NO841789L - PROCEDURE FOR THE PREPARATION OF AMINOLA GENERIC SEAT PENEM - Google Patents

Description

The present invention relates to new 2-aminolower alkyl penem compounds, process for their production, pharmaceutical preparations containing such compounds,

and their use for the production of pharmaceutical preparations or as pharmacologically active compounds.

The invention relates in particular to 2-aminolower alkyl-2-penem compounds of the formula

where R, is lower alkyl substituted by hydroxy or protected hydroxy, is carboxyl or protected carboxyl', R3 is amino, amino substituted by lower alkyl, substituted methyleneamino or protect-

tet amino and A is linear lower alkylene substituted with lower alkyl, with the proviso that R^ is different from 1-hydroxyethyl or protected 1-hydroxyethyl, when A

is linear lower alkylene geminally substituted with two methyl groups, R2 has the above meaning, and R^ is amino or protected amino, salts of such compounds of formula ^ which exhibit a salt-forming group, optical isomers of compounds of formula I and mixtures of these optical isomers , process for the preparation of compounds of formula I, pharmaceutical preparations containing such compounds, and their use for the preparation of pharmaceutical preparations or as pharmacologically active compounds.

In the above and subsequent definitions used, within the framework of the present description, preferably have the following meanings: Amino R which is substituted with lower alkyl is e.g. lower alkylamino or dilower alkylamino. In substituted methyleneamino, the methylene residue is preferably mono- or disubstituted. Substituted methylene amino is e.g. a group with the formula where X^ is hydrogen, optionally substituted amino, e.g. amino, lower alkylamino, dilower alkylamino, lower alkyleneamino, nitroamino, hydroxy or anilino, etherified hydroxy, e.g. lower methoxy or phenyl lower oxy, etherified mercapto, e.g. lower alkylthio, optionally substituted lower alkyl, e.g. loweralkyl, aminoloweralkyl, N-loweralkylaminoloweralkyl or N,N-diloweralkylamino-loweralkyl,. lower alkenyl, phenyl or monocyclic heteroaryl, such as corresponding 5- or 6-membered heteroaryl with 1-2 nitrogen atoms, and/or an oxygen or sulfur atom, such as pyridyl, e.g. 2- or 4-pyridyl, thienyl, e.g. 2-thienyl or thiazolyl, e.g. 4-thiazolyl, and X 9 is optionally substituted amino, e.g. amino, lower alkylamino, dilower alkylamino, lower alkyleneamino, hydrazino or anilino, etherified hydroxy, e.g. lower methoxy or phenyl lower oxy, or etherified mercapto, e.g. lower alkylthio.

In preferred residues of formula (IA), X is hydrogen, amino, lower alkylamino or lower alkyl and amino.

Residues of the formula (IA), which have a hydrogen atom on the α-atom in the substituent X₂ or the substituent X₂, e.g. residues with the formula (IA), where X-^ is amino, lower alkylamino, nitroamino, hydrazino, anilino or optionally substituted lower alkyl and/or X 2 is amino, lower alkylamino, hydrazino or anilino, can also exist in the tautomeric forms in which X| respectively is correspondingly substituted or unsubstituted methylene or imino.

In the present specification, the term "lower" means

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

Lower alkyl R, which is substituted with hydroxy, is especially lower alkyl which is substituted in the α-position of the penem ring skeleton with hydroxy and means e.g. 1-hydroxypropyl-1-yl, 2-hydroxypropyl-2-yl, 1-hydroxybut-1-yl, 2-hydroxybut-2-yl and primarily hydroxymethyl or 1-hydroxyethyl.

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

Lower alkylene amino especially has 4 to 6 carbon chain links and means e.g. pyrrolidino or piperidino.

Low-area coke is e.g. methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy or tert.-butoxy, while phenyl lower alkyl oxy e.g. is benzyloxy.

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

Lower alkyl is e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

Amino lower alkyl is e.g. 2-aminoethyl or 3-aminopropyl.

N-lower alkylamino lower alkyl is e.g. 2-methyl- or 2-ethyl1-aminoethyl1, while N,N-dilower alkylaminolower alkyl e.g. is 2-dimethylaminoethyl or 2-diethylaminoethyl.

Lower range alkenyl is e.g. allyl, n-propenyl or isopropenyl.

The linear lower alkylene in the residue A has 1-7, preferably 1-4 carbon atoms, and is e.g. methylene, ethylene, 1,3-propylene, 1,4-butylene, and also 1,5-pentylene. Such a lower alkylene radical is mono- or polysubstituted, such as mono- or disubstituted with lower alkyl with 1-4 carbon atoms, especially with 1-2 carbon atoms, such as n-propyl, n-butyl or especially methyl or ethyl. 2-lower alkyl substituents can be arranged with the same carbon atom (geminal), on neighboring carbon atoms (vicinal) or on two different carbon atoms in the lower alkylene chain which are separated by at least one methylene group.

Such a residue A is, for example, the lower alkylidene, such as ethylidene ("methyl-methylene"), 1,2-propylene, 2-lower alkyl-, such as 2-methyl-1,2-propylene, 1,2-butylene, 2-lower alkyl- , as 2-methyl-or 2-ethyl-1-1,2-butylene, 3-lower alkyl-, as 3-methyl-1,2-butylene, 1,3-butylene, 2-lower alkyl-, as 2-methyl-1 ,3-butylene, 3-lower alkyl-, such as 3-methyl-1,3-butylene, or 2,2-dilower alkyl-, such as 2,2-dimethyl-1,3-butylene, whereby carbon atom 1 in these residues is connected with the penem ring skeleton, or also 1,2-propylene, 2-lower alkyl-, such as 2-methyl-1,2-propylene, 1,2-butylene, 2-lower alkyl-, such as 2-methyl- or 2-ethyl- 1,2-butylene, 3-lower alkyl-, such as 3-methyl-1,2-butylene, or 3,3-dilower alkyl-, such as 3,3-dimethyl-1,2-butylene, whereby carbon atom 2 in these residues is connected with the penem ring skeleton. Preferred residues A are 1,2-propylene, 1,2-butylene, 1,3-butylene and 2-methyl-1,2-propylene which are connected to the penem ring skeleton over carbon atom 1, as well as 1,2-propylene which is forbidden with the penem ring skeleton over carbon atom 2.

The functional groups present in the compounds of formula I, such as hydroxy, carboxy or amino groups, in particular the hydroxy group in the residue R^, the carboxyl group R»

and an amino group R^, is optionally protected with conventional protecting groups, which are used in penem-, penicil-

lin, cephalospirin and peptide chemistry.

Such protecting groups can be easily split off, i.e. without

that unwanted side reactions take place, for example solvolytic, reductive or also under physiological conditions.

Protecting groups of this kind, as well as their introduction and cleavage, are for example described 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. In, Schroeder and 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 in the residue can, 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 phenyl lower oxycarbonyl which is optionally substituted with nitro, e.g. 4-nitrobenzyloxycarbonyl. Other suitable hydroxy protecting groups are e.g. trisubstituted silyl, such as trilower alkylsilyl, e.g. trimethylsilyl or tert-butyl-dimethylsilyl, 2-halo-lower alkyl groups, e.g. 2-chloro-, 2-bromo-, 2-iodo- and 2,2,2-trichloroethyl, and 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 groups is the trilower alkylsilyl group.

A carboxyl group R2 is usually protected in esterified form, whereby the ester group is easily cleavable under gentle conditions, e.g. under mildly reductive, such as hydrogenolytic, or mildly solvolytic, such as acidolytic or especially basic or neutral hydrolytic conditions.

A protected carboxyl group can in particular also be

an esterified carboxyl group that is cleavable under physiological conditions or can be easily converted to another functional converted carboxyl group, such as to another esterified carboxyl group.

Such esterified _carboxyl groups R^ 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, where i.a. lower alkoxycarbonyl, e.g. methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl or tert.-butoxycarbonyl, and (hetero-)arylmethoxycarbonyl with 1-3 aryl residues or a monocyclic heteroaryl residue, whereby these are optionally mono- or polysubstituted with 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 mentioned above, substituted benzyloxycarbonyl, e.g. 4-nitrobenzyloxycarbonyl, optionally, e.g. as above, substituted diphenylmethoxycarbonyl, e.g. diphenylmethoxycarbonyl, or triphenylmethoxycarbonyl, or optionally, e.g. as above, substituted picolyloxycarbonyl, e.g. 4-picocyloxycarbonyl, or furfuryloxycarbonyl, such as 2-furfuryloxycarbonyl. Other suitable groups are lower alkanoylmethoxycarbonyl, such as acetonyloxycarbonyl, aroylmethoxycarbonyl, where the aroyl group is preferably benzoyl which is optionally substituted, e.g. with halogen, such as bromine, e.g. phenacyloxycarbonyl, halolower oxycarbonyl, such as 2-halolower oxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, or w-halogeno-lower oxycarbonyl, where lower alkoxy contains 4-7 carbon atoms, e.g. 4-chlorobutoxycarbonyl, phthalimidomethoxycarbonyl, lower alkenyloxycarbonyl, e.g. allyloxycarbonyl, or ethoxycarbonyl which is substituted in the 2-position with lower alkylsulfonyl, cyano or trisubstituted silyl, such as trilower alkylsilyl or triphenylsilyl, e.g. 2-methylsulfonyl-ethoxycarbonyl, 2-cyanoethoxycarbonyl, 2-trimethylsilylethoxycarbonyl or 2-(di-n-butyl-methyl-silyl)-ethoxycarbonyl.

Other protected carboxyl groups that exist in esterified form are corresponding organic silyloxycarbonyl, further corresponding organic stannyloxycarbonyl groups.

These contain silicon or the tin atom is preferably lower alkyl, especially methyl or ethyl, further lower alkoxy, e.g. methoxy, as substituents. Suitable silyl or stannyl groups are primarily trilower alkylsilyl, especially trimethylsilyl or dimethyl-tert-butylsilyl, or correspondingly substituted stannyl groups, e.g. tri-n-butylstannyl.

An esterified carboxyl group R' which is cleavable under physiological conditions is primarily an acyloxymethoxycarbonyl group, where acyl e.g. means the residue from an organic carboxylic acid, primarily an optionally substituted lower alkane carboxylic acid, or where acyloxymethyl forms the residue of a lactone, 1-lower carboxyl oxycarbonyl, or also 1-lower oxycarbonyloxy carbonyl, where lower alkyl e.g. is methyl, propyl, butyl or especially ethyl or lower alkoxy, e.g. methoxy, 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-crotonolactonyl or 4-butyrolacton-4-yl, indanyloxycarbonyl, e.g. 5-indanyloxycarbonyl, 1-ethoxycarbonyloxyethoxycarbonyl, methoxymethoxycarbonyl or

1- methoxyethoxycarbonyl.

Preferred protected carboxyl groups R^ are the 4-nitrobenzyloxycarbonyl, lower alkenyloxycarbonyl and ethoxycarbonyl groups which are substituted in the 2-position with lower alkylsulfonyl, cyano or trilower alkylsilyl, as well as above all the esterified carboxyl groups which are cleavable under physiological conditions, such as e.g. lower alkanoyloxymethoxycarbonyl or 1-lower oxycarbonyl-oxy-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 amino, nitro or azido group. In a corresponding acyl-amino group, acyl is, for example, the acyl residue in an organic acid with e.g. up to 18 carbon atoms, especially an alkane carboxylic acid which is optionally substituted, e.g. with halogen or phenyl, or benzoic acid which is optionally substituted, e.g. with 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, halo-lower alkanoyl, such as 2-haloacetyl, especially 2-fluoro-, 2-bromo-, 2-iodo-, 2,2,2-trifluoro- or 2,2 ,2-trichloroacetyl, optionally substituted benzoyl, e.g. benzoyl, halobenzoyl, such as 4-chlorobenzoyl, lower alkoxybenzoyl, such as 4-methoxybenzoyl, or nitrogenoyl, such as 4-nitrobenzoyl.

