FR2515178A1 - INTERNAL 2-OXO-1 AZETIDINESULPHONIC ACID SALTS AND PROCESS FOR PREPARING THE SAME - Google Patents

Abstract

COMPOUNDS OF FORMULA: (CF DRAWING IN BOPI) IN WHICH R IS A RADICAL ALKYL, HALOALKYL, ARYL OR ARYLALKYL. THESE COMPOUNDS ALLOW THE PREPARATION OF 4-SUBSTITUTE DERIVATIVES OF 2-OXO-1-AZETIDINE-SULPHONIC ACIDS, WHICH HAVE ANTIBACTERIAL ACTION.

Description

Internal salts of 2-oxo-1 azetidine sulfonic acids, and their method of

  preparation The 3-lactams of formula:

IR NH SO 2-R

i 2

  C CH

I I e

C N-SO 3 M

  show an antibacterial action.

  In formula I and throughout the specification, the symbols have the following definitions: R is a hydrogen atom or a methoxy radical; R 1 is an acyl radical; R 2 is an alkyl, haloalkyl, aryl or arylalkyl radical; and

  M is a hydrogen atom or a Qation.

  The following are the definitions of

  different terms used to describe the 8-lactams according to

  These definitions apply to terms as used throughout the specification (unless otherwise limited in a particular case), either as such or as a part of the specification.

a larger group.

  The terms "alkyl" and "alkoxy" refer to

  straight or branched chain radicals.

  with 1 to 10 carbon atoms.

  The terms "alkanoyl" and "alkenyl" also refer to straight or branched chain groups.

  groups having from 1 to 10 carbon atoms are preferred.

  The terms "cycloalkyl" and "cycloalkenyl" refer to groups having 3, 4, 5, 6 or 7 carbon atoms. The terms "halo" and "halogen" refer to the

  fluorine, chlorine, bromine or iodine atoms.

  The term "aryl" denotes a phenyl radical optionally substituted with 1, 2 or 3 amine groups (-NH 2), halogen atoms, hydroxyl groups, trifluoromethyl radicals, alkyl (from 1 to 4 carbon atoms) or

  alkoxy (1 to 4 carbon atoms).

  The term "acyl" includes all organic radicals derived from an organic acid (i.e., a carboxylic acid) by removal of the hydroxyl group. Certainly, certain acyl radicals are preferred, but this preference should not be avoided. The following are typical examples of acyl radicals which have been used in the past to acylate 3-lactam antibiotics, including 6-aminopenicillanic acid and its derivatives, as well as that 7 aminocephalosporanic acid and its derivatives; see, for example, Cephalosporins and Penicillins, edited by Flynn, Academic Press (1972), German Patent Application Laid-open Oct. 10, 1978 under No. 2,716,677, Belgian Patent No. 867,994 published December 11, 1978, USN Patent 4 152,432 issued May 1, 1979, US Patent No. 3,971,778 issued July 27, 1976, U.S. Patent No. 4,172,199 issued October 23, 1979, and British Patent No. 1; 348,894 published March 27, 1974 Parts of these references which describe various acyl radicals are incorporated herein by reference. The following list of acyl radicals is presented to point to other examples of the term "acyl"; It should not be considered as limiting the definition of this term. Typical examples of acyl groups are: (a) aliphatic radicals having the formula: wherein Ra is an alkyl radical; cycloalkyl; alkoxy; alkenyl; cycloalkenyl; cyclohexadienyl; or alkyl or alkenyl substituted by one or more halogen atoms, cyano, nitro, amine or mercapto groups, or

  alkylthio or cyanomethylthio radicals.

  (b) Carbocyclic aromatic radicals having the formula: ## STR2 ##

CH-C '

R e d l

CH 2 -O-C-,

or R he

H 2 -S-C-

  wherein N is 0, 1, 2 or 3; Rb, Rc and Rd are each, independently, a hydrogen or halogen atom, a hydroxyl, nitro, amine or cyano group, or a trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy group;

15178

  from 1 to 4 carbon atoms, or aminomethyl; and Re is an amine or hydroxyl group, a carboxylic salt, a protected carboxyl group, a formyloxy radical, a sulfonic salt, a sulfoamino salt, an azide group, a halogen atom, or a hydrazine, alkylhydrazine, phenyl radical or

  hydrazine or (alkylthio) thioxomethyllthio.

