DK164404B - 3-AMINO-2-OXO-AZETIDIN DERIVATIVES, ANALOGUE PROCEDURES FOR PREPARING THEREOF, AND MEDICINES CONTAINING THE DERIVATIVES - Google Patents

Abstract

1. Claims : For the contracting states : BE, SE, CH, DE, FR, GB, IT, LI, LU, NL Products of general formula (I) : see diagramm : EP0114128,P43,F6 in which R represents a hydrogen atom, an alkyl, alkenyl or alkynyl radical having at the most 12 carbon atoms, optionally substituted by one or more radicals chosen from carboxy radicals, optionally salified or esterified ; amino, methylamino, dimethylamino and diethylamino radicals ; the phenyl radical optionally substituted by one or more radicals chosen from the following radicals : hydroxy, methyl, methoxy, chloro, bromo, fluoro ; fluoro, chloro, bromo or iodo radicals ; nitrile, CONH2 or CONH SO2 R" radicals in which R" represents an alkyl radical having from 1 to 4 carbon atoms ; a phenyl radical, an amino, methyl or dimethylamino radical ; a heterocyclic amino radical chosen from piperidino, morpholino piperazino or 4-ethyl-2,3-dioxo-1-piperazino radicals ; - a cycloalkyl radical having from 3 to 8 carbon atoms or a radical : see diagramm : EP0114128,P44,F1 salified or esterified, in which nc represents a whole number from 0 to 5, - one of the following radicals : acetyl, propionyl or benzoyl, carbamoyl, dimethylamino carbonyl, phenyl or benzyl optionally substituted by alkyl, alkoxy or halogen ; R1 represents a hydrogen atom, an alkyl, alkenyl, alkynyl or thioalkyl radical having a the most 12 carbon atoms, optionally substituted by one or more radicals chosen from azido or alkylthio radicals having from 1 to 4 carbon atoms or a phenylthio radical, optionally salified or esterified carboxy radicals, amino, methylamino, dimethylamino or diethylamino radicals, the phenyl radical, optionally substituted by one or more radicals chosen from hydroxy, halogeno, trifluoromethyl, amino, alkyl or alkoxy radicals having from 1 to 4 carbon atoms ; fluoro, chloro, bromo or iodo radicals, nitrile, CONH2 or CONH SO2 R" radicals in which R" represents an alkyl radical having from 1 to 4 carbon atoms, a phenyl radical, an amino, methyl or dimethylamino radical, a heterocyclic amino radical chosen from piperidino, morpholino, piperazino or 4-ethyl-2,3-dioxo-1-piperazino radicals ; a heterocyclic aryl radical chosen from the following radicals : thienyl, furyl, pyrannyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, pyridinyl or pyrimidinyl ; and the following radicals : acetoxy, propionyloxy, benzoyloxy, acetylamino, benzylcarbonyl, carbamoyloxy, methylaminocarbonyloxy or dimethylaminocarbonyloxy, acetyl, propionyl, and benzoyl, - a free, esterified or salified carboxy radical, - a phenyl radical optionally substituted by one of the following radicals : alkyl, trifluoromethyl, alkoxy, alkylthio, halogen, hydroxyl, amino or hydroxylakyl, a heterocyclic radical chosen from the following radicals : thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolinyl, imidazolyl, triazolyl, tetrazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, triazinyl optionally substituted by an alkyl, carboxy, carboxy alkyl, aminoalkyl or dialkylaminoalkyl radical, - an acetyl, propionyl, n-butyryl or benzoyl radical, optionally substituted by alkoxy or hydroxy, - a carbamoyl, methyl or dimethylcarbamoyl radical, - a azido radical. R2 represents a nitrogen-containing heterocycle optionally substituted by one or more of the radicals chosen from the group formed by the following radicals : nitro, carboxy, CF3 , nitrile, halogen, sulpho, alkylsulpho, (CH2 )n SO3 H, (CH2 )n NHSO3 H, (CH2 )n SO2 NH2 , (CH2 )n CO2 H, in which n represents a whole number from 1 to 4 and containing at least one acid hydrogen, X represents a CH radical or a nitrogen atom, the wavy lines indicate that the OR radical can exist in cis or trans form or in the form of a cis-trans mixture, the products of formula (I) being in racemic or optically active form, as well as the salts of the products of formula (I) withthe bases and acids. 1. Claims : For the contracting state AT Process for preparing the products of general formula (I) : see diagramm : EP0114128,P48,F3 in which R represents a hydrogen atom, an alkyl, alkenyl or alkynyl radical having at the most 12 carbon atoms, optionally substituted by one or more radicals chosen from carboxy radicals, optionally salified or esterified ; amino, methylamino, dimethylamino and diethylamino radicals ; the phenyl radical optionally substituted by one or more radicals chosen from the following radicals : hydroxy, methyl, methoxy, chloro, bromo, fluoro ; fluoro, chloro, bromo or iodo radicals ; nitrile, CONH2 or CONH SO2 R" raidcals in which R" represents an alkyl radical having from 1 to 4 carbon atoms ; a phenyl radical ; an amino, methyl or dimethylamino radical ; a heterocyclic amino radical chosen from piperidino, morpholino piperazino or 4-ethyl-2,3-dioxo-1-piperazino radicals ; - a cycloalkyl radical having from 3 to 8 carbon atoms or a radical : see diagramm : EP0114128,P48,F1 salified or esterified, in which nc represents a whole number from 0 to 5, - one of the following radicals : acetyl, propionyl, or benzoyl, carbamoyl, dimethylamino carbonyl, phenyl or benzyl optionally substituted by alkyl, alkoxy or halogen ; R1 represents a hydrogen atom, an alkyl, alkenyl, alkynyl or thioalkyl radical having at the most 12 carbon atoms, optionally substituted by one or more radicals chosen from azido or alkylthio radicals having from 1 to 4 carbon atoms or a phenylthio radical, optionally salified or esterified carboxy radicals, amino, methylamino, dimethylamino or diethylamino radicals, the phenyl radical, optionally substituted by one or more radicals chosen from hydroxy, halogeno, trifluoromethyl, amino, alkyl or alkoxy radicals having from 1 to 4 carbon atoms ; fluoro, chloro, bromo or iodo radicals, nitrile, CONH2 or CONH SO2 R" which R" represents an alkyl radical having from 1 to 4 carbon atoms, a phenyl radical, an amino, methyl or dimethylamino radical, a heterocyclic amino radical chosen from piperidino, morpholino, piperazino or 4-ethyl-2,3-dioxo-1-piperazino radicals ; a heterocyclic aryl radical chosen from the following radicals : thienyl, furyl, pyrannyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, pyridinyl or pyrimidinyl ; and the following radicals : acetoxy, propionyloxy, benzoyloxy, acetylamino, benzylcarbonyl, carbamoyloxy, methylaminocarbonyloxy or dimethylaminocarbonyloxy, acetyl, propionyl, and benzoyl, - a free, esterified or salified carboxy radical, - a phenyl radical optionally substituted by one of the following radicals : alkyl, trifluoromethyl, alkoxy, alkylthio, halogen, hydroxyl, amino or hydroxyalkyl, a heterocyclic radical chosen from the following radicals : thienyl, furyl, pyrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolinyl, imidazolyl, triazolyl, tetrazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, triazinyl optionally substituted by an alkyl, carboxy, carboxy alkyl, aminoalkyl or dialkylaminoalkyl radical, - an acetyl, propionyl, n-butyryl or benzoyl radical, optionally substituted by alkoxy or hydroxy, - a carbamoyl, methyl or dimethylcarbamoyl radical, - an azido radical. R2 represents a nitrogen-containing heterocycle optionally substituted by one or more of the radicals chosen from the group formed by the following radicals : nitro, carboxy, CF3 , nitrile, halogen, sulpho, alkylsulpho, (CH2 )n SO3 H, (CH2 )n NHSO3 H, (CH2 )n SO2 NH2 , (CH2 )n CO2 H, in which n represents a whole number from 1 to 4 and containing at least one acid hydrogen, X represents a CH radical or a nitrogen atom, the wavy lines indicate that the OR radical can exist in cis or trans form or in the form of a cis-trans mixture, the products of formula (I) being in racemic or optically active form, as well as the salts of the products of formula (I) with the acids and bases, characterized in that a product of formula (II) : see diagramm : EP0114128,P49,F1 cis or trans, racemic or optically active, in which formula either R1 p represents R1 , R1 having the previously indicated significance, or R1 p represents the substituent R1 in which the reactive functions are protected and either R2 p represents R2 , R2 having the previously indicated significance, or R2 p represents the substituent R2 in which the reactive functions are protected, is treated with a product of formula (III) : see diagramm : EP0114128,P49,F3 syn or anti, in which Rb represents a hydrogen atom or a protector group of the amino radical and Rp represents a protector group of the hydroxyl radical or Rp represents R, R having the significance indicated in claim 1, or Rp represents a radical R in which the reactive functions are protected, so as to obtain a product of formula (IV) : see diagramm : EP0114128,P49,F5 syn or anti, racemic or optically active, in which Rp, R1 p, R2 p and Rb have the previous significance, which product is submitted, if necessary and if desired, to any one of the following reactions, in any order : a) cleavage by hydrolysis, hydrogenolysis or by the action of the thiourea of the protector group or groups which can be represented by Rb and Rp or can be contained in Rp, R1 p and R2 p ; b) esterification or salification of the carboxy or sulpho radicals which can be contained in the radicals Rp, R1 p and R2 p ; c) salification by an acid of the amino radical or radicals ; d) resolution of the molecule so as to obtain an optically active product.

Description

- i -

DK 164404 B

The invention relates to novel 3-amino-2-oxo-azetidines with a nitrogen-containing heterocyclic ring in the 1-position, an analogous process for their preparation, and 5 drugs containing the 3-amino-2-oxo-azetidines. The new compounds have a useful antibiotic effect.

The invention relates to the compounds of the general formula (I1) of the characterizing part of claim 1 as well as salts of the compounds of formula (I ') with bases and acids.

Among the heterocyclic groups which may signify, in particular, the various possible isomers are mentioned. Thus, R denote pyrrol-2-yl or pyrrol-3-yl, pyrazol-3-yl or pyrazol-4-yl, imidazol-2-yl or imidazol-4-yl, 1,2,3-triazol-4-yl. yl or 1,2,4-triazol-3-yl.

Among the compounds of formula (I ') above, the invention relates in particular to the compounds of formula (I1) wherein R' represents hydrogen, methyl, phenyl, difluoromethyl, 1-methyl-1-carboxyethyl, cyanmethyl, carboxymethyl or (methylsulfonyl) represents hydrogen, methyl, fluoromethyl, trifluoromethyl, ethoxycarbonyl or carbamoyl, and R * 2 represents 1H-tetrazol-5-yl or 1,3,4-triazol-2-yl, which is optionally substituted with trifluoromethyl or carboxymethyl.

Tetrazolyl and especially: 3 - ((2- (2-aminothiazol-4-yl) -2-methoxyiminoacetyl) amino) -4-methyl-1- (1H-tetrazol-5-yl) -2-azetidinone are preferred. , cis or trans, syn isomer, racemic or optically active, 30 - 3 - ((2- (2-aminothiazol-4-yl) ~ 2-carboxymethoxyiminoacetyl) amino) -4-ethyl-1- (1H -tetrazol-5-yl) -2-azetidinone, cis or trans, syn isomer, racemic or optically active, - 3 - ((2- (2-aminothiazol4-yl) -2- (1-carboxy-1-methyl) ) -ethoxyiminoacetyl) -amino) 4-methyl-1- (1H-tetrazol-5-yl) -2-35 -azetidinone, cis or trans, syn-isomer, racemic or optically active, 2-

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- 3 - ((2- (2-aminothiazol-4-yl) -2-methoxyiminoacetyl) -amino) -4-fluoromethyl-1- (1H-tetrazol-5-yl) -2-azetidinone, cis or trans, syn isomer, racemic or optically active, 3 - ((2- (2-aminothiazol-4-yl) -2-fluoromethoxyimino-acetyl) amino) -4-methyl-1- (1H-tetrazol-5-yl) ) -2-azetidinone, cis or trans, syn-isomer, racemic or optically active.

The invention also relates to an analogous process for the preparation of the compounds of general formula (I1), and this method is characterized by the characterizing part of claim 10 4.

In the case where R 1 p comprises hydroxyl or amino, it may be advantageous to protect these groups by eliminable protecting groups.

Protecting groups for the amino group can e.g. be an alkyl group, preferably tert-butyl or tert-amyl, it may also be aliphatic, aromatic or heterocyclic acyl groups and carbamoyl.

One may also mention low molecular weight alcanoyl groups such as e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl. R 1 p may also comprise a low molecular weight alkoxy or cycloalkoxycarbonyl group such as e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, isopropyloxycarbonyl, butyloxycarbonyl, tert-butyloxycarbonyl, pentyloxycarbonyl, hexoxyloxycarbonyl, benzoyl, toluolyl, naphtoyl, mesophthyl, phthaloyl, benzyloxycarbonyl.

The acyl groups may be substituted by e.g. chlorine, bromine, iodine or fluorine.

One may mention chloroacetyl, dichloroacetyl, trichloroacetyl, bromoacetyl or trifluoroacetyl.

A low molecular weight aralkyl group such as benzyl, 4-methoxybenzyl or phenylethyl, trityl, 3 94-dimethoxybenzyl or benzhydryl can also be used.

A haloalkyl group such as trichloroethyl may also be used.

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Chlorobenzoyl, p-nitrobenzoyl, p-tert-butylbenzoyl, phenoxyacetyl, caprylyl, n-decanoyl, acryloyl, trichloroethoxycarbonyl can also be used.

Methylcarbamoyl, phenylcarbamoyl, naphthylcarbamoyl and similar thiocarbamoyl groups can also be used.

Allyl, benzyloxyalkyl, alkoxyalkoxyalkyl or also ω-phenylsulfonylalkyl may also be used.

The list above is not limiting, it is clear that other protecting groups for the amino groups, which groups are especially known in the peptide chemistry, can also be used.

The hydroxyl group protecting group can be selected from the following list:

It may be an acyl group such as e.g. formyl, acetyl, chloroacetyl, bromoacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, benzoylformyl, p-nitrobenzoyl. Ethoxycarbonyl, methoxycarbonyl, propoxycarbonyl, g, $, g-trichloroethoxycarbonyl, benzyloxycarbonyl, tert-butoxycarbonyl, 1-cyclopropylethoxy-carbonyl, tetrahydropyranyl, tetrahydrothiopyranyl, methoxytetrahydropyrl Chloroethyl, 1-methyl-1-methoxyethyl, phthaloyl.

Other acyl groups such as propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl and pivaloyl may also be mentioned.

One may also mention phenylacetyl, phenylpropionyl, mesyl, chlorobenzoyl, p-nitrobenzoyl, p-tert-butylbenzoyl, caprylyl, acryloyl, methylcarbamoyl, phenylcarbamoyl, naphthylcarbamoyl.

Of course, when the substituents do not represent a hydrogen atom, the values of the substituents Rb, as well as the values of the protecting groups which Rp may or may not represent, especially when R p comprises an amine, can be taken from the above lists.

The same goes for the groups that R2p can include.

In a preferred embodiment of the process, the compound of formula (II) is treated with a functional derivative of a compound of formula (III). This functional derivative may e.g. be a halide, a symmetric - 4 -

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or mixed anhydride, an amide or an activated ester.

Examples of mixed anhydride include those formed with isobutyl chloroformate and with pivaloyl chloride, and the mixed carboxylic acid sulfonic acid anhydrides such as e.g.

5 is formed with p-toluenesulfonyl chloride. Examples of activated esters include the ester formed with 2,4-dinitrophenol and the one formed with hydroxybenzothiazole.

Examples of halide include the chloride and the bromide.

One may also mention the acid azide or acid amide.

The anhydride can be formed in situ through the action of N, N'-disubstituted carbodiimide, e.g. N, N'-dicyclohexylcarbodiimide.

The acylation reaction is preferably carried out in an organic solvent such as methylene chloride. However, other solvents such as tetrahydrofuran, chloroform or dimethylformamide may be used.

When an acid halide is used and when a molecule of halide acid is generally released during the reaction, the reaction is preferably carried out in the presence of a base such as sodium hydroxide, potassium hydroxide, sodium or potassium carbonate, bicarbonate, sodium acetate, triethylamine, pyridine, morpholine. or N-methylmorpholine.

The reaction temperature is usually room temperature or below.

When Rb represents a hydrogen atom, a mixed carboxylic acid sulfonic acid anhydride is preferably used.

Depending on the values of Rb, R1p, R2p and Rp, the compounds of formula (IV) may optionally be compounds of formula (1 ') -.

The compounds of formula (IV) are compounds of formula (I1) when R b represents a hydrogen atom, when R p does not represent a protecting group for the hydroxyl group or does not represent a group R 'with a protected group, and finally when R group R 2 wherein a reactive group is protected and R 4 does not denote a heterocyclic group comprising a protecting group.

