BE891491A - 7-ACYLAMINOCEPHALOSPORANIC ACID DERIVATIVES AND PROCESS FOR THEIR PREPARATION - Google Patents

Description

       

  The present invention relates to new

  
  <EMI ID = 1.1>

  
pharmaceutically acceptable salts.

  
More specifically, it relates to

  
new 7-acylaminocephalosporanic acid derivatives.

  
and their pharmaceutically acceptable salts, which have

  
  <EMI ID = 2.1>

  
preparation, a pharmaceutical composition comprising them, and a method for their therapeutic use in the treatment of infectious diseases

  
in humans and animals.

  
Accordingly, an object of the present invention

  
  <EMI ID = 3.1>

  
nocephalosporanic and their pharmaceutically acceptable salts, which are highly active against a certain

  
number of pathogenic microorganisms and are useful as antimicrobial agents, especially for oral administration.

  
Another object of the present invention is to

  
provide procedures for the preparation of new

  
derivatives of 7-acylaminocephalosporanic acid and their

  
salts.

  
Another object of the present invention is to

  
providing a pharmaceutical composition comprising as <EMI ID = 4.1>

  
wheat.

  
Yet another object of the present invention is to provide a method for using these acid derivatives.

  
  <EMI ID = 5.1>

  
only acceptable in the treatment of infectious diseases by pathogenic microorganisms in humans and animals.

  
The desired derivatives of 7-acylaminocephalosporanic acid having the syn configuration are new and can be represented by the following general formula:

  

  <EMI ID = 6.1>


  
  <EMI ID = 7.1>

  
R2 is a lower dialkyloxyalkyl group, the alkyl group having one or more substituents selected from the group consisting of hydroxy, protected hydroxy, alkoxy, carboxy, protected carboxy, cycloalkylcarbonyloxy

  
and heterocyclic groups; a lower carbonyloxyalkyl (lower) alkoxy group; an azidoalkoxy (lower) carbonyloxyalkyl lower group; a lower aroyloxyalkyl group; an alkanoyl (upper) oxyalkyl group; phthalidyl group, or phthalidylidene group-

  
  <EMI ID = 8.1>

  
the thio (-S-) or sulfinyl (-SO-) group, and the dotted line represents the nucleus of 2- or 3-cephem.

  
Among the compounds (I). the compounds (la) are more useful as antimicrobial agents and can be represented by the following formula:

  

  <EMI ID = 9.1>


  
  <EMI ID = 10.1>

  
is a lower dialkylalkanoyloxyalkyl group; an alkyl group having one or more substituents selected from the group consisting of hydroxy, protected hydroxy, alkoxy, carboxy, cycloalkylcarbonyloxy and heterocyclic groups; lower (lower) carbonyloxyalkylalkoxy; azidoalkoxy (lower) carbonyloxyalkyl lower;

  
  <EMI ID = 11.1>

  
lower, phthalidyl or lower phthalidylidenealkyl,

  
and R <3> is a lower alkyl group.

  
Suitable pharmaceutically acceptable salts of the desired compounds (I) are conventional non-toxic salts and can comprise a salt with a base or an addition salt with an acid such as a salt with a mineral base, for example a metal salt alkaline (for example a sodium salt, a potassium salt, etc.), an alkaline earth metal salt (for example a calcium salt, a magnesium salt, etc.), an ammonium salt; a

  
salt with an organic base, for example an organic amine salt (for example a triethylamine salt, a pyridine salt, a picoline salt, a tethanolamine salt, a triethanolamine ael, a dicyclohexylamine salt, a salt

  
  <EMI ID = 12.1>

  
edition with a mineral acid (for example a hydrochloride, a hydrobromide, a sulfate, a phosphate, etc.); an addition salt with a sulfonic acid or an organic carboxylic acid (for example a formate, an acetate, a trifluoroacdtate, a maleate, a tartrate, a methane-

  
  <EMI ID = 13.1> example arginine, aspartic acid, 1 ^ glutamic acid, etc.) and the like.

  
According to the present invention, the desired compounds (I) and their pharmaceutically acceptable salts can be prepared by the methods as illustrated by the following reaction scheme:

  
Method 1:

  

  <EMI ID = 14.1>


  
Method 2:

  

  <EMI ID = 15.1>
 

  
Method 3:

  

  <EMI ID = 16.1>


  
Method 4:

  

  <EMI ID = 17.1>
 

  
Method 5:

  

  <EMI ID = 18.1>


  
Method 6:

  

  <EMI ID = 19.1>


  
  <EMI ID = 20.1> <EMI ID = 21.1>

  
  <EMI ID = 22.1>

  
is a lower dihydroxyalkyl group, X is the hydroxy group or its reactive derivative, and the dotted line represents the 2- or 3-cephem nucleus.

  
In the above description and in the subsequent description of the present invention, examples and suitable illustrations of the various definitions to be included in the scope of protection of the present invention are explained in detail as follows.

  
The term "lower" is intended to mean a group having 1 to 6 carbon atoms, and the term "upper" is intended to mean a group having 7 to 20 carbon atoms, unless otherwise indicated.

  
The suitable "amino protected" group may include an amino group substituted with a conventional amino group protecting group which is used in penicillin and cephalosporin compounds, for example an acyl group as mentioned below, an aralkyl group.

  
  <EMI ID = 23.1>

  
lower alkyl (e.g. benzyl, benzhydryl, trityl, etc.), a lower (lower) carbonylalkylidene alkoxy group or its tautomer enamine (e.g.

  
  <EMI ID = 24.1>

  
dimethylaminomethylene group, etc.) etc.

  
The suitable "acyl" group may include an aliphatic acyl group, an aromatic acyl group, a heterocyclic acyl group and an aliphatic acyl group substituted by one or more heterocyclic aromatic group (s).

  
The aliphatic acyl group can comprise saturated or unsaturated, cyclic or acyclic acyl groups, such as a lower alkanoyl group (for example formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, iseryleryl, pivaloyl, hexanoyl, etc. groups). ), a (lower) sulfonyl alkane group (e.g. <EMI ID = 25.1>

  
etc.), a (lower) carbonyl alkoxy group (for example methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, etc.), a lower alkenoyl group (for example acryloyl, methacryloyl, crotonoyl groups, etc.) , a cyclo- group

  
  <EMI ID = 26.1>

  
hexanecarbonyl, etc.) amidino and the like.

  
The aromatic acyl group can comprise an aroyl group (for example benzoyl, toluoyl, xyloyl groups, etc.), an arenesulfonyl group (for example

  
benzenesulfonyl group, tosyle group, etc.) and the like.

  
The heterocyclic acyl group may include a heterocyclic carbonyl group (e.g. groups

  
  <EMI ID = 27.1>

  
zolylcarbonyl, thiadiazolylcarbonyl, tetrazolylcarbonyl, etc.) and the like.

  
  <EMI ID = 28.1>

  
more than one aromatic group may include a lower aralkanoyl group such as a lower phenylalkanoyl group (e.g. phenylacetyl, phenylpropionyl, phenylhexanoyl etc.), an aralkoxy (lower) carbonyl group such as a phenylalkoxy (lower) carbonyl group (e.g. benzyloxycarbonyl, phenethyloxycarbonyl, etc.), a lower phenoxyalkanoyl group (e.g., phenoxyacetyl, phenoxypropionyl, etc.) and the like.

  
The aliphatic acyl group substituted by one or more heterocyclic groups can include the thienylacetyl, imidazolylacetyl, furylacetyl,

  
  <EMI ID = 29.1>

  
These acyl groups can also be substituted by one or more suitable substituents such as lower alkyl groups (for example methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, etc.), halogen (for example chlorine, bromine, iodine, fluorine), lower alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, etc.), (lower alkyl) thio (for example methylthio, ethylthio, propylthio, isopropylthio, butylthio, pentylthio, hexylthio, etc. ), nitro and the like, and a preferred acyl group bearing this or these substituents may be a mono (or di or tri) halo group

  
  <EMI ID = 30.1>

  
dichloroacetyl, trifluoroacetyl, etc.), mono (or di or tri) halo (lower alkoxy) carbonyl (for example chloromethoxycarbonyl, dichloromethoxycarbonyl, 2,2,2-trichloroetho-,

  
  <EMI ID = 31.1>

  
nyl (lower alkoxy) carbonyl (e.g. nitrobenzyloxycarbonyl, chlorobenzyloxycarbonyl, methoxybenzyloxycarbonyl, and the like.

  
  <EMI ID = 32.1>

  
me "dialkanoyloxy (lower alkyl)" mention may be made of formyloxy, acetoxy, propionyloxy, butyryloxy, isobutyryloxy, ualeryloxy, isovaleryloxy, pivaloyloxy, hexanoyloxy, heptanoyloxy, octanoyloxy, nonanoyloxy, decanoyloxy, or the like, or the like. CI to

  
  <EMI ID = 33.1>

  
As part "lower alkyl" in the terms "dialkanoyloxy (lower alkyl)", "protected carboxy (lower alkyl)", "carboxy (lower alkyl)", "di (hydroxyprotected) (lower alkyl)", and "dihydroxy (alkyl lower) "methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopen-

  
  <EMI ID = 34.1>

  
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl or the like groups, and preferably a

  
  <EMI ID = 35.1> As "hydroxy protected" and "hydroxy pro-

  
  <EMI ID = 36.1>

  
laughing) "we will mention the hydroxy group protected by a conventional protecting group, for example with a ketone compound such as a di (lower alkyl) ketone, for example acetone, methyl ethyl ketone, methyl-n-propyl ketone, diethyl ketone , 2-hexanone, 3-hexanone, tbutylmethylketone, etc.), cyclohexanone, biacetyl,

  
  <EMI ID = 37.1>

  
zophenone, and the like.

  
As "alkoxy" we will cite a linear alkoxy or

  
  <EMI ID = 38.1>

  
heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, tridecyloxy, tetradecyloxy; pentadecyloxy or ana-

  
  <EMI ID = 39.1>

  
As part "protected carboxy" and "protected carboxy" in the term "(protected carboxy) - (lower alkyl)", there may be mentioned an esterified carboxy such as a group (alkoxy

  
  <EMI ID = 40.1>

  
ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, etc.), a mono group
(or di or tri) phenyl- (lower alkoxy) carbonyl which can carry a nitro group (for example a benzyloxy-

  
  <EMI ID = 41.1>

  
nyle, benzhydryloxycarbonyle, trityloxycarbonyle, etc.) etc.

  
As a suitable "cycloalkylcarbonyloxy" group,

  
  <EMI ID = 42.1>

  
As "heterocyclic group * <1> suitable, mention may be made of a saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one heteroatom

  
such as an oxygen, sulfur, nitrogen atom, etc. Particularly preferred is a heterocyclic group such as an unsaturated heteromonocyclic group with 3 to 8 links and

  
  <EMI ID = 43.1>

  
nitrogen, such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, dihydropyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl
(e.g. 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl,

  
  <EMI ID = 44.1>

  
tetrazolyl, 2H-tetrazolyl, etc.) etc. and the like.

  
As the "(lower alkoxy) carbonyloxy (lower alkyl)" group, methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, 2-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl, 1-isopropoxycarbonyloxyethyl and the like will be mentioned.

  
As group "azido (lower alkoxy) carbonyloxy
(lower alkyl) "include azidomethoxycarbonyloxymethyl, 2-azidoethoxycarbonyloxymethy &#65533; e, 1- (2azidoethoxycarbonyloxy) ethyl, 2- (2-azidoethoxycarbonyloxy) ethyl, etc. and the like.

  
As a suitable "aroyloxy (lower alkyl)" group, mention may be made of a benzoyloxy (lower alkyl) group.

  
  <EMI ID = 45.1>

  
toluoyloxy (lower alkyl) (e.g. toluoyloxym ethyl, 1-toluoyloxyethyl, etc.) and the like.

  
As the group "(higher alkanoyloxy) - (lower alkyl)", mention may be made of 2,3-dimethylpentanoyloxymethyl, tridecanoyloxymethyl, octanoyloxymethyl, tetra- groups.

