromide. The mixture is stirred under a stream of nitrogen at 60.degree. C. for 6 hours. After cooling, the reaction mixture is purified

  
  <EMI ID = 309.1>

  

  <EMI ID = 310.1>


  
  <EMI ID = 311.1>

  
6-H), 5.73 ppm (1H, doublet, 7-H), 6.97 ppm (1H,

  
singlet, thiazole-5-H).

  
EXAMPLE 5

  
(1) To 10 ml of tetrahydrofuran are added 833 mg of acid

  
  <EMI ID = 312.1>

  
diimide and the mixture is stirred at room temperature for 45 minutes. The precipitate is separated by filtration and

  
  <EMI ID = 313.1>

  
mixed ration of 650 mg of 7-aminodesacetoxycephalosporanic acid and 2 ml of bis (trimethylsilyl) acetamide in methyl chloride

  
  <EMI ID = 314.1>

  
room temperature overnight, then the solvent is distilled off under reduced pressure. To the resulting oil is added 50 ml of water along with 50 ml of ethyl acetate and the mixture is adjusted to pH about 2.5 with 1N hydrochloric acid. The two layers are separated, then extracted with twice 50 ml of ethyl acetate. The ethyl acetate layers are combined, washed with water and dried. The ethyl acetate is then removed by distillation to obtain

  
  <EMI ID = 315.1>

  
methoxyiminoacetamido] -desacetoxycephalosporanic in the form of an oil.

  
(2) All of the above product is dissolved in 25 ml

  
of tetrahydrofuran, then thiourea is added, followed by 632 mg of sodium acetate trihydrate. The mixture is stirred at room temperature for 4 hours. The precipitate is collected by filtration, washed with ether and dissolved in 10 ml of water. The solution is adjusted to pH around 7.0 with bicarbonate

  
sodium and purified by column chromatography on "Amber-

  
  <EMI ID = 316.1>

  

  <EMI ID = 317.1>


  
  <EMI ID = 318.1>

  
3-CH3) '3.46 ppm (2H, quartet, 2-CH2), 4.00 ppm (3H, singlet, = NOCE,), 5.17 ppm (1H, doublet, 6-H), 5.76 ppm
(1H, doublet, 7-H), 6.99 ppm (1H, singlet, thiazole 5-H)

  
The minimum inhibition concentrations (ug / ml) of some of these compounds according to the above examples are as follows:

  
(see page 50)
  <EMI ID = 319.1>
 [Note] The following abbreviations are used to designate

  
the microorganisms used.

  
  <EMI ID = 320.1>

  
Serr: Serratia P: Proteus Ent: Enterobacter Cit: Citrobacter

  
EXAMPLE 6

  
(1) In 20 ml of dry tetrahydrofuran are dissolved 500 mg

  
  <EMI ID = 321.1>

  
acetic and, while stirring, 182 mg of triethylamine are added. The mixture is cooled to -10 [deg.] C, after which 245 mg of isobutyl chloroformate are added dropwise. The mixture is stirred at this temperature for 2 hours. To the resulting mixed acid anhydride solution is added a solution (cooled in ice) of 180 mg of triethylamine and 492 mg of 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid. in 50% aqueous tetrahydrofuran. The mixture is stirred while cooling with ice for one hour and then at room temperature for 2 hours. Most of the tetrahydrofuran is removed by distillation under reduced pressure and 100 ml of water and 40 ml of ethyl acetate are added to the residue. The mixture is adjusted to a pH of about 2 with 1N hydrochloric acid.

   The two layers are separated and the aqueous layer is extracted twice with 50 ml of ethyl acetate each time. The ethyl acetate layers are combined, washed with water, dried and concentrated. By the process

  
  <EMI ID = 322.1>

  
cephem-4-carboxylic acid in the form of an oil.

