IE52421B1 - Carbapenen compounds - Google Patents

Abstract

There are described bicyclic compounds of the general formula wherein one of the symbols R<1> and R<2> represents hydrogen and the other represents hydrogen or a substituted or unsubstituted C1-4-alkylgroup and X represents a substituted or unsubstituted C1-3-alkanoyloxy group, an unsubstituted or substituted C3-7- cycloalkylthio, C2-6-alkenylthio or heterocyclylthio group or a substituted C1-4-alkylthio or phenylthio group, their readily hydrolyzable esters, pharmaceutically compatible salts as well as hydrates of these compounds. There are also described the manufacture of these substances and their use in the treatment or prophylaxis of infectious diseases as well as intermediates useful in the manufacturing process.

Description

The invention is also concerned with processes for the manufacture of the compounds defined hereinbefore, pharmaceutical preparations based on these compounds and their manufacture, as well as the use of these compounds as medicaments, especially for the treatment and prophylaxis of infectious diseases.

C1_4-alkyl groups can be straight-chain or branehed-chain. Substituted C^_4~alkyl groups can have the following substituents: fluorine, chlorine, bromine; a group -S(O)n-R' in which n is 0, 1 or 2 and R1 is Cj,_3-alkyl; a group -CO-R' in whioh R* is hydroxy, C^-alkoxy, C1_3-alkyl, amino, C1_3~alkylamino or di-C^_3~ -alkylamino; an amino group -NR'R in which R'-and R represent hydrogen or C^_3-alkyl; or a group -OR' in which R' is hydrogen, methyl,- -SOjH or -CHjOCOR wherein R is Cp^-alkyl. 2 Examples of substituents denoted by R /R are: methyl, ethyl, isopropyl, 3-chloropropyl, mesyImethyl, 2-(methoxycarbonyl)-ethyl, hydroxymethyl, 1-hydroxyethyl, 1-hydroxypropyl, 1-hydroxy-l-methylethyi , -3-methaxypropyl, 1-sulphoxyethyl, l-hydroxy-2,2,2-trifluoroethyl, l-(pivaloyloxymethoxy) -ethyl and 1-aminoethyl. · The following come into consideration as substituents in the X-group: C1_3~alkanoyloxy groups can be substituted by hydroxy, Cj_3-alkoxy, phenyl or C^_3-alkylthio.

Substituted C1_4~alkylthio groups can carry one or more substituents R, whereby R can signify: Phenyl, which in turn can be substituted by one or more fluorine., chlorine or bromine atoms, C^_3~alkyl, C1_4~alkylthio, C1_3~alkanoyl, carboxyl or Cj_3~alkoxyoarbonyl groups; or by 'a group -(CH2)n~NRR' or -(CH2)n-NHCR»NR' or -(CH,) -N=CR-N(R'), in which n can be 0, 1, ζ η z 2 or 3 and R and R' are hydrogen or C^_3-alkyl; fluorine, bromine; an oxime or oxime ether group =N-0R' (wherein R' is hydrogen or C2_3~alkyl) in the syn- or antiposition; a 3-7 membered monocyclic, saturated, unsaturated or aromatic heterocycle containing 1-4 hetero atoms (nitrogen, oxygen, sulphur; which can be substituted by one or more fluorine, chlorine or bromine atoms, Cj_3-alkyl, Cj_4-alkylthio, C^j-alkanoyl, carboxyl or C^^-alkoxycarbonyl groups; or a group -(CHj^-NRR1 or - (CHj) n-NH-CR=NR' or -(CH2)n-N=CR-N(R')2 in which n can be 0, 1, 2 or 3 and R and R' are hydrogen or Cp^-alkyl, as well as by oxo groups); a C3_g-cyoloalkyl group; a group -S(0)^-8' (wherein n is 1 or 2 and R' is 5 C^-alkyl); a group -COR' [wherein R' is Cj_3-alkyl, phenyl, phenyloxy, benzyloxy, C3_g-cycloalkyl or a 3-7 membered hererocycle containing 1-4 hetero atoms (nitrogen, oxygen, sulphur), which can be substituted in the manner described above].

Substituted phenylthio groups can be substituted by one or more fluorine, chlorine or bromine atoms, one of the groups -(CH,) -NRR', -(CH,) -NR-CR'-NR and -(CH,) 2 n i η 2 n -N-CR-NR'R (wherein n is 0, 1, 2 or 3 and R, R' and Rf are 15 hydrogen, C^_3-alkyl or C^_3-alkanoyl) or also by C^_3~ -alkyl, C^_3~alkanoylamino, hydroxy, C^_4-alkoxy or acyloxy groups.

C3_7“cycloalkylthio groups can be substituted by one of the groups -(CH,) -NRR', -(CH,) -NR-CR'-NR and -(CH,) 20 -N-CR-NR'R (wherein n is 0, 1, 2 or 3 and R, R' and R are hydrogen, Cj_3~alkyl or C1_3~alkanoyl, or by oxo, hydroxy, Cj_4-alkyl, C^_4~alkoxy, carboxyl or alkoxycarbonyl groups or by acyl groups of an aliphatic or aromatic C^_y-carboxylic acid.

C2_g-alkenylthio groups can have 1 or 2 double bonds and can be substituted by one of the groups -(CH2)n-NRR', -(CH,) -NR-CR'«NR” and -(CH,) -NCR-NR'R (wherein n is 2 n l n 0, 1, 2 or 3 .and R, R' and R are hydrogen, C^^-alkyl or C1_3~alkanoyl) or also by c^-alkyl, phenyl, a 3-7 membered saturated, unsaturated or aromatic heterOcycle con taining 1-4 hetero atoms (nitrogen, oxygen, sulphur); cyano, carboxyl, C1_4~alkoxyoarbonyl, aminocarhonyl or acylamino.

Heterocyclylthio groups are preferably 4-7 membered and monocyclic and can be saturated, unsaturated or aromatic. They preferably contain 1-4 hetero atoms (nitrogen, oxygen, sulphur). They can be mono-substituted or multiply-substituted by fluorine, chlorine or bromine, an oxo or imino group or-a C|_5-alkyl, C^_’3- . -alkylthio, hydroxy, cyano, N-oxido, trifluoromethyl, C1_4~alkoxy, C^_4~alkanoyloxy, phenyloxy, C1_4~alkanoyl, phenoxycarbonyl, pivaloyloxymethoxycarbonyl, carbamoyl, Cj_3-alkylcarbamoyl or di-C^_3-alkylcarbamoyl group or by -(CH,) -NRR', -(CH,) -NR-CR'=NR or -(CH,) -N=CR-NR'R n 2 n 2 n wherein n is 0, 1, 2 or 3 and R, R' and R are hydrogen, C^j-alkyl, C-^-alkanoyl; or by -(CHj^COR1 wherein n is 0, 1, 2 or 3 and R* is hydroxy, C^_3-alkoxy, amino or -NH-(CH2)in-NH2 in which m is 2, 3 or 4? or also by -(CH,) OH wherein n is 0, 1, 2 or 3. ζ n Examples of groups denoted by X are: 2-(acetylamino)-vinylthio, (l-methyl-lH-tetrazol-5-yl}-thio, (1,4,5,6tetrahydro-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-l,2-dihydro-2-oxo-4-pyrimidinyl)-thio, (5-methyll,3,4-thiadiazol-2-yl)-thio and acetoxy..

As readily hydrolyzable esters of the compounds of formula I there are to be understood those esters which are cleaved especially under physiological conditions. Examples of such esters are the lower alkanoyloxyalkyl esters (e.g. the acetoxymethyl, pivaloyloxymethyl, 1-acetoxyethyl and 1-pivaloyloxyethyl ester), the lower alkoxycarbonyloxyalkyl esters (e.g. the methoxycarbonyloxymethyl, 1-ethoxycarbonyloxyethyl and 1-isopropoxycarbonyloxyethyl ester), the lactonyl esters (e.g. the phthalidyl and thiophthalidyl ester), the lower alkoxymethyl esters (e.g. the methoxymethyl ester) and the lower alkanoylamidomethyl esters (e.g. the acetamidomethyl ester), the benzyl and cyanomethyl esters, as well as the (2-oxo-1,3-dioxol-4-yl)-methyl ester. The term lower, as used above, refers to groups containing 1 to 4 carbon atoms.

Examples of salts of the compounds of formula I are s alkali metal salts such as the sodium salt and the potassium salt, 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 Ν,Ν'-dibenzylethylene-diamine) as well as salts with amino acids such as, e.g., salts with arginine or lysine. The salts can be mono-salts, di-salts or tri-salts. The salt formation can be effected not only on the carboxyl group in the 2-position but also on a group of a substituent which is capable of salt formation.

Further, the compounds of formula I can form addition salts with organic or inorganic acids. Examples of such salts are hydrohalides (e.g. hydrochlorides, hydrobromides or hydroiodides) and other mineral acid salts (e.g. sulphates, nitrates, phosphates and the like), alkylsulphonates and monoarylsulphonates such as ethanesulphonates, toluenesulphonates, benzenesulphonates and the like and salts with other organic acids such as acetates, tartrates, maleates, citrates, benzoates, salicylates, ascorbates and the like.

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

The compounds provided by the invention can be manufactured by cyclizing a compound, of the formula 2 wherein R , R and X have the significance given above, R^ is a readily cleavable group and R , 6 R and R represent C^_g-alkyl, phenyl or p-methoxyphenyl, if necessary cleaving off protecting groups present in a substituent and, if desired, re-esterifying the ester obtained, if desired converting an ester into the free acid or salt thereof by cleavage of the group R^ and, if desired, converting a product obtained into a hydrate.

The cyclization of a compound of formula II can be carried out in a manner known per se, preferably in an inert organic solvent (e.g. ethyl acetate, benzene, toluene, xylene or dioxan) at a temperature between about 50°C and 150°C. ' - ίο By cleavage of the group R3 from the ester group in a manner known per se there are obtained the corresponding free acids of formula I or their salts. The term readily cleavable group used in connection with R3 means a group which permits an ester cleavage under mild conditions, especially reductively (e.g. hydrogenolytically) or hydrolytically (e.g. enzymatically). Examples of suitable groups denoted by R3 are benzyl (whereby the phenyl ring can be substituted by halogen, nitro, alkoxy or acyloxy), preferably o- and p-nitrobenzyl or p-methoxybenzyl, benzhydryl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-iodoethyl, 2-trimethylsilylethyl, aoetonyl or allyl. R can also represent the.group of an ester whioh is cleavable under physiological conditions such as have been mentioned earlier as readily hydrolyzable esters.

The conversion of free acids of formula X or their salts into readily hydrolyzable esters can be carried out in a manner known per se; for example, by reaction with a reactive esterifying reagent such as, for example, a com20 pound X-CH2-O-CO-R or in which X can be bromine, iodine or another leaving group, R can be a straight-chain or branched-chain C1_4-alkyl group and R' can be hy5 drogen or a usual substituent.

A re-esterification is conveniently carried out via the free acid.

Of course, a substituent present in a compound I can also be modified within the scope of the given definitions ]_□ by means of generally known reactions.

The compounds of formula I are generally not isolated as the free acids, but are obtained directly as their salts or the hydrates of these salts in the course of the manufacturing process and purification process. Thereby, salt formation can also be effected on an optionally present substituent which is capable of salt formation (e.g. a hydroxy or amino group). Further, it is possible for a basic group in a substituent (e.g. an amino group or an amidino group) to form an internal salt with an acidic 2o group (e.g. the carboxyl group in the 2-position). A salt-exchange can be carried out according to 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, whereby the products can be purified by crystallization or chromatography. 52431 Hydrates are for the most part obtained automatically in the course of the manufacturing process or as a result of the hygroscopic properties of an initially anhydrous product. For the controlled manufacture of a hydrate, a completely or partially anhydrous product can be exposed to a moist atmosphere (e.g. at about +10°C to +40°C).

The compounds provided by the present invention are generally obtained as a 5R/5S mixture. When the mixture is a 1:1 mixture, then the stereochemistry of the product is denoted by the notation rac-(5RS,etc), for example pivaloyloxymethyl rac-(5RS,6SR)-6-[ (RS)-1-hydroxyethyl]-3-[[(l-methyl-lH-tetrazol-5-yl)-thio] -methyl]-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate. If,on the other hand, there are obtained mixtures which are not exactly 1:1, which can be the case with products of enantioselective reactions, for example of enzymatic reactions, then their stereochemistry is characterized by the notation (5R,etc and 5S, etc), for example sodium (5R,6S and 5S,6R)-6-hydroxymethy1-3-[C(1-methyl-lH-tetrazol20 -5-yl)-thio]-methyl]-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

The present invention embraces, however, not only these mixtures, but especially also the pure 5R forms. Resolution of the 5R/5S mixtures into the pure 5R or 5S forms can be carried out according to one of the classical methods, con52421 venlently at a preliminary stage. Thus, for example, a diastereomeric pair of salts of a racemic compound of formula XI or a pair of diastereomeric derivatives of a compound of formula VIII-1 can be separated. The racemate resolution can also be carried out at the stages of the compounds of formulae XI, X, VIII or VII.

