NO834189L - PROCEDURE FOR THE PREPARATION OF 6-HYDROXY-LOWER GENERIC COOL-PENEM COMPOUNDS - Google Patents

Abstract

1. Claims (for the Contracting States : BE, CH, LI, DE, FR, GB, IT, LU, NL, SE) 2-heterocyclyl-lower alkyl-6-hydroxy-lower alkyl-2-penem compounds of the formula see diagramm : EP0110826,P37,F1 in which R1 represents hydrogen or methyl, R2 represents hydroxy or protected hydroxy, R3 represents carboxy or protected carboxy R'3 , especially esterified carboxy R'3 that can be cleaved under physiological conditions, R4 represents a monocyclic, optionally partially saturated 5-membered heteroaryl radical that has from 1 to 4 ring nitrogen atoms and is bonded via a tertiary ring nitrogen atom to the radical -(CH2 )m - or a corresponding partially saturated 6-membered heteroaryl radical having from 1 to 3 ring nitrogen atoms, 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, carboxy-lower alkyl, amino-lower alkyl, di-lower alkylamino-lower alkyl, sulpho-lower alkyl, amino, lower alkylamino, di-lower alkylamino, lower alkyleneamino, lower alkalnoylamino, carboxy, lower alkoxycarbonyl, optionally N-mono- or N,N-di-lower alkylated carbamoyl, cyano, sulpho, sulphamoyl, phenyl that is optionally substituted by lower alkyl, nitro, lower alkoxy and/or by halogen, cycloalkyl, nitro, oxo and/or oxido, the radicals designated "lower" containing up to 7 carbon atoms, and m represents an integer from 1 to 4, salts of compounds of the formula I that have a salt-forming group, optical isomers of compounds of the formula I and mixtures of these optical isomers. 1. Claims (for the Contracting State AT) Process for the manufacture of compounds of the formula see diagramm : EP0110826,P40,F1 in which R1 represents hydrogen or methyl, R2 represents hydroxy or protected hydroxy, R3 represents carboxy or protected carboxy R'3 , especially esterified carboxy R'3 that can be cleaved under physiological conditions, R4 represents a mono-cyclic, optionally partially saturated 5-membered heteroaryl radical that has from 1 to 4 ring nitrogen atoms and is bonded via a tertiary ring nitrogen atom to the radical -(CH2 )m - or a corresponding partially saturated 6-membered heteroaryl radical having from 1 to 3 ring nitrogen atoms, 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, carboxy-lower alkyl, amino-lower alkyl, di-lower alkylamino-lower alkyl, sulpho-lower alkyl, amino, lower alkylamino, di-lower alkylamino, lower alkyleneamino, lower alkanoylamino, carboxy, lower alkoxycarbonyl, optionally N-mono- or N,N-di-lower alkylated carbamoyl, cyano, sulpho, sulphamoyl, phenyl that is optionally substituted by lower alkyl, nitro, lower alkoxy and/or by halogen, cycloalkyl, nitro, oxo and/or oxido, the radicals designated "lower" containing up to 7 carbon atoms, and m represents an integer form 1 to 4, their salts, their optical isomers and mixtures of their optical isomers, characterised in that a) an ylide compound of the formula see diagramm : EP0110826,P40,F2 in which R1 , R2 , R'3 , R4 and m have the meanings given under formula I, a hydroxy group R2 and any functional groups which may additionally be present in the radical R4 preferably being in protected form, Z represents oxygen or sulphur and X (anion) represents either a trisubstituted phosphonio group or a diesterified phosphono group together with a cation, is cyclised, or b) a compound of the formula see diagramm : EP0110826,P40,F3 in which R1 , R2 , R'3 , R4 and m have the meanings given under formula I, a hydroxy group R2 and any functional groups which may additionally be present in the radical R4 preferably being in protected form, is treated with an organic compound of trivalent phosphorus, or c) a compound of the formula see diagramm : EP0110826,P40,F4 in which R1 , R2 , R'3 and m have the meanings given above, and Q represents a reactive esterified hydroxy group, is reacted with an agent that introduces the azaheterocyclyl radical R4 , and, if desired or necessary, in a resulting compound of the formula I a protected hydroxy group R2 is converted into a free hydroxy group, and/or, if desired, in a resulting compound of the formula I a protected carboxy group R'3 is converted into the free carboxy group R'3 , and/or, if desired, other protected functional groups present in the radical R4 are converted into the free functional groups, and/or, if desired, a resulting compound of the formula I a radical R4 is converted into a different radical R4 , and/or, if desired, a resulting compound having a salt-forming group is converted into a salt, or a resulting salt is converted into the free compound or into a different salt, and/or, if desired, a resulting mixture of isomeric compounds is separated into the individual isomers.

Description

The present invention relates to a method for production

of 6-hydroxylower alkyl penem compds.

The invention relates in particular to the process for the preparation of 2-heterocyclyl laverealalkyl-6-hydroxylaverealalkyl-2-penem compounds with the formula:

where is hydrogen or methyl, R 2 means an optionally protected hydroxyl group, is carboxyl or protected carboxyl R^ ' t R 4 is an unsaturated, monocyclic azaheterocyclyl residue which is attached to the residue "(C^) via a tertiary ring nitrogen atom, and m is an integer from 1-4, salts of such compounds of formula I which exhibit a salt-forming group, optical isomers of compounds of formula I and mixtures of these optical isomers.

The definitions used above and in the following preferably have the following meanings in the context of the present description: 3

An unsaturated, monocyclic azaheterocyclyl residue R^, which is bound to the residue~(CH2^over a tertiary ring nitrogen atom, is in particular a corresponding, optionally partially saturated 5-membered heteroaryl residue with 1 to 4 ring nitrogen atoms, as a corresponding aza-, diaza-,

■*triaza- or tetraza-cyclic radical of an aromatic character, or a corresponding dihydro-residue, or a corresponding partially saturated 6-membered heteroaryl radical with 1 to 3 ring nitrogen atoms, as a corresponding aza-, diaza- or triaza-cyclic radical , e.g. a corresponding dihydro or tetrahydro residue. These residues are

-"unsubstituted or may be substituted, with especially mono- or also poly-, as especially disubstituted, with possibly

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, hydroxyl lower alkyl, lower carboxy lower alkyl, carboxy lower alkyl, optionally N-lower alkylated amino lower alkyl, e.g. amino lower alkyl or di lower alkyl amino lower alkyl, sulfola lower alkyl, optionally substituted, including protected amino, e.g. amino, lower alkylamino, dilower alkylamino, lower alkyleneamino or acylamino, such as lower alkanoylamino, optionally functionally converted including protected carboxyl or sulfo, e.g. carboxyl, substituted carboxyl, as lower alkoxycarbonyl, optionally substituted carbamoyl, as N-mono- or N,N-dileveralkylated carbamoyl, cyano, sulfo or sulfamoyl, cenyl, cycloalkyl, nitro, oxo and/or oxydo which is optionally substituted with lower alkyl, nitro , lower alkoxy and/or halogen.

In the present description, the term means: "lower"

which is used in connection with definitions of groups or compounds, that the corresponding groups or compounds, unless otherwise expressly defined, contain up to and including 7, preferably up to and including 4 carbon atoms.

Low-area coke is e.g. methoxy, further aethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy or tert-butyloxy, as well as 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 alkyl 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, further n-pentyl, n-hexyl or n-heptyl.

Hydroxyl lower alkyl is e.g. hydroxymethyl, 2-hydroxyethyl or 2,3-dihydroxypropyl.

Lower alkyl lower alkyl is e.g. methoxymethyl, 2-methoxy-ethyl, aethoxymethyl or 2-aethoxyethyl.

Carboxylavealkyl is e.g. carboxymethyl, 1-carboxy-, 2-carboxy or 1,2-dicarboxyethyl.

Amino lower alkyl is e.g. aminomethyl or 2-aminoethyl, while diloweralkylaminoloweralkyl e.g. dimethylaminoethyl, 2-dimethylaminoethyl or 2-diethylaminoethyl.

Sulfolaverealkyl is e.g. sulfomethyl or 2-sulfoethyl.

Lower alkylamino is e.g. methylamino, ethylamino, n-propylamino, isopropylamino or n-butylamino, while dilaverealkylamino e.g. is dimethylamino, diethylamino, di-n-propylamino or diisopropylamino.

Lower alkyleneamino especially has 4-6 carbon chain links and means e.g. pyrrolidino or piperidino.

Lower alkanoylamino is e.g. acetylamino or propionylamino.

Lower oxycarbonyl is e.g. methoxycarbonyl or aethoxycarbonyl1.

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

Cycloalkyl preferably contains 3 - 8, primarily 5

or 6 ring joints and is e.g. cyclopentyl or cyclohexyl,

further cyclopropyl as well as cycloheptyl.

Corresponding 5-membered, optionally partially saturated heteroaryl residues R 1 , are e.g. porrolyl or hydropyrrolyl which is optionally substituted with lower alkyl or halogen, e.g. 1-pyrrolyl, 3-methyl-1-pyrrolyl, 3,4-dichloro-1-pyrrolyl,

further 2,3- or 2,5-dihydro-1-pyrrolyl, diazolyl, such as e.g. imidazolyl or pyrazolyl, which is optionally substituted with lower alkyl, e.g. 1-imidazolyl or 1-pyrazolyl, triazolyl,

as 1H-1,2,3-triazol-H.yl, 2H-1,2,3-triazol-2-yl,

1H-1,2,4-triazol-1-yl or 1H-1,3,4-triazol-1-yl, which is optionally substituted with lower alkyl, carboxy lower alkyl or phenyl, e.g. the corresponding unsubstituted residues, 4- or 5-methyl-1,2,3-triazol-1-yl, 3-methyl- or 3-phenyl-1H-1,2,4-triazol-1-yl, or tetrazolyl, such as 1H-tetrazol-1-lyl or 2H-tetrazol-2-yl, which is optionally substituted with lower alkyl, carboxylaverealkyl, sulfolaveraalkyl, dilaverealkylaminoloweralkyl, amino or phenyl which is optionally substituted with halogen, e.g. the corresponding unsubstituted residues, 5-amino-, 5-methyl-, 5-carboxymethyl-, 5-(2-carboxyethyl)-, 5-sulfomethyl-, 5-(2-dimethylaminoethyl)- or 5-phenyl-2H-tetrazole -1-yl or 5-amino-, 5-methyl-, 5-carboxymethyl-, 5-sulfomethyl-, 5-(2-dimethylaminoethyl)- or 5-phenyl-2H-tetrazol-2-yl.

Corresponding 6-membered, partially saturated heteroaryl residues R4 are

e.g. dihydro-1-pyridyl, such as 2H-1,2-dihydro- or 4H-1,4-dihydro-1-pyridyl, is unsubstituted or specially substituted with oxo and optionally additionally with halogen, e.g. 2-oxo-2H-1,2-dihydro-1-pyridyl or 4-oxo-4H-1,4-dihydro-1-pyridyl, dihydro-1-pyrimidinyl, as 2H-1,2-dihydro- or 4H- 1,4-dihydro-1-pyrimidinyl, which is optionally substituted in particular with oxo and optionally additionally with lower alkyl, amino, dilower alkylamino or carboxy,

e.g. 2-OXO-1,2-dihydro-1-pyrimidinyl, 6-methyl-, 5-methyl-, 6-amino-, 6-dimethylamino-, 5-carboxy- or 6-carboxy-2-oxo-1,2 -dihydro-1-pyrimidinyl or 4-oxo-1,4-dihydro-1-pyrimidinyl, or dihydro- or tetrahydrotriazinyl, which is optionally

substituted with a lower alkyl and/or up to 2 oxo, e.g. 2H-1,2-dihydro-1,3,5-triazin-1-yl, 2H-1,2-dihydro-1,2,4-triazin-1-yl, 2H-1,2,5,6- tetrahydro-1,2,4-triazin-1-yl or 4H-1,4,5,6-tetrahydro-1,2,4-triazin-1-yl, e.g. lower alkyl-1,4,5,6-tetrahydro-5,6-dioxo-1,2,4-triazin-1-yl, e.g. 4-methyl-1,4,5,6-tetrahydro-5,6-dioxo-1,2,4-triazin-1-yl.

The functional groups present in the compounds with

formula I, such as hydroxy, carboxy, amino or sulfo groups, especially the hydroxy group R~ and the carboxyl group, are optionally protected by protective groups, which are used in penem-,

penicillin, cephalosporin and peptide chemistry.

Such protective groups are easily cleavable, for example solvolytically, reductively or also under physiological conditions, i.e. without unwanted side reactions taking place.

Protective groups of this kind as well as their introduction and cleavage 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, 1981,

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

Houben-Weyl, "Methoden der Organischen Chemie", Volume 15/1, Georg Thieme Verlag, Stuttgart, 1974.

In compounds of formula (I), a hydroxy group can be R2, and so on

a hydroxy group present in the residue R^, for example be protected with acyl residues. Suitable acyl residues are e.g. lower alkanoyl, which is optionally substituted with halogen, e.g. acetyl or trifluoroacetyl, benzoyl which is optionally substituted with nitro, e.g. benzoyl, 4-nitrobenzoyl or 2,4-dinitrobenzoyl, lower alkoxycarbonyl, which is optionally substituted with halogen,

e.g. 2-bromoethoxycarbonyl or 2,2,2-trichloroethoxycarbonyl, or phenyllower oxycarbonyl, which is optionally substituted with nitro, e.g. 4-nitrobenzyloxycarbonyl. Further 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 group, e.g.

2-chloro-, 2-bromo-, 2-iodo- and 2,2,2-trichloroethyl, and phenyl lower alkyl which is optionally substituted with halogen, e.g. chlorine, lower alkoxy, e.g. methoxy, and/or nitro, as corresponding benzyl. Preferred as hydroxy protecting group is trilower alkylsilyl.

A carboxyl group, and further also a carboxyl group present in the residue R4, is usually protected in esterified form, whereby the ester group is easily cleavable under gentle conditions, e.g. under mild reductive, such as hydrogenolytic or mild solvolytic, such as acidolytic or especially basic or neutral hydrolytic conditions. A protected carboxyl group can further constitute a carboxyl group that is cleavable under physiological conditions or can be easily converted into another functional converted carboxyl group, such as e.g. to another esterified carboxyl group.

Such esterified carboxyl groups contain as esterifying groups primarily lower alkyl groups which are branched in the 1-position or suitably substituted in the 1- or 2-position. Preferred carboxyl groups which are present in esterified form

is i.a. lower alkoxycaiboyl, e.g. methoxycarbonyl, aethoxy. carbonyl, isopropoxycarbonyl or tert.-butoxycarbonyl and (hetero-)arylmethoxycarbonyl with 1-3 aryl residues or a mono-lytic heteroaryl residue, whereby these are optionally mono- or poly-substituted with e.g. lower alkyl, such as tert.-lower alkyl, e.g. tert-butyl, halogen, e.g. chlorine and/or nitro. Examples of such groups are possibly e.g. as above

mentioned, substituted benzyloxycarbonyl, e.g. 4-nitrobenzyloxycarbonyl, optionally, e.g. as above, substituted.

diphenyl-methoxycarbonyl, e.g. diphenylmethoxycarbonyl, or triphenylmethoxycarbonyl, or optionally, e.g. as above, substituted picolyloxycarbonyl, e.g. 4-picolyloxycarbonyl, or furfuryloxycarbonyl, as 2-furfuryloxycarbonyl. Further suitable groups are lower alkanoyl-methoxycarbonyl, such as acetonyloxycarbonyl, aroylmethoxycarbonyl, where the aroyl group is preferably benzoyl which is optionally substituted with e.g. halogen, such as bromine, e.g. phenacyloxycarbonyl, halogenolower oxycarbonyl, such as 2-halogenolower oxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, or o-halogeno-lower oxycarbonyl, where lower alkoxy contains 4-7 carbon atoms, e.g. 4-chloro-butoxycarbonyl, phthalimidomethoxycarbonyl, lower alkenyloxycarbonyl, e.g. allyloxycarbonyl, or aethoxycarbonyl which is substituted in the 2-position with. lower alkylsulfonyl, cyano or trisubstituted silyl, such as trilower alkylsilyl or triphenylsilyl, e.g. 2-methylsulfonylethoxycarbonyl, 2-cyanoethoxycarbonyl, 2-trimethylsilylethoxycarbonyl or 2-(di-n-butyl-methyl-silyl)-ethoxycarbonyl.

