CS248721B2 - Production method of carbapanem-derivatives - Google Patents

Description

The present invention relates to a novel process for the preparation of carbapenem antibiotics containing a substituent of the general formula at position 2

Further described is the preparation of carbapenem antibiotics of formula (I) wherein:

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

R ⁵ represents an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl, araliphatic, heteroaryl, heteroaraliphatic, heterocyclyl or heterocyclyl-aliphatic residue and

Ě N ~~ in which

R ⁸ represents a hydrogen atom and

R1 represents a radical selected from the group consisting of hydrogen and optionally substituted alkyl, alkenyl and alkynyl groups of up to 10 carbon atoms, cycloalkyl and cycloalkylalkyl groups of 3 to 6 carbon atoms in the cycloalkyl moiety of 1 to 6 carbon atoms in the alkyl, phenyl moiety aralkyl, aralkenyl and aralkynyl, wherein the aryl moiety is a phenyl moiety and the aliphatic moiety contains up to 6 carbon atoms, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclyl-

means a nitrogen-containing aromatic heterocyclic ring attached to an alkylene group as defined by A through a ring carbon atom, quaternized with R ⁵ .

alkyl groups in which the heteroatom or heteroatoms are selected from the group consisting of one to four oxygen, nitrogen and sulfur atoms, and wherein the alkyl moiety attached to the heterocyclic radical contains 1 to 6 carbon atoms, wherein said substituent or substituents of the aforementioned radicals are independently selected from the group consisting of alkyl groups having 1 to optionally substituted halogen, hydroxyl carboxyl group, halogen atoms, radicals of the formula carbon atoms, amino group, or -OR 3

O

II —OCNR3R4

O

II

CNR3R4 — NR3R4

O —SR ⁹

O — CN — N3 —OSO3R3

O

II —OS — R9

II o

O

II — NR3S — R9

O — OP (O) · (OR3) (OR4) — NR ³ C = NR 4

R 3 —NR 3 CO 2 R 4 and —NO 2

O

II — s — NR3R4

II o o

II —NHCNR3R4 o

II

R 3 CNN 4 - —CO 2 R 3 = O 0

II —OCR3 —SR5

O

II —SR9 in which

R3 and R4 are each independently hydrogen, alkyl, alkynyl or alkynyl having up to 10 carbon atoms each, cycloalkyl, cycloalkylalkyl or alkylcycloalkyl having 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 up 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 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 radicals is attached form a five- or six-membered nitrogen-containing heterocyclic ring, and

R 9 is as defined above for R 3 except hydrogen, or

R 1 and R ⁸ together form an alkylidene group having 2 to 10 carbon atoms, optionally substituted by a hydroxyl group,

R ⁵ is optionally substituted al 5

an alkyl, phenyl, aralkyl, aralkenyl or aralkynyl group wherein the aryl moiety is an alkyl, phenyl, alkynyl or alkynyl group containing up to 10 carbon atoms, a cycloalkyl or cycloalkylalkyl group having from 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 6 carbon atoms in the alkyl moiety. the phenyl moiety and the aliphatic moiety contains up 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 an alkyl moiety bound to the heterocyclic moiety contains from 1 to 6 oxygen atoms, wherein the abovementioned optionally substituted radicals R ⁵ bear one to three substituents independently selected from the group consisting of C 1 -C 6 alkyl groups optionally substituted with amino, fluoro or chloro oru, carboxyl, hydroxyl or carbamoyl, fluorine, chlorine and bromine, the radicals of the formula -OR ^3, -OCO2R ^3, -OCOR ^3, -OCONR ³ R ^4,

O

II —OS — R ⁹ , o

Oxo, -NR ³ R 4,

R5CONR4-, -NR3CO2R ⁴ -NR3CONR3R4,

O

II — NR3S — R ⁹

II o

—SR ³ ,

The -SO 3 R ^3, -CO 2 R ^3, -CONR ³ R ^4, -CN, a phenyl group optionally substituted with one to three fluorine atoms, chlorine and bromine, alkyl having 1 to 6 carbon atoms, -OR ^3, -NR ³ R ⁴ , -SO ³ R ³ , -CO ² R ³ or - CONR ³ R ⁴ , wherein R ³ , R ⁴ and R ⁹ in the radicals of the substituents of R ⁵ are as defined above, or R ⁵ may be attached to the radical

at another ring position to form a fused heterocyclic or heteroaromatic ring system which may contain other heteroatoms selected from oxygen, sulfur and nitrogen,

R ¹⁵ represents a hydrogen atom or an optionally substituted alkyl, alkenyl or alkynyl group having up to 10 carbon atoms, a cycloalkyl, cycloalkylalkyl or alkylcycloalkyl group having 3 to 6 carbon atoms in the cycloalkyl and 1 to 6 carbon atoms in the alkyl moiety, a spirocycloalkyl group having 3 to 6 carbon atoms, phenyl, aralkyl, aralkenyl or aralkynyl group wherein the aryl moiety is a phenyl moiety and the aliphatic moiety contains up to 6 carbon atoms, a heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl group wherein the heteroatom or heteroatoms in the above heterocyclic moieties are selected from having 1 to 4 oxygen, nitrogen and sulfur atoms, 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 tri alkylamino, hydroxyloxy, alkoxy, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chlorine, bromine and fluorine atoms, cyano and carboxyl, wherein the alkyl moieties in the above-mentioned carboxylic acid protecting or common carboxyl protecting group by the fact that when R2 is a hydrogen atom or a protecting group, a charge-balancing anion is also present, and the substituents contain 1 to 6 carbon atoms,

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

R ² represents hydrogen, an anionic Na-

means an optionally substituted mono-, bi- or polycyclic aromatic heterocyclic radical containing at least one nitrogen atom in the ring, attached to the radical A by a ring carbon atom and containing a nitrogen atom quaternized by R @ 6 group, and pharmaceutically acceptable salts thereof according to the following reaction scheme:

(til)

(IV)

vt _t

РПрЭ.а. fS subtract%

cbnó »ic i

Groups

i V)

A preferred variant of the process described above is shown in the following modified reaction scheme:

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) as p-toluenesulfonic anhydride, anhydride, p-nitrobenzene sulfonic anhydride, 2,4,6-triisopropylbenzensulfonové acid, methanesulfonic acid anhydride, trifluoromethanesulfonic acid anhydride, diphenyl chlorophosphate, toluenesulfonyl chloride, ^{p-bromobenzyloxybenzene:} nitrophenylsulfochloride etc., where L is the corresponding leaving group such as toluenesulfonyloxy, p- nitrobenzenesulfonyloxy, diphenoxyphosphinyloxy, or another cleavable group which is introduced by conventional procedures and is known in the art. The reaction to introduce · · leaving group at the 2-position of intermediate III is advantageously carried out in the presence of a base such as diisopropylethylamine, triethylamine, 4-dimethylaminopyridine, etc., At a temperature ranging from about -20 · · to +40 ^o C, most preferably at about 0 ^C 'C The leaving group L of the intermediate of formula (IV) may also be a halogen atom, in which case this group is introduced by reacting the intermediate of formula (III) with a halogenating agent such as (1B6N5) 3RB2, (C6H5O6PBrz, oxalyl chloride and the like). in the presence of a base such as diisopropylethylamine, triethylamine, 4-dimethylaminopyridine and the like. The intermediate of formula IV may optionally be isolated, but is conveniently used in the next step without isolation or purification.

The intermediate of formula (IV) is converted to the intermediate of formula (II) by conventional substitution reaction. Thus, an intermediate of formula IV can be reacted with an approximately equimolar amount of a heteroaralkylmercaptan of formula

A -

represents a straight or branched alkylene group having 1 to 6 carbon atoms and represents a mono-, bi- or polycyclic aromatic heterocycle containing a ring-quaternizable nitrogen which ring is bonded to residue A via a ring carbon atom, in an inert organic solvent such as dioxane dimethylformamide, dimethylsulfoxide or acetonitrile and in the presence of a base such as diisopropylethylamine, triethylamine, sodium bicarbonate, 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 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 group of intermediate 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

R ⁵ —X 'wherein

R ⁵ is as defined above, and

X ‘represents a conventional leaving group such as a halogen atom (chlorine, bromine or iodine, most preferably iodine) or an ester residue of a sulfonic acid such as a mesylate, tosylate or trifluoromethanesulfonate residue.

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

The intermediate of formula (Г) comprises a balancing ion X '(for example an ion derived from the alkylating agent used), which can be replaced in this or a later reaction step, i.e. after the deprotection step, by another balancing ion, for example such an ion which is more pharmaceutically acceptable. This replacement is carried out in a conventional manner. Alternatively, the counterion can be removed during the deprotection step.

Deprotecting the carboxylic lunkce represented by R ² 'in the intermediate of formula Г is accomplished by conventional procedures 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 (G) may be used in a suitable solvent such as a mixture of dioxane, water and ethanol , 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 0 to 50 ° C, for about 0.24 to 4 hours. When R ² 'is as o-nitrobenzyl, cleavage may к the protecting group used also photolysis. Such protecting groups, such as 2,2,2-trichloroethyl, can be removed by a slight reduction with zinc. The allyl protecting group can 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 carboxyl-protecting groups may be removed by methods known in the art. Finally, as mentioned above, those compounds of formula Г in which R ² 'represents a physiologically hydrolyzable ester group such as acetoxymethyl, phthalidyl, indanyl, pivaloyloxymethyl, methoxymethyl and the like can be applied directly to the patient without deprotection, as such esters are hydrolyzed under physiological conditions in vivo.

The above described process has several disadvantages. For example, the process described above is carried out in several reaction stages, the number of which would be advantageous to reduce. Also, the overall yield of the reaction is rather low and the quaternization step is carried out with the already prepared carbapenem derivative. It would therefore be desirable to have a new process for the preparation of the compounds of formula (I) which:

1. included fewer reaction steps,

2. provide higher yields,

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

4. could be used to facilitate the preparation of quaternary amino derivatives using a wide variety of amines, such as sterically hindered amines and amines with low pK _b values.

The present invention provides a novel process for the preparation of carbapenem derivatives of formula (I) by halogen atoms, radicals of the formula --OR ³

O II —OCNR ³ R ⁴

O

II — CN ³ R ^{4 —} NR ³ R ⁴

in which

R ⁸ 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 C 3 -C 6 cycloalkylalkyl radicals, 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 heteroaryl or heterocyclyl groups or moieties are the corresponding mono-, bi- or polycyclic radicals containing up to 18 ring members, preferably 5 or 6 ring members, and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur atoms, and wherein the alkyl moiety attached to the heterocyclic radical contains 1 to 6 carbon atoms, substituent or substitue the radicals mentioned above are independently selected from the group consisting of alkyl groups having 1 to 6 carbon atoms, optionally substituted with amino, halogen, hydroxyl or carboxyl groups,

O

II —S — NR ³ R ⁴

II o

O

II — NHCHR ³ R ⁴

O

II

R ³ CNR ⁴ - —CO ² R ³ = O 0

II _τ —OCR ³ —SR ³ O

II —SR ⁹ o

II —SR ⁹

II o

—CN —N3 —OSOsR ³

О —OS — R ⁹

II о

о

II — NR ³ S — R ⁹

II о —OP (O) (OR ³ ) i (OR ⁴ ) — NR ³ C = NR ⁴

Ø ³ —NR ³ CO ₂ R ⁴ and —NO 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 heteroaryl or heterocyclyl groups or moieties are the corresponding mono-, bi- - or polycyclic radicals containing up to 18 ring members, preferably 5 or 6 ring members, and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur atoms 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

R ⁹ is as defined above for R ³ except hydrogen, or

R 1 and R ⁸ 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 moiety wherein the heteroaryl or he 16 terocyclyl moieties or moieties are the corresponding mono-, bi- or polycyclic moieties containing up to 18 members ring, preferably 5 or 6 ring members, and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur atoms, and the alkyl moiety bound to the heterocyclic radical contains 1 to 6 carbon atoms, wherein the above-mentioned optionally substituted radicals R are ⁵ nes one to three substituents independently selected from the group consisting of alkyl groups of 1 to 6 carbon atoms optionally substituted by amino, fluorine or chlorine, carboxyl, hydroxy or carbamoyl, fluorine, chlorine and bromine, radicals of the formula -OR ³ , -OCO2R ^3, -OCOR ^3, -OCONR ³ R ^4,

O

II —OS — R ⁹ ,

II o —oxo, —NR ³ R ⁴ ,

R ³ CONR ⁴ -, - NR ³ CO ₂ R ⁴ , - NR ³ CONR ³ R ⁴ , O - NR ³ S - R ⁹ ,

II o

—SR ³ ,

O

-WITH

-SO 3 R ^3, -CO 2 R ^3, or to protecting groups can also be present in a charge-balancing anion, -CONR3R4, -CN, a phenyl group optionally substituted with one to three fluorine atoms, chlorine and bromine, alkyl having 1 to 6 carbon atoms, -OR ^3, -NR ³ R ^4, -SO5R ^3, - CO2R3 or -CONR3R4, wherein R3, R ⁴ and R ⁹ radicals in the substituents R @ ⁵ have the above meanings, or R5 may be attached to the remainder

