DD211562A5 - PROCESS FOR PREPARING 2-HETEROCYCLYL-N-ALKYL-2-PENEM COMPOUNDS - Google Patents

Abstract

2-Heterocyclylniederalkyl-2-penem compounds of the formula I, wherein R 1 is hydrogen or methyl, R 2 deep an optionally protected hydroxyl group, R 3 deep carboxyl or protected carboxylic R 3 is deep, R deep 4 an over a ring carbon atom is represented on the radical - (CH deep 2) deeply m-bonded unsaturated monocyclic heterocyclyl radical and m is an integer of 1 to 4, salts of those compounds of formula I which have a salt-forming group, optical isomers of Compounds of the formula I and mixtures of these optical isomers have antibiotic properties. The compounds are prepared by methods known per se.

Description

Process for the preparation of 2-heterocyclyl-lower alkyl-2-penem compounds

Field of application of the invention

The present invention relates to a process for the preparation of novel 2-heterocyclyl-lower alkyl-2-penem compounds and of pharmaceutical preparations containing these compounds.

Characteristic of the known technical solutions

From German Patent Application No. 3,224,055, European Patent Application 2210 and European Patent 3960 are in the 6-position u.a. by hydroxynolower and substituted in the 2-position by various organic radicals substituted penem-3-carboxylic acid compounds having antibiotic activity become known.

Object of the invention

The object of the invention is to provide processes for the preparation of novel 2-heterocyclyl-lower alkyl-2-penem compounds having valuable pharmacological properties and of pharmaceutical preparations containing such compounds. '

Explanation of the essence of the invention

The object of the present invention is to find, starting from easily accessible starting compounds, novel antibiotically active 2-heterocyclyl-lower alkyl-2-penem compounds and processes for their preparation.

-Ia-

According to the invention compounds of the formula

RHH

> - (CH_) -R ₇ (I),

^{m 4}

^E 3

wherein R is hydrogen or methyl, R _{0 is} an optionally protected hydroxyl group, R_ is carboxyl or protected carboxyl R. ' is

R, a bonded via a Ringkohlensfcoffatom to the rest - (CH ₀ ) - Hm

NEN, unsaturated, monocyc.lischen heterocyclyl radical having 1 to 4 ring nitrogen atoms and optionally an additional ring heteroatom of the group oxygen and sulfur and m is an integer from 1 to 4, salts of those compounds of formula I having a salt-forming group , optical isomers of compounds of formula I, mixtures of these optical isomers and pharmaceutical preparations containing such compounds.

The definitions used hereinbefore and hereinafter preferably have the following meanings in the context of the present description:

E.in via a ring carbon atom to the radical - (CH) - bonded, unsaturated monocyclic heterocyclyl radical R, is in particular a corresponding 5-membered or 6-membered heteroaryl radical or partially saturated heteroaryl radical having 1 to 4 ring nitrogen atoms and optionally an additional ring heteroatom of the group oxygen and sulfur, such as a corresponding 5-membered aza, diaza, triaza, tetraza, oxaza, oxadiaza, thiaza, thiadiaza or thiatriaza cyclic residue of aromatic character or a corresponding dihydroxy group. Radical, or a corresponding 6-membered aza-, diaza and triaza-cyclic radical of aromatic character, and a corresponding dihydro, and also tetrahydro radical. These residues are unsubstituted or may be replaced by optionally etherified or esterified, including protected hydroxy, e.g. Hydroxy, lower alkoxy, lower alkanoyloxy or halogen, optionally etherified mercapto, e.g. Mercapto, lower alkylthio or phenylthio, lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl, carboxy lower alkyl, optionally N-lower alkylated amino lower alkyl, e.g. Amino lower alkyl or di-lower alkylamino lower alkyl, lower alkyl, optionally substituted, including protected amino, e.g. Amino, lower alkylamino, di-lower alkylamino, lower alkyleneamino or acylamino such as lower alkanoylamino, optionally functionally modified, including protected carboxyl or sulfo, e.g. Carboxyl, esterified carboxyl such as lower alkoxycarbonyl, optionally substituted carbamoyl such as N-mono- or N, N-di-lower alkylated carbamoyl, cyano, sulfo or sulfamoyl, optionally lower alkyl, nitro, lower alkoxy. and / or halogen-substituted phenyl, cycloalkyl, nitro, oxo and / or oxido substituted, such as in particular • mono- or poly-, in particular disubstituted, be.

In the present specification, the term used in connection with definitions of groups or compounds means

"Lower" that the corresponding groups or compounds, unless expressly defined otherwise, contain up to and including 7, preferably up to and including 4 carbon atoms.

Lower alkoxy is e.g. Methoxy, further ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy or tert-butyloxy, and n-pentyloxy, n-hexyloxy or n-heptyloxy.

Lower alkanoyloxy is e.g. Acetyloxy or propionyloxy.

Halogen is e.g. Fluorine, chlorine, bromine or iodine.

Lower alkylthio is e.g. Methylthio, ethylthio, n-propylthio, isopropylthio or n-butylthio.

Lower alkyl is e.g. Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, furthermore n-pentyl, n-hexyl or n-heptyl.

Hydroxy-lower alkyl is e.g. Hydroxymethyl, 2-hydroxyethyl or 2,3-dihydroxypropyl1.

Lower alkoxy lower alkyl is e.g. Methoxymethyl, 2-methoxyethyl, ethoxymethyl or 2-ethoxyethyl.

Carboxy-lower alkyl is e.g. Carboxymethyl, 1-carboxy, 2-carboxy or 1,2-dicarboxyethyl.

Amino-lower alkyl is e.g. Aminomethyl or 2-aminoethyl, while di-lower alkylamino-lower alkyl e.g. Dimethylaminomethyl, 2-dimethylaminoethyl or 2-diethylaminoethyl.

Sulfo-lower alkyl is e.g. Sulfomethyl or 2-sulfoethyl.

Lower alkiamino is e.g. Methylamines), ethylamino, n-propylamino, isopropylamino or n-butylamino, while di-lower alkylamino e.g. Dimethylamino, diethylamino, di-n-propylamino or diisopropylamino.

Lower alkyleneamino in particular has 4 to 6 carbon chain members and means e.g. Pyrrolidino or piperidino.

Lower alkanoylamino is e.g. Acetylamino or propionylamino. Lower alkoxycarbonyl is e.g. Methoxycarbonyl or ethoxycarbonyl.

N-mono-lower alkylated carbamoyl is e.g. N-methyl, N-ethyl or N-propylcarbamoyl while N, N-di-lower alkylated carbamoyl e.g. Ν, Ν-dimethyl or Ν, Ν-diethylcarbamoyl.

Above all, cycloalkyl contains 3 to 8, primarily 5 or 6 ring members and is e.g. Cyclopentyl or cyclohexyl, furthermore cyclopropyl and cycloheptyl.

Corresponding 5-membered optionally partially saturated heteroaryl radicals R, are e.g. optionally lower alkyl substituted pyrrolyl or dihydropyrrolyl, e.g. 1-methyl-2-pyrrolyl or 4,5-dihydro-3-pyrrolyl, optionally lower alkyl substituted diazolyl, such as imidazolyl, e.g. 2-imidazolyl, optionally triazolyl substituted by lower alkyl, carboxy-lower alkyl or phenyl, such as 1H-l, 2,3-triazol-4-yl, 1H-l, 2,4-triazol-3-yl, 1H-l, 2, 4-triazol-5-yl or 4H-l, 2,4-triazol-3-yl, for example the corresponding unsubstituted radicals, 1-methyl-1H-1,2,3-triazol-4-yl, 5-methyl-1H-1, 2,4-triazol-3-yl, 3-methyl-1-phenyl-1H-l , 2,4-triazib-5-yl, 4,5-dimethyl, 4-carboxymethyl or 4-phenyl-4H-l, 2,4-triazol-3-yl optionally substituted by lower alkyl, carboxy-lower alkyl, lower-sulfo-alkyl, lower-di-lower alkylamino-lower alkyl or optionally substituents, such as halogen,

phenyl containing substituted tetrazolyl such as IH- or 2H-tetrazol-5-yl, e.g. lH-tetrazol-5-yl, l-methyl-lH-tetrazol-5-yl, 1-carboxymethyl-lH-tetrazol-5-yl, 1- (2-carboxyethyl) -lH-tetrazol-5-yl, 1- Sulfomethyl-1H-tetrazol-5-yl, 1- (2-sulfoethyl) -1H-tetrazol-5-yl, 1- (2-dimethylaminoethyl) -1H-tetrazol-5-yl, 1-phenyl-1H-tetrazole 5-yl or 2-methyl-2H-tetrazol-5-yl, optionally substituted by lower alkyl or amino-substituted thiazolyl, such as 2-thiazolyl, or isothiazolyl, such as 3-isothiazolyl, for example 2-thiazolyl, 4,5-dimethyl-2-thiazolyl or 3-isothiazolyl, optionally substituted by lower alkyl or amino thiadiazolyl, such as l, 2,3-thiadiazol-4-yl, l, 2,3-thiadiazol-5-yl , l, 3,4-thiadiazol-2-yl, 1, 2,4-thiadiazol-3-yl or 1,2,4-thiadiazol-5-yl «j, for example the corresponding unsubstituted groups, furthermore 2-methyl-l, 3,4-thiadiazol-5-yl, 2-amino-l, 3,4-thiadiazol-5-yl or 3-methyl-l, 2,4-thiadiazole 5 ~ yl, thiatriazolyl, eg 1,2,3,4-thiatriazol-5-yl, optionally substituted by lower alkyl and / or phenyl oxazolyl or isoxazolyl such as 2-oxazolyl, 5-oxazolyl or 5-isoxazolyl, e.g. the corresponding unsubstituted groups, further 4-methyl-5-oxazolyl, 4,5-diphenyl-2-oxazolyl or 3-methyl-5-isoxazolyl, or optionally substituted by lower alkyl or optionally substituted by nitro-substituted phenyl oxadiazolyl, such as 1,2 , 4-Oxadiazol-5-yl, 1,2,4-Qxadiazol-3-yl or 1,3,4-oxadiazol-2-yl, eg the corresponding unsubstituted groups, furthermore 2-methyl-1,3,3-oxadiazol-5-yl, 2-phenyl-1, 3,4-oxadiazol-5-yl or 5- (4-nitrophenyl) -1,3, 4-oxadiazol-2-yl.

Corresponding 6-membered optionally partially saturated heteroaryl radicals R are e.g. optionally substituted by halogen and / or oxido pyridyl, such as 2-, 3- or 4-pyridyl, e.g. 2-pyridyl, 3-pyridyl, 1-oxido-2-pyridyl or 4-chloro-1-oxido-2-pyridyl, optionally substituted by lower alkyl, hydroxy, lower alkoxy, halogen and / or oxido-substituted pyridazinyl, such as 6-pyridazinyl, e.g. 3-hydroxy-6-pyridazinyl, 2-oxido-6-pyridazinyl, 3-chloro-1-oxido-6-pyridazinyl, 3-methyl-2-oxido-6-pyridazinyl, 3-methoxy-1-oxido-6 pyridazinyl or 3-ethoxy-1-oxido-6-pyridazinyl, optionally

1,2-dihydropyrimidinyl substituted by lower alkyl, amino, di-lower alkylamino, oxo and / or carboxy, such as 1,2-dihydro-4-pyrimidinyl, e.g. 2-0xo-l, 2-dihydro-4-pyrimidinyl, 6-methyl, 5-methyl, 6-amino, 6-dimethylamino, 5-carboxy or 6-carboxy-2-oxo-l, 2- dihydro-4-pyrimidinyl, or optionally substituted by lower alkyl and / or by up to two oxo-substituted triazinyl, such as 1,2,4-triazin-3-yl, in particular N-lower alkyl-sialo-dioxo-1'-triazine S-yl, eg 1-, 2- or 4-methyl-5,6-dioxo-l, 2,4-triazin-3-yl.

The functional groups present in the compounds of the formula I, such as hydroxyl, carboxy, amino or sulfo groups, in particular the hydroxyl group R and the carboxyl group R ", are optionally protected by protecting groups which are present in the penem, penicillin, cephalosporin and peptide chemistry.

Such protecting groups are light, i. without unwanted side reactions take place, for example, solvolytic, reductively or under physiological conditions, cleavable.

Protecting groups of this type as well as their introduction and removal are described for example in

J. F. W. McOmie, "Protective Groups in Organic Chemistry," Plenum Press, London, New York, 1973,

T.W. Greene, "Protective Groups in Organic Synthesis," Wiley, New York,

"The Peptides", Vol. I, Schroeder and Luebke, Academic Press, London, New York, 1965 and

Houben-Weyl, "Methods of Organic Chemistry", Volume 15/1, Georg Thieme Verlag, Stuttgart, 1974.

In compounds of the formula (I), a hydroxy group, furthermore a hydroxygx 'group present in the radical R, can be protected, for example, by acyl radicals. Suitable acyl radicals are e.g. optionally substituted by halogen substituted lower alkanoyl, e.g. Acetyl or trifluoroacetyl, optionally nitro substituted benzoyl, e.g. Benzoyl, 4-nitrobenzoyl or 2,4-dinitrobenzoyl, optionally lower halogenated lower alkoxycarbonyl, e.g. 2-bromoethoxycarbonyl or 2,2,2-trichloroethoxycarbonyl, or optionally nitro-substituted phenyl-lower alkoxycarbonyl, e.g. 4-nitrobenzyloxycarbonyl. Other suitable hydroxy protecting groups are e.g. trisubstituted silyl, such as tri-lower alkylsilyl, e.g. Trimethylsilyl or tert-butyl-dimethylsilyl, 2-halo-lower alkyl groups, e.g. 2-chloro, 2-bromo, 2-iodo and 2,2,2-trichloroethyl, and optionally halogen, e.g. Chlorine, lower alkoxy, e.g. .Methoxy, uiid / or nitro substituted phenyl-lower alkyl, such as corresponding benzyl. Preferred as hydroxy protecting group is in particular the tri-lower alkylsilyl group.

A carboxyl group R ", furthermore also one in the radical R, existing

j 4

Carboxyl group, is. usually protected in esterified form, the ester group being protected under mild conditions, e.g. under weakly reductive, such as hydrogenolytic, or gently solvolytic or especially basic or neutral hydrolytic conditions, easily cleavable. A protected carboxyl group may further be an esterified carboxyl group which can be cleaved under physiological conditions or easily converted into another functionally modified carboxyl group such as another esterified carboxyl group.

Such esterified carboxyl groups contain as esterifying groups in the first position branched or in the 1- or 2-position suitably substituted lower alkyl groups. Preferred esterified carboxyl groups include lower alkoxycarbonyl, e.g. Methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl or tert-butoxycarbonyl, and (hetero) arylmethoxycarbonyl of 1 to 3

Aryl radicals or a monocyclic heteroaryl radical, these optionally being e.g. by lower alkyl, such as tert-lower alkyl, e.g. tert-butyl, halogen, e.g. Chloro, and / or nitro mono- or polysubstituiert. Examples of such groups are optionally e.g. As mentioned above, substituted benzyloxycarbonyl, e.g. 4-nitrobenzyloxycarbonyl, optionally, e.g. as mentioned above, substituted diphenylmethoxycarbonyl, e.g. Diphenylmethoxycarbonyl, or triphenylmethoxycarbonyl, or optionally, e.g. as mentioned above, substituted picyloxycarbonyl, e.g. 4-picolyloxycarbonyl, or furfuryloxycarbonyl, such as 2-furfuryloxycarbonyl. Other suitable groups are lower alkanoylmethoxycarbonyl, such as acetonyloxycarbonyl, aroylmethoxycarbonyl, wherein the aroyl group is preferably optionally, e.g. by halogen, such as bromine, substituted benzoyl, e.g. Phenacyloxycarbonyl, halo-lower alkoxycarbonyl such as 2-halo-lower alkoxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, or di-halo-lower alkoxycarbonyl wherein lower alkoxy contains 4-7 carbon atoms, e.g. 4-chlorobutoxycarbonyl, phthalimidomethoxycarbonyl, lower alkenyloxycarbonyl, e.g. Allyloxycarbonyl, or in the 2-position by lower alkylsulfonyl, cyano or trisubstituted silyl, such as tri-lower alkylsilyl or triphenylsilyl, substituted ethoxycarbonyl, e.g. 2-methylsulfonylethoxycarbonyl, 2-cyanoethoxycarbonyl, 2-trimethylsilylethoxycarbonyl or 2- (di-n-butyl-methyl-silyl) -ethoxycarbonyl.