Other protected carboxyl groups present in the ester

form are corresponding organic silyloxycarbonyl groups, and further corresponding organic stannyloxycarbonyl groups. In these, the silicon or tin atom preferably contains lower alkyl, especially methyl or ethyl, further lower alkoxy, e.g. methoxy, as substituents. Suitable silyl or stannyl groups are primarily tri-lower alkylsilyl, especially trimethylsilyl or dimethyl-tert-butylsilyl, or correspondingly substituted stannyl groups, e.g. tri-n-butylstannyl.

An esterified carboxyl group that is cleavable under physiological conditions is primarily an acyloxymethoxycarbonyl group, where acyl e.g. means the residue of an organic carboxylic acid, primarily an optionally substituted lower alkane carboxylic acid, or where acyloxymethyl forms the residue of a lactone, 1-lower alkyl-lower oxycarbonyl or also 1-lower alkoxycarbonyl-oxy-lower alkylcarbonyl, where lower alkyl e.g. is methyl, propyl, butyl or especially ethyl and lower alkoxy, e.g. methoxy, aethoxy, propoxy or butoxy. Such groups are e.g. lower alkanoyloxymethoxycarbonyl, e.g. acetoxymethoxycarbonyl or pivaloyloxymethoxycarbonyl, aminolower alkanoyloxymethoxycarbonyl, especially α-aminoloweralkanoyloxymethoxycarbonyl, e.g. glycyloxymethoxycarbonyl, L-valyloxymethoxycarbonyl, L-leucyloxymethoxycarbonyl, phthalidyloxycarbonyl, 4-crotonal-acetonyl or 4-butyrolactonyl, indanyloxycarbonyl, e.g. 5-indanyloxycarbonyl. 1-ethoxycarbonyloxyethoxycarbonyl, methoxymethoxycarbonyl or 1-methoxyethoxycarbonyl.

Preferred protected carboxyl groups R^' are 4-nitrobenzyl-

; the oxycarbonyl group, the lower alkenyloxycarbonyl group and the Aethoxycarbonyl group which is substituted in the 2-position with lower alkylsulfonyl, cyano or trilower alkylsilyl, as well as the esterified carboxyl groups which are cleavable under physiological conditions, such as lower alkanoyloxymethoxycarbonyl and 1-lower oxycarbonyl-

0oxy-lower oxycarbonyl.

A protected amino group can, for example, be in the form of an easily cleavable acylamino, acylimino, etherified mercaptoamino, silyl or stannylamino group or as an enamino, nitro-

5or azido group.

In a corresponding acylamino group, acyl is, for example, the acyl residue

of an organic acid with e.g. up to 18 carbon atoms, especially an alkanecarboxylic acid which is optionally substituted with e.g. halogen!0 or phenyl, or optionally benzoic acid which is substituted by halogen, lower alkoxy or nitro, or a carbonic acid half-ester. Such acyl groups are, for example, lower alkanoyl, such as formyl, acetyl or propionyl, halolower alkanoyl, such as 2-halo-acetyl, especially 2-fluoro-, 2-bromo-, 2-iodo-, 2,2,2-trifluoro- or 2,2 ,2-tri-35chloroacetyl, optionally substituted benzoyl, e.g. benzoyl, halo-benzoyl, such as 4-chlorobenzoyl, lower alkoxybenzoyl, such as 4-methoxy-

benzoyl, or nitrobenzoyl, such as 4-nitrobenzoyl. In particular, also lower alkenyloxycarbonyl, e.g. allyloxycarbonyl, or optionally lower alkoxycarbonyl, which is substituted in the 1- or 2-position is suitable, such as lower alkoxycarbonyl, e.g. methoxy

or ethoxycarbonyl, optionally substituted benzyloxycarbonyl, e.g. benzyloxycarbonyl or 4-nitrobenzyloxycarbonyl, aroylmethoxycarbonyl, where the aroyl group is preferably benzoyl which is optionally substituted with e.g. halogen, such as bromine, e.g. phenacyloxycarbonyl, 2-halolower oxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, or 2-(tris-substituted silyl)ethoxycarbonyl, such as 2-trilower alkylsilylethoxycarbonyl, e.g. 2-trimethylsilylethoxycarbonyl or 2-(di-n-butyl-methyl-silyl)-ethoxycarbonyl, or 2-triarylsilylethoxycarbonyl, such as 2-triphenylsilylethoxycarbonyl.

In an acylimino group, acyl is, for example, the acyl residue of a

organic carboxylic acid with e.g. up to 12 carbon atoms, especially a corresponding aromatic dicarboxylic acid, such as phthalic acid. One such group is primarily phthalimino.

An etherified mercaptoamino group is primarily a phenylthioamino group or a pyridylthioamino group, which is optionally substituted with lower alkyl, such as methyl or tert.-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine or bromine, and/or nitro. Corresponding groups are, for example, 2- or 4-nitrophenylthioamino or 2-pyridylthioamino.

A silyl or stannylamino group is primarily an organic silyl or stannylamino group, where the silicon or tin atom preferably contains lower alkyl, e.g. methyl, ethyl n-butyl or tert.-butyl, further lower alkoxy, e.g. methoxy, as substituents. Corresponding silyl or stannyl groups are primarily trilower alkylsilyl, especially trimethylsilyl, further dimethyl-tert-butylsilyl, or similarly substituted stannyl, e.g. tri-n-butylstannyl.

Other protected amino groups are e.g. enaraino groups, which at the double bond in the 2-position contain an electron-withdrawing substituent, for example a carbonyl group. Protecting groups of this type are, for example, 1-acyl-lower alk-1-en-2-yl residues, where acyl e.g. means the corresponding residue from a lower alkane carboxylic acid, e.g. acetic acid, a benzoic acid which is optionally substituted, e.g. with lower alkyl, such as methyl or -tert.butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and/or nitro, or especially a carbonic acid half-ester, such as a carbonic-lower alkyl half-ester, e.g. -methyl half-esters or -ethyl half-esters, and lower alk-1-ene, especially 1-propene. Corresponding protecting groups are primarily 1-lower alkanoyl-prop-1-en-2-yl, e.g. 1-acetyl-prop-1-en-2-yl, or 1-lower oxycarbonyl-prop-1-en-2-yl, e.g. 1-ethoxycarbonyl-prop-1-en-2-y1.

A protected sulfo group is primarily an esterified sulfo group that is esterified with an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or has aliphatic alcohol, in e.g. a lower alkanol, or with a silyl or stannyl residue, such as tri-lower alkylsilyl. In a sulfo group, the hydroxy group can, for example, be esterified like the hydroxy group in an esterified carboxyl group.

Salts of compounds produced according to the invention are primarily pharmaceutically usable, non-toxic salts of compounds of formula I. Such salts are formed, for example, from acidic groups present in the 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 alkyl amines, e.g. triethylamine, hydroxyl lower alkyl amines, e.g. 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine - or tris-(2-hydroxyethyl)amine, basic aliphatic esters of carboxylic acid, e.g. 4-aminobenzoic acid-2-diethylaminoethyl esters, lower alkylene amines, e.g. 1-ethylpiperidine, cycloalkylamines,

e.g. dicyclohexylamine, or benzylamines, e.g. N,N'-dibenzylethylenediamine, dibenzylamine or N-benzyl-g-phenethylamine. Compounds of formula I with a basic group, e.g.

with an amino group, can form acid addition salts, e.g.

with inorganic acids, such as hydrochloric, sulfuric or phosphoric

acid, or with suitable organic carboxylic or sulphonic acids, e.g. acetic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, oxalic acid, citric acid, benzoic acid, mandelic acid, malic acid, citric-ascorbic acid, methanesulfonic acid or 4-toluenesulfonic acid. Compounds of formula I with an acidic and with a basic group can exist in the form of internal salts, that is to say in zwitterionic form.

Pharmaceutically unsuitable salts can also be used for isolation and purification. For therapeutic use, only the pharmaceutically usable, non-toxic salts are mentioned, which are therefore preferred.

In the penem compounds of formula I, the two asymmetric carbon atoms in the 5- and 6-position can be present in R, S or racemic R,S configuration. Preferred are compounds in which the configuration of the 5-carbon atoms corresponds to that of the natural penicillin (5R configuration). The hydrogen atoms in the 5- and 6-position can stand

in cis- or preferably in trans position in relation to each other. In the preferred configuration, the substituent in the 6-position assumes the S configuration. Compounds of formula I where the major R 1 is methyl have an additional chirality center (carbon atom 8), which may be in the S-, in the racemic R,S- or preferably in the R configuration. According to the invention, in particular compounds of formula I are prepared where R1 means hydrogen or methyl, R2 means hydroxyl or protected hydroxyl, R^ is carboxyl or protected carboxyl R^', especially esterified carboxyl which is cleavable under physiological conditions, R^ is an optionally partially saturated 5 -membered heteroaryl residue with 1-4 ring nitrogen atoms which are bound to the residue -(CH2)m- via a tertiary ring nitrogen atom, as a corresponding aza-, diaza-, triaza- or tetraza-cyclic residue of aromatic character or a corresponding

dihydro residue, or a corresponding partially saturated 6-membered heteroaryl residue with 1 to 3 ring nitrogen atoms, such as a corresponding aza-, diaza- or triaza-cyclic residue, e.g.

a corresponding dihydro or tetrahydro residue, whereby these residues are unsubstituted or substituted by hydroxy, lower alkoxy, lower alkanoyloxy, halogen, mercapto, lower alkylthio, phenylthio, lower alkyl, hydroxyl lower alkyl, lower carboxy lower alkyl, carboxy lower alkyl, amino lower alkyl, di lower alkyl amino lower alkyl, sulfola lower alkyl, amino, lower alkyl amino, di lower alkyl amino , lower alkyleneamino, lower alkanoylamino, carboxyl, lower alkoxycarbonyl, optionally N-mono-

or N,N-diloweralkylated carbamoyl, cyano, sulfo or sulfamoyl, optionally phenyl, which is substituted by lower alkyl, nitro, lower alkoxy and/or halogen, cycloalkyl,

nitro, oxo and/or oxido, and m means an integer from 1 to 4, salts of compounds of formula I, which exhibit a salt-forming group, optical isomers of compounds of formula I

and mixtures of these optical isomers.

In preferred compounds of formula I, 1-pyrrolyl or dihydro-1-pyrrolyl, which is optionally substituted by lower alkyl or halogen, stands for 1-imidazolyl or 1-pyrazolyl, which is optionally substituted by lower alkyl, 1,2,3-, 1 ,2,4- or 1,3,4-triazol-1-yl, which is optionally substituted with lower alkyl, carboxylaverealkyl or phenyl, 1- or 2-tetrazolyl which is optionally substituted with lower alkyl, carboxylaveraalkyl, sulfolaveraalkyl, dilaveraalkylaminoloweralkyl or amino, dihydro- 1-pyridyl, such as unsubstituted or substituted with oxo and possibly additionally halogen, dihydro-1-pyrimidinyl which is unsubstituted or substituted with oxo. and optionally additionally with lower alkyl, amino, dilower alkylamino or carboxy or dihydro- or tetrahydro-1-triazinyl which is optionally substituted with lower alkyl and/or oxo.

The invention primarily concerns compounds of formula I, where R^ is hydrogen or methyl, R2 means hydroxyl, R^ means carboxyl, lower alkanoyloxymethoxycarbonyl or 1-lower- alkoxycarbonyloxy-lower oxycarbonyl, R4 means 1H-tetrazol-1-yl or 2H-tetrazol-2 -yl which is optionally substituted with amino, lower alkyl, carboxyl lower alkyl, sulpho lower alkyl or di lower alkyl-amino lower alkyl, or 1,2,4-triazol-1-yl which is optionally substituted with lower alkyl, carboxy lower alkyl or phenyl, and m means an integer from 1 -4, pharmaceutically usable salts of such compounds of formula I, which contain 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 mainly concerns (5R, 6S)-configured compounds of formula I, where R^ is hydrogen, R2 is hydroxyl, R^ is carboxyl, R4 is 1-H-tetrazol-1-yl or 1H-1,2,4-triazole -1-yl and m is an integer from 1 to 4, and pharmaceutically acceptable salts of compounds of formula I.

The invention relates above all to the preparation of the compounds of formula I mentioned in the examples and their pharmaceutically usable salts.

The compounds in the present invention are produced using methods known per se.

The new compounds are produced, for example, by

a) a ylide compound of the formula

where R^, R2, R3<1>, R4 and m have the meanings given under formula I, whereby a hydroxy group R2 and possibly further contained functional groups in the residue R^ are preferably present in protected form, Z means oxygen or sulfur and $ either means a triply substituted phosphonio group or a doubly esterified phosphono group together with a cation is ring-closed, or

b) a compound of the formula:

where R^, R2R^<1>, R^ and m have the meanings given under formula I,

whereby a hydroxy group R2 and optionally additionally contained functional groups in the residue R^ are preferably present in protected form, treated with an organic compound of trivalent phosphorus, or

c) a compound of formula,

where R^ , R2, R^<1>P9m have the meanings given above and Q

means a reactive esterified hydroxy group, is reacted with an agent which introduces the azaheterocyclyl residue R^,

and, if desired or necessary, transferred in an achieved connection

with formula I a protected hydroxyl group R2 in the free hydroxyl group, and/or if desired, transferred in a compound obtained with formula I a protected carboxyl group 'in the free or in another protected carboxyl group R3', and/or if desired, further transferred in the residue R^ contained protected functional groups in the free functional groups, and/or if desired, transferred in an obtained compound of formula I a residue R^ into another residue R^, and/or if desired, transferred an obtained compound with salt-forming groups in a salt or a salt obtained in the free compound or in another salt, and/or, if desired, a mixture of isomeric compounds obtained is divided into the individual isomers.

a. Cyclization of the compound of formula II

The group X ffi in the starting material with formula II is one of the phosphonio or phosphono groups common in Wittig condensation reactions, especially a triaryl, e.g. triphenyl-,

or trilower alkyl-, e.g. tri-n-butylphosphonio group, or a phosphono group which is doubly esterified with lower alkyl, e.g. aethyl, whereby the symbol X in the case of a phosphono group additionally comprises cations of a strong base, especially a suitable metal, such as e.g. alkali metal, e.g. lithium, sodium or potassium ion. Preferred as group X is on the one hand triphenylphosphonio and on the other hand diethylphosphono together with an alkali metal, e.g. sodium ion.

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

The ring closure can take place spontaneously, i.e. during the production of the starting materials, or during heating, e.g. in a temperature range from approx. 30° to 160°C, preferably from approx. 50° to approx. 100°C. The reaction is preferably carried out in a suitable inert solvent, such as in an aliphatic, cycloaliphatic or aromatic hydrocarbon, e.g. hexane, cyclohexane, benzene or toluene, a halogenated hydrocarbon, e.g. methylene-

chloride, an ether, e.g. diethyl ether, dimethoxyethane, or diethylene glycol dimethyl ether, a cyclic ether, e.g. dioxane,

or tetrahydrofuran, a carboxylic acid amine, e.g. dimethylformamide, a dilave alkyl sulfoxide, e.g. dimethyl sulfoxide, or a lower alkanol, e.g. methanol, ethanol or tert.-butanol, or in a mixture thereof, and if necessary in an inert gas-,

e.g. nitrogen atmosphere.

A starting compound of formula II, in which X is a phosphono group together with a cation, is preferably prepared in situ, whereas a compound of formula

where X' means a phosphono group, is treated with a suitable basic reagent, such as an inorganic base, e.g. an alkali metal carbonate, such as sodium or potassium carbonate.

b. Cyclization of the compound of formula III

An organic compound of trivalent phosphorus is derived, e.g. from phosphoric acid and is especially an ester of this with a lower alkanol, e.g. methanol or ethanol, and/or an optionally substituted aromatic hydroxy compound, e.g. phenol or pyrocatechin, or an amide ester of the same with the formula P(0Ra)(R^)2 f where R& and R^ independently of each other mean lower alkyl, e.g. methyl, or aryl, e.g. phenyl. Pre-

drawn compounds of trivalent phosphorus are trialkylphosphites, e.g. trimethyl phosphite or triethyl phosphite.

