CA1201439A - Process for preparing new 3-amino 2-oxo azetidine 1-sulfamic acid derivatives - Google Patents

Abstract

The present invention relates to a process for preparing products of general formula (I): <IMG> (I) where R is hydrogen, alkyl, alkenyl or alkynyl optionally substituted, R1 represents - (CH2) nX where n is an integer of 1 to 4 and X is halogen, cyano, O-R'1, R'1 being hydrogen or alkyl, or X is SR "1 'R" 1 being hydrogen, alkyl or heterocycle, or X is <IMG>, where R' and R "are hydrogen or alkyl or form with nitrogen a heterocycle, or X is azido, thiocyanato or isothiocyanato, as well as their pharmaceutically acceptable salts, the products of formula I being in the cis or trans form or of mixture, racemic or optically active and the oxime being syn. The compounds of formula (I) and their pharmaceutically acceptable salts are useful as active medicaments in particular on gram (-) bacteria.

Description

43 ~

The subject of the present invention is a method to prepare products of general formula (I):

I

~
SN

/ ~ (I) \ OR SO3H

in which R represents a hydrogen atom or a raclical alkyl, alkenyle or alkynyle, linear or branched, having at most 12 carbon atoms, possibly substituted kills, Rl represents a radical - (CH2) nX in which n represents an integer from 1 to 4 and X represents a halogen atom, a cyano radical, an O-R'l radical in the ~ uel R '~ represents a hydrogen atom or a radical alkyl, or X represents a radical SR "l in which R"
represents a hydro atom ~ an alkyl radical or a heterocycle or X represents a radical -N / R '~ in which R 'and R "represent a hydrogen atom or a radical alkyl having 1 to 4 carbon atoms, or R 'and R "
form with the nitrogen atom to which they are linked, a heter rocycle or X represents an azido, thiocyanato or isothiocyanato, thus ~ ue the salts of the products of formula (I) with bases or acids, the line undulates meaning that the products may be in the cis form or trans or as a cis-trans mixture, the products of formula I being in racemic or optically active form ve, the oxime being in the syn form.
Among the values of R we can cite:
a) The methyl, ethyl, propyl, isopropyl, butyl radicals i.

: 1 2 () 1 ~ 3 ~

sec-butyl, tert-butyl, pentyl, iso-pentyl, sec-pentyl, tert-pentyle, neo-pentyle, hexyle, iso hexyle, sec-hexyle, tert-hexyl, heptyle, octyl, decyle, undecyle, dodecyle;
b) The vinyl, allyl ~, l-propenyl, butenyl, pentene radicals nyle, hexenyl;
c) ethynyl, propargyl, butynyl radicals;
The radicals indicated above in paragraphs a) to c) may themselves be substituted by one or more radicals such as optionally salified carboxy radicals or esterifies, alkoxycarbonyl such as methoxycarbonyl, ethoxy-carbonyl, carbamoyl, dimethyl-carbamoyl, amino, di-alky-lamino tel ~ eu dimethylamino, diethylamino, alkylamino tel ~ EU methylamino, halogen such as chlorine, bromine, iodine, fluorine, alkoxy such as methoxy, ethoxy, propyloxy, alkylthio tel ~ eu methylthio, ethylthio, aryl such as phenyl, or heterocyl aryl cli ~ eu such ~ eu tetrazolyl, pyridinyl, arylthio such ~ eu phenyl-optionally substituted thio, heterocyclic-thio aryl such as tetrazolylthio, thiadiazolylthio optionally substituted with an alkyl such as methyl.
Among the values of R we can cite more part culiere-the values hydrogen, methyl, carboxy ethyle possible-slightly esterified or soiled, l-carboxy l-methyl ethyl if necessary-slightly esterified or salified, 2-amino ethyl, difluoromethyl.
Among the values of Rl we can cite more party ~
especially the ch] .oromethyl, chloroethyl, chloro-propyl, l-chloro-l-methyl ethyl, chlorobutyleO
Mention may also be made of brominated, iodinated radicals, or corresponding fluorescent, in particular bromomethyl and fluoromethyl. We can also cite cyanomethyl, cyanoethyl and the corresponding alkyl radicals.
Among the values of R'l we can cite the radicals preferably alkyl having 1 to 4 carbon atoms mentioned above in a), in particular the methyl radical.
Among the values of R "l we can also cite 12 ~ 3 ~

alkyl radicals, preferably having from 1 to 4 atoms carbon in particular methyl.
Among the heterocycles that R "l can represent, mention may be made of the pyridyl radicals, 1,2,3-1,2,5-1,2,4 or 1,3,4-thiadiazolyle; 1H tetrazolyl, 1,3-thiazolyl, 1,2,3-1,2, ~ or 1,3,4-triazolyle; 1,2,3-1 ~ 2,4 or 1,2,5 or 1,3, ~
oxadi.azolyle, these radicals being unsubstituted or substituted by one or more radicals chosen from the Eormé group for example by methyl, ethyl propyl, isopropyl, methoxy, ethoxy, propyloxy, isopropyloxy, amino, hydroxy-carbonylmethyl, dimethylaminoethyl and diethylaminoethyl.
Mention may be made more particularly of the radicals l-methyl tetrazolyle, 2-methyl 1,3,4-thiadiazolyle, 3-methyl 1,2, ~ -thiadiazolyle, 3-methoxy 1,2,4-thiadiazolyle, 1,3, ~ -thiadiazoyl-5-yle and more especially the l-methyl radical tetrazolyl.
/ R ' The radical -N can represent in particular a "
amino, dimethylamino, methylamino, ethyamino, diethyl- radical amino, piperidino, morpholino.
The sulfo group in position 1 as well as the carboxy group which the radical R may contain may be salified.
Among the salts which can be prepared are:
cite the sodium, potassium, lithium, calcium salts, magnesium, ammonium. Mention may also be made of the salts of organic base such as ~ trimethylamine, diethy] amine, triethylamine methylamine, propylamine, N, N-dimethyl-ethanolamine, tris (hydroxymethyl ~ aminomethane, ethanol-amine, pyridine, picoline, dicyclohexyl-amine, N ', N'-dibenzylethylenediamine, morpholine, benzylamine, procalne, lysine, arginine, histidine, N-methyl glucamine.

12q ~ 39 Products of formula I can be presented in the form of salts of organic or mineral acids since these products contain at least one salifiable amino radical.
Among the acids with which we can sali ~ ier the amino groups of the products of formula I, it is possible mention among others, acetic and trifluoroacetic acids, malelque, tartaric, methanesulfonic, benzenesulfonic, p-toluenesulfonic, hydrochloric, hydrobromic, sulfuric, phosphoric. Formula I products can also be in the form of internal salts.
The preferred products are cis products.
The invention more particularly relates to a process for preparing products of general formula (I'j:
NH

NOT
~ CONH ~ r ~ CH2) n X

\ OR2 ~ N (I ') isomers ~ y ~, in cis form, in which R2 represents a hydrogen atom or a linear or branched alkyl radical optionally substituted by one or more halo atoms gene, a carboxyl, amino or cyano radical, does not represent the integer 1 or 2 and X 'represents a fluorine atom, a 2-pyridinylthiomethyl radical or a thiocyanato radical, in racemic or optically active form, as well as salts of products of formula (I ') with bases or acids.
The invention also more particularly for subject a process for preparing the products of general formula (I '), as defined above, in which n represents the number 1 and X 'represents a dluor atom, as well as ~ 20 ~ 439 those in which R2 represents a hydrogen atom or a methyl, difluoromethyl, carboxymethyl radical optionally-slightly salified or esterified, an aminoethyl, cyano-methyl, l-methy]. l-carboxyethyl, optionally salified or esterifies.
A more particular subject of the invention is a process for preparing the products described below in examples and especially 4-fluoromethyl acid 3- ~ 2-(2-amino 4-thiazolyl) 2-methoxyimino acetamido ~ 2-oxo azé
tidine l - sulfamic cis, syn isomer, racemic or opti-only active and its salts, as well as 4-fluoromethyl acid 3- ~ 2- (2-amino 4-thiazolyl) 2-difluoromethoxyimino acetamido ~

2-oxo azetidine 1-sulfamic cis, syn-isomer, racemic or optically active and its salts.
It is understood that the products of formula I
above can be presented either in the form indicated by said formula I, either in the form imine tautomer Iz: H;
NOT
. ~ \
S NH
~ ~ ~ CONH ~ Rl (Iæ) OR \ S03H

The lactam nucleus is numbered as follows 0 ~ 2 ~

) 143 ~

The products called cis are the 5 products of formula :
4 ~ ~ l o // \ SO3H

Trans products are formula products:
, Rl ~ - --r . ~, SO3H

The process for preparing the formula products (I), object of the invention, is characterized in that one processes a product of formula ~

H2N \ a f (II) .NOT
0 ~ \ ~
racemic or optically active, formula in which either ~ 5 Ra represents Rl, Rl having the meaning indicated above above, that is Ra represents Rl in which the functions active are protected and A represents a hydrogen atom or a sulfo radical, by a product of formula III

NIHRb SN
~ ~ (III) NOT

OR'b iZ ~ 39 in which Rb represents a hydrogen atom or a protective group of the amino radical and R'b represents a protecting group for the hydroxyl radical or R'b represents R, R having the meaning indicated above, where R'b represents a radical R in which the reactive functions are protected to obtain a product of ormule IV:

N ~ IRb ~ N
\ = / ~ CONH JJRa (IV) OR'b racemic or optically active, in which Rb, R'b, Ra and A have the previous significance, product that we submit if necessary, and 5i desired, to any one or more of the following reactions, in any order:
a) cutting by hydrolysis, hydrogenolysis or by action of the thiou.ree of the protective group (s) that may represent feel Rb and R'b or include R'b and Ra;
b) esterification or salification of the carboxy radical that may contain the radical R'b and salification of the radical sulfo;
c) salification with an acid of the amino radical (s);
d) sulfamation of products in which the radical A
represents a hydrogen atom;
e) splitting of the molecule to obtain an opti-only active.
In the formula III Ra can represent general.
lie the radical Rl. However in cases where Rl represents a - (CH2) nX in which X represents in particular a radical hydroxyl or amino, it may be advantageous to protect these lZ (~ 39 radicals by removable protective groups.
Protective groups for the amino radical can be for example the alkyl radicals, preferably tert-butyl or tert-amyl, they can also be understood among the acyl, aliphatic, aromatic or heterocyclics and the carbamoyl group.
Mention may also be made of alkanoyl groups lower such as for example formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, suc-cinyle, pivaloyl. R 'can also represent a group lower alkoxy or cycloalkoxycarbonyl such as for example, methoxycarbonyle, ethoxycarbonyle, propoxycarbonyle, l-cyclo-propylethoxycarbonyle, isopropyloxycarbonyle, butyloxycarbonyle, tert-butyloxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, a benzoyl, toluolyl, naphthoyl, phthaloyl, mesyl group, phenylacetyle, phenylpropionyle, an aralkoxycarbonyl group, such as benzyloxycarbonyl.
The acyl groups pe ~ ivent be substituted by example by a chlorine, bromine, ~ 'iodine or fluorine. We can cite ra ~ icaux chloroacétyle, dichloro-acetyl, trichloroacetyl, bromoacetyl or trifluoroacetyl.
It is also possible to use an aralkyl group lower such as benzyl, 4-methoxybenzyl or phenylethyl, trityl, 3,4-di-methoxybenzyl or diphenylmethyl.
It is also possible to use a haloalkyl group such as trichloroethyl.
It is also possible to use a chloro-benzoyl, para-nitrobenzoyl, para-tert-butylbenzoyle, phe-noxyacetyle, caprylyl, n-decanoyl, acryloyl, trichloro-ethoxycarbonyl.
One can also use a methyl-carbamoyl, phenylcarbamoyl, naphthylcarbamoyl, as well as the corresponding thiocarbamoyles.
The above list is not exhaustive, it is - \

~ 2 ~

evident that other protective groups of the amines, groups known in particular in peptide chemistry, can also be used.
The hydroxyl radical protection group can be chosen from the list below.
It can be an acyl group such as for example formyl, acetyl, chloroacetyl, bromoacetyl, dichloro-acetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, benzoylformyl, p-nitrobenzoyl.
Mention may also be made of ethoxycarbonyl groups, methoxycarbonyl, propoxycarbonyl, ~ trichloroethoxycar-bonyle, benzyloxycarbonyle, tert-butoxycarbonyle, l-cyclo-propylethoxycarbonyl, tetrahydropyrannyl, tetrahydro-thiopyrannyl, methoxytetrahydropyrannyl, trityl, benzyl, ~ -methoxybenzyl, diphenylmethyl, trichloroethyl, l-methyl l-methoxyethyl, phthaloyl.
We can also cite other acyls such as propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl and pivaloyl.
Mention may also be made of phenylacetyl radicals, phenylpropionyl, mesyl, chlorobenzoyl, paranitrobenzoyl, paratertbutylbenzoyle, caprylyl, acryloyl, methylcarbamoyl, phenylcarmaboyl naphthylcarbamoyl.
Of course the values of the R- substituents when this does not represent a hydrogen atom, as well as the values of the protective groups that can possibly represent or include R'b, in particular when R'b contains an amine, can be taken in the lists mentioned above.
In a preferential mode of execution of the procedure, the product of formula (II) is treated with a functional derivative of a product of formula (III). This functional derivative can be for example a halo ~ enure, a symmetrical anhydride or mixed, an amide or an activated ester.

