FI76348B - FOERFARANDE FOER FRAMSTAELLNING AV 6-HYDROXILAOGALKYL-2-AZAHETEROARYL-LAOGALKYL-PENEM-FOERENINGAR. - Google Patents

Abstract

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

Description

7 6 3 4 8

Process for the preparation of 6-hydroxy-lower alkyl-2-azaheteroaryl-lower-alkyl-penem compounds - For the preparation of 6-hydroxy-alkylalkyl-2-azaheteroaryl-lagalkyl-penem-föreningar in DE-A-29 50 898 and EP-A: o 3960 describes 6-hydroxyalkyl-penem compounds having an aminoalkyl substituent at the 2-position. The aforementioned DE application and U.S. Patent No. 4,272,437 describe 6-unsubstituted penem compounds in which the amino group of such a substituent is part of a heterocyclic ring, for example phthalimido, dimethylpyrazol-1-yl or tetrazolyl. It has now been found that 6-hydroxyalkyl-penem compounds having an N-azaheteroaryl-alkyl substituent at the 2-position have improved pharmacological properties over the prior art compounds.

In particular, the invention relates to a process for the preparation of 2-heteroaryl-lower alkyl-6-hydroxy-lower alkyl-2-penem compounds of formula I

H I

'“R / CD.

J '\ / 2' 4 * 3 in which hydrogen or methyl has the formula, R2 is a hydroxyl group, R3 is a carboxyl or an esterified carboxyl group which can be cleaved under physiological conditions, R4 is a triazolyl or tetrazolyl bonded to the radical - (CH2) m- via a ring nitrogen atom and m is an integer from 1 to 4, and for the preparation of salts of the compounds of formula I having a salt-forming group.

In this specification, the term "lower" as used in connection with the definitions of groups or equivalents means that the corresponding groups or equivalents, unless expressly stated otherwise, contain at most 7, preferably at most 4, carbon atoms.

Halogen is, for example, fluorine, chlorine, bromine or iodine. Lower alkyl is, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, sec-butyl or tert-butyl, further n-pentyl, n-hexyl or n-heptyl.

Lower alkoxycarbonyl is, for example, methoxycarbonyl or ethoxycarbonyl.

Triazolyl is, for example, 1H-1,2,3-triazol-1-yl, 2H-1,2,3-triazol-2-yl, 1H-1,2,4-triazol-1-yl or 1H-1,3 , 4-triazol-l-yl. Tetrazolyl, is, for example, 1H-tetrazol-1-yl or 2H-tetrazol-2-yl.

The process has functional groups present in the compounds of formula I, i. a hydroxy group R2 and a carboxyl group R3, preferably protected with protecting groups used in penem, penicillin, cephalosporin and peptide chemistry.

Such protecting groups can be easily cleaved, i. without the occurrence of undesirable side reactions, for example solvolytically, by reduction or also under physiological conditions.

Protecting groups of this type and their attachment and cleavage are described, for example, in J.F.W. McOmie, "Protective Groups in Organic Chemistry", Plemun Press, London, New York, 1973, T.W. Greene, "Protective Groups in Organic Synthesis," Wiley, New York, 1981, "The Peptides," Vol. I, Schroeder and Luebke, Academic Press, London, New York, 1965 and

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

In the compounds of the formula I, the hydroxy group R2 may be 3 76348 protected, for example, by acyl radicals. Suitable acyl residues are, for example, optionally halogen-substituted lower alkanoyl, e.g. acetyl or trifluoroacetyl, optionally nitro-substituted benzoyl, e.g. benzoyl, 4-nitrobenzoyl or 2,4-dinitrobenzoyl, optionally halogen-substituted lower alkoxycarbonyl, e.g. 2-bromoethoxycarbyl. , 2,2-trichloroethoxycarbonyl, or optionally nitro-substituted phenyl-lower alkoxycarbonyl, e.g. 4-nitrobenzyloxycarbonyl. Other suitable hydroxy protecting groups include, for example, trisubstituted silyl such as trialkylalkylsilyl, e.g. trimethylsilyl or tert-butyldimethylsilyl, 2-halo-lower alkyl groups, e.g. 2-chloro, 2-bromo-f-iodo and 2,2,2-trichloroethyl, and optionally phenyl-lower alkyl substituted by halogen, e.g. chlorine, lower alkoxy, e.g. nitro, and / or nitro, such as the corresponding benzyl. The preferred hydroxy protecting group is considered to be trialamyl-alkylsilyl.

The carboxyl group R3 is conventionally protected in esterified form, the ester group being easily cleaved under mild conditions, e.g. mildly reducing, such as hydrogenolytic, or mildly solvolytic, such as acidolytic, or especially basic or neutrally hydrolytic. The protected carboxyl group may further denote, under physiological conditions, an esterified carboxyl group which can be easily cleaved to another functionally modified carboxyl group, such as another esterified carboxyl group.

Such esterified carboxyl groups include, as esterifying groups, lower alkyl groups which are branched in the 1-position or suitably substituted in the 1- or 2-position. The preferred carboxyl groups in esterified form are e.g. lower alkoxycarbonyl, e.g.

4,76348 methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl or tert-butoxycarbonyl, and (hetero) arylmethoxycarbonyl having 1-3 aryl residues or one monocyclic heteroaryl residue, these being mono- or polysubstituted by, for example, e.g., lower alkyl. lower alkyl, e.g. tert-butyl, halogen, e.g. chlorine and / or nitro. Examples of such groups are, for example, optionally substituted benzyloxycarbonyl as described above, e.g. 4-nitrobenzyloxycarbonyl, optionally e.g. substituted diphenylmethoxycarbonyl as described above, e.g. diphenylmethoxycarbonyl, or triphenylmethoxycarbonyl, or optionally substituted as described above. picoyloxycarbonyl, e.g. 4-picolyloxycarbonyl, or furfuryloxycarbonyl such as 2-furfuryloxycarbonyl. Other suitable groups include lower alkanoylmethoxycarbonyl, such as acetonyloxycarbonyl, aroylmethoxycarbonyl, where the aroyl group preferably represents, for example, benzoyl optionally substituted by halogen, such as bromine, e.g.

2,2,2-trichloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, or ω-halo-lower alkoxycarbonyl, in which the lower alkoxy contains 4 to 7 carbon atoms, e.g. , or ethoxycarbonyl substituted in the 2-position by lower alkylsulfonyl, cyano or trisubstituted silyl, such as trialempalkylsilyl or triphenylsilyl, e.g. 2-methylsulfonyl-ethynyl-ethoxy-dimethylcarbonyl-2-cyanoethoxycarbonyl, 2-cyanoethoxycarbonyl, metyylisilyy-butyl-yl) ethoxycarbonyl.

Other protected 5,76348 carboxyl groups in esterified form are the corresponding organic silyloxycarbonyl groups, further the corresponding organic stanynyloxycarbonyl groups. In these, the silicon or tin atom preferably contains a lower alkyl, in particular methyl or ethyl, as a substituent, further lower alkoxy, e.g. methoxy. Suitable silyl or trans-stanyl groups are preferably trialem-alkylsilyl, in particular trimethylsilyl or dimethyl-tert-butylsilyl, or correspondingly substituted stanyl-groups, e.g. tri-n-butylstannyl.

Under physiological conditions, the esterified carboxyl group to be cleaved is primarily an acyloxymethoxycarbonyl group in which acyl represents, e.g. is e.g. methyl, propyl, butyl or especially ethyl and lower alkoxy is e.g. methoxy, ethoxy, propoxy or butoxy. Such groups include, for example, lower alkanoyloxymethoxycarbonyl, e.g. acetoxymethoxycarbonyl or pivaloyloxymethoxycarbonyl, amino-lower alkanoyloxymethylcarbonyloxylcarbonyloxymoxy-oxyloxymethoxycarbonyl, e.g. glycyloxy-methoxycarbonyl, e.g. 4-butyrolactonyl, indanyloxycarbonyl, e.g. 5-indanyloxycarbonyl, 1-ethoxycarbonyloxyethoxycarbonyl, methoxymethoxycarbonyl or 1-methoxyethoxycarbonyl.

Preferred protected carboxyl groups 1 * 3 'are 4-nitrobenzyloxycarbonyl, lower alkenyloxycarbonyl and 2-lower alkylsulfonyl, cyano or triallylalkylsilyl-substituted ethoxycarbonyl group, and, under physiological conditions, lower alkanoyloxymethoxycarbonyl and 1-lower alkoxycarbonyloxy-lower alkoxycarbonyl.

The salts of the compounds of the invention are primarily pharmaceutically acceptable, non-toxic salts of the compounds of formula I. Such salts are formed, for example, from the acidic groups present in the compounds of the formula I, e.g. carboxyl groups, and are preferably metal or ammonium salts, such as alkali metal or alkaline earth metal, e.g. sodium, potassium, magnesium or calcium salts, and ammonium salts. basic aliphatic carboxylic acids of ammonia or suitable organic amines, such as lower alkylamines, e.g. triethylamine, hydroxy-lower alkylamines, e.g. 2-hydroxyethylamine, bis- (2-hydroxyethyl) amine or tris- (2-hydroxyethyl) amine esters, e.g. 4-aminobenzoic acid 2-diethylaminoethyl ester, lower alkyleneamines, e.g. 1-ethylpiperidine, cycloalkylamines, e.g. dicyclohexylamine, or benzylamines, e.g. N, N'-dibenzylethylenediamine, dibenzylamine With 3-phenethylamine. The acid group-containing compounds of the formula I can also be present in the form of internal salts, i. in the form of a zwitterion.

Pharmaceutically unsuitable salts may also be used for isolation or purification. Only pharmaceutically acceptable, non-toxic salts are used for therapeutic use, which is therefore preferred.

Compounds of formula I having methyl have a chiral center (carbon atom 8) which may exist in the S, racemic R, S or preferably R configuration.

The invention relates in particular to a process for the preparation of pharmaceutically acceptable salts of the compounds of the formula I and the salt-forming group of the compounds of the formula I, in which R 1 is 76348 is hydrogen or methyl, R 2 is hydroxyl, R 3 is carboxyl, lower alkanoyloxymethoxycarboxyalkyl, R 4 represents 1H-tetrazol-1-yl, 2H-tetrazol-2-yl or 1,2,4-triazol-1-yl and m represents an integer from 1 to 4.

The invention relates mainly to a process for the preparation of compounds of formula I having the (5R, 6S) configuration and pharmaceutically acceptable salts of compounds of formula I, wherein R 1 is hydrogen, R 2 is hydroxyl, R 3 is carboxyl, R 4 is 1H-tetrazol-1- yl or 1H-1,2,4-triazol-1-yl and m is an integer from 1 to 4.

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

The compounds of the present invention are prepared according to a method known per se.

The new compounds are prepared by enclosing a ring of formula a h il

R ^ j-CH (CH 2 R 4 ^ * ~

Il (II).

</ ylide compound according to the symbols R 1, R 2. R 4 and m are as defined in formula I, wherein the hydroxy group R 2 is preferably in protected form, R 3 'represents a protected carboxyl, Z represents oxygen or sulfur and X® represents either a triple substituted phosphonio group or a double esterified phosphono group together with the cation, and in the resulting compound of formula I, the protected functional group 8 76348 is converted to a free functional group, and in the resulting compound of formula I, if desired, the free carboxyl group R3 is converted to a cleavable esterified carboxyl group under physiological conditions, and / or the resulting salt-containing compound is the resulting salt to the free compound or another salt. Cyclization of a compound of formula II

The group X® in the starting material of formula II is one of the phosphonio or phosphono groups conventionally used in the Wittig condensation reaction, in particular a triaryl, e.g. triphenyl, or trialempalkyl group, e.g. tri-n-butylphosphonium group, or lower alkyl, e.g. ethyl double. an esterified phosphono group, wherein the symbol X® further comprises, in connection with the phosphono group, a strong base cation, in particular a suitable metal such as an alkali metal, e.g. lithium, sodium or potassium ion. Preferred as the group X® are, on the one hand, triphenylphosphonio and, on the other hand, diethylphosphone together with an alkali metal, e.g. sodium ion.

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

Ring closure can occur spontaneously, i. in connection with the preparation of the starting materials, or by heating, e.g. in the temperature range of about 30 to 160 ° C, preferably about 50 to about 100 ° C. The reaction is preferably carried out in a suitable inert solvent such as an aliphatic, cycloaliphatic or aromatic hydrocarbon, e.g. hexane, cyclohexane, benzene or toluene, halogenated hydrocarbon, e.g. methylene chloride or ethylene ether, e.g. in dimethyl ether, cyclic ether, e.g. dioxane or tetrahydrofuran, carboxylic acid amide, e.g. dimethylformamide, dialkylalkyl sulfoxide, e.g. dimethylsulfoxide, or lower alkanol, e.g. inert and ethanol, e.g. atmosphere.

