CS261240B2 - Method of carbapeneme derivatives production - Google Patents

Abstract

Disclosed is a new and more efficient process for producing carbapenem antibiotic derivatives having a 2substituent of the general formula <IMG> in which A represents a C1-C6 straight or branched chain alkylene group; R5 represents an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl, araliphatic, heteroaryl, heteroaraliphatic, heterocyclyl or heterocyclyl-aliphatic radical; and <IMG> represents a nitrogen-containing aromatic heterocycle attached to the alkylene group A at a ring carbon atom and quaternized by substituent R5.

Description

The present invention relates to a novel process for the preparation of carbapenem antibiotics bearing a substituent of the formula EMI2.0 wherein:

represents a straight or branched alkylene group having 1 to carbon atoms,

represents an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl, araliphatic, heteroaryl, heteroaraliphatic, heterocyclyl or heterocyclyl-aliphatic residue and represents a nitrogen-containing aromatic heterocycle attached to alkylene group A via a ring carbon atom and quaternized with a substituent.

Choung J. Kim has described the preparation of carbapenem antibiotics of formula I wherein:

(AND)

R 0 represents a hydrogen atom; represents a radical selected from the group consisting of hydrogen and optionally substituted alkyl, alkenyl and alkynyl groups having 1 to 10 carbon atoms, cycloalkyl and cycloalkylalkyl groups having 3 to 6 carbon atoms in the cycloalkyl portion having 1 to 6 carbon atoms in the alkyl portion, phenyl group, aralkyl, aralkenyl and aralkynyl groups wherein the aryl moiety is a phenyl moiety and the aliphatic moiety contains 1 to 6 carbon atoms, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl groups wherein the heteroatom or heteroatoms are selected from one to four oxygen, nitrogen, and and wherein the alkyl moiety attached to the heterocyclic radical contains from 1 to 6 carbon atoms, wherein said substituent or substituents of the above-mentioned radicals are selected from the group consisting of alkyl groups of 1 to 6 carbon atoms, optionally substituted with amino, halogen, hydroxy a hydroxyl group or a carboxyl group, halogen atoms, radicals of the formula

-OR ³ ,

O

II 3 4

-OCNR ^J R ⁴

O

II 3 4 -CNR 4 R 3

O

II 3 4 -NHCNR R

3II

R CNR

-what ₂ r ³ = 0

O

H 3 • 0CR ^J

II -SR

II -SR

II о

-CN

О зР

-NR S-R 11 O

-OP (O) (OR ³⁾ (OR ⁴⁾

4

-nr ^j co ₂ r ·

-N ° 2 in which

R ³ and R ⁴ are each independently hydrogen, alkyl, alkenyl or alkynyl of 1 to 10 carbon atoms, cycloalkyl, cycloalkylalkyl or alkylcycloalkyl of 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl a phenyl, aralkyl, aralkenyl or aralkynyl group wherein the aryl moiety is a phenyl moiety and the aliphatic moiety contains 1 to 6 carbon atoms, a heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl group wherein the heteroatom or heteroatoms are selected from one to four atoms oxygen, nitrogen and sulfur and the alkyl moiety attached to the heterocyclic moiety contains 1 to 6 carbon atoms, or

R ³ and R ⁴ together with the nitrogen atom to which at least one of these residues is attached form a five- or six-membered nitrogen-containing heterocyclic ring, and

R is as defined above for R except hydrogen, or together form an alkylidene group of 2 to 10 carbon atoms, optionally substituted by a hydroxyl group, r5 is an optionally substituted alkyl, alkenyl or alkynyl group containing from 1 to 10 carbon atoms, a cycloalkyl or cycloalkylalkyl group C 3 -C 6 cycloalkyl and C 1 -C 6 alkyl, aralkyl, aralkenyl or aralkynyl wherein the aryl moiety is a phenyl moiety and the aliphatic moiety contains 1 to 6 carbon atoms, a heteroaralkyl, heterocyclyl or heterocyclylalkyl moiety; wherein the heteroatom or heteroatoms in the heterocyclic radicals are selected from the group consisting of 1 to 4 oxygen, nitrogen and sulfur atoms, and the alkyl moiety attached to the heterocyclic radical contains 1 to 6 carbon atoms, wherein the abovementioned optionally substituted radicals R ⁵ are one to three substituents independently selected from the group consisting of alkyl groups of 1 to 6 carbon atoms, optionally substituted with amino, fluorine or chlorine, carboxyl, hydroxy or carbamoyl, fluorine, chlorine and bromine, radicals of the formula

-oco ₂ y ³

-OCOR ³

-OCONR ³ R ⁴

O

-oxo

4 -NR ^J R

R ° C0NR 34

-NR COjR

4

-NR CONR R

O

-s ° ₃ ^r3

-co ₂ r ^3v

4

-CONR ^J R

-CN or phenyl, optionally substituted with one to three substituents selected from the group consisting of fluorine, chlorine and bromine atoms, 3 to 43 alkyl groups of 1 to 6 carbon atoms, -OR, -NR R,. -SO-R,

93

-CO-R and -CONR R, wherein R, R and R in the R substituents are as defined above, or R ⁵ may be attached to the residue.

o ⁺ at another ring position to form a fused heterocyclic or heteroaromatic ring system, which may contain additional heteroatoms selected from oxygen, sulfur and nitrogen, R 15 represents a hydrogen atom or an optionally substituted C 1 -C 10 alkyl, alkenyl or alkynyl group C 3 -C 6 cycloalkyl, cycloalkylalkyl or C 3 -C 6 alkylcycloalkyl, C 1 -C 6 alkyl, spirocycloalkyl C 3 -C 6, phenyl, aralkyl, aralkenyl or aralkynyl wherein the aryl moiety is phenyl the residue and the aliphatic moiety contains 1 to 6 carbon atoms, a heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl group, wherein the heteroatom or heteroatoms in the above heterocyclic moieties are selected from the group consisting of 1 to 4 oxygen, nitrogen and sulfur atoms, and alkyl the moieties attached to these heterocyclic moieties contain 1 to 6 carbon atoms, wherein the substituent or substituents of the above radicals are selected from the group consisting of amino, mono-, di- and trialkylamino, hydroxyl, alkoxy, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chloro, bromo and fluoro, cyano and carboxyl, wherein the alkyl moieties in the above substituents contain 1 to 6 carbon atoms,

A represents a straight or branched alkylene group having 1 to 6 carbon atoms,

R is a hydrogen atom, an anionic charge, or a conventional, easily cleavable carboxyl protecting group, provided that when R is a hydrogen atom or a protecting group, a charge balancing ion is also present, and is an optionally substituted mono-, bi-, or polycyclic aromatic heterocyclic radical containing at least one nitrogen atom in the ring, which ring is attached to the remainder A by a carbon atom in the ring and contains in the ring a nitrogen atom quaternized by the group R1, and their pharmaceutically acceptable salts, according to the following reaction scheme:

R ° -L

---------->

(IV)

HS-A - θί

------------->

-X '

(ΙΊ possible cleavage of the protecting group

(AND)

The following modification of the reaction scheme describes a preferred variant of the process described above.

cleavage of the protecting group --------------------->

(II)

соон (На)

(la)

The above process is carried out by reacting the starting material of formula III in an inert organic solvent such as methylene chloride, acetonitrile or dimethylformamide with an approximately equimolar amount of the reagent of formula R ° -L in which L is a corresponding leaving group such as toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, diphenoxyphosphinyloxy or other known and commonly used leaving groups such as p-toluenesulfonic anhydride, p-nitrobenzenesulfonic anhydride, 2,4,6-triisopropylbenzenesulfonic anhydride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, , toluenesulfonyl chloride, p-bromobenzenesulfonyl chloride and the like. The reaction for introducing the leaving group into the 2-position of the intermediate of formula III is preferably carried out in the presence of a base such as diisopropylethylamine, tri ethylamine, 4-dimethylaminopyridine and the like, at a temperature of about -20 ° C to +40 ° C, most preferably at about 0 ° C.

The leaving group L in the intermediate of formula (IV) may also be a halogen which is introduced by reacting the intermediate of formula (III) with a halogenating agent such as (CgHg) ₃ -Cl ₂ , (C ₆ H ₅ ) ₃ PBr ₂ , (C ₆ H). ₅ O) ₃ PBr ₂ , oxalyl chloride and the like, in a solvent such as dichloromethane, acetonitrile, tetrahydrofuran and the like, in the presence of a base such as diisopropylethylamine, triethylamine, 4-dimethylaminopyridine and the like. for the next reaction step without isolation or purification.

In the next step, the intermediate of formula (IV) is converted into the intermediate of formula (II) by conventional substitution reaction. Thus, the intermediate of formula (IV) may be reacted with approximately an equimolar amount of a heteroaralkylmercaptan of the formula

HS-A'-Q1 in which

AND

O represents a straight or branched C1-C16 alkylene group and represents a mono-, bi- or polycyclic aromatic heterocycle containing a ring-quaternizable nitrogen, which heterocycle is attached to the residue A via a ring carbon atom, in an inert organic solvent such as dioxane , dimethylformamide, dimethylsulfoxide or acetonitrile, in the presence of a base such as diisopropylethylamine, triethylamine, hydrogen 261240 sodium carbonate, potassium carbonate or 4-dimethylaminopyridine. The temperature in this substitution reaction is not critical, but is preferably operated at a temperature in the range of about -40 ° C to 25 ° C. Most conveniently, the reaction is carried out under cooling, for example at a temperature of about 0 ° C to -10 ° C.

The quaternization of the nitrogen atom in the ring of the heteroaralkyl radical of the intermediate of formula II is carried out by reacting the intermediate of formula II in an inert organic solvent with at least an equivalent amount (up to about 50% molar excess) of the alkylating agent of formula

in which

X 'is as defined above and represents a conventional leaving group such as a halogen atom (bromine or iodine chlorine, most preferably iodine) or an ester of the corresponding sulfonic acid ester, such as the methanesulfonic, toluenesulfonic or trifluoromethanesulfonic acid ester residue.

Examples of suitable non-reactive organic solvents for this reaction include chloroform, methylene chloride, tetrahydrofuran, dioxane, acetone, dimethylsulfoxide and dimethylformamide. The reaction temperature in this alkylation is not critical. Preferably, the temperature is from about 0 ° C to 40 ° C, most preferably at room temperature.

The intermediate of formula I * contains a balancing ion X '(derived, for example, from the alkylating agent used), which can be replaced at this stage or a later reaction stage, i.e., after deprotection, with another balancing ion, such as a pharmaceutical ion. more acceptable. This replacement is carried out in the usual manner. Alternatively, the balancing ion may be removed during the deprotection.

*

The R-protecting group of the carboxyl function in the compound of formula (I *) can be cleaved by conventional methods such as solvolysis, chemical reduction or hydrogenation. When a protecting group cleavable by catalytic hydrogenation, such as a p-nitrobenzyl, benzyl, benzhydryl or 2-naphthylmethyl group, is used, such an intermediate of formula I * in a suitable solvent such as dioxane, water and ethanol, tetrahydrofuran, aqueous potassium monohydrogen phosphate and isopropanol, and the like, in the presence of a hydrogenation catalyst such as palladium on carbon, palladium hydroxide, platinum oxide, etc., at a temperature of from 0 to 50 ° C for about 0.24 to 4 hours.

hydrogen at a pressure of 0.1 to 0.4 MPa. If R represents, for example, an o-nitrobenzyl group, it can also be cleaved by photolysis. Such protecting groups, such as 2,2,2-trichloroethyl, can be removed by a slight reduction with zinc. The allyl protecting group may be cleaved using a catalyst consisting of a mixture of the palladium compound and triphenylphosphine in a suitable aprotic solvent such as tetrahydrofuran, methylene chloride or diethyl ether. Similarly, other conventional carboxyl function protecting groups may be cleaved by methods known in the art. Finally, as mentioned above, those compounds of formula I * wherein R is a physiologically hydrolyzable ester moiety such as acetoxymethyl, phthalidyl, indanyl, pivaloyloxymethyl, methoxymethyl, and the like can be administered directly to the patient, i.e. without cleavage of the protecting group, since such esters are hydrolyzed in vivo under physiological conditions.

The above described process has some disadvantages. For example, the described process proceeds through several reaction steps, the number of which would be advantageous to reduce. Also, the overall yield of the reaction is very low and the quaternization step is carried out only with the carbapenem compound itself. It would be desirable to have a new process for the preparation of a compound of formula (I) which would:

1) involve fewer reaction steps,

2) gave higher yields,

(3) allow the preparation of a quaternized amine first and then its coupling to the carbapenem nucleus at a later stage of synthesis; and

4) facilitated the preparation of quaternary amine products from a wide variety of amines, i.e. also from sterically hindered amines and amines with low pK 2 values.

Accordingly, the present invention provides a novel process for the preparation of carbapenem derivatives of formula (I)

(I) re which

7 represents a hydrogen atom and represents a radical selected from the group consisting of hydrogen and optionally substituted alkyl, alkenyl and alkynyl groups having 1 to 10 carbon atoms, cycloalkyl and cycloalkylalkyl groups having 3 to 6 carbon atoms in the cycloalkyl moiety having 1 to 6 carbon atoms in alkyl, phenyl, aralkyl, aralkenyl and aralkynyl groups wherein the aryl moiety is a phenyl moiety and the aliphatic moiety contains 1 to 6 carbon atoms, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl groups wherein the heteroatom or heteroatoms are selected from one to one four oxygen, nitrogen and sulfur atoms, and wherein the alkyl moiety attached to the heterocyclic moiety contains 1 to 6 carbon atoms, wherein said substituent or substituents of the above-mentioned moieties are selected from the group consisting of alkyl groups of 1 to 6 carbon atoms optionally substituted amino, halogen, hydroxyl or carboxyl, halogen atoms, radicals of the formula

-OR ³ ,

O ti 3 4

-OCNR R

О

O

-S-NR ³ R ⁴ Å

Ь 34 4 -NHCNR ^J R * o

3 ^M 4 1TCNR -co ₂ r ³ = 0

O

II 3 • OCR ^J

-SR ³

O

I 9 • SR *

O ¹¹ 9 SR *

II o

-CN ^N 3 • OSO ₃ R ³

O

9 -OS-R *

II o

-NR ³ SR ⁹ II O

OP (О) (OR ⁴ ) (OR ⁴ )

-NR ³ C = NR ⁴

-nr ³ co ₂ r ⁴

In which

4

R and R are each independently hydrogen, alkyl, alkenyl or alkynyl of 1 to 10 carbon atoms, cycloalkyl, cycloalkylalkyl or alkylcycloalkyl of 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl moiety, a phenyl, aralkyl, aralkenyl or aralkynyl group wherein the aryl moiety is a phenyl moiety and the aliphatic moiety contains 1 to 6 carbon atoms, a heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl group wherein the heteroatom or heteroatoms are selected from one to four oxygen atoms, nitrogen and sulfur and the alkyl moiety attached to the heterocyclic moiety contains 1 to 6 carbon atoms; or

4

R and R together with the nitrogen atom to which at least one of these radicals is attached form a five- or six-membered nitrogen-containing heterocyclic ring, and

is as defined above for R ³ except hydrogen, or together form an alkylidene group of 2 to 10 carbon atoms, optionally substituted with a hydroxyl group, means an optionally substituted alkyl, alkenyl or alkynyl group containing from 1 to 10 carbon atoms each, a cycloalkyl or cycloalkylalkyl group; C 3 -C 6 cycloalkyl and C 1 -C 6 alkyl, phenyl, aralkyl, aralkenyl or aralkynyl wherein the aryl moiety is a phenyl moiety and the aliphatic moiety contains 1 to 6 carbon atoms, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl a group in which the heteroatom or heteroatoms in the heterocyclic radicals are selected from the group consisting of 1 to 4 oxygen, nitrogen and sulfur atoms, and the alkyl moiety attached to the heterocyclic radical contains 1 to 6 carbon atoms, wherein the abovementioned optionally substituted radicals in the R ^{5 is} one to three substituents independently selected from the group consisting of C 1 -C 6 alkyl optionally substituted by amino, fluoro or chloro, carboxyl, hydroxy or carbamoyl, fluoro, chloro, and bromo; formulas