G at another ring position to form a fused heterocyclic or heteroaromatic ring system which is a corresponding bi- or polycyclic residue containing up to 18 ring members and 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen;

R 15 represents a hydrogen atom or an optionally substituted alkyl, alkenyl or alkynyl group having 1 to 10 carbon atoms, a cycloalkyl, cycloalkylalkyl or an alkylcycloalkyl group containing 3 to 6 carbon atoms in the cycloalkyl and 1 to 6 carbon atoms in the alkyl moiety; (C až-C uhlíku) 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, heteroaralkyl, heterocyclyl or heterocyclylalkyl group in which heteroaryl or heterocyclyl groups are present; the moieties are the corresponding mono-, bi- or polycyclic moieties containing up to 18 ring members, preferably 5 or 6 ring members, and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur atoms, and alkyl moieties attached to these heterocyclic moieties containing 1 to 6; and wherein the substituent (s) 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, bromo, bromo 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 ² is hydrogen, an anionic charge or an ester protecting group of carboxyl functionality containing up to 20 carbon atoms provided that when R2 represents a hydrogen conductivity

means a mono-, bi- or polycyclic aromatic heterocyclic radical containing up to 18 ring members, at least one nitrogen atom and 0 to 5 additional heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted on carbon atoms 1 to 5, preferably 1-3 substituents independently selected from the group consisting of alkyl groups of 1 to 4 carbon atoms, alkyl groups of 1 to 4 carbon atoms substituted by one to three hydroxyl groups, amino groups, alkylamino groups of 1 to 4 carbon atoms, dialkylamino groups containing in each C 1 -C 4 alkyl moieties, C 1 -C 4 alkoxy, carboxyl groups, halogen atoms, preferably chlorine, bromine or fluorine, or sulfo groups, and C 3 -C 6 cycloalkyl groups, C 3 -C 6 cycloalkyl groups 6 carbon atoms in the cycloalkyl and 1 to 4 carbon atoms in the alkyl moiety; optionally substituted with one to three substituents listed above in connection with C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, amino, C 1 -C 4 alkylamino, dialkylamino each C 1 -C 4 alkyl moieties, halogen atoms, C 1 -C 4 alkanoylamino, C 1 -C 4 alkanoyloxy, carboxyl, sulfo, radicals of the formula

O

II —C — O-alk wherein alk represents a C1 -C4 alkyl group, a hydroxyl group, an amidino group, a guanidino group, a phenyl group, a phenyl group substituted with one to three substituents independently selected from amino, halogen atoms, hydroxyl groups , trifluoromethyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, carboxyl and sulfo groups, and phenylalkyl Groups containing 1 to 4 carbon atoms in the alkyl moiety in which the phenyl moiety may be optionally substituted with the 1 to 3 substituents listed above in relation to the phenyl group and the al248721 keel moiety may be optionally substituted with one to three substituents listed above in relation to the alkyl moieties C 1 -C 4 groups and heteroaryl or heteroaralkyl groups wherein the heterocyclic moiety is a mono-, bi- or polycyclic moiety containing up to 18 ring members, preferably 5 or 6 ring members, and 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms, and the alkyl moiety contains 1 to 6 carbon atoms, said heteroaryl and heteroaralkyl groups being optionally substituted on the heterocyclic ring by one to three substituents independently selected from the group consisting of hydroxyl, amino, halogen atoms, trifluoromethyl, alkyl groups of 1 to 4 atoms carbon, (C 1 -C 4) alkoxy, (C 1 -C 4) alkylamino, (C 1 -C 4) alkylamino, carboxyl and sulfo, and one to three substituents selected from the hydroxyl group in the alkyl moiety, amino, alkyl (C 1 -C 4) amino, (C 1 -C 4) dialkylamino, (C 1 -C 4) alkoxy, carboxyl, halogen and sulfo group, and on optionally present ring nitrogen atoms, with the exception of quaternized nitrogen by one up to three substituents independently selected from the group consisting of alkyl groups of 1 to 4 carbon atoms, alkyl groups of 1 to 4 carbon atoms substituted with one to three hydroxyl groups, amino groups, alkylamino groups of 1 to 4 carbon atoms, diialkylamino groups of 1 to 4 atoms C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxy, carboxyl, halogen or sulpho groups; C 3 -C 6 -cycloalkyl; C 1 -C 6 -cycloalkylalkyl; and C 1 -C 6 -alkyl optionally substituted by one to one with three uve substituents as defined above in connection with alkyl groups having 1 to 4 carbon atoms, furthermore phenyl, phenyl substituted with one to three substituents independently selected from the group consisting of amino, halogen atoms, hydroxyl, trifluoromethyl, alkyl groups of 1 to 4 atoms C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, carboxyl and sulfo; and C 1 -C 4 phenylalkyl; wherein the phenyl moiety may be optionally substituted with one to three substituents listed above in relation to the phenyl group, and the alkyl moiety may be optionally substituted with one to three substituents indicated in connection with the alkyl groups of 1 to 4 carbon atoms, and heteroaryl and heteroaralkyl groups, in wherein the heterocyclic moiety is as defined above and the alkyl moiety contains 1 to 6 carbon atoms, said heteroaryl and heteroaralkyl groups being optionally substituted in the heterocyclic ring by one to three substituents independently selected from the group consisting of hydroxyl, amino, halogen, trifluoromethyl C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, carboxyl and sulfo, and C 1 -C 4 alkyl; three substituents selected from the group consisting of hydroxyl, amino, (C 1 -C 4) alkylamino, (C 1 -C 4) dialkylamino, (C 1 -C 4) alkoxy, carboxyl, sulfonyl halogens, and their pharmaceuticals Useful salts, characterized in that the intermediate of the general formula IV

in which

R ^1, R ^8, and R ^{1 S} are as defined above, R ² 'is as defined above, a carboxy protecting group and

L is a conventional leaving group, such as toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, diphenylphosphinyloxy or halogen, reacted with a thiol of formula VII hs-a-Qt-r ⁵ χθ (vil)

in which

А а —О 'have the meaning given above, and

X ^- represents a balancing anion, in an inert solvent and in the presence of a base, to form a carbapenem derivative of the general formula Г

in which

are as defined above, from which optionally carboxy protecting group R ² 'is cleaved to give the corresponding unprotected compound of formula (I) or a pharmaceutically acceptable salt thereof.

The carbapenem compounds 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 the formula and to be named as 7-oxo-1-azabicyclo [3.2.0] hept-2-eu-carboxylic acid derivatives. The stereochemistry of the protons at the 5 and 0 positions of both cis and trans, however, has preferred compounds of 5R, 6S (trans) stereochemistry, 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. More specifically, R ⁸ can be a hydrogen atom and R ¹ can be a hydrogen atom or one of the substituents mentioned, for example, in European Patent Application No. 38,869 (see definition of R e). Alternatively, R ⁸ and R 1 may be taken together to form a C 2 -C 10 alkylidene group or a C 2 -C 10 alkylidene group 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 ¹⁵ may be a hydrogen atom or any other one of the 1-position substituents other than the hydrogen atom described, for example, in European Patent Application 54,917 (see the definition of R 1 or R ² in the cited application) or in U.S. Pat. Preferred substituents other than R ¹⁵ are C 1 -C 6 alkyl, most preferably methyl, phenyl and phenylalkyl C 1-6 carbon atoms in the alkyl moiety. The substituent R ¹⁵ , other than hydrogen, may be either in the β-configuration and in it and the invention includes both individual α- and β-isomers as well as 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 such moieties form part of more complex substituents, for example cycloalkylalkyl, heteroaralkyl or aralkenyl substituents, 247272, in such cases they contain alkyl, alkenyl and alkenyl groups preferably of 1 to 6, most preferably 1 to 4 carbon atoms.

b) The term "heteroaryl" refers to mono-, bi- and polycyclic aromatic heterocyclic groups containing up to 18 ring members with 1 to 4 oxygen, nitrogen or sulfur atoms, preferably five- or six-membered heterocyclic rings, such as thienyl, furyl ring , 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 up to 18 ring members and 1-4 oxygen, nitrogen or sulfur atoms, preferably five- or six-membered heterocyclic radicals, such as morpholinyl, piperazinyl , piperidyl, pyrazolinyl, pyrazolidinyl, imidazolidinyl, imidazolinyl, pyrrolnyl, pyrrolidinyl and the like.

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

By "carboxyl function protecting group" is meant a known ester group containing up to 20 carbon atoms which can be used to protect the carboxyl function during the chemical reactions described below and which can be cleaved, if desired, by methods which do not cause any significant destruction of the remainder of the molecule, for example by chemical or enzymatic hydrolysis, treatment with chemical reducing agents under mild conditions, irradiation with ultraviolet radiation, or 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. Such protective skiupins 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. The compounds represented by the general formula (I) in the form of acid addition salts can be represented by the general formula

(R ² = hydrogen or a protecting group) wherein X "is an anion of an acid, 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 basic groups are present in the radical R @ ¹ or in the substituent R @ ⁵ on the radical, 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-β-phenethylamine, N, N'-dibenzylethylenediamine and the like) in the case of acidic groups.

Compounds of formula (I) wherein:

R ² is hydrogen, an anionic charge or an ester hydrolyzable under physiological conditions, and the "pharmaceutically acceptable salts are useful as antibacterial agents. The remaining 248721 compounds of formula (I) are valuable intermediates that can be converted to the aforementioned biologically active compounds.

According to a preferred embodiment, compounds of formula (I) are prepared wherein R ⁸ is hydrogen and R ¹ is hydrogen, ethyl,

СНз \

CH—,

OF

СНз

СНз он \ l

C— or

OF

СНз

ОН

СНзСН—.

Preferred compounds of this subgroup are those compounds wherein R @ ¹ represents a group

OH

The most preferred compounds have an absolute configuration of 5R, 6S, 8R.

In accordance with another preferred embodiment, the invention includes compounds of formula I wherein R ¹ and R ⁸ together form an alkylldene radical of formula

HOCHz \

C =

OF

НзС

The alkylene moiety (i.e., " 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 in which A represents a radical - (гг) _п -, where n is 1 or 2, and in accordance with a particularly preferred embodiment, those compounds in which A represents a radical —CH2—, are produced.

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

^R5 is preferably optionally -substituted alkyl having 1 to 6 carbon atoms, alkenyl having 2 to 10 carbon atoms, an alkynyl group having 2 to 10 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, a cycloalkylalkyl group containing from 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 6 carbon atoms in the alkyl moiety, a phenyl group, a phenylalkyl group having 1 to 6 carbon atoms in the alkyl moiety, a phenylalkenyl group having 2 to 6 carbon atoms in the alkenyl moiety, a phenylalkinyl group having 2 to 6 carbon atoms in an alkynyl moiety, a heteroaryl group, a heteroaralkyl group in which the alkyl moiety contains 1 to 6 carbon atoms, a heterocyclyl group or a heterocyclylalkyl group having 1 to 6 carbon atoms in the alkyl moiety.

The heteroaryl moiety (or heteroaryl moiety of the heteroaralkyl moiety) of R ⁵ may be a mono-, bi- or polycyclic aromatic heterocyclic group containing from 1 to 4 oxygen, nitrogen or sulfur atoms. Preferably, they are 5- or 6-membered heterocyclic rings, such as o a thienyl, furyl, thiadiazolyl, oxadiazolyl, triazolyl, isothiazolyl, thiazolyl, imidazolyl, isoxazolyl, tetrazolyl, oxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, heterocyclyl or heterocyclyl moiety moiety; 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, 5- or 6-membered heterocyclic rings such as morpholinyl, piperazinyl, piperidyl, pyrazolinylo ring are preferred pyrazolidinyl, imidazolidinyl, imidazolinyl, pyrrolinyl and pyrrolidinyl.

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, preferably with one to three substituents, which are amino, fluorine and chlorine atoms, carboxyl, hydroxy or carbamoyl groups, (b) fluorine, chlorine or bromine atoms, ( c) the residue -OR ^3, (d) residues -OCO2R ³ (e) radicals -OCOR ^3, (f) residues - OCONR ³ R ^4, (g)

O II residues —O — S — R ⁹ ,

O (h) oxo groups, (i) —NR ³ R ⁴ , (1) —R ³ CONR ⁴ -, (k) —NR ³ CO a R ⁴ , (1) —NR ³ CONR ³ R ⁴ , (m)

O

II — NR ³ —S — R ⁹ ,

II o

(n) —SR ³ , (o) —SOR ⁹ , (P)

O o

(q) -SO 3 R ³ (R) -CO 2 R ³ (s) -CONR ³ R ^4, (t) -CN and C atoms, fluorine, chlorine and bromine, alkyl groups having 1 to 6 carbon atoms, -OR ³ , -NR ³ R ⁴ , -SO ² R ³ , -CO ² R ^3, and -CONR ³ R ⁴ , wherein the substituents R ³ and R ⁴ given above for the meanings of R ⁵ are independently selected from the group consisting of hydrogen, alkyl, alkenyl and (C 1 -C 10) alkynyl, cycloalkyl, cycloalkylalkyl and C 3 -C 6 -alkylcycloalkyl groups having 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 groups, wherein the heteroaryl and heterocyclyl group or moiety is as defined above for R ⁵ and the alkyl moiety bound to these heterocycles. the radicals containing 1 to 6 carbon atoms, or R ³ and R ⁴ together with the nitrogen atom to which at least one of these symbols is attached, may form a five- or six-membered nitrogen-containing heterocyclic ring (as defined above for R ⁵ ), and R ⁹ is as defined above for R ³ except hydrogen. The most preferred R ⁵ substituent is C 1 -C 6 alkyl, especially methyl.

