GB2151628A - Azetidine intermediates - Google Patents

Abstract

Products of formula (II): <IMAGE> racemic or optically active, [in which A represents a hydrogen atom or a sulpho radical; the wavy line indicates that the product is in its cis or trans form or in the form of a cis-trans mixture; and Ra represents a group R1 or a group R1 whose reactive functions are protected; where R1 represents a radical -(CH2)n-X; in which n represents an integer from 1 to 4; and X represents a halogen atom; a cyano radical; a radical O-R'1 in which R'1 represents a hydrogen atom or an alkyl radical; or X represents a radical S-R''1 in which R''1 represents a hydrogen atom, an alkyl radical or a heterocyclic radical; or X represents a radical <IMAGE> in which R' and R'' are the same or different and each represents a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, or R' and R'' together with the nitrogen atom to which they are attached form a heterocyclic radical; or X represents an azido, a thiocyanato or an isothiocyanato radical; with the proviso that when A represents a hydrogen atom, Ra cannot represent a methylthio, hydroxymethyl, azidomethyl, aminomethyl or alkoxymethyl radical] are novel compounds useful as intermediates in the production of the pharmaceutical azetidine compounds described in specification 2,111,482 from which the present case is divided out.

Description

SPECIFICATION Azetidine intermediates The present invention relates to certain azetidine-2-one products which are novel and which are useful in the production of azetidine compounds which are described and claimed in application no. 82-30366 (serial no. 2,111,482) from which the present application is divided out.

According to the parent invention there is provided a compound which is an azetidine of formula (I)

or a salt thereof, in which R represents a hydrogen atom or a linear or branched, alkyl, alkenyl, or alkynyl radical having at most 1 2 carbon atoms, which radical is optionally substituted; R1 represents a radical -(CH2)n-X; in which n represents an integer from 1 to 4; and X represents a halogen atom; a cyano radical; a radical O-R', in which R', represents a hydrogen atom or an alkyl radical; or X represents a radical S-R", in which R"1 represents a hydrogen atom, an alkyl radical or a heterocyclic radical; or X represents a radical

in which R' and R" are the same or different and each represents a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, or R' and R" together with the nitrogen atom to which they are attached form a heterocyclic radical; or X represents an azido, a thiocyanato or an isothiocyanato radical; and the wavy line indicates that the compound is in its cis or trans form or in the form of a cistrans mixture; the oxime group in the compound being in the syn form, and the compound being in the racemic or an optionally active form.

Among the values for R there can be mentioned: (a) Methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, iso-pentyl, sec-pentyl, tert-pentyl, neo-pentyl, hexyl, iso-hexyl, sec-hexyl, tert-hexyl, heptyl, octyl, decyl, undecyl, or dodecyl, groups.

(b) Vinyl, allyl, 1-propenyl, butenyl, pentenyl, or hexenyl, groups.

(c) Ethynyl, propargyl, or butynyl, groups.

The groups mentioned above in paragraphs (a) to (c) can themselves be substituted by one or more radicals, possibly salified or esterified (so that the radical is for example alkoxycarbonyl such as methoxycarbonyl or ethoxycarbonyl), carbamoyl, dimethylcarbamoyl, amino, dialkylamino (such as dimethylamino or diethylamino), alkylamino (such as methylamino), cyano, halogen (i.e. chlorine, bromine, iodine or fluorine), alkoxy (such as methoxy, ethoxy or propyloxy), alkylthio (such as methylthio or ethylthio), aryl (such as phenyl), aryl heterocyclic radicals (such as tetrazolyl or pyridinyl), optionally substituted arylthio (such as optionally substituted phenylthio), or aryl heterocyclic-thio radicals (such as tetrazolylthio or thiadiazolylthio) optionally substituted by an alkyl group such as methyl.

Among the values for R there can be mentioned more particularly the values hydrogen, methyl, optionally esterified or salified carboxyethyl, optionally esterified or salified 1-carboxy-1methylethyl, 2-aminoethyl or difluoromethyl.

Among the values for Rt, there can be mentioned more particularly chloromethyl, chloroethyl, chloropropyl, 1-chloro-1-methylethyl, or chlorobutyl radicals. There can also be mentioned the corresponding bromine, iodine or fluorine analogues, in particular bromomethyl or fluoromethyl.

There can also be mentioned alkylcyano radicals such as methylcyano or ethylcyano.

Among the values for R',, there can be mentioned the alkyl radicals, preferably having from 1 to 4 carbon atoms, mentioned above in (a), in particular the methyl radical.

Among the values for P"1. there can also be mentioned the alkyl radicals, preferably having from 1 to 4 carbon atoms, mentioned above in (a), in particular methyl.

Among the heterocyclic radicals which P"1 can represent, there can be mentioned pyridyl, 1,2,3- 1,2,5- 1,2,4- or 1,3,4- thiadiazolyl, 1 H-tetrazolyl, 1 3-thiazolyl, 1,2,3- 1,2,4- or 1,3,4triazolyl or 1,2,3- 1,2,4- 1,2,5for 1,3,4-oxadiazolyl, these radicals either being not substituted, or substituted by one or more radicals chosen from the group formed, for example, by methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propyloxy, isopropyloxy, amino, hydroxycarbonylmethyl, dimethylaminoethyl and diethylaminoethyl radicals.

There can be mentioned more particularly 1-methyltetrazolyl, 2-methyl-1 , 3,4-thiadiazolyl, 3 methyl-1 2,4-thiadiazolyl, 3-methoxy-1 ,2,4-thiadiazolyl, 1, 3,4-thiadiazol-5-yl and, more especially, 1 -methyltetrazolyl radicals.

The radical

can represent in particular an amino, dimethylamino, methylamino, ethylamino, diethylamino, piperidino, or morpholino radical.

The azetidines of formula (I) can form salts. The azetidines can form salts with bases and acids.

The sulpho group in position 1 as well as the carboxy group which the radical R can contain can be be salified.

Among the salts which can be prepared, there can be mentioned the sodium, potassium, lithium, calcium, magnesium, or ammonium salts. There can also be cited the salts with organic bases such as trimethylamine, diethylamine, triethylamine, methylamine, propylamine, N.Ndimethylethanolamine, tris (hydroxymethyl) aminomethane, ethanolamine. pyridine, picoline.

dicyclohexylamine, N',N'-dibenzylethylenediamine, morpholine, benzylamine, procaine, lysine, arginine, histidine or N-methyl glucamine.

The azetidines can be in the form of salts with organic or mineral acids, since the azetidines contain at least one salifiable amino radical.

Among the acids with which the amino groups of the azetidines of formula (I) can be salified, there can be mentioned, among others, acetic, trifluoroacetic, maleic, tartaric, methanesulphonic, benzenesulphonic, p-toluene-sulphonic, hydrochloric, hydrobromic, sulphuric, or phosphoric acid. The azetidined of formula (I) can also be in the form of internal salts.

The preferred compounds are the cis compounds More particularly, the parent invention provides a compound which is an azetidine of formula (I')

syn isomer, in the cis form, in which R2 represents a hydrogen atom or a linear or branched alkyl radical containing up to 1 2 carbon atoms, which radical is optionally subjected by one or more substituents selected from halogen atoms and carboxyl, amino and cyano radicals; n' represents the integer 1 or 2; and X' represents a fluorine atom, a 2-pyridinylthiomethyl radical or a thiocyanato radical; the azetidine being in the racemic or an optically active form; or a salt of this azetidine.

The parent invention provides more particularly the azetidines of formula (I') in which n' represents the number 1 and X' represents a fluorine atom, as well as those in which R2 represents a hydrogen atom or a methyl or difluoromethyl radical, an optionally salified or esterified carboxymethyl radical, an aminoethyl or cyanomethyl radical, or an optionally salified or esterified 1-methyl-1-carboxyethyl radical.

More particularly, the parent invention provides the compounds described in its Examples, and especially 4-fluoromethyl-3-[2-(2-amino-4-th iazolyl)-2-methoxyim inoacetamido]-2-oxo-azeti- dine-1-sulphonic acid, cis, syn isomer, racemic or optically active, or a salt thereof, or 4fluoromethyl-3-[2-(2-am ino-4-thiazolyl)-2-d ifluoromethoxyim inoacetamido]-2-oxo-azetid i ne- 1 -sç 1- phonic acid, cis, syn isomer, racemic or optically active, or a salt thereof.

