SE454779B - 2,6-DISUBSTITUTED PENEM SOCIETIES, PROCEDURES FOR PREPARING THEREOF, AND PHARMACEUTICAL COMPOSITION THEREOF WITH ANTIBACTERIAL EFFECT - Google Patents

Description

Wherein g Z is hydrogen or an easily removable ester protecting group and Y is (a) methoxymethoxyhydroxyethyl, formamidomethyl or 2,2-dimethyl-1,3-dioxolanyl, in which case X is alkyl of 1 to 6 carbon atoms; (b) hydroxy-substituted alkyl of 1 to 6 carbon atoms, in which case X is aminocyclobutyl or (c) hydrogen, in which case X is and alkyl is lower alkyl of 1 to 6 carbon atoms; (i) -enzyme Pow alkynz, where n is an: content of 1 - s (ii) - (CH2) NHOH, where Q is an integer of 1-6; n (iii) - (cH2) n ~, (su wherein Q is an integer 1 - 6; mv; .l AB 1 (lv) - (CH2) nOCO (CH2) mNR R, where Q and Q are independently AB others are 1 or 2 and R and R are independently hydrogen or alkyl having 1 to 6 carbon atoms, (v) - (CH) NHC (R) = NH, where n is an integer from 1 to 6 and R c is alkyl having 1 to 6 carbon atoms, phenyl or wcz, where m is 1 or 2 or m (Vi) CH -CH -C 2 -OCH N 3 and pharmaceutically acceptable salts thereof.

The compounds of formula I, wherein Z is hydrogen (and their pharmaceutically acceptable salts and physiologically hydrolysed esters), are potent antibacterial agents. Other compounds are useful intermediates for the preparation of the biologically active penem compounds. The substituent groups disclosed above for the 2- and 6-positions of the penem ring can be further defined as follows: lower alkyl includes both straight and branched chain, saturated aliphatic hydrocarbon groups having 1 to 6 carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, etc. Preferred lower alkyl substituents have 1-4 carbon atoms and in especially 1-2 carbon atoms. 454,779 Cr; Since an asymmetric carbon atom is present in the 2-substituted compounds of formula I, such compounds may exist either in the form of racemic mixtures (R, S-form) or as individual right-turning and left-turning (R- and S-forms). ) optical isomers. Preferred compounds are those whose configuration at the 5-carbon atom corresponds to that of natural penicillin (SR configuration). The substituents in the 6 and 6 positions of the 2,6-disubstituted penem compounds may be in the cis or trans position relative to each other. In case the penem-6 substituent contains an asymmetric carbon atom, the resulting isomers are identified in the following as the isomers A, B, C and D. The preferred isomer in compounds of this type is isomer B.

Separation of the various optical and geometric isomers can be performed in a conventional manner and by cleavage methods well known to those skilled in the art.

The present invention includes the compounds of formula I in the form of isomer mixtures and also in the form of the individually separated and cleaved isomers.

The pharmaceutically acceptable salts include non-toxic carboxylic acid salts, for example non-toxic metal salts such as salts of sodium, potassium, calcium, aluminum and magnesium, ammonium salts and salts with non-toxic amines such as trialkylamines (triethylamine), orocaine, dibenzylamine, N -benzyl- [9-phenethylamine, 1-phenenamine, N, N'-dibenzylethylenediamine, N-alkylpiperidine and other amines which have been used for the preparation of salts of penicillins and cephalosporins. When a basic group is present, the present invention also includes the pharmaceutically acceptable acid addition salts, for example salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid and sulfuric acid, or with suitable organic carboxylic acids or sulfonic acid, such as trifluoroacetic acid, p-toluenesulfonic acid, maleic acid, acetic acid, citric acid, oxalic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid and malic acid. Compounds which contain an acidic group and an alkaline group may also be present in the form of internal salts, ie. such as a zwitterion. The preparation of the salts described above can be carried out according to conventional procedures for the preparation of salts of β-lactam antibiotics, such as penicillins and cephalosporins.

The term "easily removable ester protecting group" refers to such a group which has acquired a very special meaning in the field of β-lactam and peptide. Many such groups are known, which are used to protect the carboxyl group during subsequent chemical reactions and which can later be removed by other methods to obtain the free carboxylic acid. Known ester protecting groups include 2,2,2--trichloroethyl, tertiary alkyl of 4-6 carbon atoms, tertiary alkenyl of 5-7 carbon atoms, tertiary alkynyl of 5-7 carbon atoms, alkoxymethyl, alkanoylmethyl of 2-7 carbon atoms, N-phthalimidomethyl, benzoylmethyl, halobenzoylmethyl, benzyl, p-nitrobenzyl, o-nitrobenzyl, benzhydryl, trityl, trimethylsilyl, triethylsilyl, α, β-trimethylsilylethyl and the like. The choice of ester protecting group depends on the subsequent reaction conditions to which the group must be subjected and the conditions which it is desired to use to remove the group. The choice of the appropriate group is a purely professional measure. For use as a chemical intermediate, the most preferred ester is the p-nitrobenzyl ester, which can be easily removed by catalytic hydrogenation. For the preparation of compounds which contain functional groups which are reducible under such conditions for the removal of the ester group, a preferred alternative is the β -trimethylsilylethyl ester, which can be removed by treatment with fluoride ions. Within the framework of easily removable ester-protecting groups, physiologically cleavable esters also fall, ie. the esters which in the field of penicillin and cephalosporin are known to be easily broken down in the body to the corresponding acid. Examples of such physiologically cleavable esters include indanyl, phthalidyl, methoxyimethyl, glycyloxymethyl, phenylglycyloxymethyl, thienylglycyloxymethyl and acyloxymethyl of the formula O in n Particularly preferred esters of this type are methoxymethyl, acetoxymethyl, pivaloyloxymethyl, phthalidyl and indanyl.

It will be apparent that the compounds of formula I may exist in different solvation states and the anhydrous as well as the solvated (including hydrates) forms fall within the scope of the invention.

The preferred compounds of formula I are those wherein Y is hydrogen.

The compounds of formula I may be prepared by one or more of the reaction alternatives set forth below. The different syntheses can be divided into three main processes depending on the stage in which the 6-substituent, i.e. Y, incorporated. Thus, in Process I, the 6-substituent is incorporated into the starting material; in process II Y is incorporated at the end of the synthesis and in process III the substituent Y is incorporated in an intermediate step of the synthesis. Each of the three main processes can in turn vary the process for incorporating the desired 2-substituent, ie. In general, it is preferred to incorporate the substituent Y in an intermediate step of the synthesis and to incorporate the substituent X by * Im acylation of the mercaptide intermediate III or IIIa, as shown below, as these methods have been found to be most generally useful.

The reaction steps in process I are shown in the following reaction scheme: 7 454 77? Method I (variation 1): Early introduction of the Z-substituent - ¶ o ““ ~ ° ^ = X2 Sw Y-cxæx-onc csI _ '-a .'- 0 \ H 2 "* så * ___;' YM. Så x I 'cao | ___ è / ___ N | v' SOClz o 'xx cozn "oæ-N Oh co2a ~ f' o YI sc-x Pøs Ywx så * A - +> I, N Cl bas / J / : J / pø ° ° .V3 I y RI C02 X s. ° y l g avïägsn. mi. 5 / f-'R / av skydds- í / x ° fl fuøp “o cola 454 779 Procedure '(variation 21: Late introduction of the Z-à-substituent Y on: c ï v-cxæx-onc cszš II “Zcæm š 'o N \ Pa 715 _ a YR SÅC SAc * f --è --à»' C | H ° soclz --N n ox of xx coza "_ cpza 'YR i SAc K: m3 Y \\ .. 'SAC MA J-: xql Cl bas - / Å-Ií P93 bas o ïJJ ”0 YI cozx' coza 'Y' ff '“ W- sM X _ (!: I_ QY sc-x AN P9 _' N Pø 0 3 0 Y 3 _ COZR "C023" íïwx s Y ¶ ix avïägsn. Av 'LL S s / ås protection group x 0 N í m2? ° _ CO2n ll XCO = acyïeríngsmedeï MA = tungmetaïïsalt f »fw: 9 454 779 I (variation 3): Late incorporation of the Z-substituent _ _ Y ° ^ ° ø3csua Y-CH-Cd-OAC CSI; N _šííïïš_æ>. 0 \ fl YY. ”“ ~ Sc fl; ---> “-“ øa - ~> (1130 SOC12 --N n --N OH 0 / \ H CO 2 R 0% Y.

COZR 'y Y .LL sCøa PøB I scøa MA "' -'9 ---> N Cl bass N pøs bass - 0 O COZR" u COZR "Y 0 Ü R" s "xg (9 'kx' SC * a ___) ~ .---> N 2:33 N Pøz 0 - o COZR "COZR 'Y“ g_ 5 Y i I x avïägsn. of now 5 â-N / protecting group qix o _ ^ 0.

In process I, a vinyl ester (Y = H or a - group having the meaning given in formula I above) containing the desired 6-substituent is converted to the optionally 1-substituted 4-acetoxy-2-azetidinone by a cycloadering reaction with chlorosulfonyl isocyanate (CSI), followed by reduction with an organic reducing agent such as sodium sulfite. The CSI reaction is conveniently carried out in an inert W organic solvent, such as diethyl ether, at a temperature of 0 ° C or less. The reduction step may be carried out in an aqueous or aqueous organic reaction mixture at a temperature of 0 DEG C. or below and at a moderate basic pH.

After formation of the 4-acetoxy-2-azetidinone, Process I can be divided into three different routes. According to a synthetic route (variation 1), the azetidinone is reacted with a thiol acid X-g-SH, wherein X has the meaning given above in connection with formula I, or a salt thereof in a suitable solvent (for example aqueous or aqueous organic). Displacement of the acetoxy group results in the incorporation of the desired 2-substituent into the azetidinone at this stage. The displacement reaction is preferably carried out at room temperature or below and at a moderately basic pH value (about 7.5). When Y has a meaning other than hydrogen, the cis and trans isomers of the azetidinone obtained are preferably separated (for example by chromatography) at this stage of the process. Variations 2 and 3 above convert the 4-acetoxy-2-α2etidinone to the 4-acetylthio-2-azetidinone and 4-trityltio-2-azetidinone products, respectively, by nucleophilic displacement with thioacetic acid and triphenylmethyl mercaptan (or a salt thereof, such as the sodium salt). The 4-thioazetidinone is then reacted with a glyoxylate ester O u HC-CO 2 R ", wherein R" is an easily removable ester protecting group, such as p-nitrobenzyl or trimethylsilylethyl, or a reactive oxo derivative thereof, such as a hydrogenated gv 11,454,779 inert organic solvent (e.g. benzene, toluene, xylene or the like) and preferably at elevated temperature (e.g. from 50 ° C up to reflux temperature is preferred). When a hydrate of the ester is used, the water obtained can be removed azeotropically or with a molecular sieve. The hydroxy ester product is formed as a mixture of epimers, which may optionally be purified by chromatography or used directly in subsequent steps.

Conversion of the hydroxy ester to the corresponding chlorine ester is achieved by reaction with a chlorinating reagent (for example SOCl 2, POCl 3, PCl 5 or the like) in an inert organic solvent (for example tetrahydrofuran, diethyl ether, methylene chloride, dioxane or the like) in the presence or absence of a base , preferably an aliphatic tertiary amine (for example triethylamine) or a heterocyclic tertiary amine (for example pyridine or collidine). The reaction is advantageously carried out at a temperature of from about -10 ° C to room temperature.

The chlorine ester product is obtained as a mixture of epimers, which may optionally be purified for use in subsequent steps.