In addition, R ^5, together with another atom in the ring of the residue, may form a fused heterocyclic or heteroaromatic ring, which ring may contain additional heteroatoms, preferably one or two heteroatoms selected from oxygen, nitrogen and sulfur. So grouping

G ~ ^RI (u) a phenyl radical optionally substituted with one to three substituents independently selected from the group zahrnujímůže mean residue e.g.

Particularly preferred are those compounds in which

R ⁸ represents a hydrogen atom and R ¹ represents a group

OH

СНзСН— and especially compounds with absolute configuration 5R, 6S, 8R.

In accordance with a preferred embodiment, it is a grouping

preferably represents a substituted or unsubstituted mono-, bi- or polycyclic aromatic heterocycle containing at least one nitrogen in the ring and optionally up to five additional heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen atoms, which heterocycle is attached to residue A via a ring carbon atom and its ring nitrogen atom is quaternized with R ⁵ .

In a preferred embodiment described above, those compounds wherein A is - [CH 2) _n -, wherein n is 1 or 2, and most preferably those in which A is -CH 2 -, and wherein [a R ¹ and R ⁸ together form a group

HOCH2 \

c = /

Or wherein (b) R ⁸ represents a hydrogen atom and R ¹ represents a hydrogen atom, a group

CH3CH2—,

СНз \

CH—,

OF

СНз

СНз ОН \ l с— z

СНз or

ОН

AND

СНзСН—.

an aromatic five- or six-membered nitrogen-containing heterocyclic ring containing optionally up to three additional heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen atoms. The aromatic heterocycle may, where possible, be non-fused to another ring, which may be a saturated or unsaturated carbocyclic ring, preferably a carbocyclic ring containing 4 to 7 carbon atoms, an aromatic carbocyclic ring, preferably a phenyl ring, a 4- to 7-membered heterocyclic ring. a ring (saturated or unsaturated) containing one to three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen atoms and the radical NR ¹¹ where R ¹¹ represents hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted by one or two substituents independently from each other selected from the group of radicals consisting of -OR ^3, -NR ³ R ^4, -CO 2 R ^3, oxo, phenyl, fluorine, chlorine and bromine, the radicals -SO 3 R ^3, and -CONR ³ R ⁴ or phenyl optionally substituted one to three substituents independently selected from the group consisting of alkyl groups of 1 to 6 atoms hlíku, radicals -OR ^3, -NR ³ R ^4, fluorine, chlorine and bromine, the radicals - SO 3 R ^3, -CO 2 R ³ and CONR ³ R ⁴ wherein R ³ and R ⁴ in these radicals R ¹¹ are as defined above in connection with the radical R ¹ , or a 5- to 6-membered heteroaromatic ring containing one to three heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen atoms and NR ¹¹ , wherein R ¹¹ is as defined above. A five- or six-membered aromatic quaternized ring or an optionally non-fused carbocyclic, heterocyclic or heteroaromatic ring, or both, may be optionally substituted on available ring atoms, preferably up to five substituents for the entire ring system. Suitable substituents are listed above in connection with the moiety representing a moiety selected from the group consisting of

a] residues of the general formula

In a preferred embodiment described above, those compounds in which A represents a group - (CH 2 -), wherein n is a number of 1 or 2, most preferably those compounds in which A represents a group -CH 2, and wherein (a) R 1 and R ⁸ together form a group

CHOOSE \ C =

OF

CH 3 or (b) R 8 represents a hydrogen atom and R 1 represents a hydrogen atom, a group

CHsCHz—,

CHs \ CH—,

OF

CHs

CH3 OH

OF

CH3 or

OH

AND

CHsCH—

Especially preferred are those. compounds wherein R 8 represents a hydrogen atom and R 1 represents a residue

OH

AND

CH3CH2, and in particular compounds with the absolute configuration of 5R, 6S, 8R.

In accordance with yet another preferred embodiment, compounds of formula I in which the moiety is formed are produced

⁵ R

Ή «·

in which

R 6, R 7 and R 14 are independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted with preferably one to three hydroxyl groups, C 1 -C 4 alkylamino groups carbon, C1-C4 dialkylamino in each alkyl moiety, C1-C4 alkoxy, amino, sulfo, carboxyl or halogen atoms (chlorine, bromine, fluorine or iodine, preferably chlorine, fluorine or bromine), C 3 -C 6 cycloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, amino, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino in each alkyl moiety halogen atoms (chlorine, bromine, fluorine or iodine, preferably chlorine, fluorine or bromine), alkanoylamino groups having 1 to 4 carbon atoms, alkanoyloxy groups having 1 to 4 carbon atoms; up to 4 carbon atoms, carboxyl, radicals of the formula

O

II — C — Oalk, where alk is C1 -C4 alkyl, hydroxyl, amidino, guanidino, phenyl, phenyl substituted with one, two or three amino groups, halogen atoms (chlorine, bromine, fluorine or iodine) (preferably chlorine, fluorine or thunder), hydroxyl groups, trifluoromethyl groups, (C 1 -C 4) alkyl or (C 1 -C 4) alkoxy groups, furthermore C 1 -C 4 -phenylalkyl groups in the alkyl part, wherein the phenyl part it may be optionally substituted with one to three substituents listed above in relation to the phenyl group, and the alkyl moiety may be optionally substituted with one. up to three substituents listed above in connection with β-C 1-4 alkyl groups. and heteroaryl and heteroaralkyl groups wherein the heteroatom or heteroatoms in the above heterocyclic radicals are selected from the group consisting of one to four oxygen, nitrogen and sulfur atoms and the alkyl moiety attached to the heterocyclic radical contains 1 to 6 carbon atoms, or wherein

R ⁶ , R ⁷ or R ^{10 taken} together form a fused saturated carbocyclic ring, a fused aromatic carbocyclic ring, a fused non-aromatic heterocyclic ring or a fused heteroaromatic ring, which fused rings are optionally substituted with one or two substituents listed above for R ⁶ , R ^{6 7} and R ¹⁰ ,

(b) residues of the general formula

carbon atoms, hydroxyl group, amidino group, guanidino group, phenyl group, phenyl groups substituted with one, two or three amino groups, halogen atoms (chlorine, bromine, fluorine or iodine, preferably chlorine, fluorine or bromine), hydroxyl groups, trifluoromethyl groups, alkyl groups (C 1 -C 4) groups or (C 1 -C 4) alkoxy groups; furthermore, C 1 -C 4 phenylalkyl groups in the alkyl moiety, wherein the phenyl moiety may be substituted with one to three substituents listed above in relation to the phenyl group and the alkyl moiety may be substituted. be optionally substituted with one to three substituents listed above in connection with alkyl groups of 1 to 4 carbon atoms, and further heteroaryl and heteroaralkyl groups, wherein the heteroatom or heteroatoms in the above heterocyclic radicals are selected from the group consisting of one to four oxygen atoms, nit or to sulfur and alikylová portion in the aforementioned heteroaralkyl radicals contain 1 to 6 carbon atoms or optionally substituted to form fused carbocyclic, heterocyclic or heteroaromatic ring optionally bearing one or two substituents mentioned above,

c) radicals of the formula optionally substituted on carbon atoms by one to three substituents independently selected from the group consisting of alkyl groups of 1 to 4 carbon atoms, alkyl groups of 1 to 4 carbon atoms substituted with preferably one to three hydroxyl groups, alkylamino groups of 1 up to 4 carbon atoms, sulfo groups, dialkylamino groups containing from 1 to 4 carbon atoms in each alkyl moiety, alkoxy groups having 1 to 4 carbon atoms, amino groups, carboxyl groups or halogen atoms (chlorine, bromine, fluorine or iodine, preferably chlorine, fluorine or bromo groups), cycloalkyl groups of up to 6 carbon atoms, alkoxy groups of 1 to 4 carbon atoms, alkylthio groups of 1 to 4 carbon atoms, amino groups, alkylamino groups of 1 to 4 carbon atoms, dialkylamino groups of 1 to 4 carbon atoms in each alkyl moiety halogens (chlorine, bromine, fluorine or iodine, preferably chlorine, fluorine) or bromine), (C 1 -C 4) alkanoylamino, (C 1 -C 4) alkanoyloxy, carboxyl, radicals of the formula

O-C-Oalk, wherein al'k represents an alkyl group of 1 to 5;

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, alkyl groups of 1 to 4 carbon atoms substituted, preferably, one of 2448721

d) radicals of formula (I) with up to three hydroxyl groups, C 1 -C 4 alkylamino groups, sulfo groups, C 1 -C 4 dialkylamino groups in each alkyl moiety, C 1 -C 4 alkoxy groups, amino groups, carboxyl groups or halogen atoms ( chlorine, bromine, fluorine or iodine, preferably chlorine, fluorine or bromine), C 3 -C 6 cycloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, amino, C 1 -C 4 alkylamino groups C 1 -C 4 dialkylamino, in each alkyl moiety C 1 -C 4, halogen atoms (chlorine, bromine, fluorine or iodine, preferably chlorine, fluorine or bromine), C 1 -C 4 alkanoylamino, C 1 -C 4 alkanoyloxy groups carbon atoms, carboxyl, radicals of formula

O

II-C-Oalk, where alk is C1 -C4 alkyl, hydroxyl, amidino, guianidino, phenyl, phenyl substituted with one, two or three amino groups, halogen atoms (chlorine, bromine, fluorine or fluorine; iodine, preferably chlorine, fluorine or bromine), hydroxyl groups, trifluoromethyl groups, alkyl groups of 1 to 4 carbon atoms or alkoxy groups of 1 to 4 carbon atoms, and phenylalkyl groups of 1 to 4 carbon atoms in the alkyl moiety, wherein the phenyl moiety it may be optionally substituted with one to three substituents mentioned above in relation to the phenyl group and the alkyl moiety may be optionally substituted with one to three substituents mentioned above in relation to the alkyl groups of 1 to 4 carbon atoms, and further heteroaryl and heteroaralkyl groups, or heteroatoms in the above-mentioned heterocycles The alkyl moieties in the above heteroaralkyl moiety contain 1 to 6 carbon atoms, or which are optionally substituted to form a non-fused carbocyclic, heterocyclic or heteroaromatic ring, optionally substituted with one or more carbon atoms. the two substituents listed above,

which are optionally substituted on carbon atoms. a substituent selected from the group consisting of alkyl groups of 1 to 4 carbon atoms, alkyl groups of 1 to 4 carbon atoms substituted with preferably one to three hydroxyl groups, alkylamino groups of 1 to 4 carbon atoms, dialkylamino groups containing 1 to 4 in each alkyl moiety carbon atoms, sulfo groups, (C 1 -C 4) alkoxy, amino, carboxyl or halogen atoms (chlorine, bromine, fluorine or iodine, preferably chlorine, fluorine or bromine), and cycloalkyl groups of 3 to 6 carbon atoms , (C 1 -C 4) alkoxy, (C 1 -C 4) alkylthio, amino, (C 1 -C 4) alkylamino, (C 1 -C 4) dialkylamino, halogen atoms (chlorine, bromine, fluorine or iodine) (preferably chlorine, fluorine or bromine), (C 1 -C 4) alkanoylamino, (C 1 -C 4) alkanoyloxy groups carboxyl, radicals of the formula