  Preferred carbocyclic aromatic acyl groups include those having the formula:

HO CH 2-C-,

  O (Re is preferably a carboxylic salt or a sulphonic salt) and

S CH-Cl-

he

HO '-C-

  R e (Re is preferably a carboxylic salt or a sulfonic salt) and O CH-C-R e (Re is preferably a carboxylic salt or a sulfonic salt). (c) heteroaromatic groups having the formula: ## STR2 ## wherein Rf (CH 2) nC-, ## STR2 ## C, or OO He He

RF-C-C-

  wherein N is 0, 1, 2 or 3; Re has the same definition as above; and Rf is an optionally substituted five, six or seven membered heterocyclic ring containing 1, 2, 3 or 4 (preferably 1 or 2) nitrogen, oxygen or sulfur atoms. Typical examples of heterocyclic rings are thienyl radicals, furyl, pyrrolylel pyridinyl, pyrazolyl, pyrazinyl, thiazolyl,

  pyrimidinyl and tetrazolyl Typical examples of substitute

  are halogen atoms, hydroxyl, nitro, amine, cyano groups, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or O groups;

HOOC-CH-CH 2 -O-C-NH-.

  NH 2 Preferred heteroaromatic acyl radicals include radicals having the above formulas in

  which Rf is a 2-amino-4-thiazolyl, 2-amino-5- radical

  halo-4-thiazolyl, 4-aminopyrimidin-2-yl, 5-amino-1,2,4-

  thiadiazol-3-yl, 2-thienyl, 2-furanyl or 6-aminopyridine -

2-yl.

  (d) 11 (4-substituted-2,3-dioxo-1) radicals

  piperazinyl) carbonyllaminolarylacetyl having the formula o O

_C-CH-NH-C-N N-R

  Wherein R is an aromatic group (including carbocyclic aromatic groups such as those having the formula

R

  Rb d and heteroaromatic groups as they are encompassed

  in the definition of Rf); and Rh is an alkyl radical,

  a substituted alkyl radical (the alkyl radical being substituted by one or more halogen atoms, or by one or more cyano, nitro, amine or mercapto groups), an arylmethyleneamine radical (that is to say N = CH-Rg o Rg has the same

  definition as above), an arylcarbonylamine radical (that is,

  O ie -NH-C-R oR has the same definition as above) or g g

an alkylcarbonylamine radical.

  The radicals II (4-substituted-2,3-dioxo-1-

  piperazinyl) carbonyllaminolarylacetyl include

  those in which Rh is an ethyl radical, phenylmethylene

amine or 2-furylmethyleneamine.

  (e) (substituted oxyimino) arylacetyl radicals having the formula o

-C-C = N-O-R.

  wherein Rg has the same definition as above and R1 is a hydrogen atom or an alkyl, cycloalkyl, alkylaminocarbonyl, arylaminocarbonyl (i.e. same definition as above) or substituted alkyl gg (the alkyl radical being substituted by one or more halogen atoms or by one or more cyano, nitro, amine, mercapto, alkylthio groups, by one or more aromatic groups (according to definition of R), by one or more carboxyl groups (including their salts), by

  one or more radicals amide, alkoxycarbonyl, phenyl

  methoxycarbonyl, diphenylmethoxycarbonyl, hydroxyalkoxy

  phosphinyl, dihydroxyphosphinyl, hydroxy (phenylmethoxy) -

  phosphinyl or dialkoxyphosphinyl).

  Radicals (substituted oxyimino) arylacetyl

  preferred include those wherein R is 2-

  amino-4-thiazolyl The radicals in which R 1 is a methyl, ethyl or carboxymethyl radical are also preferred.

  1-carboxy-1-methylethyl or 2,2,2-trifluoroethyl.

  (f) (Acylamino) arylacetyl radicals having the formula

O O

He He

-C-CH-NH-C-R.

  In which R has the same definition as above and R 1 is a substituent of formula

R

  ## STR2 ## an amine, alkylamine, (cyanoalkyl) amine, amide, alkylamide, (cyanoalkyl) amide group, or a substituent of formula

NH O I

he NH 2 OI

-CH 2 -NH-C N / -CH-CH 2-C-NH-CH 3,

HO

-N (CH 2 -CH 2 OH) 2, CH 3,

OH

H OH

N o 'N O.

N, or N-CH.

  Preferred (acylamino) arylacetyl radicals having the above formula include those radicals in which R 1 is an amine or amide group.

  radicals in which Rg is a phenyl radical or 2-

thienyl.