Other esterified carboxy groups present in esterified form are corresponding organic silyloxycarbonyl, further corresponding organic stalyloxycarbonyl groups. In these, the silicon or tin atom preferably contains lower alkyl, in particular methyl or ethyl, furthermore lower alkoxy, e.g. Methoxy, as a substituent. Suitable silyl or stannous groups are primarily tri-lower alkylsilyl, especially trimethylsilyl or dimethyl-tert-butylsilyl, or appropriately substituted stannyl groups, e.g. Tri-n-butylstannyl.

An esterified carboxyl group cleavable under physiological conditions is primarily an acyloxymethoxycarbonyl group in which acyl is e.g. the residue of an organic carboxylic acid, primarily an optionally substituted lower alkanecarboxylic acid, or wherein acyloxymethyl forms the residue of a lactone, 1-lower alkoxy-lower alkoxycarbonyl or 1-lower alkoxycarbonyloxy-lower alkoxycarbonyl wherein lower alkyl e.g. For example, methyl, propyl, butyl or especially ethyl and lower alkoxy z. B, methoxy, ethoxy, propoxy or butoxy. Such groups are e.g. Lower alkanoyloxymethoxycarbonyl, e.g. Acetoxymethoxycarbonyl or 'pivaloyloxymethoxycarbonyl, amino-lower alkanoyloxymethoxycarbonyl, especially a-aminone: .dereralkanoyloxymethoxycarbonyl, e.g. Glycyloxymethoxycarbonyl, L-valyloxymethoxycarbonyl, L-leucyloxymethoxycarbonyl, phthalidyloxycarbonyl, 4-crotonolactonyl or 4-butyrolactone-4-yl, indanyloxycarbonyl, e.g. 5-indanyloxycarbonyl, 1-ethoxycarbonyloxyethoxycarbonyl, methoxymethoxycarbonyl or 1-methoxyethoxycarbonyl.

Preferred protected carboxyl groups R 'are the 4-nitrobenzyloxycarbonyl, lower alkenyloxycarbonyl and the 2-membered lower alkylsulfonyl, cyano or tri-lower alkylsilyl substituted ethoxycarbonyl group and physiologically cleavable esterified carboxyl groups such as lower alkanoyloxymethoxycarbonyl and 1-lower alkoxycarbonyloxy-lower alkoxycarbonyl.

A protected amino group may, for example, be in the form of an easily cleavable acylamino, acylimino, etherified mercaptoamino, silyl or stannylamino group or as an enamino, nitro or azido group. '·

In a corresponding acylamino group, for example, acyl is the acyl radical of an organic acid with e.g. up to 18 carbon atoms, especially an optionally, e.g. by halogen or phenyl, .sub. -substituted alkanecarboxylic acid or optionally, e.g. by halogen, lower alkoxy or nitro, substituted benzoic acid, or a carbonic monoester. Such acyl groups are, for example, lower alkanoyl,

such as Fonnyl, acetyl or propionyl, halo-lower alkanoyl, such as 2-haloacetyl, in particular 2-fluoro, 2-bromo, 2-iodo, 2,2,2-trifluoro or 2,2,2-trichloroacetyl, optionally substituted benzoyl , eg Benzoyl, halobenzoyl such as 4-chlorobenzoyl, lower alkoxybenzoyl such as 4-methoxybenzoyl, or nitrobenzoyl such as 4-nitrobenzoyl. In particular, lower alkenyloxycarbonyl, e.g. Allyloxycarbonyl, or lower alkoxycarbonyl optionally substituted in the 1- or 2-position, such as lower alkoxycarbonyl, e.g. Methoxy or ethoxycarbonyl, optionally substituted benzyloxycarbonyl, e.g. Benzyloxycarbonyl or 4-nitrobenzyloxycarbonyl, aroylmethoxycarbonyl, wherein the aroyl group is preferably optionally, e.g. by halogen, such as bromine, substituted benzoyl, e.g. Phenacyloxycarbonyl, 2-halo-lower alkoxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, or 2- (trisubstituted silyl) -ethoxycarbonyl, such as 2-tri-lower alkylsilylethoxycarbonyl, e.g. 2-trimethylsilylethoxycarbonyl or 2- (di-n-butylmethyl-silyl) -ethoxycarbonyl, or 2-triarylsilylethoxycarbonyl such as 2-triphenylsilylethoxycarbonyl.

In an acylimino group acyl is, for example, the acyl radical of an organic dicarboxylic acid having for example up to 12 carbon atoms, in particular a corresponding aromatic dicarboxylic acid such as phthalic) acid. Such a group is primarily phthalimino.

An etherified mercaptoamino group is primarily a phenylthioamino group or a pyridylthioamino group which is optionally substituted by lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine or 3rom, and / or nitro. Ent-, speaking groups are for example 2- or 4-Nitrophenylthioamino or 2-pyridylthioamino.

A silyl or stannylamino group is primarily an organic silyl or stannylamino group, wherein the silicon or stannylamino group. Tin atom, preferably lower alkyl, e.g. Methyl, ethyl, η-butyl or tert-butyl, further lower alkoxy, e.g. Methoxy, as a substituent.

Corresponding silyl or stannyl groups are primarily tri-lower alkylsilyl, especially trimethylsilyl, further dimethyl-tert-butylsilyl, or appropriately substituted stannyl, e.g. Tri-nbutylstannyl.

Further protected amino groups are e.g. Enaminogruppen containing at the double bond in the 2-position an electron-withdrawing substituent, such as a carbonyl group. Protecting groups of this kind are, for example, 1-acyl-lower-alk-1-en-2-yl radicals, in which acyl is e.g. the corresponding residue of a lower alkanecarboxylic acid, e.g. Acetic acid, an optional, e.g. lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as methoxy, halo, such as chloro and / or nitro substituted benzoic acid, or especially a carbonic acid half ester, such as a carbonic acid lower alkyl half ester, e.g. methyl-half ester or -ätnylhalbesters, and Niederalk-1-en, in particular 1-propene means. Corresponding protecting groups are primarily 1-lower alkanoylprop-1-en-2-yl, e.g. 1-acetyl-prop-1-en-2-yl, or 1-lower alkoxycarbonyl-prop-1-en-2-yl, e.g. l-ethoxycarbonyl-prop-l-en-2-yl.

A protected sulfo group is primarily an esterified one such as an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic. Alcohol, e.g. a lower alkanol, or with a silyl or stannyl radical, such as tri-lower alkylsilyl, esterified sulfo group. In a sulfo group, for example, the hydroxy group may be etherified as the hydroxy group in an esterified carboxyl group.

Salts of compounds of the invention are primarily pharmaceutically acceptable non-toxic salts of compounds of formula I. Such salts are exemplified by the acidic groups present in compounds of formula I, e.g. Carboxyl and sulfo groups, and are primarily metal or ammonium salts, such as alkali metal and alkaline earth metal, e.g. Sodium, potassium, magnesium or calcium salts, as well as ammonium salts with ammonia or suitable organic amines, such as lower alkylamines, e.g. Triethylamine, hydroxy-lower alkyl amines, e.g. 2-hydroxyethylamine, bis (2-

hydroxyethyl) amine or tris (2-hydroxyethyl) amine, basic aliphatic esters of carboxylic acids, e.g. 4-aminobenzoic acid 2-diethylaminoethyl ester, lower alkylene amines, e.g. 1-ethylpiperidine, cycloalkylamines, e.g. Dicyclohexylamine, or benzylamines, e.g. Ν, Ν'-dibenzylethylenediamine, dibenzylamine or N-benzyl-ß-phenethylamine. Compounds of formula I having a basic group, e.g. with an amino group, acid addition salts, e.g. with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulphonic acids, e.g. Acetic, succinic, fumaric, maleic, tartaric, oxalic, citric, benzoic, mandelic, malic, ascorbic, methanesulfonic or 4-toluenesulfonic acid form. Compounds of the formula I having an acidic and a basic group may also be present in the form of internal salts, .d.h. in zwitterionic form.

For isolation or purification it is also possible to use pharmaceutically unsuitable salts. For therapeutic use, only the pharmaceutically acceptable, non-toxic salts, which are therefore preferred.

In the penem compounds of formula I, the two asymmetric carbon atoms in the 5- and 6-position may be in the R, S or racemic R, S configuration. Preference is given to the compounds in which the configuration of the 5-carbon atom corresponds to that of natural penicillin (5R configuration). The hydrogen atoms in the 5- and 6-position may be in the cis position or preferably in the trans position. In the preferred configuration, the 6-position substituent occupies the S configuration. Compounds of the formula I in which R is methyl have, at the carbon atom 1 of the side chain, a further center of chirality, which may be in the racemic R, S configuration, the S or in particular the R configuration.

The invention relates in particular to compounds of the formula I in which R is hydrogen or methyl, R 1 is hydroxyl or protected hydroxyl, R is carboxyl or protected carboxyl R ', especially under physiological conditions, is a cleavable esterified carboxyl R 1,

R. a via a ring carbon atom to the rest - (CH_) - bound 4 Zm

5-membered or 6-membered heteroaryl radical or partially saturated heteroaryl radical having 1 to 4 ring nitrogen atoms and optionally an additional ring heteroatom of the group oxygen and sulfur, such as a corresponding 5-membered aza-, diaza-, triaza-, tetraza-, oxaza-, oxadiaza-, thiaza-, thiadiaza- or thiatriazacyclic radical of aromatic character or a corresponding dihydro radical, or a corresponding 6-membered aza-, diaza- or triaza-cyclic radical of aromatic character or a corresponding dihydro or tetrahydro radical wherein these groups are unsubstituted or substituted by hydroxy, lower alkoxy, lower alkanoyloxy, halogen, mercapto, lower alkylthio, phenylthio, lower alkyl, hydroxy lower alkyl, lower alkoxy, lower alkyl, lower alkyl, lower alkyl, lower alkyl, lower alkylamino, lower alkoxycarbonyl, optionally N mono- or N, N-din lower alkyl substituted carbamoyl, cyano, sulfo, sulfamoyl, optionally substituted by lower alkyl, nitro, lower alkoxy and / or halogen substituted phenyl, cycloalkyl, nitro, oxo and / or oxido and m is an integer from 1 to 4, salts of compounds of the formula I, which have a salt-forming group, optical isomers of compounds of the formula I and mixtures of these optical isomers.

The invention relates in the first place to compounds of the formula I in which R is hydrogen or methyl, R is hydroxyl, R is carboxyl, lower alkanoyloxymethoxycarbonyl, e.g. Pivaloyloxymethoxycarbonyl, or L-lower alkoxycarbonyloxy-lower alkoxycarbonyl, e.g. 1-Aethoxycarbonyloxyethoxycarbonyl, R, denotes a ring carbonyl

to the rest (CH ") - bound, optionally by

£ m

alkyl, carboxy-lower alkyl, sulfo-lower alkyl or di-lower alkylamino-lower alkyl substituted tetrazolyl, such as IH- or 2H-tetrazol-5-yl, e.g. 1H-Tetrazol-5-yl, 1-methyl-1H-tetrazol-5-yl, 1-carboxymethyl-1H-tetrazol-5-yl, 1-sulfomethyl-1H-tetrazol-5-yl, 1- (2-dimethylaminoethyl) ) -LH-tetrazol-5-yl or 2-methyl-2H-tetrazol-5-yl, optionally substituted by lower alkyl or amino-substituted thiadiazolyl, such as 1,3,4-thiadiazol-2-yl, for example 1,3,4-thiadiazol-2-yl or 2-methyl-l, 3,4-thiadiazol-5-yl, optionally lower alkyl substituted oxadiazolyl, such as l, 3,4-oxadiazol-2-yl, e.g. 2-methyl-1, 3,4-oxadiazol-5-yl, or pyridyl, e.g. 2-pyridyl, and m is an integer from 2 to 4, pharmaceutically acceptable salts of those compounds of formula I containing a salt-forming group, optical isomers, e.g. the (5R, 6S) isomer, of compounds of formula I and mixtures of these optical isomers.

The invention relates primarily to (5R, 6S) -configured compounds of the formula I in which R _{1 is} hydrogen, R 6 is hydroxyl, R 6 is carboxyl, R 4 is tetrazol-5-yl substituted by lower alkyl or lower-alkylamino-lower alkyl, eg 1-methyl- lH-tetrazol-5-yl, 1- (2-dimethylaminoethyl) -lH-tetrazol-5-yl or 2-methyl-2H-tetrazol-5-yl, or lower alkyl substituted l, 3,4-oxadiazol-2 yl, for example 2-methyl-l, 3,4-oxadiazol-5-yl, and m is 3, and pharmaceutically acceptable salts of compounds of formula I.

Above all, the invention relates to the compounds of the formula I mentioned in the examples and their pharmaceutically usable salts.

The compounds of the present invention are prepared by methods known per se.

The new connections are e.g. prepared by a) an ylide compound of the formula

(II)

wherein EL, R ", R ', R, and m have the meanings given under formula I, wherein the functional groups contained in the radicals R 2 and / or R optionally present in slotted form, Z is oxygen or sulfur and X *" represents either a trisubstituted phosphonium group or a doubly esterified phosphonium group together with a cation, ring-closing, or

b) a compound of the formula

HH

R_-CH ~~ * 2 I

SC- (CH ₀ ) -R. 2 m 4

^R 3

wherein R-, "R ₂ 5 ^R o> ^r a ^{and m have} the meanings given under formula I, wherein the functional groups contained in the radicals R ₂ and / or R, optionally present in slotted form, with an organic compound of the trivalent Treated and phosphorus

if desired or necessary, in an available compound of formula I, convert a protected hydroxyl group R "into the free hydroxyl group, and / or, if desired, in a compound of formula I obtainable, a protected carboxyl group R 'in the free or in another protected Carboxyl group R ', and / or, if desired, further in the radical R containing protected functional groups transferred to the free functional groups, and / or, if desired, in an available compound

of the formula I converts a radical R, in another radical R, and / or, if desired, converts an available compound having a salt-forming group into a salt or an available salt into the free compound or into another salt, and / or if desired, separating an available mixture of isomeric compounds into the individual isomers, and / or processing an available compound into a pharmaceutical preparation.

a) Cyclization of the compound of formula II

The group λ ~ in the starting material of the formula II is one of the commonly used in Wittig condensation reactions phosphonio or phosphono, in particular a triaryl, for example triphenyl, or Triniederalkyl-, eg tri-n-butylphosphoniogruppe, or by lower alkyl, eg ethyl, di-esterified phosphono group, wherein the symbol 5i in the case of the phosphono group additionally comprises the cation of a strong base, in particular a suitable metal, such as alkali metal, for example lithium, sodium or potassium ion. Preferred groups x ~ are on the one hand triphenylphosphonio and on the other hand diethylphosphono together with an alkali metal eg sodium ion.

The ylide compounds of the formula II are also referred to in the isomeric Ylen form as phosphorane compounds. In phosphonio compounds of formula II, the negative charge is neutralized by the positively charged phosphonium group. In phosphono compounds of formula II, the negative charge is neutralized by the cation of a strong base which, depending on the manner of preparation of the phosphono starting material, e.g. an alkali metal, e.g. Sodium, lithium or potassium ion, may be. The phosphono starting materials are therefore used as salts in the reaction.