O

II-C-Oalk, wherein alk is C1-C4alkyl, hydroxyl, amidino, guanidino, phenyl, phenyl substituted with one, two or three amino groups, halogen atoms (chlorine, bromine, fluorine or iodine, preferably chlorine, fluorine or bromine), hydroxyl groups, trifluoromethyl groups, (C 1 -C 4) alkyl or (C 1 -C 4) alkoxy groups, furthermore phenylalkyl (C 1 to 4 carbon atoms) in the alkyl moiety, where the phenyl group may be optionally substituted with one to three substituents listed above for the phenyl group and the alkyl moiety may be optionally substituted with one to three substituents listed above for the alkyl groups of 1 to 4 carbon atoms, and heteroaryl or heteroaralkyl groups wherein the heteroatom or heteroatoms are selected from the group consisting of one to four oxygen, nitrogen or sulfur atoms and the alkyl moiety in the aforementioned heteroaralkyl group contains 1 to 6 carbon atoms, (e) a radical of formula (I) wherein X is oxygen, sulfur or NR wherein R is an alkyl group of 1 to 4 carbon atoms, C 1 -C 4 alkyl substituted with one to three hydroxyl groups, amino groups, C 1 -C 4 alkylamino groups, C 1 -C 4 diarkylamino groups in each alkyl moiety, C 1 -C 4 alkoxy groups, carboxyl groups , halogen atoms or sulfo groups, furthermore a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkyl alkyl group having 3 to 6 carbon atoms in the cycloalkyl and 1 to 4 carbon atoms in the alkyl part, optionally substituted with one to three substituents mentioned above in connection with the alkyl groups with 1-4 carbon atoms, phenyl, phenyl subs substituted with one to three substituents independently selected from the group consisting of amino, halogen atoms, hydroxyl, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylamino of 1 to 4 carbon atoms, dialkylamino containing in each alkyl moiety having from 1 to 4 carbon atoms, a carboxyl group and a sulfo group, furthermore represents a phenylalkyl group having from 1 to 4 carbon atoms in the alkyl moiety in which the phenyl moiety may be optionally substituted with one to three substituents mentioned above in relation to the phenyl group and the alkyl moiety may be optionally substituted with one to three substituents listed above in connection with alkyl groups of 1 to 4 carbon atoms, heteroaryl or heteroaralkyl groups wherein the heteroatom or heteroatoms are selected from the group consisting of 1 to 4 oxygen, sulfur and nitrogen atoms and the alkyl moiety in the aforementioned heteroaralkyl group contains 1 to 6 carbon atoms, the heteroaryl or heteroaralkyl group being optionally substituted in the heterocyclic moiety by one to three substituents independently selected from the group consisting of hydroxyl, amino, halogen atoms, trifluoromethyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino in each alkyl moiety, carboxyl and sulfo groups, and one to three substituents in the alkyl moiety selected from the group consisting of hydroxyl, amino, (C 1 -C 4) alkylamino, (C 1 -C 4) dialkylamino, (C 1 -C 4) alkoxy, carboxyl, halogen and sulfo, wherein the aforementioned heteroaromatic the residue is optionally substituted on carbon atoms by one or more substituents independently selected from the group consisting of alkyl groups of 1 to 4 carbon atoms, alkyl groups of 1 to 4 carbon atoms substituted with preferably one to three hydroxyl groups, amino groups, alkylamino groups of 1 to 4 4 carbon atoms, dialkylamino groups containing from 1 to 4 carbon atoms in each alkyl moiety, (C1 -C4) alkoxy, sulfo, carboxyl or halogen atoms (chlorine, bromine, fluorine or iodine, preferably chlorine, fluorine or bromine), C 3 -C 6 cycloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, amino, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, halogen atoms in each alkyl moiety (chlorine, bromine, fluorine or iodine, preferably chlorine, fluorine or b romu), (C1-C4) alkanoylamino, (C1-C4) alkanoyloxy, carboxyl, radical of the formula

O

II — C — Oalk, where alk is C1 -C6 alkyl, hydroxyl, amidino, guanidino, phenyl, phenyl substituted with one, two or three amino groups, halogen atoms (chlorine, bromine, fluorine or iodine); chlorine, fluorine or bromine), hydroxyl groups, trifluoromethyl groups, C 1 -C 4 alkyl groups or C 1 -C 4 alkoxy groups, furthermore a C 1 -C 4 phenylalkyl group in the alkyl moiety, wherein the phenyl moiety may be optionally substituted with one to three substituents listed above in relation to the phenyl group, and the alkyl moiety may be optionally substituted with one to three substituents listed above for the alkyl groups of 1 to 4 carbon atoms, and heteroaryl and heteroaralkyl groups in which the heteroatom or heteroatoms are selected from the group consisting of day to four oxygen, nitrogen or sulfur atoms; and the alkyl moiety in the aforementioned heteroaralkyl radical contains 1 to 6 carbon atoms, or is optionally substituted to form a fused carbocyclic, heterocyclic or heteroaromatic ring optionally substituted with one or two of the above substituents; ) a residue of the general formula

К + w -NR ⁵ wherein X is oxygen, sulfur .or · NR, wherein R is alkyl of · 1-4 carbon atoms, alkyl having 1 to 4 carbon atoms substituted by one to three hydroxyl groups, amino, alkylamino (C1-C4) -alkynyl, (C1-C4) -alkylamino, (C1-C4) -alkoxy, (C1-C4) -alkoxy, carboxyl, halogen or sulfo-groups, (C3-C6) -cycloalkyl, (C3-C6) -cycloalkyl) up to 6 carbon atoms in the cycloalkyl and 1 to 4 carbon atoms in the alkyl moiety, optionally substituted with one to three substituents listed above in connection with the alkyl groups of 1 to 4 carbon atoms, phenyl, phenyl substituted with one to three substituents independently of one another selected from the group consisting of amino, halogen atoms, hydroxyl group; upin, trifluoromethyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, carboxyl and sulfo; a C 1 -C 4 -phenylalkyl group in which the phenyl moiety may be optionally substituted with one to three of the above substituents in relation to the phenyl moiety and the alkyl moiety may be optionally substituted with one to three substituents listed above. substituted with one to three substituents listed above in connection with alkyl groups of 1 to 4 carbon atoms, heteroaryl or heteroaralkyl groups wherein the heteroatom or heteroatoms are selected from the group consisting of one to four oxygen, sulfur or nitrogen atoms and the alkyl portion of the heteroaralkyl group contains 1 heteroaryl and heteroaralkyl groups optionally substituted in the heterocyclic ring by one to three substituents independently selected from the group consisting of hydroxyl, amino, halogen atoms, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy (C až-C uhlíku) alkyl, (C až-C alky) alkylamino, (C až-C dial) dialkylamino, carboxyl and sulfo groups, and one to three substituents selected from the group consisting of Cnu-C substitu alkyl; hydroxyl, amino, (C 1 -C 4) alkylamino, (C 1 -C 4) dialkylamino, (C 1 -C 4) alkoxy, carboxyl, halogen and sulfo, wherein the aforementioned heteroaromatic radical is optionally substituted on the carbon atom with a substituent selected from the group consisting of alkyl groups of 1 to 4 carbon atoms, alkyl groups of 1 to 4 carbon atoms substituted with preferably one to three hydroxyl groups, amino groups, alkylamino groups of 1 to 4 carbon atoms, dialkylamino groups containing in each C 1 -C 4 alkyl moieties, C 1 -C 4 alkoxy, sulfur, carboxyl or halogen atoms (chlorine, bromine, fluorine or iodine, preferably chlorine, fluorine or bromine), C 3 -C 6 cycloalkyl groups C1-4 alkoxy, alk C 1 -C 4 ylthio, amino, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, halogen atoms (chlorine, bromine, fluorine or iodine, preferably chlorine, fluorine or bromine) , (C1-C4) alkanoylamino, (C1-C4) alkanoyloxy, carboxyl, radical of the formula

O

II — C — Oalk, where alk is C1 -C4 alkyl, hydroxyl, amidino, guanidino, phenyl, phenyl substituted with one, two or three amino groups, halogen atoms (chlorine, bromine, fluorine or iodine); preferably chlorine, fluorine or bromine), hydroxyl groups, trifluoromethyl groups, alkyl groups of 1 to 4 carbon atoms or alkoxy groups of 1 to 4 carbon atoms, furthermore a phenylalkyl group of 1 to 4 carbon atoms in the alkyl moiety in which the phenyl moiety may be optionally substituted with one to three substituents listed above for the phenyl group, and the alkyl moiety may be optionally substituted with one to three substituents listed above for the alkyl groups of 1 to 4 carbon atoms, and a heteroaryl or heteroaralkyl group wherein the heteroatom or heteroatoms are selected from the group consisting of one to th the three oxygen, nitrogen and sulfur atoms and the alkyl portion of the above heteroaralkyl group contains 1 to 6 carbon atoms, and (g) radicals of formula

N- ~~ N — R 5 t R 1 1 N-R

~ R

wherein R is C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted with one to three hydroxyl groups, amino groups, C 1 -C 4 alkylamino groups, C 1 -C 4 dialkylamino groups in each alkyl moiety , (C 1 -C 4) alkoxy, carboxyl, halogen or sulpho groups, a (C 3 -C 6) cycloalkyl group, a cycloalkylalkyl group containing up to 6 carbon atoms in the cycloalkyl and 1 to carbon atoms in the alkyl moiety optionally substituted by one to three substituents listed above in connection with alkyl groups of 1 to 4 carbon atoms, phenyl, phenyl substituted by one to three substituents independently selected from the group consisting of amino, halogen atoms, hydroxyl, trifluoromethyl, alkyl groups of 1 to 4 atoms at C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, carboxyl and sulfo; and C 1 -C 4 phenylalkyl; wherein the phenyl moiety may be optionally substituted with one to three substituents listed above in relation to the phenyl group, and the alkyl moiety may be optionally substituted with one to three substituents listed above with respect to the C 1-4 alkyl groups, or a heteroaryl or heteroaralkyl group; wherein the heteroatom or heteroatoms are selected from the group consisting of one to four oxygen, sulfur and nitrogen atoms and the alkyl portion of the heteroaralkyl group contains 1 to 6 carbon atoms, wherein the heteroaryl and heteroaralkyl group is optionally substituted in the heterocyclic ring by 1 to 3 substituents independently selected from the group consisting of hydroxyl, amino, halogen atoms, trifluoromethyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, dialkylamino groups in each alkyl moiety in each case of 1 to 4 carbon atoms, a carboxyl group and a sulfo group, and in the alkyl moiety with one to three substituents selected from the group consisting of hydroxyl, amino, (C 1 -C 4) alkylamino, (C 1 -C 4) dialkylamino, C1-C4alkoxy, carboxyl, halogen and sulfo. The radicals R @ ⁵ and R @ ⁵ may also be combined to form an unfused heterocyclic or heteroaromatic ring.

In a preferred embodiment described above, those compounds wherein A is - (CH 2) n - are preferred, wherein n is a number of 1 or 2, more preferably those in which A is --CH 2 - and wherein ( (a) R ¹ and R ⁸ together form a grouping

HOCH2 \

C = /

CH 3 or (b) R ⁸ represents a hydrogen atom and R 1 represents a hydrogen atom, a CH 3 CH 2 - group in which

R 6, R 7 and R 10 are independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, carboxyl, and carbamoyl,

^R is as defined above and preferably represents an alkyl group having 1 to 6 carbon atoms, most preferably methyl.

In the above preferred embodiment, preferred are those compounds wherein A is - (CH 2) n - wherein n is an integer of 1 or 2, most preferably those wherein A is -CH 2 - and wherein ( (a) R 1 and R 8 together form a grouping

CHs \ CH—,

OF

CH3

HOCH2 \

C = Z CH 3

CHs OH \ l c— /

CH3 or

OH

CH3CH—.

Particularly preferred are those in which R 8 represents a hydrogen atom and R 1 represents a group

OH

AND

CH3CH2, especially compounds with the absolute configuration of 5R, 6S, 8R.

In accordance with a particularly preferred embodiment of the process of the invention, compounds of formula (I) are prepared in which or (bj R 8 represents a hydrogen atom and R 1 represents a hydrogen atom, a CH 3 CH 2 - group).

CH3 \

CH—

OF

CH3

CH3 OH

CH3 or

OH

I онзсн-.

Particularly preferred are those in which R 8 represents a hydrogen atom and R 1 represents a residue

AND

OH

CH3CH2 represents a radical of formula

especially compounds with the absolute configuration of 5R, 6S, 8R.

In accordance with a further preferred embodiment, the present invention provides a process for the preparation of compounds of formula (I), wherein the grouping of formula (I) is a compound of formula (I).

a radical of formula (a) in which

R ⁵ represents a C 1 -C ⁶ alkyl group, most preferably methyl a

R ⁶ represents a C 1 -C 4 alkyl group, most preferably a methyl group, a radical of formula (e) in which:

R ⁵ is C 1 -C 4 alkyl, most preferably methyl, and

R ⁶ represents a hydrogen atom or a C 1 -C 4 alkyl group, a radical of formula (b)

in which

R ⁵ represents a C 1 -C 4 alkyl group, most preferably a methyl group, and

R ⁶ and R ⁷ are each hydrogen or C 1 -C 4 alkyl, the radical of formula (c) -YJ in which:

R ⁵ represents a C 1 -C 4 alkyl group, most preferably methyl a

R represents a (C1-C4) alkyl group or a (C1-C4) phenylalkyl group, the radical of formula (d)

in which

R ⁵ represents a C 1 -C 4 alkyl group, most preferably a methyl a group

R represents a C 1 -C 4 alkyl group, most preferably a methyl group, or a radical of formula (f)

in which

R ⁵ represents a C 1 -C ⁶ alkyl group, most preferably a C 4 -C 4 alkyl group, most preferably a methyl group.

Within the above-described preferred embodiment, preferred compounds are those in which A represents - (CH _{2) n} - wherein n is the integer 1 or 2 and most preferred are those compounds wherein A is a group - CH ₂ - and wherein (a) R ¹ and R ⁸ together form a grouping

BOY?

\

C =

OF

Or where (b) R ⁸ represents a hydrogen atom and R ¹ represents a hydrogen atom, CH 3 CH 2 -,

СНз \ CH—,

OF

CHs or

СНз OH \ l c /

СНз

OH

AND

СНзСН—.

Particularly preferred are those compounds wherein R ⁸ is hydrogen and R ¹ is a group

OH

СНзСН—, especially compounds with absolute configuration 5R, 6S, 8R.

