BE858516A - NEW MONOCYCLIC TINS AND THEIR PREPARATION PROCESS - Google Patents

Description

       

   <EMI ID = 1.1>

  
their preparation process <EMI ID = 2.1>

  
antibiotic intermediates and their preparation process.

  
In the Federal Republic's patent application

  
 <EMI ID = 3.1>

  
clavulanic acid and salts thereof, in the pure state, from fermentations of streptomyces clavuligerus.

  
The bicyclic compounds which are the subject of the present invention are named with reference to "clavam" which is the name given to the related heterocycle of formula A:

  

 <EMI ID = 4.1>


  
by analogy to the term “cephalic” used for the designation of compounds of the cephalosporin type in J. Amer. Chem. Soc, 1962,

  
 <EMI ID = 5.1>

  
The Applicant has successfully prepared new monocyclic betalins related to clavulanic acid and, consequently, the present invention relates to compounds which correspond to the following formula (I):

  

 <EMI ID = 6.1>


  
 <EMI ID = 7.1>

  
 <EMI ID = 8.1>

  
hydrogen, a hydroxyl group, an esterified hydroxyl group, an acylated hydroxyl group or the residue of a sulfurized nucleophile;

  
 <EMI ID = 9.1>

  
each represent an aliphatic group, an araliphatic group

  
 <EMI ID = 10.1>

  
alkyl radicals having up to 8 carbon atoms, aralkyl radicals having up to 6 carbon atoms in the part <EMI ID = 11.1>

  
alkyl or aryl radicals, the aryl and aralkyl groups in question being advantageously monocyclic; a cyclo group

  
 <EMI ID = 12.1>

  
attached are a 6- or 7-membered heteroatom optionally containing an additional heteroatom, for example, an oxygen, nitrogen or sulfur atom, as is the case with the piperidino, morpholino or thiamorpholino group, or else R , R <2> and R <3> can together form part of a heterocyclic aromatic ring, for example a pyridinium or collidinium group, or of a polycyclic group, for example a bicyclic heterocyclic system, for example a quinuclidino group;

  
 <EMI ID = 13.1>

  
trimethylammonium and triethylammonium radicals are very particularly preferred.

  
 <EMI ID = 14.1>

  
addition of acids of compounds of formula (I). Salts of this kind can be formed with organic acids or with inorganic acids. As suitable organic acids, mention may be made of carboxylic acids, for example citric acid, formic acid, tartaric acid and acetic acid, or sulfonic acids, for example p-toluenesulfonic acid; as suitable inorganic acids, there may be mentioned mineral acids, for example, nitric acid, hydrochloric acid, sulfuric acid and perchloric acid.

  
The compounds in accordance with the invention are, in general,

  
mixtures of epimers in position 4 of azetidin-2-one and

  
in solution, they also constitute a mixture of geometric isomers around the double bond of the side chain in position 1, due to the possibility of equilibrium arising from the fact

  
 <EMI ID = 15.1>

  
normally as either one of the possible E and Z isomers.

  
 <EMI ID = 16.1>

  
etherified -OR where R5 represents a substituted or unsubstituted hydrocarbyl group, for example an aliphatic radical, an araliphatic or aromatic radical, or a heterocyclic group attached through a carbon atom. So, for example, R5 <EMI ID = 17.1>

  
substituted, which may contain 1 to 6 carbon atoms, or

  
 <EMI ID = 18.1>

  
carboxyl, esterified carboxyl (for example alkoxy carbonyl in

  
 <EMI ID = 19.1>

  
carbon; an aralkyl group which may have from to 6 carbon atoms in the alkyl part or an aryl group, such an aryl or aralkyl group preferably being monocyclic and optionally carrying one or more halogen atoms or one or more. nitro or C1-C4 alkoxy radicals; a cycloalkyl group which may have 3 to 7 carbon atoms or a heterocyclic ring

  
5-7 membered, saturated or unsaturated, attached through a carbon atom, for example an oxygen atom, such a cycloalkyl or heterocyclic group optionally carrying a C1-C4 alkoxy group, preferably attached , to the bonded carbon atom

  
to the ether function.

  
By way of illustrative R5 groups, mention may be made of the following radicals: methyl, ethyl, propyl, isopropyl, butyl, allyl, propargyl, hydroxyethyl, 1-ethoxyethyl, acetonyl, 4nitrobenzyl, cyanomethyl, carboxyethyl, ethoxycarbonylmethyl, phenyl, benzyl, phenethylmethyl, phenyl, benzyl, phenethyl cyclohexyl, 1-methoxycyclohexyl and tetrahydropyranyl.

  
The substituted hydroxyl groups referred to above include acylated and etherified hydroxyl groups. In general, the acylated hydroxyl groups correspond to the following formula: R COp in which R6 represents a hydrocarbyl group as defined in connection with R5, the relatively simple R6 groups, such as C1-C4 alkyl radicals, for example methyl, being preferred, while etherified hydroxyl radicals respond

  
 <EMI ID = 20.1>

  
 <EMI ID = 21.1>

  
also, preferred ..

  
R5 may also represent a silyl group having up to 24 carbon atoms, which may bear 3 hydrocarbyl groups. These groups, which may be identical or different, may be chosen from alkyl, alkenyl, cycloalkyl, aralkyl and aryl radicals. These groups are preferably alkyl radicals

  
 <EMI ID = 22.1>

  
representative examples of silyl radicals, mention may be made of the groups <EMI ID = 23.1>

  
 <EMI ID = 24.1>

  
hydroxyl of the formula: -OR7 in which R7 represents,

  
 <EMI ID = 25.1>

  
which can be substituted, for example, by one or more radicals

  
 <EMI ID = 26.1>

  
or mono- or di-substituted amino, or a carboxyl or carboxyl group

  
 <EMI ID = 27.1>

  
 <EMI ID = 28.1>

  
 <EMI ID = 29.1>

  
may be the same or different, represent atoms of

  
 <EMI ID = 30.1>

  
which may be substituted, for example, by halogen atoms; aralkyl radicals, for example benzyl; or aryl radicals,

  
 <EMI ID = 31.1>

  
nitrogen atom to which they are attached, forming a heterocyclic ring preferably having 5 to 7 members, which may optionally contain an additional heteroatom, for example a nitrogen atom,

  
 <EMI ID = 32.1>

  
next: O.CS.NH R9 in which R9 has the aforementioned meanings other than hydrogen.

  
As illustrative groups, the following radicals may be mentioned: methyl, ethyl, propyl, isopropyl, butyl, amyl, allyl, propenyl, propargyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, benzyl, thienylmethyl, phenyl, thienyl,

  
 <EMI ID = 33.1>

  
carbonylLenzyl, aminomethyl and α-aminobenzyl.

  
The R4 group can also represent the residue of a sulfided nucleophile, for example an acylthio or thoacylthio group, a thioether group or a sulfonated or oxidized tallow derivative of the aforementioned thioether group or a thibl group. In general, these remains can be

  
 <EMI ID = 34.1> <EMI ID = 35.1> araliphatic, aromatic or heterocyclic) or by the formula:
-SC = Y.R (in which Y represents an oxygen atom or <EMI ID = 36.1>

  
 <EMI ID = 37.1>

  
identical or different, represent hydrogen atoms or aliphatic, araliphatic or aromatic groups or form, together with the nitrogen atom to which they are attached, a heterocyclic ring).

