DE3201957A1 - DERIVATIVES OF 7-OXO-1-AZABICYCLO- (3.2.0) -HEPT-2-EN-2-CARBONIC ACID - Google Patents

Description

25th

35

wherein one of the substituents R and R is hydrogen and the other is hydrogen or a substituted or unsubstituted C ^^ - alkyl group and X is a substituted or unsubstituted C ₁ , alkanoyloxy group, an unsubstituted or substituted C _3. , - Cycloalkylthio, C "g- Alkenylthio or heterocyclylthio radical or a substituted C _1. -Alkylthio or phenylthio radical, their easily hydrolyzable esters, pharmaceutically acceptable salts and hydrates of these compounds.

The invention also relates to processes for the preparation of the above-defined compounds, pharmaceutical

Mn / 12/14/81

jzu ι ΰ ο /

-Jutian preparations based on these compounds and their production, and the use of these compounds as medicaments, in particular for treatment and Infectious disease prophylaxis.

C _1. Radicals can be straight or branched. Substituted C. .. -alkyl radicals can have the following substituents: fluorine, chlorine, bromine; a radical -S (O) -R 'with η = 0, 1, 2 and R' = C _1. , - alkyl; a radical -CO-R ¹ with R ¹ = hydroxy, C ₁ , -alkoxy, (^ - alkyl, amino, C _1. , - alkylamino or di-C _1. , - alkylamino; an amino radical -NR ¹ R " , where R ¹ and R "represent hydrogen or C _1. , - alkyl; or a radical OR ¹ with R ¹ == hydrogen, methyl, SO ₃ H, CH ₂ OCOR" (R "= Cj ^ -alkyl ).

1 2
Examples of R / R substituents are: methyl,

Ethyl, isopropyl, 3-chloropropyl, mesylmethyl, 2- (methoxycarbonyl) -ethyl, Hydroxymethyl, 1-hydroxyethyl, 1-hydroxypropyl, 1-hydroxy-l-methylethyl, 3-methoxypropyl, 1-sulfoxyethyl, l-hydroxy-2,2,2-trtfluoroethyl, l- (pivaloyloxymethoxy) ethyl, 1-aminoethyl.

The following are possible as substituents in the X radical:. 25th

C ₁ --Alkanoyloxy groups may be substituted by hydroxyl, C ₁ alkoxy, phenyl or C ₁ _ ₃ alkylthio.

Substituted C. _1-alkylthio radicals can carry one or more substituents R, where R may refer to:

Phenyl, which in turn can be substituted by one or more fluorine, chlorine or bromine atoms, C ₁ -C alkyl, C ₁ -C alkylthio, C -C alkanoyl, carboxyl or C ₁ alkoxycarbonyl groups; or by a group

- (CH ₉ ) -NRR ¹ or - (CH-) -NHCR = NR ¹ or - (CH ₀ ) -N = CR-N (R ') ", In Zn 2n

where η = 0, 1, 2, 3 and R and R 'H or C.., -

320 ^; "57

Is alkyl;

Fluorine, bromine;

an oxime or oxime ether residue = N-OR '(R' = H or C _1. , - alkyl) in the syn or anti position;

a 3-7-membered, monocyclic, saturated, unsaturated or aromatic heterocycle with 1-4 heteroatoms (N, O, S; which can be substituted by one or more fluorine, chlorine or bromine atoms, C _1. , - alkyl- , C ^ .- alkylthio, C ₁ -.- alkanoyl, carboxyl or C ₃ alkoxycarbonyl or a group - (CH ₃₎ -NRR ¹

or - (CH ,,) -NH-CR = NR ¹ or - (CH ₀ ) -N = CR-N (R ') _o , where η = 2 η Zn Z

Can be 0, 1, 2, 3, and R and R ¹ is H or C ₁ _ ₃ alkyl, as well as by oxo groups);

a C 1 -C cycloalkyl radical;

a radical -S (O) -R ¹ (with η = 1 or 2 and R ¹ = C, _-

η 1—3

Alkyl);

a radical -COR ¹ [ ^{where R 1} = C ₁ , -alkyl, phenyl, phenyloxy, benzyloxy, C ₃ _ _g -cycloalkyl or a 3-7-membered heterocycle with 1-4 heteroatoms (N, O, S), the can be substituted in the above manner.

Substituted phenylthio radicals can be substituted by one or more fluorine, chlorine or bromine atoms, one of the groups - (CH ₂ J _n -NRR ¹ , - (CH ₃ ) _n ~ NR-CR '= NR "and - (CH ₂ ) _n -N = CR-NR'R "(with η = 0, 1, 2, 3 and R, R ¹ and R" is H or C ₁ _ ₃ alkyl, c._ ~ ₃ alkanoyl) or by Ci ₃ -Alkyl, C._ ₃ -alkanoylamino, hydroxy, C.sub.3 -alkoxy or acyloxy groups.

C ₃ -Cycloalkylthio radicals can be substituted by one of the groups - (CH ₉ ) -NRR ¹ , - (CH ₉ ) -NR-CR '= NR "and - (CH ₂ J _n -N = CR-NR ¹ R" (with η = 0, 1, 2, 3 and R, R ¹ and

R "H or C ₁ , -alkyl, C. ^ - alkanoyl) or by oxo, hydroxy, C _{.. -Alkyl, C 1-4} -alkOXy, carboxyl or alkoxycarbonyl groups or by acyl radicals of an aliphatic or aromatic C.., - Carboxylic acid. ...

C _"fi -Alkenylthioreste may have 1 or 2 double bonds and be substituted by one of the groups

- (CH ₀ ) -NRR ¹ , - (CH ₀ ) "-NR-CR '= NR" and - (CH ₀ ) -N = CR-NR ¹ R "2 η 2 η Ζ η

(with η = 0, 1, 2, 3 and R, R ¹ and R "H or C ₁ _ ₃ -alkyl, c. -alkanoyl) or by C., ₃ -alkyl, phenyl, a 3-7- membered saturated, unsaturated or aromatic heterocycle with 1-4 heteroatoms (N, O, S); cyano, carboxyl, C.. -alkoxycarbonyl, aminocarbonyl or acylamino.

H.eterocyclylthio radicals are preferably 4-7 membered and monocyclic and can be saturated, unsaturated or aromatic. They preferably contain 1-4 heteroatoms (N, 0, S). They can be substituted one or more times by fluorine, chlorine or bromine, an oxo- or imino-

'20 group or a Cg-alkyl, C ₁ ~ ₃ alkylthio, hydroxyl, cyano, N-oxido, trifluoromethyl, C. _1-alkoxy, C. _{1-alkanoyloxy,} phenyloxy, C. _1-alkanoyl , Phenoxycarbonyl, .pivaloyloxymethoxycarbonyl, carbamoyl, C _1. , - alkylcarbamoyl or di-C ₁ --alkylcarbamoyl radical or by - (CH ₂ J _n -NNR ¹ , - (CH ₂ ) _n -NR-CR '= NR "or - (CH ₂ J _n -N = CR-NR ¹ R" with η = 0, 1, 2, 3 and R, R ¹ and R "= H, 'C _{1 3} ~ alkyl, C _{1 3} - Alkanqyl; or by - (CH ₀ ) COR ¹ with η = 0, Γ, 2, 3 and R '= hydroxy, C _1-3 -AlkOXy, Amino' or -NH- (CH ₂ ) _{m -NH 2} , in which m = 2, 3, 4 '; or by - (CH ₀ ) OH with η = 0, 1,

2, 3. · "·

Examples of radicals X are: 2- (acetylamino) vinylthio, (1-methyl-1H-tetrazol-5-yl) -thio, (1, 4, 5, 6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl) -thio, (2,5-dihydro-6-hydroxy-2-methyl-5-oxQ-as-triazin-3-yl) thio, (1-ethyl, 2-dihydro-2-oxo-4-pyrimidinyl) thio, (5-methyl-1,3,4-thiadiazol-2-yl) -thio, Acetoxy.

3 2 O 1 ^r 5 7

Λ -,

Easily hydrolyzable esters of the compounds of the formula I are to be understood as meaning those esters which in particular be cleaved under physiological conditions. Examples of such esters are the lower alkanoyloxyalkyl esters, e.g. the acetoxymethyl, pivaloyloxymethyl, 1-acetoxyethyl and 1-pivaloyloxyethyl esters; the lower ones Alkoxycarbonyloxyalkyl esters such as the methoxycarbonyloxymethyl, 1-ethoxycarbonyloxyethyl and 1-isopropoxycarbonyloxyethyl esters; the lactonyl esters, e.g. the phthalidyl and thiophthalidyl esters; the lower alkoxymethyl esters, e.g. the methoxymethyl ester; and the lower alkanoyl amidomethyl esters, e.g., the acetamidomethyl ester; the benzyl and cyanomethyl esters, as well as the (2-oxo-1,3-dioxol-4-yl) methyl esters.

Examples of salts of the compounds of formula I are alkali metal salts such as the sodium and potassium salts; the ammonium salt; Alkaline earth metal salts such as the calcium salt; Salts with organic bases, such as salts with amines, e.g. salts with N-ethyl-piperidine, procaine or N, N'-dibenzylethylenediamine, as well as salts with amino acids, such as salts with arginine or lysine. The salts can be mono-, di- or Be trisalts. In addition to the carboxyl group in the 2-position, the salt formation can also take place on one for salt formation capable group of a substituent.

The compounds of the formula I can also form addition salts with organic or inorganic acids. Examples of such salts are hydrohalides, for example Hydrochloride, Hydrobromide, Hydroiodide, as well as others Mineral acid salts, e.g. sulfates, nitrates, phosphates and the like, alkyl and monoaryl sulfonates, such as ethanesulfonates, Toluenesulfonates, benzenesulfonates and the like. And salts with other organic acids such as acetates, tartrates, maleates, citrates, benzoates, salicylates, ascorbates and the like.

AZ

Finally, the compounds of the formula I (including the salts and esters) can be hydrated. The hydration can occur in the course of the manufacturing process occur or occur gradually as a result of the hygroscopic properties of an initially anhydrous product.

The compounds according to the invention can thereby getting produced; that you can get a compound of the formula

Il

COOR3

1 2
wherein R, R and X are as defined in claim 1,

3 4 5

R is an easily cleavable radical and R, R and RC represent ₁ -alkyl, phenyl or p-methoxyphenyl, cyclized, splitting off any protective groups present in a substituent and, if desired, transesterifying the ester obtained, if necessary by splitting off the radical. R is converted into the free acid or its salt and, if necessary, a product obtained is converted into a hydrate.

The cyclization of a compound · II can be carried out in a manner known per se, preferably in an inert organic solvent, for example ethyl acetate. Benzene, toluene, xylene, dioxane, at temperatures between approx. 50 ^° C. and 150 ^° C., are carried out.

By splitting off the radical R from the ester group in a manner known per se, the corresponding free Acids or their salts of the formula I are obtained. An easily cleavable radical R is to be understood as meaning groups which an ester cleavage under mild conditions, in particular reductive (e.g. hydrogenolytic) or hydrolytic (e.g.

3 201 ') 5 7

enzymatic). Examples of suitable radicals R are benzyl (where the phenyl ring is replaced by halogen, nitro, Alkoxy or acyloxy may be substituted), preferably o- and p-nitrobenzyl or p-methoxybenzyl, benzhydryl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-iodoethyl, 2-trimethylsilylethyl, Acetonyl or allyl. The residues R also include residues that can be cleaved under physiological conditions Esters in question as they are easily hydrolyzable esters have already been mentioned above.

• The conversion of free acids of the formula I or their salts into easily hydrolyzable esters can be carried out in a manner known per se, for example by reaction with a reactive esterification reagent, such as a compound X-CH ₂ -O-CO-R or

or
20th

where X can be bromine, iodine or another leaving group, R a straight or branched-chain C _1. -alkyl radical and R ^{1 can be} hydrogen or a customary substituent.

A transesterification is expediently carried out via the free acid.
30th

Of course, by means of generally known reactions, a substituent of a compound I can also be used in the context of the given definitions can be modified.

The compounds of the formula I are generally not isolated as free acids, but in the course of the preparation and purification processes are obtained directly as their salts and hydrates of these salts, respectively. Here can

-JZU Γ. ■ · / AH

Salt formation can also take place at any substituent capable of salt formation which may be present, for example a hydroxyl or amino group. It is also possible that a basic group in a substituent, for example an amino or an amidino group, forms an inner salt with an acidic group, for example the carboxyl group in the 2-position. Salting can be carried out by techniques known per se at temperatures of preferably 0 to 25 ^° C. in a solvent such as water, ethanol, methanol, acetone, ethyl acetate or mixtures thereof, and the products can be purified by crystallization or chromatography.

Hydrates are mostly obtained automatically in the course of the manufacturing process or as a result of the hygroscopic properties of an initially anhydrous product. Gezielte.n for the manufacture of a hydrate, a completely or partially anhydrous product can be a moist atmosphere, be exposed at about +10 ⁰ C to +40 ⁰ C, for example. . .

The compounds of the invention are generally obtained in a mixture with their optical antipodes, i.e. as 5R / 5S mixtures. Is it l: l mixtures, the stereochemistry of the products is determined by the designation rac- (5RS, etc.) indicated, for example pivaloyloxymethyl-rac- (5RS, 6SR) -6 - [(RS) -1-hydroxyethyl] -3 - [[(l-methyl-lH-tetrazole-5- yl) thio] methyl] -7-oxo-lazabicyclo [3.2.0] hept-2-en-2-carboxylate. If, however, inaccurate 1: 1 mixtures are obtained, as is the case with products from enantioselective reactions, for example from enzymatic reactions Stereochemistry by the designation (5R, etc. and 5S, etc.) characterized, for example sodium (5R, 6S and 5S, 6R) -. 6-hydroxymethyl-3 - [[(1-methyl-1H-tetrazol-5-yl) -thio] -methyl] -7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate.

32C-57

However, the present invention includes not only these mixtures, but in particular also the pure 5R forms. The 5R / 5S mixtures can be split into the pure 5R or SS forms using one of the classic methods, expediently at a preliminary stage. For example, a diastereomeric salt pair of a racemic compound XI or a pair of diastereomeric derivatives of a compound VIII-I are separated. The resolution can also the steps of compounds XI, X, VIII or VII are carried out.

A special subgroup of the compounds according to the invention are compounds of the formula

CHo-X

Yes

COOH

where X means the same as above,

and their easily hydrolyzable esters, pharmaceutically acceptable salts and hydrates of these compounds.

Particularly preferred are compounds in which the configuration at the centers 5, 6 and in substituents of 6-position corresponds to those of natural thienamycin, for example sodium- (5R, 6S) -6 - [(R) -I-hydroxyethyl] -3- [ C (1-methyl-1H-tetrazol-5-yl) -thio] -methyl-1-T-oxo-1-azabicycloCB.Z.0] hept-2-en-2-carboxylate.

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AU

Reaction scheme

.EtOOC

XIV

OHC

XIII

EtOOC

XII

EtOOC

XI

O 'Ό

-NH

In WW

Si

{-1

IX-I

VIII-I

VII

3201: ".-I

Reaction scheme (cont.)

Λ φ »#

COOR ³

COOR ³

I 3

COOR ³

VII

VI IV

R ¹ ....

H ·

-N

COOR ³

- ^, II

ό / LU

At \ y /

The starting compounds II can be prepared by the Reaction sequence shown in the scheme can be obtained.