In the other cases, the effect on the connection with - 5 -

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the formula (IV) of one or more hydrolysis or hydrogenolysis agents or of thiourea for the purpose of eliminating the group Rb when it denotes a protecting group for the amino group, eliminating the group Rp when denoting a protecting group for the hydroxyl group, and eliminating the others protecting groups which may include the groups Rp, Rp and Rp.

The nature of the reagents which should be used in all these cases is well known to those skilled in the art. Examples of such reactions are listed below in the experimental section.

Below is a non-exhaustive list of 10 agents which can be used to eliminate. the different groups.

The elimination of the group Rb can be accomplished by hydrolysis which may be acidic or basic or using hydrazine.

Preferably acidic hydrolysis is used to eliminate the alkoxy and cycloalkoxycarbonyl groups optionally substituted, such as tert.-pentyloxycarbonyl or tert.-butyl-oxycarbonyl, aralkoxycarbonyl, optionally substituted, such as benzyloxycarbonyl, trityl, diphenylmethyl, diphenylmethyl, diphenylmethyl 4-methoxybenzyl.

The acid which is preferably used can be selected from hydrochloric, benzenesulfonic or p-toluenesulfonic, formic or trifluoroacetic acids. However, other inorganic or organic acids may be used.

The basic hydrolysis is preferably used for the elimination of acyl groups such as trifluoroacetyl.

The base which is preferably used is an inorganic base such as sodium or potassium hydroxide. Magnesium oxide, barium oxide or an alkali metal carbonate 3 ° or bicarbonate such as sodium or potassium bicarbonate, earbonide or other bases may also be used.

Sodium or potassium acetate may also be used.

Hydrolysis using hydrazine is preferably used to eliminate such groups as phthaloyl.

The group Rb can also be eliminated by a system of zinc and acetic acid (for haloalkyl and especially for trichloroethyl), diphenylmethyl, benzyloxycarbonyl is preferably eliminated.

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- 6 - by hydrogen in the presence of a catalyst.

The chloroacetyl group is eliminated by the action of thiourea in neutral or acidic environment following the reaction type described by MASAKI, J.A.C.S., SK), 4508, (1968).

5 Other methods known in the literature can be used to abolish protection.

Among the preferred groups are formyl, acetyl, ethoxycarbonyl, mesyl, trifluoroacetyl, chloroacetyl and trityl.

Trityl and chloroacetyl are particularly preferred. Benzyl is preferred as group R „p 10.

The acid which is preferably used is trifluoroacetic acid or formic acid.

Elimination of the group Rp or the protecting groups comprising Rp, Rp, or Rp, when necessary, is carried out under conditions similar to those described above regarding elimination of Rb.

You can use acidic hydrolysis to eliminate alkyl or aralkyl which is optionally substituted.

Preferably, an acid selected from hydrochloric acid, formic acid, trifluoroacetic acid and p-toluenesulfonic acid is used.

The other values of the groups R 1 or R p or protecting groups comprising R p, R 1 p or R 2 P are, when desired, eliminated by methods known to those skilled in the art.

You preferably work under moderate conditions, ie.

25 at room temperature or at low heating.

The elimination of the benzyl group or of a benzyloxyalkyl group on the substituent R2P is preferably carried out by hydrogenolysis.

For example, the elimination of the allyl group on R2P is performed. by the action of the rhodium triphenylphosphine chloride complex.

The elimination of alkoxyalkoxyalkyl is carried out e.g. by the action of zinc bromide or titanium chloride.

Elimination of the ω-phenylsulfonylalkyl group is carried out e.g. using strong base such as an alkali metal alcoholate.

For example, when Rb, Rp, Rp or R2p are or include eliminable groups belonging to these various types, several of the above listed agents may be affected by the compounds (IV).

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The conversion of the compounds to salt can be carried out by the usual methods.

The conversion to salt of the compounds wherein R p, R 1 p or R 2 P comprise a carboxy or sulfone group can e.g. is obtained by acting on a compound in acid form or on a solvate, e.g. the ethanolic solvate or on a hydrate of this acid, of an inorganic base such as sodium or potassium hydroxide or sodium or potassium carbonate or bicarbonate. Salts of inorganic acids such as trisodium-1 ° phosphate can also be used. Salts of organic acids can also be used.

A list of such organic acids can be found e.g. in French Patent No. 2,476,087.

As sodium salt, sodium acetate, sodium 2-ethylhexanoate or sodium diethyl acetate are preferably used.

The conversion to salt can be achieved by the action of an organic base or an amino acid.

The optional esterification of the compounds wherein Rβ, Rβ or R2β comprises an acidic group is also carried out under classical conditions.

The optional cleavage of the racemic molecules of formula (II) or (IV) can be carried out by conventional methods.

An optically active organic carboxylic acid or sulfonic acid such as tartaric acid, diben-2ioyltartaric acid, camphosulfonic acid or glutamic acid may be used. The decomposition of the salt thus obtained is obtained by an inorganic base such as sodium bicarbonate or by an organic base such as tertiary amine, e.g. triethylamine.

In particular, the invention relates to a process as described above which is characterized in that a compound of formula (II) is used in which R 1 is a hydrogen atom, a methyl group, fluoromethyl, trifluoromethyl, ethoxycarbonyl or carbamoyl, and R 2 P represents a group of 1H-tetrazol-5-yl or 1,3,4-triazol-2-yl, optionally substituted with a trifluoromethyl group or carboxymethyl group and a compound of formula (III) wherein Rb represents a protecting group for the amino group and Rp represents a protecting group for the hydroxyl group, a methyl group, phenyl, -

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difluoromethyl, 1-methyl-1-carboxyethyl, cyanmethyl, carboxymethyl or methylsulfonylcarbamoylmethyl.

The compounds of formula (II): 5

0 XR2P

may be prepared by reacting a compound of formula (V):

H

H (V) 15 k.

κ2ρ where R 1 p and R 2 P have the same meaning as above, in the presence of a strong base, with a compound of formula (VI): 20 Rap n.

> - - <r0Ap R'ap 11 (VI) 0 where Aβ represents a hydrogen atom or an ester group, and Rap 25 and R'ap have such values that either Rap and R'ap each represent a hydrogen atom, or also denote one symbol represents a hydrogen atom, and the other represents a protecting group for the amino group, or Rap and R'ap together form a divalent protecting group for the amino group, to give a compound of formula (VII):

Rap \ .Λ *> γ — S 1 R'aP (VII)

35) \ NH

ApO. 0 \

R2P

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- 9 - where Ap, R ^ p, R2 ^ 'RaP ° 9 R'aP ^ is the same meaning as above, and the wavy line indicates that the substituent lp may be in a or 3' position, which compound with formula (VII), if desired, subjected one or the other of the following reactions in any order: a) separation into the two isomers.

b) protecting the group NH 1, when Rap and R'ap each represent a hydrogen atom, which compound of formula (VII) in the form of a single isomer or a mixture of isomers, when Aβ 10 represents an ester group, is subjected to a hydrolyzing agent and then a 3-lactamization agent to give a compound of formula (VIII):

RaPNi_ ^ R'ap ^ (VIII) / "Λ

0 R2P

which compound, if necessary, and if desired, is subjected to any of the following reactions in any order: a) separation of the isomers b) excision (by hydrolysis, hydrogenolysis or thiourea action) by one of the groups Rap and R'ap or these two groups when one represents a protecting group or both together form a protecting group to obtain an expected compound of formula (II).

The strong base which is preferably used is butyl lithium in the presence of a secondary amine such as diisopropylamine. However, an alkali metal alcoholate such as potassium tert-butylate can be used.

In addition to the above protecting groups for the amino group, Rap and R'ap together may represent a divalent group such as the benzylidene group or the group \ / CSi \ / \ - 10 -

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Ap can denote one of the above ester groups. Among these, a low molecular weight alkyl group such as methyl or ethyl is preferred.

If the amino group of formula (VII) is free, either because the process has been carried out using a compound of formula (VI) wherein Rap and R'ap each represent a hydrogen atom or because the protecting group of these two substituents denotes, when cleaved during the reaction between the compounds of formula (V) and (VI), optionally a protection of this amino group is taken. One of the known reagents from the above mentioned categories of protecting groups is then used. With the preferred embodiment of the method, the amino group is protected with a trityl group using trityl chloride in the presence of a base, preferably an amine such as triethylamine.

The hydrolysis of the group -C C Aβ is carried out when Aβ represents an ester group, by the action of a base such as sodium or potassium hydroxide in a solvent such as dioxane followed by an acidification, e.g. with hydrochloric acid.

The cyclization reaction, which allows the compounds of formula (VIII) to be obtained, is preferably carried out in the presence of an agent for β-lactamization which leads to the preparation of a reactive carbonyl derivative.

Preferably, the mixed carboxylic acid sulfonic acid anhydride is prepared in the presence of tosyLcHLoride and a base, preferably diazabicyclooctane or triethylamine. Bromine triphenylphosphine may also be used.

Any reactions to abrogate the protection of the protected amino group designated by the group 30 Rap R'ap are carried out under the above conditions, e.g. acid hydrolysis. Likewise, it may be desirable to cleave the protecting group optionally comprising the substituent R 5 P.

The compounds of formula (II) can also be prepared by reacting a (3-lactone of formula (IX)):

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Rap / Ap R'ap I (IX)

^ -O

Wherein R 2 p, Rap and R'ap have the same meaning as above, with a compound of formula (A): h 2n - R 2 p (A) 10 wherein R 2 p has the same meaning as above, to obtain a compound of formula (A) X): ^ OH RfapxXN) R1p 15 (X) ^ -NH χ '0 R2p which compound of formula (X) is, if desired, subjected to any of the following reactions in any order: a) separation of the isomeric, in the case where R 2a does not represent a hydrogen atom, (b) protecting the NE 2 group when Rap and R'ap each denote a hydrogen atom, or modifying the protecting group as one or the other. of Rap and R'ap, or which Rap and R'-ap together form, and which compound of formula (X) in the form of an isomer or mixture of isomers is subjected to the action of a cyclizing agent to give a compound of formula (VIII): R'ajT (VIII) 35 Jr * \ r2p

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- 12 - which compound of formula (VIII) can be separated into its isomers: and which, when Rap or R'ap, denotes a protecting group for the amino group, or when Rap or R'ap together denotes a divalent protecting group for the amino group, below -5 throws the action of a reagent for cleavage by hydrolysis, hydrogenolysis or the action of thiourea to give an expected compound of formula (II).

The effect of the compounds of formula H2N-R2p on the compounds of formula (IX) is preferably carried out in the presence of a trialkyl aluminum such as trimethyl aluminum.

The reagent A that is effectively used for the launch is then a compound of the formula: ^ alkyl 15 R2pNH - Al 'NS'S> valkyle

The protection of the amino group or any modification of the protecting group is carried out under the usual 20 conditions described above.

For the continuation of the reaction, it is preferred that the amino group be protected by a group such as benzyloxycarbonyl.

The cyclizing agent which enables the compounds of formula (X) to proceed to the compounds of formula 25 (VIII) is preferably diethyldiazodicarboxylate in the presence of triphenylphosphine. However, a dialkyl chloramine or carbon tetrachloro <3 »could also be used in the presence of triphenylphosphine or tris-dimethylaminophosphine. Finally, pyridine disulfide could be used. Likewise, the hydroxy group of compound (X) can be activated by a group such as mesylate. The cyclization is then carried out in the presence of a base such as sodium bicarbonate or sodium carbonate (see Chem. Pharm. Bull. 29, 1063 (1981)).

Any final treatment of the compounds of formula (VIII) is carried out under the above conditions.

Like the cleavage of the compounds of formula (II) or (IV), the optional cleavage of the racemic molecules of formula (VII) and (X) can be carried out by conventional methods.

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An optically active organic carboxylic acid or sulfonic acid such as tartaric acid, dibenzoxyltartaric acid camphosulfonic acid or glutamic acid can be used, the cleavage of the salt thus obtained being carried out by means of an inorganic base such as sodium 3 bicarbonate or an organic base such as a tertiary amine, eg. triethylamine.

In particular, the process described above may consist in utilizing a compound of formula (IX) wherein R 1 p represents a hydrogen atom or a methyl group and obtaining a compound (II), where R 2 p represents a hydrogen atom or a methyl group.

The compounds of formula (II) can also be prepared by reacting a compound of formula (XI):

Rap ^ R p> N \ / 1 R'ap i-I (XI) 20 JN \ is where R- ^ p, Rap and R'ap are defined as above, with a compound of formula 25 y-r2p (XII) wherein R 2 P is defined as above and Y represents a nucleofug group, in the presence of a base to give a compound of formula (VIII), which can be separated into its isomers and which is denoted by Rap or R'ap a protecting group for the amino group, or when Rap and R'ap together represent a divalent protecting group for the amino group, may subject the action of a reagent to cutting by hydrolysis or hydrogenolysis or the effect of thiourea to give an expected 33 compound of formula (II) .

Preferably, the nucleofuge group Y is a halogen atom, especially fluorine or chlorine, a group -O-SC 2 -CF 2, -O-SC 2 -O or -O-SC 2 -CH 2 or also quaternary ammonium.

DK 164404 B

- 14 -

The base used may be a metal hydride, an alkali metal alcoholate, an alpha-calcium metal amide or a tertiary amine. An amide such as sodium or lithium diisopropylamide or sodium or lithium trimethylsilylamide is preferably used.

The reaction is preferably carried out in a solvent or in a mixture of solvents such as methylated dioxane, tetrahydrofuran, an alkane, a cycloalphane, dimethylformamide, dimethylsulfoxide, hexamethylphosphphotriamide, toluene, benzene or xylene.

In particular, the reaction is carried out by using as a starting compound a compound of formula (XI) whose amino group is protected.

The Rap and R'ap groups may be one of the groups described above.

Any reactions to abrogate the protection of the amino group are carried out under the above conditions, e.g. by acid hydrolysis.

If the group R2P comprises a protecting group, it can preferably be peeled off using one of the methods 20 above.

The compounds of formula (XII) wherein Y represents a halogen atom and R 2 p represent an optionally protected tetrazolyl group are novel compounds.

The compounds of formula (XII) can be further prepared by converting a compound of formula (A) into a corresponding diazo derivative, followed by its action on a metal halide.

These compounds can be further prepared by a process of treating an isocyanate of formula (a) p-N = C = O (a) where p is a protecting group with hydrazine to convert the obtained compound (b) 35

DK 164404 B

- 15 "0

II

p-NH-C-NH-NH 2 (b)

5 to an azide (c) Q

(c) upon cycling the azide Yed action of phosphorus penta-chloride to obtain the expected halogen tetrazole, which may be subjected to a halogen exchange reaction.

An example of such a preparation is given below in the experimental section.

The compounds of formula (XII) wherein Y represents a group of 15-O-SO2-CF3 / -O-SO2 O or O-SO2-CH3 can be prepared from corresponding hydroxyl derivatives, e.g. by the action of a suitable sulfonyl chloride.

The compounds of formula (XII) wherein Y represents a quaternary ammonium group can be prepared from a compound 20 of formula (A) by quaternization, e.g. using an alkyl iodide.

The compounds of formula (XI) having transconfiguration can be prepared by reacting a base with a compound of formula (XII):

Rap X X * R'ap '' ^ (XIl>

30 I

JN \ 0 Rc having cis configuration in the form of one or the other of the diastereoisomers or a mixture thereof, in which Formula 35 (XI) R R, Rβ and R'ap have the same meaning as above, and R c represents a hydrogen atom or a protecting group to give a compound of formula (XI2): - 16 -

DK 164404 B

Rap

Nn vRxP

/ V, ^ c R, ap (XI).

5 with trans-configuration / in the form of one or the other of the diastereoisomers or a mixture thereof, in which formula ^ (XI2) R-β, Rap, R'ap and Rc have the same meaning as above as optionally subject to the effect of a means of cutting off the protecting group R.

C

Under preferred conditions for carrying out the above processes, the following applies: 15 - The base used is an alkali metal alcoholate or an alkali metal amide, especially potassium tert-butylate, sodium or lithium diisopropylamide or sodium or lithium trimethyl silylamide.

- Man works in a solvent or a mixture of Δ solvents such as ethylhex, dioxane, tetrahydrofuran, an alkane, a cycloalkane, dimethylformamide, dimethylsulfoxil, hexamethylphosphphotriamide, toluene, benzene or xylene.

As a starting compound, a compound of formula (XI ^) is used, wherein Rap and R'ap are preferably defined as above and R is a protecting group for the amino group,

ISLAND

which may be selected from the list of amine protecting groups above and which may contain an asymmetric carbon atom. For example, the group 1-phenylethyl may be mentioned.

The means for cutting off the protecting group Rc may be one of the above. The cut-off of the protective group R

V

could possibly lead to the simultaneous cutting of the Rap and R'ap groups. The group 1-phenylethyl may e.g. is eliminated by the action of ammonium persulfate in acetonitrile.

The compounds of the general formula (I ') have a very good antibiotic effect on gram-negative bacteria, especially on coliform bacteria, Klebsiella, Salmonella and Proteus.