The reaction is preferably carried out in an inert solution

agent, such as an aromatic hydrocarbon, e.g. benzene or toluene, an ether, e.g. dioxane or tetrahydrofuran, or a halogenated hydrocarbon, e.g. methylene chloride or chloroform, at a temperature from approx. 20° to approx. 80°C, preferably from approx. 40° to approx. 60°C, whereby 1 target equivalent of a compound of formula III is reacted with 2 target equivalents of the phosphorus compound Preferably, the compound of formula III is placed in an inert solvent and the phosphorus compound is added dropwise, preferably dissolved in the same inert solvent, over a longer period of time, e.g. during a period of 2 - 4 hours.

i The starting compounds with formula III can be prepared, for example, by an azetidinone with the formula:

is treated with a compound of the formula R^'-COOH or in particular

a reaction derivative, such as an acid halide, e.g. acid chloride,

thereof at a temperature of from 20° to 80°C, preferably at 40° to 60°C, in an inert solvent, such as one of those mentioned in the reaction of compounds of formula III to compounds of

formula I. When using an acid halide, preferably 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 in particular an alkali metal or alkaline earth metal carbonate or hydrogen carbonate, e.g. potassium carbonate or calcium carbonate

In a preferred embodiment of the method, the starting material with formula III is prepared as indicated and this is reacted without isolating the reaction mixture with the organic compound of trivalent phosphorus, whereby the end products with formula I are produced.

c. Introduction of the azaheterocyclyl residue

In the compounds of formula (IV), reactive esterified hydroxy Q means, for example, hydroxy which is esterified with halogen hydrogen acid, organic sulphonic acids, such as lower alkane or optionally substituted benzene sulphonic acids, lower alkane carboxylic acids or phosphinic acids, and is primarily halogen,

e.g. chlorine, bromine or iodine, sulphonyloxy, e.g. methane-, benzene-, 4-toluene- or 4-bromo-benzenesulfonyloxy, lower alkanoyloxy, e.g. acetoxy, or phosphinoyloxy, e.g. dimethyl or diphenylphosphinoyloxy.

An agent which introduces the azaheterocyclyl residue R 2 is particular

a compound with the formula R^-H, where the ring nitrogen atom that attaches to the residue~(CH2^m~'^is a hydrogen atom.

The turnover takes place e.g. in the presence of a basic condensing agent, for example an alkali or alkaline earth metal hydroxide or carbonate, e.g. sodium hydroxide, sodium carbonate, potassium hydroxide, potassium carbonate or calcium carbonate, sodium carbonate, potassium hydroxide, potassium carbonate or calcium carbonate, an alkali metal lavereal alkanolate, e.g. sodium methanolate, sodium ethanolate or potassium tert-butanolate, an aromatic amine, e.g. pyridine or quinoline, or a tertiary aliphatic amine, such as a trilower alkylamine, e.g. triethylamine or diisopropylethylamine, in an inert solvent, such as a lower alkanol, e.g. methanol or tert-butanol, an amide, e.g. dimethylformamide, or by using liquid amine as a basic condensing agent in excess amine at room temperature or a higher or lower temperature, e.g. at approx. -20° to approx. +80°C.

Such starting materials with formula II are preferably used,

III and IV, which belong to the initially mentioned as particularly preferred compounds of formula I, especially compounds of formula II or III, which exhibit a 3S,4R configuration, or of formula IV, which exhibit a 5R,6S configuration.

In an achievable compound of formula I, where one or more functional groups are protected, these can, e.g. protected amino, carboxyl, hydroxy and/or sulfo groups, are released in a manner known per se by means of solvolysis, especially hydrolysis, alcoholysis or acidolysis, or by reduction, especially hydrogenolysis or chemical reduction, possibly stepwise or simultaneously.

In a compound of formula I with a protected ammonium group which is obtained according to the invention, this can in a manner known per se, e.g. depending on the nature of the protecting group, is preferably transferred to the free amino group by means of solvolysis or reduction. For example, 2-halolower oxycarbonylamino (possibly after conversion of a 2-bromolower oxycarbonylamino group to a 2-iodolower oxycarbonylamino group), aroylmethoxycarbonylamino or 4-nitrobenzyloxycarbonylamino can be cleaved by treatment 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 can also be cleaved by treatment with a nucleophilic, preferably salt-forming reagent, such as sodium diphenolate, and 4-nitrobenzyloxycarbonylamino can also be cleaved by treatment with an alkali metal, e.g. sodium dithionite. Optionally substituted benzyloxycarbonylamino can e.g. is split by means of hydrogenolysis, i.e. by treatment with hydrogen in the presence of a suitable hydride catalyst, such as a palladium catalyst,

and allyloxycarbonylamine, by reaction with a palladium compound, e.g. tetrakis(triphenylphosphine)palladium, in the presence of triphenylphosphine and treatment with a carboxylic acid, e.g. 2-ethylhexanoic acid, or a salt thereof. An amino group that is protected

with an organic silyl or stannyl group can e.g. is released by means of hydrolysis or alcoholysis, and an amino group which is protected with 2-halolower alkanoyl, e.g. 2-chloroacetyl,

can be liberated by treatment with thiourea in the presence of a base or with a thiolate salt, such as an alkali metal thiolate, of thiourea and subsequent solvolysis, such as alcoholysis or hydrolysis of the condensation product obtained. An amino group protected by 2-substituted silylethoxycarbonyl can be transferred to the free amino group by treatment with a salt of hydrofluoric acid, which releases fluoride anions, 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 tetralower alkylammonium fluoride, e.g. tetraethylammonium fluoride. An amino group that is protected in the form of an azido or nitro group is transferred, for example, by reduction to free amino, for example by catalytic hydrogenation with hydrogen in the presence of a hydrogenation catalyst such as e.g. platinum oxide, palladium or Raney nickel, or by treatment with a sieve in the presence of an acid, such as acetic acid.

An amino group protected in the form of a phthalimido group,

can be transferred to the free amino group by reaction with hydrazine. Furthermore, an arylthioamino group can be converted to amino by treatment with a nucleophilic reagent, such as sulfuric acid.

In a compound of formula I, where R^ means a protected carboxyl group Rj<1> and/or where the residue R^ contains protected carboxyl as a substituent, which is produced according to the invention, the carboxylic acid can be released in a manner known per se. Thus, tert.-lower alkoxycarbonyl or lower alkoxycarbonyl which is substituted in the 2-position with a trisubstituted silyl group or in the 1-position with lower alkoxy or optionally substituted in diphenyl-methoxycarbonyl, e.g. is transferred into free carboxyl during 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. Optionally substituted benzyloxycarbonyl can be cleaved e.g. by means of hydrogenolysis, i.e. by treatment with hydrogen in the presence of a

metallic hydrogenation catalyst, such as a palladium catalyst.

Furthermore, suitable substituted benzyloxycarbonyl, such as 4-nitrobenzyloxycarbonyl, can also 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, such as a chromium II salt, e.g. chromium II chloride, usually in the presence of a hydrogen-releasing agent, which together with the metal can produce nascent hydrogen, such as a suitable carboxylic acid, e.g. one possibly, e.g. with hydroxy, substituted lower alkanecarboxylic acid, e.g. acetic acid, formic acid or glycolic acid, or an alcohol or thiol, to which water is preferably added, is transferred into free carboxyl. The removal of an allyl protecting group can e.g. take place by reaction with a compound of palladium, e.g. tetrakis(triphenylphosphine)palladium, in the presence of triphenylphosphine with the addition of a carboxylic acid, e.g. 2-ethylhexanoic acid, or a salt thereof. By treatment with a reducing metal or metal salt, as above

described, 2-nalogenlower oxycarbonyl (possibly after conversion of a 2-bromolower oxycarbonyl group into a corresponding 2-iodolower oxycarbonyl group) or aryoyl-methoxycarbonyl can also be converted to free carboxyl, whereby aroyl-methoxycarbonyl can likewise be cleaved off by treatment with a nucleophilic, preferably salt-forming reagent, which sodium thiophenolate or sodium iodide. Substituted 2-silylethoxycarbonyl can also, by treatment with a salt of hydrofluoric acid which emits a fluoride anion, 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 tetralower alkylammonium fluoride, e.g. tetrabutylammonium fluoride, is transferred in free carboxyl. Carboxyl esterified with an organic silyl or stannyl group, such as trilower alkylsilyl or -stannyl, is usually released solvolytically, e.g. by treatment with water or an alcohol. A lower alkoxycarbonyl group which is substituted in the 2-position with lower alkyl-sulfonyl or cyano can e.g. by treatment 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, is transferred in free carboxyl.

In compounds which can be prepared according to the invention with

formula I, where 1*2 is a protected hydroxy group and/or where the residue R4 contains protected hydroxyl as a substituent,

the protected hydroxy group can be transferred in a manner known per se in the free hydroxy group. For example, a hydroxy group that is protected with a suitable acyl group or an organic silyl or stannyl group is released, as a

corresponding protected amino group, a trilower alkylsilyl-

group, e.g. also with tetrabutylammonium fluoride and acetic acid (under these conditions carboxy groups which are protected with trisubstituted silyl ethoxy are not split off). A 2-halogen lower alkyl group and an optionally substituted benzyl group are cleaved off reductively.

A protected, especially esterified, sulfo group is released analogously to a protected carboxyl group.

On the other hand, compounds of formula I, where means carboxy, can also be transferred to compounds of formula I, where R 1 is a protected carboxyl group, especially an esterified carboxyl group. Thus, the free carboxyl group can be esterified, e.g. by treatment with a suitable diazo compound, such as a diazole veralkane, e.g. diazomethane, or a phenyldiazolavere-alkane, e.g. diphenyldiazomethane-, if necessary in the presence of a Lewis acid, such as e.g. boron trifluoride, or by "reaction with an alcohol suitable for esterification, in the presence of an esterification agent, such as a carbodiimide, e.g. dicyclohexylcarbodiimide,

as well as carbonyldiimidazole. Esters can also be produced by reacting a salt of the acid, possibly produced in situ, 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. Furthermore, acid halides, such as chlorides (prepared e.g. by treatment with oxalyl chloride), activated esters, (formed e.g. with N-hydroxy-nitrogen compounds, such as N-hydroxy-succinimide) or mixed anhydrides (obtained e.g. with haloformic acid lower alkyl esters, such as chloroformic ethyl 1- or chloroformic isobutyl ester, or with haloacetic acid halides,

as trichloroacetic acid chloride) by reaction with alcohols,

optionally in the presence of a base, such as pyridine, is transferred in an esterified carboxyl group.

In a compound of formula I with an esterified carboxyl group

can this be transferred in another esterified carboxyl group,

e.g. 2-chloroethoxycarbonyl or 2-bromomethoxycarbonyl by treatment with an iodine salt, e.g. sodium iodide, to 2-iodoethoxycarbonyl. Furthermore, the carboxyl protecting group can be removed as described above in compounds of formula I, which contain a protected carboxyl group in esterified form,

and an obtained compound of formula I, with a free carboxyl group or a salt thereof is transferred by reaction with the reactive ester of a corresponding alcohol to a compound of formula I, where R-. is an esterified carboxyl group that is cleavable under physiological conditions.

In compounds of formula I, a residue R^ can also be transferred i

another residue R^.

Thus, for example, in compounds of formula I, where the heterocyclyl residue R is substituted with a carboxyl group, this carboxyl group can be transferred by means of methods known per se into a functional converted carboxyl group, such as in an esterified carboxyl group or in optionally substituted carbamoyl. For example, by reacting a compound of formula I, where R^ is heterocyclyl substituted with carboxyl, with an alcohol, especially a lower alkanol, a compound of formula I, where R^ is heterocyclyl substituted with esterified carboxyl, especially lower alkoxycarbonyl, is obtained , whereby work is preferably done in the presence of a suitable condensation agent, e.g. a carbodiimide or the remaining water is removed by azeotropic distillation. On the other hand, carboxyl groups on the residues R2 can also be transferred

in reactive functional derivatives, such as mixed anhydrides, e.g. acid halides, or activated esters, and convert these by reaction with an alcohol, e.g. lower alkanol, ammonia - or a primary or secondary amine, e.g. a lower alkyl or

dilave alkylamine, in correspondingly esterified or amidated carboxyl groups, whereby when using mixed anhydrides it is preferably worked in the presence of an acid binding agent, such as an aromatic or tertiary amine or an alkali metal or alkaline earth metal carbonate.

If a heteroaryl residue R exhibits a hydroxy group, then

4

lets this take place in the usual way. The reaction to the corresponding lower alkyl heteroaryl ethers takes place, for example, in the presence of bases, such as alkali metal hydroxides or carbonates, e.g. sodium hydroxide or potassium carbonate, with the help of the lower alkyl sulfates or lower alkyl halides, or with diazolaveralkanes, or, in the presence of a dehydrating agent, for example dicyclohexylcarbodiimide, with the help 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 alkane carboxylic acid, e.g. acetic acid, as an anhydride thereof, e.g. the symmetrical anhydrides 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 takes place, for example, by alcoholysis or, preferably, hydrolysis, e.g. by base-catalyzed hydrolysis, e.g. in the presence of sodium hydroxide.

In connection with formula I, where R 1 means heterocyclyl which is substituted with amino, the amino group can be transferred in a substituted amino group, such as a lower alkylamino, dilower alkylamino, lower alkyleneamino or lower alkanoylamino group. The transfer in a lower alkylamino or dilower alkylamino group takes place, for example, by reaction with a reactive esterified lower alkanol, for example a lower alkyl halogenyl 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. In an analogous manner, amino treatment with a lower alkylene dihalide or -disulfonate

is transformed into lower alkylene amino and by treatment with the reactive functional derivative of a lower alkane carboxylic acid, e.g. the corresponding carboxylic acid halide, is transformed into lower alkanoylamino.

Salts of compounds of formula I with salt-forming groups can be prepared in a manner known per se. Thus, salts of compounds of formula I with a free carboxyl

group is produced e.g. by treatment with metal compounds, such as alkali metal salts of suitable organic carboxylic acids,

e.g. sodium salts of α-ethylcaproic acid, or with inorganic alkali or alkaline earth metal salts, e.g. sodium hydrogen carbonate, or with ammonia or with a suitable organic amine, whereby stoichiometric amounts or only a small excess of the salt-forming agent are preferably used. Acid addition salts of compounds of formula I are obtained in the usual way, e.g. by treatment with a suitable acid or a suitable anion exchange reagent. Inner salts of compounds of formula I can e.g. is formed by neutralization of salts, such as acid addition salts, at the iso-electric point, e.g. with weak bases, or when treated with ion exchangers.

Salts can normally be transferred in the free compounds, metal and ammonium salts, e.g. by treatment with suitable acids and acid addition salts, e.g. by treatment with a suitable basic agent.

Obtained mixtures of isomers can be divided in a manner known per se into the individual isomers, mixtures of diastereomeric isomers, e.g. by fractional crystallization, adsorption chromatography (column or thin layer chromatography) or other suitable separation methods.

The splitting of obtained racemates into their optical antipodes can take place in different ways.

One of these methods consists in trading in a race food

an optically active excipient, the thereby obtained mixture of

two diastereomeric compounds are separated using suitable physico-chemical methods and the individual diastereomeric compounds are then split into the optically active compounds.

Racemates that are particularly suitable for division into antipodes are those that have an acidic group, such as e.g. racemates of compounds of formula I, where R^ is carboxy. These acidic racemics can be reacted with optically active bases, e.g. esters of optically active amino acids, or (-)-brucine, (+)-quinidine,

(-)-quinine, (+)-cinchonine, (+)-dehydroabiethylamine, (+)- and (-)-ephedrine, (+)- and (-)-1-phenyl-ethylamine or their N-mono-

or N,N-dialkylated derivatives to mixtures consisting of two diastereomeric salts.

In racemates containing a carboxyl group, this carboxyl group can also be or be esterified with an optically active alcohol, which is written off, after which the carboxyl group is released after isolation of the desired diastereomers.

For racemate separation, the hydroxy group can also be esterified with optically active acids or their reactive, functional derivatives, whereby diastereomeric esters are formed. Such acids are, for example (-)-abietic acid, D(+)- and L(1)-malic acid, N-acylated optically active amino acid, ( + )- and (-)-camphoric acid, ( + )- and

(-)-ketopoic acid, L(+)-ascorbic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid (8) , ( + )- or (-)-α-bromocamphor-ir-sulf onic acid, D(-)-quinic acid, D(-)-isoascorbic acid, D(-)- and L(+)-mandelic acid, (+)-1-menoxyacetic acid, D(-)- and L(+)-tartaric acid and their dio-O-benzoyl and di-O-p-touyl derivs. By reaction with optically active isocyanates, such as with (+)- or (-)-1-phenylethyl isocyanate, compounds of formula (I), where R 1 denotes protected carboxy and R 2 hydroxy, can be transformed into a mixture of diastereomeric urethanes.

Basic breed foods, e.g. compounds of formula I, where the residue R 1 is substituted with amino, can form diastereomeric salts with the aforementioned optically active acids.

The cleavage of the separated diastereomers in the optically active compounds of formula I likewise takes place by means of usual methods. The acids or bases are freed from the salts, e.g. by treatment 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 dividing the race foods consists in 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 most soluble optical antipode crystallized out.