The ring closure can be spontaneous, i. in the preparation of the starting materials, or by heating, e.g. in a temperature range of

about 30 ° C to 16O ° C, preferably from about 50 ⁰ C to about 100 ⁰ C, take place. The reaction is preferably carried out in a suitable inert solvent, such as in an aliphatic, cycloaliphatic or aromatic hydrocarbon, eg hexane, cyclohexane, benzene or toluene, a halogenated hydrocarbon, for example methylene chloride, an ether, for example diethyl ether, dimethoxyethane or diethylene glycol dimethyl ether, a cyclic ether, for example dioxane or tetrahydrofuran, a carboxamide, for example dimethylformamide, a Diniederalkylsulfoxid, for example dimethyl sulfoxide, or a lower alkanol, for example methanol, ethanol or tert-butanol, or in a mixture thereof, and, if necessary, in an inert gas, eg nitrogen f atmosphere, performed.

A starting compound of formula II, wherein X 1 is a phosphono group together with a cation, is preferably prepared in situ by reacting a compound of formula

^ HH I I <<II

R-CH.f-S-C- (CHJ-R. (Ha)

2 IL I m 4

κ * \

C / CH-X '

wherein X ^{f represents} a phosphono group, with a suitable basic reagent, such as an inorganic base, for example an alkali metal carbonate, such as sodium or potassium carbonate, or an organic base, such as a tri-lower alkylamine, for example triethylamine, or an amide-type cyclic base, such as a corresponding Diazabicycloalkene compound, for example, 1,5-D! Azabicyclo [5.4.0] undec-5-ene treated.

b. Cyclization of the compound of formula III

An organic compound of the trivalent phosphorus is derived e.g. phosphorous acid and in particular is an ester of

the same with a lower alkanol, for example methanol or ethanol, and / or an optionally substituted aromatic hydroxyl compound, eg phenol or pyrocatechol, or an amide ester thereof of the formula P (OR) -N (IL) ₇ , wherein R and TL independently of one another are lower alkyl, for example, methyl, or aryl, for example phenyl. Preferred compounds of the trivalent phosphorus are tri-lower alkyl phosphites, for example trimethyl phosphite or triethyl phosphite.

The reaction is preferably carried out in an inert solvent such as an aromatic hydrocarbon, for example benzene or toluene, an ether, for example dioxane or tetrahydrofuran, or a halogenated hydrocarbon, for example methylene chloride or chloroform, at a temperature of about 20 ° to about 80 ⁰ C, preferably from about 40 ° to about 60 ⁰ C, carried out, wherein reacting 1 molar equivalent of a compound of formula III with 2 molar equivalents of the phosphorus compound. The compound of the formula III is preferably initially introduced in an inert solvent and the phosphorus compound, preferably dissolved in the same inert solvent, is added dropwise over a relatively long period of time, for example over a period of from 2 to 4 hours.

The starting compounds of the formula III can be prepared, for example, by reacting an azetidinone of the formula

S-C- (CHj-R. (IV) "2m. 4

with a compound of formula R'-COOH or, especially, a reactive derivative such as an acid halide such as the acid chloride thereof, at a temperature of 20 ° to 80 ° C, preferably at 40 ° to 60 ⁰ C, in an inert solvent such as one of the compounds in the reaction of compounds of formula III

of formula I, treated. When using an acid halide it is preferred to work in the presence of an acid binding agent such as a tertiary aliphatic amine, e.g. Triethylamine, an aromatic amine, e.g. Pyridine, or more particularly an alkali metal or alkaline earth metal carbonate or bicarbonate, e.g. Potassium carbonate or calcium carbonate.

In a preferred embodiment of the process, the starting material of the formula III is prepared as described and reacted without isolation from the reaction mixture with the organic compound of the trivalent phosphorus, the end products of the formula I being formed.

Preference is given to using those starting materials of the formulas II and III which lead to the compounds of the formula I mentioned at the outset as being particularly preferred, in particular compounds of the formulas II and III which have a 4R, 3S configuration.

In an available compound of formula I wherein one or more functional groups are protected, these, e.g. protected amino, carboxyl, hydroxyl and / or SuIfogruppen, in a conventional manner by solvolysis, in particular hydrolysis, alcoholysis or acidolysis, or by reduction, in particular hydrogenolysis or chemical reduction, optionally be released gradually or simultaneously.

In a compound of the formula I with a protected amino group which can be obtained according to the invention, it can be prepared in a manner known per se, e.g. depending on the nature of the protecting group, preferably converted by solvolysis or reduction, in the free amino group. For example, 2-halo-lower alkoxycarbonylamino (optionally after conversion of a 2-bromo-lower alkoxycarbonylamino)

amino group into a 2-iodo-lower alkoxycarbonylamino group), aroylmethoxycarbonylamino or 4-nitrobenzyloxycarbonylamino are cleaved by treating with a suitable chemical reducing agent such as zinc in the presence of a suitable carboxylic acid such as aqueous acetic acid or catalytically with hydrogen in the presence of a palladium catalyst. Aroylmethoxycarbonylamino may also be prepared by treating with a nucleophilic, preferably salt-forming reagent such as sodium thiourethiophenolate and 4-nitrobenzyloxycarbonylamino also by treatment with an alkali metal, e.g. Sodium dithionite be cleaved. Optionally substituted benzyloxycarbonylamino may be e.g. by means of hydrogenolysis, i. by treating with hydrogen in the presence of a suitable hydrogenation catalyst, such as a palladium catalyst, and allyloxycarbonylamino, by reacting with a compound of palladium, e.g. Tetrakis (triphenylphosphine) palladium, in the presence of triphenylphosphine and treatment with a carboxylic acid, e.g. 2-Aethylhexansäure, or a salt thereof, are cleaved. An amino group protected with an organic silyl or stannyl group can be z.3. by hydrolysis or alcoholysis, one represented by 2-halo-lower alkanoyl, e.g. 2-chloroacetyl, protected amino group by treatment with thiourea in the presence of a base or with a thiolate salt, such as an alkali metal thiolate, the thiourea and subsequent solvolysis, such as alcoholysis or hydrolysis of the resulting condensation product are released. An amino group protected by 2-substituted silylethoxycarbonyl may be prepared by treating with a fluoride anion-providing salt of hydrofluoric acid such as an alkali metal fluoride, e.g. Sodium fluoride, in the presence of a macrocyclic polyether ("crown ether") or with a fluoride of an organic quaternary base such as tetra-lower alkylammonium fluoride, e.g. Tetraethylammonium fluoride, converted into the free amino group. An amino group protected in the form of an azido or nitro group is e.g. converted by reduction into free amino, for example by catalytic hydrogenation with hydrogen in the presence of a hydrogenation catalyst such as platinum oxide, palladium or Raney nickel,

or by treatment with zinc in the presence of an acid such as acetic acid. A protected in the form of a phthalimido group amino group can be converted by reacting with hydrazine in the free amino group. Furthermore, an arylthioamino group may be converted to amino by treatment with a nucleophilic reagent, such as sulfurous acid.

In a compound of the formula I obtainable by the process in which R is a protected carboxyl group and / or in which the radical R contains protected carboxyl as substituent, the carboxyl group can be released in a manner known per se. Thus, tert.-lower alkoxycarbonyl or lower 2-position substituted by a trisubstituted silyl group or in the 1-position by lower alkoxy-substituted lower alkoxycarbonyl or optionally substituted Dxphenylmethoxycarbonyl. by treatment with a carboxylic acid such as formic acid or trifluoroacetic acid, optionally with the addition of a nucleophilic compound such as phenol or anisole, into free carboxyl. Optionally substituted benzyloxycarbonyl may be e.g. by means of hydrogenolysis, i. be cleaved by treatment with hydrogen in the presence of a metallic hydrogenation catalyst, such as a palladium catalyst. Further, suitably substituted benzyloxycarbonyl such as 4-nitrobenzyloxycarbonyl may also be obtained by means of chemical reduction, e.g. by treatment with an alkali metal, e.g. Sodium dithionite, or with a reducing metal, e.g. Tin, or metal salt, like one. Chromium II salt, e.g. Chromium-II-chloride, usually in the presence of a hydrogen donating agent capable of producing nascent hydrogen together with the metal, such as a suitable carboxylic acid, e.g. an optional, e.g. by hydroxy, substituted lower alkanoic acid, e.g. Acetic acid, formic acid or glycolic acid, or an alcohol or thiol, preferably adding water, convert into free carboxyl. The cleavage of an allyl protecting group can be e.g. by reacting with a compound of palladium, e.g.

Tetrakis (triphenylphosphine) palladium, in the presence of triphenylphosphine and with the addition of a carboxylic acid, e.g. 2-Aethylhexanoic acid, or a salt thereof. By treating with a reducing metal or metal salt as described above, one can also convert 2-halo-lower alkoxycarbonyl (optionally after conversion of a 2-bromo-lower alkoxycarbonyl group to a corresponding 2-iodo-lower alkoxycarbonyl group) or aroylmethoxycarbonyl into free carboxyl, aroylmethoxycarbonyl also being prepared by treatment with a nucleophilic, preferably salt-forming reagent, such as sodium thiophenolate or sodium iodide can be cleaved. Substituted 2-silylethoxycarbonyl may also be prepared by treatment with a hydrofluoric acid hydrofluoric acid salt such as an alkali metal fluoride, e.g. Sodium fluoride, in the presence of a macrocyclic polyether ("crown ether") or with a fluoride of an organic quaternary base such as tetra-lower alkylammonium fluoride, e.g. Tetrabutylammonium fluoride are converted into free carboxyl. Carboxylated with an organic silyl or stannyl group, such as tri-lower alkylsilyl or stannyl, may be solvolytically, e.g. be released by treatment with water or an alcohol. A lower alkoxycarbonyl group substituted at the 2-position by lower alkylsulfonyl or cyano may be e.g. by treating with a basic agent such as an alkali metal or alkaline earth metal hydroxide or carbonate, e.g. Sodium or potassium hydroxide or sodium or potassium carbonate, are converted into free carboxyl.

In compounds of the formula I which can be obtained according to the process in which R _{9 represents} a protected hydroxy group and / or in which the radical R contains protected hydroxyl as a substituent, the protected hydroxy group can be converted into the free hydroxyl group in a manner known per se. For example, a hydroxy group protected by a suitable acyl group or an organic silyl or stannyl group is released as a suitably protected amino group, a tri-lower alkylsilyl group eg with tetrabutylammonium fluoride and acetic acid (under these conditions, trisubstituted silylethoxy protected carboxyl groups are not cleaved). A 2-halo-lower

kylgruppe and an optionally substituted Benz.ylgruppe are cleaved reductively.

A protected, in particular esterified, sulfo group is liberated analogously to a protected carboxyl group.

On the other hand, compounds of the formula I in which R denotes carboxy can also be converted into compounds of the formula I in which R represents a protected carboxyl group, in particular an esterified carboxyl group. Thus, the free carboxyl group can be e.g. by treating with a suitable diazo compound, such as a diazo-lower alkane, e.g. Diazomethane, or a phenyldiazole-lower alkane, e.g. Diphenyldiazomethane, if necessary, in the presence of a Lewis acid, e.g. Boron trifluoride, or by reacting with an alcohol suitable for esterification in the presence of an esterifying agent such as a carbodiimide, e.g. Dicyclohexylcarbodiimid, as well as carbonyldiimidazole, esterify. Esters can also be prepared by reacting an optionally in situ prepared salt of the acid with a reactive ester of an alcohol and a strong inorganic acid such as sulfuric acid or a strong organic sulfonic acid such as 4-toluenesulfonic acid. Further, acid halides, such as chlorides (prepared, for example, by treatment with oxalyl chloride), activated esters (formed, for example, with N-hydroxy nitrogen compounds, such as N-hydroxysuccinimide) or mixed anhydrides (eg with haloformic acid lower alkyl esters, such as chloroformateMuräthyl- or isobutyl chloroformate, or with Halogenessigsäurehalogeniden, such as trichloroacetic acid chloride) by reaction with alcohols, optionally in the presence of a base such as pyridine, are converted into an esterified carboxyl group.

In a compound of formula I having an esterified carboxyl group, this may be converted to another esterified carboxyl group, e.g. 2-chloroethoxycarbonyl or 2-bromoethoxycarbonyl by treatment

- 24 -

with an iodine salt, e.g. Sodium iodide, in 2-iodoethoxycarbonyl. Further, in compounds of formula I containing an esterified carboxy group, the carboxy protecting group can be cleaved as described above and a resulting compound of formula I having a free carboxyl group or a salt thereof by reacting with the reactive ester of a corresponding alcohol in a compound of formula I, wherein R ~ is a cleavable under physiological conditions esterified carboxyl group Ri.

In compounds of the formula I it is also possible to convert a radical R 1 into another radical R 1.

Thus, for example, in compounds of formula I in which the heterocyclyl radical R is substituted by a carboxyl group, this carboxyl group can be converted to a functionally modified carboxyl group, such as an esterified carboxyl group or optionally substituted carbamoyl, by methods known per se. For example, by reacting a compound of formula I wherein R is carboxyl-substituted heterocyclyl with an alcohol, especially a lower alkanol, one obtains a compound of formula I wherein R is esterified carboxyl, especially lower alkoxycarbonyl, substituted heterocyclyl, preferably in the presence of a suitable condensing agent, eg a carbodiimide, or the resulting water removed by azeotropic distillation. On the other hand, one can use carboxyl groups on radicals R, also in reactive functional derivatives, such as mixed anhydrides, e.g. Acid halides, or activated esters, and convert them by reaction with an alcohol, e.g. Lower alkanol, ammonia or a primary or secondary amine, e.g. a lower alkyl or di-lower alkylamine, converted into corresponding esterified or amidated carboxyl groups, which is preferably when using mixed anhydrides in the presence of an acid-binding agent, such as an aromatic

or tertiary amine or an alkali metal or alkaline earth metal carbonate.

Has a heteroaryl radical R, a hydroxy group, it can be etherified in the usual way. The reaction to the corresponding lower alkyl heteroaryl ethers is carried out, for example, in the presence of bases such as alkali metal hydroxides or carbonates, e.g. Sodium hydroxide or potassium carbonate, with the aid of di-lower alkyl sulfates or lower alkyl halides, or with Diazoniederalkanen, or, in the presence of a dehydrating agent, for example dicyclohexylcarbodiimide, with the aid of lower alkanols. Furthermore, hydroxy can be converted to esterified hydroxy, e.g. Lower alkanoyloxy, for example, by reaction with the reactive derivative of a corresponding lower alkanecarboxylic acid, e.g. Acetic acid, such as an anhydride thereof, e.g. the symmetrical anhydride thereof or a mixed anhydride with a hydrohalic acid, if necessary in the presence of a basic condensing agent such as an alkali metal hydroxide or carbonate, or a nitrogen base, e.g. Pyridine. The conversion of lower alkanoyloxy to hydroxy is carried out, for example, by alcoholysis or, preferably, hydrolysis, e.g. by base catalyzed hydrolysis, e.g. in the presence of sodium hydroxide.

In compounds of formula I wherein R, is heterocyclyl substituted by amino, the amino group can be converted to a substituted amino group such as a lower alkylamino, di-lower alkylamino, lower alkyleneamino or lower alkanoylamino group. The conversion into a lower alkylamino or di-lower alkylamino group takes place, for example, by reaction with a reactive esterified lower alkanol, for example a lower alkylamino or lower alkylamino group.

alkyl halide or sulfonate, in the presence of a basic condensing agent such as a hydroxide or carbonate of an alkali or alkaline earth metal or a heteroaromatic nitrogen base, e.g. Pyridine. Analogously, amino can be prepared by treating with a lower alkylene dihalide or disulfonate in lower alkylene amino and treating with the reactive functional derivative of a lower alkanecarboxylic acid, e.g. the corresponding carboxylic acid halide, be converted into Niederalkanoylamino.