In particular, also lower alkenyloxycarbonyl, e.g. allyloxycarbonyl, or lower alkoxycarbonyl which is optionally substituted in the 1- or 2-position is suitable, as lower alkoxycarbonyl, e.g. methoxy- or ethoxycarbonyl, optionally substituted benzyloxycarbonyl, e.g. benzyloxycarbonyl or 4-nitrobenzyloxycarbonyl, aroyloxycarbonyl, in which the aroyl group is preferably benzoyl which is optionally substituted, e.g. with halogen, such as bromine, e.g. benazyloxycarbonyl, 2-halolower oxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, or 2-(trisubstituted silyl)ethoxycarbonyl, such as 2-trilower alkylsilylethoxycarbonyl, e.g. 2-trimethylsilylethoxycarbonyl or 2-(di-n-butylmethylsilyl)ethoxycarbonyl, or 2-triarylsilylethoxycarbonyl, such as 2-triphenylsilylethoxycarbonyl.

In an acylimino group, acyl is, for example, the acyl residue in an organic dicarboxylic 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 phenyl-thioamino 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, or a pyridylthioamino group. 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 silicon-

respectively the 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

correspondingly substituted stannyl, e.g. tri-n-butylstannyl.

Other protected amino groups are e.g. enamino groups,

which contains an electron-withdrawing substituent, for example a carbonyl group, at the double bond in the 2-position. Protective 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 with e.g. lower alkyl, such as methyl or tert.-butyl, lower alkoxy such as methoxy, halogen, such as chlorine, and/or nitro, or in particular a carbonic acid half-ester such as a carbonic lower-

alkyl half-esters, e.g. -methyl half-ester or -ethyl half-ester, and lower alk-1-ene especially 1-propene. Corresponding protecting groups are primarily l-lower alkanoylprop-l-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-yl.

Preferred protected amino groups are e.g. azido, phthalimido, nitro, lower alkenyloxycarbonylamino, benzyloxycarbonylamino which is optionally substituted with nitro, 1-lower alkanoyl-lower alk-1-en-2-ylamino or 1-lower alkenyloxycarbonyl-lower alk-1-en-2-ylamino.

Salts of compounds according to the invention are primarily pharmaceutically acceptable, non-toxic salts of compounds of formula I. Such salts are formed, for example, by compounds of formula I, where R~ is carboxyl and are primarily metal or ammonium salts, such as alkali metal and alkaline earth metal, e.g. sodium, potassium, magnesium or potassium salts, as well as ammonium salts with ammonia or suitable organic amines, such as lower alkylamines, e.g. triethylamine, hydroxyl lower alkylamines, 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 ester, lower alkylene amines, e.g. 1-ethylpiperidine, cycloalkylamines, e.g. dicyclohexylamine, or benzylamines, e.g. N,N'-bienzylethylenediamine, dibenzylamine or N-benzyl-o-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 acid, sulfuric acid 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, ascorbic acid, methanesulfonic acid or 4-toluenesulfonic acid. Compounds of formula I with an acidic and with a basic group can also exist in the form of internal

salts, i.e. in zwitterionic form.

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

The penem compounds of formula I exhibit R configuration at carbon atom 5, and S configuration at carbon atom 6. The compounds of formula I may have additional centers of chirality in the substituents R-^ and/or A, each of which may be present in R-, S or the racemic R,S configuration.

In connection with formula I, where R^ is lower alkyl with 2-

7 carbon atoms which are asymmetrically substituted in the a-position (at carbon atom 1'), especially I'-ethyl, the substituents at carbon atom 1' preferably take the R-configuration.

The invention relates in particular to compounds of formula I, where R^ is lower alkyl which is substituted by hydroxy or protected hydroxy, R 2 means carboxyl or protected carboxyl R^, R 3 is amino, lower alkylamino, dilower alkylamino, a group of the formula -N=C(X-L, X2 ) , where X.^ is hydrogen, amino, lower alkylamino, dilower alkylamino, lower alkyleneamino, nitroamino, hydrazino, anilino, lower alkoxy, phenyl lower alkyl, lower alkylthio, lower alkyl, amino lower alkyl, N-1 lower alkyl amino, lower alkyl, N,N-di lower alkyl amino lower alkyl, lower alkenyl, phenyl, pyridyl, e.g. 2- or 4-pyridyl, thienyl, e.g. 2-thienyl, or thiazolyl, e.g. 4-thiazolyl, and X^ is amino, lower alkylamino, dilower alkylamino, lower allyleneamino, hydrazino, anilino, lower alkoxy, phenyl lower alkyl or lower alkylthio, or protected amino, and A is linear lower alkylene substituted with lower alkyl of 1-4 carbon atoms, provided that R^ is different from 1-hydroxyethyl or protected 1-hydroxyethyl, when A is linear lower alkylene geminally substituted with two methyl groups, R^ has the above meaning, and R^ is amino or protected amino, salts

of such compounds of formula I, which contain a salt-forming group, optical isomers of compounds of formula I, which have centers of chirality in the radicals R₁ and/or A, and mixtures of these optical isomers.

The invention applies above all to compounds of formula

In where R^ is lower alkyl which is substituted with hydroxy, tri-lower alkylsilyloxy, 2-halo-lower alkyloxy, 2-halo-lower oxycarbonyloxy or phenyl lower alkylcarbonyloxy which is optionally substituted with nitro, R^ means carboxyl, lower alkenyloxycarbonyl, benzyloxycarbonyl which is optionally substituted with nitro, lower alkanoyl methoxycarbonyl, 2-halogeno-lower oxycarbonyl, 2-trilower alkylsilyl-ethoxycarbonyl or an esterified carboxyl group which is cleavable under physiological conditions, e.g. 1-lower oxycarbonyllyoxylower oxycarbonyl, lower alkanoyloxymethoxycarbonyl, α-aminoloweralkanoyloxy ethoxycarbonyl or phthalidyloxycarbonyl, R^ means amino, lower alkylamino, dilower alkylamino, a group of the formula

-N=C(X-^,X 2 ), where X^ is hydrogen, amino, lower alkylamino, lower alkyl, phenyl or pyridyl, e.g. 2-pyridyl, and X^

is amino, lower alkylamino or dilower alkylamino,

azido, phthalimino, nitro, lower alkenyloxycarbonylamino, benzyloxycarbonylamino optionally substituted with nitro, 1-lower alkanoyl-lower alk-l-en-2-ylamino or 1-lower alkenyloxycarbonyl-lower alk-l-en-2-ylamino, and A is linear lower alkylene which is mono- or disubstituted with lower alkyl of 1-4 carbon atoms, provided that R^ is different from 1-hydroxyethyl or protected 1-hydroxyethyl, when A is linear lower alkyl geminally substituted with two methyl groups, R^ has the above meaning, and R^ is amino, or protected amino, salts of such compounds of formula I, which exhibit a salt-forming group, optical isomers of compounds of formula I, which have centers of chirality in the residues R^ and/or A, and mixtures thereof optical isomers.

The invention primarily applies to compounds of formula

Where I means lower alkyl which is substituted by hydroxy and A means linear lower alkylene of 1-4 carbon atoms, which is monosubstituted with methyl or ethyl, or where R^ means hydroxymethyl and A means linear lower alkylene of 1-

4 carbon atoms that are disubstituted with methyl or ethyl,

and where R 2 is carboxyl, 1-lower oxycarbonyloxycarbonyl or lower alkanoyloxymethoxycarbonyl and R 2 is amino, lower alkylamino or formamidino, salts of such compounds of formula I, optical isomers of compounds of formula I, which have chirality centers in the residues R 2 and/or A, and mixtures of these optical isomers.

The invention mainly relates to compounds of formula

In where R^means hydroxymethyl or 1-hydroxyethyl, and A

is ethylene or 1,3-propylene which is monosubstituted with methyl or ethyl or where R^ is hydroxymethyl and A means ethylene which is disubstituted with methyl, and where R^ is carboxyl and R^ is amino, and salts of such compounds' with formula I.

The invention further relates to the pure optical isomers of such compounds of formula I, which have additional chirality centers in the substituents R^ and/or A, especially (1'R) isomers of compounds of formula I, where R^ is 1' -hydroxyethyl, and salts of such compounds with formula I.

The invention applies in particular to those compounds with formula

I and their salts mentioned in the examples.

The compounds in the present invention can be prepared using methods known per se.

The new compounds are produced e.g. by that

a) a ylide compound of formula

where R^, R^, R-,°9A have the meanings indicated under formula I, Z means oxygen or sulfur and X<+>is either a 3-fold substituted phosphonium group or a doubly esterified phosphono group together with a cation, are closed, or

b) a compound of formula

where R^, R^, R^ and A have the meanings indicated below

formula 1, is treated with an organic compound of 3-valent phosphorus, and if desired or necessary, in an obtainable compound of formula I, a protected hydroxy group in the residue R^ is transferred to the free hydroxy group, and/or if desired, in an obtainable compound with formula I, a protected carboxyl group R^ is transferred to the free carboxyl group or in another protected carboxyl group R^ or a free carboxyl group R2 to a protected carboxyl group R^, and/or if desired, a protected amino group R^ is transferred to the free amino group or a free amino group R^ is transferred to a substituted amino group, and/or if desired, an obtainable compound with salt-forming groups is transferred to a salt or an obtainable salt to the free compound or to another salt, and/or if desired, an obtainable compound is split mixture of isomeric compounds with formula I to the individual isomers.

In the starting compounds of formulas II and III, functional groups, such as a free hydroxy group in the residue R^ and especially a triamino group R^ , are preferably protected with conventional protecting groups, e.g. with one of the above.

a) Cyclization of the compound of formula II.

The group X<+> in the starting material of formula II is one of them

phosphonio or phosphono groups common in Wittig condensation reactions, especially a triaryl, e.g. tri-phenyl-, or tri-lower alkyl-, e.g. tri-n-butylphosphonium group or a phosphono group which is doubly esterified with lower alkyl, e.g. ethyl, whereby the symbol X<+> in the case of the phosphono group additionally includes the cation of a strong base, especially a suitable metal, such as alkali metal, e.g. lithium, sodium or potassium ion. Preferred as group X<+> is on the one hand triphenylphosphonium 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 phosphonio compounds of formula II, the negative charge is neutralized by the positively charged phosphonio group. In phosphono compounds with formula II, the negative charge is neutralized with the cation in a strong base, which, depending on the method of preparation for the phosphono starting material, can be e.g. an alkali metal, e.g. sodium, lithium or potassium ion. The phosphono starting materials are therefore used 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 approx. 160°C, preferably from approx. 50 to approx. 100°C. The reaction is preferably carried out in a suitable inert solvent, such as an aliphatic, cycloaliphatic or aromatic hydrocarbon, e.g. hexane or

benzene, a halogenated hydrocarbon, e.g. methylene chloride,

an ether, e.g. ethyl ether, a carboxylic acid amide, e.g. dimethylformamide, a lower alkyl sulfoxide, e.g. dimethylsulfoxide or a lower alkanol, e.g. methanol, or in a mixture thereof, and if necessary, in an inert gas, e.g. nitrogen atmosphere.

b. Cyclization of the compound of formula III.

An organic compound of 3-valent phosphorus is derived, e.g.

of the phosphoric acid and is especially an ester thereof 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(OR )„-N(R, )0, where R and R, independently of each other, mean lower alkyl, e.g. methyl, or aryl, e.g. phenyl. Preferred compounds of 3-valent phosphorus are trialkyl phosphites, e.g. trimethyl phosphite or triethyl phosphite.

The reaction is preferably carried out in an inert solvent, 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 molar equivalent of a compound of formula III is reacted with 2 molar equivalents of the phosphorus compound. preferably the compound of formula III is dissolved 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.

In a preferred embodiment of the method, the starting material of formula III is prepared in situ, as described below under step 1.5, and it is reacted without isolation from the reaction mixture with the organic compound of 3-valent phosphorus, whereby the end products of formula I arise.

Such starting materials with the formulas are preferably used

II and III, leading to the compound of formula I which is initially mentioned as particularly preferred.

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

In a compound of formula I which can be obtained according to the invention with a protected amino group R., this can on

in and of itself known way, e.g. depending on the nature of the protecting group, preferably by means of solvolysis or reduction is transferred to the free amino group R^ . 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 thiophenolate, 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 hydrogenolysis, i.e. by treatment with hydrogen in the presence of a suitable hydrogenation catalyst, such as a palladium catalyst, and allyloxycarbonylamino, by reaction with a compound of palladium, 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 protected with an organic silyl or stanyl

group, can be released e.g. by means of hydrolysis or alcoholysis, an amino group protected with a 2-halogen - lower 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 resulting condensation product. 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 gives off a fluoride anion, such as an alkali metal fluoride, e.g. sodium fluoride, in the presence of a macrocyclic polyether ("crown ether") or 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 to free amino, e.g. by reduction, for example by catalytic hydrogenation with hydrogen in the presence of a hydrogenation catalyst such as platinum oxide or palladium or by treatment with zinc in the presence of an acid, such as acetic acid.

