NO824067L - AMINOBUTYLFORBINDELSER. - Google Patents

Description

The invention relates to the method for

position of new 2-aminobutyl-6-hydroxymethyl-2-penemfor-

bonds.

From German Offfenlegungsschrift 2950898 and from Euro-

peisk application no. 3960, 2-penem compounds have become known which in the 2-position contain an amino lower alkyl substituent and in the 6 position a 1-hydroxy lower alkyl group. These connec-

ser are valuable antibiotically active substances, which can especially be used as antibacterial antibiotics. As particularly preferred, the aforementioned publications highlight such penem-

compounds which in the 6-position contain a 1-hydroxyethyl

group, and thus in addition to the two asymmetry centers already present in the penem skeleton (C atoms 5 and 6) have an outer

lower center of asymmetry at C atom 1' of the side chain. The division of the resulting four possible enantiomer pairs usually proves to be complicated, time-consuming and thus expensive.

2-aminobutyl-6-hydroxymethyl-2-penem compounds

has not yet been known. It was made a surprising discovery, that such compounds next to the parenteral also

has a high oral effect. Since they only have the two, too pretty-

the system has its own asymmetry centers and therefore only two enantiomer pairs are possible, the isolation of the pharmacological

is particularly active stereoisomers.

The invention relates in particular to the production of

new 2-aminobutyl-6-hydroxymethyl-2-penem compounds with for-

flour

in which

R, means any substituted amino group, R? means hydroxy

or a residue R<A>£ which, together with the carbonyl group -C(=0)-, forms a protected carboxyl group, and R^ means a possible be-

substituted hydroxy group, as well as their salts, their optical isomers and mixtures of their optical isomers.

The definitions used above and below preferably have the following meanings within the scope of the invention:

. A substituted amino group R is a protected amino group or also a methyleneamino group, in which the methylene residue is preferably mono- or disubstituted, e.g. in group with formula

in which

X-^ means hydrogen optionally substituted amino, e.g. amino, lower alkylamino, dilower alkylamino, lower alkyleneamino, nitroamino, hydrazino or anilino, etherified hydroxy, e.g. lower alkoxy or phenyl lower alkyl, etherified mercapto, e.g. lower alkylthio, optionally substituted lower alkyl, e.g. loweralkyl, aminoloweralkyl, N-loweralkylaminoloweralkyl or N,N-diloweralkylaminoloweralkyl, loweralkyl, phenyl or monocyclic heteroaryl, as corresponding 5- or 6-

linked heteroaryl with 1 to 2 nitrogen atoms, and/or an oxygen or sulfur atom, and X2 means optionally substituted amino, e.g. amino, lower alkylamino, dilower alkylamino, lower alkyleneamino, nitroamino, hydrazino or anilino, etherified hydroxy, e.g. lower methoxy or phenyl lower oxy, or esterified mercapto, e.g. lower alkylthio.

In the present invention, the expressions "lower" used in connection with the definition of the group and the compound mean that the corresponding groups resp. compounds, if nothing else is expressly defined, contain up to 7, preferably up to 4 carbon atoms.

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 alkyleneamino especially has 4 to 6 carbon chain members, and means e.g. pyrrolidino or piperidino.

Low-area coke is e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or tert.-butoxy, while phenyl lower realoxy is e.g. 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 alkylaminolower alkyl is e.g. 2-methyl or 2-ethylaminoethyl, while N,N-dialverealkylaminoloweralkyl e.g. means 2-dimethylaminoethyl or 2-diethylaminoethyl.

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

Monocyclic 5- or 6-membered heteroaryl with 1 to 2 nitrogen atoms and/or oxygen or sulfur atoms is e.g. furyl, as 2-furyl, thienyl, as 2-thienyl, oxazolyl, as 2-oxazolyl, thiazolyl, as 2- or 4-thiazolyl, pyridyl, as 2-,

3- or 4-pyridyl, or pyrimidyl, such as 2-, 4- or 5-pyrimidyl.

The methyleneamino group of formula IA is, for example, correspondingly substituted guanidino, isourea or isothiourea linked over a nitrogen atom with the butyl group, imidoether or imidothioether and especially amidino groups.

In a guanidino residue of formula IA, x^f means. e.g. amino, lower alkylamino, e.g. methylamino, dilavealkylamino, e.g. diethylamino, nitroamino, hydrazino or anilino and X2 means e.g. amino or lower alkylamino, e.g. methylamino. Examples of such guanidiho groups are guanidino, N-methyl-, N,N-dimethyl- or N,N,N'-trimethylguanidino, N-phenylguanidino or aminoguanidino.

In an isourea resp. isothiourea residue of formula Ia means X^ in particular amino, lower alkylamino, e.g. methylamino, dialverealkylamino, e.g. dimethylamino or anilino, and X2means e.g. lower alkoxy, e.g. methoxy or ethoxy, resp. lower alkylthio, e.g. methylthio or ethylthio. Such groups are e.g. the N,N,0-trimethylisourea group, and the N,N-dimethyl-S-ethyl, N-phenyl-S-ethyl or N,S-dimethylisothiourea group.

In imidoether- or the imidoether residue of formula

IA is X2f. e.g. lower alkoxy, e.g. methoxy or ethoxy or "benzyloxy, resp. lower alkylthio, e.g. methylthio or ethylthio, and X^ has the same meaning as X.,, or means hydrogen, lower alkyl, e.g. methyl or phenyl. Corresponding groups are e.g. methylformamidate, S-methylthiobenzimidate, methylbenzyloxycarbimidate or diethyldithiocarbimidate group.

In amidino groups of formula IA, X represents f. e.g. hydrogen, lower alkyl, e.g. methyl, amino lower alkyl, e.g. 2-aminoethyl, lower alkenyl, e.g. allyl, phenyl, thienyl, e.g. 2-thienyl, thiazolyl, e.g. 4^-thiazolyl, or pyridyl, e.g. 2-, 3- or 4-pyridyl, and X2 means, for example, amino, lower alkylamino, e.g. methylamino or isopropylamino, dilave alkylamino, e.g. dimethylamino or lower alkyleneamino, e.g. piperidino. Suitable amidino groups are e.g. benzamidino, 4-pyridylcarboxamidino, 1-piperidinylmethyleneimino, or especially formamidino, acetamidino, N-methyl-, N-isopropyl- or N,N-dimethylformamidino.

The functional groups present in the compound with formula I such as carboxy, amino or hydroxy groups, especially the amino group R^, the carboxyl group -C(=0)-R2 and the hydroxy group R^ are optionally protected with protective groups used in penem, penicillin, cephalosporin and peptide chemistry.

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

Protection groups of this type, as well as their introduction and separation are. for example mentioned in

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

T.W. Greene, "Protective Groups in Organic Synthésis", Wiley, New York, 1981,

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

Houben-Weyl, "Methoden der Organisehen Chemie", Band

15/1, Georg Thieme Verlag, Stuttgart, 1974.

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

In a corresponding acylamino group, acyl is, for example, the acyl residue of an organic acid with e.g. up to 18 carbon atoms, especially one possibly e.g. with halogen or phenyl substituted alkanecarboxylic acid, or optionally e.g. with halogen, lower alkoxy or nitro, substituted benzoic acid, or a carboxylic acid half-ester. Such acyl groups are, for example, lower alkanoyl, such as formyl, acetyl or propionyl, halolower 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 nitrobenzoyl, such as 4-nitrobenzoyl. In particular, lower alkenyloxycarbonyl, e.g. allyloxycarbonyl, or optionally in the 1- or 2-position substituted lower alkoxycarbonyl suitable as lower alkoxycarbonyl, e.g. methoxy- or ethoxycarbonyl, optionally substituted benzyloxycarbonyl, e.g. benzyloxycarbonyl or 4-nitrobenzyloxycarbonyl, aroylmethoxycarbonyl, in which the aroyl group preferably optionally means e.g. with halogen, such as bromine, substituted benzoyl, e.g. phenacyloxycarbonyl, 2-halolower oxycarbonyl, e.g. 2-, 2,2-trichloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromomethoxycarbonyl or 2-iodoethoxycarbonyl or 2-(tris-substituted silyl)ethoxycarbonyl, such as 2-trilower alkylsilylethoxycarbonyl, e.g. 2-trimethylsilylethoxycarbonyl or 2-(di-n-butyl-methyl-silyl)-ethoxycarbonyl, or 2-triarylsilylethoxycarbonyl, such as 2-triphenylsilylethoxycarbonyl.

In an acylimino group, acyl is, for example, the acyl residue of 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 one optionally with lower alkyl, such as methyl or tert.-butyl, lower alkoxy,

such as methoxy, halogen, such as chlorine or bromine, and/or nitro, substituted phenylthioamino group or a pyridylthioamino group.

Corresponding groups are, for example, 2- or 4-nitrophenylthioamino, or 2-pyridylthioamino.

, A silyl or stannylamino group is in the first

range of an organic silyl resp. stannylamino group, in which silicon resp. the tin atom preferably contains lower alkyl as substituents, e.g. methyl, ethyl, n-butyl, or tert.-butyl, further lower alkoxy, e.g. methoxy. Corresponding silyl or stannyl groups are primarily trilower alkylsilyl, especially trimethylsilyl, further dimethyl-tert-butylsilyl, or similarly substituted stannyl, e.g. tri-n-butylstannyl. The silicon atom of a silylamino group can also only be substituted with two lower alkyl groups, e.g. methyl groups, and amino, hydroxy or carboxyl groups of another molecule with formula I. Compounds with such protective groups allow, e.g. prepared using dimethyldichlorosilane as silylating agent.

Further protected amino groups are e.g. an-amino group, which at the double bond in the 2-position contains an electron-withdrawing substituent, for example a carbonyl group. Protected amino groups of this type are, for example, 1-acyl-lower alk-1-en-2-yl amino residues, in which acyl e.g. means the corresponding residue of a lower alkane carboxylic acid, e.g. acetic acid, a possibly e.g. with lower alkyl, such as methyl or tert.-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and/or nitro substituted benzoic acid, or especially a carboxylic acid half-ester, such as a carboxylic acid-lower alkyl half-ester, e.g. -methyl half-ester or -ethyl half-ester, such as lower alk-1-ene- means in particular 1-propene. Correspondingly protected amino groups are primarily 1-lower alkanoyl-prop-1-en-2-yl-amino, e.g. 1-acetyl-prop-1-en-2-yl-amino, or 1-lower oxycarbonyl-prop-1-en-2-yl-amino, e.g. 1-Ethoxycarbonyl-prop-1-en-yl-amino.

In a protected carboxyl group with the formula -C(=O)-R9', there is in particular a forether.t.hydroxy group which, together with the carbonyl grouping, forms a preferably light, cleavable, e.g. reductive as hydrogenolytic or solvolytic as acidolytic or especially basic or neutral hydrolytic, or one under physiological conditions cleavable or easily in another functionally modified carboxyl group such as another esterified carboxyl group, transferable esterified carboxyl group.

Such esterified carboxyl groups contain as esterifying groups primarily branched in the 1-position or suitably substituted lower alkyl groups in the 1- or 2-position. Preferred carboxyl groups present in esterified form include lower alkoxycarbonyl, e.g. methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl or tert.-butoxycarbonyl, and (hetero-)arylmethoxycarbonyl with 1 to 3 aryl residues, or one monocyclic heteroaryl residue, these possibly e.g. is mono- or poly-substituted with lower alkyl such as tert.-lower alkyl, e.g. tert-butyl, . halogen, e.g.

chlorine, and/or nitro. Examples for such groups are possibly e.g. as mentioned above substituted benzyloxycarbonyl, e.g. 4-nitrobenzyloxycarbonyl, possibly e.g. as mentioned <:>.. above substituted diphenylmethoxycarbonyl, e.g. diphenylmethoxycarbonyl or triphenylmethoxycarbonyl or optionally e.g.

as mentioned above substituted picolyloxycarbonyl, e.g. 4-picolyloxycarbonyl, ..or furfuryloxycarbonyl, such as 2-furfuryloxycarbonyl. Further suitable groups are lower-alkanoylmethoxycarbonyl, such as acetonyloxycarbonyl, aroylmethoxycarbonyl, in which the aroyl group e.g. possibly means e.g. with halogen such as bromine substituted benzoyl, e.g. phenacyloxycarbonyl, halogeno-lower oxycarbonyl, such as 2-halogeno-lower oxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl,

or two-halogen lower oxycarbonyl, in which the lower alkoxy contains 4-7 carbon atoms, e.g. 4-chlorobutoxycarbonyl, phthalimidomethoxycarbonyl, lower alkenyloxycarbonyl, e.g. allyloxycarbonyl, or in the 2-position with lower alkylsulfonyl, cyano or trisyl substituted silyl, such as trilower alkylsilyl or triphenylsilyl, substituted ethoxycarbonyl, e.g. 2-methylsulfonyl-ethoxycarbonyl, 2-cyanoethoxycarbonyl, 2-trimethylsilylethoxycarbonyl or 2-(di-n-butyl-methyl-silyl)-ethoxycarbonyl.