-OCOR ³

-OCONR ³ R ⁴

О ¹¹ 9

-OS-R

II

О

-0X0

R ³ CONR ⁴ -nr ³ co ₂ r ⁴

-NR ³ CONR ³ R ⁴

O

O

S ° ₃ R ^{3 'CO} 2 ^{R 3} CONR ³ R ^4'

-CN or phenyl optionally substituted with one to three substituents selected from the group consisting of fluorine, chlorine and bromine atoms,

3,443 alkyl groups having 1 to 6 carbon atoms, -OR, -NR R, -SO-R,

3 4 3 4 9

-CO ₉ R and -CONR R, wherein R, R and R in the radicals ^{of the} 5 substituents of R are as defined above, or R ³ may be attached to a residue at another ring position to form a fused heterocyclic or heteroaromatic ring system containing up to 10 ring members, which may contain another heteroatom selected from the group consisting of oxygen, sulfur and nitrogen,

represents a hydrogen atom or an optionally substituted (C 1 -C 10) alkyl alkenyl or alkynyl group, a cycloalkyl, cycloalkylalkyl or (C 3 -C 6) cycloalkyl and (C 1 -C 6) alkylcycloalkyl group, a (C 3 -C 6) spirocycloalkyl group , phenyl, aralkyl, aralkenyl or aralkynyl, wherein the aryl moiety is a phenyl moiety and the aliphatic moiety contains 1 to 2

6 carbon atoms, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl, wherein the heteroatom or heteroatoms in the above heterocyclic moieties are selected from the group consisting of: And the alkyl moieties attached to these heterocyclic moieties contain 1 to 6 carbon atoms, the substituent or substituents of the above moieties being selected from the group consisting of amino, mono-, di- and trialkylamino, hydroxyl, alkoxy, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chloro, bromo and fluoro, cyano and carboxyl, wherein the alkyl moieties in the above substituents contain 1 to 6 carbon atoms, AND represents a straight or branched alkylene group having 1 to 6 carbon atoms, R ² means a hydrogen atom, an anionic charge or a conventional readily cleavable carboxyl function protecting group as defined below, provided that: 2 - when R is a hydrogen atom or a protecting group, a charge-balancing ion is also present, and -θ ^{+ _} means a five- or six-membered heteroaromatic ring containing, optionally in addition to the quaternized nitrogen atom, 1 to 3 additional heteroatoms selected from nitrogen and sulfur, optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl groups of 1 to 4 carbon atoms, optionally substituted with phenyl, C 1 -C 4 alkoxy, carboxyl, and carbamoyl, the ring of which is bonded to the remainder of A by a ring carbon atom and contains a nitrogen atom quaternized with R 1 in the ring,

and pharmaceutically acceptable salts thereof, characterized in that it is an intermediate of general formula (I)

of formula IV · F - yV ^L # ^ COOR ² in which 0 R ¹ , R ⁸ and R ¹⁵ are as defined above, R ² ' represents a conventional, easily cleavable carboxyl function protecting group; and L means a conventional leaving group such as toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, diphenoxyphosphinyloxy or halogen,

is reacted with a thiol of formula VII

HS-A —θ ⁺ -κ ⁵ _χ in which

A and the radical-1-N ⁺ -R ⁵ are as defined above and (VII)

X represents a balancing anion in which, in an inert solvent and in the presence of a base, to form a carbapenem compound of formula 1 '

COOR ² is as defined above, from which the carboxyl 2 'protecting group is then optionally cleaved.

R to form the corresponding free compound of formula I useful salts.

or a pharmaceutically acceptable function thereof

The present invention also includes intermediates of formula (VII).

Carbapenem derivatives of formula (I) are potent antibacterial agents or intermediates useful in the preparation of such agents.

The compounds of formula I above contain a carbapenem core of the formula

and thus may be named as 1-carba-2-penem-3-carboxylic acid derivatives. Alternatively, the above compounds may be considered to contain the basic structural core of formula *

and to name them as 7-oxo-1-azabicyclo [3.2.0] hept-2-enecarboxylic acid derivatives. Although the invention encompasses compounds with relative proton stereochemistry at both the cis and trans positions 5 and 6, however, preferred compounds have the stereochemistry of 5R, 6S (trans), as is the case with thienamycin.

The compounds of formula (I) may be unsubstituted at the 6-position or substituted at that position by the substituents described above for other carbapenem derivatives.

1

More specifically, R can be a hydrogen atom and R can be a hydrogen atom or one of the substituents mentioned, for example, in published European patent application.

No. 38,869 (see definition Κθ) · Alternatively, R and R together may form an alkylidene group of 2 to 10 carbon atoms or an alkylidene group of 2 to 10 carbon atoms substituted with, for example, a hydroxy group.

The compounds of formula (I) may also be unsubstituted at the 1-position (R ¹⁵ = H) or be substituted at that position by the substituents described previously for other carbapenem derivatives. More specifically, R can be a hydrogen atom or any of the 1-position substituents other than the hydrogen atom described, for example, in European Patent Application Publication No. 54,917 (see the definition of R or R in the cited application) or in U.S. Pat. Preferred substituents other than hydrogen, R ¹⁵ , include C 1 -C 6 alkyl, most preferably methyl, phenyl and C 1 -C 6 phenylalkyl. R @ ¹ is different from hydrogen, may be in either the alpha or beta configuration and the invention includes both the individual alpha- and beta-isomers and mixtures thereof.

The general terms R ¹ , R ⁸ and R ¹⁵ have the following meanings:

a) The aliphatic alkyl, alkenyl and alkynyl groups may have a straight or branched chain of 1 to 10 carbon atoms, preferably 1 to 6 and most preferably 1 to 4 carbon atoms. When these groups form part of more complex substituents, for example cycloalkylalkyl, heteroaralkyl or aralkenyl substituents, in such cases they contain alkyl, alkenyl and alkynyl groups preferably of 1 to 6, most preferably 1 to carbon atoms.

b) Heteroaryl refers to mono-, bi- and polycyclic aromatic heterocyclic groups containing 1 to 4 oxygen, nitrogen or sulfur atoms, preferably five- or six-membered heterocyclic rings, such as thienyl, furyl, thiadiazolyl, oxadiazolyl, triazolyl, isothiazolyl, thiazolyl, imidazolyl, isoxazolyl, tetrazolyl, oxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrazolyl and the like.

c) The term heterocyclyl includes mono-, bi- and polycyclic saturated or unsaturated non-aromatic heterocyclic radicals containing from 1 to 4 oxygen, nitrogen or sulfur atoms, preferably five- or six-membered heterocyclic radicals, such as morpholinyl, piperazinyl, piperidinyl, pyrazolinyl, pyrazolidinyl, imidazolidinyl, imidazolinyl, pyrrolinyl, pyrrolidinyl and the like.

d) Halogens are chlorine, bromine, fluorine and iodine, preferably chlorine, fluorine or bromine.

By a conventional, easily cleavable protecting group of a carboxyl function is meant a known ester group which can be used to protect the carboxyl function during the chemical reactions described below, with which, if desired, it can be cleaved by methods causing no significant destruction of the remainder of the molecule. by chemical or enzymatic hydrolysis, by treatment with chemical reducing agents under mild conditions, by irradiation with ultraviolet radiation or by catalytic hydrogenation. Examples of such ester protecting groups include benzhydryl, p-nitrobenzyl, 2-naphthylmethyl, allyl, benzyl, trichloroethyl, silyl, such as trimethylsilyl, phenacyl, p-methoxybenzyl, acetonyl, o-nitrobenzyl, 4-pyridylmethyl and 1-alkyl groups. up to 6 carbon atoms such as methyl, ethyl or tert-butyl. These protecting groups include those that are hydrolyzed under physiological conditions, such as the pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl groups. Particularly preferred carboxyl protecting groups are a p-nitrobenzyl group which is readily cleaved by catalytic hydrogenolysis and an allyl group which can be cleaved by a tetra (triphenylphosphine) palladium catalyzed reaction.

The above-mentioned pharmaceutically acceptable salts include non-toxic acid addition salts, for example salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid and the like, and salts with organic acids such as maleic acid, acid acetic acid, citric acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid, lactic acid, gluconic acid and malic acid. Compounds corresponding to formula I, in the form of acid addition salts, may be represented by formula (R = hydrogen or a protecting group)

8 ^r1S 4 + V / S-A-θΙ ⁺ -Η ⁵ X ~ O/ ⁴ COOR ^{2 *}

wherein X represents an acid anion. Anion X may be selected to provide a pharmaceutically acceptable salt for therapeutic application, but in the case of the intermediate compounds of formula I, X may also be a toxic anion. In such a case, the ion may subsequently be removed or replaced with a pharmaceutically acceptable anion to form an effective end product suitable for therapeutic use. When acidic or basic groups are present in the radical R @ ¹ or in the substituent R @ ⁵ , the compounds according to the invention can also form suitable salts with bases or acids on these functional groups. These include, for example, acid addition salts for basic groups and salts with metals (e.g., sodium, potassium, calcium and aluminum), ammonium salts and salts with non-toxic amines (e.g., trialkylamines, procaine, dibenzylamine, 1-efenamine, N- benzyl-beta-phenethylamine, N, N'-dibenzylethylenediamine and the like) in the case of acidic groups.

Compounds of formula I in which R represents a hydrogen atom, an anionic charge, or an ester group hydrolysable under physiological conditions, and pharmaceutically acceptable salts thereof, are useful as antibacterial agents. The remaining compounds of formula (I) are valuable intermediates which can be converted to the aforementioned biologically active compounds.

In accordance with a preferred embodiment, compounds of formula (I) are prepared wherein:

1

R represents a hydrogen atom and R represents a hydrogen atom, an ethyl group, a group

CH, OH i

or

OH I сн ₃ сн-.

Preferred compounds of this subgroup are those wherein R ¹ is

OH is CH ₃ CH-, with the most preferred compounds having the absolute configuration of 5R, 6S, 8R.

In accordance with another preferred embodiment, the invention includes compounds of formula I, 18 wherein R and R together form an alkylidene radical of formula

BOY,

The alkylene residue (i.e., substituent A) in the compounds of formula (I) may be straight or branched chain and may contain 1 to 6 carbon atoms. According to a preferred embodiment, those compounds are produced wherein A is (CH ₂ ) _n -, where n is 1 or 2, and in accordance with a particularly preferred embodiment, those compounds in which A is -СН ₂ - .

The alkylene radical A is bonded via a ring carbon atom to the N-substituted quaternized aromatic heterocycle of the general formula:

is preferably an optionally substituted alkyl, C 1 -C 10 alkenyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 3 cycloalkylalkyl group and (1-6C) alkyl, phenyl, (1-6C) phenylalkyl, (2-6C) alkenyl, (2-6C) phenylalkynyl), heteroaryl, heteroaralkyl wherein the alkyl moiety contains 1 to 6 carbon atoms, heterocyclyl or heterocyclylalkyl having 1 to 6 carbon atoms in the alkyl moiety.

The heteroaryl moiety (or heteroaryl moiety of the heteroaralkyl moiety) in the meaning of R ⁵ may be a mono-, bi- or polycyclic aromatic heterocyclic group containing from 1 to 4 oxygen, nitrogen or sulfur atoms. They are preferably 5- or 6-membered heterocyclic rings, such as thienyl, furyl, thiadiazolyl, oxadiazolyl, triazolyl, isothiazolyl, thiazolyl, imidazolyl, isoxazolyl, tetrazolyl, oxazolyl, pyridyl, pyrazinyl, pyrazinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl. The heterocyclyl moiety (or heterocyclyl moiety of the heterocyclylalkyl moiety) of R ⁵ may be a mono-, bi- or polycyclic saturated or unsaturated non-aromatic heterocyclic group containing 1 to 4 oxygen, nitrogen or sulfur atoms. Preferred are 5- or 6-membered heterocyclic rings, such as morpholinyl, piperazinyl, piperidyl, pyrazolinyl, pyrazolidinyl, imidazolidinyl, imidazolinyl, pyrrolinyl and pyrrolidinyl rings.

The radical R ⁵ may be optionally substituted by one to three substituents independently selected from the group consisting of:

(a) alkyl groups having 1 to 6 carbon atoms, optionally substituted with preferably one to three substituents which are amino, fluorine and chlorine atoms, carboxyl, hydroxy or carbamoyl groups, (b) fluorine, chlorine or bromine atoms, (c) ) -OR ³ , (d) -OCO ₂ R ³ , (e) -OCOR ³ , (f) -OCONR ³ R ⁴ ,

O

II 9 (g) residues -O-S-R,

No.

O (h) oxo groups, (i) -NR ³ R ⁴ radicals, (j) R ³ CONR ⁴ -, (k) -NR ³ CO ₂ R ⁴ , (1) NR ³ CONR ³ R ⁴ ,

O

19 (m) -NR-S-R, fl

O (n) -SR ³ , (o) -SOR ⁹ ,

O (p) -SR ⁹ , uo (q) -SO ₃ R ³ , (r) -CO ₂ R ³ , (s) -CONR ³ R ⁴ , (t) -CN, and (u) a phenyl radical, optionally substituted one to three substituents independently selected from the group comprising fluorine, chlorine and bromine, alkyl groups having 1 to 6 carbon atoms, -OR ^3, -NR ³ R ^4, -SO-R ^3, -CO R ³ and _about -CONR ³ R ⁴ , wherein the substituents

4 5 ^

R and R given above for R are independently selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl of 1 to 10 carbon atoms, cycloalkyl, cycloalkylalkyl and alkylcycloalkyl groups of 3 to 6 carbon atoms in the cycloalkyl ring; and 1 to 6 carbon atoms in the alkyl, phenyl, aralkyl, aralkenyl and aralkynyl moiety wherein the aryl moiety is phenyl and the aliphatic moiety contains 1 to 6 carbon atoms, and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl moieties in which heteroaryl and heterocyclyl moieties a group or moiety is as defined above for R ⁵ and the alkyl moieties attached to these heterocyclic radicals contain 3 to 6 carbon atoms, or R and R together with the nitrogen atom to which at least one of these is attached may form five- or 5-carbon atoms; a six - membered nitrogen containing heterocyclic 5 9 3 ring (as is as defined above for R 1, and R is as defined above for R, except hydrogen. The most preferred R @ 1 substituent is C1 -C6 alkyl, in particular methyl.

In addition, R ^5, together with another atom in the ring of the radical

to form a fused heterocyclic or heteroaromatic ring containing up to 10 members, which ring may contain another heteroatom selected from oxygen, nitrogen and sulfur atoms. So grouping

C ^{n +} - ^{r 5} can be, for example, a residue

or

According to a preferred embodiment, compounds of formula (I) in which:

C ^{n +} - ^{r S} represents a radical selected from the group consisting of (a) radicals of the general formula

in which

C 1 -C 6 alkyl;

are independently selected from the group consisting of hydrogen and alkyl of 1 to 4 carbon atoms,

optionally substituted on carbon atoms by one to three substituents independently selected from C 1 -C 4 alkyl, wherein R 0 is C 1 -C 6 alkyl, (c) radicals of formula

R ⁵ 1 R ⁵ RS | R ⁵ 1 R ⁵ I RS AND AND N ^ N ' _ ÍN ^or ° iCJh

which are optionally substituted on carbon atoms by one or two substituents independently selected from the group consisting of alkyl groups of 1 to 4 carbon atoms and wherein R ¹ represents an alkyl group of 1 to 6 carbon atoms, (d) radicals of the formula

which are optionally substituted on a carbon atom in the ring by a C 1 -C ⁶ alkyl group, and wherein R ⁶ represents a C 1 -C 6 alkyl group, (e) a radical of formula

Г ” ⁵ or

X

wherein X is S or NR in which R represents alkyl having 1 to 4 carbon atoms, R ⁶ represents an alkyl group having 1 to 6 carbon atoms and wherein the free carbon ring atoms are optionally substituted by alkyl having 1 to 4 carbon atoms (f) a radical of formula

wherein X is sulfur or NR, wherein R is C 1 -C 4 alkyl, R ³ is C 1 -C 6 alkyl, and the free ring carbon atoms are optionally substituted with C 1 -C 4 alkyl, (g) residues of formula + c

N = N-R ⁵

in which R represents an alkyl group having 1 to 1 carbon atoms.