  
  <EMI ID = 46.1>

  
As group "phthalidylidene (lower alkyl)"

  
mention may be made of 3-phthalidylidenemethyl, 1- (3-phthalidylidene) ethyl, 2- (3-phthalidylidene) ethyl, 1- (3-phthalidylidene) propyl, 2- (3-phthalidylidene) propyl, 3- (3-phthalidy) groups -

  
  <EMI ID = 47.1>

  
As "reactive hydroxy derivative" for X, an acid radical such as a halogen will be mentioned (for example

  
chlorine, bromine, iodine, etc.), a sulfonate, a sulfate etc.

  
  <EMI ID = 48.1>

  
dialcanoyloxy (lower alkyl) groups (for example diacetoxymethyl, 1,2-diacetoxyethyl, 1,2-dinonanoyloxyethyl, 1,2-dipropionyloxypropyl, 1,3-dipropionyloxypropyl,

  
  <EMI ID = 49.1>

  
dioctanoyloxypropyle, 1,3-dinonanoyloxyprop yl, 1,3-didécanoyloxypropyle, 1,3-dinonanoyloxybutyle, 1,3-dinonanoyloxypentyle, 1,3-dinonanoyloxyhexyle, 2-nonanoyloxy-l-nona'-

  
  <EMI ID = 50.1>

  
alkyl (for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, etc.);

  
dihydroxy (lower alkyl) (for example 1,2-dihydroxyethyl, 1,2-dihydroxypropyl, 1,3-dihydroxypropyl,

  
  <EMI ID = 51.1>

  
xybutyl, 1,4-dihydroxybutyl, 1,2-dihydroxypentyl, 1,3-dihydroxypentyl, etc.);

  
di (protected hydroxy) (lower alkyl) such as

  
  <EMI ID = 52.1>

  
etc., etc.

  
dialkoxy (lower alkyl) (e.g. dimethoxymethyl, 1,2-dimethoxyethyl, 1,2-dipropoxyethyl, 1,3-

  
  <EMI ID = 53.1> <EMI ID = 54.1>

  
ethyl, 2-octyloxy-1-octyloxymethylethyl, 2-dodecyloxy1-dodecyloxymethylethyl, etc., and preferably di (C.-

  
  <EMI ID = 55.1>

  
carboxy (lower alkyl) (e.g. carboxymethyl, carboxyethyl, 1-carboxypropyl, 2-carboxypropyl, 3-carboxypropyl, 1-carboxybutyl, 2-carboxybutyl, 4-carboxybutyl, 5-carboxypentyl, 6-carboxyhexyl, etc.);

  
(protected carboxy) (lower alkyl) such as an esterified carboxy (lower alkyl) group, etc., and preferably (lower alkoxy) carbonyl (lower alkyl (for example methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonylmethyl, t-butoxycarbonylmethyl-e. t- butoxycarbonylpropyle, 1-t-butoxycarbonylpropyle, 3-t-butoxycar-

  
  <EMI ID = 56.1>

  
loxycarbonylmethyl, 2-benzyloxycarbonylethyl, 3- (4-nitrobenzyloxycarbonyl) propyl, 3-benzhydryioxycarbonylpropyl, 1-benzhydryloxycarbonylpropyl, 5-benzhydryloxycarbonyl-

  
  <EMI ID = 57.1>

  
benzyloxycarbonyl) hexyl, trityloxycarbonylmethyl, etc.) etc.

  
cycloalkylcarbonyloxy (lower) alkyl (e.g. cyclobutylcarbonyloxyméthyle, cyclopentylcarbonyloxyméthyle, cyclopentylcarbonyloxyéthyle, cyclopentylcarbonyloxypropyle, cyclopentylcarbonyloxybutyle, cyclopentylcarbonyloxypentyle, cyclopentylcarbonyloxyhexyle, cyclohexylcarbonyl oximeter ethyl, cyclohexylcarbonyloxyethyl, cyclohexylcarbonyloxybutyle, cyclohexylcarbonyloxypropyle, etc.), and

  
  <EMI ID = 58.1>

  
A heterocyclic group (lower alkyl) such as an unsaturated heteromonocyclic group (lower alkyl)

  
  <EMI ID = 59.1>

  
ridylethyl, pyridylpropyl, pyridylbutyl, pyridylpentyle, <EMI ID = 60.1>

  
triazolylethyl, tetrazolylmethyl, tetrazolylbutyl, tetrazolylpentyl, etc.), and preferably pyridyl (alkyl

  
  <EMI ID = 61.1>

  
alkoxycarbonyloxy (lower alkyl) (e.g. methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, 2-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl, 1-

  
  <EMI ID = 62.1>

  
azidoethoxycarbonyloxymethyl, 1- (2-azidoethoxycarbonyloxy) ethyl, 2- (2-azidoethoxycarbonyloxy) ethyl, etc.) and

  
  <EMI ID = 63.1>

  
methylpentanoyloxymethyl, trid6canoyloxymethyl, oetanoyloxymethyl, tetradecanoyloxymethyl, tetradecanoyloxyethyl-

  
  <EMI ID = 64.1> butyl, t-butyl, pentyl, hexyl, etc.

  
Methods 1 to 6 for the preparation of the compound (I) of the invention are explained in detail in the following.

  
(1) Method 1

  
Compound (I) or a salt thereof can be prepared

  
  <EMI ID = 65.1>

  
with an esterifying agent corresponding to the formula: X-R2

  
(III) in which R <2> and X are both as defined. above. As suitable salts of the compound (11) mention will be made of those given as an example for the compound (I).

  
The reaction can be carried out in the presence

  
an organic or mineral base such as an alkali metal
(e.g. lithium, sodium, potassium, etc.), alkaline earth metal (e.g. calcium, etc.), an alkali metal hydride (e.g. sodium hydride), a alkaline earth metal hydride (e.g. calcium hydride, etc.), an alkali metal hydroxide

  
(e.g. sodium hydroxide, potassium hydroxide, etc.), an alkali metal carbonate (e.g.

  
sodium carbonate, potassium carbonate, etc.), of an alkali metal bicarbonate (for example sodium bicarbonate, potassium bicarbonate, etc.),

  
of an alkali metal alcoholate (e.g. methylate

  
sodium, sodium ethylate, potassium t-butoxide, etc.), an alkali metal salt of alkanoic acid (e.g. sodium acetate, etc.), a trialkylamine

  
(for example triethylamine, etc.), a pyridine (for example pyridine, lutidine, picoline, etc.),

  
quinoline, etc. and it can also be done

  
in the presence of a metal iodide (e.g. iodide

  
sodium, etc.).

  
This reaction is usually carried out in a conventional solvent which does not adversely affect

  
  <EMI ID = 66.1>

  
trahydrofuran, dimethyl sulfoxide, pyridine, dioxane, methanol, ethanol, water, acetone, aceto-nitrile, chloroform, benzene, methyl chloride

  
  <EMI ID = 67.1>

  
methylphosphoramide, etc. or a mixture of these.

  
When alcohol is used as the esterifying agent (III), the reaction is preferably carried out in the presence of a condensing agent such as a

  
  <EMI ID = 68.1>

  
N-cyclohexyl-N '- (4-diethylaminocyclohexyl) carbodiimide,

  
N, N'-diethylcarbodiimide, N, N'-diisopropylcarbodiimide, N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide, etc.),

  
  <EMI ID = 69.1>

  
sulfonic acid ester of N-hydroxybenzotriazole derivative (for example 1- (4-chlorobenzenesulfonyloxy) -6chloro-1H-benzotriazole, etc.), of a combination of trialkyl phosphite or triphenylphosphine and tetrachloride. carbon disulfide or. diazenedicarboxylate (for example diethyl diazenedicarboxylate, etc.) of a phosphorus compound (for example of an ethyl polyphosphate, an isopropyl polyphosphate, a phosphoryl chloride, phosphorus trichloride, etc.),

  
thionyl chloride, benzenesulfonyl chloride, oxalyl chloride, an N-ethylbenzisoxazolium salt,

  
  <EMI ID = 70.1>

  
tif (designated under the name of "Vilsmeier reagent") formed by the reaction of an amide such as N, N-di (lower alkyl) formamide (for example dimethylformamide, etc.), N-methylformamide, etc. . with a halogenated compound such as thionyl chloride, phosphoryl chloride or phosgene, molecular sieves, etc.

  
The reaction temperature is not critical and the reaction is usually carried out with cooling, at a temperature above room temperature.

  
Some of the starting compounds (III) used in process 1 are new and can be prepared, for example from known compounds by conventional methods. The detailed explanation of these processes is given in preparations 2 to 6 below,

  
(2) Method 2:

  
The compound of the invention (Ic) or one of its salts can be prepared by oxidizing the compound (Ib) or one of its salts.

  
  <EMI ID = 71.1>

  
ter the salts given as an example for the compound (I).

  
The oxidation reaction of the invention can be

  
  <EMI ID = 72.1>

  
formation of

  

  <EMI ID = 73.1>


  
  <EMI ID = 74.1>

  
. for example using an oxidizing agent such as m-chloroperbehzoic acid, perbenzoic acid, peracetic acid, ozone, hydrogen peroxide, periodic acid, etc ...

  
The reaction of the invention is usually carried out in a solvent such as water * acetone, dio-

  
  <EMI ID = 75.1>

  
what other solvent which does not adversely affect the reaction.

  
Reaction temperature is not critical

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

  
(3) Method 3:

  
The compound (la) or one of its salts can be prepared by reducing the compound (le) or one of its salts.

  
As suitable salts of the compound (le), mention will be made of those given as examples for the compound (I).

  
The reduction according to the invention can be

  
  <EMI ID = 76.1>

  
formation of

  

  <EMI ID = 77.1>


  
  <EMI ID = 78.1>

  
for example, using

  
phosphorus trichloride, a combination of stan-

  
  <EMI ID = 79.1> of a trihaloacetic anhydride (for example trifluoroacetic anhydride, etc.).

  
The reduction is usually carried out in a

  
  <EMI ID = 80.1>

  
benzene, hexane, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, or any other solvent which does not adversely affect the reaction.

  
The reaction temperature is not critical and the reaction can usually be carried out with cooling or at room temperature.

  
(4) Method 4:

  
The compound (le) or one of its salts can be prepared by subjecting the compound, (Id) or one of its salts to a reaction for removing the protecting group from carboxy in R &#65533;

  
  <EMI ID = 81.1>

  
As a suitable process for the elimination reaction, a conventional process such as hydrolysis will be mentioned.

  
reduction etc.

  
(i) For hydrolysis

  
The hydrolysis is preferably carried out in the presence of an acid.

  
As the appropriate acid, mention may be made of a mineral acid (for example hydrochloric acid, hydrobromic acid, sulfuric acid, etc.), an organic acid (for example formic acid, acetic acid, tri- acid

  
  <EMI ID = 82.1>

  
(benzenesulfonic acid, p-toluenesulfonic acid, etc.), an acid ion exchange resin, etc. When an organic acid such as trifluoroacetic acid and p-toluenesulfonic acid is used in this reaction,

  
the reaction is preferably carried out in the presence of agents

  
  <EMI ID = 83.1>

  
The acid suitable for this hydrolysis can be chosen according to the nature of the protective group to be removed, for example this hydrolysis can preferably be used in cases where the carboxy protecting group is a substituted or unsubstituted lower alkyl group, a mono group (or di or tri) substituted or unsubstituted phenyl (lower alkyl), etc.

  
Hydrolysis is usually carried out in a conventional solvent which does not act in an unfavorable direction

  
  <EMI ID = 84.1>

  
propanol, t-butyl alcohol, tetrahydrofuran, N, N-dimethylformamide, dioxane or a mixture thereof, and in addition the above acids can also be used as a solvent when in liquid form .

  
The hydrolysis chain reaction temperature is not critical, and the reaction is usually carried out with cooling to a temperature above

  
  <EMI ID = 85.1>

  
(II) For the reduction:

  
The reduction is carried out in a conventional manner comprising chemical reduction and catalytic reduction.