The phosphorus intermediate can be obtained by reacting the chloroester with a suitable phosphine (preferably triphenylphosphine or a tri (lower alkyl) phosphine such as triethylphosphine or tri-n-butylphosphine) in an inert organic solvent such as dimethylformamide, dimethylsulfoxide, tetrahydrofuran oxyethane, dioxane or an aliphatic, cycloaliphatic or aromatic hydrocarbon (for example hexane, cyclohexane, benzene, toluene or the like) in the presence of a base, preferably an organic tertiary amine such as triethylamine, pyridine or 2,6--lutidine. The reaction is advantageously carried out at temperatures from room temperature to the reflux temperature IatUI of the solvent system.

At this stage, the process can once again take two pathways. According to variation I (where the 2-substituent has already been incorporated), the phosphorus intermediate is converted to the desired penem compound by performing a thermal cyclization in an inert organic solvent at a temperature from just above room temperature to the reflux temperature of the solvent system. . The cyclization is most conveniently performed under reflux conditions. Suitable inert organic solvents include aliphatic, cycloaliphatic and aromatic hydrocarbons (for example benzene, toluene, hexane, cyclohexane), halogenated hydrocarbons (for example methylene chloride, chloroform, carbon tetrachloride), ethers (diethyl ether, dioxane, tetrahydroxyuranamide, dimethoxyhydrouran) for example dimethylformamide), di-C 1 -C 6 alkylsulfoxides (for example dimethylsulphoxide) or a C 1 -C 4 alkanol (for example methanol, ethanol, t-butane) or a mixture thereof.

According to variations 2 and 3, the phosphorane is converted to a heavy metal mercaptide of the formula §__J_: fw / mä M 0 COzí-l 'III eLLer saçcoocxa <[:: Ni P coza "Illa wherein Q is preferably phenyl or lower alkyl, x is 1 el- clay 2 and M are Cu (II), Pb (II) or Hg (II) when x is 2 or Ag (I) when x is 1. The mercaptide formation is obtained by reacting the phosphorane with a salt of Hg (II), Pb (II), Cu (II) or Ag (I) or with (methoxycarbonyl) mercury (II) acetate in a methanolic solvent and in the presence of an organic or inorganic base such as aniline, pyridine, collidine 2,6-lutidine, an alkali metal carbonate or the like. A preferred base is pyridine. The reaction may be carried out at room temperature or, if desired, under moderate cooling or heating. The anion (A) of the heavy metal salt may be any anion which gives a soluble salt in the selected solvent, for example NO3 ", crgcoo", aF4 ", F", C104 ", NO2, CNO etc. The mercaptide intermediate is then reacted \ m ed an acylating agent capable of introducing the group X-å-, wherein X is the desired penem-2 substituent. The acylating agent 0 O (X-3- (D) may be the acid X-8-OH or a reactive functional derivative thereof, such as an acid halide (preferably acid chloride), acid azide, acid anhydride, mixed anhydride, active ester, active thioester, etc. The acylation is carried out in an inert solvent (for example a halogenated hydrocarbon such as methylene chloride, or an ether such as dioxane, tetrahydrofuran or diethyl ether) and, when an acid derivative is used, in the presence of an acid acceptor such as a tri (lower alkyl) amine (for example triethylamine) or a tertiary organic base such as pyridine, collidine or 2,6-lutidine When the free acid is used the acylation is carried out in the presence of a suitable condensing agent, for example a carbodiimide such as N, N'-dicyclohexylcarbodiimide .

The acylation of the mercaptide can be carried out within a wide temperature range but is preferably carried out at a temperature from about -200 to + 25 ° C. After the acylation, the resulting phosphorane is cyclized, as described above, to obtain the desired penem ester.

The formation of the phosphorane via the mercaptide intermediate (variations 2 and 3) has been found to result in products of much better purity than those obtained by the more conventional method of variation i.

Once the carboxyl-protected penem compound has been formed, the protecting group can be removed by conventional unblocking methods (eg hydrolysis, hydrogenation or photolysis) to give the unblocked penem compound. The removal of the p-nitrobenzyl ester can be effected, for example, by catalytic hydrogenation in the presence of a noble metal catalyst such as palladium or rhodium comprising derivatives thereof such as oxides, hydroxides or halides, the catalyst optionally being deposited on a conventional support such as coal or diatomaceous earth. A non-reducible aqueous or anhydrous inert solvent is used, such as water, ethanol, methanol, ethyl acetate, tetrahydrofuran, diethyl ether or dioxane. The hydrogenation can be carried out at atmospheric pressure or elevated pressure and takes place ëm e fl At room temperature for a period of approx. 1-5 hours, depending on the solvent and catalyst used. If an equivalent amount of a base, such as an alkali metal or alkaline earth metal hydroxide or an amine, is used during the hydrogenation, the product can be recovered in the form of a carboxylic acid salt. The removal of the β -trimethylsilylethyl ester, another useful protecting group, is conveniently accomplished by treatment with a fluoride ion source. Other ester protecting groups can be similarly removed by methods well known to those skilled in the art.

In a second main process (Method II), the reaction steps are as follows: Process II (variation 1): Early introduction of the 2-substituent I I c 0Ac u _ cxz-ca-oAe cszš xC'5 * °: _ g; pH 7.5 0 \ H o u ° SC-X så-X I '““ "'“ ”5> '- * - E> fl l N §H ° IJ - soclz ___ _ ___N 0 \ H cozn o, YOK.

COZR '0 o Il Il sc-x ø sc-x A' 3 - +> I _____> ¿[:: lf Cl bas m pøa o o COZR ”C023 * l S. f Y s x y. x ¶ _________; '. N / bas '0 N co R "o 2' co2R" Y avïägsn. av 'h_ 5 _ protecting group áí :: TÜ ::%?>' x N o _ cozn 454 779 M Method II (variation 2): Late introduction of the Z substituent 0A: _ Clíz fl C fl- OAC CSI; ÅC5N5 à H 7 5 __ oi: N \ H P I SAC> SA: E I CHÛ I. _ socl Ä- “N l N ou 2 O xa cozn '04" - _ cøza' SÄC PøB SAC MA N. cl bas Nypíä bas ° Y ° COZR '7 C023'- I SM a' “ä x_c_ ® __ sC- X A ---% --- 9 1 N P9 N Pø o 3. 0 Y 3 C023 'coza "s YA i / XY} K fl / s. ___- à bas i / x O / lr- fl- N CO2R “Q coza" Y avïägsn. av 5 X Sk dd y Sgwpø N / _ o Procedure II (variation 3): OA: CHi = CH-OAC CSIE. NIN _ 0 \ * a 11 454 779 Late introduction of the 2-substituent ø3CSNa pH 7.5 ïí; 5Cø3 §H ° / JI soclz co R "2 ° Y CO2R" pø3 scø3 MA bas l ___-> _N \\ Tá¿pø3 bas 0 o cozn "co2R“ 'o 2 E ï / SM X_c_ G) svx b. <4L “" N 0 Pø3 N Pø3 o C02R "cozn" Y s Y> ñï ~ N // bas I / X on N COZR Q _ cog "removal.of \" "" "" "" __f? protection group 454 779 18 As can be seen, process II is essentially the same as process I (except that Y must be hydrogen) up to the thermal cyclization step which gives it However, if desired, a 6-substituent is now introduced at this stage by reacting the 2-penem compound with a suitable electrophile in an inert solvent (for example tetrahydrofuran, diethyl ether, dimethoxyethane or the like) and In the presence of a strong base, in this process the 2-penem compound can be reacted in the form of the free acid (obtained by deblocking as described above) in the presence of about two equivalents of base or alternatively a suitable 2-penem ester can be used in the presence of about one equivalent of base. One can use any ester which is inert with respect to the anion chemistry (the reaction involves anion formation with base, followed by reaction of the electrophile with the penem anion), for example lower alkyl such as methyl, ethyl, n-propyl or t-butyl, phenyl, trichloroethyl, methoxymethyl, silyl such as trimethylsilyl or t-butyldimethylsilyl or the like. Penem esters with activated methylene groups, such as p-nitrobenzyl, are not suitable, and if the 2-penem ester is of this type, it must first be unblocked and either used as the free acid or converted to a suitable ester. The special base used is not critical and the usual strong bases, such as sodium hydride, phenyllithium or butyllithium, are suitable. However, in particular a lithium disilylamide or a lithium dialkylamide, such as lithium dicyclohexylamide (LDCA), lithium diethylamide, lithium dimethylamide or lithium diisopropylamide (LDA) is used.

The electrophile is selected to give the desired Y-substituent upon reaction with the anion. After formation of the desired 2,6-penene compound, any ester protecting group can be removed as indicated above to obtain the deprotected product.

The third main reaction procedure (Method III) is shown in the following reaction scheme: Method III (variations 1 and 2). scøg - scø3 ____ ¿> Ä x J :: --N 0 xa 0 \ B Y Yvk scøa -> _] bas o¿ - N \ B avlägsn. of MA / bass protection group 454 779 20 oç-NïJ / .OH COZR "SOCIZ Yu,, scø3 / - e: c1 0 / cozzz '~ Pø3 bass fl» B o% COzR' MA / bass in YR., sn N 'io * ao li l / xc- (-9 OY "- sÉ-x' _J.N 04 \ a removal of protection fi group u YM., sc-x o4" "'N \ H (šHO COZR" i?' in sc-x H / fïN 0 o / Y CO R "J / SOCI: 21 Pø of = /, - ~ N“ O II I COZR J / removal of protection group Y s XN / ° co 'a 2 454 279 OYH SC-X 0 C02R 'Pø3.

Pass O Y R SC-X: N P CO R ”C023 remote. of protecting group B = blocking group for ring nitrogen The 4-trityltio-2-azetidinone in process III is formed in the manner described according to process II (variation 3).

The ring nitrogen in the azetidinone is then protected by a conventional, easily removable blocking group, such as triorganosilyl (for example trimethylsilyl or t-butyldimethylsilyl), methoxymethyl, methoxyethoxymethyl, tetrahydropyranyl or the like. The introduction of the desired Y substituent into the 1-position of the azetidinone is then effected by reacting a suitable electrophile with the N-protected azetidinone in the presence of a strong base (the reaction conditions are those described above in connection with process II ).

At this stage, the process can take place along two paths, depending on the time of blocking of the azetidinone.

In one way, the N-protected intermediate is unblocked by conventional methods (e.g. acid hydrolysis) and then converted to the 2,6-penem compound via ester formation, chlorination of the hydroxy ester, conversion of the chlorester to a phosphorane, conversion of the phosphorane to a heavy metal mercaptide, acylation of the mercaptide by 0.

X-g-Q, thermal cyclization of the obtained phosphorane to obtain the 2,6-penem ester and removal of the carboxyl protecting group. The reaction conditions for these steps are those revealed in connection with process II (variation 3).

An alternative route involves the conversion of the N-protected azetidinone to a heavy metal mercaptide, acylation of mercaptin. time with the group XCC) removal of the N-protecting group, reaction of the azetidinone liberated from the protecting group with the glyoxylate ester, chlorination, reaction of the chloroester with phosphine to obtain the phosphorane, cyclization of the phosphorane to obtain the penem ester and removal , of the carboxyl protecting group to give the 2,6-penem compound. The reaction conditions for these steps have been revealed above.

In the preparation of the 2-penem or 2,6-penem compounds according to the above procedures, the free functional groups of the substituents X or Y, which, not participating in the reaction, can be temporarily protected in a manner known per se, such as free amino groups by acylation, tritylation or silylation, free hydroxyl groups, for example by etherification or esterification.

In addition, in the compounds of formula I according to methods known per se, it is possible to functionally modify the 2- and / or 2,6-substituents during or after the cessation of the reactions described above to obtain other substituents which fall within the scope of present invention.