  
 <EMI ID = 38.1>

  
alkyl, alkenyl or alkynyl radicals, which may contain

  
from 1 to 6 carbon atoms; aralkyl groups which may contain from 1 to 6 carbon atoms in the alkyl part or aryl groups, the aryl and aralkyl groups in question preferably being monocyclic; cycloalkyl groups, which may have from 3 to 7, preferably 5 or 6, carbon atoms; or

  
5-7 membered heterocyclic rings attached through a carbon atom, containing 1 or more heteroatoms, such as nitrogen, sulfur and oxygen and may carry one or more

  
 <EMI ID = 39.1>

  
Such groups may themselves carry substituents such as hydroxyl or substituted hydroxyl, carboxyl or substituted carboxyl, amino or substituted amino, or cyano.

  
By way of illustrative R <1> <1> groups, mention may be made of the following radicals: methyl, ethyl, propyl, butyl, allyl,

  
 <EMI ID = 40.1>

  
phenyl, benzyl, cyclohexyl and pyridyl.

  
As illustrative R .C = Y.- groups, mention may be made of the following radicals: ethoxythiocarbonyl, carbamoyl, thiocarbamoyl, dimethylthiocarbamoyl, thiobenzoyl, benzoyl, thioacetyl, and acetyl.

  
 <EMI ID = 41.1>

  
the latter may, for example, contain from 5 to 7 ring atoms,

  
including one or more other heteroatoms selected, for example, from nitrogen, oxygen and sulfur atoms and may be, for example, a piperidino, piperazino, morpholino and tniomorpholino ring,

  
The substituted hydroxyl radicals include the acylated and etherified hydroxyl radicals as defined above. Substituted carboxyl groups can have the following formula:
COOR15 in which R15 represents an aliphatic, araliphatic or aromatic radical, while the substituted amino radicals

  
 <EMI ID = 42.1>

  
 <EMI ID = 43.1> <EMI ID = 44.1>

  
The compounds according to the present invention are esters in which the symbol R represents an esterified carboxyl group which is conveniently derived from an alcohol (aliphatic or araliphatic), a phenol or a stannanol. Such an alcohol, phenol or stannanol, used to esterify the carboxyl radical, preferably does not contain more than 24 carbon atoms.

  
Therefore, the R group can be represented by the

  
 <EMI ID = 45.1>

  
straight or branched chain alkenyl or alkyl, unsubstituted or substituted, preferably having 1 to 8 carbon atoms,

  
for example, a methyl, ethyl, propyl, or isopropyl group,

  
butyl, sec-butyl, tert-butyl or allyl, desirable substituents:
being, for example, alkoxy radicals, for example methoxy;

  
halogen atoms, i.e. fluorine, chlorine, bromine

  
iodine or cyano radicals; acyloxy, for example alkanoyioxy,

  
such as acetoxy or pi.valoyloxy; acyl radicals, -for example p-bromobenzoyl and alkoxycarbonyl, for example ethoxycarbonyl;

  
an aralkyl group having up to 20 carbon atoms, in particular an arylmethyl group, for example a benzyl group

  
or substituted benzyl, suitable ring substituents being

  
halogens, for example chlorine .; nitro radicals, by

  
o- or p-nitro example; sulfonyl; cyano; alkyl, for example pmethyl or alkoxy, for example p-methoxy; a diphenylmethyl group

  
or triphenylmethyl or a fur-2-yl-methyl, thien-2-ylmethyl group

  
or pyridylmethyl. in which the heterocyclic groups may also be substituted, for example, by a lower alkyl group, preferably methyl;

  
an aryl group having up to 12 carbon atoms,

  
for example, a phenyl or substituted phenyl group, suitable substituents being halogen atoms, for example chlorine;

  
nitro radicals, for example o- or p-nitro; cyano radicals; alkyl radicals, for example p-methyl or alkoxy, 'for example p-methoxy;

  
a cycloalkyl group containing not more than 12 atoms

  
carbon, for example adamantyl;

  
a heterocyclic group containing no more than 12

  
 <EMI ID = 46.1>

  
oxygen, as is the case with tetrahydropyranyl radicals or <EMI ID = 47.1>

  
carbon, for example a stannyl group bearing 3 substituents which may be the same or different and are chosen from the alkyl, alkenyl, aryl, aralkyl, cycloalkyl, alkoxy or aralooxy radicals. Such groups include methyl, ethyl, propyl, n-butyl, phenyl and benzyl radicals.

  
The esters which will be used when it is subsequently desirable to prepare a carboxylic acid or a salt thereof are advantageously those which split under conditions which do not lead to the appearance of side reactions.

  
 <EMI ID = 48.1>

  
arylmethyl esters, for example p-nitrobenzyl and benzhydryl esters; such esters can be cleaved off by reduction, for example, by hydrogenolysis, for example, on a catalyst based on a noble metal.

  
The compounds according to the present invention constitute useful intermediates for the synthesis or the purification of β-lactam compounds, for example, of compounds which respond

  
to formula (II):

  

 <EMI ID = 49.1>


  
 <EMI ID = 50.1>

  
represents a carboxyl or esterified carboxyl group and salts

  
 <EMI ID = 51.1>

  
such compounds are described and claimed in the patent application

  
 <EMI ID = 52.1>

  
Compounds of formula (II) possess the ability to inhibit p-lactamases generated by both gram-positive and gram-negative organisms, such as strains.

  
 <EMI ID = 53.1>

  
cloacae, Pseudomonas aeruginosa, indole-positive Proteus species and Bacteroides fragilis. The compounds of formula (II) <EMI ID = 54.1>

  
It was also found that the compounds of the formula
(I) were also of interest for the purification of the esters of the above-mentioned formula (II), since they can give a crystalline substance from which one can easily regenerate the esters of the formula (II) in a high state. purity.

  
The compounds of formula (II) can easily be prepared.

  
 <EMI ID = 55.1>

  
 <EMI ID = 56.1>

  
for example be carried out by heating, for example at 50-100 [deg.] C, preferably at reflux, in a suitable liquid medium. when using an acid addition salt of a compound of formula (I)

  
it may be advantageous to incorporate in the liquid medium an equivalent of an acid binding agent. The liquid medium is preferably an inert low boiling liquid, for example an ester, such as ethyl acetate, a halogenated hydrocarbon, such as 1, 2-dichloroethane or lo chloroform, a hydrocarbon , such as

  
benzene, a ketone, such as acetone or an ether, such as tetrahydrofuran. Liquids with high boiling points, such as amides, for example dimethylformamide, can also be used. When it is desired to obtain an acid of formula (II) or a salt

  
of the latter, this compound can be prepared by scission of an ester initially produced.

  
Certain compounds of formula (I) are also suitable

  
for the production of esters of dienes of formula (III)

  

 <EMI ID = 57.1>


  
in which R represents an esterified carboxyl group, as will be described more particularly in the remainder of this specification.