A special sub-group of compounds provided by the present invention comprises compounds of the formula wherein X has the significance given above, as well as their readily hydrolyzable esters, pharmaceutically compatible salts as well as hydrates of these compounds. Particularly preferred are compounds in which the configuration at the centres 5 and 6 and in the substituents in the 6-position correspond to those of natural thienamycin, for example sodium (5R,6S)-6-[(R)-l-hydroxyethyl]-3-[[(l-methyl-lH-tetrazol-5-yl)-thio]-methyl]-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

The starting materials of formula II can be prepared as illustrated in the following Reaction Scheme in which R^ and 2 R are as hereinbefore defined and R' represents an alkyl group containing 1-4 carbon atoms: Reaction Scheme E tOOC^^X^ OH Γϊ Γϊ (J C) VJ ~~ \_/ XIV XIII VII Reaction Scheme (continued) R2 H COOR3 R2 H COOR3 III II Having regard to the foregoing Reaction Scheme, reduction of ethyl 3,3-ethylenedioxybutyrate (XIV, with diisobutylaluminium hydride in hexane/tetrahydrofuran at -80°C to -60°C yields 3,3-ethylenedioxybutyraldehyde (XIII) whioh can be converted by reaction with, for example, txiethyl phosphonoaoetate in a mixture of methylene chloride and 28% aqueous sodium hydroxide in the presence of benzyl triethylammonium chloride into a E/Z mixture of ethyl 5,5-ethylenedioxy-2-hexenoate (XII). Ethyl 3-amino-5,5-ethylenedioxy10 -caproate (XI) can be obtained by the addition of ammonia under normal pressure or elevated pressure (autoclave) to the unsaturated ester of formula XII, the E- and the Z-isomer being equally suitable. The reaction is preferably carried out in alcohol saturated with ammonia at a temp15 erature between 20°C and 100°C. Cyclization of the saturated ester of formula XI to 4-(2,2-ethylenedioxypropyl)-2-azetidinone (X) can be carried out in a manner known per se; for example, by reaction with trimethylchlorosilane in the presence of triethylamine and sub20 sequent treatment with 1 equivalent of ethylmagnesium bromide. 2 The introduction of a substituent R or R in the 3-position of the azetidinone of formula X with the formation of a compound of formula VIII can be carried out in a manner known per se by reacting the intermediately produced dilithium salt of formula IX /from the azetidinone of formula X with 2 equivalents of an alkyl lithium com52421 pound (e.g. butyl lithium) in tetrahydrofuran at -20°C to +2O°C_7 with a corresponding electrophilic reagent, conveniently under a protective gas, at a temperature between -1OO°C and +50°C. An alternative procedure for 1 2 the introduction of the substituents R and R in the 3-position of the azetidinone ring of a conpound of formula X consists in firstly replacing the β-lactam hydrogen by a trialkylsilyl group such as the tert.-butyl-dimethylsilyl group (by reacting a compound of formula X with tert.·-10 butyldimethylchlorosilane in dimethylformamide in the presence of triethylamine) and reacting the lithium salt of formula IX-1, formed intermediately by reacting the silyl compound of formula X-l with 1 equivalent of a strong base, for example with lithium diisopropylamide in tetrahydro15 furan at a low temperature (-78°C), with an electrophilic reagent in a manner analogous to reaction IX—»VIXI. The compound of formula VIII-1 obtained can then either be brominated directly to give a compound of formula Vll or can firstly be converted by cleavage of the silyl group (e.g. by means of tetrabutylammonium fluoride in tetrahydrofuran) into 4-(2,2-ethylenedioxypropyl)-2-azetidinone (VIII). In the course of the described introduction of a substituent 1 2 R or R there are usually obtained cis/trans mixtures (relative to the 425 -ethylenedioxopropyl group) which, if desired, can be separated using usual separation methods, for example chromatography on silica gel, fractional crystallization or distillation.

An alternative synthesis of compounds of formula VII is illustrated in Example 22: 1 Vll XVIII 2 In the above reaction sequence R and R are as hereinbefore defined and R' represents an alkyl group containing 1-4 carbon atoms.

It can be convenient to keep functional groups which 1 2 are introduced with the substituents R or R in protected form during the further synthesis. Such functional groups can be especially the hydroxy, the amino or the carboxyl function. Protecting groups known for these functions can be used insofar as their removal is possible at a suitable stage in the synthesis. The functions masked by protecting groups can already be present in the electrophilic reagent which is reacted with the dilithium salt of formula IX or 10 the lithium salts of formula IX-1 or XVII. On the other hand, it can be convenient subsequently to protect functions which result firstly with the introduction of the substituents 1 2 R and R (e.g. a hydroxy function).

By brominating of a compound of formula VIII with 15 bromine in an alkanol of the formula R'OH as the solvent there is obtained a bromoketal of formula VII. In this reaction (preferably in methanol or ethanol at a temperature between 10°C and 60°C) a trans-ketalization takes place; the ethylenedioxy group being converted into a dialkoxy grouping. As mentioned above, a silyl compound of fonnula VIII-1 can also be used in the bromination reaction, since the silyl group is cleaved off under the reaction conditions.

The esters of formula VI can be prepared from the azetidinones of formula VII according to generally known methods, for example by reaction with glyoxyl esters of the formula OHC-COOR3 or their hemiacetals. In this case, the two reaction partners are conveniently heated to boiling in an inert solvent such as benzene or toluene and the low molecular reaction products (water and alcohol) formed are distilled off azeotropically from the reaction solution.

It is, however, also possible to convert compounds of formula VII with glyoxylic acid monohydrate firstly into an acid (R3=H) corresponding to the ester of formula VI and to esterify this subsequently with a suitable alkylating agent in the presence of a base. The reaction with glyoxylic acid monohydrate is carried out, for example, in dimethylformamide at room temperature in the presence of a water-binding agent (e.g. a molecular sieve). By successive addition of a base (e.g. potassium carbonate or triethylamin) and an alkylating agent such as iodomethyl pivalate, the carboxylate group (R3~, for example, K or triethyl ammonium) is then esterified in situ.

By reacting an ester of formula VI with thionyl chloride in an inert organic solvent such as tetrahydrofuran in the presence of a base (e.g. pyridine or 2,6-lutidine) at a temperature between -30°C and +20°C there is obtained an ester of formula V which is converted with a trisubsti4 5 6 tuted phosphine of the formula PR R R , most advantageously with triphenylphosphine, in a manner known per se, i.e. in an aprotic solvent (e.g. dioxan, tetrahydrofuran or dimethylformamide) , at a temperature between 0 and 60°C into the R4,R5,R6-substituted phosphorane of formula IV. The free ketone of formula III is obtained from this ketal by acid hydrolysis under the usual conditions, for example, with aqueous sulphuric acid, phosphoric add, hydrochloric acid or hydrobromic acid in an organic solvent such as acetone, dioxan or ethanol. Undesired side-reactions such as the hydrolysis of the phosphorane can be avoided by the maintenance of low temperatures (-10°C to 0eC).

It is also possible to cleave the ketal function under anhydrous conditions by transfering ' the protecting group onto another ketone (e.g. acetone) in the presence of an acid catalyst.

Finally, the bromoketones of formula III are reacted with organic compounds containing the group X which have a nucleophilic oxygen or sulphur atom to form the compounds of formula II. The reaction can be carried out in an inert organic solvent (e.g. methylene chloride, ethyl acetate, dimethylformamide, dimethyl sulphoxide, acetonitrile or ethanol) at a temperature of -80°C up to the reflux temperature of the reaction mixture, preferably between -20°C and +40°C. The hydrogen bromide liberated during the reaction is conveniently bound by a weak, non-nucleophilio organic base such as a trialkylamine or an amidine or an inorganic base (sodium or potassium carbonate).

The compounds provided by the present invention are active against gram-positive and gram-negative bacteria, for example against Staphylococci, Streptococci, Salmonellae and Escherichia coli, and are active as S-lactamase inhibitors.

Antibacterial activity in vitro In the following Table there are compiled the minimum inhibitory concentrations (MIC) of some representative compounds of formula I against a series of pathogenic microorganisms.

MIC (Mg/ml) Organism 3 Compo 7 und of 9 Example 19 i 23 E.coli 1346 5 12.5 0.05 0.06 0.2 25922 - >50 - 0.25 - TEM 1* - >100 0.05 0.25 0.2 ” 1527 E* - - 0.1 0.25 0.2 Klebs, pneumoniae 418* - - 0.05 0.12 0.1 Prot. vulgaris 1028* - - 0.1 0.12 0.4 . Prot. mirabilis 2117* - - 0.2 0.25 0.8 Prot. mirabilis 29H - - 0.4 1 0.8 Strept. faecalis 6 - >100 1.6 2.1 24 Strept. pyogenes 815 0.3 <6 - - - Staph, aureus 6538 1.2 <6 0.025 0.12 0.4 887* >40 £6 0.05 0.12 0.8 Serratia marcescens . 803/15* >40 >100 0.8 8.5 1.5 Serratia marcescens 69438 - >100 1.6 17 3 . Klebs, aerogenes 1O82E* - >100 0.4 0.5 6 Enterobacter cloacae 908* - >100 1.6 17 12 Enterobacter cloacae 13047* - >100 3.2 34 3 Salmonella typh. BA - 25 0.05 0.06 0.2 Pseudomonas aer. 1559E* - - 25 >34 >24 ba* - >100 25 >34 >24 Acinetobacter anitr. 51-156 - - 1.6 8.5 0.8 - * 0-Lactamase producing organism.

The compound of Example 7 was tested on DST agar + 7.5% blood and the remainder were tested on DST agar (Diagnostic Sensitivity Test Agar) alone.

Antibacterial activity in vlVo.

The compounds of Examples 6, 7 and 9 were tested for antibacterial activity (ED50) against systemic infections in mice. The compounds were administered twice (1 and 3 hours after the infection).

• ED50 (mg/kg) Compound of Example Infection 6 7 9 Escherichia coli 1346 8.3 sc >25 SC 2.1 SC Streptococcus pyogenes (515 10 SC 12.5 SC <3 sc 50 p.o. >12 p.o. Proteus mirabilis 2117 >25 sc 17 sc Serratia marcescens 69438 >25 sc - - 0-Lactamase inhibition The 0-lactamase inhibiting activity (ΙΟ^θ; nitrocefin as substrate) of the compound of Example 9 against various β-lactamase is as follows: Enzyme IC50 (Mg/ml) E. coli 1024 0.191 K. pneumoniae NCTC 418 0.063 P. vulgaris 1028 0.0005 E. coli RTEM 0.035 The compounds provided by the present invention can be used for the prophylaxis and therapy of infectious diseases. For adults there comes into consideration a daily dosage of- about 0.05 g to about 4 g, especially about 0.1 g to about 2 g. The parenteral administration is especially preferred.

The products provided by the present invention can be used as medicaments, fox example in the form of pharmaceutical preparations which contain them in admixture with a pharmaceutical, organic or inorganic inert carrier material suitable for enteral or parenteral administration such as, for example, water, gelatine, gum arabio, lactose, starch, magnesium stearate, talc, vegetable oils, Vaseline etc. The pharmaceutical preparations can be made up in a solid form (e.g. as tablets, dragees, suppositories or capsules) or in a liguid form (e.g. as solutions, suspensions or emulsions). If necessary, the pharmaceutical preparations can be sterilized and/or can contain adjuvants such as preserving, stabilizing, wetting or emulsifying agents, salts for varying the osmotic pressure, anaesthetics or buffers. They can also contain still other therapeutically valuable substances. The compounds of formula I and their salts or hydrates are preferably administered parenterally and for this purpose are preferably made available as lyophilizates or dry powders for dilution with usual agents such as water or isotonic sodium chloride solution. The readily hydrolyzable esters of the compounds of formula 1 and their salts or hydrates can also be administered enterally.

The pharmaceutical preparations can contain the compounds provided by the invention in amounts of about 2515 -1000 mg, preferably 50-500 mg, per unit dosage form.

The following Examples illustrate the present invention: Example 1 A solution of 385 mg of pivaloyloxymethyl rac-2-[3(1-ethyl-l,2-dihydro-2-oxo-4-pyrimidinyl)-thio_7~aoetonyl]5 -4-oxo-a-(triphenylphosphoranylidene)-1-azetidineacetate in 50 ml of toluene was boiled under reflux for 1 hour under an argon atmosphere. The clear solution was cooled, diluted with a small amount of ethyl acetate and freed from solvent in vacuo. The residue was chromatographed on silica gel using ethyl acetate as the eluent. The fractions containing the product were concentrated and the residual oil was crystallized from ethyl acetate/hexane. There were obtained 55 mg of pivaloyloxymethyl rac-3-[/~(1-ethyl-l,2-dihydro-2-oxo-4-pyrimidinyl)-thio_7-methyl]-7-oxo-l-azabicyclo15 (3.2.0]hept-2-ene-2-carboxylate as yellow crystals of m.p. 141-143°C.

IR (CHC1,): υ „ 1785, 1750, 1736, 1659, 1622, 1614 cm*1. ,3 ΣΠαΧ The starting material was prepared as follows: (a) A solution of 348.4 g of ethyl 3,3-ethylenedioxy-butyrate in 2 1 of hexane and 0.2 1 of tetrahydrofuran was treated within 90 minutes at a temperature of -70°C to -67°C with 1.79 1 of a 1.12M solution of diisobutylaluminium hydride 52431 in hexane. The clear solution was left to stand at -75°C for a further 2 hours and then treated with 100 ml of methanol within 2 minutes. Now, the cooling bath was removed and a solution of 100 ml of glacial acetic acid in 100 ml of hexane was added within 8 minutes. The mixture was now warmed to -20°C within 10 minutes and then treated within 5 minutes with 200 ml of saturated ammonium chloride solution. The temperature of the solution was allowed to rise to 0°C within 10 minutes and the solution was stirred at 0-3°C for a further 15 minutes. Now, the precipitate was filtered off and the suction filter material was back-washed with 600 ml of methylene chloride. The filtrate was washed with 300 ml of saturated sodium chloride solution, a precipitate again resulting. The mixture was suction filtered once more, the filtrate was separated and the organic phase was washed with a further 300 ml of saturated sodium chloride solution. The suction filter residue was extracted with a total of 1.8 1 of methylene chloride and the extracts were washed with the sodium chloride solutions. The organic phases were dried over sodium sulphate, the solvent was removed under reduced pressure and the residual oil was distilled in a water-jet vacuum. The fraction boiling between 40 and 95°C was subsequently fractionated over a 80 cm long Vigreux column. There were obtained 184 g of 3,3-ethylenedioxybutyraldehyde of b.p.70-73°C.

NMR (CDC13): δ 1.43 (s, 3H)» 2.73 (d,J-3 Hz, 2H)j 4.00 (s, 4H)| 9.75 (t,J-3 Hz, 1H) ppm. (b) A mixture of 300 ml of 28% aqueous sodium hydroxide and 600 ml of methylene chloride, pre-cooled to O’C, was treated while stirring vigorously within 25 minutes with a solution of 130.1 g of 3,3-ethylenedioxybutyraldehyde, 224.2 g of triethyl phosphonoacetate and 7.4 g of benzyltriethylammonium chloride in 540 ml of methylene chloride, the temperature rising to 15°C. The mixture was left to warm to 20°C within 10 minutes and was stirred at this temperature for a further 30 minutes. Then, the mixture was 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 sulphate, concentrated completely and the residual oil was fractionated over a 50 cm long Vigreux column. After a fore-run, there were obtained 179 g of ethyl 5,5-ethylenedioxy-2-hexenoate of b.p. θ 3 70-76’C as an E/Z mixture (ratio about 6:1).