  
(2) All of the above product is dissolved in 15 ml of tetrahydrofuran and then 226 mg of thiourea and 406 mg of sodium acetate trihydrate are added. The mixture is stirred at room temperature for 4 hours. The precipitate is collected by filtration, dissolved in 10 ml of water, adjusted to pH about 7 with sodium bicarbonate and purified by column chromatography on "Amberlite XAD-2 *: By this method, 120 mg are obtained.

  
  <EMI ID = 323.1>

  
sodium carbamoyloxymethyl-3-cephem-4-carboxylate

  
  <EMI ID = 324.1>

  
finds that this product is identical to the product obtained in Example 1.

  
EXAMPLE 7

  
(1) In 45 ml of dry tetrahydrofuran is dissolved 1.11 g

  
  <EMI ID = 325.1>

  
acetic, and, while stirring, 815 mg of tri-n-butylamine are added. The mixture is cooled to -10 [deg.] C and 544 mg of isobutyl chloroformate are added dropwise. The mixture is stirred

  
  <EMI ID = 326.1>

  
racetyl) -carbamoyloxymethyl-3-cephem-4-carboxylic in 40 ml of 50% aqueous tetrahydrofuran is added. The mixture is stirred while cooling with ice for 1 hour and at room temperature for 2 hours. Most of the tetrahydrofuran is removed by distillation under reduced pressure and the residue is diluted with 25 ml of water and washed with

  
  <EMI ID = 327.1> 50 ml of ethyl acetate are added thereto and the pH is adjusted to about 2.5 with 1N hydrochloric acid. The mixture is separated into two layers. The aqueous layer is further extracted twice with 50 ml of ethyl acetate each time. The extracts are combined, washed with 100 ml of a saturated aqueous solution of sodium chloride, dried and finally concentrated. By the above process, 1 g of 7- [2- (2-chloroacetami-

  
  <EMI ID = 328.1>

  
carbamoyloxymethyl-3-cephem-4-carboxylic acid in the form of an oil.

  
(2) All of the above product is dissolved in 22 ml

  
  <EMI ID = 329.1>

  
mg of sodium acetate trihydrate. The mixture is stirred at room temperature for 4 hours. The precipitate is collected

  
  <EMI ID = 330.1>

  
of water. The solution is adjusted to pH of about 7 with sodium bicarbonate and purified by column chromatography on "AMBERLITE XAD-2" By the above process, 153 mg are obtained.

  
  <EMI ID = 331.1>

  
sodium carbamoyloxymethyl-3-cephem-4-carboxylate

  
  <EMI ID = 332.1>

  
this product is identical to the compound obtained in Example 1.

  
EXAMPLE 8

  
In 20 ml of tetrahydrofuran are dissolved 277 mg of acid

  
  <EMI ID = 333.1>

  
and 270 mg of tert-butyl-7-aminodesacetoxycephalosporanic acid, then 206 mg of dicyclohexylcarbodiimide are added. The mixture is allowed to react while stirring at room temperature for 6 hours. The precipitated urea derivative is separated by filtration and the filtrate is poured into 50 ml of water and extracted with ethyl acetate. The ethyl acetate layer is washed with 0.5N hydrochloric acid, water and a saturated aqueous solution of sodium chloride in the order shown, se-

  
  <EMI ID = 334.1> <EMI ID = 335.1>

  
(2) All of the above product is dissolved in 12 ml

  
  <EMI ID = 336.1>

  
mg of sodium acetate trihydrate. The mixture is stirred at room temperature for 8 hours. The reaction mixture is diluted with 30 ml of water and extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried and concentrated. The resulting oil is purified by chromatography on silica gel. By this process, 128 mg of tertio-

  
  <EMI ID = 337.1>

  
quartet, 2-CH2), 4.00 ppm (3H, singlet, = NOCE 3) 1

  
5.05 ppm (1H, doublet, 6-H), 5.98 ppa (1H, doublet doublet, 7-H), 6.66 ppm (1H, singula &#65533;, thiazole
-5-H), 8.28 ppm (1H, doublet, 7-CONH).