The starting compound of formula II wherein X® is a phosphono group together with a cation is preferably prepared in situ by

R H H

f1 ^ | Il R -CH--5-p ^ S-C- (CH-) -R, f TT \ 2 j I 2 m 4 (IIa) f / y-x '

B

a compound according to which X 'represents a phosphono group is treated with a suitable basic reagent such as an inorganic base, e.g. an alkali metal carbonate such as sodium or potassium carbonate.

Preference is given to starting materials of the formula II which lead in particular to the compounds of the formula I which are initially mentioned as being particularly preferred, in particular to the compounds of the formula II having the 3S, 4R configuration.

In the available compound of formula I in which one or more functional groups are protected, these, e.g. protected carboxyl and hydroxy groups can be liberated in a manner known per se by solvolysis, in particular by hydrolysis, alcoholysis or acidolysis, or by reduction, in particular by hydrogenolysis or chemical reduction. , possibly gradually or simultaneously.

10 7634 8

In the compound of the formula I obtained in the process, in which R3 represents a protected carboxyl group 1 * 3 ', the carboxyl group can be liberated in a manner known per se. Thus, tert, -alkoxyalkoxycarbonyl or lower alkoxycarbonyl substituted in the 2-position with a trisubstituted silyl group or 1-lower alkoxycarbonyl or optionally substituted diphenylmethoxycarbonyl or optionally substituted diphenylmethoxyacetate with other acid such as a compound such as phenol or anisole. The optionally substituted benzyloxycarbonyl can be cleaved, e.g., by hydrogenolysis, i. by treatment with hydrogen in the presence of a metallic hydrogenation catalyst such as a palladium catalyst. Furthermore, a suitably substituted benzyloxycarbonyl, such as 4-nitrobenzyloxycarbonyl, can also be converted to the free carboxyl by chemical reduction, e.g. by treatment with an alkali metal, e.g. sodium dithionite, or a reducing metal, e.g. tin, or a metal salt, e.g. chromium II salt. chromium-11 chloride, usually in the presence of a hydrogen donor capable of producing hydrogen together with a metal, such as the addition of a suitable carboxylic acid, e.g. optionally e.g. hydroxy-substituted lower alkanecarboxylic acid, e.g. acetic acid, formic acid or glycolic acid, or alcohol, or alcohol preferably water. Cleavage of the allyl protecting group can be effected, for example, by reaction with a palladium compound, e.g. 11 70343 by first converting 2-bromialempialkoksikarbonyyliryhmä the corresponding 2-jodialempialkokakarbonyyliryhmäksi) or aroyylimetoksikarbonyyli converted into a free carboxyl, which aroyylimetoksikarbonyyli can be cleaved by treatment of the same nucleophilic, preferably salt-forming reagent rea-like nukleotiofenolaatilla or sodium iodide. the substituted 2-silylethoxycarbonyl can also be converted into free carboxyl by treatment with with a fluoride anion-producing salt of hydrofluoric acid, such as an alkali metal fluoride, e.g. sodium fluoride, a macrocyclic poly-e in the presence of an ether ("crown ether") or with a fluoride of an organic quaternary base such as tetra-lower alkyl ammonium fluoride, e.g. tetrabutylammonium fluoride. The carboxyl esterified with an organic silyl or stanyl group, such as trialemalkylsilyl or stannyl, can be liberated solvolytically in a conventional manner, e.g. by treatment with water or alcohol.

The lower alkoxycarbonyl group substituted in the 2-position by lower alkylsulfonyl or cyano can be converted to the free carboxyl, e.g. by treatment with a basic substance such as an alkali metal or alkaline earth metal hydroxide or carbonate, e.g. sodium or potassium hydroxide or sodium or potassium.

In the compounds of the formula I which can be obtained according to the process, in which R2 represents a protected hydroxy group, the protected hydroxy group can be converted into the free hydroxy in a manner known per se. For example, a hydroxy group protected by a suitable acyl group or an organic silyl or stanynyl group may be liberated such as a correspondingly protected amino group, a trialkylalkylsilyl group, e.g. also with tetrabutylammonium fluoride and acetic acid (under these conditions it is not cleaved by trisubstituted carboxy). The 2-halo-lower alkyl group and the optionally substituted benzyl group are cleaved by reduction.

Furthermore, in compounds of formula I containing a protected carboxyl group in esterified form, the carboxyl group can be cleaved as described above and the resulting free carboxyl group-containing compound of formula I or a salt thereof reacted with a reactive ester of the corresponding alcohol to give a compound of formula I wherein R3 esterified carboxylic group to be cleaved under

M M

I.

Salts of the salt-forming groups of the compounds of the formula I can be prepared in a manner known per se. Thus salts of groups of formula I containing a free carboxyl group may be formed, for example, by treatment with metal compounds such as alkali metal salts of suitable organic carboxylic acids, e.g. sodium salt of α-ethylcaproic acid or alkali or alkaline earth metal salts, e.g. sodium hydrogen carbonate or ammonium carbonate. with an organic amine, preferably using stoichiometric amounts or only a small excess of the salt-forming agent. Internal salts of the compounds of formula I can be formed, e.g., by neutralizing the salts, e.g., by treatment with ion exchangers.

The salts can be converted into the free compounds in a conventional manner, for example by treating the metal and ammonium salts with suitable acids.

In all subsequent modifications of the compounds of formula I obtained, the reactions which take place under neutral, temporal or slightly acidic conditions are preferred.

The process also comprises those embodiments in which the compounds obtained as intermediates are used as starting materials and the remaining steps of the process are carried out with these, or the process is interrupted at some stage. Furthermore, 13 7 034 8 starting materials can be used in the form of derivatives or formed in situ, possibly under reaction conditions. For example, a starting material of formula II wherein Z is oxygen can be prepared from a compound of formula II wherein Z is, as will be described later, an optionally substituted methylidene group, by ozonation and subsequent reduction of the formed ozonide, according to the method (Step 3.3) below. , followed by cyclization in the reaction solution to a compound of formula I.

Compounds of formula II and its precursors can be prepared according to Reaction Schemes I, II and III: 14 7634 8

Reaction Scheme I R. H H

I1 I I Rj H H z · R „-CH-A ---- ^ _ 1! \ 11 2 1 --► R2_CH I-? ~~ S-C- (CH ,,) -R.

. · -UH Step 1.1 £ 1 2 m 5 ft (V!) I (vi) T Step 1.2 • l "! Ehi 'R2 CH *' jl ~ SC” ^ CH2 ^ n "R5 ^ _- j —-- SC-1CH ^^ - R ^ / "Wx, False 1-3 / R · 'R3 R · <VIII) I step 1.4 <* H>

11 \ \ «step 1.4. \ »H

VCH— —S-C (CHJ -R «_ 1 1 \

2 I 1 2 m 5 ^ R -CH-ί- * vvwSM

</ 'F-P / “% © -, £> r: i 3 Rf (II ·) (rx) 3

In the compounds of formulas V, VII, VIII and II ', Z' is oxygen, sulfur or also a methylethylene group optionally substituted by one or two substituents Y, which can be converted by oxidation to the oxo group Z. The substituent γ of this methylidene group 5 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 in particular including a carboxyl group esterified with an optically active alcohol such as 1-menthol, e.g. one of the optionally substituted substituents mentioned in connection with Rj -carbonyl or arylmethoxycarbonyl residues or also 1-menyloxycarbonyl. The methylidene group Z 'preferably contains one of said substituents. Emphasis is placed on the methoxycarbonylmethylidene, ethoxycarbonylmethylidene and 1-menthyloxycarbonylmethylidene group Z '. The latter can be used for the preparation of optically active compounds of formulas V ', VII, VIII and II'.

15

In the compounds of formulas V-IX and II ', the residue R2 is preferably one of said protected hydroxy groups, e.g. optionally substituted 1-phenyl-lower alkoxy, optionally substituted phenyl-lower alkoxycarbonyloxy, or trisubstituted silyloxy.

Step 1.1;

The thio-azetidinone of formula V is obtained by treating a 4-W-azetidinone of formula VI, wherein W represents a nucleo-fugic starting group, with the formula

R4- (CH2) m-C (= Z ') -SH

with a mercapto compound or a salt thereof, e.g. an alkali metal such as sodium or potassium salt, and, if desired, in the resulting compound of formula V wherein R 2 is hydroxy, the hydroxy is converted to protected hydroxy.

The nucleophilic starting group W in the starting material of formula VI is a residue to be replaced by a nucleophilic residue R4- (CH2) m-C (= Z ') - S-. Such groups W are, for example, acyl-oxy radicals, sulfonyl radicals Rq-SO2-, in which Rq is an organic residue, an azido or a halogen. The acyloxy residue W is an acyl, e.g. a residue of an organic carboxylic acid, including an optically active carboxylic acid, and denotes, for example, lower alkanoyl, e.g. acetyl or propionyl, optionally substituted benzoyl, e.g. benzoyl or 2,4-dinitrobenzoylalkyl; e.g.

5 phenylacetyl, or an acyl residue of one of the above optically active acids. In the sulfonyl residue R0-SC> 2 ", Rq is, for example, optionally hydroxy-substituted Alem-alkyl, such as methyl, ethyl or 2-hydroxyethyl, further also correspondingly substituted optically active Alem-10-alkyl, e.g. (2R9- or (2S) -1-hydroxyprop 2-yl, optically active residue-substituted methyl, such as camperyl, or benzyl, or optionally substituted phenyl, such as phenyl, 4-bromophenyl or 4-methylphenyl The halogen residue W is, for example, bromine, iodine or especially chlorine. W is preferably methyl or 2-hydroxyethylsulfonyl, acetoxy or chlorine.

Nucleophilic substitution can be performed under neutral or weakly basic conditions in the presence of water and optionally a water-miscible organic solvent. The basic conditions can be adjusted, for example, by the addition of an inorganic base such as an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate, e.g. sodium, potassium or calcium urea hydroxide, carbonate or hydrogen carbonate. Suitable organic solvents are, for example, water-miscible alcohols, such as lower alkanols, such as methanol, ethanol, ketones, e.g., lower alkanones, such as acetone, amides, e.g., lower alkanecarboxylic acid amides, such as dimethylformamide, acetonitrile and the like. The reaction is usually carried out at room temperature, but it can also be carried out at elevated or reduced temperature. The reaction can be accelerated by the addition of a salt of hydroiodic acid or thiocyanic acid, e.g. an alkali metal salt such as sodium.

Both optically inactive cis- or trans-compounds of formula VI and mixtures thereof or corresponding optically active compounds can be used in the reaction. The associated group R 1 - (C 1 -C 3 - C (= Z ') -S- is directed from the group (R 2, 1CH-) to the trans position of the moiety, regardless of whether W is a group (R 1, R 2, In the cis or trans position of the CH, although trans isomers are mainly formed, cis isomers can also be temporarily isolated, and the separation of the cis and trans isomers takes place as described above, according to conventional methods, in particular by chromatography and / or by crystallization.

The subsequent ozonation of the methylidene group Z * can be carried out as described below. The resulting racemate of kaa-10 van V can be separated into optically active compounds.

An azetidinone of formula VI, wherein R 2 and W each represent acetoxy and R 2 represents hydrogen, is disclosed in DE-A-29 50 898.

Other azetidinones of formula VI can be prepared according to methods known per se, for example by reacting a vinyl ester of formula (R1, R2) CH-CH = CH-W with chlorosulphonyl isocyanate and reacting the resulting cycloaddition product with a reducing agent, e.g. with sodium sulfite. In this synthesis, mixtures of cis and trans isomers are usually obtained, which can be separated into the pure cis or trans isomers, if desired, e.g. by chromatography and / or crystallization or distillation. The pure cis and trans isomers exist as racemic earths and can be separated into their optical antipodes, for example, when the acyl of the acyloxy residue W in the compounds of formula VI is derived from an optically active acid. The compounds of formula VI, in particular their optically active representatives, can also be prepared according to the methods shown in Reaction Schemes II and III below. Step 1.2;

The α-hydroxycarboxylic acid compound of formula VII is obtained by reacting a compound of formula V with a glyoxylic acid compound of formula OHC-R 1 or a suitable derivative thereof, such as a hydrate, hemihydrate or hemiacetal, e.g. a lower alkanol, e.g. methanol or ethanol. and, if desired, in the compound of formula VII thus obtained, wherein R 2 is hydroxy, is converted to hydroxy-protected hydroxy.