NMR (CDClj): Signals of the E-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)j 4.16 (g, J=7 Hz, 2H); 5.85 (d, J=16 Hz, 1H) ·, 6.92 (dxt, J=16 and 7.5 Hz, 1H) ppm. 3ΰ Signals of the Z-isomer: inter alia δ 3.03 (d, J-6.5 Hz, 2H)f 5.83 (d, J-11.5 Hz, IH) j 6.30 (dxt, J-11.5 and 6.5 Hz, IH) ppm. (c) Firstly a solution of 200.2 g of ethyl 5,5-ethylenedioxy-2-hexenoate (about 6s1 E/Z mixture) in 2 1 of absolute ethanol was pressurized in a stirring autoclave with about 250 g of ammonia gas and then the pressure was brought to 20 bar with nitrogen. The mixture was heated 10 at 70°C for 40 hours. The cooled solution was freed from solvent, 200 ml of ether were added and the mixture was again concentrated completely. The residual oil was taken up in 275 ml of ether and left to stand at 0’C for 2 hours. Crystallized-out rac-3-amino-5,5-ethylenedioxycaproic acid 15 amide was separated by filtration. The concentrated filtrate was taken up in 600 ml of ether/hexane (1:2, v/v) and the solution was extracted with four 200 ml portions of water. The individual extracts were washed with two 300 300ml portions of ether/hexane (1:2, v/v). The combined aqueous 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 sulphate and concentrated completely. Distillation of the residual oil in a high vacuum gave 131 g of pure ethyl 25 rac-3-amino-5,5-ethylenedioxycaproate of b.p.Q 3 95-100°C.

NMR (CDC13): 6 1.28 (t, J-7 Hz, 3H)f 1.38 (s, 3H)} 1.74 (broad s, 2H)j 1.76 (d, J=6 Hz, 2H); 2.05-2.72 (m, AB-part of ABX-system, 2H); 3.21-3.72 (m, IH) j 3.98 (s’, 4H) ; 4.13 (q, J-7 Hz, 2H) ppm. (d) To a solution of 108.6 g of ethyl rac3-amino-5,5-ethylenedioxycaproate in 330 ml of ether were added dropwise while stirring at 0-5°C within 15 minutes 54.3 g of trimethylchlorosilane and immediately thereafter 50.6 g of triethylamine, a thick precipitate forming. The mixture was left to warm to 15°C within 30 minutes while stirring and subsequently left to stand at room temperature for 24 hours.

Then, the mixture was suction filtered through a filter while excluding moisture and the reaction vessel and suction filter material were back-washed with a total of 150 ml of ether. The filtrate was treated while stirring within 40 minutes at 0-5 °C with 290 ml of a 1.92M ethylmagnesium bromide/ether solution, a gas evolution occurring.

The heterogeneous mixture was stirred at room temperature for 16 hours. Then, the mixture was cooled to 0°C and 170 ml of semi-saturated ammonium chloride solution were added dropwise at a temperature of 0-10°C, a thick precipitate resulting. The pH of the mixture was lowered to about 7 by adding about 180 ml of 3N hydrochloric acid, the majority of the precipitate passing into solution. The aqueous phase was separated and the organic phase was extracted with two 200 ml portions of water. The aqueous phases were combined, saturated at 0°C with sodium chloride and extracted four times with 500 ml of methylene chloride each time. The methylene chloride extracts were dried over sodium sulphate and concentrated completely. In order to separate polar byproducts, the residual oil was filtered through 200 g of silica gel using ethyl acetate for the elution. Crystallization of the eluate (freed from solvent) from ether/hexane yielded 49.6 g of pure rac-4-(2,210 -ethylenedioxypropyl)-2-azetidinone of m.p. 43-45°C.

IR (CHC1,): v „ 1756 cm-1.

J IucLX (e) A solution of 3.42 g of rac-4-(2,2-ethylenedioxypropyl) -2-azetidinone in 36 ml of methanol was treated at room temperature with 4 ml of a 1M solution of bromine in methanol. The solution was warmed at 50®C for 3 minutes, decolourization occurring. Now, a further 16 ml of 1M solution of bromine in methanol was added dropwise within 8 minutes and subsequently the solution was cooled to 33°C. The mixture was stirred at this temperature for a further 24 minutes and the light yellow solution was then poured into a mixture of 30 ml of saturated sodium carbonate solution, 10 ml of 0.1N sodium thiosulphate solution and ice. The mixture 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 concentrated completely in vacuo. The residual oil was chromatographed on silica gel using ethyl aeetate/hexane (2:1, v/v) as the eluent. The fractions containing the product were concentrated and the residue was crystallized from ethyl aeetate/hexane. There were obtained 2.03 g of rac-4-(3-bromo-2,2-dimethoxypropyl)-2-azetidinone of m.p. 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 treated with 3 g of molecular sieve 4A and stirred at room temperature for hours under argon. Then, 2.07 g of solid potassium carbonate were added thereto and the mixture was stirred for a further 30 minutes. The mixture was cooled to 0°C, treated with a solution of 6.8 g of iodomethyl pivalate in ml of dimethylformamide and subsequently stirred at room temperature for a further 1 hour. The mixture was diluted with 100 ml of ethyl acetate and 30 ml of ether and then washed three times with 50 ml of water each time. The organic phase was dried over sodium sulphate, concentrated completely and the residual oil was chromatographed on silica gel with ethyl aeetate/hexane (2:1, v/v). There were obtained 3.3 g of pivaloyloxymethyl rac-2-(3-bromo-2,2-dimethoxypropyl)-a-hydroxy-4-oxo-l-acetidineacetate (diastereomeric mixture) as an oil.

IR (CHCl3): vmax 3528, 1760 cm-1.

Rf: 0.37/0.43 (double spot, SiO2, ethyl acetate/ hexane 2:1, v/v). (g) 1.02 g of 2,6-lutidine were added at -23°C to a solution of 3.2 g of pivaloyloxymethyl rae-2-(3-bromo-2,2-dimethoxypropyl)-a-hydroxy-4-oxo-l-azetidineacetate in 60 ml of tetrahydrofuran. Then, a solution of 1.04 g of thionyl chloride in 11 ml of tetrahydrofuran was added dropwise with'in 1 minute, the temperature being held below -20eC by cooling. The mixture was stirred at -20°C for 20 minutes and then at room, temperature for 20 minutes.

Then, the precipitate was filtered off under suction and the suction filter material was back-washed with 40 ml of toluene. The filtrate was concentrated completely in vacuo, the residue was taken up in 20 ml of toluene and again concentrated completely.

The oil obtained was dissolved in 22 ml of dimethylformamide, treated at room temperature with a solution of 2.44 g of triphenylphosphine in 7 ml of dimethylformamide and the solution was left to stand for 1 hour. Then, the majority of the solvent was removed in a high vacuum at a temperature of 30°C, the residual oil was taken up in 70 ml of methylene chloride and the solution was washed twice with 50 ml of pH 7 phosphate buffer each time. The aqueous phases were extracted with 100 ml of methylene chloride and the combined organic phases were dried over sodium sulphate and concentrated completely. The residual oil was chromatographed on silica gel, firstly the excess triphenylphosphine being eluted with methylene chloride and then the product being eluted with ethyl acetate. The fractions containing the product were concentrated. There were obtained 3.2 g of pivaloyloxymethyl rac-2-(3-bromo5 -2,2-dimethoxypropyl)-4-oxo-a-(triphenylphosphoranylidene)-1-azetidineacetate as a colourless, amorphous material.

XR (CHClj): vffiax 1741, 1635 cm-1. (h) A solution of 3 g of pivaloyloxymethyl rae-2-(3-bromo-2,2-dimethoxypropyl)-4-oxo-a-(triphenylphosphoranylidene)10 -1-azetidineacetate in 115 ml of acetone, cooled to 4°C, was added dropwise within 2 minutes to 38 ml of 48% hydrobromic acid, pre-cooled to 4°C, the temperature of the mixture rising to 20eC. The mixture was cooled to 4 °C within 3 minutes and stirred at this temperature for a further 10 ' minutes. Then, the colourless solution was poured on to 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 with three 100 ml portions of methylene chloride. The organic phases were washed with 80 ml of pH 7 phosphate buffer solution, dried over sodium sulphate and concentrated completely. The resulting oil was chromatographed on silica gel using ethyl acetate for the elution. The fractions containing the product were concentrated and the residue was treated with hexane. There were obtained 2.03 g of pure pivaloyloxymethyl rac-2-(3-bromoaeetonyl)-4-oxo-a-(triphenylphosphoranylidene)-1-azetidineacetate as white crystals of m.p. 1I7-118°C.

IR (CHC1,): v „ 1745, 1640 cm1.

IQaX· (i) 447 mg of pivaloyloxymethyl rac-2-(3-bromoacetonyl)-4-oxo-a-(triphenylphosphoranylidene)-1-azetidineacetate and 114 mg of l-ethyl-4-thiouracil were dissolved in 20 ml of methylene chloride and the solution was concentrated completely within 10 minutes at a temperature of 50°C and under reduced pressure. The residue was dissolved in 20 ml of methylene chloride and the solution was concen10 trated within 10 minutes under the same conditions. This procedure was repeated once more, then the residual oil was taken up in 50 ml of methylene chloride and the yellow solution was washed successively with dilute sodium hydrogen carbonate solution and sodium chloride solution.

The aqueous phases were back-extracted with methylene chloride, the combined organic phases were dried over sodium sulphate and concentrated completely. Chromatography of the residual oil on silica gel using acetone/methylene chloride (1:1, v/v) as the eluent gave 427 mg of pure pivaloyloxymethyl rac-2-[3-/-(1-ethyl-l,2-dihydro-2-qxo-4-pyrimidinyl)-thio_7~acetonyl]-4-oxo-a-(triphenylphosphoranylidine)-1-azetidineacetate as a yellow oil.

IR (CHC1-): υ 1741, 1660cm1. luaX S3431 Example 2 275 mg of pivaloyloxymethyl rac-2-(3-acetoxyacetonyl)-4-oxo-a-(triphenylphosphoranylidene)-1-azetidineacetate were cyclized according to the procedure described in Example 1. There were obtained, after purification of the crude product by chromatography, about 150 mg of pivaloyloxymethyl rac-3-(acetoxymethyl)-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate as a colourless oil.

IR (CHC1-): 1789, 1749, 1635 cm-1, max The starting material was prepared·as follows: A solution of 383 mg of pivaloyloxymethyl rac-2-(3-bromoacetonyl)-4-oxo-a-(triphenylphosphoranylidene)-1-azetidineacetate in 9 ml of dimethylformamide was treated with 54 mg of sodium acetate and the mixture was stirred at room temperature for 16 hours. Then, the mixture was diluted with 50 ml of methylene chloride and the solution was washed successively with water and saturated sodium chloride solution. The aqueous phases were extracted with methylene chloride, the combined organic phases were dried over sodium sulphate and concentrated completely. The resulting oil was filtered through silica gel in order to remove polar material, the elution being carried out using ethyl acetate. The pure fractions were concentrated completely and the residual material was crystallized from ethyl acetate/hexane. There were obtained 314 mg of pure pivaloyloxymethyl rac-2-( 3-acetoxy-acetonyl)-4-oxo-a-(triphenylphosphoranylidene)-l-azetidineacetate of m.p. 139-141°C.

IR (CHC13): vwav 1741, 1637 cm1.

Example 3 A 0.05M pH 7 phosphate buffer solution was prepared by adding IN sodium hydroxide to an agueous sodium dihydrogen phosphate solution. To 40 ml of this solution were added lo successively 168 mg of sodium hydrogen carbonate-and 0.3 ml of a suspension of pig liver esterase EC 3.1.1.1 (about 300 units) in 3.2M ammonium sulphate solution. The clear solution was warmed to 36°C and treated while stirring with a solution of 102 mg of pivaloyloxymethyl rac-3-(acetoxy15 methyl)-7-oxo-l-azabicyolo[3.2.0]hept-2-ene-2-carboxylate in 1.5 ml of dimethyl sulphoxide. The mixture was stirred at 36°C for 30 minutes, cooled and extracted with four 40 ml portions of ether. The ether phases were back-extracted with 10 ml of water, the combined agueous phases were filtered and the pH of the filtrate was adjusted to 7.06 with 0.1N hydrochloric acid. This solution contained about 28 mg of sodium (5R and 5S)-3-(acetoxymethyl)-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

OV (Η,Ο): λ 262 nm (extinguishable with hydroxylamine). z msLX Example 4 p-Nitrobenzyl rac-7-oxo-3-[(phenethylthio)-methyl]-l-azabieyclo[3.2.0]hept-2-ene-2-carboxylate was hydrogenated at normal pressure in a mixture of dioxan/ethanol/water in the presence of sodium hydrogen carbonate using palladium/ carbon (5%) as the catalyst. The catalyst was filtered off, the filtrate was diluted with water and extracted with four portions of ether. The aqueous phase contained sodium rac-7-oxo-3-((phenethylthio)-methyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

The starting material was prepared as follows: (a) 27 ml of solvent were distilled off continuously within 2 hours at normal pressure from a solution of 1.89 g of rac-4-(3-bromo-2,2-dlmethoxypropyl)-2-azetidinone and 2.46 g of p-nitrobenzyl glyoxylate ethyl hemiacetal in 50 ml of toluene. The cooled solution was concentrated completely and the residue remaining was chromatographed on silica gel. Elution with a mixture of acetone/methylene chloride/hexane (1:4:1, v/v/v) yielded 3.25 g of p-nitrobenzyl rac-2-(3-bromo-2,2-dimethoxypropyl)-a-hydroxy-4-oxo-1-azetidineacetate as a diastereomeric mixture.

XR (CHC13): 3530, 1765, 1611, 1530, 1500 cm1. 2421 Rf: About 0.2 (S102, acetone/CH2Cl2/hexane 1:4:1, v/v/v/). (b) When 3.25 g of p-nitrobenzyl rao-2-(3-bromo-2,2-dimethoxypropyl)-a-hydroxy-4-oxo-l-azetidineacetate (diastereo meric mixture) were subjected to the conditions described in Example 1(g), then there were obtained, after crystallization from methylene ohloride/hexane, 2.48 g of p-nitrobenzyl rac-2-(3-bromo-2,2-dimethoxypropyl)-4-oxo-a-(triphenylphosphoranylidene) -1-azetidineacetate as white crystals of m.p. 189-19O°C.