  
(3) All of the above product is dissolved in a mixture of 1 ml of trifluoroacetic acid and 0.1 ml of anisole, and the solution is stirred at room temperature for 1 1/2 hours, after which l ether is added. The precipitate obtained is collected by filtration and washed with ether. By the above process, 70 mg of trifluoroacetate of the acid

  
  <EMI ID = 338.1>

  
this product is identical to the. product obtained in Example 5. EXAMPLE 9

  
By acylation of the 7-amino group of the corresponding cephalosporin coapose in a manner identical to that described in the example

  
  <EMI ID = 339.1>

  
heterocyclic thiol compounds, in a manner identical to that described in Example 4 (Process B), the following compounds are prepared: <EMI ID = 340.1> Sodium 3- (2-methyl-1,3,4-thiadiazol-5-yl) thio-methyl-3-cephem-4carboxylate (Method B) <EMI ID = 341.1>

  
6.94 ppm (1H, singlet, thiazole 5-H), 7.95 ppm (1H, singlet, triazole 4-H) <EMI ID = 342.1>

  
disodium cephem-4-carboxylate (Method B)

  
  <EMI ID = 343.1>

  
CH2), 3.96 ppm (3H, singlet, = NOCH3), 4.72 ppm (2H,

  
  <EMI ID = 344.1>

  
5.72 ppm (1H, doublet, 7-H), 6.95 ppm (1H, singlet, thiazole 5-H) <EMI ID = 345.1>

  
(Method A, B)

  
NMR spectrum (60 MHz, in D20): 3.01 ppm (6H, singlet

  
  <EMI ID = 346.1> 3

  
(3H, singlet, = NOCE,), 5.18 ppm (1H, doublet, 6-H), 5.74 ppm (1H, doublet, 7-H), 6.96 ppm (1H, singlet, thiazole 5- H) <EMI ID = 347.1> <EMI ID = 348.1>

  
sodium boxylate (Method 3)

  
  <EMI ID = 349.1>

  
singlet, thiazole 5-H)

  
The minimum inhibitory concentration (in &#65533; g / ml) of some of the compounds prepared above is as follows:

  

  <EMI ID = 350.1>


  
EXAMPLE 10

  
280 mg of sodium carbonate are dissolved in a mixture of 20 ml of water and 10 ml of methanol, then 477 mg of acid are added.

  
  <EMI ID = 351.1>

  
waving. Then, after 25 minutes, 300 mg of potassium carbonate and 300 mg of dimethyl euphate are added. After a further 25 minutes, the reaction mixture is concentrated under reduced pressure.

  
  <EMI ID = 352.1>

  
  <EMI ID = 353.1>

  
compound obtained in Example 3.

  
EXAMPLE 11

  
(1) To a suspension of 5.54 g of 2- (2-chloracetamido-

  
  <EMI ID = 354.1>

  
re of methylene, 2.42 g of triethylamine are added to obtain a solution. While cooling with ice and stirring, 4.16 g of phosphorus pentachloride is added all at once to the above solution. After 5 minutes the ice bath is removed and the mixture is stirred at room temperature for 20 minutes, after which it is concentrated under reduced pressure. : To the residue, 150 ml of hexane are added and then decanted twice. After adding 90 ml of anhydrous tetrahydrofuran, the precipitated triethylamine hydrochloride is separated by filtration, which makes it possible to obtain a chloride solution.

  
  <EMI ID = 355.1>

  
in tetrahydrofuran.

  
In addition, to a suspension of 4.28 7-aminodeacetoxycephalosporanic acid in a mixture of 50 ml of water and / 50 ml of tetrahydrofuran is added, while cooling with ice, 4.44 g of triethylamine for have a homogeneous solution. While cooling with ice, the acid chloride solution prepared above is added dropwise to the above solution over 15 minutes. The mixture is stirred at room temperature for 2 hours, after which a saturated aqueous solution of sodium chloride is added. The mixture is adjusted to pH about 2 with dilute hydrochloric acid and extracted with ethyl acetate.