Or -NR ⁵ R - carbon atoms and R ^w is an alkyl group

In accordance with a particularly preferred embodiment of the process of the invention, compounds of formula (I) in which the moiety is formed are prepared

O ⁺ - ^{r 5} represents a radical of formula

are independently selected from the group consisting of hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, carboxyl and carbamoyl, and is as defined above, preferably being alkyl of 1 to 6 atoms carbon, most preferably methyl.

Within the above preferred embodiment, preferred compounds are those in which A represents a radical ^ ^de j ^e Л integer equal to 1 or 2, most particularly those in which

A is -CH ₂ - and wherein

(A) R and R together form a grouping; or

1 (b) R is hydrogen and R is hydrogen, CH ₃ CH ₂ -,

OH

I or CH ₃ CH-.

1

Particularly preferred are those compounds in which R represents a hydrogen atom and represents

OH the residue CH ₃ CH-, especially compounds with the absolute configuration of 5R, 6S, 8R.

In accordance with another preferred embodiment, the invention provides a process for the preparation of compounds of formula (I), wherein the moiety. —Θ ^ -β ⁵ means a radical of formula (a)

wherein C 1 -C 4 alkyl is most preferably methyl, and

each independently represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms,

represents a (C1-C4) alkyl group, most preferably a radical of formula (b) in which the methyl group is a methyl group;

and

in each case hydrogen or C1-C4alkyl, the radical of formula (c) in which:

R — NN — R ⁵ ~ Έ = Ι

C 1 -C 4 alkyl, most preferably methyl and C 1 -C 4 alkyl or C 1 -C 4 phenylalkyl, the radical of formula (d) wherein:

is C1 -C4 alkyl, most preferably methyl

represents a C1-C4 alkyl group, most preferably a methyl group, or a C1-C4 carboxyalkyl group in the alkyl moiety, the remainder of formula (e)

in which

represents a (C1-C4) alkyl group, most preferably a methyl group and is a (C1-C4) alkyl group, most preferably a methyl group,

represents a C 1 -C 4 alkyl group, most preferably a methyl group, a radical of formula (f) wherein the radical of formula (g)

in which it is an alkyl group having 1 to 4 carbon atoms and

represents a (C1-C4) alkyl group or a radical of formula (h)

in which it is an alkyl group having 1 to 4 carbon atoms and

represents an alkyl group having 1 to 4 carbon atoms.

Within the preferred embodiment described above, those are preferred

A represents a residue '( ^CH 2 ^ n' V 3 ^{е a} number of 1 or 2, compounds in which A represents a group -CH 2 - and wherein the compounds in which and most preferred are those

8 (a) R and R together form a grouping

or where

1 (b) R is hydrogen and R is hydrogen, CH 2 CH 2 -,

OH

I or CH ₃ CH- ./

1

Particularly preferred are those compounds wherein R is hydrogen and R is OH.

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

In accordance with the most preferred embodiment of the process of the invention, those compounds are produced in which the group -O ⁺ ' ^rS represents a radical of the formula (a »ΟΟΟ);

_(d) - '^ З'-снгСНгСНз сн ₃ (e) \ +

CH ₃

CH ₃

CH ₃

AND

CH ₃

(к) CH ₃ CH ₃ (1) С ^Н н з ^ CH _3/7 "W (m) C _with y— ^сн з CH ₃ Μ NN CH ₃ (о) r --- ^CO 2 ~ Jk 1L> 1 CH ₃ (ρ) Г -U ^ • co ₂ ^- (q) / СН ₃ - / Ί *> r ^N сн ₃ (г) сн ₃ —О ⁺ -сн ₃ / ^сн 3 . (8) - ^ У_сн ₃ (t) ^с \ ³ сн ₃ (at) сн ₃ сн ₃ or <| Н ₃ (IN) 1 сн ₃

In this preferred embodiment, preferred compounds are those wherein A represents the residue of ^"Ch 2 ^ n ^{'/ wherein} - the ^number of 1 ° ° or 2, and most particularly those in which A is -CH2- and wherein

8 (a) R and R together form a grouping

or where

1 (b) R is a hydrogen atom and R is a hydrogen atom, CH ^C C ^-,

OH

I or CH ₃ CH-.

1

Particularly preferred are those compounds wherein R is hydrogen and R is

OH is the CHgCH moiety especially of the compounds having the absolute configuration of 5R, 6S, 8R.

of the formula in which it represents a hydrogen atom or a methyl group

R ¹⁵

represents a hydrogen atom, an anionic charge or a conventional readily cleavable carboxyl function protecting group, provided that when R is a hydrogen atom or a protecting group, a sinking ion is also present, and wherein the group -SA- ^ N ⁺ -R ⁵ represents a radical of formula ( (a) (b) (c)

-SCH ₂ -Q-CH 3

-SCH ₂ CH ₂ -_ _SC H ₂ -Z ^ = _N + ^X CH ₃ (d)

(E)

CH ₃ / ^{Ν ±} \\

-sch ₂ ch ₂ —у (£) (g) (h) (i) (j) (k) (l) (m) ' ^{SCH 2--} <Q> ^ CH ₂ CH ₂ CH ₃

(n)

CH ₃ (o)

-SCH ₂

whose HH-NME spectrum (deuterium oxide, δ values) contains signals: 1.23 (3H, doublet, J = 6.4 Hz), 3.12 (2H, quartet quartet, J = 2.7, 6.0 Hz 4.07 to 4.68 (10H, multiplet), the following characteristic J = 1.4, 8.9 Hz), 3.39 (1H, 8.19 (1H, singlet);

(q)

whose 1 H-NMR spectrum (deuterium oxide, δ values) contains signals: 1.23 (3H, doublet, J = 6.4 Hz), 3.15 · (2H, quartet quartet, J = 2.6, 6.0 Hz), 3.95-4.65 (10H, multiplet), the following characteristic J = 3.7, 9.0 Hz), 3.37 (1H, 8.62 (1H, singlet);

(r) (s) (t) (u)

or

(аа)

In accordance with the most preferred embodiment of the invention, compounds of formula I in which the moiety is produced are produced

O ⁺ - ^r5 or

represents a residue

represents a hydrogen atom or a methyl group.

In the above embodiment, preferred are those compounds wherein A is - (CH ₂ ) _n -, wherein n is a number in which A is -CH ₂ -, and wherein

8 (a) R and R together represent a moiety or wherein or 2, and most preferably those

BOY.

\ _C.

(B) R ⁸ is hydrogen and R ³ is hydrogen, CH ₃ CH ₂ -,

OH

I or CH ₃ CH-.

Particularly preferred are those compounds,

Wherein R is hydrogen and R is a group

OH

CH ₃ CH-, and in particular compounds with the absolute configuration of 5R, 6S, 8R.

In the process according to the invention, the formula IV utilizes intermediates corresponding to the general formula

(IV), which are described, for example, in European Patent Publication No. 38,869 and European Patent Publication No. 54,917, and which may be prepared by the general methods described in the cited works. The symbol L represents a conventional leaving group (as defined by X in European Patent Application No. 38,869), such as chlorine, bromine or iodine, benzenesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, methanesulfonyloxy, phosphoromethanesulfonyloxy, trichloromethanesulfonyloxy, triethylsulfonyloxy, triethylsulfonyloxy, triethylsulfonyloxy. A preferred leaving group is diphenoxyphosphinyloxy. The intermediates of formula (IV) are usually prepared in situ by reacting an intermediate of formula (III) wherein:

R ¹ , R ⁸ , R ¹⁵ and R ² with suitable acylation

are as defined above with an agent of formula (III)

R ° -L

A preferred intermediate of formula IV wherein L is diphenoxyphosphinyloxy may be prepared by reacting a ketoester of formula III in an inert organic solvent such as methylene chloride, acetonitrile or dimethylformamide with an approximately equimolar amount of diphenyl chlorophosphate in the presence of a base such as diisopropylethylamine, triethylamine 4-dimethylaminopyridine and the like, at a temperature of about -20 ° C to +40 ° C, most preferably at about 0 ° C. The intermediate may optionally be isolated, but is conveniently used as a starting material for the process of the invention without isolation or purification.

In the process according to the invention, the carbapenem intermediate of formula IV is reacted with a quaternary amine thiol of formula VII

HS - A - VR ⁵ (VII)

X 'wherein the group A · - ^^ N * -R ⁵ has the abovementioned meaning and

X represents a balancing anion.

This reaction is carried out in an inert solvent such as acetonitrile, a mixture of acetonitrile and dimethylformamide, tetrahydrofuran, a mixture of tetrahydrofuran and water, a mixture of acetonitrile and water or acetone, in the presence of a base. The nature of the base does not play a decisive role. Examples of suitable bases include sodium hydroxide, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,5-diazabicyclo [4.3.0] non-5-ene, and trialkylamines with 1 up to 4 carbon atoms in each alkyl moiety, such as triethylamine, tributylamine or tripropylamine. The reaction of the intermediate IV with the thiol VII can be carried out over a wide range of temperatures, for example at -15 ° C to room temperature, but is preferably carried out at a temperature of about -15 ° C to +15 ° C, most preferably at about 0 ° C.

The carbapenem product formed by the reaction of a quaternary amine thiol of formula VII with an intermediate of formula IV contains a balancing anion [e.g. (C 8 H 4 O 4 Pf 4, S 2 or an anion contained in a quaternary thiol) which can be replaced at this stage by another balancing anion, Alternatively, the balancing anion can be removed in the next reaction step to remove the protecting group.If the quaternized carbapenem derivative and the balancing anion form an insoluble product, such a product may be removed from the The reaction mixture crystallizes on its formation and can be isolated in pure form by filtration.

After the formation of the desired carbapenem derivative, the carboxyl protecting group 2 'of the R function in the compound of formula (I') may optionally be cleaved by conventional methods such as solvolysis, chemical reduction or hydrogenation. When a protecting group such as p-nitrobenzyl, benzyl, benzhydryl or 2-naphthylmethyl is cleaved by catalytic hydrogenation, the intermediate of formula (I *) may be used in a suitable solvent such as a mixture of dioxane, water and ethanol, in a mixture of tetrahydrofuran, diethyl ether and a buffer, in a mixture of tetrahydrofuran, an aqueous solution of potassium monohydrogen phosphate and isopropanol and the like, treated with hydrogen at a pressure of 0.1 to 0.4 MPa in the presence of a hydrogenation catalyst such as palladium on carbon, palladium hydroxide, platinum oxide and the like at a temperature of from 0 to 50 ° C for about 0.24 to 4 hours. If '

For example, R represents an o-nitrobenzyl group, such a protecting group can also be cleaved by photolysis. Such protecting groups, such as 2,2,2-trichloroethyl, can be removed by slight reduction with zinc. The allyl protecting group may be cleaved using a catalyst consisting of a mixture of a palladium compound and triphenylphosphine in a suitable aprotic solvent such as tetrahydrofuran, methylene chloride or diethyl ether. Similarly, other conventional protecting groups may be cleaved by methods known in the art. Finally, as noted above, may be compounds of general formula V ^- wherein '

R represents a physiologically hydrolyzable ester moiety, such as an acetoxymethyl group, a phthalidyl group, an indanyl group, a pivaloyloxymethyl group, a methoxymethyl group and the like, to be applied directly to the patient without cleavage of the protecting group since these esters hydrolyze in vivo under physiological conditions.

It will be appreciated that if a radical R ¹ , R ⁸ , R ⁵ or R ¹¹ contains a quaternized heteroaromatic group attached to substituent A, a functional group which may be detrimental to the intended course of the reaction, such a group may be protected by conventional means. and then cleave the protecting group to regenerate the desired functional group. Suitable protecting groups and procedures for introducing and removing these groups are well known in the art.

As with other beta-lactam antibiotics, the compounds of formula (I) may be converted into pharmaceutically acceptable salts by known methods, which are substantially equivalent to non-salt compounds for purposes of the invention.

For example, a compound of formula (I) wherein R is an anionic charge can be dissolved in a suitable inert solvent and an equivalent amount of pharmaceutically acceptable acid is added to the solution, the desired acid addition salt can be isolated by conventional procedures, for example solvent precipitation, lyophilization and the like. If other basic or acidic functional groups are present in the compound of formula (I), the corresponding pharmaceutically acceptable acid addition salts and base addition salts may be prepared by known methods.

A compound of formula I wherein R is a hydrogen atom or an anionic charge, or a pharmaceutically acceptable salt thereof, can also be converted by a conventional method to the corresponding compound wherein R is a physiologically hydrolyzable ester group, or a compound of formula I wherein R is a conventional carboxyl-protecting group may be converted to the corresponding compound wherein R represents a hydrogen atom, an anionic charge, or a physiologically hydrolyzable ester group, or a pharmaceutically acceptable salt thereof.

Certain products within the scope of Formula I may form optical isomers or may exist as mixtures of epimers. It will be appreciated that the invention encompasses all of these optical isomers and mixtures of epimers. For example, when the substituent at the 6-position is a hydroxyethyl group, such substituent may be in either the R or S configuration and the invention includes both these isomers and a mixture of epimers.

Intermediate thiols of formula VII may be prepared, for example, from the corresponding thioacetate of formula wherein A is as defined above and the moiety

-Pn represents a mono-, bi- or polycyclic aromatic heterocyclic radical containing a quaternizable nitrogen in the ring, which ring is bonded to the radical A via a ring carbon atom. The aforementioned thioacetate is quaternized by reaction with a suitable alkylating agent of the formula

in which

is as defined above and represents a conventional leaving group such as a halogen atom (chlorine, bromine or iodine, most preferably iodine) or a sulfonate ester residue, such as a methanesulfonate (mesylate), toluenesulfonate (tosylate) or trifluoromethanesulfonate (triflate) residue in an inert organic solvent as in diethyl ether, dichloromethane, methylene chloride, dioxane, benzene, xylene, toluene or mixtures thereof. The temperature of this alkylation reaction is not critical, preferably at a temperature in the range of about 0 ° C to 40 ° C.

Prior to reaction with the intermediate carbapenem derivative of formula (IV), the quaternized thioacetate is subjected to acidic or basic hydrolysis to give the intermediate quaternary thiol of formula (VII). This hydrolysis is preferably carried out immediately prior to the reaction with the compound of the formula IV in order to minimize the decomposition of the relatively unstable quaternary thiol of the formula VII.

With a suitable choice of solvents, the reaction starting with the intermediate of formula III and ending with the resulting product of formula I can be carried out without isolation of the various intermediates, i.e. in a single reaction vessel. Such a procedure is illustrated below in Example 7.

Carbapenem derivatives of the formula I in which R represents a hydrogen atom, an anionic charge or a physiologically hydrolyzable carboxyl-protecting group, and their pharmaceutically acceptable salts, are effective antibiotics against various gram-positive and gram-negative bacteria and can be used, for example, as animal feed additives. to stimulate growth, as a preservative for food and feed, as bacbaricides for industrial applications, for example in water based and white water based paper based coatings, to inhibit the growth of harmful bacteria, and as a disinfectant to kill or inhibit the growth of harmful bacteria in healthcare and dental equipment. However, the disclosed compounds are particularly useful in the treatment of infectious diseases in humans and other animals caused by Gram-positive and Gram-negative bacteria.