A fourth method uses the difference in reactivity

in the optical antipodes to biological material such as micro-organisms or isolated enzymes.

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

The separation of diastereomers in the individual racemates and the racemates in the optical antipodes can be carried out in a freely chosen method step, i.e. e.g. also on the starting compound step for formulas II to IV or on a freely chosen step in the later described method for preparing the starting materials of formula II or IV.

In all subsequent transformations of obtained compounds of formula I, such reactions are preferred, which take place under neutral, alkaline or slightly acidic conditions.

The method also includes such embodiments, according to which compounds that precipitate as intermediates are used as starting materials and the remaining method steps are carried out with these, or the method is interrupted at any step. Furthermore, starting substances can be used in the form of derivatives or formed in situ, possibly under the reaction conditions. For example, a starting material of formula II, where Z is oxygen, can be prepared in situ from a compound of formula II, where Z is a, as described later, possibly substituted methylidene group, by ozonization and subsequent reduction of the formed ozonide, analogously to the method stated further below (step 3.3), after which the ring closure to the compound of formula I takes place in the reaction solution.

The starting compounds with the formulas II, IV and V and the advantages can be prepared as indicated in the reaction schemes I, II and III:

In the compounds of formulas V, VII, VIII and II<1>, Z<1>

oxygen, sulfur or also a methylidene group which is substituted with one or two substituents Y, which by oxidation can generally be transferred into an oxo group. A substituent Y in this methylidene group is an organic residue, for example optionally substituted lower alkyl, e.g. methyl or ethyl, cycloalkyl, e.g. cyclopentyl or cyclohexyl, phenyl or phenyl lower alkyl, e.g. benzyl, or especially one, including with an optically active alcohol, such as 1-menthol, esterified carboxyl group, e.g. one of the optionally substituted lower alkoxycarbonyl or arylmethoxycarbonyl radicals mentioned under R. or also 1-menthyloxycarbonyl. The methylidene group Z' preferably carries one of the aforementioned substituents. Emphasis should be placed on the methoxycarbonylmethylidene, ethoxycarbonylmethylidene and 1-methyloxycarbonylmethylidene groups Z'. The latter can be used for the preparation of optically active compounds with the formulas V, VII, VIII and II•.

In the compounds with the formulas V', VII, VIII and II', R, either stands for the residue R^ or for a reactive esterified hydroxy group Q.

In the compounds of the formulas V<*> to IX and II<1>, the radical R2 is preferably one of the aforementioned protected hydroxy groups, e.g. optionally substituted 1-phenyllower oxy, optionally substituted phenyllower oxycarbonyloxy, or trisubstituted silyloxy.

Step 1. 1. : A thio-azetidinone of formula V is obtained by treating a 4-W-azetidinone of formula VI, where W is a nucleofugic leaving group, with a mercapto compound of the formula:

or a salt, e.g. an alkali metal, such as sodium or potassium salt thereof, and if desired, an obtained compound of formula V<1>, where R2 is hydroxy, hydroxy in protected hydroxy, is transferred. The nucleofuge leaving group W in a starting material of formula VI is a residue that can be replaced by the nucleophilic residue

Such groups W are, for example, acyloxy acid residues, sulfonyl residues RQ-SO2-, where Rq is an organic residue, azido or halogen,

In an acyloxy acid residue W, acyl is e.g. the residue of an organic carboxylic acid, including an optically active carboxylic acid, and means, for example, lower alkanoyl, e.g. acetyl or propionyl, optionally substituted benzoyl, e.g. benzoyl or 2,4-dinitrobenzoyl, phenyl laveralkanoyl, e.g. phenylacetyl, or the acetyl residue of one of the optically active acids mentioned above. A sulfonyl residue Rq-SO2- is RQ, for example optionally with hydroxy substituted lower alkyl, such as methyl, ethyl or 2-hydroxyethyl, further also correspondingly substituted optically active lower alkyl, e.g. (2R)- or (2S)-1-hydroxyprop-2- yl, with methyl substituted with an optically active residue, such as camphoryl, or benzyl, or optionally substituted phenyl, such as phenyl, 4-bromo-phenyl or 4-methylphenyl. A halogen residue W is e.g. bromine, iodine or especially 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 an organic solvent which is miscible with water. The basic conditions can, for example, be set with the addition of 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 hydrogen carbonate. As organic solvents, e.g. water-miscible alcohols are used, e.g. lower alkanols, such as methanol or ethanol, ketones, e.g. lower alkanones, such as acetone, amides, e.g. lower alkanecarboxylic acid amides, such as dimethylformamide, acetonitrile and the like. The reaction is usually carried out at room temperature, but can also be carried out at an elevated or lowered temperature. By adding a salt of hydroiodic acid or thiocyanic acid, e.g. an alkali metal, such as sodium salts, the reaction can be accelerated.

In the reaction, both optically inactive cis-

or trans compounds of formula VI, as well as mixtures thereof, or corresponding optically active compounds. The incoming group R5~(CH2) -C(= Z' ) -S- is preferably directed in the trans position by the group (R^, R2)CH-, regardless of whether W

is in the cis- or trans-position to the group (R 1 , R 2 )CH-. Although the trans isomers are predominantly formed, the cis isomers can also occasionally be isolated. The separation of the cis- and trans-isomers takes place as described above, using conventional methods, in particular with chromatography and/or by crystallization.

The subsequent ozonization of a methylidene group Z' can be carried out as indicated further below. An obtained racemeat of formula V' can be divided into the optically active compounds.

An azetidinone of formula VI, where R2 and W mean acetoxy and R^ means hydrogen, is described in DE Off.skrift no. 29 50 898.

Other azetidinones of formula VI can be prepared by means of

methods known per se, for example when a vinyl ester with the formula (R1,R2)CH-CH=CH-W is reacted with chlorosulfonyl isocyanate and the resulting cycloadduct is reacted with a reducing agent, e.g. sodium sulfite. By means of this synthesis, mixtures of cis- and trans-isomers are usually obtained, which, if desired, can be fulfilled in the pure cis- or trans-isomers, e.g. by chromatography and/or crystallization or distillation. The pure cis- and trans-isomers exist as racemates and can be divided into their optical antipodes, for example when acyl in an acyloxy acid residue W in compounds of formula VI originates from an optically active acid. The compounds of formula VI, especially their optically active representatives, can also be prepared by the method indicated below in reaction schemes II and

III.

Step 1. 2: A cc-hydroxycarboxylic acid compound of the formula

VII is obtained by reacting a compound of formula V with a glyoxylic acid compound of formula OHC-R^' or a suitable derivative thereof, such as a hydrate, hemihydrate or hembacetal,

e.g. a hemiacetal with a lower alkanol, e.g. methanol or ethanol, and if desired, transfer hydroxy in an obtainable compound of formula VII where R 2 is hydroxy to protected hydroxy.

The compound VII is usually obtained as a mixture of both isomers (with regard to the grouping ^CH '■^OH). The pure isomers thereof can also be isolated.

The attachment of the glyoxylic acid ester compound to the nitrogen atom

in the lactam ring takes place at room temperature or, if necessary, during heating, e.g. to approx. 100°C, and that in the absence of an actual condensation agent and/or without the formation of a salt. When using the hydrate of the glyoxylic acid compound, water is formed, which if necessary is removed by distillation, e.g. azeotropically or using a suitable dehydrating agent, such as a molecular sieve. Preferably work is done in the presence of a suitable solvent, such as e.g. dioxane, toluene or dimethylformamide, or solvent mixture, if desired or necessary in an inert gas atmosphere, such as nitrogen.

Pure optically inactive cis- or trans-compounds of formula V, as well as mixtures thereof, or corresponding optically active compounds can be used in the reaction. An obtained raceme of formula VII can be divided into the optically active compounds.

Step 1. 3: Compounds of formula VIII, where Xq stands for a reactive esterified hydroxy group, especially for halogen or organic sulfonyloxy, are prepared by converting the secondary hydroxy group in a compound of formula VII to a reactive esterified hydroxy group, especially for halogen, f .ex. chlorine or bromine, or to an organic sulfonyloxy group, such as lower alkanesulfonyloxy, e.g. methanesulfonyloxy, or arenesulfonyloxy, e.g. benzene- or 4-methylbenzenesulfonyloxy.

In the starting compounds of formula VII, R preferably stands

for a protected hydroxy group.<2>

The compounds of formula VIII can be obtained in the form of mixtures of the isomers (with regard to the grouping —-CHrv^x^ or in the form of pure isomers.

The above reaction is carried out by treatment with a

suitable esterification agent, e.g. with a thionyl halide, e.g.

-chloride, a phosphoroxyhalide, especially -chloride, a halogen-phosphonium halide, such as triphenylphosphonium 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 tertiary amine, e.g. triethylamine, diisopropylethylamine or "polystyrene hydrogen base", or a heterocyclic base of the pyridine type, e.g. pyridine or collidine. Preferably work is done in the presence of a suitable solvent, e.g. dioxane or tetrahydrofuran, or a solvent mixture, if necessary under cooling and/or in an inert gas atmosphere, such as nitrogen.

In such an obtainable compound of formula VIII, a reactive esterified hydroxy group XQ can be transformed in a manner known per se into another reactive esterified hydroxy group. Thus, when treating the corresponding chlorine 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, a chlorine atom can be replaced with a bromine or iodine atom.

In the reaction, both pure optically inactive cis- or trans-compounds of formula VII as well as mixtures thereof, or corresponding optically active compounds can be used. An obtained raceme of formula VIII can be divided into the optically active compounds.

f

Step 1. 4: The starting material of formula II' is obtained by treating a compound of formula VIII, where XQ stands for a reactive esterified hydroxy group, with a suitable phosphine compound, such as a lower alkylphosphine, e.g. tri-n-butyl phosphine, or a triaryl phosphine, e.g. triphenylphosphine, or with a suitable phosphite compound, such as a tri-lower alkyl phosphite, e.g. triethyl phosphite, or an alkali metal dilave alkyl phosphite, e.g. diethyl phosphite, by which, depending on the choice of reagents, a compound of formula II (respectively II<1>) or IIa can be obtained.

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 a solvent mixture. Depending on the reactivity, work is done during cooling or at an elevated temperature, between approx. -10° and +100°C, preferably at approx. 20° to 80°C, and/or in an inert gas atmosphere, such as nitrogen. To prevent oxidation processes, catalytic amounts of an antioxidant can be added, e.g. hydroquinone.

Thereby, work is usually carried out using a phosphine compound in the presence of a basic agent, such as an organic base, e.g. an amine, such as triethylamine, diisopropylethylamine or "polystyrene-Hunigbase", and then comes directly to the ylide starting material of formula II (respectively II'), which is formed from the corresponding phosphonium salt.

In the reaction, both pure, optically inactive cis- or trans-compounds of the formula VIII, as well as mixtures thereof, or corresponding optically active compounds can be used. An up-

reached racemate with the formula II<1> can be divided into the optically active compounds.

Step 1. 4a: A starting compound of formula II', where Z' stands for oxo, can further be obtained, when a mercaptide of formula IX,

where M stands for a metal cation, is treated with an acylation

agent which introduces the residue RC-(CH0) -C(=0)-.

b2. m

In the starting material with formula IX, the metal cation M is, for example, a cation of the formula M or M 12, whereby M in particular stands for a silver cation and M<+>in particular stands for the divalent cation of a suitable transition metal, e.g. copper, lead or mercury.

An acylating agent which introduces the residue R,-- (CH 2 ) m-C ( =0) - is e.g. acid R^-(CH2)m-COOH or a reactive functional derivative thereof, such as an acid halide, e.g. chloride or bromide, azide or anhydride thereof.

The acylation takes place when the free acid with the formula R^-(CH2)m~C00H is used, e.g. in the presence of a suitable water-extracting agent,

as a carbodiimide, e.g. N,N'-dicyclohexylcarbodiimide, or when an acid derivative is used, in the presence of a suitable acid binding agent such as a tertiary aliphatic or aromatic base, e.g. diethylamine, pyridine or quinoline, in an inert solvent, such as a chlorinated hydrocarbon, e.g. methylene chloride, or an ether, e.g. diethyl ether or dioxane, at room temperature or during heating or cooling, e.g. in a temperature range from approx.

-50° to approx. +60°C, especially at approx. -30°C to approx. +20°C. The starting compounds with formula IX can, for example, be prepared by an azetidinone with the formula

by reaction with an alkali metal salt, e.g. the sodium salt, of a thiolower alkanecarboxylic acid, e.g. thioacetic acid, or then triphenylmethyl mercaptan is transferred to a compound of formula

wherein W means triphenylmethylthio or lower alkanoylthio, e.g. acetylthio, this compound is transferred analogously to the methods described in reaction steps 1.2, 1.3 and 1.4, to a compound with the formula

and this in the presence of a base, e.g. pyridine or tri-n-butylamine, in a suitable solvent, e.g. diethyl ether or methanol, is reacted with a salt of the formula MA where M has it

above meaning, but especially stands for a silver cation,

and A is a common anion, which favors the solubility of the salt. MA in the chosen solvent, e.g. the nitrate, acetate or fluoride anion.

Compounds of the formula (II')/where P*5 stands for a reactive esterified hydroxy group can be converted to compounds of the formula (II') by reaction with an agent which introduces the azaheterocyclyl residue R^, where R^ stands for the residue R^ , whereby, for example, the reaction conditions specified in the method

c) is used.

The ylides of formula II<1>, where Z<1> is oxygen or sulfur, can

used directly in the ring closure reaction to produce the final product with formula I. In connection with formula II',

where R 2 is a protected hydroxy group, e.g. easily cleavable protected hydroxy group, such as trisubstituted silyloxy, however, the hydroxy protecting group can first be cleaved off and the obtained compound of formula II', where R2 is hydroxy, used in the ring closure reaction.

In the compounds II', V, VII and VIII, an optionally substituted methylidene group Z' can be largely transferred to the oxo group by ozonization and subsequent reduction of the formed ozonide, according to the method described later in step 3.3.

Step 1. 5:

The starting compound of formula (IV) is obtained by ring-closing a ylide of formula (II'), where Z<1> means oxygen or sulphur, and R,- stands for a reactive esterified hydroxy group Q.

The cyclization can, for example, be carried out as described (method a) in the preparation of compounds of formula (I) from the ylides of formula (II).

Starting compounds of formula VI, where W is a sulfonyl residue HO-A-SO2-, can also be prepared according to the following reaction core

II.

In the compounds with the formulas (Xa) to (Xc) and (Via) A represents a lower alkylene residue with 2 to 3 carbon atoms between the two heteroatoms and is primarily ethylene or 1,2-propylene, but can also be 1,3-propylene , 1,2-, 2,3- or 1,3-butylene.

In the compounds with the formulas (Xa) to (Xc), each of the residues R a and R, o stands for hydrogen or for an organic residue which is connected to the ring carbon atom via a carbon atom, whereby both residues R^ and R to can be linked to each other, i first row for hydrogen, lower alkyl, e.g. methyl, ethyl, n-propyl or isopropyl, optionally substituted phenyl, or phenyl lower alkyl, e.g. methyl, ethyl, n-propyl or isopropyl, optionally substituted phenyl, or phenyl lower alkyl, e.g. benzyl, or when taken together, the lower alkyl preferably of 4 to 6 carbon atoms, e.g. 1,4-butylene or 1,5-pentylene.

In the compounds of formulas (Xb), (Xc) and (Via), the residue R2 is hydroxy or preferably one of the aforementioned protected hydroxy groups, e.g. optionally substituted 1-phenyl lower alkyloxy, optionally substituted phenyl lower alkylcarbonyloxy or trisubstituted silyloxy.

Step, 2. 1:

A compound of the formula (Xb) is obtained by reacting a bicyclic compound of the formula (Xa) with a metallization reagent and an electrophile which introduces the residue (R.j,R2)CH- and then treating the obtained product with a proton source.

Suitable metallation reagents are e.g. substituted and unsubstituted alkali metal amides, alkali metal hydrides or alkali metal averealkyl compounds, where the alkali metal e.g. is sodium or especially lithium, e.g. sodium or lithium amide, lithium bis-trimethylsilylamide, sodium hydride, lithium hydride and preferably lithium diisopropylamide and butyllithium.

Electrophiles that introduce the residue (R.j,R2)CH- are, for example, compounds with the formula R.j-CH = 0 or functional derivatives thereof with the formula (R^ ,R,>) CH-X, where X is a nucleofugous leaving group, especially halogen, f .ex. chlorine, bromine or iodine, or sulphonyloxy, e.g. methanesulfonyloxy or 4-toluenesulfonyloxy. Preferred electrophiles introducing the residue (R-jR-^CH-

is formaldehyde, optionally substituted benzyloxymethyl chloride and acetaldehyde.