  
The dienes in question are described in the application for

  
 <EMI ID = 58.1>

  
 <EMI ID = 59.1>

  
 <EMI ID = 60.1>

  
clavulanic acid of the type described in the patent application

  
of the Federal Republic of Germany (DOS) 2708330; it has also been reported that these diene esters also exert an activity

  
 <EMI ID = 61.1>

  
The compounds according to the invention can conveniently be prepared by the reaction of a compound of formula (II) in which R17 represents an esterified carboxyl group or of a compound of formula (IV)

  

 <EMI ID = 62.1>


  
 <EMI ID = 63.1>

  
 <EMI ID = 64.1>

  
have the aforementioned meanings), so as to obtain the desired compound of formula (I).

  
When R4 represents a group which can be easily removed, for example a dichloroacetoxy group, this group will tend to be eliminated in the presence of a base, so as to generate a diene of the formula (III). When it is desired to obtain a compound of formula (I) in which R represents such an easy group

  
to be removed, this compound is conveniently prepared from a substance of the formula (I) in which R4 represents a hydroxyl group.

  
In general, the conversion of a compound of the formula (II) to a compound of the formula (I) can be carried out using a weaker base than that required for the conversion of a compound of the formula (IV). Thus, for example, one can use a tertiary aromatic base, such as pyridine, to successfully convert a compound of formula (II), while a stronger base, such as triethylamine, is generally required for conversion.

  
 <EMI ID = 65.1>

  
On the other hand, we can transform a compound of

  
 <EMI ID = 66.1>

  
represents the residue of a weak base, such as pyridine, by reaction with the weak base, in the presence of a catalytic amount <EMI ID = 67.1>

  
However, the use of simpler trialkylamines, for example, those in which each alkyl group has 1 to 6 carbon atoms, in particular those in which the alkyl groups are methyl, ethyl, propyl or butyl radicals, is preferable and trimethylamine and triethylamine constitute the particularly preferred trialkylamines for the two series of compounds.

  
The reaction can be carried out in a suitable non-hydroxylated solvent, for example, an ester, such as ethyl acetate, an amide such as dimethylformamide, a halogenated hydrocarbon, such as dichloromethane or chloroform, a ketone, such as as acetone, or an ether such as diethyl ether. Ltamine can

  
 <EMI ID = 68.1>

  
ethyl acetate or dimethylformamide as a solvent.

  
The reaction can be carried out at a temperature which ranges from -40 to +30 [deg.] C, a temperature of +10 to +20 [deg.] C being preferred; in certain cases, it may be advantageous to carry out a subsequent cooling in order to facilitate the isolation of the product of formula (I) in the pure state.

  
 <EMI ID = 69.1>

  
of the reaction mixture by employing conventional separation and isolation techniques. As mentioned above,

  
 <EMI ID = 70.1>

  
and normally readily crystallize in some of the aforementioned solvents. It frequently happens that the compounds according to the present invention crystallize from the reaction solution by allowing the latter to stand for a certain period of time,

  
 <EMI ID = 71.1>

  
obtain a solid by using simple purification means,

  
for example by trituration with fresh solvent. For the preparation of the diacid addition salts of the compounds corresponding to formula (I)

  
 <EMI ID = 72.1>

  
appropriate, such as dimethylfcrmamide or water and add an equivalent of the appropriate acid.

  
The compounds of formula (IV) from which the compounds according to the invention can be prepared can themselves be prepared in various ways from clavulanic acid or from its salts or from its esters or from its reactive derivatives. , such as halogenated derivatives (i.e. compounds of formula IV,

  
 <EMI ID = 73.1> <EMI ID = 74.1>

  
halogenated are described in the German application (DOS) n [deg.] 2657081.

  
 <EMI ID = 75.1>

  
represents a hydrogen atom can be prepared by catalytic hydrogenolysis carried out as described in German patent application (DOS) n [deg.] 2657081 and South African patent n [deg.] 76/1953.

  
The compounds of formula (IV) in which R represents an etherified hydroxyl group can be prepared by the etherification of an ester of clavulanic acid, as described in German patent application (DOS) n [deg .] 2657048 and

  
South African Patent No. [deg.] 76/5550.

  
 <EMI ID = 76.1>

  
Suitable silyl halide, for example dimethylsilyl chloride or t-butyl-dimethylsilyl chloride.

  
 <EMI ID = 77.1>

  
which R4 represents an acylated hydroxyl group of the formula <EMI ID = 78.1>

  
reaction of clavulanic acid or an ester thereof on

  
 <EMI ID = 79.1>

  
above meanings and Y represents a hydroxyl group or a substituent which can be easily removed). The reaction in question

  
 <EMI ID = 80.1>

  
prevent breakage of the bicyclic nucleus. The use of neutral or moderately acidic or basic conditions and temperatures varying from -70 [deg.] C to +35 [deg.] C, is preferable. When a carboxylic acid is initially produced, it can be converted to an ester by

  
implementing the methods described in the remainder of this memorandum.

  
Thus, one can react the clavulanic acid or

  
an ester of the latter on a reactive derivative of a carboxylic acid, for example a halide or an anhydride, for example uii chloride

  
 <EMI ID = 81.1>

  
free antibiotic carboxylic acid or, more preferably, an ester thereof, preferably under moderate asic conditions, for example, in the presence of a pyridine base, in

  
a solvent such as an ether, for example tetrahydrofuran or dioxane or an ester, for example ethyl acetate, or a halogenated hydrocarbon, for example methylene chloride, or a substituted amide, for example dimethylacetamide.

  
A mono-N-substituted thiocarbonate or carbonate can also be prepared using an isocyanate of the formula R9NCO ...

  
 <EMI ID = 82.1>

  
the aforementioned meanings. The reaction is preferably carried out by reacting an ester of clavulanic acid with an isocyanate or an isothiocyanate, optionally in the presence of a moderate organic base, for example pyridine, so as to obtain the acyl derivative of the compound of formula (IV).

  
The di-substituted carbonates can be prepared as described below in connection with compounds of formula (I).

  
The compounds of formula (IV) in which R4 represents the residue of a sulfurized nucleophile can easily be prepared by reacting an ester of a halogenated derivative of clavulanic acid with a sulfurized nucleophile, as described in Application of the Federal Republic of Germany (DOS) 2708330. Other methods of preparing such sulfur compounds are also described in the aforementioned application.

  
Compounds of formula (I) wherein R represents an acyloxy group can be prepared from compounds of

  
 <EMI ID = 83.1>

  
acylation carried out as described above with regard to compounds of formula (IV). In addition, the compounds of formula (I) in which R4 represents a disubstituted carbamate group can be prepared by reacting a compound of formula (I) in which

  
 <EMI ID = 84.1>

  
 <EMI ID = 85.1>

  
abovementioned fications other than hydrogen and X represents a halogen atom, for example a chlorine atom), preferably, in the presence of a weak base, as an acceptor of hydrogen halide.

  
The carbamoyl halide can be prepared by reacting a carbonyl dihalide, such as phosgene, with a secondary amine. A compound of formula CI can also be reacted)

  
 <EMI ID = 86.1>

  
carbonyl, this reaction being followed by the reaction on a secondary amine.