   The ethyl acetate layer is washed with a saturated aqueous solution of chloride, sodium, dried over magnesium sulfate and concentrated to have 8 g of yellowish white powder. The powder is washed with 50 ml of methanol and the insoluble parts are collected by filtration. By the above process 4.6 g of 7- [2- (2-chloracetamidothia-

  
  <EMI ID = 356.1> <EMI ID = 357.1>

  
5.18 ppm (1H, doublet, 6-H), 5.78 ppm (1H, doublet x2,

  
  <EMI ID = 358.1>

  
(2) The above product is reacted and treated in the same way as in Example 5- (2) to have 7- [2- (2-amino-

  
  <EMI ID = 359.1>

  
Sodium sporanate as a white powder. In the NMR spectrum and in the other properties, this product is identical to the product obtained in Example 5.

  
EXAMPLE 12

  
In 25 ml of dimethylformamide, the

  
  <EMI ID = 360.1>

  
sodium sacetoxycephalosporanate and while cooling with ice, 3.75 g of iodomethyl pivalate are added followed by a further 3 ml of dimethylformamide. After 17 minutes, add
100 mml of ethyl acetate to the reaction mixture and the insoluble products are separated by filtration. The filtrate is washed with water, a 5% aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride.

  
  <EMI ID = 361.1>

  
sium. The ethyl acetate is then removed by distillation and the resulting oil (2.4 g) is purified by chromatography on silica gel. In the above process, 1 g is obtained

  
  <EMI ID = 362.1>

  
iminoacetamido] deacetoxycephalosporanate as a white powder.

  
  <EMI ID = 363.1>

  

  <EMI ID = 364.1>


  
  <EMI ID = 365.1> 6-H), 5.94 ppm (2H, singlet, -OCH20), 6.86 ppm (1H, singlet, thiazole, 5-H)

  
EXAMPLE 13

  
  <EMI ID = 366.1>

  
methoxyaminoacetamidoj-desacetoxycephalosporanic prepared by the process of Example 11- (1) is dissolved in an ice-cooled solution of 149 mg of triethylamine in 7 ml of dimethylformamide. After adding 715 mg of pivalate <EMI ID = 367.1>

  
Reaction mixture, 40 ml of ethyl acetate are added and the mixture is washed with water, a 5% aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, in the order given, then it is dried over magnesium sulfate: The ethyl acetate is removed by distillation to obtain 0.8 g of crude pivaloyloxymethyl7- [2- (2-chloracetamidothiazol-4-yl) -2- (syn) -methoxyiminoacetamido1-desacetoxycephalosporanate as a brown oil.

  
This product is dissolved in 3 ml of dimethylacetamide, then 206 mg of thiourea are added thereto. The mixture is stirred at room temperature all night. To this mixture, we add

  
40 ml of ethyl acetate and washed twice with 30 ml of a saturated aqueous sodium chloride solution each time and / or dried over magnesium sulphate. The ethyl acetate is removed by distillation and the resulting brown oil (0.4 g)

  
is purified by chromatography on silica gel. By this pro-

  
  <EMI ID = 368.1>

  
as a white powder.

  
The NMR spectrum and the other properties of this product show that it is identical to the product obtained in Example 12. EXAMPLE 14

  
Has a suspension of 831 mg of 2- (2-chloroacetamido-

  
  <EMI ID = 369.1>

  
re of methylene, 360 mg of triethylamine and 624 mg of phosphorus pentachloride are added. The mixture is stirred at room temperature for 20 minutes, after which 100 ml of hexane are added. The oil which has been separated is obtained by decanting the hexane and dissolved in 15 ml of tetrahydrofuran, which gives a solution of 2- (2-chloracetamidothiazol- chloride).

