LU86410A1 - PROCESS FOR THE PREPARATION OF CARBAPENEMAS - Google Patents

Description

ί - ··, / '’'; There

Process for the preparation of carbapenems 1

CD.MJ 4F - 1 - SY-1767A

Field of the invention n -

The present invention relates to a new process for the preparation of antibiotic carbapenems carrying in position 2 a substituent of formula: -S-A-Ir— R-R5 i ...

where A represents an alkylene radical in straight chain, 5 or branched in C ^ -Cg, R represents an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl, araliphatic, heteroaryl, heteroaraliphatic, heterocyclic or heterocycloaliphatic radical optionally substituted, and 0Λ an aromatic nitrogen heterocycle attached to the alkylene radical A by a ring carbon atom and quaternized by the substituent R.

2. Known state of the art

The carbapenems prepared by the process of the present invention are the subject of patent applications of the United States of America no 425,755 of September 28, 1982, 530,011 of September 9, 1983 and 705,780 of February 22, 1985.

These patent applications describe the preparation of antibiotic carbapenems of formula:

RiJljp ^ ys-A-Q & 5 0v ~ N x: oor2 8 ^ where R represents a hydrogen atom and R is chosen from the hydrogen atom and the alkyl, al-cenyl and alkynyl radicals of 1 to 10 atoms carbon; cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part CD.MJ - 2 - is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all substituted or unsubstituted and whose substitute (s) for the abovementioned radicals are chosen independently from C ^ -Cg-alkyl optionally amino, halogenated, hydroxylated or carboxylated halo -OR3 0

H 3 4 -OCNR R

0

Il 3 4 -CNR R

3 4 -NR R

3 NR 3 4

-S02NR R

0 11 3 4

-NHCNR R

0 31 '4 R CNR - V 3

-C02R

= 0 0 -OCR3 -SR3 0

There 9

-SR

CD.MJ - 3 - ο

There 9

-SR

II

o

-CN

-n3 -0S03R3 0 H 9

-OS-R

v 11

^ O

O

3II 9

-NR S-R

II

O

-OP (O) (OR3) (OR4) 3 4

-NR C = NR

k3 3 4

-NR C02R

-NO, 4 ^,, 3

where, with regard to the above-mentioned substituents, the radicals R

and R are independently selected from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl, cycloalkyl-coyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aral-coyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part v has 1 to 6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen and sulfur atoms and in which the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms 3 4, or else R and R taken together with the nitrogen atom to which at least one of them is linked, can form a pentagonal nitrogen heterocyclic radical CD.MJ - 4 - 9/3 or hexagonal; R is defined as R, except that it cannot be a hydrogen atom; or where R and R, taken together, represent a C2-C ^ Q-alkyl-dene or C ^ -C ^ -alkylidene radical substituted by hydroxyl; R ^ is chosen from alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and ^ of 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclic and heterocyloalkyl in which the heteroatom (s) of the abovementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and in which the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all substituted or unsubstituted; the above-mentioned radicals R being optionally substituted by 1 to 3 radicals independently chosen from: C ^ -Cg-alkyl optionally amino, fluorinated, chlorinated, carboxylated, hydroxylated or carbamoylated fluoro, chloro or bromo -OR1 -oco9r1

-OCOR

3 4

V -OCONR R

O

There 9

-OS-R II

O

-oxo

3 4 -NR R

3 4 R CONR - 3 4

-NR C0, R

CD.MJ - 5 - ^ 3 4

-NR CONR R

ο 3 * 1 9

-NR S-R

II

o -SR3 0 t Û

-SR

0 0 \ ^ 9

-S-R

^ -SO, R3 * 3 -co9r -y Z 3 4

-CONR R

-CN; or phenyl optionally substituted with 1 to 3 radicals 3 3 4 fluoro, chloro, bromo, C - ^ - Cg-alkyl, -OR f -NR R, -SO R3, -CO ^ R3 or -CONR3R4, where R3, R4 and R9 in these substituents of R are as defined above; 5 or can R be combined with O? at another point in the cycle so as to form a heterocyclic or condensed heteroaromatic radical, the cycle of which may contain additional heteroatoms, chosen from 0, N and S; R is chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkyl-cloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; spirocycloalkyl of 3 to 6 carbon atoms; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms; CD.MJ - 6 - heteroaryl, heteroaralkyl, heterocyclic and hetero-rocycloalkyl of which the heteroatom (s) in the above-mentioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all of which are substituted or unsubstituted and whose substituent (s) with respect to the abovementioned radicals are chosen from amino, mono-, di- and trialkylamino, hydroxyl, alkoxy, mercapto, alkylthio, phenylthio, sulfamoyl radicals , amidino, guanidino, nitro, chloro, bromo, fluoro, cyano and carboxyle; and in which the alkyl parts in the abovementioned substituents have 1 to 6 carbon atoms; A represents a C ^ -Cg-alkylene radical in a straight or branched chain; R ^ represents a hydrogen atom, an anionic charge or a conventional easily removable protective radical of the carboxyl function, it being understood that when R represents a hydrogen atom or a protective radical, a counter ion is also present, and Q® represents a substituted or unsubstituted mono-, bi- or polycyclic aromatic heterocyclic radical comprising at least one nitrogen atom in the ring and united to the radical A by a ring carbon atom and comprising a ring nitrogen atom which is quaternized by the radical R; or of a pharmaceutically acceptable salt of these compounds, by the process illustrated in the reaction scheme below: CD.MJ - 7 - R8 B f R1 - R »-I ^" ^ COOR2 '

III

*. R1 B l15 r1_L_Pyb ”- * O t J-s - ^ COOR2 '

IV

8 B “^ R1! i / ^ Λ r, ^ '/' ν, S ..... Α · {·· N r

--Γ | T R £ -x 'L

ty N ^ COOR2 ’

II

R R15, R ii e r ~ \ ® s. © r1 - rN 'v /' R x.

I j release ^ / 7 “~ N 11 5 * possible ÿ COOR *> r I * CD.MJ - 8 - R15 R8 H] ^ \ ®,

Ji ^ s-a-h n -r R 1 | ^ f ~ * -coor ’

According to a preferred variant of the above process, the diagram is modified as indicated below: 8 H r15 ^ 1 ^ release ff-N - ^ CDOR2 '

* 0 II

11 r15

cr N ^ CODB

Ha II * 15 R8 B 1 Γ ^ ® 5

Rl ^^ Θ g coow la t For the execution of the above process, the starting compound III is reacted in an inert organic solvent such as methylene chloride, acetonitrile or dimethylformamide, with an amount to roughly equimolar of a Re-L reactant, such as p-toluenesulfonic anhydride, p-nitro-benzenesulfonic anhydride, 2,4,6-triisopropylben-zenesulfonic anhydride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride , CD chlorophosphate, diphenyl MJ - 9 -, toluenesulfonyl chloride, p-bromobenzenesulfonyl chloride, etc. where L represents the corresponding labile radical such as toluene-tallow onyloxy, p-nitrobenzenesulfonyloxy, diphenoxyphos-phinyloxy or another well-known and conventionally fixed labile radical. The reaction to fix the labile radical in position 2 of intermediate III is advantageously carried out in the presence of a base, · * such as diisopropylethylamine, triethylamine, 4-dimethylaminopyridine, etc., at a temperature of - 'around -20 to + 40 ° C, and preferably about 0 ° C. The labile radical L of intermediate IV can also be a halogen, in which case this radical is fixed by reaction of intermediate III with a halogenating agent such as 0 ^ PB ^, or a similar compound in a solvent such as CH3CN , THF, etc., in the presence of a base such as diisopropylethylamine, triethylamine, 4-dimethylaminopyridine, etc. Intermediate IV can be isolated if desired, but is advantageously used for the next stage without isolation or purification.

Intermediate IV is then converted to intermediate II by a standard displacement reaction. Thus, intermediate IV can be reacted with an approximately equimolar amount of a heteroaralkyl mercaptan of formula: HS-α- ^ ΓΛ where A represents an alkylene radical in a straight or branched chain at C - ^ - Cg and

O

CD.MJ - 10 - represents a heterocyclic aromatic radical mono-, bi- or polycyclic containing a nitrogen atom quater-nisisable in the cycle, which cycle is joined to A by a carbon atom of the cycle, in an inert organic solvent , such as dioxane, dimethylformamide, dimethylsulfoxide or acetonitrile and in the presence of a base such as diisopropylethylamine, triethylamine, sodium hydrogencarbonate, potassium carbo-nate or 4-dimethylaminopyridine. The temperature for the displacement reaction is not critical, but is preferably about -40 ° C to 25 ° C. Most advantageously, the reaction is carried out under cooling, for example, from about 0eC to about -10 ° C.

The quaternization of ring nitrogen in the heteroaralkyl radical of intermediate II is carried out by reaction of intermediate II in an inert organic solvent with at least one equivalent (up to a molar excess of approximately 50%) d 'an alkylating agent of formula: R5-X' 5 where R is as defined above and X 'represents a conventional labile radical, for example halo (chloro, bromo or iodo, but preferably iodo) or an entity sulfonic ester, such as methanesulfonate, toluene-tallow onate or trifluoromethanesulfonate. Examples of suitable inert organic solvents are chloroform, methylene chloride, tetrahydrofuran, dioxane, acetone, dimethyl sulfoxide and dimethylformamide. The temperature for alkylation is not critical and temperatures of about 0 ° C to 40 ° C are preferred. Most advantageously, the reaction is carried out at room temperature.

Intermediate 1 'will include a counter ion X' (for example provided by the alkylating agent uti CD.MJ - 11 - lized) which is associated with it at this stage or at a later stage, say after unlocking, but which can be replaced by another counter ion, for example pharmacologically more acceptable, according to conventional techniques. Alternatively, the counter ion can then be removed during the unlocking.

The deblocking stage eliminating the protective radical 2 1 R from the carboxyl function of the intermediate 1 ′ is carried out according to conventional techniques, such as solvolysis, chemical reduction or hydrogenation. When the protective radical is a p-nitrobenzyl, benzyl, benzhydryl or 2-naphthylmethyl radical which can be removed by catalytic hydrogenation, the intermediate 1 'in a suitable solvent such as dioxane-water-ethanol, tetrahydrofuran-hydrogen phosphate of aqueous dipotassium-isopropanol or an analogous medium can be reacted with hydrogen under a pressure of 1 to 4 atmospheres in the presence of a hydrogenation catalyst such as palladium on carbon, palladium hydroxide, l platinum oxide, etc., at a temperature of 0 to 50 ° C for a period of about 0.24 to 4 hours. When R is an o-nitrobenzyl radical, photolysis is also suitable for unblocking. Protective radicals such as 2,2,2-trichloroethyl can be removed by moderate reduction using zinc. The protective allyl radical can be removed using a catalyst comprising a mixture of a palladium compound and tri-phenylphosphine in a suitable aprotic solvent such as tetrahydrofuran, methylene chloride or diethyl ether. Likewise, other radicals which protect the carboxyl function can be removed according to methods known to those skilled in the art. Finally, as 2 'indicated above, the compounds of formula I', where R represents a physiologically hydrolysable ester radical, CD.MJ - 12 - such as acetoxymethyl, phthalidyl, indanyl, pivaloyl-oxymethyl, methoxymethyl, etc., can be administered directly to the patient without release because these esters are hydrolyzed in vivo under physiological conditions.

The process described above exposes to various drawbacks. For example, it includes several stages of which it would be advantageous to reduce the number. The overall yield of the reaction is moreover quite low and the quaternization is carried out on the carba-penem as is. It would therefore be interesting to have a new process for preparing the compounds of formula I which (1) would comprise a smaller number of stages, (2) would give a better yield, (3) would allow the quaternized amine to be formed first. place, then fix it on the carbapenem nucleus at a later stage of the synthesis and (4) could be applied to more easily form quaternary amines with very diverse amines, i.e. sterically hindered amines and those with a low pKb. Overview of the invention

The present invention relates to a new process for the preparation of carbapenem derivatives of the formula: R15 R8 H 1 / N © 5 4 "” -SoOR2 3 i where R represents a hydrogen atom and R is chosen from the atom of hydrogen and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl and cycloalkyloylalkoyl of 3 to 6 CD.MJ - 13 - carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms; hetero-aryl, heteroaralkyl, heterocyclic and heterocyclo-alkyl of which the heteroatom or atoms the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all of which are substituted or unsubstituted and whose substituent or substituents are radic the above are independently selected from C ^ -Cg-alkyl optionally amino, halogenated, hydroxylated or carboxylated halo -OR3 0

Il 3 4 -OCNR R

0 -cnr3r4 -nr3r4 ^ NR3 ”^ nr3r4 3 4

-S02NR R

0 k II 3 4

-NHCNR R

0 r3cnr4- -co2R3 = 0 0 -OCR3 -SR3 CD.MJ - 14 - ο

There 9

-SR

Ο

There 9

-SR

II

O

-CN

-N3 -oso3r3

O

There 9

-OS-R II

O

O

3 II 9 -NR S-R II

0 -OP (O) (OR3) (OR4) 3 4

-NR C = NR

1 3

R

3 4

-NR C02R

-n ° 2 where, with regard to the abovementioned substituents, the radicals 3 4 R and R are chosen independently from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl, cycloalkyl-alkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; - aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms; and heteroaryl heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 atoms of oxygen, nitrogen and sulfur and in which the alkyl parts associated with the heterocyclic parts have 3 4 1 to 6 atoms of carbon, or alternatively R and R, taken together-CD.MJ - 15 - ble with the nitrogen atom to which at least one of them is united, can form a heterocyclic nitrogen pentagonal or hexagonal radical; R is defined as R, except that it cannot be a hydrogen atom; or else I g where R and R, taken together, represent a radical C2-Cio-alk ° ylidene or C2 ~ C ^ Q-alkyllene substituted by hydroxyl; R3 is chosen from alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cyclo ^ alkyl and cycloalkyl and cycloalkylalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and of 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) of the above-mentioned heterocyclic parts are chosen from 1 to 4 atoms of oxygen, nitrogen or sulfur and in which the alkyl parts associated with the heterocyclic parts have 1 to 6 atoms of carbon, all substituted or unsubstituted; the aforementioned radicals R being optionally substituted by 1 to 3 radicals chosen independently from: C ^ -Cg-alkyl optionally amino, fluorinated, chlorinated, carboxylated, hydroxylated, or carbamoylated fluoro, chloro or bromo ^ -OR3 -oco7r3 -OCOR3 -oconr3r4

O

II 9

-OS-R

II

o -oxo 3 4

-NR R

CD.MJ - 16 - 3 4 R CONR - 3 4

-NR C02R

-nr3conr3r4 0

3II 9 -NR S-R II

O

3

-SR

O

p * f 9

-S-R

O O ^ / 9

? -S-R

-SO.R3 J 3 -co9r

z 3 4 -CONR R

-CN; or phenyl optionally substituted with 1 to 3 radicals 3 3 4 fluoro, choro, bromo, C.-Cg-alkyl, -OR, -NR R -SO3R3, -C02R3 or -CONR3R4, where R3, R4 and R9 in these substituents R3 are as defined above; 5 or R can be combined with O®.

at another point in the cycle so as to form a condensed heterocyclic or heteroaromatic radical, the cycle of which may contain additional heteroatoms, chosen from 0, N and S; R is chosen from the hydrogen atom and the alkyl, alkenyl and alkynyl radicals of 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkyl-cloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; spirocycloalkyl of 3 to 6 carbon atoms; phenyl; aralkyl, aralkenyl and CD.MJ - 17 - aralkynyl in which the aryl part is a phenyl radical and the aliphatic part has 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl parts associated with the heterocyclic parts have 1 to 6 carbon atoms, all substituted or unsubstituted and whose substituent (s) with respect to the abovementioned radicals are chosen from amino, mono-, di- and trialcoylamino, hydro-xyl, alkoxy, mercapto, alkylthio, phenylthio, sulfa-hub, amidino, guanidino radicals , nitro, chloro, bromo, fluoro, cyano and carboxyl; and in which the alkyl parts in the abovementioned substituents have 1 to 6 carbon atoms; A represents a radical C, -Cfi-alkylene in a straight chain 2 J- t> or branched; R represents a hydrogen atom, an anionic charge or a conventional easily removable radical protecting the carboxyl function, it being understood that when R represents a hydrogen atom or a protective radical, a counter ion is also present, and -O ® represents a substituted or unsubstituted mono-, bi- or polycyclic aromatic heterocyclic radical comprising at least one nitrogen atom in the ring and united to the radical A by a carbon atom of the ring and comprising a ring nitrogen atom which is quaternized by the radical R; and their pharmaceutically acceptable salts, characterized in that a CD.MJ - 18 - intermediate is reacted with formula:

• ‘îVV

J - »- <2 *

cY COOR

TV

4ί 18 15, 2 'where R, R and R are as defined above, R represents a conventional radical which is easy to remove and protects from the carboxyl function and L represents a conventional labile radical, such as toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, diphenoxypnospninyloxy or halo, with a thiol of formula: O © 5

l-R VII

& where A and are as defined above and yO represents a counter anion, in an inert solvent and in the presence of a base to form a carbapenem of formula: R1 5 / —— N -s * 2 '(K COOR ^ where R1, R8, R15, R2 ', A, CD.MJ - 19 - and yP are as defined above and, if desired, the protective radical R is removed from the carboxyl function to obtain the compound corresponding deprotected of formula I or a pharmaceutically acceptable salt V- thereof.

A subject of the invention is also the intermediates of formula VII.

The carbapenems of formula I are potent antibacterial agents or useful intermediates for the preparation of such agents. Detailed description of the invention

The compounds of formula I above contain the carbapenem nucleus: Z_ N _1.3 and can therefore be called derivatives of 1-carba-2-penem-3-carboxylic acid. Alternatively, the compounds can be considered to include the basic structure 4 6 "--2 c" 1 and can be called 7-oxo-1-azabi-cyclo (3.2.0) hept-2-ene acid derivatives -2-carboxylic. The invention CD.MJ - 20 - relates to compounds whose relative stereochemistry of the protons 5,6 is not only cis, but also trans, but the preferred compounds have the stereochemistry 5R, 6S (trans), as in the case thienamycin.

The compounds of formula I can be free of substituent in position 6 or can carry there radicals already mentioned for other derivatives of carba-penem. More specifically, R may represent a hydrogen atom and R1 may represent a hydrogen atom or a substituent other than hydrogen mentioned, for example, in European patent application 38969 8 1 (see definition of Rg ) · As a variant, R and R, taken together, can form a C2 ~ C ^ Q-alkylidene or C2-Cio-alkylidene radical substituted, for example by a hydroxyl radical.