  
The esters of clavulanic acid can be prepared from the acid or a reactive derivative thereof, by reaction with an alcohol, a phenol or a stannanol or a reactive derivative of such a compound, so as to form the desired ester as described in Federal Republic of Germany (DOS) patent application No. 2657081. Other esters of formula (IV) can be prepared in a similar manner. .

  
 <EMI ID = 87.1>

  
The preparation of the compounds of formula (IV) frequently results in the production of small amounts of the E isomer, that is to say when the -CH2R4 group is in the trans position with respect to the cyclic oxygen atom, the main product being the Z isomer. Therefore, the starting material of the formula (IV) can be a mixture of the E and Z isomers, but the sliding of the double bond in the process according to the invention makes this characteristic. devoid of consequences.

  
The compounds of formula (IV) in their isomeric form

  
E can also be prepared directly from the E isomer of clavulanic acid by carrying out analogous methods

  
to those described above.

  
 <EMI ID = 88.1>

  
have the above meanings, can easily be prepared from the corresponding compounds of formula (IV) by reaction at elevated temperature, carried out in the presence of an organic base

  
 <EMI ID = 89.1> a suitable inert solvent, for example an ester, such as ethyl acetate. The reaction is advantageously carried out at a temperature of 50

  
at 100 [deg.] C, preferably at reflux. As indicated above, some of the compounds of formula (I) are useful for the preparation of compounds of formula (III).

  
Such compounds of formula (I) are those in which

  
 <EMI ID = 90.1>

  
Compounds of formula (I) in which R represents a substituent which can easily be removed, such as a dichloroacetoxy group, can be converted into compounds of formula (III) by reaction on a tertiary organic basis. The

  
 <EMI ID = 91.1>

  
 <EMI ID = 92.1>

  
by reaction with reagents serving to replace the hydroxyl group with an easily removable radical which is then removed in the presence of a tertiary organic base. The tertiary organic base can

  
be present during the replacement of the hydroxyl group or

  
it can be added later. The base can be, for

  
example, a tertiary amine (including a heterocyclic aromatic amine).

  
As suitable amines, mention may be made of amines bearing aliphatic, araliphatic or aromatic radicals, for example alkyl groups having up to 8 carbon atoms, aralkyl groups in which the alkyl radical contains up to 6 carbon atoms, or aryl groups, the aryl and aralkyl groups in question being advantageously monocyclic. Agree

  
 <EMI ID = 93.1>

  
nitrogen atom is part of a 5, 6 or 7 membered heterocyclic ring, optionally containing another heteroatom, for example

  
 <EMI ID = 94.1>

  
Suitable aromatic cyclics are pyridine bases, for example collidine.

  
 <EMI ID = 95.1>

  
each alkyl group advantageously contains from 1 to 6 carbon atoms, in particular the methyl, ethyl, propyl or butyl radicals, triethylamine being very particularly suitable.

  
The reaction is generally carried out in a suitable inert solvent. Such solvents preferably possess some degree of polarity and include esters, for example, ethyl acetate, ethers, for example tetrahydrofuran, ketones, for example acetone, amides, for example dimethylformamide or halogenated hydrocarbons, for example 1,2dichloroethane or chloroform,

  
The reaction is carried out at an elevated temperature, preferably at reflux, a temperature of 50 to 100 [deg.] C being preferred.

  
Thus, for example, one can react a compound of

  
 <EMI ID = 96.1>

  
in the presence of a tertiary organic base, for example triethyl-

  
 <EMI ID = 97.1>

  
or tosyl, in the presence or absence of halide ions, or

  
on other acylation reagents serving to introduce an easily removable group, or on a halogenation reagent, such as thionyl chloride, so as to generate a diene ester of the formula
(III).

  
The present invention will now be described with the aid of

  
 <EMI ID = 98.1>

  
the invention in any way.

  
The preparations below illustrate the processes by which it is possible to prepare the materials.

  
starting point used to obtain the compounds in accordance with the invention.

  
brine (50 ml) and ethyl acetate (50 ml) with 2N hydrochloric acid (15 ml) and shake everything. The separated aqueous phase was then subjected to extraction with ethyl acetate and the combined organic solutions were dried and filtered. The solution of the free acid in ethyl acetate thus obtained was hydrogenated at atmospheric pressure and at room temperature,

  
 <EMI ID = 99.1>

  
In the preparations and examples which follow, temperatures are given in degrees Celsius and "DKSO" denotes dimethyl tallow.

  
Preparation 1

  
 <EMI ID = 100.1>

  
 <EMI ID = 101.1>

  
hydrogenation after 3 minutes after the initial rapid uptake of hydrogen (approximately 630 ml) has ceased. The mixture was filtered through Kieselguhr and the organic solution washed successively.

  
with water and brine and dried. The solution was filtered, concentrated by evaporation to a volume of about 50 ml, cooled to 0 [deg.] And treated, dropwise, with

  
an excess of ethereal diazomethane. Evaporation of the solvents gave an oil which was chromatographed on a dry gel column.

  
silica and which is eluted in a mixture of ether and petroleum
(M.p. 40-60 [deg.]) (1: 2).

  
The fractions were combined on the basis of the examination by thin layer chromatography and evaporated to collect a colorless oil which was redissolved in chloroform, the chloroform solution being evaporated to give the indicated ester. in the title (1.42 g) which contained about 15%

  
 <EMI ID = 102.1>

  
include 4.90 (m, C-5H).

  
Preparation 2

  
 <EMI ID = 103.1>

  
of 4-nitrobenzyl (3.16 g). The resulting solution was stirred <EMI ID = 104.1>

  
Partitioned between ethyl acetate and brine, The organic solution was washed successively with brine, water

  
 <EMI ID = 105.1>

  
obtain an oil which crystallized on standing. Recrystallization from a mixture of ether and petroleum (P.B. 40-60 [deg.]) Afforded the ester indicated in the title (2.67 g) which contained less.

  
 <EMI ID = 106.1>

  
nitrobenzyl

  
A solution of (3R, 5R, Z) -2- (2-hydroxy-

  
 <EMI ID = 107.1>

  
ethyl acetate (40 ml) to 0 [deg.], stirred and treated

  
with pyridine (3.22 ml) and benzoyl chloride (1.39 ml). The mixture was allowed to reach room temperature, stirred for one hour and then partitioned between ethyl acetate and 0.5N hydrochloric acid. The organic phase was washed. with 0.5N aqueous sodium bicarbonate solution and water. The solution was dried over sodium sulfate and

  
it was evaporated to dryness in the presence of chromatographic silica gel (7 g). The powder thus obtained was introduced at the top of a dry column of silica gel and eluted with mixtures of petroleum spirit (m.p. 40-60 [deg.]) And ether. The fractions were collected and pooled on the basis of TLC examination and evaporated.

  
 <EMI ID = 108.1>

  
 <EMI ID = 109.1>

  
2.5 (m, COPh), 4.21 (d, J 3Hz, C-5H).