Reduction of 3,3-Ethylendioxybuttersäure ethyl ester (XIV) with diisobutylaluminum hydride in hexane / tetrahydrofuran at -80 ⁰ C to. -60 ⁰ C provides 3,3-ethylenedioxybutyraldehyde (XIII), which by reaction with, for example, Phos-'phonoessigsäure-triethyl ester in a mixture of methylene chloride and 28% sodium hydroxide solution in the presence of benzyltriethylammonium chloride in an E / Z mixture of 5.5 -Ethylenedioxy-2-hexenoic acid ethyl ester (XII) can be converted. The ethyl 3-amino-5,5-ethylenedioxy-caproate (XI) can be obtained by adding ammonia under normal pressure or elevated pressure (autoclave) to the unsaturated ester XII, the E and Z isomers being equally suitable . The reaction is preferably carried out in alcohol saturated with ammonia at a temperature between 20 ^° C. and 100 ^° C. Cyclization of XI to 4- (2,2-ethylenedioxypropyl) -2-azetid.ihon (X) can be carried out in a manner known per se, for example by reaction with trimethylchlorosilane in the presence of triethylamine and subsequent treatment with 1 equivalent of ethyl magnesium bromide.

1 2

The introduction of a substituent R or R into the

The 3-position of the azetidinone may X VIII to form a compound in a conventional manner by reacting the dilithium salt intermediate IX (generated from X with 2 equivalents of an alkyl lithium compound such as butyl lithium _r, in tetrahydrofuran at -20 ⁰ C to +20 ⁰ C ) take place with a corresponding electrophilic reagent, conveniently under a protective gas, at a temperature between -100 ⁰ C and + 5O ⁰ C. An alternative method for introducing the substituents R and R in the 3-position of the azetidinone ring of a compound X consists in first adding the β-lactam hydrogen through a trialkylsilyl group, for example the tert-butyldimethylsilyl group

320: ^c -7

• β

replace (by reacting a compound X with tert-butyldimethylchlorosilane in dimethylformamide, in the presence of triethylamine) and that by reacting the silyl compound X-I with 1 equivalent of a strong base, e.g.

with lithium diisopropylamide in tetrahydrofuran at low temperature (-78 ⁰ C), the lithium salt formed as an intermediate IX-I with an electrophilic reagent in the reaction IX - implement> VIII analogous manner. The compound VIII-I obtained can then either be brominated directly to give a compound VII

"IO or initially by splitting off the silyl group (e.g. using tetrabutylammonium fluoride in tetrahydrofuran) into 4- (2,2-ethylenedioxypropyl) -2-azetidinone (VIII) be transferred. In the course of the described introduction

1 2
of a substituent R or R, cis / trans mixtures (with respect to the 4-ethylenedioxypropyl radical) are usually obtained which, if desired, can be separated using customary separation methods, for example chromatography on silica gel, fractional crystallization or distillation.

J Z U ι: O /

An alternative synthesis of compounds VII is illustrated in Example 22:

XV

XVI

XVIII

LiO

XVII

R ² H

OR ¹

VII

% λ 'y} λ \ *

It may be useful to have functional groups that

1 2
are introduced with the substituents R or R, to be kept in protected form during the further synthesis. Such functional groups can in particular be the hydroxyl, the amino or the carboxyl function. The protective groups known for these functions can be used, provided that they can be removed at a suitable point in the synthesis. The functions masked by protective groups can already be contained in the electrophilic reagent reacted with the dilithium salt IX or the lithium salts IX-I or XVII. On the other hand, it can be useful to use functions that are only available at

1 2 the introduction of the substituents R and R arise, e.g.

a hydroxyl function, then to protect.

A bromine ketal of the formula VII is obtained by bromination of a compound VIII with bromine in an alkanol R ¹ OH as solvent. In this reaction (preferably in methanol or ethanol at a temperature between

² ^ 10 ⁰ C and 60 ⁰ C) a transketalization takes place: the 'ethylenedioxy group is converted into a dialkoxy group. As already mentioned above, a silyl compound of the formula VIII-I can also be used in the bromination reaction, since the silyl group is split off under the reaction conditions.

■ The esters of the general formula VI can according to general known methods are prepared from the azetidinones of the formula VII, for example by reaction with Glyoxyl esters of the general formula OHC-COOR or their hemiacetals. In this case the two reaction partner conveniently heated to the boiling point in an inert solvent such as benzene or toluene and the low molecular weight reaction products formed (water and alcohol) are distilled off azeotropically from the reaction solution.

'32WW -.:/

However, it is also possible to first convert compounds of the formula VII with glyoxylic acid monohydrate to one of the esters VI corresponding acid (R = H) to implement and then this to esterify with a suitable alkylating agent in the presence of a base. The reaction with glyoxylic acid monohydrate takes place, for example, in dimethylformamide at room temperature in the presence of a water-binding agent By means of, e.g., a molecular sieve. By successive addition of a base, e.g. potassium carbonate or triethylamine, and an alkylating agent such as iodomethyl pivalate, then the carboxylate group (R = e.g. K or triethylammonium) esterified in situ.

An ester V is obtained by reacting an ester VI with thionyl chloride in an inert organic solvent such as tetrahydrofuran, in the presence of a base, for example pyridine or 2,6-lutidine, at temperatures between -30 ⁰ C and +20 ⁰ C, the with a tri-substituted one

4 5 6
Phosphine PR RR, most advantageously with triphenylphosphine, in a manner known per se, ie in an aprotic solvent (for example dioxane, tetrahydrofuran, dimethylformamide), at a temperature between 0 and

4 5 6

60 ⁰ C, is converted into the R, R, R -substituted phosphorane IV. The free ketone of the formula III is obtained from this ketal by acid hydrolysis under the usual reaction conditions, for example with aqueous sulfuric, phosphoric, hydrochloric or hydrobromic acid in an organic solvent such as acetone, dioxane, ethanol. By adhering to low temperatures (-10 ⁰ C to 0 ⁰ C) can be avoided unwanted side reactions such as hydrolysis of the phosphorane, ·.

It is also possible to cleave the ketal function under anhydrous conditions by being in the presence an acidic catalyst transfers the protecting group to another ketone, e.g. acetone.

3 2 G 1 ε 5 7

<23

Finally, the bromoketones of the formula III are formed with the compounds II containing the group X. Compounds implemented that are a nucleophile. Contain oxygen or sulfur atoms. The implementation can be in an inert organic solvent, e.g.

Methylene chloride, ethyl acetate, dimethylformamide, dimethyl sulfoxide, acetonitrile or ethanol take place at temperatures from -80 ⁰ C to the reflux temperature of the reaction mixture, preferably between -20 ⁰ C and +40 ⁰ C. The hydrogen bromide released during the reaction is expediently replaced by a weak , non-nucleophilic organic base, such as a trialkylamine or amidine, or an inorganic base (sodium or potassium carbonate).

The compounds according to the invention are effective against gram-positive and gram-negative bacteria, for example against staphylococci, streptococci, salmonella and Escherichia coli, and act as ß-lactamase inhibitors.

Antibacterial activity in vitro

The table below shows the minimum inhibitory concentrations (MIC) of some representative compounds of formula I against a number of pathogenic microorganisms.

32UlUbV

• «» * »Crf ·«

* »« According to M> * for β *

Acinetobacter
anitr. 51-156 3 Ve MIC (uq / ml) .ndung au
9 , 05 s example]
19th , 06 Lei ! 3 organism 5 12th rba
7th 0 _ 0 , 25 0 2, E. coli 1346 - > 50 , 5 , 05 0 , 25 25922 _ > 100 0 /1 0 , 25 0 2 ¹¹ TEM I * _ _ 0 , 05 0 , 12 0 2 1527 E * _ _ . 0 ,1 0 , 12 0 1 Klebs. pneumoniae 418 * _ 0 t ² 0 , 25 0 4th Prot. Vulgaris 1028 * _ _ 0 , 4 0 ο * 8th Prot. Mirabilis 2117 * 0 1 ,1 O, 8th Prot. Mirabilis 29H _ > 100 1 _ 2 _ 24 Strept. faecalis 6 0 <6 , 025 , 12 Strept. pyoqenes ßl5 1 ä6 0 , 05 0 , 12 4th Staph. aureus 6538 > 40 <6 0 > 8 0 , 5 O, 8th ". 887 * > 40 > 100 0 , 6 8th 1, 5 Serratia marcescens
803/15 * > 100 1 , 4 17th , 5 3 Serratia marcescens
69438 - > 100 0 .6 0 6th Klebs. aerogenic 1082E * > 100 1 , 2 17th 12th Enterobacter
cloacae 908 * > 100 3 , 05 34 , 06 3 Enterobacter
cloacae 13047 * - 25th 0 0 Of 2 Salmonella typh. BA - _ 25th > 34 > 2 4 Pseudomonas aer. 1559E * - > 100 .2 5 , 6 > 34 , 5 > 2 4 '.BA * _ 1 8th ° r 8th

* ß-lactamase producing organism '

The compound from Example 7 was tested on DST agar + 7.5% blood, the rest on DST agar. (Diagnostic 35 Sensitivity Test Agar) alone.

3201357

¹ 1 * I 1 · · · »

Antibacterial activity in vivo

The compounds from Examples 6. 7 and 9 were tested in vivo for their antibacterial activity (ED ₅₀ ) against 5 systemic mouse infections. The preparations were applied twice (1 and 3 hours after infection).

6th ED _5C j (mg / kg ) Be ispiel
9 SC infection 8.3 Loss binding
7th the end 2.1 SC Escherichia coli 1346 10
50 SC > 25 SC O. <3 SC Streptococcus pyogenes
B15 > 25 SC
po 12.5
> 12 SC
P- 17th Proteus mirabilis 2117 > 25 SC - - Serratia marcescens
69438 SC -

β-lactamase inhibition

The ß-lactamase inhibitory effect (IC ₁₅₀ ; nitrocefin as substrate) of the compound from Example 9 against various ß-lactamases is as follows:

enzyme IC ₅₀ (µg / ml) ■ E. coli 1024
K. pneumoniae NCTC 418
P. vulgaris 1028
E. coli RTEM 0.191
0.063
0.0005
0.035

- ¹ mi

The compounds according to the invention can be used for the prophylaxis and therapy of infectious diseases will. For adults, a daily dose of about 0.05 g to about 4 g, in particular about 0.1 g to about 2 g. Parenteral administration is particularly preferred.

The products according to the invention can be used as medicaments, for example in the form of pharmaceutical preparations which contain them or in particular their salts in a mixture with a pharmaceutical, organic or inorganic inert carrier material suitable for enteral or parenteral administration, such as water, gelatin, gum arabic , Lactose, starch, magnesium stearate, talc, vegetable oils, petroleum jelly, etc. The pharmaceutical preparations can be in solid form, for example as tablets, coated tablets, suppositories, capsules; or in liquid form, for example as solutions, suspensions or emulsions. If necessary, they are sterilized and / or contain auxiliaries such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure, anesthetics or buffers. They can also contain other therapeutically valuable substances. The compounds of formula I and their salts or hydrates are preferably used for parenteral administration and for this purpose are preferably made available as lyophilizates or dry powders for dilution with customary agents such as water or isotonic saline solution. The slightly hydrolysed _T sierbaren esters of compounds of formula I and their salts and hydrates come into consideration for enteral administration.

The preparations can contain the compounds according to the invention in amounts of about 25-1000 mg, preferably 50-500 mg, per single dosage form.

32C1S57

example 1

A solution of 385 mg of pivaloyloxymethyl-rac-2- [3 - [(1-ethyl-1,2-dihydro-2-oxo-4-pyrimidinyl) -thio 3-acetonyl] -4-oxo-α- (triphenylphosphoranylidene) -l-azetidine acefate in 50 ml of toluene was refluxed for 1 hour under an argon atmosphere. The clear solution was cooled, diluted with a little ethyl acetate and in vacuo freed from solvent. The residue was chromatographed on silica gel with ethyl acetate as the eluent. The parliamentary groups which contained the product were concentrated and the remaining oil was crystallized from ethyl acetate / hexane. 55 mg of pivaloyloxymethyl-rac-3-C -C (I-ethyl-1,2-dihydro-2-oxo-4-pyrimidinyl) -thio were obtained 1 ~ methyl] -7-oxo-1-azabicycloC3.2 · 0] hept-2-ene-2-carboxylate as yellow crystals with a melting point of 141-143 ° C.

IR (CHCl3,): O 1785, 1750, 1736, 1659, 1622, 1614 cm " ¹ j max

" The starting material was made as follows:

(a) A solution of 348.4 g of 3,3-ethylenedioxy-butyric acid in 2 1 of hexane and 0.2 1 of tetrahydrofuran was added within 90 minutes at a temperature of -70 ⁰ C to -67 ⁰ C and 1.79 1 of a 1.1ZM solution of diisobutylaluminium hydride in hexane is added. The clear reaction solution was left for hours at -75 ⁰ C and then within 2 minutes with 100 ml of methanol. The cooling bath was then removed and a solution of 100 ml of glacial acetic acid in 100 ml of hexane was added within 8 minutes. The reaction mixture was then warmed within 10 minutes to -20 ⁰ C and then treated within 00 minutes with 2 ml of saturated ammonium chloride solution. The temperature of the reaction solution was allowed to within 10 minutes 0 ⁰ C rise, and stirring was for 15 minutes at 0-3 ⁰ C. Then was suction filtered from the precipitate and the filter cake with 600 ml methylene chloride washed · The filtrate was washed with 300 ml of saturated sodium chloride solution, again oin precipitate formed.

JZU \ ... JI

^ * Λ. ti W *

The mixture was suction filtered again, the filtrate was separated and the organic phase was washed with a further 300 ml of saturated sodium chloride solution. The nutsch residue was extracted with a total of 1.8 l of methylene chloride and the extracts were washed with the sodium chloride solutions. The organic phases were dried over sodium sulfate, the solvent was removed under reduced pressure and the remaining oil was distilled in a water-jet vacuum. The fraction boiling between 40 and 95 ^° C. was then fractionated over an 80 cm long Vigreux column. 184 g of 3,3-Ethylendioxybutyraldehyd was obtained from _{1 L} 70-73 ⁰ C.

NMR (CDCl ₃ ): 6 1.43 (s, 3H); 2.73 (d, J = 3 Hz, 2H); 4.00 (s, 4H); 9.75 (t, J = 3 Hz, IH) ppm, ·

(b) A ^{mixture, precooled to 0 °} C., of 300 ml of 28% strength aqueous sodium hydroxide solution and 600 ml of methylene chloride was admixed with a solution of 130.1 g of 3,3-ethylenedioxybutyraldehyde, 22 4.2 g, with vigorous stirring within 25 minutes Triethyl phosphonoacetate and 7.4 g of benzyltriethylammonium chloride in 540 ml of methylene chloride, the temperature rising ^{to 15 ° C.} It was allowed to ^{warm up to 20 °} C. within 10 minutes and stirred for a further 30 minutes at this temperature. It was then diluted with 400 ml of methylene chloride and 400 ml of water and the phases were separated in a separating funnel. The organic phase was washed neutral twice with 400 ml of water each time and the aqueous phases were extracted with 300 ml of methylene chloride. The organic phases were dried over sodium sulfate and concentrated completely and the remaining oil was fractionated over a 50 cm long Vigreux column. After a forerun, 179 g of ethyl 5,5-ethylenedioxy-2-hexenoate were obtained with a bp. _{Q 2} 70-76 ⁰ C as E / Z mixture (ratio approx. 6: 1).