The compound of formula VII is conventionally obtained as a mixture of the two isomers (grouped with respect to CH 2 OH). However, its pure isomers can also be isolated.

The incorporation of the glyoxylic acid ester compound into the nitrogen atom of the lactam ring takes place at room temperature or, if necessary, by heating, e.g. to a maximum of about 100 ° C, without the actual condensing agent and / or without salt formation. When a hydrate of a glyoxylic acid compound is used, water is formed, which is removed, if necessary, by distillation, e.g. azeotropically, or by using a suitable dehydrogenating agent, such as a molecular sieve. Preferably, the work is carried out in the presence of a suitable solvent, such as, for example, dioxane, toluene or dimethylformamide or a mixture of solvents, if desired or necessary, under an atmosphere of an inert gas such as nitrogen.

Both pure optically in-cis cis- or trans-compounds of formula V and mixtures thereof or corresponding optically active compounds can be used in the reaction. The resulting racemate of formula VII can be resolved into optically active compounds.

Step 1.3: Compounds of formula VIII wherein XQ represents a reactive esterified hydroxy group, especially halogen or organic sulfonyloxy, are prepared by converting a secondary hydroxy group in a compound of formula VII to a reactive esterified hydroxy group, especially a halogen, e.g. halogen, e.g. chlorine or bromine, e.g. , such as lower alkanesulfonyloxy, e.g. methanesulfonyloxy, or arenesulfonyloxy, e.g. benzene or 4-methylbenzenesulfonyloxy.

In the starting compounds of formula VII, R 2 preferably represents a protected hydroxy group.

The compounds of formula VIII can be obtained as mixtures of isomers 1976348 (relative to the grouping CH2v XQ) or in the form of pure isomers.

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

5-chloride, phosphorus oxyhalide, especially chloride, halophosphonium halide such as triphenylphosphonide bromide or diiodide, or a suitable organic sulfonic acid halide such as chloride, preferably a basic, preferably organic, basic base of an amine, such as an organic base. , in the presence of diisopropylethylamine or a "polystyrene-Hunig base" or a pyridine-type heterocyclic base, e.g. pyridine or collidine. Preferably, work is carried out in the presence of a suitable solvent, e.g. dioxane or tetrahydrofuran or a mixture of solvents, if necessary with cooling and / or in an atmosphere of an inert gas such as nitrogen.

In the compound of formula VIII thus obtained, the reactive esterified hydroxy group XQ can be converted into another reactive esterified hydroxy group in a manner known per se. Thus, for example, a chlorine atom can be converted by treatment of 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, to an iodine atom.

Both pure optical inactive cis- or trans-compounds of formula VII and mixtures thereof, or similar optically active compounds, can be used in the reaction. The resulting racemate of formula VIII can be resolved into optically active compounds.

30 Step 1.4:

The starting material of formula II1 is obtained by treating a compound of formula VIII in which XQ represents a reactive esterified hydroxy group with a suitable phosphine compound such as a trialkylalkylphosphine, e.g.

35 with tri-n-butylphosphine, or with a triarylphosphine, e.g. triphenylphosphine, or with a suitable phosphite compound, such as a trialempalkyl phosphite, e.g. triethyl phosphite, 76348 20 or an alkali metal dialkylalkyl phosphite, e.g. depending on the compound of formula II (or II 'or Ha).

The above reaction is preferably carried out in the presence of a suitable inert solvent such as a hydrocarbon, e.g. hexane, cyclohexane, benzene, toluene or xylene, or an ether, e.g. dioxane, tetrahydrofuran or diethylene glycol dimethyl ether, or a solvent mixture. Depending on the reactivity, the work is carried out under cooling or at an elevated temperature, approximately -10 to + 100 ° C, preferably about 20 to 80 ° C and / or in an atmosphere of an inert gas such as nitrogen. Catalytic amounts of an antioxidant, e.g. hydroquinone, may be added to prevent oxidative processes.

In this case, the phosphine compound 15 is conventionally used in the presence of a basic substance, such as an organic base, e.g. an amine, such as triethylamine, diisopropylethylamine or a "polystyrene-Hiinig base", and thus directly gives the ylide of formula II (or II '). a starting material formed from the corresponding phosphonium salt.

Both pure, optically inactive cis- or trans-compounds of formula VIII as well as mixtures thereof or corresponding optically active compounds can be used in the reaction. The resulting racemate of formula II 'can be separated into optically active compounds.

Step 1.4a;

The starting compound of formula II1 in which Z 'represents oxo can be further prepared by treating a mercaptide of formula IX in which M represents a metal cation with an acylating agent linking the residue R 1 - (C

In the starting material of the formula IX, the metal cation M is, for example, a cation of the formula M + or M + + / 2, in which M + denotes in particular a silver cation and M + + denotes in particular a divalent cation of a suitable transition metal, e.g. copper, lead or mercury.

The acylating agent linking the residue Rd- (CH ~) -C (= O) - is e.g.

4 2 m acid R4- (C1-4) m-CO3H or a reactive functional derivative thereof 21 76348, such as an acid halide, e.g. chloride or bromide, azide or anhydride.

The acylation occurs when a free acid of the formula R 1 - (CH 2) m “COOH” is used, e.g. in the presence of a suitable dehydrating agent such as carbodiimide, e.g. Ν, Ν'-dicyclohexylcarbodiimide, or when an acid derivative is used , in the presence of a suitable acid scavenger such as a tertiary aliphatic or aromatic base, e.g. triethylamine, pyridine or quinoline in an inert solvent such as a chlorinated hydrocarbon, e.g. methylene chloride or ether, e.g. diethyl ether or dioxane, at room temperature. e.g. in the temperature range of about -50 to about + 60 ° C, especially at about -30 to about + 20 ° C.

The starting compounds of formula IX can be prepared, for example, by the following formula:

R. H H

'l \ - · ~ —W (VI)

\ NH

S

azetidinone is converted by reacting it with a thio-lower alkanecarboxylic acid, e.g. thioacetic acid, or an alkali metal salt of triphenylmethyl mercaptan, e.g. the sodium salt of formula

R. 9 H

11% i R 2 -CH 2 v .- (VI ·)

. · NH

</ 20, where W represents triphenylmethylthio or lower alkanoylthio, e.g. acetylthio, is converted according to the methods described in reaction steps 1.2, 1.3 and 1.4 to the formula 76348 22

R. H H

1 M.

R2-CH! jp ~ w '(IX ·)

B

in the presence of a base, e.g. pyridine or tri-n-butylamine, in a suitable solvent, e.g. diethyl ether or methanol with a salt of formula MA, wherein residue M has the meaning given above but in particular represents a silver cation, and A represents a useful anion which promotes the MA Liu hardness of the salt in the chosen solvent, e.g. a nitrate, acetate or fluoride anion.

The ylides of formula II 'wherein Z' is oxygen or sulfur can be used directly in the cyclization reaction to prepare the final products of formula I. However, also in compounds of formula II * where R 2 is a protected hydroxy group, e.g. a hydrolytically easily cleaved protected hydroxy group such as trisubstituted silyloxy, the hydroxy protecting group can be cleaved first and then the resulting compound of formula II 'wherein R 2 is hydroxy can be used for the cyclization reaction.

In compounds II1, V, VII and VIII, the optionally substituted methylidene group Z 'can be converted to the oxo group Z by ozonation and subsequent reduction of the ozonide formed, according to the procedure described in step 3.3 below.

7 6 3 4 8 23

The starting compounds of formula VI wherein W is a sulfon-5-yl residue HO-A-SC 2 - / can also be prepared according to the following Reaction Scheme II.

Reaction Scheme II

H ς R1 H H s i — fN __ I I I Step 2.1 2 il (Xa) (Xb) jvhihe 2.2 * 1 H H * 1 H H 8 / *

1 i 1 «S

R2_CH - J -? ^ SO2-A-OH - R2-CH ^ {- Y \ -NH ^ Step 2.3. · -N ö

'/ X

8. s (Via) (Xc)

In the compounds of formulas Xa-Xc and Via, A represents a lower alkylene residue having 2-3 carbon atoms between the two heteroatoms, and is preferably ethylene or 1,2-propylene, but may also be 1,3-propylene. , 1,2-, 2,3- or 1,3-butylene.

In the compounds of formulas Xa-Xc, each of the radicals Ra and R 1 represents hydrogen or an organic residue attached via a carbon atom to the ring carbon-15 atom, wherein both radicals Ra and R 1 may be linked to one another, preferably hydrogen, lower alkyl, e.g. methyl, ethyl, n- propyl or isopropyl, optionally substituted phenyl or phenyl-lower alkyl, e.g. benzyl, or together lower alkyl, preferably having 4 to 6 carbon atoms, e.g. 1,4-butyl-76348 24 ethylene or 1,5-pentylene.

In the compounds of the formulas Xb, Xc and Via, the residue 1 * 2 is hydroxy or preferably one of said protected hydroxy groups # e.g. optionally substituted 1-phenylalem-5-alkoxy, optionally substituted phenyl-loweralkoxycarbonyloxy or trisubstituted silyloxy.

Step 2.1:

The compound of formula Xb is obtained by reacting a bicyclic compound of formula Xa with a metallating agent and a residue (R 1 R 11 CHCH-linking electrophile) and then treating the resulting product with a proton source.

Suitable metallization reagents are, for example, substituted or unsubstituted alkali metal amides, alkali metal hydrides or alkali metal lower alkyl compounds in which the alkali metal is e.g. sodium or especially lithium, e.g. sodium or lithium amide, lithium bis-trimethylsilylamide, lithium hydride, sodium hydride -isopropylamide and butyllithium.

Examples of electrophiles having a residue (Ι, Ι, ΙΟΗ) are compounds of the formula R 1 -CH = O or functional derivatives of the formula (R 1, R 2) CH-X, in which X is a nucleofugic starting group, in particular halogen, e.g. chlorine, bromine or iodine, or sulfonyloxy, e.g. methanesulfonyloxy or 4-toluenesulfonyloxy Preferred CH-linking electrophiles for the residue (R 1, R 2) are formaldehyde, optionally substituted benzyloxymethyl chloride and acetaldehyde.

Solvents suitable for the metallization reaction must not contain active hydrogen and such solvents 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 triamide.

The metallized intermediate does not need to be isolated, but after the metallization reaction it can be reacted with a residual (R 1, R 2> CH-linking electrophile. The metallization reaction takes place at temperatures between about -100 ° C and about room temperature / preferably below -30 ° C / preferably under an atmosphere of an inert gas such as nitrogen The further reaction may take place under the same conditions, in which case formaldehyde is introduced into the reaction mixture in gaseous, monomeric form.

The monomeric formaldehyde is obtained, for example, by thermal depolymerization of paraformaldehyde or by thermal decomposition of formaldehyde dicyclohexyl hemiacetal.

Both antipodes of the compounds of formula Xa and racemic or diastereomeric mixtures thereof can be used for the metallation reaction.

Adhesion of the CH-linking electrophile of the residue (R. 1, R 2) to the substrate generally occurs stereospecifically. If an azetidinone of the formula Xa having the R-configuration on the carbon atom 4 of the azetidinone ring is used as the starting material, then a compound of the formula Xb having the R-configuration on the carbon atom 4 of the azetidinone ring and the S-configuration on its carbon atom 3, i.e. electrophile infection occurs mainly in the trans position.

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

In the obtained compound of formula Xb in which R 2 is hydrogen, the hydroxy group can be protected in a manner known per se, e.g. by etherification or esterification, in particular as described above.

The preparation of optically active and optically inactive starting compounds of formula 30 Xa is described, for example, in EP patent application 23887.

Step 2.2;

A sulfone of formula Xc can be prepared by treating a thio compound of formula Xb with an oxidizing agent 35 and, if desired, converting a compound of formula Xc wherein R 2 is hydroxy according to the process to a compound of formula Xc wherein R 2 is a protected hydroxy group.

26 76348

Suitable oxidizing agents are, for example, hydrogen peroxide, organic peracids, in particular aliphatic or aromatic percarboxylic acids, e.g. peracetic acid, perbenzoic acid, chloroperbenzoic acid, e.g. , e.g. sodium hypochlorite. However, the conversion can also take place by means of anodic oxidation.

The oxidation is preferably carried out in a suitable inert solvent, for example a halogenated hydrocarbon, e.g. methylene chloride, chloroform or carbon tetrachloride, an alcohol, e.g. methanol or ethanol, a ketone, e.g. acetone, ether, e.g. diethyl ether, dioxaneurane or tetrahydrofuran or tetrahydrofuran in dimethylformamide, a sulfone, e.g. dimethylsulfone, a liquid organic carboxylic acid, e.g. acetic acid, or water or a mixture of these solvents, in particular an aqueous mixture, e.g. aqueous acetic acid, at room temperature or under cooling or slightly heating, i.e. at about -20 ° C to about + 90 ° C, especially at about room temperature.