The penem compounds in the form of the free acids can be converted into pharmaceutically acceptable salts thereof or into readily removable esters thereof (especially physiologically cleavable esters). Salts can be prepared by reacting the free acid with a stoichiometric amount of a suitable non-toxic acid or base in an inert solvent, followed by recovery of the desired salt, for example by lyophilization or precipitation. Esters (especially physiologically cleavable esters) can be prepared in a manner analogous to the preparation of the corresponding esters of penicillins and cephalosporins. The resulting isomer mixtures can be cleaved into the separate isomers according to known methods.

Mixtures of diastereomeric isomers can be separated, for example, by fractional crystallization, adsorption chromatography (column or thin layer chromatography) or other suitable separation methods. The resulting racemates can be cleaved in the antipodes in the usual manner, for example by preparing a mixture of diastereomeric salts with optically active salt-forming reagents, separating the diastereomeric salts and converting the salts into the free compounds or by fractionation. crystallization from optically active solvents.

Accordingly, the present invention also provides a process for the preparation of compounds of formula I, which process comprises cyclizing a compound of the formula o Ezl-x 'Y 5 "' 1: ï: NP (Q) o Y .3 cola" wherein Q is phenyl or lower alkyl, R "is an easily removable ester group and X and Y have the meanings given above, in an inert organic solvent at a temperature from just above room temperature to the reflux temperature of the solvent, by methods known per se. the removable ester group and possibly other protecting groups and that, if Y is hydrogen, the product may be converted to another desired product, where Y has a meaning other than hydrogen, by treating said product with a corresponding electrophile in a inert solvent in the presence of a strong base.

The penem compounds in the form of the free acids provided by the present invention and the pharmaceutically acceptable salts and physiologically cleavable esters fp! æv zs 454 77? of said acids have been shown to be potent broad-spectrum antibacterial agents which are useful in the treatment of infectious diseases in animals, including man, caused by both gram-negative and gram-positive organisms.

The compounds also have value as nutritional supplements in animal feed and as agents for the treatment of mastitis in livestock.

The 2-penemic acids (and physiologically cleavable esters and pharmaceutically acceptable salts thereof) provided by the present invention (ie, compounds of general formula I, wherein Y = H) exhibit antibacterial activity per se and are also useful. intermediates (preferably in the carboxyl-protected form) for the preparation of the 2,6-disubstituted penem compounds I via anion formation and reaction with an electrophile.

The active compounds provided by the present invention may be formulated as pharmaceutical compositions which, in addition to the active ingredient, contain a pharmaceutically acceptable carrier or diluent. The compounds can be administered both orally and parenterally. The pharmaceutical preparations may be in solid form such as capsules, tablets or dragees or in liquid form such as solutions, suspensions or emulsions. In the treatment of bacterial infections in humans, the active compounds of the present invention may be administered orally or parenterally in an amount of 5-200 mg / kg / day and preferably about 5-20 mg / kg / day in divided doses, for example three or four - ra times per day. They are administered in dosage units containing, for example, 125, 250 or 500 mg of active ingredient together with suitable physiologically acceptable carriers or diluents.

According to the present invention there is also provided a method of combating bacterial infections in animals, in particular warm-blooded animals, which method comprises administering an acid of formula I or a physiologically cleavable ester thereof or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof to an infected host animal in an amount sufficient to combat such an infection.

The invention is further illustrated by the following exemplary embodiments, in which the temperature indications refer to degrees Celsius. For convenience, some abbreviations are used in the examples.

The following is an explanation of the meaning of less obvious abbreviations: CSI chlorosulfonyl isocyanate pet. ether petroleum ether k.p. boiling point NMR nuclear magnetic resonance ether diethyl ether (unless otherwise stated) Celite diatomaceous earth product LAH lithium aluminum hydride n-BuLi n-butyllithium MIBK p I methyl isobutyl ketone Et czns- Tr ~ C (C6H5) 3 Me C143 - THF tetrahydrofuran Phylamine DMFN -nitrobenzyl glyoxylate THF tetrahydropyranyl TFA trifluoroacetic acid HMPT (or HMPA) hexamethylphosphoric triamide EtOAc ethyl acetate DMSO dimethylsulfoxide AC CH3CO-MS CH3SO2-DMAP-4-dimethylaminopyridine Ethyl-pyridyl penem-3 ~ carboxylic acid n's 3 ((282): 'WEUZ: H (: co) 2-9- (ca2) 2co2ca3 ---- + 2g-ecn2> 2co2n ---- a 1 2 9 _ 9 A mixture of 11.2 g (50 mmol) of compound 1 and 10 ml of SN NaOH was stirred and cooled (i = 0> 2P-tcH2) 2cou1 ----- + (azel: -P-cgzyzccsn 2 - 4 ice bath) for 15 minutes and at room temperature for 15 minutes The mixture was extracted with ether and the extract was discarded.The aqueous solution was acidified with SN HCl and extracted with CH after drying and evaporation of the solvent, 0 g (95%) of compound 2 were obtained in the form of an oil with the following data NMR J (cnc13); 4.1 (m, m), 1.8 - 2.9 (m, m) 1.2 (GH, t).

To a cooled (ice bath) solution of 2.26 g (1.076 mmol) of compound 2 was added dropwise 2.74 g (1.88 ml; 21.5 mmol) of oxalyl chloride. The mixture was kept at room temperature for 6 hours and then evaporated to dryness. Traces of (COCl) 2 were azeotroped with benzene to give 2.4 g (quantitative yield) of compound 3 in 0 / I as a crude product having the following data: IR1 \ fC '/ 1800; \\ Cl 1755 cm'1. NMR δ: 4.3 m, m), 3.0 - 3.7 (2: ~ 1, m) 2.0 - 3.0 454 779 ° C (2H, m), 1.4 (6H, m ). The product was treated with H25 / TEA according to a standard method to obtain 1.9 g (80%) of compound 4 in the form of an oil with an estimated purity of so%. nun: 8 '4.1 (au, q), 2.7 - 3.5 (za, m), 1.7 - 2.5 (2H, m) 1.33 (6H, t). To 1.9 g (8.4 mmol) of compound 4 was added under nitrogen ml of a 1M solution of NaHCO 3, followed by the addition of 0.813 g ( 6.3 mmol) of compound 5 in 3 ml of water The pH of the mixture was adjusted to 7-8 by adding additional NaHCO 3 After the mixture was allowed to stand for 4 hours it was extracted with CHCl concentration and concentration obtained 1.05 g (56.4% based on compound 5) of the solid compound 6 with a melting point of s4-s7 °; NMR J q), 4.2 ma) 3.8 (in q) 3.5 (1 fl, q), 2.6-3.2 (ZH, m), 1.3 (GH). 1.7 - 2.4 (2 H, m). A mixture of 260 mg (0.88 mmol) of compound 6 and 198 mg (0.88 mmol) of p-nitrobenzyl glyoxalate was refluxed in 6 ml of benzene in a Dean Stark apparatus for 16 hours, after evaporation of the benzene, 453 mg of compound 7 were obtained in the form of on-ox oil; Nm; 6 a, 3 (zu, a) 7.6 (zu, a), 3 -5.7 (4H) 4.9 (OH), 4.2 (4H) 3.55 (1H 9), 3.4 (1H, g), 2.5-3.2 (za, m) 1 , 7-2,5 (za, m) 1,3 (en) 29 454 779 S ¿cH =, 2g, ° = ,, 2 s \ fÉ / ljcnzæzz- «o: c) 2 ¶ i * if" \ 504 mg (0.88 mmol) of the crude product 7 was dissolved in 0.9 ml of a 1M solution of pyridine in THF, to which was added dropwise and with stirring and cooling (ice bath) 0 9 ml of a 1M solution of SOCl 2 in THF and the mixture was stirred in the cold for minutes and at room temperature for 40 minutes, then 10 ml of benzene were added and the solid was filtered off, the filtrate was concentrated in vacuo to give 463 mg (quantitative yield) of crude product 8; NMR: δ 8.3 (2H, d ), 7.6 (2H, d), 6.1 (1H, s), 5.7 (1H, m), 5.3 (ZH, d), 4.2 (4B), 1-8-3 Δ (6H, m) 1.3 (6H). s \ ¶ / f 5 \ ïí / ---- + ll dL: I: š; 1 o N \ ïJ ° 3 o Pua co Pwa 2 2 (cn2) 2§- (o: :) 2 å 2 Till en solution of 463 mg (0.88 mmol) of the crude product 8 in 4 ml of THF was added 236 mg (0.9 mmol) of triphenylphosphine and 96 mg (0.9 mmol) of 2,6-lutidine and the mixture was allowed to stand at room temperature under 65 hours. It was then filtered, the filtrate was concentrated and the residual oil was chromatographed on a silica gel column with ethyl acetate-2% EtOH as eluent to give 203 mg (30.6%) of compound 9 as an oil which solidified on stand; melting point 126-12s °. 454 779 30 (cxz) 23 (O: r.) 2 S ~ ïE // 5 g _ _______, NI lcu21z coszwz N Pøs 0 N 'cozvua PNB 2 2 ._ A solution of 470 mg (0.635 mmol) of the compound 9 refluxed in 30 ml of toluene for 5 hours, followed by concentration and chromatography on silica gel-ethyl acetate to give 167 mg (56%) of compound 10 as an oil; IR 1795, 1710 cm -1. NMR: δ 8.3 (ZH, d) 7.7 (ZH, d) 5.7 (1H, m), 5.38 (2H, d) 4.1 (4H) 1.8-3.8 (6H, 1.35 (GH). S (cu2) 2-gT (o1 -: :) 2 i * IN] w? - (cx-xzåwzn) 2 ° 'o _ cola C02PNB ll To a solution of 59 mg (0.66 mmol) of compound 10 in 3 ml of THF and 1 ml of ether were added 9 mg (1.07 mmol) of NaHCO 3, 1 ml of water and 60 mg of 10% Pd celite and the mixture was hydrogenated at a pressure of 2. 07 x 10 5 Pa for 2 hours The product was isolated in the usual manner to give 36 mg (86%) of compound II as an oil; IR (CHCl 3) 1798, 1730, 1710 etc. NMR; δ 9.0 (cozn ), 5.6 (m, m) 4.4 (m), 3.6 (1H, q), 3.15 (1H, q) 1.7-3.0 (4H, m), 1.3 (6H). 31 454 779 Exemgel 2 1- (p-nitrobenzyloxycarbonylmethyltriphenylphosphoranyl) -4- (silver mercaptidyl) -2-azetidinone 5Ag 'I Jijí / P ° =. O Y CO PNB 2 ° ^ ° Trsn | I .. + N 2 O + NH 4 - 90 ml of a methanol suspension of 13.8 g (0.5 mmol) of triphenylmethyl mercaptan was degassed for 0.5 hours with a stream of nitrogen. 2.4 g (0.05 mol) of sodium hydride in mold of a 50% oil dispersion was added portionwise. The resulting solution was stirred for 5 minutes and 7.7 g (0.059 mol) of 4-acetoxyazetidinone in 55 ml of water were added rapidly. Precipitation of 4-triphenylmethylmercaptoaazethidinone (2) occurred immediately. The mixture was stirred for 4 hours at room temperature. The solid was filtered off, washed with water and dissolved in methylene chloride. The methylene chloride solution was washed with dilute HCl, water, aqueous sodium bicarbonate solution, water and brine and dried over magnesium sulfate. The product was obtained in a yield of a9, a% with the melting point 146.5-147, s °. 454 779 32 Analysis: Ber. for C 22 H 19 NOS: C 76.49 H 5.54; N 4.05; S 9.28 Found: C 7.54; H 5.60; N 4.00; S 9.36. nun; Δ (ppm, cnc13) 7.60 - 7.10 (1sa, m, u-cricyi). 4.62 (1H, bs, NH), 4.40 (1fl, dd, J4_3tranS = 3.0 J4_3 cis = S, H-4), 3.24 (in, add, Jgem = 15, J3_, cis = s, J3_NH = 1.8, H-3), 2.81 (ia, add, Jgem = 15, J3_4 trans = 3.0 J3_NH = 1.2, u ~ 3> In: «) c = o (cac13 ) 1760, -0 NH 3340. g, T: STI: 7 ST: E: PNB ííïïï / Å + çiïjl / I '- “2'“ '_ ”* ou pa ÄR ° .NY - °' W". OzpNa Cozp fi a 2. ~ - in 4.54 g (0.02 mol) of hydrated p-nitrobenzyl glyoxylate and 6.90 g (0.02 mol) of azetidinone (2) were refluxed for 24 hours in benzene via a Dean-Stark condenser filled with Additional molecular sieves Additional glyoxylate (2 x 454 mg, 2 mmol) was added at reflux (18 hours) after each addition.