NMR (CDCl ₃ ): signals of the Ε isomer: δ 1.28 (t, J = 7 Hz, 3H); 1.33 (s, 3H); 2.53 (d, J = 7.5 Hz, 2H); 3.93 (s, 4H); 4.16 (q, J = 7 Hz, 2H); 5., 85

3201Γ57

3-θ -

(d, J = 16 Hz, IH); 6.92 (dxt., J = 16 and 7.5 Hz, IH) ppm

Signals of the Z isomer: inter alia δ 3.03 (d, J = 6.5 Hz, 2H); 5.83 (d, J = II, 5 Hz, 1H);

6.30 (dxt, J = II, 5 and 6.5 Hz, IH) ppm

(c) A solution of 200.2 g of ethyl 5,5-ethylenedioxy-2-hexenoate (approx. 6: 1 E / Z mixture) in 2 1 abs. Ethanol

Approx. 250 g of ammonia gas were initially injected into a stirred autoclave and the pressure was then brought to 20 bar with nitrogen. The reaction mixture was ^{heated to 70 °} C. for 40 hours. The cooled reaction solution was freed from the solvent, 200 ml of ether were added and again concentrated completely. The remaining oil was taken up in 275 ml of ether and allowed to stand for 2 hours at 0 ⁰ C. Rac-3-amino-5,5-ethylenedioxycaproamide which had crystallized out was separated off by filtration. The concentrated filtrate was taken up in 600 ml of ether / hexane (1: 2, v / v) and the solution was extracted 4 times with 200 ml of water. The individual extracts were washed twice with 300 ml of ether / hexane (1: 2, v / v). The combined water phases were saturated with sodium chloride and extracted with a total of 750 ml of methylene chloride. The methylene chloride extract was dried over sodium sulfate and concentrated completely. Distillation of the remaining ÖIS in a high vacuum yielded 131 g of pure rac-3-amino-5,5-ethylendioxycapronsäure ethyl ester of boiling point. _"3 95-100 ⁰ C.

NMR (CDCl ₃ ): 6 1.28 (t, J = 7 Hz, 3H); 1.38 (s, 3H); 1.74

(broad s, 2H); 1.76 (d, J = 6 Hz, 2H);

2.05-2.72 (m, AB part of ABX system, 2H);

3.21-3.72 (m, 1H); 3.98 (s, 4H); 4.13

(q, J = 7 Hz, 2H) ppm
35

JZU ISO

2-4-

(d) To a solution of 108.6 g of ethyl rac-3-amino-5,5-ethylenedioxycaproate in 330 ml of ether, 54.3 g of trimethylchlorosilane and immediately thereafter 50 were added dropwise with stirring at 0-5 ° C , 6 g of triethylamine, a thick precipitate forming. The reaction mixture was allowed to ^{warm up to 15 °} C. within 30 minutes with stirring and then to stand at room temperature for 24 hours. Then, with the exclusion of moisture, it was sucked off through a filter and reaction

^ O vessel and filter residue washed with a total of 150 ml of ether. The filtrate was added within 40 minutes at 0-5 ⁰ C with 290 ml of a 1,92m ethylmagnesium bromide / ether solution was added, and there was gas evolution. The heterogeneous reaction mixture was stirred for 16 hours at room temperature. Then was cooled to 0 ⁰ C and added dropwise to 170 ml of half-saturated ammonium chloride solution at a temperature of 0-10 ⁰ C, w.obei a thick precipitate formed. By adding approx. 180 ml of 3N hydrochloric acid, the pH of the reaction mixture was lowered to about 7, with most of the precipitate going into solution. The water phase was separated off and the organic phase was extracted twice with 200 ml of water. The water phases were combined, ^{saturated with sodium chloride at 0 °} C. and extracted 4 times with 500 ml of methylene chloride each time. Die.Methylenchloridextrakte were dried over sodium sulfate and completely concentrated. To separate off polar by-products, the remaining oil was filtered through 200 g of silica gel, eluting with ethyl acetate. Crystallization of the eluate from which the solvent has been removed

³ ^ ether / hexane provided 49.6 g of pure rac- 4- (2,2-ethylene-. Dioxypropyl) -2-azetidinone, mp 43-45 ° C.

IR (CHCl ₃ ): £> _max 1756 cm " ¹

"■ '

3201 ^C 57

- 2 * 5 -

(e) A solution of 3.42 g of rac-4- (2,2-ethylenedioxypropyl) -2-azetidinone in 36 ml of methanol was admixed with 4 ml of an 1M solution of bromine in methanol at room temperature. The reaction ^{solution was heated to 50 °} C. for 3 minutes, with discoloration occurring. A further 16 ml of 1M solution of bromine in methanol were then added dropwise within 8 minutes and at the same time the reaction solution was cooled to 33 ° C. The mixture was stirred at this temperature for a further 24 minutes and the pale yellow reaction solution was then added to a mixture of 30 ml of saturated sodium carbonate solution , 10 ml 0.1 IN sodium thiosulphate solution and ice. It was extracted with a total of 200 ml of methylene chloride. The organic phases were washed with sodium chloride solution, dried over sodium sulphate and completely concentrated in vacuo. The remaining oil was on silica gel with ethyl acetate / hexane (2: 1, v / v) as eluent, the fractions containing the product were concentrated and the residue was crystallized from ethyl acetate / hexane, giving 2.03 g of rac-4- (3-bromo-2,2-dimethoxypropyl) -2-azetidinone from smp.

94-95 ° C.

(f) A solution of 6., 30 g of rac-4- (3-bromo-2, 2-dimethoxypropyl) -2-azetidinone and 2.58 g of glyoxylic acid monohydrate in 17 ml of dimethylformamide was mixed with 3 g of molecular sieve 4A and stirred for 5 hours under argon at room temperature. Then 2.07 g of solid potassium carbonate were added and the mixture was stirred for a further 30 minutes. The reaction mixture was cooled to 0 ⁰ C, treated with a solution of 6.8 g of iodomethyl pivalate in 6 ml of dimethylformamide, and then stirred for 1 hour at room temperature. The reaction mixture was diluted with 100 ml of ethyl acetate and 30 ml of ether and then washed 3 times with 50 ml of water each time. The organic phase was dried over sodium sulphate, concentrated completely and the remaining oil on silica gel with ethyl acetate / hexane (2: 1, v / v) This gave 3.3 g of pivaloyloxymethyl-rac-2- (3-bromo-2,2-dimethoxypropyl) -a-hydroxy-4-oxo-1-azetidine acetate (mixture of diastereomers) as an oil.

~ ό ζ υ ι y ö /

IR (CHCl _3): "^ max ^3528, 1760 cm" ¹

Rf: 0.37 / 0.43 (double spot; SiO ₃ , ethyl acetate / ■

Hexane 2: 1, ν / ν)

(g.) To a solution of 3.2 g of pivaloyloxymethyl-rac-2- (3-bromo-2,2-dimethoxypropyl) -a-hydroxy-4-oxo-1-azetidine acetate in 6.0 ml of tetrahydrofuran were added at -23 ° C added 1.02 g of 2,6-lutidine. Then, within 1 minute trains dropwise a solution of 1.04 g of thionyl chloride in 11 ml of tetrahydrofuran, the temperature being maintained by cooling below -20 ⁰ C. The reaction mixture was stirred for 20 minutes at -20 ⁰ C and then 20 minutes at room temperature. The precipitate was then filtered off with suction and the material on the filter was washed with 40 ml of toluene. The filtrate was completely concentrated in vacuo, the residue was taken up in 20 ml of toluene and again completely concentrated.

The oil obtained was in 2 2 ml of dimethylformamide dissolved at room temperature with a solution of 2.44 g Triphenylphosphine in 7 ml of dimethylformamide was added and the solution was left to stand for 1 hour. Then was in a high vacuum at a temperature of 30 ° C most of the solvent is removed, the remaining oil in 70 ml Methylene chloride was added and the solution was washed twice with 50 ml of pH 7 phosphate buffer each time. The water phases were extracted with 100 ml of methylene chloride, and the combined organic phases were dried over sodium sulfate and completely constricted. The remaining oil was chromatographed on silica gel, initially with The excess triphenylphosphine and methylene chloride. then the product was eluted with ethyl acetate. The parliamentary groups which contained the product were concentrated. ■ 3.2 g of pivaloyloxymethyl-rac-2- (3-bromo-2,2-dimethoxypropyl) -4-oxo-a- (triphenylphosphoranylidene) - 1-azetidine acetate as a colorless, amorphous material.

IR (CHCl ₃ ):. "^ _7n ,,, 1741, 1635 cm" ¹

3201857

. (h) A solution, cooled to 4 ° C., of 3 g of pivaloyloxymethyl-rac-2- (3-bromo-2,2-dimethoxypropyi) -4-oxo-α- (triphenylphosphoranylidene) -l-azetidine acetate in 115 ml of acetone was used was added dropwise to 38 ml of ^{48% hydrobromic acid precooled to 4 °} C. within 2 minutes, the temperature of the reaction mixture rising ^{to 2.0 ° C.} It was cooled to 4 ^° C. within minutes and stirred at this temperature for a further 10 minutes. The colorless solution was then poured onto 27.6 g of sodium carbonate, 90 ml of 0.6M pH 7 phosphate buffer solution and 50 g of ice and the mixture was extracted 3 times with 100 ml of methylene chloride each time. The organic phases were washed with 80 ml of pH 7 phosphate buffer solution, dried over sodium sulfate and concentrated completely. The resulting oil was chromatographed on silica gel, eluting with ethyl acetate. The fractions which contained product were concentrated and hexane was added. This gave 2.03 g of pure pivaloyloxymethyl-rac-2- (3-bromacetonyl) -4-oxo-a- (triphenylphosphoranylidene) -lazetidinacetat as white crystals of mp. 117-118 ⁰ C.

IR (CHCl ₃ ): - ~ ^ _max ¹⁷⁴⁵ '1640 cm " ¹

(i) 447 mg of pivaloyloxymethyl-rac-2 - (- 3-bromoacetonyl) -4-oxo-a- (triphenylphosphoranylidene) -1-azetidine acetate and 114 mg of 1-ethyl-4-thiburacil were in 20 ml of methylene chloride dissolved and the solution within 10 minutes at a temperature of 50 ° C under reduced pressure constricted. The residue was dissolved in 20 ml of methylene chloride and the solution under the same within 10 minutes Conditions narrowed. This procedure was repeated again, then the remaining oil in 50 ml of methylene chloride added and the yellow solution successively with dilute sodium hydrogen carbonate solution and sodium chloride solution washed. The water phases were extracted with methylene chloride, the combined organic Phases dried over sodium sulfate and completely constricted. Chromatography of the remaining oil on silica gel with acetone / methylene chloride (1: 1, v / v) as the eluent

3 / ü

- a-e -

gave 427 mg of pivaloyloxymethyl-rac-Z-CS-C (1-ethyl-1 _/ 2-dihydro-2-oxo-4-pyrimidinyl) -thio] -acetonyl] -4-oxo-a- (triphenylphosphoranylidene) -l- azetidine acetate as yellow

OeI.
5

IR (CHCl ₀ ): "^" 1741, 1660 cm " ¹ 'j max

Example 2

2 75 mg pivaloyloxymethyl-rac-2- (3-acetoxyacetonyl) -4-oxo-a- (triphenylphosphoranylidene) -l ~ azetidine acetate were cyclized according to the procedure described in Example 1. It was obtained after purification by chromatography of the crude product about 150 mg pivaloyloxymethyl-rac-3 - '^ (acetoxymethyl) -7-oxo-1-azabicyclo !! 3. 2.-0] hept-2-en-2-carboxylate as a colorless oil.

IR (CHCl,): £> 1789, 1749, 1635 cm " ¹ j max

The starting material was prepared as follows:

A solution of 383 mg of pivaloyloxymethyl-rac-2- (3-bromoacetonyl) -4-oxo-a- (triphenylphosphoranylidene) -1-aceti— Dinacetat in 9 ml of dimethylformamide was mixed with 54 mg of sodium

. Acetate and the reaction mixture for 16 hours stirred at room temperature. It was then diluted with 50 ml of methylene chloride and the solution successively with water and washed saturated sodium chloride solution. The water phases were extracted with methylene chloride

combined organic phases dried over sodium sulfate and concentrated completely. The resulting oil was filtered through silica gel to remove polar material, eluting with ethyl acetate. The pure substances were concentrated completely and the remaining material was crystallized from ethyl acetate / hexane. This gave 314 mg? Ivaloyloxymethyl-rac-2- (3-acetoxyacetonyl) -4-oxo-a- (triphenylphosphoranylidene) -1-azetidinacetat of mp. 139-141 ⁰ C.

3201337

IR (CHCl,): O 1741, 1637 cm " ¹ 3 max '

Example 3

A 0.05M pH 7 phosphate buffer solution was prepared by adding 1N sodium hydroxide solution to an aqueous sodium dihydrogen phosphate solution. 168 mg of sodium hydrogen carbonate and 0.3 ml of a suspension of pig liver esterase EC 3.1.1.1 (approx. 300 units) in 3.2M ammonium sulfate solution were added successively to 40 ml of this solution. The clear solution was heated to 36 ° C. and treated with a solution of 102 mg of pivaloyloxymethyl-rac-3- (acetoxymethyl) -7-oxo-1-azabicyclo C3.2.0] -hept-2-ene-2-carboxylate while stirring added in 1.5 ml of dimethyl sulfoxide. The mixture was stirred for 30 minutes at 36 "C ₁ , and the reaction mixture was extracted 4 times with 40 ml of ether each time. The ether phases were back-extracted with 10 ml of water, the combined water phases were filtered and the pH of the filtrate was added with 0.1N hydrochloric acid 7.06 set.

This solution contained a mixture of about 28 mg of sodium (5R and 5S) -3- (acetoxymethyl) -7-oxo-1-azabicyclo [3.2.03-hept-2-en-2-carboxylate.

UV (H ₀ O): λ = 262 nm (extinguish with hydroxylamine & max

bar)

Example 4

p-Nitrobenzyl-rac-7-oxo-3 - [(phenethylthio) methyl] -1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate was in a mixture of dioxane / ethanol / water in the presence of sodium hydrogen carbonate hydrogenated with palladium carbon (5%) as a catalyst at normal pressure. The catalyst was filtered off off, diluted with water and extracted with 4 portions of ether. The water phase contained sodium rac-7-oxo-3-C (phenethylthio) methyl] -1-azabicyclo [3.2.0] hept-2-en-2-carboxylate.

The finishing material was made as follows:

(a) From a solution of 1.89 g of rac-4- (3-bromo-2,2-di-. methoxypropyl) -2 ~ azetidinone and 2.46 g of glyoxylic acid-pnitrobenzyl ester-ethyl-hemiacetal.in 50 ml of toluene were 27 ml of the solvent within 2 hours at normal pressure continuously distilled off. The cooled reaction solution was concentrated completely and the remaining solution Chromatographed residue on silica gel. A mixture of acetone / methylene chloride / hexane (1: 4: 1, v / v / v) eluted 3.25 g p-Nitrobenzyl-rac-2- (3-bromo-2,2-dimethoxypropyl) -ot-hydroxy-4-oxo-1-azetidine acetate as a mixture of diastereomers.

IR (CHCl _{3): m} ^ _ 3530, 1765, 1611, 1530, 1500 cm ^"1

Rf: approx. 0.2 (SiO ₂ , acetone / CH ₂ C1 ₂ / hexane 1: 4: 1,

ν / ν / ν)

(b) Subjecting 3.25 g of p-nitrobenzyl-rac-2- (3-bromo-2,2-dimethoxypropyl) -a-hydroxy-4-oxo-1-azetidine acetate (mixture of diastereomers) to the in Example 1 (g) The reaction conditions described were obtained after crystallization from methylene chloride / hexane 2/48 g of p-nitrobenzylrac-2- (3-bromo-2,2-dimethoxypropyl) -4-oxo-α- (triphenylphosphoranylidene) -l-azetidine acetate as white crystals of mp. 189-190 ⁰ C.