  
Preparation 4

  
 <EMI ID = 110.1>

  
4-nitrobenzyl carboxylate

  
A solution of imidazole (1.67g) in ethyl acetate (25ml) was added to a stirred solution of (3R, 5R, Z) -2- (2-hydroxyethylidene) clavam-3- 4-nitrobenzyl carboxylate (8.44 g) in ethyl acetate (125 ml) containing tert- <EMI ID = 111.1>

  
butyldimdthylsilyl (3.69 g). After 30 minutes, the mixture was filtered.

  
 <EMI ID = 112.1>

  
to fractionation in a column of silica gol. The appropriate fractions were combined and evaporated to obtain

  
 <EMI ID = 113.1>

  
ethyl acetate (25 ml), at 0 [deg.], with pyridine (1.61 ml) this treatment being followed by treatment with acetyl chloride (0.43 ml) ). The mixture was stirred at room temperature for 3 hours and

  
 <EMI ID = 114.1>

  
0.5N hydrochloric acid. The organic phase was washed with saturated aqueous sodium bicarbonate solution, water and brine and then dried over sodium sulfate. Evaporation of the solvent gave an oil which crystallized on standing to give the title ester (1.19 g), m.p. 62.5-63.5 &#65533;,

  
 <EMI ID = 115.1>

  
triethylamine (0.84 ml) in ethyl acetate (15 ml), at room temperature, for 24 hours. The crystalline mass thus obtained was broken up; it was collected: washed with ethyl acetate and ether and then dried in vacuo to obtain

  
 <EMI ID = 116.1>

  
 <EMI ID = 117.1>

  
 <EMI ID = 118.1>

  
water (3 ml), so as to obtain a substance (0.066 g) having a melting point of 116-118 [deg.] and spectral characteristics similar to those shown above.

Example 2

  
 <EMI ID = 119.1>

  
1-ene-2-olate

  
A solution of (3R, 5R, Z) -2- was allowed to stand.

  
 <EMI ID = 120.1>

  
amine (0.55 ml) in dimethylformamide (1 ml) at room temperature for 18 hours and then diluted with ether. The oil thus obtained was triturated with ethyl acetate to give a solid which was collected and dried in vacuo to give the title salt (0.358 g),

  
 <EMI ID = 121.1>

  
 <EMI ID = 122.1>

  
include 4.42 + 4.78 (m, C-4 H azetidinyl), 7.0 and 7.4 (m,

  
 <EMI ID = 123.1>

  
(0.7ml) in dimethylformamide (0.5ml) at room temperature for 4 hours and then diluted with ethyl acetate. The crystalline precipitate thus obtained was collected, washed.

  
with ethyl acetate and with ether and then it was

  
vacuum-dried to collect the salt indicated in the title

  
 <EMI ID = 124.1>

  
and 9.06 + 9.08 (t, J 7Hz, CH2CH3).

Example 4

  
 <EMI ID = 125.1> <EMI ID = 126.1>

  
at room temperature for 5 hours. The supernatant layer of the deposited solid was decanted which was then washed with ethyl acetate and ether. The solid was dried in vacuo to obtain the title salt (0.502 g)

  
 <EMI ID = 127.1>

  
A solution of methyl (3R, 5R, Z) -2- (2hydroxyethylidene) clavam-3-carboxylate (2.0 g) and triethylamine (2.8 ml) in ethyl acetate was allowed to stand. (50.ml), at room temperature, for 1.5 hours, diluted with

  
 <EMI ID = 128.1>

  
18 hours overtime. The crystalline solid was collected

  
 <EMI ID = 129.1>

  
4.80 (m, C-4H azetidinyl), 6.50 (s, CO2CH3) and 8.78 (t, J 7Hz, N (CH2CH3) 3).

Example 6

  
 <EMI ID = 130.1>

  
triethylamine (0.27 ml) in ethyl acetate (10 ml), at room temperature,. for 5 hours, a period during which an oil is deposited. The mixture was allowed to stand for an additional 18 hours and then the oil supernatant layer was decanted. Trituration of the oil with ethyl acetate

  
gave a solid which was collected, washed with ether and dried in vacuo, to obtain the salt indicated in the title

  
 <EMI ID = 131.1>

  
 <EMI ID = 132.1> <EMI ID = 133.1>

  
(m, C-4 H azetidinyl), and 8.81 + 8.88 (t, J 7 Hz, N (CH2CH3) 3) '

Example 7 ....

  
 <EMI ID = 134.1>

  
4-nitrobenzyl clavame-3-carboxylate (0.5 g) in acetate

  
 <EMI ID = 135.1>

  
Ethyl acetate (1.3 N), (2.5 ml). Soon an oil began to separate and the mixture was diluted with ethyl acetate.

  
and allowed to stand at room temperature for 24 hours. The crystalline solid thus obtained was collected, washed with ethyl acetate and with ether and then dried in vacuo to collect the title salt.

  
 <EMI ID = 136.1>

  
4.64 + 4.96 (m, C-4 H azetidinyl), 6.78 (s, N (CH3) 3) and 9.04
(t, J 7 Hz, CH2CH3).

Example 8

  
 <EMI ID = 137.1>

  
1-ene-olate (4.5 g) in ethyl acetate (250 ml) at reflux, for 2 minutes to cause dissolution. The cooled solution was concentrated to a volume of about 20 ml, was

  
 <EMI ID = 138.1>

  
the crystalline mass thus obtained, it was collected, washed with ether and dried under vacuum so as to collect the indicated ester

  
 <EMI ID = 139.1>

  
A solution of 4-nitrobenzyl 2-ethylclav-2-nd-3carboxylate (0.10 g) in ethyl acetate was hydrogenated.
(7 ml) for about 1 minute at atmospheric pressure and

  
 <EMI ID = 140.1>

  
(0.10 g). The catalyst was filtered off, through Kieselguhr and washed with ethyl acetate (10ml). The combined organic solutions were extracted with a pH 7 buffer.

  
(2 x 10 ml). The aqueous extract was washed with ether and had it <EMI ID = 141.1>

  
a solution of the acid indicated in the title. A fraction of the above solution freshly prepared, diluted in the proportion

  
 <EMI ID = 142.1>

  
an absorbance of 1.49 in a 1 cm cell.

Example 10

  
 <EMI ID = 143.1>

  
1-yl) but-1-en-2-olate

  
A stirred suspension of 4-nitrobenzyl 2-ethylclav-2e-3-carboxylate (0.32 g) in ethyl acetate (3 ml) was treated with triethylamine (0.27 ml). The mixture was stirred for 18 hours and the precipitate was collected, washed with ethyl acetate and ether and then dried in vacuo to obtain the indicated salt. in the title
(0.363 g). The physical and spectral characteristics of the product were similar to those described in Example 1.

Example 11

  
 <EMI ID = 144.1>

  
A solution of 4-nitrobenzyl 2-ethylclav-2-nd-3carboxylate (0.69 g) and pyridine (0.37 ml) was allowed to stand in

  
 <EMI ID = 145.1>

  
hours and an oil settled. We separated the supernatant layer

  
and the oil was triturated with acetate, ethyl so as to obtain

  
 <EMI ID = 146.1>

  
 <EMI ID = 147.1>

  
 <EMI ID = 148.1>

  
and 6.69 (dd, J 17 and 4Hz, and d, J 17Hz, C-3 azetidinyl protons and 9.09 (t, J 7Hz, CH2CH3).