In particular, these compounds can be used as drugs - 17 -

DK 164404 B

in the treatment of colibacillosis and associated infections, in infections due to Proteus, Klebsiella and Salmonella, and in other infections caused by gram-negative bacteria.

Accordingly, the invention relates, as drugs, and in particular as antibiotic drugs, to the compounds of formula (I ') and their pharmaceutically acceptable salts.

The invention relates, in particular, as drugs and, in particular, as antibiotic drugs, to the compounds of formula (I *)

jcTTrC

V 5 i-15 v R 2 wherein R 'represents a hydrogen atom or a straight or branched alkyl group of 1-6 carbon atoms optionally substituted by one or more groups selected from free, esterified or salt converted carboxy, amino , mono or dialkylamino, aryl, halogen, nitrile, CONHSO2R ", wherein R" represents alkyl, aryl or amino, or R 'represents an alkylcarbonyl group or arylcarbonyl group or a phenyl group, R "represents a hydrogen atom or an alkyl group which is optionally substituted by one or more groups selected from halogens, azido, hydroxyl, mercapto, aryl, amino, nitrile, alkylthio, or arylthio, optionally oxidized, acyl, acyloxy, acylamino, aralkylcarbonyl, carbamoyloxy, alkyl or dialkylcarbamoyloxy represents an alkenyl or alkynyl group optionally substituted with a phenyl group or with one or more halogen atoms, or R 1 represents a thioalkyl group optionally substituted with carb represents a phenyl group optionally substituted with halogen, CF 2, amino, hydroxy, alkyl or alkoxy, or R 4 represents an esterified carboxy group, a carbamoyl group

DK 164404B

Or an azido group, R'2 represents tetrazolyl, triazolyl, imidazolyl, pyrazolyl or pyrrolyl optionally substituted by one or more groups selected from nitro, carboxy, CF3, nitrile, halogen, sulfo, alkylsulfo, (Cl 2 SC 2 H, (CH 2) nNHSO 2 H, (CH 2) n SO 2 NH 2, (CH 2) n 2 H, where n represents an integer from 1-4, the compounds having syn isomerism and the wavy line indicating that the compounds may are in cis or trans form or in the form of a cis-trans mixture, the compounds of formula (I1) being in racemic or optically active form, as well as the salts of the compounds of formula (I1) with bases and acids.

The invention also relates in particular, as drugs, and especially as antibiotic drugs, to the compounds described in the Examples and in particular to - 3 - ((2- (2-aminothiazol-4-yl) -2-methoxyiminoacetyl) -amino) -4- methyl 1- (1H-tetrazol-5-yl) -2-azetidinone, cis or trans, syn isomer, racemic or optically active, - 3 - ((2- (2-aminothiazol-4-yl) -2- carboxymethoxyiminoacetyl) amino) -4-methyl-1- (1H-tetrazol-5-yl) -2-azetidinone, cis or trans, syn isomer, racemic or optically active, - 3 - ((2- ( 2-aminothiazol-4-yl) -2- (1-carboxy-1-methyl) -ethoxy-imino-acetyl) -amino) -4-methyl-1- (1H-tetrazol-5-yl) -2-azetidinone, cis or trans, syn-isomer, racemic or optically active, - 3 - ((2- (2-aminothiazol-4-yl) -2-methoxyimino-acetyl) -amino) -4-fluoromethyl-1- (1H- tetrazol-5-yl) -2-azetidinone, cis or trans, syn isomer, racemic or optically active, - 3 - ((2- (2-aminothiazol-4-yl) -2-fluoromethoxyiminoacetyl) -amino) - 4-methyl-1- (1H-tetrazol-5-yl) -2-azetidinone, cis or trans, syn isomer, racemic or is optically active.

Pharmaceutical compositions containing as active ingredient can be prepared in at least one of the drugs mentioned above.

These compositions may be administered by oral, rectal, parenteral, or topical application in topical application to the skin or mucous membranes.

They may be in solid or liquid form and may be present in the pharmaceutical forms commonly used in human medicine.

DK 164404B

- 19 - such as e.g. unsweetened or unsweetened tablets, gelatine capsules, granules, suppositories, injection preparations, po: made cream, gel. They are manufactured according to the usual methods.

The active ingredient (s) may be incorporated therein together with the additives normally used in these pharmaceutical compositions such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous carriers, fats of animal or vegetable origin, paraffin derivatives, glycols , wetting agents, dispersing and emulsifying agents, and preservatives.

In particular, these compositions may be in the form of a powder intended for dissolution at the site of use in a suitable carrier, e.g. apyrogenic sterile water.

The dose administered varies according to the condition being treated, the patient concerned, the mode of administration and the compound in question. It can e.g. range from 0.250 to 4 g per day. per day by oral route in humans in the case of the compound of Example 1 or also between 0.500 and 1 g 3 times a day by intra-muscular route.

The compounds of formula (I1) and their salts can also be used as disinfectants for surgical instruments.

The compounds of formula (V) used as starting compounds in the preparation can be prepared by reacting an amine of formula (A): 25 r2p nh2 (A) 1 - 20 -

DK 164404 B

with an aldehyde of formula (B): R-jP CHO (B) 5 Eb. immediately obtaining a compound of formula (C) is possible Alk0 ορ Γ-H (C) H-k 10 10 where Alk represents an alkyl group usually corresponding to the alcanol in which the reaction is carried out. The compounds of formula (C) are converted to compounds of formula (II), usually by. heating, e.g. in a solvent such as xylene.

An example of such a reaction is described in the n experimental part.

The compounds of formula R 1 p NH 2 can be prepared by the usual methods. An example of such a compound, 2-benzyl-5-aminotetrazole is described in JACS, 76, 923 (1954).

The compounds of formula (VI) derived from glycine can be prepared by conventional methods.

The compounds of formula (IX) can also be prepared by conventional methods. When R 1 p represents a hydrogen atom, the compound of formula (IX) is the lactone of serine, optionally protected by the amino group. When R 1 p represents a methyl group, the compound of formula (IX) is a threonine derivative. The lactone of N-trityl-L-serine is described in JACS, 81, 6086.

The compounds of form (XI), wherein R represents a protecting group, can be prepared from the compounds of formula (XI) by methods well known to those skilled in the art. They can be further manufactured, like. the compounds with the fomel (XI) itself, by a method described in Belgian Patent No. 894,785.

In addition to the compounds described in the Examples, the following compounds can be prepared within the scope of the present invention. The substituents R 1, R 2 and R 2 are those of formula (I ').

21 "DK 164404 B

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22 DK 164404 B

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24 DK 164404 B

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DK 164404 B

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7 'DK 164404 B

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29 DK 164404 B

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- 30 DK 164404 B

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DK 164404 B

EXAMPLE·!; (3SR, 4RS) -3 - ((2- (2-Aminothiazol-4-yl) -2-methoxy-iminoacetyl) amino) -4-methyl-1- (1H-tetrazol-5-yl) -2- azetidinone, syn-isomer.

a) Hydrochloride of (3SR, 4RS) -3-amino-4-methyl-1- (1H-5-tetrazol-5-yl) -2-azetidinone.

To a reflux, a solution of 990 mg (3SR, 4RS) hydrochloride of 3-amino-4-methyl-1- (2- (phenylmethyl) -2-H-tetrazol-5-yl) -2-azetidinone in heating is heated. ethanol (800 ml) is then added to coal (18%) in 5 ml of ethanol.

A hydrogen stream is allowed to pass for 15 minutes. under reflux, then filter and evaporate under reduced pressure. 692 mg of the expected compound is obtained.

b) Mixed anhydride between p-toluenesulfonic acid and 2- (2-tritylaminothiazol-4-yl) -2-methoxyiminoacetic acid, syn isomer.

640 mg of p-toluenesulfonyl chloride are added to a solution of 1.5 g of 2- (2-tritylaminothiazol-4-yl) -2-methoxyiminoacetic acid, syn isomer, in 25 ml of acetone and 0.5 ml of triethylamine.

Stir for 30 min. at room temperature.

c) (3SR, 4RS) -3 - ((2- (2-tritylamino) -thiazol-4-yl) -2-methoxy-aminoacetyl) -amino) -4-methyl-1- (1H-tetrazole-5 -yl) -2-azetidinone, syn-isomer.

The solution obtained above is poured into a solution of 692 mg of hydrochloride of (3SR, 4RS) -3-amino-4-methyl-1- (1-tetrazol-5-yl) -2-azetidinone in 30 ml of acetonitrile and 1 , 5 ml of triethyl 25 amine. Stir at room temperature for 1½ hours. 0.5 ml of acetic acid is added, the precipitate is sucked off, washed twice with 2 ml of acetone, and after drying an initial yield of 460 mg of the expected compound is obtained. The filtrate is evaporated under reduced pressure to 5 ml and taken up in 50 ml of ethyl acetate. Wash with 10 ml of water, dry the organic phase and evaporate under reduced pressure. The compound is taken up in 5 ml of ethyl acetate and stirred and ice-cooled. After crystallization, vacuum for 1½ hours at 0 ° C, wash the crystals twice with 3 ml of acetone and then with ether. Thus, a second yield of 555 mg of the expected compound which is identical to the first yield is obtained. You unite the two - 32 -

DK 164404 B

yields a total of 1.015 g of compound. SMP approx. 200 ° C.

d) (3SR, 4RS) -3 - ((2- (2-Aminothiazol-4-yl) -2-methoxyimino-acetyl) -amino) -4-methyl-1- (1H-tetrazol-5-yl) - 2-azetidinone, syn-isomer.

5 Heat to 50 ° C for 30 min. the above obtained 1.015 g of compound in 5 ml of 66% formic acid. The precipitated triphenyl carbinol is filtered off and washed with 2 ml of 66% formic acid and then with 2 ml of water. The filtrate is diluted with 25 ml of water and evaporated under reduced pressure to approx. 5 ml. The crystals formed are suctioned off, washed with water and then with 3 x 2.5 ml of methanol and finally with ether. The compound is dried at 70 ° C for 4 hours under reduced pressure. Finally, 471 mg of the expected compound is obtained with SMP above 260 ° C and Rf = 0.25, eluent: ethyl acetate, ethanol and water (70:20: 15 10).

Analysis: C- HH · ^NgO₂S = 351.34 Calculated: C% 37.6 H% 3.73 S% 9.12 Found: 37.2 3.7 8.8 (3SR, 4RS) - hydrochloride of 3-amino-4-methyl-1- (2- (phenyl-methyl) -2-H-tetrazol-5-yl) -2-azetidinone is prepared as follows: a) N- (1-methoxyethyl) -2- (phenylmethyl) -2H-tetrazole-5-amine.

A mixture of 15 g of 2-benzyl-5-amino-tetrazole prepared according to JACS, 76, 25923 (1954) in 300 ml of methanol and 15 ml of pure acetaldehyde is stirred for 18 hours at room temperature. Evaporate under reduced pressure to 25-30 g and then elute on a column of 400 g of silica gel with ether containing 0.5% triethylamine. Finally, 18.8 g of the expected compound with SMP is obtained approx. 60 ° C and Rf = 0.6, eluent: ether added 0.5% triethylamine.

b) N-Ethylidene-2- (phenylmethyl) -2H-tetrazol-5-amine.

To the reflux, 4.78 g of the compound obtained above is heated in 100 ml of xylene. Distill at constant volume with the addition of pure xylene. Thus, 35 ml are distilled off in 30 minutes. After 30 min. During the process, the solvent is evaporated under reduced pressure and dried to constant weight under reduced pressure. 4.18 g is thus obtained

DK 164404B

- 33 - the expected compound / which crystallizes.

c) (2SR, 3SR) and (2SR, 3RS) -2-amino-3- (2- (phenylmethyl) -2-H-tetrazol-5-yl-amino) -butanoic acid methyl ester.

A solution was cooled to -60 ° C under argon of 10 ml of 5 diisopropylamine in 100 ml of anhydrous tetrahydrofuran and added over 5 minutes. 40 ml of 15% butyllithium in hexane.

The temperature rises to -30 ° C. Stir for 5 min. at -30 ° C, return to -50 ° C and slowly add 11.5 g of methyl ester of N- (benzylidene) glycine in 30 ml of tetrahydrofuran. Stir for 10 min. at -50 ° C and then again add 13 g of N-ethylidene-2- (phenylmethyl) -2H-tetrazol-5-amine in 20 ml of tetrahydrofuran. The temperature is allowed to rise to -30 ° C and stirred at this temperature for 30 minutes. and then pour the solution into a mixture of 130 ml of 2N hydrochloric acid and 520 ml of water. The mixture is stirred for 30 minutes. at room temperature. The solution is washed with ether and then concentrated ammonia water is added to a pH of 8.5-9. Extract with methylene chloride and then dry. The filtrate is evaporated under reduced pressure. There are thus obtained 19 g of resin which is chromatographed under pressure on silica gel eluting with a mixture of methylene chloride, methanol and concentrated ammonia water (97.5: 2.5: 0.4). There are available on the order of 7.22 g of trans compound and 3.9 g of cis compound.

d) (2SR, 3RS) -2- ((triphenylmethyl) amino) -3- (2-phenylmethyl) -2H-tetrazol-5-yl amino) -butanoic acid methyl ester.

Reflux for 16 hours is heated a mixture of 6 g of cis compound prepared above and 7 g of trityl chloride in 60 ml of tetrahydrofuran and 4.2 ml of triethylamine and then allowed to re-enter room temperature and filter. It is evaporated under reduced pressure and then taken up in 200 ml of methylene chloride. Wash with water, dry and evaporate to dryness. The chromatograph is on silica gel eluting with a mixture of hexane and ethyl acetate (7: 3). 7.45 g of the expected compound are thus isolated with R f = 0.25 (hexane and ethyl acetate (7: 3)).

E) (2SR, 3RS) -2- (tritylamino) -3- (2- (phenylmethyl) -2H-tetrazol-5-yl-amino) -butanoic acid.

To reflux for 40 hours, a mixture of 7.45 g of the above-obtained compound, 150 ml of dioxane, is heated.

DK 164404 B

6 ml of ION sodium hydroxide solution and 12 ml of water and then evaporate under reduced pressure. It is taken up in 150 ml of water, 150 ml of ethyl acetate and 30 ml of 2N hydrochloric acid. Decant, extract with ethyl acetate and dry. Evaporates to dryness. The crystals are taken up in ether, ice-cooled, suctioned and washed with ether and then dried at 60 ° C for 18 hours. 6.22 g of white crystals with melting point are thus isolated. 200 ° C.

f) (3SR, 4RS) -4-methyl-1- (2- (phenylmethyl) -2H-tetrazol-5-yl) -3- (tritylamino) -2-azetidinone.

Stir for 2 min. at room temperature a solution of 4.88 g of acid prepared above in 50 ml of methylene chloride and 2.4 g of diazabicyclooctane is cooled to -40 ° C. Then add in 1 min. 9.5 ml., Tosyl chloride (1M) in methylene chloride. Stir for 15 min. at -40 ° C and then allowing the temperature to rise to 0 ° C over 1 hour. Wash with water, dry and evaporate under reduced pressure.

The residue is chromatographed on silica gel eluting with a mixture of isopropyl apples and methylene chloride (5:95).

Thus, 1.99 g of the expected compound is obtained. Rf = 0.40, eluent: isopropyl apples and methylene chloride (5:95).

g) (3SR, 4RS) hydrochloride of 3-amino-4-methyl-1- (2- (phenylmethyl) -2H-tetrazol-5-yl) -2-azetidinone.

Stir for 15 min. at room temperature a mixture of 1.97 g of the substance prepared under f), 20 ml of methylene chloride and 1 ml of 8M hydrochloric acid in methanol. It is evaporated under reduced pressure, taken up in 5 ml of methylene chloride and poured into 50 ml of ether with vigorous stirring. The expected connection feels out. Suck, wash with ether and then dry under reduced pressure at 60 ° C for 2 hours. 1.02 g of the expected compound are obtained (SMP about 200 ° C), Rf = 0.4, eluent: methylene chloride, methanol and concentrated ammonia water (96: 4: 0.5%).

EXAMPLE 2: (3SR, 4SR) -3 - ((2- (2-Aminothiazol-4-yl) -2-methoxy-imino-acetyl) -amino) -4-methyl-1- (1H-tetrazole) 5-yl) -2-acetidione.

a) Hydrochloride of (3SR, 4SR) -3-amino-4-methyl-1- (1H-tetrazol-5-yl) -2-azetidinone.

- 35 -

DK 164404 B

As in step a) of Example 1, one works from 495 mg of hydrochloride of (3SR, 4SR) -3-amino-4-methyl-1- (2- (phenylmethyl) -2H-tetrazol-5-yl) - 2-azetidinone and receive 361 mg of the expected compound.

B) (3SR, 4SR) -3 - ((2- (2-tritylamino- (thiazol-4-yl) -2-methoxyimino-acetyl) -amino) -4-methyl-1- (1H-tetrazole-5 -yl) -2-azetidinone.