The compounds of formula I can also be free of substituent in position 1 (R = H) or can carry in this position radicals already mentioned for other carbapenem derivatives. More specifically, r may represent a hydrogen atom or any of the substituents other than hydrogen in position 1, indicated, for example, in the application for 1 2

European patent 54917 (see definitions of R or R

in this document) or in U.S. Patent No. 4,350,631. Substituents R. other than hydrogen which are preferred are in particular C 1 -C 4, -alkyl radicals, more especially methyl; °,] _5 phenyl; and phenyl (C ^ -C ^) alkyl. The substituent R other than hydrogen can have the configuration o (or j!> And the invention relates to the separated isomers c <andß, as well as their mixtures.

1 8

To clarify the definitions of R, R and 15 R, the following indications may be given: (a) the aliphatic radicals "alkyl", "alkenyl" and "alkynyl" may be in a straight chain CD.MJ - 21 - or branched and have 1 to 10 carbon atoms, but preferably have 1 to 6 and most preferably 1 to 4; when they are part of another substituent, as in cycloalkylalkyl, heteroalkyl or aralkenyl radicals, the alkyl, alkenyl and alkynyl radicals preferably have 1 to 6 and more especially 1 to 4 carbon atoms, (b ) the “heteroaryl” radicals are in particular heterocyclic aromatic mono-, di- and polycyclic radicals, containing 1 to 4 O, N or S atoms, the preference going to pentagonal or hexagonal heterocycles such as thienyl, furyl, thiadiazolyl, oxa-diazolyl , triazolyle, isothiazolyle, thiazolyle, imidazolyle, isoxazolyle, tétrazolyle, oxazolyle, pyridyle, pyrazinyle, pyrimidyle, pyridazinyle, pyrro-lyle, pyrazolyle, etc.

(c) the “heterocyclic” radicals are in particular saturated or unsaturated mono-, di- or polycyclic non-aromatic heterocyclic radicals containing 1 to 4 O, N or S atoms, preference being given to pentagonal or hexagonal heterocyclic radicals such as morpholinyl, piperazinyl , piperidyl, pyra-zolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, etc.

(d) the "halo" radicals are the chloro, bromo, fluoro and iodo radicals, the preference going to the chloro, fluoro or bromo radicals.

The term "conventional radical which is easy to remove protective of the carboxyl function" should be understood to mean a known ester radical which has already been used to block a carboxyl radical during the chemical reaction stages described below and which can be eliminated when the thing is desired, according to methods which bring about no appreciable destruction of the rest of the molecule, for example by chemical hydrolysis or enzyma CD.MJ - 22 - tick, treatment using chemical reducers under moderate conditions, exposure in ultraviolet light or catalytic hydrogenation. Examples of such protective ester radicals are the benzhydryl, allyl, p-nitrobenzyl, 2-naphthylmethyl, benzyl, trichloroethyl, silyl radicals such as trimethyl-silyl, phenacyl, p-methoxybenzyl, acetonyl, o-nitro-benzyl, 4-pyridylmethyl and C ^ -C ^ -alkyl such as methyl, ethyl or t-butyl. These protective radicals include those which are hydro-lysed under physiological conditions such as the pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl radicals. A protective radical of the carboxyl function which is particularly advantageous is the p-nitrobenzyl radical, easily removed by catalytic hydrogenolysis.

The pharmaceutically acceptable salts mentioned above are in particular the addition salts of non-toxic acids, for example the salts formed with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid , sulfuric acid, etc., and the salts formed with organic acids such as maleic acid, acetic acid, citric acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid, lactic acid, gluconic acid and malic acid. The compounds of formula I in the form of acid addition salts can be represented by the formula: rB H R15 R -! - E — A-C '' ^ Lr5 X®

1 I

w CD.MJ - 23 - 7 where R represents a hydrogen atom or protective radical and 0 represents the anion of an acid. The counter anion can be chosen to give a pharmaceutically acceptable salt suitable for administration for therapeutic purposes, but in the case of the intermediate compounds of formula I,> 0 can also represent a toxic anion. In such a case, this ion can be eliminated or replaced subsequently by a pharmaceutically acceptable anion giving a clean active final product for therapeutic purposes. When acidic or basic radicals are present in the ra-1 5 dical R or R or in the radical

O

a subject of the invention is also the base addition or appropriate acid salts of these functional radicals, for example the acid addition salts in the case of a basic radical and the salts with metals (for example example sodium, potassium, calcium and aluminum), ammonium salt and salts with non-toxic amines (e.g. trialcoylamines, procaine, dibenzylamine, 1-ephenamine, N ~ benzyl- / 5-phenethylamine, N, N '-dibenzylethylenedia- mine, etc.) in the case of an acid radical.

2

The compounds of formula I, where R represents a hydrogen atom, an anionic charge or a physiologically hydrolysable ester radical, as well as their pharmaceutically acceptable salts are useful as antibacterial agents. The other compounds of formula I are interesting intermediates which can be converted into the abovementioned biologically active compounds.

According to a preferred embodiment, the subject of the invention is the compounds of formula I, in which CD.MJ - 24 - 8 i R represents a hydrogen atom and R represents a hydrogen atom or a CH ^ -CF radical ^ -

CH- CH, OH OH

3 \ 3 \ 1 I

CH-, ^ C- or CH3CH- CH 3 ^ CHj '"' '

In this subclass, the preferred compounds are those in the formula of which R'L represents

OH

CH3CH- and more especially the compounds having the absolute configuration 5R, 6S, 8R.

According to another preferred embodiment, the invention relates to the compounds of formula I 1 8, where R and R, taken together, represent an alkylidene radical of formula: hoch2 ^ C = CH3

The alkylene radical (that is to say the radical "A") in the compounds of formula I may be in a straight or branched chain and may have 1 to 6 carbon atoms. According to a preferred embodiment, the invention relates to these compounds in the formula of which A represents “(CH2 ^ n ~ with n representing 1 or 2 and according to a particularly preferred embodiment, it relates to the compounds in the formula of which A represents -CH2-.

The alkylene part "A" is joined by a ring carbon atom to an N-substituted aromatic heterocycle of general formula: CD.MJ - 25 - Γ '* 5 {Î4— "5 where R preferably represents a C ^ -C ^ -alkyl radical, Cz-Cio-alkenyl, C2-C ^ Q-alkynyl, C ^ -Cg-cycloalkyl, C ^ -Cg-cycloalkyl-C ^ -Cg-alkyl, phenyl, phenyl-C ^ -Cg-alkyl, phenyl-C2-Cg-alkenyl, phenyl-C2-C6-alkynyl, heteroaryl, heteroaralkyl of which the alkyl part has 1 to 6 carbon atoms, heterocyclic or heterocycloalkyl of which the alkyl part has 1 to 6 atoms of carbon. The heteroaryl radical (or the heteroaryl part of a heteroalkyl radical) R may be a heterocyclic aromatic mono-, bi- or polycyclic radical containing 1 to 4 atoms 0, N, or S, preference being given to pentagonal heterocyclic radicals or hexagonal such as thienyl, furyl, thiadiazoyl, oxadiazolyl, triazolyl, isothiazolyl, thiazolyl, imidazolyl, isoxazolyl, tetrazolyl, oxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyrida-zinyl, pyrrolyl and pyrazolyl. The heterocyclic radical (or the heterocyclic part of a heterocycloalkyl radical) R can be a saturated or unsaturated, mono-, bi- or polycyclic non-aromatic heterocyclic radical containing 1 to 4 O, N or S atoms, preference being given to pentagonal or hexagonal heterocyclic radicals such as morpholinyl, pi-perazinyl, piperidyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, pyrrolinyl and pyrroli-dinyl.

The radical may optionally be substituted by 1 to 3 radicals chosen independently from: (a) C ^ -Cg-alkyl optionally substituted by radicals, preferably 1 to 3, which are amino, fluoro, chloro, carboxyl radicals , CD.MJ - 26 - hydroxyl or carbamoyl (b) fluoro, chloro or bromo (c) -OR1 (d) -0C02R1 (e) -OCOR1 (f) -OCONR1R2 (g) o -oS.R ȏ (h ) -oxo (i) -NR1R2 (j) r1conr2- (k) -NR1C02R2 (l) -nr1conr1r2 (m) 0 3 "9

-NR S-R

II

0 (n) -SR1 9

(o) -SOR

(p) 0

There 9

-S-R

li o (q) -S03R1 (r) -C02R3 (s) -conr1r2 (t) -CN; or (u) phenyl optionally substituted with 1 to 3 substituents chosen independently from the radicals 3 3 4 fluoro, chloro, bromo, C, -C, -alkyl, -OR, -NR R, CD.MJ - 27 - 3 314 bv 2 -SO, R, -CO_R or -CONR R, or, in connection with the abovementioned c-3 4 3 constituents of R, the radicals R and R are chosen independently from hydrogen atoms and the alkyl, alkenyl and alkynyl of 1 to 10 carbon atoms; cycloalkyl, cycloalkyl-alkyl and alkylcycloalkyl of 3 to 6 carbon atoms in the ring of the cycloalkyl part and from 1 to 6 carbon atoms in the alkyl parts; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl part is a phenyl radical and in which the aliphatic part has 1 to 6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclic and heterocycloalkyl in which the heteroaryl and heterocyclic radical or a part of a radical is as defined above with respect to R and the alkyl parts associated with these heterocyclic parts 3 have 1 to 6 carbon atoms ; or else R and 4 R, taken together with the nitrogen atom to which at least one of them is united, form a heterocyclic nitrogen pentagonal or hexagonal radical (as defined above with respect to R); and R is as defined above with the exception that it cannot be a hydrogen atom. A radical especially preferred for R is a radical C ^ -Cg-alkyl and especially methyl.

5

In addition, the radical R, together with another atom of the cycle of the radical o? can form a heterocyclic or heteroaromatic condensed radical whose ring can contain additional hetero atoms, preferably 1 or 2, chosen between O, N and S. For example / ^ s © 5 // f N - R can be JL-— CD.MJ - 28 - or j) Λ = / © "W ©

The radical -XJ * is preferably a substituted or unsubstituted mono-, bi- or polycyclic aromatic heterocyclic radical comprising at least one nitrogen atom in the ring and 0 to 5 additional ring heteroatoms chosen from O, S and N, this heterocyclic radical being united to the radical A by a ring carbon atom and comprising a ring nitrogen atom quaternized by the radical R. The heteroaromatic radical ~ On- may optionally be substituted for the ring carbon atoms available by preferably 1 to 5 and especially 1 to 3 substituents chosen independently from 'C 1 -C 4 -alkyl radicals; C ^ -C4 ~ alkyl substituted by preferably 1 to 3 hydroxyl, amino, C ^ -C4 ~ alkylamino, di (C ^ -C ^) alkylamino, C ^ -C ^ -alkoxy, carboxyl, halo radicals (considered below as meaning chloro, bromo, fluoro or iodo; preferably chloro, bromo or fluoro) or sulfo; C ^ -Cg-cycloalkyl; C ^ -C ^ -cycloalkyl (C ^ -C ^) alkyl optionally substituted with 1 to 3 substituents mentioned above in connection with the C ^ -C ^ -alkyl radicals; C ^ -C ^ alkoxy; C ^ -C4 ~ alkylthio; CD.MJ - 29-amino; C ^ -C ^ -alkyllamino; di (C ^ -C ^) alkyllamino; halo; C ^ -C ^ -alkanoylamino; C ^ -C ^ -alkanoyloxy; carboxyl; tallow; -CC ^ -C ^ -C ^ -alkyl; hydroxyl; amidino; guanidi-no; phenyl; phenyl substituted with 1 to 3 substituents independently selected from amino, halogeno, hydroxyl, trifluoromethyl, C ^ -C ^ -alkyl, C ^ -C ^ -alkoxy, C ^ -C ^ -alkylamino, di (C ^ -C ^) alkyllamino, carboxyl and sulfo; phenyl (C ^ -C ^) alkyl in which the phenyl part is optionally substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part is optionally substituted with 1 to 3 substituents mentioned above with respect to the radicals C ^ -C ^ -alkyl; and heteroaryl or heteroaralcoyl in which the heteroatom (s) are chosen from 1 to 4 atoms 0, S or N and in which the alkyl part associated with the heteroaralkyl radical has 1 to 6 carbon atoms, these heteroaryl and heteroaralkyl radicals being optionally substituted in the heterocyclic part with 1 to 3 substituents chosen independently from the hydroxyl, amino, halogen, trifluoromethyl, C ^ -C ^ -alkyl, C ^ -C ^ -alkoxy, C ^ -C ^ -alkylamino, di (C ^ -C) radicals ^) - alkyllamino, carboxyl and sulfo, and in the alkyl part with 1 to 3 substituents chosen from hydroxyl, amino, C ^ -C ^ -alkoylamino, di (C ^ -C ^ Jalcoyl-amino, C ^ -C) radicals ^ -alkoxy, carboxyl, halo and sulfo In addition, nitrogen atoms of the available ring (other than the quaternized nitrogen atom) can be substituted by 1 to 3 substituents chosen independently from the radicals C ^ -C ^ -alkyl; C ^ -C ^ -alkyl substituted by preferably 1 to 3 hydroxyl, amino, C ^ -C ^ -al-coylamino, di (C ^ -C ^) alkylamino, C ^ - radicals C ^ -alkoxy, carboxyl, halo or sulfo; C ^ -Cg-cycloalkyl; C ^ -Cg-cycloalkylMc ^ -C ^) alkyl optionally substituted with 1 to 3 substituents mentioned above in connection with the C ^ -C ^ -alkyl radicals; phenyl, phenyl optionally CD.MJ - 30 - substituted by 1 to 3 substituents independently chosen from amino, halo, hydroxyl, trifluoromethyl, C ^ -C ^ -alkyl, C ^ -C ^ -alkoxy, C ^ - radicals C ^ -alkyl-amino, di (C ^ -C ^) alkylamino, carboxyl and sulfo; phe-nyl (C1 ~ C4) alkyl in which the phenyl part can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and in which the alkyl part can optionally be substituted> · in 1 to 3 substituents mentioned above above about the C ^ -C ^ -alkyl radicals; and heteroaryl or hetero-; aralkyl in which the heteroatom (s) are chosen from 1 to 4 atoms 0, S or N and in which the alkyl part associated with the heteroaralkyl radical has 1 to 6 carbon atoms, the heteroaryl and heteroaralkyl radicals being optionally substituted in the heterocyclic part by 1 to 3 substituents independently selected from hydroxyl, amino, halogen, trifluoromethyl, C ^ -C ^ -alkyl, C ^ -C ^ -alkoxy, C ^ -C ^ -alkyl-amino, di (C1 ~ C4) alkylamino radicals , carboxyl and sulfo and in the alkyl part with 1 to 3 substituents chosen from hydroxyl, amino, C ^ -C ^ -alkoylamino, di- (C1-C4) alkylamino, C ^ -C ^ -alkoxy, carboxyl, halo radicals and sulfo. The substituents specially preferred for the nitrogen and carbon atoms of the ring are the C 1 -C 6 -alkyl and especially methyl radicals.

In the preferred embodiment described above, preference is given to the compounds in the formula of which A represents a radical * ^ CH2 ^ n- 'n represents 1 or 2 and more especially to those in the formula of which A represents a radical - CH ~ - and 18 ^ plus (a) R and R, taken together, represent a radical H0CHo 2 "> 0 * 3 CD.MJ - 31 - 8 Ί or (b) R represents a hydrogen atom and R represents a hydrogen atom or a CH ^ CH ^ - radical,

CH- CH-, OH OH

3 \ 3 \ I I

CH-, ^ C- or CH-.ÇH- / / 3 CÎT CH3 ^

Particularly preferred compounds are those in the formula of which R represents a hydrogen atom and R "*" represents a radical

OH

CH3CH- and more especially the compounds having the absolute configuration 5R, 6S, 8R.

According to a preferred embodiment, the radical is a pentagonal or hexagonal nitrogen aromatic heterocyclic radical comprising 0 to 3 additional heteroatoms chosen from 0, S and N. This aromatic heterocycle can, when possible, be condensed with another ring which can be a saturated or unsaturated carbocycle and preferably a C ^ -Cj carbocycle, an aromatic carbocycle and preferably a phenyl ring, a square to heptagonal heterocycle (saturated or unsaturated) comprising 1 to 3 heteroatoms chosen from 0, S, N or NR, where R represents a hydrogen atom or a C 1 -C 6 -alkyl radical optionally substituted by 1 or 2 substituents chosen independently 3 3 4 3 from the radicals -OR, -NR R, -CO-R, oxo, phenyl, 3 z 3 4 fluoro, chloro, bromo, -S03R and -CONR R, or a phenyl radical optionally substituted with 1 to 3 CD.MJ - 32 substituents chosen independently from the radicals C.-Cft-al- 3 3 4 1 b 3 coyle, -OR, -NR R, fluoro, chloro, bromo, -S O ^ R,

3 3 4 3 4 J

-CO "R and -CONR R, R and R in these substituents 11 ^ R being defined as above with respect to the substituent R · 1-, or a heteroaromatic radical pentagonal or hexagonal comprising 1 to 3 heteroatoms chosen between 0, S and N or NR ^, where R ^ is as defined above. The quaternized pentagonal or hexagonal aromatic ring or, as the case may be, the carbocyclic, heterocyclic or heteroaromatic ring condensed on this first ring or else the two rings may optionally be substituted on available ring atoms by substituents, in a total number preferably maximum of five for the whole ring system, which are the substituents mentioned above about the radical

O

In this preferred embodiment described above, preference is given to compounds in the formula of which A represents a radical ~ ^ CH2 ^ n_ ° ù n represents 1 or 2 and more especially to those in the formula of which A represents a radical - CH_- and 18 ^ plus (a) R and R, taken together, represent a HOCH- 2 \ CHf 8 1 radical where (b) R represents a hydrogen atom and R represents a hydrogen atom or a CH3CH2 radical ~,

CH-, CH_ OH OH

3 \ 3 \ I I

J ^ CH-, ^ C- or CH3CH- CH3 "^ CH3 ^ CD.MJ - 33 -

Particularly preferred compounds are those in the formula of which R represents a hydrogen atom and R "* · represents a radical

OH

CH3CH- and more especially the compounds having the absolute configuration 5R, 6S, 8R.