  
As suitable reducing agents which can be used in chemical reduction, a combination of a metal (for example tin, zinc, iron, etc.) or a metallic compound (for example chromium chloride, chromium acetate, etc.), and an organic or mineral acid (e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, ptoluenesulfonic acid, hydrochloric acid, l hydrobromic acid, etc.).

  
As catalysts suitable for use in catalytic reduction, there may be mentioned conventional catalysts such as platinum catalysts (for example a platinum plate, a platinum sponge, platinum black, colloidal platinum, oxide of platinum, platinum wire, etc.), palladium catalysts (e.g. palladium sponge, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate , palladium on barium carbonate, etc.), nickel catalysts (e.g. reduced nickel, nickel oxide, Raney nickel), etc.), cobalt catalysts (e.g. cobalt reduced, Raney cobalt, etc.), iron catalysts (e.g. reduced iron,

  
Raney iron, etc.), copper catalysts (e.g. reduced copper, Raney copper, Ullman copper, etc.) etc.

  
The manner of carrying out the reduction can be chosen according to the nature of the protective group to be eliminated, for example chemical reduction can be preferably used when the protecting group of the carboxy is a halo (lower alkyl) group or an analogous group and the catalytic reduction is preferably used when the protective group of the carboxy is a substituted or unsubstituted mono (or di or tri) phenyl (lower alkyl) group, etc.

  
The reduction is usually carried out in a conventional solvent which does not influence the reaction such as water, methanol, ethanol, propanol, N, N-dimethylformamide or a mixture of these. In addition, when.

  
the above acids to be used in chemical reduction are in liquid form, they can also be used as solvent. In addition, a solvent usable in catalytic reduction can be the solvent indicated above, and another conventional solvent such that diethyl ether, dioxane, tetrahydrofuran,

  
etc. or a mixture of these.

  
The reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling or hot.

  
The methods indicated above can be chosen according to the nature of the protective group to be eliminated.

  
  <EMI ID = 86.1>

  
prepared by subjecting the compound (If) or a salt thereof

  
to an elimination reaction of the protective group of the hy-

  
  <EMI ID = 87.1> The appropriate salt of the compound (If) can be one

  
  <EMI ID = 88.1>

  
The reaction is carried out by a conventional process such as hydrolysis, reduction etc.

  
The process of hydrolysis and reduction, and the reaction conditions * (e.g. reaction temperature, solvent, etc.) are practically the same as

  
  <EMI ID = 89.1>

  
carboxy protector in process 4.

  
The present invention includes cases where the

  
or the protected amino groups, and / or the protected carboxy group (s) are transformed into the free amino group (s) and / or the corresponding free carboxy group (s), respectively, during the reaction.

  
  <EMI ID = 90.1>

  
The compound (Ii) or a salt thereof can be prepared by subjecting the compound (Ih) or one of its salts to

  
the amino group protecting group removal reaction in R.

  
at

  
As suitable salt of the compound (Ih), mention may be made of those given as an example for the compound (I).

  
  <EMI ID = 91.1>

  
sic such as hydrolysis, reduction, etc.

  
The hydrolysis and reduction process, and

  
the reaction conditions (for example reaction temperature, solvent, etc.) are practically the same as those given as an example for the removal of the carboxy protecting group in process 4.

  
The present invention covers cases where the protected carboxy group (s) and / or the protected hydroxy group (s) are converted into the free carboxy group (s) and / or the corresponding free hydroxy group (s), respectively, during the reaction.

  
  <EMI ID = 92.1>

  
alkyl can be prepared by the procedures given above, and detailed explanations are given for these in the examples below.

  
  <EMI ID = 93.1>

  
Maceutically acceptable are new and exhibit high antimicrobial activity, they inhibit the development of a wide variety of pathogenic microorganisms including gram-positive and gram-negative microorganisms and they are useful as antimicrobial agents, especially for oral administration.

  
For therapeutic administration, the compounds of the invention (1) and their pharmaceutically acceptable salts

  
  <EMI ID = 94.1>

  
conventional ceutique containing this compound as active ingredient, in mixture with p harmaceutically acc.eptable supports such as an organic or mineral solid or liquid excipient suitable for oral, parenteral and external administration.

  
The compounds of the invention and their pharmaceutically acceptable salts have a high antimicrobial activity. and will be used for administration by injection, suppository or oral in particular - for oral administration, their preparation being explained, for example as indicated below.

  
Pharmaceutical preparations can be in solid form, such as tablet, granule, powder, capsule

  
or in a liquid form such as solution, suspension, syrup, emulsion, lemonade, etc.

  
If necessary, auxiliary substances, stabilizing agents, wetting agents and all other additives which are commonly and conventionally used in cephalosporin preparations such as lactose, magnesium stearate can be incorporated into the above preparations. , white clay, sucrose corn starch, talc, stearic acid, gelatin, agar-agar, pectin, peanut oil, olive oil

  
  <EMI ID = 95.1>

  
depends on the age, age of the patient, the nature of the disease, the nature of the compounds (I) administered, etc. In general, a patient can be administered amounts of between 1 mg and approximately 4000 mg or even more per day. An average single dose of approximately 50 mg, 100 mg,

  
250 mg, 500 mg, 1000 mg, 2000 mg of the compounds (I) of the invention can be used for the treatment of infectious diseases caused by pathogenic microorganisms.

  
The following examples are given by way of illustration of the present invention.

  
Preparation 1

  
N-nonanoyie chloride (23 g) was added dropwise to a stirred solution of glycerin (6.0 g) in dry pyridine (60 ml) between 0 and 5 [deg.] C for
The mixture was stirred at the same temperature for one hour, and then allowed to stand at room temperature overnight. The resulting mixture

  
was poured into water and ice (300 ml), and extracted with ethyl acetate (50 ml x 2). The extract was washed with water (10 ml), an aqueous solution

  
  <EMI ID = 96.1>

  
sodium chloride (40 ml) in turn, and then dried over anhydrous magnesium sulfate. The solution was evaporated in vacuo, and the residue was subjected to chromatography.

  
  <EMI ID = 97.1>

  
mixture of chloroform and acetone (30: 1). The eluate was evaporated in vacuo to give 1,3-di-n-nonanoyloxy2-propanol, m.p. 30-31 [deg.] C.

  
  <EMI ID = 98.1>

  
J = 7Hz), 2.87 (1H, broad s), 3.9-4.4 (5H, broad s).

  
Preparation 2

  
Bromoacetyl chloride (113 g) was added dropwise to a stirred solution of 4-nitrobenzyl alcohol (9.2 g) and pyridine (10 ml) in dry tetrahydrofuran (100 ml) at 0 [deg. ] C for 50 minutes. The mixture was stirred between 0 and 5 [deg.] C for 30 minutes and evaporated in vacuo. The residue was dissolved in a mixture of chloroform (70 ml) and water (20 ml), and then the organic layer

  
  <EMI ID = 99.1>

  
dilute aqueous solution of hydrochloric acid and water, in turn, and then dried over anhydrous magnesium sulfate. The solution was evaporated in vacuo, and the residue was recrystallized from methanol to give crystals (6.74 g) of 4-nitrobenzyl bromoacetate.

  
  <EMI ID = 100.1>

  
7.52 (2H, d, J = 9Hz), 8.23 (2H, d, J = 9Hz). Preparation 3

  
The following compounds were obtained in a similar manner to that of Preparation 2.

  
(1) 4-nitrobenzyl 6-bromohexanoate

IR (Film): 1740, 1605 cm-1

  
  <EMI ID = 101.1>

  
J = 7Hz), 3.7 (2H, t, J = 6Hz), 5.3 (2H, s), 7.5 (2H, d, J = 9Hz), 8.2 (2H, d, J = 9Hz). Preparation 4

  
Sodium iodide (3.5 g) was slowly added to a stirred solution of 4-nitrobenzyl bromoacetate (5.0 g) in acetone (50 ml) at room temperature for 5 minutes, and the solution was stirred at the same temperature for 2.25 hours. The resulting mixture

  
was evaporated in vacuo, and the residue was dissolved in a mixture of ethyl acetate (40 ml) and water (15 ml). The organic layer was separated, washed with saturated aqueous sodium chloride solution and aqueous sodium thiosulfate solution, in turn, and then dried over anhydrous magnesium sulfate. After the solution was evaporated in vacuo, the residue was allowed to stand in a refrigerator overnight and triturated with methanol (10 ml) to give crystals (5.25 g) of 4 iodoacetate -nitrobenzyl, pf 62.5 to 63.5 [deg.] C.

  
  <EMI ID = 102.1>

  
7.55 (2H, d, J = 9Hz), 8.25 (2H, d, J = 9Hz). Preparation 5

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

  
(1) 4-nitrobenzyl 6-iodohexanoate

  
  <EMI ID = 103.1>

  
J = 6Hz), 3.15 (2H, t, J = 6Hz), 5.17 (2H, s), 7.43 (2H, d, Jr9Hz), 8.15 (2H, d, J = 9Hz) ,

  
(2) 4-nitrobenzyl 4-iodobutyrate

  
  <EMI ID = 104.1>

  
phem-4-carboxylic acid (syn isomer, 10.0 g) in N, Mdimethylformamide, dry (100 ml) while cooling with

  
ice, and stirred at 400C for 3.5 hours. The resulting solution was poured into a mixture of ethyl acetate (300 ml) and water (500 ml) and adjusted. a pH of 1.5 with 6N hydrochloric acid. After separation from

  
the organic layer, the aqueous layer was extracted with ethyl acetate (100 ml x 2). The organic layer and the extract were combined and washed with a saturated aqueous sodium bicarbonate solution, an aqueous solution

  
  <EMI ID = 105.1>

  
of sodium chloride Lour in turn. After treating the solution with activated charcoal, the solution was dried over anhydrous magnesium sulfate.

  
The solution was evaporated in vacuo, and the residue was triturated with diethyl ether (100 ml). The precipitates were combined by filtration, washed with diethyl ether (20 ml) twice and dried over phosphorus pentoxide in vacuo to give 7- [2- (2-

  
  <EMI ID = 106.1>

  
N-butyl 4-carboxylate (syn- isomer, 7.6 g).

  
IR (Nujol): 3250, 3170, 3050, 1790, 1780, 1770,

  
1725, 1700, 1660, 1635, 1565,

  
  <EMI ID = 107.1> <EMI ID = 108.1>

  
(4H, wide), 3.62 (2H, d, J = 4Hz), 3.88

  
(3H, s), 4.17 (2H, t, J = 6Hz), 5.10 (1H, d, J = 5Hz), 5.85 (1H, dd, J = 5Hz, 8Hz), 6.47
(1H, t, J = 4Hz), 7.35 (1H, s), 8.45 (1H, s), 9.63 (1H, d, J = 8Hz), 12.82 (1H, s).

  
EXAMPLE 2

  
Molecular sieves (3 A) (10 g) were added to a solution of 7- [2- (2-formamidothiazol-4-yl) - acid

  
  <EMI ID = 109.1>

  
syn, 5 g) in dry pyridine (45 ml) and stirred at room temperature for 40 minutes. Dry tetrahydrofuran (15 ml) and 2,2-dimethyl-4-hydroxymethyl-1,3dioxolane (1.6 g) were added to the solution and then cooled with water and ice. After adding dicyclohexylcarbodiimide (3.8 g) to the solution, the latter was

  
  <EMI ID = 110.1>

  
with water and ice (300 ml) and separated by filtration. The filtrate was extracted with ethyl acetate
(300 ml) twice. Water and ice were added to the extract and the solution was adjusted to pH 3

  
to 4 with 3N hydrochloric acid and washed with a saturated aqueous solution of sodium chloride. The organic layer was adjusted to a pH of 7 to 8 with a saturated aqueous solution of sodium bicarbonate and washed with

  
some water. The solution was dried over anhydrous magnesium sulfate. The solution was evaporated in vacuo to give a brown oil (3.6 g). The oil was purified by column chromatography on silica gel to

  
  <EMI ID = 111.1>

  
3.5-3.7 (2H, m), 3.96 (3H, s), 3.6-4.6

  
 <" <EMI ID = 112.1>

  
J = 5Hz, 9Hz), 6.5-6.8 (1H, m), 7.85 (1H, d, J = 9Hz), 8.57 (1H, s), 11.7 (1H, large s ).