An amino group that is 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.

Furthermore, a free amino group can be transferred to a substituted amino group in a manner known per se. Thus, for example, amino by reaction with a corresponding acyl halide, such as -chloride, can be transferred to acylamino R^ and with a B-dicarbonyl compound, such as a 1-lower alkanoyl acetone or an acetoacetic acid lower alkyl ester transferred to 1-lower alkanoyl, respectively. The conversion of amino groups into amide-diono, guanidino, isourea, isothiourea, imidoether and imidothioether groups can, for example, be carried out according to the methods described in DE off. publication no. 2652679. Thus, for example, compounds of formula I, where R^ is amino, by reaction with trimethylsilyl chloride and an imido halide with the formula /Jx yY^) C=X^/ Y ? , where means halogen, e.g. chlorine, and Y^ means an anion, e.g. chloride, are transferred to amidines and by reaction with substituted isourea or isothioureas with the formula (X^-^OX,,, where Y^ means lower alkoxy or lower alkylthio, are transferred to guanidines. Furthermore, a free amino group can be transferred to an amino group that is mono- or disubstituted with lower alkyl. The introduction of lower alkyl groups takes place, for example, by reaction with correspondingly reactive lower alkyl esters, such as -halides, e.g. chlorides or -bromides, or -sulfonates, e.g. -methane- or -p-toluene-sulfonates, in the presence of a basic condensing agent, such as an alkali or alkaline earth metal- hydroxide or carbonate, eg potassium hydroxide or sodium carbonate, in an inert solvent, such as a lower alkanol, at room temperature or elevated or lowered temperature, eg at about -20 to +80°C.

In a compound of formula I which can be obtained according to the invention, where R 2 means a protected carboxyl group R 1 , the carboxyl group 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 diphenylmethoxycarbonyl can be transferred to free carboxyl, e.g. by treatment with a carboxylic acid, such as formic acid or trifluoroacetic acid, optionally with the addition of a nucleophilic compound, such as phenol or anisole. Optionally substituted benzyloxycarbonyl can be cleaved e.g. by hydrogenolysis, i.e. 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 be transferred to free carboxyl 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-donating agent, which together with the metal can produce nascent hydrogen, such as a suitable carboxylic acid, e.g. a lower alkane carboxylic acid which is optionally substituted, e.g. with hydroxy, e.g. acetic acid, formic acid or glycolic acid, or an alcohol or thiol, whereby water is preferably added. The removal of an allyl protecting group can e.g. take place by reaction with a compound of palladium, e.g. tetrakis(tri-phenylphosphine) palladium, in the presence of triphenylphosphine and with the addition of a carboxylic acid, e.g. 2-ethylhexanoic acid, or a salt thereof. By treatment with a reducing metal or a reducing metal salt, as described above, 2-halo-lower oxycarbonyl (possibly after conversion of a 2-bromo-lower oxycarbonyl group to a corresponding 2-iodo-lower oxycarbonyl group) or aroylmethoxycarbonyl can also be converted to free carboxyl, whereby aroyl-methoxycarbonyl can likewise is cleaved by treatment with a nucleophilic, preferably salt-forming reagent, such as sodium thiophenolate or sodium iodide. Substituted 2-silylethoxycarbonyl can also be converted to free carboxyl by treatment with a salt of hydrofluoric acid which releases 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. Carboxyl which is esterified with an organic silyl or stannyl group, such as trilower alkylsilyl or -stannyl, can be liberated in the usual way solvolytically, e.g. by treatment with water or an alcohol. A lower alkoxycarbonyl group which is substituted in the 2-position with lower alkylsulfonyl or cyano, can e.g. is transferred into the free carboxyl by treatment with a basic agent, such as an alkali metal or alkaline earth metal hydrazide or carbonate, e.g. sodium or potassium hydroxide, or sodium or potassium carbonate.

In compounds of formula I which can be prepared according to the invention, where the radical R, is substituted with protected hydroxy, the protected hydroxy group can be transferred in a manner known per se to 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 correspondingly protected amino group, a tri-lower alkylsilyl group, e.g. with tetrabutylammonium fluoride and acetic acid (under these conditions carboxyl groups protected by trisubstituted silylethyl groups are not cleaved). A 2-halogen lower alkyl group and an optionally substituted benzyl group are cleaved off reductively. On the other hand, compounds of formula I where R^ denotes carboxy can also be transferred to compounds of formula I, where R^ constitutes a protected carboxyl group R^, in particular an esterified carboxyl group RJ, and primarily an esterified carboxyl group that is cleavable under physiological conditions. 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 phenyldiazolav-erealkane, 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-hydroxynitrogen compounds, such as N-hydroxy-succinimide) or mixed anhydrides (obtained e.g. with haloformic acid) -lower alkyl esters, such as chloroformate ethyl or chloroformate isobutyl ester, or with haloacetic acid halides, such as trichloroacetic acid chloride), by reaction with alcohols, possibly in the presence of a base, such as pyridine, are transferred to an esterified carboxyl group.

In a compound of formula I with an esterified carboxyl group Ri, this can be transferred to another esterified carboxyl group R^, e.g. 2-chloroethoxycarbonyl or 2-bromomethoxycarbonyl by treatment with an iodine salt, e.g. sodium iodide, to 2-iodoethoxycarbonyl. Furthermore, in compounds of formula I containing a carboxyl group R^ which is protected in esterified form, the carboxyl protecting group can be cleaved off as described above and a compound of formula I obtained with a free carboxyl group or a salt thereof, by reaction with the reactive ester of a corresponding alcohol is transferred to a compound of formula I, where R^ is an esterified carboxyl group which is cleavable under physiological conditions.

Salts of compounds of formula I with salt-forming groups can be prepared in a manner known per se. Thus, salts can be formed of compounds of formula I with the free carboxyl group R^, e.g. by treatment with metal compounds, such as alkali metal salts of suitable organic carboxylic acids, e.g. the sodium salt 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 ion 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 isoelectric point, e.g. with weak bases, or when treated with ion exchangers.

Salts can be transferred in the usual way to 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 into the individual isomers using methods known per se, mixtures of diastereomeric isomers e.g. by fractional crystallization, adsorption chromatography (column or thin-layer chromatography) or other suitable separation methods.

The cleavage of the obtained racemates into their optical antipodes can take place in different ways. One of these methods consists in reacting a racemate with an optically active auxiliary substance, the resulting mixture of two diastereomeric compounds is 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, wherein R 1 is carboxy. These acidic racemates can be reacted with optically active bases, e.g. esters of optically active amino acids, or (-)-brucine, (+)-quinidine, (-)-quinine, (+)-quinchonine, (+)-dehydroabiethylamine, ( + )- and (-)-ephedrine, (+ )- and (-)-1-phenylethylamine or their N-mono- or N,N-dialkylated derivatives to mixtures, consisting of two diastereomeric salts.

In the carboxyl group containing racemates, this carboxyl group can also be esterified or esterified with an optically active alcohol, such as (-)-menthol, (+)-borneol, (+)- or (-)-2-octanol, whereupon the carboxyl group is released after re - achieved isolation of the desired diastereomer.

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(- )-malic acid, N-acylated, optically active amino acid, (+)- and (-)-camphanic acid, (+)- and (-) -ketopic acid, L-(+)-ascorbic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid (3), (+)- or ( - )-a-bromocamphor-TT-sulfonic acid, D ( - )-quinic acid, D ( - )-isoascorbic acid, D(-)- and L(+)-mandelic acid, (+)-1-menthoxyacetic acid, D(-)- and L(+)-tartaric acid and their di-O-benzoyl and di-O-p-to-luyl derivs.

By reaction with optically active isocyanates, such as with (+)- or (-)-1-phenylethyl isocyanate, compounds of formula (I), where R- means protected carboxy and lower alkyl substituted by hydroxy, can be converted into a mixture of diastereomers urethanes.

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

The cleavage of the separated diastereomers in the optically active compounds of formula I also takes place using usual methods. The acids or bases are freed from the salts, e.g. when treated 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.

A further method of dividing the racemates, consists

in chromatography on optically active absorption layers, for example on cane sugar.

According to a 3rd method, the racemates can be dissolved in optically active solvents and the most soluble optical antipode is crystallized.

In a 4th method, the different reactivity of the optical antipodes to biological material such as microorganisms or isolated enzymes is used. According to a 5th method, the racemate is dissolved and one of the optical antipodes is crystallized by adding a small amount of 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. on the step for the starting compounds of formulas II or III, or on

a freely chosen step in the methods described below for preparing the starting compounds of formula II.

In all compounds of formula I as obtained by

of the subsequent conversions, such reactions are preferred which take place under neutral or alkaline conditions.

The method also includes such embodiments, after which compounds resulting 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 an optionally substituted methylidene group as described below, by ozonization and subsequent reduction of the formed ozonide, analogously to the method further below, (step 2.3), after which the ring closure to the compound of formula I takes place in the reaction solution.

The starting compounds with the formulas II and III and the preceding steps can be prepared as indicated in the reaction schemes I and II:

Reaction nucleus 1.

In the compounds of the formulas IV, VI, VII and II<1>, Z' is oxygen, sulfur or also a methylidene group which is optionally substituted with one or two substituents Y, which can be transferred to an oxo group Z by oxidation. 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 a carboxyl group which is esterified with an optically active alcohol, such as 1-menthone, e.g. one of the optionally substituted lower alkoxycarbonyl or arylmethoxycarbonyl residues mentioned under R2, or also 1-menthyloxycarbonyl. The methylidene group Z' has preferred one of the aforementioned substituents. Emphasis should be placed on the methoxycarbonyl methylidene and ethoxycarbonyl methylidene groups.

In the compounds with formulas IV to VIII as well as II<1>, the residue preferably contains one of the aforementioned protected hydroxy groups, e.g. optionally substituted 1-phenyllower oxy, optionally substituted phenyllower oxycarbonyloxy or trisubstituted silyloxy, and a free amino group R^ is preferably present in protected form.

Step 1. 1: A thio-azetidinone of formula IV is obtained by

a 4-W-azetinon of the formula V, where W means a nucleofugic leaving group, is treated with a mercapto compound of the formula

or a salt, e.g. an alkali metal-, such as a sodium or potassium salt thereof, and if desired, is transferred into an obtainable compound of formula IV, where R^ is lower alkyl substituted with hydroxy, hydroxy to protected hydroxy.

The nucleofuge leaving group W in a starting material of formula V is one with the nucleophilic residue

R3-A-C(=Z')-S-

replaceable remainder. Such groups W are, for example, acyloxy residues, sulfonyl residues Ro-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 acyl residue from one of the optically active acids mentioned above. In a sulfonyl residue RQ-SO2- is

Rq is, for example, lower alkyl which is optionally substituted with hydroxy, such as methyl, ethyl or 2-hydroxyethyl, also correspondingly substituted optically active lower alkyl, e.g.

(2R)- or ("S)-1-hydroxyprop-2-yl, methyl which is substituted with an optically active residue, such as campheryl, or benzyl, or optionally substituted phenyl, such as phenyl, 4-bromophenyl or 4-methylphenyl. A halogen residue W is, for example, 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 a water-miscible organic solvent.

The basic conditions can, for example, be set by adding an inorganic base, such as an alkali metal or alkaline earth metal hydroxide, carbonate or hydrogen carbonate, e.g. of sodium, potassium or calcium hydroxide, carbonate or bicarbonate. As an organic solvent, it can e.g. alcohols that are miscible with water 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, etc. 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 the hydroiodic acid or the thiocyanic acid, e.g. an alkali metal, such as the sodium salt, the reaction can be accelerated.

In the reaction, both (3S,4S)- and also (3S,4R)-configured compounds of formula V or mixtures thereof can be used. The constituent group R^-A-C(=Z')-S- is preferably directed by the group R^ in the trans position, regardless of whether W is in the cis or trans position to the group R^. Self

if the trans-(3S,4R)-isomer is 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 by chromatography and/or by crystallization.