The mixture was diluted with ether, washed with a 5% aqueous solution of HCl, water, a 5% aqueous solution of sodium bicarbonate, water and brine. The product was dried over magnesium sulfate to give 12 g in quantitative yield.

A small portion of the epimer mixture was separated on a silica gel plate (CH 2 Cl 2 ether 6: 4).

Isomer A: Rf = 0.87 m.p. = 170.5 - 171, s ° NMR = δ (ppm, cnc13> 8.07 (za, a, J = 9, Hm ar @ mater>, 7.45 (part of d, Ho aromatics), 7.40 -7.00 (15H, m, trityl), 5.25 (ZH, s, CH 2 -PNB), 4.75 (1H, s, HCO), 4.37 (1H, dd, J = g 3-4 trans 3, J3_4 cis = 4, H ~ 3), 2.83 (1H, dd, Jcem = 16, J4_3 cis = 4, 3-4), 2.10 (1H, dd, Jgem = 16, J 4_3 trans = 3, H-4), 1.42 (bS, OH).

IR; -9 czo (cHc13) 1770, 1760 (sxu1ara), 1) OH 347s, 1) NO2 1525 33 454 779 Isomer B: Rf = 0.75, m.p. NMR: δ (ppm, CDCl 3) δ 13.13 (2H, d, J = 9, Hm arcmater), 7.47 (2H, d, J = 9, Ho aromatics), 7.40 - 7.00 (ISH, m, trityl),, 30 (3H, S, CH 2 -PNB, H 2 -O), 4.45 (1H, t, J = 3.5, H ~ 4), 2.90 - 2.70 (2H, AB part of ABx, 11-4), 1.55 (bs, OH). zn = gc = o (cnc13) 1767, 1755 (skulara), * Omz lszsnüoñ zsoo.

ST: ST: _ soc12 N OH pyzidine N C1 \ E: Pna \ 1:; Wæ 2 lu Å 1so m1 of a can <-15 °) THF solution (dried over molecular sieves) of 12 g (21.7 mmol) azetidinone (3) was treated with 1.9 g (24.1 mmol; 1.94 mL) of pyridine and dropwise with 2.86 g (24 mmol; 1.88 mL) of thionyl chloride under a nitrogen atmosphere. The mixture was stirred for 45 minutes at -150. The precipitate was filtered off and washed with benzene. Evaporation of the solvent gave a residue which was taken up in benzene and treated with activated carbon to give 11.7 g of product in a yield of 94% on crystallization from chloroform. mmm 6 (ppm, cnc13) 8.17 (zu, a, J = a, Hm aromatics), 7.67 - 7.00 (17H, m, Ho aromatics, Tr-H), 5.80 (s, HC -Cl), 5.37, 33 (25, HC-Cl, CH 2 -PNB), 4.81 (1H, m, H-4), 3.27 - 2.40 (ZH, m, H-3 ) Im fi czo (mar-film) 1785, 177o0NO2 1525. sr: 'sr: o; [T _ 'd' '? ° \ 1 /, c1 2,6 luti ln 04- \\ f, 3. co Pua ozvua 2 å 34 454 779 100 ml of a THF solution (distilled over LAB) of 11.6 g (20.2 mmol) of chlorazetidinone (4) were treated with 7.86 g (30, D mmol) of triphenylphosphine and 2 , 36 g (2.56 mL; 22.0 mmol) of 2,6-loptidine. The mixture was refluxed for 72 hours. The precipitate was filtered off and washed with ether. The organic solution was washed with a 2% aqueous solution of HCl and a%% aqueous solution of sodium bicarbonate and dried over magnesium sulfate. Evaporation of the solvent gave a residue which was purified through a silica gel pad (200 g). The desired phosphorus was eluted with 30, 40 and 50% ether-benzene and 11.4 g of proauctite were obtained: yield of 70.4% and melting point 201-2020. _ Analysis: Ber. for C 49 H 4 ON 2 O 5 SP: C 73.57; H 5.04; N 3.50; S 4.01. Found: C 73.58; H 4.91; N 3.44; S 3.87. m; .g Cæ- (cnc13> 114o, w) phosphorus (1620, 1610), v.) 7 '_ Agne: saw _ ----- 1 in KfPQB .- pyriåin! H YPÖJ o _- 1525.

NO 2 lv »Im 1.6 g (2 mmol) of 4-tritylmercaptoazetidinone were dissolved in 20 ml of CH 2 Cl 2 and the solvent was evaporated at 55-600. The phosphorane (5) having a temperature of 55-600 was dissolved in 32 ml of methanol, which had been preheated to 55-600. Immediately after obtaining a methanol solution of compound 6, it was treated with a preheated (55-600) mixture of 16 ml of methanolic 0.15 M silver nitrate solution (1.2 equivalents) and 174 mg (178 μl; 2.2 mmol). ; 1.1 equivalents) pyridine. The heating bath was then removed immediately. The mixture was stirred at room temperature for 2 hours and at 0 DEG C. for 1 hour.

The silver mercaptide 6 was filtered off, washed twice with cold (00) methanol and three times with ether. 1.2 g of product were obtained in a yield of 84.5% and with a melting point of 130-1350 (decomposition).

IR: -QC = O (CHCl 3) 1795, 1725 (shoulder), 00 phosphorane (1620, 1605), 1) NO 1530. - 2 454 779 Example 3 Sodium Z-hydroxyaminopropylpenem-B-carbgylate CO 2 Na 1) NaOH 5 ! / ”\ O / ^ \ co: =” ”“ ”“ “§“ 'f ”* // \\ // \\ c Iozu I 2 2) xci onc 02” ozu J.

To 320 ml of a cold 5% aqueous solution of sodium hydroxide was added 21.6 g (0.134 mol) of the ester 1. The resulting mixture was stirred at room temperature for 2 hours and then concentrated to 250 ml and acidified with cone - centered HCl. The mixture was extracted with ethyl acetate (4 x 200 ml) and the organic extracts dried over sodium sulphate. Concentration on a rotary evaporator gave an oil in a yield of 13.2 g (75%). nf / \\ «/ få \ C0 fi1 + sm fl; A solution of 13.2 g (0.1 mol) of the acid 2 in 25 ml of SOCl 2 was stirred for 2 hours at 300. After evaporation of thionyl. the chloride was distilled off in vacuo at a temperature of 76-780 (0.2 mm Hg). 8.8 g (58.3%) of the product were obtained as a colorless liquid; NMR: (CDCl 3) δ § ppm: 2.40 (2H, m, β-cnzh (pure): 1550 cm -1 ('UNO); 1790 Cm-2 _ S A92 h, f ^ \\, f ”\\ C '1) H23 /; = 3N \ 1 0' CCI å. DA:, f-N. 2) Naacoa / i ° Id 4-13, 0 1 (1) C = O, acid chloride). f 4 Iu 3.15 (2H, t, <> 1-c1a2); 4.5o (214, t, 'J-cuz) IR. 454,779 g of 3. A solution of 19.46 g (0.128 mol) of compound 3 in 200 ml of methylene chloride was rapidly added to a cold (0-10 °) stirred solution of 36 ml (0.256 mol) of triethylamine in 500 ml of methylene chloride. , sun had been saturated at 0-5 ° with H28. The mixture was stirred at -10 ° for 1 hour and then a stream of nitrogen gas was passed; the solution to eliminate excess H25. The mixture was washed with 10% hydrochloric acid, the organic extract; was concentrated to a volume of about 150 ml and then added; 10.9 g of sodium bicarbonate and 500 ml of water were added. The pH value Q was adjusted to about 7.5 with sodium bicarbonate or hydrochloric acid. The resulting mixture was cooled to 0 ° and 16.8 g (013 mol) of 4-acetoxy-2-azetidinone in 20 ml of water were added with vigorous stirring. After 4 hours, the mixture was extracted with ethyl acetate. The extracts were washed with 10% hydrochloric acid, saturated sodium bicarbonate and brine, dried over sodium sulfate and evaporated. The residue was purified by Éolonn, chromatography (SiO 2, eluent: ether and then ether -5 -5% ethyl acetate) to give an oil which on crystallization from ethyl acetate-hexane gave compound 4 in an amount of 3.5 g (1.2.5%) as a white powder, m.p. 45-470). ímømz '\\ I /! ~ \\ ~ ,, ^ \\\ 2 0; PNa $ \ š // ø \\\ / ,, \\: N ° 2 No' v NH 0 0. A mixture of 1.09 g (5 mmol) of the azetidinone 4 and 1.2 g (5.25 mmol) of p-nitrobenzyl glyoxylate hydrate in 100 ml of benzene was refluxed for 18 hours. with a Dean ~ Stark trap filled with 4Å molecular sieves. Evaporation of the solvent gave the glyoxylate adduct in an amount of 2.1 g as an oil. lu- t lm av,. 2.1 g of the azetidinone glyoxylate were dissolved in 50 ml of tetrahydrofuran and 0.57 ml (7 mmol) of pyridine were added to the solution. the slurry was cooled: in o ° and o, s m1 (7 mmol) socl was added slowly. The mixture was stirred for 1 hour at Og and then filtered before evaporation to dryness. Filtration of the material over a pad of silica gel with CH 2 Cl 2 gave a foam in a yield of 1.9 g (85%). s \ ~, f \\, f \\ 'j 6 a, Y \ ^ i NO N \ ,,: l Le-muaif a 2 / co Pas * 0 $ = Pø3 COIFNB Im 1 To a solution of 6.2 g (14 mmol) of chlorazetidinone in 300 ml of THF were added 5.5 g (0.02 mol) of triphenylphosphine and 2.4 ml (0.02 mol) of 2,6-lutidine. The mixture was heated at 45 ° for 20 hours. Lutidine hydrochloride was filtered off and washed with ether. The filtrate was then evaporated. The residue was purified by chromatography on a silica gel column, eluting with dichloromethane and a mixture of dichloromethane and ethyl acetate. Evaporation of the eluent gave a white solid in an amount of 2.9 g and in a yield of 30%.