According to another preferred embodiment, the invention relates to the compounds of formula I, where ί '5

- ^ ___ / - R

represents a radical chosen from U1 <w "’

Pr where R ^, R ^ and R · * "0 are independently selected from the hydrogen atom and the C ^ -C ^ -alkyl radicals; C ^ -C ^ -alkyl substituted preferably by 1 to 3 hydroxyl radicals , C ^ -C ^ -alkyllamino, diiC ^ -C ^ alkyl) amino, C ^ -C ^ -alkoxy, amino, sulfo, carboxyl and halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo) ; C ^ -Cg-cycloalkyl; C ^ -C ^ -alkoxy; C ^ -C ^ -alkoylthio; amino; C ^ -C ^ -alkoylamino; di (C ^ -C ^ -alkyl) amino; halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo); C ^ -C ^ -alkanoyl-amino; C ^ -C ^ -alkanoyloxy; carboxyl; -CO ^ -C ^ -C ^ -alkyl; hydroxyl; amidino ; guanidino; phenyl, phenyl substituted CD.MJ - 34 - by one, two or three amino radicals, halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo), hydroxyl, trifluoromethyl; C ^ -C ^ -alkyl or C1-C4-alkoxy; phenyl (C1 ~ C4) alkyl, the phenyl part of which can optionally be substituted by 1 to 3 radicals mentioned above in connection with the phenyl radical and the pa rtie alkyl may optionally be substituted by 1 to 3 substituents mentioned above in connection with the radicals C ^ -C4-alkyl; and heteroaryl or heteroaralkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl part associated with the heteroaralkyl part has 1 to 6 carbon atoms, or else where two of R6, R7 and R10, taken together, can represent a condensed saturated carbocyclic radical, a condensed aromatic carbocyclic radical, a condensed non-aromatic heterocyclic radical or a condensed heteroaromatic radical, which condensed rings are optionally substituted by 1 or 2 substituents defined above with respect to R ^, R7 and R ^; R5

(b) ”_ I

© i ®i

I I

optionally substituted on a carbon atom by 1 to 3 substituents independently chosen from C1-C4-alkyl radicals; C ^ -C ^ -alkyl substituted by preferably 1 to 3 hydroxyl radicals, C ^ -C4 ~ alkylamino, CD.MJ - 35 - di (C ^ -C ^) alkylamino, C ^ -C ^ -alkoxy, amino, sulfo, carboxyl and halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo); C ^ -Cg-cycloal-coyle; C ^ -C4 ~ alkoxy; C ^ -C ^ -alkylthio, amino; C ^. ~ CA ~ alcoylamino; di (C ^ -C ^ -alkyl) amino; halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo); C ^ -C ^ -alkanoylamino; C ^ -C ^ -alkanoyloxy; carboxyl; -CC ^ -C ^ -C ^ -alkyl; hydroxyl; amidino; guanidino; phenyl, phenyl substituted by one, two or three amino radicals, halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo), hydroxyl, trifluoromethyl; C ^ -C4 ~ alkyl or C ^ -C ^ -alkoxy; phe-nyl (C ^ -C4) alkoxyl in which the phenyl part can optionally be substituted by 1 to 3 substituents mentioned above with respect to the phenyl radical and the al-coyl part can optionally be substituted by 1 to 3 substituents mentioned above above with regard to the C ^ -C4 -alkyl and heteroaryl or heteroaralkyl radicals in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl part associated with the part heteroaralkyl has 1 to 6 carbon atoms, or optionally substituted to form a carbocyclic, heterocyclic or heteroaromatic radical condensed optionally substituted by 1 or 2 of the substituents defined above; R5 R5 S * © I © i © | (c) ~ “T Ί ^ 1 CD.MJ - 36 - ® f 5 -ff 14- t ~ O 'or optionally substituted on a carbon atom by 1 or 2 substituents chosen independently from the radicals C ^ -C ^ - alkyl; C ^ -C4-alkyl substituted by preferably 1 to 3 hydroxyl radicals, C ^ -C ^ -alkoylamino, di (C ^ -C ^) alkylamino, C ^ -C4 ~ alkoxy, amino, sulfo, carboxyl and halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo); C ^ -Cg-cycloalkyl; C1-C4 ~ alkoxy; C ^ -C ^ -alkylthio; amino; C - ^ - C ^ -alkylamino; di (C ^ -C4 ~ alkyl) amino; halo (chloro, bromo, fluoro or iodo ·, preferably chloro, fluoro or bromo); C ^ -C ^ -alkanoylamino; C ^ -C ^ -alkanoyloxy; carboxyl-, -C02 ~ ci ~ C4-alkyl; hydroxyl; amidino; guanidino; phenyl, phenyl substituted by one, two or three amino radicals, halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo), hydroxyl, trifluoromethyl, Ci-C4-alkyl or C ^ -C4 ~ alkoxy; phenyl (C1 ~ C4) alkyl in which the phenyl part can optionally be substituted with 1 to 3 substituents mentioned above with respect to the phenyl radical and the alkyl part can optionally be substituted with 1 to 3 substituents mentioned above with regard to the radicals C ^ -C4 ~ alkyl and hetero-aryl or heteroaralkyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl part associated with the heteroaralkyl part counts 1 containing 6 carbon atoms, or optionally substituted to form a carbocyclic, heterocyclic or fused heteroaromatic radical optionally substituted with 1 to 2 of the substituents defined above,

(d) B5 RS RS

®N ®N ®, N

x? N <? N "· N" H— Il - - Il>, IJ - V "X ^ · B5 n R5 Rs

®N ®N ®N

^ V \ ** N

\ 'I, n ° u I i

/ y £ ^ N

optionally substituted on a carbon atom by 1 substituent independently chosen from C 1 -C 4 -alkyl radicals; C ^ -C ^ -alkyl substituted by preferably 1 to 3 hydroxyl radicals, C ^ -C ^ -alkoylamino, di (C ^ -C ^ -alkyl) amino, C ^ -C ^ -alkoxy, amino, sulfo, carboxyl and halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo); C ^ -Cg-cyclo-alkyl; C ^ -C ^ -alkoxy; C ^ -C ^ -alkylthio; amino; C ^ -C ^ -alkyllamino; di (C ^ -C ^ -alkyl) amino; halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo); C ^ -C ^ -alkanoylamino; C ^ -C ^ -alkanoyloxy; carboxyl; -C02-C1-C4-alkyl; hydroxyl; amidino; guanidino; phenyl, phenyl substituted by one, two or three amino radicals, halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo), hydroxyl, trifluoromethyl, C ^ -C ^ -alkyl or C ^ -C ^ - alkoxy; phenyKC ^ -C ^ Jalcoyl, the phenyl part of which can optionally be substituted with 1 to 3 substituents mentioned above in connection with the phenyl radical and CD.MJ - 38 - alkyl part can optionally be substituted with 1 to 3 substituents mentioned above above about the C ^ -C ^ -alkyl radicals; and heteroaryl or heteroaralcoyl in which the heteroatom (s) in the aforementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl part associated with the heteroaralkyl part has 1 to 6 carbon atoms; (e) _ © t © s

---- N-RS r-N-R

- \ or -4 “I

where X represents 0, S or NR where R represents a C ^ -C ^ -alkyl radical; C ^ -C ^ -alkyl substituted by 1 to 3 hydroxyl, amino, C ^ -C ^ -alkylamino, di (C ^ -C ^) - alkylamino, C ^ -C ^ alkoxy, carboxyl, halo or sulfo radicals; C ^ -Cg-cycloalkyl; C ^ -Cg-cycloalkyl (C - ^ - C ^) alkyl optionally substituted with 1 to 3 substituents mentioned above in connection with the radicals C ^ -C ^ -alkyl; phenyl; phenyl substituted with 1 to 3 substituents independently selected from amino, halo, hydroxyl, trifluoromethyl, C ^ -C ^ -alkyl, C ^ -C ^ -alkoxy, C ^ -C ^ -alkylamino, di (C ^ -C) radicals ^) alkylamino, carboxyl and sulfo) phenyl (C ^ -C ^) alkyl, the phenyl part of which may optionally be substituted with 1 to 3 substituents mentioned above in connection with the phenyl radical and the alkyl part of which may optionally be substituted with 1 with 3 substituents mentioned above in connection with the C 1 -C 4 -alkyl radicals; and heteroaryl and heteroaralkyl in which the heteroatom (s) are chosen from 1 to 4 atoms 0, S, or N and the alkyl part associated with the heteroaralkyl radical has 1 to 6 carbon atoms, CD.MJ - 39 - these heteroaryl and heteroaralkyl radicals being optionally substituted in the heterocyclic part by 1 to 3 substituents chosen independently from the hydroxyl, amino, halogen, trifluoromethyl, C ^ -C ^ -alkyl, C ^ -C ^ -alkoxy, C ^ -C ^ -alkylamino, di ( C ^ -C4) alkyllamino, carboxyl and sulfo, and in the alkyl part with 1 to 3 substituents chosen from hydroxyl, amino, C ^ -C ^ -alkylamino, diiC ^ -C ^ al-coylamino, C ^ -C4 radicals ~ alkoxy, carboxyl, halo and sulfo, this radical being optionally substituted on a carbon atom by 1 or more substituents chosen independently from C 1 -C 4 -alkyl radicals; C ^ -C4 ~ alkyl substituted by preferably 1 to 3 hydroxyl radicals, C ^ -C4-alkylamino, di (C ^ -C ^ -alkyl) amino, C ^ -C4 ~ alkoxy, amino, sulfo, carboxyl or halo ( chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo); C ^ -Cg-cycloalkyl; C ^ -C4 ~ alkoxy; C ^ -C4 ~ alkylthio, amino; C ^ -C4-alkyllamino; di (C ^ -C4-alkyl) amino; halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo); C ^ -C4-alkanoyl-amino; C ^ -C ^ -alkanoyloxy; carboxyl; -C02-C1-C4-alkyl; hydroxyl; amidino; guanidino-, phenyl; phenyl substituted by one, two or three amino radicals, halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo), hydroxyl, trifluoromethyl, C ^ -C4 ~ alkyl or C ^ -C4-alkoxy; phenyl (C ^ -C4) alkyl in which the phenyl part can optionally be substituted by 1 to 3 substituents mentioned above with respect to the phenyl radical and in which the alkyl part can optionally be substituted with 1 to 3 substituents mentioned above in connection C ^ -C ^ -alkyl radicals; and heteroaryl and heteroaralkyl in which the heteroatom (s) of the abovementioned heterocyclic parts are chosen from 1 to 4 oxygen, nitrogen or sulfur atoms and the alkyl part associated with the heteroaralkyl part has 1 to CD.MJ - 40 - [6 carbon atoms, or optionally substituted to form a condensed carbocyclic, heterocyclic or heteroaromatic radical optionally substituted by 1 or 2 of the substituents defined above, (f) 5

R

\ ®

N-X ïs-X

5 If H— [1-1- HMb. Γ + '.

© 5 0.

X N-R N-N-R5! or 11 i

k  J

where X represents O, S or NR where R represents a C1-C4-alkyl radical; C ^ -C ^ -alkyl substituted by 1 to 3 hydroxyl, amino, C ^ -C ^ -alkylamino radicals; diiC ^ -C ^ -alkyl) amino, C ^ -C ^ -alkoxy, carboxyl, halo or tallow; C ^ -Cg-cycloalkyl; C3-C6 ~ cycloalkyl (C ^ -C ^) - alkyl optionally substituted with 1 to 3 substituents mentioned above in connection with the radicals C ^ -C4-alkyl; phenyl; phenyl substituted with 1 to 3 substituents independently chosen from amino, halo, hydroxyl, trifluoromethyl, C ^ -C ^ -alkyl, Cj, -C4 ~ alkoxy, C ^ -C4 ~ alkylamino, di (C ^ -C4) alkylamino radicals , carboxyl and tallow; phenyl (C ^ -C4) alkyl in which the phenyl part can optionally be substituted by 1 to 3 CD.MJ - 41 - substituents mentioned above with respect to the phenyl radical and in which the alkyl part can optionally be substituted by 1 to 3 substituents mentioned above in connection with the C ^ -C ^ -alkyl radicals; and heteroaryl and heteroaralkyl in which the heteroatom (s) are chosen from 1 to 4 atoms 0, S or N and the alkyl part associated with the heteroaralkyl radical has 1 to 6 carbon atoms, these heteroaryl and heteroaralkyl radicals being optionally substituted in the part heterocylic with 1 to 3 substituents independently chosen from hydroxyl, amino, halogen, trifluoromethyl, C ^ -C ^ -alkyl, C ^ -C ^ -alkoxy, C ^ -C ^ -alkylamino, di (C ^ -C ^) radicals ) alkyllamino, carboxyl and sulfo, and in the alkyl part with 1 to 3 substituents chosen from the hydroxyl, amino, C ^ -C ^ -al-coylamino, di (C ^ -C ^) alkylamino, C ^ -C ^ radicals -alkoxy, carboxyl, halo and sulfo; this heteroaromatic radical being optionally substituted on a carbon atom by a substituent chosen from C ^ -C ^ -al-coyl * C ^ -C ^ -alkyl radicals preferably substituted by 1 to 3 hydroxyl, C ^ -C ^ radicals -alkylamino, di (C ^ -C ^ -alkyl) -amino, C ^ -C ^ -alkoxy, amino, sulfo, carboxyl or halo (chloro, bromo, fluoro or iodo; preferably chlo-ro, fluoro or bromo) ; C ^ -Cg-cycloalkyl; C ^ -C ^ -alkoxy; C ^ -C ^ -alkylthio; amino-, C ^ -C ^ -alkyllamino-, di (C ^ -C ^ -alkyl) amino; halo (chloro, bromo, fluoro or iodo; * · preferably chloro, fluoro or bromo); C ^ -C ^ -alkanoyl- amino; C ^ -C ^ -alkanoyloxy; carboxyl; -CC ^ -C ^ -C ^ -alkyl, -hydroxyl; amidino; guanidino; phenyl; phenyl substituted by one, two or three amino, halo (chloro, bromo, fluoro or iodo; preferably chloro, fluoro or bromo), hydroxyl, trifluoromethyl -, C - ^ - C ^ -alkyl or C ^ -C4- radicals alkoxy; phenyl (C ^ -C ^) alkyl, the phenyl part of which can optionally be substituted with 1 to 3 substituents mentioned above in connection with the radical CD.MJ - 42 - phenyl dical, and the alkyl part of which can optionally be substituted with 1 with 3 substituents mentioned above in connection with the C 1 -C 4 -alkyl ·, and heteroaryl and heteroaralkyl radicals in which the heteroatom (s) of the aforementioned heterocyclic parts are chosen from 1 to 4 atoms of oxygen, nitrogen or of sulfur and the alkyl part associated with the heteroaralkyl part has 1 to 6 carbon atoms, and (g) ® 5 5 ®

K --------- N-R R -N-K N —— N

I I I I. f> \ I

NOT . N-R N N-R R -N v N-R

Y V V

5 ®

N-N-R R -N-N-R N-N-R

J1 'J' I ° U «S © · 1 where R represents a C ^ -C4 ~ alkyl radical; C ^ -C ^ -alkyl substituted by 1 to 3 hydroxyl, amino, C ^ -C4 ~ alkylamino, di (C ^ -C4) alkylamino, C ^ -C4-alkoxy, carboxyl, halo or tallow radicals; C ^ -Cg-cycloalkyl; C ^ -Cg-cycloalkyl (C ^ -C4) alkyl optionally substituted with 1 to 3 substituents mentioned above in connection with the radicals C ^ -C4 ~ alkyl; phenyl; phenyl substituted with 1 to 3 substituents independently selected from amino, halo, hydroxyl, trifluoromethyl, C ^ -C4 ~ alkyl, C ^ -C4 ~ alkoxy, C ^ -C4-alkylamino, di (C ^ -C4) alkylamino radicals, carboxyl and sulfo-, phenyl (C1 ~ C4) -alkyl in which the phenyl part can optionally be substituted with 1 to 3 substituents mentioned above CD.MJ - 43 - about the phenyl radical and in which the alkyl part can optionally be substituted with 1 to 3 substituents mentioned above in connection with the C 1 -C 4 -alkyl radicals; and heteroaryl and heteroaralkyl in which the heteroatom (s) are chosen from 1 to 4 atoms 0, S or N and the alkyl part associated with the heteroaralkyl radical has 1 to 6 carbon atoms, these heteroaryl and heteroaralkyl radicals being optionally substituted in the heterocyclic part by 1 to 3 substituents independently selected from the radicals hy- = droxyl, amino, halo, trifluoromethyl, C ^ -C ^ alkyl, C ^ -C ^ -alkoxyf C ^ -C ^ -alkylamino, di (C ^ -C ^) alkylamino, carboxyl and sulfo, and in the alkyl part with 1 to 3 substituents chosen from hydro-xyl, amino, C ^ -C ^ -alkylamino, di (C ^ -C ^) alkyllamino, C ^ -C4 ~ alkoxy, carboxyl, halo and sulfo. The radicals R and can also be taken together to form a condensed heterocyclic or heteroaromatic radical.

In the preferred embodiment described above, preference is given to the compounds in the formula of which A represents a radical - (CH 2) - where n represents b Ω 1 or 2 and more especially to those in the formula of which A represents a radical -CH-- and further (a) R ^ and 8 ^ R, taken together, represent a radical

HOCH

CH3 ^

8 I

or (b) R represents a hydrogen atom and R represents a hydrogen atom or a CH3CH2- radical,

CH- CH- OH OH

3 \ I I

^ CH-, ^ C- or CH3CH- 0 * 3 C »^ CD.MJ - 44 -

Particularly preferred compounds are those in the formula of which R represents a hydrogen atom and R ^ represents a radical.

OH

CH3CH- and more especially the compounds having the absolute configuration 5R, 6S, 8R.

According to another preferred embodiment, the invention relates to the compounds of formula I where / ^ N © 5

-4- N-R

represents a radical of formula (a) *. 5 R ^ 5 6 7

where R represents a C.-Cg-alkyl radical and R, R

10, and R each independently represent a hydrogen atom or a C 1 -C 4 -alkyl radical;

" AT

he . He or V Rs

JK

Λ J

CD.MJ - 45 - 5 where R represents a C ^ -Cg-alkyl radical and the accessible carbon atoms of the ring are optionally substituted with 1 to 3 substituents independently chosen from C ^ -C ^ -alkyl radicals; s Λ -n. -n5 R5

R I

Μ 'V' R5 "Y 4" -f- 5 where R represents a C ^ -Cg-alkyl radical and the accessible carbon atoms of the ring are optionally substituted by 1 or 2 substituents chosen independently from the radicals C ^ -C ^ -alkyl; (d) RS RS R5

© '©, J © J

CD.MJ - 46 - R5 f * "

© 1 @ 1 © I

II, I II oU i] 5 where R represents a C ^ -Cg-alkyl radical and an accessible carbon atom of the ring is optionally substituted by a C ^ -C ^ -alkyl radical; te) © 5 © 5 -M-R _JJ-R5

- or —1. I

5 where R represents a C ^ -Cg-alkyl radical, X represents 0, S or NR where R represents a C ^ -C ^ -alkyl radical and one or more of the accessible carbon atoms of the ring are optionally substituted by C radicals ^ -C ^ -alkyl; (f) Θ5 © 5 π- -Ά- *? - "Çk ·. / 3 ~ · 'N_χ Nf-R5 R \ © _, Λ J“ 3'v "5, where R represents a radical C ^ -Cg -alkyl, X represents 0, S or NR where R represents a radical C ^ -C ^ -alkyl and one or more of the accessible carbon atoms of the ring are optionally substituted by radicals CD.MJ - 47 - C ^ -C ^ -alkyl; and {g) G) 5 3J N-R ^ © k> R '' N - = - N, i - ”- * r5 <^ <Y> 'r'’ ’5 · © 'R5. ©

-NrR N-N-R

I 5 © l

"Or R-S

5 where R represents a C ^ -C ^ -alkyl radical and R represents a C ^ -C ^ -alkyl radical.