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

An azetidinone of formula V, where R is acetoxymethyl,

is described in DE official letter Mr. 2950898. Other azetidinones of formula V can be prepared using methods known per se, for example by reacting a vinyl ester with the formula R^-CH=CH-W with chlorosulfonyl isocyanate and the resulting cycloadduct is reacted with a reducing agent, e.g. e.g. sodium sulfite. In this synthesis, mixtures of cis and trans isomers are usually obtained, which can be separated into the pure (3S) isomers, e.g. by chromatography and/or crystallization or distillation. The racemic (3S,4RS)-isomer obtained can, as described above, be divided into the pure (3S,4R)-antipodes. The optically active compounds of formula V can also be prepared using the method indicated below in reaction scheme II.

Step 1. 2:

An α-hydroxycarboxylic acid compound of formula VI is obtained by reacting a compound of formula IV with a glyoxylic acid compound of the formula OHC-R^ or a suitable derivative thereof, such as a hydrate, hemihydrate or a hemiacetal, e.g. a hemiacetal with a lower alkanol, e.g. methanol or ethanol, and if desired, transferred in an obtainable compound of formula VI, where R 1 is lower alkyl substituted with hydroxy, hydroxy transferred in protected hydroxy.

The compound VI is usually obtained as a mixture of the two isomers (with regard to the grouping ^CH^OH). But the pure isomers thereof can also be isolated.

The attachment of the glyoxylic acid ester compound to the nitrogen atom in the lactan ring takes place at room temperature or, if necessary, during heating, e.g. to approx. 100°C, and this 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 during the 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.

Step 1. 3;

Compounds of formula VII, 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 VI to a reactive, esterified hydroxy group, especially to halogen, e.g. 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 VI, R preferably stands for lower alkyl which is substituted with a protected hydroxy group.

The compounds of formula VII can be obtained in the form of mixtures of the isomers (with regard to the grouping ^CH^ 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 phosphorus oxyhalide, especially -chloride,

a halophosphonium halide, such as triphenylphosphonium dibromide or diiodide, or a suitable organic sulfonic acid halide, such as -chloride, preferably in the presence of a basic agent, primarily an organic, basic middec, 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 a compound of formula VII which can be obtained in this way, a reactive, esterified hydroxy group Xq can be converted in a manner known per se into another reactive, esterified hydroxy group. Thus, e.g.

a chlorine atom 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, is utilized with a bromine or iodine atom.

Step 1. 4:

The starting material of formula II<1> is obtained by treating a compound of formula VII, where Xq stands for a reactive esterified hydroxy group, with a suitable phosphine compound, such as a trilower 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 dilaveral alkyl phosphite, e.g. -diethyl phosphite.

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, e.g. between -10 and +100°, preferably at approx. 20-80°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.

When using a phosphine compound, it is usually worked in the presence of a basic agent, such as an organic base, e.g. an amine, such as triethylamine, diisopropylethylamine or "polystyrene-honeybase", and the ylide starting material of formula II (resp. II<1>) is then obtained directly, which is formed from the corresponding phosphonium sheet.

A starting compound of formula II', where X is a phosphono group together with a cation, is preferably prepared in situ, an obtainable compound of the 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.

Step 1. 4a:

A starting compound of formula II<1>, where Z' stands for oxo, can further be obtained by treating a mercaptide of formula VIII, where M stands for a metal cation, with an acylating agent which introduces the residue R^-A-C(=0) -.

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

+ 2 + for example a cation with the formula M , or M /2, where M + in particular stands for a salt cation and M 2 + e.g. stands for the divalent cation in a suitable transition metal, e.g. copper, lead or mercury.

An acylating agent which introduces the residue R^-A-C^O)- is e.g. the acid R^-A-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^-A-COOH, e.g. in the presence of a suitable water-extracting agent, such 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. triethylamine, 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 to approx. +20°C.

The starting compounds with formula VIII 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 triphenylmethylmercaptan is transferred to a compound with the formula where W means triphenylmethylthio or lower alkanoylthio, e.g. acetylthio, this 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 is converted in the presence of a base, e.g. pyridine or tri-n-butylamine, in a suitable solvent, e.g. diethyl

ether or methanol, with a salt of formula MA, where M has the above meaning, but in particular 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.

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

can be used directly in the ring closure reaction to produce the end products of formula I. But in compounds of formula II', where the residue contains as a substituent a protected hydroxy group, e.g. a hydrolytically easily cleavable protected hydroxy group, such as trisubstituted silyloxy, the hydroxy protecting group can also be first cleaved off and then used in the ring closure reaction the obtained compound of formula II', where R^ is lower alkyl which is substituted by hydroxy.

Step 1. 5:

A compound of formula (III) is obtained by treating an azetidinone of the formula (IV), where Z' means sulphur, with a compound of the formula R^-COOH or in particular a reactive derivative thereof, such as an acid halide, e.g. the acid chloride, at a temperature from 20 to 80°C, preferably at 40-60°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 is preferably worked 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 the compounds II', IV, VI and VII, an optionally substituted methylidene group Z<1> can be transferred to the oxo group Z by ozonization and subsequent reduction of the formed ozonide, according to the method described below in step 2.3.

The starting compounds of formula V, where W is a sulfonyl residue of the formula F^-SC^-, can also be prepared according to the following reaction scheme II.

Reaction nucleus II.

In the compounds of the formulas (XI) - (XIV) and (Va) R-^ in particular stands for lower alkyl which is substituted with a protected hydroxy group.

Step 2. 1:

Compounds of formula (XII) can be prepared by epimerizing a compound of formula (XI).

The epimerization takes place, for example, in the presence of a basic agent, such as an amine, e.g. a tri-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 , C/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 0-50°C, preferably at room temperature.

In the compounds of formula (XII) which can be obtained according to the invention, a protected hydroxy group contained in the residue R can be replaced with another protected hydroxy group, 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 removed first and a solvolytically cleavable hydroxy group is introduced into the obtained compound of formula XII, where R 1 is lower alkyl substituted with hydroxy.

The cleavage of the hydrolytically 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 of formula FV<->X^, where R' means the hydroxy protecting group and X^ e.g. means a reactive, esterified hydroxy group, for example halogen, e.g. chlorine, bromine or iodine, or sulfonyloxy, such as methanesulfonyloxy, benzenesulfonyloxy or 4-toluenesulfonyloxy.

The starting compounds with formula (XI) are known, for example, from DE off. document 3039504 and from GB patent application 2061930.

Step 2. 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 radical R .

o

A suitable basic agent is, for example, one of the basic agents mentioned under step 2.1, especially one of the mentioned bicyclic amines, 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 (R -X^), where X^ 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 turnover is preferably carried out in two stages, whereby

in the first step the penam compound of the formula (XII) is treated with at least equimolecular amounts of the basic agent and an obtainable intermediate of the formula

where indicates the protonated form (cation) of the basic agent, is preferably reacted with the esterifying agent from the reaction mixture without isolation. 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. 0-50°C, preferably at room temperature. In a preferred embodiment of the method, the penam compound of formula (XII) is prepared in situ, by first treating a compound of formula (XI) as described under step 2.1 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 further with the esterifying agent to the compounds of formula (XIII).

Step 2. 3:

An oxalyl-azetidinone of the formula (XIV) can be prepared by ozonizing a compound of the formula (XIV), and the ozonide formed is reductively cleaved to the oxo compound.

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

An ozonide obtained as an intermediate is cleaved reductively to a compound of formula XIV, usually without isolation, whereby catalytically activated hydrogen is used, e.g. hydrogen in the presence of a heavy metal hydrogenation catalyst,

as a nickel, further palladium catalyst, preferably on a suitable carrier material, such as calcium carbonate or coal, 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 converted into the corresponding epoxide compounds or oxides, whereby the epoxide formation can take place due to a C, C double bond and the oxide formation due to a present oxide-forming hetero-, such as sulphur- , phosphorus or nitrogen atom. Such compounds are e.g. suitable substituted ethylene compounds (which in the reaction are converted into ethylene oxide compounds), such as tetracyanethylene, or particularly suitable sulphide compounds, (which in the reaction convert-

nes to sulfoxide compounds), such as dilave alkyl sulfides,

primarily dimethyl sulphide, suitable organic phosphorus compounds such as a phosphine (which in the reaction is converted into a phosphine oxide) which is optionally substituted with phenyl and/or lower alkyl, e.g. methyl, ethyl, n-propyl or n-butyl, such as trilower alkyl phosphines, e.g. tri-n-butyl-phosphine, or triphenylphosphine, further trilower alkyl phosphites (which in the reaction are converted into phosphoric acid trilower alkyl esters), usually in the form of corresponding alcohol adduct compounds, such as trimethyl phosphite, or phosphoric acid tri-amides, which optionally contain lower alkyl which substituents, such as hexalower alkyl phosphoric acid triamide, e.g. hexamethylphosphoric acid triamide, the latter preferably in the form of a methanol adduct, further suitable nitrogen bases (which in the reaction are converted into the corresponding N-oxides),

as heterocyclic nitrogen bases of an aromatic character, e.g. bases of the pyridine type and especially pyridine itself. The splitting of the usually non-isolated ozonide normally takes place under the conditions used for their preparation, i.e. in the presence of a suitable solvent or solvent mixture, as well as during cooling or slight heating, whereby work is preferably done at temperatures from approx. -10 to approx. +25°C and the reaction usually ends at room temperature.

Step 2. 4:

An azetidinone of formula (Va) can be prepared by solvolyzing an oxalyl-azetidinone of 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. diethyl ether, an aromatic hydrocarbon, such as benzene, a halogenated hydrocarbon, such as methylene chloride or chlorobenzene, an ester such as ethyl acetate, etc., at temperatures between approx. room temperature and approx. 6 5°C.

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

During the ozonolysis, possibly small amounts of acid occur, which can cause the cleavage of a solvolytically easily cleavable hydroxy protecting group in the residue R^, e.g. a trisubstituted silyl residue. The resulting connection with the formula

where R| means lower alkyl which is substituted with hydroxy, can, for example, be separated chromatographically from the protected azetidinone (Va) and by renewed reaction with the agent of the form R'-X3 which introduces the hydroxy protecting group R<1>, transferred to the azetidinone of the formula (Va).

In the compounds with the formulas (II), (II'), (III), (VI), (VII) and (XII) to (XIV), a protected carboxyl group R^ according to methods known per se, can be transferred to a other protected carboxyl group R.!, whereby in consideration of the further functional groups which may possibly be contained in these compounds, the same methods can be used, which are indicated for the conversion of these substituents in the compounds of formula (I).

The invention also applies to new starting products as well as the intermediate products obtained according to the invention, such as those with the formulas (II) to (VIII), (incl. II', Ila, Va and Vb) as well as the stated methods for production

by them.

Such starting materials are preferably used and the reaction conditions are chosen so that the compounds which are 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. Compounds of formula I, where R^ means hydroxyl lower alkyl, R^ means carboxyl or an esterified carboxyl group which is cleavable under physiological conditions, and R^ is amino, lower alkylamino, dilower alkylamino or substituted methyleneamino, and pharmacologically acceptable salts of such compounds with salt-forming groups, have anti-material 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 meningitidis and Neisseria genorrhoeae, against enterobacteria, e.g. Escherichia coli, Proteus mirabilis and Klebsiella pneumoniae, against Haemophilus influenzae, Pseudomonas aeruginosa and anaerobes, e.g. Bacteroides sp., and Clostridium sp., in minimal concentrations from approx. 0.02 to approx. 64 ug/ml. In vivo, in case of systemic infection in mice, e.g.

with Staphylococcus aureus, Escherichia coli or Strepto-

coccus pyogenes, EDj was found on subcutaneous or oral application. Q values of va. 0.3 to 100 mg/kg.

The new compounds can therefore be orally or parenterally applicable anti-bacterial antibiotics, e.g. in the form of corresponding pharmaceutical preparations, find application in the treatment of infections.

Compounds of 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 of formula I .

The pharmacologically usable compounds according to the present invention can e.g. is used for the production of pharmaceutical preparations, which contain a therapeutically effective amount of the active substance together with or in admixture with inorganic or organic, solid or liquid, pharmaceutically acceptable carriers, which are suitable for oral or parenteral use, i.e. intramuscular, subcutaneous or intraperitoneal administration.