According to the most preferred embodiment of the process according to the invention, those compounds in which the groupings are produced are produced

represents the remainder of formula (a) (ь) \ =. _w ⁺ \ ^Сн з

CH ₃

Лэ

Cd) - 0 ⁺ ^ ^- ^ ^{сн г сн} 2 ^{сн з}

CH ₃

4'8 721

In particular: compounds having the absolute configuration of 5R, 6S, 8R.

Particularly preferred compounds of the invention are those of the formula

5Í)

OH

or '/' CHdΛ · ’<

(and)-

Ν — N '' X

CH ₃

Within . of this preferred embodiment are those wherein A is - (cH 2) h - where n is an integer of 1 or 2, and most preferably those in which A is -CH 2 - and wherein (a) R 1 and R 8 together form a grouping

HOCH2 \

C =

OF

CH 3 or wherein (b) R 8 is hydrogen and R 1 is hydrogen, CH 3 CH 2 -,

CHs \

CH—,

OF

CHS

CH3 OH

OF

CH3 of him oH

AND

CH3CH—.

in which . .

R ² stands for. atom. hydrogen, anionic charge or conventional. an easily cleavable protecting group of the carboxyl function, provided that it is R2. a hydrogen atom or a protecting group, a buffer ion is also present, and wherein the moiety "S-A" is a radical of formula

(b) -SCH 2 CH 2 O 3 -Cl 3

Particularly preferred are those in which

R 8 represents a hydrogen atom and R 1 represents a residue

(о

(h)

(a)

^сн 3 (а) (о)

^сн з>

сн ₇

(к)

whose 1 H-NMR spectrum (deuterium oxide, δ values) contains the following characteristic signals:

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 to 4.68 (10H, multiplet)

8.19 (1H, singlet);

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

(Ί)

which represents a radical of formula ^X H-NMR (deuterium oxide) .delta following characteristic signals:

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 to 4.65 (10H, multiplet)

8.62 (1H, singlet);

ch ₃

In the above embodiment, preferred are those compounds wherein A is - (CH 2) _n - wherein n is an integer of 1 or 2, and most preferably those compounds wherein A is -CH 2 - and wherein (a R ¹ and R ⁸ together represent a grouping

HOCHž

X

C =

OF

Or wherein (b) R ⁸ is hydrogen and R ¹ is hydrogen, CH 3 CH 2 -,

CH31

X CH—, Z

СНз

СНз он

XI с— Z

СНз or

ОН

СНзСН—.

Particularly preferred are those wherein R ⁸ is hydrogen and R ¹ is a group

OH

And especially compounds with the absolute configuration of 5R, 6S, 8R.

In the process of the invention, 247272 is used at a temperature of about 0 ° C. The intermediate can be optionally isolated, but is conveniently used as a starting material for the process according to the invention without isolation or purification.

In the process according to the invention, the carbapenem intermediate of formula (VII) uses intermediates corresponding to formula (IV)

which are described, for example, in European Published Application No. 38,869 and European Patent Application No. 54,917, and which can be prepared by the general methods described in U.S. Pat. cited works. The symbol L represents a conventional leaving group (defined in the European Published Application No. 38,869 by the symbol "X"), such as chlorine, bromine or iodine, benzenesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, methanesulfonyloxy, di-trifluoromethanesulfonyloxy, trifluoromethanesulfonyloxy, trifluoromethanesulfonyloxy The preferred leaving group is diphenoxyphosphinyloxy The intermediates of formula (IV) are usually prepared in situ by reaction of an intermediate of formula (III).

in which

R 1, R 8, R 15 and R ² 'are as defined above, and a suitable acylating agent of formula

R ° —L

A preferred intermediate of formula IV wherein L is diphenoxyphosphinylnyloxy 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 chlorosilate in the presence of a base such as diisopropylethylamine, triethylamine , 4-dimethylaminopyridine and the like, at a temperature from about -20 ° C to +40 ° C, most preferably 1-S-A-N + -R ^S

X ~ (VII) in which grouping

has the above meaning,

X - represents the counterion 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 of formula (IV) with the thiol of formula (VII) can be carried out over a wide range of temperatures, for example from -15 ° C to room temperature, but preferably from about -15 ° C to +15 ° C, most preferably at about 0 ^o 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 [for example (C6H5O2PO4-, Cl- or an anion contained in a quaternary thiol) which can be replaced at this stage by another balancing anion, for example Alternatively, the balancing anion can be removed in a subsequent 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 reaction. 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 function protecting group R ² 'in the compound of formula (Г) can optionally be cleaved by conventional methods such as sololysis, 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 (G) 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, oxide platinum or the like at a temperature of from 0 to 50 ° C for about 0.24 to 4 hours. When R ² 'is as o-nitrobenzyl group, such protecting group can be cleaved also by photolysis. Such protecting groups, such as 2,2,2-trichloroethyl, can be cleaved off by a 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 mentioned above, those compounds of formula Г in which R ² 'is a physiologically hydrolyzable ester moiety such as acetoxymethyl, phthalidyl, indanyl, pivaloyloxymethyl, methoxymethyl, and the like can be administered directly to the patient without cleavage of the protecting group since these esters are hydrolyzed in vivo under physiological conditions.

It will be understood that if a radical R, ¹ R ⁸ , R ⁵ or R ¹⁵ , or a quaternized heteroaromatic group attached to substituent A contains a functional group which may be detrimental to the intended course of the reaction, such a group may be protected by a conventional protecting group. and the protecting group is then cleaved 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 β-lactam antibiotics, the compounds of formula (I) may be converted by known methods into pharmaceutically acceptable salts which, for purposes of the invention, are substantially equivalent to non-salt compounds. For example, the compound of formula I wherein R ² is an anionic charge, dissolved in a suitable inert solvent а к solution then add an equivalent amount of a pharmaceutically acceptable acid. The desired acid addition salt can be isolated by conventional procedures, for example by solvent precipitation, lyophilization, and the like. When other basic or acidic functional groups are present in the compound of formula (I), the corresponding pharmaceutically acceptable acid addition salts and addition salts can be prepared. with bases.

A compound of formula I wherein R ² is a hydrogen atom or an anionic charge, or a pharmaceutically acceptable salt thereof, can also be converted by conventional methods to the corresponding compound wherein R ² is a physiologically hydrolyzable ester group, or a compound of formula I wherein R 2 ² is a conventional carboxyl-protecting group, may be converted to the corresponding compound wherein R ² 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 a 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

CH ₃ CS-A wherein A is as defined above and the group

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

R ⁵ —X '

SO in which

R 5 is as defined above, and

X '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, , 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 formula IV in order to minimize the decomposition of the relatively unstable quaternary thiol of 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 2 represents a hydrogen atom, 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 feed additives for growth stimulating animals, as food and feed preservatives, as bactericides for industrial applications, for example, in water based and white water based paper formulations to inhibit the growth of harmful bacteria, and as disinfectants to kill or inhibit the growth of harmful bacteria at medical and dental facilities. However, the disclosed compounds are particularly useful for 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 can 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. These compositions may be in a 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 route 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 examples, which are not intended to limit the scope of the invention in any way.

The abbreviations used in these examples have the following meanings:

Methyl

Et = ethyl

Ph = (enyl

Ac = acetyl

Ms = methanesulfonyl (mesyl)

Ts = p-toluenesulfonyl (tosyl) Tf = trifluoromethanesulfonyl PNB = p-nitrobenzyl

Example 1

Preparation of 3- [4- (N, N-dimethyl-1,2,3-triazolium) methylthio] -6- [li (R) -hydroxyethyl] -7-oxo-1-azabicyclo [3.2.0] hept -2-ene-2-carboxylate

A. Preparation of Isomers A

a) MeOTf

b) aqueous NaOH

SAc /

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) of stirring under nitrogen. methylene trifluoromethanesulfonate. After 0.5 hour the cooling bath was removed and after 1 hour the solvent was evaporated under reduced pressure. The oily residue is dissolved in a few milliliters of water, the solution is cooled in ice, a cold solution of 305 mg (7.59 mmol) of sodium hydroxide in a few milliliters of water is added, and the reaction mixture is 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), then the resulting suspension was transferred to a pressure vessel using 20 ml of terahydrofuran and 20 ml of water. After the addition of 30 ml of ether and 1.0 g of 10% palladium on carbon, the mixture is hydrogenated at 50 psi for 1 hour, then the organic phase is washed twice with 5 ml of water each time. The combined aqueous phases are filtered, and the filtrate is concentrated under high vacuum (ca 67 Pa) for 1.5 hours. The residual yellow solution was subjected to medium pressure chromatography on a reverse phase column (35 x 90 mm), eluting with water. After lyophilization, 395 mg of a carbapenem derivative is slightly contaminated with some inorganic material. This product after purification by high resolution chromatography (10 x 300 mm, Microhondapack C-18 column, multiple injections, water as eluent) gave 310 mg (57%) of the isomers A as a red-yellow powder.

-NNMR (deuterium oxide, δ in ppm):

1.23 (3H, doublet, J = 6.4Hz),

3.10 (2H, doublet, J = 9.1 Hz),

3.24 (1H, quartet, J = 2.7, 6.1 Hz),

4.03 to 4.71 (10H, m),

8.46 (1H, singlet).

IC (nujol): 1760 cm ^-1 .

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

A _max 296 (ε = 7,500).

B. Preparation of Isomer B and Isomer C

(experimental structure)

a) MeOTf

b) aqueous NaOH

N-Me

N

To January! to a cooled solution of 1; 2θ g (7; 02 mmol) of 4- (methanethiolphetate) -2-methyl-1,2,3-triazole in 6 ml of dry methylene chloride is added dropwise under nitrogen to 1.60 l (14.0 ininols) The mixture was allowed to warm to room temperature, stirred for 16 hours, then an additional 0.40 mL (3.56 mmol) of methyl methanesulfonate was added and the reaction was stirred at room temperature for 3 hours with a solvent. The oily residue is triturated with lithium, the resulting gummy product is dissolved in 5 ml of water, the solution is cooled in ice, and a solution of 844 mg (21.1 mmol) of sodium hydroxide in 5 ml of water is added. agitation for 0.75 hours is diluted with water to a volume of 60 ml and adjusted to pH 8 by addition of solid potassium hydrogen phosphate (40.7 ml of this solution (about 4.7 g of triazolium-thiol mixture) with stirring, to an ice-cooled solution of 2.00 g (3.45 mmol) of enol phosphate in 60 ml of tetrahydrofuran was added. The mixture was stirred under ice-cooling for 0.5 hours and then transferred to a pressure vessel containing a suspension of 2.00 g of 10% palladium on carbon in 60 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 mmHg) for 1.5 hours. The residual solution is subjected to medium pressure chromatography on a reverse phase column (45 x 130 less), using water as the eluent. After lyophilization of the eluate, 595 mg of a mixture of isomeric carbamates, contaminated with small amounts of inorganic material, were obtained. The aforementioned isortic products are separated and purified by high performance liquid chromatography (Mlcrobbndapack C-18; 10 x 300 mm, multiple slag, water as eluent). So the rivers were washed out; acquiring:

isomer B in a yield of 193 ing (13%);

1 H-NMR (déuterium oxide, δ in ppm):

1.23 (3H, doublet); 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 to 4.68 (10 M, OD);

8.19 (1H, shinglet).

IR (nujbl): 1755 cm-1

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

Λ max 296 nm · (έ = 6,700) and the isomer of Yields 2.4 mg (24%);

@ 1 H-NMR (d6-d3, 8 in jbpm):

1.23 (3H, doublet, J = 6.4 Hz),

3.15 (2H, quartet, J = 3.7, 9.0 Hz),

3.27 (1H, quartet, J = 2.6, 6.0 Hz),

3.95 to 4.65 (10H, m),

8.62 (1H, singlet).

1.52 (3H, triplet, J = 7.1Hz, 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).

IR (nujol): 1750 cm ^-1 .

UV (phosphate buffer, pH 7.4, 0.05 M): λ _max 298 nm (ε = 7,600).

Example 2

B. 1R-Thiadlazol-a-ylmethanol (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 [S. I. Ramsby, S.O. Ogren, S.B. Rose and N.

E. Stjernstrom, Acta Pharm. Succica 10,

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

O i!

CClib Cfb.OH —-- JI \\

TO! 4,

XA. Ethyl 1,2,3-thiadiazol-4-ylcarboxylate [C. D. Hurd and R.I. Sea, J. Am. Chem. Soc., 77, 5, 359 (1955)].

O i!

mco £

o il

COEt n soci, c ----- *

CH ₄ COEt ^ó II o

A solution of ethyl N, N-ethoxycarbonylhydrazonopropionate (31.2 g, 0.154 mol) in thionyl chloride (80 ml) was stirred at 23 ° C for 3 hours and then heated to 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 incipient crystallization. The mixture was allowed to stand for a while at 23 ^Q 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. 3.17 g of product (13%) are obtained, m.p. 86 ° C.

IR (KBr):

v _max 1,720 (ester) cm ^-1 .