The oxidation can also be carried out gradually by first oxidizing at a lower temperature, i.e. at about -20 to about 0 ° C to the sulfoxide, which is optionally isolated, followed by a second step, preferably at a higher temperature, at about room temperature, to oxidize the sulfoxide to the sulfone of formula XC.

For finishing, any excess oxidizing agent that may still be present can be removed by reduction, especially by treatment with a reducing agent such as thiosulfate-30a, e.g. sodium thiosulfate.

Both optically inactive compounds of formula Xb and corresponding optically active compounds, especially those having the 3S, 4R configuration in the azetidinone ring, can be used in the reaction.

35 Step 2.3:

Compounds of formula Via may be prepared by solvolysing a bicyclic amide of formula Xc with a suitable solvolysis reagent and, if desired, converting a free hydroxy group Rj to a protected hydroxy group Rj in a compound of formula Via obtained according to the method.

Suitable solvolysis reagents are, for example, organic acids, e.g. lower alkanecarboxylic acids, such as formic acid or acetic acid, or sulfonic acids, e.g. 4-toluenesulfonic acid or methanesulfonic acid, mineral acids, e.g. sulfuric acid, or lower alkanediols, e.g. ethylene-10 niglycol.

Said solvolysis reagents are added undiluted or diluted with water. Solvolysis can also be performed with pure water. The solvolysis with the acidic reagent is preferably carried out in an aqueous solution of the reagent and at a temperature in the range of about -20 to about 150 ° C, preferably in the temperature range from room temperature to 110 ° C.

Both optically inactive compounds of formula Xc, e.g. racemates or diastereomeric mixtures, and the corresponding optically active compounds, especially those having the 3S, 4R configuration in the azedino-ring, can be used for the reaction.

The resulting isomeric mixtures of the compounds of formulas Xb, Xc and Via, such as racemates or diastereomeric mixtures, can be separated in a manner known per se, e.g. as described above, into individual isomers, such as antipodes.

The optically active trans compounds of formula VI to be used according to the invention can be prepared according to the following reaction scheme III:

Reaction Scheme III 7 6 3 4 8 28 Ϊ

R2-m? V

(XI) R3

Step 3.1

ΐ1 I A /, 1 H V

..... \ ~ Y \,, R2_; ι_> ν * 0

! _i X vrihe 3.2 »2 II

<XH) * i (XIII) Γ '"

Ri I Phase 3.3

I1 T - -SO -R * 1 "H

V "o__R2-ch„ J — p * ·

J-NH ^ e 3.4 I_I

* / \ „

Cvib) /% 17 (xiv) Rj

In the compounds of the formulas XI-XIV and VIb, R 2 denotes hydroxy or, in particular, a protected hydroxy group.

Step 3.1;

The compounds of the formula XII are known or can be prepared in a manner known per se. They can also be prepared according to a new process by epimerizing a compound of formula XI and, if desired, converting a protected hydroxy group R 1 in a compound of formula XII obtained according to the process into another protected hydroxy group R 2.

The epimerization takes place, for example, with a basic substance, such as an amine, e.g. a trialkylalkylamine, e.g. triethyl-7 6 3 4 8 29 amine or ethyldiisopropylamine, a tertiary amine, e.g. Ν, Ν-dimethylaniline, an aromatic amine, e.g. pyridine, or a bicyclic amine, e.g. 1,5-diazabicyclo- (5.4.0) undec-5-ene or 1,5-diazabicyclo (4.3.0) non-5-ene, 5 or an alkali metal lower alkanolate, e.g. sodium methanolate, sodium ethanolate or in the presence of potassium tert-butanolate in an inert solvent, for example an ether, e.g. diethyl ether, dimethoxyethane, tetrahydrofuran or dioxane, acetonitrile or dimethylformamide, optionally at a slightly elevated or reduced temperature, e.g. 0-50 ° C, preferably at room temperature.

In the compounds of formula XII obtainable according to the process, the protected hydroxy group may be tarred with another protected hydroxy group, for example a hydrolytically cleavable protected hydroxy group with a solvolytically cleavable protected hydroxy group. Hydroxy protecting groups include, in particular, the above-mentioned hydrogenolytically cleavable protecting groups, for example, as described above, substituted 1-phenyl-lower alkyl or phenyl-lower alkoxy-20-carbonyl, solvolytically cleavable protecting groups, for example, as described above, trisubstituted silyl.

The reaction can be carried out by first removing the hydrogenolytically cleavable hydroxy protecting group and attaching the resulting compound of formula XII, if hydroxy is a solvolytically cleavable hydroxy protecting group.

The cleavage of the hydrogenolytically cleavable protecting group takes place, for example, with hydrogen or a hydrogen donor, e.g. cyclohexene or cyclohexadiene, in the presence of a hydrogenation catalyst, such as a palladium catalyst, e.g. or in ethanol, ether, e.g. dioxane or tetrahydrofuran, or also in water or a mixture thereof, at a temperature of about 0 to about 80 ° C, preferably at room temperature. The cleavage can also be performed with a reducing metal, such as zinc, or a reducing alloy, e.g. a 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 coupling of the solvolytically cleavable hydroxy-protecting group takes place, for example, with a compound of the formula R 1 -X 2 in which 1 * 2 is a hydroxy-protecting group and is e.g. a reactive esterified hydroxy group, for example halogen, e.g. chlorine, bromine or iodine, or sulfonyloxy, e.g. tanesulfonyloxy, benzenesulfonyloxy or 4-toluene-10 sulfonyloxy.

The reaction takes place in an inert solvent such as ether, e.g. diethyl ether, dioxane or tetrahydrofuran, a hydrocarbon, e.g. benzene or toluene, a halogenated hydrocarbon, e.g. a carbonate, e.g. sodium or potassium hydroxide or sodium or potassium carbonate, an alkali metal amide or hydride, e.g. sodium amide or sodium hydride, an alkali metal lower alkanolate, e.g. sodium methoxide or ethanolate or potassium tert-butanolate, or an amine, e.g. in the presence of triethylamine, pyridine or imidazole, at room temperature or at elevated or reduced temperature, e.g. at about -20 to about 80 ° C, preferably at room temperature.

The starting compounds of the formula XI are known, for example, from DE-A-30 39 504 and GB-A-2,061,930.

Step 3.2;

A compound of formula XIII can be prepared by treating a penam compound of formula XII with a basic agent and an esterifying agent linking the residue R.

o

A suitable basic substance is, for example, one of the basic substances mentioned in 3.1, in particular one of the bicyclic amines mentioned, further also an alkali metal amide or 35-hydride, e.g. sodium amide or sodium hydride.

The residue Rq is, for example, one of the organic residues mentioned in connection with step 1.1, in particular optionally substituted lower alkyl, e.g. methyl, ethyl or 2-hydroxyethyl, or benzyl.

The esterifying agent linking the residue R is, for example, a compound of the formula Rq 'X4 in which is reactive esterified hydroxy, e.g. halogen, such as chlorine, bromine or iodine, or sulphonyloxy, such as methanesulphonyloxy, benzenesulphonyloxy or 4-toluenesulphonyl prune. Ethylene oxide is also suitable for the incorporation of the 2-hydroxyethyl residue.

The reaction is preferably carried out in a two-step process, the first step comprising treating the penam compound of formula XII with at least an equimolar amount of a basic substance to give a compound of formula * l T "> Μ2Θ, Θ ........ .1 (XI Ia) / j" The intermediate of claim 9, wherein B represents the protonated form (cation) of the basic substance, is preferably reacted with the esterifying agent without isolation from the reaction mixture. The reaction is carried out in an inert solvent, for example an ether, e.g. diethyl ether, dimethoxyethane, tetrahydrofuran or dioxane, acetonitrile, dimethylformamide or hexamethylphosphoric triamide, optionally at a slightly elevated or reduced temperature, e.g.

At 0-50 ° C, preferably at room temperature. In a preferred embodiment of the process, a penam compound of formula XII is prepared in situ by first treating a penam compound of formula XI as described in step 3.1.

a compound of formula XIII with a catalytic amount of a basic agent, e.g., 1,5-diazabicabicyclo (5.4.0) indec-5-ene, and then further reacted with at least an equimolar amount of the same basic agent and esterifying agent to give compounds of formula XIII.

7 6 3 4 8 32

Step 3.3;

The oxalyl azetidinone of formula XIV can be prepared by ozonating a compound of formula XIII and cleaving the resulting ozonide by reduction to the oxo-5 compound.

The ozonation is usually carried out with an ozone-oxygen mixture in an inert solvent such as a lower alkanol, e.g. methanol or ethanol, a lower alkanone, e.g. acetone, optionally a halogenated hydrocarbon, e.g. a halogen-lower alkane such as methylene chloride or carbon tetrachloride, the mixture, preferably with cooling, e.g. at temperatures of about -80 to about 0 ° C.

The intermediate ozonide is conventionally cleaved without isolation by reduction to give a compound of formula XIV using catalytically activated hydrogen, e.g. hydrogen in the presence of a heavy metal hydrogenation catalyst such as nickel, further palladium on carbon 20 chemical reducing agents such as reducing heavy metals, including heavy metal alloys or amalgams, e.g. zinc in the presence of a hydrogen donor such as an acid, e.g. acetic acid, or an alcohol, e.g. lower alkanol, reducing inorganic salts, e.g. alkali metals, e.g. , or alkali metal hydrogen sulfites, e.g. sodium hydrogen sulfite, in the presence of a hydrogen donor such as an acid, e.g. acetic acid, or water, or reducing organic compounds such as formic acid. Compounds which can be easily converted to the corresponding epoxide compounds or oxides can also be used as reducing agents, in which case the epoxide formation can take place on the basis of a C, C double bond and the oxide formation on the basis of the oxide-forming heteror, such as sulfur, phosphorus or nitrogen. Such compounds include, for example, suitably substituted ethylene compounds (which are converted in the reaction to ethylene oxide compounds), such as tetracyanoethylene, or especially suitable sulfide compounds (which are converted in the reaction to sulfoxide-fatty compounds), such as dialkyl alkyl sulfides, phosphine substituted by phenyl and / or lower alkyl, e.g. methyl, ethyl, n-propyl or n-butyl (which is converted to phosphine oxide in the reaction), such as trialkylalkyl phosphines, e.g. tri-n-butylphosphine, or triphenylphosphine , further trialalkyl alkyl phosphites (which are converted in the reaction to lower alkyl esters of phosphoric acid), conventionally in the form of the corresponding alcohol addition products, such as trimethyl phosphite, or phosphoric acid triamides, optionally containing a lower alkyl substituent, such as hexa-lower alkyl, hexa-lower alkyl hexamethyl phosphoric acid tretramide, the latter preferably in the form of a methanol adduct, further suitable nitrogen bases (which are converted in the reaction to the corresponding N-oxides), such as aromatic heterocyclic nitrogen bases, e.g. pyridine-type bases and in particular pyridine itself. Conventionally, the cleavage of uninsulated ozone normally takes place under the conditions used to prepare it, i. in the presence of a suitable solvent or solvent mixture and with cooling or slight heating, preferably at temperatures of about -10 to about + 25 ° C, and the reaction is usually stopped at room temperature.

25 Step 3.4:

The azetidinone of formula VIb can be prepared by solvolyzing an oxalyl azetidinone of formula XIV.

The solvolysis can be carried out as hydrolysis, alcoholysis or also as hydrazinolysis. The hydrolysis is carried out with water, for example in a water-miscible solvent. The alcoholysis is conveniently carried out with a lower alkanol, e.g. methanol or ethanol, preferably in the presence of water and an organic solvent such as a lower alkanecarboxylic acid lower alkyl ester, e.g. acetic acid ethyl ester, preferably at room temperature, optionally with cooling or heating, e.g. At a temperature of C. The hydrazinolysis is carried out with a conventionally substituted hydrazine, e.g. phenyl or nitrophenylhydrazine, such as 2-nitrophenylhydrazine, 4-nitrophenylhydrazine or 2,4-dinitrophenylhydrazine, preferably used in an amount such as 5 eq. in an ether such as tetrahydrofuran, dioxane, diethyl ether, an aromatic hydrocarbon such as benzene or toluene, a halogenated hydrocarbon such as methylene chloride, chlorobenzene or dichlorobenzene, an ester such as ethyl acetate and the like at about 65 ° C to about room temperature temperatures.