Salts of compounds of the formula I with salt-forming groups can be prepared in a manner known per se. Thus, salts of compounds of formula I having a free carboxyl group, e.g. by treating with metal compounds, such as alkali metal salts of suitable organic carboxylic acids, e.g. the sodium salt of α-ethyl-caproic acid, or with inorganic alkali or alkaline earth metal salts, e.g. Form sodium bicarbonate, or with ammonia or with a suitable organic amine, preferably using stoichiometric amounts or only a small excess of the salt-forming agent. Acid addition salts of compounds of the formula I are obtained in a customary manner, e.g. by treatment with a suitable acid or a suitable anion exchange reagent. Internal salts of compounds of formula I can e.g. by neutralizing salts, such as acid addition salts, to the isoelectric point, e.g. with weak bases, or by treatment with ion exchangers.

Salts can be converted to the free compounds in the usual way, metal and ammonium salts e.g. by treatment with suitable acids and acid addition salts e.g. by treating with a suitable basic agent.

Geines obtained from isomers can be separated into the individual isomers by methods known per se, mixtures of diastereomeric isomers, e.g. by fractional crystallization, adsorption chromatography (column or thin layer chromatography) or other suitable separation methods.

The cleavage of racemates obtained in their optical antipodes can be done in various ways.

One of these ways consists of reacting a racemate with an optically active excipient, separating the resulting mixture of two diastereomeric compounds by means of suitable physico-chemical methods, and then cleaving the individual diastereomeric compounds into the optically active compounds.

Particularly suitable racemates for separation into antipodes are those having an acidic group, e.g. Racemates of compounds of formula I, wherein R is carboxy. These acidic racemates can be reacted with optically active bases, e.g. Esters of optically active amino acids, or (-) - brucine, (+) - quinidine, (-) - quinine, (+) - cinchonine, (+) - dehydroabietylamine, (+) - and (-) - ephedrine, (+ ) - and (-) - l-phenylethylamine or their N-mono- or Ν, Ν-dialkylated derivatives to give mixtures consisting of two diastereomeric salts.

In carboxyl-containing racemates, this carboxyl group may also be esterified by an optically active alcohol such as (-) - menthol, (+) - borneol, (+) - or (-) - 2-0ctanol, followed by isolation of the desired Diastereomers the carboxyl group is released.

For the separation of racemates, the hydroxy group can also be esterified with optically active acids or their reactive, functional derivatives

to form diastereomeric esters. Such acids include (-) - abietic acid, D (+) - and L (-) - malic acid, N-acylated optically active amino acid, (+) - and (-) - camphanic acid, (+) - and (-) - Ketopic acid, L (+) - ascorbic acid, (+) - camphoric acid, (+) - camphorl-O-sulfonic acid (β), (+) - or (-) - α-bromopanher-TT " ^see below ^: nitric acid, D (-) -ChinasMure, D (-) - isoascorbic acid, D (-) - and L (+) - commercial acid, (+) - l-menthoxyacetic acid, D (-) - and L (+) - tartaric acid and their di-O-benzoyl and di-Op-toluyl derivatives.

By reaction with optically active isocyanates, such as (+) - or (-) - 1-phenylethyl isocyanate, compounds of formula (I) wherein R is protected carboxy and R is hydroxy can be converted to a mixture of diastereomeric urethanes.

Basic racemates, e.g. Compounds of the formula I in which the radical R 1 is substituted by amino may form diastereomeric salts with the said optically active acids.

The cleavage of the resolved diastereomers into the optically active compounds of the formula I likewise takes place by customary methods. From the salts are freed the acids or the bases, e.g. by treating with stronger acids or bases than those originally used. From the esters and urethanes, the desired optically active compounds are obtained, for example, after alkaline hydrolysis or after reduction with a complex hydride such as lithium aluminum hydride.

Another method for separating the racemates consists in the chromatography on optically active absorption layers, for example on cane sugar.

According to a third method, the racemates can be dissolved in optically active solvents and the less soluble optical antipode crystallized out.

In a fourth method, one uses the different reactivity of the optical antipodes to biological material such as microorganisms or isolated enzymes.

According to a fifth method, the racemates are dissolved and one of the optical antipodes is crystallized by seeding with a small amount of an optically active product obtained by the above methods.

The separation of diastereomers into the individual racemates and the racemates into the optical antipodes may be carried out at any stage of the process, i. e.g. also at the stage of the starting compounds of the formulas II or III or at any stage of the process described below for the preparation of the starting compounds of the formula II.

In all subsequent conversions obtained compounds of formula I are those reactions which take place under neutral, alkaline or weakly acidic conditions.

The process also includes those embodiments in which intermediates are used as starting materials and the remaining process steps are carried out with them, or the process is stopped at any stage. Further, starting materials may be used in the form of derivatives or formed in situ, optionally under the reaction conditions. For example, a starting material of formula II wherein Z is oxygen can be prepared from a compound of formula 11 wherein Z is an optionally substituted methylidene group as described below by ozonization followed by reduction of the ozonide formed, analogously to the procedure given below.

Ren (step 3.3), are prepared in situ, whereupon in the reaction solution, the cyclization to the compound of formula I.

The starting compounds of the formulas II and IV and the precursors can be prepared as indicated in Reaction Schemes I, II and III:

Reaction scheme I

R ₂ -CH.

H H

NH

(V)

R.

R ₂ -CH-

H H

ζ ¹

H H

step

Z '

R -CH / w-j

NH

IHH

(Iv) Level 1.2

Z '

R is -CH ~ w ~ · f -sc (CH ₀₎ -R ₇

2 I 2 m 4

step

^R 3

^R 3

(VII)

step

Z ¹

R ₉ -CH f; ~~ SC (CH ₀ ) -R

I j I 2 m

(VI)

R, HH

-N

- - -. is. HH

Stage 1.4a 1 c <

ä R ₂ -CH.j ^ SM

^R 3

(II ¹ )

(VIII)

In the compounds of the formulas IV, VI, VII and II ', Z' is oxygen, sulfur or else a methylidene group optionally substituted by one or two substituents Y, which can be converted into an oxo group Z by oxidation. A substituent Y of this methylidene group is an organic radical, for example optionally substituted lower alkyl, for example methyl or ethyl, cycloalkyl, for example cyclopentyl or cyclohexyl, phenyl or phenyl-lower alkyl, for example benzyl, or in particular one, including one, optically active alcohol, such as 1-menthol esterified carboxyl group, for example one of the optionally substituted lower alkoxycarbonyl or arylmethoxycarbonyl radicals mentioned under R "or also 1-menthyloxycarbonyl. The methylidene Z ¹ preferably carries one of said substituents. Of particular note are the Methoxycarbonylmethyliden-, Aethoxycarbonylmethyliden- and 1-Menthyloxycarbonylmethylidengruppe Z ¹ . The latter can be used for the preparation of optically active compounds of the formulas IV, VI ₅ VII and II.

In the compounds of the formulas IV to VIII and II '. the radical R is preferably one of the said protected hydroxy groups, ζ.B. optionally substituted 1-phenyl-lower alkoxy, optionally substituted phenyl-lower alkoxycarbonyloxy, or trisubstituted-silyloxy.

Step 1.1 : A thio-azetidinone of formula IV is obtained by reacting a 4-W-azetidinone of formula V, wherein W represents a nucleofugic leaving group, with a mercapto compound of the formula

R. - (CH ₀ ) -C (= Z ') - SH 4 2 m

or a salt, e.g. an alkali metal such as sodium or potassium salt thereof, and, if desired, in an available compound of formula IV wherein JR. Hydroxy, hydroxy is converted to protected hydroxy.

The nucleofuge leaving group W in a starting material of formula V is a through the nucleophilic radical

R- (CHj -C (= Z ') - S-4 2 m

Such groups W are, for example, acyloxy radicals, sulfonyl radicals R-SO-, in which R _{q is} an organic radical, azido or halogen. In an acyloxy radical W, acyl zE is the radical of an organic carboxylic acid, including an optically active carboxylic acid, and is, for example, lower alkanoyl, eg acetyl or propionyl, optionally substituted benzoyl, eg benzoyl or 2,4-dinitrobenzoyl, phenyl-lower alkanoyl, eg phenylacetyl, or the acyl radical one of the above optically active acids. In a sulfonyl radical R -SO - R is, for example, optionally hydroxy-substituted lower alkyl. such as methyl, ethyl or 2-hydroxyethyl, and also corresponding substituted optically active lower alkyl, for example (2R) - or (2S) -1-hydroxyprop-2-yl, substituted by an optically active radical methyl, such as camphoryl, or benzyl, or optionally substituted phenyl, such as phenyl, 4-bromophenyl or 4-methylphenyl. A halogen radical W is, for example, bromine, iodine or, in particular, chlorine. W is preferably methyl or 2-hydroxyethylsulfonyl, acetoxy or chlorine.

The nucleophilic substitution can be carried out under neutral or weakly basic conditions in the presence of water and optionally a water-miscible organic solvent. The basic conditions may be, for example, by adding an inorganic base such as an alkali metal or alkaline earth metal hydroxide, carbonate or hydrogen carbonate, e.g. of sodium, potassium or calcium hydroxide, carbonate or bicarbonate. As organic solvents, e.g. water-miscible alcohols, e.g. Lower alkanols, such as methanol or ethanol, kerones, e.g. Lower alkanones such as acetone, amides, e.g. Lower alkanecarboxylic acid amides such as dimethylformamide, acetonitrile and the like can be used. The reaction is usually at room temperature

carried out, but can also be carried out at elevated or reduced temperature. By adding a salt of hydriodic acid or thiocyanic acid, e.g. an alkali metal such as sodium salt, the reaction can be accelerated.

Both optically inactive cis or trans compounds of the formula V, as well as mixtures thereof, or corresponding optically active compounds can be used in the reaction. The incoming group R- (CH) -C (= Z ') -S- is selected from the group (R, R) .CH-, preferably in

¹ T " Lm III -L L.

regardless of whether W belongs to the group (R ₁ JR ₉ ) CH- in the cis or trans position. Although the trans isomers are predominantly formed, occasionally the cis isomers can also be isolated. The separation of the cis and trans isomers is carried out as described above, by conventional methods, in particular by chromatography and / or by crystallization.

The subsequent ozonization of a methylidene group Z 'can be carried out as indicated below. A obtained racemate of the formula IV can be separated into the optically active compounds.

An azetidinone of the formula V in which R and W are each acetoxy and R is hydrogen is described in German Offenlegungsschrift No. 29 50 898.

Other azetidinones of formula V can be prepared by methods known per se, for example by reacting a vinyl ester of formula (R, R) CH-CH = CH-W with chlorosulfonyl iso-anoate and subjecting the resulting cycloadduct to a reducing agent, e.g. Sodium sulfite, reacted. In this synthesis, mixtures of cis and trans isomers are usually obtained which, if desired, are converted to the pure cis or trans isomers, e.g. by chromatography and / or crystallization, distillation or sation, can be separated. The pure cis and trans isomers are available as racemates and can in their optical

Antipodes' are separated, for example, when acyl in an acyloxy W in compounds of the formula. V is derived from an optically active acid. The compounds of the formula V, in particular their optically active representatives, can also be prepared by the methods given below in Reaction Schemes II and III.

Step 1.2 : A ct-hydroxycarboxylic acid compound of the formula VI is obtained by reacting a compound of the formula IV with a glyoxylic acid compound of the formula OHC-R 'or a suitable derivative thereof, such as a hydrate, hemihydrate or hemiacetal, for example a hemiacetal with a Lower alkanol, for example methanol or ethanol, and, if desired, in an available compound of formula VI, wherein R is hydroxy, hydroxy is converted into protected hydroxy.

The compound VE, is usually obtained as a mixture of the two isomers (with respect to the group CH ^ OH). But you can also isolate the pure isomers of it.

The addition of the Glyoxylsäureesterverbindung to the nitrogen atom of the lactam ring takes place at room temperature or, if necessary, with heating, for example to about 100 ⁰ C, in the absence of an actual condensing agent and / or without formation of a salt instead. When using the hydrate of the glyoxylic acid compound, water is formed which, if necessary, is removed by distillation, eg, azeotropically, or by use of a suitable dehydrating agent, such as a molecular sieve. Preferably, the reaction is carried out in the presence of a suitable solvent such as dioxane, toluene or dimethylformamide, or solvent mixture, if desired or necessary, in the atmosphere of an inert gas such as nitrogen.

s> - ο τ '»'

Pure optically inactive cis or trans compounds of the formula IV, as well as mixtures thereof, or corresponding optically active compounds can be used in the reaction. A obtained racemate of the formula VI can be separated into the optically active compounds.

Step 1.3: Compounds of the formula VH in which X is a reaction-- 'o

esterified hydroxy group, in particular halogen or organic sulfonyloxy, are prepared by reacting, in a compound of the formula VI, the secondary hydroxy group into a reactive esterified hydroxy group, in particular halogen, e.g. Chlorine or bromine, or into an organic sulfonyloxy group such as lower alkanesulfonyloxy, e.g. Methanesulfonyloxy, or arenesulfonyloxy, e.g. Benzene or 4-methylbenzenesulfonyloxy, converts.

In the starting compounds of the formula VI, R preferably represents a protected hydroxy group.

The compounds of the formula VII can be obtained in the form of mixtures of the isomers (with respect to the group CH - ^ - X) or in the form of pure isomers.

The above reaction is carried out by treatment with a suitable esterifying agent, e.g. with a thionyl halide, e.g. chloride, a phosphorus oxyhalide, especially chloride, a halophosphonium halide such as triphenylphosphono dibromide or diiodide, or a suitable organic sulfonic acid halide such as chloride, preferably in the presence of a basic, primarily an organic basic agent such as an aliphatic, certified amine, e.g. Triethylamine, diisopropylethylamine or "polystyrene-Hünigbase", or a pyridone-type heterocyclic base, e.g. Pyridine or collidine. Preferably work

in the presence of a suitable solvent, e.g. Dioxane or tetrahydrofuran, or a solvent mixture, if necessary, with cooling and / or in the atmosphere of an inert gas such as nitrogen.

In a compound of the formula VII which is obtainable in this way, a reactive esterified hydroxy group X can be converted in a manner known per se into a

other reactive esterified hydroxy group are converted. So you can, for example a chlorine atom by treating the corresponding chloro compound with a suitable bromide or iodide salt, such as lithium bromide or iodide, preferably in the presence of a suitable solvent, such as ether, by a bromine or iodine atom, respectively.

In the reaction, both pure optical inactive cis or trans compounds of the formula VIaIs, mixtures thereof, or corresponding optically active compounds can be used. A obtained racemate of the formula VII can be separated into the optically active compounds.

Step 1.4: The starting material of formula II 'is obtained by reacting a compound of formula VII in which X is a reactive esterified hydroxy group with a suitable phosphine compound such as a tri-lower alkyl phosphine, e.g. Tri-n-butyl-phosphine, or a triarylphosphine, e.g. Triphenylphosphirt, or with a suitable phosphite compound, such as a Triniederalkylphosphit, e.g. Triethyl phosphite, or an alkali metal lower alkyl phosphite, e.g. -diäthylphosphit, treated, which can be obtained depending on the choice of the reagent, a compound of formula II (or II ') or Ha.

The above reaction is preferably carried out in the presence of a suitable inert solvent such as a hydrocarbon, e.g. Hexane, cyclohexane, benzene, toluene or xylene, or an ether, e.g. Dioxane, tetrahydrofuran or diethylene glycol dimethyl ether, or

made a solvent mixture. Depending on the reactivity is carried out under cooling or at elevated temperature, for example between -10 ° and + 100 °, preferably at about 20 ° to 80 °, and / or in the atmosphere of an inert gas, such as nitrogen. To prevent oxidative processes, catalytic amounts of an antioxidant, e.g. Hydroquinone, to be added.