Example 12

  
4-nitrobenzyl 2-ethylclav-2-nd-3-carboxylate

  
A suspension of 1- (4-nitro-

  
 <EMI ID = 149.1>

  
olate (0.05 g) in ethyl acetate (10 ml), for 5 minutes, to cause dissolution. The solution was evaporated to obtain an oil which crystallized on trituration with ether to give the title ester (0.035 g). The spectral characteristics of the product were similar to <EMI ID = 150.1>

  
 <EMI ID = 151.1>

Example 13

  
 <EMI ID = 152.1>

  
4-triethylammonioazetidin-1-yl) but-1-en-2-olate (0.205 g) in

  
dimethylformamide (1 ml). After 10 minutes, the solution was diluted with ether and the supernatant layer of deposited oil was decanted. Trituration of this oil with ether gave a solid which was collected, washed with ether and dried under vacuum to obtain the salt indicated in the title.

  
 <EMI ID = 153.1>

  
but-1-en-2-ol-4-toluenesulfonate (0.041 g) in ethyl acetate (30 ml), for 5 minutes. The mixture was cooled as well

  
 <EMI ID = 154.1>

  
so as to obtain the ester indicated in the title (0.032 g) of which

  
the spectral characteristics were similar to those described in Example 8.

Example 15

  
 <EMI ID = 155.1>

  
A solution of (3R, 5R, Z) -2- (2-N, N-dimethylthiocarbamoylthioethylidene) clavam-3-carboxylate of

  
 <EMI ID = 156.1>

  
ethyl acetate (1 ml), at room temperature, for 1

  
 <EMI ID = 157.1>

  
thus formed with ether so as to obtain a solid which was collected and dried under vacuum to obtain the salt indicated in

  
 <EMI ID = 158.1>

  
4.90 (obscured) (m, C-4H azetidinyl), 8.82 + 8.90 (t, J7Hz, <EMI ID = 159.1>

  
and triethylamine (0.06 ml) in ethyl acetate (1 ml)

  
at room temperature for 1 hour and then diluted with ether. The oil thus formed was triturated with ether to obtain a solid which was collected and dried in vacuo.

  
 <EMI ID = 160.1>

  
for an approximately 1: 1 mixture of isomers include 4.50 + 4.90
(obscured) (m, C-4H azetidinyl), 6.9-7.3 (m, -CH2CH2S-), 8.80 + 8.88 (t, J 7Hz, N (CH2CH3) 3).

Example 17

  
 <EMI ID = 161.1>

  
nloazetidin-1-yl) but-1-en-2-olate

  
A solution of (3R, 5R, Z) -2- (2-ben-

  
 <EMI ID = 162.1>

  
and triethylamine (0.03 ml) in ethyl acetate (1 ml)

  
at room temperature for 1 hour. The crystalline solid thus formed was collected and dried in vacuo to obtain

  
 <EMI ID = 163.1>

  
encompass 2.13 + 2.45 (COPh complex multiplets), 4.48 + 4.90
(obscured) (m, C-4 H asetidinyl), 8.82 + 8.90 (t, J 7 Hz, N (CH2

  
 <EMI ID = 164.1>

  
and triethylamine (0.35 ml) in ethyl acetate (2 ml)

  
at room temperature, for 1 hour, and then decanted

  
the supernatant layer of the deposited oil. Trituration of this oil with ethyl acetate gave a solid which was collected, washed with ether and dried in vacuo, to obtain the salt.

  
 <EMI ID = 165.1> <EMI ID = 166.1>

  
(0.046 g) and triethylamine (0.02 g) in ethyl acetate (1 ml), at room temperature, for 1 hour. The mixture was diluted with ether and the precipitated solid was collected and dried in vacuo to obtain the salt indicated in.

  
 <EMI ID = 167.1>

  
 <EMI ID = 168.1>

  
(CH2CH3) 3).

Example 20

  
 <EMI ID = 169.1>

  
reaction mixture with petroleum ether (40-60 [deg.]) (50 ml) and the precipitated solid was collected and dried in vacuo of

  
 <EMI ID = 170.1>

  
and triethylamine (1.73 ml) in ethyl acetate (20 ml)

  
 <EMI ID = 171.1>

  
ether so as to obtain a solid which has been collected and

  
 <EMI ID = 172.1>

  
 <EMI ID = 173.1>

  
 <EMI ID = 174.1>

  
to obtain a solid which was collected and dried under vacuum., so

  
 <EMI ID = 175.1>

  
(m, C-4H azetidinyl), 5.48 (m, C-2 H tetrahydropyranyl), 8.1 to 8.7 (m, C-3, C-4 and C-5 tetrahydropyrannyl protons), 8.82 and

  
 <EMI ID = 176.1>

  
at room temperature for 23 hours and then diluted with ether (150 mL). The oil thus obtained was triturated with

  
ether so as to obtain a solid which was collected and dried under vacuum to obtain the salt indicated in the title (13.27 g)

  
 <EMI ID = 177.1>

  
 <EMI ID = 178.1>

  
ethyl acetate (20 ml), at room temperature, for 18

  
 <EMI ID = 179.1>

  
ether, then it was dried under vacuum to obtain the salt

  
 <EMI ID = 180.1> <EMI ID = 181.1>

  
ethsnol liberated), at reflux, for 12 minutes. Examination by thin layer chromatography at this time indicated a

  
 <EMI ID = 182.1>

  
of 4-nitrobenzyl. The solution was treated with triethylamine.
(0.101 g), this treatment being followed by treatment with mesyl chloride (0.1 ml) and then refluxing continued for a further 5 minutes. The cooled solution was diluted with petroleum spirit (about 225 mL) and some precipitated solid was filtered off. The filtrate was washed with brine, dried over sodium sulfate and concentrated to obtain a crystalline solid. The solid was collected, washed with petroleum gasoline and dried under vacuum to obtain the title ester (0.112 g),

  
 <EMI ID = 183.1>

  
 <EMI ID = 184.1>

  
4.01 (dd, J2 & 3Hz, C-5H), 4.03 (dd, J2 & 17Hz, olefinic proton) 4.32 (dd, J2 & 10Hz, olefinic proton).

Example 26

  
 <EMI ID = 185.1>

  
olate (0.217 g) in chloroform dried over alumina (30 ml), one

  
added triethylamine (0.050 g) followed by methanesulfonyl chloride (0.068 g). The mixture was moderately heated at reflux for 17 minutes and then allowed to cool to 25 [deg.]. The reaction mixture was poured into petroleum ether.
(40-60 [deg.]) (200 ml) to 0 [deg.] And the suspension thus obtained was filtered. The filtrate was evaporated until an oil was collected which solidified.

  
 <EMI ID = 186.1>

  
(0.038 g). The spectral characteristics of this product were similar to those described in Example 25.