Solvents which are suitable for the metallation reaction must not contain active hydrogen and are e.g. hydrocarbons, e.g. hexane, benzene, toluene or or xylene, ethers, e.g. diethyl ether, tetrahydrofuran or dioxane, or acid amides, e.g. hexamethylphosphoric acid triamide.

The metallated intermediate does not need to be isolated, but can

in connection with the metallation reaction is reacted with the electrophile which introduces the residue (R ,R2)CH-. The metallation reaction takes place at temperatures from approx. -100° to approx. room temperature, preferably below -30QC, preferably in an inert gas, such as nitrogen atmosphere. Further trading can take place under the same conditions. Thereby, the formaldehyde is preferably introduced in gaseous monomeric form into the reaction mixture. Monomeric formaldehyde can, for example, be obtained by thermal depolymerisation of paraformaldehyde or by thermal decomposition of formaldehyde-cyclohexyl hemiacetal.

For the metallation reaction, both the antipodes of the compounds of the formula (Xa) as well as their racemic or diastereomeric mixtures can be used.

Attacked by the electrophile which introduces the residue (R^,R2)CH-,

on the substrate, generally takes place stereospecifically. If an azetidinone with the formula (Xa) is used as starting material

with R configuration with carbon atom 4 in azetidinone rings,

predominantly a compound with the formula (Xb) occurs with R-configuration at carbon atom 4 and S-configuration at carbon atom 3 in the azetidinone ring, i.e. the attack by the electrophile takes place predominantly trans-standing.

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-releasing compound, preferably still at lower temperatures.

In an obtained compound of formula (Xb), where R2hydrogen,

the hydroxy group can be protected in a manner known per se,

e.g. by etherification or esterification, especially as described above.

The production of optically active and optically inactive starting compounds with the formula (Xa) is described, for example, in the European application no. 23887.

Step 2. 2:

A sulfone with the formula (Xc) can be prepared by treating the thio compound with the formula (Xb) with an oxidizing agent and, if desired, transferring a compound obtained according to the method with the formula (Xc), where R2 is hydroxy, to a compound with the formula (Xc ), where R2 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. nitric acid, chromic acid, potassium permanganate, or alkali metal hypochlorites, e.g. sodium hypochlorite. However, the transfer can also take place by anodic oxidation.

The oxidation is preferably carried out in a suitable inert solvent, for example a halogen hydrocarbon, 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. aqueous acetic acid, at room temperature, or during cooling or slight heating, i.e. at approx. -20° to approx. +90°C, preferably at approximately room temperature. The oxidation can also be carried out in stages, as it is first oxidized at a lower temperature, i.e. at approx. -20°C to approx. 0°C, to sulfoxide, which is possibly isolated, whereupon in a second step, preferably at a higher temperature, approx. at room temperature, the sulfoxide is oxidized to the sulfone of the formula (Xc).

Any surplus still present can be used for processing

of oxidizing agent is destroyed by reduction, especially by treatment with a reducing agent, such as a triosulphate, e.g. sodium thiosulfate.

In the reaction, both optically inactive compounds with the formula (Xb) and corresponding optically active compounds can be used, especially those with a 3S,4R configuration in the azetidinone ring.

Step 2. 3:

Compounds of the formula (Via) can be prepared by solvolyzing a bicyclic amide of the formula (Xc) with a suitable solvolysis reagent, and if desired, a free hydroxy group R2 in a compound of the formula (Via) obtained according to the method is transformed into a protected hydroxy group R2•

Suitable solvolysis reagents are, for example, organic acids, e.g. lower alkane carboxylic acid, such as formic or acetic acid, or sulphonic acid, e.g. 4-toluenesulfonic acid or methanesulfonic acid, mineral acids, e.g. sulfuric or hydrochloric acid, further lower alkanols, e.g. methanol or ethanol, or lower alkanediols, e.g. ethylene glycol.

The mentioned solvolysis reagents are added undiluted or diluted with water. The solvolysis can also be carried out with clean water. The solvolysis with the acidic reagent preferably takes place in

aqueous solution of this reagent and temperatures from approx. -20°

to approx. 150°C, preferably at room temperature to 110°C.

In the reaction, both optically inactive compounds with the formula (Xc) can be used, e.g. racemates or diastereomer mixtures, as also corresponding optically active compounds, especially those with 3S,4R configuration in the azetidinone ring.

Obtained isomeric mixtures of compounds with the formulas (Xb),

(Xc) and (Via), as racemates or diastereomer mixtures, can be separated in a manner known per se, e.g. as described above in the individual isomers, as antipodes.

Useful optically active trans compounds of formula (VI) can also be prepared according to the following reaction nucleus III:

In the compounds with the formulas (XI) to (XIV) and (VIc) is R2

for hydroxy or especially for a protected hydroxy group.

Step 3. 1;

Compounds of formula (XII) are known or can be prepared in a manner known per se. They can also be produced according to a new method, in which a compound of formula (XI) is epimerized and, if desired, a protected hydroxy group R2 in a compound of formula (XII), which is obtained according to the method, is transferred to another protected hydroxy group<R>2.

The epimerization takes place, for example, in the presence of a basic agent, such as an amine, e.g. a lower alkylamine, e.g. triethylamine or ethyldiisopropylamine, a tertiary amine, e.g. N,N-dimethylaniline, an aromatic amine, e.g. pyridine, or a bicyclic amine, e.g. 1,5-diazabicyclo(5,4,0)undec-5-ene or 1,5-diazabicyclo(4,3,0)non-5-ene, or an alkali metal lower-alkanolate, e.g. sodium methanolate, sodium ethanolate or potassium tert.-butanolate, in an inert solvent, for example an ether, e.g. diethyl ether, dimethoxyethane, tetrahydrofuran or dioxane, acetonitrile or dimethylformamide, possibly at a somewhat elevated or lowered temperature, e.g. at 0° to 50°C, preferably at room temperature.

In the compounds of formula (XII) obtained in the process, a protected hydroxy group R2 can be replaced by another protected hydroxy group R2, for example a hydrogenolytically cleavable protected hydroxy group with a solvolytically cleavable protected hydroxy group. Hydroxy protecting groups are in particular the above-mentioned, hydrogenolytically cleavable protecting groups, for example as indicated substituted 1-phenyl lower alkyl or phenyl lower oxycarbonyl, solvolytically cleavable protecting groups for example as indicated trisubstituted silyl.

The reaction can be carried out so that the hydrogenolytically cleavable hydroxy protecting group is first removed, and a solvolytically cleavable hydroxy protecting group is introduced into the obtained compound of formula XII, where R 2 is hydroxy.

The cleavage of the hydrogenolytically cleavable protecting group takes place e.g. with hydrogen or a hydrogen donor, e.g. cyclohexene or cyclohexadiene, in the presence of a hydrogenation catalyst, such as a palladium catalyst, e.g. palladium on charcoal, in an inert solvent, such as a halogenated hydrocarbon, e.g. methylene chloride, a lower alkanol, e.g. methanol or ethanol, an ether, e.g. dioxane or tetrahydrofuran, or also in water or in mixtures thereof, at a temperature from approx. 0° to approx. 80°C, preferably at room temperature. The separation can also be carried out with a reducing metal, such as zinc, or a reducing metal alloy, e.g. copper-zinc alloy, in the presence of a proton-releasing agent, such as an organic acid, e.g. acetic acid, or also a lower alkanol, e.g. ethanol.

The introduction of the solvolytically cleavable hydroxy protecting group takes place, for example, with a compound with R2'-X^, where R2<1> denotes the hydroxy protecting group and X^ e.g. a reactive esterified hydroxy group, for example halogen, e.g. chlorine, bromine or iodine, or sulfonyloxy, such as methanesulfonyloxy, benzenesulfonyloxy or 4-toluenesulfonyloxy.

The reaction takes place in an inert solvent, such as an ether, e.g. diethyl ether, dioxane or tetrahydrofuran, a hydrocarbon, e.g. benzene or toluene, a halohydrocarbon, e.g. methylene chloride, in dimethyl sulfoxide or acetonitrile,

in the presence of a basic condensing agent, such as an alkali metal hydroxide or carbonate, e.g. sodium or potassium hydroxide or sodium or potassium carbonate, an alkali metal amide or hydride, e.g. sodium amide or sodium hydride,

an alkali metal lower alkanolate, e.g. sodium methanolate or -ethanolate or potassium tert-butanolate, or an amine, e.g. triethylamine, pyridine or imidazole, at room temperature at elevated or lowered temperature, e.g. at approx. -20° to approx.

80°C, preferably at room temperature.

The starting compounds with the formula (XI) are known, for example, from DE off. document 3 039 504 and GB patent application 20 61 930.

Step 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 esterification agent which introduces the residue RQ.

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

A residue RQ is, for example, one of the organic residues mentioned under step 1.1, especially optionally substituted lower alkyl, e.g. methyl, ethyl or 2-hydroxyethyl, or benzyl.

An esterifying agent which introduces the residue RQ is e.g. a compound of the formula RQ-X 4 , where X 4 means reactive esterified hydroxy, e.g. halogen, such as chlorine, bromine or iodine, or sulfonyloxy, such as methanesulfonyloxy, benzenesulfonyloxy or 4-toluenesulfonyloxy. Ethylene oxide is also suitable for introducing a 2-hydroxyethyl residue.

The reaction is preferably carried out in two steps, whereby in the first step the penam compound of the formula (XII) is treated with at least equimolecular amounts of the basic agent, and the obtained intermediate with the formula where B © is the pronounced form (cation) of the basic agent , is preferably reacted without isolation from the reaction product with the esterification agent. The reaction is carried out in an inert solvent, for example an ether, e.g. diethyl ether, dimethoxyethane, tetrahydrofuran or dioxane, in acetonitrile, dimethylformamide or hexamethylphosphoric acid triamide, possibly at a somewhat elevated or lowered temperature, e.g. at approx. 0°C to 50°C, preferably at room temperature. In a preferred embodiment of the method, the penam compound of the formula (XII) is prepared in situ, whereby a compound of the formula (XI) as described under step 3.1, is first treated with catalytic amounts of the basic agent, e.g. 1,5-diazabicyclo(5,4,0)undec-5-ene, and then reacted with at least equimolar amounts of the same basic agent and the esterifying agent further to the compounds of the formula (XIII).

Step 3. 3:

An oxalyl-azetidinone of the formula (XIV) can be prepared by

a compound of the formula (XIII) is ozonized and the ozonide formed is reductively cleaved to the oxo compound.

Ozonation 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 alkanol, e.g. acetone, an optionally halogenated hydrocarbon, e.g. a halolower alkane, such as methylene chloride or carbon tetrachloride, or in a solvent mixture, including an aqueous mixture, preferably under cooling, e.g. at temperatures from approx. -80° to approx. 0°C.

An ozonide obtained as an intermediate is usually cleaved

without being isolated, reductively to a compound of the formula XIV, whereby catalytically activated hydrogen is used, e.g. hydrogen in the presence of a heavy metal hydrogenation catalyst, such as a nickel and further palladium catalyst, preferably on a suitable support material, such as calcium carbonate or carbon, or chemical reducing agents, such as reducing heavy 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 alkanol, reducing inorganic salts, such as alkali metal iodides, e.g. sodium iodide, or alkali metal hydrogen sulphites, e.g. sodium hydrogen sulphite, 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. As reducing agents, compounds can also be used which can easily be transformed into corresponding epoxide compounds or oxides, whereby the epoxide formation can take place due to a C,C double bond and the oxide formation can take place due to a present oxide formation hetero-, such as sulphur- , phosphorus or nitrogen atom. Such compounds are e.g. suitable substituted ethylene compounds (which in the reaction are transformed into ethylene oxide compounds), such as tetracyanethylene, or particularly suitable sulphide compounds (which in the reaction are transformed into sulphoxide compounds), such as the lower alkyl sulphides, primarily dimethyl sulphide, suitable organic phosphorus compounds, such as a phosphine which is optionally substituted with phenyl and/or lower alkyl, e.g. methyl, ethyl, n-propyl or n-butyl,

(which in the reaction is transformed into a phosphine oxide), such as lower alkyl phosphines, e.g. tri-n-butylphosphine, or triphenylphosphine, further trilower alkyl phosphites (which in the reaction are transformed into phosphoric acid trilower alkyl esters), usually in the form of corresponding alcohol adduct compounds, such as trimethyl phosphite, or phosphoric acid triamides, which likewise contain lower alkyl as substituents, such as hexalower alkyl phosphoric acid triamide, e.g. . hexamethylphosphoric acid triamide, the latter preferably being in the form of a methanol adduct, further suitable nitrogen bases (which in the reaction are transformed into the corresponding N-oxides), such as heterocyclic nitrogen bases of an aromatic character, e.g. bases of the pyridine type and especially pyridine itself. The cleavage of the usually unisolated ozonide normally takes place under the conditions used for its preparation, i.e. in the presence of a suitable solvent or solvent mixture, as well as under cooling or slight heating, whereby temperatures of

about. -10° to approx. +25°C and the reaction usually ends at room temperature.

Step 3. 4:

An azetidinone with the formula (VIb) can be prepared by solvolyzing an oxalyl-azetidinone with the formula (XIV).

The solvolysis can be carried out as hydrolysis, as alcoholysis

or also as hydrazinolysis. The hydrolysis is carried out with water, possibly in a solvent that is miscible with water. The alcoholysis is usually carried out with a lower alkanol, e.g. methanol or ethanol, preferably in the presence of water and an organic solvent, such as a lower alkane carboxylic acid lower alkyl ester, e.g. acetic acid ethyl ester, preferably at room temperature,

if necessary during cooling or heating, e.g. at a temperature from approx. 0° to approx. 80°C. The hydrazinolysis is carried out in a conventional manner with a substituted hydrazine. e.g. with phenyl or a nitrophenylhydrazine, such as 2-nitrophenylhydrazine, 4-nitrophenylhydrazine or 2,4-dinitrophenylhydrazine, which is preferably used in approx. equimolar amounts, 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, at temperatures between approx. room temperature and approx. 65°C.

In a preferred embodiment of the method, one starts with a compound of the formula (XIII), which, as indicated, is ozonized and then cleaved reductively to oxalyl-azetidinone, with the formula (XIV) which, without isolation from the reaction mixture, is further converted to azetidinone of the formula (VIb).

During the ozonolysis, small amounts of acid may occur which can cause the cleavage of a solvolytically easily cleavable residue R2, e.g. a trisubstituted silyl residue. The thereby obtained compound of formula one can, for example chromatographically, be separated from protected azetidinone (VIb) and by renewed reaction with the agent of formula R2'-X^ which introduces the hydroxy protecting group R2', be transferred to azetidinone of formula (VIb).

In the compounds of the formulas (II), (II'), (III), (IV), (VII)

to (IX) and (XII) to (XIV), a protected carboxyl group R2' can be transformed into

another protected carboxyl group R3', whereby, taking into account further functional groups that may possibly be contained in these compounds, the same methods are used, which are indicated for the transformation of these substituents in the compounds of formula (I).

The invention likewise relates to new output products as well

as according to the method obtainable new intermediates, such as those of the formulas (II) to (IX), (XIII) and (XIV), as well as the specified methods for their preparation.

Such starting materials are preferably used and the reaction conditions are chosen so that the compounds listed above as particularly preferred are obtained.

The compounds of formula I exhibit valuable pharmacological properties or can be used as intermediates for the preparation of such compounds with valuable pharmacological properties. and R. has the meaning given under formula I and pharmacologically usable salts of such compounds with salt-forming groups have antibacterial effects. For example, they are effective in vitro against Gram-positive and Gram-negative cocci, e.g. Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Streptococcus faecalis, Neisseria mengingitidis,

and Neisseria gonorrhoeae, in minimal concentrations from approx. 0.01 to approx. 16 yg/ml and against Gram-negative rods,

such as Enterobacteriaceae, Haemophilus influenzae and Pseudomonas aeruginosa, and anaerobes, e.g. Bacteroides sp.,

in minimal concentrations from approx. 0.1 to approx. 16 ug/mg.

In vivo, in case of systemic infection in mice, e.g. in the case of Staphylococcus aureaus or Streptococcus pyogenes, ED^^ values of approx. 2 to approx. 100 mg/kg.