  (g) 3-substituted-2-oxo-1-llll radicals

  imidazolidinylcarbonylaminaminarylacetyl having the formula

0 O C

he l

-C-CH-NH-C-N N-R

R CH 2 -CH 2

  g in which Rg has the same definition as above and Rk is

  a hydrogen atom, an alkylsulfonyl radical, aryl

  methyleneamine (i.e., -N = CH-R o R has the same

g g.

  I definition as above), -C-Rm (where R is a hydrogen atom or an alkyl radical optionally substituted by halogen), an aromatic group (as defined by Rg above), an optionally substituted alkyl radical. by one or more halogen atoms or cyano groups,

nitro, amine or mercapto.

  The 3-substituted-2-oxo-1-imidazolidinyl radicals

  Preferred carbonyllaminolarylacetyl compounds having the above formula include those wherein R8 is phenyl or 2-thienyl. Rk is also preferred in which Rk is hydrogen or methylsulfonyl,

  phenylmethyleneamine or 2-furylmethyleneamine.

  The term "cation" as used throughout this specification refers to any atom or group of positively charged atoms. The "-SO 3 M +" substituent of the atom of Blactam nitrogen according to the present invention includes all sulfonic acid salts. Of course, the pharmaceutically acceptable salts are preferred, but other salts are also useful for purifying the products according to the invention, or as intermediates for Preparation of pharmaceutically acceptable salts The cationic portion of the sulfonic acid salts according to the present invention can be obtained from organic or inorganic bases. This cationic part includes, but is not limited to, the following ions: ammonium; ammonium

  substituted, such as alkylammonium (for example tetra-n-butyl-

  ammonium, hereinafter called tetrabutylammonium); alkali metals, such as lithium, sodium and potassium; alkaline earth metals, such as calcium and magnesium; pyridinium; dicyclohexylammonium; hydrabaminium;

  benzathipium; N-methyl-D-glucaminium.

  As indicated under formula I and in the definitions following formula I, M may be a hydrogen atom. The corresponding compounds are often referred to in the art as "internal salts" because of the simultaneous presence of a positive charge and a charge

negative in the molecule.

  The subject of the invention is the ε-lactams which have been described above, and whose stereochemistry at the center of asymmetry in position 3 of the lactam nucleus is the same as the configuration on the carbon atom at position 6 of the natural penicillins (penicillin G for example), and that the configuration on the carbon atom in position 7

  natural cephamycins (cephamycin C for example).

  The β-lactams of formula I have an action on a range of gram-negative and gram-positive organisms. The compounds according to the present invention can be used as agents to combat bacterial infections (including infections of the urinary tract and respiratory infections) in mammalian species such as domestic animals (eg dogs, cats,

  cows, horses, etc.) and in humans.

  To combat bacterial infections in mammals, a compound according to the present invention may be administered to a mammal to be treated at a dose of from about 1.4 mg / kg / day to about 350 mg / kg / day,

  preferably from about 14 mg / kg / day to about 100 mg / kg / day.

  All modes of administration that have been used in the past to reach the focus of penicillin and cephalosporin infection are also contemplated for the new 6-lactams according to the present invention. These modes of administration include oral administration,

  intravenous, intramuscular, and in the form of suppositories.

  The compound of formula I may be prepared from an azetidine having formula II

A -NH - ,, S 2 R

CH-CH

  C-NH. The introduction of a sulpho (SO 3) group at the 1-position of a compound of formula II gives the corresponding compound having the formula III SO -R A 1 -NH 2 2 CH-CH

Q / 3

  The conversion can be carried out by reacting a compound of formula II with a complex of pyridine and sulfuric anhydride. The reaction can be carried out in an organic solvent or a mixture of organic solvents, preferably a mixture of a polar solvent such as dimethylformamide and a halogenated hydrocarbon such as dichloromethane. This reaction gives a compound of formula III in which M is a pyridinium ion. Instead of using a ready-made complex of pyridine and sulfuric anhydride, to form the complex in situ, using, for example as reagents, the chlorosulfonyltrimethylsilyl ester and the pyridine or else a complex of dimethylformamide and of sulfuric anhydride, of 2-picoline and of sulfuric anhydride, or of 2,6 -lutidine and sulfur trioxide. With the aid of conventional techniques (for example ion exchange resins, crystallization or extraction of ion pairs) the pyridinium salt obtained by the preceding procedure can be converted into other salts. these techniques for transforming the products of formula I, or any of the intermediates

described here in other salts.