A suspension of mixed anhydride of p-toluene sulfonic acid and 2- (2-tritylamino-4-thiazolyl) -2-methoxyimino-acetic acid, syn isomer, prepared as in step b) in Example 1 is poured out. from 450 mg of 2- (2-tritylamino-thiazol-4-yl) -2-methoxy-imino-acetic acid, syn isomer, and 190 mg of p-toluenesulfonyl chloride in a solution of 209 mg hydrochloride of (3SR, 4SR) - 3-Amino-4-methyl-1- (1H-tetrazol-5-yl) -2-azetidinone in 25 ml of acetonitrile and 0.45 ml of triethylamine. Stir for 16 hours at room temperature, then add 0.2 ml of acetic acid and evaporate under reduced pressure. It is taken up in 60 ml of ethyl acetate, washed with water and then dried over the organic phase. It is evaporated to dryness, taken up in 3 ml of ethyl acetate and stirred and allowed to crystallize.

20 After 2 hours at 0 ° C, suction. The precipitate is washed with ethyl acetate and then with ether. There is thus obtained 0.21 g of the expected compound, Rf = 0.4, eluent: ethyl acetate, ethanol and water (70:20:10).

c) (3SR, 4SR) -3 ((2- (2-Aminothiazol-4-yl) -2-methoxyimino-acetyl) -amino) -4-methyl-1- (1H-tetrazol-5-yl) - 2-azetidinone.

Heat to 50 ° C for 15 minutes. 190 mg of the compound obtained above in 1.5 ml of 65S formic acid. It is allowed to re-enter room temperature during Jo min. then adding 2 ml of water and filtering. The filtrate is evaporated under reduced pressure, the residue is taken up in 4 ml of absolute ethanol and evaporated under reduced pressure. This operation is repeated 3 times and the remainder is taken up in 2.5 ml of acetone. A solution and then a crystallization are observed. One is cooled for 30 min. and then sucks. The crystals are washed with ether and then dried under reduced pressure at 40 ° C. Thus, 75 mg of the expected compound with SMP is obtained approx. 220 ° C and Rf = 0.25, eluent: ethyl acetate, ethanol and water (70:20:10).

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DK 164404 B

(3SR, 4SR) - The hydrochloride of 3-amino-4-methyl-1- (2- (phenylmethyl) -2H-tetrazol-5-yl) -2-azetidinone is prepared as follows: a) (2SR, 3SR) -2- (tritylamino) -3- (2- (phenylmethyl) -2-H-tetrazol-5-yl-amino) -butanoic acid methyl ester.

As indicated in step d), in the preparation of Example 1, one is employed from 7 g of trans compound from step c) in the preparation of Examples 1 and 8 g of trityl chloride. 9r42 g of the expected compound with SMP is obtained approx. 160 ° C and Rf = 0.25, eluent: hexane and ethyl acetate (7: 3).

b) (2SRf 3SR) -3- (2- (phenylmethyl) -2H-tetrazol-5-yl-amino) -2- (tritylamino) -butanoic acid.

As described in step e) of the preparation of Example 1, 9.42 g of the compound above is used. 8.3 g of the 15 expected compound are obtained. SMP approx. 200 ° C.

c) (3SR, 4SR) -4-methyl-1- (2- (phenylmethyl) -2H-tetrazol-5-yl) -3 - ((triphenylmethyl) amino) -2-azetidinone.

As indicated in step f), in the preparation of Example 1, 8.3 g of the compound prepared above is used. 20 g of the expected compound are obtained.

d) (3SR, 4SR) - hydrochloride of 3-amino-4-methyl-1- [2- (phenylmethyl) -2H-tetrazol-5-yl) -2-azetidinone.

As described in step g), in the preparation of Example 1, one is employed from 1.7 g of the compound prepared above. 790 mg of the expected compound are obtained.

Example 3: (3S) -3 - ((2- (2-Aminothiazol-4-yl) -2-methoxyiminoacetyl) amino) -1- (1H-tetrazol-5-yl) -2-azetidinone.

a) (3S) -3 - ((2-Tritylamino-thiazol-4-yl) -2-methoxyimino-acetyl) -amino) -1- (1H-tetrazol-5-yl) -2-azetidinone.

As described in step c) of Example 1, one works from 660 mg of hydrochloride of (3S) -3-amino-1- (1H-tetrazol-5-yl) -2-azetidinone and the mixed anhydride of p-toluene sulfonic acid and 2- (2-tritylamino thiazol-4-yl) -2-methoxyimino-acetic acid, syn isomer, prepared as indicated in step b) of Example 1, to give the expected compound. SMP approx. 220 ° C, Rf = 0.4, eluent: ethyl acetate, ethanol and water (70:20:10).

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DK 164404 B

b) (3S) -3 - ((2- (2-Aminothiazol-4-yl) -2-methoxyiminoacetyl) amino) -1- (1H-tetrazol-5-yl) -2-azetidinone.

Heat to 50 ° C for 15 minutes. a mixture of 150 mg of the compound prepared in (a) in 2 ml of 66% formic acid. It is allowed to re-enter room temperature, filter out the obtained tri-phenyl-carbinol, wash it with 2 ml of 66% formic acid. The filtrate is evaporated under reduced pressure. Absorb in 10 ml of absolute ethanol, evaporate and repeat the operation 3 times. The residue is taken up in 1 ml of acetone, suctioned, washed with ether, dried under reduced pressure at 60 ° C for 1 hour and 48 mg of the expected compound with SMP above 260 ° C, Rf = 0.1, eluant : ethyl acetate, ethanol and water (70:20:10).

The hydrochloride of 3-amino-1- (1H-tetrazol-5-yl) -2-azetidinone used as starting material in Example 3 is prepared as follows: a) (2S) -2-Tritylamino-3-hydroxy -N (phenyl-2-methyl-2H-tetrazol-5-yl) -propionamide.

Reflux for 15 min. a mixture of 25 ml of trimethylaluminum (2M) in hexane, 3.5 g of 2-phenylmethyl-20-5-amino-2H-tetrazole and 100 ml of tetrahydrofuran, and then add 6.6 g of lactone of N-trityl-L-serine . Reflux for 3 hours, cool to 10 ° C and add 10 ml of ethanol very slowly and with stirring. It is evaporated to dryness and taken up in 300 ml of methylene chloride and 200 ml of water adjusted to a pH of 4 with hydrochloric acid. The organic phase is decanted, filtered, washed with 200 ml of 0.05 M hydrochloric acid, dried, filtered and evaporated to dryness. Ethyl acetate and ice-cooler are taken up in 20 ml. The crystals formed are extracted, washed with ether and dried under reduced pressure. 5.3 g of the expected compound are obtained, SMP 202-204 ° C.

b) (2S) -2-Amino-3-hydroxy-N- (2-phenylmethyl) -2H-tetrazol-5-yl) propionamide.

Stir at room temperature for 15 min. a mixture of 3.5 g of the compound prepared above, 25 ml of methylene chloride and 1.7 ml of 8M hydrochloric acid in methanol. Suck, wash with 2 x 10 ml methylene chloride and then 2 x 20 ml ether. Male - 38 -

DK 164404 B

dries under reduced pressure to obtain 1.95 g of the expected compound.

c) (2S) -2- (phenylmethyl-oxy-carbonylamino) -3-hydroxy-N N (2-phenylmethyl-2H-tetrazol-5-yl) -propionamide.

A mixture of 1.94 g of the above-prepared compound, 25 ml of water, 2 g of sodium bicarbonate and 25 ml of methylene chloride is vigorously stirred and then 2.5 ml of benzyl chloroformate (50% in toluene) is added. The mixture is stirred at room temperature in toluene, decanted, extracted with 1 x 25 ml of methylene chloride. The organic phase is washed with 20 ml of 0.05M hydrochloric acid and then dried. The solvent is evaporated under reduced pressure to give 2.45 g of the expected compound.

d) (3S) -1- (2- (phenylmethyl-2H-tetrazol-5-yl) -3- (phenylmethyloxycarbonylamino) -2-azetidinone.

15 ml of 1M solution of a tetrahydrofuran of di; ethyl diazodicarboxylate are added at 10 ° C to a mixture of 2 g of compound from step c) and 1.75 g of triphenylphosphine in 50 ml of tetrahydrofuran. Stir for 15 min. at 10 ° C, evaporate under reduced pressure, chromatograph on silica gel with a mixture of methylene chloride and ethyl acetate (85:15), and obtain 1.3 g of the expected compound after tearing off with ether. SMP approx. 150 ° C.

Analysis: ^ 19 ^ 18 ^ 6 ®3

calculated; C% 60.3 H% 4.79 N% 22.21 Found: 60.3 4.8 22.0 e) The hydrochloride of 3-amino-1- (1H-tetrazol-5-yl) -2-aze tidinon.

To reflux, a mixture of 1.3 g of the compound prepared above was heated in 80 ml of absolute ethanol and then 1 ml of 8M hydrochloric acid in methanol and 800 mg of palladium on coal (18%) were added. A hydrogen stream is passed until complete hydrogenation. Filter, evaporate to dryness to give 660 mg of compound. EXAMPLE 4: (3SR, 4RS) -3 - ((2- (2-aminothiazol-4-yl) -2 - ((difluoro-methoxy) -imino) -acetyl) -amino) -4-methyl-1- (1H-tetrazol-5-yl) -2-azetidinone, syn isomer.

- 39 -

DK 164404 B

EL. ^ Y ^ ^ SShloridet of SSRI ^ ^ R ^ -S-amino - ^ - methyl-L- ^ l-H-tetra-22il5zYiil2 ~ azetidinone.

The procedure is as in step a) of Example 1 using 890 mg of (3SR, 4RS) hydrochloride of 3-amino-4-methyl-1- (2- (phenyl-5-methyl) -2-H-tetrazole-5 -yl) -2-azetidinone, 20 ml of ethanol (70%) and 750 mg of palladium on coal (18%). After 15 min. hydrogenation gives the expected compound which is used immediately. 5i_§iSSå®t_SSiiY ^ £ i§_§i_BltoluensulfonsYre_02_2-X2-tritylamino-in &i2S2ililYiil2; Xdifluormethoxy) _- iminoeddikesyreJt_syn isomer.

The procedure is as in step b) of Example 1 using 325 mg of p-toluenesulfonyl chloride and 815 mg of 2- (2-tritylamino-thiazol-4-yl) -2-difluoromethoxyimino acetic acid, syn isomer, disclosed in French Patent No. 2,461,713 in 25 ml of acetone and 0.25 ml of triethylamine.

C) _3SR5_4R5O3-J2-2-j [2-tritylamino-3-thiazol-4-yl-2-difluoromethoxy] -in2) -acetyl) -amine-2 4-methyl-l -_ (lH-tetraz2l-5-yl) 2-azetidinone _- ^ _syn-is25} is.

The suspension obtained in step B is added to a solution of the compound obtained in step A in 45 ml of acetonitrile 20 and 0.75 ml of triethylamine. Stir for 2 hours at room temperature, add 0.35 ml of acetic acid and evaporate to dryness under reduced pressure. The residue is taken up in ethyl acetate, added 15 ml of 1M sodium bicarbonate solution, extracted from the precipitate, taken up in water, acidified to a pH of 3-4 with 2N hydrochloric acid, extracted with ethyl acetate, washed with an aqueous sodium chloride solution , dries, evaporates to dryness under reduced pressure, absorbs the residue in ethyl acetate, ice-cools, sucks, cleans the crystals with ethyl acetate and then with ether, dries under reduced pressure and receives 308 mg of the expected compound.

30 SMP approx. 220 ° C.

i§§il3; XX2-X ^ inothiazol-4-yl) ^ - 2-j (difluoromethoxymimino- S22 £ Y ^ Jz2SiiB2izizS®tiiYizIziizi z £ 2 ££! 222lz5zYiiz2ZÉ5§ti ^ iB2Bi_®YS ~ is2mer.

Heat for 15 min. to 50 ° C 290 mg of the compound obtained in the previous step 35 in 2.15 ml of 66% formic acid. The precipitated triphenylcarbinol is suctioned off, washed with 2 ml of 66% formic acid and the filtrate evaporated to dryness under reduced pressure. The residue is taken up in ethanol and evaporated again during diminution - 40 -

DK 164404 B

pressure. This operation is repeated and then stripped with acetone, suctioned off, washed with acetone and then with ether and dried under reduced pressure to obtain 150 mg of the expected compound. SMP above 260 ° C.

Analysis: C1] L Hi; l Ng And SF2 = 387.33

Calculated: C% 34.11 H% 2.86 F% 9.81 N% 32.55 S% 8.28

Found: 34.1 3.0 9.6 32.1 8.2 HMK Spectrum (DMSO): 1Q 1.39-1.45 ppm: Cg 3 + CH 4.6 ppm: 5.47 to 5.63 ppm: 7.04 ppm: in thiazole 6.4-7.15-7.95 ppm: CH F2 7.37 ppm: NH2

9.7-9.8 ppm: NH-CO

Example 5: (3SR, 4RS) -3 - ((2- (2-aminothiazol-4-yl) -2 - ((1-propenyloxy) imino) -acetyl) amino) -4-methyl-1 - (1H-tetrazol-5-yl) -20-azetidinone, syn-isomer.

A) Mixed anhydride of β -toluenesulfonic acid - gimim23j [2-tritylamino-thiazole - ^ - Yl ^ -g- ^ l-grogenyloxy ^ -jjClacetic acid ^ syn isomer.

The procedure is as in step b) of Example 1 using 265 mg of p-toluenesulfonyl chloride and 630 mg of 2- (2-tritylamino-thiazol-4-yl) -2- (1-propenyloxy) iminoacetic acid, syn isomer ( described in French Patent No. 2,361,893) in 8 ml of acetone and 0.2 ml of triethylamine.

B) SSR (R) RS) ^ - 3- (^ 2 - (2-Tritylamino-3-thiazol-4-yl) - 2- (1-grogenyl-3-tidinone) isomer.

As in step c of Example 1, one works from the suspension obtained in step A above and the hydrochloride of (3SR, 4RS) -3-amino-4-methyl-1- (1H-tetrazol-5-yl) -2-azetidinone prepared according to Step A of Example 4. An initial yield of 400 mg of 35 is obtained from the expected compound, by evaporating the mother liquors, taking up the residue in ethyl acetate, extracting with an aqueous sodium bee bona top solution, decanting, acidifying the aqueous phase, extracting with ethyl acetate, washes with water, dries and evaporates to dryness under reduced pressure. 140 mg of compound are obtained,

DK 164404B

- 41 - which is identical to the first yield. SMP approx. 220 ° C.

C3- (3SRi_4RS) _- 3-XX2-XX2-aminothiazol24-yl) -2-X1-grogenYloxY) _-non ^ syn isomer.

5 Heat for 15 minutes. to 50 ° C 380 mg of the compound obtained in step B in 2.8 ml of 66% formic acid, allows to re-enter room temperature, eliminates the precipitation by filtration, evaporates the filtrate to dryness under reduced pressure, absorbs the residue in water, sucks, wash with water, dry at 50 ° C under reduced pressure and get 185 mg of the expected compound. SMP above 260 ° C.

Analysis: C13 H15 Ng O3 S = 377.37

Calculated: C% 41.37 HS 4.01 N * 33.40 S% 8.50 Found: 41.3 4.0 33.3 8.5 NMR Spectrum (DMSO): 1.38-1.45 ppm: C§3-CH 4.58-4.64 ppm: N-OCH2 4.61 ppm: H4 5.14 to 5.42 ppm: = CH_ 20 Å 5.5 to 5.64 ppm: H3 5, 77 to 6.14 ppm: CH = CH2 6.8 ppm: in thiazole 7.24 ppm: NH2 9.4-9.49 ppm: NHCO EXAMPLE 6: (3SR, 4RS) -3 - ((2- (2-Aminothiazol-4-yl) -2 - ((carboxy-methoxy) -imino) -acetyl) -amino) -4-methyl-1- (1H-tetrazol-5-yl) -2-azetidinone, syn. isomer.

^ thiazole-X-YlX - ^ - XXtert ^ -butoxycarbonyl ylmethylX-oxyX-iminoacetic acid acid synthesis isomer.

As in Example 1, step b is worked out from 480 mg of p-toluenesulfonyl chloride and 1.38 g of 2- (2-tritylaminothiazol-4-yl) -2- ((tert-butoxycarbonylmethyl) oxy) iminoacetic acid , syn isomer, prepared as in French Patent No. 2,445,830, in 15 ml of acetone and 0.36 ml of triethylamine.

35 - 42 -

DK 164404 B

B) _ (3SR, _ £ RS) _- 3- ^ J! 2 ~ j (2-tritYlaminothiazole-4-γΙ tert ^^ but-2ΧΣ222 ^ 2Υΐ ™ §έΙΐΥΐΙζ22Σΐζΐ ^ Ϊ22ΐζ2 £ 2ί: ΥΐΙζ2ΐ! Ϊ22ζ1ΐ ™ 2ί:! ΪΥΐΐ1Ζ.1Ιΐί · ϊ '' t® £ i552il§ZZiIz2zSSStiÉiS2Si 2iil§E ·

As in Example 4, step C is used, using the suspension used in step A above and the hydrochloride of (3SR, 4RS) -3-amino-4-methyl-1- (1H-tetrazol-5-yl) -2 -azetidinone prepared in Example 4, Step A. Obtained 850 mg of the expected compound. SMP approx. 270 ° C.