-

3 ~

As an example of mixed anhydride, there may be mentioned for example that formed with isobutyl chloroformate and that formed with pivaloyl chloride and anhy-drides mixed carboxylic-sulfonic forms for example a ~ ec paratoluanesulfonyl cllloride. For example active ester, we can mention the Form ester with the 2,4-dinitrophenol and that formed with hydroxyb ~ nzothiazole.
As an example of a halide, mention may be made of chloride or bromide.
Mention may also be made of the acid azide or the amide acid.
Anhydride can be formed in situ by action of NN'-disukstitued carbodiimide, for example N, N-dicyclo-hexylcarbodiimide.
The acylation reaction is carried out first.
in an organic solvent such as methylene chloride.
One can however use other children such as tetrahydrofuran, chloroform or dimethylformamide.
I. When using an acid halide and generally when a hydrohalic acid molecule is released during the reaction, we perform the reaction preferably in the presence of a base such as soda, potash, sodium carbonates and acid carbonates or potassium,]. 'sodium acetate, triethylamine, pyridine, morpholine or N-methylmorpholine.
The reaction temperature is generally lower or equal to room temperature.
~ when Rb represents a hydrogen atom, we preferably uses a mixed carboxylic anhydride-sulfonic.
Depending on the values of Rb, R'b and Ra ~ the products of formula (IV) may or may not constitute products of formula (I).
The products of formula IV) constitute products 39 ~

of formula (I) when Rb represents a hydrogen atom, when R'b does not represent a protective group of the hydroxyl radical or does not represent a radi.cal R
with a protected function, finally when Ra does not does not have a radical R1 in which a reactive function is protected and that A does not represent a hydrogen atom.
In other cases, the action on the product of Formula (IV) of one or more hydrolysis agents, hydro-genolysis or thiourea aims to eliminate the radical Rb when the latter represents a protective radical of the dical amino, to eliminate the radical R'b when the latter represents a group protecting the hydroxyl radical and to eliminate other protective groups that can-wind include the radicals Ra and R'b.
The nature of the reagents to be brought into play in all these cases are well known to those skilled in the art. Examples such reactions are given later in the section experimental.
A non-exhaustive list is given below means that can be used to eliminate different groupings.
Elimination of the Rb group can be carried out by hydrolysis, this being acidic, basic or using hydrazine.
We preferentially use acid hydrolysis to remove the alkoxy and cycloalkoxycarbonyl groups, optionally substituted, such as tert-pentyloxycarbonyl or tert-butyloxycarbonyl, aralkoxycarbonyl groups possibly substituted such as benzyloxycarbonyl, trityl, diphenylmethyl, tert-butyl or 4-methoxybenzyle.
The acid which is preferably used can be chosen from the group consisting of hydrochloric acids, benzenesulfonic or paratoluene sulfonic, formic or ~ 2 ~ 439 trifluoroacetic. We can however use other mineral or organic acids.
Basic hydrolysis is used preferentially-to eliminate acyl groups such as trifluoro-acetyl.
The base we use pre ~ erence is a mineral base such as sodium hydroxide or potassium hydroxide sium. You can also use magnesia, barite or an alkali metal carbonate or acid carbonate such as sodium or potassium carbonates and acid carbonates-sium or other bases.
You can also use sodium acetate or potassium.
Hydrolysis using hydrazine is used preferably to remove groups such as phthaloyl.
The Rb group can also be eliminated by the zinc-acetic acid system ~ eu (for the trichloro- group ethyl), diphenylmethyl, benzyloxycarbonyl groups are preferably eliminated by hydrogen in the presence of a catalyst.
The chloroacetyl group is eliminated by action thiourea in neutral or acid medium depending on the type of reaction described by MASAKI JACS, 90, ~ 508 (1968).
We can also use other methods of deprotection known in the literature, for example the oxidative break, especially for the benzyl group.
Among the preferred groups, mention may be made of formyl, acetyl, ethoxycarbonyl, mesyl groups, trifluoroacetyl, chloroacetyl, trityl. We prefer in particular the trityl and chloroacetyl radicals.
The acid that is preferably used is the acid trifluoroacetic or formic acid.
Elimination of the radical R'b or of the groups protectors that include R'b or Ra ~ when it is 3L2 ~

necessary, is carried out under conditions similar to those described above for the elimination of ~ b Among others, acid hydrolysis can be used to remove any alkyl or aralkyl radicals substitutes ~
We preferentially use an acid chosen from the group formed by hydrochloric acids, formic, trifluoroacetic and sulfonic paratoluene.
The other values of the radicals Rb or R'b or protective groups which comprise R'b or ~ a are, when ~ ue this is desired, eliminated according to known methods of the man of the trade. It is preferable to operate in con moderate editions, i.e., at room temperature or slightly warm.
Naturally, one can when for example Rb or R'b or Ra are or include eliminable groups belonging to different types, act on the products (IV) several agents envisaged in the lists previous rations.
Products can be salified according to the usual methods.
Salification can, for example, be obtained by action on a product in acid form or on a solvate, for example the ethanolic solvate, or a hydrate of this acid, a mineral base such as sodium hydroxide or potassium, carbonate or sodium acid carbonate or potassium. You can also use acid salts minerals such as trisodium phosphate. We can also-use organic acid salts.
A list of such acid salts can be found.
organic for example in the French patent ~ F 2,476,087.
Preferably used as sodium salts, sodium acetate, sodium 2-ethyl hexanoate or die-thyl sodium acetate ~

126) ~

Salification can also be obtained by action of an organic base or an amino acid.
The possible esterification of the products in which R has an acid function is also effective killed under classic conditions.
Sul ~ amatation of products of formula IV
in which ~ represents a hydrogen atom is carried out using sulfuric anhydride or a reactive derivative of this anhydride.
The pyridine complex is preferably used sulfuric anhydride but one can also use other sulfuric anhydride complexes with dioxane or trimethyl-amine, The reaction is carried out in a usual solvent such as ethyl acetate, chloroform or dimeth ~ l-formamide. We can operate at room temperature. When we you can use the pyridine-sulfuric anhydride complex.
isolate the products in the form of pyridinium salts.
The possible duplication of racemic molecules of formula II or IV can be carried out according to the methods usual.
Carbo organic acid can be used or optically active sulfonic like tartaric acids, tartaric, camphor sulfonic or glutamic dibenzoyl, the decomposition of the salt thus obtained being effected by means a mineral base such as sodium bicarbonate or an organic base such as a tertiary amine, for example for example triethylamine.
The present invention especially relates to a 3n process as described above, characterized in that we use, by its implementation, a product of formula II in which A represents a hydrogen atom and a product of formula III in which Rb represents a protective group of the amino radical and in that the ~ 14 -12 ~ 43 ~

sulfamation is carried out on a product of formula IV
in which Rb represents a protective grouping of the amino radical.
The protective group represented by Rb is 5- preferably the trityl radical.
The sulfamation is carried out pre ~ erence with the pyridine-sulfuric anhydride complex.
The present invention also relates to a process for the preparation of products of formula IIj character-rise in that we act a product of ~ ormule V
at \ C ~
N (V) Rp in which Ra has the meaning indicated above and Rp represents a protecting group for the imino radical, with a product of Eormule VI:
R'p N-CH2COB (VI) R "
p in which R'p and R "p represent one, a hydro-gene and the other a protective group of the amino radical, where R'p and R "p together represent a protective group divalent and B represents a hydroxyl or halogen radical, to obtain a product of ~ ormule VII:
R ' / N \ 3 ~ sJRa R "
P ¦ (VII) ~ N ~ \

lZC) 14 ~ 3 ~

in which Ra, Rp, R'p and R "p have the above meaning tooth, product of formula VII which is subjected to the reactions following:
a) Cutting by hydrolysis, hydrogenolysis or action of the thiourea of the radical Rp;
b) Possible sulfamation of the amine in position l;
c) Cut by hydrolysis, hydrogenolysis or action of thiourea of the radicals R 'and R ";
PP
d) ~ possible doubling of the molecule to obtain a optically active product.
The protective group Rp can be chosen in the list of substituents previously stated for the amines.
For reasons explained below, we prefer nevertheless use a benzyl radical or 2, ~ -dimethoxy benzyl or equivalent: equivalent.
In addition, the protective group Rp may contain an asymmetric carbon atom and the inv ~ ntion has thus in particular the subject of a process as previously defined;
characterized in that a pro duit of formula (V) in which Rp represents a protecting group for the imino radical comprising an asymmetric group sticks and isolates a product of formula (VII) in the form optically active.
These optically active foxmule (VII) products ~ 5 lead to the products of formula (I) optically active according to the method described above.
As a pxotective group, mention may be made in particular the l-phenyl ethyl group.
An example of preparation of a product of formula (VII) optically active is provided below in the section experimental.
The radicals R'p and ~ "p can be chosen from the same list of protective radicals stated above. We prefer to use the phthaloyl radical.

3 ~

Group B can represent a halogen atom.
The acid chloride is preferred.
When B represents a halogen atom, the action of product V on product VI is carried out in the presence of a base such as triethylamine or a metal such as zinc.
When B represents a hydroxyl radical ~ on operates in the presence of a dehydrating agent such as anhydride, preferably trifluoroacetic anhydride.
~ 'action of products of formula V with products of formula VI preferentially gives the products cis. Trans products are obtained by isomerization in basic environment.
The first deprotection reaction aims, when you want to perform sulfamation of products resulting, the selective unblocking of the radical Rp.
It is therefore preferably used, as indicated below.
above, a benæyl or di-methoxy benzyl radical which is unblocks using, preferably an oxidant such as potassium peroxodisulfate.
It is preferably carried out in a tal solvent which the water-acetic acid or acetonitrile mixture.
Possible sulfamation of products including the secondary amine in position 1 is free is carried out as shown above.
The possible second unlocking operation has intended to release the amine in position 3 by elimination of the radicals R'p and R "p. When, as indicated above, we operate with a phthalimido radical, elimination is carried out, as indicated above, by hydrazine from preferably a hydrazine hydrate in a solvent such as dimethylformamide.
Of course, especially in the case where ~
the sulfamation of the products of formula is not carried out ~ a ~ 3 ~

IV, the radicals Rp, R'p and Rl'p can be eliminated simultaneously.
The duplication is as indicated above, carried out in the usual manner.
According to the present invention, it is also possible prepare products of formula (IIa):

H2N ~, ~. (C ~ 12) nX "
.
(IIa) _ NOT
O '\ A

in which A has the meaning indicated above, n represents an integer from 1 to 4 and X "represents X, X having the meaning indicated above, except of a halogen atom, let X "represent X in which a reactive function is protected by a process by which a product of formula VIII is treated:
R ' R "/ ~ ~ (C ~ l2) nHal q ¦ ¦ (VIII) I

~ \ A

in which R'q and Rllq each represent a hydro-gene or have the meaning of R'p and R "p indicated above, by a reactive derivative of the cyano radical, of the radical -OR'l -SR "
.R ' -N, -SCN or -NCS to obtain a product of formula IX:
\ R "