SWW; 2.0 g (3 mmol) of the phosphorane 7 in 150 ml of toluene were refluxed for 2.5 hours. Evaporation of the solvent gave an oil which was purified by chromatography on a silica gel column and eluted with dichloromethane and a 9: 1 mixture of dichloromethane and ethyl acetate. Evaporation of the solvent gave a syrup which crystallized in ethyl acetate-hexane as a white solid in an amount of 0.82 g and in a yield of 40.7%. s _ No 30 \? d / DE N 2 = ïmfa --- ~ __, o ^ _ WHZO-Nai-ICO co: Na 3 2, i US o Nfáš // \\ / ß \\ H .mo C02Nc Im To a solution of 50 mg (0.127 mmol) of the ester 8 in 25 ml of a 2: 3 mixture of tetrahydrofuran and ether was added 10 ml of water, 10 mg (0.127 mmol) of sodium bicarbonate and 50 mg of 30% palladium on diatomaceous earth. The reaction mixture was hydrogenated under a pressure of 3.4 x 10 5 Pa for 3 hours at 250, filtered over a pad of celite and washed with ether. The aqueous solution was lyophilized to give 30 mg of a yellow powder of hygroscopic compound. 39 454 779 Example 4 2- (4'-Phthalimido-1'-butyl) genem-3-carboxylic acid o S: ß 0 o. to. 0 f o 0 TEA-H25 N / ”\ / ^ \ / J \ c1 ---- å; / ^ \ / \ ~} k¿a I | To a solution of triethylamine hydrosulfide, which had been prepared in advance by bubbling H25 gas through 200 ml of a methylene chloride solution of 8.8 ml (63.7 mmol) of triethylamine, was added dropwise 75 ml of a methylene chloride solution of .65 g (40.2 mmol) of compound 1 (Gabriel Ber. il, 2010) at 0 DEG for a period of 30 minutes. The mixture was stirred at 0 ° C for 15 minutes and at room temperature for 2 hours. The organic solution was diluted with 125 mL of methylene chloride and washed with 2 x 15 mL of 1N HCl, 2 x 15 mL of water and brine. It was dried over magnesium sulphate and the solvent was evaporated, yielding 10.5 g (100%) of compound 2 as a white solid, m.p. 93-940. fcoc13) 6: 7; 5 _ 8 (43, mi, 4147 (LH, knxai s). 3.5 - 3.9 (25, Q), 215 _ 2.9, 2ä 'm) 11.4 Ia§ Ha, mL Analyz Calc for C 13 H 13 NO 3 S: C 59.29; H 4.97; N 5.32; S 127.17.

Found: C 58.92; H 4.91; N 5.42; S 12.31. 454 779 w Ae NaHCO 3 A suspension of 3.04 g (1, 6 mmol) of compound 2 in a solution of 1M sodium bicarbonate (11, 6 ml) was stirred for 15 minutes under nitrogen at room temperature. To the suspension was added 1.5 g (11.6 mmol) of compound 3 and the resulting mixture was stirred for 1.5 hours at room temperature. The reaction mixture was diluted with water and extracted with methylene chloride. The organic phase was dried and evaporated in vacuo to give 3.82 g of solid 4, m.p. 95-960.

IR = (cHc13) 1775. 1710 = m / ml; + myR; 6 7.8 (an, d, J = zaz), 7.05 (iznbred s), s zs un, aa, ads * â fl z. attans - sm,: Js - 3.0 _ J (mn m, gs -2) 0 (4a, m) Ana1ys = Ber. for cl¿nl6N2o4s = c 57.62; H 4.85; N 8.43; s 9.64.

Found: C 57.43; H 4.82; N 8.44; S 9.71. ? ac Yw-co ca - <§> -.-- o - ° 2 2 '2 \ ./ \ / \ / - _¶ ° / _, I g \ N 41 454 779 ml of a benzene solution of 3,0 g (9.04 mmol) of the compound 4 and 2.22 g (9.8 mmol) of p-nitrobenzyl glyoxalate were refluxed for 21 hours under a Dean-Stark condenser filled with 3Å molecular sieves. Evaporation of the solvent gave 5.4 g of the compound 5 as an oil (100%). 1 I IR: (xenthazoo - asoo. 1170, 1710, lszs = m'1 Tm fl? (Cocla) 618.21 (za, a J - s fi z). 7.15 (43, a J - 2nz>, vis: (Én, a, J - sar, sis: (la. Bred sl. S sz san,: =>, 4, ss (1s, tn fi ai S), a, s - å, v (zu. M), 2, 45 (la.

I då Jçw I ISE-íz, Jcis I SHz) 3,02 (IH, dä, .Jgem I 151-12, Jtrans - saa), 2,4 - 2,9 (za, m), 1,4 - 2 4.9 g (9.05 mmol) of the azetidine glyoxalate were treated at 0 DEG C. with 15 ml of thionyl chloride for 0.5 hours and at room temperature for 1 hour. The excess thionyl chloride was distilled off. simultaneously with benzene in vacuo to give compound 6 as a yellow syrup (5.0 g; 100%).

NMR (CDCl 3) Il s 95 :), 671 (LH. Broad si, s, so - s, as (za. M). S) s2 (2æ, '2s>. 2.4 - 4.0 (za. m), 3 ,; - 3 ,: (13, m), 2, s - 3805 (ZZ-i, m), 2.50 - 2.85 (25, m), 1.5 - 1.9 ( 48, m).

O 'C) o sa / \ ~ / ^ \ É'ä§: Išä) __; Ö Ö ¶ \ æ?: _ ° v J U 1 I N _ '* .. _ C ° 2 _ .. 2 @, ~ ° 2. CO 2® .12 _ @ - .. 02 Z [m 454 779 42 A solution of 21.6 g (38.8 mmol) of compound 6 in 85 ml of tetrahydrofuran (distilled over LAB) was treated with .2 g (38.8 mmol triphenylphosphine and 5.0 ml (42.9 mmol) of 02,6-lutidine for 18 hours at 400. The mixture was diluted with 30 ml of a 1: 1 mixture of benzene and ether, washed with water, 1N HCl, saturated sodium bicarbonate , brine and dried over magnesium sulfate. Evaporation of the solvent gave a dark brown oil which was passed through a silica gel column (700 g) eluting with benzene ether to give 16.0 g (53%) of compound 7 as a thick oil.

I xxx (coola) 52812 (ZH, d, J = 932), 778 (Si-i, d, JI ZHZ), 7.152 (leï-ï, S), 572 (ia, broad s) 4.18 (ln, 2s). 4730 - 4752 (ia, aa, 3.5 - 3.8 (za, m), zia - 3.5 (zu, m), 2.1 - 2.9 (4H, m), 1.5 - 1 9 (4H, m) and Q q ßšfíjczz io: A i | ~. | Lm A solution of 5.0 g (6.4 mmol) of the phosphorane 7 in 35 ml of toluene was refluxed for 3 hours. the agent gave a residue which was allowed to pass through a silica gel column (100 g), eluting with benzene followed by ether to give 600 mg of the ester 8 as an oil.

. IR = (rent ¥} 7soÄ 1110. zszo em'l bm fl 6: a) 22 (za, a, J - saz), 7362 «4s, a. J = 252), 7.65 (1H. É. J = saz). 5.69 (lä, aa, Jcís - 43 :,: trans = zaz), -.35 (25. 25). 4,12 (IH. 5G ". J = léi-ïz, -7. - fI-Iz). 3 S0 gem cis l _ .. _ _, .. _-. ._ a .. _ (m, od , .Igen -6nz. Jcrans ana), BIL, 3.8 (an, m), 215 3.0 (Tri, m), 1.4 - 2 | 0 (411, m). 43 454 779 ._ o A 2-phase mixture prepared from 196 mg (0.39 mmol) of the ester 8 in 2 ml of ether, 4 ml of tetrahydrofuran and 32 mg (0.39 mmol) sodium bicarbonate in 2 ml of water was hydrogenated on 190 mg of 30% palladium on diatomaceous earth in a Parr shaker at a hydrogen pressure of 2.8 x 105 Pa. After 4.5 hours the mixture was filtered over a pad of celite and the pad was washed with water and tetrahydrofuran. The aqueous liquids were combined and the organic phase separated, the aqueous solution was washed with ether, acidified with 3 x 0.4 ml of 1N hydrochloric acid and extracted (after each acid addition) with 4 x 2 ml of ethyl acetate, the organic extracts were washed with brine and dried over magnesium sulphate and the solvent was evaporated by evaporation to give acid 9 in an amount of 67 mg (47 mg). %) as a yellow solid. ia; ¿Nu5 ° 1): 117s, 1705, 1690 cm'l.

Nb4R (ansa) 6 = 7.92 (an, sy, 5.71 (za, aa,: cis - aaz. Attans - zn =>, 3.90 <1a, aa, Jgem - is a =. Acis - que ), 3,41 ris, aa. _. 16 Hz 'J. Zxza, 3 3 - 4 ,: (sa, m), - 2,7 - 3,05 zu. Ml, gen trans 1 ~;, s- Ao ua, mL Exemgel 5 Sodium 2- (acetonylmethyloxime) -penem-3-carboxylate sl IA - /; n3. 2 n â * _h “wcaa C018! 454 779 1 2.0 g (4.54 mmol) of the ketal 1 was treated at 0 DEG C. with 20 ml of 95% TFA for 15 minutes. The mixture was diluted. with brine and extracted with methylene chloride (4 x 30 mL) The methylene chloride extracts were washed with brine (3 times) and brine and dried over magnesium sulfate.

The product was obtained in an amount of 1.44 g (80%) ._ ma., Cvnawsgv (za, d. S - 9. m »aranates, ejso (za. D. - oc j J = 9, no aromatics, s , vo -. ~., 2s ir .. GHz-From HCO, -w - LK = \ 0H>. 4.75 (lä. bs. os). 3.76 centr. of ABs, CiiI-cø). 3.47 part of a dd. J3_4 cis 1 5. H-3). 3.05 (28, Zód, Jgem I 15. J - 3.75-3). 2.30. 2.28 (1.67H, 25, CH3), 1.98 (1333H, s. C83) 3-4 :: ans vc = ° (caczsi 1780, 1755, vNoz 1525. s ° "" sr 1 gc fl cocz -: z-fcu: r __, / "Cocf2 3 '------ 0 II Ü" HN "H 6%" d \ /' Y co ass - Cozna 2 lw - \ i; 50 ml of a methylene chloride solution of 1.44 g (3.63 mmol) of the ketone 2 were treated at 0 DEG C. under a nitrogen atmosphere with 334 mg (1.1 equivalents) of methoxylamine hydrochloride, 367 mg (0.5 ml; 1 equivalents) of triethylamine were then added dropwise to the mixture. It was stirred at room temperature for 45,454,779 for 18 hours The reaction mixture was diluted with methylene chloride, washed with aqueous brine (2 times) and brine and dried over magnesium sulfate to give 1.52 g of product (98%). ): a., 12 nu, a, .vs, am aronaterhafo (za, a. .w .. g H0 azw fi te fl) fs: so-s) (m. 0:53, dei-av as middel av. om, s, ss-zv0 (part of 0-1 OS (43, m, GHz-PNB. 3-4, HCO), JJBC-SJGO cis. HB regardless, Cßzco, part of 05), 1) vc-o (CZ -ICIJ) 1770, 1750, 1690. 91, 1,90, 1, aa (sa, ss, casa IR = T_ ° ÜÉ '& ~ oc fi3 scccxz- L-ca: - 1 SCOCH -C-C-I. 2 _ l 50Cl2 ._ l 4 hxf / OH Wrídi ”" Yu I.

CO2PNB CO2PNE in lu ml of a cold (-150) THF solution (distilled over LAH) of 1.52 g (3.57 mmol) of the azetidinone 3 was treated dropwise with 325 mg (0.332 ml; 4.10 mmol; 1, 15 equivalents) pyridine and 488 mg (0.299 ml; 4.10 mmol; 1.15 equivalents) of thionyl chloride under a nitrogen atmosphere. The mixture was stirred for 15 minutes at -150. The solid was filtered off and washed with benzene. The resulting solution was evaporated and the residue was taken up in benzene and treated with charcoal to give 1.2 g of product (76%). mm δ ppm, coc13> = 8.23 (211, d, Hm aromatics), 7.80 (211, d, Ho aromatics), 6.12, 6.08 (1H, 2s, HC-Cl), 5.75 - 5.55, 111, m, 11-4), 5.40, 5.10 (za, zs, cuz-PNB), 3.95 - 3.80 (an, ss, 00113), 3.80 - 2.95 (411, m, zn-s, cnz-co), 2.00 - 1.85 (3H, 4s, CH3).