C) __X3SRi_4RS) _- 3 - (- (2- (2-Airiinothiazol-4-Yl) _- 2 -X_ (carboxymethylethoxyl) _-iminoHacetyl) -amino- (1-methyl-1H-1-HztetrazolZSzXljLi) zazetidi- non ^ syn-isomer ·

Stir for 5 min. at room temperature a solution of 830 mg of the compound obtained in step B above in 2.5 ml of trifluoroacetic acid, evaporates to dryness under reduced pressure, absorbs the residue in 5 ml of 66% formic acid, heats for 15 minutes. to 50 ° C, cools and eliminates the precipitation by filtration. The filtrate is evaporated to dryness under reduced pressure 3 times, taking up the residue in ethanol and then acetone. Crystallization is initiated, ice-cooled, the crystals extracted, washed with acetone and then dried with ether at 50 ° C under reduced pressure to obtain 240 mg of the expected compound. SMP above 260 ° C.

NMR Spectrum (JDMSO): 1.39-1.45 ppm: C§3-CH 25 Ca. 4.58 ppm: 5.48 to 5.63 ppm:

4.62 ppm: OCI-CO

6.81 ppm: in thiazole

7.25 ppm: NH2 9.38-9.48 ppm: NHCO

Example 7: (3SR, 4RS) -3 - ((2- (2-Aminothiazol-4-yl) -2 - ((1-carboxy-1-methylethoxy) -imino) -acetyl) -amino) -4-methyl 1-1- (tetrazol-5-yl) -2-azetidinone, syn-isomer.

A) __ Mixed_anhydride_of_ £ -toluenesulfonic acid_and_2 -_ (2-tritYlainiriothiazolz4zyl) .z2zi £ 2 ££ 4Z ^ H £ 22Y22 £ ^ 22YizizS2 £ iiYi2ti} 25 ^ izi5ii222É

- 43 -

DK 164404 B

As in Example 1, step b) is used from 325 mg of p-toluenesulfonyl chloride and 970 mg of 2- (2-tritylaminothiazol-4-yl) -2- ((1-tert-butoxycarbonyl-1-methylethyl) -oxy) iminoacetic acid, syn isomer, prepared as in French Patent No. 2,421,906, 5 in 17.5 ml of acetone and 0.25 ml of triethylamine.

Si-l ^ Br-iESizlzillilS-tritylaminothiazole - ^ - Yl ^ - ^ - Xl-tert ^ - fe2 £ 25Y2Sil222YiziZ22j; iiYi®i: k2 £ Yiz ^ i22Lz22iri = Yliz2i! Ii! I2zizii2 £ i} Yi22 iiz £ 2 iÉi222i._2Y2zi225! 2i *

As in Example 4, step C is used using the suspension obtained in step A above and the hydrochloride of (3SR, 4RS) -3-amino-4-methyl-1- (1H-tetrazol-5-yl) -2 -azetidinone prepared in Example 4, Step A. 1.07 g of the expected compound are obtained. SMP approx. 220 ° C.

C) (2SRi (4RS) _z3zXj.2zi (2-aminothiazolz4-yl) _z2zlll “Carboxyzlzii} 2β ^ Yi_ (2β (oxy) _-mino) -acetyl) -amino] _-4-methyl-lj [ tetrazol-35-yl) - 2- 222 pounds

As in Example 6, step C is used from 950 mg of the compound obtained in step B above. The crude product is purified by chromatography on silica gel eluting with water. Steam is evaporated to dryness, the residue is taken up in methanol, filtered, eliminated under reduced pressure, crystallized from acetone, dried at 50 ° C under reduced pressure to afford 157 mg of the expected compound. SMP above 260 ° C.

NMR Spectrum (DMSO):

1.35-1.42 ppm: Cg3-CH

I, 42 ppm: (CH3) 2 4.28 ppm: 5.28 to 5.43 ppm: H3 6.75 ppm: in thiazole 7.15 ppm: NH2

II, 34-11.44 ppm: NHCO

Example 8: (3SR, 4RS) -3 - ((2- (2-aminothiazol-4-yl) -2- (methoxy-imino) -acetyl) amino) -4-ethyl-1- (1H-tetrazole) 5-yl) -2-azetidinone.

A] __ __ Hydrochlorid_af (3SRi_4RS) _- 3-amino-4-ethyl-l - (l-H-tetrazol-SzYiizii ^ zetidinon.

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DK 164404 B

As in Example 1, step a) is used from 2 g (3SR, 4RS) hydrochloride of 3-amino-4-ethyl-1- (2- (phenylmethyl) -2H-tetrazol-5-yl) -azetidinone, but hydrogenating the solution twice in succession.

5β (13SRi (4RS) - 3 - [[2- (2-Tritylamino-thiazol-4-yl)] - 2-methoxy]

65 ml of acetonitrile and 2.85 ml of triethylamide Itil were added to the compound obtained in step A and then a suspension of mixed anhydride of p-toluenesulfonic acid and 2- (2-tritylamino-4-thiazolyl) -2- methoxyiminoacetic acid, syn isomer, prepared as in step b) of Example 1 from 2.9 g of 2- (2-tritylaminothiazol-4-yl) -2-methoxyiminoacetic acid, syn isomer, and 1.24 g of p-toluene sulfonyl chloride. Stir for 1½ hours at room temperature, add 0.4 ml of acetic acid and continue the reaction as in step 15 b) of Example 2. 1.86 g of crude product which is recrystallized from acetone are obtained. 1 g of the expected compound is obtained.

SMP approx. 260 ° C, Rf = 0.27, eluent: ethyl acetate, ethanol and water (7: 2: 1).

C) ³X3SRr_4RS ^ -3 - 2- (2-Amino-thiazol-4-yl-2-methoxyimino) [- (2-methyl) -amino) -4-3-yl-1- (1-H3tetrazole-5-yl) yl) -2-azetidinone.

Heat for 15 min. to 50 ° C 1 g of the compound obtained in the previous step in 5 ml of 66% formic acid. It is allowed to re-enter room temperature, filter, evaporate the filtrate, add 25 ml of water, cool down, filter, evaporate the filtrate to dryness under reduced pressure, take up the residue in 10 ml of acetone, filter, evaporate the filtrate to 3 ml and allow to crystallize. The crystals are aspirated, washed with acetone, dried under reduced pressure and 270 mg of the expected compound are obtained.

SMP approx. 210 ° C. Rf = 0.15, eluent: ethyl acetate, ethanol 50 and water (7: 2: 1).

MMR Spectrum (DMSO): 0.9-0.98-1.05 ppm and 1.67 to 2.22 ppm: Ethyl 3.87 ppm: N-OCH3 4.22 ppm: Hj 4.87 to 4 , 99 ppm: H3 6.74 ppm: Hg in thiazole 7.24 ppm: NH3

9.3-9.4 ppm: NH-CO

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DK 164404 B

The (3SR, 4RS) hydrochloride of 3-amino-4-ethyl-1- (2-phenylmethyl-2H-tetrazol-5-yl) -2-azetidinone used as the starting compound of Example 1 is prepared as follows: 5l_NzXli gthoxYpropyl ^) = 22X2henylmethYl _) _- 2-H-tetrazol-5-amine.

As in step a), the preparation according to Example 1 is based on 2 g of 2-benzyl-5-aminotetrazole and 2 ml of propionaldehyde.

2.12 g of the expected compound are obtained. Rf = 0.57, eluent: ether.

? 2! _N-EropYliden-2-XEhenYlmethYlX-2-H-tetrazol-5-amine.

As in step b), in the preparation of Example 1, one works from 20 g of the compound obtained in step a above. 17.5 g of the expected compound are obtained.

Sl_I2§Ri.3SR ^ -_ (02_X2SRi3RS)> - 2-Amino-3-X2-X2henylmethylX-2-H-15 As in the preparation of Example 1, step c) is used, using the substance obtained in step b) above. 14.07 g of trans-compound with SMP is obtained approx. 60 ° C and 6.2 g of cis compound with SMP approx. 105 ° C.

3SRX22-Tritylamino-3-X2-Xghenylmethyl) -2-H-tetrazole-2-pyrroloSroino-pentanoic acid methyl ester.

As indicated in step <l) of the preparation of Example 1, one is employed from 21 g of trans compound prepared as in step c) above. 29.8 g of the expected compound are obtained.

SMP approx. 190 ° C.

E) (2SR-3SRX-2-tritylamino-3-X2-xphenylmethyl) <2 H-tetrazole

As in step e) of the preparation according to Example 1, 29.8 g of the ester prepared above are used.

26.3 g of the expected compound are obtained. SMP approx. 175 ° C.

3 ° I I_1 3SRj_4SR ^ -4-ethyl ^ l-Xg-Xphenylmethyl) -2-H-tetrazol-5-yl-ll Ei Ei £ li

Work as in (f) in the preparation for: exeriipélul · starting from 5.18 g of acid prepared above. 2.55 g of the expected compound are obtained. Rf = 0.42, eluent: methylene chloride and in sopropyl ether (95: 5).

g) (3SRi4SR) hydrochloride_of_3-amino-34-ethyl-1-X2 -_ (Ehenylmy-y2Yill2lSl5E2E2O2; 5-Yl) -2-azetidinone.

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DK 164404 B

As in step g), the preparation of Example 1 is used using 2.4 g of the above-prepared trityl derivative. 1.15 g of the expected compound are obtained. SMP 202 ° C. Rf = 0.52, eluent: ethyl acetate, ethanol and water 5 (7: 2: 1).

Example 9: (3SR, 4RS) -3 - ((2- (2-Aminothiazol-4-yl) -2-methoxy-imino) -acetylamino) -4-ethyl-1- (1H-tetrazol-5-yl) azetidinone. 3-Amino-4-ethyl-1-Xl-H-tetra2ol-5-yl-2-azetidinone.

As in Example 1, step a) is worked from 1.08 g (3SR, 4RS) hydrochloride of 3-amino-4-ethyl-1- (2- (phenylmethyl) -2-H-tetrazol-5-yl) -2-azetidinone under 2x hydrogenation of the solution for 15 min. After filtration, evaporate to dryness, taking up the residue 3 times in ethanol and 2 times in acetonitrile.

II-1βBiil§113iXX2-Xtrityl ^ inothiazol-4-yl] - 2-methoxyiminoacetyl) - (amino) -4-ethyl-1- (1-H-tetrazol-5-yl-2-azetidinone).

The procedure is as in Step B of Example 8, using the substance obtained in Step A above and a suspension of mixed anhydride of p-toluenesulfonic acid and 2- (2-tritylaminothiazol-4-yl) -2-methoxyiminoacetic acid, syn. isomer, prepared as in step b) of Example 1 from 1.56 g of 2- (2-tritylaminothiazol-4-yl) -2-methoxyiminoacetic acid, syn isomer, and 670 mg of p-toluene-2β sulfonyl chloride. 2 g of crude product is obtained, which is dissolved in acetone and precipitated again by ether. 1.18 g of the expected compound are obtained. SMP 210 ° C.

2l_i25R ^ 4RS) _- 3-XX23j [2-aminothia; Zol-4-yl) _2 -_ (methoxyimino) _- ace tyl) _- amino) _2 £ i§thYl-l -_ (LH tetrazol-5-yl) _- 2-azetidinone.

As in step b) of Example 1, one is based on 870 mg of the compound prepared in step B above. The crystals are washed with acetone and then with ether. 370 mg of the expected compound is obtained. SMP approx. 260 ° C (dec.). Rf = 0.2, eluent: ethyl acetate, ethanol and water (7: 2: 1).

NMR Spectrum (DMSO): 0.88-0.95-1.03 ppm: CH3 in ethyl 3.85 ppm: N-OCH3 4.33 ppm: - 47 -

DK 164404 B

5.47 to 5.63 ppm: 6.78 ppm: in thiazole 7.25 ppm: NE ^

9.43-9.53 ppm: NH-CO

5 (3SR, 4RS) hydrochloric! of 3-amino-4-ethyl-1- (2- (phenylmethyl) -2-H-tetrazol-5-yl) -2-azetidinone used as the starting compound of Example 9 is prepared as follows: 5i.3RS) -2-Tritylamino-3-j [2- (phenylmethyl) -2-H-tetrazole-5-one As in step d), in the preparation of Example 1, one works from 14 g of cis compound obtained as in step c) of the preparation according to Example 8. 19.87 g of the expected compound are obtained. SMP 140 ° C, Rf = 0.17, eluent: hexane. and ethyl acetate (7: 3).

B) (2SR 2 RS) - 2-Triethylamino-3- (2- (phenylmethyl) -2-H-tetrazol-5-yl) -aminopentanoic acid.

As indicated in step c) in the preparation according to Example 1, one works from 19.8 g of the compound obtained in the previous step. 4.4 g of the expected compound is obtained. SMP approx. 205 ° C, 20 Rf = 0.27, eluent: ethyl acetate and hexane. (7: 3).

El.X SRiiRS ^ ^ - ^ - ethyl-L-X ^ -Xphenylmethyl ^ -g-H-tetrazol-S-yl ^ -S-tritylamino-2-azetidinone.

As in step f), the preparation of Example 1 is used using 4.75 g of acid prepared as above. 1.82 g of the expected compound are obtained. Rf = 0.4, eluent: methylene chloride and isopropyl ether (95: 5).

2zH-tetrazol-5-yl) _; 2-azetidinone.

As in step g) of the preparation according to Example 1, one works from 1.8 g of the compound obtained above. 1.8 g of the expected compound are obtained. Rf = 0.66, eluent: ethyl acetate, ethanol and water (7: 2: 1).

Example 10: (3SR, 4RS) -5- (3 - ((2- (2-aminothiazol-4-yl) -2-methoxyiminoacetyl) amino) -4-methyl-2-oxo-1-azetidinyl ) -2-H-tetrazole-2-acetic acid.

5-X3 = 2 [2- (23-Inothiazol24-Yl)> 32-methoxy-amino-acetyl) -amino) -4-methyl-2-oxo-1-azetidinyl] -2-H -tetrazole-2- - 48 -

DK 164404 B

2.27 g (3SR, 4RS) -3 - ((2- (2-tritylamino) -5-thiazol-4-yl) -2-methoxyiminoacetyl) amino-4-methyl-1- ( 1-H-tetrazol-5-yl) -2-azetidinone in 35 dimethylformamide, recharge at room temperature and add 170 mg of sodium hydride (55% in oil), stir for 15 minutes, add 1 ml of tert.-butyl bromoacetate and charge leave for 16 hours with stirring. The reaction mixture is poured into 250 ml of aqueous 0.1 M monosodium phosphate solution, extracted with ether, washed with water, dried and evaporated to dryness under reduced pressure. Chromatograph the rest. on silica gel (eluent: methylene chloride and acetone (9: 1)) to obtain 1.3 g of the expected compound 15 and 130 mg of corresponding 1-substituted derivative.

B1 (3SR4RRS) ~ 5 ~ (3-YO27j (2-3-inothazgl-4-yl) 2-methoxy-aminoacetyl-6-SiS2ilir-5-methyl-2-oxo-1-azetidinyl) -2-H tetrazole-2-acetic acid.

Stir for 10 min. 960 mg of the 20 compound prepared in step A in 3 / ml trifluoroacetic acid, evaporates to dryness under reduced pressure and takes up the residue in 6 ml of 66% formic acid, heats for 15 minutes. to 50 ° C and allow to re-enter room temperature.

The insoluble material is aspirated off, the filtrate is evaporated under reduced pressure for crystallization, water is added, stirred for 30 minutes, suctioned off, washed with water and dried under reduced pressure. After recrystallization of ethanol, the expected compound is obtained. SMP approx. 240 ° C, RF = 0.14, eluent: ethyl acetate, ethanol and water (7: 2: 1).

NMR Spectrum (DMSO):

1.38-144 ppm: C§3-CH

3.89 ppm: OCH3 4.55 ppm: CH3-Cg 5.55 ppm: H3 5.67 ppm: N-Cg2-C00H 6.83 ppm: H 2 in thiazole

9.41-9.51 ppm: NH-CO

Example 11: (3SR, 4SR) -3- ((2 - (- aminothiazol-4-yl) -2-methoxyminoacetyl) amino) -4- (fluoromethyl) -1- (1H-tetrazol-5-yl) ) -2- azetidinone.

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DK 164404 B

2.22 g of hydrochloride of (3SR, 4SR) -3-amino-4-fluoromethyl-2-azetidinone prepared as in Belgian Patent No. 894,785 in 60 ml of methylene chloride are stirred for 3 hours at room temperature. , 2 ml of triethylamine and 4.1 g of trityl chloride. 100 ml of methylene chloride is added, washed with water, dried and evaporated to dryness under reduced pressure. The crystals are taken up in isopropyl ether, sucked off, washed with isopropyl ether and then with pentane, dried under reduced pressure at 50 ° C to obtain 4.36 g of the expected compound. SMP 200-202 ° C (decomposition).