EXAMPLE 3

THIS

  
Molecular sieves (3 A) (15 g) were added to a solution of 7- [2- (2-formamidothiazol-4-yl) - acid

  
  <EMI ID = 113.1>

  
syn, 8.2 g) in dry pyridine (80 ml), and stirred

  
at room temperature for 30 minutes. Dry tetrahydrofuran (15 ml) and 2-hydroxymethylpyridine (2.2 g) were added to the solution and cooled with water and ice. After addition of dicyclohexylcarbodiimide
(6.2 g) in the solution, this was stirred between 0 and 3 ° C. under an atmosphere of nitrogen gas for 4 hours and, moreover, at room temperature for 14 hours. Ethyl acetate (200 ml) was added to the resulting mixture and separated by filtration. The filtrate was set to a

  
  <EMI ID = 114.1>

  
removed the organic layer from the resulting solution, ethyl acetate (400 ml) was added to the aqueous solution. This was adjusted to a pH of 8 to 9 with a saturated aqueous solution of sodium bicarbonate. The aqueous layer was extracted with a mixed solution of ethyl acetate (200 ml) and tetrahydrofuran (200 ml). The organic layer was combined and washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo to give an orange-colored oil (6.0 g). The oil was purified by column chromatography on silica gel to give pure oil (3.5 g). The oil was sprayed with diisopropyl ether to give a pale yellow powder (2.8 g of 7- [2- (2-formamidothiazol-4-yl) -2-

  
  <EMI ID = 115.1>

  
  <EMI ID = 116.1>

  
IR (Nujol): 3250, 3150, 3050, 1760, 1730,

  
1690, 1650 cm- <1>

  
  <EMI ID = 117.1>

  
5.20 (1H, d, J = 5Hz), 5.37 (2H, s), 5.98 (1H, dd, J = 5H2, 8Hz), 6.5-6.8 (1H, m), 7.3-8.1

  
(4H, m), 8.5-8.8 (2H, m), 9.75 (1H, d, J = BHz).

EXAMPLE 4

  
Dicyclohexylcarbodiimide (6.5 g) was added to a stirred solution of 7- [2- (2-formamidothiazol-) acid.

  
  <EMI ID = 118.1>

  
syn mother, 8.6 g) and 2-n-nonanoyloxy-1-n-nonanoyloxymethylethanol (7.8 g) in a mixture of dry pyridine (80 ml) and dry tetrahydrofuran (25 ml) at 3 [deg. ] C, and then stirred between 0 and 5 [deg.] C for 4 hours and left to stand

  
at room temperature overnight. The resulting mixture was poured into water and ice * (450 ml)

  
and extracted with ethyl acetate (450 ml). Some water
(50 ml) was added to the extract and adjusted to a pH of 2 to

  
3 with 20% sulfuric acid. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride (100 ml x 2) and an aqueous solution of sodium bicarbonate, in turn, and dried. on anhydrous magnesium sulfate. After removing the solution in vacuo, the residue was subjected to column chromatography on silica gel (370 g) with a mixture of chloroform and acetone (5: 1). The eluate was evaporated in vacuo to give a powder (4.62 g) of 7- [2- (2-formamida-

  
  <EMI ID = 119.1>

  
te of 2-n-nonanoyloxy-1-n-nonanoyloxymethylethyl (syn isomer).

  
  <EMI ID = 120.1>

  
6.48-6.65 (1H, m), 7.16 (1H, s) ,. 7.85 (1H,

  
  <EMI ID = 121.1>

  
EXAMPLE 5

  
7- [2- (2-aminothiazol-4-yl) -2-methoxy- acid

  
  <EMI ID = 122.1> was dissolved in a mixed solution of dry dimethyl sulfoxide (90 ml) and dry dimethylformamide (30 ml). After adding triethylamine (1.58 g) to the solution stirred at 9 [deg.] C for 2 minutes, iodomethyl cyclohexanecarboxylate (4.2 g) was added thereto with stirring for 5 minutes, and then stirred with ice cooling for 35 minutes. Water and ice (500 ml) were added to the resulting solution and extracted with ethyl acetate three times. The solution was subsequently washed with a dilute aqueous solution of

  
  <EMI ID = 123.1>

  
of sodium and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solution was evaporated in vacuo, and the residue was purified by column chromatography on silica gel (100 g) with a mixed solution of chloroform and acetone (10: 3). The eluate was evaporated in vacuo to give the purified residue. The residue was sprayed with diisopropyl ether and dried in vacuo to give

  
  <EMI ID = 124.1>

  
cyclohexylcarbonyloxymethyl cephem-4-carboxylate (syn isomer, 4.0 g).

  
IR (Nujol): 3410, 3300, 1775, 1745, 1670,

  
  <EMI ID = 125.1>

  
To a cold solution of the above compound in

  
  <EMI ID = 126.1>

  
hydrochloric by stirring the mixture, then the precipitates were collected by filtration so as to give

  
  <EMI ID = 127.1>

  
methyl, (syn isomer).

  
EXAMPLE 6

  
To a solution of 7- [2- (2-aminothiazol-4-yl) -2-

  
  <EMI ID = 128.1>

  
(syn isomer, 5.0 g) in N, N-dimethylformamide

  
  <EMI ID = 129.1>

  
and the solution was stirred for 3 hours at room temperature. The fractional mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and water, in turn, and dried over anhydrous magnesium sulfate. The solution was evaporated in vacuo to give

  
  <EMI ID = 130.1>

  
t-butoxycarbonylmethyl cephem-4-carboxylate (syn isomer, 3.2 g), m.p. 188-190 [deg.] C (decomposition).

  
IR (Nujol): 3250, 3080, 1775, 1730, 1654,

  
  <EMI ID = 131.1>

EXAMPLE 7

  
A mixture of 7- [2- (2-formamidothiazol-4-yl) 2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid (syn isomer, 6.0 g) and molecular sieves (20 g) in the dry pyridine (60 ml) was stirred at 0 to 5 ° C. for one hour, and 2-n-octyloxy-1n-octyloxymethylethanol (4.6 g) was added thereto. Benzenesulfonyl chloride (2.6 g)

  
was added dropwise to the solution stirred between -5

  
  <EMI ID = 132.1>

  
hour. The resulting mixture was poured into crushed ice (300 g), adjusted to a pH of 1 to 2 with sulfuric acid.

  
  <EMI ID = 133.1>

  
(300 ml). The extract was washed with an aqueous solution

  
of sodium chloride, an aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, in turn, and dried over anhydrous magnesium sulfate. The solution was evaporated under reduced pressure, and the residue was subjected to column chromatography

  
on silica gel (200 g) with a mixture of chloroform and methanol (20: 1). The eluate was evaporated in vacuo

  
  <EMI ID = 134.1>

  
(8H, m), 4.0 (3H, s), 4.9-5.2 (2H, m) 5.3 (1H, d, J = 5Hz), 5.7-6.7 (3H, m), 7.2 <EMI ID = 135.1>

EXAMPLE 8

  
Dicyclohexylcarbodiimide (3.96 g) was

  
  <EMI ID = 136.1>

  
stirred at 0-5 [deg.] C for 4.75 hours, and additionally at room temperature for one hour. The resulting mixture was poured into water and ice (350 ml)

  
  <EMI ID = 137.1>

  
(50 ml) was added to the extract and adjusted to a pH of

  
  <EMI ID = 138.1>

  
was separated and washed with a saturated aqueous solution of sodium chloride (100 ml x 2) and an aqueous solution of sodium bicarbonate, in turn, and dried over anhydrous magnesium sulfate, after evaporation of the solution under empty, the residue was subjected to column chromatography on silica gel (266 g) with a mixture of chloroform and methanol (20: 1). The eluate was evaporated in vacuo to give a powder (6.24 g) of

  
  <EMI ID = 139.1>

EXAMPLE 9

  
The following examples were obtained in a manner similar to that of Examples 1 to 8.

  
  <EMI ID = 140.1>

  
do] -3-cephem-4-n-hexyl carboxylate (syn isomer).

  
IR (Nujol): 3250, 3170, 3050, 1790, 1740, 1720,

  
  <EMI ID = 141.1> <EMI ID = 142.1>

  
do] -3-cephem-4-n-octyl carboxylate (syn-isomer).

  
IR (Nujol): 3250, 3150, 3050, 1790, 1730, 1690,

  
  <EMI ID = 143.1>

  
1.90 (12H, wide), 3.60 (2H, d, J = 4Hz), 3.90 (3H, s), 4.17 (2H, t, J = 6Hz), 5.13

  
  <EMI ID = 144.1>

  
6.50 (1H, t, J = 4Hz), 7.22 (1H, s), 8.50
(1H, s), 9.67 (1H, d, J = 8Hz), 12.77 (1H, s)

  
  <EMI ID = 145.1>
-2-n-butoxy-1-n-butoxymethylethyl -2-cephem-4-carboxylate (syn isomer), m.p. 82 to 84 [deg.] C.

  
  <EMI ID = 146.1>

  
R.M.N. (CDC13, 6): 0.7-1.1 (6H, m), 1.1-2.7

  
(8H, m), 3.3-3.7 (8H, m), 4.0 (3H, s), 4.8-5.4 (3H, m), 5.7-6.6 (3H , m), 7.2
(1H, s), 7.8 (1H, d, J = 9Hz), 8.5 (1H, s),
11.7 (1H, large)

  
  <EMI ID = 147.1> le (syn isomer),

  
  <EMI ID = 148.1>

  
J = 8Hz, 5Hz), 6.66 (1H, t, J = 4Hz), 6.72
(1H, s), 7.48 (2H, d, J = 9Hz), 7.93 (1H, d, J = 8Hz), 8.20 (2H, d, J = 9Hz).

  
  <EMI ID = 149.1>

  
5- (4-nitrobenzyloxycarbonyl) pentyl cephem-4-carboxylate (syn isomer).

  
  <EMI ID = 150.1>

  
(1H, s), 7.45 (2H, d, J = 10Hz), 7.83 (1H, d, J = 9Hz), 8.15 (2H, d, J = 10Hz)

  
  <EMI ID = 151.1>

  
1-diphenylmethoxycarbonylpropyl cephem-4-carboxylate (syn-isomer), m.p. 133 to 138 [deg.] C (decomposition).

  
  <EMI ID = 152.1>

  
5.17 (1H, m), 5.80 (1H, m), 6.60 (1H, m), <EMI ID = 153.1>

  
n-hexyl cephem-4-carboxylate (syn isomer).

  
IR (Nujol): 3500, 3250, 3100, 3000-2200, 1780,

  
  <EMI ID = 154.1>

  
n-octyl cephem-4-carboxylate (syn isomer).

  
IR (Nujol): 3500, 3260, 3100, 3000-2200, 1780,

  
  <EMI ID = 155.1>

  
(1H, d, J = 5Hz), 5.90 (1H, dd, J = 5Hz, 8Hz), 6.58 (1H, t, J = 4Hz), 6.80 (1H, s), 7.23
(2H, s), 9.67 (1H, d, J = 8Hz).

  
  <EMI ID = 156.1>

  
n-decyl cephem-4-carboxylate (syn-isomer).

  
IR (Nujol): 3500, 3260, 3100, 3000-2000, 1780,

  
  <EMI ID = 157.1>

  
1.83 (16H, wide). 3.63 (2H, d, J = 4Hz), 3.87 (3H, s), 4.20 (2H, t, J = 6Hz), 5.15 (1H,

  
  <EMI ID = 158.1>

  
syn).