For example, exhibits

Sodium (5R,6S)-2-(tetrazol-1-ylmethyl)-6-hydroxylmethyl-2-penem-3-carboxylate (compound 1),

Sodium (5R,6S)-2-(2-(tetrazol-1-yl)-ethyl)-6-hydroxymethyl-2-penem-3-carboxylate (compound 2),

Sodium (5R6S)-2-(4-(tetrazol-1-yl)-butyl)-6-hydroxymethyl-2-penem-3-carboxylate (compound 3),

Sodium (5R6S)-2-(2-(1,2,4-triazol-1-yl)-ethyl)-6-hydroxymethyl-2-penem-3-carboxylate (compound 4),

in

Sodium-(5R,6S)-2-(3-(tetrazol-1-yl)-propyl)-6-hydroxymethyl-2-penem-3-carboxylate (Compound 5)

in the aforementioned in-vitro test the following values:

In vivo. in the case of the systemic infection in mice, the following ED,, ^-values are given:

The compounds produced according to the invention can be used for the treatment of infections as orally or parenterally applicable antibacterial antibiotics, e.g.

in the form of corresponding pharmaceutical preparations.

Compounds with formula I, where at least one of the functional groups present is in a protected form, whereby a protected carboxyl group is different from a physiologically cleavable esterified carboxyl group, can be used as intermediates for the production of the above-mentioned pharmacologically active compounds, with formula I.

The pharmacological compounds produced according to the present invention can, e.g. used for the production of pharmaceutical preparations, which contain an effective amount of the active substance together with, or in a mixture with, inorganic or organic, solid or liquid, pharmaceutically acceptable carriers, which are suitable for oral or parenteral administration,

i.e. intramuscularly, subcutaneously or intraperitoneally.

For oral administration, tablets or gelatin capsules are used,

containing the active substance together with diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, and lubricant, e.g. silica, talc, stearic acid or salts 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 root starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and if desired, explosives, e.g. starches, agar, alginic acids or a salt thereof, such as sodium alginate, and/or fizzy mixes or absorbents, colourings, flavorings or sweeteners.

For parenteral administration, infusion solutions are primarily suitable, preferably isotonic aqueous solutions or suspensions, whereby these can be prepared before use, e.g.

from lyophilized preparations, which contain the active

the substance alone, or together with a carrier material, e.g. mannitor. Such preparations may be sterilized and/or contain excipients, e.g. preservatives, stabilisers, cross-linking and/or emulsifiers, solubility mediators, salts for regulating the osmotic pressure, and/or buffers.

The present pharmaceutical preparations, which if desired may contain further pharmacologically valuable substances, are produced in a manner known per se, e.g. using conventional mixing, dissolving or lyophilization methods, and contains from approx. 0.1% to 100%, especially from approx. 1% to approx. 50%, lyophilisate up to 100% of the active substance.

Depending on the nature of the infection and the condition of the infected organism, daily doses from approx. 0.1 g to approx. 5 g for the treatment of warm-blooded people and animals with approx. 70 kg weight.

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

In the examples, the following abbreviations are used:

Example 1: (3S,4R)-3-(tert.butyl-dimethylsilyloxymethyl)-4-(5-(tetrazol-1-yl)-valeroylthio)-azetidin-2-one).

A solution of 293 mg of (3S,4R)-3-(tert.butyldimethylsilyloxymethyl)-4-methylsulfonyl-azetidin-2-one in 5 ml of abs. THF is added at room temperature with stirring to a mixture of 204.8 mg of 5-(tetrazol-1<1->yl)-thiovaleric acid in 1.1 ml of caustic soda and 5 ml of water. The mixture is then kept at pH 10 by adding 0.1 N caustic soda. After 2 hours of reaction at room temperature, dilute with ethyl acetate and separate the aqueous phase. It is extracted twice with ethyl acetate and the combined extracts are washed with brine. After drying over sodium sulfate and evaporation in high vacuum, the residue is chromatographed on silica gel with toluene and ethyl acetate (1:2) as eluent.

TLC (silica gel): toluene-ethyl acetate (2:3) Rf = 0.17

IR (methylene chloride): 2.94, 5.66, 5.96 ym.

The starting compound 5-(tetrazol-1<1->yl)-thiovaleric acid can be prepared as follows:

1aa) 5-(N-formylamino)-valeric acid- ethyl residues

1.8 g of 5-amino-valeric acid ethyl ester hydrochloride in 40 ml of formic acid ethyl ester is added to 1.4 ml of triethylamine and then heated for two hours at reflux. The precipitate is filtered off, washed with a little formic ethyl ester and evaporated on a rotary evaporator under reduced pressure. The residue is distributed between methylene chloride and sodium bicarbonate solution, the organic phase is then washed with salt water, dried and evaporated. The title compound is obtained, as. oil.

IR (methylene chloride): 5.78, 5.92, 6.64 um.

1 ab) 5-isocyanovaleric acid ethyl ester

8.5 g of 5-(N-formylamino)-valeric acid ethyl ester in 50 ml of methylene chloride is added to 17.15 ml of triethylamine. While cooling in an ice bath, 25 ml of a 20% phosgene solution in toluene is added dropwise and the mixture is further stirred for 1.5 hours at 0°. The reaction mixture is poured onto ice water, the organic phase is separated, dried and evaporated. The title compound obtained is purified by distillation.

Kp (0.3 torr) 70°

IR (methylene chloride): 4.68, 5.83, 7.3, 8.6 ym

1ac) 5-(tetrazol-1-yl)-valeric acid ethyl ester

3.6 g of 5-isocyanovaleric acid ethyl ester is heated in 72 ml of a 0.9 M HN 2 solution in benzene for 24 hours under argon at reflux temperature. After evaporation and purification by chromatography on silica gel, ■ (eluent: toluene/

ethyl acetate: 1/1) the pure title compound is obtained.

IR (methylene chloride): 3.2, 5.85, 7.32 ym.

1 ad) 5-(tetrazol-1-yl)-valeric acid

Dissolve 2.12 g of 5-(tetrazol-1-yl)-valeric acid ethyl ester in 5 ml of methanol and add 4.28 ml of a methanolic NaOH solution (3N). After 2.5 hours of stirring at room temperature, the solvent is distilled off and the residue is taken up in water. After washing with ethyl acetate, the aqueous phase is acidified (pH 3) and extracted twice with ethyl acetate. After drying and evaporation, the pure title compound is obtained.

NMR (DMSO-d6): 612.1 ppm (1H, broad), 9.5 ppm (1H, s), 4^.55 ppm

(2H,t), 2.3 ppm (2H,t), 1.7 ppmi4H,m).

1ae) 5-(tetrazol-1-y1)-valeric acid chloride

1 g of 5-(tetrazol-1-yl)-valeric acid is heated in 12 ml of absolute benzene with 0.6 ml of thionyl chloride and 2 drops of DMF for 20 minutes at reflux temperature. After evaporation and reduced pressure, the title compound is obtained.

IR (methylene chloride): 3.18, 5.62, 6.78 ym.

1af) 5-(tetrazol-1-yl)-thiovaleric acid

Dissolve 5 g of 5-(tetrazol-1-yl)-valeric acid chloride in 4.5 ml of absolute methylene chloride and add dropwise at 0° to 35.5 ml of a solution of pyridine and H2S in methylene chloride (30 ml of pyridine and 6 g of H2S in 100 ml methylene chloride). The mixture is then stirred for one hour at 0°C under a nitrogen atmosphere. The reaction mixture is collected

1 chloroform, the aqueous phase is acidified to pH 2 with

2 N H2SO4 and extracted twice with chloroform. The combined organic phases are washed twice with 25 ml of 10% NaHCO 3 solution. Then adjust to pH 3 with 2 N H2SO4

and the title compound is extracted by repeated extraction with chloroform. After drying over sodium sulfate and evaporation, the title compound is obtained.

IR (methylene chloride): 3.9, 5.9, 8.6, 9.1 ym.

The starting material (3S,4R)-3-(tert.-butyldimethylsilyloxymethyl)-4-methylsulfonyl-azetidin-2-one can be prepared as follows: 1ba) (3S,5R,6R)-2,2-dimethyl-6-( tert .- butyldimethylsilyloxymethyl)- penam- 3- carboxylic acid methyl ester- 1, 1- dioxide

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

DC silica gel, toluene/ethyl acetate (4:1): Rf = 0.56

IR (CH 2 Cl 2 ) 3.4, 5.57, 5.65 um.

1bb) 2-(( 3S, 4R)- 3-( tert.-butyl- dimethylsilyloxymethyl)- 4- methylr

sulfonyl-2-oxo-azetidin-1-yl)-3-methyl-2- butenoic acid methyl ester A solution of 202 g (0.51 Mol) (3R,5R,6R)-2,2-dimethyl-6-(tert. -butyl-dimethylsilyloxymethyl-penam-3-carboxylic acid methyl ester-1,1-dioxide in 800 ml tetrahydrofuran is added 9 ml DBU and

stir for 5 minutes at room temperature. A further 95 ml of DBU is then added and further stirred for 30 minutes at room temperature. 42.3 ml (0.68 mol) of methyl iodide are then added while cooling. After a reaction duration of 3 hours, crystallized DBU hydroiodide is filtered off and the filtrate

steamed. The residue is taken up in ethyl acetate and the solution is washed with 1N sulfuric acid, water and bicarbonate solution. The aqueous phases are extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulphate and the solution is evaporated to a thick oil.

DC silica gel, toluene ethyl acetate (4:1; Rf = 0.42

IR (CH 2 Cl 2 ) 5.63, 5.81, 6.17 um.

lbc) ( 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- 2-Butenoic acid methyl ester in 400 ml of methylene chloride is treated at -10°

with an ozone/oxygen mixture. The binding of the starting material is checked by thin-layer chromatography. After completion of the reaction, 30 ml of dimethylsulphide are added and the mixture is stirred further for 3 hours at room temperature. The solution is evaporated and the residue taken up in a mixture of 160 ml of methanol, 24 ml of ethyl acetate and 3 ml of water and heated for 40 minutes at 70°. solution

the agent is then drawn off and the residue is drawn twice with toluene. The crystallizing oil is taken up in methylene chloride, and the crystals consisting of (3S), (4R)-3-hydroxymethyl-4-methylsulfonyl-azetidin-2-one are isolated by filtration. The filtrate is evaporated and (3S,4R)-3-(tert.butyl-dimethylsilyloxymethyl)-4-methylsulfo-yl-azetidin-2-one is obtained in pure form by chromatography on silica gel with toluene/ethyl acetate (3:1).

( 3S, 4R )- 3- hydroxymethyl- 4- methylsulfonyl- azetidin- 2- one: DC, silica gel, toluene/ethyl acetate (1:1), Rf = 0.36, IR: (CH2C12) 2.96, 3, 54, 5.61 etc.

(3S,4R)-3-(tert.butyl-dimethylsilyloxymethyl)-4-methylsulfonyl-azetidin-2-one: DC; silica gel, toluene ethyl acetate (1:1 Rf = 0.06.

A solution of 14.6 g (81.5 mmol) (3S,4R)-3-hydroxymethyl-4-methyl-sulfonyl-azetidin-2-one in 40 ml of dimethylformamide is added to 24 g (183 mmol) of tert-butyldimethylchlorosilane and 11 g (163 mmol) of imidazole for 45 minutes at room temperature. The solvent is then removed under high vacuum and the residue is taken up in ethyl acetate.

The organic phase is washed successively 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 evaporated 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-(5-(tetrazol-1-yl)-valeroylthio)-2-oxo-azetidin-1-yl)-2-hydroxyacetic acid - 2- triethylsilyl ethyl ester.

A mixture of 248 mg of (3S,4R)-3-(tert.butyl-dimethylsilyloxymethyl)-4-(5-(tetrazol-1-yl)-valeroylthiol)-azetidin-2-one and 273.5 mg of glyoxylic acid -2-trimethylsilylcetyl ester ethyl hemiketal in 5.3 ml toluene and 1.06 ml DMF is added to 2.4 g molecular sieve (type 4Å 1/16 from the company Dr. Bender&Dr. Hobein AG, Ziirich) and stirred at 100° bath temperature for 5 hours under protective gas. Mixtures are filtered after cooling over hyflo and the filter residue is washed with toluene. Evaporation of the filtrate and drying at 40° in high vacuum gives the product as a yellow oil.

DC (silica gel): toluene-ethyl acetate (2:3) Rf = 0.31 and 0.2

IR (methylene chloride). 2.86, 5.67, 5.78, 5.98 etc.

Example 3: 2-((3S,4R)-3-tert.butyl-dimethylsilyloxymethyl-4-(5-(tetrazol-1-yl)-valeroylthio)-2-oxo-azetidin-1-yl)-2-triphenyl -phosphoranylideneacetic acid- 2- trimethylsilyl ethyl ester

To a solution of 700 mg of 2-((3S,4R)-3-tert.butyl-dimethylsilyloxymethyl-4-(5-(tetrazol-1-yl)-valeroylthio)-2-oxo-azetidin-1-yl)- 2-Hydroxyacetic acid-2-trimethylsilyl ethyl ester in 4.3 ml of tetrahydrofuran is added with stirring at -15° successively 0.13 ml of thionyl chloride and 0.25 ml of triethylamine over the course of 10 minutes.

The white suspension is stirred for one hour at 0° and filtered over "hyflo". After washing the residue with toluene, it is evaporated on a rotary evaporator and dried in a high vacuum. The residue is dissolved in 3.7 ml of dioxane, 0.28 g of triphenylphosphine and 0.12 ml of 2,6-lutidine are added and stirred for 18 hours at 50°. The mixture is filtered over "hyflo" and this residue is washed with toluene. The combined filtrates are evaporated and chromatography of the residue on 40 g of silica gel with toluene/ethyl acetate (4:1) gives the pure product.

TLC (silica gel) toluene-ethyl acetate (2:3): Rf = 0.28

IR (methylene chloride): 5.72, 5.93, 6.23, 9.1 um.

Example 4: (5R, 6S)-2-(4-(tetrazol-1-yl)-butyl)-6-tert.-butyl-dimethyl-silyloxymethyl)-2-penem-3-carboxylic acid-2-trimethylsilyl ethyl ester

0.8 g 2-((3S,4R)-3-tert-butyl-dimethylsilyloxymethyl-4-(5-tetrazol-1-yl)-valeroylthio)-2-oxoazetidin-1-yl)-2-triphenylphosphoranalidene- Acetic acid 2-trimethylsilyl ethyl ester is dissolved in 300 ml of toluene and stirred under a nitrogen atmosphere for 1.25 hours at reflux temperature. Evaporation of the solvent and chromatography of the residue on silica gel with the eluent toluene/ethyl acetate

(2:1) gives the pure product.

TLC (silica gel) toluene-ethyl acetate (2:3): Rf = 0.45

IR (methylene chloride): 5.62, 5.92, 6.34, 7.65 um.

Example 5: (5R, 6S)-2-(4-(tetrazol-1-yl)-butyl)-6-hydroxymethyl-2-penem-3-carboxylic acid-2-trimethylsilyl ethyl ester

163 mg of (5R,6S)-2-(4-(tetrazol-1-yl)-butyl)-6-tert-butyldimethyl-silyloxymethyl-2-penem-3-carboxylic acid-2-trimethylsilyl ethyl ester is dissolved in 4.8 ml abs. THF and add under a nitrogen atmosphere after cooling to -80° 0.17 ml of acetic acid. Then 18.2 ml of a 0.1 M tetrabutylammonium fluoride solution in THF is added dropwise, the mixture is allowed to come to room temperature and stirred for two hours

at this temperature. The solvent volume is evaporated on a rotary evaporator to 2 ml, and the residue divided between 25.3 mg of sodium bicarbonate in 10 ml of water and 10 ml of ethyl acetate. The organic phase is separated, the aqueous phase is extracted twice more with ethyl acetate. The organic extracts are washed once more with water and dried over sodium sulfate.

Evaporation in high vacuum gives the crude product which is chromatographed on

10 g silica gel with eluent toluene-ethyl acetate (1:1).

DC (silica gel) toluene-ethyl acetate (2:3): Rf = 0.12

IF (methylene chloride): 2.78, 5.62, 5.92, 6.33, 7.65 ym.

Example 6: Sodium-(5R,6S)-2-(4-(tetrazol-1-yl)-butyl)-6-hydroxymethyl-2-penem-3-carboxylate

106 mg of (5R,6S)-2-(4-(tetrazol-1-yl)-butyl)-6-hydroxymethyl-2-penem-3-carboxylic acid-2-trimethylsilyl ethyl ester are dissolved in 2 ml of abs. THF and cooled to -30°. After adding 10 ml of tetrabutylammonium fluoride solution in THF, the temperature is brought to 0°. After 10 minutes of stirring at this temperature, 13 ml of ethyl acetate and 13 ml of water are added to the mixture. In an ice bath, the solution is then brought to pH 3 by the dropwise addition of 4N HCl. The water phase The water phase is then rinsed off and the ethyl acetate phase is extracted with 10.6 ml of a 0.05 M NaHCO-j solution. The organic phase is extracted once more with 0.5 ml NaHCO 3 (0.05 M) and 4 ml H 2 O.