According to a particularly preferred embodiment, the invention relates to the compounds of formula I where -θ '- * represents a radical of formula CD.MJ - 48 - where and R ^ are independently chosen from hydrogen atoms and C ^ -C ^ -alkyl, C ^ -C ^ -alkoxy, carboxyl and carbamoyl radicals and R "* is as defined above and preferably represents a C ^ -Cg-alkyl radical and more advantageously -CH ^ ·

In the preferred embodiment described above, the preferred compounds are those where A represents - (CH ^ J ^ with n representing 1 or 2, and especially those where A represents -CH „- and 1 8 ✓ ^ (a) R and R represent HOCH, or (b) R represents a hydrogen atom and R represents a hydrogen atom or radical

CH-.CH--, CH- CH-, OH OH

32 '3χ 3 | , CH-, ^ C-, or CH-CH-.

/ / 3 CH3 CH3 8

Particularly preferred compounds are those where R represents a hydrogen atom and R "*" represents

OH

CH3CH- and more especially the compounds having the absolute configuration 5R, 6S, 8R.

According to another preferred embodiment, the invention relates to the compounds of formula I where

-U N-R

represents a radical of formula CD.MJ - 49 - <3 ~ '5 where R represents a C.sub.1 -alkyl radical, more advantageously methyl 6 71 ** and R and R each represent a hydrogen atom or a C ^ -C ^ -alkyl radical; (b) R5 © 'r6 -ϋ-> 5 where R represents a C, -C.-alkyl radical, more favorably methylated, and R and R represent hydrogen atoms or C ^ radicals - C ^ -alkyl; “--A- 5 where R represents a C ^ -C ^ -alkyl radical, more preferably methyl, and R represents a C ^ -C ^ -al-r coyl or phenyl (C ^ -C ^) alkyl radical; -ff H- ± a ^ -R6 R5 where R ^ represents a C ^ -C ^ -alkyl radical, more preferably methyl, or carboxy (C ^ -C ^) alkyl and R ^ represented- CD.MJ - 50 - sente a C ^ -C ^ -alkyl radical, more preferably methyl, or carboxy (C ^ -C4) alkovle; R5

(e) I

-Ù /

R

5 where R represents a C ^ -C ^ -alkyl radical, more preferably methyl, and R represents a C ^ -C ^ -alkyl radical, more preferably methyl; -o * 5 or R represents a C ^ -C ^ -alkyl radical, more preferably methyl; <9>

-f I

/ N ^ N

R5 where represents a C ^ -C ^ -alkyl radical and R represents a C ^ -C ^ -alkyl radical or (h) R5

Lt 5 R // where R represents a C ^ -C ^ -alkyl radical and R represents a C ^ -C4-alkyl radical.

CD.MJ - 51 -

In the embodiment described above, the preferred compounds are those where A represents

with n representing 1 or 2, and especially those where A

represents -CH-- and 1 8 ^ (a) R and R together represent HOCH- ^ C = CH ^ 8 1 or (b) R represents a hydrogen atom and R represents a hydrogen atom or radical

CH-CH--, CH0 CH0 OH OH

O c. Ô O | | ^ CH—, ^ C-, or CH-CH-.

X / 3 CH3 CHf * * * 8

Particularly preferred compounds are those where R represents a hydrogen atom and R1 represents

OH

CH3CH- and more especially the compounds having the absolute configuration 5R, 6S, 8R.

According to a highly preferred embodiment, the invention relates to the compounds of formula I where 5

-U N-R

represents a radical of formula (a) _ <b> __f ~ \ ch3 CD.MJ - 52 - C \ 30> -y (c) (a) / ^ ° 2 ° 2 ° 3 ^ © r © "T) ( fl © Γ * ε \ _ © ^ 3 ω XI -0 ~ "s ch3

Yi / =) (i> “X I 5 ^ 2 © i;“) _ / N \

IJ

®j CH, <*> | (1) XXti © C <S & ch3 CH3 CD.MJ - 53 - CH3

i — N

(m) (t®cE, M \ V

/ CH3 <o> "P" "= f

I / _ / "VN

V "Λ _» /

Jh3 ^ co®

frS * »“ U

"^ K_Î -f ^ 3 | \ - 'ch3 ce3%

HJ

_ œ \ 3 © - -0 @ OU <V> ^ 3 'cS, i * 3 CH3 CD.MJ - 54 -!

In the embodiment described above, the preferred compounds are those where A represents - (CH_) - 2 n

with n representing 1 or 2, and especially those where A

represents -CH-- and 1 8 ^ (a) R and R together represent HOCH „^ C = c” 3 8 1 or (b) R represents a hydrogen atom and R represents a hydrogen atom or radical

CH, CH--, CH- CH, OH OH

3 2 3>. I I

CH-, ^ C- or CH3CH-.

CH3 ^ CH3 ^

Particularly preferred compounds are those where R ^ represents a hydrogen atom and R represents

OH

CH3CH- and more especially the compounds having the absolute configuration 5R, 6S, 8R.

Specific compounds forming the subject of the invention are those of formula OH R15 (R) '·· .- ^ S — A — R5 XOOR2 where R · ^ represents a hydrogen atom or methyl radical, R represents an atom of hydrogen, an anionic charge or a protective radical of the conventional carboxyl function and easy to eliminate, with the restriction that when-2 that R represents a hydrogenated atom or protec-CD.MJ - 55 - radical, a counter ion is also present and where —S — A — represents U) -SCH2 — K — CH3 / 'S © (b) -SCHECK r N — CH, 2Λ ^ / CH, © \ <=> -SCS ^ y' S «« -SCH2— \ X) \ = - B © \ CH3 CH, (e) -SCH2CH2 — C y (f) -SCH, - (fw — CH -CH -CH, 2 w CD.MJ - 56 - CH, ch Y ©? 3 / N— \, N © ^ -SChA Ί <h> "SCH2" ^ Y ^ H3 ch3 ®Γ3 c ^ '* 3 ll) -SCH2 — I <3> -SCH2- \ S5 — CH, CH3 (k) -SCH ^ 'j) (1) -sL3 - / ^ ß- * B3

®L

CH 3

OJ

CH_ I 2 0 ") .och - / 'Νχι Λ ï / <n)

© T’— 'I

CH, A

3 CH f © CH3 CH3 (o) (p) / A ©

-SCH- —C N -SCH, N

Y- Eu, CH3 whose NMR spectrum (ϋ £ θ) has characteristic peaks at &: 1.23 (3H, d, J = 6.4 Hz), 3.12 (2H, q, J = 1.4 , 8.9 Hz), 3.39 (1H, q, 3 = 2.1, 6.0 Hz), 4.07-4.68 CD.MJ - 57 - f (10H, m), 8.19 (1H, s); ^ H3 ch3 whose spectrum "* Ή NMR (D2O) has characteristic peaks a6: 1.23 (3H, d, J = 6.4 Hz), 3.15 (2H, q, 3 = 3.1, 9 , 0 Hz), 3.37 (1H, q, J = 2.6, 6.0 Hz), 3.95-4.65 (10H, m), 8.62 (1H, s); coo® /

CH

^ -sch (s) m (+) 2I> ·. - “oL, (t) 9 ^ 3 (U) CH,

-SCH - (Γ -SCH, - (T N

21_Λη2οοο® KJ

(V)

KO «‘ K

-scï2- ^ m3 / ¾ / ¾ 'Λ Θ ®N \ (x) -SGH ^ V N-C33 (yJ -sch2— /' u CD.MJ - 58 -

© J-H

/ \ ® · or (aa) -SCS. — C | J

ch3 ch3 2 'Njj ch3

According to a highly preferred embodiment, the invention relates to the compounds of formula I where 5

- (- N — R

V_ / represents CH- I © / CH3

Os and R represents a hydrogen atom or methyl radical.

In the embodiment described above, the preferred compounds are those where A represents - (CH2 ^ n ~ with n representing 1 or 2, and especially those where A represents -CH_- and 1 g * (a) R and R together represent HOCH- 8 n or (b) R represents a hydrogen atom and Rx represents a hydrogen atom or radical

CH-CH, -, CH- CH- OH OH

32 3 I I

CH-, ^ C-, or CH-CH-.

CD.MJ - 59 - 8

Particularly preferred compounds are those where R represents a hydrogen atom and represents

OH

CH3CH- and more especially the compounds having the absolute configuration 5R, 6S, 8R.

In the process of the present invention, the intermediate of formula is used:

RB * 1S

’TrV.

cY COOR2

IV

Mistletoe has been described, for example, in European patent applications 38869 and 54917 and which can be prepared according to the general methods which are specified therein.

L represents a conventional labile radical (defined as "X" in European patent application 38869), for example chloro, bromo, iodo, benzenesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, methane-tallow onyloxy, trifluoromethanesulfonyloxy, diphenoxy-phosphinyloxy or di (trichloroethoxy) phosphinyloxy. The preferred labile radical is the diphenoxyphosphi-nyloxy radical. The intermediates of formula IV are, in general, formed in situ by reaction of an intermediate of formula: R8 f15

„‘ I-pY

/ '- N - “N. 2 '

Cr COOR

III

CD.MJ - 60 - 1 δ 15 21 where R, R, R and R are as defined above, with one, 0 appropriate acylating agent R -L. The preferred intermediate IV where L represents a diphenoxyphosphinyl-oxy radical can be prepared by reacting ketoester III in an inert organic solvent, such as methylene chloride, acetonitrile or dimethylformamide, with an approximately equimolar amount of chloro diphenyl phosphate in the presence of a base such as diisopropylethylamine, triethylamine, 4-di-methylaminopyridine or a similar compound at a temperature of about -20 ° C to + 40 ° C, and more preferably about 0 ° C. Intermediate IV can be isolated, if desired, but can be advantageously used as a starting compound for the process of the invention without having been isolated or purified.

In the process of the invention, the intermediate carbapenem IV is reacted with a quaternary aminothiol of formula:

HS-A-H fo-IT

VII χΘ where t-C '& s

V _ ^ - R

is as defined above and xP represents a counter anion. The reaction is carried out in an inert solvent, such as acetonitrile, acetonitrile-dimethylformamide, tetrahydrofuran, tetrahydrofuran-water, ace-tonitrile-water or acetone, in the presence of a base. The nature of the base is not critical. Examples of suitable bases are sodium hydroxide, diiso CD.MJ - 61 - propylethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,5-diazabicyclo [4.3.0 ] non-5-ene and tri (C ^ -C4) -alkylamines such as triethylamine, tributylamine or tripropylamine. The reaction of intermediate IV and thiol VII can be carried out over a wide temperature range, for example from -15 ° C to room temperature, but is preferably carried out at a temperature of about -15 ° C at + 15 ° C and more advantageously at around 0 ° C.

The carbapenem produced by the reaction of quaternary aminothiol VII with intermediate IV comprises a counter anion associated with it (for example (CgH ^ O) 2PO2 ^ 'c · ^ or 11 anion associated with quaternary thiol) which can, with this stage, be replaced by a different counter anion, for example pharmaceutically more acceptable, according to conventional techniques. Alternatively, the counter anion can be removed during the later stage of deprotection. When the quaternized carbapenem and the counter anion form an insoluble compound, it can deposit in crystals as it forms and be collected in the purity state by filtration.

After the formation of the desired carbapenem, 2 1 the radical R protecting the carboxyl function in the compound 1 ′ can optionally be removed using conventional techniques, such as solvolysis, chemical reduction or hydrogenation. When the protective radical used is a p-nitrobenzyl radical, ben-. zyle, benzhydryl or 2-naphthylmethyl which can be eliminated by catalytic hydrogenation, the intermediate 1 'in a suitable solvent, such as dioxane-water-ethanol, tetrahydrofuran-diethyl ether buffer, tetrahydrofuran-hydrogen dipotassium hydrogen phosphate isopropanol , etc., can be reacted with hydrogen under a pressure of 1 to 4 atmospheres CD.MJ - 62 - in the presence of a hydrogenation catalyst, such as palladium on carbon, palladium hydroxide, platinum oxide, etc., at 0-250 ° C for about 0.24-4 hours. When R is a radical such as o-nitrobenzyl, photolysis is also suitable for deprotection. Protective radicals of the 2,2,2-trichloroethyl type can be removed by moderate reduction using zinc.

The protective allyl radical can be removed using a catalyst comprising a mixture of a palladium compound and triphenylphosphine in a suitable aprotic solvent such as tetrahydrofuran, methylene chloride or diethyl ether. Likewise, other conventional radicals which protect the carboxyl function can be eliminated according to methods known to those skilled in the art. Finally, as indicated above, the compounds of formula I ′, where R represents a physiologically hydrolysable ester, for example acetoxymethyl-phthalidyl, indanyl, pivaloyloxymethyl, metho-xymethyl, etc., can be administered directly without deprotection because these esters are hydrolyzed in vivo under physiological conditions.

1 8

It should be noted that when R, R, 5 15,.

R or R or the quaternary heteroaromatic radical attached to the substituent A contains a functional radical which could hinder the desired progress of the reaction, this radical can be protected using a conventional radical for this purpose and then deprotected for the regeneration of the desired functional radical. Suitable protective groups and methods for introducing and removing them are well known to those skilled in the art.

As in the case of other antibiotic lactams, the compounds of general formula I can be converted according to known techniques into pharmaceutically acceptable salts which, for the purposes of the invention CD.MJ - 63 - tion, are substantially equivalent to the compounds not salified. For example, one can dissolve a compound of formula I, where R represents an anionic charge, in a suitable inert solvent and then add an equivalent of a pharmaceutically acceptable acid. The desired acid addition salt can be isolated according to conventional techniques, for example, precipitation by a solvent, lyophilization, etc. When other basic or acidic functional radicals are present in the compound of formula I, base addition salts and pharmaceutically acceptable acid addition salts can be prepared in an analogous manner according to known techniques.

A compound of formula I, in which R represents a hydrogen atom or an anionic charge, or a pharmaceutically acceptable salt of this compound can also be converted according to known techniques to

, 2 a corresponding compound in the formula of which R

represents a physiologically hydrolyzable ester radical or else a compound of formula I, where R represents a conventional radical protecting the carbo-xyl function, can be converted into the corresponding compound in the formula of which R represents a hydrogen atom, a anionic charge or a physiologically hydrolyzable ester radical, or alternatively a pharmaceutically acceptable salt of this compound.

It should be noted that some of the products of formula I can be formed in the form of optical isomers and also of their epimeric mixtures. The subject of the invention is all these optical isomers and these epimer mixtures. For example, when the substituent in position 6 is a hydroxyethyl radical, this can have the R or S configuration and the resulting isomers as well as their epimer mixtures are within the scope of the invention.

CD.MJ - 64 -

The intermediate thiols of formula VII can be prepared, for example, from the corresponding thioacetates of formula: where A is as defined above, and

-O

represents a heterocyclic aromatic mono-, bi-, or polycyclic radical containing a nitrogen atom which can be quaternized in the ring, which radical is united to the radical A by a ring carbon atom. The thio-acetate is quaternized by reaction, in an inert organic solvent, such as diethyl ether, dichloromethane, dioxane, benzene, xylene, toluene or a mixture of these, with an agent of 'appropriate alkylation of formula: 5 R -X' 5 where R is as defined above and X 'represents a conventional labile radical such as halo (chloro, bromo or iodo, but preferably iodo) or a sulphonic ester radical as mesylate , tosylate or triflate. The temperature for the alkylation reaction is not critical and temperatures of about 0 ° C to 40 ° C are preferred.

Before the reaction with the intermediate carbapenem IV, the quaternized thioacetate is subjected to an acidic or basic hydrolysis which gives off the intermediate thiol CD.MJ - 65 - VII. This hydrolysis is preferably carried out immediately before the condensation with intermediate IV in order to minimize the decomposition of the relatively unstable quaternary thiol VII.

Thanks to the judicious choice of solvents, the reaction of intermediate III to the final product I can be carried out without isolation of the various intermediate compounds, that is to say by an "all in one" process. Such a process is illustrated below by Example 7.

The new carbapenem derivatives of general formula I, in which R represents a hydrogen atom, an anionic charge or a physiologically hydro-lysable radical protecting the carboxyl function, as well as their pharmaceutically acceptable salts, are powerful antibiotic agents against various gram-positive and gram-negative bacteria and can be used, for example, as additives for animal feed in order to promote their growth, as preservatives for food, as bactericides in industrial applications, for example base paints aqueous and white stationery waters to hinder the growth of harmful bacteria, as well as disinfectants for the destruction of harmful bacteria or for inhibiting their growth on medical and dental equipment. However, they are especially useful for the treatment of infectious diseases caused in humans and animals by gram-positive or gram-negative bacteria.

The pharmaceutically active compounds which are the subject of the invention can be administered as such or in the form of pharmaceutical compositions comprising, in addition to the active carbapenem derivative, a CD.MJ - 66 - pient or pharmaceutically acceptable diluent. These compounds can be administered in various ways, those of main interest being the oral route, the topical route and the parenteral route (for example by intravenous or intramuscular injection). The pharmaceutical compositions can be presented in solid form such as capsules, tablets, powders, etc. or in liquid form such as solutions, suspensions or emulsions. The compositions for injection, which is the preferred route of administration, may be presented in ampoules containing a unit dose or in multi-dose packages and may contain accessory agents such as suspending agents, stabilizers and dispersants . The compositions can be ready for administration or presented as a powder to be diluted at the time of administration with an appropriate vehicle such as sterile water.

The dose administered largely depends on the nature of the compound, the particular composition, the route of administration, the species and condition of the host, the site of administration and the nature of the pest. The choice of the preferred dose and route of administration in particular is within the competence of the physician. Generally, however, the compounds are administered parenterally or orally to mammals in an amount of about 5 to 200 mg per kg per day. Administration is generally carried out in divided doses, for example in three or four doses per day.

The following examples illustrate the invention without limitation.