In a preferred embodiment of the process, a compound of formula XIII is started, which is ozonated as shown and then cleaved by reduction to oxalyl azetidinone of formula XIV, which is further reacted without isolation from the reaction mixture to form azetidinone of formula VIb.

Ozonolysis potentially produces small amounts of acid that can result in the cleavage of a solvolytically readily cleavable residue 1, e.g., a trisubstituted silyl residue. The compound of formula 11 thus formed can be separated, for example, from the chromatographically protected azetidinone (VIb) and converted by reacting with a hydroxy-protecting group-containing compound of formula R2-X3. with azetide non of formula VIb.

76348 35

Preferably, the starting materials and reaction conditions are selected to give the highly preferred compounds described above.

The compounds of the formula I have valuable pharmacological properties and have, for example, antibacterial effects. For example, they affect gram-positive and gram-negative cooks in vitro, e.g., Staphylococcus aureus, Streptococcus pyogenes. Against Streptococcus pneumoniae, Streptococcus faecalis, Neisseria meningitidis and Neisseria gonorrhoeae at minimum concentrations of about 0.01 to about 16 ug / ml and against gram-negative rod bacteria such as Enterobactriaceas, Haemophilus influenzae and Pseudomonas aer. Bacteroides sp. against at minimum concentrations of about 0.1 to about 16 ug / ml. In vivo, systemic infections in mice caused by, for example, Staphylococcus aureus or Streptococcus pyogenes, result in subcutaneous or oral administration of EDsQ values of about 2 to about 100 mg / kg.

For example, having sodium (5R, 6S) -2- (tetrazol-1-ylmethyl) -6-hydroxymethyl-2-penem-3-carboxylate (Compound 1), sodium (5R, 6S) -2- [2 - (tetrazol-1-yl) ethyl] -6-hydroxymethyl 2-penem-3-carboxylate (Compound 2), 36 7 6 3 4 8 sodium (5R, 6S) -2- (4- ( tetrazol-1-yl) butyl) -6-hydroxymethyl 2-penem-3-carboxylate (Compound 3), sodium (5R, 6S) -2- (2- (1,2,4-triazole 1-yl) -ethyl) -6-hydroxymethyl-2-penem-3-carboxylate (Compound 4), 5 sodium (5R, 6S) -2- (3- (tetrazol-1-yl) -propyl) -6-hydroxymethyl-2-penem-3-carboxylate (Compound 5), in said in vitro test the following values: 1 "MIC (pg / tol), in vitro _., Compound

Organisms _____ 1 2 3 4 5

Staphylococcus aureus 10 B 0.1 0.1 0.05 0.1 0.1

Staphylococcus aureus 2999 i + p + 0.2 0.1 0.05 0.2 0.1

Staphylococcus aureus A124 0.5 1 2 1

Staphylococcus aureus Wood 46 0.1

Streptococcus pyogenes Aronson 0.2 0.1 0.05 0.2 0.2

Streptococcus pneumoniae 111/84 0.2 0.05 0.05 0.05 0.05

Streptococcus faecalis D 3 64 32 16 32 16

Neisseria meningitidis 1316 0.05 0.05 0.02 0.05 0.05

Neisseria gonorrhoeae 1317-4 0.01 0.05 0.01 0.05 0.01

Haemophilus influenzae-NCTC 4560 2 4 0.5 4 4

Escherichia coli 205 211 21

Escherichia coli 205 R + TEM 212 21

Escherichia coli 16 21422

Escherichia coli 2018 1 l

Escherichia coli UB1005 2 1 2 2 1

Escherichia coli DC 2 2 1 2 2 1

Klebsiella pneumoniae 327 212 11

Serratia marcescens 344 16 4 8 16 4

Enterobacter cloacae P99 4 2 8 4 4 - ~ L ——---. 76348 37 'MIC (pg / tal), in vitro ~~. Compound

Organisms _______ 12 3 4 5

Enterobacter cloacae ATCC 13047 16 2 16 8 4

Proteus mirabilis 774 422 42

Proteus mirabilis 1219 4 2 2 4 4

Proteus rettgeri 856 16 4 4 44

Proteus morganii 2359 4 2 2 4 2

Proteus morganii 1518 844 44

Pseudomonas aeruginosa ATCC 12055> 128> 128 »* 128> 128> 128

Pseudomonas aeruginosa K 799/61 8 4 1 4 l

Pseudomonas aeruginosa 143738 R> 128> 128

Clostridium perfringens 194 1 0.1 0.1 0.2 0.2

Bacteroides fragilis L 01 0.5 0.1 0.5 0.2 0.1

In vivo, the following EDj-Q values are formed in a mouse systemic infection: ED5q (mg / kg), in vivo

Organism Comb. 1 2 3 4 5

Staphylococcus aureus 10B s.c. 6-13 40 14 44 30 p.o. > 100 86> 30> 30> 30

Streptococcus * pyogenes s.c. 2 2.5 5.5 7 3 ^ 5

Aronson p.o. 44 8-23> 10> 10> 30

Escherichia coli 2018 s.c. > 30 30 30 34 45 p.o. > 30> 30> 100 100> 100 (s.c .: subcutaneously; p.o .: orally) 38,763 4 8

The compounds of the invention have advantageous properties over the related compounds of the prior art, such as in vitro comparative experiments with (5R, 6S) -6-hydroxymethyl-2 - [(tetrazol-1-yl) methyl] -2-penem-3- carboxylic acid (sodium salt, Example 19, Compound A), racemic 2 - [(tetrazol-1-yl) methyl] -2-penem-3-carboxylic acid (sodium salt, Example 76, U.S. Pat. No. 4,272,437, Compound B), compound ( 5R, 6S) -2- [3- (tetrazol-1-yl) -propyl] -6-hydroxymethyl-2-penem-3-carboxylic acid (sodium salt, Example 21, Compound C) and (5R, 6S) -2- ( Between 3-aminopropyl) -6-hydroxymethyl-2-penem-3-carboxylic acid (Example 88, EP 3960, compound D) the following is observed: 39 7 6 3 4 8 in vitro MIC (ng / ml)

Microorganism compound compound 'compound compound

A i 5 c L D

Staphylococcus aureus 10 B 0.1 1 0.1 0.1

Staphylococcus aureus 2999i + p + 0.2 1 0.1 0.1

Staphylococcus aureus AI24 0.5 8 1 0.5

Streptococcus pyogenes Aronson 0.2 1 0.2 0.2

Streptococcus pneumoniae III / 84 0.2 0.5 0.05 0.5

Streptococcus faecalis D3 64> 128 16 64

Neisseria meningitidis 1316 0.05 0.05 0.05 1

Neisseria gonorrhoeae 1317/4 0.01 0.01 0.01 0.5

Haemophilus influenzae NCTC 4560 2 4 4 16

Escherichia coli 205 2 8 1 16

Escherichia coli 205 2 128 1 16

Escherichia coli 16 2> 128 2 8

Escherichia coli UB 1005 2 8 1 16

Escherichia coli DC2 2 8 1 16

Klebsiella pneumoniae 327 2 8 1 8

Serratia marcescens 344 16 32 4 32

Enterobacter cloacae P99 4 848

Enterobacter cloacae ATCC 13047 16> 128 4 32

Proteus mirabilis 774 4 16 2 16

Proteus mirabilis 1219 4> 128 4 16

Proteus rettgeri 856 16 32 4 64

Morganella morganii 2359 4 16 2 16

Morganella morganii 1518 8 32 4 32

Pseudomonas aeruginosa K 799/61 8 16 1 32

Staphylococcus aureus 10B AN 0.1 1 0.1 0.1

Escherichia coli 205 AN 2 8 1 16

Clostridium perfringens 194 AN 1 2 0.2 4

Bacteroides fragilis L 01 AN 0.5 8 0.1 2 (AN: incubated anaerobically) 40 7 634 8

The novel compounds can be used as antibacterial antibiotics for oral or parenteral administration, e.g. in the form of similar pharmaceutical preparations for the treatment of infections.

The pharmacologically useful compounds of the present invention can be used, for example, for the preparation of pharmaceutical preparations containing an effective amount of the active ingredient together or in admixture with inorganic or organic, solid or liquid pharmacologically acceptable carriers suitable for oral or parenteral administration, i. intramuscularly, subcutaneously or intraperitoneally.

For oral administration, tablets or gelatin capsules are used which contain the active ingredient together with diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine and lubricants, e.g. dairy, talc, stearic acid or nihonic acid. such as magnesium or calcium stearate and / or polyethylene glycol; tablets also contain binders, e.g. magnesium aluminum silicate, starches such as corn, wheat, rice or arrowroot starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and if desired disintegrant, disintegrant. nitric acid or a salt thereof, such as sodium alginate, and / or effervescent mixtures or adsorbents, colorants, flavors or sweeteners.

Formulations suitable for parenteral administration are preferably infusion solutions, preferably isotonic aqueous solutions or suspensions, which are prepared before use, e.g. from lyophilized preparations containing the active ingredient alone or in combination with a carrier material, e.g. mannitol. Such preparations may be sterilized and / or may contain adjuvants, e.g., preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers.

The present pharmaceutical preparations, which may, if desired, contain other pharmacologically valuable substances, are prepared in a manner known per se, e.g. by conventional mixing, dissolving or lyophilizing methods, and contain from about 0.1 to 100%, in particular from about 1 to about 50 % lyophilizates to 100% active substance.

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

The following examples illustrate the invention. Temperatures are shown in degrees Celsius.

The following abbreviations are used in the examples: 20 DC: thin layer chromatogram, IR: infrared spectrum, UV: ultraviolet spectrum,

Sp. : melting point, DBI: 1,5-diazabicyclo (5.4.0) undec-5-ene, THF: tetrahydrofuran, DMF: dimethylformamide

Example 1: (3S, 4R) -3- (tert-Butyl-dimethylsilyloxymethyl) -4- (5- (tetrazol-1-yl) -valeroylthio) -azetidin-2-one To a solution of 293 mg (3S , 4S) -3- (tert-butyldimethylsilyloxymethyl) -4-methylsulfonyl-azetidin-2-one in 5 ml of abs. THF, a solution of 204.8 mg of 5- (tetrazol-11-yl) -thiovaleric acid in 1.1 ml of sodium hydroxide solution and 5 ml of water is added with stirring. The mixture is then kept by adding 0.1N sodium hydroxide solution at pH 10. The reaction is kept at room temperature for 2 hours, after which it is diluted with ethyl acetate and the aqueous phase is separated.

42 76348

It is extracted twice with ethyl acetate and the combined extracts are washed with brine. Dry over sodium sulfate and evaporate under high vacuum, then chromatograph the residue using toluene and ethyl acetate (1: 2) as eluent.

TLC (silica gel): toluene-ethyl acetate (2: 3) Rf = 0.17 IR (methylene chloride): 2.94; 5.66; 6.96 et seq.

The starting compound 5- (tetrazol-1'-yl) -thiovaleric acid can be prepared as follows: 1aa) 5- (N-Formylamino) -valeric acid ethyl ester To 1.8 g of 5-amino-valeric acid-ethyl ester hydrochloride is added 40 in 1 ml of formic acid ethyl ester in 1.4 ml of triethylamine and then heated to reflux for 2 hours. The precipitate is filtered off, washed with a small amount of formic acid ethyl ester and evaporated on a rotary evaporator under reduced pressure. The residue is partitioned between methylene chloride and sodium bicarbonate solution, the organic phase is then washed with brine, dried and evaporated. The title compound is obtained as an oil.

IR (methylene chloride): 5.78; 5.92; 6.64 et al.

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

Kp. (0.3 torr) 70 °, 30 IR (methylene chloride): 4.68; 5.83; 7.3; 8.6 ym.

1ac) 5- (Tetrazol-1-yl) -valeric acid ethyl ester 3.6 g of 5-isocyanovaleric acid ethyl ester are heated in 72 ml of a 0.9 M solution of HN 2 O in benzene for 24 hours under argon at reflux temperature. Evaporate and purify by chromatography on silica gel (eluent: toluene / ethyl acetate: 1/1) to give the pure title compound.

43 7 6 3 4 8 IR (methylene chloride): 3.2; 5.85; 7.32 μια.

lad) 5- (Tetrazol-1-yl) -valeric acid 2.12 g of 5- (tetrazol-1-yl) -valeric acid ethyl ester are dissolved in 5 ml of methanol and 4.28 g of methanolic NaOH solution are added. (3N). After stirring for 2.5 hours at room temperature, the solvent is evaporated off and the residue is taken up in water. Wash with ethyl acetate, then acidify the aqueous phase (pH 3) and extract twice with ethyl acetate. After drying and evaporation, the pure title compound is obtained.