Furthermore, protected carboxyl groups present in esterified form are corresponding organic silyloxycarbonyl, further corresponding organic stannyloxycarbonyl groups. These

contains silicon or tin atoms, preferably lower-

alkyl, especially methyl or ethyl, ..further lower alkoxy, e.g. metoky, as substituents. Suitable silyl resp. stannyl protecting groups are primarily lower alkylsilyl, especially trimethylsilyl or dimethyl-tert-butylsilyl, or correspondingly substituted stannyl groups, e.g. tri-n-butylstannyl.

A cleavable esterified carboxyl group under physiological conditions is primarily an acyloxymethoxycarbonyl group, in which acyl e.g. means the residue of an organic carboxylic acid, primarily an optionally substituted lower alkane carboxylic acid, or in which acyloxymethyl forms the residue of a lactone, 1-lower alkyl-lower alkyloxycarbonyl or also 1-lower alkylcarbonyloxy-lower alkylcarbonyl, in which lower alkyl e.g. is methyl, propyl, butyl or especially ethyl, and lower alkoxy e.g. is methoxy, ethoxy, propoxy, or butoxy. Such groups are e.g. lower alkanoyloxymethylcarbonyl, e.g. ethoxymethoxycarbonyl or pivaloyloxymethoxycarbonyl, aminolower alkanoyloxymethoxycarbonyl, especially ct-aminoloweralkanoyloxymethoxycarbonyl, e.g. glycoloxymethoxycarbonyl, L-valyloxymethoxycarbonyl, L-leucyloxymethoxycarbonyl, phthalidyloxycarbonyl, e.g. 3-phthalidyloxycarbonyl, 4-crotono-lactonyl or 4-butyrolacton-4-yl, indanyloxycarbonyl, e.g. 5-indanyloxycarbonyl, 1-ethoxycarbonyloxyethoxycarbonyl, methoxy-methoxycarbonyl or 1-methoxyethoxycarbonyl.

In connection with formula I, a hydroxy group can

R^for example be protected with acyl residues. Suitable acyl-

residues are e.g. optionally substituted lower alkanoyl, e.g. acetyl- or trifluoroacetyl, optionally substituted benzoyl,

e.g. benzoyl, 4-nitro-benzoyl or 2,4-dinitrobenzoyl, optionally substituted lower alkoxycarbonyl, e.g. 2-bromoethoxycarbonyl or 2,2,2-trichloroethoxycarbonyl or optionally substituted phenyl lavereal oxycarbonyl, e.g. 4-nitrobenzyloxycarbonyl. Further hydroxy protecting groups are e.g. trisubstituted silyl, trilower alkylsilyl, e.g. trimethyl-

silyl or tert-butyl-dimethylsilyl, 2-haloalkyl groups, e.g. 2-chloro-, 2-bromo-, 2-iodo- and 2,2,2-trichloroethyl, and even

tually substituted 1-phenyl lower alkyl, which optionally with halo-

gene, e.g. chlorine, lower alkoxy, e.g. methoxy or nitro substituted benzyl.

Salts of compounds according to the invention are primarily pharmaceutical usable non-toxic salts,

such as those of the compounds of formula I wherein R 2 is hydroxy.

Such salts are primarily metal or ammonium salts, such as alkali metal and alkaline earth metal, e.g. sodium, potassium, magnesium or calcium salts, as well as ammonium salts with ammonia or suitable organic amines, such as lower alkyl amines, e.g. triethylamine, hydroxyl lower alkylamines, e.g. 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine, or tris-(2-hydroxyethyl)amine, basic aliphatic esters of carboxylic acids, e.g. 4-aminobenzoic acid-2-diethylaminoethyl ester, lower alkylene amines,

e.g. 1-ethylpiperidine, cycloalkylamines, e.g. dicyclohexylamines or benzylamines, e.g. N,N'-dibenzylethylenediamine, dibenzylamine or N-benzyl-8-phenethylamine. Compound of formula I with a basic group, e.g. those in which R^ means amino, 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. Compound of formula I with an acidic and with a basic group, e.g. such in which R^

means amino, and R2 means hydroxy, can also exist in the form of internal salts, i.e. in zwitterionic form.

In the penem compound of formula I, the two asymmetric carbon atoms in the 5- and 6-position can be present in R, S or the racemic R,S configuration. Preferred are the compounds in which the configuration of 5-carbon atoms corresponds to that of natural penicillin (5R configuration). The hydrogen atoms in the 5- and 6-position can be in the cis- or preferably in the trans-position to each other. In the preferred configuration, the 6-hydroxymethyl substituent assumes the S configuration.

Compounds according to the invention have valuable pharmacological properties and can be used as intermediates for the production of such compounds with valuable pharmacological properties. The compound of formula I, in which R^ means an amino group, or an optionally substituted methylene amino group<*>A, R 2 means hydroxy or, together with the carbonyl group, an esterified carboxyl group cleavable under physiological conditions, and R., is hydroxy, or pharmacologically usable salts of such compounds with salt-forming groups, have antibacterial effects. For example, they are active

in vitro against gram-positive and gram-negative organisms, e.g. Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Streptococcus faecalis, Neisseria menigitidis, Neisseria gonorrhoeae, Enterobacteriaceae, Haemophilus influenzae, Pseudomonas aeruginosa and Bacterides sp. in minimal concentration of approx. 0.5 to approx. 64 ug/ml. In vivo, in the case of systemic infection in mice, e.g. by means of Staphylococcus aureus or Streptococcus pyogenes, it is given by oral application

of the compound according to the invention a minimum effective dose-

area ..of approx. 0.65 to 3 mg/kg.

In the following test report, the effect of the compound with formula I is shown using selected compounds: Test report:

I. Compounds examined.

An antibiotic effect of the following compounds was investigated: 1. trans-2-(4-aminobutyl)-6-hydroxymethyl-penem-3-carboxylic acid (Example 19). 2. (5R,6S)-2-(4-aminobutyl)-6-hydroxymethyl-penem-3-carboxylic acid (Example 28).

II. Experimentally:

A The antibiotic activity of the test compound in vitro was determined by the agar dilution method according to Ericsson H.M., and Sherris, S,C. 1971, Acta Path. Microb. Scand. Section

B, suppl. No. 217, vol. 1-90, in DST agar. Minimum concentrations found that still inhibit the growth of the test organisms (MIC = minimum inhibitory concentrations) are stated in micrograms per ml.

(ug/ml) for the investigated compounds in Table I.

B. The chemotherapeutic effect in vivo against systemic infections in female SPF, MF2 mice was determined according to the method of Zak, 0., et al., 1979, Drugs Exptl. Clin, Res. 5, 45-59.

They found EDC values in milligrams of substance per kilogram mouse (mg/kg)

o u

for a number of microorganisms indicates for the subcutaneous (s.c) resp. orally (p.o.) applied test compounds in Table 2.

III. Test results:

The new compounds can therefore find use as orally or parenterally applicable antibacterial antibiotics, e.g. in the form of corresponding pharmaceutical preparations

rates for treatment of infections.

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

The invention relates in particular to connection with

formula I, in which R^ denotes amino, 1-acyl-lower alk-1-en-2-yl-amino or a mono- or disubstituted methylene amino group, R 2 denotes hydroxy or, together with the carboxyl group, an esterified carboxyl group cleavable under physiological conditions, and R^ is hydroxy, their salts, or optical isomers and mixtures of their optical isomers, as well as their protected derivatives.

The invention relates above all to a compound of formula I, in which R^ is amino, R,, means hydroxy, lower alkanoyloxymethoxy, aminoloweralkanoyloxymethoxy, phthalidyloxy, 4-crotonolactonyloxy, 4-butyrolacton-4-yloxy, indanyloxy, 1-loweralkoxy-loweralkoxy or 1-loweralkoxy -carbonyl-oxylavereal oxy, and R 1 is hydroxy, their salts, especially their pharmaceutically acceptable salts, their optical isomers and mixtures of their optical isomers.

To be highlighted are the compounds of formula I, wherein R₂ is amino, and R₂ is hydroxy and R₂ is hydroxy, their optical isomers, especially 5R,6S isomers, and their pharmaceutically usable salts.

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

The compounds according to the invention are produced according to methods known per se.

The new compounds are prepared by ring-closing a ^Lid compound of formula

wherein R, means a protected amino group, Z means oxygen or sulphur, X' means either a triply substituted phosphono group or a doubly esterified phosphono group together with a cation,

Rj2\ has the above-mentioned meaning, and R^ means an optionally protected" hydroxy group, and if desired or necessary a protected amino group R^ is transferred in a formed compound of formula I to the free or to another protected amino group R^ and/or if desired in an obtained compound of formula I, a protected carboxyl group -C(=0)-R2 is transferred into a free or in another protected carboxyl group -C(=0)-R2, and/or if desired transferred in a formed compound of formula I, in which R^

means amino, R^ to a substituted amino group, and/or if necessary a protected hydroxy group R^ is transferred to the free hydroxy group R^, or a free hydroxy group R^ to a protected hydroxy group R3 and/or if desired, a formed compound is transferred with salt-forming groups to a salt, or a formed salt to the free compound or to another salt, and/or if desired, a formed mixture of isomeric compounds is divided into the individual isomers.

A group X in the starting material of formula II is

one of the phosphonio or phosphono groups common in Wi.tti.g condensation reactions, especially a triaryl, e.g. triphenyl-, or trilaverealkyl-, e.g. tri-n-butylphosphonio group, or one with lower alkyl, e.g. ethyl, doubly esterified phosphono group, the symbol X (8 for the case of the phosphono group in addition

contains the cation of a strong base, especially a suitable metal-sora alkali metal-, e.g. lithium, sodium or potassium ions. <Preferred as group X is on the one hand tri-phenylphosphono, and on the other hand diethylphosphono together with an alkali metal, e.g. sodium ion.

The ylide compounds of formula II are designated therein

^ isomeric Ylene form also as phosphorane compounds. In the phosphonium compound of formula II, the negative charge is neutralized,

the positively charged phosphonium group. In the phosphono compound of formula II, the negative charge is neutralized with the cation of a strong base, which, depending on the method of preparation of the phosphono starting material, e.g. can be an alkali metal, e.g. sodium, lithium or potassium ion. Phosphono starting materials are therefore used as salts in the reaction.

The ring closure can take place spontaneously, i.e. during the production of starting substances or during heating, e.g. in a

temperature range of approx. 30 to 160°C, preferably at approx. 50° to 100°C. The reaction is preferably carried out in a suitable inert solvent, such as in an aliphatic, cycloaliphatic or aromatic hydrocarbon, e.g. hexane, cyclohexane, benzene or toluene, a halogenated hydrocarbon, e.g. methylene chloride, an ether e.g. diethyl ether, dimethoxyethane, or diethylene glycol dimethyl ether, a cyclic ether, e.g. dioxane or tetrahydrofuran, a carboxylic acid amide, e.g. dimethylformamide, a di-lower alkyl sulfoxide, e.g. dimethylsulfoxide or a lower alkanol, e.g. methanol, ethanol or tert-butanol or in a mixture thereof, and if necessary in inert gas, e.g. nitrogen atmosphere.

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

wherein X<1>means a phosphono group treated with a suitable basic reagent such as an inorganic base, e.g. an alkali metal carbonate,

such as sodium or potassium carbonate, or an organic base,

as a tri-lower alkylamine, e.g. triethylamine, or a cyclic base of the amidine type, as a corresponding diazabicycloalkene compound, e.g. 1,5-diazabicyclo^~5.4.0/undec-5-ene.

Preferably, starting materials of formula II are used, which lead to the initially particularly preferred compounds of formula I, for example compound of formula II which has a 3S,4R configuration.

For the preparation of a compound of formula I which contains a free amino group R^ and/or a free carboxyl group -C(=O)-R2 and/or free hydroxy group R^, such hydroxy, amino and/or carboxyl protecting groups are preferably used that allow split in a reaction step, for example reductive,

as hydrogenolytic.