IR (CHCl,): v 1737, 1620, 1607 cm-1, j max (c) When 2.77 g of p-nitrobenzyl rac-2-(3-bromo-2,2-dimethoxypropyl)-4-oxo-a-(triphenylphosphoranylidene)-1-azetidineacetate were subjected to the procedure described in Example 1(h), then there were obtained 1.35 g of p-ni.trobenzyl rac-2-(3-bromoaoetonyl)-4-oxo-a-(triphenylphosphoranylidene) -1-azetidineacetate as white crystals of m.p. 127-128°C.

IR (CHCl,): υ 1742, 1636, 1609, 1579,1525 cm1, w ZuaX (d) A solution of 1.32 g of p-nitrobenzyl rac-2-(3-bromoacetonyl)-4-oxo-a-(triphenylphosphoranylidene)-1-azetidineacetate and 0.29 g of 2-phenyl-ethyl mercaptan in 20 ml of methylene chloride was treated with 0.21 g of triethylamine and stirred at room temperature for 1 hour.

The mixture was diluted with methylene chloride and washed successively with dilute sodium hydrogen carbonate solution and saturated sodium chloride solution. The organic phase was dried over sodium sulphate, concentrated completely and the residue was chromatographed on silica gel. Elution with a mixture of ethyl acetate/hexane (1:1, v/v) yielded 1.07 g of p-uitrobenzyl rac-4-oxo-2-[3-(phenethylthio)-acetonyl]-a-(triphenylphosphoranylidene)-1-azetidineacetate. (e) By subjecting p-nitrobenzyl rae-4-oxo-2-[3-(phenethylthio)-acetonyl]-a-(triphenylphosphoranylidene)-1-azetidineacetate to the cyclization conditions described in Example 1 there was obtained, after purification by chromatography, p-nitrobenzyl rac-7-oxo-3-((phenethylthio)-methyl]-1-aza15 bicyclo[3.2.0]hept-2-ene-2-carboxylate.

Example 5 Sodium rac-3-[(cyclohexylthio)-methyl]-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate was obtained by subjecting p-nitrobenzyl rac-3-[(cyclohexylthio)-methyl]20 -7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate to the hydrogenation conditions described in Example 4.

The starting material was prepared as follows: (a) 1.32 g of p-nitrobenzyl rac-2-(3-bromoacetonyl)-4-oxo-a-(triphenylphosphoranylidene)-1-azetidineacetate and 0.24 g of cyclohexyl mercaptan were reacted according to the pro5 cedure described in Example 4(d). After purification by chromatography, 0.96 g of p-nitrobenzyl rac-2-[3-(cyclohexylthio)-acetonyl]-4-oxo-a-(triphenylphosphoranylidene)-1-azetidineacetate was isolated. (b) By subjecting p-nitrobenzyl rac-2-[3-(oyclohexylthio)10 -acetonyl]-4-oxo-α-(triphenylphosphoranylidene)-1-azetidineacetate to the cyclization conditions described in Example 1 there was obtained, after purification by chromatography, p-nitrobenzyl rac-3-[(oyclohexylthio)-methyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

Example 6 A solution of 267 mg of pivaloyloxymethyl rac-trans-3-ethyl-2-[3-[(1-ethyl-l,2-dihydro-2-oxo-4-pyrimidinyl)-thio]-acetonyl]-4-oxo-a-(triphenylphosphoranylidene)-1-azetidineacetate in 12 ml of toluene was heated to 100°C for 3 hours under an argon atmosphere. The solution was concentrated completely and the residue was chromatographed on silica gel. Elution with a mixture of methylene chloride/acetone (6:1 v/v) yielded the pure product which could be crystallized from ethyl acetate with the addition of hexane. There were obtained 122 mg of pivaloyloxymethyl rac-6a-ethyl-3-[[(l-ethyl-l,2-dihydro-2-oxo-4-pyrimidinyl)—thio]-methyl]-7-oxo-5a-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate as white crystals of melting point 105-106°C.

IR (CHC1,): 1784, 1756, 1735, 1661, 1624, 1610 cm-1. lucuC NMR (CDC13): δ 1.01 (t, J-7Hz,3H) ·, 1.24 (s,9Hj 1.38 (t,J-7Hz,3H)j 1.67-1.95 (m,2H)j 2.90-3.22 (m,3H); 3.79-3.96 (m,3H)j 4.37/4.52 (AB-system, J-14Hz,2H)j 5.88/5.97(AB-system, J-5Hz,2H)j 6.20 (d,J-7Hz,lH)j 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-l,3-dioxolan-2-yl)-methyl]-2-azetidinone in 12 ml of tetrahydrofuran was treated at -20°C with 4 ml of a 1.635M butyl lithium/ hexane solution and left to stand for 90 minutes in an ice-bath under an argon atmosphere. The brown-yellow solution was cooled to -40°c,treated with a solution of 360 mg of ethyl bromide in 0.8 ml of tetrahydrofuran and then left to stand in an ice-bath for 90 minutes. The mixture was poured into ice-cold saturated sodium chloride solution and extracted with ethyl acetate. The extracts were washed once more with saturated sodium chloride solution, dried over sodium sulphate and concentrated completely. By chromatography of the residue on silica gel using ethyl acetate/hexane (2:1, v/v) as the eluent there was obtained pure rac-trans-3-ethyl-4-[(2-methyl-l,3-dioxo5 lan-2-yl)-methyl]-2-azetidinone. Crystallization from ether/hexane gave 122 mg of white crystals of melting point 44-45°Q.

IR (CHCl,): v „ 3422, 1752 cm-1. ύ ΤΠπΧ (b) About 4 ml of 21.6 ml of a IM solution of bromine in 10 methanol were added to 4.3 g of rac-trans-3-ethyl-4-[(2-methyl-l,3-dioxolan-2-yl)-methyl]-2-azetidinone-in 30 ml of methanol and the mixture was warmed to 50°C. After about 3 minutes, decolourization occurred, whereupon the remainder of the bromine solution was added dropwise within 1 minute. The colourless solution was poured into 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 with 50 ml of ethyl acetate each time. The organic phases were washed with a mixture of 30 ml of saturated sodium hydrogen carbonate solution and 20 ml of IN sodium thiosulphate solution as well as with 30 ml of saturated sodium chloride solution, dried over sodium sulphate and concentrated completely. The residual oil was chromato25 graphed on silica gel using ethyl acetate as the eluent.

By crystallization of the purified product from ethyl 5242 acetate/hexane there were obtained 2.99 g of rac-trans-4-(3-bromo-2,2-dimethoxypropyl)-3-ethyl-2-azetidinone as white crystals of melting point 77-79°C. (c) The procedure described in Example 1(f)-(h) was used 5 on 2.8 g of rac-trans-4-(3-bromo-2,2-dimethoxypropyl)-3-ethyl-2-azetidinone. After purification by chromatography and crystallization from ethyl acetate/hexane, there was obtained 0.51 g of pivaloyloxymethyl rac-trans-2-(3-bromoacetonyl)-3-ethyl-4-oxo-a-(triphenylphosphoranylidene)-ΙΙΟ -azetidineacetate as white crystals of melting point 128-129’C. (d) 333 mg of pivaloyloxymethyl rac-trans-2-(3-bromoacetonyl)-3-ethyl-4-oxo-a-(triphenylphosphoranylidene)-1-azetidineaoetate and 78 mg of l-ethyl-4-thiouracil were reacted according to the procedure described in Example 4(d). After purification by chromatography, 291 mg of pivaloyloxymethyl rac-trans-3-ethyl-2-[3-[(1-ethyl-l,2-dihydro-2-oxo-4-pyrimidinyl)-thio]-acetonyl]-4-oxo-a-(triphenylphosphoranylidene) -l-azetidineaoetate were obtained as a white foam.

IR (CHCl,): 1745 with shoulder at 1720, 1662, 1627, w TnaX 1580, 1514 cm-1.

Example 7 A solution of 151 mg of pivaloyloxymethyl rac-trans52421 -3-ethyl-2-[3-[(5-raethyl-l,3,4-thiadiazol-2-yl)-thio]-acetonyl]-4-oxo-a-(triphenylphosphoranylidene)-1-azetidine acetate in 12 ml of toluene was heated to 100°C for 1.5 hours under an argon atmosphere. After purification by chromatography, 79 mg of pivaloyloxymethyl rac-6a-ethyl-3-[[(5-methyl-1,3,4-thiadiazol-2-yl) —thio]-methyl]-7-oxo-5a-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate were > isolated as a pale yellow oil.

NMR (CDC13): δ 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,lH); 4.40/4.59 (AB-system, J“14Hz,2H)j 5.86/5.94 (AB-system,. J=6Hz/2H) ppm.

The starting material was prepared as follows: 1.33 g of pivaloyloxymethyl rac-trans-2-(3-bromoacetonyl)-3-ethyl-4-oxo-a-(triphenylphosphoranylidene)-1-azetidineacetate and 0.26 g of 2-mercapto-5-methyl-l,3,4-thiadiazole were reacted in an analogous manner to the procedure described in Example 4(d). After purification by chromatography, 1.24 g of pivaloyloxymethyl rac-trans-3-ethyl-2-[3-[(5-methyl-l,3,4-thiadiazol-2-yl)-thio]-acetonyl]-4-oxo-a-(triphenylphosphoranylidene)-1-azetidineacetate were obtained as an amorphous powder.

IR (CHC1-): v „ 1740, 1636 cm-1. . 0 ΙΠαΧ Example 8 A solution of 270 mg of pivaloyloxymethyl rac-(2RS, 3SR)-2-[3-[(l-methyl-lH-tetrazol-5-yl)-thio]-acetonyl]-4-ΟΧΟ-3-[(RS)-1-(trimethylsilyloxy)-ethyl]-a-(phosphoran5 ylidene)-1-azetidineacetate in 32 ml of toluene was heated to 105°C for 1 hour under an argon atmosphere. The colourless solution was diluted with 50 ml of ethyl acetate and concentrated completely in vacuo. The residue was filtered through silica gel in order to separate the tri10 phenylphosphine oxide, the elution being carried out 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, the solution was treated with 35 mg of ammonium fluoride and stirred at room temperature for 40 minutes. The mixture was diluted with 30 ml of ethyl acetate, concentrated completely in vacuo and the residue was chromatographed on silica gel using ethyl acetate/methylene chloride (1:1, v/v) as the eluent. There were obtained 60 mg of pivaloyloxymethyl rac-(5RS,6ER)-6-[(RS)-l-hydroxyethyl]-3-[[(1-methyl-lH-tetrazol-5-yl)-thio]-methyl]-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate as a colourless oil.

IR (CHC13): vmax 3616, 3446, 1780, 1752, 1732, 1623 cm-1.

The starting material was prepared as follows: (a) To a solution of 34.2 g of rac-4-[2,2-ethylenedioxypropyl]-2-azetidinone and 31.7 g of tert.butyldimethylchlorosilane in 160 ml of dimethylformamide, cooled to O’C, were added dropwise within 2 minutes 22.2 g of triethylamine, a precipitate resulting immediately. The mixture was stirred at O’C for 1 hour, then diluted with 500 ml of ether and washed 5 times with 200 ml of water.

The aqueous phases were back-extracted with 250 ml of ether. The organic phases were dried over sodium sulphate, freed from solvent on a rotary evaporator and the residual oil was distilled in a high vacuum. There were, obtained 53.5 g of rac-1-(tert.rbutyldimethylsilyl)-4-[ (2-methy 1-l,3-dioxolan-2-yl)-methyl]-2-azetidinone as a colourless oil of b.p.Q 3 125-13O°C.

IR NMR (CHC13): (CDC13,: 1728 max δ 0.22 (s 1.62-2.34 2.70-3.31 20 3.51-3.85 ppm. 6H)f 0.98 (s,9H)j 1.31 (s,3H); (m,AB-part of an ABX-system, 2H); (m,AB-part of an ABX-system, 2H)j (m,X-part, IH) ; 3.85-4.03 (m,4H) (b) A solution of 3.66 g of diisopropylamine in 90 ml of tetrahydrofuran was cooled to -78’C and treated within 5 minutes with 24 ml of a 1.635M butyl lithium/hexane solution. The mixture was stirred at -78’C for 20 minutes under an argon atmosphere and subsequently within 5 minutes a solution of 8.55 g of rac-1-(tert.-butyidimethylsilyl)-4-[{2-methyl-l,3-dioxolan-2-yl)-methyl]-2-azetidinone in 90 ml of tetrahydrofuran was added dropwise thereto. After stirring at -78°C for a further 30 minutes, the solution was treated with 2.22 g of methyl acetate. The mixture was left to warm to 0°C within 5 minutes and stirred at this temperature for a further 20 minutes. The mixture was poured into 150 ml of. saturated sodium chloride solu10 tion and subsequently extracted with a total of 400 ml of ethyl acetate. The organic phase was washed neutral with saturated sodium chloride solution, dried over sodium sulphate and concentrated completely. The residue was chromatographed on silica gel using ethyl acetate/hexane (1:2, v/v) as the eluent and the material obtained after concentrating the pure fractions was distilled in a high vacuum. '4.49 g of rac-trans-3-acetyl-l-(tert.-butyldimethylsilyl)-4-[(2-methyl-l,3-dioxolan-2-yl)-methyl]-2-azetidinone were obtained as a colourless oil of b.p.Q_04 118-12O°C.

IR (CHC1-): υ „ 1743, 1712 cm1. ΓΠαΧ NMR (CDC13) : 0 0.22 (s,3H); 0.26 (s,3H)f 0.98 (s,9H)} 1.32 (s,3H); 1.66-2.37 (m,2H); 2.30 (s,3H)j 3.75-4.00 (m,4H); 4.00-4.25 (m,2H) ppm. 53431 (c) A mixture of 14.3 g of rac-trans-3-acetyl-l-(tert.-butyldinethyl.silyl)-4-[(2-methyl-l,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. The catalyst 5 was filtered off, the filtrate was concentrated completely in vacuo and the residue was crystallized from hexane.