NMR (DMSO-d 6); δ 12.1 ppm (1H, broad), 9.5 ppm (1H, s), 4.55 ppm (2H, t), 2.3 ppm (2H, t), 1.7 ppm (4H, m) .

Lae) 5- (Tetrazol-1-yl) -valeric acid chloride 1 g of 5- (tetrazol-1-yl) -valeric acid is heated in 12 ml of absolute benzene with 0.6 g of thionyl chloride and 2 drops of DMF. minutes at reflux temperature. Evaporate under reduced pressure to give the title compound.

IR (methylene chloride); 3.18; 5.62; 6.78 μια.

1af) 5- (Tetrazol-1-yl) -thiovaleric acid 5 g of 5- (tetrazol-1-yl) -valeric acid chloride are dissolved in 4.5 ml of abs. methylene chloride and 35.5 ml of a solution of pyridine and H 2 S in methylene chloride (30 ml of pyridine and 6 g of H 2 S in 100 ml of methylene chloride) are added dropwise at 0 °. It is then stirred for 1 hour at 0 ° under a nitrogen atmosphere. The reaction mixture is taken up in chloroform, acidified to pH 2 with 2N H2SO4 and extracted twice with chloroform. The combined organic phases are washed twice with 25 ml of 10% NaHCO3 solution. The pH is then adjusted to 3 with 2N 2 SO 4 and the title compound is extracted several times with chloroform. Dry over sodium sulfate and evaporate to give the title compound.

IR (methylene chloride): 3.9; 5.9; 8.6; 9.1 μια.

Starting material (3S, 4R) -3- (tert-butyldimethylsilyloxymethyl) -4-methylsulfonyl-azetidin-2-one can be prepared as follows: 76348 44 lba) (3S, 5R, 6R) -2,2-dimethyl- 6- (tert-butyylidimetyylisilyy-oxymethyl) -penam-3-carboxylic acid methyl ester-1,1-dioxide

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

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

lbb) 2 - ((3S, 4R) -3- (tert-butyl-dimethylsilyloxymethyl) -4-methylsulfonyl-2-oxo-azetidin-1-yl) -3-methyl-2-butenoic acid methyl ester To a solution in which is 202 g (0.51 moles) of (3S, 5R, 6R) -2,2-dimethyl-6- (tert-butyldimethylsilyloxymethyl) -penam-3-carboxylic acid methyl ester 1,1,1-dioxide in 800 ml of tetra- hydrofuran, mixed with 9 ml of DBU and stirred for 30 minutes at room temperature. 95 ml of 25 DBU are then added and the mixture is stirred for 30 minutes at room temperature. 42.3 ml (0.68 mol) of methyl iodide are then added under cooling. After 3 hours, filter off the crystallized DBU hydroiodide and evaporate the filtrate. The residue is taken up in ethyl acetate and the solution is washed with 1N sulfuric acid, water and bicarbonate solution. The aqueous phases are extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solution is evaporated to a thick oil.

DC (silica gel), toluene / ethyl acetate (4: 1); R f = 0.42, 35 IR (CH 2 Cl 2) 5.63; 5.81; 6.17 et seq.

45 76348 1bc) (3S, 4R) -3-Hydroxymethyl-4-methylsulfonyl-azetidin-2-one and (3S, 4R) -3- (tert-butyl-dimethylsilyloxymethyl) -4-methylsulfonyl-azetidin-2-one

Solution of 25 g (61.7 nunol) of 2 - ((3S, 4R) -3- (tert-5-butyl-dimethylsilyloxymethyl) -4-methylsulfonyl-2-oxo-azetidin-1-yl) -3- methyl butenoic acid methyl ester in 400 ml of methylene chloride, treated at -10 ° with a mixture of ozone and oxygen. The roofing of the starting material is checked by thin layer chromatography. After completion of the reaction, 10 ml of dimethyl sulfide are added and stirring is continued for 3 hours at room temperature. The solution is evaporated and the residue is taken up in a mixture of 160 ml of methanol, 24 ml of ethyl acetate and 3 ml of water and heated to 70 ° within 40 minutes. 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 to give (3S, 4R) -3- (tert-butyl-dimethylsilyloxymethyl) -4-methyl-sulfonyl-azetidin-2-one by chromatography on silica gel with toluene / ethyl acetate (3: 1) in pure form.

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

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

To 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 added 24 g (183 mmol) of tert-one. butyldimethylchlorosilane and 11 g (163 mmol) of imidazole within 45 minutes at room temperature. The solvent is then removed under high vacuum and the residue is taken up in ethyl acetate. The organic phase is washed successively with 1N sulfuric acid, water and sodium bicarbonate solution. The aqueous phases are extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate and evaporated on a rotary evaporator. The crystalline residue is pure (3S, 4R) -3- (tert-butyl-dimethylsilyloxymethyl) -4-methylsulfonyl-azetidin-2-one.

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

To a mixture of 248 mg of (3S, 4R) -3- (tert-butyl-dimethylsilyloxymethyl) -4- (5- (tetrazol-1-yl) -valeroyl-10-lithio) -azetidin-2-one and 273.5 mg of glyoxylic acid 2-trimethylsilylethyl ester ethyl hemiketal in 5.3 ml of toluene and 1.06 ml of DMF are added, 2.4 g of molecular sieve (type 4A 1/16, Dr.Bender / Dr.Bobein AG, Zurich) and stirred at a bath temperature of 100 ° for 5 hours under an inert gas atmosphere. After cooling, the mixture is filtered through Hyflo and the filter cake is washed with toluene. Evaporation of the filtrate and drying at 40 ° under high vacuum gives the product as a yellow oil.

DC (silica gel): toluene-ethyl acetate (2: 3); R f = 0.31 and 0.2, IR (methylene chloride): 2.86; 5.67; 5.78; 5.96 et seq.

Example 3; 2 - ((3S, 4R) -3-tert-butyl-dimethylsilyloxymethyl-4- (5- (tetrazol-1-yl) -valeroylthio) -2-oxo-azetidin-1-yl) -2-25-triphenylphosphoranylideneacetic acid trimetyylisilyylietyy-2-methyl ester

To a solution of 700 mg of 2 - ((3S, 4R) -3-tert-butyl-dimethylsilyloxymethyl-4- (5- (tetrazol-1-yl) -valeroylthio) -2-oxo-azetidin-1-yl) 2-Hydroxy-acetic acid 2-tri-30-methylsilylethyl ester in 4.3 ml of tetrahydrofuran is added with stirring at -15 ° successively 0.13 ml of thionyl chloride and 0.25 ml of triethylamine over 10 minutes. The white suspension "is stirred for 1 hour at 0 ° and filtered through Hyflo. The residue is washed with toluene, then evaporated on a rotary evaporator and dried under high vacuum. The residue is dissolved in 3.7 ml of dioxane, 0.28 g of triphenylphosphine and 0, 12 ml of 2,6-lutidine and 76348 47 are stirred for 18 hours at 50 [deg.] C. The mixture is filtered through Hyflo and this residue is washed with toluene, the combined filtrates are evaporated and the residue is chromatographed on 40 g of silica gel with toluene / ethyl acetate (4: 1). ) gives a pure product.5 DC (silica gel) toluene-ethyl acetate (2: 3); Rf = 0.28, IR (methylene chloride): 5.72; 5.93; 6.23; 9.1 μπι.

Example 4; (5R, 6S) -2- (4- (Tetrazol-1-yl) -butyl) -6-tert-butyl-dimethylsilyloxymethyl) -2-penem-3-carboxylic acid 2-tri-10-methylsilyl ethyl ester 0.8 g 2 - ((3S, 4R) -3-tert-butyl-dimethylsilyloxymethyl-4- (5- (tetrazol-1-yl) -valeroylthio) -2-oxoacetidin-1-yl) 2-Triphenylphosphoranylideneacetic acid 2-trimethylsilylethyl ester is dissolved in 300 ml of toluene and stirred under nitrogen for 1.25 hours at reflux temperature. The solvent is evaporated and the residue is chromatographed on silica gel using toluene / ethyl acetate (2: 1) as eluent to give pure product.

DC (silica gel) toluene-ethyl acetate (2: 3); = 0.45, 20 IR (methylene chloride): 5.62; 5.92; 6.34; 7.65 ym.

Example 5: (5R, 6S) -2- (4- (Tetrazol-1-yl) -butyl) -6-hydroxymethyl-2-penem-3-carboxylic acid 2-trimethylsilylethyl ester 163 mg (5R, 6S) -2- (4- (Tetrazol-1-yl) -butyl) -6-tert-butyl-dimethylsilyloxymethyl-2-penem-3-carboxylic acid 2-trimethylsilylethyl ester is dissolved in 4.8 ml of abs. THF and 0.17 ml of acetic acid are added thereto after cooling to -80 ° under a nitrogen atmosphere. 18.2 ml of a 0.1M solution of 0.1M tetrabutylammonium fluoride in THF are then added dropwise and the mixture is allowed to warm to room temperature and then stirred for 2 hours at this temperature. The solvent is evaporated to 2 ml on a rotary evaporator and the residue is partitioned between a solution of sodium bicarbonate (25.3 mg) in 10 ml of water and ethyl acetate (10 ml). The organic phase is separated, the aqueous phase is extracted twice more with ethyl acetate. The organic extracts are washed once more with water and dried over sodium sulfate.

48 7634 8

Evaporation under high vacuum gives a crude product which is chromatographed on 10 g of silica gel using toluene / ethyl acetate (1: 1) as eluent.

DC (silica gel) toluene-ethyl acetate (2: 3); = 0.12.5 IR (methylene chloride): 2.78; 5.62; 5.92; 6.33; 7.65 et al. Example 6: Sodium (5R, 6S) -2- (4- (tetrazol-1-yl) butyl) -6-hydroxymethyl-2-penem-3-carboxylate 106 mg (5R, 6S) -2- (4- (Tetrazol-1-yl) -butyl) -6-hydroxymethyl-2-penem-3-carboxylic acid 2-trimethylsilyl-ethyl ester is dissolved in 2 ml of abs. THF and cooled to -30 °. 10 ml of a solution of tetrabutylammonium fluoride in THF are added, after which the temperature is brought to 0 °. After stirring for 10 minutes at this temperature, 13 ml of ethyl acetate and 13 ml of water are added to the mixture. In an ice bath, the solution is then adjusted to pH 3 by dropwise addition of 4N HCl. The aqueous phase is then separated and the ethyl acetate phase is extracted with 10.6 ml of 0.05 M NaHCO3 solution. The organic phase is extracted once more with 0.5 ml of NaHCO3 (0.05 M) and 4 ml of H2O. The combined aqueous phases are freed from the remaining solvent under high vacuum and lyophilized.

UV (water) λ, = 305 nm. roaks

Example 7: 2 - ((3S, 4R) -3- (tert-butyl-dimethylsilyloxymethyl) -4- (2- (tetrazol-1-yl) -acetylthio) -2-oxo-azetidin-1-yl) - 2-Triphenylphosphoranylideneacetic acid allyl ester 5 g of 2 - ((3S, 4R) -3- (tert-butyl-dimethylsilyloxymethyl) -4-mercapto-2-oxo-azetidin-1-yl) -2-triphenylphosphine-30 the silver salt of foranylideneacetic acid allyl ester is dissolved in 50 ml of abs. methylene chloride, first 0.99 ml of pyridine is added and then treated dropwise at 0 ° over 10 minutes with a solution of 2- (tetrazol-1-yl) -acetic acid chloride. Stir for 1 hour at 0 °, then remove the cooling bath and stir for a further 15 minutes at room temperature. The insoluble material is filtered off through Hyflo, after which the filtrate is washed with aqueous sodium bicarbonate solution and brine, dried and evaporated. The pure compound is obtained by chromatography on silica gel (eluent toluene-ethyl acetate 6: 1-1: 1), IR (methylene chloride): 5.71; 5.92; 5 6.18 et seq.

Starting material 2 - ((3S, 4R) -3- (tert-butyl-dimethyl-silyloxymethyl) -4-mercapto-2-oxo-azetidin-1-yl) -2-triphenylphosphoranylideneacetic acid allyl ester (silver salt) is obtained as follows 7aa) (3S, 4R) -3- (tert-butyl-dimethylsilyloxymethyl) -4-triphenylmethylthioazetidin-2-one 12.5 g of triphenylmethyl mercaptan are suspended in 70 ml of methanol at 0 ° and added over 10 minutes. a total of 2.2 g of a 50% solution of sodium hydride in oil. An emulsion of 11.1 g of 3- (tert-butyl-dimethylsilyloxymethyl) -4-methylsulfonyl-azetidin-2-one in 70 ml of acetone and 70 ml of water is then added dropwise over 30 minutes. After stirring for 30 minutes at 0 ° and for one hour at room temperature, the reaction mixture is evaporated on a rotary evaporator, then methylene chloride is added and the aqueous phase is separated. The organic solution is washed with brine and dried over sodium sulfate. After evaporation, the crude title compound is purified by chromatography on silica gel (eluent toluene / ethyl acetate 19: 1).