15β, 13βR ^ 4SR} -1-Q-ben2Yl.t_e.tr ^ gp3L-5-yl) -3-tritylamino-4-fluoro-1

3.6 g of the compound obtained in the previous step is dissolved in 60 ml of tetrahydrofuran and then the solution-2Q gene is cooled to -40 ° C. Stir for 3 min. 15 ml of 0.66M sodium bis-trimethylsilylamide in tetrahydrofuran, stir for 5 min. at -30 ° C and then cools to -60 ° C to obtain a suspension which is slowly poured into a solution of 2 g of 5-fluoro-1-benzyltetrazole in 900 ml of toluene. Stir for 30 min. at room temperature, 50 ml of aqueous 1M monosodium phosphate solution is added, decanted, dried and evaporated to dryness under reduced pressure. The residue is chromatographed on silica gel (eluent: benzene and ethyl acetate (97: 3)). 2.6 g of crude product is isolated, which is recrystallized in ether. 2.18 g of the expected compound are obtained. KF = 0.4, eluent: benzene and ethyl acetate (95: 5). Qi_SZÉE22i} i2 £ ^ in _2f_i3SRi4SR) _- l-j (l-benzyltetrazole = 5-yl) - 3-amino-ilil22 S§ £ £ methyl-2-azetidinone.

Stir for 30 min. at room temperature 2.18 g of the above compound in 60 ml of methylene chloride and 1.3 ml of 5M hydrogen chloride solution in a mixture of methanol and water (97: 3). The precipitate is suctioned off, washed with methylene chloride and then with ether, dried and given 1.17 g of the expected compound.

SMP 180-200 ° C (decomposition).

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DK 164404 B

D) __ HYdrochlorid_af_X3SRi4SR) _- 3-amino-4-fluoromethyl-l - <(L-H StiSSSil ^ ^ ^ lZizi azetidinone.

Hydrogenate for 30 min. at 40 ° C a mixture of 1.17 g of the hydrochloride from the previous step in 50 ml of methanol added with 160 mg of 5 palladium on charcoal (18%). Filter, evaporate the filtrate to dryness, under reduced pressure to obtain 836 mg of the expected compound. RF = 0.1, eluent: ethyl acetate, ethanol and water (7: 2: 1).

? l_l ^ §5ri§ ^ lz ^ zii2iitritylamino-Xthiazol34-Yl) _- 2-methoxYimino) _2 1 ° 5 £ ®tZiilSSii52zål £ ili2SSS £ iiZizillizSz £ ®i £ å22il5lXiiz2zS5§tidinone.

102 mg of the compound of the previous step is dissolved in 3 ml of acetonitrile and 0.2 ml of triethylamine. This solution is slowly poured into a suspension of mixed anhydride of 15 p-toluenesulfonic acid and 2- (2-tritylaminothiazol-4-yl) -2-methoxy-acetic acid, syn isomer, prepared as in step b) of Example 1 from 203 mg of 2- (2-tritylaminothiazol-4-yl) -2-methoxyimino acetic acid, syn isomer and 88 mg of p-toluenesulfonyl chloride. Stir 0 minutes for 30 minutes, add 0.05 ml of acetic acid, evaporate to 20 ml under reduced pressure, take up in ethyl acetate, wash with water, dry and evaporate to dryness. The residue is again taken up with 1 ethyl acetate, ice-cooled, suctioned off and the crystals dried. 186 mg of the expected compound is obtained. SMP 200 ° C.

11-SR3SR4 -S-XXg-Xg- ^ inothiazole - ^ - Yl ^ -g-methoxymiminoacetyl ^ - (amino) ~ 4- (fluoromethyl) ^ - 1-yl-H-tetrazol-S-yl -g-azetidinone.

Heat for 15 min. to 50 ° C 202 mg of the above compound in 4 ml of 66% formic acid. You cool down, suction and evaporate the filtrate under reduced pressure. You absorb in water and extract the crystals which you wash with water with 30 acetone and then with ether. 88 mg of the expected compound are isolated. SMP approx. 250 ° C. Bf = 0.2, eluent: ethyl acetate, ethanol and water (7: 2: 1).

NMR Spectrum (DMSO): 3.86 ppm: OCH 3 from 5.60 to 5.74 ppm: H 3 6.78 ppm: H 1 - in thiazole 7.22 ppm: NH 2

9.44-9.53 ppm: NH-CO

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DK 164404 B

The 5-fluoro-1-benzyltetrazole used as the starting compound of Example 11 is prepared as follows:

9.7 ml of hydrazine hydrate in 50 ml of 5 tetrahydrofuran and 50 ml of ether are cooled to inert atmosphere and 26.6 g of benzyl isocyanate are added to 100 ml of ether. Stir for 16 hours, allowing to re-enter room temperature and extracting the precipitate, washing with ether, absorbing it in 250 ml of methanol, refluxing, filtering, evaporating the filtrate to 50 ml under reduced pressure, adding ethyl acetate under elimination of the methanol by distillation, evaporating to 100 ml, ice-cooling, suctioning the crystals, washing them with ethyl acetate and drying them under reduced pressure. 25.56 g of the expected compound are obtained. SMP 115 ° C.

15 b ^ Azide ^ of ^ - ^ phenylmethyl ^ -carbamic acid.

8.19 g of sodium nitrite are added to a solution of 19.5 g of amide from the previous step in 331.5 ml of water and 58.5 ml of 2N hydrochloric acid, which is kept at a temperature below 25 ° C. Stir for 1 hour, suck the precipitate, wash it with water, dry it and get 18.9 20 g of it. expected connection. SMp approx. 85 ° C. c) __ 5; chloro-1-benzyl tetrazole.

A solution of 23.5 g of phosphorus pentachloride in 250 ml of trichlorethylene is slowly added with stirring to a suspension of 15.8 g of the compound obtained in the previous step in 150 ml of tetrachlorethylene. The mixture is heated to reflux, cooled and poured into an aqueous sodium bicarbonate solution, decanted, extracted with methylene chloride, washed with an aqueous sodium chloride solution, dried and evaporated to dryness under reduced pressure. The residue is chromatographed on silica gel (eluent; hexane and ethyl acetate (7: 3)) to obtain 6.85 g of the expected compound.

d) __ 5-fluoro-l-benzyltetrazole.

In 3 liters of acetonitrile, 16 g of crown ether (18-6) and 20 g of potassium fluoride are mixed. 500 ml of solvent 35 is distilled off under argon flow and 7.9 g of the compound obtained in the previous step is added. It is heated to reflux for 65 hours, filtered and evaporated to dryness under reduced pressure. The residue is taken up in benzene, evaporated to dryness, chromatographed - 52 -

DK 164404 B

the residue on silica gel (eluent: hexane and ethyl acetate (7: 3)) to obtain 5.73 g of the expected compound. Rf = 0.23, eluent: hexane and ethyl acetate (7: 3).

Example 12: (3S) -3- ((2- (2-Aminothiazol-4-yl) -2-methoxyimino-acetyl) amino) -1- (3-trifluoromethyl-1H-1,2,4-triazole -5-yl) -2-azetidinone.

As in step a) of Example 3, one is based on hydrochloride of (3S) -3-amino-1- (1-H1, 2,4-triazol-5-yl) -2-azetidinone and mixed anhydride of p. -toluenesulfonic acid and 2- (2-tritylamino-thiazol-4-yl) -2-methoxyiminoacetic acid, syn-isomer, prepared as in step b) in Example 1. The synthesis is continued as in step b) in Example 3 and obtained expected connection. Rf = 0.15-0.2, eluent: methylene chloride, acetone and methanol (75: 17: 8).

NMR Spectrum (DMSO): 3.85 ppm: (s) OCHg 3.75 to 4.33 ppm: (m) H4 - 5.19 ppm: (m) Hg 6.78 ppm: (s) Hg thiazole 7.22 ppm: (s)

9.31 ppm: (d) NH-CO

IR spectrum (nujol) 1780-1663 cm -1: -C = 0 1530 cm -1: secondary amide 1588 cm conjugated system 1150-1200 cm -1: CF

-1 J

1025 and 1045 cm: oxime

The hydrochloride of (3S) -3-amino-1- (1H1, 2,4-triazol-5-yl) -2-azetidinone used as the starting compound of Example 12 is prepared as follows: S-amino-S-trifluoromethyl-l ^ g ^^ - triazole.

At room temperature, 10 g of 2-phenylmethylhydrazine carboxymidamide is stirred in 100 ml of methanol with 2.7 g of sodium methylate and then 6 ml of ethyl trifluoroacetate is added, stirred for 1 hour and evaporated to dryness under reduced pressure. The residue is taken up in 250 ml ether and 100 ml water, decanted, extracted with ether, dried in the organic phase and evaporated to dryness. The residue is taken up in ether, chromatographed on silica gel eluting with ether and isolated 7.1 g of crude product which is precipitated with isopropyl - 53 -

DK 164404 B

eats, sucks and dries. 6.25 g of the expected compound are obtained. SMP 126 ° C.

b) __ H 2 -chlorochloride of "XSS ^ -S-amino-1- [1- [H-1" - triazole-B- [1,2-] 2- zididinone.

As in steps a, b, c, the dogei preparation according to Example 3 is worked from the compound obtained in the previous step and the lactone of N-trityl-L-serine.

EXAMPLE 13; (3S) -3 - ((2- (2-Aminothiazol-4-yl) -2-methoxyimino-acetyl) amino) -1- (4-nitro-3-trifluoromethyl-1H-pyrazol-5-yl) - 2- azetidinone.

1- [1- (3-trifluoromethyl-4-nitropyrazol-5-yl) -2-azetidinone.

It is cooled to -35 ° C 925 mg of 3-tert-butoxycarbonylamino-2-azetidinone prepared according to French Patent No. 2,509,299 in 20 ml of tetrahydrofuran and 6.25 ml of 0.8M sodium bis-trimethylsilylamide in tetrahydrofuran are added. stirring for 15 min. at -35 ° C and adding 2.2 g of 1- (2- (phenylthio) ethyl) -3-trifluoromethyl-4-nitro-5-fluoropyrrazole. It is allowed to re-enter room temperature, pour 20 into 100 ml of 1M aqueous monosodium phosphate solution and extract with ether. Dry the organic phase, evaporate, chromatograph the residue on silica gel (eluent: hexane and ethyl acetate (75:25)) and isolate 1.65 g of the expected compound. Rf = 0.22, eluent: hexane and ethyl acetate (8: 2).

B) β-β-β-3-tertA-butoxycarbonyll ^ino-1- (1- (2-j (phenylsulfonyl) β-ethyl I-3-trifluoroethyl-nitropyrrazole-S azetidinone.

It is stirred twice at intervals of 5 min. 400 mg of m-chloroperbenzoic acid to a solution of 1.05 g of the compound obtained in the previous step in 10 ml of methylene chloride. Allow to stir for 30 min. at room temperature, add 40 ml of methylene chloride, wash the organic phase with an aqueous potassium bicarbonate solution, dry and evaporate to dryness. 1.05 g of the expected compound are isolated.

Rf = 0.45, eluent: methylene chloride and ethyl acetate (9: 1).

35 C) (SS 3 S-tert 3 -butoxycarbonylamino-1-3 nitro-5-trifluoromethyl-EIIUSSSilålZIIIIzSzetidinone.

2.4 ml of 1.45M solution of potassium tert.-butylate in tetrahydrofuran is added to 1.60 g of the compound prepared in step B above in 80 ml of ether. Stir for 15 min. and adds - 54 -

DK 164404 B

3.3 ml of 1N hydrochloric acid and then 20 ml of water, decant, extract with ether, dry the organic phase and evaporate to dryness under reduced pressure. After chromatography on silica gel (eluent: methylene chloride and methanol (96: 4)), 580 mg of crude product is isolated, which is recrystallized from a mixture of isopropyl ether (5: 3). 503 mg of the expected compound is obtained. SMP 200-210 ° C (dec.), Bf = 0.3, eluent: methylene chloride and methanol (9: 1).

10 EY £ raz2l "5-yl)" 2-azetidine2n

Stir for 15 min. at room temperature 452 mg of the compound prepared in step C above in 5 ml of trifluoroacetic acid and evaporate to dryness. The residue is taken up in 15 ml of acetonitrile and evaporated. This operation is performed 4 times and the solvent is evaporated under reduced pressure to give 476 mg of the expected compound. Rf = 0.2, eluent: methylene chloride and methanol (8: 2).

E) (3S) -3 - [2- (2-Tritylamine-2-thiazyl] -42-yl] -2-meth-2-yl-yimin-2-acetyl) -cmingl-1 ^ (4-nitro-3-trifluoromethyl-1H-pyrrazol-5-yl) -2- 20 azetidinone.

A solution of 475 mg of the compound prepared above in 15 ml of acetonitrile and 0.35 ml of triethylamine is added to a suspension of the mixed anhydride of p-toluenesulphonic acid and 2- (2-tritylaminothiazol-4-yl) -2-methoxyiminoacetic acid , 25 syn isomers prepared as in step b) of Example 1 from 600 mg of acid and 256 mg of p-toluenesulfone chloride. After stirring for 1 hour at room temperature, the methylene chloride is taken up, washed with an aqueous 1M monosodium phosphate solution and 0.1N hydrochloric acid, dried over the organic phase and evaporated to dryness.

After chromatography of the residue on silica gel (eluent: methylene chloride and methanol (94: 6)), 657 mg of the expected compound were isolated. Rf = 0.4, eluent: methylene chloride and methanol (9: 1).

F) (3S) -3- (2- (2-Aminothiazol-4-yl) -2-methoxyiminoacetyl) -3- 5ΐΒΪΕ2ΐΐΧζϋΐ2ΐ £ ΐ2Ζ3Γ ££ ΐ £ 1 ^ 2ϊ52 ^ 1ιγ1-1Η-ργΓη§ζο1-5 γ1) _- 2- azetidinone.

As in step b) in Example 3, one is based on 610 mg - 55

DK 164404 B

of the compound prepared in step E above and receiving 257 mg of the expected compound. SMP 200-210 ° C. Rf = 0.45, eluent: ethyl acetate, ethanol and water (85: 10: 5). NMR Spectrum (DMSO): δ 3.87 ppm: N-OCH 3 4.11 to 4.42 ppm: H4 5.18 ppm: H3 6.77 ppm: in thiazole

7.22 ppm: NH2 9.36-9.44 ppm: NH-CO

IR spectrum (nujol) 1790 (shoulder) 1763 (max) 1750-1680-1655 cm -1: C = 0 1603-1585-1537-1528 cm -1: aromatic groups.

The starting compound of Example 13 used 1- (2- (phenylthio) ebhyl) -3-trifluoromethyl-4-nitro-5-fluoropyrrazole is prepared as follows: a) 3-Bromo-4-nitro-5-trifluoromethylpyrrazole .

14 g of 3-bromo-5-trifluoromethyl-pyrrazole are heated to 80 ° C in 100 ml of pure sulfuric acid and added over 15 minutes.

20 g of potassium nitrate. After 45 minutes of stirring at 80 ° C, cool and pour on ice, extract with methylene chloride, dry the organic phase and evaporate to dryness under reduced pressure at 50 ° C. 16.9 g of the expected compound are isolated. SMP 50-60 ° C.

B) __ 1-X2-Xphenylthio) -ethyl 1) 3 - 3-trifluoromethyl-4-nitro-5-k 2

1.95 g of sodium hydride (55% in oil) is added to 10.4 g of the above compound in 100 ml of dimethylformamide. After 15 minutes of stirring at room temperature, 10 g of 2-phenylthio-1-bromethane are added and heated to 80 ° C for 16 hours. It is cooled, poured on 600 ml of water, extracted with ether, dried over the organic phase and evaporated under reduced pressure. Hexane is cooled in ice cooler, the crystals are extracted, washed with hexane, with isopropyl ether and again with hexane.

After recrystallization from isopropyl ether, 6.2 g of the expected compound are isolated. After chromatography on silica gel of the mother liquor (eluent: hexane and ethyl acetate (8: 2)), a second yield of 6.1 g of identical compound is obtained, i.e.

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DK 164404 B

12.3 g of the expected compound. SMP 66-68 ° C.

c) 1- (2- (ghenylthio) ethyl) -3-trifluoromethyl-4-nitro-5-fluoropyrrazole.

To reflux under inert atmosphere, 5 g of crown ether (18-6), 1200 ml of acetonitrile and 7 g of potassium fluoride are heated, and 200 ml of solvent are distilled and 6.2 g of the compound obtained in the previous step is added. It is heated for 2 hours to reflux, filtered and evaporated to dryness.

The residue is taken up in benzene, evaporated under reduced pressure 10 and 4.8 g of the expected compound are obtained.

Example 14: Trifluoroacetate of (3SR, 4SR) -3 - ((2- (2-aminothiazol-4-yl) -2 - ((1-carboxy-1-methylethoxy) -imino) -acetyl) -amino) -4 - (fluoromethyl) -1- (tetrazol-5-yl) -2-azetidinone.