In this case, the use of a phosphine compound is usually carried out in the presence of a basic agent, such as an organic base, for example an amine, such as triethylamine, diisopropylethylamine or "polystyrene Hünigbase", and passes directly to the ylide starting material Formula II (or II ¹ ), which is formed from the corresponding phosphonium salt.

Pure, optically inactive cis or trans compounds of the formula VII, as well as mixtures thereof, or corresponding optically active compounds can be used in the reaction. A obtained racemate of the formula II can be separated into the optically active compounds.

Level 1.4a

A starting compound of the formula II 'in which Z' is oxo can furthermore be obtained by reacting a mercaptide of the formula VIII in which M is a metal cation with a radical

Treated R- (CH ₀ ) -C (= 0) - introducing acylating agent. 4 L m

In the starting material of the formula VIII, the metal cation M is present.

For example, a cation of the formula M or M / 2, where M is in particular a silver cation and M is e.g. for the divalent cation of a suitable transition metal, e.g. Copper, lead or mercury, stands.

An acylating agent which introduces the radical R 1 - (CH ₂ -C (= O) - is, for example, the acid R ₄ - (CH ₂₎ -COOH or a reactive functional derivative thereof, such as an acid halide, eg chloride or bromide, azide or Anhydride thereof.

The acylation takes place when the free acid of the formula R - (CH) -COOH is used, for example in the presence of a suitable dehydrating agent such as a carbodiimide, for example Ν, Ν'-dicyclohexylcarbodiimide, or, if an acid derivative is used, in the presence a suitable acid-binding agent, such as a tertiary aliphatic or aromatic base, for example triethylamine, pyridine or quinoline, in an inert solvent, such as a chlorinated hydrocarbon, eg methylene chloride, or an ether, eg diethyl ether or dioxane, at room temperature or with heating or cooling, eg in a temperature range from approx. -50 ° to approx. + 6O ⁰ C,. especially at about -30 ° to about + 20 ° C.

The starting compounds of the formula VHI can be prepared, for example, by reacting an azetidinone of the formula

RHH

-γ W (V)

NH

(f

by reacting with an alkali metal salt, e.g. the sodium salt, a thio-lower alkanecarboxylic acid, e.g. Thioacetic acid, or the Triphenylmethylmercaptans in a compound of formula

R ₁ HH

where W is triphenylmethylthio or lower alkanoylthio, e.g. Acetylthio, means this analogous to the process described in the reaction steps 1.2, 1.3 and 1.4 in a compound of the formula

RHH

¹ ί \ R-CH · --- W ¹ (VIII ')

transferred and these in the presence of a base, e.g. Pyridine or tri-n-butylamine, in a suitable solvent e.g. Diethyl ether or methanol, having a salt of the formula MA, wherein M has the above meaning, but in particular is a silver cation, and A represents a common anion, which promotes the solubility of the salt MA in the chosen solvent, e.g. the nitrate, acetate or fluoride anion, is reacted.

The ylides of the formula II ¹ , wherein Z 'is oxygen or sulfur, can be used directly in the cyclization reaction for the preparation of the end products of the formula I. However, it is also possible in compounds of the formula II 'in which R is a protected hydroxy group, for example a hydrolytically readily cleavable protected hydroxy group such as trisubstituted silyloxy, first to split off the hydroxy protective group and then the resulting compound of the formula II' in which R is hydroxyl, in the cyclization reaction.

In the compounds II ', IV, VI. And VII, an optionally substituted methylidene group Z' can be converted into the oxo group Z by ozonization and subsequent reduction of the ozonide formed, in accordance with the process described below in step 3.3.

Starting compounds of the formula V in which W is a sulfonyl radical HO-A-SO ₂ - can also be prepared according to the following Reaction Scheme II.

Reaction scheme II

\ R _n -CH-

· I \%. R -CH "^

II stage 2.1 ² i 1

X R R,

at? from

(IXa) (IXb) -

Stage 2.2

, 1HH * 1 HH WJ-

R-CH · -j | - ^ SO ₂ -A-OH RCH ^ jT ^ Λ

H ^ Level 2.3

^R a ^R b. (Va) (IXc)

In the compounds of the formulas (IXa) - (IXc) and (Va) A represents a lower alkylene radical having 2 to 3 carbon atoms between the two heteroatoms and is primarily ethylene or 1,2-propylene, but may also be 1,3- Propylene, 1,2-, 2,3- or 1,3-butylene.

In the compounds of formulas (IXa) - (IXc) each of the radicals R.

and R is hydrogen or an organic radical attached via a carbon atom to the ring carbon atom, the two

Radicals R and R, may be linked to each other, primarily a °

for hydrogen, lower alkyl, e.g. Methyl, ethyl, n-propyl or isopropyl, optionally substituted phenyl, or phenyl-lower alkyl, e.g. Benzyl, or when taken together, lower alkylene preferably having 4 to 6 carbon atoms, e.g. 1,4-butylene or 1,5-pentylene.

In the compounds of formula (IXb), (IXc) and (Va), the radical R_ is hydroxy or preferably one of said protected hydroxy groups, e.g. optionally substituted 1-phenyl-lower alkoxy, optionally substituted phenyl-lower alkoxycarbonyloxy or trisubstituted-silyloxy.

Stage 2.1

A compound of the formula (IXb) is obtained by reacting a bicyclic compound of the formula (IXa) with a metallating reagent and an electrophile introducing the radical (R, R) CH- and then treating the resulting product with a proton source.

Suitable metalating reagents are e.g. substituted and unsubstituted alkali metal acetals, alkali metal hydrides or alkali metal lower alkyl compounds wherein the alkali metal is e.g. Sodium or especially lithium, e.g. Sodium or lithium amide, lithium bis-trimethylsilylamide, sodium hydride, lithium hydahydride, and preferably lithium diisopropylamide and butyl lithium.

The radical (R, R ₉ ) CH-introducing electrophiles are, for example, compounds of the formula R-CH = O or functional derivatives thereof of the formula (R, R) CH-X, where X is a nucleofugic leaving group, in particular halogen, for example chlorine, bromine or iodine, or sulfonyloxy, for example methanesulfonyloxy or 4-toluenesulfonyloxy. Preferred radical (R, R) CH-introducing electrophiles are formaldehyde, optionally substituted benzyloxymethyl chloride and acetaldehyde.

Solvents suitable for the metallation reaction must not contain any active hydrogen and are e.g. Hydrocarbons, e.g. Hexane, benzene, toluene or xylene, ethers, e.g. Diethyl ether, tetrahydrofuran or dioxane, or acid araids, e.g. Hexamethylphosphoramide.

The metallated intermediate does not need isolation, but can be reacted with the rest of the (R, R ") CH-introducing electrophile following the metallation reaction. The metallation reaction is carried out at temperatures of about -100 ⁰ C to about room temperature, preferably below -30 ⁰ C, preferably in an inert gas, such as nitrogen atmosphere. Further implementation can take place under the same conditions. In this case, formaldehyde is preferably introduced into the reaction mixture in gaseous, monomeric form. Monomeric formaldehyde is obtainable, for example, by thermal depolymerization of paraformaldehyde or by thermal decomposition of formaldehyde cyclohexylhemiacetal.

Both the antipodes of compounds of formula (IXa) and their racemic or diastereomeric mixtures can be used for the metallation reaction.

The attack of the rest of the (R ₁₅ R ₂ ) CH- introducing electrophile to the substrate is generally stereospecific. If the starting material used is an azetidinone of the formula (IXa) with R configuration at the carbon atom 4 of the azetidinone ring, a compound of the formula (IXb) with R configuration at the carbon atom 4 and S configuration at the carbon atom 3 of the azetidinone ring predominantly results. Rings, ie, the electrophile attack is predominantly trans-continuous.

After the reaction, the reaction product is treated with a proton source, e.g. with water, an alcohol such as methanol or ethanol, an organic or inorganic acid, e.g. Acetic acid, hydrochloric acid, sulfuric acid, or a similar proton donating compound, preferably again at low temperatures.

In an obtained compound of the formula (IXb) wherein R is hydrogen, the hydroxy group can be prepared in a manner known per se, e.g. by Veräthem or esterification, in particular as described above protect.

The preparation of optically active and optically inactive starting compounds of the formula (IXa) is described, for example, in European Patent Application No. 23887.

Stage 2.2

A derivative of formula (IXc) may be prepared by treating the thio compound of formula (IXb) with an oxidizing agent and, if desired, a compound of formula (IXc), wherein IL is hydroxy, in a compound of formula (IXc) wherein R is a protected hydroxy group.

Suitable oxidizing agents are, for example, hydrogen peroxide, organic peracids, especially aliphatic or aromatic percarboxylic acids, e.g. Peracetic acid, perbenzoic acid, chloroperbenzoic acid, e.g. 3-chloroperbenzoic acid, or monoperphthalic acid, oxidizing inorganic acids and their salts, e.g. Nitric acid, chromic acid, potassium permanganate, or alkali metal hypochlorites, e.g. Sodium hypochlorite. The transfer can also be done by anodic oxidation.

The oxidation is preferably carried out in a suitable inert solvent, for example a halohydrocarbon, e.g. Methylene chloride, chloroform or carbon tetrachloride, an alcohol, e.g. Methanol or ethanol, a ketone, e.g. Acetone, an ether, e.g. Diethyl ether, dioxane or tetrahydrofuran, an amide, e.g. Dimethylformamide, a sulfone, e.g. Dimethyl sulfone, a liquid organic carboxylic acid, e.g. Acetic acid, or in water or a mixture of these solvents, especially an aqueous mixture, e.g. wässriv

ger acetic acid, at room temperature, or with cooling or gentle heating, ie at about -2O ° C 'to about +90 ⁰ C, preferably carried out at about room temperature. The oxidation can also be carried out in stages, by first oxidizing at low temperature, ie at about -2O ⁰ C to about 0 ⁰ C »to the SuIfoxid, which is optionally isolated, whereupon in a second step, preferably at a higher temperature, about at room temperature, the sulfoxide is oxidized to the sulfone of formula (IXc).

For work-up, any remaining excess oxidant may optionally be obtained by reduction, in particular by treatment with a reducing agent such as a thiosulphate, e.g. Sodium thiosulfate, to be destroyed.

Both optically inactive compounds of the formula (IXb) and corresponding optically active compounds, in particular those having a 3S, 4R configuration in the azetidinone ring, can be used in the reaction.

Stage 2.3

Compounds of formula (Va) can be prepared by solvolysing a bicyclic amide of formula (IXc) with a suitable solvolysis reagent and, if desired, in a compound of formula (Va) obtainable by the process, a free hydroxy group R "into a protected hydroxy group R "Converts.

Suitable solvolysis reagents are, for example, organic acids, e.g. Lower alkanecarboxylic acids, such as formic acid or acetic acid, or sulfonic acids, e.g. 4-toluenesulfonic acid or methanesulfonic acid, mineral acids, e.g. Sulfuric or hydrochloric acid, furthermore lower alkanols, e.g. Methanol or ethanol, or lower alkanediols, e.g. Ethylene glycol.

The solvolysis reagents mentioned are added undiluted or diluted with water. The solvolysis can also be carried out with pure water. The solvolysis with the acidic reagent preferably takes place in aqueous solution of this reagent and at temperatures of about -20 ⁰ C to about 150 ⁰ C, preferably at room temperature to 110 ⁰ C instead.

Both optically inactive compounds of formula (IXc), e.g. Racemates or diastereomer mixtures, as well as corresponding optically active compounds, in particular those with 3S, 4R configuration in the azetidinone ring, can be used.

Obtained mixtures of isomers of compounds of formula (IXb), (IXc) and (Va), such as racemates or mixtures of diastereomers, can be prepared in a manner known per se, e.g. as described above, into the individual isomers, such as antipodes, are separated.

Optically active trans compounds of the formula (V) which can be used according to the invention can also be prepared according to the following Reaction Scheme III:

^R l

_{R CH [I} "

H _ -Λ 2

Reaction scheme III

</ χ / Stage 3.2 ^ (XII) ^R 3 Level 3.1 <' f "CH Uiuti * - H ⁰ W ⁰ I ι χ ^R 3

NH

Stage 3.4-

(Vb)

1 H H

(XIII)

I R2-CH in «

0 '

Stage 3.3

C = O R '

(XIV)

In the compounds of the formulas (XI) - (XIV) and (Vb), R _{3 is} hydroxy or in particular a protected hydroxy group.

Stage 3.1

Compounds of the formula (XII) are known or can be prepared in a manner known per se. They may also be prepared by a novel process by epimerizing a compound of formula (XI) and, if desired, in a compound of formula (XII) obtainable in the process, a protected hydroxy group R "into another protected hydroxy group R_.

The epimerization takes place, for example, in the presence of a basic agent, such as an amine, for example a tri-lower alkane amine, for example triethylamine or ethyldiisopropylamine, a tertiary amine, for example Ν, Ν-dimethylaniline, an aromatic amine, for example pyridine, or a bicyclic amine, for example 1 , S-diazabicyclo ^ Ojundec-S-ene or 1,5-diazabicyclo [4,3,0] non-5-ene, or an alkali metal lower alkanolate, eg Natriuramethanolat, sodium ethoxide or potassium tert-butoxide, in an inert solvent , For example, an ether, for example diethyl ether, dimethoxyethane, tetrahydrofuran or dioxane, acetonitrile or dimethylformamide, optionally at slightly elevated or reduced temperature, for example at 0 ⁰ C to 50 ⁰ C, preferably at room temperature.

In the compounds of the formula (XII) obtainable by the process, a protected hydroxy group R "can be replaced by another protected hydroxyl group R", for example a hydrogenolytically cleavable protected hydroxy group by a solvolytically cleavable protected hydroxy group. Hydroxy protecting groups are, in particular, the abovementioned hydrogenolytically removable protecting groups, for example substituted 1-phenyl-lower alkyl or phenyl-lower alkoxycarbonyl, solvolytically removable protective groups, for example trisubstituted silyl as indicated.

The reaction can be carried out by first removing the hydrogenolytically removable hydroxy protective group and introducing into the resulting compound of the formula XII in which R is hydroxyl, a hydroxy group which can be cleaved off by hydrolysis.

The cleavage of the hydrogenolytically cleavable protecting group is e.g. with hydrogen or a hydrogen donor, e.g. Cyclohexene or cyclohexadiene, in the presence of a

Hydrogenation catalyst, such as a Palladiumkacalysators, eg palladium on carbon, in an inert solvent, such as a halogenated hydrocarbon, for example methylene chloride, a lower alkanol, for example methanol or ethanol, an ether, for example _# dioxane or tetrahydrofuran, or in water or in mixtures thereof, at a temperature of about 0 ° to about 80 ⁰ C, preferably at room temperature. The cleavage can also be carried out with a reducing metal, such as zinc, or a reducing metal alloy, eg copper-zinc alloy, in the presence of a proton-donating agent, such as an organic acid, eg acetic acid, or else a lower alkanol, eg ethanol ,

The introduction of the solvolytically removable hydroxy protective group is carried out, for example, with a compound of the formula R'-X_, where R 'is the hydroxy-protecting group and X_ is e.g. a reactive esterified hydroxy group, for example halogen, e.g. Chloro, bromo or iodo, or sulphonyloxy, such as methanesulfonyloxy, benzenesulfonyloxy or 4-Toluolsulfonylox3 / j.

The reaction is carried out in an inert solvent, such as an ether, for example diethyl, dioxane or tetrahydrofuran, a hydrocarbon, eg benzene or toluene, a halohydrocarbon, eg methylene chloride, in dimethyl sulfoxide or acetonitrile, in the presence of a basic condensing agent, such as an alkali metal hydroxides or carbonates For example, sodium or potassium hydroxide or sodium or potassium carbonate, an alkali metal amide or hydride, for example, sodium amide or Nacriurnhydrid, a Alkaline tallnicderalkanolats, for example, sodium methoxide or ethoxide or potassium tert-butoxide, or an amine, for example triethylamine, pyridine or imidazole , at room temperature or elevated or reduced temperature, for example at about -20 ° C to about 80 ⁰ C, preferably at room temperature.