In a connection obtained according to the invention with

formula I with a protected amino group R^, this can in a manner known per se f, e.g. depending on the type of protecting group, preferably by means of solvolysis or reduction is transferred in the free amino group R^. For example, 2-halogen-lower-alkoxycarbonylamino (possibly after conversion of a 2-bromo-lower-alkoxycarbonylamino group to a 2-iodo-lower-alkoxy-carbonylamino group), aroylmethoxycarbonylamino or 4-nitro-benzyloxycarbonylamino can be cleaved by treatment with a suitable chemical reducing agent such as zinc in the presence of suitable carboxy-

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 also by treatment with an alkali metal-

e.g. sodium dithionite. Optionally substituted benzyloxycarbonylamino can e.g. split using hydrogenolysis, e.g.

by treatment with hydrogen in the presence of a suitable hydrogenation catalyst, such as a palladium catalyst and aryloxycarbonylamino by reaction with a compound of palladium, e.g. tetrakis(triphenylphosphine)palladium, in the presence of triphenylphosphine and treatment with carboxylic acid, e.g. 2-ethylhexanoic acid or a salt thereof. In one with an organic silyl or stannyl group

protected amino group can e.g. released by hydrolysis or alcoholysis, one with 2-halolower alkanoyl,

e.g. The 2-chloroacetyl protected amino group is released 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 formed condensation product. A 2-substituted silylethoxycarbonyl protected amino group can, by treatment with a fluoride anion-yielding salt of hydrofluoric acid such as an alkali metal fluoride, e.g. sodium fluoride, in the presence of a macromolecular polyether ("crown ether") or with a fluoride of an organic quaternary base, such as tetralower alkylammonium fluoride,

e.g. tetraethylammonium fluoride is transferred in the free amino group. An amino group protected in the form of an azido or nitro group is transferred, e.g. by reduction to free amino, for example by catalytic hydrogenation with hydrogen in the presence

by a hydrogenation catalyst such as platinum oxide, palladium or Raney nickel, or by treatment with zinc in the presence of a

acid such as acetic acid. An amino group protected in the form of a phthalimido group can be transferred into 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 R^ can be transferred in a manner known per se into a substituted amino group. Thus, for example, amino by reaction with a corresponding acyl halide such as -chloride can be transferred to acylamino R^, and with a 3-dicarbonyl compound such as a 1-lower alkanoylacetone or a:, acetoacetic acid lower alkyl ester to 1-lower alkanoyl resp. 1-lower oxycarbonylprop-1-en-2-ylamino. The conversions of amino groups into amidino, guanidino, isourea, isothiourea, imidoether and imidothioether groups can, for example, be carried out according to one of those in the German Offenlegungsschrift no.

26 52 679 said method. Thus, for example, a compound of formula I in which R^ means amino by reaction with trimethylsilyl chloride and an imido halide of formula £ (X,, Y,) C=X2_/ Y2 , in which Y1 means halogen, e.g. chlorine, and Y2et anion, e.g. chloride is transferred to amidines and by reaction with a substituted isourea resp. isothiourea of formula (X1Y3)C=X2, in which Y^ means lower alkoxy or lower alkylthio is transferred in guanidines.

A compound of formula I obtained according to the method in which R2 means a residue R<A>2 which, together with the carbonyl group -C(=0)- forms a protected carboxyl group, can be transferred in a manner known per se to a compound of formula I, in which R2 means hydroxy. Thus, tert.-lower alkoxycarbonyl or in the 2-position with a trisubstituted silyl group or in the I-position with lower alkoxy substituted lower alkoxycarbonyl or optionally substituted <:>.phenylmethoxycarbonyl, 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, is transferred to free carboxyl. Any substituted benzyloxycarbonyl can e.g. is cleaved by means of hydrogenolysis, i.e. by treatment with hydrogen in the presence of a metallic hydrogenation catalyst such as a palladium catalyst. Furthermore, suitable substituted benzyloxycarbonyl such as 4-nitrobenzyloxycarbonyl can also 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 reduced metal, e.g., tin or metal salt, such as a chromium II salt,

e.g. chromium II chloride, usually in the presence of a hydrogen-releasing agent, which together with the metals manages to produce a nascent hydrogen as a suitable carboxylic acid, e.g. a possibly e.g. with hydroxy substituted lower alkane carboxylic acid, e.g. acetic acid, formic acid or glycolic acid, or an alcohol or thiol, preferably adding water. The removal of an allyl protecting group can e.g. take place by reaction with a compound of palladium, e.g. tetrakis(triphenylphosphine)palladium, in the presence of triphenylphosphine and with the addition of a carboxylic acid, e.g. 2-ethylhexanoic acid, or a salt thereof. By treatment with a reducing metal or metal salt, as mentioned 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, aroylmethoxycarbonyl being likewise cleaved by treatment with a nucleophilic preferably salt-forming reagent such as sodium thiophenolate or sodium iodide. Substituted 2-silylethoxycarbonyl can also, by treatment with a fluoride anion-yielding salt of hydrofluoric acid, such as an alkali metal fluoride, e.g. sodium fluoride in the presence of a macrocyclic polyether ("crown ether") or with a fluoride of an organic quaternary base such as tetralower alkylammonium fluoride, e.g. tetraethylammonium fluoride is transferred to free carboxyl. With an organic silyl or stannyl group such as tri-lower alkylsilyl or -stannyl, esterified carboxyl can be liberated solvolytically in the usual way, e.g. by treatment with water or an alcohol.

A lower alkylsulfonyl or cyano-substituted lower alkoxycarbonyl group in the 2-position can be transferred into free carboxyl,

e.g. by treatment with a basic agent such as an alkali metal or alkaline earth metal hydroxide or carbonate, e.g. sodium

or potassium hydroxide or sodium or potassium carbonate.

On the other hand can also connection with formula

In which R_ means hydroxy is transferred to the compound of formula I, in which R2 means a residue R., which together with the carbonyl group

-C(=0)- forms a protected carboxyl group, especially an etherified carboxyl group. Thus, the free carboxyl group can be esterified, e.g. by treatment with a suitable diazo compound such as a diazole veralkane, e.g. diazomethane, or a phenyldiazo-lower alkane, e.g. diphenyldiazomethane, if necessary in the presence of a Lewis acid, such as e.g., boron trifluoride or by reaction with an alcohol suitable for esterification in the presence of an esterification agent such as a carbodiimide, e.g. dicyclohexylcarbodiimide and carbonyldiimidazole. Esters can also be prepared by reacting a possibly in situ produced salt of the acid with a reactive ester of the alcohol and a strong inorganic acid such as sulfuric acid or a strong organic sulphonic acid such as 4-toluenesulphonic acid. Furthermore, acid halides can. as chlorides (prepared e.g. by treatment with oxalyl chloride), activated esters (formed e.g. with N-hydroxynitrogen compounds such as N-hydroxysuccinimide) or mixed anhydrides (formed e.g. with hemigenformic acid lower alkyl esters, such as chloroformic ethyl

or chloroformic acid isobutyl ester, or with haloacetic acid halides such as trichloroacetyl chloride) by reaction with alcohols, possibly in the presence of a base such as pyridine, is transferred in an esterified carboxyl group.

In a compound of formula I with an esterified carboxyl group, this can be transferred into another esterified carboxyl group, e.g. 2-chloroethoxycarbonyl or 2-bromoethoxycarbonyl by treatment with an iodine salt, e.g. sodium iodide to 2-iodoethoxycarbonyl. Furthermore, in connection with formula I which contains a carbonyl group protected in esterified form, the carboxyl group can be cleaved off as mentioned above, and a formed compound of formula I 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, in which A together with the carbonyl group forms an esterified carboxyl group that can be split under physiological conditions. 1 compounds of formula I obtained according to the method, in which R^ means a protected hydroxy group, this can be transferred in a manner known per se to a free hydroxy group R^. For example, a hydroxy group protected with a suitable acyl group or an organic silyl or stannyl group is released as a correspondingly protected amino group. A 2-halogen lower alkyl group and an optionally substituted benzyl group are cleaved off reductively.

Furthermore, a compound of formula I obtained according to the method, in which R^ means hydroxy, can be transferred in a manner known per se to a compound of formula I, in which R^ means a protected hydroxy group. Thus, hydroxy by reaction with an acyl halide, e.g. a halide such as the chloride of an optionally substituted lower alkanecarboxylic acid, optionally substituted benzoic acid or an optionally substituted lower alkyl or phenyl lower alkyl half-ester of the carboxylic acid is transferred to an optionally substituted lower alkanoyloxy, benzoyloxy, lower alkoxycarbonyloxy or phenylloweralkoxycarbonyloxy. Furthermore, by reacting with trisubstituted silyl halides or optionally substituted 1-phenyl lower alkyl halide, a compound of formula I is obtained, in which R^ means trisubstituted silyloxy

respectively optionally substituted 1-phenyl lower real oxy.

Salts of compounds of formula I with salt-forming groups can be prepared in a manner known per se. Thus, one can form salts of compounds of formula I with a free carboxyl group, 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 amide, preferably using stoichiometric amounts or only a small excess of the salt-forming agent. Acid addition salts of compounds with formula I are obtained in a similar way, e.g. by treatment with a suitable acid, or a suitable ion exchange reagent. Inner salts of compound of formula

In which e.g. means amino and R2 means hydroxy, can e.g.

formed by neutralization of salts such as acid addition salts

to the isoelectric point, e.g. with weak bases, or when treated with ion exchangers.

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

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

The cleavage of formed racemates into their optical antipodes can take place in different ways.

One of these ways 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 can be split into the optically active compounds.

TiX. splitting in antipodes particularly suitable racemates are those which have an aur group, such as e.g. racemate of for-lunde Ise of formula £, h<y>ori R2 is hydroxy. These acidic racemates can be reacted with optically active bases, e.g. esters of optically active amino acids, or (-)-brucine, (+)-quinidine, (-)-quinine, (+)-cinchonine, (+)-dehydroabiethylamine, )+)- and (-)-ephedrine, (+ )- and (-)-1-phenyl-ethylamine or their N-mono- or N,N-dialkylated derivatives to mixtures consisting of two diastereomeric salts. In racemates containing a carboxyl group, this carboxyl group can also be esterified or esterified with an optically active alcohol such as (-)-menthol, (+)-borneol, (+)- or (-)-2-octanol, whereupon after isolation of the desired the diastereomeric carboxyl group is released. For racemate separation, the hydroxy group can also be esterified with optically active acids or their reactive functional derivatives, forming diastereomeric esters. Such acids are, for example (-)-abietic acid, D(+)- and L(-)-malic acid, N-acylated optically active amino acids, (+)- and (-)-campanic acid, (+)- and (-) -ketopic acid , L ( + )-ascorbic acid, _(_*.)..-. Camphoric acid, (+)-camphor-10-sulfonic acid(8), (+)- or (-)-α-bromocamphor-TT-sulfonic acid, D (-)-chinic 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-toluyl derivatives.

When reacted with optically active isocyanates, such as

with (+)- or (-)-1-phenylethyl isocyanate, compound of formula I, in which R, means protected amino and R- means a residue RA^ can be converted into a mixture of diastereomeric urethanes.

Basic breed foods, e.g. connection with formula

In, in which. R^ means amino can form diastereomeric salts with the aforementioned optically active acids.

The cleavage of the separated diastereomers in the optically active compounds of formula I likewise takes place according to usual methods. The acid or base is liberated from the salts,

e.g. when treated with stronger acids or bases, than those originally used. The desired optically active compounds are obtained from the esters and urethanes, for example after alkaline hydrolysis, or after reduction with a complex hydride such as lithium aluminum hydride.

A further method for the separation of racemates consists in chromatography on optically active absorption layers, e.g.

show cane sugar.

According to a third way, the racemates can be dissolved in optically active solvents, and the heavier soluble optical antipode crystallizes out.

A fourth method uses the different reactivity of the optical antipodes towards biological materials, such as microorganisms or isolated enzymes.

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

The division of the diastereomers into the individual race-,. mater and racemate in the optical antipodes can be carried out at a desirable method step, i.e. e.g. also on the step of starting material with formula II or on a desirable step of the below mentioned process for the preparation of

starting materials of formula II.

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

The method also includes the embodiments according to which the compounds formed as intermediates are used as starting materials and the remaining method steps are carried out with these, or the method is interrupted at one or another step, furthermore starting materials 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 in which Z represents oxygen can be prepared in situ from a compound of formula II, in which Z represents a optionally substituted methylidene group as described below by ozonization and subsequent reduction of the formed ozonide, analogous to the method further specified below (step 3.3), whereby the cyclization takes place in the reaction mixture to form a compound of formula I.

The starting compounds of formula II and their precursors can be prepared as indicated in reaction schemes I, II and

III.

In the compounds of formula IV, V, VI and II' means

Z' oxygen, sulfur or also a corresponding one or two substituents in a substituted methylidene group which, by oxidation, can be transferred to an oxo group Z. A substituent Y of this methylidene group is an organic residue, for example optionally substituted lower alkyl, e.g. methyl or ethyl, cycloalkyl, e.g. cyclopentyl or cyclohexyl, phenyl or phenyl lower alkyl, e.g. benzyl or especially one inclusive'with an optically active alcohol such as 1-menthol, esterified carboxyl group, e.g. one. of the optionally substituted lower alkoxycarbonyl or arylmethoxycarbonyl residues mentioned under R2 or also 1-methyloxycarbonyl. This methylidene group preferably has one of the aforementioned substituents. To be highlighted are the methoxy-carbonylmethylidene-, ethoxycarbonylmethylidene- and 1-menthyloxy-carbonylmethylidene group Z'. The latter can be used for the preparation of optically active compounds of formula IV to VI

and II.