43 ~

R ' ~ '2) n q (IX) NOT

in which X ", A, R'q and Rl'q have the indicated values previously, product that is submitted if necessary and if desired, to any one or more of the reactions following:
a) Cleavage by hydrolysis, hydrogenolysis or by the action of the thiourea of the groups represented by Rlq and Rllq when these are different from a hydrogen atom;
b) Sulfamation of products in which the radical A
represents a hydrogen atom;
c) Doubling of the molecule to obtain an opti-quernent active.
The action, on the product of formula VIII, of reacted derivatives of the radicals which it is desired to substitute has the halogen atom is carried out under the conditions usual.
The exchange between the halogen atom and a mercapta for example is preferably made using a salt of alkali metal of this mercaptan such as the sodium salt.
The exchange between the halogen atom and an acetate alkali metal such as sodium or potassium acetate allows the introduction of a protected hydroxyl radical which is can release and then etherify if desired.
The action of an amine, possibly protected by one of the radicals indicated above, allows to introduce / R ' a radical -N \ possibly protected.
R "

~ Z ~ L4 ~ 39 We can act on an alkali metal azide, preferably sodium azide, lice introduce the radical azido. You can also act on a cyanide or a thio-alkali metal cyanate to obtain the products in which X represents these radicals or an isothiocyanate.
Subsequent deprotection operations, sulfamation and also possible splitting are carried out as indicated above.
The invention particularly ob ~ and a method of preparation of products of formula (I) as defined above above, characterized in that Ra represents a radical fluoromethyl.
The products of Eormule ~ general tI) have very good antibiotic activity on bacteria gram (-), especially on coliform bacteria, the] cleb-siella, salmonella and proteus.
The products of formula 5I) as defined above above, as well as their pharmaceutically acceptable salts can therefore be used as medicaments and in particular antibiotic drugs.
These products can in particular be used as drugs to treat colibacillosis and infection associated conditions, in proteus infections, with klebsiella and salmonella and other conditions caused by bacteria at ~ .ram (-).
Among the drugs according to the invention, we retain in particular the products of general formula (I '):

~
SN
CONH ~ l / 2 n R2 \ SO3H

~ Z6) ~ 9 ~ 39 syn isomer, in cls form, in which R2 represents a hydrogen atom or a linear or branched alkyl radical fié optionally substituted by one or more atoms halogen, a carboxyl, amino or cyano radical, does not represent smells the whole number 1 or 2 and Xl represents a defluor atom, a 2-pyridinylthiomethyl radical or a radical thiocyanato, in racemic or optically active form, as well as the salts of the products of Eormule (I ') with the pharmaceutically acceptable bases or acids.
Among the drugs according to the invention, we retain still the products of formula (I ') as defined above above, in which n 'represents the number 1 and X' represents smells of a fluorine atom, as well as their salts with bases or pharmaceutically acceptable acids, and the pro-duits of formula (I ') as defined above, in which R2 represents a hydrogen atom or a radical methyl, difluoromethyl, optionally carboxymethyl salified or esterified, an aminoethyl, cyanomethyl radical, l-methyl l-carboxyethyl possibly soiled ~ ié or estéri-fié, as well as their salts with bases or pharmaceutically acceptable acids.
Among the drugs according to the invention, we retain finally the products described in the examples and especially 4-fluoromethyl 3-L2- (2-amino 4-thiazolyl) 2-methoxy- acid iminoacetamidQ / 2-oxo azetidine l-sulfamic cls, isomer syn, racemic or optically active and its pharmaceu-tically acceptable as well as 4-fluoromethyl acid 3- ~ 2-(2-amino 4-thiazolyl) 2-difluoromethoxyiminoacetamido ~
2-oxo azetidine l-SIllfamic cis, syn isomer, racemic or optically active and its pharmaceutically acceptable salts.
The products of general formula (I?, As well as their addition salts with bases and pharmaceutical acids ceutically acceptable can therefore be used to prepare pharmaceutical co ~ positions containing them, ~ 21 -~ 2 ~ 3 ~

as an active ingredient.
These compositions can be administered by buccal, rectal, parenteral or locally topical application to the skin and mucous membranes.
In particular, general formula products (I) in which A represents a cleavable ester such that propionyloxymethyl ester, can be administered orally.
They can be solid or liquid and present in pharmaceutical forms commonly used in human medicine such as, for example, premiums, simple or coated, capsules, granules, suppositories ~ injectable preparations, ointments, creams, gels; they are prepared according to the usual methods. The active ingredient (s) can be incorporated into the excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, stearate magnesium, cocoa butter, aqueous vehicles or not, fatty substances of animal or vegetable origin, derivatives paraffinics, glycols, various wetting agents, dispersants or emulsifiers, preservatives.
These compositions can, in particular, be presented in the form of a powder intended to be dissolved extemporane-in a suitable vehicle, for example sterile water non-pyrogenic.
The dose administered is variable depending on the condition treated, the subject in question, the route of administration and the product considered. It can be, for example, understood between 0.250 g and ~ g per day, orally in humans, with the product described in Example 1 given below, or still made up between 0.500 g and 1 g three times a day, intramuscularly.
Products of general formula (I) and their salts 12 ~ 1435 ~

can also be used as disinfectants for Surgical instruments.
The procedure of in ~ ention allows to prepare new intermediate products, namely products of general formula (IV):

NHRb ~ N
~ - ~ / CONH "~ R
OR'b ~ A (IV) in which Rb, R'h, A and Ra have the indicated meaning above, thus ~ ue the products of formula (II):

, H2N "~ Ra ~ 1 (II) ~ _ N

in which A and Ra have the meaning indicated above, it being understood that in said formula (II), when A represents feels a hydrogen atom, Ra cannot represent unradical methylthiol, hydroxymethyle, azidomethyle / aminome-thyle or alkoxymethyle.
The products of formula (V), which are not known, can be prepared by the action of an aldehyde of formula RaCHO possibly under foxme of hydrate Ra-CH (OH) 2 on a protected amine of formula RpNH2.
Examples of such preparations are given in the experimental part.

12 ~ 1 ~ 3 ~

In addition to the products described in the examples which illustrate the invention without, however, limiting it, the following products are products that can be obtained held within the framework of the present invention; the substi-killing X, R, A and Rl are those indicated in the formula (I).

lZ ~ 39 - - Rl. , _ _.

_.
2 3 --CH2Cl ~ (CH2) 3Br _CH2Cl (2) 2 3 -CH 2C 1 ~ (CH 2) 2I 2 -CH (CH3) 2 CH2-H2C-C - CH -CH2 ~ nC4H9 -CEI2Cl -CH = CH2 -CH2 - Cll 2 - CH = Cll 2 ~ CEI 2 C 1 `~ O ~ - CH 2 Cl 2 2 2 - (C112) 2-N ~ NCH3 -CH2 - & - C02EI -CH2Cl (2) 2 NOO -CH2 -C (CH3) 2C02H-CE12Cl-CH2 ~ -N (CH3) 2 2 -CIH-C02H 2 -CH2-CH2-N (cH3) 2-CH2Cl.

-CH2C02C2H5 -CH2Cl H -CH20CH3 -CH 2 CO 2 tBu 2 CH 3 -CH 2CH 3 C El 2 -CH2Cl -cH2cH2NH2-CH20CH3 -C (CH3) 3 2 CH2C02H-CH20CEI3 -CH; ~ -CH = CH-C02H 2 -C (CEI3) 2C2 2 -CH20CH3 - ~ E-1702 ~ 1 -CH2Cl -CE ~ 2CH2Br -CH20CH3 , -CH2C ~ ~ CH2Cl CH2CH2I -CH20CH3 (CH2) 2 C 2 -CH2C02C2H5 -CH20CH3 --Rl R ~

_ _ _ _ _ __ -CH2-CON112 CH2 -CH2C02 tBu -CH20CH3 (2) 2 C 2 C (CH3) 2 2 2 5 -CH20CH3 - (CH2) 2Cl 2 -C (CH3) 2C02tBU -CH20cH3 -CH 2CH 3 2 (2 3 -CH 2B r (2) 2 3 -CH2Br - (CH2) 2I 2 - CH (CH 3) 2 2 -H 2C-C-CH 2 nc4H9 -CH2Br -HC = CH2 2 -CH2-CH = CH2 -CH2Br - (CH23 2-N ~ -CH2Br -Cil2C211 -CH2Br - (CH2) 2-NONCH3 -CH2Br - & - C02H -CH2Br _ (CH2) 2-NOO -CH2Br -C (CH3) 2C2H-CH2Br -CH2 ~ jN (CH3) 2 2 CH 3 C 2 -Cll 2 -CH 2 -N (CH 3) 2 2 -cH2co2c2lI5-CH2B ~ CH3 2 -CH2C02tBu -CH2Br -CH2CH2NH2 C 2 -Cl 2 ~ IC02H-CH2Br H -CH2Br . -C (CH3) 3-CH2Br H. -CH2 SCH3 -CH 2-CH = CH-C02HCH 2 CH 3 2 3 3 ~

RR 1 R ~ 1 ~ _ _ _ _ _ ~

- (C112) 2 CN-CH 2Br -C (CH 3) 2C0 2H -CH SCE-I

-CH -CONH CH2 -CH2CH2Br 2 3 - (C ~ l2) 213r -CH2Br -CH2CH2I 2 SC 3 (CH2) 2Cl 2 -cH2co2c2H5 2 3 -CH2CO2tBu C 2 3 -CH -CONH2 -CH2l ~

. -C (CH3) 2CO2C2 5 -CH2SCH3 - (CH2) 2Br -CH20H

(3) 2 2 2 3 (C 2) 2 -CH2 ~ l -CH2CH3 2 - (CH2) 3Br -CH20H
(2) 2 3 -CH20H H -CH2SCN

-Cll (C113) 2 -Cl-l OH CH 3 2 ~ nC4H9 -CH20H -CH2CH2NH2 -CH2SCN

--CH 2-CH = CH 2-CH 20H 2 2 -CH 2SCN

-CH 2C 2H -CH 20H -C (CH 3) 2C2H -CH 2SCN

- & - Co2 ~ I -CH20H - (CH2) 2I -CH20H
, - (CH 3) 2 C02H -CH 20H -H 2C-C-CH C 2 ilL ~ 0 ~ 3 ~ 3 Rl _ _ _ 'Rl -', . _ _. . _ 3 -CH2H -CH = CH2 -CH2H
I2co2c2H5-CH2H ~ 2 2 ~ -CH20H.

. -CH2C02tBu-CH20H - (CH2) 2- ~ JONCH-CH20H

-Cc2El5o2H-CH2H (CH2) 2 ~ CH2H

-C (CH3) 3-CH20H -CH2j-N (CH3) 2 -CH20H

-CH2-CH = CH C02H -CH2H -CH2-CH2-N (cH3) 2 -CH2H

- ~ C ~ 3E-1702H-CH20EI CH3 -CH20H
-CH3CN -CH20H -C} 12CH2-NH2 2 - (CH2) 2cNCH2H. -CH2H
H CH2NH2 -CH2-CH = CH2 -CH2SH

CH3CH2NH2 2 2 ~ CH2SH
-CH2CH2NH2CH2NH2 - & - C02H -CH2SH

2 2CH2N ~ T2 - (CH3) 2C02H -CH2SH

-C (CH3) 2C02HCH2NH2 3 -CH2SH

-CH2CH2BrCH2NH2 -CH2C02C2H5 -CH2SE ~

, --CH2CH2ICH2NH2 --CH2C02tBU - CH2SH

- 28 ~

~ 20 ~ 3 ~

RR ~ ~ _ _ _ __ _ I _ _. _.
H CH2N3 -CcE2H5o2H -CH2SH

CH3 CH2N3 -C (CH3) 3-CH2SH

. -C112CH2NH2 C 2 3 -CEl2-cH = cH-co2H-CH2SH
-CH2c2H CH2N3 -C3T-lco2H 2 -C (CH3) 2C2H CH2N3 --CII2CN -CH2SH

H CH2 ~ CS - (CH2) 2CN - CH2SH

CH 3 CH 2N CS _ CH -CONH -CH 2SH

-cEl2cll2NH2 CH2 ~ CS- (CH2) 2 ~ 3r -CH2SH

CH 2 2H: CH 2NCS- (CEI 2) 2 Cl -CH 2 -CH2CH3 CH2SH - (CH2) 3BrC 2 - (CH ~) 2CH3 CH2SH -C (CH3) 2C02H --CH2NCS

-CH (CH3) 2 CH2SH H --CH2N (CH3) 2 -nc4H9 CH2SH CH3-CH2N (CH3) --CH 2 CH 2NH 2 OE12N (a-13) --C ~ l 2C2HCH2N (CH3) , - (CH 2) 2I -CH2SH

iZ ~ 13 ~

!
R Rl _ __, -HC = CH 2 -CH 2SH

- (CH2) 2-N ~ -CH2S ~ I

- (CH 2) 2- ~ ONC 3 -CH 2SH

(2) 2 NOO -CH2SH

-CH2 ~ -N (CH3) 2 -CH2SH
-CH 2-CH 2 N (CM 3) 2 -CH 2SH

-C (CH3) 2C02 ~ 1 -CH2N (CH3) 2 ~ CH2CN -CH2F

-CI13 2 ~

-CHF2 __ Example 1: ~ 4-chloxomethyl 3 / 2- (2-amino 4-thiazolyl) acid 2-me-thoxyimino aceta_ido7 2-oxoazetidine l-sulfamic cis, syn, racemic.
Stage A: 4-chloromethyl 3- / 2- (2-trit ~ lamino 4-thiazolyl) 2 methoxyimino acetamido7 2-oxo azetidine s ~ n.
________ _ ~ ____________ __._________________ _ A suspension of 2.32 g of acid is cooled 2- (2-tritylamino 4-thiazolyl) 2-methoxyimino acetamido syn isomer in 23 cm3 of methylene chloride and adds 594 mg dicyc] .ohexyl carbodiimide, stir 20 minutes at cold and add a 441 mg solution of hydrochloride