  
  <EMI ID = 370.1>

  
5-yl) thiomethyl-3-cephem-4-carboxylic acid and 660 mg of triethylamine are dissolved in 15 ml of 50% aqueous tetrahydrofuran and, while cooling with ice, the acid chloride solution prepared previously is added drip to this solution. The mixture is stirred while cooling with ice for 2 hours, after which the mixture reacts.

  
  <EMI ID = 371.1> dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer is washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The ethyl acetate is removed by distillation and the residue is treated with ether. The resulting crystals are collected by filtration. By this process, 1.3 g of 7- [2- (2-

  
  <EMI ID = 372.1>

  
This product is identical to the intermediate product prepared in the first part of the process described in Example 2. 5.8 g

  
  <EMI ID = 373.1>

  
of dimethylacetamide and, while cooling with ice, 1.53 g of thiourea is added. The mixture is stirred at room temperature for 15 hours. To this reaction mixture is added 200 ml of ice water and the pH of the mixture is adjusted to 3.5 with sodium bicarbonate. The resulting precipitate is collected by filtration and dissolved in 10% aqueous sodium bicarbonate solution. The solution is then passed over a

  
  <EMI ID = 374.1>

  
Sodium 4-carboxylate as a white powder.

  
The. NMR spectrum and other properties of this product show that it is identical to that obtained in Example 2. EXAMPLE 15

  
  <EMI ID = 375.1>

  
  <EMI ID = 376.1>

  
  <EMI ID = 377.1>

  
add 0.85 g of iodomethyl pivalate. The mixture is stirred for 15 minutes. After adding 40 ml of ethyl acetate,

  
the reaction mixture is washed with water, 5% aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution in the order listed, then dry over magnesium sulfate. The ethyl acetate is removed by distillation under reduced pressure and the residue is dissolved in

  
  <EMI ID = 378.1>

  
ether is added, then cooled. The resulting precipitate is collected by filtration. By this process, 0.4 g is obtained

  
  <EMI ID = 379.1> <EMI ID = 380.1>

  

  <EMI ID = 381.1>


  
  <EMI ID = 382.1>

  
thiazole-5'3).

  
EXAMPLE 16

  
In 20 ml of methylene chloride are dissolved 2.776 g of 2- (2-chloracetamidothiazol-4-yl) -2- (syn) -methoxyiminoacetic acid and 1.2 g of triethylamine, then 2.08 g of pentachloride are added phosphorus. The mixture is stirred at the temperature <EMI ID = 383.1> of hexane. The resulting oily precipitate is separated and dissolved in 20 ml of tetrahydrofuran to have a solution of 2- (2-chloracetamidothiazol-4-yl) -2- (syn) -methoxyiminoacetyl chloride. In addition, 3.143 g of 7-amino-3-acetylacetoxymethyl-3-cephem-4-carboxylic acid and 2.20 g of triethylamine are

  
  <EMI ID = 384.1>

  
solution is added dropwise, while cooling with ice and stirring, the acid chloride solution prepared previously. The mixture is stirred while cooling with ice for 2 hours, after which water is added. The mixture is adjusted to pH 2 with dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer is washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The ethyl acetate is then removed by distillation and ether is added to the residue. The resulting crystalline product is collected by filtration. By this process, 4.168 g of 7- [2- (2-chloracetamidothiazol

  
  <EMI ID = 385.1> <EMI ID = 386.1>

  
5.13 ppm (1H, doublet, 6-H), 5.80 ppm (1H, doubletx2, 7-H), 7.40 ppm (1H, singlet, thiazole 5-H).