The pharmaceutical compounds produced by the process of the invention can be used alone or can be formulated into pharmaceutical compositions containing, in addition to the active carbapenem component, a pharmaceutically acceptable carrier or diluent. The compounds may be administered by a variety of routes, of which oral, topical or parenteral (e.g., intravenous or intramuscular injection) is of crucial importance.

The pharmaceutical compositions may be in solid form (such as in the form of capsules, tablets, powders, etc.) or in liquid form (such as in the form of solutions, suspensions or emulsions). Formulations for injection, which are preferred preparations, may be presented in unit dosage forms in ampoules or containers containing multiple unit doses, and may contain excipients such as suspending agents, stabilizers and dispersing agents. The compositions may be in ready-to-use form or in powder form, which upon reconstitution is reconstituted with a suitable vehicle, such as sterile water.

The dosage employed depends largely on the active ingredient, the nature of the dosage form, the mode of administration, the condition of the patient, the site of infection and the organism to be controlled. The choice of the appropriate dosage and route of administration is, of course, a matter for the attending physician, but in general, the compounds of the invention may be administered to a mammal in need of treatment at a level of about 5 to 200 mg / kg / day. The total daily dose is generally administered in several divided doses, for example three to four times daily.

The invention is illustrated by the following non-limiting examples.

The abbreviations used in these examples have the following meanings:

M - methyl Et = ethyl Ph - phenyl Ac = acetyl Ms = methanesulfonyl (mesyl) Ts ^with p-toluenesulfonyl (tosyl) Tf ₽ trifluoromethanesulfonyl PNB = p-nitrobenzyl

Example 1

Preparation of 3- [4- (Ν, Ν-dimethyl-1,2,3-triazolium) methylthio] -6-alpha- [1- (R) -hydroxyethyl] -7-oxo-1-azabicyclo [3.2.1] O] hept-2-ene-2-carboxylate

Preparation of isomers

SAc

Me

a) MeOTf

b) aqueous NaOH

To an ice-cooled solution of 590 mg (3.52 mmol) of 4- (methanthiolacetate) -1-methyl-1,2,3-triazole in 2 ml of dry methylene chloride was added dropwise 0.58 ml (5.16 mmol) with stirring under nitrogen. methyl trifluoromethylsulfonate. After 0.5 hour the cooling bath was removed and after 1 hour the solvent was evaporated under reduced pressure. The oily residue was dissolved in a few milliliters of water, cooled in ice, treated with a cold solution of 305 mg (7.59 mmol) of sodium hydroxide in a few milliliters of water and stirred for 0.75 hours. The reaction solution is diluted to 25 ml with water and adjusted to pH 7.5 by addition of solid sodium dihydrogen phosphate monohydrate. 14 ml of this solution (about 1.9 mmol of triazolium thiol) is added to an ice-cooled, stirred solution of 1.0 g (1.72 mmol) of enol phosphate in 10 ml of tetrahydrofuran. The mixture was stirred for 0.75 hours (during this reaction a small amount of crystalline material, probably sodium monohydrogen phosphate) precipitated, and then the resulting suspension was transferred to a pressure vessel using 20 ml of tetrahydrofuran and 20 ml of water. After addition of 30 ml of ether and 1.0 g of 10% palladium-on-carbon, the mixture is hydrogenated for 1 hour at 50 psi, then the organic phase is separated and washed twice with 5 ml of water each time. The combined aqueous phases were filtered, and the filtrate was concentrated under high vacuum (1.5 mm Hg) for 1.5 hours. The residual yellow solution was subjected to medium pressure chromatography on a reverse phase column (35x90 mm), eluting with water. After freeze-drying, 395 mg of a carbapenem derivative is slightly contaminated with some inorganic material. This product after purification by high resolution chromatography (10x300 mm, Microbondapack C-18 column, multiple injections, water as eluent) gave 310 mg (57%) of Isomer A as a red-yellow powder.

1 H-NMR (deuterium oxide, δ in ppm):

1.23 (3H, doublet, J = 6.4 Hz), 3.10 (2H, doublet, J = 9.1 Hz), 3.24 (1H, quartet, J = 2.7, 6.1 Hz) ), 4.03-4.71 (10H, m), 8.46 (1H, singlet).

IR (nujol) 1760 cm ¹

UV (phosphate buffer, pH 7.4, 0.05M):

^X max ^{296 (ε} = ^7,500) '

B. Preparation of isomer V and isomer C (experimental structure)

SAc

a) MeOTf

d) _H2 / Pd-C

To an ice-cooled solution of 1.20 g (7.02 mmol) of 4- (methanthiolacetate) -2-methyl-1,2,3-triazole in 6 ml of dry methylene chloride was added dropwise 1.60 ml (14.0 mmol) of methyltrifluoromethane under nitrogen. sulfonate. The mixture was allowed to warm to room temperature, stirred for 16 hours, then an additional 0.40 mL (3.56 mmol) of methyl trifluoromethanesulfonate was added and after a further 3 hours at room temperature the solvent was evaporated under reduced pressure. The oily residue was triturated with ether, the resulting gum was dissolved in 5 mL of water, cooled in ice, and a solution of 844 mg (21.1 mmol) of sodium hydroxide in 5 mL of water was added. After stirring for 0.75 hours, the reaction solution was diluted to 60 ml with water and adjusted to pH 8 by addition of solid potassium dihydrogen phosphate. 40 ml of this solution (ca. 4.7 mmol of a mixture of isomeric triazolium thiols) was added to the solution while stirring. of an ice-cooled solution of 2.00 g (3.45 mmol) of enol phosphate in 60 ml of tetrahydrofuran, stirred under ice-cooling for a further 0.5 hours, then transferred to a pressure vessel containing a suspension of 2.00 g of 10% palladium on carbon in 60 ml. ml of ether. The resulting mixture was hydrogenated at 50 psi for 1 hour, then the organic phase was separated and washed twice with 10 ml of water each time. The combined aqueous phases are filtered and the filtrate is concentrated under high vacuum (about 5 mm Hg) for 1.5 hours. The residual solution was subjected to medium pressure chromatography on a reverse phase column (45x130 mm), eluting with water. After lyophilization of the eluate, 595 mg of a mixture of isomeric carbapenems contaminated with a small amount of inorganic material is obtained. The above isomeric products were separated and purified by high performance liquid chromatography (Microbondapack C-18 column, 10x300 mm, multiple injection, water as eluent). In the order in which they were washed, the following are obtained:

isomer V in 153 mg (13%);

¹ H-NMR (deuterium oxide, δ in ppm):

1.23 (3H, doublet, J = 6.4 Hz), 3.12 (2H, quartet, J = 1.4, 8.9 Hz),

3.39 (1H, quartet, J = 2.7, 6.0 Hz), 4.07-4.68 (10H, multiplet), 8.19 (1H, singlet).

IR (Nujol): 1755 cm ¹

UV (phosphate buffer, pH 7.4, 0.05M):

λ 296 nm (e = 6700) max

isomer C in 284 mg (24%);

¹ H-NMR (deuterium oxide, δ in ppm):

1.23 (3H, doublet, J = 6.4 Hz), 3.15 (2H, quartet, J = 3.7, 9.0 Hz), 3.37 (1H, quartet, J = 2.6, 6.0 Hz), 3.95-4.65 (10H, m), 8.62 (1H, singlet).

iC (nujol). 1,750 cm ¹ .

UV (phosphate buffer, pH 7.4, 0.05M):

^A max ^{298 nm <ε} = ⁷⁶⁰⁰⁾ ·

Example 2 (5R, 6S) -6- (1R-Hydroxyethyl) -3- (2-methyl-1,2,3-thiadiazolium-4-ylmethylthio) -7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate

A. Ethyl 1,2,3-thiadiazol-4-ylcarboxylate [c. D. Hurd and R.I. Sea, J. Am. Chem.

O

II / N NHCOEt II / ^C \

CHq COEt ³ II o

SOCI ₉ -

O

II

COEt

A solution of 31.2 g (0.154 mol) of ethyl alpha-N-ethoxycarbonylhydrazonopropionate in 80 ml of thionyl chloride was stirred at 23 ° C for 3 hours and then heated at 70 ° C for 20 minutes. The thionyl chloride was evaporated and the residue was triturated four times with 30 ml of hexane each. The resulting red solid was dissolved in 150 mL of dichloromethane, washed with saturated sodium bicarbonate solution and water, dried over sodium sulfate and concentrated until crystallization began. The mixture was allowed to stand for a while at 23 ° C and the crystals were filtered off. 16.8 g of product are obtained. Yield 69%. The filtrate was concentrated and the residue was purified by silica gel column chromatography using dichloromethane as eluent. Yield 3.17 g (13%), m.p. 86 ° C.

IC (KBr technology):

v _v 1,720 (ester) cm max @ 1 H-NMR (CDCl3, .delta. in ppm):

1.52 (3H, triplet, J = 7.1 Hz, CH ₃ CH ₂ O), 4.57 (2H, quartet, J = 7.1 Hz, CH ₃ CH ₂ O), 9.47 (1H , singlet, proton of the thiadiazole residue).

В. 1,2,3-thiadiazol-4-ylmethanol [s. I. Ramsby, S.O. Ogren, S. B. Ross and N. E. Stjernstrom, Acta Pharm. Succica 10,

285-296 (1973); C.A., 79,137,052 W (1973)]

O

To a suspension of 18.35 g (0.116 mol) of ethyl 1,2,3-thiadiazol-4-ylcarbamate (ylate in 400 ml of ether), 2.47 g (0.065 mol) of lithium aluminum hydride was added portionwise over 1 hour. After stirring at 23 ° C, an additional 2.47 g (0.065 mol) of lithium aluminum hydride was added and stirring was continued for 24 hours, followed by the addition of 7 ml of water, 7 ml of 15% sodium hydroxide solution and 21 ml of sodium hydroxide solution. The ethereal solution was extracted five times with 100 ml of ether each time, the ether extracts were combined, dried (MgSO4) and concentrated. The crude product (5.4 g) was purified by chromatography. on a column (4x16 cm) of 120 g of silica gel using ether as the eluent to give 1.3 g (7%) of ethyl 1,2,3-thiadiazol-4-ylcarboxylate and 2.45 g (18%) of 1, 2,3-thiadiazol-4-ylmethanol.

IC (film): _{ν max} 3,380 (OH) cm ^-1 .

¹ H-NMR (CDCl 3, δ ppm):

2.31 (1H, s, OH), 5.22 (2H, s, _CH2 O), 8.50 (1H, s, proton thiadiazole residue).

C.

1,2,3-thiadiazol-4-ylmethanol methanesulfonate

CH ₂ OH

MsCl ^NEt 3

CH ₂ OM $

A solution of 0.75 g (6.5 mmol) of 1,2,3-thiadiazol-4-ylmethanol in 20 ml of dichloromethane was cooled to 5 ° C under nitrogen and treated with 1.018 ml (7.3 mmol) of triethylamine and 0.565 ml. ml (7.3 mmol) of methanesulfonyl chloride. After 15 minutes, the cooling bath was removed and the reaction mixture was stirred for 2 hours. The resulting solution was washed twice with 2 ml of 1N hydrochloric acid solution and water each time, dried over magnesium sulfate and magnesium oxide, and concentrated. The residue was purified by silica gel column chromatography (1.5x21 cm) using ether as the elution solvent. 0.90 g (71%) of 1,2,3-thiadiazol-4-ylmethanol methanesulfonate is obtained. ·

IC (film): v _max 1,350 (SO ₂ ), 1,172 (SO ₂ ) cm ^-1 .

¹ H-NMR (CDCl 3, δ ppm):

3.09 (3H, s, CHP, 5.75 (2H, s, _CH2), 8.72 (1H, s, proton thiadiazole residue).

UV (dichloromethane): R _max 251 (с = 1990).

Analysis for ^C 6 g of ^H 2 ^N ° 3 ^S calculated: 24.73% C, 3.11% H, 14.42% N, 33.02% S; Found: C 24.78, H 3.09, N 14.66, S 31.94.

Further, 0.13 g (19%) of di- (1,2,3-thiadiazol-4-ylmethyl) ether was obtained.

IC (film): _max 1,272, 1,242, 1,200, 986, 805, 728 cm ¹ .

@ ¹ H-NMR (CDCl3) .delta. ₍ S in ppm):

5.16 (singlet, 4H, CH _2), 8.42 (singlet, 2H, protons of the thiadiazole residue).

D. 4-Acetylthiomethyl-1,2,3-thiadiazole

To a solution of 0.90 g (4.6 mmol) of 1,2,3-thiadiazol-4-ylmethanesulfonate in 9 mL of tetrahydrofuran was added 2 mL of aqueous sodium thioacetate solution (prepared from 0.38 mL (5.3 mmol) of thiol acetic acid). of acid and 0.445 g (5.3 mmol) of sodium bicarbonate]. The resulting mixture was stirred at 23 ° C for 1 h, then diluted with 75 mL of ether, washed three times with 3 mL of water each time, and dried over magnesium sulfate, concentrated. The crude product was purified by silica gel column chromatography (1.4x10 cm), eluting with 50% ether in hexane, to give 0.60 g (75%) of the desired product.

IR (film): ν _max 1675 (C = O) cm ^-1 .

¹ H-NMR (CDCl 3, δ ppm):

2.37 (3H, s, _CH3), 4.58 (2H, s, _CH2), 8.44 (1H, s, proton thiadiazole residue).

Analysis: 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-thiadiazolium trifluoromethanesulfonate

CF ₃ SO ₃ Me 1 0 II CH ₂ SCCH ₃ / CF ₃ SO ₃ 0 II CH ₂ SCCH ₃ • t - CF ₃ SO 3

To a solution of 0.60 g (3.44 mmol) of 4-acetylthiomethyl-1,2,3-thiadiazole in a mixture of 4 ml of ether and 0.4 ml of dichloromethane, several crystals of the title compounds are added and over 5 minutes 0.407 ml (3). (6 mmol) of methyl trifluoromethanesulfonate. The reaction mixture was stirred at 23 ° C under nitrogen for 6 hours. The precipitated white solid, which is a mixture of the title compounds, is filtered off and washed with ether. Yield: 1.05 g (90%).

IR (KBr): ^max * (C = 0) cm @ H-NMR (DMSO-d₆, δ values in ppm):

2.43 (3H, s, CH ₃ COS), 3.33 (s, CH ^ on nitrogen in 3-position)

4.57 (singlet, CH ₃ on nitrogen at position 2), 4.66 (2H, singlet, CH ₂ ),

9.55 (proton on nitrogen at position 2 of the thiadiazolium residue), 9.66 (proton on nitrogen at position 3 of the thiadiazolium residue).

H, 2.68; N, 8.28. S, 28.43;

Found: C 24.61, H 2.57, N 8.41, S 28.21.

F., 4-mercaptomethyl-2-methyl-1,2,3-thiadiazolium trifluoromethanesulfonate and 4-mercaptomethyl-3-methyl-1,2,3-thiadiazolium trifluoromethanesulfonate

O

A solution of 1.05 g (3.1 mmol) of a mixture of 4-acetylthiomethyl-2-methyl-1,2,3-thiadiazolium trifluoromethanesulfonate and 4-acetylthiomethyl-3-methyl-1,2,3-thiadiazolium trifluoromethanesulfonate in 10 ml 6N hydrochloric acid was heated to 65 ° C under a nitrogen atmosphere for 1.75 hours. After evaporation of the solvent under reduced pressure, 0.91 g of a yellow-colored syrupy compound is obtained, which is used as is in the following stage without purification.