  
IR (Nujol): 3550, 34U0, 3300, 3150, 1780, 1730,

  
  <EMI ID = 159.1> 5.16 (1H, d, J = 5Hz), 5.34 (2H, s), 5.89 (1H,

  
  <EMI ID = 160.1>

  
2-n-octyloxy-1-n-octyloxymethylethyl cephem-4-carboxylate (syn isomer).

  
  <EMI ID = 161.1>

  
(1H, q, J = 5Hz, 9Hz), 6.3-6.7 (1H, m), 7.27
(1H, s), 7.90 (1H, d, J = 9Hz)

  
(14) 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3 ..

  
  <EMI ID = 162.1>. 5.27. (1H; m), 5.6 (2H, broad s), 6.05 (1H, q, J = 5Hz, 9Hz), 6.47-6.67 (1H, m), 6.78 (1H,
(1H, s), 7.70 (1H, d, J = 9Hz) <EMI ID = 163.1>

  
(8H, m), 3.2-3.8 (10H, m), 4.0 (3H, s), 5.02
(1H, d, J = 5Hz), 5.24 (1H, m), 5.7-6.2 (3H,

  
  <EMI ID = 164.1>

  
(1H, d, J = 8Hz).

  
To a cold solution of the, previous compound in

  
  <EMI ID = 165.1>

  
hydrochloric by stirring the mixture, then the precipitates were collected by filtration so as to give

  
  <EMI ID = 166.1>

  
noacetamido] -3-cephem-4-carboxylate of 2-N-butoxy-1-butoxymethylethyl (syn-isomer).

  
  <EMI ID = 167.1>

  
(4H, m), 3.4-3.7 (2H, m), 4.05 (3H, s), 4.15-4.50 (4H, m), 5.10 (1H, d, J = 5Hz), 5.2-5.8 (3H, m), 6.10 (1H, q, J = 5Hz, 8Hz), 6.5-6.7 (1H, m), 6.76 (1H , s), 7.93 (1H, d, J = 8Hz)

  
  <EMI ID = 168.1>

  
2,3-dihydroxypropyl cephem-4-carboxylate (syn-isomer)

  
  <EMI ID = 169.1>

  
1.80 (4H, wide), 3.63 (2H, d, J = 4Hz), 3.85
(3H, t), 4.18 (2H, t, J = 6Hz), 5.12 (1H, d,

  
  <EMI ID = 170.1>

  
9.60 (1H, d, J = 8Hz).

EXAMPLE 10

  
A solution of 3-chloroperbenzoic acid (0.9 g) in methylene chloride (10 ml) was added dropwise to a stirred solution of 7- [2- (2-formamidothiazol-

  
  <EMI ID = 171.1>

  
in methylene chloride (30 ml) between -7 and -30C for 30 minutes, and then stirred at 0 [deg.] C for 35 minutes. The resulting mixture was washed with dilute aqueous sodium bicarbonate solution and saturated aqueous solution of sodium chloride, in turn and dried over anhydrous magnesium sulfate. After removing the solvent from

  
  <EMI ID = 172.1>

  
written on a column on silica gel (120 g) with a mixture of chloroform and mithanol (20: 1). The eluate was evaporated in vacuo to give a powder (2.44 g)

  
  <EMI ID = 173.1>

  
acetamido] -3-cephem-4-carboxylate of 2-n-octyloxy-1-n-octy-loxymethylethyl (syn isomer).

  
IR (Nujol): 3200 (wide), 1795, 1730, 1695,

  
  <EMI ID = 174.1>

  
s).

EXAMPLE 11

  
The following compounds were obtained in a manner similar to that of Example 10.

  
(1) 7- [2- (2-formamidothiazol-4-yl) -2-methoxy- 1-oxide

  
  <EMI ID = 175.1>

  
188 [deg.] C.

  
IR (Nujol): 3500, 3260, 3170, 1790, 1735,

  
  <EMI ID = 176.1>

  
(10H, m), 3.93 (3H, s), 4.72 (1H, d, J = 5Hz), 5.2-5.5 (1H, m), 6.15-6.55 (2H ,

  
  <EMI ID = 177.1>

  
8.60 (1H, s), 11.8 (1H, large s)

EXAMPLE 12

  
  <EMI ID = 178.1>

  
do] -3-cephem-4-carboxylate of 2-n-octyloxy-1-n-octyloxy-methylethyl (syn isomer, 2.34 g) and sodium iodide

  
  <EMI ID = 179.1>

  
for 45 minutes, and stirred between 0 and 5 [deg.] C for 2 hours. The resulting mixture was poured into water and ice (200 ml) and then extracted with acetate

  
  <EMI ID = 180.1>

  
aqueous sodium thiosulfate, aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, in turn, and then dried over anhydrous magnesium sulfate. After evaporation of the solution in vacuo, the residue was subjected to column chromatography on silica gel (100 g) with a mixture of chloroform and methanol (2C: 1). The eluate was evaporated in vacuo to give a powder (1.57 g) of

  
  <EMI ID = 181.1>

  
thylethyl (syn isomer, 1.57 g).

  
IR (Nujol): 3200 (large), 1785, 1725, 1680,

  
  <EMI ID = 182.1>

  
(1ÛH, m), 4.0 (3H, s), 5.07 (1H, d, J = 5Hz), 5.1-5.4 (1H, m), 6.05 (1H, q, J = 5Hz, 8Hz), 6.5-6.7 (1H, m), 7.22 (1H, s), 7.85 (1H, d, J = 8Hz), 8.53 (1H, s).

EXAMPLE 13

  
The following compounds were obtained in a manner similar to that of Example 12.

  
  <EMI ID = 183.1>

  
do] -3-cephem-4-carboxylate of 2-n-dodecyloxy-1-n-dodecyloxymethylethyl (syn isomer).

  
IR (Nujol): 3350, 3300, 3200, 1780, 1730,

  
  <EMI ID = 184.1>

  
(1H, d, J = 9Hz), 8.50 (1H. S).

  
  <EMI ID = 185.1>

  
do] -3-cephem-4-carboxylate of 2-n-butoxy-1-n-butoxymethylethyl (syn-isomer), m.p. 83 to 87 [deg.] C.

  
  <EMI ID = 186.1>

  
R.M.N. (CDC13.6): 0.65-1.8 (14H, m), 3.30-3.83

  
(10H, m), 3.93 (3H, s), 5.03 (1H, d, J = 5Hz), 5.23 (1H, m), 6.00 (1H, q, J = 5Hz, 8Hz ), 6.43-6.73 (1H, m), 7.20 (1H, s), 7.80 (1H, d, J = 8Hz), 8.50 (1H, s), 11.8 ( 1H, large s).

  
EXAMPLE 14

  
  <EMI ID = 187.1>

  
rane (50 ml) and methanol (15 ml) was subjected to catalytic reduction under a hydrogen atmosphere, under 1 atmosphere, until the absorption of hydrogen had ceased. After removing the insoluble substance by filtration, the filtrate was concentrated in vacuo. The residue

  
was triturated with ethyl acetate to give a

  
  <EMI ID = 188.1>

  
(syn isomer), m.p.> 250 [deg.] C

  
IR (Nujol): 3600, 3410, 3260, 1770, 1720,

  
  <EMI ID = 189.1>

  
(2H, m), 6.75 (1H, s), 7.2 (2H, large s), 9.60 (1H, d, J = 8Hz).

  
EXAMPLE 15

  
  <EMI ID = 190.1>

  
butoxycarbonylmethyl (syn isomer, 1.5 g) with stirring

  
at room temperature. The reaction mixture was stirred for one hour at the same temperature. Then, the resulting solution was added dropwise to diisopropyl ether (150 ml). The precipitates were collected by filtration and washed with diisopropyl ether. The precipitates were dissolved in an aqueous solution of sodium bicarbonate. The aqueous solution was adjusted to pH 2.5 with concentrated hydrochloric acid. The precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure to give 7- [2- (2-

  
  <EMI ID = 191.1>

  
carboxymethyl carboxylate (syn isomer, 0.85 g), the infrared and nuclear magnetic resonance spectra being the same as those of the desired compound of the example
14.

EXAMPLE 16

  
The following compounds were obtained in a manner similar to that of Examples 14 and 15.

  
(1) 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-

  
5-carboxypentyl cephem-4-carboxylate (syn-isomer), m.p. 120-140 [deg.] C.

  
IR (Nujol): 3400 (shoulder), 3280, 3170

  
  <EMI ID = 192.1>

  
J = 6Hz), 3.60 (2H, large d, J = 4Hz), 3.83
(3H, s), 4.16 (2H, t, J = 5Hz), 5.10 (1H, d, J = 5Hz), 5.82 (1H, q, J = 5Hz, 8Hz), 6.5
(1H, t, J = 4Hz), 6.72 (1H, s), 7.15 (2H,

  
  <EMI ID = 193.1>

  
3-carboxypropyl cephem-4-carboxylate (syn-isomer).

  
IR (Nujol): 3400 (shoulder), 3280, 3170, 1770,

  
  <EMI ID = 194.1>

  
(2H, t, J = 6Hz), 3.66 (2H, large d, J = 4Hz), 3.90 (3H &#65533; s), 4.26 (2H, t, J = 6Hz), 5, 17
(1H, d, J = 5Hz), 5.90 (1H, q, J = 5Hz, 8Hz), 6.60 (1H, t, J = 4Hz), 6.80 (1H, s), 7.20

  
  <EMI ID = 195.1>

  
  <EMI ID = 196.1>

  
1-carboxypropyl cephem-4-carboxylate (syn-isomer), m.p. 145 to 154 [deg.] C (decomposition).

  
  <EMI ID = 197.1>

  
(2H, quintet, J = 6Hz), 3.67 (2H, m), 3.87
(3H, s), 4.95 (1H, m), 5.13 (1H, d, J = 5Hz), 5.83 (1H, m), 6.60 (1H, m), 6.73 ( 1H,

  
  <EMI ID = 198.1>

EXAMPLE 17

  
12 N hydrochloric acid (1.4 ml) was added to a solution of 7- [2- (2-formamidothiazol-4-yl) -2-me-

  
  <EMI ID = 199.1>

  
thyl-1,3-dioxolan-4-yl) methyl (syn isomer, 1.8 g) in

  
methanol (40 ml), and stirred at room temperature for 2 hours. After adding water and ice (200 ml)

  
to the resulting solution, the solution was adjusted to a pH of 7 to 8 with a saturated aqueous solution of sodium bicarbonate. The solution was extracted with a mixed solution of ethyl acetate (200 ml) and tetrahydrofuran (100 ml) twice. The extract was washed with saturated aqueous sodium chloride solution and dried

  
on. anhydrous magnesium. The solution was evaporated in vacuo to give a brown oil (1.2 g). The oil was purified by column chromatography on neutral alumina to give a yellow oil (0.7 g). The oil was sprayed with diethyl ether to give a pale yellow powder (0.5 g) of 7- [2- (2-aminothia-

  
  <EMI ID = 200.1>

  
J = 8Hz).

  
To a cold solution of the above compound in ethyl acetate, hydrochloric acid was added dropwise while stirring the mixture, then the precipitates were collected by filtration so as to give

  
  <EMI ID = 201.1>

  
(syn isomer).

  
  <EMI ID = 202.1>

  
n-butyl late (syn isomer, 7.5 g) in methanol (120 ml) for 5 minutes while cooling with ice, and stirred at room temperature for 4.25 hours. The resulting solution was poured into cooled water
(75 ml), and adjusted to a pH of 5.5 with a 4N aqueous sodium hydroxide solution at 5 [deg.] C. After treating the solution with activated charcoal (0.38 g), the solution was concentrated in vacuo. The aqueous residue was stirred with cooling on ice for 30 minutes. The precipitates were collected by filtration, washed with water (10 ml x 2) and then dried over phosphorus pentoxide to give a yellow powder (6.55 g) of 7- [2- (2-aminothiazol- 4-yl) -2-methoxyiminoacetamido] -3-cephem-4-n-butyl carboxylate
(syn isomer).