It is to be understood that the azetidines can be presented either in the form indicated by the said formula (I), or in the tautomeric imine form lz:

The lactam nucleus is numbered as follows:

The azetidines designated cis have the formula:

The trans products are the products with the formula:

The parent invention also provides a process for the preparation of the products with the general formula (I) as defined above, characterized in that a product with the formula (all):

racemic or optically active, in which formula either R, represents R1, R1 having the significance indicated above, or R" represents R1 in which the reactive functions are protected and A represents a hydrogen atom or a sulpho radical, is treated by a product with the formula (III):

or an acid functional derivative thereof, in which Rb represents a hydrogen atom or a protector group for the amino radical and R'b represents a protector group for the hydroxyl radical or R'l, represents R, R having the significance indicated above, or R'i, represents a radical R in which the reactive functions are protected, so as to obtain a product with the formula (IV):

racemic or optically active, in which Pb, R'b, Pa and A have the previous significances, which product, if necessary and if desired, is submitted to any one or more of the following reactions, in any order whatsoever: (a) separation by hydrolysis, hydrogenolysis or by action of thiourea of the protector group or groups which Rb and R'b can represent or which R'b and R, can include, (b) esterification or salification of the carboxy radical, which the radical R't, can include and salification of the sulpho radical, (c) salification by an acid of the amino radical or radicals, (d) sulphonation of the products in which the radical A represents a hydrogen atom, (e) resolution of the molecule so as to obtain an optically active product.

In the formula (II), Pa can represent generally the radical Rt. However in the case where P1 represents a -(CH2)nX radical, in which X represents in particular a hydroxyl or amino radical, it can be advantageous to protect these radicals by separable protector groups.

The protector groups for the amino radical can for example be alkyl radicals, preferably tertbutyl or tertamyl, they can also be included among the acyl, aliphatic, aromatic or heterocyclic groups or the carbamoyl group.

There can also be cited the lower alkanoyl groups, such, for example, as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl. Rb can also represent a lower alkoxy or cycloalkoxycarbonyl group such, for example, as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1 -cyclopropylethoxycarbonyl, isopropyloxycarbonyl, butyloxycarbonyl, tert-butyloxycarbonyl, pentyl-oxycarbonyl, hexyloxycarbonyl, a benzoyl, toluolyl, naphthoyl, phthaloyl, mesyl, phenylacetyl, phenylpropionyl group, or an aralkoxycarbonyl group such as benzyloxy-carbonyl.

The acyl groups can be subsituted for example by a chlorine, bromine, iodine or fluorine atom. There can be cited the chloroacetyl, dichloroacetyl, trichloroacetyl, bromoacetyl or trifluoroacetyl radicals.

There can also be used a lower aralkyl group such as benzyl, 4-methoxybenzyl or phenylethyl, trityl, 3,4-dimethoxybenzyl or diphenylmethyl.

A haloalkyl group such as trichloroethyl can also be used.

There can also be used a chlorobenzoyl, para-nitrobenzoyl, para-tert-butylbenzoyl , phenoxyacetyl, caprylyl, n-decanoyl, acryloyl, or trichloroethoxycarbonyl group.

There can also be utilized a methyl-carbamoyl, phenylcarbamoyl, naphthylcarbamoyl group, as well as the corresponding thiocarbamoyls.

The above list is not limitative, it is obvious that other amine protector groups, groups known in particular in the chemistry of the peptides, can equally be utilized.

The protection group for the hydroxyl radical can be chosen from the list below: It can be an acyl group, for the hydroxyl radical can be chosen from the list below: It can be an acyl group such, for example, as formyl, acetyl, chloroacetyl, bromoacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, benzoylformyl, p-nitrobenzoyl. There can also be cited the ethoxycarbonyl, methoxycarbonyl, propoxycarbonyl, ssssss-trichloroethoxycarbonyl, benzyloxycarbonyl, tert-butoxycarbonyl, 1 cyclo-propylethox- ycarbonyl, tetra-hydropyrannyl, tetrahydrothiopyrannyl, methoxytetrahydropyrannyl, trityl, benzyl, 4-methoxybenzyl, diphenylmethyl, trichloroethyl, 1-methyl 1-methoxyethyl and phthaloyl groups.

Other acyls such as propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl and pivaloyl can also be cited.

The radicals phenylacetyl, phenylpropionyl, mesyl, chlorobenzoyl, para-nitrobenzoyl, para-tertbutylbenzoyl, caprylyl, acryloyl, methylcarbamoyl, phenylcarbamoyl and naphthylcarbamoyl can also the cited, Naturally, the values of the substituents Pb, when these do not represent a hydrogen atom, as well as the values of the protector groups which R'b can possibly represent or include, in particular when R'b includes an amine, can also be taken from the lists mentioned above.

In a preferential manner of carrying out the process, the product with the formula (II) is treated with a functional derivative of a product with the formula (III). This functional derivative can for example be a halide, a symmetric or mixed anhydride, an amide or an activated ester.

As example of a mixed anhydride, there can be cited, for example, that formed with isobutyl chloroformate and that formed with pivaloyl chloride and the mixed carboxylic-sulphonic anhydrides formed, for example, with para-toluene sulphonyl chloride. As example of activated ester, there can be mentioned the ester formed with 2,4-dinitrophenol and that formed with hydroxybenzothiazole.

As example of halide, there can be cited the chloride or bromide.

There can also be cited the acid azide or the acid amide.

The anhydride can be formed in situ by the action of carbodiimide NN' di-substituted, for example, N,N-dicyclohexylcarbodiimide.

The acylation reaction is preferably carried out in an organic solvent such as methylene chloride. Other solvents can, however, be utilized, such as tetrahydrofuran, chloroform or dimethylformamide.

When an acid halide is utilized, and in a general way when a hydrohalic acid molecule is liberated in the course of the reaction, it is preferable to carry out the reaction in the presence of a base such as sodium hydroxide, potassium hydroxide, carbonates and acid carbonates of sodium and potassium, sodium acetate, triethylamine, pyridine, morpholine or N-methylmorpholine.

The reaction temperature is, in general, less than or equal to the ambient temperature.

When Rb represents a hydrogen atom, it is preferred to use a carboxylic sulphonic mixed anhydride.

According to the values for Pb, R',, and Pa, the products with the formula (IV) may or may not constitute products with the formula (I).

The products with the formula (IV) constitute products with the formula (I) when Rb represents a hydrogen atom, when R'l, does not represent a protector group for the hydroxyl radical or does not represent a radical R including a protected function, and finally when Pa does not represent a radical R, in which a reactive function is protected and when A does not represent a hydrogen atom.

In the other cases, the action on the product with the formula (IV) of one or more hydrolysis or hydrogenolysis agents or of thiourea has the purpose of eliminating the radical Rb when the latter represents a protector radical of the amino radical, of eliminating the radical R'b when the latter represents a protector group of the hydroxyl radical, and of eliminating the other protector groups which the radicals Pa and R'h can include.

The kind of reagents to be put in action in all these cases is well known to an expert in the subject. Examples of such reactions are given further on in the experimental part.

There is given below a non-exhaustive list of the means which can be employed to eliminate the different groups.

The elimination of the group P1, can be effected by hydrolysis, the latter being acid, basic, or utilizing hydrazine.

It is preferential to utilize acid hydrolysis to eliminate the alkoxy and cycloalkoxycarbonyl groups, possibly substituted, such as tert-pentyloxycarbonyl or tert-butyloxycarbonyl, the aralkoxycarbonyl groups, possibly substituted, such as benzyloxycarbonyl, and the trityl, diphenylmethyl, tert-butyl or 4-methoxy-benzyl groups.

The acid which is preferably utilized can be chosen from the group constituted by hydrochloric, benzene sulphonic or para-toluene sulphonic, formic or tri-fluoro acetic acid. Other mineral or organic acids can however also be used.

It is preferred to use basic hydrolysis to eliminate acyl groups such as trifluoroacetyl.

The base which it is preferred to use is a mineral base such as sodium or potassium hydroxide. There can also be utilized magnesia, baryta, or a carbonate or acid carbonate of an alkali metal such as the carbonates and acid carbonates of sodium or potassium or other bases.

There can also be used sodium or potassium acetate.

Hydrolysis using hydrazine is utilized for preference to eliminate groups such as phthaloyl.