IR (CHCl ₀ ): ->). 1737, 1620, 1607 cm " ¹ ά max

(c) Subjecting 2.77 g of p-nitrobenzyl-rac-2- (3-bromo-

2,2-dimethoxypropyl) -4-oxo-a- (triphenylphosphoranylidene) -1-azetidine acetate Following the procedure described in Example 1 (h), 1.35 g of p-nitrobenzyl-rac-2- (3-bromoacetonyl) -4-oxo-a- (triphenylphosphoranylidene) -lazetidine acetate were obtained as white crystals, m.p. 127-128 ° C.

IR (CHCl-): τ) ■ 1742, 1 & 36, 1609, 1579, 1525 cm " ¹ o in 3.x

3201: 37

3?

-Slid) A solution of 1.32 g of p-nitrobenzyl-rac-2- (3-bromoacetonyl) -4-oxo-a- (triphenylphosphoranylidene) -l-azetidine acetate and 0.29 g of 2-phenyl-ethyl mercaptan in 20 ml of methylene chloride 0.21 g of triethylamine was added and the mixture was stirred at room temperature for 1 hour. One diluted with methylene chloride and washed successively with dilute Sodium hydrogen carbonate solution and saturated sodium chloride solution. The organic phase was over sodium sulfate dried, concentrated completely and the residue chromatographed on silica gel. A mixture of ethyl acetate / hexane (1: 1, v / v) eluted 1.07 g of p-nitrobenzylrac-4-oxo-2- [3- (phenethylthio) -acetonyl] -a- (triphenylphosphoranylidene ) -1-azetidine acetate.

(e) By applying the cyclization conditions described in Example 1 to p-nitrobenzyl-rac-4-oxo-2- [3- (phenethylthio) acetonyl] -α- (triphenylpho sphoranylids) -. 1-azetidine acetate was obtained after chromatographic Purification of p-nitrobenzyl-rac-7-oxo-3 - [(phenethylthio) methyl] -1-azabicyclo [3.2.0] hept-2-en-2-carboxylate.

Example 5

■ Sodium rac-3 - [(cyclohexylthio) methyl] -7-oxo-1-azabicyclo [3.2.0] hept-2-en-2-carboxylate was obtained, by p-nitrobenzyl-rac-3-C (cyclohexylthio) methyl] -7-oxo-lazabicyclo [3.2.0] hept-2-en-2-carboxylate the hydrogenation conditions described in Example 4 subjected.

The starting material was prepared as follows:

(a) 1.32 g of p-nitrobenzyl-rac-2- (3-bromoacetonyl) -4-oxo-a- (triphenylphosphoranylidene) -1-azetidine acetate and 0.24 g of cyclohexyl mercaptan were according to the example 4 (d) described procedure implemented. After purification by chromatography, 0.96 g of p-nitrobenzyl-rac-2-C was isolated 3- (cyclohexylthio) acetonyl] -4-oxo-ot- (triphenylphosphoranylidene ) -l-azetidine acetate.

3 2 ϋ Ί - b

(b) By applying the cyclization conditions described in Example 1 to p-nitrobenzyl-rac-2-C3- (cyclohexylthio) -acetonyl] -4-oxp-a- (triphenylphosphoranylidene) -l-azetidine acetate After purification by chromatography, p-nitrobenzyl-rac-3-C (cyclohexylthio) - was obtained. methyl] -7-OXO-I-azabicyclo !! 3. 2. O Jhept-2-en-2-carboxylate.

Example 6

A solution of 267 mg of pivaloyloxymethyl-rac-trans -3-ethyl-2- [3 - [(1-ethyl-1,2-dihydro-2-oxo-4-pyrimidinyl) -thio] -acetonyl] -4-oxo -a- (triphenylphosphoranylidene) -lazetidinacetat in 12 ml toluene was heated for 3 hours under an argon atmosphere at 100 ⁰ C. The reaction solution was concentrated completely and the residue was chromatographed on silica gel. A mixture of. Methylene chloride / acetone (6: 1, v / v) eluted the pure product, which could be crystallized from ethyl acetate with the addition of hexane. 122 mg of pivaloyloxymethylrac-6a-ethyl-3 - [[(1-ethyl-1,2-dihydro-2-oxo-4-pyrimidinyl) -thio] -methyl] -7-oxo-Sa-l-azabicyclo [ 3.2.0] hept-2-ene-2-carboxylate as white crystals of melting point 105-106 ⁰ C.

IR (CHCl,): 0 _m- 1784, 1756, 1735, 1661, 1624, 1610cm " ¹

NMR (CDCl ₃ ): 6 '1.01 (t, J = 7Hz, 3H); '1.24 (s, 9H); 1.38

(t, J = 7Hz, 3H); 1.67-1.95 (m, 2H); 2.90-3.22 • · (m, 3H); 3.79-3.96 (m, 3H); 4.37 / 4.52 (AB-

System, J = 14Hz, -2H); ' 5, 88/5, 97 (AB system, J = 5Hz, 2H); 6.20 (d, J = 7Hz, IH); 7.35 (d, J = 7Hz,

IH) ppm

The starting material was prepared as follows:

(a) A solution of 0.513 g of rac-4 - [(2-methyl-1,3-dioxolan-2-yl) methyl] -2-azetidinone in 12 ml of tetrahydrofuran was at -20 ° C with 4 ml of a 1.635M butyllithium / Hexane solution added and for 90 minutes in an ice bath in

QO Π ¹ '"OZU ι

left to stand in an argon atmosphere. The brown-yellow solution was cooled to -40 ⁰ C, treated with a solution of 360 mg of ethyl bromide in 0.8 ml of tetrahydrofuran, and then for 90 minutes in an ice bath was allowed to stand. It was poured onto ice-cold saturated sodium chloride solution and extracted with ethyl acetate. The extracts were washed again with saturated sodium chloride solution, over sodium. dried sulfate and concentrated completely. Chromatography of the residue on silica gel with ethyl acetate / hexane (2: 1, v / v) as the eluent gave pure rac-trans-3-ethyl-4-C (2-methyl-i, 3-dioxolan-2-yl) methyl] -2-azetidinone. Crystallization from ether / hexane gave 122 mg of white crystals of melting point 44-45 ⁰ C..

IR (CHC1.J: τ) 3422, 1752 cm " ¹

ό ΠΙ 3.X

(b) To 4.3 g of rac-trans-3-ethyl-4 - [(2-methyl-1,3-dioxolan-2-yl) methyl] -2-azetidinone in 30 ml of methanol were added approx ml of 21.6 ml of an IM solution of bromine in methanol and heated to 50 ^° C. After about 3 minutes, discoloration occurred, whereupon the remainder of the bromine solution was added dropwise within 1 minute. The colorless reaction solution was poured onto a mixture of 30 ml of saturated sodium chloride solution and 20 g of ice, saturated with solid sodium chloride and extracted successively with 50 ml of ether and twice 50 ml of ethyl acetate each time. The organic phases were washed with a mixture of 30 ml of saturated sodium hydrogen carbonate and 20 ml of IN sodium thiosulfate solution and with 30 ml of saturated sodium chloride solution, dried over sodium sulfate and concentrated completely. The remaining oil was chromatographed on silica gel with ethyl acetate as the eluent. Crystallization of the purified product from ethyl acetate / hexane gave 2.99 g rac-trans-4- (3-bromo-2, 2-dimethoxypropyl) i-3-ethyl-2-azetidinone as white crystals of melting point 77-79 ⁰ C.

12 ·· -vüLO ::

(c) The procedure described in Example 1 (f) - (h) was carried out in an analogous manner on 2.8 g of rac-trans-4- (3-bromo-2,2-dimethoxypropyl) -3-ethyl-2 -azetidinone applied. After chromatographic purification and crystallization from ethyl acetate / hexane, 0.51 g of pivaloyloxymethyl- ' rac-trans-2- (3-bromoacetonyl) -3-ethyl-4-oxo-a- (triphenylphosphoranylidene ) -l-azetidine acetate as white crystals with a melting point of 128-129 ° C.

(d) 333 mg of pivaloyloxymethyl-rac-trans-2- (3-bromoacetonyl) -3-ethyl-4-oxo-a- (triphenylphosphoranylidene) -1-azetidine acetate and 78 mg of l-ethyl-4-thiouracil were according to the in Example 4 (d) described method implemented. After purification by chromatography, 291 mg were isolated Pivaloyloxymethyl-rac-trans -3-ethyl-2- [3 - [(1-ethyl-1,2-dihydro-2-oxo-4-pyrimidinyl) -thio] -acetonyl] -4-oxo-a- (triphenylphosphoranylidene ) -1-azetidinace.tat as white foam.

IR (CHCl,.): '£> 1745 with shoulder, at 1720, 1662, 1627,

■ 3 IUcIX «

1580, 1514 cm

Example 7

A solution of 151 mg of pivaloyloxymethyl-rac-trans-3-ethyl-2- [3 - [(5-methyl-1,3,4-thiadiazol-2-yl) -thio] -acetonyl] -4-oxo-a - (triphenylphosphor.anyliden) -1-azetidinacetat in 12 ml of toluene were added for 1.5 hours, heated under an argon atmosphere at 100 ⁰ C. After purification by chromatography, 79 mg of pivaloyloxymethylrac-6a-ethyl-3 - [[(5-methyl-1,3,4-thiadiazol-2-yl) -thio] -methyl] -7-oxo-5a-1-azabicyclo were isolated [3.2.0] hept-2-en-2-carboxylate as a pale yellow oil.

NMR (CDCl ₃ ): 6 1.00 (t, J = 7Hz, 3H); 1.07 (s, 9H); 1.43-2.17

(m, 2H); 2.73 (s, 3H); 2.92-3.30 (m, 3H); 3.70-4.13 (m, 1H); 4.40 / 4.59 (AB system, J = 14Hz, 2H); 5.86 / 5.94 (AB system, J = 6Hz / 2H) ppm

The starting material was prepared as follows:

1.33 g pivaloyloxymethyl-rac-trans-2- (3-bromoacetonyl) -3-ethyl-4-oxo-a- (triphenylphosphoranylidene) -1-azetidine- acetate and 0.26 g of 2-mercapto-5-methyl-1,3,4-thiadiazole were implemented in a manner analogous to the method described in Example 4 (d). After purification by chromatography, 1.24 g of pivaloyloxymethyl-rac-trans-3-ethyl-2-C3 - [(5-methyl-1,3,4-thiadiazol-2-yl) -thio] - acetonyl] -4-oxo-α- (triphenylphosphoranylidene) -1-azetidine acetate as an amorphous powder.

IR (CHCl ₃ ): "^ _max 1740, 1636 cm" ¹ Example 8

A solution of 270 mg of pivaloyloxymethyl-rac- (2RS, 3SR) -2- [3 - [(1-methyl-1H-tetrazol-5-yl) -thio] -acetonyl] -4-OXO-3-C (RS ) -l- (trimethylsilyloxy) -ethyl3-a- (phosphorus- anyliden) -l-azetidinacetat in 32 ml of toluene was heated under an argon atmosphere at 105 ⁰ C for 1 hour. The colorless reaction solution was diluted with 50 ml of ethyl acetate and completely concentrated in vacuo. To separate off the triphenylphosphine oxide, the residue was filtered through silica gel, eluting with ethyl acetate / methylene chloride (1: 1, v / v). The fractions containing the cyclization product were concentrated. The residue was taken up in 17 ml of methanol, 35 mg of ammonium fluoride were added to the solution and the mixture was stirred at room temperature for 40 minutes. It was diluted with 30 ml of ethyl acetate and completely concentrated in vacuo, and the residue was chromatographed on silica gel with ethyl acetate / methylene chloride (1: 1, v / v) as the eluent. 60 mg of pivaloyloxymethyl-rac- (5RS, 6 SR) -6 - [(RS) -1-hydroxyethyl] -3-CC (1-methyl-1H-tetrazol-5-yl) -thio] -methyl] - were obtained 7-oxo-lazabicycloC3.2.0] hept-2-en-2-carboxylate as a colorless oil.

IR (CHCl,): - ^ 3616, 3446, 1780, 1752, 1732, 1623 cm " ¹ j max

The starting material was prepared as follows:

(a) To a ^{solution, cooled to 0} ° C., of 34.2 g of rac-4- (2,2-ethylenedioxypropyl) -2-azetidinone. and 31.7 g of tert-butyldimethylchlorosilane in 160 ml of dimethylformamide were added dropwise within 2 minutes, 22.2 g of triethylamine, a precipitate immediately forming. The mixture was stirred for 1 hour at 0 ^° C., then diluted with 500 ml of ether and the reaction mixture was washed 5 times with 200 ml of water.

The water phases were extracted with 250 ml of ether. The organic phases were dried over sodium sulfate, freed from the solvent on a rotary evaporator and the remaining oil was distilled in a high vacuum. 53.5 g of rac-l- (tert-butyldimethylsilyl) -4 - [(2-methyl-1,3-dioxolan-2-yl) methyl] -2-azetidinone with bp. 125-130 ⁰ C as a colorless oil.

IR (CHCl ₃ ): ^ m _3x ¹⁷²⁸

NMR (CDCl ₃ ): δ 0.22 (s, 6H); 0.98 (s, 9H); 1.31 (s, 3H);

1.62-2.34 (m, AB part of an ABX system, 2H); 2.70-3.31 (m, AB part of an ABX system, 2H); 3.51-3.85 (m, X part, 1H); "3.85-4.03 (m, 4H) ppm

(b) A solution of 3.66 g of diisopropylamine in 90 ml tetrahydrofuran was cooled to -78 ⁰ C and within 5 minutes with 24 ml of hexane was added a solution of 1,635M Butyllithiüm /. The mixture was stirred for 20 minutes at -78 ° C. under an argon atmosphere and then a solution of 8.55 g of rac-1- (tert-butyldimethylsilyl) -4 - [(2-methyl-l, 3- dioxolan-2-yl) methyl] -2-azetidinone in 90 ml of tetrahydrofuran. After another 30 minutes stirring at -78 ⁰ C, the reaction solution with 2.22 g of methyl acetate was added. The mixture was allowed to warm to 0 ° C. within 5 minutes and stirred at this temperature for a further 20 minutes. The reaction mixture was poured onto 150 ml of saturated sodium chloride solution and then extracted with a total of 400 ml of ethyl acetate. The organic phase was

Λ Q p 1

• j Δ J ι

W 3.

3? -

Washed neutral with saturated sodium chloride solution, dried over sodium sulfate and concentrated completely. The residue was chromatographed on silica gel with ethyl acetate / hexane (1: 2, v / v) as the eluent and the material of the concentrated pure fractions was distilled in a high vacuum. 4.49 g of rac-trans-3-acetyl-1- (tert-butyldimethylsilyl) -4 - [(2-methyl-1,3-dioxolan-2-yl) methyl] -2-azetidinone were obtained as colorless OeI from Sdp._ _. 118-120 ⁰ C.

IR (CHCl ₀ ): 0 1743, 1712 cm " ¹ 3 max

NMR (CDCl ₃ ): δ 0.22 (s, 3H); 0.26 (s, 3H); 0.98 (s, 9H);

1.32 (s, 3H); 1.66-2.37 (m, 2H) '; 2.30 (s, 3H); 3.75-4.00 (m, 4H); 4.00-4.25 (m, 2H) ppm 15

(c) A mixture of 14.3 g of rac-trans -3-acetyl-1- (tert-butyldimethylsilyl) -4 - [(2-methyl-1,3-dioxolan-2-yl) methyl] -2 -azetidinone and 0.78 g of platinum oxide in 70 ml of ethyl acetate was hydrogenated at normal pressure for 8 hours.