  A second method for introducing the sulfo group at the 1-position of an azetidine of formula II is to first silylate the compound and then to subject the silylated compound obtained to undergo a silyl transposition reaction.

  Typical examples of silylating agents are trifluoride

  monosilyl acetamid, a combination of

  trimethylsilyl and triethylamine, and the trifluoro-

  bis-trimethylsilyl acetamide, and a typical example reagent usable for the transposition reaction

  silyl is trimethylsilyl chlorosulfonate.

  Removal of the protecting group of an azetidine of formula III gives a zwitterion having formula IV

-R

NH

3 CH-CH 2 2

  The techniques for removing the protecting group used are conventional, and will depend on the particular protecting group (A 1) that is present. Treatment with an acid (eg formic acid or trifluoroacetic acid) ) cut of the molecule one

  triphenylmethyl or t-butoxycarbonyl protecting group.

  A benzyloxycarbonylamine protecting group can be

  cut from the molecule by treatment with trimethyl iodide

  silyl or by catalytic hydrogenation The treatment with phosgene or phosphorus pentachloride makes it possible to cut the molecule an amide protecting group The zwitterions of formula IV are new intermediates, and as such they form an integral part of the present invention.

invention.

  Conventional acylation techniques can be used to prepare the product of formula I (wherein R is a hydrogen atom) from a zwitterion of formula IV. Typical examples of acylation techniques include reaction with a halide carboxylic acid or carboxylic acid anhydride The reaction with a carboxylic acid is best in the presence of a carbodiimide and a substance capable of

  in situ form an active ester such as N-hydroxybenzoate

  When the acyl radical (R 1) contains reactive functional groups (for example amine or carboxyl), it may be necessary to first protect these functional groups, and then to carry out the reaction. acylation, and finally to eliminate the protective group of the

resulting product.

  The lactams of formula I in which R is a methoxy radical can be prepared from the corresponding compound of formula I wherein R is a hydrogen atom. The halogenation of the nitrogen of the amide group of a non-methoxyl compound of formula I gives, in situ, an intermediate having the formula V ci

I C 502-R 2

R -CH-CH

Ri H

C N-SO 3 M '

  Reaction of an intermediate of formula V with a methoxylating agent, for example with an alkali metal methoxide, gives a product of formula I in which R is a methoxy radical. The reaction can be carried out in an organic solvent, for example in a polar organic solvent such

  than dimethylformamide at a reduced temperature.

  Another method of synthesis for preparing the compounds of formula I wherein R is a methoxy radical is to first alkoxylate a compound of formula II wherein A 1 NH is a carbamate (eg A 1 is a benzyloxycarbonyl radical), then to introduce a

  sulfo group at the 1-position of the resulting compound.

  Removal of the protecting group and acylation, using the procedures described above, give the

  products of formula I wherein R is a methoxy radical.

  The azetidinones of formula II can be synthesized by various procedures. The secopenicillins having the formula

VI A-NH S-R

i CH CH O

"C N-C-O-OR 3 3

C

CH 3 CH 3

  wherein R 3 is alkyl, halogenated alkyl, aryl or arylalkyl, may be oxidized and acid treated to provide the corresponding azetidinone of formula II. Alternatively, a cis azetidinone of formula II can be treated with a thiolate having formula VII

R 2-S X,

  wherein X is a cation (preferably an alkali metal) to give a mixture of diastereoisomers having the formula

VIII -R

A _NH c SR 2 CH-CH

I I

z C-NH Oç and IX

A -NHN / S-R 2

CH-CH

I I

g C NH.

  The above two compounds can be separated by conventional chromatographic or fractional crystallization techniques. The oxidation of a compound of formula VIII or IX gives the corresponding azetidinone of formula II. oxidation agents are potassium permanganate, ozone, hydrogen peroxide

and metachloroperbenzoic acid.

  Yet another mode of operation allowing

  to prepare the azetidinones of formula II makes use of 2-

  azetidinone-4-disulfides having the formula X

A -NH N, / S-S-R

CH-CH O

CH 3 CH

i I ,? j / CN-C-C-OR 3 O

CH 3 CH

  Treatment of an azetidinone of formula X with triphenylphosphine or trimethoxyphosphine gives the corresponding azetidinone of formula VI, which can be oxidized and treated with an acid to give the corresponding azetidinone of formula II. a compound of formula VI to remove the protecting group (A 1) and then protect it again with a different grouping before proceeding

to oxidation.