G. (5R, 6S) -6- (1R-Hydroxyethyl) -3- (2-methyl-1,2,3-thiadiazolium-4-ylmethylthio) -7-oxo-

-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate

10% Pd on carbon -------------> ether, tetrahydrofuran, water

To a cold (5 ° C) solution of 1.7 g (2.92 mmol) of (5R, 6S) -p-nitrobenzyl-6- (1R-hydroxyethyl) -3- (diphenylphosphono) -7-oxo-1-azabicyclo [ 3,2,0] Hept-2-ene-2-carboxylate in 10 ml of tetrahydrofuran is added a solution of 0.9 g of a crude mixture of 4-mercaptomethyl-2-methyl-1,2,3-thiadiazolium trifluoromethanesulfonate and 4-mercaptomethyl- 3-methyl-1,2,3-thiadiazolium trifluoromethanesulfonate in a mixture of 15 ml of 0.3 M phosphate buffer (pH 7.2) and 5 ml of tetrahydrofuran. The reaction mixture was stirred for 1 hour while maintaining its pH at 7.2 with 2N sodium hydroxide solution. Stirring is then continued for 1 hour, then 50 ml of ether, 1 g of 10% palladium on carbon are added and the resulting mixture is hydrogenated at 23 DEG C. under 50 mm Hg for 2 hours. The reaction mixture is filtered through a pad of diatomaceous earth, the organic phase is separated, diluted with 50 ml of ether and 20 ml of 0.3 M phosphate buffer (pH 7.2) and hydrogenated at 350 kPa for 2 hours in the presence of 2 g of 10% palladium on carbon. . The aqueous phases of both the first and second hydrogenolysis were combined, washed with ether and purified by PrepPak 500-C / 18 column chromatography using water as eluent. 0.22 g of crude material is obtained which, after purification by high performance liquid chromatography using water as eluent, affords 0.040 g (4%) of the title compound (after lyophilization).

iC (KBr-technique): v _max 3,400 (wide band, OH), 1,745 (C = O of the beta-lactam group),

580 (carboxylate) cm ^-1 .

1 H-NMR (deuterium oxide, δ in ppm):

1.23 (3H, doublet, J = 6.3 Hz, CH-jCHOH), 3.04, 3.05, 3.16 (2H, multiplet, H-4), 3.38 (1H, double doublet, J = 2.8 Hz, J = 6mHz, H-6), 3.9 to 4.6 (2H, multiplet, H.5, CH ₃ CHOH), 4.51, 4.53 (two singlets, SCH ₂ ), 4.61 (singlet, N ⁺ CH ₃ ).

UV (water): 224 (ε = 4,345), 262 (ε 4 4,980), 296 (ε 6,885).

max [л] ²³ = 18 ° (с = 0.18, water).

- 4 ^T 1/2 ^{= 9.8 hours} * (measured at a concentration of 10 M in phosphate buffer pH 7.4 at 36.8 ° C).

Example 3

Potassium-3- [5- (1-carboxylatomethyl-3-methyl-1,2,3-triazolium) methanthio] -6-alpha- [1- (R) -hydroxyethyl] -7-oxo-1-azabicyclo [3] 2, o] hept-2-ene-2-carboxylate

c) H ₂ / palladium on carbon

To a suspension of 9.00 g (70.9 mmol) of 1-methyl-1,2,3-triazole-4-carboxylic acid [c. Pederson, Acta. Chem. Scand., 1959, £ 3,888] in 200 ml of dry tetrahydrofuran, 2.83 g (70.9 mmol) of lithium aluminum hydride are added in small portions with stirring. After stirring at room temperature for 15 hours, 20 ml of a 20% aqueous sodium hydroxide solution (in portions of about 1 ml) were carefully added. The resulting suspension is filtered and the solid material is washed five times with 75 ml of tetrahydrofuran each time. The combined tetrahydrofurano solutions were dried over magnesium sulfate and the solvent was evaporated. The yellow oily residue was subjected to flash column chromatography (90x35 mm) of silica gel using 100 ml of hexane each time, firstly 1: 1 ethyl acetate / hexane and then 1: 3 then finally ethyl acetate / methanol 9: 1. 1 as eluents. 3.18 g (40%) of 4-hydroxymethyl-1-methyl-1,2,3-triazole are obtained as a colorless oil.

@ 1 H-NMR (CDCl3, .delta. In ppm):

4.07 (3H, singlet), 4.73 (2H, doublet), 7.52 (1H, singlet).

IR (neat): 3320 cm @ -1.

An ice-cooled solution of this alcohol (4.67 mL, 41.3 mmol) and triethylamine (7.47 mL, 53.7 mmol) in methylene chloride (200 mL) was added dropwise with stirring to methanesulfonyl chloride (3.82 mL, 49.6 mmol). After 0.5 hours the solvent was evaporated and the solid residue was taken up in 30 ml of acetonitrile. 7.06 g (62.0 mmol) of potassium thiolacetate was added to the obtained solution, and the suspension was stirred at room temperature for 3 hours. An additional 3.0 g (26.3 mmol) of potassium thiolacetate was added thereto, and stirring was continued. 16 hours. The resulting dark colored suspension is concentrated, 10 ml of water are added to the residue, and the mixture is extracted five times with 40 ml of methylene chloride each time. The combined extracts were dried over magnesium sulfate and the solvent was evaporated. The oily residue was subjected to silica gel column chromatography (90x36 mm) very rapidly, first using hexane and then a mixture of equal portions of hexane and ethyl acetate as eluents.

5.95 g (84%) of 4- (methanthiolacetate) -1-methyl-1,2,3-triazole were obtained as a slightly pink solid.

@ 1 H-NMR (CDCl3, .delta. In ppm):

2.40 (3H, singlet), 4.10 (3H, singlet), 4.20 (2H, singlet), 7.53 (1H, singlet).

IR (Nujol mull): 1675 cm ^1st

A solution of the triazole (1.00 g, 5.85 mmol) and ethyl bromoacetate (1.48 mL, 13.3 mmol) in dry acetonitrile (10 mL) was heated at 60 ° C under nitrogen for 90 h. The solvent was evaporated and the oily residue was triturated four times with 25 ml of ether each time. 1-methyl-3- (ethylcarboxymethyl) -4-methanthiolacetate-1,2,3-triazolium bromide is obtained as a brownish resinous mass which is used directly.

To a ice-cooled solution of this triazolium bromide in 20 mL of water was added a cold solution of 0.66 g (12 mmol) of potassium hydroxide in 5 mL of water with stirring. After 20 minutes, the mixture was diluted to a volume of 35 mL and the pH of the resulting solution was adjusted to 8.0 by addition of solid potassium dihydrogen phosphate. This solution was added with stirring to an ice-cooled solution of enol phosphate in 35 mL of tetrahydrofuran. After 0.5 hours the mixture is transferred to a pressure vessel containing 35 ml of ether and 1.5 g of 10% palladium on carbon and hydrogenated at 280 kPa for 55 minutes. The organic phase was separated and washed twice with 5 ml of water each time. The combined aqueous phases are filtered and the filtrate is concentrated under high vacuum. The residue was chromatographed on a reverse phase column (35x120 mm), eluting with water. Lyophilization of the fractions containing the carbapenem compound 1.20 g of a green solid, which is subjected chromatogfafii new column for high performance liquid chromatography (PrepPAK-500 / C _1Q) using 2% aqueous acetonitrile as the eluant. Fractions containing the carbapenem derivative were pooled and lyophilized. The material was re-chromatographed on a high performance liquid chromatography column (Mickrobondapack C-18, 10x300 mm), eluting with water. After lyophilization, 190 mg (17%) of pure title compound was obtained as a pale yellow solid.

Ifi-NMR (deuterium oxide, δ in ppm):

1.24 (3H, doublet, J = 6.4 Hz), 3.07 (2H, doublet, J = 9 Hz), 3.38 (1H, quartet, J = 2.7, 6.0 Hz), 4.02-4.30 (3H, multiplet), 4.29 (3H, singlet), 5.23 (2H, singlet), 8.52 (1H, singlet).

- 1

Ic (nujol suspension): 1750 cm.

UV (phosphate buffer, pH 7.4):

^Λ max ^{296 nm (E} = ^7,520) *

Example 4

Potassium-3- [4- (1-carboxylatomethyl) -3-methyl-1,2,3-triazolium) methanthio] -6-alpha- [1- (R) -hydroxyethyl] -7-oxo-1-azabicyclo [beta] 3 2, o] hept-2-ene-2-carboxylate

O

HOC- =

HSCCHII 3 o

a) MeOTf

A mixture of ethyl azidoacetate (30.0 g, 0.23 mol) and propiolic acid (14.3 ml, 0.23 mol) in toluene (75 ml) was stirred at room temperature. The reaction proceeds slightly exothermally for 1.5 hours and then rapidly exotherms rapidly, so ice cooling is required. After this exothermic phase, the reaction mixture was refluxed for 0.5 hour, then cooled in ice, the crystalline material was filtered off and washed with a small amount of toluene. 33.3 g (72%) of the raw material consisting of a single isomer is obtained, which by analogy with earlier work (C. Pederson, Acta. Chem. Scand., 1959, 13, 888) is probably 1- (ethylcarboxymethyl) -1, 2,3-triazole-4-carboxylic acid.

³ H-NMR (perdeuterodimethylsulfoxide, δ in ppm):

1.20 (3H, triplet, J = 7Hz), 4.15 (2H, quartet, J = 7Hz), 5.42 (2H, singlet), 8.67 (1H).

A solution of this carboxylic acid (5.00 g, 25.1 mmol) and triethylamine (3.68 mL, 26.4 mmol) in dry methylene chloride (50 mL) was added with stirring to an ice-cooled solution of 2.52 mL (26.4 mmol) of ethyl. of chloroformate in 50 ml of dry methylene chloride, the resulting purple solution was stirred for 0.5 hour, washed with 10 ml of water and dried over magnesium sulfate, and the solvent was evaporated. The resulting crude mixed anhydride was dissolved in 50 mL of tetrahydrofuran and the solution was slowly added to an ice-cooled suspension of 0.72 g (18.9 mmol) of sodium borohydride in 50 mL of tetrahydrofuran. After stirring for half an hour, an additional 0.30 g (7.9 mmol) of sodium borohydride was added and the reaction mixture was cooled in ice for 1 hour before adding 5 ml of water and 3 ml of 10% aqueous hydrochloric acid after 10 minutes. After gas evolution had ceased, 2 g of solid potassium carbonate were added with stirring, the organic phase was removed and the remaining white paste was extracted with further tetrahydrofuran. The combined organic phases were dried over magnesium sulfate and the solvent was evaporated. The residue was flash chromatographed on silica gel using hexane first, then ethyl acetate / hexane, and finally ethyl acetate as eluents. 2.04 g (44%) of 1- (ethylcarboxymethyl) -4-hydroxymethyl-1,2,3-triazole are obtained as a crystalline solid.

@ 1 H-NMR (CDCl3, .delta. In ppm):

1.28 (3H, triplet, J = 7Hz), 4.23 (2H, quartet, J = 7Hz), 4.75 (2H, singlet), 4.85 (2H, singlet), 7.73 ( 1H, singlet).

To an ice-cooled solution of 5.47 g (20.8 mmol) of triphenylphosphine in 100 mL of dry tetrahydrofuran was added dropwise 4.11 mL (20.8 mmol) of diisopropyl azodicarboxylate under nitrogen. After 0.5 hours, an ice-cooled solution of 1.93 g (10.4 mmol) of the above alcohol and 1.49 ml (20.8 mmol) of thiol acetic acid in 50 ml of tetrahydrofuran was added under nitrogen, the mixture was allowed to react for 2 hours at room temperature. cooling with ice and then an additional 12 hours at room temperature, then the solvent was evaporated. The remaining reaction mixture was subjected to flash chromatography on silica gel (40 g) using hexane and mixtures of 5%, 10%, 15% .... 50% ethyl acetate in hexane (100 ml each) as eluents. The fractions containing the desired thioacetate were combined and re-chromatographed on silica gel (60 g) using the following solvent combinations as eluents (200 ml each): hexane, 5%, 10%, 15%, 20% ethyl acetate in hexane and 22, 5%,%, 27.5% ... 35% ethyl acetate in hexane. 1.24 g (49%) of 1- (ethylcarboxymethyl) -4-methanthiolacetate-1,2,3-triazole were obtained as a crystalline solid and an additional 1.40 g of triphenylphosphine oxide contaminated material was obtained. The product obtained above has the following physical constants.

¹ H-NMR (values <5): 1.28 (3H, triplet, J = 7 Hz), 2.37 (3H, singlet), 3.87 (2H, singlet),

3.90 (2H, quartet, J = 7Hz), 5.12 (2H, singlet), 7.63 (1H, singlet).

IC (nujol suspension): 1735, 1780 ст *.

To an ice-cooled solution of 1.00 g (4.12 mmol) of the above-prepared triazole in 5 ml of dry methylene chloride was added dropwise 0.51 ml (4.53 mmol) of methyl trifluoromethanesulfonate with stirring. The cooling bath was removed after 0.5 hours and after a further 0.5 hours the solvent was evaporated in a water pump vacuum. The white solid residue was suspended in 15 ml of water, the suspension was cooled in ice with stirring, 0.69 g (12.4 mmol) of potassium hydroxide in 5 ml of water was added thereto, and the mixture was stirred for 1 hour. The reaction mixture is diluted to 30 ml with water and adjusted to pH 8.0 by addition of solid potassium dihydrogen phosphate. a portion of the obtained solution (22 ml, ca 3.0 mmol of thiol carboxylate) was added with stirring to an ice-cooled solution of 1.60 g (2.76 mmol) of enol phosphate in 30 ml of tetrahydrofuran and after 0.5 hours from the reaction mixture under high vacuum removes tetrahydrofuran. The residual yellow solution was subjected to reverse phase column chromatography (35 and 120 mm), using first 300 ml of water and then 5, 10, 15 ... 30% aqueous acetonitrile (100 ml each) as eluents. Lyophilization of the desired fractions gave 930 mg of p-nitrobenzyl ester as a yellow solid. This material was transferred to a pressure vessel containing 25 ml of ether, 25 ml of tetrahydrofuran and 25 ml of phosphate buffer [prepared by dissolving 1.36 g (0.01 mol) in 100 ml of water and adjusting the pH to 7.4 by adding 45% aqueous potassium hydroxide. ], and 900 mg of 10% palladium on carbon. Hydrogenation is carried out for 1 hour at a pressure of 280 kPa, then the organic phase is separated and washed twice with 5 ml of water each. The combined aqueous phases are filtered and concentrated under high vacuum. The residual solution is chromatographed on a reverse phase column (35x120 mm), eluting with water. Fractions containing the carbapenem derivative were pooled and lyophilized. 1.21 g of a light greenish solid is obtained which, after purification by high performance liquid chromatography (10x300 mm, Microbondapack C-18, water as eluent) affords 480 mg of the pure title compound. Yield 41%.

@ ¹ H-NMR (deuterium oxide, .delta. In ppm)

1.23 (3H, doublet, J = 6.4 Hz), 3.11 (2H, doublet, J = 9 Hz), 3.37 (1H, quartet, J = 3.0, 6.1 Hz), 4.02 (7H, multiplet), 5.18 (2H, singlet), 8.53 (1H, singlet).

M · -1

IC (nujol suspension): 1750 cm.

UV (phosphate buffer pH 7.4) p

Λ _max ²⁰⁵ nm (f «7 810).

Example 5

3- [5- (1,4-Dimethyl-1,2,4-triazolium) methanthio] -6-alpha- [1- (R) -hydroxyethyl] -7-oxo-1-azabicyclo [3.2.0] 2-Hept-2-ene-2-carboxylate

A. 1-Methyl-5-methanthiolacetate-1,2,4-triazole

(a) MsCl / NEt ₃

(b) CH-CSH / NEt, 3 | 3 o

To an ice-cooled solution of 565 mg (5.0 mmol) of 1-methyl-5-hydroxymethyl-1,2,4-triazole [r. Jones and D. Ainsworth, J. Amer. Chem. Soc., 1955, 77, 1.938] and 0.91 ml (6.5 mmol) of triethylamine in 5 ml of methylene chloride were added dropwise with stirring 0.46 ml (6.0 mmol) of methanesulfonyl chloride. After 20 minutes, an additional 1.05 ml (7.5 mmol) of triethylamine and then 0.53 ml (7.5 mmol) of thiol acetic acid are added, and stirring is continued for 45 minutes. The reaction mixture is diluted with methylene chloride and washed with water, the aqueous phase is extracted three times with 5 ml of methylene chloride each time, the combined organic phases are dried over magnesium sulphate and the solvent is evaporated off. The residue was subjected to silica gel column chromatography to obtain 570 mg of 1-methyl-5-methanthiolacetate-1,2,4-triazole as a yellow oil and, in addition, a contaminated 200 mg fraction, from which after preparative thin layer chromatography Silica gel yields an additional 100 mg of pure material. The total yield of the product was 85%.