IR; 15 = C = o (camp 1790, 1765 skulara, 1700, JNO 1530. _ 2 454 779 46 "'* W" u-xm_ å scocnz-c-ca, Ü l SCOÜI2 ° C'CHJ: ï-ï-ï -a I - cl o NYPQ; K øgP fi å 1 2 J CO PNB ml of a THF solution (distilled over LAH) of 1.2 g (2.70 mmol) of the chlorazetidinone 4 was treated with 1.06 g (4.05 mmol; 1.5 equivalents) of triphenylphosphine and 318 mg (0.346 ml; 2.97 mmol; 1.1 equivalents) of 2,6-lutidine The mixture was stirred for 4 days at room temperature under a nitrogen atmosphere diluted with ethyl acetate and washed with a 2% aqueous solution of hydrochloric acid, water, a 2% aqueous solution of sodium bicarbonate, water and brine. The solution was then dried over magnesium sulphate and the solvent was evaporated. The compound 5 in the form of a crude product was purified on a silica gel column (10 times). weight of the product) and elution with ethyl acetate to give 770 mg of pwauk: (45%). "IR; wjço (cnc13) 1755, 1695, J 1630 - 1610, 'J NO2 1525.' ~ _ scocnz-à-cas' 5 1 I,. ---- li --- 4 I É ca, -ä-cH_ J ok "V3 'Toluer ok * LJ, c02? N3 C02Pn 3 lw 700 mg (1.05 mmol) of the phosphorane 5 was refluxed in the toluene for 4.5 hours. Toluene evaporation gave a residue which was passed through a silica gel column (ratio 1: 15) and eluted with 4% of ether-benzene. There was thus obtained compound 6 as a crystalline material in an amount of 251 mg (62%) and having a melting point of 116-1250. 47 454 779 Analysis. Ber. for C 17 H 17 N 3 O 6 S: C 52.17; H 4.38; N 10.74 Found: C 51.15; H 4.18 N 10.33.

IOAQI; Hppm. cxxanvrvo (za, a, man íaranaterhi-.z (m, d, m, aIW- fi te fl f 5.00 mi. s, cnzena), ges (ma, .-. ~. a-snfa fl s - z, 1o mi, n , case, cz-zz, xs), 1.71, 1.12, 1.65 (an, s, C33), -vüo (anal) 1181, 1142, nos, vN ° 2 Ü-V- (21: 03) Å fl ax: 318 (EI 8420), 262 (EI 12,539) .1530_ S -wocnz u-ocz-x.

I i CH -ELCH 3 ._. L .__. {I cn -ë-cn _ \ 2 a uaaco N 2 3 2 3 o * co: ma CO 2 N <1 i lv A mixture of lšlmg (0,386 mmol) of the ester 6 in 20 ml of THF, 40 ml of ether and 32 mg 0.38l mmol) of sodium bicarbonate in 20 ml of water was shaken in a Parr hydrogenator for 3 hours at a hydrogen pressure of 2.4 x 105 Pa using 200 mg of 30% Pb on celite as catalyst. The catalyst was filtered off and washed with water and ether. The resulting aqueous mixture was washed with 3 x 60 ml of ether and lyophilized to give 32 mg of product (30%). fsçpm, mßongso (m, a-s). 3.75 (s. Ocaa). 0.77 (s, ma). v (nujo: mun) 1770, zaoo, lacø.

C = 0 u.v. (H o) A 1300 (c - 2,300), 255 i: - 2,40%. 2 max 454 779 as - 'z Exemgel 6 (oQ 2 IL + clcocs cx cl "'“ '' oæ -_. \ Çs 2, 2 - I; i 1 :: A solution of 1.1 g (1.6 mmol) of compound I and 0.16 ml (1.6 mmol) of compound II in 30 ml of methylene chloride were cooled in an ice bath and treated dropwise with a 1M solution of pyridine in methylene chloride (1.7 ml; 1.7 mmol) The resulting reaction mixture was stirred at room temperature for 1 hour and then filtered over celite and washed with methylene chloride.

The filtrate and washings were combined and washed successively with 5 ml of 1N hydrochloric acid, ml of water, 5 ml of 1N sodium bicarbonate and brine, dried over magnesium sulphate and evaporated in vacuo to give 900 mg (87%) of compound III as an amorphous solid. material. This was used in subsequent steps without further purification. 49 454 779 for NM; (çncia) 6.e, z> un. a, -74 Hz), 1.55 (isx-x, m). 6.72 HH. <1 /: -9 az) s.v cis. m), s.o zzx. 2: 2. 2-SS KIH- 2 => '2-B (° “' ml 'S \ E / ^ \ tac1 |. 2 + (jf-0)? --____ fi NYPç-É 3 cozvss O \\» /' ~ \\ ___ än- <) Ö g wa; cozans v A mixture of 1.3 g (2 mmol) of compound III and 0.65 ml (3 mmol) of compound IV was heated for 4 hours at 800. The reaction mixture was diluted with 10 ml of methylene chloride and washed with 2 x 5 ml of water. The organic layer was dried over magnesium sulfate and evaporated in vacuo to give 1.4 g (90%) of compound V as an amorphous solid. It was used in subsequent steps without further purification. in ccxc; 3> =; vss. : ess c = '* ana 7.55 (15 E, m), mo (EE-i, d, J = 9 í-íz), S.7 (1'ri, m), 5.1 hr., 25). 4.72: za, eg: = 12 az, s = s sz), 2.6 (4s, m>} 1.4 (aa, 5 :, 1.2a (as, sz. 454 779 í so __, / 5 \ v / ^ \ -gm- () I ö 2 -_-_______ + k / ø, l, co ma I ïm ~ <) 2 L ”O 2 V _ - cozvaa _A solution of 1.6 g (2.06 mmol) of the compound V in 60 ml of the toluene was refluxed for 5 hours, the solvent was evaporated in vacuo and the residual oil was chromatographed on 30 g of silica gel, eluting with benzene followed by ether, first removing a non-polar material and then giving ethyl acetate 620 mg (62%) of compound VI as a white solid with a melting point of 83 DEG-84 DEG C. from the ether. za (cncza) 1790, 1710 == 'l una: ícoclaä 6 a.2 (za. e, J = 9 az) 7.6 (za, a, J = 9 az) 7.5 (za. S) 5.65 (1H, dä, Jtrans = 4 H2- acis = 2 na), s.z2 (za, 2s), 4.75 12H, éq J = l2 H2- J = ö H => - 3-BS (La. aa,: gen -: s az, stxans - 4 az), 3.5 (la. aa,: gem ~ 15 az. _ 3 - 2 5.1), 2.3-3.3 (1H, m), 1.4 (SH, s), 1.28 (GH, s). S 7 f; 27 / ^ \ ca (o «O2 _________ * 3 IS § (Û fx * o4-2í '2 : o_? xs C- H * '2 VI VI I To a solution of 200 m g (0.4 mmol) of compound VI in 8 ml of tetrahydrofuran and 4 ml of ether were added 34 mg (0.4 mmol) of sodium bicarbonate in 4 ml of water and 200 mg of 30% Pd / celite, followed by hydrogenation for 2 hours at a print of 2.8 x 105 Pa. The mixture was filtered and the layers separated. After washing the aqueous phase with 2 x 5 ml of methylene chloride, it was cooled with ice, acidified with 1 ml of 1N hydrochloric acid and extracted with 5 x 5 ml of chloroform. The organic extracts were dried over sodium hydroxide and evaporated in vacuo to give 76 mg (52%) of compound VII as an oil.

IR (CHCIB) mo, mo and, una (cocia) 6 e.s un. m, s.ss ua. aa, Jtrans I 43:., Jcis I 2 Hz), 4.72 (25, dt; 3-12 Hz, .7-6 Hz), 4.2- .l (23, m), L-å-Ll (ZH, m), 2.7-3.4 (25, m), 1-35 (53, S), 1-75 (68. s).

Exemgel 7 9 9 | Q + c: c (cH2> 3P (OC2H5> 2 ----- * N 3 J: V: P _., Èozpzçs SViCn2) 3P (OCZnS 2 i 1 Il 1 _-_ “Yï fl oog 0, .. [ To an ice-cold mixture of 1.324 g (2 mmol) of compound 1 and 0.54 g (2.2 mmol; crude product) of compound 2 in 15 ml of CH 2 Cl 2 was added dropwise a 1 M solution of pyridine in CH 2 Cl 2 (2.2 The mixture was stirred at room temperature for 1 hour and filtered over celite. The filtrate was washed successively with 0.5N hydrochloric acid, water, 0.5 M sodium bicarbonate and brine. It was then dried over magnesium sulphate and filtered over celite charcoal to give 0.9 g of an oil after evaporation to dryness, the oil was chromatographed on silica (10% water) and eluted with ethyl acetate to give 0.5 g of the compound. 3 (32.8%). - - mm 6 (ppm. Cociz) 7.oa.a (m, m), 4.as.e (an, m, 4.1 (an, q), 3.3-4.2 (za , m) 2.7 (za, m), 1.s (za. nn, 1.3 (SH. =) - 0.4 g (0.52 mmol) of the compound 3 in 35 ml of toluene was refluxed for 4 hours and indu to dryness to give an oil containing compounds 3, 4 and ø3P = O.

This was chromatographed on silica (10% water), eluting with ethyl acetate to give 0.1 g of the pure compound 4, followed by 0.15 g of the compounds 3 and 4. xxx 6 (ppm, cncza). 8.3 (za, a), 1.67 (25, d), 5.7 (H. Q), 5.33 (ZH, d), 4.2 (GH, q), 3.83 (H, q), 3.4 (ë, .q), 2.9 (ZE, m), 1.9 (25, m), 1.3 (GH, t). IR (neat) 1790 cm -1 (5-lahtam) 1710 cm -1? (es: e:) L S 9 'I' | P (ozt); __ x 02PN3 | a cl .wq,, / 駧šš: vao 3 m '11 NI A mixture of 0.1 g (0.207 mmol) of compound 4, 0.1 g% Pd / celite and 17 mg (0.207 mmol) of sodium bicarbonate in ml of THF, 5 ml of ether and 5 ml of water were hydrogenated at an initial pressure of 2.8 x 105 Pa for 2 hours. The mixture was filtered over celite and the layers were separated. The basic aqueous layer was washed well with ethyl acetate and acidified with 1N hydrochloric acid. It was extracted with CH 2 Cl 2 and dried over magnesium sulfate. The solution was evaporated to give 48 mg (66.5%) of compound 5. IR spectrum 5 1790 M 454 729 0 (β-lactam) 6 1700 βg-O fl 1.

Exemgel 8 s v ¿»-N COZNI \ ï // \\ // cl '3. ; \ ”/” \\ gwmw ~ V = e> * “MH _ * 4 e 2 0 g 3 '\ â 3 coexa I 2 cozpxa Å 3 e 3 A mixture of 1.07 g (1.66 mmol) of compound 1 and 0.42 g (3 mmol) of compound 2 in 3 ml of CH 2 Cl 2 were heated at 80 for 5 hours. The crude oil was chromatographed on silica (3% water) and eluted with ether, a 1: 1 mixture of ether and ethyl acetate and ethyl acetate: 5% EtOH to give 1.0 g (82%) of compound 3 The oil crystallized when allowed to stand; melting point (ever) 138-4o °. xx; a (ppm, cnczs) s.2 (za. a; 1.os.ø <11a, ml. 4.6-ss (sn, m). 3.8 (sa, s), 3.6 (aa, s), 1.5-3.5 (ëä, m) -? 9 wX / Pwhelz 5 P (c. ° | e) 2 II ° _íiC:;. H Fií / okt; D ° 3 Ö Qá-m Y Cozee COZPSB É Z \ 0,5 g ( 0.69 mmol) of compound 3 in 30 ml of toluene was refluxed for 4 hours, the solution was evaporated to dryness and the product was chromatographed on silica (3% water) eluting with Et 2 O: EtOAc (1: 1) followed by EtOAc: 10% EtOH, 454 779 54 to give 0.18 g (58%) of the compound 4. pu-m 6 (ppm. C 1 -C 18 -s 2 s (an, a). 1.6 (za, a), s.es (a, q), 5 .: (za. a). Le (as, s) 2.6 (ax-gm, z.7-ae (zu, m), 1.sz.s ma, m.