DC (toluene-ethyl acetate 19: 1); R f = 0.64, IR (methylene chloride): 2.95; 5.68; 8.95; 12.0 m.

7ab) 2 - ((3S, 4R) -3- (tert-butyl-dimethylsilyloxymethyl) -4-triphenylmethylthio-2-oxo-azetidin-1-yl) -2-hydroxy-30-acetic acid allyl ester 8.4 g: to (3S, 4R) -3- (tert-butyl-dimethylsilyloxymethyl) -4-triphenylmethylthioazetidin-2-one and 8.23 g of glyoxal acid allyl ester-ethyl heme acetal in 170 ml of abs. toluene is added to 27 g of molecular sieve (4A) and stirred for 10 hours at 55 °. Filter and evaporate on a rotary evaporator under reduced pressure, then purify the crude product by chromatography on silica gel 50 763 4 8 (eluent toluene / ethyl acetate 95: 9).

TLC (silica gel, toluene / ethyl acetate 10: 1): = 0.37 and 0.28, IR (CH 2 Cl 2); 2.84; 5.68; 5.73 et seq.

5 7 ac) 2 - ((3S, 4R) -3- (tert-butyl-dimethylsilyloxymethyl) -4-triphenylmethylthio-2-oxo-azetidin-1-yl) -2-triphenylphosphoranylideneacetic acid allyl ester

To a solution of 604 g of 2 - [(3S, 4R) -3- (tert-butyl-dimethylsilyloxymethyl) -4-triphenylmethylthio-2-oxo-10-azetidin-1-yl] -2-hydroxyacetic acid allyl ester in 5 ml: tetrahydrofuran, 80 ul of thionyl chloride and 88 ul of pyridine are added successively at -15 ° over 5 minutes. The white suspension is further stirred for one hour at -10 ° and filtered through Hyflo. The residue is washed with toluene-15 and then evaporated on a rotary evaporator. The residue is dissolved in 3 ml of dioxane, 293 mg of triphenylphosphine and 0.13 ml of 2,6-lutidine are added and the mixture is stirred for 2 hours at a bath temperature of 115 °. The mixture is filtered through Hyflo and the residue is washed with toluene. The combined filtrates are evaporated. Chromatography of the residue on silica gel gives a pure product (eluent toluene / ethyl acetate 95: 5).

DC (silica gel, toluene / ethyl acetate 1: 1); = 0.18, IR (CH 2 Cl 2): 5.73; 6.23 et seq.

7ad) Silver salt of 2 - ((3S, 4R) -3- (tert-butyl-dimethylsilyloxymethyl) -4-mercapto-2-oxo-azetidin-1-yl) -2-triphenylphosphoranyl-acetic acid allyl ester 7.5 g 2 - ((3S, 4R) -3- (tert-butyl-dimethylsilyloxymethyl) -4-triphenylmethylthio-2-oxo-azetidin-1-yl) -2-30 triphenylphosphoranylideneacetic acid allyl ester is taken up in 87 ml of ether and 70 ml of 0.5 M aqueous silver nitrate solution are added at room temperature. A mixture of 3.6 ml of tributylamine and 0.18 ml of trifluoroacetic acid and 25 ml of ether is then added dropwise and the reaction mixture is stirred for 20 minutes. The solid is then suction filtered and washed with ether, water and once more with ether. Finally, for purification, the solid is slurried in 51 76348 40 ml of ether and 40 any water, filtered off with suction and dried.

IR (CH 2 Cl 2): 5.68; 6.17 et seq.

A solution of the starting material 2- (tetrazol-1-yl) -acetic acid chloro-5-din can be prepared as follows: 7ba) 2- (Tetrazol-1-yl) -acetic acid ethyl ester in 500 ml of 1.3 N nitric acid (NH 4) A solution of isocyanoacetic acid ethyl ester is added dropwise to a solution of benzene in benzene and the reaction mixture is then heated under reflux for 24 hours. After evaporation, the crude title compound is purified by chromatography on silica gel (eluent: toluene-ethyl acetate 1: 1), IR (methylene chloride); 3.16? 5.73; 6.80; 8.23 ym.

7bb) 2- (Tetrazol-1-yl) -acetic acid According to Example 1ad), 25.6 g of 2- (tetrazol-1-yl) -acetic acid ethyl ester are reacted to give the title compound.

IR (tetrahydrofuran): 5.73 μm.

7bc) 2- (Tetrazol-1-yl) -acetic acid chloride 1.58 g of 2- (tetrazol-1-yl) -acetic acid are suspended in 27 ml of abs. methylene chloride and 1.9 ml of 1-chloro-1-dimethylaminoisobutene (CDIB) are added. Stir for 30 minutes at room temperature, then add another 0.5 ml of CDIB and stir for another 90 minutes. This acid chloride solution (IR (methylene chloride): 3.20; 5.57 et seq.) Is further reacted directly.

Example 8: 2 - ((3S, 4R) -3- (tert-butyl-dimethylsilyloxymethyl) -4- (3- (tetrazol-1-yl) -propionylthio) -2-oxo-azetidin-1-yl) - 30 2-Triphenylphosphoranylideneacetic acid allyl ester

According to Example 7), 5 g of the silver salt of Example 7ad) are reacted with a solution of 3- (tetrazol-1-yl) -propionic acid chloride to give the title compound.

IR (methylene chloride): 5.88; 5.92; 6.17 et seq.

35 Starting material 3- (Tetrazol-1-yl) -propionic acid chloride is prepared as follows: 52 7 634 8 8a) 3- (Tetrazol-1-yl) -propionic acid 4.5 g of tetrazole, 4.5 ml of acrylic acid and 15 drops of pyridine stirred for 8 hours at 90 °. After cooling, 150 ml of water are added to the reaction mixture, acidified with HCl (conc.) And evaporated on a rotary evaporator under reduced pressure. The crystalline residue is extracted three times with methyl ethyl ketone and the combined organic phases are dried over sodium sulfate. After evaporation, the crystalline residue is mixed with isopropanol / ether and filtered.

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

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

According to Example 7bc), 1.75 g of 3- (tetrazol-1-yl) -propionic acid are reacted to give the title compound. IR 15 (methylene chloride): 3.18, 5.63, etc. The resulting solution is immediately further reacted.

Example 9: 2 - ((3S, 4R) -3- (tert-butyl-dimethylsilyloxymethyl) -4- (4- (tetrazol-1-yl) -butyrylthio) -2-oxo-azetidin-1-yl) - 20 2-Triphenylphosphoranylideneacetic acid allyl ester

According to Example 7, 5 g of the silver salt obtained in Example 7ad) are dissolved in 10 ml of abs. methylene chloride, 1.13 ml of pyridine are added and cooled to 0 °, followed by reaction with 2.61 g of 4- (tetrazol-1-25 yl) butyric acid chloride to give the title compound.

IR (methylene chloride): 5.71; 5.93; 6.17 et seq.

Starting material 4- (Tetrazol-1-yl) butyric acid chloride is prepared as follows: 9a) 4- (Tetrazol-1-yl) butyric acid ethyl ester to 0.84 g of 4-aminobutyric acid ethyl ester hydrochloride and 0.9 g: To 4 ml of sodium azide are added 4 ml of orthomuric acid triethyl ester and 6 ml of acetic acid and the mixture is refluxed for 7 hours. After cooling, the reaction mixture is taken up in ethyl acetate and aqueous sodium bicarbonate-35 solution, the organic phases are separated and washed four more times with aqueous sodium bicarbonate solution. Wash with water and brine, then dry the ethyl acetate phase 76348 53 with sodium sulfate and evaporate to give the title compound.

IR (methylene chloride): 3.16; 5.81; 6.76; 8.4 pm.

9b) 4- (Tetrazol-1-yl) -butyric acid 5.65 g of 4- (tetrazol-1-yl) -butyric acid ethyl ester are heated in 42.7 ml of acetic acid, in 8.1 ml of conc. HCl and 17.2 mL of water for 3 hours at 100 °. After cooling, the reaction mixture is evaporated three times with toluene and ether each time on a rotary evaporator under reduced pressure. Dry under high vacuum to give the title compound.

NMR (DMSO-d 6): δ = 2.3 (4H, m); 4.6 (2 H, t); 8.7 (1H, broad); and 9.53 ppm (1H, s).

9c) 4-Tetrazol-1-yl) butyric acid chloride

According to Example 1ae), 0.31 g of 4- (tetrazol-15-yl) -butyric acid is converted into the title compound.

IR (methylene chloride): 3.18; 5.62 and others.

Example 10: 2 - ((3S, 4R) -3- (tert-butyl-dimethylsilyloxymethyl) -4- (3- (1,2,4-triazol-1-yl) -propionylthio) -2-oxo-azetidine -20 1-yl) -2-triphenylphosphoranylideneacetic acid allyl ester

According to Example 7, a solution of 3- (1,2,4-triazol-1-yl) -propionic acid chloride is reacted with 5 g of the silver salt shown in Example 7ad) to give the title compound.

IR (methylene chloride): 5.72; 5.92; 6.17 et seq.

Starting material 3- (1,2,4-triazol-1-yl) -propionic acid chloride is prepared as follows: 10a) 3- (1,2,4-triazol-1-yl) -propionic acid

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

IR (KBr): 3.21; 5.85; 6.58 et seq.

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

According to Example 7bc), 1.72 g of 3- (1,2,4-triazol-1-yl) -propionic acid are reacted to give the title compound. 35 IR (methylene chloride): 5.62 μm.

76348 54

Example 11; (5R, 6S) -2 - ((Tetrazol-1-yl) methyl) -6- (tert-butyldimethylsilyloxymethyl) -2-penem-3-carboxylic acid allyl ester 5 According to Example 4, 2 .3 g 2 - ((3S, 4R) -3- (tert-butyl-dimethylsilyloxymethyl) -4- (2- (triazol-1-yl) -acetylthio) -2-oxo-azetidin-1-yl) - 2-Triphenyl-phoranylideneacetic acid allyl ester takes 25 minutes after heating to react to give the title compound.

IR (methylene chloride): 5.60; 5.90; 6.33 et seq.

Example 12: (5R, 6S) -2- (2- (Tetrazol-1-yl) -ethyl) -6- (tert-butyl-dimethylsilyloxymethyl) -2-penem-3-carboxylic acid allyl ester 15 According to Example 4, 4 g of 2 - ((3S, 4R) -3- (tert-butyl-dimethylsilyloxymethyl) -4- (3- (tetrazol-1-yl) -propionylthio) -2-oxo-azetidin-1- yl) -2-triphenylphosphoranylideneacetic acid allyl ester after heating for 45 minutes to give the title compound.

IR (methylene chloride): 5.62; 5.90; 6.33 et seq.

Example 13; (5R, 6S) -2- (3- (Tetrazol-1-yl) -propyl) -6- (tert-butyl-dimethylsilyloxymethyl) -2-penem-3-carboxylic acid allyl ester 25 According to Example 4, 3 , 2 g of 2 - ((3S, 4R) -3- (tert-butyl-dimethylsilyloxymethyl) -4- (4- (tetrazol-1-yl) -butyrylthio) -2-oxo-azetidin-1-yl) - 2-Triphenyl-phosphoranylideneacetic acid allyl ester after heating for 2 hours to give the title compound.

IR (methylene chloride): 5.62; 5.88; 6.33 et seq.

Example 14; (5R, 6S) -2- (2- (1,2,4-triazol-1-yl) ethyl) -6- (tert-butyl-dimetyylisiiyylioksimetyyli-yl) -2-penem-3-carboxylic acid allyl ester According to Example 4, 3.2 g of 2 - ((3S, 4R) -3- (tert-butyl-dimethylsilyloxymethyl) -4- (3- (1,2,4-triazol-1-yl) are converted. -propionylthio) -2-oxo-azetidin-1-yl) -2-tri-55,734,8-phenylphosphoranylideneacetic acid allyl ester after heating for 75 minutes to give the title compound.

IR (methylene chloride): 5.61; 5.88; 6.33 μπι.

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

According to Example 5, 1.15 g of (5R, 6S) -2 - ((tetrazol-1-yl) methyl) -6- (tert-butyldimethylsilyloxymethyl) -2-penem-3-carboxylic acid allyl ester are obtained. reacts to the title compound of 10 countries.