2 "The catalyst was filtered off, the filtrate was completely concentrated in vacuo and the residue was crystallized from hexane. 12.4 g of a mixture of 2 isomeric alcohols in a ratio of 3: 2 were obtained Main components are isolated in pure form: rac- (3SR, 4RS) - l- (tert-butyldimethylsilyl) -3 - [(RS) -1-hydroxyethyl] -4 - [(2-methyl-l, 3-dioxolane 2-yl) methyl] -2-azetidinone of melting point 81-82 ⁰ C.

IR (CHCl ₃ ): - ^ _max ³⁵⁰ ° f ¹⁷³⁵

NMR (CDCl ₃ ): 6 0.22 (s, 3H); 0.24 (s, 3H); 0.96 (s, 9H); . 1.34 (d, J = 6Hz, 3H); 1.41 (s, 3H); 1.82-2.27 (m, 2H); 2.96 (dxd, J = 9Hz and 2Hz, IH); 3.15 (d, J = 5H, 1H); 3.54-3.61 (m, 1H); 3.94-4.02

(m, 4H) ppm

By repeatedly crystallizing the mother liquor material from ethyl acetate / hexane could rac- (3SR, 4RS) -I- (tert-butyldimethylsilyl) -3- [(SR) -1-hydroxyethyl] -4- [. (2-methyl-1,3-dioxolan-2-yl) methyl] -2-azetidinone with a melting point of 86-88 "C.

IR (CHCl,): -o 3630, 3588, 3504, 1728 cm ^-1

ö Iu 3.x

NMR (CDCl ₃ ): 6 0.22 (s, 3H); 0.24 (s, 3H); 0.96 (s, 9H); 1.32 (d, J = 6Hz, 3H); 1.36 (s, 3H); 1.78-2.27

(m, 2H); 2.46 (d, J = 5Hz, 1H); 3.15 (dxd, J = SHz and 2.5Hz, IH); 3.59-3.68 (in, 1H); 3.89-4.01 (m, 4H); 4.03-4.16 (m, 1H) ppm

(d) A cooled to 0 ⁰ C solution of 79 g of rac- (3SR, 4RS) -l- (tert-butyldimethylsilyl) -3 - [(RS) -1-hydroxyethyl] -4 - [(2-methyl- 1,3-dioxolan-2-yl) methyl] -2-azetidinone in 720 ml of pyridine was admixed with 63.7 g of 2,2,2-trichloroethyl chloroformate while stirring. In the process, lumps formed which, after a while, dissolved into a fine precipitate. The mixture was stirred for 17 hours at room temperature and most of the solvent was then removed on a rotary evaporator in a high vacuum. The concentrated reaction mixture was taken up in 2 l of ethyl acetate, washed 3 times with 600 ml of water each time, and the aqueous phases were back-extracted with 1 l of ethyl acetate. The organic phases were dried over sodium sulfate, the solvent was removed on a rotary evaporator and the remaining oil was freed from polar impurities by filtration through silica gel with ethyl acetate / hexane (1: 1, v / v) as the eluent. Concentration of the pure fractions gave 126 g of crude rac- (3SR, 4RS) -I- ■ (tert-butyldimethylsilyl) -3 - [(RS) -l- (2,2,2-trichloroethoxycarbonyloxy) ethyl] -4 - [(2-methyl-1,3-dioxolan-2-yl) methyl] -2-azetidinone

35 as OeI.

IR (CHCl ₃ ): v " _max ¹⁷ 58, 1740 cm

-1·

3 201 U ^ 'Ζ *' / ' -i ι: *

(e) A preheated to 60 ⁰ C solution of 126 g of crude rac- (3SR, 4RS) -l- (tert-butyldimethylsilyl) -3 - [(RS) -I- (2,2,2-trlchlorethoxycarbonyloxy) - ethyl] -4 - [(2-methyll, 3-dioxolan-2-yl) methyl] -2-azetidinone in 700 ml of methanol were treated with 4 g of bromine while stirring. After about 3 minutes of stirring at 60 ^° C., discoloration occurred. Now the R.eaktionslösung were within 8 minutes another 36 g of bromine are added dropwise while keeping the reaction temperature within 3 minutes at 40 ⁰ C lowered. After complete addition the temperature was kept still weitere.12 minutes at 40 ^0C, the reaction solution was almost colorless. The mixture was cooled to 10 ^° C., neutralized by adding 41 ml of aqueous ammonia (25%), mixed with 8.6 g of ammonium fluoride and stirred for 1 hour at room temperature. The yellow solution was concentrated to about half its volume on a rotary evaporator and then taken up in 1.2 l ethyl acetate / ether (1: 1, v / v). It was washed 3 times with 450 ml of saturated sodium chloride solution each time and the water phases were extracted again with a total of 1.3 l of ethyl acetate. The organic phases were dried over sodium sulfate, freed from the solvent in vacuo and the residue was chromatographed on silica gel. A mixture of ethyl acetate / methylene chloride / hexane (1: 1: 1, v / v / v) eluted the prepurified product, which could be crystallized from ethyl acetate with addition of hexane. 57 g of rac- (3SR, 4RS) -4- (3-bromo-2,2-dimethoxypropyl) -3 - [(RS) -l- (2,2,2-trichlorethoxycarbonyloxy) -ethyl] -2- were obtained azetidinone as colorless crystals of mp. 84-85 ⁰ C.

(f) A mixture of 23.58 g of rac- (3SR, 4RS) -4- (3-bromo-2,2-dimethoxypropyl) -3 - [(RS) -l- (2,2,2-trichloroethoxycarbonyloxy) -ethyl] -2-azetidinone, 4.89 g of glyoxylic acid monohydrate and 15 g of molecular sieve 4A in 25 ml of dimethylformamide were stirred for 20 hours at room temperature. The reaction mixture was cooled to -10 ⁰ C and treated with 5.25 g of triethylamine. After 5 minutes, 13.3 g of iodomethyl pivalate were added, the temperature being kept at 3 ° C. by cooling. The mixture was stirred for 15 minutes at 3 ° C and

JZU

even more. 2 0 minutes at room temperature. Then it was decanted off from the molecular sieve and at the same time with 200 ml Diluted ethyl acetate. It was washed 3 times with 100 ml of half-saturated sodium chloride solution each time and extracted .Water phases again with 2 00 ml of ethyl acetate. The organic phases were dried over sodium sulfate and freed from solvent in vacuo. Chromatography of the Residue on silica gel with ethyl acetate / hexane (1: 1, v / v) gave 15.5 g of pivaloyloxymethyl-rac- (2RS, 3SR) -2- (3-bromo-2,2-dimethoxypropyl) -4-oxo-3 - [(RS) -1- (2,2,2-trichloro - ' ethoxycarbonyloxy) ethyl 1-a-hydroxy-1-azetidine acetate (Mixture of diastereomers) as a colorless oil.

IR (CHCl ₀ ): -ύ 3528, 1769 cm " ¹ 3 max

NMR (CDCl ₃ ): ia 6 1.23 (s, 9H); 1.50 (d, J = 6Hz, 3H);

2.20-2.60 (m, 2H); 3.05-3.3θ '(m, 7H); 3.48 (broad s, 2H); 4.73 (s, 2H) ppm

(g) to a cooled to -20 ⁰ C solution of 15.5 g of pivaloyloxymethyl rac- (2RS, 3SR) -2- (3-bromo-2,2-dimethoxypropyl) -4-oxo-3 - [(RS ) -1- (2,2,2-trichloroethoxycarbonyloxy) -ethyl] -a-hydroxy-1-azetidine acetate (mixture of diastereomers) in 200 ml of tetrahydrofuran were added 3.50 g of 2,6-lutidine. Then, within 1 minute was added dropwise a solution of 3.74 g of thionyl chloride in 40 ml of tetrahydrofuran, the temperature being maintained by cooling below -20 ⁰ C. The reaction mixture was stirred for 20 minutes at -20 ⁰ C and 20 minutes at room temperature. Then the

™ Precipitation filtered off with suction and the filter material washed with 360 ml of toluene. The filtrate was completely concentrated in vacuo, and the residue was taken up in 150 ml of toluene. taken and again completely concentrated.

The oil thus obtained was taken up in 75 ml of dimethylformamide, and a solution of 8 g of triphenylphosphine in 23 ml of dimethylformamide was added. It was left with RauinUomporalur lotion and en t for 1 hour ^; i.> rrii, o el, inn the rjrö «s l.ori part

32 or:

- Ai -

of the solvent in a high vacuum at a temperature of 30 ^° C. The residue was taken up in 300 ml of methylene chloride, the solution was washed twice with 40 ml of 1M pH 7 phosphate buffer each time and the aqueous phases were re-extracted with 500 ml of methylene chloride. The organic phases were dried over sodium sulfate, freed from the solvent in vacuo and the remaining oil was chromatographed on silica gel. A mixture of ethyl acetate / methylene chloride / hexane (1: 1: 1, v / v / v) initially eluted excess triphenyl

10 · phosphine and then the product. Complete concentration of the pure fractions gave 14.89 g of pivaloyloxymethyl-rac- (2RS, 3SR) -2- (3-bromo-2,2-dimethoxypropyl) -A- oxo-3 - [(RS) -l- (2 , 2,2-trichlorethoxycarbonyloxy) -ethyl] -a- (triphenylphosphoranylidene) -l-azetidine acetate as an amorphous powder.

IR (CHCl ₃ ): ^ max ^{1747/1634 cm -1}

(h) A ^{solution, cooled to -10 0} C, of 2.66 g of pivaloyloxymethyl-rac- (2RS, 3SR) -2- (3-bromo-2,2-dimethoxypropyl) -4- oxo-3-C (RS) -1- (2,2,2-trichloroethoxycarbonyloxy) -ethylΙα- (triphenylphosphoranylidene) -l-azetidinacetat in 75 ml acetone was stirred with 75 ml of pre-cooled to -10 ⁰ C was added 48% hydrobromic acid, keeping the temperature at 10 ⁰ C rose. The mixture was cooled to 0 ° C. within 3 minutes, stirred for a further 15 minutes at this temperature and the colorless reaction solution was poured onto a mixture of 17.4 g of sodium carbonate, 150 ml of 1M pH 7 phosphate buffer solution and 150 g of ice. It was extracted with a total of 400 ml of methylene chloride. The organic phase was washed with 50 ml of 1M pH 7 phosphate buffer solution, dried over sodium sulfate and concentrated completely. 2.45 g of crude pivaloyloxymethyl-rac- (2RS, 3SR) -2- (3-bromoacetonyl) -4-OXO-3 - [(RS) -1- (2,2,2-trichlorethoxycarbonyloxy) -ethyl] were obtained - α- (triphenylphosphoranylidene) -l-azetidine acetate as a white solid.

IR (CHCl ₃ ): v> 1750 with shoulder at 1710, 1641 cm

HZ

4 * -

(i) A solution of 428 mg pivaloyloxymethyl-rac- (2RS, 3SR) -2- (3-bromoacetonyl) -4-oxo-3 - [(RS) -1- (2,2,2-trichloroethoxycarbonyloxy) -ethyl] -α- (triphenylphosphorus anylidene.) 1-azetidine acetate and 64 mg of 5-mercapto-1-methyl-1H-tetrazole 60 mg of triethylamine were added in 10 ml of methylene chloride and then for 2 hours at room temperature stirred, one diluted with 10 ml of methylene chloride and washed with 10 ml of saturated sodium bicarbonate and Sodium chloride solution. The water phases were extracted with a little methylene chloride, the organic phases dried over sodium sulfate and concentrated completely.

The residue was dissolved in 3 ml of ice-cold 90% acetic acid. 1.5 g of zinc powder were added and the ^{mixture was stirred at 0 °} C. for 20 minutes. The reaction mixture was diluted with 40 ml of methylene chloride and washed successively with 15 ml of saturated sodium carbonate solution and twice with 25 ml of water each time. The water phases were re-extracted twice with ml of methylene chloride each time, and the organic phases were dried over sodium sulfate and concentrated completely.

The residue was in a mixture of 3 ml of methylene chloride and 1.5 ml of pyridine. added and the solution was mixed with 0.44 g of trimethylchlorosilane. One stirred during 1 hour at room temperature, diluted with 35 ml of ethyl acetate and washed successively with 15 ml of 5% sodium hydrogen carbonate solution and 25 ml of saturated sodium chloride solution. The water phases were washed with 60 ml of ethyl acetate extracted, the organic phases dried over sodium sulfate and concentrated completely. The residue was on silica gel with ethyl acetate / hexane (1: 1, v / v) as Eluent chromatography location. 198 mg of pivaloyloxymethyl-rac- (2RS, 3SR) -2- [3 - [(1-methyl-1H-tetrazol-5-yl) -thio] -acetonyl] -4-oxo-3- [ (RS) -l- (trimethylsilyloxy) -ethyl] -a- (triphenylphosphoranylidene) -1-azetidine acetate as a colorless oil.

IR (CHCl ₃ ): ^ _max ! 747, 1640 cm " ¹

3201 ^ 7

Example 9

A 0.05M pH 7 phosphate buffer solution was prepared by adding 1N sodium hydroxide solution to an aqueous sodium dihydrogen phosphate solution, and 1.5 ml of a suspension of pig liver esterase EC 3.1.1.1 (approx. 1500 units) in 3.2M ammonium sulfate solution to 150 ml of this solution given. Then a solution of 228 mg of pivaloyloxymethyl-rac- (5RS, 6SR) -6 - [(RS) -l-hydroxyethyl] -3 - [[(l-methyl-lH-tetrazol-5-yl) - thio] ~ methyr] -7-oxo-1-azabicyclo [3. 2. 0] hept-2-en-2-carboxylate in 3 ml of methanol, a fine precipitate being formed. The mixture was stirred for 3.5 hours at 23 ° C. and the pH of the reaction mixture was kept at 7.1 by adding 0.1N sodium hydroxide solution. The still slightly cloudy solution was extracted 4 times with 50 ml of ether each time and the ether phases were still 2 times back extracted with 50 ml of water. The aqueous phases were ml concentrated in vacuo at a temperature of 0-20 ⁰ C to about 30 and RP-18 silica gel (LiChroprep, 40-6 to 3) with 3 / aqueous 6igem Methanol (v / v) chromatographed. The fractions which contained the product were combined, concentrated and the solution adjusted to pH 7.1 with 0.1 IN sodium hydroxide solution was lyophilized to give a mixture of sodium (5R, 6S and 5S, 6R) -6 - [(R and S) -I-hydroxyethylD-S-CCd-methyl-lH-tetrazole-S-yD-thiol-methyl] - 7-oxo-l-azabicyclo [3.2.0] hept-2-en-2-carboxylate as a white, amorphous powder.

UV (H "O): λ = 278 nm (can be erased with hydroxylamine)

<£ ITIcOC

IR (KBr): -o 1758, 1603, 1400 cm " ¹

Max

NMR (DMSO-dg): 1.15 (d, J = 6Hz, 3H); 2.66-2.86 (m, 2H); 3.03

(dxd, J = 7Hz and 2.5Hz, IH); 3.80-3.96 (m, 2H); 3.97 (s, 3H); 4.40 / 4.66 (AB system, J = 12Hz,

2H) ppm

JZ-J

sr ©

Example 10

126 mg pivaloyloxymethyl-rac- (2RS, 3SR) -2- [3 - [(5-methyl-1,3,4-thiadiazol-2-yl) -thio] -acetonyl] -4-oxo-3- [(RS) -l- (trimethylsilyloxy) -ethyl] -a- (triphenylphosphoranylidene) -lazetidine acetate were subjected to the cyclization procedure described in Example 8. One received after chromatographic purification. 2 4 mg eivaloyloxymethylrac- ( 5RS, 6SR) -6- [(RS) -1-hydroxyethyl] -3- C [• (5-methyl-1,3,4-thiadiazol-2-ylJ-thiol-methylJ-V-oxo-1-azabicycloCB .2.O] - hept-2-en-2-carboxylate as a colorless oil.