CD.MJ - 67 - EXAMPLE 1

Preparation of 3- [4- (N, N-dimethyl-1,2,3-triazolium) -methylthio] -6o (- [l- (R) -hydroxyéthyl 3- 7-oxo-l-azabicy-clo [3.2 .03hept-2-ene-2-carboxylate

OH

co2u N t: h3

A. Preparation of isomer A

fHH H

/ SAc ft) MeOTf / \ T \ ^ \ Γ b) Aq. NaOH 1 \ _s / yi

AiU Y *

Tl> -OP (Oè), A—

O02PNB

d) H2 / Pd-C

Methyl trifluoromethane sulfonate (0.58 ml, 5.16 millimoles) is added dropwise to an ice-cold stirred solution of 4- (methanethiolacetate) -1-methyl-1,2,3-triazole (590 mg , 3.52 millimoles) in dry methylene chloride (2 ml) under nitrogen. After 0.5 hour, the bath is removed and after 1 hour, the solvent is removed in vacuo. The residual oil is dissolved in a few ml of water and this solution is cooled in an ice bath. A cold solution of sodium hydroxide (305 mg, 7.59 millimoles) in a few ml of water is then added thereto and the reaction mixture CD.MJ - 68 - is stirred for 0.75 hours. The solution is diluted to 25 ml with water and the pH is adjusted to 7.5 by addition of solid sodium dihydrogen phosphate monohydrate. 14 ml of this solution (about 1.9 millimole of the triazoliumthiol) are then added to an ice-cold stirred solution of enol phosphate (1.0 g, 1.72 millimole) in tetrahydrofuran (THF 10 ml). The mixture is stirred for 0.75 hours (it deposits during this reaction a little crystalline substance, probably Ν32ΗΡ0 ^). The suspension is transferred to an autoclave using a little THF (20 ml) and water (20 ml). Ether (30 ml) and 10% palladium on charcoal (1.0 g) are added and the mixture is hydrogenated (2.76 bar) for 1 hour. The organic phase is separated and washed with water (2x5 ml). The combined aqueous phases are filtered and the filtrate is concentrated under high vacuum (about 0.66 millibar, 1.5 hours).

The yellow solution is then chromatographed (column with phase inversion under medium pressure, 35 mm × 90 mm, H 2 O as eluent) to obtain, after lyophilization, 395 mg of the carbapenem weakly contaminated with a little inorganic substance. It is purified by HPLC (Waters Microbondapack C-18 column, 10 mm × 300 mm with multiple injections, H 2 O as eluent) to obtain 310 mg (57%) of the A isomer in the form of a yellowish powder: 1 H NMR (D20) 6: 1.23 (3H, d, J = 6.4 Hz), 310 (2H, d, J = 9.1 Hz), 3.24 (1H, q, J = 2.7, 6 , 1 Hz), 4.03-4.71 (10H, m), 8.46 (1H, s); IR (Nujol) 1760 cm “1; UV (phosphate buffer, pH 7.4, M = 0.05) \ max: 296 nm (£ = 7,500).

B. Preparation of the B isomer and of the C isomer CD.MJ - 69 - £) MeOTf SAc ^ b) aq. NaOH χ __N 7) ”7

^ —Me TR H

(structure j il

proposed) ç / O

co2pnb

(3) H ^ / Pd-C OH

T Π H

J Λ-S / \ - N ^ Me, # ^ NsJ / / 3 ^ ^ ° 'Θ Çj'1' C02

Methyl trifluoromethane sulfonate (1.60 ml, 14.0 millimoles) is added dropwise to an ice-cold solution of 4- (methanethiolacetate) -2-methyl-1,2,3-triazole (1.20 mg, 7.02 millimoles) in methylene chloride (6 ml) under nitrogen. The mixture is allowed to warm to room temperature and stirred for 16 hours. Additional methyl trifluoromethanesulfonate (0.40 ml, 3.56 mmol) is added and after 3 hours at room temperature, the solvent is removed under reduced pressure.

The residual oil is triturated in ether and the resulting gum is dissolved in water (5 ml). The solution is cooled in an ice bath and a solution of sodium hydroxide (844 mg, 21.1 millimoles) in water (5 ml) is added thereto. After 0.75 hours of stirring, the solution is diluted to 60 ml with water and CD.MJ - 70 - adjusts its pH to 8 by addition of solid potassium dihydrogen phosphate. 40 ml of this solution (about 4.7 millimoles of a mixture of the isomeric triazoliumthiols) are then added to an ice-cold stirred solution of enol phosphate (2.00 g, 3.45 millimoles) in THF (60 ml) . The mixture is stirred in an ice bath for 0.5 hour, then it is transferred to an autoclave containing a suspension of 10% palladium on carbon (2.00 g) in ether (60 ml). The mixture is hydrogenated (2.76 bars) for 1 hour. The organic phase is separated and washed with water (2 x 10 ml). The combined aqueous phases are filtered and the filtrate is concentrated in vacuo (about 0.66 millibar, 1.5 hours). The remaining solution is then chromatographed (phase inversion column under medium pressure, 45 mm x 130 mm, H2O as eluent) to obtain, after lyophilization, 595 mg of a mixture of isomeric carbapenems which a small amount of inorganic substance contaminates.

The carbapenems are separated and purified by HPLC (Waters Microbondapack column C-18, 10 mm x 300 mm, multiple injections, H2O as eluent) to obtain, in the order of elution: isomer B, 153 mg (13%); 1H NMR (D20) ^: 1.23 (3H, d, J = 6.4 Hz), 3.12 (2H, q, J = 1.4, 8.9 Hz), 3.39 (1H, q , J = 2.7, 6.1 Hz), 4.07-4.68 (10H, m), 8.19 (1H, s); ς IR (Nujol) 1755 cm UV (phosphate buffer, pH 7.4, Μ ^, Οδί'λ: 296 nm max (£ = 6700); the isomer C, 284 mg (24%) 1U NMR (D20) S: 1.23 (3H, d, J = 6.4 Hz), 3.15 (2H, q, J = 3.7, 9.0 Hz), 3.37 (1H, q, J = 2, 6.0 6.0 Hz), 3.95-4.65 (10H, m), 8.62 (1H, s); IR (Nujol) 1750 cm ^; UV (phosphate buffer, pH 7.4, Μ = 0.05) λ: 296 nm iti ax CD.MJ - 71 - (ε = 7600).

EXAMPLE 2 (5R, 6S) 6- (ÎR-Hydroxyethyl) -3- (2-methyl-1,2,3-thiadi-azolium-4-ylmethylthio) -7-oxo-l-azabicyclo [3.2,0] hept -2-ene-2-carboxylate

OH

^ rA_s / v »7 ~ Λθ

NcocP 3 A. 1,2,3-Thiadiazol-4-ylcarboxylate d 1 ethyl ^ - U 0 "Il

^ NHCOEt cW

X

CH ^ ^ gOEt ^ ^ C.D. Hurd and R.I. Mori, J. Am. Chem. Soc. , 77, 5359 (1955).

A solution of ethyl d -N-carbethoxyhydra-zonopropionate (31.2 g, 0.154 mol) in thionyl chloride (80 ml) is stirred at 23 ° C for 3 hours and heated to 70 ° C for 20 minutes. The thionyl chloride is evaporated and the residue is triturated in hexane (4 x 30 ml). The red solid was dissolved in dichloromethane (150 ml) and the solution was washed with saturated sodium bicarbonate solution and water. After drying over Na2SO4, the solution is concentrated until the compound crystallizes. After standing at 23 ° C for some time, the crystals are filtered: 16.8 g, m.p. 86 ° C, 69%. The filtrate is concentrated and CD.MJ - 72 - is purified by chromatography on a column of silica gel which is eluted with dichloromethane to obtain 3.17 g of the solid, PF 86 ° C, 13%: IR (KBr) "\): 1720 (ester) cm ^; .. max NMR (CDC13) 6: 1.52 (3H, t, J = 7.1 Hz, CH3CH20), 4.57 (2H, q, J = 7, 1 Hz, CHgCHjO), 9.47 (1H, s, H of thiadiazole). B. 1,2,3-Thiadiazol-4-ylmethanol ^ ~

JoET ΛΟΗ 0 "" ·. 0 ^ S.I. Rämsby, S.O. Oegren, S.B. Ross and N.E. Stjernström Acta Pharm. Succica., 10, 285-96 (1973); C.A., 79, 137052W (1973).

Lithium aluminum hydride (2.47 g; 0.065 mol) is gradually added over 1 hour to a suspension of ethyl 1,2,3-thiadiazol-4-ylcarboxylate (18.35 g, 0.116 mole) in ether (400 ml). The reaction mixture was stirred at 23 ° C for 7 hours and lithium aluminum hydride (2.47 g, 0.065 mole) was added thereto. Stirring is continued for 24 hours before successively adding water (7 ml), 15% sodium hydroxide solution (7 ml) and water (21 ml). After 15 minutes of stirring, the ethereal solution is decanted and the gum is extracted with ether (5 x 100 ml). The ethereal extracts are combined, dried (MgSO 4) and concentrated (5.4 g). The crude product is purified on a column of silica gel (120 g, 4 x 16 cm) which is eluted with ether to obtain 1.3 g (7%) of 1,2,3-thiadiazol-4- ethyl ylcarboxylate and 2.45 g (18%) of 1,2,3-thiadiazol-4-ylmethanol: IR (film) \): 3380 (OH) cm-1; max 'CD.MJ - 73 - 1H NMR (CDC13) <S: 2.31 (1H, s, OH), 5.22 (2H, s, CH20), 8.50 (1H, s, H of thiadiazole) .

C. 1,2,3-Thiadiazol-4-ylmethanol methanesulfonate m - * / '09? 09 ._ / - CH „OMs O —_- / 1 NEt3

A solution of 1,2,3-thiadiazol-4-ylmethanol (0.75 g, 6.5 millimoles) in dichloromethane (20 ml) to which triethylamine is added is cooled to 5 ° C. in a nitrogen atmosphere. (1.018 ml, 7.3 millimoles) and methanesulfonyl chloride (0.565 ml, 7.3 millimoles). After 15 minutes, the ice bath is removed and the reaction mixture is stirred for 2 hours.

The solution is washed with an IN solution of hydrochloric acid (2 x 2 ml) and water, dried (MgSO 4 + MgO) and concentrated. The residue is purified by chromatography (column of silica gel 1.5 x 21 cm) which is eluted with ether to obtain 0.90 g (71%) of 1,2,3-thiadiazol-4- methanesulfonate ylmethanol IR (film) N): 1350 (SO „) cm“ 1, 1172 (SO0) cm “1; H NMR (CDCl3) <5: 3.09 (3H, s, CH3), 5.75 (2H, s, CH2), 8.72 (1H, s, H of thiadiazole); UV (CH0C10) ”X: 251 nm (6 = 1990).

2 2 rn âx

Analysis for C6H6N2 ^ 3S

calculated C, 24.73; H, 3.11; N, 14.42; S, 33.02% found C, 24.78; H, 3.09; N, 14.66; S, 31.94% 0.13 g (19%) di- (1,2,3-thiadiazol-4-ylmethyl) ether IR (film) "0; 1272, 1242, 1200, 986, 805, 728 cm “1; h: NMR (CDCI 3) 6: 5.16 (s, 4H, CE ^), 8.42 (s, 2H, the H of thiadiazole).

CD.MJ - 74 - D. 4-Acetylthiomethyl-1,2,3-thiadiazole 0 s

_ ^ CK, OMs II N SCCB

r $ / - £ *

S S

An aqueous solution (2 ml) of sodium thiolacetate (prepared from thiol-acetic acid (0.38 ml, 5.3 millimoles) and sodium bicarbonate (0.445 g, 5.3 millimoles)) is added to a solution of 1,2,3-thiadiazol-4-ylmethanol methanesulfonate (0.90 g, 4.6 millimoles) in tetrahydrofuran (9 ml). The resulting mixture is stirred at 23 ° C. for 1 hour and diluted with ether (75 ml). The organic solution is washed with water (3 x 3 ml), dried (MgSO 4) and concentrated. The crude product is purified by chromatography (silica gel column 1.4 x 19 cm) which is eluted with 50% ether in hexane to collect 0.60 g (75%) of the compound: IR ( film) \>: 1675 (C = 0) cm-1; ± 1 H NMR (CDCl 3) <5: 2.37 (3H, s, CHg), 4.58 (2H, s, CH2), 8.44 (1H, s, H of thiadiazole);

Analysis for C5HgN2OS2 calculated C, 34.47; H, 3.47; N, 16.08; S, 36.80% found C, 34.48; H, 3.83; N, 16.28; S, 36.80% E. 4-acetylthiomethyl-2-methyl-1,2,3-thiadiazolium trifluoromethanesulfonate and 4-acetylthiomethyl-3-methyl-1,2,3-thia-diazolium trifluoromethanesul-fonate CD.MJ - 75 - ο Υπί ΐ (> CP3SOi ό re **.

s \ s} cr.EOj

A few crystals of the title compounds and methyl trifluoromethanesulfonate (0.407 ml, 3.6 millimoles) are added over 5 minutes to a solution of 4-acetylthiomethyl-1,2,3-thiadiazole (0.60 g, 3.44 millimoles) in a mixture of ether (4 ml) and dichloromethane (0.4 ml). The reaction mixture is stirred at 23 ° C under a nitrogen atmosphere for 6 hours. The white solid, which is a mixture of the two compounds mentioned in the title, is collected by filtration and washed with ether to collect 1.05 g (90%).

IR (KBr) Ό r 1675 (C = 0) cm-1; "M cix NMR (DMSO, d-6) 6: 2.43 (3H, s, CH3COS), 3.33 (s, CH3 on N-3), 4.57 (s, CH ^ on N-2) , 4.66 (2H, s, Cf ^), 9.55 (H of thiadiazolium N-2), 9.66 (H of thiadiazolium N-3); Analysis for C ^ H ^ N ^ O ^ S ^ F ^ calculated C, 24.85; H, 2.68; N, 8.28; S, 28.43% found C, 24.61; H, 2.57; N, 8.47; S, 28.21% F. 4-mercaptomethyl-2-methyl-1,2,3-thiadiazolium trifluoromethanesulfonate and 4-mercaptomethyl-3-methyl-1,2,3-thiadia-zolium trifluoromethanesul-fonate CD.MJ - 76 - ο

II

N — 1 / CH2SCCH3 .üEi ^ L H '# "t cr," - NS ^ CF3S03 \ s ^ 3 3

A solution of a mixture of 4-acetylthiomethyl-2-methyl-1,2,3-thiadiazolium and 4-acetyl trifluoromethanesulfonate is heated at 65 ° C. in a nitrogen atmosphere for 1.75 hours. tylthiomethyl-3-methyl-1,2,3-thiadiazolium (1.05 g, 3.1 millimoles) in 6N hydrochloric acid (10 ml).

The solvent is evaporated off under reduced pressure to leave 0.91 g of a yellow syrup remaining. This compound is used without purification in the next stage.

G. (5R, 6S) 6- (ÎR-Hydroxyethyl) -3- (methyl-1,2,3-thiadia-zolium-4-ylmethylthio) -7-oxo-l-azabicyclo [3.2.0] -hept- 2-ene-2-carboxylate SH '' • sïV3 * 2 * 1 * _

'' '• λ-S 10 Pd / C

J ', ^ "0P <0Ph> 2 -► -► p» 7, a “λ * · ΓΟΟΡΝΕ 7 2

OH

COO s

A cold solution (5 ° C) of (5R, 6S) 6- (1R-hydroxyethyl) -3- (diphenylphosphono) -7- CD.MJ - 77 - oxo-1-azabicyclo [3.2.0] hept is reacted P-nitrobenzyl -2-ene-2-carboxylate (1.7 g, 2.92 millimoles) in tetrahy-drofuran (10 ml) with a solution of a crude mixture of 4-mercaptomethyl-2- trifluoromethanesulfonate methyl-1,2,3-thiadiazolium and 4-mercaptomethyl-3-methyl-1,2,3-thiadiazolium trifluoromethanesulfonate (0.9 g) in a phosphate buffer mixture (pH 7.2 , 0.3M, 15 ml) and tetrahydrofuran (5 ml) · The reaction mixture is stirred for 1 hour while maintaining the pH at 7.2 using a 2N sodium hydroxide solution. Stirring is continued for 1 hour before adding ether (50 ml) and 10% palladium on charcoal (1 g). The resulting mixture is hydrogenated at 23 ° C at 3.10 bar for 2 hours and filtered through Celite. The organic phase is separated, diluted with ether (50 ml) and with phosphate buffer (pH 7.2, 0.3M, 20 ml), then hydrogenated (2 g of 10% palladium on charcoal) for 2 hours at 3.45 bar. The aqueous phases are combined (of the first hydrogenolysis and of the second), they are washed with ether and they are purified by chromatography on PrePak 500-C / 18 which is eluted with water to collect 0.22 g of the raw material.

The latter is purified by HPLC with water as elution solvent to collect 0.040 g (4%) of the title compound after lyophilization IR (KBr) O max: 3400 (large, OH), 1745 (C = 0 / 3-lactam), 1580 (carboxylate) cm-1; 1H NMR (D20) 6: 1.23 (3H, d, J = 6.3 Hz, CH3CHOH), 3.04, 3.05, 3.16 (2H, m, H-4), 3.38 ( 1H, dd, J = 2.8 Hz, J = 6.0 Hz, H-6), 3.9-4.6 (2H, m, H-5, CH3CHOH), 4.51, 4.53 ( 2 "s", SCH2), 4.61 (s, N + CH3); UV (H00) λ m = v: 224 nm (£ = 4345), 262 nm (£ = 4980), 296 nm (£ = 6885); [d] ^ 3 18 ° (c 0.18, H2O);

Tl / 2 = 9.8 hours (measured at a concentration of 10 ~ 4 M CD.MJ - 78 - in phosphate buffer pH 7.4 at 36.8 ° C). EXAMPLE 3 3- [5- (1-Carboxylatomethyl-3-methyl-I, 2,3-triazolium) -methanethio] -60t- [1- (R) -hydroxyethyl 3-7-oxo-1-azabicy-cloC3. 2.0lhept-2-ene-2-carboxylate potassium®

Jhh Ç 2 v% ro 'BOÎv ^ n. 1) IAH »CS- ^ V% t.) -► X /

Nj 2) MsCl / NEt3 J

XSCOCH

/.

Λ ßrCH COEt ^ o2rt

ACS '"' O

Y

a) KOH

»CO PNB 2

c) H ^ / Pâ-C

i1 CD.MJ - 79 - φ ο oh ^ .co y

VP I

Lithium aluminum hydride (2.83 g, 70.9 millimoles) is gradually added to a stirred suspension of 1-methyl-1,2,3-triazole-4-carboxylic acid (9.00 g, 70.9 millimoles) (see C. Pederson, Acta. Chem. Scand., 1959, 1 ^, 888) in dry THF (200 ml). The mixture is stirred at room temperature for 15 hours, at the end of which a 20% aqueous solution of sodium hydroxide (20 ml) is carefully added in aliquots of about 1 ml. The resulting granular suspension is filtered and the solid is washed with THF supplements (5 x 75 ml). The combined solutions are dried (MgSO 4) in THF and the solvent is removed. The resulting yellow oil is subjected to rapid chromatography on a column of silica gel (90 x 35 mm) [100 ml aliquots of hexane, ethyl acetate-hexane mixtures (1: 1) and (1: 3), and finally ethyl acetate-methanol (9: 1) as eluent]. 4-hydroxymethyl-1-methyl-1,2,3-triazole (3.18 g, 40%) is thus obtained in the form of a colorless oil 1H NMR (CDCl3) 6: 4.07 (3H, s) , 4.73 (2H, d), 7.52 (1H, s); IR (pure) 3320 cm ^.