  
  <EMI ID = 203.1>

  
6.51 (1H, t, J = 4Hz), 6.73 (1H, s), 7.18 (2H, s), 9.60 (1H, d, J = 8Hz).

EXAMPLE 19

  
The following compounds were obtained in a similar manner to those of Examples 17 and 18.

  
  <EMI ID = 204.1>

  
n-hexyl cephem-4-carboxylate (syn isomer).

  
IR (Nujol): 3500, 3250, 3100, 3000-2200, 1780,

  
  <EMI ID = 205.1>

  
1.90 (8H, wide), 3.65 (2H, 'd, J = 4Hz), 3.90
(3H, s), 4.23 (2H, t, J = 6Hz), 5.17 (1H, d, J = 5Hz), 5.90 (1H, dd, J = 5Hz, 8Hz), 6.57 (1H, t, J = 4Hz), 6.8U (1H, s), 7.23 (2H, s), 9.67
(1H, d, J = 8Hz)

  
  <EMI ID = 206.1> n-octyl cephem-4-carboxylate (syn isomer)

  
IR (Nujol): 3500, 3260, 3100, 3000-2200, 1780,

  
  <EMI ID = 207.1>

  
3.90 (3H, s), 4.23 (2H, t, J = 6Hz), 5.17 (1H, d, J = 5Hz), 5.90 (1H, dd, J = 5Hz, 8Hz), 6.58
(1H, t, J = 4Hz), 6.80 (1H, s), 7.23 (2H, s), 9.67 (1H, d, J = 8Hz)

  
  <EMI ID = 208.1>

  
n-decyl cephem-4-carboxylate (syn isomer)

  
IR (Nujol): 3500, 3260, 3100, 3000-2000, 1780,

  
  <EMI ID = 209.1>

  
1.83 (16H, wide), 3.63 (2H, d, J. = 4Hz), 3.87 (3H, s), 4.20 (2H, t, J = 6Hz), 5.15
(1H, d, J = SHz), 5.87 (1H, dd, J = 5Hz, 8Hz),

  
  <EMI ID = 210.1>

  
6.74 (1H, s), 7.0-8.6 (6H, m), 9.59 (1H, d, J = 8Hz)

  
  <EMI ID = 211.1>

  
(10H, m), 4.0 (3H, s), 5.05 (1H, d, J = 5Hz), 5.1-5.4 (1H, m), 5.75 (2H, large s) 6.07

  
  <EMI ID = 212.1> <EMI ID = 213.1>

  
(10H, m), 4.05 (3H, s), 5.05 (1H, d, J = 5Hz), 5.27 (1H, m), 5.6 (2H, large s), 6.05 (1H,

  
q, J = 5Hz, 9Hz), 6.47-6.67 (1H, m), 6.78

  
(1H, s), 7.70 (1H, d, J = 9Hz)

  
  <EMI ID = 214.1>

  
(3H, m), 6.52 (1H, wide s), 6.71 (1H, s), 7.97 (1H, d, J = 8Hz)

  
(8) 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-

  
  <EMI ID = 215.1>

  
(4H, m), 3.4-3.7 (2H, m), 4.05 (3H, s), 4.15-4.50 (4H, m), 5.10 (1H, d, J = 5Hz), 5.2-5.8 (3H, m), 6.10 (1H, q, J = 5Hz, 8Hz), 6.5-6.7 (1H, m), 6.76 (1H , s), 7.93 (1H, d, J = 8Hz)

  
  <EMI ID = 216.1>

  
4-nitrobenzyloxycarboxymethyl cephem-4-carboxylate (syn isomer).

  
  <EMI ID = 217.1>

  
4.83 (2H, s), 5.05 (1H, d, J = 5Hz), 5.28
(2H, s), 5.75 (2H, broad s), 6.06 (1H, q,

  
  <EMI ID = 218.1>

  
(1H, s), 7.48 (2H, d, J = 9Hz), 7.93 (1H, d, J = 8Hz), 8.20 (2H, d, J = 9Hz).

  
  <EMI ID = 219.1>

  
5- (4-nitrobenzyloxycarbonyl) pentyl cephem-4-carboxylate (syn isomer).

  
  <EMI ID = 220.1>

  
5.17 (2H, s), 5.73 (2H, broad s), 6.05 (1H, q, J = 9Hz, 5Hz), 6.4-6.6 (1H, m), 6.70 (1H,

  
  <EMI ID = 221.1>

  
J = 6Hz), 3.4-3.6 (2H, m), 4.0 (3H, s), 4.3
(2H, t, J = 6Hz), 5.02 (1H, d, J = 5Hz), 5.18
(2H, s), 5.63 (2H, large s), 6.03 (1H, q ,.

  
J = 9Hz, 5Hz), 6.52 (1H, q, J = 6Hz, 4Hz),

  
  <EMI ID = 222.1>

  
(1H, d, J = 9Hz), 8.13 (2H, d, J = 8Hz)

  
(12) 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -

  
  <EMI ID = 223.1>

  
5.17 (1H, m), 5.80 (1H, m), 6.60 (1H, m), <EMI ID = 224.1>

  
5-carboxypentyl cephem-4-carboxylate (syn-isomer), m.p. 120 to 140 [deg.] C.

  
  <EMI ID = 225.1>

  
6.5 (1H, t, J = 4Hz), 6.72 (1H, s), 7.15
(2H, large s), 9.57 (1H, d, J = 8Hz)

  
  <EMI ID = 226.1>

  
3-carboxypropyl 3-cephem-4-carboxylate (syn isomer).

  
IR (Nujol): 3400 (shoulder) 3280, 3170,

  
  <EMI ID = 227.1>

  
(2H, t, J = 6Hz), 3.66 (2H, large d, J = 4Hz), 3.90 (3H, s), 4.26 (2H, t, J = 6Hz), 5.17

  
  <EMI ID = 228.1>

  
6.60 (1H, t, J = 4Hz), 6.80 (1H, s), 7.20
(2H, large s), 9.70 (1H, d, J = 8Hz)

  
  <EMI ID = 229.1>

  
syn). m.p. 145 to 154 [deg.] C (decomposition).

  
  <EMI ID = 230.1>

  
(2H, quintet, J = 6Hz), 3.67 (2H, m), 3.87
(3H, s), 4.95 (1H, m), 5.13 (1H, d, J = 5Hz),

  
  <EMI ID = 231.1> le (syn isomer).

  
IR (Nujol): 3410. 3300, 1775, 1745, 1670,

  
1620 cm- <1> <EMI ID = 232.1>

  
Carboxymethyl 3-cephem-4-carboxylate (syn isomer).

  
IR (Nujol): 3600, 3410, 3260, 1770, 1720,

  
  <EMI ID = 233.1>

  
6.87 (2H, m), 6.75 (1H, s), 7.2 (2H, broad s), 9.60 (1H, d, J = 8Hz). Preparation 6

  
P-Toluenesulfonyl chloride (1.2 g) was

  
  <EMI ID = 234.1>

  
for 7 minutes. The reaction mixture was stirred at 0-5 [deg.] C for 2 hours and at room temperature overnight. The resulting solution was poured into water and ice (50 ml) and extracted with ethyl acetate (40 ml). The extract was washed with dilute hydrochloric acid (20 ml) and a saturated aqueous solution of sodium chloride (20 ml), in turn, and dried over

  
anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give an oil (920 mg) of p-

  
  <EMI ID = 235.1>

  
s), 3.2-3.75 (7H, m), 3.83-4.30 (2H, m), 7.27 (2H, d, J = 8Hz), 7.75 (2H, d, J = 8Hz). Preparation 7

  
  <EMI ID = 236.1>

  
  <EMI ID = 237.1>

  
room temperature and heated to reflux for 11 hours. To me- <EMI ID = 238.1>

  
The resulting mixture was evaporated under reduced pressure, and the residue was dissolved in a mixture of water (20 ml) and diethyl ether (10 ml). The aqueous solution was separated and extracted with diethyl ether, and then the organic layer and the extract were combined. The organic solution was washed with saturated aqueous sodium chloride solution twice, and dried over anhydrous magnesium sulfate. The solvent was evaporated under

  
  <EMI ID = 239.1>

  
m).

EXAMPLE 20

  
To a stirred solution of 2,3-di-n-octyl.oxy-1-propyl iodide (529 mg) in dimethylsulfoxide (14 'ni) was added 7- [2- (2 -aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic (syn-isomer, <EMI ID = 240.1> dried in water and ice (200 ml), adjusted to pH 8 with an aqueous solution of sodium bicarbonate and extracted with ethyl acetate (140 ml). The extract was washed with saturated aqueous sodium chloride solution (50 ml) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. After washing the residue with n-hexane (8 ml), the residue was triturated with petroleum ether and then the precipitates were combined by filtration to give 7- [2- (2-

  
  <EMI ID = 241.1>

  
2,3-di-n-octyloxypropyl carboxylate (syn isomer, 160 mg), m.p. 75 to 78 [deg.] C.

  
IR (Nujol): 3400 (shoulder), 3300, 3200 (&#65533; pau-

  
  <EMI ID = 242.1> 5.03 (1H, d, J = 6Hz), 5.4-6.2 (3H, m), 6.4-6.65 (1H, m), 6.72 (1H , s),

  
  <EMI ID = 243.1>

  
To a cold solution of the above compound in ethyl acetate, hydrochloric acid was added dropwise while stirring the mixture, then the precipitates were collected by filtration so as to give 7- [2 hydrochloride - (2-aminothiazol-4-yl) -2-methoxyimino-

  
  <EMI ID = 244.1>

  
pyle (syn isomer).

  
  <EMI ID = 245.1>

  
do] -2-cephem-4-carboxylate of 2-isopropoxy-1-isopropoxymethylethyl (syn isomer).

  
IR (Nujol): 3500, 3250, 1775, 1745 (shoulder),

  
  <EMI ID = 246.1>

  
m), 7.18 (1H, s), 7.95 (1H, d, J = 9Hz), 8.53 (1H, s),

  
11.8 (1H, large s)

  
(2) 7- [2- (2-formamidothiazol-4-yl) -2-methoxyiminoacetami-

  
  <EMI ID = 247.1>

  
methylethyl (syn isomer).

  
IR (Nujol): 3500, 3300, 3250, 1775, 1750

  
  <EMI ID = 248.1>

  
J = 5Hz), 4.05 (3H, s), 4.9-5.3
(2H, m), 5.35 (1H, d, J = 4Hz), 5.8-6.1 (2H, m), 6.3-6.6 (1H, m), 7.3 (1H , s), 8.0 (1H, d, J = 9Hz), 8.7 (1H, s), 11.8 (1H,

  
  <EMI ID = 249.1>

  
  <EMI ID = 250.1>

  
cm

  
(4) 7- [2- (2-formamidothiazol-4-yl) -2-methoxyiminoacetami-

  
do] -3-cephem-4-carboxylate of 2-t-butoxy-1-t-butoxymethylethyl (syn isomer).

  
  <EMI ID = 251.1>

  
  <EMI ID = 252.1>

  
(syn isomer).

  
IR (Nujol): 3400, 3300, 3200 (shoulder), 1775,

  
1725, 1675 cm- <1> EXAMPLE 21

  
  <EMI ID = 253.1>

  
was stirred at 0-5 [deg.] C for 4 hours and then allowed to stand at the same temperature overnight. The resulting mixture was poured into water and ice (500 ml) and extracted with ethyl acetate (450 ml). Water and ice (70 ml) were added to the extract and then the solution was adjusted to pH 2 to 3 with 20% sulfuric acid. The organic layer was separated and washed with a saturated aqueous solution of sodium chloride (200 ml) and an aqueous solution of sodium bicarbonate, in turn. The solution was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure.

   The residue was subjected to column chromatography on silica gel with a mixture of chloroform and acetone (3: 1). The eluate was concentrated under reduced pressure to give 7- [2- (2- formamidothia-

  
  <EMI ID = 254.1>

  
7.23 (1H, s), 7.87 (1H, d, J = 8Hz), 8.5 (1H, s).