UV (EtOH): λ = 292 nm

Max

The starting compounds for Examples 10, 12, 13, 14 and 18 were prepared as follows:

(a) Pivaloyloxymethyl-rac- (2RS, 3SR) -2- (3-bromoacetonyl) -4-OXO-3-C (RS) -1- (2,2,2-trichloroethoxycarbonyloxy) -ethyl] -α- ( triphenylphosphoranylide.n) -l-azetidine acetate was reacted according to the method described in Example 8 (i) with the difference that instead of 5-mercapto-1-methyl-1H-tetrazole

in Example 10 5-mercapto-2-methyl-1,3,4-thiadiazole, in Example 12 2-mercapt'o-pyrimidine, in Example 13 4-acetamino-thiophenol, in Example 14 1,2,3,4-tetrahydro-4-methyl-3-thioxo-

as-triazine-5,6-dione, in Example 18 methyl-l-methyl-o-mercapto-lH-l, 2,4-

triazole-3-carboxylate

was used.

'■ Was obtained after chromatographic purification in Example 10: .Pivaloyloxymethyl-rac- (2RS, 3SR) -2- [3 - [(5-methyl-1,3,4-thiadiazol-2-yl) -thio] -acetonyl] -4-oxo-3- [(RS) -l- (trimethylsilyloxy) -ethyl] -a- (triphenylphosphoranyli-

den) -l-azetidine acetate as a white foam.

IR (CHCl ₀ ): v> 1749, 1640 cm " ¹ 3 x max '

in Example 12: pivaloyloxymethyl-rac- (2RS _; 3SR) -4-oxo-3- [(RS) -I-. (trimethylsilyloxy) ethyl] -2- [3- (2-pyriinidinyl-thio) acetonyl3-a- (triphenylphosphoranylidene) -1-azetidine acetate as a colorless oil.

IR (CHCl ₃ ): v _max 1739 with shoulder at 1715, 1632 cm " ¹

in Example 13: pivaloyloxymethyl-rac- (2RS, 3SR) -2- [3 - [(pacetaminophenyl) -thio] -acetonyl] -4-oxo-3 - [(RS) -1- (trimethylsilyloxy) -ethyl] - a- ( triphenylphosphoranylidene.) - l-azetidine acetate as an amorphous powder.

" ¹

IR (CHCl-): ύ 3436, 3322, 1744, 1712, 1636 cm

J ITl 3.JC

in Example 14: pivaloyloxymethyl-rac- (2RS, 3SR) -2- [3 - [(1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl) - thio] acetonyl] -4-oxo-3 - [(RS) -1- (trimethylsilyloxy) ethyl] -α- (triphenylphosphoranylidene) -1-azetidine acetate as a colorless oil.

IR (CHCl,): υ. 3394, 1750, 1712 ', 1616, 1595 cm " ¹

ό ΓΠ3.Χ

in Example 18: pivaloyloxymethyl-rac- (2RS, 3SR) -2- [3- [3- (methoxycarbonyl) -l-methyl-lH-l, 2,4-triazol-5-yl] -thio] -acetonyl] -4-OXO-3 - [(RS) -1- (trimethylsilyloxy) -ethyl] -α- (triphenylphosphoranylidene) -1-azetidine acetate as a colorless oil.

IR (CHCl3,): 5 1741, 1715, 1636 cm " ¹

j max

Example l 11 ^

Pivaloyloxymethyl-rac- (5RS, 6SR) -6 - [(RS) -1-hydroxyethyl] -3 - [[(5-methyl-1,3,4-thiadiazol-2-yl) -thio] -methyl] 7-oxo-l-azabicyclo [3.2.0] hept-2-en-2-carboxylate was used in

SX

subjected to the hydrolysis process described in Example 9 in an analogous manner. It was obtained after RP-18 silica gel chromatography a mixture of sodium (5R, 6S and 5S, 6R) -6 - [(R and S) -l-hydroxyethyl] -3 - [[(5-.methyl-1,3, 4-thiadiazo1-2- yl) -thio] -methyl] ~ 7-oxo-1-azabicyclo [3.2-0] hept- 2-en-2-carboxylate.

UV (H "O): λ = 278 nm (with hydroxylamine different

Ct ITIcUC

exercise after 287 rim).

'·

Example 12

163 mg pivaloyloxymethyl-rac- (2RS, 3SR) -4-oxo-3 - [(RS) -l- (trimethylsilyloxy) -ethyl] -2- [3- (2-pyrimidinyl-thio) - acetonyl] -a- (triphenylphosphoranylidene) -l-azetidine acetate were subjected to the procedure described in Example 8 with the difference that the reaction time of the Cyclization reaction was 3 hours. After purification by chromatography, 42 mg of pivaloyloxymethylrac- (5RS, 6SR) -6 - [(RS) -1-hydroxyethyl] -7-OXO-3 - [(2-pyrimidinyl-thio ) -methyl l-l-azabicycl'oiC 3.2. 0] hept-2-en-2-carboxylate as a colorless oil.

IR (CHCl,): \> 3618, 3450., 1775, 1753, 1622, 1567, 1551 cm

The preparation of the starting material is described in Example 10 (a).

Example 13

157 mg pivaloyloxymethyl-rac- (2RS, 3SR) -2- [3- [(pacetaminophenyl ) -thio] -acetoriyl] -4-oxo-3- [(RS) -I- (trimethylsilyloxy) -ethyl] -α- (triphenylphosphoranylidene) -lazetidine acetate were subjected to the procedure described in the example in an analogous manner. -Man isolated after chromatographic purification 33 mg pivaloyloxymethyl-rac- (5RS, 6SR) -3 - [[(p-acetaminophenyl) -thio] -methyl] -6-C (RS) -I-

32C 1 " ^: x 7

hydroxyethyl] -7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate as an amorphous powder.

IR (CHCl,): i> "3618, 3434, 3382, 1778, 1755, 1695, 1619 cm "

NMR (CDCl ₃ ): δ 1.22 (s, 9H); 1.31 (d, J = 6Hz, 3H); 1.91 (d, J = 4Hz, 1H); 2.17 (s. 3H); 2.85-3.10 (m, 2H); 3.08 (dxd, J = 6.5Hz and 3Hz, IH); 3.89 / 4.07 (AB system, J = 13Hz, 2H); 4.07-4.18 (m, 2H);

5.68 / 5.78 (AB system, J = 5.5Hz, 2H); 7.34 (d, J = 8.5Hz, 2H); 7.36 (s, 1H); 7.44 (d, J = 8.5Hz, 2H) ppm

The preparation of the starting material is described in Example 10 (a).

Example 14

400 mg pivaloyloxymethyl-rac- (2RS, 3sR) -2- [3 - [(1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl) -thio] -acetonyl] -4-oxo-3 - [(RS) -1- (trimethylsilyloxy) -ethyl] -a- (triphenylphosphoranylidene) -1-azetidine acetate were subjected to the procedure described in Example 8 in an analogous manner. It was obtained after purification by chromatography 31 mg pivaloyloxymethyl-rac- (5RS, 6SR) -6-C (RS) -1-hydroxyethyl] -3 - [[(1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-astriazirr -3-yl ) -thio] -methyl] -7-oxo-1-azabicyclo [3.2. 0] hept-2-en-2-carboxylate.

,

UV (EtOH): λ = 280 nm (with NH, OH shift to

max -C-

289 nm)

The preparation of the starting material is described in Example 10 (a).

SH

-w-

Example 15

That. Product from Example 14 was made in an analogous manner the procedure described in Example 9 was subjected. A mixture of sodium (5R, 6S and 5S, 6R) -6 - [(R and S) -l-hydroxyethyl3-3 - [[(1,4,5,6-tetrahydro-4-methy1-5,6-dioxo-as-triazin-3-yl) -thio] -methyl] -7- oxo-lazabicycloC3.2.0] hept-2-ene-2-carboxylate.

UV (H ₂ O): \ _max = 283 nm

Example 16

186 mg of pivaloyloxymethyl-rac- (2RS, 3SR) -2- [3-t [2,5-dihydro-2-methyl-5-oxo-6 - [(pivaloyloxy) methoxy] -as-triazin-3-yl ] -thio] -acetonyl] -4-oxo-3-C (RS) -! - (trimethylsilyloxy) -ethyl] -α- (triphenylphosphoranylidene) -l-azetidine acetate were described in a manner analogous to that in Example 8 Procedure implemented. After purification by chromatography, 65 mg of pivaloyloxymethyl-rac- (5RS, 6SR) -6 - [(RS) -l-hydroxyethyl] -3 - [[[2,5-dihydro-2-methyl-5-oxo-6r [ (pivaioyloxy methoxy] -as-triazin-3-yl] -thio] -methyl] -7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate as a colorless oil.
25th

IR (CHCl,): v> 3692, 3614, 3370, 1775, 1753, 1737, 1670, 1620 cm "

NMR (CDCl ₃ ): 6 1.22 (s, 18H); 1.31 (d ", J = 6Hz, 3H); 1.80 (d, J = 4.5Hz, 1H); 2.97-3.23 (m, 2H); 3.18

(dxd, J = 6.5Hz and 2Hz, IH); 3.70 (s, 3H); 4.13-4.28 (m, 2H); 4th, 40 / 4.54 (AB system, J = 13.5Hz, 2H); 5.88 / 5.97. (AB system, J = 7Hz, 2H); 5.93 (s, 2H) ppm 35

The starting material was prepared as follows:

3 2 O 1 ^no .

(a) To a solution of 858 mg of pivaloyloxymethyl-rac- (2RS, 3 SR) -2- (3-bromoacetonyl) -4-OXO-3 - [(RS) -1- (2,2,2-trichlorethoxycarbonyloxy) -ethyl] -a- (triphenylphosphoranylidene) ■ 1-azetidine acetate and 159 mg of 1,2,3,4-tetrahydro-2-methyl-3-thioxo-as-triazine-5,6-dione in 10 ml of dimethylformamide were 202 mg Triethylamine added to 2 ml of methylene chloride and then stirred for 20 minutes at room temperature. The clear solution was cooled to 0 ⁰ C, 242 mg of iodomethyl pivalate was added and a further 15 minutes at 0 ^0C and 15 for minutes

"Stirred for 10 th at room temperature. It was diluted with ethyl acetate and washed successively with 5% sodium hydrogen carbonate and saturated sodium chloride solution. The organic Phase was dried over sodium sulfate, completely concentrated and the residue chromatographed on silica gel with ethyl acetate as the mobile phase.

The purified product was prepared in analogy to the method described in Example 8 (i) with zinc in 90% Acetic acid and then treated with trimethylchlorosilane. It was obtained after purification by chromatography 196 mg pivaloyloxymethyl-rac- (2RS, 3SR) -2- [3 - [[2,5-dihydro-2-methyl-5-oxo-6 - [(pivaloyloxy) methoxy] -as-triazin-3-yl ] -thio] -acetonyl] -4-oxo-3 - [(RS) -l- (trimethylsilyloxy) -ethylΙα- ( triphenylphosphoranylidene) -1-azetidine acetate as a colorless oil.

Example 17

The product from Example 16 was subjected to the process described in Example 9 in an analogous manner.

A mixture of (5R, 6S 'and 5S, 6R) -6 - [(R and S) -l-hydroxyethyl] -3 - [[2,5-dihydro-6-hydroxy-2- methyl-5- oxoas-triazin-3-yl) -thio] -methyl] -7-oxo-1-azabicyclo [3.2.0] -hept-2-en-2-carboxylic acid Disodium salt, 35

UV (H ₀ O): λ = 242, 281 ran
2 max

IR (KBr): τ-> 1755, 1602 with shoulder 1650, 1404 cm " ¹

Max

Example 18

180 mg pivaloyloxymethyl-rac- (2RS, 3SR) -2- [3 - [[3- (methoxycarbonyl ) -l-methyl-lH-1,2,4-tr.iazol-5-yl] -thio3-acetonyl] -4-oxo ~ 3 - [(RS) -1-trimethylsilyloxy) -ethyl] -α- ( tri- phenylphosphoranylidene) -l-azetidine acetate were subjected to the procedure described in Example 8. One received after chromatographic purification approx. 70 mg pivaloyloxymethylrac- (5RS, 6SR) -6- [ (RS) -l-hydroxyethyl} -3- [[[3- (methoxycarbonyl) -l-methyl-lH-l, 2,4-triazol-5-yl] -thio] -methyl] -7- oxo-l-azabicyclo [3.2.0] hept-2-en-2-carboxylate as a colorless oil.

IR (CHCl ₀ ): -> 3680, 3608, 3440, 1780, 1742, 1620 cm " ¹ 3 max

NMR (CDCl ₃ ): δ 1.22 (s, 9H); 1.32 "(d, J = 6Hz, 3H); 1.82 (broad -OH signal); 3.03-3.15 '(m, 2H); 3.26 (dxd, J = 6.5Hz and 3Hz, IH); 3.89 (s, 3H); 3.98 (s, 3H), 4.10-4.25 (m, 2H); 4.42 / 4.42 (degenerate AB system , J = 13.5Hz, 2H);

5.85 / 5.93 (AB system, J = 5.5Hz, 2H) ppm

The production of the starting material is in example 10 (a).

.

Example 19

The product from Example 18 was subjected to the process described in Example 9 in an analogous manner. A mixture of sodium (5R, 6S and 5S, 6R) -6 - [(R and S) -1-hydroxyethyl1-3-C [C3- (methoxycarbonyl) ~ 1-methyl-1H-1,2, 4-triazol-5-yl] thio] methyl] -7-oxo-1-azabicyclo [3. 2. 0] hept-2-en-2-carboxylate.

UV (H ₉ O): λ = 278 nm (can be _{erased with NH 0} OH) / max 2

IR (KBr): -5 1738 with shoulder 1755, 1591, 1395 cm " ¹

ITl 3 X

3Λ Λ ι r- f jl U;

• Example 20

0.6 g of pivaloyloxymethyl-rac-trans-2- [3 - [(1-methyl-1H-tetrazol-5-y.l ) -thio] -acetonyl] -3- [1-methyl-l- (trimethylsilyloxy) -ethyl] -4-oxo-a- (triphenylphosphoranylidene) -l- Azetidine acetate followed the cyclization procedure described in Example 8 subjected, with the difference that to remove the trimethylsilyl protective group the chromatographed Cyclization product in 60 ml of methanol in the presence of 0.6 g of ammonium fluoride for 4 hours Room temperature was stirred. It was isolated after .chromatographic Purification 52 mg pivaloyloxymethyl-rac-öa- (l-hydroxy-l-methylethyl) -3 - [[(l-methyl-lH-tetrazol-5-yl) -thio] -methyl] -7-oxo.-5a- 1-azabicycloC3.2. 0] hept-2-en-2-carboxylate as a colorless oil.

UV (EtOH): λ = 296 nm (can be _{erased with NH 0} OH)

max 2

IR (CHCl,): -0> 3690, 3610, 1,779, 1752, 1730, 1622 Cm ^-1 20

The starting material was prepared as follows:

(a) A solution of 8.56 g of rac-4 - [(2-methyl-1,3-dioxolan-2-yl) methyl] -2-azetidinone in 15 0 ml of tetrahydrofuran was at ^{-30 0} C within 65.5 ml of a 1.6M butyllithium / hexane solution were added for 4 minutes and the mixture was then left to stand for 90 minutes in an ice bath in an argon atmosphere. The brown-yellow solution was cooled to -30 ⁰ C and treated with a solution of 3.2 g of acetone in 10 ml of tetrahydrofuran.