The Rb group can also be eliminated by the zinc-acetic acid (for the trichloroethyl group), the diphenylmethyl benzyloxycarbonyl groups are preferably eliminated by hydrogen in the presence of a catalyst.

The chloroacetyl group is eliminated by the action of thiourea in a neutral or acid medium, according to the type of reaction described by MASAKI J.A.C.S., 90, 4508. (1968).

There can also be utilized other methods known in the literature for removing protection. for example separation by oxidizing, particularly for the benzyl group.

Among the preferred groups, there can be cited formyl, acetyl, ethoxycarbonyl, mesyl.

trifluoroacetyl, chloroacetyl, trityl. The trityi and chloroacetyl radicals are particularly preferred.

The acid which is used for preference is trifluoroacetic acid or formic acid.

The elimination of the R'b radical or the protector groups which R'l, and R, contain, when this is necessary, is carried out in similar conditions to those previously deascribed for the elimination of Pb.

Acid hydrolysis, among other processes can be used to eliminate alkyl or aralkyl radicals, possibly substituted.

It is preferred to use an acid chosen from the group formed by hydrochloric, formic, trifluoroacetic and paratoluene sulphonic acids.

The other values for the radicals Rb or P', or the protector groups which R'" or R, contain are eliminated, when this is desired, according to processes known to the expert. It is preferred to operate in moderate conditions, that is to say, at ambient temperature or on slight heating.

Naturally, when, for example Re, or R'E, or Pa are or contain groups which can be eliminated but belonging to different types, several agents included in the previous lists can be made to act on the products (IV).

Salification of the products can be carried out according to the usual methods.

Salification can, for example, be obtained by the action on a product in the acid form or on a solvate, for example, the ethanol solvate or a hydrate of this acid, of a mineral base such as the hydroxide of sodium or potassium, the carbonate or the acid carbonate of sodium or potassium.

There can also be utilized the salts of mineral acids such as tri-sodium phosphate. Salts of organic acids can also be used.

A list of such salts of organic acids will be found, for example, in the French patent BF 2 476 C87.

As salts of sodium it is preferred to utilize the acetate, the 2-ethyl hexanoate or the diethyl acetate.

Salification can also be obtained by the action of an organic base or of an amino acid.

The esterification, if required of the products in which R includes an acid function is also carried out in standard conditions.

The sulphonation of the products with the formula (IV) in which A represents a hydrogen atom is carried out by sulphuric anhydride or by a reactive derivative of this anhydride.

It is preferred to utilize the complex pyridine sulphuric anhydride but there can also be utilized other complexes of sulphuric anhydride with dioxan or trimethylamine.

The reaction is carried out in a usual solvent such as ethyl acetate, chloroform or dimethylformamide, and it can be done at ambient temperature. When the complex pyridinesulphuric anhydride is utilized, the products can be isolated in the form of salts of pyridinium.

The resolution of the racemic molecules with the formula (II) or (IV) if required can be carried out according to the usual methods.

An optically active carboxylic or sulphonic organic acid, such as tartaric, camphosulphonic or glutamic acid can be used, the decomposition of the salt so obtained being carried out by means of a mineral base such as sodium acid carbonate or of an organic base such as a tertiary amine, for example triethylamine.

The parent invention is especially concerned with a process as described above, characterized in that, in order to put it into operation, a product with the formula (II) in which A represents a hydrogen atom and a product with the formula (III) in which Rb represents a protector group for the amino radical are used, and in that the sulphonation is carried out on a product with the formula (IV) in which Rb represents a protector group of the amino radical.

The protector group which Rb represents is for preference the trityl radical.

It is preferred to carry out the sulphonation with the complex sulphuric pyridine anhydride.

The products with the formula (II) can be prepared by a process characterized in that a product with the formula (V)

in which Pa has the significance indicated above and Rp represents a protector group for the imino radical, is made to act on a product with the formula (Vl):

in which R'p and R"p represent the one a hydrogen atom and the other a protector group for the amino radical, or R'p and R"p together represent a divalent protector group and B represents a hydroxyl radical or a halogen, so as to obtain a product with the formula (VII):

in which Pa, P,, R'p and R"p have the previous significances, which product with the formula (VII) is submitted to the following reactions: (a) separation by hydrolysis, hyrogenolysis or action of thiourea of the radical Pp; (b) optional sulphonation of the amine in position 1; (c) separation by hydrolysis, hydrogenolysis or action of thiourea of the radicals R'p and R"p; (d) optional resolution of the molecule so as to obtain an optically active product.

The protector group Rp can be chosen from the list of substituents given previously for amines.

For reasons explained below, it is however preferred to utilize a benzyl radical or 2,4dimethoxy benzyl or an equivalent.

In addition, the protector group Rg, can contain an asymmetric carbon atom, and the process defined above can be carried out in particular by employing at the start a product with the formula (V) in which Rl, represents a protector group of the imino radical containing an asymmetric group and isolating a product with the formula (VII) in the optically active form.

These optically active products with the formula (VII) lead to optically active products with the formula (I) according to the process previously described.

As a protector group, there can be cited particularly the 1-phenyl ethyl group.

An example of the preparation of an optically active product with the formula (VII) is provided further on in the experimental part.

The radicals R'" and R",, can be chosen from the same list of protector radicals given above. It is preferred to use the phthaloyl radical.

The group B can represent a halogen atom. The acid chloride is preferred.

When B represents a halogen atom, the action of the product (V) on the product (VI) is carried out in the presence of a base such as triethylamine or of a metal such as zinc.

When B represents a hydroxyl radical, the operation is done in the presence of a dehydratation agent such as an anhydride, preferably trifluoroacetic anhydride.

The action of the products with the formula (V) with the products with the formula (VI) gives cis products preferentially. Trans products are obtained by isomerization in a basic medium.

When it is required to sulphonate the resulting products, the object of the first de-protection reaction is the selective de-blocking of the radical Pp. Therefore, as indicated above, it is preferred to utilize a benzyl or di-methoxy benzyl radical, which is preferably de-blocked by an oxidiser such as potassium peroxodisulphate.

It is preferred to operate in a solvent such as a water-acetic acid mixture or acetonitrile.

The sulphonation, if it is required, of products in which the secondary amine in position 1 is free is carried out as indicated above.

The possible second de-blocking operation has the object of liberating the amine in position 3 by elimination of the radicals R'p and R"p When, as indicated above, one is operating with a phthalimido radical, the elimination is effected, as indicated above, by hydrazine preferably a hydrazine hydrate in a solvent such as dimethylformamide.

Naturally, in particular in the case where the sulphonation of the products with the formula (IV) is not carried out, the radicals Pp, R'l, and R"p can be eliminated simultaneously.

Resolution, as indicated above, is carried out in the usual manner.

The products with the formula (lea):

in which A has the significance indicated above, n represents a whole number betwen 1 and 4 and X" represents X, X having the significance indicated above. with the exception of a halogen atom, or X" represents X in which a reactive function is protected, can be prepared by a process in which a product with the formula (VIII):

in which Rlq and Rliq each represent a hydrogen atom or have the significance of R'p and R"p indicated above, is treated by a reactive derivative of the cyano radical, of the radical -OR',, -SR""

-SCN or -NCS, so as to obtain a product with the formula (IX)

in which X", A, R', and R", have the values indicated previously, which product is if necessary and if desired, submitted to any one or more of the following reactions: (a) separation by hydrolysis, hydrogenolysis or by action of thiourea of the groups represented by R', and R", when these are different from a hydrogen atom, (b) sulphonation of the products in which the radical A represents a hydrogen atom, (c) resolution of the molecule so as to obtain an optically active product.

The action on the product with the formula (VIII) of the reactive derivatives of the radicals which it is wished to substitute for the halogen atom is carried out in the usual conditions.

For example, the exchange between a halogen atom and a mercaptan is preferably carried out by an alkali metal salt of this mercaptan such as a sodium salt.

The exchange between the halogen atom and an acetate of an alkali metal such as sodium or potassium acetate enables a protected hydroxyl radical to be introduced which can be liberated and then if desired etherified.

The action of an amine, possibly protected by one of the radicals indicated above enables a radical

possibly protected, to be introduced.

An azide of an alkali metal, preferably sodium azide, can be made to act in order to introduce the azido radical. A cyanide or a thiocyanate of an alkali metal can equally be made to act so as to obtain the products in which X represents these radicals or an isothiocyanate.