Methanesulfonyl chloride (3.82 ml, 49.6 millimoles) is added dropwise to a stirred ice solution of alcohol (4.67 ml, 41.3 millimoles) and triethylamine (7.47 ml, 53 , 7 millimoles) in methylene chloride (20 ml). After 0.5 hour, CD.MJ - 80 - the solvent is removed and the solid residue is taken up in acetonitrile (30 ml). Then potassium thiolacetate (7.06 g, 62.0 millimoles) is added and the suspension is stirred for 3 hours at room temperature. Additional potassium thiolacetate (3.0 g, 26.3 mmol) is added and the suspension is stirred for a further 16 hours. The dark suspension is then concentrated and water (10 ml) is added thereto. This mixture is extracted with methylene chloride (5 x 40 ml). The combined extracts are dried (MgSO4) and the solvent is removed. The residual oil is subjected to rapid chromatography on a column of silica gel (90 x 36 mm) [hexane, then mixture of hexane and acetyl (1: 1) as eluent. 4- (methanethiolacetate) -1-methyl-1,2,3-triazole (5.95 g, 84%) is thus obtained in the form of a weakly pink solid: 1 H NMR (CDCl3) ό: 2.40 (3H, s), 4.10 (3H, s), 4.20 (2H, s), 7.53 (1H, s); IR (Nujol) 1675 cm.

A solution of triazole (1.00 g, 5.85 millimoles) and ethyl bromoacetate (1.48 ml, 13.3 millimoles) in dry acetonitrile (60 ° C. is heated for 90 hours under nitrogen). 10 ml). The solvent is removed and the residual oil is triturated in ether (4 x 25 ml) to allow the 1-methyl-3- (ethylcarboxymethyl) -4-methanethiolacetate-1,2,3-triazolium bromide to remain. the shape of a brownish gum that we use directly.

A cold solution of KOH (0.66 g, 12 millimoles) in water (5 ml) is added to an ice-cold stirred solution of triazolium bromide in water (20 ml). After 20 minutes, the mixture is diluted to 35 ml and sufficient solid potassium dihydrogen phosphate is added thereto to bring the pH of the solution to 8.0. The solution is then added to an ice-cold stirred solution of CD.MJ-81-enol phosphate in THF (35 ml). After 0.5 hour, the mixture is transferred to an autoclave containing ether (35 ml) and 10% palladium on charcoal (1.5 g). The hydrogenation is carried out at 2.76 bars for 55 minutes. The organic phase is then separated and washed with water (2 x 5 ml). The combined aqueous phases are filtered and the filtrate is concentrated under high vacuum. The residue is chromatographed on a phase inversion column (35 x 120 mm) which is eluted with water. By lyophilization of the fractions containing the carbapenem, 1.20 g of a green solid are obtained. We rechromatograph it on a device

Waters Prep 500 HPLC (PrePak-500 / C.Q column) using 2% acetonitrile in water as the eluent. The fractions containing the carbapenem are combined and lyophilized. The solid is rechromatographed by HPLC (Waters Microbondapack C-18 column 10 × 300 mm) with water as eluent to obtain, after lyophilization, in the form of a pale yellow solid, the pure compound mentioned in the title (190 mg , 17%): 1H NMR (D20) 6: 1.24 (3H, d, J = 6.4 Hz), 3.07 (2H, d, J = 9 Hz), 3.38 (1H, q, J = 2.7, 6.0 Hz), 4.02-4.30 (3H, m), 4.29 (3H, s), 5.23 (2H, s), 8.52 (1H, s ); IR (Nujol) 1750 cm ^; UV (phosphate buffer, pH 7.4), Xmax: 296 nm (8 = 7520). EXAMPLE 4 - 3- [4- (1-Carboxylatomethyl-3-methyl-1,2,3-triazolium) -

methanethio] -6ç ^ - [l- (R) -hydroxyethyl] -7-oxo-l-azabicy-clo [3.2.0] hept-2-ene potassium carboxylate OH

F H ~

Af-rv ^ J © & CD.MJ - 82 - H0? -5 H0 ^ N- CO Et + _►

PtOCCH ^ a) EtOCCl, NEt0 II 3

Ja

bd / nH

N N v £ 0 And 0 OC-H ") * 3 HSCCS.

a 3 ▼ »cs ^ V == \ CD.MJ - 83 -

μ) MeOlf b) ΧΟΕ OH

Y * g e) \ ίΟ · ® <οφ) ΐ CO ^ PNä

▼ d) H ^ / Pd-C

V H H ÇH3 £> AI_La I © wro ^ s®

A mixture of ethyl azidoacetate (30.0 g, 0.23 mole) and propiolic acid (14.3 ml, 0.23 mole) in toluene (75 ml) is stirred at room temperature. The reaction is moderately exothermic for 1.5 hours, then becomes strongly exothermic and necessitates cooling in an ice bath. After the exothermic phase, the reaction mixture is heated to reflux for 0.5 hour. After cooling in an ice bath, the crystalline substance is collected by filtration and washed with a little toluene. The crude solid thus obtained (33.3 g, 72%) is a single isomer which is probably l- (ethylcarboxymethyl) -1,2,3-triazole-4-carboxylic acid, by analogy with a previous work (C Pederson, Acta. Chem. Scand., 1959, 1-3, 888): 1H NMR (DMSO-dg) ό: 1.20 (3H, t, J = 7 Hz), 4.15 (2H, q, J = 7 Hz), 5.42 (2H, s), 8.67 (1H, 3).

A solution of the carboxylic acid (5.00 g, 25.1 mmol) and triethylamine (3.68 ml, 26.4 mmol) in dry methylene chloride (50 ml) is added to an ice-cold stirred solution of ethyl chloroformate (2.52 ml, 26.4 mmol) in CD.MJ - 84 - dry methylene chloride (50 ml). The purple solution is stirred for 0.5 hour, then washed with water (10 ml), dried (MgSO 4) and the solvent is removed. The crude mixed anhydride is dissolved in THF (50 ml) and the solution is added slowly to an ice-cold suspension of sodium borohydride (0.72 g, 18.9 millimoles) in THF (50 ml). After 0.5 hours of stirring, additional sodium borohydride (0.30 g, 7.9 millimoles) is added and the reaction mixture is stored in an ice bath for 1 hour. Water (5 ml) is then added and after 10 minutes 10% aqueous HCl (3 ml).

At the end of the evolution of gas, solid potassium carbonate (2 g) is added with stirring. The organic phase is separated and the residual white paste is extracted with a supplement of THF. The combined organic phases are dried (MgSO 4) and the solvent is removed.

By rapid chromatography on a column of silica gel eluted with hexane, mixtures of ethyl acetate and hexane and finally ethyl acetate, we obtain l- (ethylcarboxymethyl) -4- hydroxymethyl-1,2,3-triazole (2.04 g, 44%) in the form of a crystalline solid: 1H NMR (CDCl3) 6: 1.28 (3H, t, J = 7 Hz), 4, 23 (2H, q, J = 7 Hz), 4.75 (2H, s), 4.85 (2H, s), 7.73 (1H, s).

Diisopropyl azodicarboxy-late (4.11 ml, 20.8 mmol) is added dropwise to an ice-cold solution of triphenylphosphine (5.47 g, 20.8 mmol) in dry THF (100 ml) under nitrogen. After 0.5 hour, an ice solution of alcohol (1.93 g, 10.4 millimoles) and thiol-acetic acid (1.49 ml, 20.8 millimoles) in THF is added to this mixture. dry (50 ml), under nitrogen. The mixture is kept in an ice bath for 2 hours, then at room temperature for a further 12 hours, after which the solvent is removed. The reaction mixture is subjected to chroma CD.MJ - 85 - rapid tography on silica gel (40 g; elution with aliquots of 100 ml of hexane and ethyl acetate at 5, 10, 15. ..50% in hexane). The fractions containing the thiolacetate are combined and re-chromatographed on silica gel (60 g) [which is eluted with 200 ml aliquots of hexane and ethyl acetate at 5, 10, 15 and 20% in hexane and 22.5, 25, 27.5 ... 35% ethyl acetate in hexane]. 1.24 g (49%) of 1- (ethylcarboxymethyl) - 4-methanethiolacetate-1,2,3-triazole are thus obtained in the form of a crystalline solid: 1H NMR £: 1.28 (3H, t, J = 7 Hz), 2.37 (3H, s), 3.87 (2H, s), 3.90 (2H, q, J = 7 Hz), 5.12 (2H, s), 7.63 (1H, s); IR (Nujol) 1735, 1780 cm-1; in addition 1.40 g of a substance contaminated with triphenylphosphine oxide.

Methyl trifluoromethane sulfonate (0.51 ml, 4.53 millimoles) is added dropwise to an ice-cold stirred solution of the triazole (1.00 g, 4.12 millimoles) in dry methylene chloride (5 ml) . After 0.5 hour, the bath is removed and, after another 0.5 hour, the solvent is removed in vacuo. A white residue is thus obtained which is suspended in water (15 ml) and this mixture is stirred and cooled in an ice bath.

A solution of KOH (0.69 g, 12.4 millimoles) in water (5 ml) is added and the reaction mixture is stirred for 1 hour. It is then diluted with 30 ml of water and solid potassium dihydrogen phosphate is added thereto to bring the pH to 8.0. A fraction of this solution (22 ml, about 3.0 millimoles of thiolcarboxylate) is added to an ice-cold stirred solution of enol phosphate (1.60 g, 2.76 millimoles) in THF (30 ml). After 0.5 hour, the reaction mixture is taken up and the THF is removed therefrom under high vacuum. The yellow solution is then chromatographed on a co-CD.MJ-86 - lonne with phase inversion (35 x 120 ml) which is eluted with water (300 ml), then with aliquots of 100 ml of acetonitrile at 5, 10, 15 ... 30% in water. By lyophilization of the appropriate fractions, the p-nitrobenzyl ester is obtained in the form of a yellow solid (930 mg). This is introduced into an autoclave containing ether (25 ml), THF (25 ml) and phosphate buffer [25 ml, prepared by dissolving potassium dihydrogen nophosphate (1.36 g, 0, 01 mole) in water (100 ml) and adjustment of the pH to 7.4 by addition of aqueous KOH at 45], in addition to 10% palladium on carbon (900 mg). The hydrogenation is carried out at 2.76 bars for 1 hour, then the organic phase is separated and washed with water (2x5 ml). The combined aqueous phases are filtered and concentrated under high vacuum. The residual solution is chromatographed on a phase inversion column (35 x 120 mm) which is eluted with water. The fractions containing the carbapenem are combined and lyophilized to obtain 1.21 g of a pale greenish solid. This is purified by HPLC (Waters Microbondapack C-18 column 10 x 300 mm eluted with water) to obtain in the purity state 480 g (41%) of the product announced in the title: 1H NMR (D20) 6 : 1.23 (3H, d, J = 6.4 Hz), 3.11 (2H, d, J = 9 Hz), 3.37 (1H, q, J = 3.0, 6.1 Hz) , 4.02 (7H, m), 5.18 (2H, s), 8.53 (1H, s); IR (Nujol) 1750 cm- ^; UV (phosphate buffer, pH 7.4) Xmax: 205 nm (£ = 7810). EXAMPLE 5 3- [5- (1,4-Dimethyl-1,2,4-triazolium) methanethio] -6c (- [l- (R) -hydroxyethyl] -7-oxo-l-azabicyclo [3.2.0] -hept-2-ene-2-carboxylate CD.MJ - 87 -

OB

0 \ e ^ co ^ A. l-Methyl-5-methanethiolacetate-1,2,4-triazole

fu ”. f \ T

b) CH3gSH / NEt3

Methanesulfonyl chloride (0.46 ml, 6.0 millimoles) is added dropwise to an ice-cold stirred solution of 1-methyl-5-hydroxymethyl-1,2,4-triazole (565 mg, 5.0 millimoles, see RG Jones and C. Ainsworth, Amer. Chem. Soc., 1955, TT_, 1938) and triethylamine (0.91 ml, 6.5 millimoles) in methylene chloride (5 ml). After 20 minutes, additional triethylamine (1.05 ml, 7.5 millimoles) is added, followed by thiolacetic acid (0.53 ml, 7.5 millimoles) and stirring is continued for 45 minutes. The reaction mixture is diluted with methylene chloride and washed with water. The aqueous phase is extracted with methylene chloride (3 x 5 ml) and the combined organic phases are dried (MgSO4), then the solvent is removed. By chromatography on a column of silica gel, 1-methyl-5-methanethiolacetate-1,2,4-triazole (570 mg) is obtained in the form of a yellow oil (in addition to an impure fraction (200 mg) which '' rechromatography (preparative TLC on silica gel) to obtain a further 100 mg of pure compound (total yield: 85%)]: CD.MJ - 88 - 1H NMR (CDCl3) 0: 2.38 (3H, s,) , 3.90 (3H, s), 4.25 (2H, s), 7.80 (1H, s).

B. 3— [5— (1,4-Dimethyl-1,2,4-triazolium) methanethio] - 6oc- [l- (R) -hydroxyethyl] -7-oxo-l-azabicyclo [3.2.03-hept -2-ene-2-carboxylate a) MeOTf

fi N 5Ac b) Na OH

i J

Π

CO GNP

d) Bj / Pd-C

OH

I * H? l (=) co2u

Methyl trifluoromethane sulfonate (1.20 ml, 10.7 millimoles) is added dropwise to an ice-cold solution of l-methyl-5-methanethiolacetate-1,2,4-triazole (730 mg, 4.27 millimoles ) in methylene chloride (7 ml). The reaction mixture is allowed to slowly warm to room temperature over 3 hours, at the end of which it is concentrated. The residual oil is triturated in ether to obtain the crude 1,4-dimethyl-5-methane-thiolacetate-1,2,4-triazolium trifluoromethanesulfonate which is used directly (1.46 g).

A solution of sodium hydroxide (512 mg, 12.8 millimoles) in water (5 ml) is added to an ice-cold solution of the triazolium salt (1.45 g, 4.35 mil- CD.MJ - 89 - limoles) in water (5 ml). After 45 minutes, the solution is diluted to 25 ml with water and the pH is adjusted to 7.6 with solid potassium dihydrogen phosphate. This solution is added to an ice-cold stirred solution of enol phosphate (2.00 g, 3.45 mmol) in THF (25 ml). After 30 minutes, the reaction mixture is poured into an autoclave containing ether (40 ml) and 10% palladium on carbon "(2.0 g). The hydrogenation is carried out (3.10 bars) for 1.25 hours, the reaction mixture is then diluted with ether (25 ml) and filtered, the organic phase is separated and washed with water (2 × 5 ml). ether (3 x 25 ml) the mixture of aqueous phases which are then concentrated under vacuum, by column chromatography (phase inversion, 45 mm x 130 mm, water as eluent), then lyophilization of the fractions containing the carbapenem, 650 mg of the crude compound are obtained, which is rechromatographed in order to obtain, in the purity state, the title product (450 mg, 39%): 1H NMR (D20) 6: 1.24 (3H, d, J = 6.4 Hz), 3.19 (2H, dd, J = 2.6, 9.2 Hz), 3.45 (1H, dd, J = 2.8, 6.0 Hz), 3, 91 (3H, s), 4.06 (3H, s), 4.08-4.36 (2H, m), 4.54 (2H, d, J = 2.8 Hz), 8.71 (1H , s); IR (Nujol) 1755 cm UV (phosphate buffer, pH 7.4) Amaj {: 294 nm (£ = 8202); (phos buffer phate, pH 7.4, M = 0.067, T = 37 ° C) 9.1 h.

EXAMPLE 6 (1'R, 5R, 6S) 3 - [(1,3-Dimethyl-5-tetrazolium) methylthio] - 6- (l-hydroxyethyl) -7-oxo-l-azabicyclo [3.2.0] hept- 2-ene-2-carboxylate CD.MJ - 90 - A. 5-Carbethoxy-2-methyltetrazole and 5-carbethoxy-1-methyltetrazole “Λ.

J Ve0: “- <£ V2S0“

AT

N "\ // ° rV / LH * * λ / ^ ν.

\ h “3 3 la. Diazomethane methylation

A solution of 5-carbé-thoxytétrazole (9.17 g, 0.064 mol; D. Moderhack, is cooled to 0 ° C.

Chem. Ber., 108, 887 (1975)) in ethyl ether (80 ml) (a mixture of ethanol and ether gives the same ratio of isomers) and a solution of it is added dropwise over 15 minutes. diazomethane (3 g, 0.071 mole) in ether (200 ml). The pale yellow solution is stirred for 30 minutes, then the excess diazomethane is destroyed by adding acetic acid (1 ml).

By evaporation of the solvent and distillation of the residue, a clear oil is obtained: P.Eb. 95-100 ° C / 0.66 mbar, 9.64 g, (96%). The NMR spectrum of indicates that the 1-methylated isomer and the 2-methylated isomer form a CD.MJ - 91 - mixture in the ratio 6: 4. The separation of the two isomers appears impossible by distillation and by HPLC: IR (film)> 7: 1740 cm 1 (C = 0 of ester); 1 m ax H NMR (CDClg) &: 1.53 (3H, two overlapping t, J = 7.0 Hz, CH2ÇH3), 4.46 and 4.53 (3H, 2s, CH3 of 1-methyltetrazole and 2- methyltetrazole, ratio 6: 4.

The methyl radical of the 2-isomer is weaker and corresponds to the minor product), 4.5 ppm (2H, two overlapping qs, CH ^ CH,). lb. 5-Carbethoxy-2-methyltetrazole

It VWjEt + I} r COjEt W'.n / VCBj aj

CB I

- —► ï cort 13 cha- /

A mixture of 5-carbethoxy-2-methyltetrazole and 5-carbethoxy-1-methyltetrazole (0.252 g, 1.61 millimole, 1: 1 ratio of the two isomers) in 11iodomethane is sealed in a glass tube. , 5 ml) and heated to 100 ° C for 15 hours and 130 ° C for 6 hours. By distillation of the reaction mixture, the title compound is obtained in the form of a pale yellow oil: 0.139 g (55%), P.Eb. 95-100 ° C / 0.66 mbar (air bath temperature): IR (film): 1740 cm "1 (C = 0 ester);. Max NMR (CDC13) <5: 1.46 ( 3H, t, J = 7.0 Hz, CH3CH2), 4.53 (3H, s, CH3-2), 4.5 (2H, q, J = 7.0 Hz, CH2CH3).