Example 27

  
 <EMI ID = 187.1>

  
4-nitrobenzyl ethylideneclavam-3-carboxylate (320 mg) and N, N-dimethylbenzylamine (0.29 ml) in ethyl acetate (10 ml), at room temperature, for 181 ", hours and An oil settled. Trituration of this oil gave a solid which was collected, washed and dried to obtain the salt indicated in

  
 <EMI ID = 188.1>

  
include 4.62 (m, C-4H azetidinyl), 2.46 (s, Ph).

Example 28

  
 <EMI ID = 189.1>

  
tidin-1-yl) but-1-en-2-olate

  
A solution of 4-nitrobenzyl (3R, 5R, Z) -2ethylideneclavam-3-carboxylate (320 mg) and methylpiperidine (0.245 ml) in ethyl acetate (10 ml) was allowed to stand,

  
at room temperature for 18 hours. We. collected the solid thus formed, washed and dried to obtain the salt

  
 <EMI ID = 190.1>

  
for the mixture of isomers include 4.60 (m, C-4H &#65533; azetidinyl), 6.75 and 6.95 (singlets, N-CH3).

Example 29

  
 <EMI ID = 191.1>

  
A solution of 4-nitrobenzyl (3R, 5R, Z) -2ethylideneclavam-3-carboxylate (0.316 g) in dry pyridine (2 mL) containing a drop of dry triethylamine was allowed to stand at room temperature for 18 hours. The solution thus obtained was diluted with ethyl acetate (3 ml), then with ether (30 ml) and the deposited solid was collected, which was obtained.

  
 <EMI ID = 192.1>

  
the salt indicated in the title (0.28 g), the spectral characteristics of which resembled those indicated in Example 11.

Example 30

  
 <EMI ID = 193.1>

  
A mixture of 1- (4-nitrobenzyloxycarbonyl) -1- (2-oxo-4-triethylammonioazetidin-1-yl) but-1-en-2- <EMI ID = 194.1> was lyophilized

  
 <EMI ID = 195.1>

  
obtain the salt indicated in the title (220 mg), vmax (Nujol)

  
 <EMI ID = 196.1>

  
we

  
(m, = C-CH2-).

Example 31

  
 <EMI ID = 197.1>

  
azetidin-1-yl) but-1-en-2-ol

  
A mixture of 1- (4-nitrobenzyloxy-

  
 <EMI ID = 198.1>

  
olate (210 mg) in water (10 ml) and nitric acid 1, ON
(0.5 ml) and the residue was triturated with ether so as to

  
 <EMI ID = 199.1>

  
 <EMI ID = 200.1>

  
 <EMI ID = 201.1>

OH

  
 <EMI ID = 202.1>

  
olate (180 mg) and citric acid (90 mg) in water (10 ml) and the residue was triturated with 1.! ether to obtain the

  
 <EMI ID = 203.1>

  
 <EMI ID = 204.1>

  
the mixture of isomers include 4.50 (m, C-4H azetidinyl), 7.32
(CH2 citrate).

Example 33

  
 <EMI ID = 205.1>

  
and triethylamine (0.27 ml) in ethyl acetate (15 ml),

  
at room temperature for 30 minutes and then diluted with ether until turbidity appeared. The mixture was allowed to stand for an additional 2 hours and

  
collected the precipitate thus formed, washed and dried so

  
 <EMI ID = 206.1> <EMI ID = 207.1>

  
yl) but-1-en-2-olate (400 mg) in dimethylformamide (10 ml) with methyl isocyanate (0.06 ml). Further portions of methyl isocyanate (0.1 ml) were added after 30 minutes and after an additional 3 hours. The mixture was stirred for

  
1 hour after the final addition and it was finally poured into

  
 <EMI ID = 208.1>

  
fresh ether so as to obtain the salt indicated in the title under

  
 <EMI ID = 209.1>

  
7.48 (OCONHCH3).

Example 35

  
 <EMI ID = 210.1>

  
nitrobenzyl (1.346 g) in ethyl acetate (4 ml) contemnt triethylamine (0.61 g), at room temperature, for
18 hours. The solid thus formed was collected and dried in vacuo to obtain the title salt (1.10 g).

  
 <EMI ID = 211.1> <EMI ID = 212.1>

  
the reaction mixture was poured into stirred ether (approx.
400 ml) and diluted with petroleum spirit (about 100 ml, m.p. 40-60 [deg.]). The deposited gum was triturated to obtain a solid which was collected, washed with ether and dried. We washed

  
 <EMI ID = 213.1>

  
the insoluble residue so as to obtain the salt indicated in the title

  
 <EMI ID = 214.1>

  
look like those described in Example 33.

  
 <EMI ID = 215.1>

  
1. Compounds corresponding to the following formula (I):

  

 <EMI ID = 216.1>


  
 <EMI ID = 217.1>

  
 <EMI ID = 218.1>

  
hydrogen, a hydroxyl group, an esterified hydroxyl group,

  
 <EMI ID = 219.1>


    

Claims (1)