There were obtained 12.4 g of a mixture of 2 isomeric alcohols in the ratia 3:2. By fractional crystallization from ethyl acetate/hexane the main component could· firstly be isolated in pure form: rac-(3SR,4RS)-1-(tert.-butyldime thylsilyl) -3-[(RS)-1-hydroxyethyl]-4-[(2-methyl-1,3-dioxolan-2-yl)-methyl]-2-azetidinone of melting point 81-82’C.

IR (CHC13): vfflax 3500, 1735 cm-1.

NMR (CDC13): δ 0.22 (s,3H)f 0.24 (s,3H); 0.96 (s,9H)f 1.34 (d,J-6Hz,3H); 1.41 (s,3H)j 1.82-2.27 (m,2H); 2.96 (dxd,J=9Hz and 2Hz,lH)j 3.15 (d,J-5H,1H)} 3.54-3.61 (m,lH)f 3.94-4.02 (m,4H) ppm.

Rac-(3SR,4RS)-1-(tert.-butyldimethylsilyl)-3-[(SR) -1-hydroxyethyl]-4-[(2-methyl-l,3-dioxolan-2-yl)-methyl]-2-azetidinone of 'melting point 86-88°C could be obtained by repeated crystallization of the material obtained from the mother liquors.

IR (CHC13): vmaY363O, 3588, 3504, 1728 cm1.

NMR (CDC13): δ 0.22 (s,3H)} 0.24 (s,3H); 0.96 (s,9H)j 1.32 (d,J-6Hz,3H); 1.36 (s,3H); 1.78-2.27 (m,2H); 2.46 (d,J-5Hz,lH) ·, 3.15 (dxd,J=5Hz and 2,5Hz,IH); 3.59-3.68 (m,lH)} 3.89-4.01 (m,4H); 4.03-4.16 (m,lH) ppm. (d) A solution of 79 g of rac-(3SR,4RS)-1-(tert.-butyldimethylsilyl)-3-[(RS)-l-hydroxyethyl]-4-[(2-methyl-l,3-dioxolan-2-yl)-methyl]-2-azetidinone in 720 ml of pyridine, cooled to 0°C, was treated while stirring with 63.7 g of 2,2,2-triohloroethyl chloroformate. Thereby there formed clumps which broke up to a fine precipitate after a short time. The mixture was stirred at room temperature for 17 hours and then the majority of the solvent was removed on a rotary evaporator in a high vacuum. The concentrated mixture was taken up in 2 1 of ethyl acetate, washed three times with 600 ml of water each time and the agueous phases were back-extracted with 1 1 of ethyl acetate. The organic phases were dried over sodium sulphate, the solvent was removed on a rotary evaporator and the residual oil was freed from polar impurities by filtration through silica gel with ethyl acetate/hexane (1:1, v/v). By concentration of the pure fractions there were obtained 126 g of crude rac-(3SR, 4RS)-1-(tert.-butyldimethylsilyl)-325 -[(RS)-1-(2,2,2-trichloroethoxycarbonyloxy)-ethyl)-4-[(2-methyl-l,3-dioxolan-2-yl)-methyl)-2-azetidinone as an oil.

IR (CHCl,): υ 1758, 1740 cm1. (e) A solution of 126 g of crude rac-(3SR,4RS)-l-(tert.-butyldimethylsilyl)-3-[(RS)-1-(2,2,2-trichloroethoxycarbonyloxy)-ethyl]-4-[(2-methyl-l,3-dioxolan-2-yl)-methyl]-2-azetidinone in 700 ml of methanol, pre-heated to 60°C, was treated while stirring with 4 g of bromine. After stirring at 60°C for about 3 minutes, decolourization occurred. How, a further 36 g of bromine were added dropwise within 8 minutes to the solution and thereby the temperature was lowered to 40°C within 3 minutes. After completion of the addition, the temperature was held at. 40°C for a further 12 minutes, the solution becoming almost colourless. The solution was cooled to 10°C, neutralized by the addition of 41 ml of agueous ammonia (25%), treated with 8.6 g of ammonium fluoride and stirred at room temperature for 1 hour. The yellow solution was concentrated to about half of the volume on a rotary evaporator and then taken up in 1.2 1 of ethyl acetate/ether (1:1, v/v).

The mixture was washed three times with 450 ml of saturated sodium chloride and the agueous phases were extracted with a total of 1.3 1 of ethyl acetate. The organic phases were dried over sodium sulphate, freed from solvent in vacuo and the residue was chromatographed on silica gel. Elution with a mixture of ethyl acetate/methylene chloride/hexane (1:1:1, v/v/v) yielded the pre-purified product which could be crystallized from ethyl acetate with treatment with 52431 hexane. There were obtained 57 g of rac-(3SR,4RS)-4-(3-bromo-2,2-dimethoxypropyl)-3-[(RS)-1-(2,2,2-trichloroethoxycarbonyloxy)-ethyl]-2-azetidinone as colourless crystals of m.p. 84-85°C. (f) A mixture of 23.58 g of rao-(3SR,4RS)-4-(3-bromo-2,2-dimethoxypropyl)-3-[(RS)-1-(2,2,2-trichloroethoxycarbonyloxy)-ethyl]-2-azetidinone, 4.89 g of glyoxylic acid monohydrate and 15 g of molecular sieve 4& in 25 ml of dimethylformamide was stirred at room temperature for 20 hours. The mixture was cooled to -10°C and treated with 5.52 g of triethylamine. After 5 minutes, 13.3 g of iodomethyl pivalate were added, the temperature being held at 3°C by cooling. The mixture was stirred at 3°C for 15 minutes and at room temperature for a further 20 minutes. Then, the molecular sieve was decanted off and the mixture was diluted simultaneously with 200 ml of ethyl acetate. The mixture was washed three times with loo ml of semi-saturated sodium chloride solution each time and the agueous phases were extracted with 200 ml of ethyl acetate. The organic phases were dried over sodium sulphate 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-trichloroethoxycarbonyloxy)-ethyl]-a-hydroxy-l-azetidineacetate (diasteromeric mixture) as a colourless oil.

IR (CHCl-): λ> „ 3528, 1769 cm-1. lu&X NMR (CDClj): inter alia, 6 1.23 (s,9H)j 1.50 (d,J=6Hz,3H); 2.20-2.60 (m,2H); 3.05-3.30 (m,7H)} 3.48 (broad s,2H)} 4.73 (s,2H) ppm. (g) To a solution of 15.5 g of pivaloyloxymethyl rao-(2RS,3SR)-2-(3-bromo-2,2-dimethoxypropyl)-4-oxo-3-[(RS)-1-(2,2,2-triohloroethoxyoarbonyloxy)-ethyl]-a-hydroxy-1-azetidineacetate (diastereomeric mixture) in 200 ml of tetrahydrofuran, cooled to -20°C, were added 3.50 g of 2,6-lutidine. Then, a solution of 3.74 g of thionyl chloride in 40 ml of tetrahydrofuran was added dropwise within 1 minute, the temperature being held below -20°C by cooling. The mixture was stirred at -20°C for 20 minutes and at room temperature for 20 minutes. Then, the precipitate was filtered off under suction and the suction filter material was back-washed with 360 ml of toluene. The filtrate was concentrated completely in vacuo, the residue was taken up in 150 ml of toluene and again concentrated completely.

The thus-obtained oil was taken up in 75 ml of dimethylformamide and treated with a solution of 8 g of triphenylphosphine in 23 ml of dimethylformamide. The mixture was left to stand at room temperature for 1 hour and then the majority of the solvent was removed 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 240 ml of 1M pH 7 phosphate buffer and the aqueous phases were back-extracted with 500 ml of methylene chloride. The organic phases were dried over sodium sulphate, freed from solvent in vacuo and the residual oil was chromatographed on silica gel. Elution with a mixture of ethyl acetate/ methylene chloride/hexane (1:1:1,' v/v/v) yielded firstly excess triphenylphosphine and subsequently the product.

By complete concentration of the pure fractions there were obtained 14.89 g of pivaloyloxymethyl rac-(2RS,3SR)-2-(3-bromo-2,2-dimethoxypropyl)-4-oxo-3-[(RS)-1-(2,2,2-trichloroethoxycarbonyloxy)-ethyl]-a-(triphenylphosphoranylidene) -1-azetidineacetate as an amorphous powder.

IR (CHC1-): v 1747, 1634 cm-1, j ZQoX (h) A solution of 2.66 g of pivaloyloxymethyl rae-(2RS,3SR)-2-(3-bromo-2,2-dimethoxypropyl)-4-oxo-3-[(RS)-1-(2,2,2-trichloroethoxycarbonyloxy)-ethyl]-a-(triphenylphosphoranylidene) -1-azetidineacetate in 75 ml of acetone, oooled to -1O°C, was treated while stirring with 75 ml of 48% hydrobromic acid, pre-cooled to -10°C, the temperature rising to 1O°C. The mixture was cooled to 0°C within 3 minutes, stirred at this temperature for a further 15 minutes and the colourless solution was poured into a mixture of 17.4 g of sodium carbonate, 150 ml of 1M pH 7 phosphate buffer solution and 150 g of ice. The mixture was extracted with a total of 400 ml of methylene chloride. The organic phase was washed with 50 ml of IM pH 7 phosphate buffer solution, dried over sodium sulphate and concentrated completely. There were obtained 2.45 g of crude pivaloyloxy.5 methyl rac-(2RS,3SR)-2-(3-bromoacetonyl)-4-oxo-3-t(RS)-l-(2,2,2-trichloroethoxycarbonyloxy)-ethyl]-a-(tripheny1phosphoranylidene)-1-azetidineacetate as a white solid.

IR (CHC1,): v__„ 1750, with shoulder at 1710, 1641 cm \ (i) A solution of 428 mg of pivaloyloxymethyl rac-(2RS,3SR)10 -2-(3-bromoacetonyl)-4-oxo-3-[(RS)-1-(2,2,2-trichloroethoxycarbonyloxy) -ethyl]-a-(triphenylphosphoranylidene)-1-azetidineacetate and 64 mg of 5-mercapto-l-methyl-lH-tetrazole in 10 ml of methylene chloride was treated with 60 mg of triethylamine and subsequently stirred at room temperature for 2 hours. The mixture was diluted with 10 ml of methylene chloride and washed with in each case 10 ml of saturated sodium hydrogen carbonate solution and sodium chloride solution. The aqueous phases were back-extracted with a small amount of methylene chloride, the organic phases were dried over sodium sulphate and concentrated completely.

The residue was dissolved in 3 ml of ice-cold 90% acetic acid. 1.5 g of zinc powder were added thereto and the mixture was stirred at 0°C for 20 minutes. The mixture was diluted with 40 ml of methylene chloride and washed successively with 15 ml of saturated sodium carbonate solu52421 tion and twice with 25 ml of water each time. The aqueous phases were back-extracted twice with 40 ml of methylene chloride each time, the organic phases were dried over sodium sulphate and concentrated completely.

The residue was taken up in a mixture of 3 ml of methylene chloride and 1.5 ml of pyridine and the solution was treated with 0.44 g of trimethylchlorosilane. The mixture was stirred at room temperature for 1 hour, diluted with 35 ml of ethyl acetate and washed successively with ml of 5% sodium hydrogen carbonate solution and 25 ml of saturated sodium chloride solution. The aqueous phases were back-extracted with 60 ml of ethyl, acetate,_ the organic phases were dried over sodium sulphate and concentrated completely. The residue was chromatographed on silica gel using ethyl acetate/hexane (1:1, v/v) as the eluent. 198 mg of pivaloyloxymethyl rac-(2RS,3SR)-2-[3-[(1-methyl-lH-tetrazbl-5-yl)-thio]-acetonyl]-4-oxo-3-[(RS)-1-(trimethylsilyloxy)-ethyl]-a-(triphenylphosphoranylidene)-l-azetidineacetate were isolated as a colourless oil.

IR (CHC1-): „ 1747, 1640 cm”1. max Example 9 A 0.05M pH 7 phosphate buffer solution was prepared by adding IN sodium hydroxide to an aqueous sodium dihydrogen phosphate solution and to 150 ml of this solution were added 1,5 ml of a suspension of hog liver esterase EC 3.1.1.1 (about 1500 units) in 3.2M ammonium sulphate solution. Then, while stirring a solution of 228 mg of pivaloyloxymethyl rac-(5RS,6SR)-6-[(RS)-1-hydroxyethyl]-3-[[(l-methyl-lH-tetrazol-5-yl)-thio]-methyl]-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate in 3 ml of methanol was added thereto, a fine precipitate resulting.

The mixture was stirred at 23°C for 3.5 hours and thereby lo the pH of the mixture was held at 7.1 by the addition of 0.1N sodium hydroxide. The still slightly turbid solution was extracted four times with 50 ml of ether each time and the ether phases were back-extracted twice with 50 ml of water each time. The agueous phases were concentrated to about 30 ml in vacuo at a temperature of 0-20°C and chromatographed on RP-18 silica gel(LiChroprep 'β', 40-63 pm) with 3% agueous methanol (v/v). The fractions containing the product were combined and concentrated and the solution, adjusted to pH 7.1 with 0.1N sodium hydroxide, was lyophilized.

There was obtained a mixture of sodium (5R,6S and 5S,6R)-6-[(R and S)-1-hydroxyethyl]-3-[[(l-methyl-lH-tetrazol-5-yl)-thio ]-methyl] -7-oxo-l-azabicyelo [3.2.0] hept-2-ene-2-carboxylate as a white, amorphous powder.

OV (H20): λ. = 278 nm (extinguishable with hydroxylamine) XR (KBr)s υ „ 1758, 1603, 1400 cm”1.

IQcUC NMR (DMSO-dg): 1.15 (d,J»6Hz,3H)f 2.66-2.86 (m,2H)f 3.03 (dxd,J-7Hz and 2,5Hz,lH)j 3,80-3.96 (m,2H)j 3.97 (s,3H); 4.40/4.66 (AB-system, J-12HZ, 5 2H) ppm.

Example 10 126 mg of pivaloyloxymethyl -rac-(2RS,3SR)-2-[3-[(5-methyl-1,3,4-thiadiazol-2-yl)-thio]-acetonyl]-4-oxo-3- [ (RS) -l-(trimethylsilyloxy)-ethyl] -a- (triphenylphosphoran10 · ylidene)-1-azetidineacetate were subjected to the cyclization procedure described in Example 8. After purification by chromatography, there were obtained 24 mg of pivaloyloxymethyl rac-(5RS,6SR)-6-[(RS)-1-hydroxyethyl]-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)-thio]-methyl]-7-oxo-l-azabicyclo15 [3.2.0]hept-2-ene-2-carboxylate as a colourless oil.