The mixture was stirred for a further 30 minutes at 0 ^° C. and the reaction solution was poured onto 50 g of ice. The organic phase was separated off and washed with 50 ml of saturated sodium chloride solution. The combined water phases were extracted with a total of 300 ml of methylene chloride. The organic phases were dried over sodium sulfate, concentrated completely under reduced pressure and the remaining oil was chromatographed on silica gel. A mixture of acetone and methylene chloride (1: 8, v / v) initially eluted unused

Starting material, then rac-cis-3- (1-Hydroxy-1-methylethyl) -4-C (2-methyl-1,3-dioxolan-2-yl) -methyl] -2-azetidinone, which after crystallization from ethyl acetate / Hexane as. 0.80 g of white crystals was obtained of melting point 134-135 ⁰ C. . ·

IR (CHCl3,): C> 3604, 3424, 1751 cm " ¹

Further elution gave rac-trans-3- (1-hydroxy-1-methylethyl) -4 - [(2-methyl-1,3-dioxolan-2-yl) -

methyl] -2-azetidinone comprising 1.59 g .White crystals of melting point 84 ^ 86 ⁰ C resulted from ethyl acetate / Hexlan.

IR (CHCl ₀ ): u> 3604, 3420, 1751 cm " ¹ 3 max

(b) The procedures described in Example 8 (a) and (d) - (i) were carried out in an analogous manner on 4 g of rac-trans-3- (1-hydroxy-1-methylethyl) -4 - [(2-methyl -l, 3-dioxolan-2-yl) methyl] -2-azetidinone applied. 0.96 g of pivaloyloxymethyl-rac-trans-2- [3 - [(1-methyl-1H-tetrazol-5-yl) -thio] -acetonyl] -3- [1-methyl-1- (trimethylsilyloxy) were obtained -ethyl] -4-oxo-a- (triphenylphosphoranylidene) -l-azetidine-. acetate as a colorless oil.

IR (CHCl,): ^ _{m = v} 1744, 1635 cm " ¹

Example 21

The product from Example 20 was subjected to the process described in Example 9 in an analogous manner. A mixture of sodium (5R, 6S and 5S, 6R) -6a- (1-hydroxy-1-methylethyl) -3 - [[(1-methyl-1H-tetrazol-5-yl) -thio3-methyl] was obtained 3-7-oxo-5a-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate.
.

UV (H ₀ O): 'λ = 279 nm (can be _{erased with NH 0} OH) 2 max 2

. 3201-37 59 W-.

. Example 22

230 mg pivaloyloxymethyl-rac-trans-2- [3 - [(1-methyl-IH-tetrazo1-5-yl) -thio] -acetonyl] -4-oxo-3-C (trimethyl- silyloxy) methyl] a (triphenylphosphoranylidene) -1-azetidine acetate were subjected to the procedure described in Example 8, with the difference that the reaction time the cyclization reaction was 30 minutes. After purification by chromatography, 66 mg of pivaloyloxymethylrac-6a- (hydroxymethyl) -3 - [[(1-methyl-1H-tetrazol-5-yl) - thio] methyl] -7-oxo-5a-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate as a colorless oil.

UV (EtOH): λ = 289 nm (can be erased with NH "OH)

max Z

IR (CHCl,): ^ '3440, 1782, 1752, 1619 cm " ¹

The starting material was prepared as follows:

(a) 15.8 g of tert-butyldimethylchlorosilane and 25.2 g rac-4- (3-bromo-2,2-dimethoxypropyl) -2-azetidinone were dissolved successively in 150 ml of dimethylformamide, the solution to 0 ⁰ C cooled and 22.0 g of triethylamine were added with stirring, a precipitate being formed. The mixture was stirred for 15 minutes at 0 ^° C., diluted with 1 l of ether / hexane (1: 1, v / v) and extracted 4 times with 400 ml of water each time. The water phases were back-extracted with 500 ml of ether / hexane (1: 1, v / v), and the organic phases were dried over sodium sulfate and concentrated completely. The remaining oil was taken up in a little hexane and 20 · ⁰ C allowed to stand. 31.3 g was obtained rac-4- (3-bromo-2,2-dimethoxypropyl) -l- (tert-butyldimethylsilyl) -2-azetidinone as white crystals of melting point 61-63 ⁰ C.

(b) 7.06 g of rac-4- (3-bromo-2,2-dimethaxypropyl) -1- (tert-butyldimethylsilyl) -2-azetidinone was subjected to the procedure described in Example 8 (b) in an analogous manner, with the difference that instead of methyl acetate 6.0 g

JZ (, 0 VW: ":

Methyl formate were used. Crystallization of the chromatographically purified product from ether / petroleum ether gave 2.19 g of rac-trans-4- (3-bromo-2,2-dimethoxypropyl) -1- (tert-butyldimethylsilyl) -3-formyl-2- azetidinone as white crystals of melting point 70-72 ⁰ C.

(c) A ^{solution, cooled to 0 °} C., of 788 mg of rac-trans-4-

(3-Bromo-2,2-dimethoxypropyl) -1- (tert-butyldimethylsilyl) -3-formyl-2-azetidinone in 12 ml of methanol was admixed with 38 mg of sodium borohydride and the reaction mixture was stirred for 10 minutes. It was diluted with ethyl acetate, washed with saturated sodium chloride solution, and the organic phase was dried over sodium sulfate and concentrated completely. Crystallization of the residue from ethyl acetate / hexane gave 685 mg of rac-trans-4- (3-bromo-2,2-dimethoxypropyl) -1- (tert-butyldimethylsilyl) -3- (hydroxymethyl) -2-azetidinone as white crystals from melting point 119-120 ⁰ C.

(d) 7.87 g of rac-trans-4- (3-bromo-2,2-dimethoxypropyl) -1- (tert-butyldimethylsilyl) -3- (hydroxymethyl) -2-azetidinone were added to the in Example 8 (i.e. ) and the crystalline reaction product is then stirred in 2 40 ml of methanol in the presence of 0.70 g of ammonium fluoride for 2 0 minutes at room temperature. After aqueous work-up and crystallization of the crude product from ethyl acetate / hexane, 7.66 g of rac-trans-4- (3-bromo-2,2-dimethoxypropyl) -3 - [(2,2,2-trichlorethoxycarbonyloxy) methyl] -2-azetidinone of melting point 108-109 ⁰ C.

(e) The reaction sequence described in Example 8 (f) - (i) was analogously to 5.2 g of rac-trans-4- (3-bromo-2,2-dimethoxypropyl) -3 - [(2,2,2-trichlorethoxycarbonyloxy) methyl] -2-azetidinone applied. 0.2 3 g of pivaloyloxymethyl-rac-trans-2- [3 - [(1-methyl-1H-tetrazol-5-yl) -thio] -acetonyl] -4-oxo-3-C (trimethylsilyloxy) - methyl Ια- (triphenylphosphoranylidene) -l-azetidine acetate as a colorless oil.

320

Example 23

The product from Example 22 was subjected to the process described in Example 9 in an analogous manner. A mixture of sodium (5R, 6S and 5S, 6R) -6a- (hydroxymethyl) -3 - [[(1-methyl-1H-tetrazol-5-yl) -thio] -methyl] -7-oxo was obtained -5a-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate.

UV (HO): λ = 277 nm (can be _{erased with NH 0} OH) λ . max λ

Example 24

41 mg of rac-1- (tert-butyldimethylsilyl) -3- (Z) -ethylidene-4 - [(2-methyl-1,3-dioxolan-2-yl) methyl] -2-azetidinone were dissolved in 2 ml of ethyl acetate hydrogenated in the presence of 50 mg of platinum dioxide at normal pressure. A 6: 1 cis / trans isomer mixture was obtained from which the main component could be obtained in pure form by fractional crystallization of the crude product from hexane: rac-cis-1- (tert-butyldimethylsilyl) -3-ethyl-4- [(2-methyl-l, 3-dioxolan-2-yl) methyl] -2-azetidinone, melting point 80-82 ⁰ C.

The starting material was prepared as follows:

. To a cooled to 0 ⁰ C solution of 330 mg rac- (3 SR, 4RS) -1- (tert-butyldimethylsilyl) -3 - [(SR) -1-hydroxyethyl] -4 - [(2-methyl-l, 3-dioxolan-2-yl) methyl] -2-azetidinone and 400 mg of triphenylphosphine in 20 ml of tetrahydrofuran were added 300 mg of diisopropyl azodicarboxylate and the solution was stirred at room temperature for 1 hour. It was then partitioned between water and ethyl acetate, and the organic phase was dried over sodium sulfate and concentrated completely. The residue was chromatographed on silica gel using ethyl acetate / methylene chloride / hexane (1: 1: 2, v / v / v) as the mobile phase and the purified product was crystallized from hexane. 100 mg of rac-1- (tert-butyldimethylüilyl) -3- (/ ..) - <> l hy 1 i.dfii-4-Γ (2 -methyl-1,4-dioxo 1 an- ?. -

yl) methyl] -2-azetidinone as colorless crystals from Melting point 85-86 ° C.

IR (CHCl ₀ ): -ν 1722 cm "
3 max

Example 25

1.04 g of rac-cis-1- (tert-butyldimethylsilyl) -4- C (2 - * - methyl-1,3-dioxolan-2-yl) methyl] -3- [1-methyl-1- [(2,2,2-trichloroethoxycarbonyloxy) ethyl] -2-azetidinone were subjected to the procedure described in Example 8 (e) in an analogous manner, with the difference that the bromination was carried out at a temperature of 45 ° C- Man After purification by chromatography and crystallization from ethyl acetate / hexane, 0.54 g of rac-cis-4- (3-bromo-2,2-dimethoxypropyl) -3- [1-methyl-1- (2,2,2-trichloroethoxycarbonyloxy) isolated ) ethyl] -2-azetidinone as colorless crystals of melting point 104-106 ⁰ C. ■

ir (CHCl ₃ ): '^ _max 1765 cm " ¹

The starting material was prepared as follows:

rac-cis -3- (1-hydroxy-1-methylethyl) -4 - [(2-methyl-1,3-dioxolan-2-yl ) .- methyl] -2-azetidinone was reacted in analogy to the processes described in Example 8 (a) and (d). After crystallization from hexane, rac-cis-1- (tert-butyldimethylsilyl) -4 - [(2-methyl-1,3-dioxolan-2-yl) methyl] -3- [1-methyl-1- (2,2,2-trichloroethoxycarbonyloxy) ethyl] -2-azetidinone, melting point 89-91 ° C.

Example 26

Using (-) - (3S, 4R) -1- (tert-butyldimethylsilyl) 3 - [(R) -1-hydroxyethyl] -4 - [(2-methyl-1,3-dioxolan-2-yl) methyl] -2-azetidinone as starting material for the reaction sequence described in Example 8, proceeding from step (d), and the product is subjected to that in Example 9

32C V ~:

The process described above gives sodium (5R, 6S) 6-C (R) -1-hydroxyethyl] -3 - [[(1-methyl-1H-tetrazol-5-yl) -thio] -methyl] -7 -oxo-1-azabicyclo [3.2.0] hept-2-en-2-carboxylate.
5

UV (H ₀ O): λ = 278 nm (can be _{erased with NH 0} OH) 2 max 2

The starting material was prepared as follows:

(a) A cooled to 0 ⁰ C solution of 19.8 g of rac- (3SR, 4RS) ~ 1- (tert.-butyldimethylsilyl) -3 - [(RS) -1-hydroxyethyl] -A- [(2- methyl-1,3-dioxolan-2-yl) methyl] -2-azetidinone in 120 ml of pyridine was admixed with 18.8 g of (-) - camphanic acid chloride. The mixture was stirred for 22 hours at room temperature.

Then the reaction mixture was diluted with 1.2 l of ethyl acetate and successively with 360 ml of dilute sodium hydrogen carbonate and saturated sodium chloride solution. The water phases were washed with 1 l of ethyl acetate back-extracted, the combined organic phases dried over sodium sulfate, concentrated completely and the Chromatographed residue on silica gel. A mixture of ethyl acetate / methylene chloride / hexane (1: 6: 6, v / v / v) eluted first a (+) - rotating camphanic acid ester, which could be crystallized from ether / hexane. One received (+) - (3R, 4S) -l- (tert-butyldimethylsilyl) -3-C (lS) -lcamphanoyloxyethyl] -4- [ (2-methyl-1,3-dioxolan-2-yl) methyl] -

? 0 2-azetidinone with melting point 125-127 ° C and [a] ^ = + 15.0 °

(c = 1, EtOAc). After a few mixed fractions, fractions were obtained which had a (-) - rotating component from the main component Contained camphan esters. This would be purified by crystallization from ether / hexane. One received (-) - (3s, 4r) -1- (tert-Butyldimethylsilyl) -3.-C (IR) -1-camphanoyloxyethyl] -4 - [(2-methyl-1,3-dioxolan-2-yl) -methyl] -2-

20 azetidinone with melting point 112-113 ° C and [α] = -19.9 ° (c = 1, EtOAc).

LH

(b) A solution of 0.5 g of (-) - (3S, 4R) -l- (tert-butyldimethylsilyl) -3 - [(lR) -l-camphanoyloxyethyl] -4 - [(2-methyl-1 , 3-dioxolan-2-yl) methyl] -2-azetidinone from step (a) in 10 ml toluene was added at 0 ⁰ C and 4 ml of a 1,12Μ solution of diisobutylaluminum hydride in hexane was added and the reaction mixture then for 2 hours stirred at room temperature. It was poured onto saturated sodium chloride solution and extracted with ethyl acetate. The organic phases were washed again with saturated sodium chloride solution, dried over sodium sulfate and concentrated completely. The remaining oil was chromatographed on silica gel with ethyl acetate / hexane (1: 1, v / v) as the eluent. After two crystallizations from hexane, (-) - (3S, 4R) -I- (tert-butyldimethylsilyl) -3-

.15 [(R) -l-hydroxyethyl] -4- [(2-methyl-l, 3 ~ dioxolan-2-yl) methyl] -2-azetidinone with melting point 83-84 ⁰ C and Cot] - = ± -50.8 ° (c = 1, EtOAc).

Example 27
20th

A solution, cooled to 0 ^° C., of 10 mg of sodium (5R, 6S and 5S, 6R) -6 - [(R and S) _r 1-hydroxyethyl] -3 - [[(1-methyl-tetrazole-1 H-5 -yl) -thio] -methyl] -7-oxo-1-azabicyclo- [3.2.0] hept-2-en-2-carboxylate in 0.2 ml of dimethylformamide was mixed with 7 mg of bromomethyl acetate and then for 1 hour at room temperature touched. It was diluted with ethyl acetate, washed with 0.05M pH 7 phosphate buffer, dried over sodium sulfate and concentrated completely. Chromatography of the residue on silica gel with ethyl acetate / methylene chloride as the eluent gave 1/8 mg of acetoxymethyl- (5R, 6S and 5S, 6R) -6 - [(R and S) -l-hydroxyethyl] -3 - [[(1-methyl -lH-tetrazol-5-yl) -thio] -methyl] -7-oxo-1-azabicyclo- [3.2.0] hept-2-ene-2-carboxylate as a pale yellow oil.

UV (EtOH): λ = 295 nm (can be erased with NH OH)

- C -t - 'Hill \ IU-L L. 1Λ111_ι'

max 2

..,. J
3 max

IR (CHCl-.): Ν 1771, 1738

320: "'" 7

example

By analogous use of the above Examples of procedures described in Table I

5 listed compounds of formula I are prepared. In some circumstances it can be an advantage to change the order to change the reaction steps or, in certain cases, to use different protective groups. The connections 28), 30), 43) and 44) are implemented by implementing the

10 fertilize 27), 29), 41) or 21) according to generally known methods Methods obtained, for example, with methyl formimidate in aqueous solution at pH 8-8.5.