For oral administration, tablets or gelatin capsules are used, which contain the active substance together with diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, and lubricants, e.g. diatomaceous earth, lime, 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 arrowroot starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and if desired, explosives, e.g. starch, agar, alginic acid or a salt thereof, such as sodium alginate, and/or effervescent mixtures or adsorbents, dyes, flavorings

or sweeteners.

Infusion solutions, preferably isotonic, aqueous solutions or suspensions, are suitable primarily for parenteral administration, whereby these e.g. can be prepared before use from lyophilized preparations, which contain the active substance alone or together with a carrier material, e.g. mannitol. Such preparations can 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.

Present pharmaceutical preparations which, if desired, can contain other pharmacologically valuable substances, are prepared 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 125 mg to approx. 5 g for the treatment of warm-blooded (humans and animals) of approx. 70 kg weight.

The following examples serve to illustrate the invention. The temperature is indicated in °C.

In the examples, the following abbreviations are used:

DC: Thin layer chromatogram,

IR: Infrared spectrum,

UV: Ultraviolet spectrum,

NMR: Nuclear resonance spectrum,

DBU: 1,5-diazabicyclo/5,4,O/undec-5-ene,

THF: Tetrahydrofuran,

DMF: Dimethylformamide.

Experimental part.

Example 1.

(5R,6S)-2-/T2R,S)-2-(4-nitrobenzyloxycarbonylamino)-prop-1-yl/-6-(tert.butyldimethylsilyloxymethyl)-2-penem-3-carboxylic acid- p-nitrobenzyl ester..

A solution of 6.27 g of 2-(T3S,4R)-3-(tert.butyldimethylsilyloxymethyl)-4-(3R,S)-3-(4-nitrobenzyloxycarbonylamino)-butyroylthio]-2-oxo-azetidine-1 -yl/-2-triphenylphosphoranylide acetic acid p-nitrobenzyl ester in 1 liter of toluene is stirred under an argon atmosphere for 12 hours at reflux temperature. The solvent is then evaporated and the crude product is purified by chromatography on silica gel (eluent toluene/ethyl acetate 9:1). DC (silica gel, toluene/ethyl acetate 1:1); R f = 0.56; IR (CH 2 Cl 2 ): 3430; 1780; 1715; 1510; 1340; 1310 cm"<1>.

The starting material can be prepared as follows:

a. (3R,S)-3-(4-nitrobenzyloxycarbonylamino)-butyric acid.

To a solution of (3R,S)-3-aminobutyric acid (20.6 g) in 41 ml of water and 90 ml of 5 N NaOH solution is added at 0°C solid chloroformate-4-nitrobenzyl ester (47.4 g) and the the beige colored suspension is stirred for 16 hours at room temperature. After removal of the insoluble by filtration, the filtrate is diluted with 1000 ml of water and washed 2 times with CH 2 Cl 2 . The aqueous phase is adjusted to pH 2 with HC1 4 N and extracted twice with CH2C12. The combined organic extracts are washed once with brine, dried over MgSO 4 and evaporated to the white crystals of the title compound. IR in CH2C<1>2: 3425; 1710; 1500; 1335 cm"<1>.

b. (3R,S)-3-(4-nitroenyloxycarbonylamino)-thiobutyric acid.

(3R,S)-3-(4-nitrobenzyloxycarbonylamino)-butyric acid (14.1

g) is suspended in methylene chloride (250 ml) and dissolved after cooling to -10°C by adding 15.33 ml of triethylamine.

At the same temperature, a solution of chloroformic acid isobutyl ester (7.19 ml) in 50 ml of methylene chloride is added and stirred at -10° for 1 hour. Then F^S is introduced for 2 hours. After removal of excess E^S with nitrogen, 2 N F^SO^ is added to the reaction mixture and shaken well. The organic phase is separated and extracted once with 400 ml of 1.5% NaHCO 3 solution. The aqueous phase is acidified with 2 N F^SO^, 2 g are extracted with CF^C^ and these extracts are then dried over MgSO^. After evaporation of the filtered organic solution, the title compound is obtained as a yellowish oil. IR (CH 2 Cl 2 ): 3430; 2580; 1715; c. Wed.

8.22 g of (3S,4R)-3-(tert-butyldimethylsilyloxymethyl)-4-methyl-sulfonylazetidin-2-one and 11.7 g of (3R,S)-3-(4-nitrobenzyloxycarbonylamino)-butyric acid are dissolved in 180 ml of CF^C^. The yellowish solution is first added to 180 ml of water, and then 42 ml of 1 N NaOH. The vigorously stirred emulsion is stirred for 1.5 hours at room temperature. The organic phase is then separated

1 a separatory funnel and the aqueous phase is still extracted

2 times with CF^C^. The combined organic extracts are washed with a saturated aqueous MaHCO 3 solution and then with brine, dried over MgSO 4 and evaporated. The crude product obtained is purified by chromatography on silica gel with toluene/ethyl acetate 9:1. DC (silica gel, ethyl acetate); R f = 0.65;

IR (CH 2 Cl 2 ): 3420; 1765; 1710; 1680; 1500; 1340 cm"<1>.

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

A solution of 23.6 g (85 ramoles) (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 solutions are extracted twice with ethyl acetate. The organic phase is dried with sodium sulfate and evaporated on a rotary evaporator. The product precipitates as a crystalline mass.

CD silica, toluene/ethyl acetate (4:1): Rf = 0.56.

IR (CH 2 Cl 2 ) 3.4; 5.57; 5.65 µm.

cb. 2-/-T- 3S, 4R)-3-(tert.-butyl-dimethylsilyloxymethyl)-4-methylsulfonyl-2-oxazetidin-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 of tetrahydrofuran is added to 9 ml of DBU and stirred for 5 minutes at room temperature. A further 95 ml of DBU is then added and it is 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 is evaporated. The residue is taken up in ethyl acetate and the solution is washed with 1 N sulfuric acid, water and sodium hydrogen carbonate 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 (4:12?: Rf = 0.42.

IR (CH 2 Cl 2 ) 5.63; 5.81; 6.17^im. cc. ( 3S, 4R)- 3- hydroxymethyl- 4- methylsulfonyl- azetidin- 2- one and ( 3S, 4R)- 3-( tert.- butyl- dimethylsilyloxymethyl)- 4- methyl-sulfonyl- azetidin- 2- on

A solution of 25 g (61.7 mmol) of 2-(13S,4R)-3-(tert-butyl1-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 disappearance of the starting material is checked by thin-layer chromatography. After completion of the reaction, 30 ml of dimethyl sulphide is added and the mixture is stirred 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°. The solvent is then drawn off and the residue is drawn off 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-methylsulfonyl-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:

CD, silica gel, toluene/ethyl acetate (1:1); R f = 0.36;

IR (CH 2 Cl 2 ) 2.96; 3.54; 5.65^m.

(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-methylsulfonyl-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 over 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 1 N 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.

d. 2-/ T3S, 4R)- 3-( tert.-butyl- dimethylsilyloxymethyl)- 4-/"

(3R,S)-3-(4-nitrobenzyloxycarbonylamino)-butyroyltiq/-2-oxo-azetidin-1-yl7"-2-hydroxyacetic acid-p-nitrobenzyl ester.

A mixture of 10.23 g of (3S,4R)-3-(tert-butyldimethylsilyloxymethyl)-4-(73R,S)-3-(4-nitrobenzyloxycarbonylamino)-butyroylthio/-azetidin-2-one and 10.21 g glyoxylic acid p-nitrobenzyl ester ethyl hemiacetal in 170 ml toluene and 10 ml abs.

DMF is added to 80 g molecular sieve (4A) and stirred for 16 hours at room temperature and then for 2 hours at 50°. The mixture is filtered and the filter residue is washed with toluene. Evaporation of the filtrate and drying in high vacuum at 50° gives the product as a yellow oil. TLC (silica gel, ethyl acetate): Rf = 0.67;

IR (CH 2 Cl 2 ): 3430; 1765; 1730; 1690; 1505; 1340 cm"<1>.

e. 2-/ 13S, 4R)- 3-( tert.- butyl- dimethylsilyloxymethyl)- 4-/ 13R, S)- 3-( 4- nitrobenzyloxycarbonylamino)- butyroylthio/- 2- oxo-azetidin- 1- yl7~ 2-triphenylphosphoranylideneacetic acid p-nitrobenzyl ester.

To a solution of 13.7 g of (2-/(~3S, 4R)-3-(tert-butyldimethylsilyloxymethyl)-4-/(3R,S)-3-(4-nitrobenzyloxycarbonylamino)-butyroyl <q>/ -2-oxo-azetidin-1-yl/-2-hydroxyacetic acid p-nitrobenzyl ester in 250 ml of abs. yet

o

at 0 for 30 minutes and filtered. After evaporation, the yellow foam obtained is dissolved in 100 ml of dioxane and 3.1 ml of 2,6-dimethylpyridine and 6.98 g of triphenylphosphine are added. After 17 hours of stirring at 40°, the solids are separated

and the filtrate is evaporated. The crude product is purified by chromatography on silica gel (eluent toluene-ethyl acetate 9:1).

DC (silica gel, toluene/ethyl acetate 1:1); R f = 0.36; IR (CH 2 Cl 2 ): 3430; 1745; 1715; 1615; 1510; 1430 cm"<1>.

Example 2.

(5R,6S)-2-/T2R,S)-2-(4-nitrobenzyloxycarbonylamino)-prop-1-yl_/-6-hydroxymethyl-2-penem-3-carboxylic acid-p-nitrobenzyl ester.

A solution of 3.14 g of (5R,6S)-2-(T2R,S)-2-(4-nitrobenzyloxycarbonylamino)-prop-1-yl7-6-(tert.butyldimethylsilyloxymethyl)-2-penem-3-carboxylic acid -p-nitrobenzyl ester in 50 ml abs. THF is added in sequence 1.83 ml of acetic acid and 80

ml of a 0.1 N tetrabutylammonium fluoride solution in THF.

After stirring for 4.5 hours, dilute with 1.4 1 CH 2 Cl 2 and wash with 200 ml of a saturated NaHCO 3 in H 2 O solution. The organic phase is then washed with salt water, dried over magnesium sulphate and evaporated after filtration. The crude product is purified by chromatography on silica gel (eluent: from toluene/ethyl acetate 1:1 to absolute ethyl acetate). DC (silica gel, ethyl acetate): Rf ? 0.46; IR (CH 2 Cl 2 : 3600, 3430, 1780, 1715; 1515; 1340 cm"<1>.

Example 3.

(5R,6S)-2-/T2-R,S)-2-aminopropyl-1-yl7-6-hydroxymethyl-2-penem-3-carboxylic acid.

229 mg (5R,6S)-2-(2R,S)-2-(4-nitrobenzyloxycarbonylamino)-prop-1-yl7-6-hydroxymethyl-2-penem-3-carboxylic acid p-nitrobenzyl ester in 30 ml ethyl acetate , 12 ml of THF and 24 ml of water are added to about 15 g of Pd/C (10%) and hydrated at room temperature and normal pressure for 2 hours. The catalyst is filtered off and a further 0.1 g of Pd/C (10%) is added to the reaction mixture

and then 4 ml of 0.1 N HCl and further hydrated for 1 hour. The catalyst is filtered off, the aqueous phase is separated and the organic phase is extracted again with water. The combined aqueous extracts are added with 1 equivalent of NaHCO 3 and basted with ethyl acetate. The aqueous phase is then lyophilized.

DC (Reversed Phase Opti-UPC12) in water: Rf = 0.13; UV (phosphate buffer pH 7.4); xmax= 304 nm.

Example 4.

( 5R, 6S )- 2-/ 2- methyl- 2-( 4- nitrobenzyloxycarbonylamino)- prop-l- yl/- 6-( tert.- butyldimethylsilyloxymethyl)- 2- penem- 3- carboxylic acid- p- nitrobenzyl ester.