In the compounds of formula III-VI as well as II<1>, the residues are R-. preferably one of the aforementioned protected hydroxy groups,

e.g. optionally substituted 1-phenyl lower alkyloxy, optionally substituted phenyl lower alkylcarbonyloxy or trisubstituted silyloxy and R-2 preferably means substituted amino.

Step 1.1; A tlo-azetidinone of formula IV is obtained by treating a 4-W-azetidinone of formula III in which W is a nucleofuge leaving group with a mercapto compound of formula R1-(CH2)4-C(=Z')-SH

or a salt, e.g. an alkali metal, such as sodium or potassium salt thereof, and if desired is transferred in a formed compound of formula IV, in which R^ is hydroxy, hydroxy to protected hydroxy.

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

R1-(CH2)4-C(=Z,)-S-

replaceable remainder. Such groups W are, for example, acyloxy acid residues, sulfonyl residues R o -SO2 _-, in which R o is an organic residue, azido

or halogen. In an acyloxy residue W, acyl is e.g. the remainder 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. phenyl-acetyl, or the acyl residue of one of the above-mentioned optically active acids. In a sulfonyl residue R:-SO„-, R is, for example, optional

Yes 2 o

with hydroxy substituted lower alkyl, such as methyl, ethyl or 2-hydroxyethyl, further also correspondingly substituted optically active lower alkyl; e.g. (2R)- or (2S)-1-hydroxyprop-2-yl, at an optically active residue substituted methyl, such as campheryl, or benzyl, or optionally substituted phenyl, such as phenyl, 4-bromophenyl or 4-methylphenyl. A halogen residue W is e.g. bromine, iodine or especially chlorine. W is preferably methyl- or 2-hydroxyethyl-sulfonyl, acetoxy or chlorine.

The nucleophilic substitution can be carried out under.....

neutral or slightly 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/i such as an alkali metal or alkaline earth metal hydroxide, carbonate or hydrogen carbonate, e.g.

of sodium, potassium or calcium hydroxide, carbonate or bicarbonate. As organic solvents, e.g. water-miscible alcohols 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 reduced temperature. By adding a salt of hydroiodic acid or a thiocyanic acid,

e.g. an alkali metal, such as a sodium salt, the reaction can be accelerated.

The reaction can be used both optically inactive

cis- or trans-compounds of formula III, as well as mixtures thereof, or corresponding optically active compounds. The incoming group R 3 (CH 2 ) 4 -C (=Z ') -S- is directed by the group R 3 -CH 2 - preferably. in trans position, regardless of whether W to the group

R3-CH2~is in cis- or . trans position. Although the trans-isomer is predominantly formed, the cis-isomer can also be isolated in the meantime. The separation of cis- and trans-isomers takes place, as discussed above, according to usual methods, in particular by chromatography and/or by crystallization.

The subsequent ozonization of a methylene group Z' can be carried out as indicated further below. A racemate of formula IV formed can be resolved into the optically active compounds.

An azétidinone of formula III, wherein and W are each acetoxy is disclosed in German Offenlegungsschrift No. 29

50 898. Other azetidinones with formula III can be obtained by methods known per se, for example when a vinyl ester of the formula R^-Ct^-CI^CH-W is reacted with chlorosulfonyl isocyanate, and the cycloadduct formed is reacted with a reducing agent

e.g. sodium sulfite. In this synthesis, mixtures are usually obtained

ings of cis- and trans-isomers, which, if desired, can be divided into the pure cis- or trans-isomers, e.g. by chromatography and/or crystallization or distillation. The pure cis- and trans-isomers exist as racemates and can be divided into their optical antipodes, for example when acyl in an acyloxy compound W in connection with formula III originates from an optically active acid. The compounds of formula III, especially their optically active representatives, can also be prepared according to the methods indicated below in reaction schemes II and III.

Step 1.2: An α-hydroxycarboxylic acid compound of formula V is obtained by reacting a compound of formula IV with a glyoxylic acid compound of formula 0KC-C(=0)-R2 or a suitable derivative thereof, such as a hydrate, heraihydrate or hemiacetal,

e.g. a hemiacetal with a lower alkanol, e.g. methanol or ethanol, and if desired in a formed compound of formula V, in which R^ is hydroxy, hydroxy is transferred to protected hydroxy.

Compound V is usually obtained as a mixture of those

two isomers (with respect to the grouping ^CH~0H) . However, it is also possible to isolate the pure isomers thereof.

The attachment of the glyoxylic acid ester compound to the nitrogen atom of the lactam ring takes place at room temperature or, if necessary, during heating, e.g. to approx. 100°C, namely in the absence of an actual condensing agent and/or without the formation of a salt. When using the hydrate of the glyoxylic acid compound, water is formed which, if necessary, is removed by distillation, e.g. azeotrope, or by using a suitable dehydrating agent, such as a molecular sieve. Preferably, one works in the presence of a suitable solvent such as e.g. dioxane, toluene, or dimethylformamide, or solvent mixture, if desired or necessary in the atmosphere of an inert gas such as nitrogen. In the reaction, both pure optically inactive cis- or trans-compounds of formula IV, as well as mixtures thereof, or corresponding optically active compounds can be used. A racemate of formula V formed can be resolved into the optically active compounds.

Step 1.3: Compounds of formula VI, wherein XQ denotes a react-

sionable esterified hydroxy group, especially halogen, or-—

organic sulfonyloxy, is prepared when in a compound

with formula V converts the secondary hydroxy group 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 starting compounds of formula V, R_ preferably means a protected hydroxy group.

The compounds of formula VI can be obtained in the form of

mixtures of isomers (with regard to the grouping

or in the form of pure isomers.

The above reaction is carried out by treatment with a suitable esterification agent, e.g. with a thionyl halide,

e.g. -chloride, a phosphoroxyhalide, especially -chloride, a halophosphonium halide, such as triphenylphosphonium bromide, or -diiodide, or a suitable organic sulphonic acid halide, such as -chloride, preferably in the presence of a basic, primarily an organic basic agent, such as an aliphatic, tertiary amine,

e.g. triethylamine, diisopropylethylamine or "polystyrene-Honey base" or a heterocyclic base of the pyridine type, e.g. pyridine or collidine. Preferably you work in the presence of

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

In a thus formed compound of formula VI, a reactive esterified hydroxy group XQ can be converted in a manner known per se into another reactive esterified hydroxy group. Thus, one can e.g. exchange a chlorine atom by 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,

with a bromine or iodine atom.

In the reaction, pure optically inactive cis- or trans-compounds of formula V can be used as well

mixtures thereof, or equivalent optically active compounds. A racemate of formula VI formed can be divided into the optically active ones

connections.

Step 1.4: Starting materials of formula I-11 are obtained when a compound of formula VI, in which XQ means a reactive esterified hydroxy group, is treated with a suitable phosphine compound such as a lower alkyl phosphine, e.g. tri-n-butyl-phosphine, or a triaryl-phosphine, e.g. triphenylphosphine, or with a suitable phosphite compound, such as a trilower alkyl phosphite, e.g. tri-ethyl phosphite, or an alkali metal dilute alkyl phosphite, e.g.

-diethyl phosphite, since depending on the choice of reagents you can get

a compound of formula II (resp. II<1>), or Il.a.

The above reaction is preferably carried out in the presence of a suitable inert solvent, such as a hydrocarbon, e.g.

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, you work under cooling or at an elevated temperature, e.g. between -10 and +100°C, preferably at approx. 2Q° to 80°C, and/or in an inert gas atmosphere such as nitrogen. To prevent oxidative processes, catalytic amounts of an antioxidant can be added, e.g. hydroquinone.

Thereby, one works by using a phosphine compound, usually in the presence of a basic agent, such as an organic base, e.g. an amine, such as triethylamine, diisopropylethylamine or "polystyrene-Honey base", and thus comes directly to Ylid starting materials of formula II (resp. II')

which is formed from the corresponding phosphonium salt.

Pure optically active cis- or trans-compounds of formula VI can be used in the reaction as well as mixtures or equivalent optically active compounds.

A racemate of formula II formed can be divided into

the optically active compounds.

The ylides of formula II' in which Z' is oxygen or sulphur, can be used directly in the cyclization reaction to produce end products of formula I.. However, one can also in compounds of formula II<1>, in which R^ denotes a protected hydroxy group, e.g. e.g. a hydrolytically easily cleavable protected hydroxy group, such as trisubstituted silyloxy, first

cleave off the hydroxy protecting group, and then apply it—

formed compound of formula II', in which R^ is hydroxy, in the cyclization reaction. Furthermore, in connection with formula II' in which R1 means protected amino, the amino protecting group can be cleaved off.

In the compounds II<1>, IV, V and VI, an optionally substituted methylidene group Z 1 can be transferred into the oxo group Z by ozonization and subsequent reduction of the formed ozonide, according to the methods described below in step 3.3.

The starting compound with formula III, in which W means a sulfonyl residue HO-A-SO.,-, can also be prepared according to the following reaction scheme II:

In connection with formula VII-IX and Illa means

A is a lower alkylene radical with 2 to 3 carbon atoms between them

two heteroatoms, and is primarily ethylene or 1,2-propylene, but can also be 1,3-propylene, 1,2-, 2,3- or 1,3-butylene.

In the compounds of formula VII-IX, each of the residues Rfl and R^ means hydrogen or an organic residue connected over a carbon atom with the ring carbon atom, the two residues RC= L and Rkcan be connected to each other, primarily with hydrogen, lower alkyl , e.g. methyl, ethyl, n-propyl, or isopropyl, optionally substituted phenyl or phenyl lower alkyl, e.g. benzyl or if combined, lower alkylene, preferably with 4-6 carbon atoms, e.g. 1,4-butylene or 1,5-pentylene.

In compounds of formula VIII and IX and IIIa, the residue R is hydroxy or preferably one of the aforementioned protected hydroxy groups, e.g. optionally substituted 1-phenyl lower alkyloxy, optionally substituted phenyl lower alkylcarbonyloxy or trisubstituted silyloxy.

Step 2.1: A compound of formula VIII is obtained by reacting a bicyclic compound of formula VII with a metallation reagent and an electrophile which introduces the residue R3~CH2-,

then it treats the product formed with a proton source,

and, if desired, transfer a formed compound of formula VIII, -wherein is hydroxy to a compound of formula VIII, wherein R., is protected hydroxy.

Suitable metallation reagents are e.g. substituted and unsubstituted alkali metal amides, alkali metal hydrides or alkali metal-lower alkyl compounds, in which the alkali metals e.g. sodium or especially lithium, e.g. sodium or lithium amide, lithium bis-trimethylsilylamide, sodium hydride, lithium hydride and preferably lithium diisopropylamide and butyllithium.

An electrophile that introduces the residue R^-CO^- is, for example, formaldehyde, forming compounds of formula VIII, in which R^ is hydrogen, or a functional derivative of formaldehyde of formula R2-CH2-X, in which X means a nucleofuge

leaving group, especially halogen, e.g. chlorine, bromine or iodine

or sulfonyloxy, e.g. methanesulfonyloxy or 4-toluenesulfonyloxy. Preferred electrophiles which introduce the residue R^-CH.,- are formaldehyde and optionally substituted benzyloxymethyl chloride.

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

The metallated intermediate does not need to be isolated, but can be reacted in connection with the metallation reaction with an electrophile which introduces the residue R^-CH^-. The metallation reaction takes place at temperatures of approx. -100°C to approx. room temperature, preferably below -30°C, preferably in an inert gas atmosphere, such as nitrogen atmosphere. Further sales can take place under the same conditions. Thereby, formaldehyde is preferably introduced in gaseous, monomeric form into the reaction mixture. Monomeric formaldehyde can, for example, be obtained by thermal depolymerization of paraformaldehyde, or by thermal decomposition of formaldehyde cyclohexyl hemiacetal.

For the metallation reaction, the antipodes of the compounds of formula VII can be used as well as their ra-

camic or diastereomeric mixtures.

The attack by electrophiles which introduce the residues R3-CH«2- on the substrate usually takes place in a stered-specific manner. An azetidinone of formula VII with R configuration is used as starting material, at carbon atom 4 of the azetidinone ring, then predominantly a compound of formula VIII with R configuration at carbon atom 4 and S configuration at carbon atom 3 of the azetidinone ring occurs, i.e. .the electrophile's attack takes place predominantly trans-placed.

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

In a compound of formula VIII formed wherein

R3 is hydrogen, one can protect the .-.hydroxy group on i and f o-e—

known way, e.g. by etherification or esterification, especially as discussed above.