  
  <EMI ID = 387.1>

  
3-acetylacetoxymethyl-3-cephem-4-carboxylic acid obtained in Example 16, then 1.06 g of thiourea is added. The mixture is stirred

  
at room temperature for 17 hours, after which 100 ml of ether are added. The oily precipitate is separated and dissolved

  
  <EMI ID = 388.1>

  
The solution is lyophilized and the resulting pulverulent product is added to 50 ml of methanol. Products. insolubles are separated by filtration and the filtrate is added to 300 ml of ether. The precipitate is collected by filtration. By this process we

  
  <EMI ID = 389.1>

  
350 mg of 1- (2-N, N-dimethylaminoethyl) -1H-tetrazol-5-thiol and
168 mg of sodium bicarbonate. The mixture is stirred at 55 [deg.] C for 1 hour, then the reaction mixture is passed directly.

H

  
dried on a column packed with Amberlite XAD-2 for purification. By the above process, 170 mg of 7- [2- (2-

  
  <EMI ID = 390.1>

  
sodium carboxylate in the form of a white powder. The NMR spectrum and other properties of this product show that it is identical with the product obtained in Example 9.

  
  <EMI ID = 391.1>

  
compounds prepared in the examples above on infected mice.

  
(see table page 62)

BOARD

  

  <EMI ID = 392.1>


  
  <EMI ID = 393.1>

  
Duration of observations: 7 days

  
(); Witness

  
SC = subcutaneous

  
CER = cephaloridine

  

  <EMI ID = 394.1>


  
CEX = cephalexin

  

  <EMI ID = 395.1>


  
EXAMPLE 18

  
(1) To a suspension of 55.6 g of 2- (2-chloroacetamido- acid

  
  <EMI ID = 396.1>

  
Methylene chloride, 24.3 g of triethylamine are added to obtain a solution. While cooling with ice and stirring, 41.8 g of phosphorus pentachloride are added in two batches to the above solution. After 5 minutes, the ice bath is removed and the mixture is stirred at room temperature. <EMI ID = 397.1>

  
acetyl in tetrahydrofuran.

  
Furthermore, to a suspension of 54.7 g of 7-amino-3carbamoyloxymethyl-3-cephem-4-carboxylic acid in a mixture of
400 ml of water and 400 ml of tetrahydrofuran, 61 g of triethylamine are added while cooling with ice to prepare a homogeneous solution. While cooling with ice, the acid chloride solution prepared above is added dropwise to the above solution over 30 minutes. The mixture is stirred at room temperature for 2 hours, after which time a saturated aqueous solution of sodium chloride is added. The mixture is adjusted to pH about 2 with dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer is washed with an aqueous solution, saturated with sodium chloride, dried over magnesium sulfate and concentrated to have 97.3 g of the acid.

  
  <EMI ID = 398.1>

  
mido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid. In the

  
  <EMI ID = 399.1>

  
singlet, thiazole 5-H)

  
(2) 97.3 g of the product prepared above in (1) are dissolved in 500 ml of N, N-dimethylacetamide, and while cooling with ice, 31.2 g of thiourea is added to the solution. The mixture is stirred at room temperature for 15 hours. To this reaction mixture is added 2 l of ether, then the oily product is separated. A suspension of this oily product in 300 ml of water is adjusted to pH 7 with sodium bicarbonate. The solution thus obtained is passed through a rea- column.

  
  <EMI ID = 400.1> <EMI ID = 401.1>

  
  <EMI ID = 402.1>

  
other properties, this product is identical to that obtained in Example 1 or 6.

  
The structures and properties (IR spectrum) of the compounds N [deg.] 1 to 33 obtained according to the process of the present invention are summarized in the following tables. In these tables, IR spectrum (cm-1, KBr) denotes the characteristic absorption band due to the P-lactam fraction.

BOARD

  

  <EMI ID = 403.1>
 

  

  <EMI ID = 404.1>
 

  

  <EMI ID = 405.1>
 

  

  <EMI ID = 406.1>
 

  
Injectable composition

  
  <EMI ID = 407.1>

  
  <EMI ID = 408.1>

  
xyiminoactamido / sodium cephalosporanate in 1 ml of sterilized water before use.