UV (EtOH): λπι3ν 292 nm.

The starting materials for Examples 10, 12, 13, 14 and 18 were prepared as follows: (a) Pivaloyloxymethyl rac-(2RS,3SR)-2-(3-bromoacetonyl)20 -4-oxo-3-[(RS)-l-(2,2,2-trichloroethoxycarbonyloxy)-ethyl]-a-(triphenylphosphoranylidene)-1-azetidineacetate was reacted according to the procedure described in Example 8(i) with the difference that in place of 5-meroapto-l-methyl-ΙΗ-tetrazole there were used: in Example 10 in Example 12 in Example 13 in Example 14 in Example 18 -mercapto-2-methyl-l,3,4-thiadiazole, 2-mercapto-pyrimidine, 4-aoetamino-thiophenol, 1,2,3,4-tetrahydro-4-methyl-3-thioxo-as-triazine-5,6-dione, methyl l-methyl-5-mercapto-lH-l,2,4-triazole-3-carboxylate. 1q After purification by chromatography there was obtained in Example 10: Pivaloyloxymethyl rac-(2RS,3SR)-2-[3-[(5-methy1-1,3,4—thiadiazol-2-yl)-thio]-acetonyl]-4-oxo-3-[(RS)-l-(trimethylsilyloxy)-ethyl]-a-(triphenylphosphoranylidene) -1-azetidineacetate as a white foam.

IR (CHC1-): 1749, 1640 cm1; j max in Example 12: Pivaloyloxymethyl rac-(2RS,3SR)-4-oxo-3- [ (RS) -l-(trimethylsilyloxy)-ethyl] -2- [3- (2-pyrimidinyl-thio) -acetonyl]-a-(triphenylphosphoranylidene)-1-azetidineacetate as a colourless oil.

IR (CHC13): vmay 1739 with shoulder at 1715, 1632 cm1; in Example 13: Pivaloyloxymethyl rac-(2RS,3SR)-2-[3-[(p-acetaminophenyl)-thio]-acetonyl]-4-oxo-3-[(RS)-1-( trimethyl52421 silyloxy )-ethyl]-a-(triphenylphoephoranylidene)-1-azetidineacetate as an amorphous powder.

IR (CHC13): vmax 3436, 3322, 1744, 1712, 1636 Gm-1; in Example 14: Pivaloyloxymethyl rac-(2RS,3SR)-2-[3-[(l,4, 5 5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl)-thio]-aoetonyl] -4-oxo-3- [ (RS) -1-? trimethyls ily loxy )-ethyl] -a- (triphenylphosphoranylidene)-1-azetidineacetate as a colourless oil.

IR (CHCl,): υ___ 3394, 1750, 1712, 1616, 1595 cm-1·, <3 IucUfc in Example 18: Pivaloyloxymethyl rac-(2RS,3SR)-2-[3-[3-methoxycarbonyl)-1-methyl-lH-l,2,4-triazol-5-yl]-thio]-acetonyl]-4-oxo-3-[ (RS)-1-(trimethylsilyloxy)-ethyl]-a-(triphenylphosphoranylidene)-1-azetidineacetate as a colourless oil.

IR (CHC13) .· vmax 1741, 1715, 1636 cm-1.

Example 11 Pivaloyloxymethyl rac-(5rs,6SR)-6-[(RS)-1-hydroxyethyl]-3-[[(5-methyl-l,3,4-thiadiazol-2-yl)-thio]-methyl]-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate was subjected in an analogous manner to the hydrolysis procedure described in Example 9. After chromatography on RR-18 silica'gel, there was obtained a mixture of sodium (5R,6S and 5S,6R)-6-[(R and S)-l-hydroxyethyl]-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)-thio]-methyl]-7-oxo-l-azabicyclo5 [3.2.0]hept-2-ene-2-carboxylate.

OV (H,O): = 278 nm (with hydroxylamine shift X * iTinX to 287 nm)· Example 12 163 mg of pivaloyloxymethyl rac-(2RS,3SR)-4-oxo-310 -[(RS)-l-(trimethylsilyloxy)-ethyll-2-[3-(2-pyrimidinyl-thio)-acetonyl]-a-(triphenylphosphoranylidene)-1-azetidineacetate were subjected to the procedure described in Example 8 with the difference that the cyclization time amounted to 3 hours. After purification by chromatography, there were isolated 42 mg of pivaloyloxymethyl rac-(5RS,6SR)-6-[(RS)-1-hydroxyethyl]-7-OXO-3-[(2-pyrimidinyl-thio)-methyl]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate as a colourless oil.

IR (CHC13): 3618, 3450, 1775, 1753, 1622, 1567, 1551 cm-1.

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

Example 13 157 mg of pivaloyloxymethyl rae-(2RS,3SR)-2-[3-[(p5 -acetaminophenyl)-thio]-acetonyl]-4-oxo-3-[(RS)-1-(trimethyls ily loxy) -ethyl]-a-(triphenylphosphoranylidene)-1-azetidineacetate were subjected in an analogous manner to the procedure described in Example 12. After purification by chromatography, there were isolated 33 mg of pivaloyloxymethyl rac-(5RS,6SR)-3-[[(p-acetaminophenyl)-thio]-methyl]-6-[(RS)-1-hydroxyethyl]-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate as an amorphous powder.

IR (CHC13): vmax 3618, 3434, 3382, 1778, 1755, 1695, 1619 cm-1.

NMR (CDC13): δ 1.22 (s,9H)·, 1.31 (d,J=6Hz,3H) ·, 1.91 (d, J»4Hz,lH); 2.17 (s,3H)·, 2.85-3.10 (m,2H) ·, 3.08 (dxd,J»6.5Hz and 3Hz,lH); 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)j 7.34 (d,J-8,5Hz,2H); 7.36 (s,lH)f 7.44 (d,J=8.5Hz, 2H) ppm.

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

Example 14 400 mg of pivaloyloxymethyl -rac-(2RS,3SR)-2-[3-[(1,4, ,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl)-thio]acetonyl ] -4-oxo- 3-[(RS) -1-( trimethyls ilyloxy) -ethyl ] - a5 -(triphenylphosphoranylidene)-1-azetidineacetate were subjected in an analogous manner to the procedure described in Example 8. After purification by chromatography, there were obtained 31 mg of pivaloyloxymethyl rac-(5RS,6SR) -6-[(RS)-1-hydroxyethyl]-3-[[(1,4,5,6-tetrahydro-4-methyl-5, 6-dioxo-as-triazin-3-yl)-thio]-methyl]-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-oarboxylate.

UV (EtOH):. λ = = 280 nm (with NH.OH shift to max 2 289 nm).

The preparation of the starting material is described 15 in Example 10(a).

Example 15 The product of Example 14 was subjected in an analogous manner to the procedure described in Example 9. There was obtained a mixture of sodium (5R,6S and 5S,6R)-6-[(R and S)-1-hydroxyethyl]-3-[[(l,4,5,6-tetrahydro-4-methyl-5,6dioxo-as-tria2in-3-yl)-thio]-methyl]-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

OV (Η2Ο): Xmax - 283 nm.

Example 16 186 mg of pivaloyloxymethyl rao-(2RS,3SR)—2—[3—[ [2,5-dihydro-2-methyl-5-oxo-6-[(pivaloyloxy)-methoxy)-as-tria5 zin-3-yl] -thio] -aoetonyl] -4-oxo-3- [ (RS) -l-(trimethylsilyloxy)-ethyl]-a-(triphenylphosphoranylidene)-1-azetidineacetate were subjected in an analogous manner to the procedure described in Example 8. After purification by chromatography, there were obtained 65 mg of pivaloyloxymethyl rao10 -(5RS,6SR)-6-[(RS)-1-hydroxyethyl]-3-[[[2,5-dihydro-2-methyl-5-oxo-6-[(pivaloyloxy)-methoxy]-as-triazin-3-yl]-thio]-methyl]-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-oarboxylate as a colourless oil.

IR (CHCl,): v 3692, 3614, 3370, 1775, 1753, 1737, luaX 1670, 1620 cm1.

NMR (CDC13) : δ 1.22 (s,18H) ; 1.31 (d,J-6Hz, 3H) ·, 1.80 (d,J»4.5Hz,lH)} 2.97-3.23 (m,2H) ; 3.18 (dxd,J-6.5Hz and 2Hz,lH); 3.70 (s,3H); 4.13-4.28 (m,2H)j 4.40/4.54 (AB-system, J-13.5Hz,2H); 5.88/5.97 (AB-system,J=7Hz, 2H); 5.93 (s,2H) ppm.

The starting material was prepared as follows: 53421 202 mg of triethylamine in 2 ml of methylene chloride were added to a solution of 858 mg of pivaloyloxyme-Uiyl rac-(2RS,3SR)-2-(3-bromoacetonyl)-4-oxo-3-[(RS)-1-(2,2,2—trichloroethoxyoarbonyloxy)-ethyl]-a-(triphenylphosphoran5 ylidene)-1-azetidineacetate and 159 mg of 1,2,3,4-tetrahydro-2-methyl-3-thioxo-as-triazine-5,6-dione in 10 ml of dimethylformamide and subsequently the mixture was stirred at room temperature for 20 minutes. The clear solution was cooled to 0eC, 242 mg of iodomethyl pivalate were added thereto and the mixture was stirred at 0°C for a further 15 minutes and at room temperature for 15 minutes. The mixture was diluted with ethyl acetate and washed successively with 5% sodium hydrogen carbonate solution and saturated sodium chloride solution. The' organic 'phase was dried over sodium sulphate, concentrated completely and the residue was chromatographed on silica gel using ethyl acetate for the elution. The purified product was treated with zinc in 90% acetic acid and subsequently with trimethylchlorosilane in analogy to the procedure described in Example 8(i). After purification by chromatography, there were obtained 196 mg of 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)-1-(trimethylsilyloxy)-ethyl]-a-(triphenylphosphoranylidene)-1- . -azetidineacetate as a colourless oil.

• Example 17 The product of Example 16 was subjected In an analogous manner to the procedure described in Example 9. There was obtained a mixture of disodium (5R,6S and 5S,6R)-6-[(R and S)-1-hydroxyethyl]-3-[[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)-thio]-methyl]-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

UV (H,0): λ „ 242, 281 nm. x max IR (KBr): 1755, 1602 with shoulder at 1650, max 1404 cm-1.

Example 18 180 mg of pivaloyloxymethyl rac-(2RS,3SR)-2-[3-[[3-(methoxycarbonyl)-1-methyl-lH-l,2,4-triazol-5-yl]-thio]-acetonyl]-4-oxo-3-[(RS)—1-(trimethylsilyloxy)-ethyl]-a15 -(triphenylphosphoranylidene)-1-azetidineacetate were subjected to the procedure described in Example 8. After purification by chromatography, there were obtained about 70 ng of pivaloyloxymethyl rac-(5RS,6SR)-6-[(RS)-1-hydroxyethyl]-3-[[[3-(methoxycarbonyl)-1-methyl-lH-l,2,4-triazol-5-yl]20 -thio]-methyl]-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate as a colourless oil.

IR (CHC1,): υ „ 3680, 3608, 3440, 1780, 1742, 1620 cm x w TuoX NMR (CDCl3): 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,lH); 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, σ=5·5Ηζ,2Η) ppm.

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

Example 19 The product of Example 18 was subjected in an analogous manner to the procedure described in Example 9. There was obtained a mixture of sodium (5R,6S and 5S,6R)-6-[(R and S)-1-hydroxyethyl]-3-[[[3-(methoxycarbonyl)-1-methy115 -1H-1,2,4-triazol-5-yl] -thio]-methyl] -7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

UV (H20): Xmax = 2?θ 11111 extinguishable with NH20H). vmax with shoulder at 1755, 1591, 1395 cm-1.

IR (KBr): Example 20 0.6 g of pivaloyloxymethyl rae-trans-2-[3-[(1-methy1-lH-tetrazol-5-yl) -thio] -acetonyl] -3- [1-methy 1-1-( trimethyl— silyloxy)-ethyl]-4-oxo-a-(triphenylphosphoranylidene)-15 -azetidineacetate were subjected to the cyclization procedure described in Example 8 with the difference that in order to remove the trimethylsilyl protecting group the chromatographed cyclization product was stirred at room temperature for 4 hours in 60 ml of methanol in the presence of 0.6 g of ammonium fluoride. After purification by chromatography, there were obtained 52 mg of pivaloyloxymethyl rao-6a-(1-hydroxy-1-methylethyl)-3-[[(1-methy1-1H-tetrazol-5-yl) —thio]-methyl]-7-oxo-5a-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate as a colourless oil.

UV (EtOH): \nax ” 296 8,11 (extinguishable with NHjOH).

IR (CHC1,): υ „ 3690, 3610, 1779, 1752, 1730, 1622 cm-1. J IUguC The starting material was prepared as follows: (a, A solution of 8.56 g of rac-4-[(2-methyl-l,3-dioxolan-2-yl)-methyl]-2-azetidinone in 150 ml of tetrahydrofuran was treated at -30*c within 4 minutes with 65.5 ml of a 1.6M butyl lithium/hexane solution and then left to stand for 90 minutes in an ice-bath under an argon atmosphere.

The brown-yellow solution was cooled to -30°C and treated with a solution of 3.2 g of acetone in 10 ml of tetrahydro53421 furan. After stirring at O°C for a further 30 minutes, the solution was poured on to 50 g of ice. The organic phase was separated and washed with 50 ml of saturated sodium chloride solution. The combined aqueous phases were extracted with a total of 300 ml of methylene chloride The organic phases were dried over sodium sulphate, concentrated completely at reduced pressure and the residual oil was chromatographed on silica gel. Elution with a mixture of acetone and methylene chloride (1:8, v/v) yielded firstly unreacted starting material, then rac-cis-3-(1-hydroxy-l-methylethyl)-4-[(2-methyl-l,3-dioxolan- 2-yl) -methyl] -2-azetidinone which was obtained as 0.80 g of white crystals of melting point 134-135°C after crystallization from ethyl acetate/hexane.

IR (CHC1-): v „ 3604, 3424, 1751 cm’1.