Starting compounds with formula VII can, for example, be obtained by reacting an acetate with formula

with a mercapto compound of formula HS-A-OH, and treats a formed thio compound with formula

as mentioned in European application No. 23887, with a carbonyl compound of formula (R ,R )C=0.

a d

When reacting the acetate of formula X with mercaptans of formula HS-A-OH, which in A has a chirality center, e.g. antipodes of a 2-mercapto-l-propanol, such as (2R)-2-mercapto-l-propanol, diastereomer mixtures of compounds of formula Xa arise, which can be divided into the individual antipodes by usual methods, for example as described above. The individual antipodes.g. e.g. (4R)-antipodes of formula can be further processed without configuration change to the corresponding antipodes in the intermediates II to VI, VIII and IX mentioned in the reaction schemes I and II and the final product of formula I. Then, as mentioned above.-: the introduction of optionally protected hydroxymethyl substituents in the azetidinone ring of the compound of formula VII takes place stereospecifically (trans), it is based on the assumption of compound of formula Xb that intermediates of formula II are available. VI, VIII, and IX and the final product of formula I, in which the azetidinone ring in the 4-position assumes R- and in the 3-position S-configuration.

Step 2.2: A sulfone of formula IX can be prepared in which

treats the thio compound of formula III with an oxidation

agent, and if desired, a compound of formula IX obtained according to the method, in which R^ is hydroxy, is transferred to a compound of formula IX, in which R^ is a protected hydroxy.

Suitable oxidizing agents are, for example, hydrogen peroxide, organic peracids, especially aliphatic or aromatic percarboxylic acids, e.g. peracetic acid, perbenzoic acid, chloroperbenzoic acid, e.g. 3-chloroperbenzoic acid, or monoperphthalic acid, oxidizing inorganic acids and their salts, e.g. nitric acid, chromic acid, potassium permanganate or alkali metal hypochlorides, e.g. sodium hypochloride. However, the transfer can also take place by anodic oxidation.

The oxidation is preferably carried out in a suitable inert solvent, for example a halohydrocarbon,

e.g. methylene chloride, chloroform, or carbon tetrachloride,

an alcohol, e.g. methanol or ethanol, a ketone, e.g. acetone, an ether, diethyl ether, dioxane or tetrahydrofuran, an amide, e.g. dimethylformamide, a sulfone, e.g. dimethyl sulfone, a liquid organic carboxylic acid, e.g. acetic acid or in water or a mixture of these solvents, especially an aqueous mixture, e.g. aqueous acetic acid at room temperature

temperature or during cooling or slight heating, i.e. at approx. -20°C to approx. + 90°C, e.g. at approximately room temperature. The oxidation can also be carried out in stages, as it is primarily oxidized at lower temperatures, i.e. at approx. -20°C to approx. 0°C, until sulfoxide, which is possibly isolated, after which in a second step, preferably at higher temperatures, e.g. at room temperature, the sulfoxide is oxidized to sulfone of formula IX.

For processing, any excess oxidizing agent still present can be split by reduction, especially by treatment with a reducing agent such as thiosulphate, e.g. sodium thiosulfate.

In the reaction, both optically inactive compounds with formula VIII can be used, as well as corresponding optically active compounds, especially those with 3S-,4R-con-

figuration in the azétidinone ring.

Step 2.3: Compound of formula III can be prepared as

one solvolyzes a bicyclic amide of formula IX with a suitable solvolysis reagent, which, if desired, in a compound of formula IIIa obtained according to the method, converts a free hydroxy group R. into a protected hydroxy group R.

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

The mentioned solvolysis reagents are added undiluted or diluted with water. The solvolysis can also be carried out with clean water. The solvolysis with acid reagents preferably takes place in these reagent aqueous solutions, and at temperatures from approx. -20°C to approx. 150°C, preferably at temperatures up to 110°C.

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

the ring.

Formed isomeric mixtures of compound of formula VIII, IX or purple, as racemates or diastereomer mixtures can be separated in a manner known per se,

e.g. as mentioned above in the individual isomers as antipodes.

According to the invention, optically active trans-compounds of formula III that can be used can also be prepared according to the following reaction scheme III:

in the compounds of formula XI-XIV and IIIb, R represents hydroxy or, in particular, a protected hydroxy group.

Step 3.1: Compound of formula XII is known or can be prepared in a manner known per se. They can also be prepared according to a new method by epimerizing a compound of formula XI, and if desired in a compound of formula XII obtained according to the method, a protected hydroxy group R^ is transferred to another protected hydroxy group R^.

The epimerization takes place, for example, in the presence of

a basic agent such as an amine, e.g. a tri-lower alkylamine..

f, e.g. triethylamine, or ethyl diisopropylamine, a tertiary amine, e.g. N,N-dimethylaniline, an aromatic amine, e.g. pyridine, or a bicyclic amine, e.g. 1,5-diazabicyclo 1_ 5, 4 , o7undec-5-ene or 1, 5-diazabicyclo/ 4 , 3, 0_7non-5-ene, or an alkali metal lavereal canolate, e.g. sodium methanebiate,

sodium ethanolate or potassium tert-butanolate, or an inert"

solvent, for example an ether, e.g. diethyl ether., dimethoxyethane, tetrahydrofuran or dioxane, acetonitrile or dimethylformamide, optionally at a somewhat elevated or reduced temperature, e.g. at 0°C to 50°C, preferably at room temperature.

In the compounds of formula XII obtained according to the method, a protected hydroxy group R 2 can be replaced by another protected hydroxy group R 1 , e.g. 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 by first removing the hydrogenolytically cleavable hydroxy protecting group and in the formed compound of formula XII in which R^

is hydroxy, introduce a solvolytically cleavable hydroxy protecting group.

The cleavage of a hydrogenolytically cleavable protecting group takes place e.g. with hydrogen or with 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. 8 0°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 donating agent such as an organic acid,

e.g. acetic acid or also a lower alkanol, e.g. ethanol.

The introduction of the solvolytic cleavable hydroxy protecting group takes place, for example, with a pre-

bond of formula R^-X^, in which R^' means hydroxy protecting L.-—

viewing group, X3 means e.g. a reactive esterified hydroxy group, for example halogen, e.g. chlorine, bromine or iodine, or sulfonyloxy, such as methanesulfonyloxy, benzenesulfonyloxy or 4-toluenesulfonyloxy.

The reaction takes place in an inert solvent such as an ether, e.g. diethyl ether, dioxane or tetrahydrofuran, a hydrocarbon, e.g. benzene or toluene with a halohydrocarbon, e.g. methylene chloride in dimethyl sulfoxide or acetonitrile, in the presence of a basic condensing agent such as an alkali metal hydroxide or carbonate, e.g. sodium or potassium hydroxide or sodium or potassium carbonate, an alkali metal amide or hydride, e.g. sodium amide or sodium hydride, e.g. sodium amide or sodium hydride, an alkali metal lower alkanolate, e.g. sodium methanolate or ethanolate, or potassium tert.-butanolate, or an amine,

e.g. triethylamine, pyridine or imidazole, at room temperature or elevated or lower temperature, e.g.

at approx. -20°C to approx. 80°C, preferably at room temperature.

Starting compounds with formula XI are known, for example, from German Offenlegungsschrift 3 039 504 and from British application 20 61 930.

Step 3.2: A compound of formula XIII can be prepared by treating a Penam compound of formula XII with a basic agent such as with an esterifying agent which introduces the residue Rq.

A suitable basic agent is, for example, one of the basic agents mentioned under step 3.1, especially one of the mentioned bicyclic amines, 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 esterification agent that introduces the residue R oer e.g. a compound of formula Rg-X^, in which X^ means react-

sionable esterified hydroxy, e.g. halogen such as chlorine,

bromine or iodo, or sulfonyloxy, such as methanesulfonyloxy, benzenesulfonyloxy or 4-toluenesulfonyloxy. Ethylene oxide is also suitable for introducing a 2-hydroxyethyl residue.

The reaction is preferably carried out in two steps, with the Penam compound of formula XIII being treated in the first step with at least equimolar amounts of the basic agent,

and reacts a formed intermediate with formula

wherein B means the protonated form (cation) of the basic agent, preferably without isolation from the reaction mixture with esterification agents. 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, optionally at a somewhat elevated or reduced temperature, e.g. at approx. 0 to 50°C, preferably at room temperature.

drawn embodiment of the method, the Penam compound of formula XII is prepared in situ, treating a compound of formula XI first with catalytic amounts of the basic agent, e.g. 1,5-diazabicyclo/ 5,4,0/undec-5-ene, and then reacts with at least an equimolar amount of the same basic agent and of esterifying agents further to the compounds of formula XIII.

Step 3.3: An oxalyl-azetidinone of formula XIV can be prepared by ozonizing a compound of formula XIII

and cleaves the formed ozonide reductively to oxo compound.

The ozonation is usually carried out in 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 halogen-lower alkane, such as methylene chloride or carbon tetra-

chloride, 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 formed as an intermediate is usually split without reductive isolation in a compound of formula XIV, using catalytically activated hydrogen, e.g. hydrogen in the presence of heavy metal hydrogenation catalyst such as a nickel-further palladium catalyst, preferably on a suitable support material, such as calcium carbonate or coal, or chemical reducing agent 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 diiodide 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 a reducing agent, compounds can also be used which can easily be converted into the corresponding epoxide compounds or oxides, as the epoxide formation can take place

due to a C,C double bond and the oxide formation due to a present oxyc-forming hetero-, such as sulphur, phosphorus-

or nitrogen atom. Such compounds are, for example, suitable substituted ethylene compounds (which in the reaction are converted into ebylene oxide compounds) such as tetracyanethylery or particularly suitable sulphide compounds (which in the reaction are converted into sulphoxide compounds), such as dilave alkyl sulphides primarily dimethyl sulphide, suitable organic phosphorus compounds such as optionally with phenyl and/or lower alkyl, e.g. methyl, ethyl, n-propyl, n-butyl, substituted phosphine (which in the reaction is converted to a phosphine oxide), such as trilower alkylphosphines, e.g. tri-n-butylphosphine or triphenylphosphine, also tri-lower alkyl phosphite (which in the reaction is converted into phosphoric acid tri-lower alkyl esters), usually in the form of corresponding alcohol adduct compounds such as trimethyl phosphite or phosphoric acid triamides, which optionally contain lower alkyl as substituents such as hexalower alkyl phosphoric acid triamides , e.g. hexa-

methyl phosphoric acid triamide, the latter preferably in form

of a methanol adduct, further suitable nitrogen bases (which in the reaction are converted into corresponding N-oxides) such as heterocyclic nitrogen bases of an aromatic character, e.g. bases of the pyridine type and especially pyridine itself. The splitting of the usual

vis non-isolated ozonide normally takes place under the conditions that can be used in its preparation, i.e. in the presence of a suitable solvent or solvent mixture, as well as under cooling or slight heating, preferably working at temperatures from approx. -10 to approx. +25°C, and the reaction usually ends at room temperature.

Step 3.4: An azedinone of formula IIIb 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 water-miscible solvent. The alcoholysis is usually carried out with a lower alkanol, e.g. methanol or ethanol, preferably in the presence of water or 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 hydraziholysis is carried out in the usual way with a substituted hydrazine, e.g. with phenyl or a nitrophenylhydrazine such as 2-nitrophenylhydrazine, 4-nitrophenylhydrazine, or 2,4-diiritrophenylhydrazine, which is preferably used in an approximately equimolar amount in an organic solvent such as an ether, e.g. tetrahydrofuran, dioxane, diethyl ether, an aromatic hydrocarbon such as benzene or toluene,. a halogenated hydrocarbon such as methylene chloride, chlorobenzene or dichlorobenzene, an ester such as methyl acetate, and the like at temperatures between approx. room temperature and approx. 65°C.

In a preferred embodiment of the method, the starting point is a compound of formula XIII which is ozonized as indicated, and then reductively cleaved to oxalyl-azedinone of formula XIV which is reacted without isolation from the reaction

sion mixture further to azedionone of formula IIIb.

During the ozonolysis, possibly smaller amounts of the acid occur which can cause the cleavage of a solvolytically easily cleavable residue, e.g. a trisubstituted silyl residue. The thereby formed compound of formula

can, for example, be separated from protected azetidinone by chromatogafic and by renewed reaction with agents that introduce the hydroxy protecting group R^<1> and of formula ^'""X-j be transferred into azetidinone of formula IIIb.

In the compounds of formula II, II<1>, V, VI and XII-XIV, a group R_ can be transferred to another group R2 according to methods known per se, taking into account the possible additional functional elements contained in these compounds groups, the same method as indicated in the conversion of these substituents in the compounds of formula I can be applied.

The invention likewise relates to new starting products as well as new intermediate products obtainable according to the method, such as those with the formulas II to IV, VIII, IX and XII to XIV, as well as the specified methods for their preparation.

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

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

Tablets are used for oral administration

or gelatin capsules containing the active substance together__

with diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and/or glycine and lubricants e.g. diatomaceous earth, talc, stearic acid or salts thereof,

such as magnesium or calcium stearate and/or polyethylene glycol,

tablets also containing binders, e.g. magnesium aluminum silicate, starches, such as corn, wheat, rice or arrowroot starch, gelatins, tragacanth, methylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone, and if desired explosives, e.g. starches, agar, alginic acid or salts thereof, such as sodium alginate, and/or fizzy mixes or adsorbents, colourings, flavorings or sweeteners.