Analogous to Example 1, 1.51 g of 2-(((3S,4R)-2-(tert-butyldimethylsilyloxymethyl)-4-(3-methyl-3-(4-nitrobenzyloxycarbonylamino)-butyroylthio)-2-oxo-azetin- 1-yl/-2-triphenylphosphoralideneacetic acid p-nitrobenzyl ester in 250

ml of toluene after 46 hours of stirring at reflux temperature to the title compound. DC (silica gel, toluene/ethyl acetate

J:l); R f = 0.6; IR (CH-C 16 ): 3430; 1775, 1710, 1510, 1340;

-1

1300 cm

The starting material can be prepared as follows:

a. 3- methyl- 3-( 4- nitrobenzyloxycarbonylamino)- butyric acid. Analogous to example 1a, 7.79 g of 3-methyl-3-aminobutyric acid were reacted to give the title compound. IR in CH 2 Cl 2 : 3430, 1710, 1500, 1340 cm<-1>. b. 3-methyl-3-(4-nitrobenzyloxycarbonylamino)-thiobutyric acid. Analogous to example 1b, 9.5 g of 3-methyl-3-(4-nitrobenzyloxycarbonylamino)-smoic acid is transferred to the title compound. "IR (CH 2 Cl 2 ): 3420; 2570; 1710; 1490; 1340 cm"<1>. c. (3S,4R)-3-(tert.-butyldimethylsilyloxymethyl-4-/3-methyl-3-(4-nitrobenzyloxycarbonylamino)-butyroyltiq/"-azetidin-2-one. Analogous to example 1c transfer 5.98 g 3-methyl-3-(4-nitrobenzyloxycarbonylamino)-thiobutyric acid and 3.75 g of (3S,4R)-3-(tert.butyldimethylsilyloxymethyl)-4-methylsulfonyl-azetidin-2-one to the title compound. DC (silica gel, toluene- ethyl acetate 1:1): Rf = 0.44; IR (CH2C12): 3400; 1765; 1715; 1675; 1490; 1335 cm"<1>. d. 2-/ T3S- 4R)- 3-( tert.- butyldimethylsilyloxymethyl(- 4-/ 3-methyl- 3-( 4- nitrobenzyloxycarbonylamino)- butyroyltiq/- 2-oxo- azetidin- 1- yl7- 2- hydroxyacetic acid- p- nitrobenzyl ester. Analogous to example 1d, transfer 3.75 g (3S ,4R)-3-(tert-butyldimethylsilyloxymethyl)-2-(3-methyl-3-(4-nitrobenzyloxycarbonylamino)-butyroyltiq/-azetidin-2-one and 3.57 g of glyoxyacid p-nitrobenzyl ester ethyl hemiacetal to the title compound. TLC (silica gel, toluene-ethyl acetate). Rf ? 0.43 and 0.36; IR: (CH^Cl^): 3420, 1760, 1735; 1710; 1680; 1505;

-1

1335 cm

e. 2-/ T3S- 4R)- 3-( tert.- butyldimethylsilyloxymethyl)- 4-/ 3-methyl - ( 4- nitrobenzyloxycarbonylamino) - butyroylthio/"- 2-

oxo-azetidin-1-yl7-2-triphenylphosphoranylideneacetic acid p-nitrobenzyl ester.

Analogous to example 1e, 2.32 g of 2-(3S,4R)-3-(tert-butyldimethylsilyloxymethyl)-4-(3-methyl-3-(4-nitrobenzyloxycarbonylamino)-butyroylthio)-2-oxo-azetidine are reacted -1-yl/-2-hydroxyacetic acid p-nitrobenzyl ester to the title compound. DC (silica gel, toluene/ethyl acetate 1:1).

R f = 0.47; IR (CH 2 Cl ); 3420, 1740; 1730; 1675; 1610; 1600; 1500; 1335 cm"<1>.

Example 5: (5R, 6S)-2-(2-methyl-2-(nigrobenzyloxycarbonylamino)-prop-1-yl)-6-hydroxymethyl-2-penem-3-carboxylic acid p-nitrobenzyl ester.

Analogous to example 2, 2.29 g of (5R,6S)-2-(2-methyl-2-(4-nitrobenzyloxycarbonylamino)-prop-1-yl)-6-(tert-butyldimethylsilyloxymethyl)-2-penem- 3-carboxylic acid p-nitrobenzyl ester of the title compound.

TLC (silica gel, toluene/ethyl acetate): Rf = 0.23. IR (Ct₂Cl₂): -1

3600; 3430; 1780; 1710; 1510; 1345 cm.

Example 6.

(5R,6S)-2-(2-amino-methyl-prop-1- yl)-6-hydroxymethyl-2-penem-3- carboxylic acid.

Analogous to example 3, 0.7 g of (5R,6S)-2-(2-methyl-2-(4-nitrobenzyloxycarbonylamino)-prop-1-yl)-6-hydroxymethyl-2-penem-3-carboxylic acid-p -nitrobenzyl ester to the title compound. DC (Reversed Phase Opti UPC.^) in water: Rf

0.15. UV (phosphate buffer pH 7.4); max = 307 nm.

Example 7.

( 5R, 6S)- 2-/( 3R, S)- 3-( 4- nitrobenzyloxycarbonylamino)-but-l- yl/- 6-( tert.-butyldimethylsilyloxymethyl)- 2- penem- 3-carboxylic acid- p- nitrobenzyl ester .

Analogous to example 1, 2.3 g of 2-/(3S,4R)-3-(tert-butyldimethylsilyloxymethyl)-4-/T4R,S)-4-(4-nitrobenzyloxycarbonylamino)-valeroyltiq7-2-oxo-azetidine are transferred -1-yl/-2-tri- The starting material can be prepared as follows: a. (4R,S)-4-(4-nitrobenzyloxycarbonylamino)-valeric acid. Analogous to example 9.5 g of 4-aminovalteric acid is reacted to the title compound. NMR (DMSO-dg): s = 12.0 (br: 1H),

8.3 (m; 2H), 7.7 (m; 2H), 7.25 (br; 1H), 5.2 (s; 2H), 3.6

(m; 1H), 2.25 (t; 2H), 1.7 (mM 2H), 1.1 ppm 8d; 3H).

b. (4R,S)-4-(4-nitrobenzyloxycarbonylamino)-thiovaleric acid Analogous to example 15, 15 g of (4R,S)-4-(4-nitrobenzyloxycarbonylamino)-valeric acid are transferred to the title compound. IR (CH 2 Cl 2 ): 3430; 2570; 1715; 1505; 1345 cm"<1>. c. (3S,4R)-3-(tert.-butyldimethylsilyloxymethyl)-4-/(4R,S)-4-(4-nitrobenzyloxycarbonylamino)-valeroyltiq/-azetidin-2-one.

Analogous to example 1, 11.4 g of (4R,S)-4-(4-nitrobenzyloxycarbonylamino)-thiovaleric acid and 8.31 g of (3S,4R)-3-(tert-butyldimethylsilyloxymethyl)-4-methylsulfonyl-azetidine are transferred 2-on to the title compound. TLC (silica gel, toluene/ethyl acetate 1:1), Rf = 0.14.

d. 2 -/ 1 3S, 4R)- 3-( tert.- butyldimethylsilyloxymethyl)- 4-/ T4R, S)- 4-( 4- nitrobenzyloxycarbonylamino)- valeroyltiq/- 2- oxo-azetidin-1- yl/- - 2- hydroxyacetic acid p-nitrobenzyl ester. Analogous to example 11, 11.18 g of (3S,4R)-3-tert-butyldimethylsilyloxymethyl)-4-(T4R,S)-4-(4-nitrobenzyloxycarbonylamino)-valeroyl l<q>/-azetidin-2-one are transferred and 8.14 g of glyoxylic acid p-nitrobenzyl ester ethylene hemiacetal to the title compound. DC (silica gel, toluene/ethyl acetate 1:1); Rf = 0.25

and 0.28.

e. 2-/T3S,4R)-3-(tert.-butyldimethylsilyloxymethyl)-4-/T4R,S)-4-(4-nitrobenzyloxycarbonylamino)-avleroylthio/'-2-oxo-azetidin-1-yl/" - 2 - trif enyl phosph orany lidene acetic acid p-nitrobenzyl ester.

Analogously to example 1 e, 5.2 g of 2-(T3s,4R)-3-(tert-butyldimethylsilyloxymethyl)-4-(T4R,S)-4-(4-nitrobenzyloxycarbonylamino)-valeroyltiq/-2-oxo are reacted -azetidin-1-yl/-2-hydroxyacetic acid p-nitrobenzyl ester to the title compound. TLC (silica gel, toluene/ethyl acetate 1:1): Rf = 0.32.

Example 8.

(5R,6S)-2-(3R,S)-3-(4-nitrobenzyloxycarbonylamino)-but-1-yl/-6-hydroxymethyl-2-penem-3-carboxylic acid-p-nitrobenzyl ester.

Analogously to example 2, 1.34 g of (5R,6S)-2-(3R,S)-3-(4-nitrobenzyloxycarbonylamino)-but-1-yl/-6-(tert-butyldimethylsilyloxymethyl)-2- penem-3-carboxylic acid p-nitrobenzyl ester to the title compound. IR (CH 2 Cl 2 ): 3600; 3420;

1780; 1715; 1510; 1340 cm"<1>.

Example 9.

( 5R, 6S) - 2-/ T3R, S ) - 3- amino-but-l- yl_/~- 6- hydroxymethyl- 2- penem-3- carboxylic acid.

Analogous to example 3, 0.82 g of (5R,6S)-2-((3R,S)-3-(4-nitrobenzyloxycarbonylamino)-but-1-yl)-6-hydroxymethyl-2-penem-3-carboxylic acid is reacted p-nitrobenzyl ester to the title compound. UV (phosphate buffer pH 7.4): X max = 205 nm-

Example 10.

(5R,6S)-2-/T2R,S)-1-(4-nitrobenzyloxycarbonylamino)-prop-2-yl/-6-(tert.-butyldimethylsilyloxymethyl)-2-penem-3-carboxylic acid-p-nitrobenzyl ester.

Analogous to example 1, 1.13 g of 2-(T3S,R)-3-(tert-butyl-dimethylsilyloxymethyl)-4-(2R,S)-2-methyl-3-(4-nitrobenzyloxycarbonylamino)-propionylthio are transferred /-2-oxo-azetidin-1-yl/-2-phosphoranylideneacetic acid p-nitrobenzyl ester to the title compound. TLC (silica gel, toluene/ethyl acetate 1:1), Rf = 0.4.

The starting material can be prepared as follows.

a. (2R,S)-2-methyl-3-(4-nitrobenzyloxycarbonylamino)-propionic acid.

Analogous to example ia, 5.69 g of (2R,S)-3-amino-2-methyl-propionic acid are reacted to give the title compound. IR (Cr₂C₂): 3450; 1720; 1510; 1345 cm"<1>.

b. (2R,S)-2-methyl-3-(4-nitrobenzyloxycarbonylamino)-thio-propionic acid.

Analogous to example 1b, 10.4 g of (2R,S)-2-methyl-3-(4-nitrobenzyloxycarbonylamino)-propionic acid is reacted to give the title compound. IR (CH 2 Cl 2 ): 4440; 2570; 1715; 1690; 1510; 1345

-1

cm

c. (3R,S)-3-(tert.-buty1-dimethylsilyloxymethyl-4-/T2R,S)-2-methyl-3-(4-nitrobenzyloxycarbonylamino)-propionyltiq/"-azetidin-2-one. Analogous to example 1c, 9.27 g of (2R,S)-2-methyl-3-(4-nitrobenzyloxycarbonylamino)-thiopropionic acid and 6.07 g of (3R,S)-3-(tert-butyldimethylsilyloxymethyl)-4-methylsulfonyl- azetidin-2-one to the title compound. TLC (silica gel, toluene/ethyl acetate 1:1): Rf = 0.34; IR (CFUC1.,): 3440; 3400; -1 1765; 1710; 1675; 1500; 1335 cm . d. 2-/ J3 S, 4R)- 3-( tert.-butyl- dimethylsilyloxymethyl)- 4-/ T2R, S)- 2- methyl- 3-( 4- nitrobenzyloxycarbonylamino)- propionylthio/- 2- oxo - azetidin-1-yl7-2-hydroxyacetic acid p-nitrobenzyl ester.

Analogous to example 1d, 0.98 g of (3S,4R)-3-(tert-butyldimethylsilyloxymethyl)-4-(f2R,S)-2-methyl-3-(4-nitrobenzyloxycarbonylamino)-propionyltiq/-azetidine-2 -on to the title compound. DC (silica gall, toluene/ethyl acetate 1:1); R f = 0.5; IR (CH 9 Cl 0 ): 3510; 3420; 1765; 1740; 1715; 1690

-11

cm

e. 2-/ J3 S, 4R)- 3-( tert.-butyl- dimethylsilyloxymethyl)- 4-/ J2R , S)- 2- methyl- 3-( 4- nitrobenzyloxycarbonylamino)- propionylthio/- 2- oxo - azetidin-1-yl/-2-phosphoranylidene-acetic acid p-nitrobenzyl ester.