@ 1 H-NMR (CDCl3, .delta. In ppm):

2.38 (3H, singlet), 3.90 (3H, singlet), 4.25 (2H, singlet), 7.80 (1H, singlet).

B. 3- [5- (1,4-Dimethyl-1,2,4-triazolium) methanthio] -6-alpha- [1- (R) -hydroxyethyl] -7-oxo-1-azabicyclo [з, 2 , o] hept-2-ene-2-carboxylate

a) MeOTf

b) NaOH

To an ice-cooled solution of 730 mg (4.27 mmol) of 1-methyl-5-methanthiolacetate-1,2,4-triazole in 7 ml of methylene chloride was added dropwise 1.20 ml (10.7 mmol) of methyl trifluoromethanesulfonate. The reaction mixture was allowed to warm slowly to room temperature over 3 hours and then concentrated. The oily residue gave, after trituration with ether, 1.46 g of crude 1,4-dimethyl-5-methanthiolacetate-1,2,4-triazolium trifluoromethanesulfonate, which was used directly for the next reaction. .

To an ice-cooled solution of 1.45 g (4.35 mmol) of the triazolium salt in 5 ml of water was added a solution of 512 mg (12.8 mmol) of sodium hydroxide in 5 ml of water, after 45 minutes the mixture was diluted to 25 ml with water. its pH is adjusted to 7.6 by addition of solid potassium dihydrogen phosphate. The resulting solution was added with stirring to an ice-cooled solution of 2.00 g (3.45 mmol) of enol phosphate in 25 ml of tetrahydrofuran, after 30 minutes the reaction mixture was transferred to a pressure vessel containing 40 ml of ether and 2.0 g of 10% palladium on carbon. , and hydrogenated at 50 psi for 1.25 hours. The reaction mixture is diluted with 25 ml of ether, filtered, the organic phase is separated and washed twice with 5 ml of water each time. The combined aqueous phases are washed three times with 25 ml of ether each time and concentrated in vacuo. The residue was subjected to reverse phase column chromatography (45x130 mm, water as eluent). Fractions containing the carbapenem derivative were lyophilized to give 650 mg of crude material which, after new chromatography, afforded 450 mg (39%) of the pure title compound.

1 H-NMR (deuterium oxide, δ v.ppm):

1.24 (3H, doublet, J = 6.4 Hz), 3.19 (2H, double doublet, J = 2.6,

9.2 Hz), 3.45 (1H, double doublet, J = 2.8, 6.0 Hz), 3.91 (3H, singlet), 4.06 (3H, singlet), 4.08-4. 36 (2H, multiplet), 4.54 (2H, doublet, J = γ 2.8 Hz), 8.71 (1H, singlet).

IR (Nujol mull): 1755 cm ^1st

UV (phosphate buffer, pH 7.4):

λ 294 nm (ε = 8,202). max ^T 1/2 ( ^phosphate buffer 0.067M, pH 7.4, T = 37 ° C):

9.1 hours.

Example 6 (1 * R, 5R, 6S) -3 - [(1,3-Dimethyl-5-tetrazolium) methylthio] -6- (1-hydroxyethyl) -7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate

A. 5-Ethoxycarbonyl-2-methyltetrazole a

5-ethoxycarbonyl-1-methyltetra

CH3

1a) Methylation with diazomethane

A solution of 9.17 g (0.064 mol) of 5-ethoxycarbonyltetrazole [d. Moderhack, Chem. Ber., 108, 887 (1975)] in 80 ml of ethyl ether (using an ethanol / ether mixture to give the same ratio of isomers) is cooled to 0 ° C and a solution of 3 g (0.071 mol) of diazomethane in 200 ml of ether. The light yellow solution was stirred for 30 minutes, then excess diazomethane was removed by addition of 1 mL acetic acid. Evaporation of the solvent and distillation of the residue gave 9.64 g (96%) of a clear oil, b.p. 95-100 [deg.] C./76 Pa. 1 H-NMR was a 6: 4 mixture of 1-methyl and 2-methyl isomers. The two isomers cannot be separated either by distillation or by high performance liquid chromatography.

iC (film): ⁱⁿ max? ⁴ θ cm * ^ (C = O ester residue).

@ 1 H-NMR (CDCl3, .delta. In ppm):

1.53 (3H, two overlapping triplets, J = 7.0, CH 2 CH 2), 4.46 and

4.53 (3H, two singlets, 6: 4 methyl group of 1-methyl- and 2-methyltetrazole; the 2-isomer methyl group has a lower displacement value and is contained in the mixture in a smaller amount), 4.5 (2H, two overlapping quartets, CH 2 CH 3).

1b) 5-ethoxycarbonyl-2-methyltetrazole

^CH ₃ I at ¹³⁰ ° ^C

A mixture of 5-ethoxycarbonyl-2-methyltetrazole and 5-ethoxycarbonyl-1-methyltetrazole (0.252 g, 1.61 mmol, isomer ratio 1: 1) in 0.5 mL iodomethane was sealed in a glass tube and heated at 100 ° C for 15 hours ° C and then at 130 ° C for 6 hours. Distillation of the reaction mixture afforded 0.139 g (55%) of the title compound as a pale yellow oil boiling at 95-100 ° C / 67 Pa (air bath temperature).

IC (film): at 1740 cm ^-1 (C = O ester residue).

max ¹ H-NMR (deuterochloroform, δ in ppm):

1.46 (3H, triplet, J = 7.0, CH ₃ CH ₂ ), 4.53 (3H, singlet, CH ₃ ~ 2), 4.5 (2H, quartet, J = 7.0, CH ₂₎ CH ₃ ).

2. Methylation with dimethyl sulfate.

To a solution of 1.42 g (0.01 mol) of 5-ethoxycarbonyltetrazole in 20 ml of dry acetone was added 1.38 g (0.01 mol) of anhydrous potassium carbonate and 1.26 g (0.01 mol) of dimethyl sulfate. The reaction mixture was refluxed for 12 hours, then filtered and the solvent was evaporated under reduced pressure. The residue is diluted with 30 ml of dichloromethane, the solution is washed with 10 ml of saturated sodium bicarbonate solution and 10 ml of sodium chloride solution, dried over anhydrous sodium sulfate, the solvent is evaporated off and the residue is subjected to vacuum distillation. 1.45 g (93%) of a clear oil are obtained with a boiling point of 85 DEG-110 DEG C./7 mm Hg. ¹ H-NMR indicated the presence of two isomers in a 1: 1 ratio. ·

В. 5-hydroxymethyl-2-methyltetrazole

A mixture of 5-ethoxycarbonyl-1-methyltetrazole and 5-ethoxycarbonyl-2-methyltetrazole (7.60 g, 0.049 mol, 6: 4 isomer ratio) in 50 mL dry tetrahydrofuran was cooled to 0 ° C and stirred for 15 min. 1.06 g (0.049 mol) of lithium borohydride is added in small portions. The mixture was cooled to 10 ° C for 30 minutes and then stirred at 20 ° C for 4 hours. The reaction mixture was cooled to 0 ° C and excess hydride was quenched by careful addition of 6N hydrochloric acid (until pH 7 no more gas evolved). The solvent was evaporated in vacuo and the oily residue was diluted with 200 mL of dichloromethane. The solution is washed with 10 ml of brine, dried over sodium sulfate, the solvent is evaporated and the residue is distilled under high vacuum. 1.83 g (33%) of a clear oil is obtained. ¹ H-NMR of this material indicated that the product was 5-hydroxymethyl-2-methyltetrazole.

2. Reduction of 5-ethoxycarbonyl-2-methyltetrazole

To a solution of 5-ethoxycarbonyl-2-methyltetrazole (0.139 g, 0.89 mmol) (obtained by isomerization of a mixture of methyl iodide esters) in 1 mL of dry tetrahydrofuran at 10 ° C was added 0.019 g (0.87 mmol) of solid lithium borohydride. The mixture was slowly warmed to room temperature and stirred for hours. Excess borohydride was removed by carefully adding 6N hydrochloric acid at 0 ° C (pH 7). The solvent was evaporated, the residue was dissolved in 25 ml of dichloromethane, dried over anhydrous sodium sulfate and the solvent was evaporated. 0.092 g (91%) of the desired compound is obtained, boiling under decomposition at 90 to 120 ° C / 67 Pa.

IC (film): _{ν max} 3 350 cm ¹ (wide band, OH).

¹ H-NMR (CDCl 3, δ ppm):

4.4 (2H, s, CH ₃ -2), 4.93 (2H, s, CH ₂ ~ 5).

C. 5-Acetylmercaptomethyl-2-methyltetrazole

1) MsCl, Et ₃ N

----------->

2) CH ₃ COSK

To a solution of 1.83 g (11.7 mmol) of 5-hydroxymethyl-2-methyltetrazole in 25 mL of dry dichloromethane at 0 ° C was added first 1.47 g (12.9 mmol) of methanesulfonyl chloride and then 1.30 g ( 12.9 mmol) of triethylamine, which was added dropwise over 5 minutes. After stirring at 0 ° C for 1 hour, a solution of 1.60 g (14.0 mmol) of potassium thioacetate in 10 mL of dry., Dimethyl-dimethylformamide was added. The resulting gel was stirred at 0 ° C for 3 hours, then the reaction mixture was diluted with 200 mL of dichloromethane, washed with 20 mL of brine, and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo and the oily residue was chromatographed on a silica gel column (2 x 15 cm) eluting with dichloromethane and 5% acetone in dichloromethane. This afforded 1.31 g (65%) of the title compound as a clear oil.

IR (film): ^{max 696 (c = 0} thioester residue).

@ 1 H-NMR (CDCl3, .delta. In ppm): ·

2.43 (3H, s, SAc), 4.36 (3H, s, _2-CH3), 4.38 (2H, s, _5-CH2).

D. 5-Mercaptomethyl-1,3-dimethyltetrazolium trifluoromethanesulfonate

NaOH

^cp 3 ^s ° ₃

To a solution of 5-acetylmercaptomethyl-2-methyltetrazole (0.400 g, 2.32 mmol) in dry dichloromethane (3 mL) was added methyl trifluoromethanesulfonate (0.76 g, 4.64 mmol) and the mixture was stirred at 22 ° C for 16 h. The solvent was evaporated in vacuo, the red oil was dissolved in 5 ml of deoxygenated water and 0.8 ml of 4M sodium hydroxide (3.2 mmol) was added. The mixture was stirred at 0 ° C for 40 minutes, then diluted with 7 mL of water and adjusted to pH 7.3 with saturated potassium dihydrogen phosphate solution. The resulting clear solution was stored under nitrogen and used immediately in the next reaction step.

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

OH

A solution of 0.915 g (1.58 mmol) of enol phosphate in 8 ml of tetrahydrofuran was cooled to 0 ° C and the above prepared solution of 2.32 mmol of 5-mercaptomethyl-1,3-dimethyltetrazolium trifluoromethanesulfonate (2.32 mmol) was added dropwise over 20 minutes. The pH of the reaction mixture was stable at 6.5 during the addition. After a further 20 minutes, the pH of the solution was adjusted to 7.0 with saturated sodium bicarbonate solution, transferred to a hydrogenation vessel, and diluted with 10 mL of tetrahydrofuran, 20 mL of ether and 20 g of ice, whereupon the carbapenem derivative in 10% palladium on charcoal. Hydrogenation is carried out at a pressure of 315 kPa for 90 minutes while slowly raising the temperature to 22 ° C. The catalyst is filtered off and washed with 5 ml of cold water and 20 ml of ether. The aqueous phase is washed with 20 ml of ether and evacuated for 20 minutes to remove traces of organic solvents. Chromatography on a PrepPak 500-C / 18 column (elution with water) and lyophilization of the eluate afforded 0.266 g (49%) of the title compound as a white powder with an optical rotation of [α] = + 13 ° (c - 1, 04, water).

UV (water, pH 7.4): 294 nm (U = 7500). max IC (KBr technology): ^v max ¹⁷⁵⁵ ( ^{c = 0 of the} beta-lactam residue), 1600 cm @ 2 (wide band C = O of the carboxylate residue). 1 H-NMR (deuterium oxide, . δ values in ppm): 1.24 (3H, doublet, J = 6.4 Hz, CH ^HOH), 3.0 to 3.3 (2H, m-triplet H-4), 3.42 (1H, double doublet) , J = 5.8, J = 2.9, H-6), 4 to 4.2 (2H, mithiplet, H-5 and CH ₃ CHOH), 4.34 and 4.57 (2x3H, two singlets, CH 4 -1a 3 on the tetrazole residue), 4.49 and 4.51 (2H, two singlets, CH ₂ S).

At 37 ° C and a concentration of 10 ⁴ M in phosphate buffer pH 7.4 the product has a half-life of 10.5 hours.

Example 7

Preparation of 3- (N-methylpyridin-2-yl-methanthio) -6-alpha- [1- (R) -hydroxyethyl] -7-oxo-1-azabicyclo [3.2.0] hept-2-ene- 2-carboxylate (one-pot procedure)

^CF 3 ^S ° 3 i

CH ₃ CN

О

II

ClP (OPh) ₂

NaOH ° C, 45 min

EtN (iPr) ₂ v

H ₂ O _W 0 ° C 1 h

IN

ch ₃

To an ice-cooled solution of 3 g (8.62 mmol) of ketone 1. in 30 ml of acetonitrile, 9 mmol (1.04 equivalents, 1.57 ml) of ethyl diisopropylamine was added first, followed by 9 mmol (1 mmol). (04 equivalent, 1.87 mL) of chlorodiphenyl phosphate. The reaction mixture was stirred for 45 minutes and then its sample was chromatographed on a thin layer of silica gel in ethyl acetate. The reaction solution is diluted with 60 ml of ethyl acetate, washed twice with 50 ml of cold water and brine, dried over sodium sulfate and concentrated to a foamy product at a bath temperature below 20 ° C. another reaction is used as such.

B. Preparation of thiol (4J

1) NaOH / H ₂ O ° C, 1h

2) KH ₂ PO ₄ ch ₃

An ice-cooled aqueous solution of 3.31 g (10 mmol) of thioacetate 2 ^is purged with nitrogen for 5 minutes and then a cooled solution of 0.7 g (1.75 equivalents) is added dropwise over about 5 minutes.

17.5 mmol) of sodium hydroxide in 8 ml of water. The reaction mixture turns yellow. After 75 minutes of keeping the reaction mixture under nitrogen, its pH is adjusted to 7.4 by addition of saturated aqueous potassium dihydrogen phosphate solution, the resulting mixture is diluted with 15 mL of water and this aqueous thiol solution 4 (50 mL, 0.2 mmol / ml) is used for the following reaction as such.

C. Condensation

-------------------> tetrahydrofuran-water; pH 6.5 to

7.5 0 ° C, 1 hour

To the ice-cooled solution of crude compound 2 prepared in paragraph A (8.62 mmol) in 50 ml of tetrahydrofuran was added dropwise the aqueous solution of thiol 4 prepared in paragraph 5 (5 ml of solution every 5 minutes). During the reaction, the pH of the reaction mixture is maintained in the range of about 6.5 to 7.5 (preferably 7) by the addition of cooled 2N sodium hydroxide solution. The progress of the reaction was monitored by thin layer chromatography on silica gel using ethyl acetate as the solvent system (a) or by reverse phase column chromatography (Analtech RPSF) using acetonitrile / pH 7 (4: 6) as eluent (b). ).