Starting compounds of the formula (XI) are known, for example, from German Offenlegungsschrift 3 039 504 and from British patent application 20 61 930.

Stage 3.2

A compound of the formula (XIII) can be prepared by treating a penam compound of the formula (XII) with a basic agent and with an esterifying agent introducing the radical R.

A suitable basic agent is, for example, one of the basic agents mentioned under stage 3.1, in particular one of said bicyclic amines, and also an alkali metal amide or hydride, e.g. Sodium amide or sodium hydride.

A radical R is for example one of the organic radicals mentioned under step 1.1, in particular optionally substituted lower alkyl, e.g. Methyl, ethyl or 2-hydroxyethyl, or benzyl.

An esterifying agent introducing the rest R is e.g. a Vero

Compound of formula R-X ,, wherein X, reactive esterified hydroxy, e.g. Halogen, such as chlorine, bromine or iodine, or sulfonyloxy, such as methanesulfonyloxy, benzenesulfonyloxy or 4-toluenesulfonyloxy means. To introduce a 2-hydroxyethyl radical, ethylene oxide is also suitable.

The reaction is preferably carried out in two stages, wherein in the first stage the penam compound of the formula (XII) is treated with at least equimolecular amounts of the basic agent and an obtainable intermediate of the formula

R -CHi

f \

wherein B ^ represents the protonated form (cation) of the basic agent, preferably without isolation from the reaction mixture with the esterifying agent. The reaction is in an inert solvent, for example an ether, ζ.BV diethyl ether, dimethoxyethane, tetrahydrofuran or dioxane, in acetonitrile, dimethylformamide or hexamethylphosphoric triamide, optionally at slightly elevated or lowered temperature, for example at about O ⁰ C to 50 ⁰ C, preferably at room temperature. In a preferred embodiment of the process, the penam compound of the formula (XIII) is prepared in situ by reacting a compound of the formula (XI) first with catalytic amounts of the basic agent, for example 1,5-diazabicyclo [cf. 5,4, O] undec-5-ene, and then reacted with at least equimolar amounts of the same basic agent and the esterifying agent to give the compounds of formula (XIII).

Stage 3.3

An oxalylazetidinone of formula (XIV) can be prepared by ozonating a compound of formula (XIII) and reductively cleaving the formed ozonide to the oxo compound.

The ozonization is usually carried out with an ozone-oxygen mixture in an inert solvent such as a lower alkanol, e.g. Methanol or ethanol, a lower alkanone, e.g. Acetone, an optionally halogenated hydrocarbon, e.g. a halo-lower alkane, such as methylene chloride or carbon tetrachloride, or in a solvent mixture, including an aqueous mixture, preferably lower

Cooling, for example, at temperatures of about -80 ° to about O ⁰ C performed.

An intermediate ozonide, usually without being isolated, is reductively cleaved to give a compound of formula XIV, whereby catalytically activated hydrogen, e.g. Hydrogen in the presence of a heavy metal hydrogenation catalyst, such as a nickel, further palladium catalyst, preferably on a suitable support material, such as calcium carbonate or carbon, or chemical reducing agents, such as heavy metal reducing metals, including heavy metal alloys or amalgams, e.g. Zinc, in the presence of a hydrogen donor, such as an acid, e.g. Acetic acid, or an alcohol, e.g. Lower alkanols, reducing inorganic salts such as alkali metal iodides, e.g. Sodium iodide, or alkali metal hydrogen sulfites, e.g. Sodium hydrogen sulfite, in the presence of a hydrogen donor, such as an acid, e.g. Acetic acid, or water, or reducing organic compounds such as formic acid. Also useful as the reducing agent are compounds that can be readily converted to corresponding epoxy compounds or oxides, with epoxide formation due to a C, C double bond and oxide bonding due to an existing oxide-forming hetero, such as sulfur, phosphorus or nitrogen atom can be done. Such compounds are e.g. suitably substituted aethene compounds (which are converted to ethylene oxide compounds in the reaction), such as tetracyanoethylene, or more particularly suitable sulfide compounds (which are converted to sulfoxide compounds in the reaction), such as dilower alkyl sulfides, primarily dimethyl sulfide, suitable organic phosphorus compounds such as an optionally phenyl and or lower alkyl, eg Methyl, ethyl, n-propyl or η-butyl, substituted phosphine (which is converted to a phosphine oxide in the reaction), such as tri-lower alkyl phosphines, e.g. Tri-n-butylphosphine, or triphenylphosphine, furthermore tri-lower alkyl phosphites (which in the reaction in Phoüphorsäuretriniederalkylester

usually in the form of corresponding alcohol adduct compounds such as trimethyl phosphite or phosphorous triamides which optionally contain lower alkyl as substituents, such as hexaniloalkyl phosphorous triamides, eg hexamethyl phosphorous triamide, the latter preferably in the form of a methanol adduct, further suitable nitrogen bases (described in U.S. Pat Converted into the corresponding N-oxides), such as heterocyclic nitrogen bases of aromatic character, for example pyridine-type bases and in particular pyridine itself. The cleavage of the usually unisolated ozonide normally occurs under the conditions; which is used for its preparation, ie in the presence of a suitable solvent or solvent mixture, and under cooling or gentle heating, preferably at temperatures of about -10 ⁰ C to about +25 ⁰ C and the reaction usually concludes at room temperature.

Stage 3.4

An azetidinone of formula (Vb) can be prepared by solvolysing an oxalyl-azetidinone of formula (XIV).

The solvolysis can be carried out as hydrolysis, as alcoholysis or as hydrazinolysis. The hydrolysis is carried out with water, optionally in a water-miscible solvent. The alcoholysis is usually carried out with a lower alkanol, for example methanol or ethanol, preferably in the presence of water and an organic solvent, such as a lower alkanecarboxylic acid lower alkyl ester, eg Essigsäuraächylester, preferably at room temperature, if necessary with cooling or heating, for example at a temperature of about 0 ° to about 80 ⁰ C performed. Hydrazinolysis is preferred in a conventional manner with a substituted hydrazine, for example with phenyl or a nitrophenylhydrazine, such as 2-nitrophenylhydrazine, 4-nitrophenylhydrazine or 2,4-dinitrophenylhydrazine

in an approximately equimolar amount, in an organic solvent such as an ether, e.g. Tetrahydrofuran, dioxane, diethyl ether, an aromatic hydrocarbon such as benzene or toluene, a halogenated hydrocarbon such as methylene chloride, chlorobenzene or dichlorobenzene, an ester such as ethyl acetate, and the like, carried out at temperatures between about room temperature and about 65 ° C.

In a preferred embodiment of the process, a compound of the formula (XIH) is used which is ozonated as indicated and then reductively cleaved to the oxalylazetidinone of the formula (XIV) which, without isolation from the reaction mixture, continues to form the azetidinone of the formula (Vb ) is implemented.

In the ozonolysis, small quantities of acid may be formed, which may cause the cleavage of a solvolytically readily cleavable group R, e.g. of a trisubstituted silyl radical. The resulting compound of the formula

HIGH Μι »- '

(Vb ¹ )

can, for example, chromatographically, separated from the protected azetidinone (Vb) and converted by re-reaction with the hydroxy protecting group R 'introducing agent of the formula S-2 ~ ^X 3 ^ ^{n the Acet} i ^d i ^{non of} the formula (Vb).

In the compounds of the formulas (II), (II ¹ ), (III), (VI), (VII) and (XII) to (XIV), a protected carboxyl group R j can be converted into another protected carboxyl group R by methods known per se be converted, taking into account the optionally contained in these compounds further functional groups the

same methods can be used as indicated for the conversion of this substituent in the compounds of formula (I).

The invention also relates to novel starting materials as well as novel intermediates obtainable according to the process, such as those of the formula (II) to (VIII), (XIII) and (XIV), as well as the stated processes for their preparation.

Preferably, such starting materials are used and the reaction conditions are selected so that one arrives at the compounds listed above as being particularly preferred.

The compounds of formula I have valuable pharmacological properties, or may be used as intermediates for the preparation of such compounds having valuable pharmacological properties. Compounds of the formula I in which R is hydrogen, hydrogen or methyl, R ~ is hydroxy, R "is carboxyl or a cleavable esterified carboxyl group under physiological conditions and R, which has the meaning given under formula I, and pharmacologically acceptable salts of such compounds with salt-forming groups have antibacterial effects. For example, they are in vitro against Gram positive and Gram negative cocci, eg Staphylococcus aureus , Streptococcus pyogenes , Streptococcus pneumoniae , Streptococcus faecalis , Neisseria meningitidis and Neisseria gonorrhoeae, and Gram negative rod bacteria such as Enterobacteriaceae , Haemophilus influenzae and Pseudomonas aeruginosa , and anaerobes , eg Bacteroides sp , , in minimum concentrations of about 0.01 to about 64 ^ / ml. In vivo , in the case of systemic infection of the mouse, eg by Staphylococcus aureus or Streptococcus pyogene s, ED values of about 0.3 to about 30 mg / kg are obtained by subcutaneous or oral administration. For example, sodium (5R, 6S) -2- [3- (2-methyl-tetrazo1 -5-yl) -propyl] -6-hydroxymethyl-2-penem-3-carboxylate (Compound A) and (5R, 6S .) - 2- [3- (2-Methyl-l, 3,4-oxadiazol-5-yl) -propyl] -6-hydroxymethyl-2-petiem-3-carboxylic acid (Compound B) in said in vitro -Test

the following values:

organism

MIC

Connection A

Compound B

Staphylococcus aureus 10B Staphylococcus aureus 2999i + p + Streptococcus pyogenes Aronson Streptococcus pneumoniae III / 84 Streptococcus faecalis D Neisseria meningitidis 1316 Neisseria gonorrhoeae 1317-4 Haemophilus influenzae NCTC 4560 Escherichia coli 205 Escherichia coli 205 R + TEM Escherichia coli 16 JEscherichia coli UB 1005 Escherichia coli DC 2 Klebsiella pneumoniae Serratia marcescens Enterobacter cloacae P Proteus mirabilis 774 Proteus mirabilis 1219 Proteus rettgeri 856, Proteus morganii 2359 Proteus morganii 1518 Pseudomonas aeruginosa ATCC 12055 Pseudomonas aeruginosa K 799/61 Clostridium perfringens Bacteroides fragilis L

0.2 0.2 0.2 0.2 0.2 0.1 12:05 12:05 32 32 12:01 12:05 12:01 12:01 2 2 4 1 8th 4 32 16 8th 2 1 4 2 64 16 32 16 4 2 8th 4 16 4 2 2 16 ί 8 128 > 32 2 \ ² 0.2 : 0.1 0.5 ·: 0.5

In vivo, in the case of systemic infection of the mouse by Staphylococcus aureus 1OB, subcutaneous administration produces ED ₁ , for example. Values of 3-10 mg / kg for compound A and from 0.3-30 mg / kg for compound B.

The new compounds may be administered as orally or parenterally-administrable antibacterial antibiotics, e.g. in the form of corresponding pharmaceutical preparations, for the treatment of infections find use.

Compounds of the formula I in which at least one of the functional groups present is in protected form, a protected carboxyl group being different from a physiologically cleavable esterified carboxyl group, can be used as intermediates for the preparation of the abovementioned pharmacologically active compounds of the formula I.

The pharmacologically useful compounds of the present invention may e.g. are used for the preparation of pharmaceutical preparations containing an effective amount of the active substance together or in admixture with inorganic or organic, solid or liquid, pharmaceutically acceptable excipients which may be added to the oral or parenteral, i. intramuscular, subcutaneous or intraperitoneal administration.

For oral administration, tablets or gelatin capsules containing the active ingredient together with diluents, e.g. Lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, and lubricants, e.g. Silica, talc, stearic acid or salts

, - 57 -

thereof, such as magnesium or calcium stearate, and / or polyethylene glycol; Tablets also contain binders, e.g. Magnesium aluminum silicate, starches such as corn, wheat, rice or arrowroot starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and, if desired, disintegrants, e.g. Starches, agar, alginic acid or a salt thereof, such as sodium alginate, and / or effervescent mixtures or adsorbents, dyes, flavorings or sweeteners.

For parenteral administration, infusion solutions are preferred, preferably isotonic aqueous solutions or suspensions, e.g. from lyophilized preparations which contain the active substance alone or together with a carrier material, Β.Β mannitol, can be prepared before use. Such preparations may be sterilized and / or adjuvants, e.g. Preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers.

The present pharmaceutical compositions which, if desired, may contain other pharmacologically valuable substances, are prepared in a manner known per se, e.g. by means of conventional mixing, solution or lyophilization processes, and containing from about 0.1% to 100%, in particular from about 1% to about 50%, lyophilisates up to 100% of the active ingredient.

Depending on the nature of the infection and the condition of the infected organism, daily doses of from about 0.1 g to about 5 g are used to treat warm-blooded animals (humans and animals) weighing about 70 kg.

The following examples serve to illustrate the invention. Temperatures are given in degrees centigrade.

The following abbreviations are used in the examples:

DC: thin-layer chromatogram,

IR: infrared spectrum,

UV: ultraviolet spectrum,

M.p .: melting point,

DBU: l, 5-diazabicyclo [5.4.0] undec-5-ene,

THF: tetrahydrofuran,

DMF: dimethylformamide.

a a "*

Experimental part Example 1: (3S, 4R) -3- (tert-butyl-dimethylsilyloxymethyl) -4-

[4- (2-methyl-tetrazol-5-yl) -butyroylthio] azetidin-2-one

A solution of 293.5 mg of 3- (tert-butyldimethylsilyloxymethyl) -4-methylsulfonyl-azetidin-2-one in 40 ml of abs. THF is added dropwise at room temperature while stirring, to a mixture of 242.1 mg of 4- (2'-methyl-tetrazol-5'-yl) -thiobutyric acid, 1.6 ml of 1N sodium hydroxide solution and 2.3 ml of water. The pH is adjusted to 9 with 0.1 N sodium hydroxide solution. After stirring at room temperature for 2.5 hours, ethyl acetate is added and the two phases are separated. The aqueous phase is extracted three more times with ethyl acetate and the combined ethyl acetate phases are washed once with brine. After drying and evaporation, the crude product is obtained, which is chromatographed on silica gel with the mobile phase toluene-ethyl acetate (2: 1). TLC (silica gel): toluene-ethyl acetate (2: 3): R = 0.4 IR (methylene chloride): 2.94; 5.67; 5.95 / i.

The starting material 4- (2-methyl-tetrazol-5-yl) -thiobutyric acid can be prepared as follows:

laa) 4- <tetrazol-5-yl) -butyric acid ethyl ester 3.5 g of glutaronitrile-monoethyl ester and 1.78 g of sodium azide in the presence of 1.47 g of ammonium chloride in 12.5 ml of abs. DMF stirred for 25 hours at 125 ° bath temperature. After cooling, the reaction mixture is diluted with water (150 ml), adjusted to pH 3 with concentrated HCl and extracted twice with ethyl acetate. After drying the ethyl acetate extracts and evaporation, the title compound is obtained, which is purified by recrystallization from ether. Mp .: 56 - 57 °

IR (methylene chloride): 3.1; 3.39; 5.78; 6.47; 7.3 μ.

Lab) Ethyl 4- (2-methyltetrazol-5-yl) butyrate 14 g of 4- (tetrazol-5'-yl) -butyric acid ethyl ester are dissolved in 42 ml of acetone and washed successively with 10.64 ml Triethylamine and 5 ml of methyl iodide added. After 18 hours stirring under argon at

Reflux temperature, the reaction mixture is evaporated. The residue is taken up in CH 2 Cl and washed with aqueous NaHCO 3 solution. After drying and evaporation in a water jet vacuum, the residue is distilled under high vacuum, whereby the title compound is isolated

Bp (0.2 torr) 116 ° IR (methylene chloride): 3.39; 5.78; 7.30; 8,51 μ.