For parenteral administration, infusion solutions are primarily suitable, preferably isotonic, aqueous solutions or suspensions, as these e.g.

before use can be prepared from lyophilized preparations containing the active substance alone or together with carrier material, e.g. Manitou. Such preparations may be sterilized and/or contain excipients, e.g. preservatives, stabilisers, wetting and/or emulsifiers, solubility mediators, salts for regulating the osmotic pressure, and/or buffers.

The pharmaceutical preparations which, if desired, can contain further pharmacologically valuable substances, are produced in a manner known per se, e.g. using conventional mixing, dissolving or lyophilization methods,

and contains from approx. 0.1 to 10.0%, especially from approx. 1% to approx. 50% lyophilisates up to 100% of the active substance.

Depending on the type of infection and the condition of the infected organisms, daily doses of approx. 0.1 to approx. 5 g (by oral application of (5R,6S)-2-(4-aminobutyl)-6-hydroxy-methyl-phenem-3-carboxylic acid, e.g. two daily doses to approx.

0.2 5 to lg) for the treatment of warm-blooded animals (humans and animals) of approx. 70 kg weight.

The following examples serve for further explanation

of the invention. Temperatures are given in degrees Celsius.

In the examples, the following abbreviations are used:

DC: thin layer chromatogram,

IR: infrared spectrum,

UV: ultraviolet spectrum,

mp: melting point

DBU: 1,5-diazabicyclo/ 5.4.0/undec-5-ene.

Example 1: trans-2,2-dimethyl-8-hydroxymethyl-3-oxa-6-thia-1-azabicyclo/5.2.0/nonan-9-one.

A 2.0 molar solution of n-butyllithium in n-hexane (0.11 mol) is added dropwise with stirring at -65°C and under nitrogen to a solution of 11.0 g (15.5 ml 0.11 mol), diisopropylamine in 200 ml of dry tetrahydrofuran. The mixture re-

stirred for 15 minutes at -65°C. In the course of 15 minutes, a solution of 18.7 g (0.1 mol) of 2,2-dimethyl-3-oxa-6-thia-1-azabicyclo/5 is added. 2. 0/-nonan^-9-one in 80 ml of dry tetrahydrofuran with stirring at -65°C. The mixture is then stirred for a further 10 minutes at -65°C. Formaldehyde gas is produced in a separate flask by heating formaldehyde/cyclohexanone adducts at 150°C and which is normally produced by reacting an aqueous solution of formaldehyde and cyclohexanol. An excess amount of dry formaldehyde gas is then slowly stirred over the reaction mixture at -65°C. The mixture is stirred for 30 minutes at -65°C. The cold reaction mixture is poured

on a mixture of 250 g ice and 250 g water. 250 ml of chloroform and 110 ml of 2.0 N hydrochloric acid are added. After shaking the mixture, the organic layer is separated. After adding 60 g of sodium chloride, the aqueous layer is then extracted twice with chloroform. The organic solution is dried over sodium sulfate and filtered. The solvent is removed by evaporation. The residue formed is a yellowish, oily liquid.

Example 2: (5R,7R,QS)-2,2,5-trimethyl-8-hydroxymethyl-3-oxa-6-thia-1-azabicyclo/5.2.0/nonan-9-one.

This compound is obtained in an analogous manner to example 1 by reacting metallated (5R, 7R)-2,2,5-trimethyl-3-oxa-6-thia-1-azabicyclo-/5.2.0/nonan-9-one with formaldehyde.

Example 3: trans-2,2-dimethyl-8-(4-nitrobenzyloxycarbonyloxymethyl)-3-oxa-6-thia-1-azabicyclo/5,2N-nonan-9-one.

21.6 g (0.1 mol) of solid chlorocarbonic acid 4-nitrobenzyl ester are added at -10°C to a solution of 22 g of crude trans-2,2-dimethyl-8-hydroxymethyl-3-oxa-6- thia-1-azabicyclo/ 5.2.0/ nonan-9-one in 250 ml of methylene chloride. 12.2 g (0.1 mol) solid 4-di-. methylaminopyridine is added in small portions over 30 minutes to the solution. The mixture is stirred for 4 hours at 3 to 5°C. The cold mixture is washed with 200 ml of 0.5 N aqueous hydrochloric acid and an aqueous sodium chloride solution.

The organic phase is dried over sodium sulfate and filtered. The solvent is removed by evaporation. The residue formed is a yellow foam. The recrystallization from isopropanol is a solid with a melting point of 82°C.

Example 4: (5R,7R,8S)-2,2,5-trimethyl-8-(4-nitrobenzyloxycarbonyl-oxymethyl)-3-oxa-6-thia-1-azabicyclo /~5.2.0/nonan-9- Wed.

This compound is obtained in an analogous manner to example 3 by reacting (5R, 7R, 8S)-2, 2, 5-trimethyl-3-hydroxymethyl-3-oxa-6-thia-1-azabicyclo/5.2.0?nonane- 9-one with chlorocarbonic acid-4-nitrobenzyl ester in the presence of 4-dimethylaminopyridine.

Example 5: trans-2,2-dimethyl-8-(4-nitrobenzyloxycarbonyloxymethyl)-3-oxa-6-thio-1-azabicyclo[5.2.O]nonan-9-one-6-dioxide.

47.8 g (0.25 mol) of m-chloroperbenzoic acid are added during 30 minutes at -10°C in small portions to a solution of approx. 40 g of trans-2,2-dimethyl-8-(4-nitrobenzyloxycarbonyloxymethyl)-3-oxa-6-thia-1-azabicyclo/~5.2.0/nonan-9-one in 500 ml of methylene chloride.

The mixture is then stirred for 1 hour at 0°C, washed with saturated aqueous sodium bicarbonate solution, 10% sodium bisulphite solution and again with saturated aqueous sodium bicarbonate solution. The organic layer is dried over sodium sulfate and filtered. The solvent is removed by evaporation. The residue formed is a solid which recrystallizes

seres from isopropanol. Sm.p. 158°C.

Example 6: (5R,7R,8S)-2,2,5-trimethyl-8-(4-nitrobenzyloxy-carbonyloxymethyl)-3-oxa-6-thia-1-azabicyclo/ 5.2.0/ nonan-9-one -6-dioxide.

This compound is obtained in an analogous manner to example 5 by reaction of (5R,7R,8S)-2,2,5-trimethyl-8-(4-nitrobenzyl-oxycarbonyl oxycarbonyl)-3-oxa-6-thia-1 -azabicyclo/ 5.2.0/nonan-9-one with m-chloroperbenzoic acid.

Example 7: trans-3-(4-nitrobenzyloxycarbonyloxymethyl)-4-(2-hydroxyethylsulfonyl)-azetidin-2-one.

4.35 g (10 mmol) trans-2, 2-7dimethyl-8-(4-nitrobenzyl-oxycarbonyloxymethyl)-3-oxa-6-thia-1-azabicyclo/~5.2.0/nonan-9-one-6 -dioxide is dissolved in 130 ml of glacial acetic acid and diluted with 30 ml of water. The mixing temperature is maintained for a period of 4 days at 55°C. The solvent is removed by evaporation. The residue is dissolved in ethyl acetate and washed with 30 ml of aqueous sodium bicarbonate solution. The organic layer is separated. The aqueous layer is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and filtered. The solvent is removed by evaporation. A viscous residue is obtained. Purification by chromatography and recrystallization

of isopopanol gives a solid with a melting point of 128°C.

Example 8: (3S,4R)-3-(4-nitrobenzyloxycarbonyloxymethyl)-4-1(2R)-1-hydroxy-2-propylsulfonyl/-azetidin-2-one.

This compound is obtained in an analogous manner to example 7 by hydrolyzing (5R,7R,8S)-2,2,5-trimethyl-8-(4-nitrobenzyloxycarbonyloxymethyl)-3-oxa-6-thia-1-azabicyclo 1_ 5.2 . 07nonan-9-one-6-dioxide with a solution of glacial acetic acid in water.

Example 9: trans-3-(4-nitrobenzyloxycarbonyloxymethyl)-4-[5-(4-nitrobenzyloxycarbonylamino)-valeroylthio]-azetidin-2-one.

To a 30-minute stirred suspension of 3-(4-nitrobenzyloxycarbonyloxymethyl)-4-(2-hydroxyethylsulfonyl)-

azetidin-2-one (8.536 g, 22 mmol) in 14.5 mL acetonitrile, 29 mL

acetone and 145.2 ml of phosphate buffer pH 8, are added dropwise with stirring during 60 minutes at room temperature to a mixture of 5-(4-nitrobenzyloxycarbonylamino)-thiovaleric acid, 26.4 ml of IN NaOH, 26.4 ml of water and 6 ml acetonitrile. The mixture is then stirred for exactly 90 minutes at room temperature, and the milky emulsion formed is taken up in 250 ml of vinegar. The aqueous phase is also extracted with two portions of 52 ml each of acetic acid, the extracts are combined and dried over Na 2 SO 4 . Filtration and evaporation of solvent in vacuo gives a yellowish viscous oil. Chromatography on 240 g of Merck silica gel with Cf^C^-EtOAc (3:1) gives pure amorphous product. IR in CH2 Cl: 3650, 3000, 1790, 1760, 1730, 1520, 1340, 1220 cm"<1>.

Starting materials can be prepared as follows:

a) 5-(4-nitrobenzyloxycarbonylamino)-valeric acid.

to a solution of 5-aminovaleric acid (11.7 g, 0.1

mol) in 100 ml 1N NaOH solution is added at room temperature to solid chloroformate-4-nitrobenzyl ester (28.0 g, 0.13 mol) and the resulting beige suspension is mixed over 40 minutes with 120 ml 1N NaOH solution. The reaction mixture is then stirred for 38 hours at room temperature. The mixture is washed with two

portions of 180 ml of CHCl^, and the aqueous phase is adjusted with 5N HCl to pH 2. The white suspension is filtered, and the residue is dried under high vacuum. The filtrate is extracted with CHCl 2 (2 x 250 ml), the organic phase is dried over Na 2 SO 4 and evaporated in vacuo. The residue is combined with the filter residue. crystal

sering from 200 ml of hot isopropanol gives after 3 days at 0°C

pure crystalline product of m.p. 85-87°C.

b) 5-(4-nitrobenzyloxycarbonylamino)-thiovaleric acid.

5-(4-nitrobenzyloxycarbonylamino)-valeric acid

(59.25 g, 0.2 mol) is suspended in methylene chloride (300 ml) and dissolved by the addition of triethylamine (61.2 ml, 0.44 mol).

To this solution is added dropwise with stirring at -10°C in the barrel

of 30 minutes a solution of chloroformate isobutyl ester (28.8 ml) in methylene chloride (60 ml). After the addition, stir again

for 30 minutes at 0°C. Then introduce for 60 minutes H_S"

at 0°C. After removal of excess I^S with nitrogen, the suspension is dissolved with CHCl^(1.5 L), washed with two. portions of each 250 ml aqueous 2N HC1. The organic phase is extracted with 600 ml of saturated sodium bicarbonate solution, and the aqueous phase is carefully acidified with 6N aqueous HCl in an Erlenmeyer while stirring. The aqueous solution is extracted with two portions of each 1 liter of CHCl 2 , and the organic phase is dried over Na 2 SO 4 and then filtered. Evaporation of the solvent in vacuum gives products such as yellow oil, which crystallizes in a refrigerator, m.p. about. 35°C.

Example 10: (3S,4R)-3-(4-nitrobenzyloxycarbonyloxymethyl)-4-(5-(4-nitrobenzyloxycarbonylamino)-valeroylthio)

azetidin-2-one.

Following the same procedure as described in example 2, starting from (3S,4R)-3-(4-nitrobenzyloxycarbonyloxymethyl)-4-/ (2R)-1-hydroxy-2-propylsulfonyl/-azetidine-2- on of the title compound with an identical IR spectrum. /"a/^<0>+ 61°

(c=1, CHCl 3 ).

Example 11: 2- trans -3-(4-nitrobenzyloxycarbonyloxymethyl)-4-(5-(4-nitrobenzyloxycarbonylamino)-valeroylthio)-2-oxo-azetidinyl 7-2-hydroxyacetic acid-4-nitrobenzyl ester.

A mixture of 4.79 g (8.11 mmol) trans-3-(4-nitrobenzyloxycarbonyloxymethyl)-4-(5-(4-nitrobenzyloxycarbonylamino)-valeroylthio/-azetidin-2-one and 3.10 g ( 12.16 mmol) of freshly prepared glyoxylic acid 4-nitrobenzyl ester ethyl hemiketal in 32 ml of toluene and 8 ml of N,N-dimethylformamide are mixed with 16.3 g of molecular sieve 4 Å and stirred at 40°C for 20 hours. The mixture is filtered before the filter residue is washed with vinegar. Evaporation of the filtrate and drying at 40°C in high vacuum gives a yellowish,

viscous oil (8.19 g). Chromatography on 350 g of Merck silica gel with toluene-acetic ester (7:1) and toluene-acetic ester (2:1) gives the pure title compound as an amorphous solid. IR in Cl₂Cl₂ 3440, 2940, 1780, 1750, 1725, 1515, 1350, 1230 cm<-1>.