- § (Q1 ~ 1e) 2 \ Pdßeli; , N Naucoa - CO2PSB in S gKW-e) 2 N ß COZN: å A mixture of 50 mg (0.212 mmol) of compound 4, 9.125 mg sodium bicarbonate and 50 mg 30% Pd / celite in 5 ml THF, 2 .5 ml of Et 2 O and 2.5 ml of water were hydrogenated at an initial pressure of 2.8 x 10 Pa for 2 hours. The mixture was filtered over celite and the layers separated. The basic aqueous layer was washed well with ethyl acetate and lyophilized in a high vacuum to give 28 mg of compound 5 (75.9%) as a hydroscopic product. IR (KBr) 1770 cm-1 (β-lactam), 161 cm-1 (-coo '). -. ~ ..._ .. ~, - ...-., .. ~ .._.................. _ .. ....._ .. v ...-......._.._.-..... 454 779 Exemgel9 (1 "R, SR, 6S and 1'S, SS, 6R) -2- (trans-3'-amino-1'-cyclobutyl) -6- (1" -hydroxy-1 "-ethyl) penem-3-carboxylic acid (isomer B) on COOH (1 "R, 3S, 4R and 1" S, 3R, 4S) -4- (trans-3'-azidocyclobutanoylthio) -3- (1 "-hydroxy- 1 "-ethyl) -1- (paranitrobenzyl-2" -triphenylphosphoranylidene-2 "-acetate) -2-azetidinone (_) / Os Sauce clâ - <:> ~ x3 E + 11%. so - <:> "N3 I TYS: 1 i, _ ___., ___- pa 0 N TEA, lm c 1-1 1 N \ \ C = PPh3 5 s øs? ph3 CÜOPNÉ coopxa A solution of 1.01 9 (1.43 mmol) (1'R, 3S, 4R and 1'S, 3R, 4S) silver 3- (1'-hydroxyethyl) -1- (paranitrobenzyl 2 "-triphenyl- phosphoranylidene-2" -acetate) -2- azetidinone-4-thiolate in 25 ml of dry THF, which was stored under a nitrogen atmosphere, cooled to -400 and treated successively with 0.80 ml (5.74 mmol) of triethylamine, 0.726 ml (5.72 mmol) of trimethylchlorosilane and , 10 g (1.47 mmol) of imidazole. The reaction mixture was heated to -150 and stirred for 3 hours, after which the cooling bath was removed and stirring was continued for 18 hours. The reaction mixture was cooled to -1 ° C and diluted with 25 ml of dixloromethane; it was then treated with 0.15 ml (1.85 mmol) of pyridine and 0.274 g (1.72 mmol) of trans-3-azidocyclobutanoyl chloride. The cooling bath was removed and the solution was stirred for 1 hour and treated with 0.15 ml (1.85 mmol) of pyridine and 0.274 g (1.72 mmol) of trans-s-aziaocyclobutanoylkiophia. The reaction mixture was stirred for 1 hour at 230 ° C and filtered through a pad of celite. The filtrate was diluted with 100 ml of ethyl acetate and washed with 1N hydrochloric acid, water, saturated sodium bicarbonate solution and water, dried over anhydrous magnesium sulphate and concentrated on a rotary evaporator to an orange syrup (1.47 g). To a solution of the syrup in 50 ml of dichloromethane was added 2 ml of water and 0.2 ml of TFA. The reaction mixture was stirred for 2 hours at 23 °, washed with a saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and concentrated to an orange syrup (1.1 g). Purification of the syrup was accomplished by column chromatography (silica gel 60, 20 g; eluent: EtOAc ether 35% - 70%). Evaporation of the appropriate fractions gave 0.77 g (74.4%) of the title compound as an oil. ir (pure) IÛ max: 3440 (OH), 2100 (N3), 1755 (C = C> Å-lactam), 1735 (C = O), 1680 (c = o) and 1625 cm -1 (aromat.) (1 "R, 5R, 6S and 1" S, 5S, 6R) Paranitrobenzyl 2- (trans-3'-azidocyclobutyl) 6- (1'-hydroxy-1 "ethyl) penem-3-carboxylate En solution of 2.27 g (3, 14 mmol) (1 "R, 3S, 4R and 1" S, 3R, 4S) 4- (trans-3'-azidocyclobutanoylthio) -3- (1 "-hydroxy-1" -ethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -2- -azetidinone in 40 ml of CHCl 3 was diluted with 300 ml of toluene and refluxed for 6 hours under a nitrogen atmosphere. The first 60 ml of the solution (CHCl toluene) was removed with a Dean-strong trap. The reaction mixture was cooled to 23 DEG C. and the solvent was evaporated off under reduced pressure to give an orange syrup which was purified on a silica gel column (silica gel 60, 35 g; eluent: ether-benzene (45 454 779 0-6%). Evaporation of the appropriate fractions gave 0.38 g (27.3% of the title compound, m.p. 134 DEG-135 DEG.): Calcd for C19 H19 N5 O6 S: C 51.24, H 4.30, N 15.73 , S 7.20; found: C 50.98, H 4.20, N 15.83, S 7.10; ir vw. 21: e (N31. 'Ass co Mumma .: G90 (CO PNB mer) ,: sio (m2),: ass an * (scan 'Hr-w (Cvcla) öf 2-26 (d- -5_3 na, an, CH), 2.0 ~ 2.75 (m, AH, fl-2', H -¶ '). 3.67 (óå «Jcxs-aa's; _ -1.5 az, au Ü __- 6.5 az, ia, a-6).: .A-4.55 (m. Ä fl. Fl-1'- H -23 HG-: iS n-ÖWP-I- _ a-1 * -, s.so (Asq, aa_b-1s.s az. 2H. Eg: -vn-nog). S.so la. Jä_5_ä_6- 1 .s az, za. H-sz, v.s9 (e,: H ° _Hm-as az. za, am ana), s.2o (a, -aa az, za, ao 0: zxai. uv (cxcla 23'c> Xmax = 266 (S 13050), 515m-'rio 322 ppm (C 10008).

The unreacted phosphorane was recovered mixed with Ph 3 P-O and cyclized in the manner described above to give an additional 0.145 g (10.4%) of the title compound. Total yield 37.7%. (1 "R, 5R, 6S and 1" S, SS, 6R) -2- (trans-3'-cyclobutyl (6- (1 "-hydroxyethyl) penem-1-carboxylic acid 4i :: T * '5 N : os ve / c, _. 7 »~ S _ 3 __ å. ..-. o à, DuVl-“ fl gtgr _ 520 | än; LOOPNB To a solution of 0.33 g (0.74 mmol) (l R, 5R, 6S and 1 "S, 5S, 6R) Paranitrobenzyl 2- (trans-3'-azidocyclobutyl) -6- -1" -hydroxyethyl) -penem-3-carboxylate in 40 ml of dimethoxyethane was added 40 ml of ether and 0.33 g of 10% palladium on charcoal The reaction mixture was hydrogenated for 3 hours under a hydrogen pressure of 3.1 x 103 Pa and filtered over a pad of celite. The pad was washed with water and the filtrate and washings were combined and diluted with ether. separated, washed with ether and lyophilized to give 0.20 g (95%) of product uv (H 2 O, 23 ° C) Å, max: 258 (¿'272S) and 306 (¿f36l3). with water and the white solid was filtered and dried over PZOS in high vacuum for 5 hours to give 84 mg (40%) of product. 'amz (o2o> 6: 1.34 fa. J -6 .: az.

H-2 "-a-1" xsa-1 "_5115 Hz. 1H. H-SH uv (H20. 23'C) ax, x-2'-, 2.3-2.2 (m. 4a, a-2 '. H-4 '). 3.90 (dd. JH_6_H_5-1.5 Hz. J -6.1 Hz, za, x-6), s.as td, JH_5_H A __ "=: sa (e 41:81, _: os (c 6 : 18).

The filtrate was purified by high pressure liquid chromatography to give mg of product; uv (H 2 O, 23 ° C) 7L max; 257 (8 asso) and: os (6 5033).

Example 10 Z-aminoacetoxymethyl-penane-β-carvoxylic acid lf Hzoëcfizt-gz o UQH c 2 4-azidoacetoxyacetylthio-1- (paranitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate) 2-azetidinone __________, c av.

N - n P Ya) 6 3 0 Y ÖB cozasa èo pga A cold (ice-methanol bath) solution of 586 mg (0.954 mmol) of 4-hydroxyacetylthio-1- (paranitrobenzyl 2'-triphenylphosphoranylidene-2'-acetate ) -2-azetidinone in 15 ml of methylene chloride was treated successively with 240 mg (2.0l mmol) of acetyl chloride and dropwise with 226 mg (231 ml; 3.0 mmol) of pyridine in 10 ml of methylene chloride. At the end of the addition, thin layer chromatography showed the absence of starting material. The mixture was diluted with ether and washed successively with dilute hydrochloric acid, water, a dilute aqueous solution of sodium bicarbonate, water and brine. It was dried over sodium sulfate. Purification of the residue was performed on a g silica gel column eluting with 20% ether in benzene, ether and 30% ethyl acetate in ether. Concentration of the appropriate fraction in question gave 533 mg (80.1%) of the title compound as a foam. ir 1) Inax: (CHCl 3): 1763, 1702 (C = O), 1625 (C = P 3), 1522 (NO 2) and 2110 cm -1 (N 3).

Paranitrobenzyl 2-azidoacetoxymethylpenem-3-carboxylate WWW 2, cozvus A solution of 533 mg (0.764 mmol) of phosphorane was refluxed in 90 ml of toluene for 0.5 hours using a catalytic amount of hydroquinone. The solvent was concentrated on an evaporator and the concentrated solution was passed through a 10 g silica gel column (benzene ether 48: 2). 236 mg (73.7% of the title compound) were obtained as an oil. The oil was found to be unstable at room temperature and therefore stored at -780 until use. * Fi mz Kscly 6 = 8.21 (22-1, d, i-Im aren-at.), 7.57 (IH, d. Äo arcmac. Å, 5.63 (li-i, dö, J5_6 císfd. Gsus t fl ns = 2f 3-5), 5.43 (2HC8ntï .8V ÄBQ. J = l6, CBI-PNB). .39 (za, c fi2 o>. Se: zz fi, s. C fi z-Na). 3.12: del av dd. S6_5 Cís = <, H-6>. 3.50 ppm (Lä, eid, J = 17, J = 2, ä-6): ir v (CHCl 3: 1795. gem 6-5 trans max a ivss. Zzzo 454 779 60 2-aminoacetoxymethylpenem-3-carboxylic acid d [1: š A mixture of 219 mg (0.522 mmol) of the above ester in 16 ml of THF and 30 ml of ether and 16 ml of water was shaken. 25 hours in a Parr hydrogenator at a hydrogen pressure of 3.4 x 10 5 tor. The catalyst was filtered off and washed with water Pa using 240 mg of 10% Pd / C as catalyst and ether. The aqueous phase was washed with 3 x 30 ml of ether. and lyophilized.The crude product in the form of a powder r was purified on a reversed phase high pressure liquid chromatography column to give 8 mg (6.7%) of the title compound as a white powder; l gär: (D70) 5: 5.72 mi. ¿¿, _; S_6 cis.; _ 5, J5_6 tunga, H-S), SJ? (zinoentinav ma.