The subsequent operations of possible deprotection, of sulphonation and of resolution, also possible, are carried out in the manner indicated above.

The subject of the parent invention is especially a process for preparing the products with the formula (I) as defined above, characterized in that Ra represents a fluoromethyl radical.

The products with the general formula (I) possess very good antibiotic activity on the Gram negative bacteria, particularly on the coliform bacteria, the the klebsiella, the salmonella and the proteus. These products can in particular be utilized as medicaments in the treatment of colibacilloses and associated infections, in proteus, klebsiella and salmonella infections and in other disorders caused by Gram negative bacteria. The parent specification should be consulted for further details concerning these products. The disclosure of that specification is incorporated herein by reference.

Certain of the products of formula (II) are novel, and it is to these and their production that the present invention is directed.

Accordingly, the present invention provides a product with the formula (all):

racemic or optically active, in which A represents a hydrogen atom or a sulpho radical: the wavy line indicates that the product is in its cis or trans form or in the form of a cis-trans mixture; and Pa represents a group R, or a group R, whose reactive functions are protected, Where R, represents a radical -(CH2)n-X; in which n represents an integer from 1 to 4; and X represents a halogen atom; a cyano radical; a radical O-R', in which R', represents a hydrogen atom or an alkyl radical; or X represents a radical S-R", in which R", represents a hydrogen atom, an alkyl radical or a heterocyclic radical; or X represents a radical

in which R' and R" are the same or different and each represents a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, or R' and R" together with the nitrogen atom to which they are attached form a heterocyclic radical; or X represents an azido, a thiocyanato or an isothiocyanato radical; with the proviso that when A represents a hydrogen atom, Pa cannot represent a methylthio, hydroxymethyl, azidomethyl, aminomethyl or alkoxymethyl radical.

The present invention provides in particular: 4-chloromethyl 3-amino 2-oxo azetidine hydrochloride; 4-( 1-methyl 5-mercapto 1,2,3. 4-tetrazoi)methyl 3-amino 2-oxo azetidine hydrochloride; 4-fluoromethyl 3-amino 2-oxo azetidine hydrochloride cis; or 4-thiocyanatomethyl 3-amino 2-oxo azetidine hydrochloride cis; which can be prepared as described in the following Examples.

The present invention also provides a process for preparing the product, which process comprises reacting an imine of formula (V):

in which Pa is as defined above and Rp represents a protective group for the imino radical, with a protected amine of formula (Vl):

in which one of R'p and R"p represents a hydrogen atom and the other a protective group for the amino radical, or R'p and R"p together represent a divalent protective group, and B represents a hydroxyl radical or a halogen, so as to produce an amine of formula (VII):

in which Pa, Pp, R'p and R"p are as defined above, which amine of formula (VII) is submitted to the following reactions: (a) separation by hydrolysis, hydrogenolysis or the action of thiourea of the radical Rp; (b) optional sulphonation of the amine in position 1; (c) separation by hydrolysis, hydrogenolysis or the action of thiourea of the protective radicals R'p and R"p; and (d) optional resolution of the molecule so as to obtain an optically active product.

The present invention also provides an alternative process for preparing the product which is of formula (I Ia):

in which A, n and the wavy line are as defined above, and X" represents X, X being as defined above with the exception of a halogen atom, or X" represents X in which a reactive function is protected, which process comprises reacting a halide of formula (VII I):

in which R', and R", each represent a hydrogen atom or have the significance of R'p and R"p as defined above, with a reactive derivative of the cyano radical, of the radical -OR',, -SR""

-SCN or -NCS, where R', and R", are as defined above, so as to produce a product of formula (IX):

in which X", A, Rlq and Rliq are as defined above, which product if desired is submitted to any one or more of the following reactions: (a) separation by hydrolysis, hydrogenolysis or by the action of thiourea of the groups represented by Rlq and Rliq when these are different from a hydrogen atom, (b) sulphonation of the product in which A represents a hydrogen atom, and (c) resolution of the molecule so as to obtain an optically active product.

Subordinate feature of the present products and their preparation are evident from the discussion above concerning the parent specification.

The products with the formula (V) which are not known can be prepared by the action of an aldehyde with the formula RaCHO, possibly in the form of the hydrate Ra-CH(OH)2, on a protected amine with the formula PpNH2.

Examples of such preparations are given in the experimental part.

In addition to the products of the parent invention described in the present Examples, the following products can be obtained within the scope of the parent invention; the substituents X, R, A and R, are those indicated in formula (I).

R Ri R R1 42C CH2C1 ~ -(Cfi,)3Br - ( CE-2 ) 2C < 2C1 - -CcH2)21 < -2 -CE(CH3)2 -çg2C1 '2 '2 L C 2 2 C4H9 -CIi2C1 -aCiMn2 -C-2-Ck'-CE'2 -CE,CI '(Ct2)2 2C1 CO2H C02 2 C1 --CH2C1 |~(C < < )2-ì O --C-- ,c=, w (1 '0 ' - '#2 l--Cc2H --C--C1 X(C--)2CFr C C- ;n 2CO < C2, --C-6C1 --C-A2Cl C--- -Cr-ccr C ! < s co2= zi2-1 - ^ 2 rz 5 ^c- C '2 L I - -. I -- '-9 - --- I- ------ -- --- - C CFCC~'~ C C C o.-24.les. sc2 - 42c -c (-.3 ) --C-zC1 --C(CH3)2C2F -CH-CO H qi sU2 > 23r Cl -CH 2 2 23r -C82CX 1 C:i C:R2OC3 --C-t2C1 I 2C02C2F5 -CF Cl --C2Cu2tBu -Cr.2Cl (cm2)2 Er --C-C1 -- (CH3)2Co2C2H5 -C'll2CcF3 -(CH2)2ci -2Ci (C3)2co2tu --C-a2OC'6

R R1 R R1 "CH2Br -CII,BE (CH2)3Er -CP12 Er -(CH2 )2C -CH2Br -(CH2)21 -CSi213r H2Er ). Ca"CH -Ch2Er -nC4H9 c ar -HC-C 42 Er --C-CH-CH2 2Br (C82)2 t -CY2 Br --C--:2Co2H * sw2 3r (CF)2:.ffi,'Nc:: *a-2 Er -'- -0 423r 2 -(C.;2)2-\ 0 s-*2 3r 2' L Er -'-rcr- ) NnzBr ~C.''2 C- < )2 rE Er r.2 -2 =.-2 -~ (CTLi) 2~g(C D )2 C'- 3r 3-C02C2H5 :t-r w- --C-r.aEr CO2tEu Er :2CF2:2 ~;2 Br C CC02E =.- 9r r I-. '"-2 I -'-'2 - I -. -, - -'-'2 --C-6-2--C--CFO2H -C:Er CEs.3 sc:3 ~'2" Er 1 . 2 'F2 '2 2 2 A.2 2 Er =t,C02:: ZE:.2 -(C'.22)2CN -CII2 or .rcF3)2C.a2F -CTI2 SCh H2-CCNF.2 -'-2 Er H22Er 42 SCAN3 -(C2)2 Er u.2 Er -CH22T CH2 sca, -(CX2)2cl -Cu2wr -C2C02C2E -C'rIZ 2 3

R R1 R R1 -CY;C02tBu -CH,-DMI, -CR2oH cCH3)2C02C2H5 --C-d2SCHJ -tCa-)^29r -CE2CE -CtCE3)2C 2tnU SC - (cF) 2C1 -(Csc)2Cl CH2CH3 -CH2CE -(CE2) -C.i20K ( 2 2 3 H -CH2CH H 9 SCN -CH(C5j ) 2 ^ 2 CE CE3 -Ct.5.2SC.^J nCj9 -FcCE -CSC 1 --C- -ç-2CO2 ~6, < ~C.; H2CO2H --C-aOF- (Cr3) 2CC2 c2H --C-zi2 OH -(C)21 -C1",38 -(CH3)2C02H -CF2 OH :r, < 2 - '-H C=C: us --C-rF C C I C:z- b - E t c)2 s.-2CO2iBu -CF2CE 2)2 ; C fii set E -CO2H -CH2CE ~(CE2)2- o C2H C(CE ) -CH2CH -C'R.28-N(CY3)2 -Cw" -CHz~CI Cw~CO2Y ;=d2CE .-c:(CH)2 -CH2-,F -CH-C02H -CY2 OH CF -CF OH 2 -CII2 , 2 -Ce2CN -C OH 2CF-22 -CH20H -(CH2)2cN CF.2 . H