3 2 U: //

CH ₂ -XJ

COOH

Table I.

link R ¹ H R ² X salt 1) -CH ₂ CH ₃ N -
..AJ N / A H I.
CH ^ ³ 2) H -CH ₂ CH ₃ Il 3) OH
j -CH ₂ CH ₃ ΙΧΧΓ. Il -CHCH ₂ CH ₃ 4) OH H N - M. -CHCH ₂ CH ₃ ~ ^s ι 5) OH H N-N
_.AJ II -CHCH ₂ CH ₃ I.
CH ₂ COONa 6) OH
-CH-CF ₃ H It 7) H NN
.-. AJ M. OH
-CH-CP I.
CHj 8th) H N N Il

3201

link R ¹ I. Il R ² H X ³ ν '^ p salt 9) OH
ι
-CH-CF ₃ Il H --'S ' ¹ J ^ COOCH ₂ CH ₃
H N / A 10) OH
1
-CH-CH ₃ j Il AX
-6 j COOCH ₂ CH ₃ It 11) Il Il CH CH ₃
/ »- ^q 3 Il Il Il 12) ti η - 13) Il H N / A Il . «A $ ' 14) ». It S-- N
^ A.K
- * CH ₃ Il 15) Il S-S Il " 16) Il S ^^^ COONa Il 17) Il Il 18) Il Il 19) Il

link R ¹ R ² X CHj-NH-CH-NH salt 20) OH
-CH-CH ₃ H / CH, CH, OH
(J-rf n — n
-AX
CHj-CHj-NHj N / A 21) Il Il -.AXT ""' ^: dl,
-3 '" CHjCHjNH-CH-NH -. " 22) Il Il N / A 23) Il Il M. 24) Il Il CONH j Il 25) ■ ' '· "" ■ ^s COONa Il. ^CH 3 \ _n _ _n 26) Il Il Il 27) Il · ' N-N
_, Αιι'Λ - 28) Il M. -3 _X
N-N 29) Il Il - 30) Il Il

23 '

link R ¹ i R ² I. X I. salt 31) OH
1
-CH-CH ₃ H i N / A 32) Il Il CH ₃
-N ^{/ H} Il 33) ■ ' ^CH3 \ _
- S ^ "CONHCKjCHjNHj - 34) Il CH ₃ CH _2x ^ CONH ₂ N / A 35) Il Il HjN. - 36) Il ·· HjN _X y NH-NHj - N = C>. yOYi - 37) Il Il N / A 38) Il Il N -N
AJ
I.
NHj Il 39) Il Il N -N Il COOCH ₃ N -N 40) Il Il It CHj-COONa 41) Il Il N -N
"^ I I.
CHjCHjNHj

J i. U

link i R ¹ R ² X O salt 42) OH
I.
-CH-CH ₃ H N -
-, AJ
/ CHj
CHjCHj-N
^{2 2} CH ₃ _ £) - 43) .. Il N -
-AJ O }
CHjCHj-NH-CH-NH -Xj "" " 44) M. Il ■ • CHjCHjNH-CH-NH -, xj ^i: "' - O 45) Il Il ., Xj "" N / A O
Il 46) Il Il It 47) Il Il ι ^c " ³
CH ₃ - 48) Il Il 0
Il - Λ 49) Il Il - ι °
H N / A 50) Il M. - 51) Il Il N / A

link R ¹ R ² X salt 52) OH
-CH-CH ₃ H X ^^ COOCH ₂ CH ₃ N / A 53) * Il Il 0
Jl
. »" ** "^ ** · OCHjCHjCHjCllj
-XJ Il ΜΗΝΗ, 54) Il ■■ - 55) Il Il -JO
I.
H
ι N / A 56) Il Il Il H 57) ■ · X X
--S ^^^ ~ ^N NHCH ₃ Il 58) ■ · Il N ^ J Il 59) Il ■■ fl OH 60) ■ I Il I | * ^CH 1 61) Il Il » 62) Il Il -Ρ
CO0N.1 Il

JZU ι . J ί

link R ¹ OH R ² X salt -CH-CH ₃ 63) H - CONHCH ₂ CH ₂ NH ₂ M. NH ₂ 64) Il Il X ^ V'CN N / A 65) H -JX Il Il O 66) Il I. Il I.
OCHjCHjCHj · Il CHj 67) Il ¹¹ M. cn 68) Il Il. Il CH ₃ 69) Il Il Il 70) It O
39
-0-C-CH ₃ Il H. OH _CH N-N 71) M. ~ ^{C <} " ^CH 3 L, ■ 72) Il . IXX "* · Il Il N -N · '. 73) Il I,
CH ₂ CH ₂ H

Example 29

Manufacture of dry ampoules for intramuscular administration:

A lyophilizate of 500 mg of sodium (5R, 6S) -6 - [(R) -l-hydroxyethyl] -3 - [[(1-methyl-1H-tetrazol-S-yD-thioü-methylü -T-oxo-l-azabicycloES ^. O] - · hept-2-en-2-carboxylate and filled into an ampoule. Before administration, the lyophilisate is with 2.5 ml of a 2% aqueous lidocaine hydrochloride solution are added.

Example 30

15 ■

A gelatine capsule of the following composition is produced in the usual way:

Pivaloyloxymethyl- (5R, 6S) -3-C [(1-ethyl-1,2-dihydro-2-oxo-4-pyrimidinyl) thio] methyl] - 6 - [(Rj-l-hydroxyethylJ-T-oxo-l-azabicyclo-

[3.2.0] hept-2-en-2-carboxylate

Luviskol (water-soluble polyvinylpyrrolidone)

Mannitol. 25 talc magnesium stearate

55 7 mg

500 mg 20th mg 20th mg 15th mg 2 mg

Example 31

A tablet of the following composition is produced in the usual way:

Pivaloyloxymethyl- (5R, 6S) -3 - [[(1-ethyl-1,2-dihydro-2-oxo-4-pyrimidinyl) -thio] -methyl] -6 - [(R) -l-hydroxyethyl] - 7-oxo-1-azabicyclo- [3.2.0] hept-2-ene-2-carboxylate
Lactose

Cornstarch. Polyvinylpyrrolidone magnesium stearate

400 mg

With the active ingredient, the lactose, the polyvinylpyrrolidone and 40 parts by weight of the corn starch in common Way made a granulate. This is made with the remaining 25 parts by weight of corn starch and 5 parts by weight Magnesium stearate mixed and compressed into tablets.

250 mg 70 mg 65 mg 10 mg 5 mg

Claims (21)

3r> _ r>, y \ "r ~ Claims 1. Bicyclic compounds of the general formula COOH 12 wherein one of the substituents R and R is hydrogen and the other is hydrogen or a substituted or unsubstituted C _1. -Alkyl group and X is a ^ g substituted or unsubstituted C. - alkanoyloxy group, an unsubstituted or substituted C,., - Cycloalkylthio, C ₂ _g-alkenylthio or heterocyclylthio radical or a substituted C ₁ ^ .- alkylthio or phenylthio radical, their easily hydrolyzable Esters, pharmaceutically acceptable salts and hydrates of these compounds. 2. Compounds according to claim 1, characterized 1 2 shows that one of the substituents R and R is water 25. Substance, and the other hydrogen, C. .- alkyl or C. .. -alkyl substituted by fluorine, chlorine, bromine; a radical -S (O) -R ¹ with η = 0, .1, 2 and R ¹ = C -alkyl; a radical -CO-R 'with R ¹ = hydroxy, C. --alkoxy, C ₁ --alkyl, amino, C ₁ T-alkylamino or di-C ₁ --alkylamino; an amino radical -NR ¹ R ", where R ¹ and R" represent hydrogen or C. - alkyl; or a residue OR ^1, with R _{"(1 4} alkyl = C ¹ = hydrogen, methyl, SO ₃ H, CH ₂ OCOR R"). 3. Compounds according to claim 2, characterized 1 2 indicates that one of the substituents R and R is hydrogen and the other is hydrogen, ethyl, hydroxymethyl, 1-hydroxyethyl, 1-hydroxypropyl, 1-hydroxy-2,2,2-trifluoroethyl or 1-hydroxy-1-methylethyl. OZ.U ί, -Jl 4. Compounds according to one of claims 1-3, characterized in that X is C ^ -j-alkanoyloxy or C _{1 3} -alkanoylöxy substituted by hydroxy, C ^ - alkoxy, phenyl or C ₁ - alkylthio. 5. Compounds according to any one of claims 1-3, characterized in that XC ₁ _ ₄ ~ substituted by alkylthio Phenyl, which can be substituted by one or more fluorine, chlorine or bromine atoms, C ^^ - alkyl, C ^ ₄ -alkylthio, C. .., - alkanoyl, carboxyl or C. ₃ ~ alkoxycarbonyl groups; or by a group - · - (CH-) -NRR ¹ or - (CH ₂ J _n -NH ^- CR = NR 'or - (CH ₃ ) _n -N = CR-N (R') ₂ , where η = May be 0, 1, 2, 3 and R and R ^{1 is} H or C. .., - alkyl; Fluorine, bromine; an oxime or oxime ether radical = N-OR '(R' = H or 'C _1. , - alkyl) in the syn or anti position; a 3-7-membered, monocyclic, saturated, unsaturated or aromatic heterocycle with 1-4 heteroatoms (N, O, S; which can be substituted by one or more fluorine, chlorine or bromine atoms, C _1. , - alkyl- , _{C1-alkylthio.,} C alkanoyl, carboxyl or C _{1 3} alkoxycarbonyl groups; or a group - (CH-) -NRR ¹ or - (CH ₂₎ J ₁ is -NH-CR = NR ¹ or - (CH ₂ J _n -N = CR-N (R ') _2, it being possible for η = 0, 1, 2, 3, and R and R ¹ is H or C _{1 3} alkyl, as well as by oxo groups); a C ₃ -C -cycloalkyl radical; a radical -S (O) -R ¹ (with η = 1 or 2 and R ¹ = C ₁ _ ₃ alkyl); a radical -COR ¹ [with R ¹ = c> ₃ ~ alkyl, phenyl, phenyloxy, benzyloxy, C g -cycloalkyl or a 3-7-glie- 320-057 DS ' driger heterocycle with 1-4 heteroatoms (N, 0, S), which can be substituted in the above manner, means. 6. Compounds g ^ mass one of claims 1-3, characterized in that X substituted phenylthio by one or more fluorine, chlorine or bromine atoms, one of the groups - (CH-) - NRR ¹ , - (CH ₇ ) - NR-CR '= NR "and - (CH-) -N = CR-NR ¹ R" (with η = 0, 1, 2, 3 and R, R ¹ and R "H or C ₁ , -alkyl, C ₁ , -alkanoyl) or by C., -alkyl, C ₁ , -alkanoylamino, hydroxy, C., -alkoxy or acyloxy groups. 7. Compounds according to any one of claims 1-3, characterized in that XC ₃ - cycloalkylthio or C 1 - cycloalkylthio substituted by one or more oxo- ', hydroxy, C _1. -Alkyl-, C.. -Alkoxy -, carboxyl or alkoxycarbony! Groups or by one of the groups - (CH ₉ ) -NRR ¹ , - (CH ₉ ) -NR-CR '= NR "and - (CH,) -N = CR-NR ¹ R" £ * Xl * ^. Xx & Xl (with η = 0, 1, 2, 3 and R, R ¹ and R "H or C ₁ _ ₃ ~ alkyl, C ₁ - alkanoyl) or by one or more acyl radicals of an aliphatic or aromatic C. - carboxylic acid means. 8. Compounds according to any one of claims 1-3, characterized in that XC ₂ _ _g -alkenylthio or C ", -alkenylthio substituted by one of the groups - (CH ₀ ) -NRR ', - (CH ") -NR-CR' = NR" and - (CH-) -N = CR-NR ¹ R " Zn Zn 2 η (with η = 0, 1, 2, 3 and R, R ¹ and R "H or C. ^ - alkyl, C ._, - alkanoyl) or by C., -alkyl, phenyl, a 3-7- membered saturated, unsaturated or aromatic heterocycle with 1-4 heteroatoms (nitrogen, oxygen, sulfur), cyano, carboxyl, C ₁ alkoxycarbonyl, aminocarbonyl or acylamino. JZU i:, ü! ♦ « 9. Compounds according to any one of claims 1-3, characterized in that X is a 4-7-membered, monocyclic, saturated, unsaturated or aromatic heterocycle with 1-4 heteroatoms)! (N, 0, S) represents, which may be substituted by fluorine, chlorine, bromine, oxo, imino, C ₁ .-- alkyl, C alkylthio, hydroxy, cyano, N-oxido, trifluoromethyl, C. .- alkoxy, C,.-Alkanoyl.oxy, phenyloxy, C., alkanoyl, phenoxycarbonyl, ■ pivaloyloxymethoxycarbonyl, carbamoyl, C ₁ --Alkylcarbamoyl and / or di-C ₁ o-alkyicarbamoyl or by - (CH ₇₎ NRR ^1, - (CH_) NR-CR '= NR "or - (CH ₂ ) ^ N = CR-NR ¹ R" with η = 0, 1, 2, 3 and R, R' and R "= H, C. - -Alkyl, C. ₃ alkanoyl; or by - (CH ₂ J _n COR ¹ with η - 0, 1, 2, 3 and R ^l = hydroxy, C _1-3 "alkoxy, amino or -NH- (CH ₂ ) -NH ₂ , in which m = 2, 3, 4; or by - (CH ₂ J _n OH with η = 0, 1, 2, 3 means. 10. Compounds according to any one of claims 1-3, characterized in that X is 2- (acetylamino) vinylthio, (1-methyl-1H-tetrazol-5-yl.) -thio, (1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl) -thio, (2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) thio, (1-ethyl-1,2-dihydro-2-oxp-4-pyrimidinyl) thio, (5-methyl-1,3,4-thiad.iazol-2-yl) -thio or means acetoxy. 11. Compounds according to any one of claims 1-10, such as they are defined as end products in any of Examples 1-3. 12. Compounds according to any one of claims 1-10, as defined as end products in one of Examples 4-28 are. 3 2C1C57 • 13. Compounds according to any one of claims 1-10 of the general formula; -. )H Yes COOH and their easily hydrolyzable esters, pharmaceutically acceptable salts and hydrates of these compounds. 14. Compounds of the general formula Hy-X Il wherein R, R, R, R, R, R and X have the meaning given in claim, where X also mean bromine can. 15. Compounds according to any one of claims 1-13 as active pharmaceutical ingredients. 16. Compounds according to any one of claims 1-13 as active pharmaceutical ingredients for treatment and prophylaxis of infectious diseases. 17. Pharmaceutical preparations, characterized by a content of a ■ compound according to one of the claims 1-13. O ί. 18. Pharmaceutical preparations for the treatment and prophylaxis of infectious diseases, characterized by a content of a compound according to any one of claims 1-ί3. 19. A method for producing a compound according to Claim 1, characterized in that one ■ bond of the formula _R 2 μ _R 1 10 ^H COOR 1 2
wherein R, R and X are defined as x in claim 1, R is an easily cleavable radical and R; R and R represent C. g-alkyl, phenyl or p-methoxyphenyl, cyclized, optionally splitting off the protective group present in a substituent and, if desired, the ester obtained is transesterified, if necessary by cleavage of the radical R into the free acid or its salt if necessary, a product obtained is converted into a hydrate. 20. The method according to claim 19, characterized in that 4 5-6 that R, R and R each represent a Pheriylrest. 21. Use of a compound according to any one of claims 1-13 in the treatment or prophylaxis of infectious diseases.