@ 1 H-NMR (CDCl3, < 5 ppm):

To a suspension of 18.35 g (0.116 mol) of ethyl 1,2,3-thiadiazol-4-ylcarboxylate in 400 ml of ether was added portionwise 2.47 g (0.065 mol) of lithium aluminum hydride over 1 hour. The mixture was stirred for 7 hours at 23 ^Q C bat к FNI an additional 2.47 g (0.065 mole) of lithium aluminum hydride was added and stirring was continued for 24 hours. 7 ml of water, 7 ml of 15% sodium hydroxide solution and 21 ml of water are added successively to the reaction mixture, which is stirred for 15 minutes and the ether solution is decanted off. The resinous residue is extracted five times with 100 ml of ether each time, the ether extracts are combined, dried over magnesium sulphate and concentrated. The crude product (5.4 g) was purified by column chromatography (4 x 16 cm) with 120 g of silica gel using ether as the eluent. 1.3 g (7%) of ethyl 1,2,3-thiadiazol-4-yl carboxylate and 2.45 g (18%) of 1,2,3-thiadiazol-4-ylmethanol are obtained.

IC (film): p _max 3,380 (OH) cm ^-1 .

1 H-NMR (CDCl 3, δ ppm):

2.31 (1H, singlet, OH);

5.22 (2H, singlet, CH2 O),

8.50 (1H, singlet, proton of the thiadiazole residue).

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

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 added.

β.3

Analysis: for C 6 H 5 N 2 O 5 S, 1.018 ml (7.3 mmol) of triethylamine and 0.565 ml (7.3 mmol) of methanesulfonyl chloride were added thereto. 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, dried over magnesium sulfate and magnesium oxide, and concentrated. The residue was purified by silica gel column chromatography (1.5 x 21 cm) using ether as the elution solvent. 0.90 g (71%) of 1,2,3-thiadiazol-4-ylmethanol-methanesulfonate is obtained.

IC (film):

v _wn x 1350 (SO2), 1172 · (SO2) cim-1.

1 H-NMR (CDCl 3, δ ppm):

3.09 (3H, singlet, CH3),

5.75 (2H, singlet, CH 2),

8.72 (1H, singlet, proton of the thiazole residue).

calculated:

% C, 24.73;% H, 3.11;% N, 14.42.

33.02% S, found:

% C, 24.78;% H, 3.09;

31,94% S.

Further, 0.13 g (19%) of di- (1,2,34,8-diazol-4-ylmethyl) ether was obtained.

IR · (film) in _ma x:

272, 1242, 1200, 986, 805, 728 cm @ -1. @ 4 H-NMR (CDCl3) .delta.

5.16 (singlet, 4H, CH 2),

8.42 (singlet, 2H, protons of the thiadiazole residue).

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

UV (dimethylene): v ^ 251 (ε = 1,990).

CHpOMs o

nZ CH-JcSNa _x in ^h

O

II 5CCH ₃

To a solution of 0.90 · g (4.6 mmol) of 1,2,3-triaciazol-4-ylmethanol methanesulphate in 9 ml of tetrahydrofuran was added 2 ml of aqueous sodium thioacetate solution (prepared from 0.38 ml (5.3 mmol)). thiol acetic acid and 0.445 g (5.3 mmol) of sodium bicarbonate). The resulting mixture was stirred at 23 ° C for 1 hour then. The mixture was diluted with 75 ml of ether, washed three times with 3 ml of water each time and, after drying with magnesium sulfate, concentrated. The crude product is obtained after purification. silica gel column chromatography (1.4 x 19 cm), eluting with 50% ether in hexane. 0.60 g (75%) of the desired product.

IC (film): vmnx 1675 (C = O) cm ^-1 .

1 H-NMR (CDCl 3, δ ppm):

2.37 (3H, singlet, CH 3),

4.58 (2H, singlet, CH 2),

8.44 (1H, singlet, proton of the thiadiazole residue).

Analysis:. for. C5H6N2OS2 calculated:

% C, 34.47;% H, 3.47;% N, 16.08;

36.80% S, found:

% C, 34.48;% H, 3.83;% N, 16.28.

36,80% S.

E. 4-Acetylthiomethyl-2-methyl-1,2,3-thiadiazolium trifluoromethanesulfonate. and

4-acetylthiomethyl-3-methyl-1,2,3-thiadiazolium trifluoromethanesulfonate

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 was added several crystals of the title compound and over 5 minutes 0.407 ml (3). Methyl trifluoromethanesulfonate (6 mmol) The reaction mixture was stirred at 23 ° C under nitrogen for 6 h, and the precipitated white solid consisting of a mixture of the title compounds was filtered off and washed with ether to yield 1.05 g. (90%).

IR (KBr):

i> _max 1675 (C = O) cm ^-1 .

¹ H-NMR (perdeuterodimethylsulfoxide, δ in ppm):

2.43 (3H, singlet, CH 3 COS),

3.33 (singlet, СNз on nitrogen in position 3),

4.57 (singlet, СNз on nitrogen in 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).

For C7H9N2O4S3F3 calculated:

20.27 θ / ο C, 2.38% H, 9.45 θ / ο N,

32,46% S, (V found:

H, 2.57; N, 8.47.

28.21% S.

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

O

II

CHoSCCH, ¹ J ·> ♦

6N HCl

A solution of 1.05 g (3.1 mmol) of a mixture of 4-acetyl thiomethyl-2-methyl-1,2,3-thiadiazolium trifluoromethanesulfonate and 4-acetylthiomethyl-3-methyl-1,2,3-thiaidiazolium trifluoromethanesulfonate in 10 ml of 6 N 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 product is used as is in the following stage.

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

OH

10% Pd on carbon ether, tetrahydrofuran, water

К cold ^(5? C) solution of 1.7 g (2.92 mmol) of (5R, 6S) -p-nitrobenzyl 6- (lR-hydroxyethyl) -3-diphenylphosphono] -7-oxo-azabicyclo 3 2.0] Hept-2-ene-2-carboxylate in 10 mL of tetrahydrofuran was 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. Stirring is continued for 1 hour, 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 g for 2 hours in the presence of 2 g of 10% palladium on carbon. kPa. The aqueous phases from 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 was obtained which, after purification by high performance liquid chromatography using water as eluent, afforded 0.040 g (4%) of the title compound (after lyophilization).

IR (KBr): _νnx

400 (wide belt, OH),

1745 (C = O (S-lactam)

580 (carboxylate) cm ^-1 .

@ 1 H-NMR (CDCl3) .delta. = 1.23 (3H, doublet, J = 6.3 Hz, 2H), 3.04, 3.05, 3.16 (2H, multiplet, H-4) ,

3.38 (1H, double doublet, J = 2.8 Hz, 1 = 6.0 Hz, H-6), ~ 3.9-4.6 (2H, multiplet, H-5, SNN), 4, 51, 4.53 (two singlets, SCHZ),

4.61 (singlet, N + S).

UV (water) A _max

224 (ε = 4,345),

262 (ε = 4,980)

296 (ε = 6,885).

[α] ²³ = 18 ° (с = 0.18, water).

Tj / 2 = 9.8 hours (measured at 10 ^-4 M in phosphate buffer pH 7.4 at 36.8 ° C).

Example 3

Potassium-3- [5- (1-carboxylatomethyl-3-methyl-1,2,2,3-triazolium) methanthio] -6α- [1- (R) -hydroxyethyl] -7-oxo-1-azabicyclo [ 3,2,0] hept-2-ene-2-carboxylate

9-g suspension (70.9 mmol) of 1-methyl-1,2,3-triazole-4-carboxylic acid [C. Pederson, Acta. Chem. Scand., 1959, 13, 883] in 200 ml of dry tetrahydrofuran, 2.83 g (70.9 mmol) of lithium aluminum hydride are added in small portions with stirring. The mixture was stirred for 15 hours at room temperature, followed к added carefully 20 ml of 20% aqueous sodium hydroxide solution ¹ (in doses of about 1 ml). The resulting suspension is filtered and the solid material is washed five times with 75 ml of tetrahydrofuran each time. The combined tetrahydrofuran solutions were dried over magnesium sulfate and the solvent was evaporated. The yellow oily residue was subjected to flash column chromatography (90 x 35 mm) of silica gel using 100 ml of hexane each time, firstly 1: 1 and then 1: 3 ethyl acetate and hexane, and finally 9: 1 ethyl acetate / methanol. 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, δ ppm):

4.07 (3H, singlet);

4.73 (2H, doublet),

7.52 (1H, singlet).

IC (in substance): 3,320 cm ⁴ .

To an ice-cooled solution of this alcohol (4.67 mL, 41.3 mmol) and triethylamine (7.47 mL, 53.7 mmol) in methylene chloride (20 mL) was added methanesulfonyl chloride (3.82 mL, 49.6 mmol) dropwise with stirring. 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 thiol acetate are added to the solution

The suspension was stirred at room temperature for 3 hours, then an additional 3.0 g (26.3 mmol) of potassium thiolacetate was added and stirring was continued for 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 flash column chromatography on silica gel (90 < 36 mm) using hexane first and then a mixture of equal portions of hexane and ethyl acetate as eluents to give 5.95 g (84%) of 4- (methanthiolacetate) - 1-methyl-1,2,3-iriazole as a slightly pink solid.

1 H-NMR (CDCl 3, δ in ppm):

2.40 (3H, singlet).

4.10 (3H, singlet);

4.20 (2H, singlet),

7.53 (1H, singlet).

IC (nujol suspension): 1675 cm ^-1 .

A solution of the triazole (1.00 g, 5.85 mmol) and ethyl bromoacetate (1.43 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. There was thus obtained 1-methyl-3- (ethylcarboxymethyl) -4-methanthioacetate-1,2,3-triazolium bromo-1 as a brownish gum which was 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 filtered

7G is concentrated under high vacuum. The residue was chromatographed on a reverse phase column (35 x 120 mL), eluting with water. Lyophilization of the fractions containing the cavbapenem derivative afforded 1.20 g of a green solid which was subjected to new high performance liquid chromatography column chromatography (PrepPAK-500 / C18) using 2% aqueous acetonitrile as eluent. Fractions containing the carbapenem derivative were pooled and lyophilized. The material was rechromatographed on a high performance liquid chromatography column (Microbondapack C-18, 10 x 300 mm) using water as the eluent. After lyophilization, 190 mg (17%) of pure title compound was obtained as a pale yellow solid.

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

1.21 (3II, 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 (211, singlet),

8.52 (1H, singlet).

IR (Nujol mull): 1750 cm ^1st

UV (phosphate buffer, pH 7.4): A _max

296 nm (ε — 7,520).

Example 1 a d 4

Potassium 3- [4- (1-carboxylatomethyl-3-methyl-1,2,3-triazolium) methanthio] -6a, 41- (R) -hydroxyethyl] -7-oxo-1-azabicyclo 3,2,0 ¹ hept -2-ene-2-carboxylate

kj h 1 · # · +> f ........ Ί \ _S , N \ ^: к i! N ? ..... i л // '-' X.Z \ ... AND 1 what..

243721 π

7S

О

II - нос-— ·> · о

EtGCC! -L ₂ N ₃

(a) aocct, Ш-

II 3 o

(b) NaBHj

A cS

CO 2 Ct

J

a) MeOTf

^d) H ₂ / Pd-µMt

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 is refluxed for 0.5 hour, cooled in ice, the crystalline material is filtered off and washed with a small amount of toluene. It is obtained

33.3 g (72%) of the raw material consisting of a single isomer, 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.

1 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 5.00 g (25.1 mmol) of this carboxylic acid -and 3.68 ml (26.4 mmol) of triethylamine in 50 ml of dry-methylene chloride was added to the ice-cooled solution of 2.52 ml (26, 4 mmol) of ethyl chloroformate in 50 ml of dry methylene chloride, the resulting purple solution was stirred for 0.5 hour, then washed with 10 ml of water and, after drying with magnesium sulphate, the solvent was evaporated. in 50 ml of tetrahydrofuran and the solution is slowly added to an ice-cooled suspension of 0.72 g (18.9 mmol) of sodium borohydride in 50 ml of tetrahydrofuran, and after stirring for half an additional 0.30 g (7.9 mmol) of sodium borohydride is added. The mixture was cooled in ice for 1 hour, 5 ml of water was added first, and after 10 minutes 3 ml of 10% aqueous hydrochloric acid, after the gas evolution, 2 g of solid potassium carbonate were added with stirring. The combined organic phase was dried over magnesium sulphate 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 (CDCl 3, δ 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).

An ice-cooled solution of 5.47 g (20.8 mmol) of triphenylphosphine in 100 ml of dry tetrahydrofuran was added dropwise under nitrogen.

4.11 ml (20.8 mmol) of diisopropyl azodilecarboxylate. After 0.5 hours, an ice-cold 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, and the mixture was allowed to react for 2 hours. 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%, 25%

27.5% ... 35% ethyl acetate in hexane. In this way, 1.24 g (49%) of 1- (ethylcarboxymethyl) -4-methanthiolacetate-1,2,3-triazole was obtained as a crystalline solid and an additional 1.40 g of material contaminated with triphenylphosphine oxide. The product obtained above has the following physical constants.

1 H-NMR (δ values):

1.28 (3H, triplet, J = 7Hz),

2.37 (3H, singlet);

3.87 (2H, singlet);

5.12 (2H, singlet),

7.63 (1H, singlet).

IR (nujol suspension): 1735, 1780 cm ^-1 .