R R1 | R | R1 8 CH2 -CH2~CH -CH2 5W CH3 CHZffR2 -CH2CO2H -CH2SF' -CHzCH2*E2 CR2 2 S -'cH2SH CO2H -(CF,) (CF)2C 2S -CE25! -C(CH3)2C02H CN2a -F HIC32h .3 -C-C:Er CH2' C062H3 ACE.2~ Cz22 CO2tBti -CW2SF H CH.3 2H 2 3 CE -C(CF) -C(CE)3 SF CF , 3 2 -CFTCH2N 2 -CaC-CO2F s > 2-C.zZC 2E -C-S-r -CH2COr CH2N3 -CO G fs -ClizSE 2' (CF,)2C03I cy-2 2 < '2SE - e C.v.~.{CS --C-A2F. CH3 C.CS -C'.R2-C NR2 "C:Sr CE2NCS CH-m2 CXI2s1CS CtI2S ( C.2 ) 2 Er Zi2sE CO2W CH2.NCS (CF.2)2C1 -CH2SE CH3 CH2S -(C)33r -CH2SE (CH)2cE CH2SH -C(CH3)2C02H 42NCS (CH3)2 ) 2 CH2S'A H 2N(CF3)2 -nC4 9 CF.zSX3 CH3 -CH2N(C,,3 )2

R R1 -CH2CF Nha --C-2N(C)2 2CO 2H -CH2'32 -CCF)2T -CE -F2C-CnCH -CF.SE -HC -CH2SF CE2a -(CF2)2-NCF -CE2 ski '(C2)21Y ,O -CF-2L(CF)2 -CH2sF 0 w=.i2w= -NtCm-)2 -CH2S CfI -CE SF 2 -CFCE2:Th2 -CE-SF. C (cs )2C02s --ç(ClI3 )2 CH2 CN ~csz P C92-C02H -cH F -CO H 2 CH3 2 t3 -CH F2 -CH2-Se

The present invention is illustrated by the following Examples. The Examples illustrate the present products and their production, and their use to prepare compounds of the parent invention.

Example 1: 4-chloromethyl 3-L2-(2-amino 4-thiazolyl) 2-methoxyimino acetamido] 2-oxoazetidine 1-sulphonic acid, cis, syn, racemic.

Stage A: 4-chloromethyl 3-[2-(2-tritylamino 4-thiazolyl) 2-methoxyim ino acetamido] 2-oxo azetidine, syn.

A suspension of 2.32 g of 2-(2-tritylamino 4-thiazolyl) 2-methoxyimino acetic acid, syn isomer, in 23 cm3 of methylene chloride is cooled, and 594 mg of dicyclohexyl carbodiimide is added, and after agitating cold for 20 minutes a solution of 441 mg of 4-chloromethyl 3-amino 2-oxo azetidine hydrochloride in 10 cm3 of methylene chloride and 0.4 cm3 of triethylamine are added. After agitating for 1 hour 20 minutes at ambient temperature, the dicyclohexylurea formed is separated, rinsed with methylene chloride, and 10 cm3 of a saturated solution of sodium acid carbonate and 20 cm3 of water are added to the filtrate. This is then agitated, decanted into a flask, washed again with water, the organic phase is re-extracted and dried.

After concentrating to dryness under reduced pressure, the minimum of ethyl acetate is added to the residue, which is scratched, the insoluble matter is filtered, rinsed with ethyl acetate and again concentrated to dryness under reduced pressure. The residue is dissolved in 5 cm3 of ethanol and slowly diluted with 10 cm3 of ether. Crystallization is initiated, with agitation for 2 hours, then the crystals formed are separated and rinsed with an ethanol-ether (1-2) mixture, so obtaining 688 mg of the expected product.

Analysis: C29H26OaN5SCl = 560.08 Calculated: C % 62.19 H % 4.68 N % 12.5 Found: 62.4 4.8 12.2 Stage B: 4-chloromethyl 3-[2-(2-amino 4-thiazolyl) 2-methoxyimino acetamido] 2-oxo azetidine 1-sulphonic acid, cis, syn, racemic.

(a) Sulphonation: 2.403 g of the product obtained at the previous stage is added to a solution of 1.72 g of pyridine sulphan (complex sulphuric pyridine anhydride) in 1 7.2 cm3 of dry dimethylformamide.

After agitating for 66 hours at ambient temperature, filtering off the insoluble matter, rinsing with dimethylformamide, diluting with 300 cm3 of ether, agitating, leaving to rest for 10 minutes, eliminating the ether, and washing again with ether while triturating, the gum is taken up with 20 cm3 of ethanol. After dissolving and being scratched, the expected product crystallizes out. It is agitated lightly for 30 minutes, filtered, rinsed with ethanol and then with ether.

855 mg of the expected product is obtained, which is pyridinium 4-chloromethyl 3-[2-(2tritylamino 4-thiazolyl) 2-methoxyimino acetamido] 2-oxo azetidine 1-sulphonate.

(b) Unblocking the trityl residue: A mixture of 360 mg of pyridine sulphonate previously obtained and 1.4 cm3 of formic acid with 33% water is taken to 50on. After it has dissolved, crystallization of triphenylcarbinol occurs. It is left for 10 minutes at 50go, cooled, diluted with 0.6 cm3 of water, the insoluble matter is filtered off and rinsed with water. A little ethanol is added to the filtrate, which is concentrated to dryness under reduced pressure. Water and ethanol are added and then evaporated under vacuum. 1.2 cm3 of a saturated aqueous solution of sodium acid carbonate is added to the residue. After filtering off the light insoluble matter, and rinsing with water, 3 drops of formic acid are added to the filtrate and it is scratched. The expected product crystallizes out. After agitating for 10 minutes, filtering, rinsing with water and with ether and drying, 11 3 mg of the expected product is isolated.

Analysis: C1(,H 170bNF,S2CI = 397.82 Calculated: C % 30.19 H % 3.04 Found: 29.6 3.2 Preparation: (a) 2-chloro N-phenylmethyl ethanimine.

A solution of 4 cm3 of chloroacetaldehyde in 20 cm3 of demineralized water is cooled and under agitation a solution of 2.1 4 g of benzylamine in 10 cm3 of water is introduced. After agitation for 5 minutes at 10/15*C, a gum is obtained and a turbid solution, which is extracted with 30 cm3 and then with 20 cm3 of benzene. The solution is dried, filtered, rinsed and distilled to dryness under vacuum. 3.34 g of product is obtained which is used as it is.

(b) N-benzyl 3-phthalimido 4-chloromethyl 2-azetidinone, cis.

The solution of 3.34 g of product obtained above in 20 cm3 of methylene chloride is cooled to - 50"C. While maintaining the agitation and the temperature, over 20 minutes, a solution of 4 g of phthalimido acetic acid chloride in 20 cm3 of methylene chloride is introduced; agitating is continued for one hour at 0, + SC, followed by pouring into a decanting flask, washing with 50 cm3 of demineralized water and 5 cm' of a molar aqueous solution of sodium acid carbonate, and then with demineralized water (twice 30 cm3). The washings are re-extracted with methylene chloride (20 cm3), dried, separated, rinsed and concentrated to dryness under vacuum. A crude resin is obtained (6 g) which is chromatographed on silica by means of methylene chloride with 5% of sulphuric ether. The fraction with Rf = 0.45 is isolated, taken to dryness, triturated with 10 cm3 of sulphuric ether, separated, rinsed three times with 2 cm i of sulphuric ether. After drying under vacuum. 1 .25 g of product is obtained. M.Pt. 149"C.

(c) 3-phthalimido 4-chloromethyl 2-azetidinone cis.