4-chloromethyl 3-amino 2-oxo azetidine in 10 cm3 of methylene chloride and 0.4 cm3 of triethylamine. We act 1 hour 20 minutes at room temperature, wring out the dicyclohe-~ ylurea formed, rinse with methylene chloride, add au: Eiltrate 10 cm3 of saturated acid carbonate solution of sodium and 20 cm3 of water. Shake, decant in a vial, I.ave in water again, re-extracts the organic phase and the dried.
Concentrate to dryness under reduced pressure, add to the residue the minimum of ethyl acetate, scrapes, ~ iltre Insoluble, rinse with ethyl acetate and concentrate again dry under reduced pressure. We dissolve the residue in 5 cm3 of ethanol and diluted slowly with 10 cm3 ether. We start crystallization, stir for 2 hours, wring out the dormant crystals, rinse with ethanol mixture-ether (1-2) and obtains 688 mg of expected product.
Analysis: C29 H26 3 Ns SCl = 560.08 Calculated: C% 62.19 H% 4.68 N% 12.5 Found: 62.4 4.8 12.2 Stage B: 4-chloromethyl 3-L2- (2-amino 4-thiazolyl) acid 2-methoxyimino acetamido Z 2-oxo azetidine l-sulfami ~ ue cis, ________ ________________ _____________ ____________ ______ syn, racémi ~ ue.
a) Sulfamation:
To a solution of 1.72 g of pyridine sulEan (pyridine sulfuric anhydride complex) in 17.2 cm3 3 ~

of dry dimethylformamide, where ~ adds 2.403 g of pxoduct obtained at 5tade pxéceci. Qn shakes 66 hours at tempera-ambient temperature, filters the insoluble material, rinses with dimethylfor-mamide, diluted with 300 cm3 of ether, shakes, leaves to stand for 10 minutes, remove the ether, rewash with ether in crushed, takes up the gum with 20 cm3 of ethanol. After dissolution, scraping, the expected product crystallizes.
Stir slowly for 30 minutes, filter, rinse with ethanol then ether.
855 mg of expected product is obtained, which is the 4-chloromethyl 3-L2- (2-tritylamino 4-thiaxolyl) 2-rnethoxy ~
imino acetamido_7 2-oxo azetidine l-sulfamic pyridi-nium.
b) Unlocking the remaining trityle:
A mixture of 360 mg of sulfamate is brought to 50C.
of pyridine obtained previously and 1.4 cm3 of acid ~ ormi-than 33% water. After dissolution, crystallization of triphenylcarbinol is involved. We leave 10 minutes at 50C, cools, dilutes with 0.6 cm3 of water, filters the inso-luble, rinse with water. A little ethanol is added to the filtrate and concentrated to dryness under reduced pressure. We add water and ethanol which are evaporated under vacuum. We added te to resi ~ u 1.2 cm3 of saturated aqueous solution of carbon-sodium acid nate. We filter the light insoluble material, rinse with water, add 3 drops of formic acid to the filtrate and scrape. The expected product crystallizes. Shake for 10 minutes, filter, rinse with water and ether, dry and isolates 113 mg of expected product.
Analysis: C10 H12 6 N5 2 Calculates: C% 30.19 H% 3.04 Found: 29.6 3.2 Preparation:
a) 2-chloro N- ~ henylmethyl ethanimine.
A solution of 4 cm 3 of chloro-acetaldehyde in 20 cm3 of demineralized water and introduced with stirring a solution of 2.14 g of benzylamine L3 ~

in 10 cm3 of water. The mixture is stirred for 5 minutes. at. 10 ~ 15C and obtains an eraser and a cloudy solution .. On.extralt per 30 cm3 then 20 cm3 of benzene. We dry the solution, filter, rinses and distills dry under vacuum. 3.34 g of product used as is.
b) N-benz ~ l 3- ~ htalimido 4-chloromethyl 2-azetidinone cis.
The solution of 3.34 g of is cooled to -50C.
product obtained. above in 20 cm3 of chloride methylene, then add 2.8 cm 3 of triethylamine at once.
Stirring and temperature are maintained and introduced into 20 minutes a solution of 4 g of phthalic acid chloride mido acetic acid in 20 cm3 of methylene chloride. We then stir for one hour at 0 ~ 5C, pour into a vial decant and wash with 50 cm3 of demineralized water and 5 cm3 aqueous molar solution of sodium hydrogen carbonate then with demineralized water (2 times 30 cm3). We re-extract washes with methylene chloride (20 cm3), dry, essoret rinses and concentrates dry under vacuum. We obtain a crude resin (6 ~) which is chromatographed on silica using methylene chloride to S% sulfuric ether.
The fraction of R = 0.45 is isolated, brought to dryness, paste with 10 cm3 of sulfuric ether, wring, rinse 3 times with 2 cm3 of sulfuric e-ther. Dried under vacuum and obtained 1.25 g of product. F = 149C.
c) 3- ~ htalimido 4-chloromethyl 2-azetidinone cis.
__ _ ___ ________________ ___________________ Wearing hot for 25 minutes under good stirring in an oil bath at 120C a mixture of 17.75g of product obtained previously, 31 g of peroxodisulfate potassium, 110 cm3 of water and 160 cm3 of acetic acid.
Cool to room temperature, add 50 g of phos-dipotassic phate to neutralize Eormea acidity, flushes solvents under reduced pressure, adds 250 cm3 of water and 150 cm3 of ethyl acetate, stir and then add with small portions of sodium hydrogen carbonate up 3S cessation of gas evolution, filter, acetate rinse 3 ~

ethyl, decant in ampoule, re-extracted with 50 cm3 of acetate ethyl, dries the organic phase, filters, rinses and dry center under reduced pressure. We chromatograph the residue on 200 g of teluant silica: methylene chloride at 25% ethyl acetate). We collect the rich fractions, concentrates to dryness, resumes ~ ether, resolves, wrings, rinses, dry and obtain 5.4 g of research product.
y ~ C12 Hg N2 Cl = 264.67 Calculates: C% 54.46 H% 3.43 Found: 54.7 3.5 d) 4-chlorometh ~ 1_3-amino 2-oxo azetidine hydrochloride.
To a suspension of 5.3 g of product obtained above in 5.4 cm3 of methylene chloride, dropwise added drop 12 cm3 of a solution of hydrate draæine in the dimethylformamide (2 cm3 of hydrazine hydrate and qs 20 cm3 dimethylformamide). We give up 20 minutes at rest after solidification then add to dissolve completely normal hydrochloric acid (about 30 cm3) of ~ acon ~ bring the pH to 3. Stir 18 hours at room temperature, filters the phthalhydrazide formed, rinses with water and then with ethanol finally with ether. Dried and obtained 2.844 g of product.
Dimethylformamide and water are removed under reduced pressure, takes up 2 ~ the residue with ethanol, drives it out and obtains a product to which 20 cm 3 of ethanol are added. We shake 45 minutes, wring out the crystals, rinse with ethanol and with ether. 2.466 g of expected product are finally obtained.
Example 2: Acid 4- (1-methyl 5-mercapto 1,2,3,4-tetrazol) methyl 3- C2- (2-amino 4-thiazolyl) 2-methoxyimino acetamido 2-oxo azetidine l-sulfami ~ eu, racemic cis.
Stage A- Acid 4-11-methyl 5-merca ~ to 1 ~ 2L3L4-tetrazol) methyl 3- ~ 2- (2-tritylamino 4-thiazolyl) 2-methoxyimino ___. _______________ ________________ ___________ _____ acetamidol 2-oxo azetidine 1-sulfami ~ eu ________ ______________.___________ __ a) Condensation:
Stir in the cold for 20 minutes in a bath ice water a mixture of 2.25 g of 2- (2-tritylamino acid :; ~ Z6 ~ 43 ~

4-thiazolyl) 2-methoxyimino acetic syn isomer in 21 cm3 of methylene chloride and 576 mg of dicyclohexylcar-bodiimid. Remove the bath and add a solution of 597 mg of 4- (1-methyl 5-mercapto 1,2,3,4-tetrazol hydrochloride) methyl 3-amino 2-oxo azetidine in 10 cm3 of chloride methylene and 0.38 cm3 of triethylamine. We agitate at tempe-rature room for 1 hour 20, concentrated to dryness under reduced pressure, filter, rinse with methylene chloride, ends with ether, dries and isolates 1.594 g of product containing dicyclohexyluree.
b) Sulfamation:
A mixture of 1.594 g of product is stirred for 70 hours obtained above and 0.66 g of pyridine sulfan (complex pyridine sulEuric anhydride) in 6.6 cm3 of dimethylfor-mamide. The dicyclohexyluree is filtered, rinsed with the minimum of dimethylformamide and dilutes the Eiltrate with approximately 200 cm3 of ether. Shake well, filter the insoluble matter, wash with ether, combine all the products by dissolving them in methanol, the expected product crystallizes. On Eiltre, rinse with methanol, ends with ether, dries and obtains 620 mg of expected product.
Stage B: Acid 4- (1-methyl 5-me_ca ~ to_lL2L _! __ tetrazolL
methyl 3- ~ 2- (2-amino 4-thiazolyl) 2-methox ~ imino acetamido7 ____ _____ ____________________ ___________ _______________ 2-oxo azetidine l-sulfami ~ eu.
A mixture of 620 mg of product is brought to 60C.
obtained in the previous stage in 0.8 cm3 of water and 1.62 cm3 formic acid for 12 minutes, triphenylcarbinol crystallizes. Cool, dilute with a little water. The expected product also crystallizes. We act during 10 minutes, filter, rinse with water and then paste 3 times ether. We take up the insoluble in water, add 2 cm3 aqueous sodium bicarbonate saturates, agitates, filters insoluble, rinse with water, add hydrochloric acid normal qsp pl ~ 2. The expected product crystallizes. We stir 5 minutes, filter, rinse with water, finish with ether, dry and obtain 294 mg of expected product.

lZ ~; 9143 ~

~ nalYs ~: C12ll156N9S3 1/2 ll2 Calculated: C ~ 29.63 H% 3.31 N ~ 2S, 91 S ~ 19.77 Found: 29.5 3.4 25.8 19.8 Preparation 1:
S a) 4- (1-methyl 5-mercaPtO lL_L3L4-tetrazolL methyl 3- ~ hta-limido 2-oxo azetldine cis.
A suspension of 7.6 g of ~ - is brought to 100C.
chloromethyl 3-phthalimido 2-oxo azetidine cis obtained at the pre-. preparation of example 1 c), 5.48 g of sodium salt of 1-methyl 5-mercapto 1,2,3,4-tetrazole (dihydrate), 4.3 g of iodide sodium and 57 cm3 of dimethylformamide and gives up under stirring for 3 hours at this temperature. We cool, pour into 0.75 1 of water and 150 cm3 of ethyl acetate. We rinse, shake vigorously, decant, re-extract with 75 cm3 then 45 cm3 of ethyl acetate, filters the insoluble material ~ ui is the expected product. Wash with 150 cm3 of water, re-extract and dry. After filtering, concentrated to small ~ olume under reduced pressure and filters a second jet and rinses it ethyl acetate. We combine insoluble products, che and finally isolates 5.1 g of expected product. Analysis C14H123M6S ~ 1/4 AcOEt = 366.37 Calculates: C ~ ~ 9.17 H ~ 3, ~ 5 N% 22.94 Found: ~ 9.2 3.7 23.0 b) 4-11-methyl 5-mercaPto hydrochloride lL_L3L_-tetrazol) methyl 3-amino 2-oxo azetidine.
1 cm3 of hydrate hydrate is added dropwise zine to a suspension of 5.8 ~ 5 g of product obtained above in 18.5 cm3 of dry dimethylformamide and shakes for 20 minutes at room temperature then add 19 cm3 of water and 24 cm3 normal hydrochloric acid. We obtain a final pH of 3, mouth, give up stirring overnight at temperature ambient, then filters the phthalhydrazide formed, rinses with water, concentrated to dryness under reduced pressure, adds ethanol, disintegrates, concentrates to dryness, adds methanol to dissolve when hot and concentrate to dryness. The product crystallizes.
Add 20 cm3 of methanol, deli-te, ice, spin, rinse : L2 ~ 3 ~ 31 with iced methanol, ends with ether and obtains 2.49 g of expected product in 2 jets.
Example 3: 4-c} -loromethyl 3- / 2- (2-amino 4-thiazolyl) acid _ (2-amino ethoxy) imino acetamldo7 2-oxo azetidine l-sulfa-cis mique, racemic syn.
Stage A: 4-chloromethyl 3- t2-12-tritv] amino 4-thiazolylL
2- (2-tritylamino ethoxy) imino acetamidoZ 2-oxo azetidine _yn.
1.6 ~ g of tosyl chloride are added to a solution.