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 was 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 chromatographed on a reverse phase column (35 x 120 mm), first using 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 is transferred to a pressure vessel containing 25 ml ether, 25 ml tetrahydrofuran and 25 ml phosphate buffer [prepared by dissolving 1.36 g (0.01 mni) in 100 ml water and adjusting the pH to 7.4 by adding 45% aqueous 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 remaining solution is chromatographed on a reverse phase column (35 x 120 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 (10 x 300 mm, Microbondapack C-18, water as eluent) affords 480 mg of the pure title compound. Yield 41%.

1 H-NMR (deuterium oxide, δ values 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).

IR (nujol suspension): 1750 cm ^-1 .

UV (phosphate buffer pH 7.4): A _nlax

205 nm (ε = 7,810).

Example 5

3- [5- (1,4-dimethyl-1,2,4-triazolium) methanthio] -α- [1- (R) -hydroxyethyl] -7-oxo-1-azabicyclo [3.2.0] -hept-2-ene-2-carboxylate

A. 1-Methyl-1-methyl-1,2,4-triazole-1,2,4-triazole _t ..... N

r.j X w

OH! a) M with Cl / NEt2

K 'ed _em-cooled solution of 565 mg (5.0 mmol) l-Methyl-5-hydroxymethyl-l, 2,4-triazole [RG Jones and C. Ainsworth, J. Amer. Chem. Soc., 1955, 77, 1938] 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 was added, followed by 0.53 ml (7.5 mmol) of thiol acetic acid, and at 3.90 (2H, quartart, J = 7 Hz). , the treatment is continued for -5 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-methane thioacetate-1,2,4-triazole as a yellow oil and, in addition, a contaminated 200 mg fraction, from which after preparative thin-layer chromatography a further 100 mg of pure material was obtained. The total yield of the product was 85%.

-H-NMR (CDCl3, δ ppm):

2.38 (3H, singlet).

3.90 (3H, singlet).

4.25 (3H, singlet);

7.80 (1H, singlet).

B. 3- [5- (1,4-Dimethyl-1,2,4-triazolium) methanthio] -6- [1- (R) -hydroxyethyl] -7-oxo-1-azabicyclo [3.2.1.0 &lt; 2,7 &gt; 0] he ⁱ -2-ene-2-carboxylate, a) MeOTf f ^Ac b) Ν & ΟΗ

(У н

X _ what _from e.>

243721

To an ice-cooled solution of 730 mg (4.27 mmol) of 1-methyl-5-methanthi-acetate-1,2,4-triazole in 7 ml of methylene chloride was added dropwise 1.20 ml (10.7 mmol) of methyltrifluoromethanesulfonate. 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-methanthioacetate-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. and 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 315 kPa 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 chromatographed on a reverse phase column (45 x 130 mm, water as eluent). Fractions containing the carbapenem derivative are 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, <5 ppm):

1.24 (3H, doublet, J = 6.4 Hz),

3.19 (2H, quartet, J = 2.6, 9.2 Hz),

3.45 (1H, quartet, 1 = 2.8, 6.0 Hz),

3.91 (3H, singlet);

4.06 (3H, singlet);

4.08-4.36 (2H, multiplet),

4.54 (2H, doublet, J = 2.8 Hz),

8.71 (1H, singlet).

IR (nujol suspension): 1755 cm ⁴ .

UV (phosphate buffer, pH 7.4): A _max

294 nm (ε --- 8,202).

T, /, (phosphate buffer 0.067M, pH 7.4,

T = 37 ^and C): 9.1 hours.

Example 6 (TR, 5R, 6S) -3 - ((1,3-dimethyl-5-tetrazolium) m 3 thyithio) -6- (1-hydroxyethyl) -7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate

OH

CH.-.

A. 5-Ethoxycarbonyl-2-methyltetrazole a

5-ethoxycarbonyl-1-methyltetrazole

243721 (la) 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) was cooled to 0 ° C and a solution of 3 g (0.071 mol) of diazomethane in 200 ml of ether was added over 15 minutes. The light yellow solution was stirred for 30 minutes, then excess diazomethane was removed by addition of 1 mL acetic acid. After evaporation of the solvent and distillation of the residue, it is obtained

9.64 g (96%) of a clear oil with a boiling point of 95 to 100 ° C / 67 Pa. According to 1 H-NMR, this is a 6: 4 mixture of 1-methyl and 2-methyl isomers. These two isomers cannot be separated by distillation or high performance liquid chromatography.

IC (film): ν _max 1,740 rm ⁴ (C = O ester residue).

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

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

4.46 and 4.53 (3H, two singlets, 6: 4 methyl group of 1-methyl- and 2-methyltetrazole; the 2-iso.rner methyl group has lower shift values and is contained in the mixture in a smaller amount )

4.5 (2H, two overlapping quartets, CHgCH3). '

1b) 5-ethoxycarbonyl-2-methyltetrazole

A mixture of 5-ethoxycarboinyl-2-imethyltetrazole 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 first to 15 hours. 100 ° C and then 6 hours at 130 ° C. Distillation of the reaction mixture gave 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): 1 1740 cm ^-1 (C = O ester residue).

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

1.46 (3H, triplet, J = 7.0, CH 3 CH 2),

4.53 (3H, singlet, CH 3 - 2f, -

4.5 (2H, quartet, 1 = 7.0 CH2CH3).

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). dimethylsulfate. The reaction mixture was heated to reflux for 12 hours, then filtered and the solvent ¹ 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 having a boiling point of 85 DEG -110 DEG C./0 mm Hg are obtained. @ 4 H-NMR indicates the presence of two isomers in a ratio of 1: 1.

B. 5-Hydroxymethyl-2-methyltetrazole

OF

1. Reduction of the ester mixture

A mixture of 5-ethoxycarbonyl-11-methyltetrazole and 5-ethoxycarbonyl-2-ethyltetrazole (7.60 g, 0.049 mot, 6: 4 isomer ratio) in 50 µm dry tetrahydrofuran was cooled to 0 ° C and added in small portions over 15 minutes. 1.06 g (0.049 mol) of lithium borohydride. 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 the careful addition of 6N hydrochloric acid (to pH 7 when no more gas was 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. The @ 1 H-NMR of this material indicated that the product was 5-hydroxymethyl-2-methyl-tetrazole.

2. Reduction of 5-ethoxycarbonyl-2-methyltetrazole carbonyl-2-methyltetrazole (obtained by isomerization of a mixture of esters with methyl iodide) in 1 mL of dry tetrahydrofuran at 10 ^° C add 0.019 g (0.87 mmol) of solid lithium borohydride. The mixture was slowly warmed to room temperature and stirred for 4 hours. Excess borohydride was removed by carefully adding 6N hydrochloric acid at 0 ° C (pH 7). The solvent is evaporated, the residue is dissolved in 25 ml of dichloromethane, the solution is dried over anhydrous sodium sulfate and the solvent is evaporated off. 0.092 g (91%) of the desired compound boiling under decomposition at 90% was obtained ^. up to 120 ° C / 67 Pa.

IR (film): u _max

350 · cm-1 (wide band, OH).

4 H-NMR (CDCl 3, δ ppm):

4.4 (2H, singlet, CH2-2),

4.93 (2H, singlet, CH2 - 5).

C. 5-Acetylmercaptomethyl-12-Methyl-tetrazole

To the solution

0.139 g (0.89 mmol) of 5-ethoxy-

D MsCC,

2) CH ₃ COSK

1.83 g (11.7 mmol) of a 5-hydroxy solution of methyl-2-methyltetrazole in 25 ml of dry dichloromethane at 0 ° C are added first 1.47 g (12.9 mmol) of methanesulfonyl chloride and then 1.30 g (12.9 mmol) of triethylamine was added dropwise over 5 minutes. A solution of 1.60 g (14.0 mmol) of potassium thioacetate in 10 ml of dry Ν, dimethyl-dimethylformamide was added and the mixture was stirred at 0 ° C for 1 h. 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 (05%) of the title compound as a clear oil.

IR (film): in _ma x

696 ^cm-1 (C = O thioester residue).

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

2.43 (3H, singlet, SAc),

4.36 (3H, singlet, 2-CH3),

4.38 (2H, singlet, 5-0).

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

сн ₃

ΝΆΟΗ

с tg

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. (l ^t R, 5R, 6S) -3- ((l, 3-dimethyl-5-tetrazolium) methylthio] -6- (1-hydroxyethyl) -7-oxo-azabicyclo [3,2,01hept -2-en-2-carboxylate

OH

W ° 3

OH

A solution of 0.915 g (1.58 mmol) of enol phosphate in 8 mL of tetrahydrofuran was cooled to 0 ° C and a solution of 2.32 mmol of 5-mercaptomethyl-1,3-dimethyltetrazolium trifluoromethanesulfonate prepared above 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 is saturated to about 7.0 with saturated sodium bicarbonate solution, the mixture is transferred to a hydrogenation vessel and diluted with 10 ml of tetrahydrofuran, 20 ml of ether and 20 g of ice, after which the carbapenem derivative is added. The presence of 10% palladium on charcoal is hydrogenated at a pressure of 315 kPa for a period of 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 PrePak 500-C / 18 column (elution with water) and lyophilization of the eluate gave 0.266 g (49%) of the title compound as a white powder with optical rotation [α] D ²³ = + 13 ° (c = 1.04, water).

UV (water, pH 7.4): A _max

294 nm (ε - 7,500).

IC [KBr]

ⁱⁿ max

755 (C = O-lactam residue),

600 cm @ -1 (wide band, C = O carboxylate residue).

4H-NMR (deuterium oxide, δ in ppm).

1.24 (3H, doublet, J = 6.4 Hz, CH2CHOH),

3.0-3.3 (2H, multiplet, H-4),

3.42 (1H, doublet, J = 5.8, J = 2.9,

H-6),

4 - 4.2 (2H, multiplet, H-5 and CH 3 CHOH),

4.34 and 4.57 (2 x 3H, two singlets, CHs-1 and 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- [1- (R) -hydroxyethyl] -7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate (procedure in a single reaction vessel)

v v

243721 '1Ύ' of

... _? ,

0 '

Ο

CiP (ОРЬ.) _Я

On О Н

Η / J, G ° C _and 1 / _G H 6,5-75 ¹ tefir.ir-GOi.re: p. _; CH _S θ ^Ý \ O? '{'

ХХИсЛ '

CC / PIMB

X

A. At the source of phosphate, (2)

(1.04 equivalent, 1.57 mL) of ethyl-dlisopropylamine and then 9 mmol (1.04 equivalent,

1.87 ml) of chlorodiphenyl phosphate. Reaction mixture

To an ice-cooled solution of 3 g (8.62 mmol) of ketone 1 in 30 ml of acetonitrile, 9 mmol are first added over 2 minutes.

243721 sodium chloride, dried over sodium sulphate and concentrated at a temperature below 20 ^° C

Celsius to a foamed product which is used as such for the next reaction.

B. Preparation of thiol (4) was stirred for 45 minutes and then a sample thereof was chromatographed on a thin layer of silica gel in ethyl acetate. This chromatography shows the disappearance of ketone 1. The reaction solution is diluted with 60 ml of ethyl acetate, washed twice with 50 ml of cold water each time and

SAc

1) Ηά0Η / Η ₂₀ ° C, 1b.

——---------.-Jfr гж ^ ро ^.

An ice-cooled aqueous solution of 3.31 g (10 mmol) of thioacetate 3 is purged with nitrogen for 5 minutes and then a cooled solution of 0.7 g (1.75 equivalents, 17.5 mmol) of sodium hydroxide is added dropwise over about 5 minutes. in 8 ml of water. The reaction mixture turns yellow. After keeping the reaction mixture under nitrogen for 75 minutes, its pH is adjusted to 7.4 by addition of saturated aqueous potassium hydrogen phosphate solution, the resulting mixture is diluted with 15 ml of water and this aqueous solution of thiol 4 (50 ml, 0). (2 mmol / ml) is used for the following reaction as such.

C. Condensation

i ___. 14.

tetrahydrofuran-water; pH 6,5-7,5 0 ^C 'C, hours

To the ice-cooled solution of crude compound 2 prepared in paragraph A (8.62 mmol) in 50 ml of tetrahydrofuran was added dropwise an 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 silica gel thin layer chromatography using ethyl acetate as the solvent of your system (a) or reverse phase column chromatography (Analtech RPSF), eluting with a mixture of acetonitrile and pH 4: 6 buffer.

A total of 1.15 equivalents of thiol (50 ml solution) was used. The reaction is complete at 0 ° C after 1 hour and the reaction mixture is directly used for hydrogenation after adjusting the pH to 7.

D. Hydrogenation

---------

tetrahydrofuran-water-ether at 0 ° C, 2 hours

The reaction mixture containing compound 5 (obtained in paragraph C) was transferred to a Parr flask containing 10 ml tetrahydrofuran, 10 ml 0.1M phosphate buffer (pH 7), 75 ml ether and 5 g 10% palladium on carbon, and the mixture was hydrogenated for 2 hours. 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,

4.5 x 13 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 give 1.46 g (50%) (yield calculated on starting bicyclic ketone) of Compound B as a yellow powder.

UV: λ 293- (ε = 9,000), λ 271 (ε = 11064).