J ΙΠ5Χ By further elution there was obtained rac-trans-3-(1-hydroxy-1-methylethyl)-4-[(2-methyl-l,3-dioxolan-2-yl)-methyl]-2-azetidinone which gave 1.59 g of white crystals of melting point 84-86°C from ethyl acetate/hexane IR (CHC1,): v „ 3604, 3420, 1751 cm1. ά max (b) The procedures described in Example 8(a) and (d)-(i) were used in an analogous manner on 4 g of rac-trans-3-(1-hydroxy-l-methy lethyl) -4- [ (2-methyl-l,3-dioxolan-2-yl) 52421 -methyl]-2-azetidinone. There was obtained 0.96 g of pivaloyloxymethyl rac-trans-2-[3-[(1-methy1-lH-tetrazol-5-yl)-thio]-acetonyl]-3-[1-methy1-1-(trimethylsilyloxy)-ethyl]-4-oxo-a-(triphenylphosphoranylidene)-1-azetidine5 acetate as a colourless oil.

IR (CHC13): vmax 1744, 1635 cm-1.

Example 21 The product of Example 20 was subjected in an analogous manner to the procedure described in Example 9. There was obtained a mixture of sodium (5R,6S and 5S,6R)-6a-(1-hydroxy-1-methylethyl)-3-[[(l-methyi-lH-tetrazol-5-yl)-thio]-methyl]-7-oxo-5a-l-azabicyclo[3.2.0]hept-2-ene--2-carboxylate. 0V (H20): ·« 279 nm (extinguishable with NH20H).

Example 22 230 mg of pivaloyloxymethyl rac-trans-2-[3-[(1-methyl-lH-tetrazol-5-yl)-thio]-acetonyl]-4-OXO-3-[(trimethylsilyloxy) -methyl]—a- (triphenylphosphoranylidene)-1-azetidine- acetate were subjected to the procedure described in Example 8 with the difference that the cyclization time amounted to 30 minutes. After purification by chromatography, there were obtained 66 mg of pivaloyloxymethyl rac-6a-(hydroxymethyl) 72 52431 -3- [ [ (l-methyl-lH-tetrazol-5-y 1)-thio] -methyl] -7-οχο-5σ-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate as a colourless oil.

UV {EtOH); λ „ 289 nm {extinguishable with NH-OH).

IR (CHCl,)': υ 3440, 1782, 1752, 1619 cm-1.

J IUoX The starting material was prepared, as follows: (a) 15.8 g of tert-butyldimethylchlorosilane and 25.2 g of rac-4-(3-bromo-2,2-dimethoxypropyl)-2-azetidinone were dissolved successively in 150 ml of dimethylformamide, the solution was cooled to 0°C and treated while stirring with 22.0 g of triethylamine, a precipitate forming. The mixture was stirred at 0°C for 15 minutes, diluted with 1 1 of ether/hexane (1:1, v/v) and extracted four times with 400 ml of water each time. The agueous phases were back-extracted with 500 ml of ether/hexane (1:1, v/v), the organic phases were dried over sodium sulphate and concentrated completely. The residual oil was taken up in a small amount of hexane and left to stand at -20’C. There were obtained 31.3 g of rac-4-(3-bromo-2,2-dimethoxypropyl)20 -1-(tert.-butyldimethylsilyl)-2-azetidinone as white crystals of melting point 61-63°C. (b) 7.06 g of rac-4-(3-bromo-2,2-dimethoxypropyl)-l-(tert.-butyldimethylsilyl)-2-azetidinone were subjected in an analogous manner to the procedure described in Example 8(b) with the difference that 6.0 g of methyl formate was used in place of methyl acetate. The product was purified by chromatography and then crystallized from ether/petroleum ether to give 2.19 g of rac-trans-4-(3-bromo-2,2-dimethoxypropyl hl- (tert. -butyldimethylsilyl)-3-formyl-2-azetidinone as white crystals of melting point 70-72’C. (c) A solution of 788 mg of rac-trans-4-(3-bromo-2,2-dimethoxypropyl)-1-(tert.-butyldimethylsilyl)-3-formyl-2-azetidinone in 12 ml of methanol, cooled to O’C, was treated with 38 mg of sodium borohydride and the mixture was stirred for 10 minutes. The mixture was diluted with ethyl acetate, washed with saturated sodium chloride solution, the organic phase was dried over sodium sulphate and concentrated completely. Crystallization of the residue from ethyl acetate/hexane gave 685 mg of rac-trans-420 -(3-bromo-2,2-dimethoxypropyl)-1-(tert.-butyldime thy lsilyl) -3-(hydroxymethyl)-2-azetidinone as white crystals of melting point 119-12O°C. (d) 7.87 g of rac-trans-4-(3-bromo-2,2-dimethoxypropyl)-1-(tert.-butyldimethylsilyl)-3-(hydroxymethyl)-2-azetidinone were subjected to the procedure described in Example 8(d) and the crystalline product was subsequently stirred at room temperature for 20 minutes in 240 ml of methanol in the presence of 0.70 g of ammonium fluoride. There were obtained after aqueous working-up and crystallization of the crude product from ethyl acetate/hexane 7.66 g of rae-trans-4-(3-bromo-2,2-dimethoxypropy1)-3-[(2,2,2-triohloroethoxycarbonyloxy)-methyl]-2-azetidinone of melting point' 108-109°C. (e) The reaction sequence described in Example 8(f)-(i) was used in an analogous manner on 5.2 g of rac-trans-4- (3-bromo-2,2-dimethoxypropyl)-3- [ (2,2,2-trichloroethoxycarbonyloxy)-methyl]-2-azetidinone. There was obtained 0.23 g of pivaloyloxymethyl rac-trans-2-[3-[(1-methyl-lH-tetrazol-5-yl)-thio]-aoetonyl]-4-oxo-3-[(trimethylsilyl15 oxy)-methyl]-a-(triphenylphosphoranylidene)-1-azetidineacetate as a colourless oil.

Example 23 The product of Example 22 was subjected in an analogous manner to the procedure described in Example 9. There was obtained a mixture of sodium (5R,6S and 5S,6R)-6a-(hydroxymethyl)-3-[[(l-methyl-lH-tetrazol-5-yl) —thio]-methyl]-7-oxo-5a-l-azabicyolo[3.2.0]hept-2-ene-2-carboxylate.

UV (H-0): <.,277 nm (extinguishable with NH-OH).

£ IuaX & Example 24 mg of rac-l-(tert.-butyldimethylsilyl)-3-(Z)-ethylidene-4-[(2-methyl-l,3-dioxolan-2-yl)-methyl]-25 -azetidinone were hydrogenated at normal pressure in 2 ml of ethyl acetate in the presence of 50 mg of platinum dioxide. There was obtained a 6:1 cis/trans isomeric mixture from which the main component could be isolated in pure form by fractional crystallization of the crude product from hexane: rac-cis-l-(tert.-butyidimethylsilyl)-3-ethyl-4-[(2-methyl-l,3-dioxolan-2-yl)-methyl]-2-azetidinone, melting point 80-82°C.

The starting material was prepared as follows: 300 mg of diisopropyl azodicarboxylate were added to a solution, cooled to 0°C, of 330 mg of rac-(3SR,4RS)-1-(tert.-butyidimethylsilyl)-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 and the resulting solution was stirred at room temperature for 1 hour. Then, the solution was partitioned between water and ethyl acetate, the organic phase was dried over sodium sulphate and concentrated completely. The residue was chromatographed on silica gel using ethyl acetate/methyl52421 lene chloride/hexane (1:1:2, v/v/v) for the elution and the purified product was crystallized from hexane. There were obtained 100 mg of rac-1-(tert.-butyldimethylsilyl)—3 — (Z)-ethylidene-4-[(2-methy1-1,3-dioxolan-2-yl)-methyl] -2-azetidinone as colourless crystals of melting point 85-86°C.

IR (CHC1,)·: υ „ 1722 cm1.

Example 25 1.04 g of rac-cis-l-(tert.-hutyldimethylsilyl)-410 -[(2-methy1-1,3-dioxolan-2-yl)-methyl]-3-[1-methyl-l-[(2,2,2-trichloroethoxycarbonyloxy)-ethyl]-2-azetidinone were subjected in an analogous manner to the procedure described in Example 8(e) with the difference that the bromination was carried out at a temperature of 45°C.

After purification by chromatography and crystallization from ethyl aeetate/hexane, there was obtained 0.54 g of rac-cis-4-(3-bromo-2,2-dimethoxypropyl)-3-[1-methyl-l-(2,2,2-trichloroethoxycarbonyloxy)-ethyl]-2-azetidinone as colourless crystals of melting point 104-106°C.

IR (CHC1,): υ 1765 cm1. max The starting material was prepared as follows: Rac-cis-3-(1-hydroxy-1-methylethyl)— 4 —[(2-methyl-l,3-dioxolan-2-yl)-methyl]-2-azetidinone was reacted in analogy to the procedures described in Example 8(a) and (d). After crystallization from hexane, there was obtained rac-cis-1-(tert.-butyldimethylsilyl)-4-[(2-methyl-l,3-dioxolan-2-yl)-methyl]-3-[1-methyl-l-(2,2,2-triehloroethoxycarbonyloxy)-ethyl]-2-azetidinone of melting point 89-91°C.

Example 26 When (-)-(3S,4R)-l-(tert.-butyldimethylsilyl)-3-[(R)-1-hydroxyethyl]-4-[(2-methyl-l,3-dioxolan-2-yl)-methyl]-2-azetidinone was used for the reaction·sequence Of steps (d)-(i) described in Example 8 and the product was subjected to the procedure described in Example 9, then there was obtained sodium (5R,6S)-6-[(Rj-l-hydroxyethyl]~ -3-[[(l-methyl-lH-tetrazol-5-yl)-thio]-methyl]-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.

UV (H-0): λ278 nm (extinguishable with NH.OH).

“ IuclX Z The starting material was prepared as follows: (a) A solution of 19.8-g of rac-(3SR,4RS)-l-(tert.-butyldimethylsilyl)-3-[(RS)-1-hydroxyethyl]-4-[(2-methyl-l,352421 -dioxolan-2-yl)-methyl]-2-azetidinone in 120 ml of pyridine, cooled to O’C, was treated with 18.8 g of (-)camphanic acid chloride. The mixture was stirred at room temperature for 22 hours. Then, the mixture was diluted with 1.2 1 of ethyl acetate and washed successively with in each case 360 ml of dilute sodium hydrogen carbonate solution and saturated sodium chloride solution. The agueous phase's were back-extracted with 1 1 of ethyl acetate, the combined organic phases were dried over sodium sulphate, concentrated completely and the residue was chromatographed on silica gel. Elution with a mixture of ethyl acetate/methylene chloride/hexane (1:6:6, v/v/v) yielded firstly a (+)-rotatory camphanic acid ester which could be crystallized from ether/hexane. There was obtained (+)-(3R,4S)-l-(tert.-butyldimethylsilyl)-3-[(ls)-1-camphanoyloxyethyl]-4-[(2-methy1-1,3-dioxolan-2-yl)-methyl]-2-azetidinone of melting point 125-127’C and [a]20 = + 15.0’ (c = 1, ethyl acetate). After some mixed fractions there were obtained fractions containing as the main component a (-)-rotatory camphanic ester. This was purified by crystallization from ether/hexane. There was obtained (-)-(3S,4R)-1-(tert.-butyldimethylsilyl)-3-[(lR)-1-camphanoyloxyethyl]-4-[(2-methyl-l,3-dioxolan-2-yl)-methyl]-2-azetidinone of melting point 112-113’C and [a]20 = -19.9’ (c = 1, ethyl aoetate). 5242 (b) A solution of 0.5 g of (-)-(3S,4R)-1-(tert.-butyldimethylsilyl )-3-[ (lR)-l-camphanoyloxyethyl]-4-[(2-methyl-l,3dioxolan-2-yl)-methyl]-2-azetidinone from step (a) in 10 ml of toluene was treated at O’C with 4 ml of a 1.12M solution of diisobutylaluminium hydride in hexane and the mixture was subsequently stirred at room temperature for 2 hours. The mixture was poured into saturated sodium chloride solution and extracted with ethyl acetate. The organic phases were washed again with brine, dried over sodium sulphate, concentrated completely and the residual oil was chromatographed on silica gel using ethyl acetate/hexane (1:1, v/v) as the eluent. After two-fold crystallization from hexane, there was obtained (-)-(3S,4R)-1-(tert.-butyldimethylsilyl)3-[(R)-1-hydroxyethyl3-4-[(2-methyl-l,3-dioxolan-2-yl)20 methyl]-2-azetidinone of melting point 83-84’C and [α]& = -50.8° (c = 1, ethyl acetate).

Example 27 A solution of 10 mg of sodium (5R,6S and 5S,6R)-6[(R and S)-1-hydroxyethyl]-3-[[(l-methyl-tetrazol-lH-5-yl)— thio3-methyl]-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate in 0.2 ml of dimethylformamide, cooled to 0°C, was treated with 7 mg of bromomethyl acetate and subsequently stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate,washed with 0.05M pH 7 phosphate buffer, dried over sodium sulphate and concentrated completely. Chromatography of the residue on silica gel using yellow oil.

UV (EtOH): IR (CHC13): The compounds of ethyl acetate/methylene chloride as the eluent gave 1.8 mg of acetoxymethyl (5R,6S and 5S,6R)-6-[(R and S)-1-hydroxyethyl ]-3-[ [ ( l-methyl-lH-tetrazol-5-yl) -thio] -methyl ]-7oxo-l-azabicyclo[3,2.0]hept-2-ene-2-carboxylate as a pale \nax “ 295 15111 (extin9uisllal:,le with NHjOH). v 1771' 1738 Example 28 formula I in accordance with the invention which are listed in Table I can be manufactured by analogous use of the procedures described in the foregoing Examples. Thereby, under certain circumstances it can be advantageous to alter the sequence of reactions described or in certain cases to use other protecting •groups. Compounds 28) or 30) or 43) or 44) are obtained by reacting compounds 27) or 29) or 41) or 21), respectively, according to generally known methods, for example with methyl formimidate in aqueous solution at pH 8-8.5.