  Yet another procedure for preparing the azetidinones of Formula II involves bicyclic thiazoline azetidinones having the formula XI R z C

N S

10

CH-CH

  wherein R is an acyl radical The reaction of a compound of formula XI with a compound of formula

XII

R 2 -Y,

  in which Y is a leaving group such as a halogen atom, gives the corresponding compound having the formula XIII

R 4 -NH I S-R

CH-CH 2

I I

C NH.

  Depending on the group R 4 which it acts, it may be necessary to deacylate a compound of formula XIII (which gives the corresponding 3-amino-2-azetidinone) and then to protect the amine group again beforehand.

oxidation of the compound.

  Yet another procedure for preparing the azetidinones of formula II is to react an azetidinone of formula

XIV

o Ax Iv H \ o-C-CHI

A _NH '1 \ H

CH-CH

I I

l C NH

C

  with a thiolate of formula VII to obtain the mixture

  corresponding diastereoisomers of formulas VIII and IX.

  This mixture can be converted to the desired azetidinone of formula II using the procedures described above. Yet another procedure for preparing the azetidinones of formula II is to react an azetidinone of formula XIV with a salt of formula XV

R 2-SO 2 X

  to obtain the corresponding mixture of diastereoisomers of the formulas XVI and CH 2 O 2

A 1-NCHC 502-R 2

CH-C

I I

1 1

C-NH

  It is possible to separate the compounds

  above using standard chromatography techniques

or fractional crystallization.

  Yet another procedure for preparing and preparing the azetidinones of the formula II is to react an azetidinone of the formula XVII wherein R 2 is a methyl radical with a salt of the formula XV to obtain

-A 1 NH, 1/502-R 2

  320 the corresponding mixture of diastereoisomers of formulas H-CH I t NH.

  XVI and XVII, which are separated as described above.

  With the aid of the following techniques, the following forms of hromatography have been

  Specific embodiments of the present invention.

EXAMPLE 1

  Internal salt of the acid (3 S-cis) -3-amino-4- (methylsulfonyl) -2-t isopropyl azideidinone of formula XVII, wherein R 2 is a methyl radical, with a salt of formula XV to obtain the corresponding mixture of diastereoisomers of formulas

  XVI and XVII, which can be separated as described above.

  The following examples are forms of

  Specific embodiments of the present invention.

EXAMPLE 1

  Internal salt of (3S-cis) -3-amino-4- (methylsutfonyl) -2-

oxo-1-azetidinesulfonic

  A) tetrabutylammonium salt of (3 R-cis) -4- (methyl)

sulfonyl) -2-oxo-3-l (triphenylmethyl) aminol-1-azetidine

  The sulfonic acid is stirred in 20 ml of absolute dimethylformamide

   C for 24 hours 2.01 g of (cis) -1-oxo-3-l (triphenyl)

  methyl) aminol-4-azetidinylmethyl sulfone and 3.2 g of a sulfuric pyridineanhydride complex Dimethylformamide is distilled under vacuum The residual oil is dissolved in 50 ml of dichloromethane. The resulting solution is poured into 100 ml of ice water containing 1.7 g of tetrabutylammonium bisulfate The pH is adjusted to 5.3 with 1 N potassium hydroxide. The separated organic phase is dried over sodium sulphate and the solvent is distilled to give 3.6 g of the compound. title in the form of an oil.

  B) Inner salt of (3S-cis) -3-amino-4- (methyl)

  sulfonyl) -2-oxo-1-azetidinesulfonic acid 3.4 g of the tetrabutylammonium salt of

  (3R-cis) -4- (methylsulfonyl) -2-oxo-3-ltriphenylmethyl acid) -

  aminol-1-azetidine sulfonic acid in 15 ml of a 3: 2 mixture of formic acid and dichloromethane, and the mixture is stirred at 5 ° C. for 40 minutes. The solution is then poured into 200 ml of ether and the mixture is collected and dried. composed of the title,

  yield 0.9 g, melting point 110 C with decomposition.