A total of 1.15 equivalents of thiol (50 ml solution) was used. The reaction is complete at 1 ° C after 1 hour and the reaction mixture is directly used for hydrogenation after adjusting the pH to 7.

D. Hydrogenation

315 kPa

H ₂ /10% Pd-C tetrahydrofuran-water-ether ° C, 2 h

The reaction mixture containing compound 2 (obtained in paragraph C) was transferred to a Parr flask containing 10 mL of tetrahydrofuran, 10 mL of 0.1 M phosphate buffer (pH 7), 75 mL of ether and 5 g of 10% palladium on carbon, and the mixture was stirred for 2 hours. hydrogenation at a pressure of 315 kPa at a temperature of 3 to 10 ° C. The catalyst is filtered off, washed three times with 10 ml of water each time and the pH is carefully adjusted to 6.2 with cold 2N sodium hydroxide. After addition of ether, the aqueous phase is separated and washed again with ether. The aqueous phase was freed from the organic solvent by evaporation in vacuo and then purified by Bondapak C-18 column chromatography (100 g, 4.5x13 cm) using cold distilled water as eluent. The pale yellow fractions containing the desired product by UV spectroscopy and thin layer chromatography were lyophilized to yield 1.46 g (50%) as a yellow (yield calculated on the starting bicyclic ketone) powder compound.

Example

If the procedure is repeated

as described in Example 7, except that the intermediate ketoderivative is replaced by an equimolar amount of the corresponding intermediate 1-beta-methyl derivative to give the final carbapenem derivative mentioned above.

Example 9

OH AND н | ^н ' CH ₃ 1 ³ AL Ar Ό -N - L 'COO When the procedure described in Example 7 is repeated by the intermediate ketoderivative

is replaced by an equimolar amount of the corresponding 1-alpha-methyl derivative to give the final carbapenem derivative mentioned above.

Example 10

Preparation of (5R, 6S) -3 - [(1,3-dimethylpyridinium-4-yl) methyl] thio] - [1- (R) -hydroxyethyl] -7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate (10A) a

(4R, 5R, 6S) -3 - [(1,3-dimethylpyridinium-4-yl) methyl] thio] -6- [1- (R) -hydroxyethyl] -4-methyl-7-oxo-1- azabicyclo [з, 2, θ] hept-2-ene-2-carboxylate (10B)

10A: R = H

10B: R = CH ₃

A. Preparation of 4-hydroxymethyl-3-methylpyridine

1) h

2) Ac

3) h

The general procedure described by Boekelheide for the preparation of hydroxymethylpyridines is used (V. Boekelheide, W.J. Linn, JACS, 76, 1286 (1954)). A solution of 46.0 g (0.43 mol) of freshly distilled 3,4-lutidine in 120 ml of glacial acetic acid was cooled to 0 ° C and 64 ml of 30% hydrogen peroxide was added dropwise. The resulting solution was heated in an oil bath at 75 ° C for 3 hours, then an additional 20 mL of 30% hydrogen peroxide was added, heating was continued for 18 hours, then the last 20 mL of 30% hydrogen peroxide was added. Heat at 75 ° C for 3 hours. The resulting solution was concentrated to about 100 ml in a water pump vacuum, 50 ml of water was added to the residue, and the mixture was concentrated to half volume. The resulting mixture was cooled to 0-5 ° C and basified to approximately pH 10 with cold 40% aqueous sodium hydroxide solution. The mixture was extracted five times with dichloromethane, dried over sodium carbonate and sodium sulfate, and concentrated on a rotary evaporator. The residual yellow solution gave a solid after dilution with hexane, which was filtered off and dried in vacuo. 48.0 g (83%) of 3,4-lutidine-N-oxide are obtained as an off-white solid.

The N-oxide prepared above was added portionwise to 60 ml of acetic anhydride and the resulting dark orange solution was heated in a water bath at about 90 ° C for 1 hour. The excess acetic anhydride was distilled off under reduced pressure and the residue was subjected to vacuum distillation. 39.0 g of an oily material boiling at 90 to 120 ° C / 13 Pa are obtained. Chromatography of this material on silica gel, eluting with ethyl acetate / petroleum ether (2: 3), afforded 19.0 g (30%) of pure oily 4-acetoxymethyl-3-methylpyridine.

IR (neat): 1745 cm

The above acetate was taken up in 100 ml of 10% aqueous hydrochloric acid, heated at reflux for 1 hour, cooled to 0 ° C, basified with solid potassium carbonate and extracted three times with 100 ml of dichloromethane each time. The organic extract was washed with brine and dried over sodium sulfate and evaporated. 70 DEG-72 DEG C., which, after trituration with cold ether, yielded 9.5 g (67%) of pure 4-hydroxymethyl-3-methylpyridine as a white solid, m.p. 77-80 ° C [w. Armarego, L.F., Milloy, B.A. and Sharma, S.C., JCS, 2,484 (1972) report a melting point of 81-82 ° C].

¹ H-NMR (CDCl a):

8.27, 7.41 (AB q, J = 5 Hz, 2H), 8.18 (s, 1H), 5.63 (bs, OH), 4.67 (s, _CH2), 2.20 (s, CH ₃ ).

IC (nujol): 3170 cm- ¹ .

B. Preparation of 4- (acetylthiomethyl) -3-methylpyridine

To an ice-cooled solution of 17.04 g (0.065 mol) of triphenylphosphine in 250 ml of dry tetrahydrofuran, 12.8 ml (0.065 mol) of diisopropyl azodicarboxylate was added dropwise while stirring the mechanical stirrers, followed by stirring at 0 ° C for 1 hour. to her. A solution of 4.0 g (0.032 5 mol) of 4-hydroxymethyl-3-methylpyridine in 100 ml of dry tetrahydrofuran was added dropwise, followed by 4.64 ml (0.065 mol) of freshly distilled thiol acetic acid. The resulting mixture was stirred first for 1 hour while switching to an orange-colored solution, diluted with petroleum ether, filtered, and chromatographed on silica gel with ethyl acetate / hexane as eluent to give 7.0 g of an oily material which after distillation in a bead distillation 6.0 g (100%) of pure product are obtained in the form of a yellow oil boiling at 95-100 ° C / 13 Pa (air bath).

° C and then 1 hour at room temperature, which is concentrated on a rotary evaporator. The residue of the filtrate was evaporated. Orange-colored residue using hexane first and then 10% to 50% ethyl ¹ H-NMR (CDCl 3):

8.40, 7.20 (AB q, J «5 Hz, 2H), 8.37 (s, 1H), 4.08 (s, _CH2), 2.35 (s, _CH3), 2.32 (s, CH ₃ ).

IC (in substance): 1695 cm ^-1 .

C. Preparation of 4- (acetylthiomethyl) -1,3-dimethylpyridinium trifluoromethanesulfonate

CH, SAc

CF ₃ SO ₃ “

To an ice-cooled solution of 2.95 g (0.016 mol) of the above thioacetate in 10 ml of methylene chloride was added dropwise 4.60 ml (0.04 mol) of methyl trifluoromethanesulfonate and the mixture was stirred at 0 ° C for 1 hour under nitrogen. The reaction mixture was evaporated to dryness, the residue was triturated with ether, the resulting solid material was filtered off and dried in vacuo. 4.0 g (72%) of the desired product are obtained as a white solid.

@ ³ H-NMR (CDCl3) .delta

8.72 (s, 1H), 8.58, 7.87 (AB q, J = 6Hz, 2H), 4.39 (s, N-CH _3), 4.17 (s, _CH2), 2 53 (s, CH ₃ ), 2.36 (s, CH ₃ ).

IC (in substance):

700 cm ¹ .

D. Preparation of (5R, 6S) -3- [f (1,3-Dimethyl-pyridinium-4-yl) -methyl] -thio] -6- [1 (R) -hydroxyethyl] -7-oxo-1-azabicyclo [2.2.1] c. hept-2-ene-2-carboxylate

CH ₂ SAc 1) NaOH / H ₂ O 2) OH -----------> © J 1 0 -л D CF _q SO- ' 1 Me h --- O₽ (OPh) ₂ XOjPNB

To an ice-cooled solution of 0.324 g (0.008 mol) of sodium hydroxide in 10 ml of nitrogen purged water, 1.40 g (0.004 mol) of thioacetate is added, the mixture is stirred at 0 ° C under nitrogen for 1 hour. % aqueous potassium dihydrogen phosphate is adjusted to 7.2-7.3 and the resulting solution is added dropwise to an ice-cooled solution of 1.45 g (0.002 5 mol) of enol phosphate in 20 ml of tetrahydrofuran. The mixture was stirred at 0 ° C for 1 hour, then transferred to a pressure vessel, 20 mL ether, 25 mL 0.1 M phosphate buffer (pH 7.4) and 1.4 g 10% palladium on carbon were added. the resulting mixture was hydrogenated at 50 psi for 1 hour. The reaction mixture was filtered through a pad of diatomaceous earth, which was then washed with ether and phosphate buffer pH 7.4. The aqueous phase was separated and the solvent was evaporated in vacuo. The resulting aqueous solution was applied to a reversed phase column (C Bondapak _lg) which was eluted first with water and then with 10% aqueous acetonitrile. Lyophilization of the appropriate fractions gave 0.9 g of an orange-colored solid which was rechromatographed using water and then 2% aqueous acetonitrile as eluents. After lyophilization, 0.25 g (57%) of pure desired product (10A) was obtained as a yellow solid.

@ 1 H-NMR (deuterium oxide, .delta. In ppm);

8.55 (s, 1H), 8.53, 7.96 (ABq, J = 6.8 Hz, 2H), 4.30-3.99 (m, 2H), 4.27 (s, 5J) 3.35 (dd, = 2.8 Hz, J ₂ = 6.0 Hz, 1H), 3.05 (d, J = 8.8 Hz, 2H), 2.50 (s, 3H), 1.23 (d, J = 6.3Hz, 3H).

IC (KBr): 1755, 1590 cm ^first

UV (phosphate buffer, pH 7):

295 nm (t 7 180).

Preparation of (4R, 5R, 6S) -3 - [(1,3-dimethylpyridinium-4-yl) methyl] thio] -6- [1 (R) -hydroxyethyl] -4-methyl-7-oxo-1 -azabicyclo (3.2.0) hept-2-ene-2-carboxylate

To an ice-cooled solution of 0.906 g (0.002 5 mol) of the bicyclic ketone in 10 ml of acetonitrile was added 0.544 ml (0.002 63 mol) of diphenyl chlorophosphate, 0.457 ml (0.002 63 mol) of diisopropylethylamine and 0.3 mg of 4-dimethylaminopyridine. After 50 minutes, the reaction mixture was diluted with cold ethyl acetate and washed with cold water and brine. The organic phase was dried over sodium sulfate and evaporated at room temperature to give the enol phosphate as an off-white foam. The foam was taken up in 20 mL of tetrahydrofuran, cooled to -30 ° C under nitrogen, and an aqueous solution of thiolate [prepared as described above from 0.3 g (7.5 mmol) of sodium hydroxide and 1.3 g] was added. (3.76 mmol) of thioacetate in 10 mL of water].

The reaction mixture was stirred at -30 ° C for 30 minutes, then at 0 ° C for 75 minutes, then transferred to a pressure vessel containing 20 mL ether, 30 mL 0.1 M phosphate buffer (pH 7.4) and 1.5 g. 10% palladium on carbon. The resulting mixture was hydrogenated at 50 psi for 1 hour, then filtered through Celite, the aqueous phase separated and concentrated in vacuo. The remaining solution was applied to a reverse phase column ( _C18 BondaPak) which was eluted with water. Lyophilization of the appropriate fractions yielded 1.2 g of a yellow solid which was re-chromatographed using a gradient elution from water alone to 4% aqueous acetonitrile. After lyophilization, 0.250 g (28%) of pure desired product (10B) is obtained as a yellow solid.

¹ H-NMR (deuterium oxide, δ values in ppm):

8.53 (s, 1H), 8.49, 7.81 (ABq, J = 6.2 Hz, 2H), 4.38-3.98 (m, 4H), 4.27 (s, 3H) 3.49 to 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 ^1st

UV (phosphate buffer, pH 7);

292 nm (c 7,930).

Example 11

Preparation of (5R, 6S) -3 - [(1,6-dimethylpyridinium-2-yl) methylthio] -6- (1R-hydroxyethyl) -4R-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate

A. (1,6-Dimethylpyridinium-2-yl) methylthiol trifluoromethanesulfonate

íňl? ^Me0Tf > ^{HC1 6N} > J2O ” SCCH ₃ ether CH ₃ ™ ³ CH ₃ TfO

To a solution of 1.0 g (5.52 mmol) of (6-methylpyridin-2-yl) methylthioacetate in 5 mL of dry ether was added 0.74 mL (6.5 mmol) of methyl trifluoromethanesulfonate under nitrogen and the mixture was stirred for 4 hours. Stir at 23 ° C. The ether was decanted off, the white solid was washed twice with 2 ml of ether and dissolved in 15 ml of a 6N hydrochloric acid solution (90.0 mmol). The resulting solution was heated to 70 ° C under nitrogen for 4 hours and then concentrated under reduced pressure to a yellow syrup residue. Trace hydrochloric acid was removed by distillation twice with 10 ml of water each time and the crude material was dried by reverse phase column chromatography (2.2x13.0 cm, PrepPak C-18) eluting with water. Appropriate fractions were combined and lyophilized to give 1.43 g of a white powder (85.4%). ·

IR (KBr) ν _max with 2565 (SH), 1626 (pyrldinium), 1585 (pyridinium) cm ^-1 .

UV (water) _λmax with 278 nm € € 7,355).

AND

Analysis: for ^C 9 ^H 12 ^NO 3 ^S 2 ^F 3 calculated: 35.64% С, 3.99% Η, 4.62% Ν, 21.14% S; found: 35.49% С, 4.05% Η, 4.56% Ν, 20.99% S.

в. (5R, 6S) -3 - [(1,6-dimethylpyridinium-2-yl) methylthiol-6- (1R-hydroxyethyl) -4R-methyl-7-oxo-1-azabicyclo [3.2.0] hept- 2-ene-2-carboxylate

O

1) (PhO) ₂ PCl

2) NEt (iPr) ₂

H ₂ , Pd / C ------------> Buffer 7.0 ether tetrahydrofuran

3) thiol

4) NEt (iPr) ₂

To a solution of 1.11 g (3.06 mmol) of (5R, 6S) -p-nitrobenzyl-3,7-dioxo-6- (1R-hydroxyethyl) -4RS-methyl-1-azabicyclo [3.2.0] of heptane-2-R-carboxylate (R / S = 86/14) in 90 mL of dry acetonitrile cooled to 5 ° C was added simultaneously with 0.68 mL (3.3 mmol) of diphenyl chlorophosphate under nitrogen for 10 min. and 0.57 mL (3.3 mmol) of diisopropylethylamine. The mixture was stirred at 5 ° C for 1 hour, then cooled to -30 ° C and a solution of 1.03 g (3.4 mmol) of (1,6-dimethylpyridinium-2-yl) salt was added simultaneously over 15 minutes. of methylthiol with trifluoromethanesulfonic acid in 2 ml of acetonitrile and 0.59 ml (3.4 mmol) of diisopropylethylamine. The resulting mixture was stirred at -30 ° C for 0.5 h, then warmed to 0 ° C, stirred for 1 h, then diluted with 35 mL cold water. The resulting emulsion was applied to a reverse phase column (2.5x18 cm, PrepPak C-18), which was then eluted with 25-50% aqueous acetonitrile. Lyophilization of the appropriate fractions gave 1.69 g of a sticky yellow solid which was dissolved in 40 ml of wet tetrahydrofuran, to which 70 ml of ether, 50 ml of 0.2 M sodium dihydrogen phosphate buffer and sodium hydroxide (pH 7.0) were added. and 1.69 g of 10% palladium on carbon. The resulting mixture was hydrogenated at 23 ° C at 50 psi for 2 hours, then filtered through a pad of diatomaceous earth. The two phases in the filtrate are separated, the aqueous phase is washed twice with 20 ml of ether each time and concentrated to a volume of 15 ml under high vacuum at less than 23 [deg.] C. The residue was applied to a reverse phase column (PrepPak C-18) eluting with 4% aqueous acetonitrile. After freeze-drying of the appropriate fractions, 0.23 g of the title compound is obtained in admixture with potassium potassium diphenyl phosphate (24 mol%). The crude product was purified by reversed phase column chromatography (2.5x14 cm PrepPak C-18) eluting with water (400 mL) and 10% aqueous acetonitrile (200 mL). Lyophilization of the appropriate fractions gave 0.17 g (15.3%) of a yellow powder.