.The combined aqueous phases are freed from remaining solvent

in vacuum and lyophilized.

UV (van<n>) X max, s. = 305 nm.

Example 7: 2-((3S,4R)-3-(tert.butyl-dimethylsilyloxymethyl)-4-(2-(tetrazol-1-yl)-acetylthio)-2-oxo-azetidin-1-yl)-2 - triphenyl phosphoranylidene acetic acid allyl ester

5 g of the silver salt of 2-((3S,4R)-3-(tert.butyl-dimethylsilyloxymethyl)-4-mercapto-2-oxo-azetidin-1-yl)-2-triphenylphosphoranylideneacetic acid allyl ester are dissolved in 50 ml of abs. methylene chloride, first add 0.99 ml of pyridine and then treat dropwise at 0° for 10 minutes with the solution of 2-(tetrazol-1-yl)-acetic acid chloride. After one hour of stirring at 0°, the cooling bath is removed and the mixture is stirred for 15 minutes at room temperature. After filtering off the insoluble material over "hyflo", the filtrate is washed with aqueous sodium bicarbonate solution and then with salt water, dried and evaporated. The pure compound is obtained by chromatography on silica gel (eluent toluene-ethyl acetate from 6:1 to 1:1), IR (methylene chloride): 5.71, 5.92, 6.18 µm.

The starting material 2-((3S,4R)-3-(tert.butyl-dimethylsilyloxymethyl)-4-mercapto-2-oxo-azetidin-1-yl)-2-triphenylphosphoranylideneacetic acid allyl ester (silver salt) is prepared as follows: 7aa) ( 3S, 4R)- 3-( tert. butyl- dimethylsilyloxymethyl)- 4-triphenylmethyl- thio- azetidin- 2- one

12.5 g of triphenylmethyl mercaptan is suspended in 70 ml of methanol at 0°, and a total of 2.2 g of a 50% sodium hydride suspension in oil is added in portions over the course of 10 minutes. An emulsion of 11.1 g of 3-(tert.butyl-dimethylsilyloxymethyl)-4-methylsulfonul-azetidin-2-one in 70 ml of acetone and 70 ml of water is then added dropwise over the course of 30 minutes. After stirring for 30 minutes at 0° and one hour at room temperature, the reaction mixture is evaporated on a rotary evaporator, methylene chloride is added and the aqueous phase is separated. The organic solution is washed with brine and dried over sodium sulfate. After evaporation, the crude title compound is purified by chromatography on silica gel (eluent toluene/ethyl acetate 19:1).

TLC (toluene-ethyl acetate 19:1): Rf = 0.64

IR (methylene chloride): 2.95, 5.68, 8.95, 12.0 um.

7ab) 2-( ( 3S, 4R)- 3-( tert. butyl- dimethylsilyloxymethyl)- 4- triphenyl- methylthio- 2- oxo- azetidin- 1- yl)- 2- hydroxyacetic acid allyl ester 8.4 g (3S, 4R)-3-(tert-butyl-dimethylsilyloxymethyl)-4-triphenyl-thio-azetidin-2-0n and 8.23 g of glyoxylic acid allyl ester ethyl hemiacetal in 170 ml abs. toluene is added with 27 g of mokekyl sieve (4Å) and

stirred for 10 hours at 55°. After filtration and evaporation on a rotary evaporator under reduced pressure, the crude product is purified by chromatography on silica gel. (Eluent toluene/ethyl acetate 95:5).

TLC (silica gel, toluene/ethyl acetate 10:1): Rf = 0.37

IR (CH 2 Cl 2 ): 2.84, 5.68, 5.73 um.

7ac) 2-(( 3S, 4R)- 3-( tert. butyl- dimethylsilyloxymethyl)- 4-triphenyl- methylthio- 2- oxo- azetidin- 1- yl)- 2- triphenylphosphoranylide acetic acid allyl ester

To a solution of 604 mg of 2-((3S,4R)-3-(tert.butyl-dimethylsilyloxymethyl)-4-triphenylmethylthio-2-oxo-azetidin-1-yl)-2-hydroxyacetic acid allyl ester in 5 ml of tetrahydrofuran is added with stirring at -15° successively 80 yl thionyl chloride and 88 yl pyridine over the course of 5 minutes. The white suspension is stirred for one hour at -10° and filtered over "hyflo".

After washing the residue with toluene, it is evaporated on a rotary evaporator. The residue is dissolved in 3 ml of dioxane, 293 mg of triphenylphosphine and 0.13 ml of 2,6-lytidine are added and stirred for 2 hours at 115° bath temperature. The mixture is filtered over "hyflo" and the residue is washed with toluene. The combined filtrates are evaporated. Chromatography of the residue on silica gel gives the pure product (eluent toluene/ethyl acetate 95:5).

TLC (silica gel, toluene/ethyl acetate 1:1): Rf = 0.18

IR (CH 2 Cl 2 ): 5.73, 6.23 um.

7ad) Silver salt of ( 2-(( 3S, 4R)- 3-( tert. butyl- dimethylsilyloxymethyl)-4- mercapto- 2- oxo- azetidin- 1- yl)- 2- triphenylphosphoranylideneacetic acid allyl ester

7.5 mg of 2-((3S,4R)-3-(tert.butyl-dimethylsilyloxymethyl)-4-triphenyl-methylthio-2-oxo-azetidin-1-yl)-2-triphenylphosphoranylideneacetic acid allyl ester is dissolved in 87 ml of ether and added at room temperature

70 ml of a 0.5 M aqueous silver nitrate solution. A mixture of 3.6 ml of tributylamine, 0.18 ml of trifluoroacetic acid and 25 ml of ether is then added dropwise and the reaction mixture is stirred for 20 minutes. The solid is then suctioned off and washed with ether, water and again with ether. The solid is finally suspended for purification once again in 40 ml of ether and 40 ml of water, suctioned off and dried.

IR (CH 2 Cl 2 ): 5.68, 6.17 um.

A solution of the starting material 2-(tetrazol-1-yl)-acetic acid chloride can be prepared as follows:

7ba) 2-(tetrazol-1-yl)-acetic acid ethyl ester

500 ml of a 1.3 N nitrous acid (HN 2 ) solution in benzene is added dropwise to 23.7 ml isocyanoacetic acid ethyl ester and the reaction mixture is then heated at reflux for 24 hours. After evaporation, the crude title compound is purified by chromatography on silica gel. (Eluent toluene-ethyl acetate 1:1):

IR (methylene chloride): 3.16, 5.73, 6.80. 8.23 etc.

7bb) 2-(tetrazol-1-yl)-acetic acid

Analogous to example lad), 25.6 g of 2-(tetrazol-1-yl)-acetic acid ethyl ester is reacted to the title compound.

IR (tetrahydrofuran): 5.73 µm.

7bc) 2-(tetrazol-1-yl)-acetic acid chloride

1.58 g of 2-(tetrazol-1-yl)-acetic acid is suspended in 27 ml of abs. methylene chloride and 1.9 ml of 1-chloro-1-dimethylamino-isobutene (CDIB) is added. After stirring for 30 minutes at room temperature, a further 0.5 ml of CDIB is added and stirring is continued for a further 90 minutes. This solution of the acid chloride

IR (methylene chloride) 3.20, 5.57 ym

are traded directly on.

Example 8: 2-((3S,4R)-3-(tert.butyl-dimethylsilyloxymethyl)-4-(3-(tetrazol-1-yl)-propionylthio)-2-oxo-azetidin-1-yl)-2 -tripheny1phosphoranylideneacetic acid allyl esters

Analogous to example 7), 5 g of the silver salt from example are reacted

7 ad) with a solution of 3-(tetrazol-1-yl)-propionic acid chloride to the title compound,

IR (methylene chloride): 5.88, 5.92, 6.17 ym.

The starting material 3-(tetrazol-1-yl)-propionic acid chloride is prepared as follows:

8a) 3-(tetrazol-1-yl)-propionic acid

4.5 g of tetrazole are stirred with 4.5 ml of acrylic acid and 15 drops of pyridine for 8 hours at 90°. After cooling, 150 ml of water is added to the reaction mixture, the mixture is acidified with HCl (concentrated) and evaporated on a rotary evaporator under reduced pressure.

The crystalline residue is digested 3 times with methyl ethyl ketone

and the combined organic phases are dried over sodium sulfate. After evaporation, the crystalline residue is stirred with isopropanol/

ether and filtered off.

NMR (DMSO-d 6 ) δ = 3.0 (2H,t); 4.7 (2H,t); 9.5 (lH,s) and 8-11 ppm (1H, broad).

8b) 3-(tetrazol-1-yl)-propionic acid chloride

Analogous to example 7bc), 1.75 g of 3-(tetrazol-1-yl)-propionic acid is reacted to the title compound.

IR (methylene chloride): 3.18, 5.63 ym.

The achieved solution is traded directly on.

Example 9: 2-((3S,4R)-3-(tert.butyl-dimethylsilyloxymethyl)-4-(4-(tetrazol-1-yl)-butyroylthiol)-2-oxo-azetidin-1-yl)-2 - triphenyl-phosphoranylideneacetic acid allyl esters

Analogous to example 7), 5 g of the silver salt obtained in example 7ad) is dissolved in 10 ml of absmethylene chloride, 1.13 ml of pyridine is added and, after cooling to 0°, reacted with 2.61 g of acid (tetrazol-l-yl) -

butyric acid chloride to the title compound.

IR (methylene chloride): 5.71, 5.93, 6.17 ym.

The starting material 4-(tetrazol-1-yl)-butyric acid chloride is prepared as follows:

9a) 4-(tetrazol-1-yl)-butyric acid ethyl ester

0.84 g of 4-aminobutyric acid ethyl ester hydrochloride and 0.9 g of sodium azide are added to 4 ml of orthoformic acid triethyl ester and 6 ml of acetic acid and heated for 7 hours at reflux. After cooling, the reaction mixture is taken up in an ethyl acetate and aqueous sodium bicarbonate solution, the organic phases are separated and washed a further four times with aqueous sodium bicarbonate solution. After washing with water and salt water, the ethyl acetate phase is dried

over sodium sulfate and evaporated to the title compound.

IR (methylene chloride): 3.16, 5.81, 6.76, 8.4 um.

9b) 4-(tetrazol-1-yl)-butyric acid

6.65 g of 4-(tetrazol-1-yl)-butyric acid ethyl ester is stirred in 42.7 ml of acetic acid, 8.1 ml of concentrated HCl and 17.2 ml of water for 3 hours at 100°. After cooling, the reaction mixture is evaporated three times each with toluene and ether on a rotary evaporator under reduced pressure. After drying in high vacuum, the title compound is obtained.

NMR (DMSO-d 6 ): δ = 2.3 (4H,m); 4.6 (2H,t); 8.7 (lH,broad) and 9.53 ppm (lH,s).

9c) 4-(tetrazol-1-yl)-butyric acid chloride

Analogously to example lae), 9.31 g of 4-(tetrazol-1-yl)-butyric acid is transformed into the title compound.

IR (methylene chloride): 3.18, 5.62 ym.

Example 10: 2-((3S,4R)-3-(tert.butyl-dimethylsilyloxymethyl)-4-(3-(1,2,4-triazol-1-ul)-propionylthio)-2-oxo-azetidine- 1-yl)-2-triphenyl-phosphoranylideneacetic acid allyl ester

Analogous to example 7), a solution of 3-(1,2,4-triazol-1-yl)-propionic acid chloride is reacted with 5 g of the silver salt described under example 7ad) to give the title compound.

IR (methylene chloride): 5.72, 5.92, 6.17 ym.

The starting material 3-(1,2,4-triazol-1-yl)-propionic acid chloride is prepared as follows:

10a) 3-(1,2,4-triazol-1-yl)-propionic acid

Analogously to example 8a), 2.8 g of 1,2,4-triazole are reacted with 2.88 g of acrylic acid to give the title compound.

IR (KBr): 3.21, 5.85, 6.58 ym.

10b) 3-(1,2,4-triazol-1-yl)-propionic acid chloride

Analogous to example 7bc), 1.72 g of 3-(1,2,4-triazol-1-yl)-propionic acid is reacted to give the title compound.

IR (methylene chloride): 5.62 um.

Example 11: (5R, 6S)-2-((tetrazol-1-yl)-methyl)-6-(tert.butyl-dimethylsilyloxymethyl)-2-penem-3-carboxylic acid allyl ester Analogously to example 4, 2,3 g 2-((3S,4R)-3-(tert.butyl-dimethyl-silyloxymethyl)-4-(2-(triazol-1-yl)-acetylthiol)-2-oxo-azetidin-1-yl)-2 -triphenylphosphoranylideneacetic acid allyl ester after 25 minutes of heating to the title compound.

IR (methylene chloride): 5.60, 5.90, 6.33 y.

Example 12: (5R, 6S)-2-(2-(tetrazol-1-yl)-ethyl1-6-(tert.butyl-dimethylsilyloxymethyl)-2-penem-3-carboxylic acid-a Hyle ester

Analogous to example 4, 4 g of 2-((3S,4R)-3-(tert.butyl-dimethylsilyloxy-methyl)-4-(3-(tetrazol-1-yl)-propionylthio)-2-oxo-azetidine- 1-yl)-2-triphenylphosphoranylideneacetic acid allyl ester after 45 minutes of heating to the title compound.

IR (methylene chloride): 5.62, 5.90, 6.33 ym.

Example 13,: (5R, 6S)-2-(3-(tetrazol-1-yl)-propyl)-6-(tert.butyl-dimethylsilyloxymethyl)-2-penem-3-carboxylic acid allyl ester

Analogous to example 4, 3.2 g of 2-((3S,4R)-3-(tert.butyl-dimethyl-silyloxymethyl)-4-(4-(tetrazol-1-yl)-butyrolthio)-2-oxo- azetidin-1-yl)-2-triphenylphosphoranylideneacetic acid allyl ester after two hours of heating to the title compound.

IR (methylene chloride): 5.62, 5.88, 6.33 ym.

Example 14: (5R,6S)-2-(2-(1,2,4-triazol-1-yl)-ethyl tert, butyl-dimethylsilyloxymethyl)-2-penem-3-carboxylic acid allyl ester Analogous to example 4 transferred 3.2 g of 2-((3S,4R)-3-(tert.butyl-dimethylsilyl-oxymethyl)-4-(3-(1,2;4-triazol-1-yl)-propionylthio)-2- oxo-azetidin-1-yl)-2-triphenylphosphoranylideneacetic acid-

allyl ester after 75 minutes of heating to the title compound.

IR (methylene chloride): 5.61, 5.88, 6.33 um.

Example 15: (5R, 6S)-2-((tetrazol-1-yl)-methyl)-6-hydroxymethyl-2-penem-3-carboxylic acid allyl ester

Analogously to example 5, 1.15 g of (5R,6S)-2-((tetrazol-1-yl)-methyl)-6-(tert-butyl-dimethylsilyloxymethyl)-2-penem-3-carboxylic acid allyl ester is reacted to the title compound .

IR (KBr): 5.64, 5.86, 6.33 ym.

Example 16: (5R, 6S)-2-((tetrazol-1-yl)-6-hydroxymethyl-2-penem-3-carboxylic acid e-a Hy ester

Analogously to example 5, 1.65 g of (5R,6S)-2-(2-(tetrazol-1-yl)ethyl)-6-(tert.butyl-dimethylsilyloxymethyl)-2-penem-3-carboxylic acid allyl ester is transferred to the title compound.

IR (methylene chloride): 2.78, 5.62, 5.88, 6.33 um.

Example 17: (5R,6S)-2-(3-(tetrazol-1-yl)-propyl.1)-6-hydroxymethyl-2-penem-3-carboxylic acid allyl ester

Analogous to example 5, 1.2 g of (5R,6S)-2-(3-(tetrazol-1-yl)-propyl)-6-(tert.butyl-dimethylsilyloxymethyl)-2-penem-3-carboxylic acid is transferred -allyl ester of the title compound.

IR (methylene chloride): 2.77, 5.62, 5.88, 6.33 um.

Example 18: (5R,6S)-2-(2-(1,2,4-triazol-1-yl)-ethyl)-6-hydroxy-methyl-2-penem-3-carboxylic acid allyl ester

Analogously to example 5, 2.85 g of (5R,6S)-2-(2-(1,2,4-triazol-1-yl)-ethyl)-6-(tert.butyl-dimethylsilyloxymethyl)-2-penem are transferred -3- carboxylic acid allyl ester of the title compound.