A mixture of 17.75 g of the product previously obtained, 31 g of potassium peroxodisul phate, 110 cm3 of water and 1 60 cm3 of acetic acid is heated for 25 minutes under good agitation in an oil bath at 1 20'C. It is then cooled to ambient temperature, 50 g of dipotassium phosphate is added to neutralize the acidity formed, the solvents are expeiled under reduced pressure, 250 cm3 of water and 1 50 cmj of ethyl acetate are added, and after agitation, sodium acid carbonate is added in small quantities until evolution of gas ceases. The medium is filtered, rinsed with ethyl acetate, decanted into a flask, re-extracted with 50 cmA of ethyl acetate, the organic phase is dried, filtered, rinsed and concentrated to dryness under reduced pressure. The residue is chromatographed on 200 g of silica (eluent: methylene chloride with 25% of ethyl acetate). The rich fractions are recovered, concentrated to dryness, taken up with ether, discc!ved, separated, rinsed and after drying 5.4 g of the product sought is obtained.

Analysis: C12H9N2Cl = 264.67 Calculated: C % 54.46 H % 3.43 Found: 54.7 3.5 (d) 4-chloromethyl 3-amino 2-oxo azetidine hydrochloride.

To a suspension of 5.3 g of product above in 5.4 cm3 of methylene chloride, 1 2 cm3 of a solution of hydrazine hydrate in dimethylformamide (2 cm3 of hydrazine hydrate and q.s. for 20 cm3 of dimethylformamide) is added drop by drop. After aggregation, it is left for 20 minutes, then sufficient (about 30 cm3) of normal hydrochloric acid is added to dissolve it completely, in such a way as to bring the pH to 3. After agitating for 1 8 hours at ambient temperature filtering the phthalhydrazide formed, rinsing with water, then with ethanol and finally with ether and drying 2.844 g of product is obtained. The dimethylformamide and water are expelled under reduced pressure, the residue is taken up twice with ethanol which is expelied and a product is obtained to which 20 cm3 of ethanol is added. After agitating for 45 minutes, separating the crystals formed, rinsing with ethanol and ether, there is finally obtained 2.466 g of the expected product.

Example 2: 4-(1-methyl 5-mercapto 1,2,3.4-tetrazol) methyl 3-12-(2-amino 4-thiazoly) 2-methoxyimino acetamido] 2-oxo azetidine 1-sulphonic acid, cis, racemic.

Stage A: 4-(1-methyl 5-mercapto 1,2,3, 4-tetrazol) methyl 3-[2-(2-tritylamino 4-thiazolyl) 2methoxyimino acetamidoj 2-oxo azetidine I. -suThhonic acid.

(a) Condensation: A mixture of 2.25 g of 2-(2-tritylamino 4-thiazolyl) 2-methoxyimino acetic acid, syn isomer, in 21 cm3 of methylene chloride and 576 mg of dicyclohexylcarbodiimide is agitated cold for 20 minutes in a bath of iced water. The bath is removed and a solution of 597 mg of 4-(1-methyl 5-mercapto 1,2,3,4-tetrazol) methyl 3-amino 2-oxo azetidine hydrochloride in 10 cm3 of methylene chloride and 0.38 cm3 of triethylamine are added. After agitating at ambient temperature for 1 hour 20 minutes, concentrating to dryness under reduced pressure, filtering, rinsing with methylene chloride, finishing with ether and drying, 1.594 g of product is isolated, containing dicyclohexylurea.

(b) Sulphonation: A mixture of 1.594 g of the product obtained above and 0.66 g of pyridine sulphan (complex pyridine sulphuric anhydride) in 6.6 cm3 of dimethylformamide is agitated for 70 hours. The dicyclohexylurea is filtered off, rinsed with the minimum of dimethylformamide, and the filtrate is diluted with about 200 cm3 of ether. After agitating well, filtering off the insoluble matter, washing with ether, joining all the products together and dissolving them in methanol, the expected product crystallizes out. It is filtered, rinsed with methanol and finished with ether, dried, and 620 mg of the expected product is obtained.

Stage B: 4-(1-methyl 5-mercapto 1,2,3,4-tetrazol) methyl 3-[2-amino 4-thiazolyl) 2-methoxyimino acetamido) 2-oxo azetidine 1-sulphonic acid.

A mixture of 620 mg of the product obtained in the previous stage in 0.8 cm3 of water and 1.62 cm3 of formic acid is heated to 60"C for 1 2 minutes, and triphenylcarbinol crystallizes out.

By cooling and diluting with a little water, the expected product also crystallizes. The medium is agitated for 10 minutes, filtered, rinsed with water, then triturated three times with ether. The insoluble matter is taken up in water, 2 cm3 of saturated aqueous sodium acid carbonate is added, then after agitating, filtering the insoluble matter, rinsing with water and adding normal hydrochloric acid as required for pH 2, the expected product crystallizes. After agitating for 5 minutes, filtering, rinsing with water and finishing with ether and drying, 294 mg of the expected product is obtained.

Analysis: C12H506NgS31 /2H20 = 486.51 Calculated: C % 29.63 H % 3.31 N % 25.91 S % 19.77 Found: 29.5 3.4 25.8 19.8 Preparation 1: (a) 4-( 1-methyl 5-mercapto 1,2,3, 4-tetrazol) methyl 3-phthalimido 2-oxo azetidine, cis.

A suspension of 7.6 g of 4-chloromethyl 3-phthalimido 2-oxo azetidine, cis, obtained by the preparation of example 1 c), 5.48 g of sodium salt of 1-methyl 5-mercapto 1,2,3,4-tetrazole (dihydrated), 4.3 g of sodium iodide and 57 cm3 of dimethylformamide are heated to 100"C and left under agitation for 3 hours at this temperature. It is then cooled, poured into 0.75 1 of water and 1 50 cm3 of ethyl acetate, rinsed, agitated vigorously, decanted, re-extracted with 75 cm3 and then 45 cm3 of ethyl acetate, and the insoluble matter which is the expected product is filtered off. After washing with 1 50 cm3 of water, re-extracting, drying, and filtering, it is concentrated to a small volume under reduced pressure, filtered a second time and rinsed with ethyl acetate. The insoluble products are joined together, dried, and fimally 5.1 g of the expected product is isolated.

Analysis: C14H1203N6S 1 /4 AcOEt = 366.37 Calculated: C % 49.17 H % 3.85 N % 22.94 Found: 49.2 3.7 23.0 (b) 4-( 1-methyl 5-mercapto 1,2,3,4-tetrazol) methyl 3-amino 2-oxo azetidine hydrochloride.

1 cm3 of hydrazine hydrate is added drop by drop to a suspension of 5.845 g of the product obtained above in 18.5 cm3 of dry dimethylformamide and agitated for 20 minutes at ambient temperature, then 1 9 cm3 of water and 24 cm3 of normal hydrochloric acid are added. After obtaining a final pH of 3, the mixture is stoppered, left for one night under agitation at ambient temperature, then the phthalhydrazide formed is filtered, rinsed with water, and concentrated to dryness under reduced pressure. After adding ethanol, triturating, concentrating to dryness, adding methanol hot to make a solution and concentrating to dryness, the product crystallizes.

By adding 20 cml of methanol, triturating, chilling, separating, rinsing with iced methanol and finishing with ether, 2.49 g of the expected product is obtained in two lots.

Example 3: 4-fluoromethyl 3-12-(2-amino 4-thiazolyl) 2-methoxyimino acetamido] 2-oxo azetidine 1-sulphonic acid, cis, syn, racemic.

Stage A: 4-fluoromethyl 3-[2-(2-tritylamino-4-thiazolyl) 2-methoxyimino acetamido] 2-oxo azetidine cis, syn, racemic.

0.915 g of 2-(2-tritylamino 4-thiazolyl) 2-methoxyimino acetic acid, syn isomer, 7 cm3 of acetone and 0.319 g of tosyl chloride are mixed together. After agitating for 50 minutes at 20"C, the mixture is filtered and a solution containing 0.216 g of 4-fluoromethyl 3-amino 2-oxo azetidine hydrochloride, cis, 7 cm3 of methylene chloride and 0.42 cm3 of triethylamine is added. After agitating for 45 minutes, then evaporating to dryness, water is added, the solid matter is crumbled and then separated, then triturated with acetone and separated again. The product is purified by trituration in ethyl acetate. 0.654 g of the expected product is obtained.

Analysis: C29H;,fi03N5SF 543.62 Calculated: C% 64.07 H% 4.82 N% 12.88 S% 5.90 F% 3.49 Found: 64.0 4.9 12.4 5.9 3.4 Stage B: 4-fluoromethyl 3-f2-(2-amino 4-thiazolyl) 2-methoxyimino acetamidoj 2-oxo azetidine 1-sulphonic acid, cis, syn, racemic.