CD.MJ - 92 - 2. Methylation with dimethyl sulfate

Anhydrous potassium carbonate (1.38 g, 0.01 mole) and dimethyl sulfate (1.26 g, 0.01 mole) are added to a solution of 5-carbethoxytetrazole (1.42 g, 0.01 mole) in dry acetone (20 ml).

The mixture is heated at reflux for 12 hours. The carbonate is filtered and the solvent is evaporated off under reduced pressure. The residue is diluted with dichloromethane (30 ml), washed with saturated sodium bicarbonate (10 ml) and brine (10 ml), then dried over anhydrous sodium sulfate. By evaporation of the solvent and distillation under vacuum, 1.45 g (93%) of a clear oil are obtained; P.Eb. 85-110 ° / 0.66 mbar. The NMR spectrum of indicates the presence of two isomers in a ratio of 1: 1.

B. 5-Hydroxymethyl-2-methyltetra2ole 1 CD.MJ - 93 -

By reducing the mixture of esters

Cool a mixture of 5-carbethoxy-1-methyltetrazole and 5-carbethoxy-2-methyltetrazole (6: 4 ratio) (7.60 g, 0.049 mol) in dry tetrahydro-furan (50 ml) to 0 ° C. and gradually added thereto, over 15 minutes, lithium borohydride (1.06 g, 0.049 mole).

The mixture is stored at 10 ° C for another 30 minutes, then stirred at 20 ° C for 4 hours. The mixture is cooled to 0 ° C. and the excess hydride is carefully destroyed by adding 6N HCl (pH 7 at the end of the evolution of gas). The solvent is removed in vacuo and the residual oil is diluted with dichloromethane (200 ml), the solution is washed with brine (10 ml) and finally dried over Na2SO4. By evaporation of the solvent and distillation of the residue under reduced pressure, 1.83 g (33%) of a clear oil is obtained.

The XH NMR spectrum indicates that the product is 5-hydroxymethyl-2-methyltetrazole.

2. By reduction of 5-carbethoxy-2-methyltetrazole Solid lithium borohydride (0.019 g, 0.87 millimole) is added to a solution of 5-carbetho-xy-2-methyltetrazole (0.139 g, 0.89 millimole, obtained by isomerization of the mixture of esters with methyl iodide) in dry tetrahydrofuran (1 ml) at 10 ° C.

The mixture is slowly warmed to room temperature and stirred for 4 hours. The excess borohydride is destroyed by careful addition of 6N HCl at 0 ° C (pH 7). The solvent is removed by evaporation and the residue is dissolved in dichloromethane (25 ml), then the solution is dried over anhydrous sodium sulfate. By evaporation of the solvent, the title compound is obtained in the form of a clear oil: 0.092 g (91%); P.Eb. 90-120 ° C / 0.66 mbar with decomposition; IR (filmW: 3350 cm-1 (large, OH); ·> max iH NMR (CDC13) <5: 4.4 (2H, s, CH3-2), 4.93 (2H, s, CH2-5) .

C. 5-Acetylmercaptomethyl-2-methyltetrazole 1) hisCl, Et N ^ IV "^

Methanesulfonyl chloride (1.47 g, 12.9 mmol) is added, then triethylamine (1.30 g, 12.9 mmol) dropwise over 5 minutes to a solution of 5-hydroxymethyl-2-methyltetrazole (1.83 g, 11.7 millimoles) in dry dichloromethane CD.MJ - 94 - (25 ml) at 0 ° C. The mixture is stirred at 0 ° C for 1 hour, then a solution of potassium thioacetate (1.60 g, 14.0 millimoles) in dry N, N-dimethylformamide (10 ml) is added thereto. The resulting gel is stirred at 0 ° C for 3 hours. The reaction mixture is diluted with dichloromethane (200 ml), washed with brine (20 ml) and dried over anhydrous sodium sulfate. By evaporation of the solvent under vacuum and chromatography of the resulting oil on silica gel (2 cm × 15 cm, elution with dichloromethane and with dichlo- - romethane-acetone 5%), in the form of 'a clear oil, the title compound: 1.31 g (65%); IR (film) O: 1696 cm- ^ (C = 0 thioester); . max π NMR (CDClg) &: 2.43 (3H, s, SAc), 4.36 (3H, S, 2-CH3), 4.38 ppm (2H, s, 5-0 ^).

D. 5-Mercaptomethyl-1,3-dimethyltetrazolium trifluoromethanesulfonate CF, S0, CH- I A — CH ^ SAc -2—3— α3 CH _ ..0 ^ / 3 σ3δ03

Ma ° ^ Î ^ V-CHSH

Methyl trifluoromethylsulfonate (0.76 g, 4.64 millimoles) is added to a solution of 5-acetylmercaptomethyl-2-methyltetrazole (0.400 g,

2.32 millimoles) in dry dichloromethane (3 ml) which is stirred at 22 ° C for 16 hours. By evaporation of the solvent under vacuum, a red oil is obtained. This salt is dissolved in cold oxygen-free water (5 ml) and 4N sodium hydroxide (0.8 ml, 3.2 millimoles) is added thereto. The mixture is stirred at 0 ° C.

CD.MJ - 95 - for 40 minutes, it is diluted with water (7 ml) and the pH is adjusted to 7.3 using saturated KE ^ PO ^. The resulting clear solution is stored under nitrogen and used immediately in the next step.

E. (11R, 5R, 6S) 3 - [(1,3-Dimethyl-5-tetrazolium) methyl-thio] -6- (1-hydroxyethyl) -7-oxo-1-azabicyclo [3.2.0] -hept-2 -ene-2-carboxylate

- OH

.

+ CO PNB Œ3 Ο CH CF n / a '”' \ 3 3 3 0-“ ”"

OH

H, Pd / C 3 —-

CoP ^ 3 2

A solution of enol phosphate (0.915 g, 1.58 millimole) in tetrahydrofuran (8 ml) is cooled to 0 ° C. and a solution of 5-mercaptomethyl-1,3 trifluoromethanesulfonate is added dropwise to it. -dimethyltetrazolium (2.32 millimoles, prepared above) in 20 minutes. The pH of the reaction mixture CD.MJ - 96 - is stable at 6.5 during the addition. After another 20 minutes, the pH of the solution is adjusted to 7.0 using saturated sodium bicarbonate. The mixture is introduced into a hydrogenation reactor, diluted with THF (10 ml), ether (20 ml) and ice (20 g). The carbapenem is hydrogenated over 10% palladium on activated charcoal at 3.10 bars, gradually raising the temperature to 22 ° C in 90 minutes. The catalyst is filtered and washed with cold water (5 ml) and ether (20 ml). The aqueous phase is washed with ether (20 ml) and kept under vacuum for 20 minutes to remove traces of organic solvent. By chromatography on PrePak 500-C / 18 and elution with water, one obtains, after lyophilization, in the form of a white powder, 0.266 g of the title compound (49%); [oU * 3 + 13 ° (c 1.04, H2O); UV (H2O, pH 7.4); * max: 294 nm (C = 7,500).

IR (KBr)> 3: 1755 (C = 0 β-lactam), 1600 cm -1 (wide, C = 0 carboxylate); 1H NMR (D20) 6: 1.24 (3H, d, J = 6.4 Hz, CH ^ CHOH), 3.0- 3.3 (2H, m, H-4), 3.42 (1H, dd, J = 5.8, J = 2.9, H-6), 4-4.2 (2H, m, H-5 and CH3ÇH0H), 4.34 and 4.57 (2 x 3H, 2s, CH ^ -1 and 3 of tetrazole), 4.49 and 4.51 (2H, 2s, CH2S).

The product has a half-life of 10.5 hours at 37 ° C (concentration of 10 M in phosphate buffer pH 7.4).

CD.MJ - 97 - EXAMPLE 7

Preparation of 3- (N-methylpyridine-2-yl-methanethio) -6o (- [l- (R) -hydroxyethyl] -7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate by the "all in one" process 0HH u ÇH, lOj 2H CF, SO® AI-'V © fH3 33

1 / = 0 / N

<y P) BAG

C02PNB X / 1 3 0

CBjCN Cil? (00) 2 Na0H

0eC, 45 min. EtN (iPr) 2 H20 '°° C' 1 h * 1 '! > 0H CH, © T 9 © J, 3 .. CF3S03 o / co2pnb 2 £ pH S y 5-1? 5 THF, H, 0 1 I * CD.MJ - 98 - OH pu n 5 IH2 Pd-C 10 % 5 * C, 2 h.

OH

V CH- 6 h. Preparation of enol phosphate (2)

OH 0H

AtL ^ KJM, / ±> -

0 βΜΒ CO-PNB

COjPNB 2 1 2

Ethyldiisopropylamine (9 millimoles, 1.04 equivalent, 1.57 ml) is added in approximately 2 minutes and dichlorophenyl phosphate (9 millimoles, 1.04 equivalent, 1.87 ml) in approximately 2 minutes to a solution 1_ ketone ice cream (3 g, 8.62 millimoles) in acetonitrile (30 ml). The reaction mixture is stirred for 45 minutes at the end of which the TLC

CD.MJ - 99 - (ethyl acetate, silica gel) indicates the disappearance of the ketone 1_. The solution is diluted with ethyl acetate (60 ml), washed with cold water (2 x 50 ml) and brine, then dried over sodium sulfate and concentrated (temperature bath below 20 ° C) to obtain a foam which is used as it is.

B. Preparation of thiol (4)

CH

Tf © © A * 11 Na ° H / H20 o g,? H3 <sr · 1 i

Nitrogen is bubbled for 5 minutes into an ice-cold aqueous solution of thiacetate 3 ^ (3.31 g, 10 millimoles) which is added dropwise, in about 5 minutes, to an ice-cold solution of sodium hydroxide (1.75 equivalent, 17.5 millimoles, 0.7 g) in water (8 ml). The mixture turns yellow. After 75 minutes under nitrogen, the pH is adjusted to 7.4 using a saturated aqueous solution of KF ^ PO ^. The reaction mixture is diluted with water (15 ml). This aqueous solution of thiol 4 (50 ml, 0.2 millimole / ml) is used as it is.

CD.MJ - 100 - C. Condensation OH 4 'WU ÎBF = V5 "LLf pH 6'5-7'5 ^ ΐο, ΡΝΒ ° *' 1 h * 1 S * CH, 5 co2pnb To an ice-cold solution of the compound ( crude, prepared in A, 8.62 millimoles) in tetrahydro-furan (50 ml), the aqueous solution of thiol 4 prepared in B (5 ml of solution in 5 minutes) is added dropwise. maintains the pH of the reaction mixture in the region of 6.5-7.5 (preferably 7) by addition of a cooled 2N sodium hydroxide solution. The progress of the reaction is observed by TLC (a) on silica gel with ethyl acetate, and (b) Analtech RPSF, CH ^ CN- phase inversion in pH 7 buffer (4: 6).

Finally, 1.15 equivalent of thiol (50 ml of solution) is used. The reaction is complete in 1 hour at 0 ° C and the mixture is used as it is for hydrogenation after adjusting the pH to 7.

CD.MJ - 101 - D. Hydrogenation __T 3.10 bars 8H j9 ch, KJJ THF-H20-ether * CO-, PNB 0 * C, 2 h.

^ f ÇH3 6

The reaction mixture containing compound! 5 (prepared in C) is introduced into a Parr apparatus with THF (10 ml), phosphate buffer (pH 7, 0, IM, 10 ml), ether ( 75 ml) and 10% Pd on carbon (5 g) and hydrogenated at 3.10 bar at 3-10 ° C for 2 hours. The catalyst is then separated by filtration and washed with water (3 x 10 ml), then the pH of the liquid phase is adjusted to 6.2 by careful addition of cold 2N NaOH. Ether is added and the aqueous phase is separated, which is again washed with ether. The aqueous phase is freed from the organic solvent by "bubbling under vacuum, then it is purified on a column

Bondapak C-18 (100 g, 4.5 cm x 13 cm) using cold distilled water. The light yellow fractions containing the product are lyophilized (verification by UV and TLC) to obtain 1.46 g (50%, yield calculated on the basis of the bicyclic ketone) of the compound £, which is a yellow powder.

UV Λ 29 3, £ = 9000,> 271, £ = 11.064.

CD.MJ - 102 - EXAMPLE 8 OH CH- CH- «h H I J ff) I 3

sv / N

οΐ ^ -Χοί ^ Ο) OB 1 * 3 ÇH, CV ° 3® ^ ftr-

C02PNB

O

v ClP (Op) 2 JÇ J5 I? +% Îl ^ cr3so®

Jli_XmW2 foT ^ SH

0 ^ C02PNB

0H CH- -,? H3 λ P

. . 3 @ | J y I, ^ S ^ yNv OP (00) 2 ο C02PNB VVs / ^

CH

OH ÇH, © I 3 rfXw) 0 * - - ^ co © CD.MJ - 103 -

By replacing, in the procedure of Example 7, the ketone intermediate 1 with an equimolar amount of the corresponding y * -methylated intermediate, the above final carbapenem is obtained. EXAMPLE 9 OH CH, ÇH3 P-ieocß

By replacing, in the procedure of Example 7, the ketone intermediate 1 with an equimolar amount of intermediate 10 (corresponding methylated), the above final carbapenem is obtained. EXAMPLE 10

Preparation of (5R, 6S ^) - 3- | [(1,3-dimethylpyridinium-4-yl) methyl] thio] - b- [1- (R) -hydroxyethyl 3-7-oxo-l-azabi- cyclo [3.2.0] hept-2-ene-2-carboxylate (10A) and (4R, 5R, 6S) -3- | [(1,3-dimethylpyridinium-4-yl) methyl] thioj- 6- [ 1- (R) -hydroxyethyl] -4-methyl-7-oxo-l-azabicyclo- [3.2 ♦ 0] hept-2-ene-2-carboxylate (10B) OH r XJ f »CO © ^

10 A R = H

10B R = CH3 CD.MJ - 104 -

A. Preparation of 4-hydroxymethyl-3-methylpyridine CH CH OH

(§R "· ^ 2)

") H, P

The general procedure of Boekelheide (V. Boekelheide, W.J. Linn, JACS, 76, 1286 (1954)) is applied for the preparation of hydroxymethylpyridines. Thus, a solution of 3,4-lutidine (46.0 g, 0.43 mole) freshly distilled in 120 ml of glacial acetic acid is cooled to 0 ° C. and then 64 ml of to 30 is added dropwise %. The resulting solution is heated to 75 ° C (oil bath temperature) for 3 hours. An additional 20 ml of 30% is then added and the heating is continued for 18 hours. Finally, another 20 ml of 30% ® are added and the reaction mixture is kept at 75 ° C. for a further 3 hours. The solution is then concentrated to about 100 ml under the pressure of the water pump, 50 ml of i ^ O are added and the mixture is concentrated to approximately half volume. The resulting mixture is cooled (0-5 ° C) and alkalinized to about pH 10 with cold 40% aqueous NaOH. The mixture is then extracted with (5 x) and the extract is dried (^ 200 ^ +

Na2SO4), then concentrated on a rotary evaporator to obtain a yellow solution. By diluting this solution with hexane, a solid is obtained which is collected by filtration and which is dried under vacuum to obtain 3,4-lutidine N-oxide (48.0 g, 83%), under the shape of an off-white solid.

CD.MJ - 105 -

The N-oxide is gradually added to 60 ml of acetic anhydride and the resulting dark orange solution (water bath) is heated to about 90 ° C for 1 hour. The excess acetic anhydride is then removed by distillation under reduced pressure and the boiling fraction is collected at 90-120eC / 0.13 mbar (39.0 g). By chromatography of this oil (silica gel and ethyl acetate / petroleum ether = 2: 3), pure 4-aceto-toxymethyl-3-methylpyridine (19.0 g, 30%) is obtained in the form of a oil: IR (pure) 1745 cm “1.

The acetate is then taken up in 100 ml of 10% aqueous HCl and the mixture is heated under reflux for 1 hour. The resulting solution is cooled to 0 ° C., it is made alkaline with solid K 2 CO 4 and then extracted with CH 2 Cl 2 (3 × 100 ml). The organic extract is washed (brine), dried (Na2SO 4) and evaporated to obtain 11.0 g of an off-white solid, m.p. 70-72 ° C. This solid is triturated in cold ether to obtain pure 4-hydroxymethyl-3-methylpyridine (9.5 g, 67%) in the form of a white solid, mp 77-80 ° C (mp 81-82eC according to WLF Armarego, BA Milloy, SC Sharma, JCS, 2485 (1972)).

1H NMR (CDC13) 6 8.27, 7.41 (q AB, J = 5Hz, 2H), 8.18 (s, 1H), 5.63 (s 1, -OH), 4.67 (s, CH2), 2.20 (s, CH3); IR (Nujol) 3170 cm “1.

. B. Preparation of 4- (acetylthiomethyl) -3-methylpyridine CH OH CHjSAc "y- - ér" CD.MJ - 106 -

Diisopropylazodicarboxy-late (12.8 ml, 65 mmol) is added dropwise to a mechanically stirred ice-cold solution of triphenylphosphine (17.04 g, 65 mmol) in 250 ml dry THF and the dispersion is stirred resulting at 0 ° C for 1 hour. A solution of 4-hydroxymethyl-3-methylpyridine (4.0 g, 32.5 millimoles) in 100 ml of dry THF is added dropwise to this mixture, then freshly distilled thiolacetic acid * (4.64 ml , 65 milli moles). The resulting mixture is stirred at 0 ° C for 1 hour, then at room temperature for 1 hour to obtain an orange solution. The solution is concentrated (rotary evaporator) and then diluted with petroleum ether. The resulting mixture is filtered and the filtrate is evaporated to obtain an orange oil. By chromatography of this oil (silica gel / hexane, then 10% - ► 50% ethyl acetate-hexane), 7.0 g of an oil is obtained which is distilled (ball tube) to obtain the product pure (6.0 g, 100%) as a yellow oil, P.Eb. (air bath temperature) 95-100 ° C / 0.13 mbar: 1H NMR (CDC13) 6 8.40, 7.20 (q AB, J = 5Hz, 2H), 8.37 (s, 1H ), 4.08 (s, CH2), 2.35 (s, CH3), 2.32 (s, CH3); IR (pure) 1695 cm "\ C. Preparation of 4- (acetylthiomethyl) -1,3-dimethylpyridinium trifluoromethanesulfonate CH2S * e PjSXc © i 3 3 ^ 3 CD.MJ - 107 -

Methyl trifluorome-thanesulfonate (4.60 ml, 40 millimoles) is added dropwise to an ice-cold solution of thioacetate (2.95 g, 16 millimoles) in 10 ml of methylene chloride and the mixture is stirred at 0 ° C under nitrogen for 1 hour.