IR (methylene chloride): 2.78, 5.62, 5.30, 6.35 um.

Example 19: (5R, 6S)-2-((tetrazol-1-yl)-methyl)-6-hydroxymethyl-2-penem-3-carboxylic acid, sodium salt

A solution of 310 mg of (5R,6S)-2-((tetrazol-1-yl)-6-hydroxyl-methyl-2-penem-3-carboxylic acid allyl ester in 12 ml of abs. THF is added at -10° 22 mg tetrakis-(triphenylphosphine)-palladium and then 0.31 ml of tributyltin hydride. After 25 minutes of stirring at -10°, 0.065 ml of acetic acid is added and the reaction mixture is further stirred at the same temperature for 10 minutes. After concentration at

a rotary evaporator, the residue is taken up in water-ethyl acetate, the aqueous phase is adjusted with sodium bicarbonate to pH 8.5 and separated. After further washing with ethyl acetate, clean

the title compound by chromatography on XAD/2. (Eluent water). The corresponding fractions are lyophilized in high vacuum.

UV (phosphate buffer pH 7.2): X IU3.KS • = 308 nm.

Example 20: (5R,6S)-2-(2-(tetrazol-1-yl)-ethyl)-6-hydroxymethyl-2-penem-3-carboxylic acid

Analogous to example 19, 725 mg of (5R,6S)-2-(2-(tetrazol-1-yl)-6-hydromethyl-2-penem-3-carboxylic acid allyl ester is transferred into the title compound.

UV (phosphate buffer pH 7.4): X , = 304 nm.

Example 21: (5R,6S)-2-(3-(tetrazol-1-yl)-propyl)-6-hydroxymethyl-2-penem-3-carboxylic acid, sodium salt

Analogous to example 19, 0.74 g of (5R,6S)-2-(3-(tetrazol-1-yl)-propyl)-6-hydroxymethyl-2-penem-3-carboxylic acid allyl ester is transferred to the title compound.

UV (water): X . = 302 nm.

max.

Example 22: (5R,6S)-2-(2-(1,2,4-triazol-1-yl)-ethyl-6-hydroxymethyl-2-penem-3-carboxylic acid, sodium salt

Analogously to example 19, 0.64 g of (5R,6S)-2-(2-(1,2,4-triazol-1-yl)-ethyl)-6-hydroxy-methyl-2-penem-3-carboxylic acid is transferred -allyl esters of the title compound.

UV (phosphate buffer pH 7,<4>)<:>A IT13.K, . S • = 303 nm.

Example 23: In an analogous way as described in examples 1-22,

the following compounds can be prepared: (5R,6S,8R)-2-((tetrazol-1-yl)-methyl)-6-(1-hydroxylethyl)-2-penem-3-carboxylic acid, sodium salt, UV (phosphate buffer pH 7,4): X IHdKS •=307 no

(5R,6S,8R)-2-(2-(tetrazol-1-yl)-ethyl)-6-(1-hydroxyethyl)-2-penem-3-carboxylic acid, sodium salt, UV (phosphate buffer pH 7.4) : X IT13.K , S •=308 nm.

Example 24: 2-((3S,4R)-3-(tert.butyl-dimethylsilyloxymethyl)-4-(2-(tetrazol-1-yl)-acetylthio)-2-oxo-azetidin-1-yl)-2 -triphenylphosphoranylideneacetic acid allyl esters

(Compare example 7) can also be produced as follows:

24a) 2-(( 3S, 4R)- 3-( tert. butyl- dimethylsilyloxymethyl)- 4-chloroacetylthio- 2- oxo- azetidin- 1- yl)- 2- triphenylphosphoranylideneacetic acid allyl ester

Analogously to example 7, 30 g of the silver salt of 2-((3S,4R)-3-(tert.butyl-dimethylsilyloxymethyl)-4-mercapto-2-oxo-azetidin-1-yl)-2-triphenylphosphoranylideneacetic acid allyl ester is reacted with 5 .04 ml of chloroacetyl chloride to the title compound.

IR (methylene chloride): 5.71, 5.95, 6.19 ym.

24b) 2-(( 3S, 4R)- 3-( tert. butyl- dimethylsilyloxymethyl)- 4-( 2-( tetrazol- l- yl)- acetylthio)- 2- oxo- azetidin- l- yl)- 2- triphenyl-phosphoranylideneacetic acid allyl ester

0.68 g of 2-((3S,4R)-3-(tert.butyl-dimethylsilyloxymethyl)-4-chloroacetylthio-2-oxo-azetidin-1-yl)-2-triphenylphosphoranylideneacetic acid allyl ester is dissolved in 5 ml of DMF and added 91 mg tetrazole sodium. After 16 hours of stirring, the reaction mixture is taken up in water/ethyl acetate. The organic phase is separated, dried and evaporated. The product is purified by chromatography on silica gel. (Eluent: toluene/ethyl acetate 1:1).

IR (methylene chloride): 5.71, 5.92, 6.18 ym.

Example 25: (5R, 6S)-2-((tetrazol-1-yl)-methyl)-6-(tert.butyl-dimethyl-silyloxymethyl)-2-penem-3-carboxylic acid allyl ester (Compare example 11) can also produced as follows

2 5a) ( 5R, 6S)- 2- chloromethyl- 6-( tert. butyl- dimethylsilyloxymethyl)-2- penem- 3- carboxylic acid- a Hy lester

Analogous to example 4, 0.341 g of 2-((3S,4R)-3-(tert.butyl-dimethyl-silyloxymethyl)-4-chloroacetylthio-2-oxo-azetidin-1-yl)-2-triphenyl-phosphoranylideneacetic acid allyl ester is transferred (compare Example 24a) after 45 minutes of heating to the title compound.

IR (methylene chloride): 5.60, 5.86, 6.33 ym.

25b) ( 5R/ 6S)- 2-( tetrazol- 1- yl- methyl) 6-( tert. butyl- dimethylsilyloxymethyl) - 2rpenem- 3- carboxylic acid allyl ester

0.4 g of (5R,6S)-2-chloromethyl-6-(tert.butyl-dimethylsilyloxymethyl)-2-penem-3-carboxylic acid allyl ester is dissolved in 5 ml of DMF and 91 mg of tetrazole sodium is added. After 16 hours of stirring, the reaction mixture is taken up in water/ethyl acetate. The organic phase is separated, dried and evaporated. The product is purified by chromatography on silica gel (eluent: toluene/ethyl acetate 9:1).

IR (methylene chloride): 5.60, 5.90, 6.33 ym.

Example 26: (5R, 6S)-2-(2-(tetrazol-1-yl)-ethyl)-6-hydroxymethyl-2-penem-3-carboxylic acid-1-ethoxycarbonyloxyethyl ester 1.2 g of sodium iodide is dissolved in 3.7 ml of acetone and 0.2 75 ml of ethyl-1-chloroethyl carbonate is added. The mixture is stirred at room temperature for three hours. The solution is then added dropwise to 15 ml of methylene chloride and filtered from the precipitated inorganic salts. The methylene chloride solution is evaporated to 2 ml and added at 0° to a solution of 0.3 g of (5R,6S)-2-((2R,S)-2-(tetrazol-1-yl)-ethyl)-6- hydroxymethyl-2-penem-3-carboxylic acid in 4 ml of methylacetamide. It is then stirred for three hours at 0°, then diluted with methyl acetate and washed three times with water. The organic phases are dried over sodium sulfate and evaporated on a rotary evaporator. The crude product is purified on 10 g of silica gel with the eluent ethyl acetate. The compound obtained as a white foam.

IR spectrum (methylene chloride): absorption bands at 5.59, 5.75 µm

Example 27: (5R,6S)-2-((2R,S)-2-(tetrazol-1-yl)-ethyl)-6-hydroxymethyl-2-penem-3-carboxylic acid pivaloyloxymethyl ester

0.6 g of sodium iodide is dissolved in 2 ml of acetone and 0.15 ml of pivalic acid chloromethyl ester is added. The mixture is stirred at room temperature for three hours and then added dropwise to 7.5 ml of methylene chloride.

The precipitated inorganic salts are filtered off. The methylene chloride solution is evaporated to 1 ml and added to a solution of 0.1 g of (5R,6S)-2-(tetrazol-1-yl)-ethyl)-6-hydroxymethyl-2-penem-3-carboxylic acid and 0, 07 ml of diisopropylethylamine in 4 ml of N,N-dimethylacetamide at 0°.

It is then stirred for 3 hours at 0°, then diluted with ethyl acetate and washed three times with water. The organic phase is dried over sodium sulfate and evaporated on a rotary evaporator. The crude product is purified on 10 g of silica gel with ethyl acetate as eluent. The title compound is obtained as a white foam.

IR spectrum (methylene chloride): absorption bands at 5.59 and 5.78 µm.

Example 28: Dry ampoules or vials containing

0.5 g of sodium (5R,6S)-2-(4-(tetrazol-1-yl)-butyl)-6-hydroxymethyl-2-penem-3-carboxylate as active substance is prepared as follows:

Composition (for 1 ampoule or a medicine glass):

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

Claims (13)

1. Procedure for the preparation of compounds of the formula where R.j is hydrogen or methyl, R.sub.2 means an optionally protected hydroxyl group, R.sub.j is carboxyl or protected carboxyl R.sub.3', R^ is an unsaturated ^ monocyclic azaheterocyclyl residue which is attached to the residue - (CH2) - over a tertiary ring nitrogen, and m is a integers from 1-4, salts of such compounds of formula I, which exhibits a salt-forming group, optical isomers of compounds of formula I and mixtures of these optical isomers, characterized by ata) A ylide compound of the formula where R 1 , R 2 , R 4 ', R 4 and m have the meanings given under formula I, whereby a hydroxy group R 2 and further functional groups that may be contained in the residue R- are preferably present in protected form, Z means oxygen or sulfur and X either is a triply substituted phosphonio group or a doubly esterified ptiosphono group together with a cation, is ring-closed, or b) a compound of the formula where R.j , R2 , R3' ' R4 0<? m when ^e has the meanings given under formula I, whereby a hydroxy group R2 and further functional groups that may be contained in the residue R^ , preferably present in protected form, are treated with an organic compound of trivalent phosphorus, orc) a compound with the formula where R.j , R.sub.2 , R.sub.1 and m have the meanings given above and Q means a reactive esterified hydroxy group, is reacted with an agent which introduces the azaheterocyclyl residue R.sub.1, and if desired, or necessary, in an obtained compound of formula I, a protected hydroxyl group R2 is transferred to the free hydroxyl group, and/or, if desired, in an obtained compound of formula I, a protected carboxyl group R 2 is transferred to the free or in another protected carboxyl group R^ ', and/or, if desired, further protected functional groups contained in the residue R^ are transferred to the free functional groups, and/or, if desired, in an obtained compound of formula I a residue R. is transferred to another residue R^ , and/or, if if desired, an obtained compound with salt-forming groups is transferred to a salt or an obtained salt to the 'free compounds or to another salt, and/or, if desired, an obtained mixture of isomeric compounds is divided into the individual isomers. 2. Methods according to claim 1, characterized in that R.j is hydrogen or methyl, R2 means hydroxyl or protected hydroxyl, R^ is carboxyl or protected carboxyl R^' / especially under physiological conditions cleavable esterified carboxyl R^<1> , R^ is a monocyclic, optionally partially saturated 5-membered heteroaryl residue with 1 to 4 ring nitrogen atoms or a corresponding partially saturated 6-membered heteroaryl residue with 1 to 3 ring nitrogen atoms which is bound to the residue -(CH2 )m - via a tertiary ring nitrogen atom, whereby these residues are unsubstituted or substituted with hydroxy, lower alkoxy, lower alkanoyloxy, halogen, marcapto, lower alkylthio, phenylthio, lower alkyl, hydroxyl lower alkyl, lower carboxy lower alkyl, carboxy lower alkyl, amino lower alkyl, di lower alkyl amino lower alkyl, sulfola lower alkyl, amino, lower alkyl amino, di lower alkyl amino, lower alkylene amino, lower alkanoyl amino, carboxyl, lower alkoxycarbonyl, optionally N-mono- or N,N-dilower alkylated carbamoyl, cyano, s ulfo or sulfamoyl, phenyl, cycloalkyl, nitro, oxo and/or oxido, which is optionally substituted with lower alkyl, nitro, lower alkoxy and/or halogen, and m means an integer from 1 to 4, their salts, their optical isomers and mixtures of their optical isomers. 3. Process according to claim 1 for the preparation of compounds of formula I, characterized in that R , R 2 , R 2 and m have the meanings given in claim 2 and R is a mono-cyclic five-membered aza-, diaza-, triaza- or tetraza-cyclic radical of aromatic character or a corresponding dihydro-residue or a corresponding partially saturated 6-membered aza-, diaza-, triaza-cyclic heteroaryl radical, as a corresponding dihydro- or tetrahydro-residue which is attached to the residue -(CH2 )m - over a tertiary ring nitrogen atom, whereby this residue is unsubstituted or substituted as defined in claim 2. 4. Process according to claim 1 for the production of compounds of formula I, characterized in that R , R 2 , R 2 and m have the meanings given in claim 2 and R 4 is 1-pyrrolyl or dihydro-1-pyrrolyl, which is optionally substituted with lower alkyl or halogen, 1-imidazolyl or 1-pyrazolyl which is optionally substituted with lower alkyl, 1,2,3-, 1,2,4- or 1,3,4-triazol-1-yl which is optionally substituted with lower alkyl , carboxyl lower alkyl or phenyl, 1- or 2-tetrazolyl which is optionally substituted with lower alkyl, carboxyl lower alkyl, sulpho lower alkyl, di lower alkyl amino lower alkyl or amino, dihydro-1-pyridyl which is unsubstituted or substituted with oxo and optionally additionally with halogen, dihydro-1-pyrimidinyl which is unsubstituted or substituted with oxo and optionally additionally with lower alkyl, amino, dilower alkylamino or carboxy or dihydro- or tetrahydro-1-triazinyl which is optionally substituted with lower alkyl and/or oxo. 5. Process according to claim 1 for the preparation of compounds of formula I, characterized in that R 1 is hydrogen or methyl, R2 means hydroxyl, R^ means carboxyl, loweralkanoyloxymethoxycarbonyl or 1-loweralkoxycarbonyloxy-loweralkoxycarbonyl, R4 is 1H-tetrazol-1-yl or 2H-tetrazol-2-yl which is optionally substituted with amino, loweralkyl, carboxylloweralkyl 1 , i sulpholoweralkyl, or diloweralkylaminoloweralkyl or 1H-1,2,4-triazol-1-yl which is optionally substituted with loweralkyl, carboxyloweralkyl or phenyl and m means an integer from 1 to 4, their pharmaceutically usable salts, their optical isomers, f .ex. The (5R,6S) isomers, and mixtures of their optical isomers. ■ 6. Method according to claim 1, characterized in that (5R,6S)-configured compounds of formula I are produced. 7. Process according to claim 1 for the production of compounds of formula I with (5R,6S) configuration, characterized in that R 1 is hydrogen, R 2 means hydroxyl, R 3 is carboxyl, R 4 is 1H-tetrazol-1-yl or 1H -1,2,4-triazol-1-yl and m is an integer from 1 to 4, and their pharmaceutically acceptable salts. 8. Method according to claim 1, characterized in that (5R,6S)-2-(4-(1H-tetrazol-1-y1)-butyl)-6-hydroxymethyl-2-penem-3-carboxylic acid and pharmaceutically usable salts thereof. 9. Method according to claim 1, characterized in that (5R,6S)-2-(tetrazol-1-yl)-methyl)-6-hydroxymethyl-2-penem-3-carboxylic acid and pharmaceutically usable salts thereof are produced. 10. Process according to claim 1, characterized in that (5R,6S)-2-(2-(tetrazol-1-yl)-ethyl)-6-hydroxymethyl-2-penem-3-carboxylic acid and pharmaceutically usable salts thereof are produced . 11. Process according to claim 1, characterized in that (5R,6S).2.(3-(tetrazol-1-yl)-propyl)-6-hydroxymethyl-2-penem-3-carboxylic acid and pharmaceutically usable salts thereof are produced . 12. Process according to claim 1, characterized in that (5R,6S)-2-(2-(1,2,4-triazol-1-yl)-ethyl)-6-hydroxymethyl-2-penem-3- carboxylic acid and pharmaceutically usable salts thereof. 13. Process for the production of pharmaceutical preparations, characterized in that a compound of formula I which is prepared according to claim 1 or a pharmaceutically usable salt of such a compound is mixed with a pharmaceutically usable carrier material.