Example 12: 2-/"(3S,4R)-3-(4-nitrobenzyloxycarbonyloxymethyl)-4-(5-(4-nitrobenzyloxycarbonylamino)-valeroylthio)-2-oxo-azetidinyl 7~2-hydroxyacetic acid-4-nitrobenzyl ester.

According to the same regulation as discussed in example 11

is obtained starting from the (3S,4R)-3-(4-nitrobenzyloxycarbonyloxymethyl)-4-/5-(4-nitrobenzyloxycarbonylamino)-valeroylthio7-azetidin-2-one title compound with an identical IR spectrum.

Example 13: 2-^~trans-3-(4-nitrobenzyloxycarbonyloxymethyl)-4-(5-(4-nitrobenzyloxycarbonylamino)-valeroylthio)-2-oxo-axetidinyl 7~2-chloroacetic acid-4-nitrobenzyl ester.

To a solution of 9.6 g (12.5 mmol) 2-/trans-3-(4-nitrobenzyloxycarbonyloxymethyl)-4-(5-(4-nitrobenzyloxycarbonylamino)-valeroylthio)-2-oxo-azetidininyl7-2 -hydroxy-acetic acid-4-nitrobenzyl ester in 64 ml of tetrahydrofuran is added dropwise with stirring at -15°C in sequence 1.76 ml (24.2 mmol) thionyl chloride and a solution of 3.4 ml of triethylamine in 5.6 ml of tetrahydrofuran, each once within 15 minutes. The white suspension is further stirred at 0°C for 30 minutes, mixed with 360 ml of methylene chloride, washed with 60 ml of 0.1N aqueous HCl solution and three times with 100 ml of saturated NaCl solution each time. The solution is dried over Na2SO4 and filtered. Evaporation of the solvent in vacuum gives the pure pro-

appeared as a slightly yellowish solid. IR in CH2C12: 3440,

2940, 1785. 1750, 1720, 1520, 1345, 1230 cm<-1>.

Example 14: 2-[(3S,.4R)-3-(4-nitrobenzyloxycarbonyloxymethyl)-4-(5-(4-nitrobenzyloxycarbonylamino)-valeroylthio)-2-oxo-azetidinyl 7-2-chloroacetic acid-4-nitrobenzyl ester.

According to the same regulation as discussed in example 13

is obtained starting from 2-/~(3S, 4R)-3-(4-nitrobenzyloxycarbonyloxymethyl)-4-(5-(4-nitrobenzyloxycarbonylamino)-valeroylthio)-2-oxo-azetidinyl/-2-hydroxy -acetic acid 4-nitrobenzyl ester of the title compound with an identical IR spectrum.

Example 15: 2-/trans-3-(4-nitrobenzyloxycarbonyloxymethyl)-4-(5-(4-nitrobenzyloxycarbonylamino)-valeroylthio)-2-oxo-azetidinyl 7~2-triphenylphosphoranylideneacetic acid-4-nitrobenzyl ester.

A solution of 3.7 g (4.67 mmol) of 2-(3-(4-nitrobenzyloxycarbonyloxymethyl)-4-(5-(4-nitrobenzyloxycarbonylamino)-valeroylthio)-2-oxo-azetidinyl7-2-chloroacetic acid- 4-nitrobenzyl ester and 2.79 g of triphenylphosphine (10.65 mmol) in 3.9

ml of tetrahydrofuran is placed under hydrogen for 2 days at 5°C. Dilute with 200 ml methylene chloride, wash with 50 ml saturated aqueous NaHCO 3 solution, dry with organic phase over Na 2 SO 4 and filter. Evaporation of the solvent in vacuo gives 6.6 g of a reddish oil. Chromatography on 170 g of Merck silica gel with toluene-acetic ester (2:1) gives a yellowish oil. IR in CH 2 Cl 2 : 2940, 2440, 1755, 1725, 1515, 1355, 1230 cm"<1>.

Example 16: 2-/~( 3S , 4R )-3-(4-nitrobenzyloxycarbonyloxymethyl)-4-(5-(4-nitrobenzyloxycarbonylamino)-valeroylthio)-2-oxo-azetidinyl 7-2-triphenylphosphoranylideneacetic acid-4-nitro-benzyl ester .

Following the same procedure as discussed in example 15, starting from 2-/~(3S,4R)-3-(4-nitrobenzyloxycarbonyloxymethyl)-4-(5-(4-nitrobenzyloxycarbonylamino)-valeroylthio)-2- oxo-azetidinyl7-2-chloroacetic acid-4-nitrobenzyl ester the title compound with an identical IR spectrum /_ d/D + 14°

(c=1, CHCl 3 ).

Example 17: trans-6-(4-nitrobenzyloxycarbonyloxymethyl)-2-[4-(4-nitrobenzyloxycarbonylamino)-butyl N-penem-3-carboxylic acid-4-nitrobenzyl ester.

A solution of 8.5 g (8.4 mmol) of 2-/trans-3-(4-nitro-benzyloxycarbonyloxymethyl)-4-(5-(4-nitrobenzyloxycarbonylamino)-valeroylthio)-2-oxo-azetidiyl/-2 -triphenylphosphoranylideneacetic acid-4-nitrobenzyl ester in 2.6 1 toluene is refluxed under a nitrogen atmosphere for 25 hours. Evaporation of the solvent and chromatography of the residue on 260 g of silica gel with toluene-acetic ester (3:1) gives the pure product as a colorless, amorphous solid. IR in CH 2 Cl 2 : 3040, 2940, 1790, 1750, 1720, 1605, 1520, 1345, 1230 cm<-1>.

Example 18: (5R,6S)-6-(4-nitrobenzyloxycarbonyloxymethyl)-2-1-4-(4-nitrobenzyloxycarbonylamino)-butyl N -penem-3-carboxylic acid-4-nitrobenzyl ester.

According to the same regulation as discussed in example 17

is obtained when starting from 2-/~(3S,4R)-3-(4-nitrobenzyloxy-■ carbonyloxymethyl)-4-(5-(4-nitrobenzyloxycarbonylamino)-valeroylthio)-2-oxo-azetidinyl/-2- triphenylphosphoranylideneacetic acid-4-nitrobenzyl ester the title compound with identical IR spectra.

Z~a7p° + 36° (c=1, CHCl 3 ).

Example 19: trans-hydroxymethyl-2-(4-aminobutyl)-penem-3-carboxylic acid.

A mixture of 190 mg (0.25 mmol) trans-6-(4-nitrobenzyloxycarbonyloxymethyl)-2-/ 4-(4-nitrobenzyloxycarbonyl-amino)-butyl7-penem-3-carboxylic acid-4-nitrobenzyl ester, 24 ml of dioxane and 5 ml of 0.1 N aqueous HCl solution is hydrogenated in a hydrogenation joint with a parallel-connected bottle with KOH to C02 absorption at room temperature and normal pressure over 200 mg of 10% Pd on charcoal for 90 minutes. During this time, 39 are admitted

ml of H2. The mixture is filtered through Cellite, evaporated in vacuo to a volume of 5 ml, and the resulting yellow suspension

mixed with a solution of 42 mg of NaHCO^ in 1 ml of water. The solution is applied to six "reverse phase" thin layer chromatography plates (L 254 Opti-UP C-12-20, manufactured by Antec AG, Benn-wil, Switzerland). Chromatography with CH 3 CN - H 2 O 2:3 and elution of the mobile UV-active fraction with CH 3 CN - H 2 O (4:1), partial evaporation of the eluate and lyophilization of the remaining aqueous solution to a colorless, amorphous solid. UV i

H,0 (pH 3):X m3 256 nm (2500), 318 nm (5600).

c. beanie. X

Example 20: (3S,5R,6R)-2,2-dimethyl-6-(tert-butyl-dimethylsilyl-oxymethyl)-penam-3-carboxylic acid methyl ester 1,1-dioxide.

A solution of 23.6 g (85 mmol) (3S,5R,6R)-2,2-dimethyl-6-hydroxymethyl-penam-3-carboxylic acid methyl ester-1,1-dioxide in 50 ml of dimethylformamide is stirred with 25.5 g (170 mmol) tert-butyl-dimethylchlorosilane and 11.5 g (170 mmol) imidazole at room temperature for 45 minutes. The solvent is then distilled off under high vacuum, and the residue is taken up in ethyl acetate. The solution is washed with 1N sulfuric acid and then with water, and the aqueous solutions are extracted twice with ethyl acetate. The organic phase is dried with sodium sulphate and evaporated on a rotary evaporator. The product appears as a crystalline mass. TLC: silica gel, toluene/ethyl acetate (4:1): Rf = 0.56.

IR: (CH 2 Cl 2 ) 3.4; 5.57; 5.65 mm.

Example 21: 2-/~(3S,4R)-3-(tert-butyl-dimethylsilyloxymethyl)-4-"

methyl sulfonyl-2-oxo-azetidin-1-yl 7-3-methyl-2-butenoic acid methyl ester.

A solution of 202 g (0.51 mol) of (3S,5R,6R)-2,2-dimethyl-6-(tert-butyl-dimethylsilyloxymethyl)-penam-3-carboxylic acid methyl ester-1,1-dioxide in 800 ml tetrahydrofuran is mixed with 9 ml DBU and stirred for 5 minutes at room temperature. A further 95 ml DBU was then added, stirred for 30 minutes at room temperature. 42.3 ml (0.68 mol) methyl iodide was then added while cooling. After a reaction time of 3 hours, the 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 IN sulfuric acid, water and sodium bicarbonate solution. The aqueous phases are extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solution

evaporated to a thick oil.

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

IR: (CH 2 Cl 2 ) 5.63; 5.81; 6.17 etc.

Example 22: (3S,4R)-3-hydroxymethyl-4-methylsulfonyl-azetidin-2-one and (3S,4R)-3-(tert-butyl-dimethylsilyloxy-methyl)-4-methylsulfonyl-azetidin-2- Wed.

A solution of 25 g (61.7 mmol) of 2-[(3S,4E)-3-(tert-butyl-dimethylsilyloxymethyl)-4-methylsulfonyl-2-oxo-azetidin-1-yl]-3-methyl -2-butenoic acid methyl ester in 400 ml of methylene chloride is treated at -10°C with an ozone/oxygen mixture. Pre-disappearance of the starting material is checked by thin-layer chromatography. After completion of the reaction, 30 ml of dimethyl sulphide is added and further 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°C. The solvent is then removed and the residue is extracted 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: DC, silica gel, toluene/ethyl acetate (1:1); Rf = 0.36, IR: (CH2C<1>2) 2.96; 3.54; 5.61 etc.

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

A solution of 14.6 g (81.5 mmol) of (3S,4R)-3-hydroxymethyl-4-methylsulfonyl-azetidin-2-one in 40 ml of dimethylformamide is mixed with 24 g (183 mmol) of tert.-biethyldimethylchlorosilane and 11 g (163 mmol) of imidazole for 45 minutes at room temperature. The solvent is then removed under high vacuum and the residue is taken up in ethyl acetate. The organic phase is washed in sequence with IN sulfuric acid, water and sodium bicarbonate solution. The aqueous phases are extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate and evaporated on a rotary evaporator. The crystalline residue is pure (3S,4R)-3-tert-butyl-dimethylsilyloxymethyl)-4-methylsulfonyl-azetidin-2-one.

Example 1 23: (3S,4R)-3-tert-butyl-dimethylsilyloxymethyl)-4-(5-allyloxycarbonylaminovaleroylthio)-azetidin-2-one.

A slurry of 7.0 g (32.2 mmol) of 5-allyloxycarbonylamino-thiovaleric acid in 50 ml of water is cooled to 0°C

and mixed with 1N caustic soda until pH 8. Then 30 ml of methylene chloride, 2.93 g (10 mMol) 3-(tert-butyldimethyl-silyloxymethyl)-4-methylsulfonylazetidin-2-one and 278 mg (ImMol) tetrabutylammonium chloride are added and the two-phase system is stirred well at 0°C for 3 hours. The phases are separated and washed each time once with saturated NaHCO 3 solution and saturated NaCl solution. The aqueous phases are extracted twice more with methylene chloride, the extracts are combined and dried over Na^O^. Evaporation of the solvent under vacuum gives a crude product which is chromatographed on 50 g of silica gel with toluene and ethyl acetate 2:1 as eluent. TLC (silica gel) toluene/ethyl acetate (1:1) Rf - 0.51

IR (methylene chloride): 2.90; 2.94; 5, 68; 5.88 y .