2. Compounds according to claim 1, characterized: <EMI ID = 220.1> represent alkyl groups with up to 8 card atoms! aralkyl groups in which the alkyl radical contains up to 6 <EMI ID = 221.1> <EMI ID = 222.1> <EMI ID = 223.1> nitrogen to which they are attached, a heterocyclic ring with 5, 6 or 7-membered, possibly containing an additional heteroatom! <EMI ID = 224.1> nitrogen to which they are attached, part of a heterocyclic aromatic ring. 3. Compounds according to any one of claims <EMI ID = 225.1> <EMI ID = 226.1> 4. Compounds according to any one of the claims <EMI ID = 227.1> the nitrogen atom to which they are attached, a polycyclic amine system. 5 * Compounds according to any one of the preceding claims, characterized in that R represents an etherified hydroxy group -OR 'where R5 represents an alkyl, alkenyl or unsubstituted alkynyl, containing from 1 to 6 carbon atoms; a <EMI ID = 228.1> esterified, acyl, or acylated or etherified hydroxyl; a hydra group <EMI ID = 229.1> in which the alkyl radical may contain from 1 to 6 carbon atoms or an aryl group, the aryl and aralkyl groups being monocyclic <EMI ID = 230.1> <EMI ID = 231.1> <EMI ID = 232.1> saturated or unsaturated, attached through a carbon atom, such as cycloalkyl or heterocyclic groups bearing <EMI ID = 233.1> <EMI ID = 234.1> <EMI ID = 235.1> may be substituted by one or more hydroxyl or alkoxy radicals <EMI ID = 236.1> substituted, or an esterified carboxyl or carboxyl group; <EMI ID = 237.1> <EMI ID = 238.1> <EMI ID = 239.1> or C2-C6 alkanoyl, which may be substituted by halogens, <EMI ID = 240.1> nitrogen atom to which they are attached form a 5-7 membered heterocyclic ring optionally containing another oxygen atom; nitrogen or sulfur; <EMI ID = 241.1> <EMI ID = 242.1> <EMI ID = 243.1> <EMI ID = 244.1> alkyl comprises from 1 to 6 carbon atoms or an aryl group, the aralkyl and aryl radicals in question being monocyclic; <EMI ID = 245.1> via a carbon atom and containing one or more heteroatoms and optionally carrying one or more <EMI ID = 246.1> or being substituted with a hydroxyl or substituted hydroxyl group, a carboxyl or substituted carboxyl group, an amino or substituted amino group, or a cyano group; <EMI ID = 247.1> <EMI ID = 248.1> <EMI ID = 249.1> represent hydrogen atoms or alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl or aryl radicals as defined further <EMI ID = 250.1> nitrogen atom to which they are attached, a heterocyclic ring containing from 5 to 7 ring atoms; and Y represents an oxygen or sulfur atom; <EMI ID = 251.1> a trihydrocarbylsilyl group having up to 24 carbon atoms. 6. Compounds according to any one of the claims 1 to 3, characterized in that R represents an etherified hydroxyl group -OR5 where R5 represents an alkynyl, alkenyl or unsubstituted alkyl group containing from 1 to 6 carbon atoms; a group <EMI ID = 252.1> <EMI ID = 253.1> alkyl radical contains from 1 to 6 carbon atoms; or an aryl group, the aryl or aralkyl group being monocyclic; a group <EMI ID = 254.1> saturated or unsaturated, attached through a carbon atom; or R4 represents an acylated hydroxyl group -OR ' <EMI ID = 255.1> <EMI ID = 256.1> group may be substituted by one or more hydroxyl radicals, <EMI ID = 257.1> or di-substituted; <EMI ID = 258.1> <EMI ID = 259.1> <EMI ID = 260.1> in C2-C6. which groups can be substituted by atoms <EMI ID = 261.1> together with the nitrogen atom to which they are attached, form a 5-7 membered heterocyclic ring optionally containing an additional oxygen, nitrogen or sulfur atom; or else R4 represents the residue of a sulfurized nucleophile represented by one of the following formulas: -SR <1> <1>, -SO.R <1> <1>, -SOpR and -S.C = Y.R where R represents a group <EMI ID = 262.1> <EMI ID = 263.1> <EMI ID = 264.1> or being substituted with a hydroxyl or substituted hydroxyl group, a carboxyl or substituted carboxyl group or an amino or substituted amino group; <EMI ID = 265.1> <EMI ID = 266.1> <EMI ID = 267.1> hydrogen atoms or alkyl, alkenyl, alkynyl groups, <EMI ID = 268.1> <EMI ID = 269.1> they are attached, a heterocyclic ring containing from 5 to 7 ring atonies; and Y represents an oxygen or sulfur atom. 7. Compounds according to claim 6, characterized in <EMI ID = 270.1> <EMI ID = 271.1> phenethyl, cyclohexyl or tetrahydropyranyl; <EMI ID = 272.1> butyl or amyl, a benzyl group, a phenyl group, or a <EMI ID = 273.1> <EMI ID = 274.1> <EMI ID = 275.1> thioacetyl, or acetyl. 8. Compounds according to claim 5, characterized in that R5 represents a t-butyldimethylsilyl group. 9. Compounds according to any one of the claims 1 to 3, 6 and 7, characterized in that R represents a group -COOR16 <EMI ID = 276.1> substituted or substituted, an aralkyl group having up to 20 carbon atoms, an alkyl group having up to 12 carbon atoms, a cycloalkyl group having up to 12 carbon atoms, a heterocyclic group having up to 12 carbon atoms carbon, optionally containing one or more heteroatoms in the ring system or a stannyl group having up to 24 carbon atoms. 10. Compounds according to claim 9, characterized <EMI ID = 277.1> 11. Compounds according to claim 10, characterized in that R represents a p-nitrobenzyl or benzyl group. 12. Acid addition salts of compounds according to any one of claims 1-3, 6, 7 and 9-11, formed with a carboxylic acid, a sulfonic acid or a mineral acid. 13. Salts according to claim 12, formed with citric acid, formic acid, tartaric acid, acetic acid, p-toluenesulfonic acid, nitric acid, hydrochloric acid, sulfuric acid or perchloric acid. 14. Compounds according to any one of claims 1-3, 6, 7 and 9-13, in crystalline form. 15. Process for preparing a compound corresponding to formula (I) as defined in claim 1, characterized in that a compound of formula (II) is reacted. <EMI ID = 278.1> <EMI ID = 279.1> <EMI ID = 280.1> or a compound corresponding to formula (IV) <EMI ID = 281.1> <EMI ID = 282.1> <EMI ID = 283.1> <EMI ID = 284.1> claim 1), so as to obtain a compound of the formula (I), this reaction being optionally followed by salt formation. 16. The method of claim 15, characterized in that the amine is a trialkylamine in which each alkyl group contains from 1 to 6 carbon atoms. 17. A method according to any one of claims 15 and 16, characterized in that the reaction is carried out in a non-hydroxylated solvent and in that the compound of formula (I) obtained crystallizes from solution, 18. Method according to any one of the claims <EMI ID = 285.1> <EMI ID = 286.1> 19. The method of claim 15, in substance, as described above, in particular in the examples. 20. A method according to any one of the claims 15 to 19, characterized in that the compound of formula (II) is prepared by reaction of a compound of formula (IV) at elevated temperature and in the presence of a tertiary organic base. 21. A method according to revendicatinn 20, characterized in that <EMI ID = 287.1> <EMI ID = 288.1> <EMI ID = 289.1> have the meanings given in claim 2, except <EMI ID = 290.1> 22. The method of claim 20, in substance, as described above, in particular in the examples. 23. Process for the preparation of a compound of the formula (III ' <EMI ID = 291.1> wherein R represents an esterified carboxyl group, characterized in that a compound of formula (I) in which R4 represents a hydroxyl group is reacted with a reagent serving to replace a hydroxyl group with a group which is can easily remove, which group is then removed in the presence of a tertiary organic base. 24. The method of claim 23, characterized in that the aforementioned reagent is a sulfonylation agent and in whether the operation is carried out in the presence or in the absence of <EMI ID = 292.1> halide or halogenating agent. 25. A method according to any one of claims 23 and 24, characterized in that the base is a tertiary amine bearing aliphatic, araliphatic or aromatic groups. 26. The method of claim 25, characterized in that the tertiary amine carries alkyl groups comprising up to 8 carbon atoms, aralkyl groups in which the alkyl radical contains up to 6 carbon atoms, aryl groups the aryl and aralkyl groups being monocyclic, or C3-C7 cycloalkyl groups. 2.7. Process according to Claim 26, characterized in that the base is a trialkylamine in which each alkyl group contains from 1 to 6 carbon atoms. 28. A method according to any one of the claims 23 to 27, characterized in that the reaction is carried out at a temperature <EMI ID = 293.1> 29. A process for preparing a compound of the formula (III), characterized in that a compound of the <EMI ID = 294.1> easily removed, on a tertiary organic basis. 30. Process according to claim 23, in substance, as described above, in particular in the examples. 31. Compounds of formula (III) as defined in claim 23, obtained by carrying out the process according to any one of claims 23 to 28 and 30. 32: Compounds corresponding to formula (III) as defined in claim 23, obtained by carrying out the process according to claim 29. 33. A process for preparing a compound of the formula <EMI ID = 295.1> <EMI ID = 296.1> characterized in that a compound of formula (I) is reacted <EMI ID = 297.1> acylating.