The reaction mixture is then evaporated to dryness and the residue is triturated in ether. The resulting solid is collected by filtration and dried under vacuum to obtain the product (4.0 g, 72%) in the form of a white solid: 1H NMR (CDClj) 6 8.72 (s, 1H), 8.58, 7.87 (q AB, J = 6Hz, 2H), 4.39 (s, N-CH3), 4.17 (s, CHg), 2.53 (s, CH3), 2.36 (s, CH3); IR (pure) 1700 cm ”· 1 ·.

D. Preparation of (5R, 6S) -3-f [(1,3-dimethylpyridinium- 4-yl) methyl] thio} - 6- [l- (R) -hydroxyethyl] -7-oxo-l-aza -bicyclo [3.2 .0] hept-2-ene-2-carboxylate p ^ SAc

1) KaOH / H ^ O

GL

cr.so.® cOjPkb

3) H2, Pd / C

Xτ-τΛ JHJ ~ S \ Oj ° \ θ CD.MJ - 108 -

The thioacetate (1.40 g, 4 millimoles) is added to an ice-cold solution purged with nitrogen of NaOH (0.324 g, 8 millimoles) in 10 ml of ^ O and the mixture is stirred at 0 ° C. under nitrogen for 1 hour.

After adjusting the pH to 7.2-7.3 using 10% aqueous potassium dihydro-genophosphate, the resulting solution is added dropwise to an ice-cold solution of enol phosphate (1.45 g, 2, 5 millimoles) in 20 ml of THF. The mixture is stirred at 0 ° C for 1 hour and then transferred to an autoclave.

20 ml of ether, 25 ml of 0.1M phosphate buffer (pH 7.4) and 1.4 g of 10% palladium on carbon are added to this mixture. The mixture is hydrogenated at 3.10 bars for 1 hour. The reaction mixture is filtered through a layer of Celite which is then washed with additional ether and phosphate buffer pH 7.4.

The aqueous phase is separated and the residual solvents are removed in vacuo. The resulting aqueous solution is applied to a phase inversion column (Bonda-Pak which is eluted with water, then 10% acetonitrile in water. By lyophilization of the useful fractions, 0 is collected , 9 g of an orange solid. This is rechromatographed with water, then 2% acetonitrile in water as eluent. By lyophilization, pure compound 10A is obtained in the form of a solid yellow (0.25 g, 57%): 1H NMR (D20) 08.55 (s, 1H), 8.53, 7.96 (q AB, J = 6.8 Hz, 2H), 4.30- 3.99 (m, 2H), 4.27 (s, 5H), 3.35 (dd, J1 = 2.8 Hz, J2 = 6.0 Hz, 1H), 3.05 (d, J = 8 , 8 Hz, 2H), 2.50 (s, 3H), 1.23 (d, J = 6.3 Hz, 3H); IR (KBr) 1755, 1590 cm "1; UV (phosphate buffer, pH 7) 295 nm (6 7180).

CD.MJ - 109 - E. Preparation of (4R, 5R, 6S) -3 - {[(1,3-dimethylpyridi-nium-4-yl) methyl] thio} -6- [l- (R) -hydroxyethyl ] -4-methyl- 7-oxo-l-azabicyclo [3.2.0] hept-2-ene-2-carboxylate 0 SH m D (0O) 2PC1 Λ [Α, α, Ρ 'λ ΓαΤ

C02PNB

H ·

3) H2, M / C

J * ^ ^ ° \ o © To an ice-cold solution of this bicyclic ketone (906 mg, 2.5 millimoles) in 10 ml of acetonitrile, diphenyl chlorophosphate (0.544 ml, 2.63) is successively added millimoles), diisopropylethylamine (0.457 ml, 2.63 millimoles) and 4-dimethylaminopyridine (0.3 mg). After 50 minutes, the reaction mixture is diluted with cold ethyl acetate and then washed with cold water and brine. The organic phase is dried (Na2SO 4) and evaporated at room temperature to obtain the enol phosphate in the form of an off-white foam. This foam is taken up in 20 ml of THF, the solution is cooled to -30 ° C under nitrogen and then added with an aqueous thiolate solution [prepared as above from 0.3 g of NaOH (7, 5 millimoles) and 1.3 g of thioacetate (3.76 millimoles) in 10 ml CD.MJ - 110. - of water]. The reaction mixture is stirred at -30 ° C for 30 minutes, then at 0 ° C for 75 minutes and finally transferred to an autoclave containing 20 ml of ether, 30 ml of 0.1M phosphate buffer (pH 7 , 4) and 1.5 g of 10% palladium on carbon. After hydrogenation at 3.10 bars for 1 hour, the mixture is filtered through Celite and the aqueous phase is separated and concentrated in vacuo. The resulting solution is applied to a phase inversion column (BondaPak C18) which is eluted with water. By eluting the useful fractions, 1.2 g of a yellow solid are collected. This is rechromatographed (elution with water and 4% acetonitrile in water) to obtain, after lyophilization, pure compound 10B in the form of a yellow solid (250 mg, 28%): 1H NMR (D20) 08.53 (s, 1H), 8.49, 7.81 (q AB, J = 6.2 Hz, 2H), 4.38-3.98 (m, 4H), 4, 27 (s, 3H), 3.49-3.18 (m, 2H), 2.51 (s, 3H), 1.25 (d, J = 6.7 Hz, 3H), 1.16 (d , J = 7.6 Hz, 3H); IR (KBr) 1750, 1595 cm-1; UV (phosphate buffer, pH 7) 292 nm (£ 7,930).

EXAMPLE 11

Preparation of (5R, 6S) 3- [(1,6-dimethyl-pyridinium-2-yl) methylthio] -6- (1R-hydroxyethyl) -4R-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate 0H CE.

) 1 c13 'pi -tr A. Trifluoromethanesulfonate of (1,6-dimethylpyridi-nium-2-yl) methylthiol CD.MJ - 111 -

rf ^ r, JSJV

Eth.r L

Οί3 SH. "0- CHj

Methyl trifluoromethanesulfonate (0.74 ml, 6.5 millimoles) is added to a solution of (6-methylpyridin-2-yl) methylthiol acetate (1.0 g, 5.52 millimoles) in ether dry (5 ml) maintained in a nitrogen atmosphere and stirred at 23 ° C for 4 hours. The ether is separated by decantation and the white solid is washed twice with ether (2 ml), then it is dissolved in hydrochloric acid (15 ml, 6N, 90.0 millimoles). The resulting solution was heated to 70 ° C for 4 hours under a nitrogen atmosphere and then concentrated under reduced pressure to a yellow syrup. The traces of hydrochloric acid are removed by codistillation with water (2 x 10 ml). The crude product is purified by chromatography on a phase inversion column (PrePak C-18 2.2 x 13.0 cm) which is eluted with water. The useful fractions are combined and lyophilized to obtain a white powder: 1.43 g, 85.4%; IR (KBr) O: 2565 (SH), 1626 (pyridinium), 1585 (py- m sx ^ ridinium) cm; UV (Ho0) X: 278 (6,7355); z max

Analysis for C9Hi2N03S2F3: calculated C, 35.64; H, 3.99; N, 4.62; S, 21.14% CD.MJ-112 - found, C, 35.49; H, 4.05; N, 4.55; S, 20.99% B. (5R, 6S) 3- [(1, 6-Dimethylpyridinium-2-yl) methyl-thio] -6- (1R-hydroxyethyl) -4R-methyl-7-oxo-l- azabicyclo- [3.2.0] hept-2-ene-2-carboxylate

R

OH JHj 1- (PhO) jPCl rS-rVo JJ / * 3-thiel 0 ^ ^ <· NEt (iPr) j

'COOPNB

OH CHj »» wc εΛ'Γ-τΛ »© .a.

Stamp 7.0 3 J. J // * |? “S |

Ether CT H

THF COO- '

Diphenyl chlorophosphate (0.68 ml, 3.3 millimoles) and diisopropylethylamine (0.57 ml, 3.3 millimoles) are added simultaneously over 10 minutes to a cold solution (5 ° C) of (5R, 6 £) 3,7-dioxo-6- (1R-hydroxyethyl) -4RS-methyl-l-azabicyclo [3.2.0] p-nitrobenzyl heptane-2-R-carboxylate (1.11 g, 3.06 millimoles) R / S: 86/14) in dry acetonitrile (90 ml) maintained> under a nitrogen atmosphere. The cold mixture is stirred (5 ° C) for 1 hour, cooled to -30 ° C and added simultaneously in 15 minutes to a solution of trifluoromethanesulfonate of (1,6-dimethylpyridinium-2-yl) methylthiol (1.03 g, 3.4 millimoles) in dry acetonitrile (2 ml) and diisopropylethylamine (0.59 ml, 3.4 millimoles). The resulting mixture is stirred for 30 minutes at -30 ° C, warmed to 0 ° C and stirred for 1 hour before diluting with cold CD.MJ - 113 - water (35 ml) . The resulting emulsion is poured onto the top of a phase inversion column (PrePak C-18, 2.5 x 18 cm) which is then eluted with a mixture of 25 to 50% acetonitrile in water . By lyophilization of the useful fractions, a sticky yellow solid (1.69 g) is obtained which is dissolved in wet t-trahydrofuran (40 ml). Ether (70 ml), potassium dihydro-genophosphate-sodium hydroxide buffer (pH 7.0, 0.2M, 50 ml) and 10% palladium on carbon (1.69) are added to the resulting solution. g), then the resulting mixture is hydrogenated at 2.90 bar at 23 ° C for 2 hours, after which it is filtered through Celite. The phases are separated and the aqueous phase is washed with ether (2 x 20 ml), then it is concentrated under high vacuum below 23 ° C to 15 ml, after which it is poured on top of a phase inversion column (prePak C-18). By elution with a mixture of 4% acetonitrile in water, one obtains, after lyophilization of the useful fractions, 0.23 g of the title compound in admixture with diphenyl-potassium-sodium phosphate (24 mole%). By further purification on a phase inversion column (PrePak C-18 2.5 cm x 14 cm) with water (400 ml) and a mixture of 10% acetonitrile in water (200 ml) as eluting solvents, 0.17 g (15.3%) of a yellow powder is obtained after lyophilization of the useful fractions; IR (KBr) O: 1750 (C = 0 ß-lactam), 1625 (pyridi-tn ci x ^ ^ nium), 1600 (C = 0 carboxylate) cm; 1H NMR (D20) 6: 1.12 (d, J = 7.2 Hz, CH3 on C-4), i, 24 (d, J = 6.4

Hz, CH3CHOH), 2.80 (s, CH3 on C-6 of pyridinium), 4.18 (CH3 on N

pyridinium), 4.41 (q center AB, CH2S), 7.5-8.4 (H on pyridinium); UV (0.05M buffer, pH 7.0) X: 278 (611.504); ~ _ max -256.4 ° (c 0.22, H2O); = 20.8 hours measured at 37 ° C in buffer (pH 7.4) for a concentration CD.MJ - 114 - -4 10 Μ.

EXAMPLE 12

Preparation of (5R, 6S) 3 - [(1,6-dimethylpyridinium-2- yl) -methylthio] -6- (1R-hydroxyethyl) -7-oxo-l-azabicyclo- [3.2.0 3hept-2-ene -2-carboxylate

BONE

A Ί3 © 0 cbo © A. (5R, 6S) -3 - [(1,6-dimethylpyridinium-2-yl) methylthio] -6- (1R-hydroxyethyl) -7-oxo-l-azabicylo trifluoromethanesulfonate and diphenylphosphate [3.2.0] p-nitrobenzyl hept-2-ene-2-carboxylate

MeOTf 1 3 CD.MJ - 115 -

NaOH ys.

CH

®H 1- (PhO) ^ POCl βΛγΑ. n "" NE ^ lPr) 3 3- Thiol 0 | 4- NEt (iPr)

COOPNS

OH CH

COOPNB 2 2

Diphenyl chlorophosphate (1.37 ml, 6.6 millimoles), diisopropylethylamine (1.15 ml, 6.6 millimoles) are added at a rate such that the temperature is maintained at 5 ° C. (7 to 10 minutes ) and 4-dimethylaminopyridine (6 mg, 0.05 millimole) to a cold solution (5 ° C) of (5R, 6S_) 6- (1R-hydroxy-ethyl) -3,7-dioxo-l-azabicyclo [3.2.0] p-nitrobenzyl heptane-2R-carbo-xylate (2.14 g, 6.14 millimoles) in dry acetonitrile (18 ml) maintained under a nitrogen atmosphere. The mixture is stirred for 1.5 hours at 5 ° C and used as it is, this mixture being hereinafter called "solution A". Methyl trifluoromethylsulphonate (0.85 ml, 7.5 millimoles) is added to a solution of (6-methyl-pyridin-2-yl) methylthiol acetate (1.23 g, 6.8 millimoles) in dry ether (10 ml) maintained under a nitrogen atmosphere and the mixture is stirred for 1.5 hours at 23 ° C. The ether is separated by decantation and the white powder is washed twice with ether (2 x 10 ml), then it is dissolved in water (20 ml).

CD.MJ - 116 -

The resulting aqueous solution is cooled to 0 ° C under an oxygen-free atmosphere and sodium hydroxide (3.4 ml 4N, 13.6 mmol) is added thereto. The mixture is stirred at 2 ° C for 1 hour, then the pH is adjusted to 7.6 by addition of potassium dihydrogen phosphate; this mixture being hereinafter called "solution B".

"Solution B" is added over 0.5 hours to cold "solution A" (5 ° C) while the pH is maintained between 7.25 and 7.35 by adding dropwise a hydroxide solution. sodium 4N. The mixture is stirred for 0.5 hour and applied to the top of a phase inversion column (PrePak C-18 4.0 cm x 18 cm); then the column is eluted with a mixture of 25 to 50% acetonitrile in water. By lyophilization of the useful fractions, the title compound, 2.82 g (51% (PhO ^ PC ^ -, 49%, CF3SO3 ~), 80%; IR ( KBrW: 3700-3000 (OH), 1772 (C = 0 of A-lactam), max 'J' * 1700 (C = 0 of ester), 1625 (pyridinium), 1590 (pyridinium) cm; 1H NMR (DMSO , d-6) 6: 1.15 (d, J = 6.2 Hz, CH ^ CHOH), 2.84 (s, CH3 on C-6 of pyridinium), 4.16 (s, CH3 on N of pyridinium), 4.79 (s, SC ^), 6.6-7.5 [(PhO) 2PO2 ~ ^ · 8.7 (the H's on pyridinium and the H's on the PNB ester).

B. (5R, 65) 3-C (1,6-Dimethylpyridinium-2-yl) methylthio] - 6- (1R-hydroxyethyl) -7-oxo-l-azabicyclo [3.2.0] hept-2-ene- 2-carboxylate οΠ> ^ 0Τσ \ cv ° ®0 .y.ü £ ® (PhO) -PO '“' COOPKB buffer ^ CD.MJ - 117 - OH ch coo '

Ether (50 ml), potassium di-hydrogen phosphate buffer-sodium hydroxide buffer (0.1 M, 40 ml, pH 7.0) and 10% palladium on carbon (0.87 g) are added to a solution of trifluoromethanesulfonate and diphenylphosphate (49:51) of (5R, 6 £ [) 3 - [(1,6-dimé-thylpyridinium-2-yl) methylthio] -6- (lR-hydroxyethyl) -7-oxo-l -azabicyclo [3.2.0] p-nitrobenzyl hept-2-ene-2-carboxylate (0.87 g, 1.27 millimole) in wet tetrahydrofuran (50 ml). The mixture is hydrogenated at 2.48 bars at 23 ° C for 2 hours and filtered through a layer of Celite. The two phases are separated and the aqueous phase is washed with ether (2 x 15 ml), concentrated under high vacuum to 30 ml and poured onto the top of a phase inversion column (PrePak C -18, 2.2 cm x 13 cm). The column is eluted with water. The useful fractions are combined and lyophilized to obtain 0.179 g (40%) of a yellow powder; IR (KBr) X: .1755 (C = 0 β-lactam), 1628 (pyridi-m sx ^ nium), 1590 (C = 0 carboxylate) cm-: 1H NMR (D20) 6: 1.25 ( d, J = 6.4 Hz, CH ^ CHOH), 2.82 (s, CH2 on C-6 of pyridinium), 3.12 ("dd", J = 9.2 Hz, J = 2.9

Hz, H-4), 3.39 (dd, J = 6.0 Hz, J = 2.8 Hz, H-6), 3.7-4.4 (CH ^ CHOH, H-5- CH ^ on N of pyridinium), 4.48 (s, CH2S), 7.6-8.4 (the H on pyridinium); UV (Η90) · χ: 279 (£ 9,628) with shoulder at 296;

Law II D 55.0 ° '(c 0.63, ^ 2® ^' ^ 1/2 = ^, 5 hours measured -4 to 37 ° C in pH 7.4 buffer at a concentration of 10 M. CD. MJ - 118 -

Claims (5)

2. Method according to claim 1, characterized in that the base is sodium hydroxide. 3. Method according to claim 1, characterized in that the reaction is carried out at a temperature of about -15 to + 15 ° C. 4. Method according to claim 1, 2 or 3, characterized in that the leaving radical L is a chloro, bromo, iodo, benzenesulfonyloxy, p-to-luenesulfonyloxy, p-nitrobenzenesulfonyloxy, methane-tallow onyloxy, trifluoromethanesulfonyloxy, diphenoxyphos- radical phinyloxy or di (trichloroethoxy) phosphinyloxy. 5. Method according to claim 1, 2 or 3, CD.MJ - 125 - characterized in that the leaving radical L is a diphenoxyphosphinyloxy radical. 6. Process for the preparation of a compound of formula R15 w SI Λ \ 05 ai / ysch2 — rJ-R CK N ^ coo0 15 where R represents a hydrogen atom or methyl radical and ~ 0®1 represents a radical of formula „5 r2 CD.MJ - 126 - 6 7 where R represents a C ^ -C4 -alkyl radical and R and R each independently represent a hydrogen atom or a C ^ -C ^ -alkyl radical, or a salt or a pharmaceutically acceptable ester of this compound, 2 characterized in that an intermediate of formula “is reacted. f λJA · 1 st N ^ coor2 '\ 15 where L represents a conventional leaving radical, R is as defined above and R represents a protective radical of the classic carboxyl function and easy to remove, with a thiol of formula <? - *> / ,, HS-CH .--- j- R 5 6 7 where R, R and R are as defined above, in an inert solvent and in the presence of a base to form a carbapenem of formula R15 OH H, - N kC00R2 'i ς y «where R, R and" 0'rS are as defined above and, if the thing is CD.MJ - 127 - 2' desired, the protective radical is eliminated R to obtain the corresponding deprotected carbapenem or a pharmaceutically acceptable salt thereof J CD.MJ - 128 -