4 8 7 2 2

If the procedure described in Example 7 is repeated except that the intermediate ketoderivative 1 is replaced with an equimolar amount of the corresponding intermediate β-methyl derivative, the final carbapenem derivative mentioned above is obtained.

If the procedure described in Example 7 is repeated except that the intermediate ketoderivative 1 is replaced with an equimolar amount of the corresponding .beta.-methyl derivative, the carbapenem derivative mentioned above is obtained.

Claims (7)

SUBJECT OF THE INVENTION A process for the preparation of carbapenem derivatives of the general formula I 243721 in which R 8 represents a hydrogen atom and R 1 represents a radical selected from the group consisting of hydrogen and optionally substituted alkyl, alkenyl and alkynyl groups of up to 10 carbon atoms, cycloalkyl and cycloalkylalkyl groups of 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 6 carbon atoms in the alkyl, phenyl moiety, aralkyl, aralkenyl and aralkynyl groups wherein the aryl moiety is a phenyl moiety and the aliphatic moiety contains up to 6 carbon atoms, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl groups wherein the heteroaryl or heterocyclyl groups or moieties are the corresponding mono-, or poly-cyclic moieties containing up to 18 ring members, preferably 5 or 6 ring members, and 1 to 4 bsteroatoms selected from the group consisting of oxygen, nitrogen and sulfur atoms, and wherein the alkyl moiety attached to the heterocyclic moiety contains 1 to 6 carbon atoms, wherein said substituent; substituents the above-mentioned radicals are independently selected from the group consisting of alkyl groups having 1 to 6 carbon atoms, optionally substituted with amino, halogen, hydroxyl or carboxyl groups, * halogen atoms, radicals of the formula OR3 O II —OCNR3R4 O II — CN3R4 O — S — NR 3 R 4 II O O II —NHCNR3R4.0 II R3CNR4 - —CO2R3 = 0 O II —CCR ³ —SR3 O —SR9 O II —SR9 II O — CN — N3 —OSO3R3 O —OS — R9 II o o —NR3S — R9 —NR3R ⁴ 103 104 atoms, optionally substituted by amino, fluorine or chlorine, carboxy, hydroxy, or "carbamoyl, fluorine, chlorine and bromine, the radicals of the formula -OR ^3, -OCO2R ^3, -OCOR 3, -OCONR ³ R 4, O —OS — R9, o -OP (O) (OR ³⁾ (OR 4) -NR ³ C = NR 4 and · R3 -NR3CO2R4 and wherein -NO R 3 and R 4 are each independently hydrogen, alkyl, alkenyl or alkynyl of up 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, phenyl an aralkyl, aralkenyl or aralkynyl group wherein the aryl moiety is a phenyl moiety and the aliphatic moiety contains up to 6 carbon atoms, a heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl moiety wherein the heteroaryl or heteirocyclyl moieties or moieties are the corresponding mono-, bi- or polycyclic radicals containing up to 18 ring members, preferably 5 or 6 ring members, and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur atoms 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 radicals is attached form a five- or six-membered nitrogen-containing heterocyclic ring, and R 9 is as defined above for R 3 except hydrogen, or R 1 and R 8 together form an alkylidene group having 2 to 10 carbon atoms, optionally substituted by a hydroxyl group, R5 represents an optionally substituted alkyl, alkenyl or alkynyl group containing up 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 up to 6 carbon atoms, a heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl group wherein the heteroaryl or heterocyclyl groups or moieties are the corresponding mono-, bi- or polycyclic moieties containing up to 18 ring members , preferably 5 or 6 ring members, and 1 to 4 heteroatoms selected from the group consisting of 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 carry one to three substituents independently selected from the group consisting of (C 1 -C 6) alkyl, -NR 3 R 4, R3CONR4—, —NR5GO2R4, —NR3CONR3r4, O II — NR3S — R9, II O —SR3, —SO3R3, —CO2R3, —CONR3R4, —Cn, a phenyl group optionally substituted by one to three fluorine, chlorine and bromine atoms, a (C1 -C6) alkyl group, —OR3, —NR3R4, 106 105 -SOsR ^3, -CO 2 R ³ or -CONR3R4, wherein R3, R4 and R ⁹ radicals in the substituents R @ ⁵ have the above meanings, or · R® may be joined to the rest in a position other ring to form a fused heterocyclic or a heteroaromatic ring system which is a corresponding bi- or polycyclic radical containing up to 18 ring members and 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen; R 1 represents a hydrogen atom or an optionally substituted alkyl, alkenyl or alkynyl group having up to 10 carbon atoms, a cycloalkyl, cycloalkylalkyl or alkylcycloalkyl group having 3 to 6 carbon atoms in the cycloalkyl and 1 to 6 carbon atoms in the alkyl moiety; 6-carbon atoms, phenyl, aralkyl, aralkenyl or aralkynyl wherein the aryl moiety is a phenyl moiety and the aliphatic moiety contains up to 6 carbon atoms, a heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl group wherein the heteroaryl or heterocyclyl groups or moieties are the corresponding mono- , bi- or polycyclic radicals containing up to · 18 ring members, preferably 5 or 6 ring members, and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur atoms, and the alkyl moieties attached to these heterocyclic moieties contain 1 to 5 6 carbon atoms wherein the substituent (s) of the aforementioned radicals are selected from the group consisting of amino, mono-, di- and trialkylamino, hydroxyl, alkoxy, mercapto, alkylthio, phenylthio, sulfamoyl, amidio, guanidino, nitro, chloro, bromo, bromo, bromo 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, R2 represents a hydrogen atom, an anionic charge, or an ester protecting group of a carboxyl function containing up to 20 carbon atoms, provided that when R2 represents a hydrogen atom or a protecting group, a charge-balancing anion is also present, meaning mono-, bi- or a polycyclic aromatic heterocyclic radical containing up to 18 ring members, at least one nitrogen atom and 0 to 5 additional heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, optionally substituted on carbon atoms 1 to 5, preferably 1 to 3 substituents independently selected from each other C 1 -C 4 alkyl, C 1 -C 4 alkyl substituted with one to three hydroxyl groups, amino groups, C 1 -C 4 alkylamino groups, C 1 -C 4 dialkylamino groups in each alkyl moiety, C 1 -C 4 alkoxy, carboxyl groups pins, halogen atoms, preferably chlorine, bromine or fluorine, or sulfo groups, furthermore cycloalkyl groups having 3 to 6 carbon atoms, cycloalkylalkyl groups having 3 to 6 carbon atoms in the cycloalkyl and 1 to 4 carbon atoms in the alkyl moiety optionally substituted by one to the three substituents mentioned above in connection with alkyl groups having 1 to 4 carbon atoms, alkoxy groups having 1 to 4 carbon atoms, alkylthio groups having 1 to 4 carbon atoms, amino, alkylamino groups having 1 to 4 carbon atoms, dialkylamino groups containing 1 in each alkyl moiety up to 4 carbon atoms, halogen atoms, C1-C4 alkaneylamino, C1-C4 alkanoyloxy, carboxyl, sulfo, radicals of the formula -C1-O-alk wherein alk is C1-C4 alkyl, hydroxyl amido group, guanidino, phenyl, phenyl substituted with one to three substituents selected from amino, halogen, hydroxyl, trifluoromethyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, dialkylamino groups in each alkyl C 1 -C 4 moieties, carboxyl and sulfo groups, furthermore C 1 -C 4 phenylalkyl groups in the alkyl moiety in which the phenyl moiety may be optionally substituted by 1 to 3 substituents mentioned above in relation to the phenyl group and the alkyl moiety may be be optionally substituted with one to three uve248721 substituents 107 108 as defined above in connection with alkyl groups having 1 to 4 carbon atoms, and heteroaryl or heteroaralkyl groups in which the heterocyclic moiety is a mono-, bi- or polycyclic moiety containing up to 18 ring members, preferably 5 or 6 ring members, and 1-4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen atoms, and the alkyl moiety contains 1 to 6 carbon atoms, said heteroaryl and heteroaralkyl groups being optionally substituted on the heterocyclic ring by one to three substituents independently selected from the group consisting of hydroxyl , amino, halogen atoms, trifluoromethyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, carboxyl and sulfo, and in the alkyl moiety one to three subs substituents selected from the group consisting of hydroxyl, amino, (C 1 -C 4) alkylamino, (C 1 -C 4) dialkylamino, (C 1 -C 4) alkoxy, carboxyl, halogen and sulfo, and optionally ring nitrogen atoms present, in addition to the quaternized nitrogen, with one to three substituents independently selected from the group consisting of alkyl groups of 1 to 4 carbon atoms, alkyl groups of 1 to 4 carbon atoms substituted with one to three hydroxyl groups, amino groups, alkylamino groups of 1 C 1 -C 4 dialkylamino, C 1 -C 4 alkoxy, carboxyl, halogen or sulfo, C 3 -C 6 cycloalkyl, cycloalkylalkyl containing C 3 -C 6 cycloalkyl; 4 carbon atoms in the alkyl moiety, optionally substituted with one to three substituents listed above in connection with alkyl groups of 1 to 4 carbon atoms, phenyl, phenyl substituted with one to three substituents independently selected from the group consisting of amino, halogen atoms, hydroxyl, trifluoromethyl, C 1 -C 4 alkyl, C 1 -C 4 alkyl, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, carboxyl and sulfo; C 1 -C 4 -phenylalkyl groups in which the phenyl moiety may be optionally substituted with one to three substituents listed above in relation to the phenyl moiety and the alkyl moiety may be optionally substituted with one to three substituents listed above in connection with alkyl groups having 1 to 4 carbon atoms, further heteroaryl and heteroaralkyl groups wherein the heterocyclic moiety is as defined above and the alkyl moiety contains 1 to 6 carbon atoms, the heteroaryl and heteroaralkyl groups being optionally substituted in the heterocyclic ring by one up to three substituents independently selected from the group consisting of hydroxyl, amino, halogen atoms, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, dialkylamino groups of 1 to 4 carbon atoms in each alkyl moiety , carboxyl and sulfo, and in the alkyl moiety with one to three substituents selected from the group consisting of hydroxyl, amino, (C 1 -C 4) alkylamino, (C 1 -C 4) dialkylamino, (C 1 -C 4) alkoxy groups carbon atoms and a pharmaceutically acceptable salt thereof, characterized in that the intermediate of formula (IV): R ¹ , R ⁸ and R ¹⁵ are as defined above, R ² 'represents the carboxyl functionality protecting group a as defined above L is a conventional leaving group, reacted with a thiol of formula VII X (VII) wherein 109 110 are as defined above and X 'represents a balancing anion, in an inert solvent and in the presence of a base, to form a carbapenem derivative of the general formula Γ GH R2 is a hydrogen atom, an anionic charge or a carboxyl-protecting group as defined in item 1, provided that when R2 is a hydrogen atom or a protecting group, a charge-balancing anion and pharmaceutically acceptable salts thereof are also present, The process according to claim 1, characterized in that the intermediate of formula (I) is as defined above, from which optionally carboxy protecting group R ² 'is cleaved to give the corresponding unprotected compound of formula (I) or a pharmaceutically acceptable salt thereof. 2. The process of claim 1 wherein the base is sodium hydroxide. 3. The process of claim 1 wherein the reaction is carried out at a temperature of from -15 ° C to + 15 ° C. 4. A process according to claim 1, 2 or 3, wherein the starting material is a compound of the formula IV in which R @ ² , R @ ¹ , R @ 8 and R @ ¹⁵ are as defined above and L is chlorine, bromine. iodine, benzenesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, methanesulfonyloxy, trifluoromethanesulfonyl, diphenoxyphosphinyloxy or phosphoryl trichloroethoxy). 5. A process according to claim 1, 2 or 3, wherein the starting material is a compound of the formula IV in which: R ² ', R 1, R 8 and R 15 are as defined above and L is diphenoxyphosphinyloxy. 6. The process of item 1, for producing compounds of the general formula wherein: L represents a conventional leaving group and R 2 ‘represents a carboxyl-functional protecting group as defined above, reacted with a thiol of the formula x- - VLV in which X is a balancing anion, in an inert solvent and in the presence of a base, to form a carbapenem derivative of the general formula 111 112 salts of the compound of formula (I), characterized in that the intermediate of formula (I) is: R2 &apos; and X &apos; are as defined above, from which optionally the protecting group R2 &apos; is then cleaved to give the corresponding unprotected compound of formula I or a pharmaceutically acceptable salt thereof. 7. The process of item 1 for producing compounds of formula OH O ^<; ·· in which R2 represents a hydrogen atom, an anionic charge, or. a carboxyl function protecting group as defined in item 1, if any. R 2 is a hydrogen atom or a protecting group, a charge-balancing anion is also present, and a pharmaceutically acceptable salt thereof L represents a conventional leaving group and R 2 ‘represents a carboxyl function protecting group as defined above, reacted with a thiol of the general formula CH, J ^HS ' ^{CH 2} v / ^X in which X- represents a balancing anion, in an inert solvent and in the presence of a base, to form a carbapenem derivative of the general formula in which: R 2 ‘and X - are as defined above, from which optionally protecting group R 2 pak is cleaved to form the corresponding unprotected compound of formula (I) or a pharmaceutically acceptable salt thereof.