IR (KBr): 5.64; 5.86; 6.33 et seq.

Example 16: (5R, 6S) -2 - ((Tetrazol-1-yl) -ethyl) -6-hydroxymethyl-2-penem-3-carboxylic acid allyl ester According to Example 5, 1.65 g (5R, 6S) -2- (2- (Tetrazol-1-yl) -ethyl) -6- (tert-butyl-dimethylsilyloxymethyl) -2-penem-3-carboxylic acid allyl ester to give the title compound.

IR (methylene chloride): 2.78; 5.62; 5.88; 6.33 et seq.

Example 17: (5R, 6S) -2- [3- (Tetrazol-1-yl) -propyl) -6-hydroxy-ethyl-2-penem-3-carboxylic acid allyl ester

1.2 g of (5R, 6S) -2- (3- (tetrazol-1-yl) propyl) -6- (tert-butyldimethylsilyl-5-oxymethyl) -2-penem-3- carboxylic acid allyl ester to give the title compound.

IR (methylene chloride): 2.77; 5.62; 5.88; 6.33 et seq.

Example 18: (5R, 6S) -2- (2- (1,2,4-Triazol-1-yl) -ethyl) -6-hydroxymethyl-1H-2-penem-3-carboxylic acid allyl ester

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

IR (methylene chloride): 2.78; 5.62; 5.30; 6.35 et seq.

56 76348

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

To a solution of 310 mg of (5R, 6S) -2 - ((tetrazol-1-5-yl) methyl) -6-hydroxymethyl-2-penem-3-carboxylic acid allyl ester in 12 ml of abs. THF, 22 mg of tetrakis (triphenylphosphine) palladium and then 0.31 ml of tributyltin hydride are added at -10 °. After stirring for 25 minutes at -10 °, 0.065 ml of acetic acid are added and the reaction mixture is then stirred at the same temperature for 10 minutes. Concentrate on a rotary evaporator, then take up the residue in aqueous ethyl acetate, bring the aqueous phase to pH 8.5 with sodium bicarbonate and separate. Wash further with ethyl acetate, then purify the title compound by chromatography on XAD / 2. (Eluent water). The corresponding fractions are lyophilized under high vacuum.

UV (phosphate buffer Ph 7.4): λπι & ^ 3 = 308 nm.

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

According to Example 19, 725 mg of (5R, 6S) -2- (2- (tetrazol-1-yl) ethyl) -6-hydroxymethyl-2-penem-3-carboxylic acid allyl ester are converted to the title compound.

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

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

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

UV (water): λ. = 302 nm.

max.

Example 22: (5R, 6S) -2- (2- (1 * 2,4-Triazol-1-yl) -ethyl) -6-hydroxymethyl-2-penem-3-carboxylic acid, sodium salt 35 According to Example 19 0.64 g of (5R, 6S) -2- (2- (1,2,4-triazol-1-yl)) - 6-hydroxymethyl-2-penem-3-carboxylic acid allyl ester is converted into the title compound.

57 7 634 8 UV (phosphate buffer pH 7.4): λ. = 303 nm.

ma k s ·

Example 23:

The following compounds can be prepared as described in Examples 1-22: (5R, 6S, 8R) -2 - ((tetrazol-1-yl) methyl) -6- (1-hydroxyethyl) -2-penem-3-carboxylic acid , sodium salt, UV (phosphate buffer pH 7.4): λ, = 307 nm.

max · (5R, 6S, 8R) -2- (2- (tetrazol-1-yl) ethyl) -6- (1-hydroxyethyl) -2-penem-3-carboxylic acid, sodium salt, UV (phosphate buffer pH 7, 4): λπι3) ς5 = 308 nm ·

Example 24: 2 - ((3S, 4R) -3- (tert-butyl-dimethylsilyloxymethyl) -4- (2- (tetrazol-1-yl) -acetylthio) -2-oxo-azetidin-1-yl) - 2-Triphenylphosphoranylideneacetic acid allyl ester (cf. Example 7) can also be prepared as follows: 24a) 2 - ((3S, 4R) -3- (tert-butyl-dimethylsilyloxymethyl) -4-chloroacetylthio-2-oxo-azetidine-1- yl) -2-trifenyylifos-allyl-foranylideenietikkahappo

According to Example 7, 30 g of the silver salt of 2 - [(3S, 4R) -3- (tert-butyl-dimethylsilyloxymethyl) -4-mercapto-2-oxo-azetidin-1-yl) -2-triphenylphosphoranylideneacetic acid allyl ester are reacted With 5.04 ml of chloroacetyl chloride to give the title compound.

IR (methylene chloride): 5.71; 5.95; 6.19 et seq.

24b) 2 - ((3S, 4R) -3- (tert-butyl-dimethylsilyloxymethyl) -4- (2- (tetrazol-1-yl) -acetylthio) -2-oxo-azetidin-1-yl) -2 -triphenylphosphoranylideneacetic acid allyl ester 0.68 g of 2 - ((3S, 4R) -3- (tert-butyl-dimethylsilyloxymethyl) -4-chloroacetylthio-2-oxo-azetidin-1-yl) -2-triphenylphosphoranylidene acetic acid is dissolved in 5 ml of DMF and 91 mg of tetrazole sodium are added. After stirring for 16 hours, the reaction mixture is taken up in water / ethyl acetate. The organic phase is separated, dried and evaporated. The product is purified by chromatography on silica gel. (Eluent: toluene / ethyl acetate 1: 1).

IR (methylene chloride): 5.71; 5.92; 6.18 et seq.

58 7 6 3 4 8

Example 25; (5R, 6S) -2 - ((Tetrazol-1-yl) -methyl) -6- (tert-butyl-dimethylsilyloxymethyl) -2-penem-3-carboxylic acid allyl ester 5 (See Example 1 ) can also be prepared as follows: 25a) (5R, 6S) -2-Chloromethyl-6- (tert-butyl-dimethylsilyloxymethyl) -2-penem-3-carboxylic acid allyl ester

According to Example 4, 0.341 g of 2 - ((3S, 4R) -3- (tert-butyl-dimethylsilyloxymethyl) -4-chloroacetyl-10-thio-2-oxoazetidin-1-yl) -2-triphenylphosphoranylidene acetic acid is converted into allyl ester (cf. Example 24a)) after heating for 45 minutes to give the title compound.

IR (methylene chloride): 5.60; 5.86; 6.33 et seq.

25b) (5R, 6S) -2- (Tetrazol-1-ylmethyl) -6- (tert-butyl-dimethylsilyloxymethyl) -2-penem-3-carboxylic acid allyl ester 0.4 g (5R, 6S) -2-Chloromethyl-6- (tert-butyl-dimethylsilyloxymethyl) -2-penem-3-carboxylic acid allyl ester is dissolved in 5 ml of DMF and 91 g of tetrasat-20 sol sodium are added. . After stirring for 16 hours, the reaction mixture is taken up in water / ethyl acetate. The organic phase is separated, dried and evaporated. The product is purified by chromatography on silica gel (eluent: toluene / ethyl acetate 9: 1). IR (methylene chloride): 5.60; 5.90; 6.33 et seq.

Example 26: (5R, 6S) -2- (2- (Tetrazol-1-yl) -ethyl) -6-hydroxymethyl-2-penem-3-carboxylic acid 1-ethoxycarbonyl-oxyethyl ester 1.2 g of sodium iodide are dissolved in 3 , To 7 ml of acetone and 0.275 ml of ethyl 1-chloroethyl carbonate are added.

The mixture is stirred at room temperature for 3 hours. The solution is then added dropwise to 15.0 ml of methylene chloride and filtered off from the precipitated inorganic salts. The methylene chloride solution is evaporated to 2 ml and added at 0 ° to a solution of 0.3 g of (5R, 6S) -2 - ((2R, S) -2- (tetras-35-sol-1-yl) ethyl ) -6-hydroxymethyl-2-penem-3-carboxylic acid in 4 ml of dimethylacetamide. It is then stirred for 3 hours at 0 [deg.] C., then diluted with ethyl acetate 76348 59 and washed three times with water. The organic phases are dried over sodium sulfate and evaporated on a rotary evaporator. The crude product is purified on 10 g of silica gel using ethyl acetate as eluent. The title compound is obtained as a white foam.

IR spectrum (methylene chloride): absorption bands 5.59; 5.75 and others.

Example 27: (5R, 6S) -2 - ((2R, S) -2- (Tetrazol-1-yl) -ethyl) -6-hydroxymethyl-2-penem-3-carboxylic acid pivaloyloxymethyl ester 0.6 g of sodium iodide are dissolved in 2 ml of acetone and 0.15 ml of pivalic acid chloromethyl ester are added. The mixture is stirred at room temperature for 3 hours and then added dropwise to 7.5 ml of methylene chloride. The precipitated inorganic salts are filtered off. The methylene chloride solution is evaporated to 1 ml and added at 0 ° to a solution of 0.1 g of (5R, 6S) -2 - ((2R, S) -2- (tetrazol-1-yl) ethyl) - 6-hydroxymethyl-2-penem-3-carboxylic acid and 0.07 ml of diisopropylethylamine in 4 ml of N, N-dimethylacetamide.

It is then stirred for 3 hours at 0 [deg.] 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 using ethyl acetate as eluent. The title compound is obtained as a white foam.

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

Example 28: 30 Dry ampoules or vials containing 0.5 g of sodium (5R, 6S) -2- (4- (tetrazol-1-yl) butyl) -6-hydroxymethyl-2-penem 3-carboxylate as active substance, is prepared as follows:

Composition: (per ampoule or vial): 35 active substances 0.5 g mannitol 0.05 g.

Claims (4)

60 7 6 3 4 8 The sterile aqueous solution of the active substance and mannitol is freeze-dried under aseptic conditions in 5 ml ampoules or 5 ml vials and the ampoules or vials are sealed and inspected. Claims p A process for the preparation of pharmacologically active and (5R, 6S) -configible fine compounds of the formula I wherein R 1 is hydrogen or methyl, R 2 is a hydroxyl group - R 3 is carboxyl or an esterified carboxyl group which can be cleaved under physiological conditions, R 4 is triazolyl or tetrazolyl bonded to the residue "(CH 2) m" via a ring nitrogen atom and m is an integer from 1 to 4, and for the preparation of salts of the compounds of formula I group, characterized in that a ring of formula II RZ, 1HH II R -CH-j- II <«> is enclosed. / R1, wherein R1, R2 / R4 and m are as defined in formula I, wherein the hydroxy group R2 is 76348 preferably in protected form, 113 'is a protected carboxyl, Z is oxygen or sulfur and X® is either triple substituted a phosphonio group or a double-esterified phosphono group together with a cation, and the resulting compound of formula I is converted to a free functional group, and the resulting compound of formula I is optionally converted to a free carboxyl group R3 to be cleaved to if desired, the compound is converted into a salt or the resulting salt into the free compound or another salt. Process according to Claim 1, characterized in that compounds of the formula I are prepared in which R 1 is hydrogen or methyl, R 2 is hydroxyl, R 3 is carboxyl, lower alkanoyloxymethoxycarbonyl or 1-lower alkoxycarbonyloxy-lower alkoxycarbonyl, R 4 is 1H-tetrazol-1-yl, 2H-tetrazol-2-yl or 1H-1,2,4-triazol-1-yl and m is an integer from 1 to 4, or a pharmaceutically acceptable salt thereof. Process according to Claim 1, characterized in that compounds of formula (5R, 6S) -configuration of the formula I are prepared in which R 1 is hydrogen, R 2 is hydroxyl, R 3 is carboxyl, R 4 is 1H-tetrazol-1-yl or 1H-1,2,4-triazol-1-yl and m are an integer from 1 to 4, or pharmaceutically acceptable salts thereof. Process according to Claim 1, characterized in that (5R, 6S) -2- [4- (1H-tetrazol-1-yl) -butyl] -6-hydroxymethyl-2-penem-3-carboxylate is prepared. acid, (5R, 6S) -2 - [(tetrazol-1-yl) methyl] -6-hydroxymethyl-2-penem-3-carboxylic acid, (5R, 6S) -2- [2- (tetrazole) 1-yl) -ethyl] -6-hydroxymethyl-2-penem-3-carboxylic acid, (5R, 6S) -2- [3- (tetrazol-1-yl) -propyl] -6-hydroxymethyl- 2-penem-3-carboxylic acid or (5R, 6S) -2- [2- (1,2,4-6,276.6 3 4 8 triazol-1-yl) -ethyl] -6-hydroxymethyl-2-penem- 3-Carboxylic acid or pharmaceutically acceptable salts thereof.