As in Example 7, steps E and F are used from the hydrochloride of (3SR, 4SR) -3-amino-4-fluoromethyl-1- (1H-tetrazol-5-yl) -2-azetidinone prepared as in Step D in Example 11 and the mixed anhydride of p-toluenesulfonic acid and 2- (2-tritylamino-thiazol-4-yl) -2 - ((1-carboxy-1-methylethoxy) imino) -acetic acid 20 prepared as in Example 7 You get the expected connection.

NMR Spectrum (DMSO): 1.64 ppm (s): gem-dimethyl

4.69 to 5.06 ppm (m): H4 + CH2F

5.66 ppm (m): H3 6.75 ppm (s): in thiazole

7.36 ppm (m): NH-CO

12.65 ppm: CF 3 -CO 2 H

IR spectrum (nujol) -1 1780-1675 cm: amide + trifluoroacetate 1640 cm -1: NH 2 1590 cm 1: CO, -1 1550 cm: conjugated system 1200-1143 cm 1: CF3 EXAMPLE 15: (3SR, 4RS) -3 - ((2- (2-Aminothiazol-4-yl) -2-methoxyiminoacetyl) amino) -4-fluoromethyl-1- (tetrazol-5-yl) -2-azetidinone. As in Example 11, steps A to E are used

DK 164404 B

-57- hydrochloride of (3SR, 4RS) -3-amino-4-fluoromethyl-2-azetidinone to give the expected compound. Rf = 0.2, eluent: ethyl acetate, ethanol and water (7: 2: 1).

NMR Spectrum (DMSO): δ 3.86 ppm (s): O-CH 3 4.56 to 5.22 ppm (m): CH 2 -F + H 3 + H 4 7.24 ppm (s): NH 2

9.42 ppm (d): NH-CO

IR spectrum (nujol) 10 1770-1675 cm -1: C = 0 1528 cm 1 secondary amide 1640 cm -1 (deformation): NH NH -1 Δ 1611-1592-1528 cm: conjugated system 1032 cm -1: oxime The hydrochloride of (3SR, 4RS) -3-amino-4-fluoromethyl-2-azetidinone used as the starting compound of Example 15 is prepared as follows: 20.6 g of hydrazine hydrate are added over 50 minutes to 50 ml. methanol to a solution of 61 g (3RS, 4RS, 1'SR) -3-phthalimido-4-fluoro-1- (1-phenylethyl) -2-azetidinone in 600 ml dioxane. Stir for 1 hour at room temperature and Add 175 ml of 1 N hydrochloric acid, evaporate the dioxane, add 400 ml of methanol, stir for 2 hours at 40 ° C, filter, evaporate the filtrate to dryness under reduced pressure, absorb the residue in 300 ml of water and eliminate the insoluble material by filtration. wash the filtrate with methylene chloride, add to the aqueous phase 87 ml of 2N sodium hydroxide and extract with methylene chloride, dry the organic phase, evaporate to dryness and evaporate to dryness. r 34.3 g of the expected compound. Rf = 0.4, eluent: methylene, methanol and ammonia (95: 5: 0.5). fel_lå§2riS§rii§5iz3zilE ^ 22Yii22 £ i} Yi22lz2Si22izlz ^ £ i22SB2t ^ Ziz

IzlizE3ilS2Yi§ £ llYiIz2i§2etidinon.

Stir for 15 min. at room temperature under inert atmosphere 34.3 g of the compound obtained in the previous step in 500 ml of methylene chloride with 16.6 g of benzaldehyde and 40 g of magnesium-

DK 164404 B

sulfate. Filter, evaporate the filtrate to dryness under reduced pressure and obtain 48 g of the expected compound.

c), X3SRi4RSil ^ SR2i-3- [1- (4-fluoromethyl-1-Xl-phenylethyl) -1-2-zetidinone.

Cool to 47 ° C 47.7 g of the compound obtained in the previous step in 500 ml of tetrahydrofuran and 185 ml of 0.83 M solution of sodium bis-trimethylsilylamide in tetrahydrofuran are added. Stir for 15 min. at -50 ° C and pour the solution into 500 ml of 1N hydrochloric acid. The mixture is stirred for 15 minutes, the aqueous phase is washed with ether and then with methylene chloride. 20 g of ammonium chloride are added to the aqueous phase and then 25 ml of concentrated ammonia water. Extract with methylene chloride, separate the organic phase, dry it and evaporate to dryness under reduced pressure. After chromatography on silica gel. (eluent: methylene chloride, methanol and ammonia water (97: 3: 0.5) are isolated. 19.5 g of expected compound (trans isomer), Rf = 0.3, eluent: methylene chloride, methanol and ammonia water (95: 5: 05) and 5 g of corresponding cis isomer.

d) (3SR, 4RSI1SR) -3-phthalimido-4-fluoromethyl-1- (1-phenylethyl) -2-2-azetidinone.

Reflux 19.3 g of the compound obtained in the previous step are heated for 5 hours in 500 ml of tetrahydrofuran with 20 g of N-ethoxycarbonylphthalimide and 16 ml of triethylamine. Evaporate to dryness, take up the residue in ethanol, ice-cool, 25 extract the crystals, wash them with ethanol and then with ether and isolate 19 g of compound and then 6.5 g after chromatography of the mother liquors on silica gel, eluent: benzene and acetone ( 9: 1), Rf = 0.3.

e) (3SR, 4RS) -3-Phthalimido-4-fluoromethyl-2-azetidinone.

O ft

To the reflux, 25 g of the compound obtained in the previous step is heated in 400 ml of acetonitrile and 240 ml of water and added over 15 minutes. 40 g of ammonium persulfate in 100 ml of water. The reflux is continued for 2 hours 30 minutes, cooled, saturated with sodium chloride, decanted, extracted the aqueous

O C

phase with ethyl acetate, drying the organic phases and evaporating them to dryness. After chromatography of the residue on silica gel (eluent: methylene chloride and ethyl acetate (75:25)) and

DK 164404B

- 59 - ether crystallization isolates 7.15 g of the expected compound. SMP 175-178 ° C.

I_SYåE2 £ £ £ ^ i2 iå_Sl_X3§5i4RS) _- 3-amino-4 "fluorinethYl-2-azetidinone. You set in 5 min. 1.43 g of hydrazine hydrate in 10 ml of 5 methanol to a solution of 7.1 g of the compound obtained in the previous step in 150 ml of dioxane. Stir for 30 min. at room temperature, adding 29 ml of 1N hydrochloric acid. It is evaporated under reduced pressure, taken up in 200 ml of methanol and heated to 40 ° C for 1 hour. The methanol is evaporated, taken up in 200 ml of water, 10 filtered, the filtrate evaporated under reduced pressure to give a volume of 100 ml, filtered again and the filtrate evaporated to dryness under reduced pressure. The residue is taken up in methanol, the crystals are extracted, washed with methanol and then with ether, and 3.59 g of the expected compound are isolated. SMP approx. 200 ° C (dec.), Rf = 0.2, eluent: methylene chloride, methanol and ammonia water (9: 1: 0.1).

EXAMPLE 16: An injection preparation is prepared according to the following prescription: 20 - (3SR, 4RS). -3 - ((2- (2-Aminothiazol-4-yl) -2-methoxyiminoacetyl) amino) -4-methyl 1- (1H-tetrazol-5-yl) -2-azetidinone, syn-isomer ............................... .. 500 mg - aqueous additive .......................... 5 ml EXAMPLE 17: Gelatin capsules are prepared following the prescription: - (3SR, 4RS ) -3 - ((2- (2-aminothiazol-4-yl) -2 - ((carboxy-methoxy) -imino) -acetyl) -amino) -4-methyl-1- (1H-tetrazol-5-yl) ) -2-azetidinone, syn isomer ......................... 250 mg - additive to form a gelatin capsule of ...... ........................................ 400 mg

Pharmacological study

In vitro activity, method of dilutions in liquid environment.

A series of glasses is produced, where the same amount of sterile nutrient medium is distributed. Increasing quantities of the compound to be examined are distributed in each glass and then - 60 -

DK 164404 B

graft each glass with a bacterial strain. After incubation for 24 or 48 hours in a heating cabinet at 37 ° C, the inhibition of growth is assessed by illumination, which allows the minimum inhibitory concentrations (M.I.C.), expressed as 5 µg / ml, to be determined.

The following results are obtained:

Connection Connection Connection STAMMER iflg.ex.l iflg.ex.2 iflg.ex.3 10 24h 48h 24h 48h 24h 48h

Pseudomonas aeruginosa. $ 5 «$ 5 <5 5 10 1771 m

Escherichia / coli 1894 0.08 0.08 0.3 0.3 0.15 0.15 "" 078 0.3 0.3 0.6 0.6 0.3 0.3 15 "" TEM 0.6 1.2 10 10 10 10 "" 1507 E 0.3 0.3 0.6 0.6 0.6 0.6 "" DCO 1.2 1.2 2.5 2.5 0.6 1.2 "" DC2 0.6 0.6 0.6 1.2 0.6 0.6

Salmonella, typfabmurium MZ 11 1.2 1.2 1.2 2.5 0.3 0.3 Klebsiella pneumonae 52145 1.2 2.5 2.5 2.5 1.2 1.2 "aeruginosa 1522 E 1 , 2 1.2 0.6 0.6 0.3 0.3

Enterobacter cloacae 1321 E 0.6 0.6 1.2 1.2 0.3 0.3

Serratia marcesceus 2532 20 20 20> 40 2.5 5

Proteus mirabilis A 235 0.15 0.15 0.6 1.2 0.6 0.6 Proteus vulgaris A 232 0.3 0.3 1.2 1.2 2.5 0.3 0.3

Providencia DU 48 0.6 0.6 1.2 1.2 0.3 0.6 1 35 - 61 -

DK 164404 B

Connection Connection Connection STAMMER iflg.ex.4 iflg.ex.6 iflg.ex.7 24h 48h 24h 48h 24h 48h c Pseudomonas aeruginosa 2.5 5 0.6 0.6 1771 m

Escherichia Coli 1894 <0.04 <0.04 0.6 0.6 0.6 0.6 "" 078 0.3 0.3 0.3 0.3 0.3 0.6 0.6 "" TEM 0.6 1.2 0.6 0.6 1.2 1.2 "1507 E 0.15 0.15 0.6 0.6 1.2 1.2 10" "DCO 1.2 1.2 0.6 0 , 6 0.6 1.2 "" DC2 <0.04 <0.04 0.3 0.3 0.6 0.6

Salmonella thyphimurium MZ 11 1.2 1.2 0.6 0.6 0.6 0.6

Klebsiella pneumonae 52145 5 5 2.5 2.5 2.5 2.5 "aeruginosa 1522 E 1.2 1.2 0.6 0.6 1.2 1.2 15

Enterobacter cloacae 1321 E 1.2 1.2 0.3 0.6 2.5 2.5

Serratia marcesceus 2532 20 20 2.5 5 1.2 1.2

Proteus mirabilis A 235 0.3 0.3 0.15 0.15 0.15 0.15

Proteus vulgaris A 232 0.3 0.3 0.08 0.15 0.08 0.08

Providencia DU 48 2.5 2.5 0.6 0.6 0.6 0.6 20 -

Connection STAMMER according to.ex.il 25 24h 48h

Pseudomonas aeruginosa 1771 m

Escherichia. Coli 1894 <0.04 <0.04 "" 078 0.15 0.15 30 '* "TEM 0.6 0.6" 1507 E 0.08 0.08 "DCO 0.6 0.6" DC2 0 , 0.15

Salmonella typhimurium MZ 11 0.3 0.3 Klebsiella pneumonae 52145 1.2 1.2 "aeruginosa 1522 E 0.6 0.6

Enterobacter cloacae 1321 E 0.3 0.3

Serratia marcesceus 2532 10 10

Proteus mirabilis A 235 0.15 0.15

Proteus vulgaris A 232 0.15 0.15 - 62 -

DK 164404 B

Example a: (35.45) -1 - (((1- (2-Amino-4-thiazolyl) -2 - ((4-fluoromethyl-2-oxo-1-tetrazolyl-3-azetidinyl) amino) -2 -oxoethylidene) - (amino) -oxycyclopropanecarboxylic acid Step A; (35.45) 1 ((- 1- (2-tritylamino-4-thiazolyl) -2 - (((4-fluoro-methyl-2-oxo 1-Tetrazolyl-3-acetidinyl) -amino-2-oxo-ethylidene-amino-oxy-cyclopropanecarboxylic acid 1,1-dimethylethyl ester A mixture of 1.96 g of 2- {1) is stirred until solubility. tert -butoxycarbonylcycloprop-1-oxyimino) -2- (2-triethylaminothiazol-4-yl) -acetic acid, syn isomer, described in French Patent No. 2,445,835, preparation 7, 30 ml of anhydrous acetone and 0.5 ml of triethylamine, 0.655 g of tosyl chloride is then added, and then stirred for 10 minutes at room temperature, finally 0.93 g of (3S, 4S) -3-amino-4-fluoromethyl-1- (1H-tetrazole) is added. 5-yl) -2-azetidinone in the form of chlorohydrate in solution in 15 ml of acetonitrile containing 1.5 ml of triethylamine.

20

After 5 minutes of stirring at room temperature, 0.4 ml of pure acetic acid is added. It is almost evaporated to dryness, taken up in 100 ml of ethyl acetate, the organic phase is washed with water, dried and evaporated to dryness. 2 g of an oil are obtained which are purified by chromatography on silica gel; eluent: methylene chloride and methanol (95: 5 with 0.5% acetic acid). 1.6 g of resin is obtained, which is used immediately in the next step. 1 2 3 4 5 6

Step B: 2 (35.45) -1 - ({(1- (2-amino-4-thiazolyl) -2 - ((4-fluoromethyl-2- 3-oxo-1-tetrazolyl-3-azetidinyl) amino) 2-oxoethylidene-4-amino-oxy-cyclopropanecarboxylic acid 5

A mixture of 6 1.6 g of the product obtained in step A and 8 ml of trifluoroacetic acid is stirred for 15 minutes at room temperature. Evaporates to dryness and absorbs reaction bias - 63 -

DK 164404 B

in 2x 20 ml of acetonitrile to eliminate trifluoroacetic acid. 15 ml of 66% formic acid is added. The mixture is stirred at 40 ° C for 30 minutes, allowed to re-enter room temperature, the triphenylcarbinol is filtered off and the filtrate is evaporated 5 to a quarter volume. Chromatograph on a resin column. Elute with water and then with a mixture of water and methanol (8: 2). 0.32 g of product is obtained in the form of a resin.

NMR spectrum, 90 MHz in DMSO:

10 MHtUJ

i (c) (ti

<7 ^ V-H

) = L ^ ConH L ^ -F

/ y «t

c cl) ri J M

15 \> w ^ 'y & r * XI \

(a) 1.33 ppm Co 2 H

(b) 4.44 to 5.11 ppm (c) 5.62 to 5.76 ppm (d) 6.83 ppm (e) 7.29 ppm (f) 9.32 ppm (dJ = 9 Hz)

The chlorohydrate of (3S, 4S) -3-amino-4-fluoromethyl-1- (1H-tetrazol-5-yl) -2-azetidinone used as the starting material in Step A is prepared as set forth in Example 11 in European Patent Application No. EP 0 114 128 from (3S, 4S) -3-amino-4-fluoromethyl-2-azetidinone. This azetidinone is prepared as follows in the form of chlorohydrate according to French Patent Application No. 84.00799:

Step alpha: 4-fluoromethyl-3-phthalimido-2-oxo-1- (1-phenylethyl) azetidine 35.6 ml of an aqueous solution of hydrate of fluoroacetaldehyde is stirred for 0.97 M / l, 100 ml for 10 minutes. ice-cooled aqueous saturated solution of sodium chloride and 9.8 ml of R - (+) - - 64 -

DK 164404 B

-phenylethylamine. It is extracted with chloroform (192 ml), dried and cooled to -70 ° C under inert atmosphere.

At the same time, during the course of 15 minutes while maintaining a temperature of -50 ° C -2 ° C, 16.8 g of phthalimidoacetyl chloride in 77 ml of chloroform and 7.8 g of triethylamine in 77 ml of chloroform are introduced. Heat to room temperature and leave for 1 hour. 46 ml of an aqueous 10% sodium bicarbonate solution is added and then 77 ml of water. Vigorously stir, decant, re-extract with methylene chloride, wash the organic phase with water, dry and evaporate to dryness under reduced pressure. The residue is chromatographed on silica gel eluting with a mixture of benzene and acetone (95: 5). 10.3 g of 3S, 4S isomer and 2.5 g of 3R, 4R isomer are obtained.

15

Analysis, molecular watch 352.37

Calculated: C% 68.2 H * 4.86 N% 7.95 F% 5.40 found (3S, 4S isomer): 68.4 4.9 8.0 5.3 found (3R, 4R isomer ): 67.1 4.8 7.4 5.1 alphaD: 3S, 4S isomer = -29 ° -1.5 ° (c = 1%, CH 2 OH) 3R, 4R-siomer = -50 ° -1.5 ° (c = 1%, CHCl 3).