6.3 g of 2- (2-tritylamino 4-thiazolyl) 2 (2-tritylamino ethoxy) imino acetic isomer syn in 40 cm3 methylene chloride and 1.24 cm3 of triethylamine.
Stir for 40 minutes then add in one times a solution of 1.368 g of 4-chlorome hydrochloride thyl 3-amino 2-oxo azetidine in 40 cm3 of chloride methylene and 2.4 cm3 of triethylamine. Shake 2 hours at room temperature ~ add water, stir vigorously-decanted and re-extracted with methylene chloride. We dry the organic phase, filter and concentrate to dryness. We chromatograph the residue on silica (eluent: ether).
4.9 g of expected product are obtained. Rf = 0.8.
Stage B: 4_chloromethyl __- ~ 2_ (2_tritylamino 4-thiazolyl) 2-12-tritylamino ethoxyL imino acetam doZ 2-oxo azetidine ~ yridinium l-sulfamate.
_______________ ________ A mixture is stirred for 4 days at room temperature 4.9 g of product obtained in the previous stage, 2.6 g of pyridine sulfan and 25 cm3 of ether.
We grind the insoluble matter, filter, rinse with ether, dry and obtain 6.6 g of the expected product.
Rf = 0.4 (eluent: methylene chloride, ethyl acetate, ethanol: 65-20 ~ 15.
Stage C: 4-chloromethyl_3- / 2- (2-amino 4-thiazolyl ~ acid 2- (2-amino ethoxy) imino acetamido ~ 2-oxo azetidine l-sul-________________ _________________ _______________________ fami ~ ue cis syn racémi ~ ue.
__ __ _ __ _ __L__ _L_ _____ _ __ A suspension is brought to 55-60C for 12 minutes 5.3 g of product o ~ held above in 42 cm3 of acid - \

formic at 33% water.
Cool, dilute with 30 cm3 of water, filter it triphenyl carbinol forms, rinses with water and concentrates to dryness in a water bath at 40C. We start twice with a water-ethanol mixture, the residue.
Concentrate to dryness, add water and carbonate sodium acid in aqueous solution saturated so bring the pH slightly alkaline.
Filter the insoluble, rinse with water, add 2N hydrochloric acid so as to bring the pH to 4-5.
We start crystallization, stir for one hour, filter, rinse with water and then with ether.
700 ml of expected product are obtained.
Analysis: CHONS Cl ~ 11 15 6 6 2 Calculates: C% 30.95 H% 3.54 Find: 30.9 3.8.
Example 4 Acid 4-chloromethyl 3- / 2- (2-amino 4-thiazolyl) 2-hvdroxYimino acetamido7 2-oxo azetidine l-sul ~ cis amic, syn, racemic ~
Stage A: _-chlo ~ rometh ~ Yl_3 __ / 2- (2-tritylamino 4-thiazolyl) 2-tritYloxyimino acetamidoZ 2-oxo azetidine syn.
______ ___ _______________ __________________ _ A mixture of 1.527 g of salt is stirred for 40 minutes sodium 2- (2-tritylamino 4-thiazolyl) 2-trityl-oxyimino acetic and 419 mg of tosyl chloride in 15 cm3 of methylene chloride, then add a solution of 342 mg of chlorh ~ 4-chloromethyl 3-amino2-oxo aze drate-tidine in 15 cm3 of methvlene chloride and 0.6 cm3 of triethylamine.
The mixture is stirred for 2 hours, added water, stirred, decanted, re-extracted with methylene chloride and knows the organic phase then filters. We concentrate the ~ iltrate under reduced pressure and chromatography on silica (eluent: ether).
After collecting the solvent, 736 are collected.
mg of condensate.

~ L ~ 39 Stage B: 4-chlorom ~ thyl 3- / 2- (2-trit ~ lamino 4-thlazolylL
2-tritylox ~ im_no acetamidoZ 2-oxo azetidine l-sulfamate ~ yridinium ________ A solution is left for 4 hours at room temperature.
tion of 1.248 mg of product obtained as in stage ~ and 640 mg of pyridine sulfan (pyridine complex anhydride suIfuri-que), in 6.8 cm3 of dry dimethylformamide.
Then pour into 300 cm3 of ether, grind, filters the insoluble material, rinses with ether, pastes in 10 cm3 of methanol, stir 15 minutes, Eiltre, rinse with methanol then with ether, dry, and finally obtain 1.02 g of product expected.
Stage C: 4-chloromethyl acid 3- ~ 2- (2-amino 4-th3azolyll 2-hydroxyimino acetamido7 2-oxo azetidine 1-sulfami ~ eu cis, ___ ~ .___ ____________ ~ _____________________________ ______.
synL racemi ~ ue.
A suspension of 60 is brought to 60 for 15 minutes.
1.02 g of product obtained at ~ previous stage in 9.1 cm3 formic acid has 66 ~.
We operate as described above in stage C of Example 4 and obtains 119 mg of expected product.
Example 5: 4-fluoromethyl 3- / 2- (2-amino 4-thiazolyl) acid 2-methoxvimino acetamido7 2-oxo azetidine l-sulfamiaue cis, ~ _ ~ _ syn, racemic.
Stage A: 4-fluoromethyl 3- ~ 2- (2-tritylamino 4-thiazol ~
______________________ _____ _________ ____________ ___ _ 2-methoxyimino acetamidoZ 2-oxo a_etid_ne cisL syn ~ racémi ~ Lue.
0.915 g of 2- (2-tritylamino 4- acid) is mixed thiazolyl) 2-methoxyimino acetic, syn-isomer, 7 cm3 acetone and 0.319 g of tosyl chloride. Shake for 50 minutes at 20C, filter and add a solution containing 0.216 g 4-fluoromethyl 3-amino 2-oxo hydrochloride azetidine cis, 7 cm3 of methylene chloride and 0.42 cm3 of triethylamine.
Stir for 45 minutes, evaporate to dryness, add water, delite, wring, then paste with acetone and wring. The product is purified by pasting in acetate ethyl.

~ Z ~ 3 ~ 43 ~

0.654 g of expected product is obtained.
Analysis: C29H26O3N5SF 543.62 Calculated: C ~ 64.07 ~ W ~ 4.82 N% 12.88 S% 5.90 F% 3.49 Found: 64.0 4.9 12.4 5.9 3.4 Stage B-_ Aclde 4-fluoromethyl 3- / 2- (2-amino 4-thiazolylL
2-methoxyimino acetamidoZ 2-oxo azetidine l-sulfamlgue cis, syn racemi ~ ue.
_L_ _ _ ___ _ __ a) Obtaining p ~ ridinium sulfamate.
Stirred at 20 ~ C for 88 hours, a mixture of 0.564 g of product obtained in stage A, 0.410 g of pyridine sulfan and 4.1 cm3 of dimethylformamide. We pour in 200 cm3 of ether, wring the product, add methanol, stir, wring and dry the crystals obtained. We obtain 0.473 g expected product b) Detrikylation 0.470 g of the product obtained is suspended above, in 1.87 cm3 of formic acid at 33% water, then heats up to 55-60C for 5 minutes then to 70C for 13 minutes, add 1.2 cm3 of formic acid and heat again at 70C for 15 minutes. Cool to 20C, filter, add ethanol to the filtrate and then concentrate to dryness. We add water and ethanol to the residue and then concentrate dry again. The residue is dissolved in water to which 116 cm3 of 10% sodium bicarbonate is added. We filter, add 2N hydrochloric acid since at pH 2, evaporates the water, pastes the residue in water, filters, rinses with water, then with ether, dry and obtain 0.140 g of expected product. F ~ decomposition) ~ 240C.
An ~ y ~: ClOH126N5S2 F - 381 ~ 36 Calculates: C% 31.50 H% 3.17 N% 18.36 S% 16.81 F% 4.98 Find: 31.6 3.2 18.5 16.5 5.1.
Preparation of 4-fluoromethyl 3-amino 2-oxo hydrochloride azetidine cis.
1) N-methyl N-methoxy fluoroacetamide.
27.2 g of fluoroacetyl chloride are mixed and ~ 2 ~ 143 ~

120 cm3 of methylene chloride, cools to + 5C under ga ~
inert and slowly introduces 50 cm3 of methoxymethylamine keeping the temperature below ~ 20C, then stir for 2 hours at 20C. Filter, flush the solvent out reduced pressure, rectifies residue under reduced pressure and obtains 30.9 g of the expected product.
Eb.23 = 93C.
2) Fluoroacetaldehyde hydrate 7.8 g of product obtained in the preceding stage are dissolved tooth in 133 cm3 of tetrahydrofuran, cools to 0, ~ 2C
and slowly introduces 74 cm3 of a 1M solution in hexane diisobutylaluminum hydride. We leave the temperature slowly return to room temperature, pour into a mixture of 28 cm3 of concentrated hydrochloric acid and 56 cm3 of water while cooling, stirred then distilled at atmospheric pressure spherical. 38 cm3 of expected product are obtained, diluted in water (Eb: 75 to 100.5C).
3) 4-fluoromethyl 3-phthalimido 2-oxo l- (l-phenyl ethyl) azetidine cis.
Dilute 69 cm3 of solution as obtained at previous stage in 100 cm3 of water. Cool in the bath ice for 15 minutes then add 8.8 cm3 of ~ -phenyl ethylamine DL, shakes for 10 minutes, filter, rinse with water and add 130 cm3 of methylene chloride to the filtrate.
It is heated to reflux ~ until complete dissolution, cools, decant, dry the organic phase and then cool it under gas inert at -50C. 15.4 g of chloride are added slowly phthalimidoacetyl in 60 cm3 of methylene chloride and 10.4 cm3 of triethylamine in methylene chloride. We let the temperature return to 20C and stir for one hour. 25 cm3 of 10% sodium bicarbonate are added and 60 cm3 of water, stirred, decanted, extract with methylene chloride, dries the combined organic phases, concentrates them dry, chromatograph the residue on silica eluting with chloride of methylene to 10% of ethyl ether and obtains 13.7 of expected product.

lZ ~ 19L39 Analysis C20H173N2 F = 352.37 Calculates: C% 68.17 E ~% 4.86 N ~ 7.95 F% 5.39 Found: 68.2 4.9 7.8 5.6.
4) 4-fluoromethyl 3-phthalimido 2-oxo azetidinecis, racemic.
The 13.7 g of the product obtained in the stage are dissolved above in 200 cm3 of acetonitrile and add 130 cm3 of water.
Is brought to reflux, introduced in 15 minutes a solution of 22.2 g of ammonium persulfate in 52 cm3 of water and holds reflux for one hour twenty-five minutes. We cooled, saturated with sodium chloride, decanted, washed with saturated aqueous sodium chloride solution, re-extracted with ethyl acetate, dry the combined organic phases and evaporates the solvent. The residue is chromatographed on silica eluting with methylene chloride-ethyl acetate mixture (75-25), rinses the crystals obtained with ethyl ether and 3.766 g of expected product is obtained.
IR spectrum (CHC13) Absorption at 3430 cm (-NH) and at 1790, 1770 and 1725 cm 1 (C = O ~ -lactam and phthalimido).
S) 4-fluoromethyl 3-amino 2-oxo azetidine hydrochloride cis.
1.24 g of product obtained are suspended previous stage, in 1.2 cm3 of dioxane then add 14 cm3 of a solution of 1 cm3 of hydrazine hydrate in 50 cm3 of dioxane. We hold for 45 minutes at temperature ambient then add 5 cm3 of hydrochloric acid N and main-keeps stirring for 15 hours O Concentrated to dryness, add water and 2.3 cm3 of hydrochloric acid N, stir and filtered. Ethanol is added to the filtrate and concentrated to dry. Methanol is added to the residue, then ethanol and concentrates again in dry water. We recrystallize the crystals in methanol.
0.391 g of expected product is obtained. F (Dec) _ 220C.