Ic (KBr-technique) in: 1750 (C = O beta-lactam residue), 1625 (pyridinium residue), ΠΙαΧ _ i

600 (C = O carboxylate group) cm ”.

* H-NMR (deuterium oxide, δ in ppm):

1.12 (d, J = 7.2 Hz, CH ₃ on C ₄ ), 1.24 (d, J = 6.4 Hz, N-N-N-N),

2.80 (s, CH ₃ on C 8 pyridinium residue), 4.18 (CH ₃ on pyridinium nitrogen), 4.41 (center of AB-quartet, CH ₂ S), 7.5 to 8.4 (pyridinium protons) rest).

UV (buffer, 0.05M, pH 7.0) _Л тах:.

278 nm (c 11,504).

[AJP ³ = -256.4 ° (с = 0.22, water).

^τ 1/2 ^{= 20.8} hours, measured at 37 ° C in buffer pH 7.4 for a concentration of 10 ~ ⁴ M.

Example 12

Preparation of (5R, 6S) -3 - [(1,6-dimethylpyridinium-2-yl) methylthio] -6- (1R-hydroxyethyl) -7-oxo-1-azabicyclo [з, 2,10] hept-2- en-2-carboxylate

A. (5R, 6S) -p-Nitrobenzyl-3-f (1,6-dimethylpyridinium-2-yl) methylthio] -6- (1 H -hydroxyethyl) -7-oxo-1-azabicyclo [3.1.1] trifluoromethanesulfonate and diphenylphosphate 2, o] hept-2-ene-2-carboxylate

MeOTf

CH ₃ ether

1) NaOH

2) KH ₂ PO ₄

1) (PhO) ₂ POCl

2) MEt (iPr) ₂

3) thiol

4) NEt (iPr) ₂

TfO (PhO) ₂ PO ₂

To a solution of 2.14 g (6.14 mmol) of (5R, 6S) -p-nitrobenzyl-6- (1R-hydroxyethyl) -3,7-dioxo-1-azabicyclo [3.2.0] heptane-2R- of carboxylate in 18 ml of dry acetonitrile, cooled to 5 ° C, 1.37 ml (6.6 mmol) of diphenyl chlorophosphate and 1.15 ml (6.6 mmol) of diisopropylethylamine are added at a rate to maintain the temperature under nitrogen. to 5 ° C (7-10 minutes), and then 6 mg (0.05 mmol) of 4-methylaminopyridine is added. The mixture was stirred at 5 ° C for 1.5 hours and used as such. This mixture is hereinafter referred to as solution A '.

To a solution of (6-methylpyridin-2-yl) methylthioacetate (1.23 g, 6.8 mmol) in dry ether (10 mL) was added methyl trifluoromethanesulfonate (0.85 mL, 7.5 mmol) under nitrogen. Stir for 5 hours at 23 ° C. The ether was decanted off and the white powder was dissolved in 20 ml of water after washing twice with 10 ml of ether each time. The aqueous solution was cooled to 0 ° C in an oxygen-free atmosphere. 3.4 ml of 4N sodium hydroxide (13.6 mmol) was added. The mixture was stirred at 2 ° C for 1 hour and then adjusted to pH 7.6 by addition of potassium dihydrogen phosphate. This mixture is hereinafter referred to as solution B.

To solution A cooled to 5 ° C, solution B was added over 0.5 hours, maintaining the pH of the mixture between 7.25 and 7.35 by dropwise addition of 4N sodium hydroxide solution. The resulting mixture was stirred for 0.5 h and then applied to a reverse phase column (4.0 x 18 cm, PrepPak C-18) eluting with 25% to 50% aqueous acetonitrile. Lyophilization of the appropriate fractions gave 2.82 g of the title compound as a yellow powder [51% (PhO) ₂ PO ₂ , ⁴⁹ % CF 3 SO 4). Yield 80%.

IR (KBr) at _max : 3,700-3,000 (OH), 1,772 (C = O beta-lactam residue), 1,700 (C = O ester residue), 1,625 (pyridinium), 1,590 (pyridinium) ) cm ^{1 *} .

¹ H-NMR (perdeuterodimethylsulfoxide, δ values):

1.15 (d, J = 6.2 Hz, CH ₃ CHOH), 2.84 (s, CH ₃ on C _g pyridinium group), 4.16 (s, _CH3 on pyridinium group N), 4.79 (s, SCHp, 6.6-7.5 [iPhO] ₂ -O ₂ ], 7.5-8.7 (protons of pyridinium and p-nitro-benzyl ester moiety).

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

To a solution of 0.87 g (1.27 mmol) of trifluoromethanesulfonate and diphenylphosphate (49: 5?) (5R, 6S) -p-nitrobenzyl-3-Q, 6-dimethylpyridinium-2-yl) methylthio] -6- (1R) -hydroxyethyl) -7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate in 50 ml wet tetrahydrofuran is added 50 ml ether, 40 ml 0.1 M potassium dihydrogen phosphate buffer and hydroxide sodium (pH 7.0) and 0.87 g of 10% palladium on carbon. The mixture was hydrogenated at 23 ° C under 50 psi for 2 hours, then filtered through a pad of diatomaceous earth. The two phases of the filtrate were separated, the aqueous phase was washed twice with 15 ml of ether each time, concentrated under high vacuum to a volume of 30 ml and the residue was applied to a reverse phase column (2.2x13 cm, PrepPak C-18). The column is eluted with water. Combine the appropriate fractions by lyophilization to give 0.179 g (40%) of a yellow powder.

IR (KBr) at _max : 1755 (C-O beta-lactam residue), 1628 (pyridinium residue),

590 (C = O carboxylate group) cm ¹ .

¹ H-NMR (deuterium oxide, δ in ppm):

1.25 (d, J = 6.4 Hz, CH ₃ CHOH), 2.82 (s, CH ₃ on the C 8 pyridinium residue), 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 to 4.4 (CH ₃ CHOH, H-5, CH ₃ on nitrogen of pyridinium residue), 4.48 (s, CH ₂ S), 7.6 to 8.4 (protons of pyridinium residue).

UV (water): _λmax ^: 279 nm (c 9,628) with arm at 296 nm.

[α] D ³ = 55.0 ° (c = 0.63, water).

o - 4 τ _χ / ₂ = 12.5 hours, measured at 37 ° C in pH 7.4 buffer for a concentration of 10 M.

Claims (5)

(I) OBJECT OF THE INVENTION 1 8 R and R together form an alkylidene group having 2 to 10 carbon atoms, optionally substituted by a hydroxyl group, - R ⁵ represents an optionally substituted alkyl, alkenyl or alkynyl group having from 1 to 10 carbon atoms each, a cycloalkyl or cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 6 carbon atoms in the alkyl, phenyl, aralkyl, aralkenyl or aralkynyl moiety wherein the aryl moiety is a phenyl moiety and the aliphatic moiety contains 1 to 6 carbon atoms, a heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl group wherein the heteroatom or heteroatoms in the heterocyclic moieties are selected from the group consisting of 1 to 4 oxygen, nitrogen and sulfur atoms, and the alkyl moiety attached to the heterocyclic radical contains 1 to 6 carbon atoms, wherein the above-mentioned optionally substituted radicals R @ 1 bear one to three substituents independently selected from the group consisting of C1 -C6 alkyl groups optionally substituted amino, fluorine or chlorine, carboxyl, hydroxy or carbamoyl, fluorine, chlorine and bromine, radicals of the formula -oco ₂ y ³ -OCOR ³ -OCONR ³ R ⁴ O-ol-R ⁹ i -oxo -1-NR ³ R ⁴ And o -nhAnr ³ r ⁴ r ^{3 4} 59 Inr - ^CO 2 ^r3 вО о -CN -OSO ₃ R ³ О -OP (O) (OR ³⁾ (OR ⁴⁾ A process for the preparation of carbapenem derivatives of the general formula I represents a hydrogen atom and R ¹ represents a radical selected from the group consisting of hydrogen and optionally substituted C 1 -C 10 alkyl, alkenyl and alkynyl, C 3 -C 6 cycloalkyl and cycloalkylalkyl groups in the C 1-6 cycloalkyl portion of the alkyl, phenyl portion an aralkyl, aralkenyl and aralkynyl group wherein the aryl moiety is a phenyl moiety and the aliphatic moiety contains 1 to 6 carbon atoms, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl groups wherein the heteroatom or heteroatoms are selected from one to four oxygen atoms, and wherein the alkyl moiety attached to the heterocyclic moiety contains 1 to 6 carbon atoms, wherein said substituent or substituents of the above-mentioned moieties are independently selected from the group consisting of alkyl groups of 1 to 6 carbon atoms, optionally substituted amine halogen, hydroxyl or carboxyl, halogen atoms, radicals of formula -OR • oNr ³ r ⁴ -Arr ³ r ⁴ 2. The method according to The composition of claim 1, wherein the base is sodium hydroxide. 3. The method according to The method of claim 1, wherein the reaction is carried out at a temperature in the range from -15 ° C to +15 ° C. 2 'are as hereinbefore defined, represents a conventional readily cleavable carboxyl function protecting group and is a conventional cleavable group, reacted with a thiol of formula VII (VII) wherein: A and the residue are as defined above and represents a balancing anion, in an inert solvent and in the presence of a base, to form a carbapenem compound of formula I 'wherein: R ^1, R ^8, R ^15, R ^2, А - ^ JJ ⁺ -R ⁵ X have the above meanings, from which is then optionally deprotected carboxy for R @ 2 ' R to form the corresponding free compound of formula I or a pharmaceutically acceptable salt thereof. 2-naphthylmethyl, benzyl, trichloroethyl, silyl such as trimethylsilyl, phenacyl, p-methoxybenzyl, acetonyl, o-nitrobenzyl, 4-pyridylmethyl, C 1 -C 6 alkyl, pivaloyloxymethyl, an acetoxymethyl group, a phthalidyl group, an indanyl group and a methoxymethyl group, provided that when R is a hydrogen atom or a protecting group as defined above, a charge-balancing ion is also present, and -i- N ⁺ - means a five- or six-membered heteroaromatic ring containing, optionally, in addition to the quaternized nitrogen atom, 1 to 2 3 additional heteroatoms selected from the group consisting of nitrogen and sulfur, optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl groups of 1 to 3 3 4 -CONR R -CN or phenyl optionally substituted with one to three substituents selected from the group consisting of fluorine, chlorine and bromine atoms, 3 3 4 3 alkyl groups of 1 to 6 carbon atoms, -OR, -NR R, -SO 4 R 3, ^J -CO 2 R and -CONR R, wherein R, R and R in the R substituents are as defined above, or R ⁵ may be attached to the residue at another ring position to form a fused heterocyclic or heteroaromatic ring system containing up to The 10 member of the ring member, which may contain another heteroatom selected from oxygen, sulfur and nitrogen, represents a hydrogen atom or an optionally substituted alkyl, alkenyl or alkynyl group having 1 to 10 carbon atoms, a cycloalkyl, cycloalkylalkyl or alkylcycloalkyl group having 3 to 6 carbon atoms in cycloalkyl and 1 to 6 carbon atoms in the alkyl moiety, spirocycloalkyl of 3 to 6 carbon atoms, phenyl, aralkyl, aralkenyl or aralkynyl, wherein the aryl moiety is a phenyl moiety and the aliphatic moiety contains 1 to 6 carbon atoms, heteroaryl, heteroaralkyl , heterocyclyl or hetero a cyclylalkyl group wherein the heteroatom or heteroatoms in the above heterocyclic moieties are selected from the group consisting of 1 to 4 oxygen, nitrogen and sulfur atoms, and the alkyl moieties attached to these heterocyclic moieties contain 1 to 6 carbon atoms, wherein the substituent or substituents of the above radicals are selected from the group consisting of amino, mono-, di- and trialkylamino, hydroxyl, alkoxy, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chloro, bromo and fluoro, cyano, and carboxy, in the above-mentioned substituents contain 1 to 6 carbon atoms, represents a straight or branched alkylene group having 1 to 6 carbon atoms, represents a hydrogen atom, an anionic charge or an easily cleavable carboxyl function protecting group selected from the group consisting of benzhydryl a group, an allyl group, a p-nitrobenzyl group, 3 3 4 -NR ^J CONR ^J R O -SR “ ^S0 3 ^r3 -what ₂ r ³ 3 4 -NR ^J R R ³ CONR ⁴ -nr ³ co ₂ 'r ⁴ 3 4 -NR C = NR ft ³ -NR ³ CO ₂ R ⁴ -N ° 2 in which R ³ and R ⁴ are each independently hydrogen, alkyl, alkenyl or alkynyl of 1 to 10 carbon atoms, cycloalkyl, cycloalkylalkyl or alkylcycloalkyl of 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl a phenyl, aralkyl, aralkenyl or aralkynyl group wherein the aryl moiety is a phenyl moiety and the aliphatic moiety contains 1 to 6 carbon atoms, a heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl group wherein the heteroatom or heteroatoms are selected from one to four atoms oxygen, nitrogen and sulfur and the alkyl moiety attached to the heterocyclic radical contains 1 to 6 carbon atoms, or R ³ and R ⁴ together with the nitrogen atom to which at least one of these residues is attached form a five- or six-membered nitrogen-containing heterocyclic ring, and 9 3 R is as defined above for R except hydrogen, or 4. The method according to The composition of claim 1, 2 or 3, wherein the starting materials are used (IV) wherein the leaving group L is chlorine, bromine or iodine, benzenesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, diphenoxyphethoxy or diphenoxyphosphinylo) 1. 4 carbon atoms optionally substituted by phenyl, C 1 -C 4 alkoxy, carboxyl and carbamoyl, the ring of which is bonded to the remainder of A by a ring carbon atom and contains a nitrogen atom quaternized by R 8 in the ring, and pharmaceutically acceptable salts thereof characterized in that the intermediate of formula (IV) in which: 5. Process according to claim 1, 2 or 3, characterized in that starting materials of the general formula IV are used, in which the leaving group L is diphenoxy- phosphinyloxy a the remaining general symbols have the meaning as in point 1. 6. The method according to point 1 к preparation of compounds of the formula OH <15 ^ iji ^SCH2 C ~ ⁿ ~ ^{R5 N} X ^ 0 COO in which R ¹⁵ represents a hydrogen atom or a methyl group; and _{n is} R ⁵ in which R ⁵ is C1 -C4 alkyl and R ⁶ and R ⁷ each independently represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, and pharmaceutically acceptable salts thereof, characterized in that it is an intermediate of general formula (I) formulas 2 ^H R ^ COOR ² * in which 0 L means a conventional leaving group, R ¹⁵ is as defined above and R ² ' represents a common, easily removable protecting group for the carboxyl function, is reacted with a thiol of the formula wherein: R ^5, R ⁶ and R ⁷ are in an inert solvent and in the presence of a base to produce a carbapenem compound of the formula having the abovementioned meaning, then optionally removing the protective group represented by R ^a to form the corresponding free carbapenem derivative or pharmaceutically usable sol :. 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