EXAMPLE 2

  Potassium salt of 1 3 R-1 3a, 4a (Z) ll-3-ll acid (2-amino-4-

  thiazolyl) (methoxyimino) acétyllaminol-4- (methylsulfonyl) -2-

  oxo-1-azetidine sulfonic acid is dissolved in 10 ml of absolute dimethylformamide

  the inner salt of (3S-cis) -3-amino-4- (methyl)

  sulfonyl) -2-oxo-1-azetidine sulfonic acid (0.344 g;

  Example 1), 0.202 g of (Z) -2-amino-α- (methoxyimino) acid;

  thiazoleacetic acid and 0.175 g of N-hydroxybenzotriazole The solution is cooled to 0.degree. C. and 0.101 g of

  triethylamine and then a solution of 0.202 g of dicyclohexyl-

  carbodiimide in 5 ml of tetrahydrofuran; stirring is continued for 4 hours. The dimethylformamide is distilled off in vacuo and the residue is dissolved in 20 ml.

  acetone The dicyclohexylurea is separated by filtration.

  After addition of 0.34 g of potassium perfluorobutanesulfonate to the filtrate, the title compound precipitates. Using water and then a 9: 1 mixture of water and acetone as eluants, the title compound is purified. by chromatography on "HP 20" resin column; the fractions containing the title compound are freeze dried. The product has a melting point of 218 ° C, decomposition.

EXAMPLE 3

  Internal salt of (3 R-trans) -3-amino-4- (methylsulfonyl) -

  2-oxo-1-azetidine sulfonic acid Following the procedure of Example 1, but

  substituting (trans) -1-oxo-3-l (triphenylmethyl) aminol

  4-azetidinylmethyl sulfone to the corresponding cis-isomer, the title compound is obtained, mp 127 C with

decomposition.

EXAMPLE 4

  Potassium salt of 1 3 R-1 3a, 4a (R) ll-3-1lll (4-ethyl)

  2,3-dioxo-1-piperazinyl) carbonylaminaminophenylacetyl-4-amino

  (methylsulfonyl) -2-oxo-1-azetidine sulfonic acid Following the procedure of Example 2,

  but substituting (Z) -2-amino-α- (methoxyimino) -4-

  thiazoleacetic acid with (R) -a-11 (4-ethyl-2,3-dioxo-1-

  piperazinyl) carbonyllaminol phenylacetic, the

  title compound, mp 149-153 C with decomposition.

EXAMPLES 5 to 8

  Following the procedures of Examples 1 and

  2, but replacing (cis) -1-oxo-3-l (triphenylmethyl) -

  aminol-4-azetidinylmethyl sulfone with the compound stated in

  column I below, and (Z) -2-amino-α- (methoxy)

  imino) -4-thiazoleacetic acid by the acid set forth in column II below, the product set forth in column III below is obtained. Examples 6 and 7 require a step of removal of the protecting group at the end of the The removal of the protecting group is carried out in Example 6 by treatment of the protected compound

  with trifluoroacetic acid and anisole at 15 C.

  Removal of the protecting group is carried out in Example 7 by catalytic hydrogenation (10% palladium

on charcoal) of the protected compound.

Column I) CNH so.

(C 2 \ -2

  ## STR2 ##

V 2 2

  0 C 1 (C) -N-C-O-C-O-C-O-Ci Ci N

i 12 Kli-

0 O

  (Z) O H N Column III 2 CIL III (Z) HO-C-C-O-N = C-C-NH C 1

1 2 2

CH O Ge

3 to 115 O 3

I 2 N

  ## STR2 ## wherein R 3 (C 1 -C 3) -N = C-C-NH 2 (C 1 -C); t _N S O e? i 12 N 3

8) CNH

Ji 3 so Cil __ // _ \\

2 2 / __ /

Claims (1)

Compound of formula NH ## STR5 ## in which R 2 is an alkyl, haloalkyl, aryl or arylalkyl radical A compound according to claim 1 which is internal salt of (3S-cis) -3-amino-4- (methylsulfonyl) -2-oxo-1-azetidinesulfonic acid Compound according to claim 1, which is the internal salt of the acid R-trans) -3-amino-4- (methylsulfonyl) -2-oxo-1-azetidinesulfonic acid 4 Process for the preparation of a compound of the formula NHSR 2 N 3 CH-CH NNS 03 #, characterized in that it consists of introducing a sulfo group (503) at the 1-position of a compound of the formula - / 502-R 2 A 1 NH CH CH 1 1 1 - C NH   Wherein A 1 is a protecting group of the amine function.