Iac) 4- (2-Methyl-tetrazol-5-yl) -butyric acid 10.62 g of 4- (2-methyl-tetrazol-5-yl) -butyric acid ethyl ester are dissolved in 270 ml of THF with 80.4 ml of 1N NaOH Stirred for 3 hours at room temperature. The THF is then largely stripped off on a rotary evaporator under reduced pressure, the aqueous phase is washed twice with ethyl acetate and adjusted to pH 2 with 5N HCl. Six times is extracted with 60 ml of ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated to give the title compound as a solid

 IR (methylene chloride); 3.0 to 3.6; 5.87; 6.7; 7.4; i

lad) 4- (2-Methyl-tetrazol-5-yl) butyric acid chloride 8.04 g of 4- (2-methyl-tetrazol-5-yl) -butyric acid are dissolved in 180 ml of abs. Benzene dissolved and after addition of 5.47 ml of thionyl chloride and 2 drops of DMF, the mixture is stirred for 2 hours at 50 °. After cooling and concentration, the crude product is recycled for 30 minutes in a high vacuum

 IR (methylene chloride): 3.4; 5.62; 6.73; 7.17, u

lae) 4- (2-Methyl-tetrazo1 -5-yl) -thiobutyric acid 330 mg of 4- (2-methyl-tetrazol-5-yl) -butyric acid chloride are dissolved in 0.6 ml of abs. Dissolved methylene chloride and added dropwise at 0 ° to 2.35 ml of a solution of pyridine and H ₂ S in methylene chloride (100 ml of methylene chloride, 30 ml of pyridine, 6 g H "S). Subsequently, stirring is continued for 1 hour at 0 ° under a nitrogen atmosphere. The reaction mixture

is taken up in chloroform, with 2 N H "SO, the aqueous phase is acidified to pH 2 and extracted twice with chloroform. The combined organic phases are washed twice with 2 ml of 10% NaHCO 3 solution. It is then adjusted to pH 3 with 2N H 2 SO 4, and the title compound is extracted by repeated extraction with chloroform. After drying over sodium sulfate and concentration, the title compound is obtained. IR (methylene chloride): 3.9; 5.92; 9.35; 9.8 u.

The starting material (3S, 4R) -3- (tert-butyldimethylsilyloxymethyl) -4-methylsulfonyl-azetidin-2-one can be prepared as follows:

lba) (3S, 5R, 6R) -2,2-dimethyl-6- (tert -butyl-dimethylsilyloxymethyl) -penam-3-carboxylic acid methyl ester 1,1-dioxide

A solution of 23.6 g (85 mmol) of (3S, 5R, 6R) -2,2-dimethyl-6-hydroxymethyl-penam-3-carboxylic acid methyl ester 1,1-dioxide in 50 ml of dimethylformamide is mixed with 25.5 g (170 mmol) of tert-butyl-dimethylchlorosilane and 11.5 g (170 mmol) of imidazole were stirred at room temperature for 45 minutes. Then the solvent is distilled off in a high vacuum and the residue taken up in ethyl acetate. The solution is washed with 1 N sulfuric acid and then with water, and the aqueous solutions are extracted twice with ethyl acetate. The organic phase is dried with sodium sulfate and concentrated on a rotary evaporator. The product accumulates as a crystalline mass

TLC silica gel, toluene / ethyl acetate (4: 1): R f = 0.56 IR (CH ₂ Cl ₂ ) 3.4; 5.57; 5.65 um.

lbb) 2 - [(3S, 4R) -3- (tert-butyl-dimethylsilyloxymethyl) -4-methylsulfonyl-2-oxo-azetidin-1-yl] -3-methyl-2-butenoic acid methyl ester

A solution of 202 g (0.51 mol) of (3R, 5R, 6R) -2,2-dimethyl-6- (tert-butyldimethylsilyloxymethyl) -penam-3-carboxylic acid methyl ester 1,1-dioxide in 800 ml of tetrahydrofuran are added 9 ml DBU and stirred for 5 minutes at room temperature. Then another 95 ml DBU were added and 30 min.

stirred at room temperature. Then added with cooling 42.3 ml (0.68 mol) of methyl iodide. After a reaction time of 3 hours, the crystallized DBU-hydroiodide is filtered off and the filtrate is concentrated. The residue is taken up in ethyl acetate and the solution washed with 1N sulfuric acid, water and sodium bicarbonate solution. The aqueous phases are extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solution is concentrated to a thick oil. DC. Silica gel, toluene / ethyl acetate (4: 1); R f = 0.42 IR (CH ₂ Cl ₂ ) 5.63; 5.81; 6.17 pm.

Ibc) (3S, 4R) -3-hydroxymethyl-4-methylsulfonyl-azetidin-2-one and (3S, 4R) -3- (tert-butyl-dimethylsilyloxymethyl) -4-methylsulfonyl-azetidin-2-one

A solution of 25 g (61.7 mmol) of 2- [(3S, 4R) -3- (tert-butyl-dimethylsilyloxymethyl) -4-methylsulfonyl-2-oxo-azetidin-1-yl] -3-methyl- Methyl 2-butenate in 400 ml of methylene chloride is treated at -10 ° with an ozone /

Treated oxygen mixture. The disappearance of the starting material is monitored by thin-layer chromatography. After completion of the reaction, 30 ml of dimethyl sulfide are added and stirring is continued for 3 hours at room temperature. The solution is concentrated and the residue taken up in a mixture of 160 ml of methanol, 24 ml of ethyl acetate and 3 ml of water and during. Heated to 70 ° 'for 40 minutes. The solvent is then stripped off and the residue is stripped off twice with toluene. The crystallizing OeI is taken up in methylene chloride and the crystals consisting of (3S), (4R) -3-hydroxymethyl-4-methylsulfonyl-azetidin-2-one, isolated by filtration. The filtrate is concentrated and (3S, 4R) -3- (tert-butyl-dimethylsilyloxymethyl) -4-methylsulfonyl-azetidin-2-one obtained by chromatography on silica gel with toluene / ethyl acetate (3: 1) in pure form:

(3S, 4R) -3-hydroxymethyl-4-methylsulfonyl-azetidin-2-one : TLC, silica gel, toluene / ethyl acetate (1: 1); Rf = 0.36, IR: (CH ₂ Cl ₂ ) 2.96; 3.54; 5.61 um.

(3S, 4R) -3- (tert -butyl-dimethylsilyloxymethyl) -4-methylsulfonylazetidin-2-one : TLC; Silica gel, toluene / ethyl acetate (1: 1) Rf = 0.06.

A solution of 14.6 g (81.5 mmol) of (3S, 4R) -3-hydroxymethyl-4-methyl-sulfonyl-azetidin-2-one in 40 ml of dimethylformamide is treated with 24 g (183 mmol) of tert-butyldimethylchlorosilane and 11 g (163 mmol) of imidazole for 45 minutes at room temperature. Then the solvent is removed under high vacuum and the residue taken up in ethyl acetate. The organic phase is washed successively with 1N sulfuric acid,

Washed water and sodium bicarbonate solution. The aqueous phases are extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The crystalline residue is pure (3S, 4R) -3- (tert -butyl-dimethylsilyloxymethyl) -4-methylsulfonyl-azetidin-2-one.

Example 2: 2 - [(3S, 4R) -3-tert-butyl-dimethylsilyloxymethyl-4- [4- (2-methyltetrazol-5-yl) -butyroylthio] -2-oxo-azetidin-1-yl] - -hydroxyacetic acid ^ -tr ime thy lsily ethyl ester

A mixture of 408 mg of (3S, 4R) -3- (tert-butyldimethylsilyloxymethyl) -4- [4- (2-methyl-tetrazol-5-yl) -butyroylthio] -azetidin-2-one and 450 mg of glyoxylic acid 2-Trimethylsilylethylester ethylhemiketal in 8.7 ml of toluene and 1.7 ml of N, N-Dimethy1formamid is mixed with 4 g of molecular sieve (type 4A 1/16 from Dr. Bender & Dr. Hobein AG, Zurich) and at 100 ° Bath temperature stirred for 8 hours under inert gas. After cooling, the mixture is filtered through Hyflo and the filter residue is washed with toluene. Evaporation of the filtrate and drying at 40 ° in a high vacuum gives the product as a yellow OeI. TLC (silica gel): toluene / ethyl acetate. (2: 3) R = 0.55 and 0.47 IR (methylene chloride): 2.86; 5.68; 5.8; 6.0 μ.

Example 3: 2 - [(3S, 4R) -3-tert-butyl-dimethylsilyl-oxymethyl-4- [4- (2-methyl-tetrazol-5-yl) -butyroylthio] -2-oxo-azetidine l-yl] -2-tripheny1-phosphoranylidenessigsaure ^ -trimethylsilylethylester

To a solution of 573 mg of 2- [(3S, 4R) -3-tert-butyldimethylsilyloxy

yl] -2-hydroxy-acetic acid 2-trimethylsilyl etbyl ester in 4.6 ml of tetrahydrofuran are added with stirring at -15 ° in succession 0.14 ml of thionyl chloride and 0.27 ml of triethylamine in 0.5 ml of THF within 10 minutes. The white suspension is stirred for 1 hour at 0 °, and filtered through Hyflo. After washing the residue with toluene is concentrated on a rotary evaporator and dried under high vacuum. The residue is dissolved in 4 ml of dioxane, mixed with 0.30 g of triphenylphosphine and 0.13 ml of 2,6-lutidine and stirred for 18 hours at 50 °. The mixture is filtered through Hyflo and this residue is washed with toluene. The combined filtrates are evaporated and the chromatography of the residue on 30 g of silica gel with toluene / ethyl acetate (4: 1) yields the pure product

TLC (silica gel) toluene-ethyl acetate (2: 3): R _c = 0.52 IR (methylene chloride): 5.75; 5.96; 6.25 u.

Example 4: (5R, 6S) -2- [3- (2-methyl-tetrazol-5-yl) -propyl] -6-tert.

butyl-dimethylsilyloxymethyl ^ penem-S-carboxylic acid ^ -trimethylsilyl ethyl ester

2.56 g of 2 - [(3S, 4R) -3-tert-butyl-dimethylsilyloxymethyl-4- [4- (2-methyltetrazol-5-yl) -butyroylthio] -2-oxo-azetidin-1-yl] - 2-Triphenyl-phosphoranylidenessigsäure-2-trimethylsilylethylester are dissolved in 980 ml of toluene and stirred under nitrogen atmosphere for 4 hours at reflux temperature. Evaporation of the solvent and chromatography of the residue on silica gel with the eluent toluene / ethyl acetate (5: 1) gives the pure product.

TLC (silica gel): toluene-ethyl acetate (2: 3) R = '0.63 IR (methylene chloride): 5.66; 5.93; 6.38; 7.7 μ.

Example 5: (5R, 6S) -2- [3- (2-methyl-tetrazol-5-yl) -propyl] -6-hydroxymethyl-2-propyl-3-carboxylic acid. 2-trimethyl isilylethyl! ester

94.4 mg of (5R, 6S) -2- [3- (2-methyltetrazol-5-yl) -propyl] -6-tert-butyldimethylsilyloxymethyl-2-penem-3-carboxylic acid 2-trimethyl isilylethyl ester in 2.8 ml abs. Dissolved THF and treated under nitrogen atmosphere after cooling to -80 ° with 0.1 ml of acetic acid. 10.5 ml of a 0.1 M tetrabutylammonium fluoride solution in THF are then added dropwise thereto, the mixture is allowed to come to room temperature and stirred for 2 hours at this temperature. The volume of solvent is concentrated to 1 ml on a rotary evaporator and the residue is partitioned between 14.7 mg of sodium bicarbonate in 5 ml of water and 5 ml of ethyl acetate. The organic phase is separated, the aqueous is extracted 2 more times with ethyl acetate. The organic extracts are washed once more with water and dried over sodium sulfate. Evaporation under high vacuum gives the crude product, which is chromatographed on 4 g of silica gel with the eluent toluene-ethyl acetate (1: 1). TLC (silica gel) toluene-ethyl acetate (2: 3): R _f = 0.26 IR (methylene chloride): 2.77; 5.62; 5.90; 6.33; 7.64 μ.

Example 6: Sodium (5R, 6S) -2- [3- (2-methyl-tetrazol-5-yl) -propyl] -6-hydroxymethyl-2-penem-3-carboxylate

74.5 mg of (5R, 6S) -2- [3- (2-methyl-tetrazol-5-yl) -propyl] -6-hydroxymethyl-2-penem-3-carboxylic acid 2-trimethylsilylethyl ester are dissolved in 1.5 ml of abs , Dissolved THF and cooled to -30 °. After adding 7 ml of 0.1 M tetrabutylammonium fluoride solution in THF, the temperature is raised to 0 °. After stirring for 30 minutes at this temperature, the mixture is mixed with 9 ml of ethyl acetate and 9 ml of water. The solution is then adjusted to pH 3 with 4N HCl. The water phase is then separated and the ethyl acetate solution is extracted with 7.5 ml of 0.05 M NaHCO sol. After separating the aqueous layer, the organic solution is extracted once more with 2 ml of 0.0125 M NaHC0_ solution. The watery

Phases are combined and freed from the remaining solvent on a rotary evaporator. Lyophilization gives the title compound. TLC (reversed phase Opti-UPC): acetonitrile-water (1: 1) R. = 0.9 UV (phosphate buffer pH 7.4): λ = 306 nm.

Max

Example 7 : (3S, 4R) -3- (tert-butyl-dimethylsilyloxymethyl) -4- [4- (5-methyl-1,3,4-oxadiazol-2-yl) -butyl-thio] -azetidine-2 -one

1.76 g of 3- (tert-butyldimethylsilyloxymethyl) -4-methylsulfonyl-azetidin-2-one and 1.79 g of 4- (5-methyl-l, 3,4-oxadiazol-2-yl) -thiobutyric acid are dissolved in Dissolved 50 ml of methylene chloride and treated at room temperature with 55 ml of water and 10.2 ml of 1N sodium hydroxide solution. The emulsion is stirred vigorously for 1.5 h, then the organic phase is separated and the aqueous extracted twice with methylene chloride. The combined organic phases are washed once with a saturated aqueous sodium bicarbonate solution and then with brine. After separation and drying over magnesium sulfate, the crude title compound, which is purified by chromatography on silica gel (mobile phase toluene-ethyl acetate 1: 1) is obtained after concentrating the solution. IR (methylene chloride) :. 2.93; 5.65; 5.94; 6.27; 6.37 μ.

The starting compound 4- (5-methyl-l, 3,4-oxadiazol-2-yl) -thiobutyric acid is prepared as follows:

7a) 4- (5-Methyl-l, 3,4-oxadiazol-2-yl) -butyric acid ethyl ester

2.95 g of 4- (tetrazol-5-yl) -butyric acid ethyl ester (Example laa) are heated in 32 ml of acetyl chloride at reflux for 4 hours. After evaporation in a water jet vacuum (rotary evaporator), the residue is mixed with 20 ml of o-xylene and heated for 30 minutes, until the evolution of gas has ended, at reflux. After concentration under reduced pressure, the crude product is purified by chromatography on silica gel (toluene-ethyl acetate 1: 1). The title compound obtained has the following IR data: IR (methylene chloride): 5.76; 6.23; 6.33 μ.

7b) 4- (5-Methyl-l, 3,4-oxadiazol-2-yl) -butyric acid

8.08 g of ethyl 4- (5-methyl-l, 3,4-oxadiazol-2-yl) butyrate are dissolved in 120 ml of tetrahydrofuran, combined with 45 ml of 1N sodium hydroxide solution and stirred at 80 ° for 6 hours. After evaporation of the reaction mixture, the residue obtained is taken up in a little water and

washed with methylene chloride. After acidification to pH 3 with HCl 4 N is extracted three times with methylene chloride. After drying and evaporation, the title compound is obtained

 IR (methylene chloride): 3.33; 5.85; 6.27; 6,37 u.