(a) Obtaining pyridinium sulphonate.

A mixture of 0.564 g of the product obtained in Stage A, 0.410 g of pyridine sulphan and 4.1 cm3 of dimethylformamide is agitated at 20"C for 88 hours. It is then poured into 200 cm3 of ether, the product is separated, methanol is added, then by agitating, separating 0.470 g of the product obtained above, is put into suspension in 1.87 cm3 of formic acid with 33% of water, heated to 55-60"C for 5 minutes and then to 70"C for 1 3 minutes, a further 1.2 cm3 of formic acid is added and it is then heated again to 70"C for 1 5 minutes.

After cooling to 20"C and filtering, ethanol is added to the filtrate which is then concentrated to dryness. Water and ethanol are added to the residue which is again concentrated to dryness.

The residue is dissolved in water to which 1.6 cm3 of sodium bicarbonate at 10% is added.

After filtering and adding 2N hydrochloric acid to pH 2, evaporating the water. triturating the residue in water, filtering, rinsing with water and then with ether and drying, 0. 140 g of the expected product is obtained. M.Pt. (with decomposition)240 C Analysis: C10H1206N5S2F = 381.36 Calculated: C% 31.50 H% 3.17 N% 18.36 S% 16.81 F% 4.98 Found: 31.6 3.2 18.5 16.5 5.1 Preparation of the hydrochloride of 4-fluoromethyl 3-amino 2-oxo azetidine cis (1) N-methyl N-methoxy fluoroacetamide 27.2 g of fluoroacetyi chloride and 120 cm3 of methylene chloride are mixed together, cooled to + 5"C under inert gas and 50 cm3 of methoxymethylamine is introduced slowly while keeping the temperature below 20to, then the whole is agitated for 2 hours at 20 C. After filtering, expelling the solvent under reduced pressure and distilling the residue under reduced pressure, 30.9 g of the expected product is obtained.

B.PT.-3=93'C (2) fluoroacetaldehyde hydrate 7.8 9 of the product obtained in the previous stage is dissolved in 133 cmi of tetrahydrofuran, cooled to 0- + 2"C, and 74 cm3 of a 1 M solution in hexane of diisobutylaluminium hydride is introduced slowly. After allowing the temperature to return slowly to ambient. pouring into a mixture of 28 cm3 of concentrated hydrochloric acid and 56 cm3 of water while cooling.

agitating and then distilling under atmospheric pressure, 38 cm of the expected product is obtained diluted in water. (B.Pt. 75 to 100.5to) (3) 4-fluoromethyl 3-phthalimido 2-oxo 1-(1-phenyl ethyl azetidine cis.

69 cm3 of the solution as obtained in the previous stage is diluted in 100 cm3 of water. This is cooled in an ice bath for 1 5 minutes then 8.8 cm" of s-phenyl ethylamine DL is added. with agitation for 10 minutes, filtering, rinsing with water, and then 1 30 cm3 of methylene chloride is added to the filtrate. The mixture is heated to reflux until solution is complete, cooled, decanted, the organic phase is dried then cooled under inert gas to - 50C. 15.4 g of phthalimidoacetyl chloride in 60 cm3 of methylene chloride and 10.4 cm3 of triethylamine in methylene chloride are added slowly. The temperature is allowed to return to 20"C with agitation for 1 hour. 25 cm3 of sodium bicarbonate at 10% and 60 cm3 of water are added, then by agitating.

decanting, extracting with methylene chloride, joining up the organic phases and drying them, concentrating them to dryness, and chromatographing the residue on silica, eluting with methylene chloride with 10% of ethyl ether, 1 3.7 9 of the expected product is obtained.

Analysis: C20H ,703N2F = 352.37 Calculated: C% 68.17 H% 4.86 N% 7.95 F% 5.39 Found: 68.2 4.9 7.8 5.6 (4) 4-fluoromethyl 3-phthalimido 2-oxo azetidine, cis, racemic.

1 3.7 9 of the product obtained in the previous stage is dissolved in 200 cm3 of acetonitrile and 1 30 cm3 of water is added. The mixture is taken to reflux, then over 1 5 minutes a solution of 22.2 g of ammonium persulphate in 52 cm3 of water is introduced and the whole is maintained at reflux for 1 hour 25 minutes, it is then cooled, saturated with sodium chloride, decanted, washed with a saturated aqueous solution of sodium chloride, re-extracted with ethyl acetate, the organic phases are joined together and dried and the solvent is evaporated. The residue is chromatographed on silica, eluting with a mixture of methylene chloride and ethyl acetate (75-25), the crystals obtained are rinsed with ethyl ether and 3.756 g of the expected product is obtained.

IR Spectrum (CHCI3) absorptions at 3430cm-1 (-NH) and at 1790, 1770 and 1725 cm-' (C = O ss lactame and phthalimido) (5) 4-fluoromethyl 3-amino 2-oxo azetidine hydrochloride cis.

1.24 9 of the product obtained in the previous stage is put into suspension in 1.2 cm3 of dioxan then 14 cm3 of a solution of 1 cm3 of hydrazine hydrate in 50 cm3 of dioxan is added.

This is maintained for 45 minutes at ambient temperature then 5 cm3 of N hydrochloric acid is added and the whole is maintained under agitation for 1 5 hours. It is then concentrated to dryness, water and 2.3 cm3 of N hydrochloric acid are added, with agitation and then filtered.

Ethanol is added to the filtrate which is then concentrated to dryness. Methanol is added to the residue, then ethanol and again it is concentrated to dryness. The crystals are re-crystallised from methanol.

0.391 9 of the expected product is obtained.

M.Pt. (with decomposition)"220"C Example 4: 4-thiocyanatometh yl 3-f2-(2-amino 4-thiazolyl)-2-methoxyimino acetamido]2-oxo azetidine 1-sulphonic acid, cis, syn, racemic.

Stage A: 4-thiocyanato methyl 3-Z2-(2-tritylamino 4-thiazolyl)2-methoxyimino acetamido]2-oxo azetidine cis, syn, racemic 3.1 9 9 of 2-(2-tritylamino 4-thiazolyl) 2-methoxyimino acetic acid, syn isomer, is put into suspension in 50 cm3 of methylene chloride. Under agitation 1 cm3 of triethylamine and then 1.38 9 of tosyl chloride are added. The whole is maintained under agitation at ambient temperature for 40 minutes then over 5 minutes, a solution of 1.1 62 9 of 4-thiocyanatomethyl 3-amino 2-oxo azetidine hydrochloride cis, in 40 cm3 of methylene chloride and 2 cm3 of triethylamine are added. The mixture is maintained under agitation for 4 hours, washed with water, then with water containing 4 cm3 of N hydrochloric acid, dried and concentrated to dryness. The residue is dissolved in ethyl acetate, cooled, the crystals formed are separated, washed with methanol, dried and 0.709 9 of the expected product is obtained. The mother liquors are evaporated to dryness, the residue is chromatographed on silica, eluting with a mixture of chloroform and methanol (93-7) and the further 1.069 g of the expected product is obtained.

Stage B: 4-thiocyanatomethyl 3-[2-(2-amino 4-thiazolyl)2-methoxyimino acetamidoj2-oxo azetidine 1-sulphonic acid, cis, syn, racemic.

(a) Obtaining pyridinium sulphamate At 20"C, a mixture of 1.7 9 of the product obtained at Stage A, 12 cm3 of dimethylformamide and 1.1 6 9 of pyridine sulphan is agitated for 90 hours. It is then poured into ether under agitation, the precipitate formed is taken up with methanol, cooled, then the crystals are separated. 0.544 9 of the expected product is obtained in 2 lots.

(b) De-tritylation 4 cm3 of formic acid with 33% of water is heated to 60"C then 0.42 g of the product obtained above is added and the whole is agitated at 60"C for 20 minutes. After cooling to 20 C, 40 cm3 of ethyl ether is added with agitation for 1 hour at 0- + 5 C. The precipitate is separated, rinsed with ethyl ether and triturated with a 0. 1 N aqueous solution of sodium bicarbonate. After filtering, the filtrate is acidified to pH 2 by N hydrochloric acid, cooled and the crystals formed are separated. These are washed with water, dried and 0.237 9 of the expected product is obtained. M.Pt. (with decomposition) = 265"C.