EXAMPLE 22

  
The following compounds were obtained in a manner similar to that of Examples 20 and 21.

  
  <EMI ID = 255.1>

  
methylethyl (syn isomer)

  
IR (Nujol): 3400, 3300, 3200, 1775, 1725 ,.

  
  <EMI ID = 256.1>

  
To a cold solution of the above compound in ethyl acetate, hydrochloric acid was added dropwise with stirring the mixture, then the precipitates were collected by filtration so as to give hydrochloride of 7 - [2- (2-aminothiazol-4-yl) -2-

  
  <EMI ID = 257.1>

  
poxy-1-isopropoxymethylethyl (syn isomer).

  
  <EMI ID = 258.1>

  
ethyl (syn isomer).

  
IR (Nujol): 3400, 3300, 3200, 1775, 1725, 1670

  
  <EMI ID = 259.1>

  
EXAMPLE 23

  
A solution of m-chloroperbenzoic acid (purity

  
  <EMI ID = 260.1>

  
2-isopropoxy-1-isopropoxymethylethyl 4-carboxylate
(syn isomer, 7.5 g) in methylene chloride (75 ml) between 2 and 5 [deg.] C for 25 minutes, and stirred between 0 and 5 [deg.] C for 20 minutes. Dimethyl sulfide (1 ml) was added to the resulting mixture. The resulting mixture has

  
  <EMI ID = 261.1>

  
dium and a saturated aqueous solution of sodium chloride, in turn. After drying the solution over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was triturated with diethyl ether (100 ml), and then the precipitates were collected by filtration, to give 7- [2-

  
  <EMI ID = 262.1>

  
2-isopropoxy-1-isopropoxymethylethyl phem-4-carboxylate

  
  <EMI ID = 263.1>

  
3.83 (8H, m), 3.93 (3H, s), 4.7 (1H, d, J = 5Hz), 5.2 (1H, m), 6.05-6.50 (2H, m), 7.25

  
  <EMI ID = 264.1>

  
8.50 (1H, s), 11.6 (1H, large s)

EXAMPLE 24

  
The following compound was obtained in a manner similar to that of Example 23.

  
  <EMI ID = 265.1>

  
acetamido] -3-cephem-4-carboxylate of 2-n-butoxy-1-tbutoxymethylethyl (syn-isomer).

  
IR (Nujol): 3500, 3320, 3240, 1790, 1720, 1690

  
  <EMI ID = 266.1>

  
3.9 (3H s), 4.75 (1H, d, J = 4Hz), 5.1 (1H, m), 6.2 (1H, q, J = 8Hz, 4Hz), 6.35 (1H , m) ', 7.3 (1H, s), 8.35 (1H, d, J = 8Hz), 8.5 (1H, s).

  
EXAMPLE 25

  
  <EMI ID = 267.1>

  
mother syn, 6.5 g) and sodium iodide (5 g) in dry acetone (130 ml), trifluoroacetic anhydride (7 g) was added dropwise at -2 [deg. ] C for 16 minutes,

  
and stirred between 0 and 5 [deg.] C for 1.2 hours. The resulting mixture was poured into water and ice (650 ml), and then extracted with ethyl acetate (200 ml). The extract was washed with an aqueous sulfite solution

  
sodium (50 ml) and a saturated aqueous solution of sodium chloride (50 ml), in turn. The solution was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was triturated with diethyl ether (100 ml). The precipitates were collected

  
  <EMI ID = 268.1>

  
of 2-isopropoxy-1-isopropoxymethylethyl (syn isomer, 5.6 g).

  
IR (Nujol): 3500, 3220, 1785, 1725, 1680, 1660
-1 cm

  
  <EMI ID = 269.1> 3.85 (8H, m), 3.97 (3H, s), 5.03-5.37
(2H, m), 5.8-6.2 (1H, m), 6.6 (1H, m), 7.23 (1H, s), 7.92 (1H, d, J = 8Hz), 8.57 (1H, s)

EXAMPLE 26

  
The following compound was obtained in a manner similar to that of Example 25.

  
  <EMI ID = 270.1>

  
of 2-ethoxy-1-ethoxymethylethyl (syn isomer, 2.85 g)

  
in methanol (57 ml), concentrated hydrochloric acid (1.13 ml) was added slowly at room temperature, and stirred at room temperature for 3 hours. The resulting mixture was poured into l water and ice (280 ml), adjusted to a pH of 7 to 8 with an aqueous solution of sodium bicarbonate, and then extracted with ethyl acetate (150 ml). The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the residue was subjected to column chromatography on silica gel with a

  
  <EMI ID = 271.1>

  
IR (Nujol): 3400, 3300, 3200 (shoulder), 1775,

  
1725, 1675 cm- <1> <EMI ID = 272.1>

  
(10H, m), 4.0 (3H, s), 4.9-5.4
(2H, m), 5.65-6.15 (3H, m),

  
  <EMI ID = 273.1>

  
(1H, d, J = 9Hz).

EXAMPLE 28

  
The following compounds were obtained in a manner similar to that of Example 27.

  
  <EMI ID = 274.1>

  
2-isopropoxy-1-isopropoxymethylethyl 3-cephem-4-carboxylate (syn isomer), m.p. 102 to 106 [deg.] C.

  
  <EMI ID = 275.1>

  
J = 9Hz).

  
EXAMPLE 29

  
Compound A 50 mg

  
Ethylcellulose 10 mg

  
Product says Migryol 812 1 ml

  
Compound A [i.e. 7- [2- (2-aminothiazol-

  
  <EMI ID = 276.1>

  
suspended in the product known as Migryol 812 (registered trademark of a product manufactured by the company known as Dynamit Nobel Chemicals) and in ethylcellulose to produce the composition for oral administration.

  
The following compounds were used in place of compound A [i.e. 7- [2- (2-aminothiazol-4-yl) -2methoxyiminoacetamido] -3-cephem-4-carboxylate -butoxy1-n-butoxymethylethyl (syn isomer)].

  
  <EMI ID = 277.1>
-3-cephem-4-2-pyridylmethyl carboxylate (syn isomer).

  
  <EMI ID = 278.1>
-3-cephem-4-carboxylate of 4-nitrobenzyloxycarbonylmethyl (syn isomer).

  
  <EMI ID = 279.1>
-3-cephem-4-carboxylate of 5- (4-nitrobenzyloxycarbonyl) ventile (syn-isomer).

  
  <EMI ID = 280.1>
-3-cephem-4-carboxylate of 1-diphenylmethoxycarbonylpropyl (syn isomer).

  
  <EMI ID = 281.1>

  
do] - 5-carboxypentyl 3-cephem-4-carboxylate
(syn isomer).

  
  <EMI ID = 282.1>
-3-cephem-4-carboxymethyl carboxylate (syn-isomer).

  
  <EMI ID = 283.1>

  
The mixture was stirred for 30 minutes at room temperature and poured into a mixture of cold water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, dried over magnesium sulfate and evaporated to dryness. The residue was subjected to column chromatography on silica gel (50 g) using a mixture of benzene and ethyl acetate (3: 2) as the eluent. Eluates containing a research compound were pooled and evaporated to dryness to give 7- [2- (2-aminothiazol-4-

  
  <EMI ID = 284.1>

  
120 to 125 [deg.] C. (decomposition).

  
IR (Nujol): 3450, 3370, 3150, 1790, 1760, 1680,

  
  <EMI ID = 285.1>

  
(3H, d, J = 5Hz), 3.4-3.9 (2H, m), 3.85 (3H, s), 4.5-5.1 (1H, m), 5.13 (1H , d, J = 5Hz), 5.87 (1H, 2d, J = 5Hz, 8Hz), 6.5-6.8 (2H, m),

  
  <EMI ID = 286.1>

EXAMPLE 31

  
The following compounds were obtained in a manner similar to that of Example 30.

  
  <EMI ID = 287.1> 1-ethoxycarbonyloxyethyl cephem-4-carboxylate (syn-isomer), m.p. 120 to 130 [deg.] C (decomposition).

  
  <EMI ID = 288.1>

  
(1H, t, J = 3.5Hz), 6.71 (1H, s), 6.80 (1H, q, J = 5.5Hz), 7.15 (2H, s), 9.53 (1H , d, J = 8Hz).

  
  <EMI ID = 289.1>

  
3-phthalidyl cephem-4-carboxylate (syn-isomer), m.p. 200 to 205 [deg.] C (decomposition).

  
  <EMI ID = 290.1>

  
mother syn), m.p. 133 to 137 [deg.] C (decomposition)

  
IR (Nujol): 3420, 3310, 1770, 1750, 1730,

  
  <EMI ID = 291.1>

  
3.6 (2H, m), 3.86 (3H, s), 5.12 (1H, d, J = 5Hz), 5.6-6.0 (3H, m), 6.5-6, 7 (1H, m), 6.72 (1H, s), 7.18 (2H, large s), 9.54 (1H, d, J = 9Hz).

  
  <EMI ID = 292.1>

  
the (syn isomer).

  
IR (Nujol): 3400, 3300, 1770, 1745, 1670,

  
  <EMI ID = 293.1>

  
R.M.N. (CDC13.6): 0.9-2.0 (13H, m) 3.5-3.7 (2H, m),

  
4.00 (3H, s), 5.03 (1H, d, J = 5Hz), 5.87

  
  <EMI ID = 294.1>

  
9Hz), 6.6-6.8 (1H, m), 6.67 (1H, s), 8.07 (1H, d, J = 9Hz).

  
To a cold solution of the above compound in ethyl acetate, hydrochloric acid was added dropwise with stirring the mixture, then the precipitates were collected by filtration so as to give 7- [2 hydrochloride - (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate from 1-isopropoxycarbonylo-

  
  <EMI ID = 295.1>

  
EXAMPLE 31

  
To a solution of 7- [2- (2-aminothiazol-4-yl) -2-me-

  
  <EMI ID = 296.1>

  
added 1-iodoethyl ethyl carbonate (4 g) and the mixture is stirred for 10 minutes at room temperature. The reaction mixture is poured into a mixture. cold water (150 ml) and ethyl acetate, and the organic layer separated. The aqueous layer is extracted with ethyl acetate and the combined extracts are washed with

  
  <EMI ID = 297.1>

  
under reduced pressure and subjected to chromatography on

  
  <EMI ID = 298.1>

  
invention are collected and evaporated to dryness to give amorphous precipitates of 1-ethoxycarbonyloxyethyl

  
  <EMI ID = 299.1>

  
phem-4-carboxylate (syn isomer, 0.9 g), m.p. 120 to 130 [deg.] C
(decomposition).

  
To a cold solution of the above compound in ethyl acetate, hydrochloric acid was added dropwise while stirring the mixture, then the precipitates were collected by filtration so as to give

  
  <EMI ID = 300.1>

  
nucleloxymethyl (syn isomer).

  
EXAMPLE 32

  
  <EMI ID = 301.1>

  
in a mixture of water and ethyl acetate (each in an amount of 200 ml) with stirring. The organic solution

  
  <EMI ID = 302.1>

  
sodium carbonate and then with water, followed by drying over magnesium sulfate. The resulting solution has

  
  <EMI ID = 303.1>

  
6.17 (1H, t, J = 7Hz), 6.62 (1H, m), 6.75
(1H, s), 7.63-8.25 (4H, m), 9.60 (1H, d, J = 8Hz).

  
EXAMPLE 33

  
  <EMI ID = 304.1>

  
3-cephem-4-carboxylic (syn isomer) with 2-n-dodecyloxy-1-n-dodecyloxymethylethanol in the presence of chloride

  
  <EMI ID = 305.1>

  
  <EMI ID = 306.1>

  
  <EMI ID = 307.1>

EXAMPLE 34

  
The following compounds were obtained in a manner similar to that of Examples 17 and 18.

  
(1) 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -

  
1-isopropoxycarbonyloxyethyl 3-cephem-4-carboxylate (syn isomer).