  
  <EMI ID = 409.1>

  
acetamido) cephalosporin of the formula:

  

  <EMI ID = 410.1>


  
  <EMI ID = 411.1>

  
tally be protected, or a pharmaceutically acceptable salt or ester thereof.


    

Claims (1)

2. Compound according to claim 1, characterized by <EMI ID = 412.1> eg classic protector. 4. Compound according to claim 3, characterized in that the conventional protective group is a monohalo-acetyl group. 5. Compound according to claim 2, characterized in that the remainder of a nucleophilic compound represented by R3 is a hydroxyl, mercapto., Acyloxy group derived from lower aliphatic carboxylic acid having 2 to 4 carbon atoms which may optionally be substituted, an acyloxy group derived from an aromatic carboxylic acid which may <EMI ID = 413.1> glycyloxy, a quaternary ammonium group or a heterocyclic-thio group in which the heterocyclic ring is unsubstituted or is substituted. 6. Compound according to claim 2, characterized in that R3 is a carbamoyloxy, acyloxy group derived from a lower aliphatic carboxylic acid having 2 to 4 carbon atoms or a heterocyclic-thio group in which the heterocyclic group is unsubstituted or substituted . <EMI ID = 414.1> 7. Compound according to Claim 6, characterized in that the heterocyclic group is a 5 or 6-membered group comprising 1 to 4 hetero atoms chosen from oxygen and sulfur atoms. and nitrogen, and wherein the nitrogen atom or atoms may be in the oxide form. 8. Compound according to claim 7, characterized in that the heterocyclic group is a group of the pyridyl, N-oxopyridyl, pyrimidyl, pyridazinyl, N-oxopyridazinyl, pyrazolyl, diazolyl, thiazolyl, thiadiazolyl, oxadiazolyl, triazolyl and tetrazolyl type. 9. A compound according to claim 8, characterized by <EMI ID = 415.1> diazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl or 1,2,5-oxadiazolyl; that the triazolyl group is a 1,2,3-tria- <EMI ID = 416.1> <EMI ID = 417.1> the fact that the heterocyclic group is a heterocyclic group chosen from the groups of the type 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, iH- tetrazolyl, imidazolyl and thiazolyl. <EMI ID = 418.1> 12. Compound according to claim 6, characterized in that the heterocyclic group is substituted by one or <EMI ID = 419.1> lower alkoxy, halogen, trihalo-lower alkyl, hydroxyl, mercapto, aminogen, carboxyl, carbamoyl lower alkyl substituted with a dialkyl group (lower) -amino carboxymethyl, carbamoylmethyl, carboxymethylthio, sulfomethyl and methoxycarbonylamino. 13. Compound according to claim 6, characterized in that the heterocyclic group is substituted by one or two radicals chosen from lower alkyl radicals <EMI ID = 420.1> droxyl, mercapto, aminogen, carboxyl, carbamoyl - lower alkyl substituted with dialkyl (lower) -amino and carboxymethyl '. 14. Compound according to claim 1, characterized in that the compound is the acid .7- (2- (2-aminothiazol-4-yl) -2- <EMI ID = 421.1> carboxylic acid, or its pharmaceutically acceptable salt. 15. A compound according to claim 1, characterized by <EMI ID = 422.1> acceptable. 16. A compound according to claim 1, characterized in that the compound is the acid .7- (2- (2-aminothiazol-4-yl) -2- (syn) - methoxyiminoacetamido) -cephalosporanic, or its pharmaceutically acceptable salt. 17. Compound according to claim 1, characterized in that the compound is the acid .7- (2- (2-aminothiazol-4-yl) -2- <EMI ID = 423.1> methyl-3-cephem-4-carboxylic acid, or its pharmaceutically acceptable salt. 18. Compound according to claim 1, characterized in that the compound is the acid 7- (2- (2-aminothiazol-4-yl) -2- <EMI ID = 424.1> or its pharmaceutically acceptable salt. 19. Compound according to claim 1, characterized in that the compound is the acid 7- (2- (2-aminothiazol-4-yl) '2- (syn) - methoxyiminoacetamido) -3- (2-methyl- 1,3,4-thiadiazol-5- <EMI ID = 425.1> tically acceptable. 