Analysis: C"N,;,N,;Ot;S3 (420.54) Calculated: C% 31.42 14% 2.88 N% 19.99 S% 22.88 Found: 31.2 3.2 19.7 22.6 Preparation of 4-thiocyanatomethyl 3-amino 2-oxo azetidine hydrochloride, cis.

(1) 4-iodomethyl 3-phthalimido 2-oxo azetidine, cis, racemic.

26.5 9 of 4-chloromethyl 3-phthalimido 2-oxo azetidine, cis, 30 9 of sodium iodide and 80 cm3 of dimethylformamide are mixed together, taken to 1 20'C for 2 hours then cooled and poured into a mixture of 800cm of water and 100 cm3 of ethyl acetate under agitation. The crystals formed are filtered, rinsed with water then with ethyl acetate until colourless and finally with ethyl ether. The mother liquors are taken up, decanted, the organic phase is dried, concentrated to dryness, taken up with ethyl acetate, filtered, rinsed with ethyl acetate and dried. In this way 28.4 g of the expected product is obtained in two lots.

(2) 4-thiocyanato methyl 3-phthalimido 2-oxo azetidine, cis, racem,c.

Under agitation a mixture of 1.78 g of the product obtained above in 5 cm3 of dimethylformamide is taken to 75"C then 1.5 g of potassium thiocyanate is added with agitation for 3 hours 30 minutes. After pouring into water, the precipitate is separated, washed with water and dried. It is then triturated hot in isopropyl ether, separated and dried. 1.25 g of the expected product is obtained.

(3) 4-thiocyanato methyl 3-amino 2-oxo azetidine hydrochloride, cis.

1.45 g of the product obtained at the previous stage is mixed in 1 5 cm3 of hot dioxan, cooled, then 0.3 cm3 of hydrazine hydrate is added slowly with agitation at 20"C for 50 minutes. Then 7.5 cm3 of N hydrochloric acid is added, the whole is maintained for 15 hours under agitation, the precipitate is separated, and rinsed with water; the filtrate is taken up and evaporated to dryness. 0.9149 of the expected product is obtained.

Example 5: 3-phthalimido 4-chloromethyl 2-oxo azetidine, cis, optically active.

Stage A: N-(i-phenyl)ethyl 3-phthalimido 4-chloromethyl 2-oxo azetidine, cis, optically active 2.5 cm3 of chlotoacetaldehyde hydrate at 50% in water is dissolved in 50 cm3 of water. The solution is agitated and 2.55 cm3 of (+) (1-phenyl)ethylamine is added at 0- + 5"C. After agitating for 6 minutes the precipitate is separated and rinsed with water. The precipitate is taken up by a mixture of methylene chloride and chloroform and dried. The solution is cooled under inert gas at - 50'C, then 4.5 g of phthalimido acetic acid chloride in 25 cm3 of methylene chloride and 2.74 cm3 of triethylamine in 20 cm3 of methylene chloride are added slowly and simultaneously. After allowing the temperature to rise and maintaining under agitation for 2 hours 30 minutes, pouring into a mixture of water and sodium bicarbonate, extracting with chloroform, drying, and evaporating the solvent the residue is taken up with ethanol. The insolublessmaterial is filtered and washed with a mixture of ethanol and methylene chloride. The filtrate is taken up, treated with activated charcoal, concentrated and allowed to crystallise. There is obtained, in two lots, 1.364 g of crystals. The mother liquors are taken up and chromatographed on silica, eluting with a mixture of chloroform and ethyl acetate (8-2).

1.58 g of crystals is obtained, making a total of 2.944 g of the expected product, constituted by a single diastereoisomer.

Stage B: 3-phthalimido 4-chloromethyl 2-oxo azetidine, cis. optically active.

0.3 g of the product obtained at Stage A is mixed in 2 cm3 of acetonitrile and taken to 90-95"C under agitation. A solution of 0.502 g of ammonium persulphate in 2 cm3 of water is added slowly with agitation for 1 hour 45 minutes, then by pouring into water, extracting with ethyl acetate, washing the organic phase with an aqueous solution of sodium thiosulphate, drying and evaporating the solvent, 0.058 g of the expected product is obtained.

= = + 10.5" + 1 (CHCl3) M.Pt = 172"C By continuing the synthesis as described, for example, in Example 1, 2 or 3, an optically active product corresponding to formula (I) is obtained.

Claims (14)

1. A product with the formula (all):

racemic or optically active, in which A represents a hydrogen atom or a sulpho radical; the wavy line indicates that the product is in its cis or trans form or in the form of a cis-trans mixture; and R, represents a group R, or a group R, whose reactive functions are protected; where R, represents a radical -(CH2)n-X; in which n represents an integer from 1 to 4; and X represents a halogen atom; a cyano radical; a radical O-R'1 in which R', represents a hydrogen atom or an alkyl radical; or X represents a radical S-R", in which R", represents a hydrogen atom, an alkyl radical or a heterocyclic radical; or X represents a radical

in which R' and R" are the same or different and each represents a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, or R' and R" together with the nitrogen atom to which they are attached form a heterocyclic radical; or X represents an azido, a thiocyanato or an isothiocyanato radical; with the proviso that when A represents a hydrogen atom, R, cannot represent a methylthio, hydroxymethyl, azidomethyl, aminomethyl or alkoxymethyl radical.

2. A product with the formula (all'):

racemic or optically active, in the cis form, in which n' represents the integer 1 or 2; and X' represents a fluorine atom, a 2-pyridinylthiomethyl radical or a thiocyanato radical.

3. A product according to claim 2 wherein n' represents the number 1 and X' represents a fluorine atom.

4. A product according to any one of the preceding claims substantially as described herein.

5. A product according to any one of claims 1-3 which is specifically named herein.

6. 4-Chloromethyl 3-amino 2-oxo azetidine hydrochloride.

7. 4-(1-methyl 5-mercapto 1 ,2,3,4-tetrazol)methyl 3-amino 2-oxo azetidine hydrochloride.

8. 4-Fluoromethyl 3-amino 2-oxo azetidine hydrochloride cis.

9. 4-Thiocyanatomethyl 3-amino 2-oxo azetidine hydrochloride cis.

1 0. A process for preparing a product claimed in claim 1, which process comprises reacting an imine of formula (V):

in which Ra is as defined in claim 1 and P represents a protective group for the imino radical, with a protected amine of formula (VI):

in which one of R',, and R"p represents a hydrogen atom and the other a protective group for the amino radical, or R'p and R"p together represent a divalent protective group, and B represents a hydroxyl radical or a halogen, so as to produce an amine of formula (VII):

in which Ra, Pp, R'p and R"p are as defined above, which amine of formula (VII) is submitted to the following reactions: (a) separation by hydrolysis, hydrogenolysis or the action of thiourea of the radical Rp; (b) optional sulphonation of the amine in position 1; (c) separation by hydrolysis, hydrogenolysis or the action of thiourea of the protective radicals R'p and R"p; and (d) optional resolution of the molecule so as to obtain an optically active product.

11. A process according to claim 10 wherein in formula (V) Rp represents a protective group for the imino radical including an asymmetric carbon atom and an amine of formula (VII) is isolated in optically active form.

1 2. A process for preparing a product claimed in claim 1 which is of formula (I Ia):

in which A, n and the wavy line are as defined in claim 1, and X" represents X, X being as defined in claim 1 with the exception of a halogen atom, or X" represents X in which a reactive function is protected, which process comprises reacting a halide of formula (VIII):

in which Rlq and R", each represent a hydrogen atom or have the significance of R'" and R"p as defined in claim 10, with a reactive derivative of the cyano radical, of the radical -OR'1, -SR"1,

-SCN or -NCS, where R't and R", are as defined in claim 1, so as to produce a product of formula (IX):

in which X", A, R', and P", are as defined above, which product if desired is submitted to any one or more of the following reactions: (a) separation by hydrolysis, hydrogenolysis or by the action of thiourea of the groups represented by Rlq and R", when these are different from a hydrogen atom, (b) sulphonation of the product in which A represents a hydrogen atom, and (c) resolution of the molecule so as to obtain an optically active product.

1 3. A process for preparing a product claimed in any one of claims 1-9, which process is performed substantially as described herein.

14. A process for preparing a product claimed in any one of claims 1-9, which process is performed substantially as described herein in any one of the Examples.