Analogous to example le, 2.6 g of 2-/T-3S,4R)-3- is transferred

(tert-butyldimethylsilyloxymethyl)-4-/(2R,S)-2-methyl-3-(4-nitrobenzylocy carbonyl amino)-propionylthio_/-2-oxo-azetidin-1- yl/-2- hydroxyacetic acid p-nitrobenzyl ester to the title compound. DC (silica gel, toluene/ethyl acetate 1:1); R f = 0.36; IR (CH 2 Cl 2 ): 3440; 1775; 1715; 1675; 1615; 1600 cm".

Example 11.

(5R,6A)-2-/(2R,S)-1-(4-nitrobenzyloxycarbonylamino)-prop-2-yl/-6-hydroxymethyl-2-penem-3-carboxylic acid-p-nitrobenzyl ester.

Analogous to example 2, 0.28 g of (5R;6S)-2- (T2R;S)-1-(4-nitrobenzyloxycarbonylamino)-prop-2-yl/-6-tert.-butyldimethylsilyloxymethyl)-2-penem- 3-carboxylic acid p-nitrobenzyl ester of the title compound. DC (silica gel, toluene/ethyl acetate 1:1); R f = 0.18; IR (CFUC1.,): 3440; 1775; 1715; 1510;

-1

1340 cm.

Example 12.

( 5R, 6S)- 2-/ T2- R, S)- 1- aminopropyl- 2- yl/- 6- hydroxymethyl- 2- penem-3- carboxylic acid.

Analogous to example 3, 750 mg of (4R,6S)-2-(2R,S)-1-(4-nitrobenzyloxycarbonylamino)-prop-2-yl/-6-hydroxymethyl-2-penem-3-carboxylic acid-p -nitrobenzyl ester to the title compound. UV (phosphate buffer pH 7'4): x max = 301nm.

Example 13.

The sodium salt of ( 5R, 6S)- 2-/ T2R, S)- 2-( 1- ethoxycarbonyl-prop- 1- en- 2- ylamino)- prop- 1- yl/- 6- hydroxymethyl- 2- penem-3 - carboxylic acid.

0.139 ml (1.1 mmol) of acetoacetic acid ethyl ester is added to a suspension of 0.257 mg (1 mmol) of 5R,6S)-2-(T2R,S)-2-aminoprop-1-yl/-6-hydroxymethyl-2-penem- 3-carboxylic acid and 0.15 ml of 2N caustic soda in 3 ml of isopropanol and stirred for 3 hours at room temperature. When diethyl ether is added, the product precipitates. IR spectrum (Nujol): absorption band at 3330; 1791; 1739 cm_r

Example 14.

(5R,6S)-2-/72R,S)-1-allyloxycarbonylamino-prop-2-yl/-6-(tert.butyldimethylsilyloxymethyl)-2-penem-3-carboxylic acid allyl ester.

A solution of 0.9 g of 2-(T3S,4R)-2-(tert-butyldimethylsilyloxymethyl)-4-(T2R,S)-2-methyl-3-allyloxycarbonylamino-propionyltiq/"-2-oxo-azetidine- 1-yl/-2-triphenyl phosphine-acetic acid allyl ester in 150 ml abs. toluene is stirred under an argon atmosphere for 24 hours at reflux temperature. Then the solvent is evaporated and the crude product is purified by chromatography on silica gel. (Eluent toluene-ethyl acetate 9:1 ).IR (CH 2 CL 2 ): 3440, 1780, 1710 cm"<1>.

The starting material can be prepared as follows:

a. (3S, 4R)-2-(tert.-butyl-dimethylsilyloxymethyl)-4-triphenylmethylthio-azetidin-2-one.

12.5 g of triphenylmethylmercaptan 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-butyldimethylsilyloxymethyl)-4-methylsulfonyl-azetidin-2-one in 70

ml of acetone and 70 ml of water during 30 minutes. After stirring for 30 minutes at 0° and 1 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). DC (toluene-ethyl acetate 19:1):

Rf = 0.64, IR (methylene chloride); 3390, 1760, 1117, 835 cm".

b. 2-/ T3S, 4R)- 3-( tert.- butyl- dimethylsilyloxymethyl)- 4- triphenylmethylthio- 2- oxo- azetidin- 1- yl7- 2- hydroxyacetic acid allyl ester.

8.4 g (3S,4R)-3-(tert.butyldimethylsilyloxymethyl)-4-tri-phenyl-methylthio-azetidin-2-one and 8.23 g (glyoxylic acid allyl ester ethyl hemiacetal in 170 ml abs. toluene are added 27 g

molecular sieve (2Å) and stirred for 10 hours at 55°C. 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 and 0.27; IR (CH2CH2): 3520, 1760, 1745 cm"<1>. c. 2-/ T3S, 4R)- 3-( tert.-butyl- dimethylsilyloxymethyl)- 4- triphenylmethylthio- 2- oxo- azetidin- 1- yl /- 2- triphenylphosphoranylideneacetic acid allyl ester. To a solution of 604 mg of 2- (C3S,4R)-3-(tert-butyldimethylsilyloxymethyl)-4-triphenylmethylthio-2-oxo-azetidin-1-yl/- 2-hydroxyacetic acid- allyl ester in 5 ml tetrahydrofuran is added with stirring at -15° in order 80 31 thionyl chloride and 88 ul pyridine during 5 minutes. The white suspension is stirred for 1 hour at -10° and filtered over "Hyflo". After washing the residue with toluene, 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-lutidine 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). DC (silica gel, toluene/ethyl acetate 1:1): Rf = 0 ,18; IR (CH2C<1>2): 1745, 1605 cm_rd. The silver salt of 2-/(~ 3S, 4R)- 3-( tert.-butyldimethylsilyloxymethyl )- 4- mercapto- 2- oxo-azetidin- 1- yl/- 2- triphenylphosphoranylidene- acetic acid allyl ester.

7.5 g of 2-(T3S,4R)-3-(tert-butyl-dimethylsilyloxymethyl)-4-triphenylmethylthio-2-oxo-azetidin-1-yl/-2-triphenylphosphoranyl-ideneacetic acid allyl ester are added to 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 is then added dropwise

ml of tributylamine, 0.18 ml of trifluoroacetic acid and 25 ml of ether 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 slurried for purification once more

in 40 ml of ether and 40 ml of water, filtered off with suction and dried. IR (CH 2 Cl 2 ): -1

1760, 1620 cm.

e. 2-/_~{ 3 S, 4R) - 3- ( tert. - butyl- dimethylsilyloxymethyl) - 4 - / ( 2R, S) - 2- methyl- 3- allyloxycarbonylamino- propionyltiq/"- 2-oxo- azetidine- l- yl/- 2- trif enylph osph or anylidene eddi xy real ly 1-ester.

5 g of the silver salt of the 2-(T3S,4R)-3-(tert-butyl-dimethylsilyloxymethyl)-4-mercapto-2-oxo-azetidin-1-yl/-2-triphenylphosphoranylidene-acetic acid allyl ester in 20 ml absolute methylene chloride is added to 1.7 ml of pyridine and then at 0° dropwise a mixture of 2.47 g of (2R,S)-2-methyl-3-allyloxycarbonylamino-propionic acid chloride and 10 ml of abs. methylene chloride. After 30 minutes of stirring, the solid is filtered off over "Hyflo"

and the filtrate is washed with aqueous NaHCO 3 solution and then with brine. After drying over sodium sulfate, evaporate in vacuo. The residue is purified by chromatography on silica gel (eluent toluene/ethyl acetate 4:1). TLC (silica gel, toluene/ethyl acetate 1:1): Rf = 0.3; IR (CH 2 Cl 2 ): 3440, 1750, 1715, 1680, 1610 cm<-1>.

The starting material (2R,S)-2-methyl-3-allyloxycarbonylamino-propionic acid chloride can be prepared as follows: ea. ( 2R, S )- 2- methyl- 3- allyloxycarbonylamino- propionic acid. To a solution of 10 g of (2R,S)-3-amino-2-methyl-propionic acid

in 20 ml of water and 44 ml of 5 N NaOH solution is added dropwise at 0° 11.2 ml of chloroformate allyl ester. After 15 hours of stirring at room temperature, the mixture is worked up as in example la. IR (CH 2 Cl 2 ): 3450; 1710; 1505; -1220 cm"<1>.

eb. (2R,S)-2-methyl-3-allyloxycarbonylamino-propionic acid chloride.

0.374 g of (2R,S)-2-methyl-3-allyloxycarbonylamino-propionic acid is added at 0° to 0.6 ml of thionyl chloride. The mixture is then stirred at the same temperature for 2 hours under protective glass.

It is then diluted with absolute toluene and evaporated on a rotary evaporator. IR (CH2C12): 3440, 1780, 1710, 1500,

-1

1215 cm

Example 15.

(5R,6S)-2-/J2R,S)-1-allyloxycarbonylamino-prop-2-yl/-6-hydroxymethyl-2-penem-3-carboxylic acid allyl ester.

Analogous to example 2, 138 mg of (5R,6S)-2-(2R,S)-1-allyloxycarbonylamino-prop-2-yl/-6-(tert-butyldimethylsilyloxymethyl)-2-penem-3-carboxylic acid is transferred allyl ester of the title compound: DC .(silica gel, toluene/ethyl acetate 1:1); R^

0 0.08; IR (CH 2 Cl 2 ): 3610, 3440, 1780, 1710 cm"<1>.

Example 16.

( 5R, 6S)- 2-/ 72R, S)- 1- aminopropyl- 2- yl/- 6- hydroxymethyl- 2- penem-3- carboxylic acid.

A solution of 82 mg of (5R,6S)-2-((7-2R,S)-1-allyloxycarbonyl-1-aminoprop-2-yl_/~-6-hydroxymethyl-2-penem-3-carboxylic acid allyl ester in 3.5 ml abs. THF is added at -10° with 9 mg of tetrakis-(triphenylphosphine)-palladium and then with 0.17

ml of tributyltin hydride. After 20 minutes of stirring at

-10°, 0.037 ml of acetic acid is added and the reaction mixture is stirred further after removal from the cooling bath for 30 minutes. After concentration on a rotary evaporator, the residue is taken up in 1 water-ethyl acetate, the aqueous phase is separated and the organic phase is extracted a further 3 times with water. The combined aqueous phases are lyophilized after brief concentration on

a rotary evaporator.

UV (phosphate buffer pH 7.4): x max = 301 nm.

The reaction product is identical to that produced

in example 12.

Example 17.

(5R,6S)-2-/(2R,S)-2-aminopropyl-1-yl7"-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 0.275 ml of ethyl-1-chloroethyl carbonate is added. The mixture is stirred

room temperature for 3 hours. The solution is then dripped on

15.0 ml of methylene chloride and the precipitated inorganic salts are filtered off. The methylene chloride solution is evaporated to 2 ml and added at 0° to a solution of 0.257 g (1 mmol)

(5R,6S)-2-(2R,S)-2-aminoprop-1-yl/-6-hydroxymethyl-2-penem-3-carboxylic acid in 4 ml of dimethylacetamide. It is then stirred for 3 hours at 0°, then diluted with ethyl acetate and washed 3 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 title compound is obtained as a white foam. IR spectrum (methylene chloride)_ absorption bands at 1790 and 1740 cm 1.

Example 18: (5R,6S)-2-/T2R,S)-2-aminopropyl-1-yl7-6-hydroxymethyl-2-penem. 3- carboxylic acid pivaloyloxy ethyl ester.

Dissolve 0.6 g of sodium iodide in 2 ml of acetone and add 0.15 ml of pivalic acid chloromethyl ester. The mixture is stirred for 3 hours at room temperature and then dropped onto 0.5 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 (0.4 mmol) (5R,6S)-2-/T2R,S)-2-aminoprop-1-yl/-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 3 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): Absorbent at 1790

and 1730 cm

Example 19.