20. A compound according to claim 1, characterized by <EMI ID = 426.1> 2- (s ZM) -methoxyiminoacetamido) -3- (2-ca-boxymethyl-1 3,4-thiadiazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid, or its pharmaceutically acceptable salt. <EMI ID = 427.1> <EMI ID = 428.1> 23 '. Compound according to Claim 3y, characterized in that the compound is the acid 7- (2- (2-aminothiazol-4-yl) - <EMI ID = 429.1> 1,2,3,4-Tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid, or its pharmaceutically acceptable salt. 24. A compound according to claim 1, characterized by <EMI ID = 430.1> acceptable. 25. A compound according to claim 1, characterized by <EMI ID = 431.1> losporanate. 26. A compound according to claim 1, characterized by <EMI ID = 432.1> tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylate. 27. Process for preparing a compound of formai " <EMI ID = 433.1> <EMI ID = 434.1> <EMI ID = 435.1> lement be protected, or a salt or a pharmaceutically acceptable ester of this compound, by means known per se. <EMI ID = 436.1> <EMI ID = 437.1> <EMI ID = 438.1> <EMI ID = 439.1> <EMI ID = 440.1> ment be protected, this process being characterized in that it comprises (1) the reaction of a 7-aminocephalosporin derivative of formula: <EMI ID = 441.1> <EMI ID = 442.1> compound of formula s <EMI ID = 443.1> <EMI ID = 444.1> necessary by then removing the protecting group; (2) the reaction of a compound of formula: <EMI ID = 445.1> <EMI ID = 446.1> <EMI ID = 447.1> a nucleophilic compound, if necessary by then removing the protecting group, or (3) methylation of a compound of the formula: <EMI ID = 448.1> <EMI ID = 449.1> above. 29. A pharmaceutical composition containing a compound as defined in any one of claims 1 to 26 together with a pharmaceutically acceptable excipient or diluent for / compound. 30. Compound of formula <EMI ID = 450.1> <EMI ID = 451.1> optionally be protected, or else a salt or a reactive derivative of this compound. 31. A compound according to claim 30, characterized in that R2NH represents an aminogenic group which is protected. 32. Compound according to claims 30 and 31, characterized in that the reactive derivative is an acid halide, an acid anhydride, a mixed acid anhydride, an active amide or an active ester. 33. Compound according to claims 30 and 31, characterized in that the protective group of the protected aminogenic group is an acyl group. <EMI ID = 452.1> thoxy-imino-acetic. 36. 2- (2-Chloroacetamidothiazol-4-yl) -2- chloride <EMI ID = 453.1> <EMI ID = 454.1> <EMI ID = 455.1> <EMI ID = 456.1> tally be protected, or a salt or a reactive derivative of this compound, by methods known per se. <EMI ID = 457.1> <EMI ID = 458.1> <EMI ID = 459.1> <EMI ID = 460.1> this compound, a process characterized in that it comprises (1) the reaction of a compound of formula: <EMI ID = 461.1> <EMI ID = 462.1> <EMI ID = 463.1> <EMI ID = 464.1> <EMI ID = 465.1> <EMI ID = 466.1> <EMI ID = 467.1> above, methylation of the compound obtained in which R6 is hydrogen, protection of the aminogenic group, /! 'insulation., <EMI ID = 468.1> reaction of a compound of formula (VII) with thiourea in water or in a mixture of water and a solvent miscible with water and if necessary in the presence of a basic reagent, or <EMI ID = 469.1> <EMI ID = 470.1> <EMI ID = 471.1> <EMI ID = 472.1> 40. Cephalosporins, their preparation and their use, as described above, in particular in the examples given.