R2 Η Table I Compound R1 R2 X Salt 1) H -CH2CH3 N — AJ Na 2) H -ch2ch3 a e«3 r*, COOOIj II 3) H -ch2ch3 VV'** II 4) OH 1 -CHCH2CH3 H Μ — K AJ II 5) OH -CHCHjCHj H «3 N «-* AJ II 6) OH -chch2ch3 H QtjGeoN· II 7) OH -ch-cf3 H I - ΐ II 8) OH 1 -CH-CF3 H 1 “3 Ν—N 524 21 Compound R1 R2 X Salt 9) OH J -CH-CF3 H Na 10) OH 1 -CH-CH3 H —« jOI, K II 11) 11 II 7X — Ϊ ““W II 12) tl II Oi, ca. < - 13) It II 1 Na 14) II II II 15) II It S — N Αλ “* CE, 11 16) II If 5— S II 17) ' II A' —S ' S VCOCM* II 18) II It « *Z^sX^SCMCH2Ca3 II 19) II >3 II Compound R1 R2 X Salt 20) OH -ch-ch3 H Na 21) fl If - 22) II II Na 23) II It II 24) 1* II *—w. “l II 25) II II II 26) II II Λ'\ *— CMjOW II 27) II II °x_ «•m. —i' 'CMjiiMj 28) II IIα’\ M-Η. CHj-HH-OI-MM - 29) '· II M-il, _,xA.\ CMj-CHj-NHj - 30) II li0,3 M —s ' * CX.CHjNH-CH-MH Compound R1 R2 Salt OH 31) -CH-CHj H -ΛΚ, Na 32) II II II 33) 11 II ΛΛ ' 9 α*ιιαι2£*2»Γ2 34) II II _.A? Na 35 Γ II II V\ /-¾ 36) It II /-¾ - 37) II 41 :x Na 38) II II M *N II WM, 39) II II N -»K λ:^ “s l COOCHj ft 40) II II N — 1 Λ 5 i CHj-COCS* II 41) ' tl « — H * 1 - ί CM.CHjNHj . 58481 Compound R1 R2 X Salt 42) OH 1 -CH-CH3 H X — X - 43) tl It X —X -/3 atjCXj-Mi-aMMt - 44) tl · II - 45) II II _>6 Na 46) It II 0 ll 47) II It 0 JL “3 - 48 ) II ' Λ -// - 49) II II Λ Na 50) II II —A'S - 51) ·· 9 _.a\ Na X Compound. R1 R2 X Salt 52) OH -ch-ch3 H Na 53) II 1« e A 001,0.,0,01, II 54) u <1 0 55) II If 1 κ Na 56) 1* II A II 57) II It 1 )=-\ , » .* 1 fa I If 58) II II '.-»i -fa, II 59) II II II 60) II ·' OH »Ac“3 ι Γ*®! II 61) It II -.rr II 62) -'P CS0H4 II Compound R1 R2 X Salt 63) OH 1 -CH-CH3 H COHeCWjClIjWj - 64) II II 1 a Na 65) II H -aX II 66) II II „ >6 II oaa«aa3 67) II II II 68 ) II II pa ll 69) II II A 0 -O-C-CH3 II 70) II II II 71) H0H ' ZCH3 “C K ch3 N — It - I “j It 72 ) II II _λΑ. II 73) It Η «-Ν -A.)' . II CH.CM.lt 3 • ‘^CH3 Example 29 Manufacture of dry ampoules for intramuscular administration: A lyophilizate of 500 mg of sodium (5R,6S)-6-[(R)5 -1-hydroxyethyl]-3-[[(l-methyl-lH-tetrazol-5-yl)-thio]-methyl]-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate is prepared in the usual manner and filled into an ampoule. Prior to the administration the lyophilizate is treated with 2.5 ml of a 2% aqueous lidocaine hydrochloride solution.

Example 30 An interlocking gelatine capsule containing the following ingredients is manufactured in the usual manner* Pivaloyloxymethyl (5R,6S)-3-[[(1-ethyl-l, 2-dihydro-2-oxo-4-pyrimidinyl)-thio]-methyl]-6-[(R)-1-hydroxyethyl]-7-oxo-l- -azabicyclo[3.2.0]hept-2-ene-2-carboxylate 500 mg Luviskol (water soluble polyvinylpyrrolidone) 20 mg Mannitol 20 mg Talc 15 mg Magnesium stearate 2 mg 557 mg Example 31 A tablet containing the following ingredients is manufactured in the usual manner: Pivaloyloxymethyl (5R,6S)-3-[[(1-ethyl5 -l,2-dihydro-2-oxo-4-pyrimidinyl)-thio]-methyl]-6-[(R)-1-hydroxyethyl]-7-oxo-l- -azabioyclo[3.2.0]hept-2-ene-2-carboxylate 250 mg Lactose 70 mg Maize starch 65 mg Polyvinylpyrrolidone 10 mg Magnesium stearate 5 mg 400 mg A granulate is prepared in the usual manner from the active substance, the lactose, the polyvinylpyrrolidone and 40 parts by weight of the maize starch. This granulate is mixed with the remaining 25 parts by weight of maize starch and 5 parts by weight of magnesium stearate and the resulting mixture is pressed to tablets.

Claims (5)

1. -13 for use as pharmaceutically active substances for the treatment and prophylaxis of infectious diseases. 5 2421 16. Pharmaceutical preparations, which contain a compound in accordance with any one of claims 1-13 and a pharmaceutically acceptable carrier. 17. Pharmaceutical preparations for the treatment 5 and prophylaxis of infectious diseases, which contain a compound in accordance with any one of claims 1-13 and a pharmaceutically acceptable carrier. 18. A process for the manufacture of a compound in accordance with claim 1, which process comprises cyclizing 10 a compound of the formula wherein R , R and X have the significance given in 1- 3, wherein X represents a 4-7 membered, monocyclic, saturated, unsaturated or aromatic heterocycle containing 5 1-4 hetero atoms (nitrogen, oxygen, sulphur) which can be substituted by fluorine, chlorine, bromine, oxo, imino, C^ g-alkyl, C^ ^-alkylthio, hydroxy, cyano, N-oxido, trifluoromethyl, C^^-alkoxy, C^ 4 ~alkanoyloxy, phenyloxy, C 2 _ 4 ~alkanoyl, phenoxycarbonyl, 10 pivaloyloxymethoxycarbonyl, carbamoyl, C^^-alkylcarbamoyl and/or di-C^-alkylcarbamoyl or by -(CH 2 ) n -NRR', -(CH 2 ) n ~ -NR-CR'=NR or -(CH.) -N=CR-NR'R wherein n is 0, 1, 2 or z n 1-3, wherein X represents C 2 _g-alkenylthio or C 2 _g-alkenylthio substituted by one of the groups -(CH 2 ) n -NRR', -(CH 2 )n 20 -NR-CR'=NR” and -(CH,) -N=CR-NR'R (wherein n is 0, 1, 2 z n or 3 and R, R' and R are hydrogen, C 1 _ 3 ~alkyl or C 1-3 -alkanoyl) or also by C 1 _ 3 ~alkyl, phenyl, a 3-7 membered saturated, unsaturated or aromatic heterocycle containing 1-4 hetero atoms (nitrogen, oxygen, sulphur), cyano, carboxyl, C^_ 4 ~alkoxycarbonyl, aminocarbonyl or acylamino. 9. Compounds in accordance with any one of claims 1-3, wherein X represents C 3 _ 4 -alkylthio substituted by phenyl, which can be substituted by one or more fluorine, chlorine or bromine atoms, C-^-alkyl, C.^-alkylthio, C^^-alkanoyl, carboxyl or C 3 _ 3 -alkoxycarbonyl 20 groups; or by a group -(CH 2 ) n ~NRR' or -(CH 2 ) n -NHCR=NR' or ~(CH 2 ) n -N=CR-N(R') 2 in which n can be 0, 1, 2 or 3 and R and R' are hydrogen or C^j-alkyl; fluorine, bromine; an oxime or oxime ether group =N-OR' (wherein R r is hydrogen or C^-alkyl) in the syn- or anti-position} a 3-7 membered monocyclic, saturated, unsaturated or 5 aromatic heterocycle containing 1-4 hetero atoms (nitrogen, oxygen, sulphur; which can be substituted by one or more fluorine, chlorine or bromine atoms, C 1 _ 3 ~alkyl, C ]__4 - -alkylthio, -alkanoyl, carboxyl or C 1 _ 3 ~alkoxycarbonyl groups; or by a group -(CH 2 ) n ~NRR' or -(CH 2 ) n -NH-CR=NR' 10 or -(CH,) -N=CR-N(R'), in which n can be 0, 1, 2 or 3 and 6 n J R and R' are hydrogen or C^_ 3 -alkyl, as well as by oxo groups) ; a C 3 _ g -cycloalkyl group; a group -S(0> -R' (wherein n is 1 or 2 and R* is n 15 C^-alkyl); a group -COR' [wherein R' is C-^-alkyl, phenyl, phenyloxy, benzyloxy, C 3 _g-cycloalkyl or a 3-7 membered heterocycle containing 1-4 hetero atoms (nitrogen, oxygen, sulphur), which can be substituted in the manner set forth 20 earlier in this claim!. 53421 6. ‘Compounds in accordance, with any one of claims 1-3, wherein X represents phenylthio substituted by one or more fluorine, chlorine or bromine atoms, one of the groups -(CH,) -NRR', -(CH,) -NR-CR'=NR and -(CH.) -N=CR-NR'R 5 (wherein n is 0, 1, 2 or 3 and R, R 1 and R are hydrogen, C^-alkyl or C^-alkanoyl) or also by C^-alkyl, C 1 _ 3 ~ -alkanoylamino, hydroxy, C.^-alkoxy or acyloxy groups. 7. Compounds in accordance with any one of claims 1-3, wherein X represents C^^-cycloalkylthio or C 3 _ 7 ~ 10 -cycloalkylthio substituted by one or more oxo, hydroxy, C 1 _ 4 -alkyl, C-^-alkoxy, carboxyl or alkoxycarbonyl groups or by one of the groups - (CH^-NRR', -(CH^-NR-CR^NR and -(CH,) -N=CR-NR'R (wherein n is 0,' 1, 2 or 3 and R, z n R' and R are hydrogen, C^_ 3 ~alkyl· or C^_ 3 -alkanoyl) or 15 by one or more acyl groups of an aliphatic or aromatic C^_γ-carboxylic acid. 8. Compounds in accordance with any one of claims 1-hydroxypropyl, l-hydroxy-2,2,2-trifluoroethyl or 1-hydroxy10 ~ 1-methyl-ethyl. 1 2 of the symbols R and R represents hydrogen and the other represents hydrogen, ethyl, hydroxymethyl, 1-hydroxyethyl, 1 2 wherein one of the symbols R and R represents·. hydrogen and the other represents hydrogen or a substituted or unsubstituted C^_ 4 ~alkyl group and X represents a substituted or unsubstituted C^_ 3 -alkanoyloxy group, an unsubstituted or substituted C 3 _-,-cycloalkylthio, C 2 _g-alkenylthio or heterocyclylthio group or a substituted C^_ 4 ~alkylthio or phenylthio group, their readily hydrolyzable esters, pharmaceutically compatible salts as well as hydrates of these compounds.

1. Bicyclic compounds of the general formula R in· o' COOH Ή 2”X

2. Compounds in accordance with claim 1, wherein one 1 2 of the symbols R and R represents hydrogen and the other represents hydrogen, C^_ 4 ~alkyl or C 1 _ 4 ~alkyl substituted by fluorine, chlorine, bromine; a group -S(0) -R* in which n is 0, 1 or 2 and R 1 is C^_ 3 -alkyl; a group -CO-R 1 in which R' is hydroxy, C-^-alkoxy, C^j-alkyl, amino, C^-alkylamino or di-C^_ 3 ~alkylamino; an amino group -NR'R in which R' and R are hydrogen or -alkyl; or a group -OR' in which R’ is hydrogen, methyl, -SO^H or -CHjOCOR wherein 5 R is C^-alkyl. 3. 4 5 claim 1, R is a readily cleavable group and R , R and represent C^_g-alkyl, phenyl or p-methoxyphenyl, 15 if necessary cleaving off protecting groups present in a substituent and, if desired, re-esterifying the ester obtained, if desired converting an ester into the free acid or salt thereof by cleavage of the group R and, if desired, converting a product obtained into a hydrate. 3 and R, R' and R are hydrogen, C 1 _ 3 ~alkyl or C£_ 3 ~ -alkanoyl; or by -(CHj^COR 1 wherein n is 0, 1, 2 or 3 15 and R' is hydroxy, C^_ 3 ~alkoxy, amino or -NH-(CH 2 ) m -NH 2 in which nt is 2, 3 or 4; or also by -(CH.) OH wherein n is Il 0, 1, 2 or 3. 10. Compounds in accordance with any one of claims 1-3, wherein X represents 2-(acetylamino)-vinylthio, (1-methyl20 -lH-tetrazol-5-yl)-thio , (1,4,5,6-tetrahydro-4-methyl-5,6dioxo-as-triazin-3-yl)-thio, (2,5-dihydro-6-hydroxy-2methyl-5-oxo-as-triazin-3-yl)-thio, (1-ethyl-l,2-dihydro2- oxo-4-pyrimidinyl)-thio, (5-methyl-l,3,4-thiadiazol-2yl)-thio and acetoxy. 11. Compounds in accordance with any one of claims. 1-10, which are defined as the final products in any one of Examples 1-3. 12. Compounds in accordance with any one of claims 5 1-10, which are defined as the final products in any one of Examples 4-28. 13. Compounds in accordance with any one of claims 1-10 of the general formula •CH2—* COOH Ia 10 as well as their readily hydrolyzable esters, pharmaceutically compatible salts as well as hydrates of these compounds . 14. Compounds in accordance with any one of claims 1-13 for use as pharmaceutically active substances. 15 15. Compounds in accordance with any one of claims

3. Compounds in accordance with claim 2, wherein one 4. 5 19. A process according to claim 18, wherein R , R and R 6 each represent a phenyl group. 20. Bicyclic compounds according to claim 1 substantially as hereinbefore described in the Examples.

4. Compounds in accordance with any one of claims 1-3, wherein X represents C^j-alkanoyloxy or C^-alkanoyloxy substituted by hydroxy, C^_ 3 ~alkoxy, phenyl or C 1 _ 3 -alkylthio. 15 5. Compounds in accordance with any one of claims

5. 21. A process according to claim 18 substantially as hereinbefore described in the Examples.