- ~ 2 -~ LZ ~ 439 Example 6: 4-fluoromethyl 3- / 2- (2-amino 4-thiazolyl) acid 2 ~ carboxy l ~ methyl ethoxy) imino acetamido_7 2-oxo aze-tidine l-sulfamic cis, syn, racemic.
Stage A- 4-fluoromethyl 3- / 2- (2-tritylamino_4-thiazolylL
2-11-terbutoxycarbonyl l-methyl ethoxy) lmino acetamido /
_-oxo azetldlne cisL_s ~ nL racém_ ~ eu.
0.686 g of 2- (2-tritylamino 4- acid) is mixed thiazolyl) 2- (1-terbutoxycarbonyl l-methyl ethoxy) imino acetic, syn isomer, 5 cm3 of acetone and 0.17 cm3 of triethylamine pUi9 adds 0.229 g of tosyl chloride, stir for 50 minutes, filter and add to the filtrate under stirring, a solution of 0.155 g of 40 hydrochloride fluoromethyl 3-amino 2-oxo azetidine cis in 5 cm3 of methylene chloride and 0.3 cm3 of triethylamine. We shake for 55 minutes at 20C, evaporate the solvents, add methylene chloride and water, add 2 cm3 of bicarbo-sodium nate at 10 ~, stirred, decanted, chloride extract methylene, dries the combined organic phases and concentrates dried up. The residue is chromatographed on silica, eluting with ethyl ether and obtains 0.613 g of the expected product.
The starting thiazolic product is described in French demand ~ 2,421,906.
Stage B: 4-fluoromethyl acid 3- ~ 2- (2-amino 4-thiazolyl) _______ __________________ _____ ____________________ __ 2- (1-carboxy l-methyl ethoxy) imino acetamidoZ 2-oxo azetidine l-sulfamic cis, syn, racemic.
_______________________.__________________ a) Obtaining pyridinium sulfamate.
The product obtained in stage A is dissolved and 0.36 g of pyridine sulfan in 3.6 cm3 of dimethylformamide.
Stir at 20C for 62 hours, pour into water, stir, wring and dry the precipitate obtained. We obtain 0.518 g of expected product.
b) Detritylation:
The product obtained in the previous stage is dissolved in 2.9 cm3 of triEluoroacetic acid and maintains at 20C
for 15 minutes. 29 cm3 of isopropyl ether are added, 3 ~

filters and pastes the product in ethyl acetate for 15 minutes. We filter, dry, dissolve the product in a little of water, containing 1 cm3 of 10% sodium bicarbonate, wire-tre, add 2N hydrochloric acid to the filtrate until pH2, filter partially evaporates the water, cools, spins them crystals, rinses them with ether and obtains 0.094 g of product expected. F (dec.) ~ 230C.
NMR spectrum (DMSO - 90 MH ~.) Peaks at 1.5 ppm tCH3), 3t78 at 4.94 ppm (H4 and CH2F)

5.22 - 5.27 ~ 5.32 and 5.37 ppm (H4?, 6.88 ppm (H5 thiazole syn), 9.21 and 9.31 ppm (NHCO).
Example 7: 4-thiocya_atomethyl 3- ~ 2- (2-amino 4-thia-zolyl) 2-methoxyimino ac tm dQ7 2-oxo azetidine l-sulfamic cis, syn, racemic.
Stage A- 4-thiocyanato methyl_3_ ~ 2- (2-trit ~ lamino 4_thiazoly 2-methoxyimino acetamidoZ 2-oxo azét_dine cisL synL_r ~ acemi ~ eu.
3.19 g of acid 2- (2-tritylamino 4-thiazolyl) 2-methoxyimino acetic, syn isomer, suspended in 50 cm3 of methvlene chloride. Add with stirring 1 cm3 of triethylamine then 1.38 g of tosyl chloride.
Stirring is maintained at room temperature for 40 minutes then add in 5 minutes, a solution of 1.162 g 4-thiocyanatomethyl 3-amino 2-oxo azetidine hydrochloride cis in 40 cm3 of methylene chloride and 2 cm3 of triethyl-amine. Stirring is continued for 4 hours, washing with water and then with water containing 4 cm3 of hydrochloric acid N, dry and concentrate dry. The residue is dissolved in the ace-ethyl tate, cools, wring out the crystals, wash with methanol, dry them and obtain 0.709 g of product expected. The mother liquors are evaporated to dryness, chromatographed phie the residue on silica eluting with chloroform mixture-methanol (93-7) and again obtains 1.069 g of product stretched.
Stage B- 4-thiocyanatomethyl 3- / 2- (2-amino 4-thiazolyl) acid 2-methoxyimino acetamidoZ 2-oxo azetidine l-sulfamic cis, ___ ~ _____ ~ ________ ~ _____ __________________________________ syn, racemic.
______________ ~ -D:

a) Obtaining pyridinium sulfamate.
Stir for 90 hours at 20C, a mixture of 1.7 g of product obtained in stage A, 12 cm3 of dimethylforma-mide and 1.16 g of pyridine sulfan. We pour in ether with stirring, takes up the precipitate formed by methanol, cools then wring out the crystals. We get in 2 jets, 0.544 g of expected product.
b) Detritylation:
Heated to 60C, 4 cm3 of formic acid to 33 ~
of water, then 0.42 g of product obtained above is added and stirred at 60C for 20 minutes. Cool to 20C
then add 40 cm3 of ethyl ether and stir for one hour at 0, + 5C. We spin the precipitate, rinse with ether ethyl and triturated with an aqueous solution 0.1 lN
sodium bicarbonate. Filter, acidify the filtrate to pH2 with N hydrochloric acid, cools and squeezes the crystals formed. They are washed with water, dried and obtained 0.237 g of expected product. F (dec.) = 265C.
yse: Cl1 12 6O6S3 (120.54) Calculated: C% 31.42 H% 2.88 N% 19.99 S% 22.88 Found: 31.2 3.2 19.7 22.6.
Preparation of 4-thiocyanatomethyl 3-amino hydrochloride 2-oxo azetidine cis.
1) 4-iodomethyl 3-phthalimido 2-oxo azetidine cis, racemic.
26.5 g of 4-chloromethyl 3-phthalimido are mixed 2-oxo azetidine cis, 30 g of sodium iodide and 80 cm3 of dimethylformamide. We bring to 120C for ~ two hours, re ~ stiffness, poured into a mixture of 800 cm3 of water and 100 cm3 ethyl acetate with stirring, filters the crystals formed, rinses them with water and then with ethyl acetate until discoloration and finally with ethyl ether. We take the mother liquors, decanting, drying the organic phase, concentrating dry, take up in ethyl acetate, filter, rinse with acetate ethyl tate and dry. We thus obtain in 2 jets 28.4 g of expected product.

43 ~

2) 4-thiocyanato methyl 3-phthalimido 2-oxo azetidine Ci5, racemic.
We bring ~ 75C with stirring a mixture of 1.78 g of product obtained above in 5 cm3 of dimethylformamide then add 1.5 g of potassium thiocyanate and stir gently for 3 hours 30 minutes ~ Pour into water, wring it out precipitate, wash it with water and dry it. We mash it hot in isopropyl ether, wring and dry. We where 1.25 g of expected product.
3) ~ -thiocyanato methyl 3-amino 2-oxo hydrochloride azét: idine cis.
1.45 g of product obtained in the preceding stage are mixed tooth in 15 cm3 of hot dioxane, cools then adds 0.3 cm3 of hydrazine hydrate slowly and stirred at 20C
for 50 minutes. 7.5 cm3 of acid are then added hydrochloric N, keeps stirring for 15 hours, spins precipitate, rinse with water, take up the filtrate and evaporates to dryness. 0.914 g of expected product is obtained ~
Example 8: 4-fluoromethyl 3- ~ 2- (2-amino 4-thiazolyl) acid 2-di: Eluoromethoxyimino acetamido7 2-oxo azetidine l.-sulfamic cis, syn, racemic.
Stage ~: 4-fluoromethy]. 3- ~ 2- (2-tritylamino 4-thiaæolyl) ____________________________ ____________________________ l-difluoromethoxyimino acetamidoZ 2-oxo azetidine cis, syn, _______________________ ________ ____________________ ~ ____ racemic.
0.914 g of 2- (2-tritylamino 4- acid) is mixed thiazolyl) 2-diEluoromethoxyimino acetic, syn-isomer, 7 cm3 of acetone and 0.25 cm3 of triethylamine then add 0.339 g of chloride of tos ~ le and stirred for 50 minutes.
Then adding a solution of 0.23 g of hydrochloride 4-fluoromethyl 3-amino 2-oxo azetidine cis in 7 cm3 of methylene chloride and 0.45 cm3 of triethylamine. We stir for an hour and a half, evaporate the solvents, add methylene chloride and water then 3 cm3 of hicar ~ onate of sodium at 10%, stirred, decanted, extracted the aqueous phase with methylene chloride, dries the combined organic phases, evaporates the solvent, takes up the residue in ethanol, cools, '~ ZC1 ~ 3 ~

wring out the crystals, rinse them with ethanol and then with ether ethyl and dries them. 0.537 g of product is obtained expected.
Stage B- 4-fluoromethyl 3- / 2-12-amino 4-thiazolylL acid 2-difluoromethoxylmino acetamldoZ 2-oxo azetidlne l-sul-famous cis synL racemique.
____ ______L__ _ ______ _ __ a) Obtaining pyridinium sulfamate.
The product obtained in stage A and ~ is dissolved, 37 g of pyridine sulfan in 3.7 cm3 of dimethylformamide. We stirred for 72 hours at 20C, poured into 150 cm3 of ether, filter, wash with ether and dissolve the product in ethanol.
Stir, filter the crystals formed, wash them with ether ethyl and dries them. We obtain 0.506 g of product expected.
b) Detritylation:
0.76 g of product obtained above is mixed with 4 cm3 of formic acid at 33% water. We bring to 60C for 15 minutes, dilute with water, filter, add ethanol to ~ iltrat, brings to dryness, resumes with a melan ~ e of water and etha-nol, bring to dry again, take up in water and add 2 cm3 sodium bicarbonate at 10 ~, filters an insoluble material, adds 2N hydrochloric acid to the filtrate up to pH2, center and leave to crystallize. We filter the crystals, rinse with water then with ethyl ether and dry. We obtain 0.312 ~ of expected product.
AnalySe: CloH106N5S2 3 Calculated: C% 28.78 H% 2.41 N% 16.78 S% 13.66 F% 15.36 Found: 28.9 2.5 16.6 13.4 15.3.
NMR spectrum (DMSO) 90MHz Peaks at 4.39 and 4.94 ppm (-C112-F) Peaks at 5.21 - 5.26 - 5.3 and 5.35 ppm (H3 cis) Peaks at 6.38 - 7.15 and 7.93 ppm (-CHF2) Peaks at 7.01 ppm (H5 thiazole) Peaks at 9.66 and 9.76 ppm (-CONH) IR spectrum (CHC13) : ~ 2 ~ 3 ~

Absorption at 1770 cm 1 (C = O lactam), 1675 cm (amide), 1640 cm (amide II), 1585 cm (conjugate system), 1530cm (thiazole ?, 1280 - 1270 cm (-S03H) and 1052 cm (-C = NO-).
Example 9: 4-Fluoro acid ~ 8thy1 3- ~ 2- (2-amino 4-thiazolyl) 2-hydroxyimino acetamido7 2-oxo azetidine l-sulfamic cis, syn, racemic -Stad ~ e A- 4-fluoromethyl 3- ~ 2- (2-tritylamlno 4-thiazolyl) 2-trityloxyimino acetamido7 2-oxo azetidine cisLsyn ~ racemigue ______ ___ _________________________ ~ __________ _ _ __ ~ ____ _., 0. 806 g of 2- (2-tritylamino 4- acid) is mixed thiazolyl) 2-trityloxy imino acetic, syn isomer, 5 cm3 acetone and 0.17 cm3 of triethylamine then add 0.228 g tosyl chloride. Shake for an hour then add 0.155 g 4-fluoromethyl 3-amino 2-oxo hydrochloride azetidine in 5 cm3 of methylene chloride and 0.31 cm3 triethylamine. Stir for 20 minutes, add more methylene chloride, stirred again for one hour thirty, bring to dry, add methylene chloride and water, stir, decant, dry the organic phase, evaporate the solvent and chromatograph the residue on silica, eluting with ethyl ether.
0.598 g of expected product is obtained.
Stage B- 4-Fluoromethyl 3-! 2- (2-amino 4-thiazolyl) acid 2-hydroxyiming acetamidg7 2-oxo azetidine l-sulfamic cls, syn, racémi ~ ue.
a) obtaining pyridinium sulfamate.
We operate as indicated in stage B of Example 4, from the product obtained in stage A above and obtains the expected product.
b) Detritylation.
We operate as indicated in stage B of Example 4, from the product obtained above and obtains the product expected.
Example 10: 3-phthalimido 4-chloromethyl 2-oxo azetidine cis, optically active.