7c) 4- (5-Methyl-l, 3,4-oxadiazol-2-yl) -thiobutyric acid

1.7 g of 4- (5-methyl-l, 3,4-oxadiazol-2-yl) -butyric acid in 45 ml of abs. Methylene chloride, first with 3.07 ml of triethylamine and then dropwise with a solution of 1.44 ml of isobutyl chloroformate in 15. ml abs. Methylene chloride added. After stirring for one hour at -10 °, hydrogen sulfide is introduced for 2 hours at the same temperature. The excess H "S is then purged with nitrogen and the reaction mixture is acidified with 2N H" SO. After shaking, the organic phase is separated and washed once with brine. After drying over magnesium sulfate and evaporation, the title compound remains as a yellowish OeI. IR (methylene chloride): 3.87; 5.92; 6.29; 6,39p.

Example 8 : 2 - '[(3S, 4R) - (3-tert-butyl-dimethylsilyloxymethyl) -4-

2-hydroxyacetic acid-2-trimethylsilylethylester

Analogously to Example 2, 1.31 g of (3S, 4R) -3- (tert-butyldimethylsilyloxymethyl) -4- [4- (5-methyl-1,3,4-oxadiazol-2-yl) -butyroylthio] azetidine -2-on with 2.17 g of glyoxylic acid 2-trimethylsilylethylesterethylhemiketal reacted to give the title compound. IR (methylene chloride): 2.86; 5.66; 5.78; 5.93; 6.27; 6.39 γ ..

Example 9 : 2 - [(3S, 4R) -3- (tert-butyl-dimethylsilyloxymethyl) -4- [4- (5-methyl-1,3,4-oxadiazol-2-yl) -butyroylthio] -2 -oxoazetidin-l-yl] -2-triphenylphosphoranylidenessigsaure ^ -trimethylsilylethylester

Analogously to Example 3, 0.47 g of 2 - [(3S, 4R) -3- (tert-butyl-dimethylsilyloxymethyl) -4- [4- (5-methyl-1,3,4-oxadiazol-2-yl) -butyroylthio] -2-oxo-azetidin-1-yl] -2-hydroxyacetic acid 2-trimethylsilylethyl ester are converted to the title compound.

IR (methylene chloride): 5.73; 5.93; 6.25 μ.

Example 10 : (5R, 6S) -2- [3- (5-Methyl-l, 3,4-oxadiazol-2-yl) -propyl] -6- (tert-butyl-dimethylsilyloxymethyl) -2-penem- 3-carboxylic acid 2-trimethy1-silylethylester

Analogously to Example 4, 0.14 g of 2 - [(3S, 4R) -3- (tert-butyl-dimethylsilyloxymethyl) -4- [4- (5-methyl-1,3,4-oxadiazol-2-yl) Butyroyl thio] -2-oxo-azetidin-1-yl] -2-triphenylphosphoranylidenessigsäure-2-trimethylsilylethyl ester into the title compound. IR (methylene chloride): 5.62; 5.90; 6.37 μ.

Example 11 :

hydroxymethyl-2-penem-3-carboxylic acid 2-trimethylsilylethylester

Analogously to Example 5, 0.25 g of (5R, 6S) -2- [3- (5-methyl-1,3,4-oxadiazol-2-yl) -propyl] -6- (tert-butyldimethylsilyloxymethyl) -2 1-trimem-3-carboxylic acid 2-trimethylsilylethyl ester is converted to the title compound, IR (methylene chloride): 2.77, 5.62, 5.90, 6.37 μ.

Example 12 : (5R, 6S) ^ 2- [3- (5-Methyl-l, 3,4-oxadiazol-2-yl) -propyl] -6-hydroxymethyl-2-penem-3-carboxylic acid

176 mg (5R, 6S) -2- [3- (5-Methyl-l, 3,4-oxadiazol-2-yl) -propyl] -6-hydroxymethyl-2-trimem-3-carboxylic acid 2-trimethylsilyl ethyl ester are in 6 ml abs. Dissolved THF and cooled to 0 °. The solution is added dropwise with 6.15 ml of a 0.1 N tetrabutylammonium fluoride solution in THF. After 5 min, 1 ml of this solution is added again and after a total of 2 h reaction, the reaction mixture is diluted with 10 ml of water and concentrated strongly on a rotary evaporator. The residue is treated with a little water and ethyl acetate and 4.1 ml of a 0.1 N HCl solution. The aqueous phase is separated and the organic extracted twice more with ethyl acetate. The aqueous extracts give the title compound after lyophilization

 UV (phosphate buffer pH 7.4) ^: 302 mn.

Example 13 : (5R, 6S.) - 2- [3- (5-Methyl-1,3,4-oxadiazol-2-yl) -propyl] -6- hydroxymethyl-2-penem-3-carboxylic acid-1 ethoxycarbonyloxyethyl

1.2 g of sodium iodide are dissolved in 3.7 ml of acetone and treated with 0.275 ml of ethyl 1-chlorethylcarbonat. The mixture is stirred at room temperature for 3 h. Subsequently, the solution is added dropwise to 15.0 ml of methylene chloride and filtered from the precipitated inorganic salts. The methylene chloride solution is concentrated to 2 ml and added at 0 ° to a solution of 0.325 g (ImMoI) (5R, 6S) -2- [3- (5-methyl-l, 3,4-oxadiazol-2-yl). propyl] -6-hydroxymethyl-2-penem-3-carboxylic acid in 4 ml of dimethylacetamide. The mixture is then stirred for 3 hours at 0 °, then diluted with ethyl acetate and washed three times with water. The organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The crude product is purified on 10 g of silica gel with the eluent ethyl acetate. The title compound is obtained as a white foam

 IR spectrum (methylene chloride): absorption bands at 5.59 and 5.75 u.

Example 14 : (5R, 6S) -2- [3- (5-Methy1-1,3,4-oxadiazol-2-yl) -propyl] -6-hydroxymethyl -penem-S-carboxylic acid pivaloyloxymethyl ester

0.6 g of sodium iodide are dissolved in 2 ml of acetone and treated with 0.15 ml Pivalinsäurechlormethylester. The mixture is stirred at room temperature for 3 h and then added dropwise to 7.5 ml of methylene chloride. The precipitated inorganic salts are filtered off. The methylene chloride solution is concentrated to 1 ml and added to a solution of 0.130 g (0.5 mmol) (5R, 6S) -2- [3- (5-methyl-1,4-oxadiazol-2-yl). propyl] -6-hydroxymethyl-2-penem-3-carboxylic acid and 0.07 ml of diisopropylethylamine in 4 ml of Ν, Ν-dimethylacetamide at 0 °. It is then stirred for 3 h at 0 °, then diluted with ethyl acetate and washed three times with water. The organic phase is dried over sodium sulfate and concentrated on a rotary evaporator. The crude product is purified on 10 g of silica gel with the eluent ethyl acetate. The title compound is obtained as a white foam. IR (methylene chloride): 5.59 and 5.78 / i.

Example 15: Dry ampoules or vials containing 0.5 g of sodium (5R, 6S) -2- [3- (2-methyl-tetrazol-5-yl) -propyl] -6-hydroxymethyl-2-penem-3 Carboxylate as active substance are prepared as follows:

Composition (for 1 ampoule or vial): active substance 0.5 g

Mannitol - 0.05 g

A sterile aqueous solution of the active substance and the mannitol is subjected under aseptic conditions in 5 ml vials or 5 ml vials to freeze-drying and the vials are closed and tested.

Claims (17)

invention claim 1. A process for the preparation of Z-Heterocyclylniederalkyl-Z-penem compounds of the formula R ₁ HHI? iS J ^R 3 wherein R is hydrogen or methyl, R_ is an optionally protected hydroxy 1 group, R, carboxyl or protected carboxyl Rl, R, a via a ring carbon atom to the radical - (CH ^) - bonded, unsaturated, monocyclic heterocyclyl radical with 1 to 4 ring nitrogen atoms and optionally an additional ring heteroatom of the group oxygen and sulfur and m is an integer from 1 to 4, salts of those compounds of the formula I which have a salt-forming group, optical isomers of compounds of the formula I, Mixtures of these optical isomers and of pharmaceutical preparations containing these compounds, characterized in that a) an ylide compound of the formula _R -Z , 1 H wherein R-, R--, Rl, R, and m have the meanings given under formula I, wherein the functional groups contained in the radicals R- and / or R, optionally present in protected form, Z is oxygen or sulfur and λ either a threefold substitute represents phosphonium group or a doubly esterified phosphono group together with a cation, ringschliesst, or b) a compound of the formula R ti H ¹ m for _R -CH-f p ~~ SC- (CH,) -R ² il,. 2 m 4 C = O
I wherein, R ,, R ^> ^ v ^ a ^{un <* m} ^^ ^e indicated ^for formula I, wherein the in the radicals R ~ and / or R, functional groups present are optionally in protected form, with an organic compound of the trivalent phosphorus and, if desired or necessary, in a compound of formula I obtainable, converts a protected hydroxyl group R. into the free hydroxyl group, and / or, if desired, in an available compound of formula I, a protected carboxyl group R 'in the transferred free or in another protected carboxyl group Ri, and / or, if desired, further in the radical R containing protected functional groups converted into the free functional groups, and / or, if desired, in an available compound of formula I is a radical R , in another rest R, convicted, and /. or, if desired, converting an available compound having a salt-forming group into a salt or an available salt into the free compound or into another salt, and / or, if desired, separating an available mixture of isomeric compounds into the individual isomers, and / or an available compound is processed into a pharmaceutical preparation. 2. The method according to item 1 for the preparation of compounds of formula I, wherein R ^ is hydrogen or methyl, R is hydroxyl or Protected hydroxyl means, R is carboxyl or protected carboxyl Ri, especially under physiological conditions cleavable esterified carboxyl Ri, R, a via a ring carbon atom to the radical - (CH-) - bonded 5-membered or 6-membered heteroaryl radical or partially represents saturated heteroaryl radical having 1 to 4 ring nitrogen atoms and optionally an additional ring heteroatom of the group oxygen and sulfur, these radicals being unsubstituted or substituted by hydroxy, lower alkoxy, lower alkanoyloxy, halogen, mercapto, lower alkylthio, phenylthio, lower alkyl, hydroxy lower alkyl, lower alkoxy, lower alkyl, lower alkyl , Di-lower alkylamino-lower alkyl, sulfo-lower alkyl, amino, lower alkylamino, di-lower alkylamino, lower alkyleneamino, carboxyl, lower alkoxycarbonyl, optionally N-mono- or Ν, Ν-lower alkylated carbamoyl, cyano, sulfo, sulfamoyl, optionally lower alkyl, nitro, lower alkoxy and / or halogeno substituents tuiertes phenyl, cycloalkyl, nitro, oxo and / or oxido are substituted, and m is an integer from 1 to 4, their salts, their optical isomers and mixtures of their optical isomers. 3. The method according to item 1 for the preparation of compounds of formula I, wherein R ₁ , R ", R and m have the meanings given in point 2 and R, an unsubstituted or, as indicated in point 2, substituted, via a ring carbon atom the radical - (CH ₂ ) - bonded 5-membered aza-, diaza-, triaza-, tetraza-, oxaza-, oxadiaza-, thiaza-, thiadiaza- or thiatriaza-cyclic radical of aromatic character or the corresponding dihydro radical, or represents a corresponding 6-membered aza-, diaza and triaza-cyclic radical of aromatic character or the corresponding dihydro or tetrahydro radical. 4. A process according to item 1 for the preparation of compounds of the formula I in which R is hydrogen or methyl, R 2 is hydroxyl, R, carboxyl, lower alkanoyloxymethoxycarbonyl or 1-lower alkoxycarbonyloxy-lower alkoxycarbonyl, R 1 denotes a ring carbon atom. atom to the ReSt- (CH ₇ ) - bound, optionally substituted by lower alkyl, carboxy-lower alkyl, sulfo-lower alkyl or di-lower alkylamino-lower alkyl tetra 20l, such as IH or 2H-tetrazol-5-yl, optionally substituted by lower alkyl or amino thiadiazolyl, such as 1,3,4 -Thiadiazol-2-yl, optionally substituted by lower alkyl oxadiazolyl, such as l, 3,4-oxadiazol-2-yl, or pyridyl, for example 2-pyridyl, and m is an integer from 2 to 4, their pharmaceutically acceptable salts , their optical isomers, eg the (5R, 6S) isomers, and mixtures of their optical isomers. 5. The method according to item 1 for the preparation of compounds of formula I, wherein R ₁ , R ₀ , R and m have the meanings given in point 4 and R ₄ lH-tetrazol-5-yl, l-methyl-lH-tetrazole 5-yl, 1-carboxymethyl-1H-tetrazol-5-yl, 1-sulfomethyl-1H-tetrazol-5-yl, 1- (2-dimethylaminoethyl) -1H-tetrazol-5-yl, 2-methyl-2H- tetrazol-5-yl, 1,3,4-thiadiazol-2-yl, 2-methyl-l, 3,4-thiadiazol-5-yl, 2-methyl-1,3,4-oxadiazol-5-yl or 2-pyridyl. 6. The method according to item 1 for the preparation of compounds of formula I, which have the (5R, 6S) configuration. 7. A process according to item 1 for the preparation of (5R, 6S) -configured compounds of the formula I in which R 1 is hydrogen, R _{2 is} hydroxyl, R 6 is carboxyl, R 5 is tetrazol-5-substituted by lower alkyl or di-lower alkylamino lower alkyl yl, for example 1-methyl-1H-tetrazol-5-yl, 1- (2-dimethylaminoethyl) -1H-tetrazol-5-yl or 2-methyl-2H-tetrazol-5-yl, or substituted by lower alkyl 1,3 , 4-oxadiazol-2-yl, for example 2-methyl-l, 3,4-oxadiazol-5-yl, and m is 3, and their pharmaceutically acceptable salts. 8. The method according to item 1 for the preparation of (5R, 6S) -2- [3- (2-methyl-2H-tetrazol-5-yl) -propyl] -6-hydroxy-methyl-2-penem-3-carboxylic acid and pharmaceutically acceptable salts thereof. 9. Process according to item 1 for the preparation of (5R, 6S) -2- [3- (5-methyl-1,3,3-oxadiazol-2-yl) -propyl] -6-hydroxymethyl-Z-penem-S acid and pharmaceutically acceptable salts thereof. 10. The method according to item 1 for the preparation of compounds of Formula I, characterized in that one of a compound of ff)
Formula II starts, wherein λ triarylphosphonio or Dimederalkylphosphono means together with an alkali metal ion. 11. The method according to item 1 for the preparation of compounds of formula I, characterized in that starting from a compound of formula II or III, wherein Rl 4-nitrobenzyloxycarbonyl, lower alkenyloxycarbonyl or substituted in the 2-position by lower alkylsulfonyl, cyano or tri-lower alkylsilyl substituted ethoxycarbonyl , 12. The method according to item 1 for the preparation of compounds of formula I, characterized in that starting from a compound of formula II or III, wherein R ₉ Triniederalkylsilyloxy is. 13. The method according to item 1 for the preparation of compounds of formula I, characterized in that one converts in an available compound of formula I, the carboxyl group R_ into a cleavable under physiological conditions esterified carboxyl group. 14. The method according to item 1 for the preparation of compounds of formula I, characterized in that a compound of formula II ringschliesst by heating in a temperature range of 30 ° to 160 ° in an inert solvent. 15. The method according to item 1 for the preparation of compounds of formula I, characterized in that reacting a compound of formula III with a Triniederalkylphosphit. 16. The method according to item 1 for the preparation of compounds of formula I, characterized in that treating a compound of formula III at a temperature of 20 ° to 80 "in an inert solvent with an organic compound of the trivalent phosphorus. 17. The method according to item 1 for the preparation of compounds of formula I, characterized in that starting from (3S, 4R) -configured compounds of the formulas II or III.