  
IR (Nujol): 3450, 3370, 3150, 1790, 1760,

  
  <EMI ID = 308.1>

  
To a cold solution of the above compound in ethyl acetate, hydrochloric acid was added dropwise with stirring the mixture, then the precipitates were collected by filtration so as to

  
  <EMI ID = 309.1>

  
1-isopropoxycarbonyloxyethyl methoxyiminoacetamido] -3-cephem-4-carboxylate (syn isomer).

  
  <EMI ID = 310.1>

  
1- (2-Azidoethoxycarbonyloxy) ethyl 3-cephem-4-carboxylate (syn isomer), m.p. 100 to 110 [deg.] C (decomposition).

  
  <EMI ID = 311.1>

  
1-ethoxycarbonyloxyethyl cephem-4-carboxylate
(syn isomer), m.p. 120 to 130 [deg.] C (decomposition).

  
  <EMI ID = 312.1>

  
3-phthalidyl 3-cephem-4-carboxylate (syn isomer), m.p. 200 to 205 [deg.] C (decomposition).

  
  <EMI ID = 313.1> 5.12 (1H, d, J = 4.5Hz), 5.80 (1H, dd, J = 4.5Hz, 7.5Hz), 6.65 (1H, m), 6 , 68 (1H, s), 7.56,

  
  <EMI ID = 314.1>

  
(6) 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -

  
Tetradecanoyloxymethyl 3-cephem-4-carboxylate
(syn isomer), m.p. 133 to 137 [deg.] C (decomposition).

  
IR (Nujol): 3420, 3310, 1770, 1750, 1730,

  
  <EMI ID = 315.1>

  
(2H, m), 4.00 (3H, s), 5.03 (1H, d, J = 5Hz), 5.87 (2H, s), 6.0 (2H, s), 6.03 ( 1H, ABq,

  
  <EMI ID = 316.1>

  
2- (3-phthalidylidene) ethyl cephem-4-carboxylate
(syn isomer)

  
  <EMI ID = 317.1>

EXAMPLE 35

  
The following compounds were used in place of compound A in Example 29.

  
  <EMI ID = 318.1>

  
xy) ethyl (syn isomer) (3) 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-

  
1-benzoyloxyethyl cephem-4-carboxylate (oyn isomer)

  
  <EMI ID = 319.1>

  
1-ethoxycarbonyloxyethyl 3-cephem-4-carboxylate
(syn isomer)

  
  <EMI ID = 320.1>

  
Tetradecanoyloxymethyl 3-cephem-4-carboxylate
(syn isomer)

  
  <EMI ID = 321.1>

  
2,3-dimethylpentanoyloxymethyl 3-cephem-4-carboxylate (syn isomer)

  
  <EMI ID = 322.1>

  
2- (3-Phthalidylidene) ethyl 3-cephem-4-carboxylate
(syn isomer).

  
The present invention is not limited to the exemplary embodiments which have just been described, it is on the contrary liable to modifications and variations.

  
  <EMI ID = 323.1>

CLAIMS

  
1 - Syn isomer corresponding to the formula.

  

  <EMI ID = 324.1>


  
where R <1> is a protected amino or amine group; R2 is a lower dialcanoyloxyalkyl group, the alkyl group having a

  
or several substituents chosen from hydroxy, protected hydroxy, alkoxy, carboxy, protected carboxy, cycloalkylcarbonyloxy and heterocyclic groups, an alkoxy group
(lower) lower carbonyloxyalkyl; an azidoalkoxy (lower) carbonyloxyalkyl lower group; an aroy group

  
  <EMI ID = 325.1>

  
lower alkyl; phthalidyl group or a lower phthalidylidenealkyl group; R is a lower alkyl group, Y is a thio (-S-) or sulfinyl (-SO-) group,

  
and the dotted line represents the nucleus of 2- or 3 cephem and their pharmaceutically acceptable salts.


    

Claims (1)

2 - Compound according to claim 1, characterized in that is an amino or acylamino group, R <2> is a lower dialkylalkanoyloxyalkyl group, dihydroxyal &#65533; y- <EMI ID = 326.1> esterified (lower) alkyl, cycloalkylcarbonyloxyalkyl (lower), heterocyclic alkyl (lower), alkoxy (lower) carbonyloxyalkyl (lower) ,,, azido (lower alkoxy) carbonyloxy (lower alkyl), aroyloxy (lower alkyl), (higher alkanoyioxy) (lower alkyl), phthalidyl or  <EMI ID = 327.1> addition salts with acids. 3 - Compound according to claim 2, characterized in that R is an amino group and R 'is the methyl group. 4 - Compound according to claim 2, characterized in that R <1> is an amino group, R <2> is a di (al-  <EMI ID = 328.1> 5 - Compound according to claim 4, characterized in that R is a methyl group. 6 - Compound according to claim 5, characterized  <EMI ID = 329.1> -3-cephem-4-carboxyl3te. 7 - Compound according to claim 2, characterized  <EMI ID = 330.1> 8 - Compound according to claim 7, characterized in that R is the methyl group. 9-Compa3é according to claim 8, characterized in that it is  <EMI ID = 331.1> 10 - A compound according to claim 2, characterized  <EMI ID = 332.1> 11 - Compound according to claim 10, characterized in that R is the methyl group. 12 - Compound according to claim 11, characterized in that it is 2-ethoxy-1-ethoxymethylethyl 7- [2- (2-  <EMI ID = 333.1> 4-carboxylate, 2,3-di-n-octyloxypropyl 7-l2- (2-aminothia- <EMI ID = 334.1> carboxylate. 13 - Compound according to claim 2, characterized in that R <1> is an amino group, R <2> is a car-  <EMI ID = 335.1> .14 - Compound according to claim 13, character- <EMI ID = 336.1> 15 -A compound according to claim 14, characterized in that it is carboxymethyl 7- [2- (2-aminothiazol-4-yl) -2-  <EMI ID = 337.1> 16 - Compound according to claim 2, characterized in that R <1> is an amino group, R2 is a group  <EMI ID = 338.1> 17 - Compound according to claim 16, characterized in that R is the methyl group.  <EMI ID = 339.1>  <EMI ID = 340.1> 19 - Compound according to claim 2, characterized in that R <1> is an amino group, R2 is a group  <EMI ID = 341.1> - 20 - A compound according to claim 19, character- <EMI ID = 342.1> 21 - Compound according to claim 20, character-  <EMI ID = 343.1> 22 - Compound according to claim 2, characterized in that R is an amine group, R <2> is an alcohol group  <EMI ID = 344.1> 23 - Compound according to claim22, characterized in that R is the methyl group. 24-Compound according to claim 24, characterized in that it is 1-ethoxycarbonyloxyethyl 7- [2- (2-aminothiazol-4-yl) -2--  <EMI ID = 345.1> 25 - Compound according to claim 2, characterized in that R <1> is an amino group, R2 is a group  <EMI ID = 346.1> 26 - Compound according to claim 25, characterized in that R <3> is a methyl group.  <EMI ID = 347.1> 28 - Compound according to claim 2, characterized in that R <1> is an amino group, R2 is a group  <EMI ID = 348.1>  <EMI ID = 349.1> 30 - Compound according to claim 28, character-  <EMI ID = 350.1> 31 - Compound according to claim 2, character-  <EMI ID = 351.1>  <EMI ID = 352.1> 32 - Compound according to claim 31, characterized in that R <3> is the methyl group.  <EMI ID = 353.1>  <EMI ID = 354.1> <EMI ID = 355.1> you. 34 - Compound according to claim 2, character-  <EMI ID = 356.1>  <EMI ID = 357.1> 35 - Compound according to claim 34, characterized in that R is the methyl group. 36 - Compound according to claim 35, carp, terized in that it is 3-phthalidyl 7- [2- (2-aminothiazol-  <EMI ID = 358.1> 37 - Compound according to claim = 2, character-  <EMI ID = 359.1>  <EMI ID = 360.1> 38 - Compound according to claim 37, characterized in that R is a methyl group. 39 - Compound according to claim 38, character-. laughed at in that it is 2- (3-phthalidylidene) ethyl 7- (2- (2-  <EMI ID = 361.1> carboxylate. 40 - Compound according to claim 2, characterized in that R 1 is an amino group, R2 is a group  <EMI ID = 362.1> 42 - Compound according to Claim 1, characterized in that R <1> is an acylamino group, R <2> is a dialkoxy group (lower alkyl) Y is a sulfinyl group and the dotted line represents the 3-cephem nucleus. 43 - Compound according to claim 1, character-  <EMI ID = 363.1> dialkoxy (lower alkyl), Y is a thio group, and the dotted line represents the 2-cephem ring. 44 - Antimicrobial pharmaceutical composition, comprising, as active ingredient, one or more of the compounds according to claim 1, in mixture with pharmaceutically acceptable carriers. 45 - Antimicrobial pharmaceutical composition according to claim 44, characterized in that the active ingredient is chosen from the compounds according to claim 2.  <EMI ID = 364.1> according to claim 45, characterized in that the active ingredient is chosen from the compounds according to claim 3. 47 - Antimicrobial pharmaceutical composition according to claim 44, characterized in that the active ingredient is chosen from the compounds according to claims 4 to 43.  <EMI ID = 365.1> this composition is used for oral administration. 49 - A method of treating infectious diseases due to pathogenic microorganisms, characterized in that it comprises the administration of the compounds of claim 1 to humans or infected animals. 50 - Syn isomer compound, characterized in that it meets the formula:  <EMI ID = 366.1>  <EMI ID = 367.1> terized in that R is an amino or formamido group. 52- Process for the preparation of a syn isomer corresponding to the formula:  <EMI ID = 368.1>   <EMI ID = 369.1>  <EMI ID = 370.1> alkyl having one or more substituents selected from hydroxy, protected hydroxy, alkoxy, carboxy, protected carboxy, cycloalkylcarbonyloxy, and a heterocyclic group; (lower alkoxy) carbonyloxy (lower alkyl); azido (lower alkoxy) carbonyloxy (lower alkyl); aroyloxy (lower alkyl); (superior alkanoyloxy  <EMI ID = 371.1>  <EMI ID = 372.1> a thio group (-S-), or sulfinyl (-SO-), and the dotted line represents 2- or 3-cephem nuclei, and a salt thereof, characterized in that one reacts a compound corresponding to the formula:  <EMI ID = 373.1>  <EMI ID = 374.1> above or one of these salts with a compound corresponding to the formula:  <EMI ID = 375.1>  <EMI ID = 376.1> hydroxy or one of its reactive derivatives, to give the compound (I) or one of its salts. 53 - Method according to claim 49, characterized in that one proceeds to the oxidation of a compound corresponding to the formula:  <EMI ID = 377.1>   <EMI ID = 378.1> or a salt thereof to give a compound corresponding to the formula :  <EMI ID = 379.1>  <EMI ID = 380.1> of its salts. 54 - Process according to claim 49, characterized in that a compound corresponding to the formula is reduced:  <EMI ID = 381.1>  <EMI ID = 382.1> or one of its salts to give a compound corresponding to the formula:  <EMI ID = 383.1>  <EMI ID = 384.1> laughed at by submitting a compound corresponding to the formula:  <EMI ID = 385.1>  <EMI ID = 386.1> laughing) or one of its salts, to an elimination of the pro-  <EMI ID = 387.1> responding to the formula:  <EMI ID = 388.1>  <EMI ID = 389.1> salts. 56 - Process according to claim 49, characterized in that a compound corresponding to the formula is subjected:  <EMI ID = 390.1>  <EMI ID = 391.1> above and  <EMI ID = 392.1> laughing) or a salt thereof to the elimination of the protective group  <EMI ID = 393.1> to the formula:  <EMI ID = 394.1>  <EMI ID = 395.1>  <EMI ID = 396.1> salts. 57 - Process according to claim 49, characterized in that a compound corresponding to the formula is subjected:  <EMI ID = 397.1>  <EMI ID = 398.1>  <EMI ID = 399.1>  <EMI ID = 400.1> give a compound corresponding to the formula:  <EMI ID = 401.1> in which R 2 and R <3> are as defined above, or one of its salts.