The starting material can be prepared as follows:

6.75 g (33.6 mmol) of 5-allyloxycarbonylamino-valeric acid was dissolved in 40 ml of methylene chloride and mixed with 10.2 ml (73.8 mmol) of triethylamino. A solution of 5.2 ml (40.3 mmol) of chloroformic acid isobutyl ester in 7 ml of methylene chloride is added dropwise to this solution with stirring at -10°C over the course of 30 minutes. After addition, stir again for 30 minutes at -10°C. H2S is then introduced for 60 minutes at 0°C. The solution is washed with IN sulfuric acid, then extracted first with 50 ml and then with 30 ml of saturated sodium bicarbonate solution, and the aqueous phase is acidified in an Erlenmeyer flask while stirring gently with 20% phosphoric acid. The aqueous solution is extracted three times with chloroform, and the organic phase is dried over Na 2 SO 4

and filtered. Evaporation of the solvent in vacuo and drying in high vacuum gives 5-allyloxycarbonylamino-thiovaleric acid as an oil.

IR (methylene chloride): 2.94; 3.95; 5.97; 6.75 y.

Example 24: 2-(3S,4R)-3-(tert-butyl-dimethylsilyloxymethyl)-4-(5-allyloxycarbonylaminovaleroylthio)-2-oxo-azetidine-1-yl7-2-hydroxyacetic acid allyl ester.

A mixture of 1.9 g (4.4 mmol) (3S,4R)-3-(tert-butyldimethylsilyloxymethyl)-4-(5-allyloxycarbonylamino-valeroylthio)-azetidin-2-one and 1.9 g (13 .2 mmol) of glyoxylic acid-allyl ester-ethyl hemiketal in 30 ml of toluene and 2 ml of N,N-dimethylformamide are mixed with 16 g of molecular sieve 4Å and stirred at room temperature for 16 hours. The mixture is filtered and the filter residue is washed with toluene. Evaporation of the filtrate and drying at 40°C in high vacuum gives products such as yellow oil.

DC (silica gel) toluene/ethyl acetate (2:1); Rf -0.44;

IR (methylene chloride): 2, 85, 2, 91, 5, 65, 5, 74, . 5.81 y.

Example 25: 2-/~(3S,4R)-3-(tert-butyl-dimethylsilyloxymethyl)-4-(5-allyloxy-carbonylaminovaleroylthio)-2-oxo-azet-idin-1-yl/-2-triphenylphosphoranylideneacetic acid allyl -ester .

To a solution of 2.35 g (4.32 mmol) 2-(3S,4R)-3-(tert-butyl-dimethylsilyloxymethyl)-4-(5-allyloxycarbonyl-aminovaleroylthio)-2-oxo -azetidin-1-yl/-2-hydroxyacetic acid allyl ester in 60 ml of tetrahydrofuran is added with stirring at -20°C in order 0.37 ml (5.14 mmol) of "thionyl chloride" and 0.7 ml (5.14 mmol ) triethylamine over 5 minutes. The white suspension is further stirred at -15°C for 20 minutes, mixed with methylene chloride, washed with 0.1N hydrochloric acid, and twice with saturated NaCl solution. The solution is dried over Na 2 SO 4 , filtered and evaporated in vacuum. The residue is dissolved in 7 ml tetrahydrofuran, mixed with 1.8 g (6.8 mmol) triphenylphosphine, and 0.6 ml (4.4 mmol) triethylamine and stirred at room temperature for 16 hours. It is diluted with methylene chloride, wash with saturated aqueous NaHCO^ solution, dry the organic phase over Na2SO^ and filter. Evaporation of the solvent in vacuo and chromatography of the residue on 50 g of silica gel with toluene/ethyl acetate 2:1 gives the pure product ID

DC (silica gel) toluene/ethyl acetate (1:1), Rf = 0.40,

IR (methylene chloride): 2 , 91; 5.71; 5.83; 5.95; 6.21 y .

Example 26: 2-[(3S,4R)-4-(5-AllyloxycarbonylaminonovaIeroyl-thio)-3-hydroxymethyl-2-oxo-azetidin-1-yl]-2-tri-phenylphosphoranylidene-acetic acid allyl ester.

A solution of 546 g (0.69 mmol) of 2-[(3S,4R)-3-(tert-butyl-dimethylsilyloxymethyl)-4-(5-allyloxycarbonyl-aminovaleroylthio)-2-oxo-azetidine-1- yl/-2-triphenylphosphoranylidene-acetic acid allyl ester in 12 ml of tetrahydrofuran is cooled to -10°C, mixed with 536 mg (1.7 mmol) of tetrabutylammonium fluoride and stirred for 15 minutes. Then dilute with methylene chloride,

and washed with aqueous NaHCO3 solution and NaCl solution. The organic phase is dried over Na2SO4 and evaporated in vacuo. The residue is chromatographed on silica gel with the eluent ethyl acetate.

DC (silica gel) ethyl acetate: Rf = 0.24,

IR (methylene chloride): 2.79; 2.90; 5.71; 5.83; 6.21 y.

Example 27: (5R,6S)-2-(4-allyloxycarbonylaminobutyl)-6-hydroxymethyl-2-penem-3-carboxylic acid allyl ester.

A solution of 98 mg (0.14 mmol) of 2-/~(3S>4R)-4-(5-allyloxycarbonylaminovaleroylthio)-3-hydroxymethyl-2-oxo-azetidin-1-yl/-2-triphenyl-phosphoranylidene- acetic acid allyl ester in 10 ml of toluene is heated under a nitrogen atmosphere for 16 hours at 105°C. Evaporation of the solvent and chromatography of the residue

on a preparative silica gel plate with toluene/ethyl acetate (1:1)

gives it pure product.

DC (silica gel) ethyl acetate: Rf = 0.55,

IR (methylene chloride) : 2.76; 5.58; 5.81; 6.06 y.

Example 28: (5R,6S)-2-(4-aminobutyl)-6-'hydroxymethyl-2-penem-3-carboxylic acid.

According to the same regulations as mentioned in example 19

is obtained when starting from (5R,6S)-6-(4-nitrobenzyloxycarbonyloxymethyl)-2-/4-(4-nitrobenzoyloxycarbonylamino)-butyl/- 2-penem-3-carboxylic acid-4-nitrobenzyl ester the title product. Z~a_/^° + 58° (c=1, H 2 O/NaOH).

UV in H_0 (pH 3): X<2>56 nm (2500), 318 nm (5600).

c. rricix

The same product can also be produced as follows:

A solution of 46 mg (0.11 mmol) (5R,6S)-2-(4-allyloxycarbonylaminobutyl)-6-hydroxymethyl-2-penem-3-carboxylic acid allyl ester in 2 ml methylene chloride and 1 ml diethyl ether is stirred at room temperature for 16 hours with 20 mg (0.14 mmol) of 2-ethylhexanoic acid, 10 mg of triphenylphosphine and 16 mg of tetrakis-(triphenylphosphine)-palladium. • The solution is diluted with methylene chloride and washed twice with water. The combined aqueous phases are lyophilized and the residue is chromatographed on "reverse phase" thin-layer plates (Opti-UPC12) (acetonitrile/water (2:3). j of the corresponding zones with acetonitrile/water (4:1), partial evaporation of the eluate and lyophilises. Long ay remaining aqueous \ solution likewise gives end products, with identical physical \ data.

in

Example 29: Sodium salt of (5R,6S)-2-[4-(1-ethoxycarbonylprop-1-en-2-ylamino)-butyl]-6-hydroxymethyl-2-penem-3-carboxylic acid.

0.139 ml (1.1 mmol) of acetoacetic acid ethyl ester is added - to a suspension of 0.27 mg (1 mmol) of (5R,6S)-2-(4-aminobutyl)-6-hydroxymethyl-2-penem-3-carboxylic acid and 0 .5 2M caustic soda in 3 ml isopropanol, and stirred for 3 hours at room temperature. When diethyl ether is added, the product precipitates. IR spectrum (nujol): absorption band at 3.0; 5.58; 5.75 u.

Example 30: (5R,6S)-2-(4-aminobutyl)-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 mixed with 0.275 ml of ethyl-1-chloroethyl carbonate. The mixture is stirred at room temperature for 3 hours. The solution is then dripped onto 15.0 ml of methylene chloride and filtered from the precipitated organic salts. The methylene chloride solution is evaporated in 2 ml and added at 0°C to a solution of 0.27 g (1 mmol) (5R,6S)-2-(4-amino-butyl)-6-hydroxymethyl-2-penem-3-carboxylic acid in 4 ml of dimethylacetamide. Then stir for 3 hours at 0°C, then dilute with methyl acetate, wash 3 times with water. The organic phases are dried over sodium sulphate 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 band at 5.58; 5.75 u.

Example 31: (5R,6S)-2-(4-aminobutyl)-6-hydroxymethyl-2-penem-3-carboxylic acid pivaloyloxymethyl ester.

0.6 g of sodium iodide is dissolved in 2 ml of acetone and mixed with 0.15 ml of pivalic acid chloromethyl ester. The mixture is stirred at room temperature for 3 hours and then dripped onto 7.5 ml of methylene chloride. The precipitated inorganic salts are filtered off. The methylene chloride solution is evaporated to 1 ml and added at 0°C to a solution of 0.1 g (0.4 mmol) (5R,6S)-2-(4-amino-butyl)-6-hydroxymethyl-2-penem-3 -carboxylic acid and 0.07 ml of diisopropylethylamine in 4 ml of N,N-dimethylacetamide. It is then stirred for 3 hours at 0°C, then diluted with ethyl acetate, and washed three times with water. The organic phase is dried over sodium sulfate and evaporated on a rotary evaporator. The crude product is purified on 10 g of silica gel with the eluent ethyl acetate.

The title compound is obtained as a white foam. IR spectrum (methylene-

chloride) : Absorption band at 5.58; 5.75 y.

Example 32:

Dry ampoules or vials, containing 0.5 g of (5R,6S)-2-(4-aminobutyl)-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 resp. the vials were closed and examined.

Claims (7)

1. Method for producing compound with formula wherein R, means an optionally substituted amino group, R~ means hydroxy or a residue Asom together with the carbonyl group -C(=0 )- forms a protected carboxyl group, and R^ means a protected hydroxy group, their salts, their optical isomers and mixtures of their optical isomers, characterized by ring closure of a ylide compound with formula in which R, means a protected amino group, Z means oxygen or sulphur, X means either a triply substituted phosphonio group, or a doubly esterified phosphono group together with a cation, RA<2> together with the carbonyl group -C(=0)- means a protected carboxyl group , and R^ means an optionally protected hydroxyl group, and if desired or necessary in an obtained compound of formula I, a protected amino group R^ is transferred in the free or in another protected amino group R^ and/or 'if desired in a formed compound of formula I, a protected carboxyl group is transferred -C(=0.)-R2 to the free or to another protected carboxyl group -C(=0)-R2 , and/or if desired in a formed compound of formula I, in which R^ means amino, R- is transferred ^ to a substituted amino group and/or if necessary a protected hydroxy group R^ is transferred to the free hydroxy group R-^ , or the free hydroxy group R^ to a protected hydroxy group R3 and/or if desired a formed compound with salt-forming groups is transferred to a salt or a formed salt to the free compound, or in another salt, and/or if desired, a formed mixture of isomeric compounds is divided into the individual isomers. 2. • Process according to claim 1 for the preparation of compounds of formula-I, wherein amino means 1-acyl-lower alk-1-en-2-yl-amino or a mono- or disubstituted methyleneamino group, R2 means hydroxy or together with the carbonyl group an esterified carboxyl group cleavable under physiological conditions, and R 1 means hydroxy, as well as their salts, or optical isomers and mixtures of their optical isomers. 3. Method according to claim 1, for the preparation of a compound of formula I, in which R^ means amino and R2 means hydroxy, lower alkanoyloxymethoxy, aminoloweralkanoyloxymethoxy, phthalidyloxy, 4-crotonolactonyloxy, 4-butyrolacton-4-yloxy, indanyloxy, 1-loweralkoxy-loweralkoxy or 1-lower oxycarbonyloxy-lower oxy and R., means hydroxy, their pharmaceutically acceptable salts, their optical isomers and mixtures of their optical isomers. 4. Process according to claim 1 for the preparation of compounds of formula I, in which R 1 means amino, R 2 means hydroxy, and R 2 means hydroxy, as well as their pharmaceutically usable salts, their optical isomers and mixtures of their optical isomers. 5. Process according to claim 1 for the production of compounds of formula I which in the 5-position have R-configuration and in the 6-position S-configuration and their pharmaceutically usable salts. 6. Process according to claim 1 for the production of trans-2-(4-aminobutyl)-6-hydroxymethyl-2-penem-4-carboxylic acid and pharmaceutically usable salts thereof. 7. Method according to claim 1 for the production of (5R,6S)-2-(4-aminobutyl)-6-hydroxymethyl-2-penem-3-carboxylic acid and pharmaceutically usable salts thereof.