1 ~ 0 ~

Sta ~ de A- N ~ henyl) ethyl 3- ~ htalimido 4-chloromethyl 2-___________.___ __ _____ ____ ______________________ ____ oxo azetidlne clsL o ~ acutely active.
2.5 cm3 of chloroacetaldehyde hydrate are dissolved at 50 ~ in water, in 40 cm3 of water. We stir and add to 0, + 5C, 2.55 cm3 of (+) (1-phenyl) ethylamine. We shake for 6 minutes then wring out the precipitate and rinse it ~
the water. The precipitate is taken up in a chloride chloride mixture.
methylene-chloroform and dry. The solution is cooled under inert gas at -50C, slowly and simultaneously adds 4.5 g 1 ~ phthalimido acetic acid chloride in 25 cm3 of chlo-methylene rure and 2.74 cm3 of triethylamine in 20 cm3 methylene chloride. Let the temperature rise and keeps stirring for two hours and thirty minutes.
We pour in a mixture of water and sodium bicarbonate, extract chloroform, dry, evaporate the solvent and take up the residue ethanol. The insoluble material is filtered and washed with a medium.
lan ~ e ethanol-methylene chloride. We resume the filtrate, Treats it with activated carbon, concentrates and lets it crystallize.
1.364 g of crystals are obtained in 2 jets. We take back liqueurs-mares and chromatography on silica, eluting with chloroform-ethyl acetate mixture (8-2). We obtain 1.58 g of crystals, in total 2.944 g of expected product constituted by a single diastereoisomer.
Stage B: 3- ~ htalimido 4-chloromethyl 2-oxo azetidine cis ____________ ______________________ _ ~ ________________ __ o ~ ti ~ uement active.
0.3 g of product obtained in stage A is mixed in 2 cm3 of acetonitrile and brings to 90-95 ~ C with stirring.
A solution of 0.502 g of ammonium persulfate in 2 cm3 of water, stir for one hour forty-five minutes then pour into the water, extracted with ethyl cetate, wash the organic phase with a solution aqueous thiosul ~ ate of sodium, dries and evaporates the solvent.
0.058 g of expected product is obtained. ~ D = + 10.5+ 1 (CHC13). F = 172C.
Continuing the synthesis as described, by :: LZ ~ 43 ~

example, in example 1, 2, 4 or 5, we get a product correspondent of formula I ~ optically active.
Example 11: We made a preparation ~ n ~ ection of formula -- 4-fluoromethyl acid 3- ~ 2- (2-amino 4-thiazolyl) 2-me-thoxyimino acetamido7 2-oxo azetidine l-sulfamic cis, syn, racemic ~ .. O ................. ~ .. ~ ....... ~. S00 mg - Sterile aqueous excipient ....................... ...... 5 cm3.
xample_12: We made ~ elules corresponding to the formula:
- Acid ~ -fluoromethyl 3- ~ 2- (2-amino 4-thiazolyl) 2-methoxyimino acetamido7 2-oxo azetidine l-sulfamic cis, syn, racemic ...... ~ ............................ .... 250 mg - Excipient qsp one capsule finished at .... 400 mg.
Pharmacological study of the products of the invention.
In vitro activity, dilution method in liquid medium.
We prepare a series of tubes in which we the same quantity of sterile nutritive medium is distributed. We distributes in each tube increasing quantities of product to study, then each tube is seeded with a a bacterial strain. After incubation of twenty-four or forty-eight hours in the oven at 37C, the inhibition of growth is appreciated by transillumination which used to determine the minimum inhibitory concentrations these (MIC) expressed in ~ g / cm3.
J., es rec.ul.t ~ ts SUJ.VantS are obtained:

3 ~

Product of Example 1 -MIC in ~ g / ml STRAINS
_ _ 24 H 4 ~ H
_, _ _.
Escherichia Coli Sensitive Tetracycline 7624 1.25 1.25 Escherichia Coli Resis-tant T-tracycline AT CC 11303 0.16 0.16 . . ._ _ _____ _ _ Enterobacter Cloacae 681 2.5 2.5 _. ..................................
Escherichia Coli Resistant Gentamycin Tobramycin R55 123 0.62 0.52 _ _ Klebsiella Pneumoniae Exp. 52 145 1.25 2.5 __. .. _ _ _ _ Klebsiella Pneumoniae 2536 Resist Gentamycin 2.5 2.5.
Proteus mirabilis (indol-) A 235 0.16 0.16 . . .. ..._._. _ Proteus vulgaris ~ indol + ~
A 232 0.08 0.08 . .,.
Salmonella typhimurium 420 1.25 1.25 . .......... __ Providencia From 48 0.6? 0.62 . . . _. ~ _. .
Serra-tia Resistant-so Gentamycin 2,532 5 5 . -. - '-I

3g - - -MIC in ~ g / ~ l Products of STRAINS example 3 example 4 _ _. _ Escherichia Coli Sensitive Tetracycline 7624 1.2 1.2 0.6 0.6 _ _ Resistant Escherichia Coli Tetracycline AT CC 11 303 0.6 0.6 0.6 0.6 - _ Resistant Escherichia Coli Gentamycin Tobramycin R 55 123 D 1.2 1.2 0.6 0.6 _ Klebsiella Pneumoniae Exp. 52 145 5 10 5 5 __ ____ _ Kl.ebsiella Pneumoniae 2,536 Resistant Gentamycin 2.5 2.5 2.5 2.5 _ _ _ __ Proteus mirabilis (indol-).
~ 235 0.6 0.6 0.6 1.2 __ __ _ _ Proteus vulgaris ti.ndol- ~) A 232 1.2 1.2 0.6 0.6 _ _ Salmonella typhimurium 420 2.5 5 1.2 2.5 __ _ _ Providencia Du 48 2.5 2.5 0.6 1.2 _ _ Serratia Resistant Gentamy-cinema 2,532 2.5 5 5 5 43 ~

Product of Example 5 . _ _.
STRAINS CM I in ~ g / ml _.
Pseudomonas aeruginosa ] 77lm 0.6 1.2 _ _ Escherichia coli UC 1894 ~ 0.04 ~ 0.04 _ __ _ ~ _ Escherichia coli 0 78 0.15 0.15 __.
Escher.ichia coli TEM 0.15 0.15 Escherichia col.i 1507 E 0.15 0.15 _ _ Escherichia coli DC 0 0.3 0.3 _ _ _.
Echerichia coli DC 2 0.15 0.3 _ Salmonella typhimurium.
MZ 11 0.08 0.08 _ _._ _. I
Klebsiella pneumoniae Exp. 52 145 0.3 0.3 .
Klebsiella aerogenes .
Klebsiella aerogenes 1522 E 0.15 0.15 Enterobacter cloacae 1321 E 0.08 0.08 Serratia RG 2532 0.06. 1.2 ._. _ Proteus mirabilis (indol-) A 235 0.08 0.08 _ Proteus vulgaris (indol ~) A 232 ~ 0.04 ~ 0.04 _ _ Providencia Du 48 0.3 0.3 lZ111 '~ 3 ~

Product of Example 6 C ~ M. I in ~ g / ml Pseudomonas aeruginosa 177M 0.3 0.6 _.
Escherichia coli UA 1894 0.08 0.08 . _ _ __ I
Escherichia coli 0 78 0.3 0.3 Escherichia coli TEM 0.6 0.6 . _ Escherichia coli 1507 E 0.6 0.6 _ Escherichia coli DC 0 0.6 0.6 .
Escherichia coli DC 2 0.3 0.3 .. _ ~.
Salmonella t.yphimurium MZ 11 0.6 0.6 - __.
Klebsiella pneumoniae Exp. 52 145 0.6 0.6 _ _ __.
Klebsiella aerogenes 1082 E 0.6 0.6 _ _ Klebsi.ella aerogenes 1522 E 0.3 0.3 Enterobacter cloacae 1321 E 0.3 0.3 Serratia RG 2532 0.3 0.3 _ Proteus mirabilis (indol-) ~
A 235 0.04 ~ 0.04 Proteus vulgaris (indol ~) A 232 0.04 ~ Ç0.04 Providencia Du 48 0,150,15 _.

LL ~ 3 9 Product of Example 8 _ CMI strains in ~ g / ml : ~ = __ __ 24 El ¦ _48 H
~ ~ = ~

Escherlch'a coll _ ~ 0.04 ~ -0.08 .0 78 0.08 0.08 _ _ _ __ TEM 0.15 0.15 Escher51chia coli -0.04 s0.04 Escherichia coli 0.08 0.08 Escherlchia coli ~ 0.04 50.04 Salmonella typhimurium 0.08 0.08 Exp. 52,145 0.3 0.3.
__ _ _, _ _ =

Klebsiella aerogenes 0.08 0.08 Enterobacter cloacae 0.08 0.08 Serratia RG 2532 0.6 0.6 Proteus mirabilis (indol -) ~ 0.04 ~ 0.04 Proteus vulgaris (indol +) ~ 0.04 _0.04 ., _. ~ _.
Providencia Du 48 0.3 0.3

Claims (24)

The achievements of the invention, about which them an exclusive property right or lien is claimed, are defined as follows: 1. Process for the preparation of products of formula general (I):

(I) in which R represents a hydrogen atom or a linear or branched alkyl, alkenyl or alkynyl radical, having not more than 12 unsubstituted or substituted carbon atoms killed by one or more radicals chosen from the group comprising the free, salified or esterified carboxy radicals, alkoxycarbonyl, carbamoyl, dimethylcarbamoyl, amino, dialkylamino, alkylamino, halogen, alkoxy, alkylthio, aryl, aryl heterocyclic, arylthio and heterocyclic-thio aryl;
R1 represents a radical - (CH2) nX in which n represents an integer from 1 to 4 and X represents a halo atom gene, a cyano radical, an O-R'1 radical in which R'1 represents a hydrogen atom or an alkyl radical, or X represents a radical SR "1 in which R" 1 represents a hydrogen atom, an alkyl radical or a heterocycle where X represents a radical in which R 'and R "

represent a hydrogen atom, an alkyl radical having 1 to 4 carbon atoms or R 'and R'1 form with the atom nitrogen to which they are linked, a heterocycle or X represents feels an azido, thiocyanato or isothiocyanato radical, as well as the salts of the products of formula I with the bases or pharmaceutically acceptable acids, the trait wavy meaning that the products can be found under the cis or trans form or in the form of a cis-trans mixture, the products of formula I being in racemic form or optically active, the oxime being in the syn, charac-terized in that a product of formula (II) is treated:

(II) racemic or optically active, formula in which either Ra represents R1, R1 having the meaning indicated above Also, let Ra represent R1 in which the functions reagents are protected and A represents an atom of hydro-gene or a sulfo radical, by a product of formula III:

(III) in which Rb represents a hydrogen atom or a protective group of the amino radical and R'b represents a protecting group for the hydroxyl radical or R'b represents R, R having the meaning indicated above where R'b represents a radical R in which the functions reagents are protected, to obtain a product of formula (IV) (IV) racemic or optically active in which Rb, R'b, Ra and A have the previous meaning, product that we submit if necessary, and, if desired, to any or more of the following reactions in any order than:
a) cleavage by hydrolysis, hydrogenolysis or by action of thiourea of the protective group (s) that may represent Rb and R'b or include R'b and Ra, b) esterification or salification of the carboxy radical that may contain the radical R'b and salification of the radical sulfo, c) salification by an acid of the amino radical (s), d) sulfamation of products in which the radical A
represents a hydrogen atom, e) splitting of the molecule to obtain a product optically active. 2. Method according to claim 1, for the pre-paration of products of general formula (I):

(I) in which R represents a hydrogen atom or a alkyl radical, linear or branched, having at most 12 carbon atoms unsubstituted or substituted by one or several radicals chosen from the group comprising the free, salified or esterified carboxy radicals, amino or halogen; R1 represents a radical - (CH2) nX in which n represents an integer from 1 to 4 and X represents a halogen atom, a 1-methyl tetrazolyl radical not substituted or substituted by a mercapto radical, or a thiocyanato radical, as well as the salts of the products of formula I with bases or acids pharmaceutically acceptable, the wavy line signifying that the products can be in cis or trans form or in form of a cis-trans mixture, the products of formula I
being in racemic or optically active form, oxime being in the syn form, characterized in that one treats a product of formula (II):

(II) racemic or optically active, formula in which either Ra represents R1, R1 having the meaning indicated before-cedent, that is Ra represents R1 in which the functions reagents are protected and A represents an atom of hydro-gene or a sulfo radical, by a product of formula (III):

(III) in which Rb represents a hydrogen atom or a protective group of the amino radical and R'b represents a protecting group for the hydroxyl radical or R'b represents has R, R having the meaning indicated above where R'b represents a radical R in which the functions reagents are protected, to obtain a product of formula (IV):

(IV) racemic or optically active in which Rb, R'b, Ra and A have the previous meaning, product that we submit if necessary, and, if desired, to any or more of the following reactions in sequence any:
a) cleavage by hydrolysis, hydrogenolysis or by the action of the thiourea of the protective group or groups which may represent Rb and R'b or include R'b and Ra, b) esterification or salification of the carboxy radical that may contain the radical R'b and salification of the radical sulfo, c) salification by an acid of the amino radical (s), d) sulfamation of products in which the radical A
represents a hydrogen atom, e) splitting of the molecule to obtain a product optically active. 3. Method according to claim 1, for the preparation of the products of formula (I), as defined to claim 1, characterized in that one uses, for the implementation of the process, a product of formula (II) in which A represents a hydrogen atom and a product of formula (III) in which Rb represents an amino radical protecting group and in that the sulfamation is carried out on a product of formula (IV) in which Rb represents a protective group of amino radical. 4. Method according to claim 1, for the preparation of products of formula (I), characterized in that the products of formula (II) are obtained when causes a product of formula (V) to act:

(V) in which Ra has the meaning indicated in the claim cation 1 and Rp represents a protective group from imino radical, with a product of formula (VI):

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

(VII) in which Ra, Rp, R'p and R "p have the pre-cedent, product of formula VII which is submitted if necessary and if desired, to any one or more of following reactions:
a) cutting by hydrolysis, hydrogenolysis or action of thiourea of the radical Rp;
b) sulfamation of the amine in position 1;
c) cutting by hydrolysis, hydrogenolysis or action of thiourea of the radicals R'p and R "p;
d) splitting of the molecule to obtain a product optically active. 5. Method according to claim 4, characterized in that a product of formula V is used at the start in which Rp represents a protective group of imino radical containing an asymmetric carbon and isolates a product of formula VII in optically active form. 6. Method according to claim 1, characterized in that the radical Ra represents a fluoromethyl radical. 7. Method according to claim 1, for the preparation of products of formula I, characterized in that that the products of formula (IIa):

(IIa) in which A has the meaning given in resale dication 1, n represents an integer from 1 to 4 and either X "represents X, X having the meaning indicated in the claim 1, with the exception of a halogen atom, either X "represents X in which a reactive function is protected, are obtained when processing a product of formula (VIII):
(VIII) in which R'q and R "q each represent an atom of hydrogen or represent one, a hydrogen atom and the other, an amino radical protecting group where R'p and R "p together represent a group divalent protector, by a reactive derivative of the radical cyano, from the radical -OR'1, -SR "1, , -SCN or -NCS
R'1, R "1 and having the meaning indicated in the claim 1, to obtain a product of formula (IX):
(IX) in which X ", A, R'q and R" q have the indicated values previously, product that is submitted if necessary and if desire, to any one or more of the reactions following:
a) cleavage by hydrolysis, hydrogenolysis or by the action of the thiourea of the groups represented by R'q and R "q when these are different from a hydrogen atom, b) sulfamation of products in which the radical A represents a hydrogen atom, c) splitting of the molecule to obtain a product optically active. 8. Method according to claim 1, for prepa-the products of formula (I), as defined in claim 1 and corresponding to the general formula (I '):

(I ') syn isomer, in cis form in which R2 represents a hydrogen atom or an alkyl radical, linear or branched, unsubstituted or substituted by one or more halogen atoms, a carboxyl, amino or cyano radical, n 'represents the integer 1 or 2 and X' represents a fluorine atom, a 2-pyridinylthiomethyl radical or a thiocyanato radical, in racemic form or optically active as well as the salts of the products of formula I ' with pharmaceutically acceptable bases or acids, characterized in that products are used at the start of formulas II and III in which Ra, Rb, R'b and A have the corresponding values. 9. Method according to claim 8, characterized in that n 'represents the number 1 and X' represents a fluorine atom. 10. Method according to claim 8, characterized in that products of formula (I ') are prepared, in which the substituent R2 represents a hydrogen atom or a methyl, difluoromethyl, carboxymethyl radical free, esterified or salified, an aminoethyl radical, cyanomethyl, 1-methyl 1-carboxymethyl free, esterified or salified. 11. Process for the preparation of 4-fluoro- acid methyl 3- [2- (2-amino 4-thiazolyl) 2-methoxyimino acetamido]
2-oxo azetidine 1-sulfamic cis, syn-isomer, racemic or optically active and its pharmaceutically acceptable salts tables, characterized in that the acid is reacted 2- (2-trityl-amino 4-thiazolyl) 2-methoxyimino acetic, syn isomer with 4-fluoromethyl 3-amino hydrochloride 2-oxo azetidine cis to form 4-fluoromethyl 3-[2- (2-tritylamino 4-thiazolyl) 2-methoxyimino acetamido]
2-oxo azetidine cis, racemic syn which is then submitted to a sulfamation reaction then to a reaction of detritylation to obtain the desired product that if desired, salify. 12. Process for the preparation of 4-fluoro- acid methyl 3- [2- (2-amino 4-thiazolyl) 2-difluoromethoxyimino acetamido] 2-oxo azetidine 1-sulfamic cis, syn-isomer, racemic or optically active and its pharmaceutical salts-acceptable, characterized in that one reacts 2- (2-tritylamino 4-thiazolyl) 2-difluoromethoxy- acid imino acetic, syn isomer with hydrochloride 4-fluoromethyl 3-amino 2-oxo azetidine cis to form the 4-fluoromethyl 3- [2- (2-tritylamino 4-thiazolyl) 2-difluoro-methoxyimino acetamido] 2-oxo azetidine cis, syn rac-mique which is then subjected to a sulfama reaction then to a detritylation reaction to obtain the desired product which, if desired, is salified. 13. Products of general formula (I):
(I) in which R represents a hydrogen atom or a linear or branched alkyl, alkenyl or alkynyl radical, having not more than 12 unsubstituted carbon atoms or substituted by one or more radicals chosen from the group comprising free, salified carboxy radicals or esterified, alkoxycarbonyl, carbamoyl, dimethylcarbamoyl, amino, dialkylamino, alkylamino, allogeneic, alkoxy, alkylthio, aryl, heterocyclic aryl, arylthio and heterocyclic aryl click-thio; R1 represents a radical - (CH2) nX in which n represents an integer from 1 to 4 and X represents te 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 an SR "1 radical in which R "1 represents a hydrogen atom, a alkyl radical or a heterocycle or X represents a radical in which R 'and R "represent a hydrogen atom, an alkyl radical having from 1 to 4 carbon atom or R 'and R "form with the nitrogen atom to which they are linked, a heterocycle or X represents a azido, thiocyanato or isothiocyanato radical, as well as the salts of the products of formula I with the bases or the pharmaceutically acceptable acids, the wavy line meaning that the products can be found under the cis or trans form or as a cis-trans mixture, the products of formula I being in racemic form or optically active, the oxime being in the syn form, each time they are obtained by a process according to the claim 1 or its obvious chemical equivalents. 14. Products of general formula (I):
(I) in which R represents a hydrogen atom or a alkyl radical, linear or branched, having at most 12 carbon atoms unsubstituted or substituted by one or several radicals chosen from the group comprising the free, salified or esterified carboxy radicals, amino or allogeneic; R1 represents a radical - (CH2) nX in which n represents an integer from 1 to 4 and X
represents a halogen atom, a 1-methyl- radical tetrazolyl unsubstituted or substituted by a radical mercapto, or a thiocyanato radical, as well as the salts products of formula I with bases or acids pharmaceutically acceptable, the wavy line signifies confident that the products can be in the form cis or trans or as a cis-trans mixture, the products of formula I being in racemic or optic form only active, the oxime being in syn form, each once they are obtained by a process according to the res indication 2 or its obvious chemical equivalents. 15. Products characterized in that they are as defined in claim 13, each time that they are obtained by a process according to the claim cation 3 or its obvious chemical equivalents. 16. Products characterized in that they are as defined in claim 13, each time that they are obtained by a process according to the claim cation 4 or its obvious chemical equivalents. 17. Products characterized in that they are as defined in claim 13, each time that they are obtained by a process according to the claim cation 5 or its obvious chemical equivalents. 18. Products characterized in that they are as defined in claim 13, wherein R1 represents a fluoromethyl radical, each time that they are obtained by a process according to claim 6 or its obvious chemical equivalents. 19. Products characterized in that they are as defined in claim 13, each time that they are obtained by a process according to claim 7 or its obvious chemical equivalents. 20. Products as defined in the claim 13, characterized in that they correspond to the formula general (I '):

(I ') syn isomer, in cis form in which R2 represents a hydrogen atom or an alkyl radical, linear or branched trusted, unsubstituted or substituted by one or more atoms halogen, a carboxyl, amino or cyano radical, n ' represents the integer 1 or 2 and X 'represents a fluorine atom, a 2-pyridinylthiomethyl radical or a thiocyanato radical, in racemic form or optically active as well as the salts of the products of formula I 'with pharmaceutically acceptable bases or acids;
each time they are obtained by a process according to the claim 8 or its obvious chemical equivalents. 21. Products as defined in the claim 13, characterized in that R represents a hydrogen atom or a alkyl radical, linear or branched, unsubstituted or substituted by one or more halogen atoms, a radical carboxyl, amino or cyano, n represents the number 1 and X
represents a fluorine atom, whenever they are obtained by a process according to claim 9 or its manifest chemical equivalents. 22. Products as defined in the claim 13, characterized in that the substituent R represents a hydrogen atom or a methyl or difluoromethyl radical, free, esterified or salified rarboxymethyl, a radical aminoethyl, cyanomethyl, free 1-methyl 1-carboxyethyl, esterified or salified, n represents the number 1 and X
represents a fluorine atom, whenever they are obtained by a process according to claim 10 or its obvious chemical equivalents. 23. Products according to claim 13, charac-terized in that they consist of 4-fluoro- acid methyl 3- [2- (2-amino 4-thiazolyl) 2-methoxyimino acetamido]
2-oxo azetidine 1-sulfamic cis, syn-isomer, racemic or optically active and its pharmaceutically salts acceptable, whenever obtained by a process according to claim 11 or its chemical equivalents manifestos. 24. Products according to claim 13, charac-terized in that they consist of 4-fluoro- acid methyl 3- [2- (2-amino 4-thiazolyl) 2-difluoromethoxyimino acetamido] 2-oxo azetidine 1-sulfamic cis, syn-isomer, racemic or optically active and its pharmaceutical salts-acceptable, whenever obtained by a method according to claim 12 or its equivalents manifest chemicals.