In an analogous manner as described in the previous examples, the following compounds are obtained: (5R, 6S)-2-/T- 2R, S)-2-aminobut-1-yl7-6-hydroxymethyl-2-penem-3-carboxylic acid, UV (phosphate buffer pH 7.4): x max = 302 nm. ( 5R, 6S)- 2-/ T2( R, S)- 2- aminobut- l- y1/- 6- hydroxymethyl- 2- penem-3- carboxylic acid, UV (phosphate buffer pH 7.4) : X max = 303 n.m. ( 5R, 6S) - 2- ZTlS) - l- amino- but- l- yl/~- 6- hydroxymethyl-2- penem- 3- carboxylic acid, UV (phosphate buffer pH 7.4): max: 3 08 nm: (5R,6S)-2-/TlS)-1-aminobut-1-yl7-6-hydroxymethyl-2-penem-3-carboxylic acid, UV (fosph atbuf f is pH 7'.4); X max : 307.5 nm: ( 5R, 6S)- 2-/ TlR)- l- aminoethyl7- 6- hydroxymethyl- 2- penem- 3-carboxylic acid UV (phosphate buffer pH 7.4): X max: 308 nm,

(5R, 6S)- 2-/ TlS)- 1- aminoethyl/- 6- hydroxymethyl- 2- penem- 3- carboxylic acid. UV ( f osf atbuf f is pH 7 , 4 ) : xmaKv. s: 3<0>7 nm,

( 5R, 6S )- 2-( 2- amiono- 2- methyl- prop- l- yl)- 6- hydroxymethyl- 2-penem- 3- carboxylic acid- l- ethoxycarbonyloxyethyl ester, IR spectrum (CH2C12): 1788 and 1738 cm "<1>.

( 5R, 6S)- 2-/ T3R, S)- 3- amino- but- l- yl7- 6- hydroxymethyl- 2- penem-3- carboxylic acid- l- ethoxycarbonyloxyethyl ester, IR spectrum (CH2C12): 1790 and 1736 cm "<1>.

( 5R, 6S)- 2-/( 2R, S)- 1- aminopropyl- 2- yl7- 6- hydroxymethyl- 2- penem-3- carboxylic acid- 1- ethoxycarbonyloxyethyl ester, IR spectrum (CH2C12): 1787 and 1735 cm_r

( 5R, 6S )- 2-( 2- amino- 2- methyl- propyl- 1- yl)- 6- hydroxymethyl- 2-penem- 3- carboxylic acid- pivaloyloxynrethyl ester, IR spectrum (CH 2 Cl 2 ): 1791 and 1733 cm" <1>;

( 5R, 6S)- 2-/( 3R, S) - 3- amino- but- l- yj- 7~ 6- hydroxymethyl- 2- penem-3- carboxylic acid- pivalouloxymethyl ester, IR spectrum (CH2C12): 1789 and 1732 cm<-1>;

and

( 5R, 6S)- 2-/ 12R, S)- 1- aminopropyl- 2- yl/- 6- hydroxymethyl- 2- penem-3- k yearbook sy 1 sy r e- p i vaoy lok syrne ty le st er , IR spectrum (CF₂C₂): 1788 and 1729 cm-r

Example 20: (5R,6S)-2-/TlR)-1-formamidinoethyl/-6-hydroxymethyl-2-penem-3-carboxylic acid.

A solution of 110 mg of ethyl formimidate hydrochloride and 84 mg of sodium bicarbonate in 4 ml of water is added to a solution of 24 mg of ( 5R, 6S )-2-/(~1R)-1-aminoethyl/-6-hydroxymethyl-2-penem -3-carboxylate and 84. mg of sodium bicarbonate in 1 ml of water. After stirring for 50 minutes at room temperature, 1 ml IN HC1 is added and evaporated under high vacuum. The raw substance is purified by chromatography on "OPTI UC C^"-

UV (phosphate buffer pH 7.4); X maK s: 305 nm.

Example 21.

Dry ampoules or vials, containing 0.5 g of (5R, 6S)-2-/T-2R,S)-2-aminoprop-1-yl/-6-hydroxymethyl-2-penem-3-carboxylic acid as active substance are prepared as follows:

Composition:

(for 1 ampoule or vial):

A sterile, aqueous solution of the active substance and mannitol is subjected to freeze-drying under aseptic conditions in 5 ml ampoules or 5 ml vials and the ampoules respectively. the medicine bottles are closed and tested. Instead of the active substance mentioned above, the same amount of another active substance from the preceding examples can also be used, such as (5R,6S)-2-(2-amino-2-methyl-prop-1) -yl)-6-hydroxynrethyl-2-penem-3-carboxylic acid, (5R,6S)-2-[13R,S)-3-amino-but-1-yl]-6-hydroxy >nrety1-2-penem-3-carboxylic acid or (5R,6S)-2-(T2R,S)-1-aminoprop-2-yl/-6-hydroxymethyl-2-penem-3-carboxylic acid.

Claims (16)

1. Procedure for the preparation of compounds of the formula where is lower alkyl substituted with hydroxy or protected hydroxy, R2 is carboxyl or protected carboxyl R2, R3 means amino, amino substituted with lower alkyl, substituted methyleneamino or protected amino, and A is the linear lower alkyl substituted with lower alkyl, below which provided that R is different from 1-hydroxyethyl or protected 1-hydroxyethyl, when A is linear lower alkylene geminally substituted with two methyl groups, R 2 has the above meaning, and R 2 is amino or protected amino, salts of such compounds of formula 1,^ 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 formula where R^ , R^ r R 3 and A have the meanings given under formula I, Z means oxygen or sulfur and X ® is either a three-fold substituted phosphonio group or a doubly esterified phosphono group together with a cation, is ring-closed orb) a connection with the formula where R 1 , R 2 , R 3 and A have the meanings given under formula I, is treated with an organic compound of trivalent phosphorus, and if desired or necessary, a protected hydroxy group in the residue R 1 is transferred to the free hydroxy group in an obtainable compound of formula I, and/or, if desired, transfer in an obtainable compound of formula I a protected carboxyl group R^ to the free carboxyl group, or to another protected carboxyl group, R2, or a free carboxyl group R., to a protected carboxyl group R ^, and/or if desired, a protected amino group R^ is transferred to the free amino group, or a free amino group R^ to a substituted amino group, and/or if desired, an obtainable compound with a salt-forming group is transferred to a salt or an obtainable salt of the free compound or of another salt, and/or if desired, an obtainable mixture of isomeric compounds of formula I is divided into the individual isomers. 2. Process for preparing compounds of formula I according to claim 1, where R^ is lower alkyl substituted with hydroxy or protected hydroxy, R2 means carboxyl or protected carboxyl R^, R3 is amino, lower alkylamino, dilower alkylamino, a group of the formula -N=C (X^ ,X2 ), where X^ means hydrogen . 2- or 4-pyridyl, thienyl, e.g. 2-thienyl-, or thiazolyl, e.g. 4-thiazolyl, and X2 is amino, lower alkylamino, dilower alkylamino, lower alkyleneamino, hydrazino, anilino, lower alkoxy, phenyl lower alkyl or lower alkylthio, or protected amino, and A is linear lower alkylene substituted with lower alkyl of 1-4 carbon atoms, provided that R , is different from 1-hydroxyethyl or protected 1-hydroxyethyl, when A is linear lower alkylene geminally substituted with two methyl groups, R ? has the above meaning and R^ is amino or protected amino, salts of such compounds of formula I, which contain a salt-forming group, optical isomers of compounds of formula I, which have centers of chirality in the residues R-^ and/or A, and mixtures of these optical isomers. 3. Process for preparing compounds of formula I according to claim 1, where R^ is lower alkyl which is substituted with hydroxy, tri-lower alkylsilyloxy, 2-halo lower alkyl oxy, 2-halogen lower alkyl oxycarbonyloxy or phenyl lower alkyl oxycarbonyloxy which is optionally substituted with nitro, R 2 means carboxyl, lower alkenyloxycarbonyl, benzyloxycarbonyl which is optionally substituted with nitro, lower alkanoylmethoxycarbonyl, 2-halogen lower oxycarbonyl, 2-trilower alkylsilylethoxycarbonyl or an esterified carboxyl group which is cleavable under physiological conditions, e.g. 1-lower oxycarbonyloxycarbonyl, lower alkanoyloxymethoxycarbonyl, a-aminoloweralkanoyloxymethoxycarbonyl or phthalidyloxycarbonyl, R^ is amino, loweralkylamino, diloweralkylamino, a group of the formula -N=C (X^ ,X2 ), where X^ is hydrogen, amino, loweralkylamino, loweralkyl, phenyl or pyridyl , e.g. 2-pyridyl, and X 2 is amino, lower alkyl amino or di lower alkyl amino; azido, phthalimino, nitro, loweralkenyloxycarbonylamino, benzyloxycarbonylamino optionally substituted with nitro, 1-loweralkanoyl-loweralk-l-en-2-ylamino or 1-loweralkoxycarbonyl-loweralk-l-en-2-ylamino, and A is linear loweralkylene which is mono- or disubstituted by lower alkyl with 1-4 carbon atoms, under the proviso that R, is different from 1-hydroxyethyl or protected 1-hydroxyethyl, when A is the linear lower alkylene which is geminally substituted with two methyl groups, R^ has the above meaning and R^ is amino or protected amino, salts of such compounds of formula I, which exhibit a salt-forming group, optical isomers of compounds of formula I, which have centers of chirality in the residues R^ and/or A, and mixtures of these optical isomers. 4. Process for the preparation of compounds of formula I according to claim 1, where R^ is lower alkyl substituted with hydroxy and A is linear lower alkylene of 1-4 carbon atoms, which is monosubstituted with methyl or ethyl or where R-^ is hydroxymethyl and A is linear lower alkylene of 1-4 carbon atoms, which is disubstituted with methyl or ethyl, and where R2 is carboxyl, 1-lower oxycarbonyloxycarbonyl or lower alkanoyloxymethyloxycarbonyl and R^ is amino, lower alkylamino or formamidino, salts of such compounds of formula I, optical isomers of compounds of formula I, which have chirality centers in the residues R^ and /or A, and mixtures of these optical isomers. 5. Process for preparing compounds of formula I according to claim 1, where R^ means hydroxymethyl or 1-hydroxyethyl and A is ethylene or 1,3-propylene monosubstituted with methyl or ethyl, or where R^ is hydroxymethyl and A means ethylene disubstituted with methyl, and where R 2 is carboxyl and R^ is amino, and slates of such compounds of formula I. 6. Process for the preparation of pure optical isomers of compounds of formula I according to claim 1, which have further chirality centers in the substituents R, and/or A, especially the (1'R) isomer of compounds of formula I, where R is 1V-hydroxyethyl, and salts of such compounds of formula I. 7. Process for the production of pharmaceutically acceptable salts of compounds of formula I according to claim 1. 8. Process for the production of esters of compounds of formula I according to claim 1, which are cleavable under physiological conditions. 9. Process for the production of (5R,6S)-2-(2(2R,S)-2-aminoprop-1-yl)-6-hydroxymethyl-2-penem-3-carboxylic acid and pharmaceutically acceptable salts thereof, according to claims 1. 10. Process for the production of (5R,6S)-2-(2-amino-2-methyl-prop-1-yl)-6-hydroxymethyl-2-penem-3-carboxylic acid and pharmaceutically acceptable salts thereof according to claim 1. 11. Process for the production of (5R,6S)-2- (T3R,S)-3-amino-but-1-yl/-6-hydroxymethyl-2-penem-3-carboxylic acid and pharmaceutically acceptable salts thereof according to claim 1 . 12. Process for the production of (5R,6S)-2-(1-formamidinoethyl)-6-hydroxynrety1-2-penem-3-carboxylic acid and pharmaceutically acceptable salts thereof according to claim 1. 13. Process for the production of (5R,6S)-2-(((R)-1-aminoethyl)-6-hydroxymethyl-2-penem-3-carboxylic acid and pharmaceutically acceptable salts thereof according to claim 1. 14. Process for the production of (5R,6S)-2- (TlS)-1-aminoethyl/-6-hydroxymethyl-2-penem-3-carboxylic acid and pharmaceutically acceptable salts thereof according to claim 1. 15. Process for the production of (5R,6S)-2-/T2R,S)-2-amino-but-1-yl/-6-hydroxymethyl-2-penem-3-carboxylic acid and pharmaceutically acceptable salts thereof according to claim 1 . 16. Process for the production of pharmaceutical preparations, characterized in that a compound which can be obtained according to claim 1 is mixed with a pharmaceutically acceptable carrier.