Step beta: (3S, 4S) -4-fluoromethyl-3-phthalimido-2-oxo-1-azetidine

Boil 9.8 g (3S, 4S) isomer prepared above in 150 ml of acetonitrile and 96.5 ml of water and then add 15.9 g of ammonium peroxydisulfate in 39 ml of water and heat to reflux for 1 minute. hour 30 mi-30 nuts. After cooling, the reaction mixture is saturated with sodium chloride, decanted, washed with saturated sodium chloride solution and extracted with ethyl acetate. The organic phase is washed with 100 ml of solution containing 20 g of sodium thiosulfate per ml. 100 ml of sodium chloride saturated water. The organic phase is dried and evaporated to dryness under reduced pressure, chromatographed on silica gel, eluted with a mixture of methylene chloride and ethyl acetate.

DK 164404 B

(75:25) and, after crystallization of ether, obtains 2.33 of the expected compound. Mp. = 160 + 162 ° C.

alphaD = + 7 ° -1 ° (c = 1%, CH 3 OH).

5

Step gamma:

Chlorohydrate of (3S, 4S) -4-fluoromethyl-3-amino-2-oxo-azetidine

Mix 2f3 g of the product obtained in step beta and 2.3 10 ml of dioxane and in 20 minutes add 26 ml of a solution made from 1 ml of hydrazine hydrate added dioxane to 50 ml. After 45 minutes at room temperature, 9.3 ml of 1N hydrochloric acid are added. Stir for 16 hours at room temperature under inert atmosphere, evaporate to 15 dryness under reduced pressure, take up anhydrous ethanol, evaporate to dryness, dissolve the residue to a minimum of methanol, add ethanol again and evaporate to dryness. The residue is dissolved in a minimum of methanol under reflux, ice-cooled, expelled and rinsed with cold methanol and then ether. 1.1 g of the expected product is obtained in several yields. Mp. above 220 ° C (decomposition).

Analysis: C ^HgO ^ClF = 154.57

Calculated: C% 31.08 H% 5.22 N% 18.12 Cl% 22.24 F% 12.29 Found: 32.1 5.2 17.0 20.8 11.4 alphaD = -25, 5 + -1 ° (c = 1%, CH 3 OH).

Example b: ((3S, 4S) -1 - (((1- (2-amino-4-thiazolyl) -2 - (((4-fluoromethyl-2-oxo-1-tetrazolyl-3-acetidinyl) ) -amino) -2-oxoethylidene-amino-oxy-cyclobutanecarboxylic acid Step A: (3S, 4S) -1 - (((1- (2-tritylamino-4-thiazolyl) -2 -) (((4 -Fluoromethyl-2-oxo-1-tetrazolyl-3-azetidinyl) amino) -2-oxoethylidene-amino-oxy) -cyclobutane carboxylic acid-1,1-dimethylethyl ester - 66

DK 164404 B

a) A mixture of 2.6 g of (3S, 4S) -α- (1-benzyltetrazol-5-yl) -3-tritylamino-4-fluoromethyl-2-azetidinone is kept for 25 minutes at 50 ° C. 50 ml of acetonitrile and 4.9 ml of 1N hydrochloric acid.

It is distilled to dryness under vacuum, taken up in acetonitrile and then distilled again to dryness. A white crystalline residue is obtained which is etherified. Suction and redissolve in 40 ml of methanol (solution A).

b) 400 mg of palladium, 18% on activated charcoal, is introduced into 10 ml of 10 methanol and then solution A is added. It is heated to 40 ° C and stirred for 30 minutes with hydrogen bubbling.

The catalyst is filtered off and distilled to dryness under reduced pressure at 40 ° C. The residue is taken up in acetonitrile and distilled again and then dried under reduced pressure.

c) 2.8 g of 2- (1-tert.-butoxycarbonylcyclobut-1-oxyimino) -2- (2-tritylaminothiazol-4-yl) -acetic acid, syn isomer, described in French Patent No. 2,445 .835, Preparation 6, 56 ml of acetone and 0.7 ml of triethylamine.

After solution, 0.92 g of tosyl chloride is added and then stirred for 25 minutes at room temperature (solution C). D) Mix the product from b) above with 35 ml of acetone 2 tril and 2 ml of triethylamine and then add at once 3 the solution prepared above C. Stir for 2 hours 4 at room temperature, filter out insoluble material. and 5 distills to dryness under reduced pressure.

6

Chromatograph the obtained product on silica gel; eluent: methylene chloride and methanol (95: 5 with 0.5% acetic acid) to obtain 3 g of the expected product.

- 67 -

DK 164404 B

Step B: ((3S, 4S) -1 - (((1- (2-amino-4-thiazolyl) -2 - (((4-fluoromethyl-2-oxo-1-tetrazolyl-3-azetidinyl)) -amino) -2-oxoethylidene ((amino) -oxy) -cyclobutane carboxylic acid 5 A mixture of 0.78 g of the product of step A in 2.5 g of trifluoroacetic acid is stirred for 10 minutes at room temperature. rapidly at 30 ° C under reduced pressure.

It is taken up in 5.5 ml of 66% formic acid, warmed to 50 ° C and stirred for 15 minutes and then allowed to reach room temperature over 30 minutes.

t

Insoluble material is extracted and distilled to dryness at 30 ° C under reduced pressure. It is taken up in ethanol, evaporated to dryness and obtained 0.5 g of crude product, which is dissolved in a minimum of dilute formic acid and filtered on resin eluting with water and then successively with an aqueous solution containing 10%, 20%, 30% , 40% and 20% methanol.

Evaporate to dryness to give 0.29 g of product, which is ejected with ether and then suctioned after 15 minutes and dried under reduced pressure.

25

0.286 g of the expected product is obtained. Mp. ca. 220 ° C.

Analysis: CX5HX6N9 ° 5FS = 453.41

Calculated: C% 39.73 H% 3.56 S% 7.07 Found: 39.8 3.6 7.1 alpha = -33.5 ° -2 ° (c = 0.5% in methanol) .

(3S, 4S) -1- (1-benzyltetrazol-5-yl) -3-tritylamino-4-fluoromethyl-2-azetidinone used as starting material in Step A is prepared as set forth in Example 11 of European Patent Application EP 0 114 128 from (3S, 4S) -3-amino-4-fluoro- - 68 -

DK 164404 B

methyl 2-azetidinone, the preparation of which is given in Example a) above.

(35.45) -1- (1-benzyltetrazol-5-yl) -3-tritylamino-4-fluoromethyl-2-azetidinone has the following physicochemical properties:

Mp. = 146 ° C, alphazu = -41.5 ° -2 ° (c = 0.5% in CHCl

D J

Example c (35.45) -1 - ((1- (2-Amino-4-thiazolyl) -2 - ((4-fluoromethyl-2-oxo-1-tetrazolyl-3-azetidinyl)) amino) -2- oxoethylidene) - amino) oxy) -cyclopentane carboxylic acid

Step A: (3Sf4S) -1 - (((1- (2-tritylamine-4-thiazolyl) -2 - (((((4-fluoromethyl-2-oxo-1-tetrazolyl-3-azetidinyl))) amino) -2-oxoethylidene-amino-oxy-cyclopentanecarboxylic acid 1,1-dimethyl-ethyl ester

As in Step A, as in Example b), 1.04 g of (35.45) -1- (1-benzyltetrazol-5-yl) -3-tritylamino-4-fluoromethyl-2-azetidinone and 1 2 g of 2- (1-tert-butoxycarbonylcyclopent-1-oxyimino) -2- (2-tritylaminothiazol-4-yl) acetic acid ester, syn isomer, described in French Patent No. 2,445,835, Preparation 9 .

0.92 g of the expected product is obtained.

25

Step B: (35.45) -1 - (((- (2-amino-4-thiazolyl) -2 - ((4-fluoromethyl-2-oxo-1-tetrazolyl-3-azetidinyl)) amino) -2 -Oxoethylidene-amino-oxy-cyclopentanecarboxylic acid 30 As in step B of Example b), proceed from 0.9 g of the product prepared in step A above. Finally, 0.308 g of the expected product is obtained. Mp. ca. 220 ° C.

NMR spectrum: 90 MHz in DMSO: 35

DK 164404 B

- 69 - Å «Ι.Γ) l; ' Ά;

/ V0 "" fY

<J \ s! ,, T ^ "S / NW ri ~ tf« 2 «l« T ^ (<>) 10 (a) between 1.7 and 2.03 ppm (b) 4.62 to 5.13 ppm (c) 5.57 to 5.73 ppm (d) 6.75 ppm (e) 7.3 ppm (f) 9.48 ppm (dJ = 9 Hz).

Example d

An injection preparation according to the recipe is prepared: 20 - (3S, 4S) -1 - (((1- (2-amino-4-thiazolyl) -2 -) (((4-fluoro-methyl-2-oxo-1-tetrazolyl) -3-azetidinyl) -amino-2-oxyethylidene-amino-oxy-cyclobutane carboxylic acid 500 mg - aqueous additive ...................... ... 5 ml 25

Example e

Gelatin capsules are prepared according to the recipe: - (3S, 4S) -1 - (((1- (2-amino-4-thiazolyl) -2 - (((4-fluoromethyl-2-oxo-1-tetrazolyl) 3-azetidinyl) -amino-2-oxoethylidene-amino-oxy-cyclobutane carboxylic acid 250 mg additive to form a gelatin capsule of ................... ........................... 400 mg 35 - 70 -

DK 164404 B

Pharmacological examination of compounds of Examples a and b

In vitro activity, method of dilution in aqueous environment 5 A series of glasses are prepared in which the same amount of sterile nutrient environment is distributed. Increasing amounts of the compound to be examined are distributed in each glass and then inoculated each glass with a bacterial strain. After incubation for 24 or 48 hours in a refrigerator at 37 ° C, growth inhibition is determined by illumination, which allows the minimum inhibitory concentrations (MIC) to be expressed in pg / ml to be determined. The following results are obtained:

Strain MIC in pg / ml 15

Compound Compound from Example a Example b

Pse. aeruginosa 1771 5 2.5

Pse. aeruginosa 1771m 0.15 0.15 20 Pse. aeruginosa 9027 20 10 E. coli 1894 0.08 0.04 E. coli 078 0.04 0.15 E. coli TEM 0.15 0.15 E. coli 1507 E 0.08 0.15 E. coli DC O 0.15 0.15 E. coli DC 2 0.08 0.08 • Salmon. thyphimurimum MZ11 0.15 0.3

Kle. pneumoniae 52145 0.08 0.15

Kle. aerogenes 1082 E 0.15 0.3 30 Kle. aerogenes 1522 E 0.3 0.3

Ent. cloacae P99 2.5 5

Ent. cloacae 1321 E 0.08 0.15

Serratia RG 2532 0.15 0.15

Pro. nurabilis A 235 0.04 0.02 35 Pro. vulgaris A 232 0.04 0.02

Porvidencia DU 48 0.08 0.15

DK 164404B

- 71 -

Pse = Pseudomonas E = Escherichia Salmon = Salmonella Kle = Klebsiella 5 Ent = Enterobacter Pro = Proteus 10 15

Claims (6)

H 2 wherein R 'represents a hydrogen atom or alkenyl or cycloalkyl or a straight-chain or branched alkyl group of 1-6 carbon atoms optionally substituted with one or more groups selected from free, esterified or salt converted carboxy group, amino, mono- or di-alkylamino, aryl, halogen, nitrile, CONHSC ^R "* where R" represents alkyl, aryl or amino, or R alkyl represents an alkyl carbonyl group or arylcarbonyl group or a phenyl group, Represents a hydrogen atom or an alkyl group optionally substituted by one or more groups selected from halogen, azido, hydroxyl, mercapto, aryl, amino, nitrile, allylthio or arylthio optionally oxidized, acyl, acyloxy , acylamino, aralkylcarbonyl, carbamoylloxy, alkyl or dialkylcarbamoyloxy, or R 4 represents alkenyl or alkynyl optionally substituted with a phenyl group or with one or more halogen atoms, or R 4 represents a thioalkyl group which is also Represents a phenyl group optionally substituted with halogen, CF 2, amino, hydroxy, alkyl or alkoxy, or R 4 represents an esterified carboxy group, a carbamoyl group or an azido group, R 2 represents tetrazolyl, triazolyl, imidazolyl, pyrazolyl or pyrrolyl optionally substituted with one or more groups selected from nitro, carboxy, CF 2, nitrile, halogen, sulfo, alkyl sulfo, ( CH2) nSC> 3H, (CH2) nNHSO3H, (CH2) nSO2NH2, (CH2 CC2H, where n represents an integer from 1-4, the compounds having syn isomerism and the wavy line indicating that the compounds may be in cis or trans form, or in the form of a cis-trans mixture, the compounds of formula (I1) being in racemic or optically active form, or salts of the compounds of formula (I1) having bases and acids. Compounds of formula (I1) according to claim 1, characterized in that R 'represents a hydrogen atom, methyl, phenyl, difluoromethyl, 1-methyl-1-carboxyethyl, cyanmethyl, carboxymethyl or (methylsulfony1) carbamoylmethyl, R 1 represents a hydrogen atom, methyl, fluoromethyl, trifluoromethyl, ethoxycarbonyl, carbamoyl, R 2 represents 1 H-tetrazol-5-yl or 1,3,4-triazol-2-yl, optionally substituted with trifluoromethyl or carboxymethyl. Compounds of formula (I) according to claim 1, characterized in that they are the following compounds: 25 - 3 - ((2- (2-aminothiazol-4-yl) -2-methoxyiminoacetyl) amino) -4-methyl- 1- (1H-tetrazol-5-yl) -2-azetidinone, cis or trans, syn isomer, racemic or optically active, - 3 - ((2- (2-aminothiazol-4-yl) -2-carboxymethoxyiminoacetyl) - amino) -4-methyl-1- (1H-tetrazol-5-yl) -2-azetidinone, cis or trans, syn isomer, racemic or optically active, - 3 - ((2- (2) -aminothiazol-4-yl) -2- (1-carboxy-1-methyl) -ethoxy-iminoacetyl) -amino) -4-methyl-1- (1H-tetrazol-5-yl) -2-azetidinone , cis or trans, syn-isomer, racemic or optically active, 35-3 - ((2- (2-aminothiazol-4-yl) -2-methoxyiminoacetyl) amino) -4-fluoromethyl-1- (1H- tetrazol-5-yl) -2-azetidinone, cis or trans, syn isomer, racemic or optically active, - (2- (2-aminothiazol-4-yl) -2-f) lluoromethoxyiminoacetylamino) -4-methyl-1- (1H-tetrazol-5-yl) -2-azetidinone, cis or trans, syn isomer, racemic or optically active. Analogous process for preparing the compounds of general formula (I1) according to claim 1, characterized in that a compound of formula (II) is treated: h2 \ ΛΡ 10. In (II) SN 0 \ Rap 15 cis or trans, racemic or optically active, wherein either R 1 p represents R 2, wherein R 1 has the same meaning as in claim 1, or R 2 p represents substituent R 2, wherein the reactive groups are protected and wherein R 2p is either R 2, wherein R 2 is as defined in claim 1, or R 2 p 20 represents the substituent R 2, where the reactive groups are protected, with a compound of formula (III): NHRb 25 / CC ^ H (III) NS ORp 1 2 3 4 5 6 syn or anti, wherein R b represents a hydrogen atom or a 2 protecting group for the amino group and R p represents a 3 protecting group for the hydroxyl group, or R p represents 4 R, R having the same meaning as in claim 1, or R p 5 represents a group R in which the reactive groups are 6 protected, to give a compound of formula (IV) - 75 - NHR'b ^ CONIl · R- | P An analogous process according to claim 4 for the preparation of the 2 compounds of formula (If) according to claim 1, characterized in that a compound of formula (II) is used in which R methyl, fluoromethyl, trifluoromethyl, 6 ethoxycarbonyl or carbamoyl, and R 2p represents 1H-tetrazol-5-yl or 1,3,4-triazol-2-yl, optionally substituted with trifluoromethyl or carboxymethyl, and a A compound of formula (III), wherein Rb represents a protecting group for the hydroxyl group, a methyl group, an 11 phenyl group, a difluoromethyl group, a 1-methyl-1-carboxyethyl group, a cyanmethyl group, a carboxymethyl group or a methylsulfonylcarbamoylmethyl group. - 76 - DK 164404 B 5 N (IV) S 0 N \ ORP \ p syn or anti, racemic or optically active, wherein Rp, R R 2 P and R b have the same meaning as above, which compound, if necessary and if desired, is subjected to any of the following reactions in any order: a) excision by hydrolysis, hydrogenolysis or by the action of thiourea of the protecting group (s) b) esterification or conversion into salt of the carboxy or sulfo groups which may include Rp, R1p and R2p; c) conversion to salt by an acid of the amino group or amino groups; d) cleavage of the molecule to obtain an optically active product. 1 2 3 4 5 6 7 8 9 10 11 Pharmaceuticals, characterized in that they are compounds of formula (I *) according to claims 1-3 or their pharmaceutically acceptable salts. 5 10 15