J-13.5. ca: -0). 3.96 (za. S .: H2-N52). 3.87 (la. Ae,: gem-16.5, a6_5 c¿s -as H-sm,: .4s sm: (xx. Ad. Jšem = 16-S. J6_S t, anS = 2- ä'6l = if “ max (union: 1775 '1755' _ 16.30 cm-'L (C = O): uv 1520) Ämax 306 {E4900) | 256 ~ (63000).

Example 1 11 Silver-1- (β -trimethylsilylethyl-2 '-triphenylphosphoranylidene-Z' -acetate) -Z-azetidinone-fl i-thiolate Ffäg j-tê o \; Å -trimethylsilylethyl fumarate Q 9 (l \ d, \ / §.mnJ_ I Cl 51 (CL: _ [i _ uy C \ S __ / \ / q_ (I \ 'lv? A o M 454 779 Till zo m1 av a cold (-10 °) ether solution of 4.73 g (0.4 mmol) of 2-trimethylsilylethanol H. Gerlach Helv. Chim. Acta QQ 3039 (1977) and 5.66 ml (0.07 mol) of pyridine were added dropwise ( 15 minutes) under nitrogen 3.78 ml (0.035 mol) of fumaryl chloride dissolved in 10 ml of ether The black mixture was stirred for 5 minutes at -100 and 10 minutes at room temperature Charcoal was added and the reaction mixture was filtered on a pad of celite. with 150 ml of a 1: 1 mixture of 1% sodium bicarbonate and brine.The aqueous phase was re-extracted with 30 ml of ether.The ether solutions were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain a brown solid m aterial. This compound was purified on a silica gel pad (30 g, 4 x 5 cm) eluting with 300 ml of benzene to give 4.855 9 (77%) of an oil which solidified on standing. Melting point 33-34 ° An fl_ ben gg ~ = 'c .12, n a.91; unneil c 53.35, H a.s1. 'amf (cat:) 5 = c14H28o4s1z sa {3 s.7a (zn, s, c-ca). 4.26 (4H, m. CH: -0), 1-03 <4H «m-CH; -Sih o.oe'ppm (lan, s. (Cn3) 3si>; ir 4. 1643 (c-cl, 1261 , lzsa, sez, 840 cm (S = -C> - Trimethylsilyl ethyl glyoxylate hydrate o s1 1) ° = ï "¶ï23 / s13 ccnsxgsi 2) A solution of 37 g (0,11 mmol) of di--trimethylsilylethyl fumarate in 1, 1 liter of methylene chloride was ozonized at -780 until a residual blue color was obtained, the excess ozone was evaporated with nitrogen and 2.57 ml (0.35 l mol) of dimethyl sulphide was added, the solution was gradually allowed to warm to 230. The reaction mixture was diluted with carbon tetrachloride to 2 liters and washed with 500 ml of a 1% aqueous solution of sodium carbonate, the organic phase was dried over sodium sulfate, filtered on celite and evaporated (about 250) to dryness to give 43 9 g 454 779 62 (97%) of the title compound ir (pure) 0 max 3450 grain, 1140 (esta, 12ss, sso and aao cm -1 (Si-C). 1 I- (if-trimethylsilylethylf2 '-hydroxy-2'-acetate) -4-trityltio-2-azetidinone o T: f ïutouiz Sic "rr. c ° 2 / \ / 3: To 1 N d * CO 2 4,000 g (11.6 mmol) of trimethylsilylethyl glyoxylate hydrate and 4.8 g (24.96 mmol) of 4-trityltio-2-azetidinone were refluxed in CO 2. 25 ml of benzene through a Dean-Stark condenser for 24 hours under nitrogen. The solvent was evaporated in vacuo. The product was chromatographed on a silica gel column (450 g, 8.5 x 14.5 cm) and eluted with a 1:19 mixture of ethyl acetate and methylene chloride until the title compound began to leave the column (about 1.5 liters) and then with 2 small of a 1: 9 mixture of ethyl acetate and methylene chloride.

The fractions containing the title compound were combined and evaporated to dryness to give 5.415 g (89%) of product. amz 430 (m, 25, x-c-O), 5.50 - 4.10 (JH, m, H-B, C-CH 2). 2.50 (zu, m, x-1), o.es (za, m, caz-si), 0.1 ppm (BH. S. Sl-cašu; ir xcncla) vmax = aszo a-on), 1765 lC = ° 3 ~ 1 = f == m) - 1 * °° (° = ° -1. '___ Ester), 1595 (cH, aromac.). 1257- B60. B40 Cm (~ = 1ï 1- (β -nimethylsilylethyl 2'-chloro-2'-acetate) -4-trityltio-z- -azetidinone Sïr 51 rf ___ i ° _ ° i2 ___, rf ; - o ï-: g / ç 3 3 ï /\/S+\C..3)3 63 454 7_79 A solution of 0.74 ml (10.37 mmol) of thionyl chloride in 9 ml of dry THF was added dropwise with stirring to a solution of 4.9 g (9.37 mmol) of 1- (-trimethylsilylethyl-2'-hydroxy-2'-acetate) -4-trityltio-2-azetidinone, 0.84 ml (10.38 mmol) of py ridin and 40 ml dry THF at -150 under a nitrogen atmosphere.

The mixture was stirred for 2 hours at -150. The precipitate was removed by filtration on a pad of celite and washed with SO ml of benzene. The filtrate was evaporated in vacuo at 300. The residue was dissolved in 100 ml of benzene, treated with charcoal and filtered through a pad of celite. Evaporation of the solvent gave a residue which was purified through a pad of silica (100 g, 4.7 x 11 cm), eluting with 400 ml of a 1: 1 mixture of hexane and benzene and 1 liter of a 1:19 mixture of ether and benzene. Evaporation of the appropriate fractions gave 464 g (92%) of the title compound.

1 Hmr (CDCl 3) δ: 7.30 (ISH, m. Aromat. H), 5.77 v 5.43 (11-1, 2s, cx-cl), 4-7 - 4.2 (BH, m, H-4, CH: - 0). 2.85 - 2.50 (za, m, HJ), 1.15 (25. m, CHfSi), 0.06 ppm (9H, s, Si-Cñah ir (rent) 'vmax = 1760 (c-0), see, eao cm'1 1- (β-Trimethylsilylethyl-Z '-triphenylphosphoranylidene-Z'-acetate) - -4-tritylthio-2-azetidinone '- - ST: nl' WB? í ---- +.

N Cl Lo-iutidine N p.) \ Ç * si (ca3) _ J \ Tf siæx> kÛ2, ^ \, / 1 2 ¿O2 / ^ \ o / ml of a dioxane solution of 4.12 g (7.568 mmol) of the above chloroacetidinone was treated with 2.209 g (8.424 mmol) of triphenylphosphine and 0.98 ml (8.424 mmolOl) of 2,6'lUtidiD- The mixture was refluxed for 3.5 hours. The cooled solution was filtered and the white solid was washed with THF. The filtrate was evaporated to dryness. The residue was purified on a silica gel column (200 g, 4 x 35 cm 3) using ethyl acetate-hexane (3: 7, 1 liter; 7: 3, 1 liter) to give 4.836 (83%) of the title phosphorane. . 1; (fiina vmax = ivss (c-o), ieisüíosføran), as: Gïh sno mfl. (sic). ¿._ == _. 1_1_.Ber. for cüuünozvssi: c certain. a sm. u 1.s1; FUI> I1et = c vma. a s.oa, N 1.83 \ \ Silver 1- (β -trimethylsilylethyl-2'-triphenylphosphanylidene--2'-acetate) -2-azetidinone-4-thiolate STI sAg _ + AgN0 + (nan) n + crco fl u os 3 3 3 2 ether / H 2 O / Al: TI, Psa o / \ / $ i (CH 3) 3 _ 2 oz / vâiüïiis) 3 7.64 g (10 mmol) 1 - (, β-trimethylsilylethyl-2'- triphenylphosphoranylidene-2'-acetate) -2-azetidinone was dissolved in 60 ml of ether. 80 ml of a 0.5 M aqueous solution of silver nitrate (40 mmol) was added followed by rapid addition (1 min.) Of a solution of 3 ml (1.2.5 mmol) of tributylamine and 0.154 ml (0.2 mmol) of tri fluoroacetic acid in 20 ml of ether. The mixture was stirred mechanically for 19 minutes. The precipitate was filtered off, rinsed with 200 ml of ether, triturated in 70 ml of water, filtered again and rinsed with 100 ml of ether. The light brown solid was dried in vacuo (water suction for 10 minutes and pump for 65 minutes) to give 6.42 g of the title compound. ir (CHCl 3) 1) max: 1862 (C = O, 1630 (phosphorane), 860 and 840 CH-1 (SI-C) 65 454 779 Example 12 6-formamidomethyl-2-methylpenem-3-carboxylic acid, sodium and sin / “fl g S 'H ca Jifq = 0š:% š) é: Ä potassium salts trans-1- (t-butyldimethylsilyl) -3-methanesulfonyloxymethyl-4-tritylthio-2-azetidinone H x Có H g HIJ 3 M 50 ":: t: 11.5c °: \ \. S1 (cH3) 2 § <(CH3) 2 t-Bu t" 3 "A solution of 8.0 g (l6.36 mmol) trans-l- (t-butyldimethylsilyl) -3-hydroxymethyl-4-trityltio-2-azetidinone in 50 ml of dichloromethane was treated at 50 with 1.4 ml (18 mmol) of methanesulfonyl chloride in 10 ml of dichloromethane and 2.5 ml ( 18 mmol) of triethylamine, stirring was continued for 1 hour under nitrogen, then the solution was washed successively with cold 1M hydrochloric acid, 1M sodium bicarbonate solution and brine, dried over magnesium sulphate and evaporated in vacuo. the hydroxy and mesylate compounds) were treated a second time as before to obtain 90 g (97%) of the mesylate as an amorphous solid. was used as such in subsequent steps without further purification. An analytical sample was recrystallized by melting. unkt n 167-168 ur with lenchloride '«P E Y' 1; (rent) V .1ß5C; 1. *; N-mun) mm: (zm, mm «4 (me == m = u max '' 3 3,9 (ia, aa,: = aaz, axzä, 3.2 < 2H, bs), 2-8 KBH- S), 0-95 [mu] S7 0.3cm = 1.5H, 5M 454 779, 66 Trans-3-methanesulfonyloxymethyl-4-trityltio-2-azetidinone and trans-3-azidomethyl - 4-trityltio-2-azetidinone HH ~~ 5.SCO H g Scø H 3 RIU * 3 H50? U JN /, _ ~ å scø: N \. N ______ * 3 Si (CHJ) 2 '0' H ox t -Bu A solution of 21.0 g (37.0 mmol) of trans-1- (t-butyldimethylsilyl) -3-methanesulfonylmethyl-4-trityltio-2-azetidinone in 90 ml of HMPA was cooled in an ice bath and treated with 2 7 g (41.2 mmol) of sodium azide in 10 ml of water The reaction mixture was stirred at room temperature for 1 hour, diluted with ethyl acetate, washed with 5 x 100 ml of water, dried over magnesium sulphate and evaporated in vacuo. The methanesulfonyloxymethyl-4-trityltio-2-azetidinone was diluted with 90 ml of HMPA, treated at room temperature with 2.7 g (4l, 2 mmol) of sodium azide in 10 ml of water, heated at 600 for 2 hours and triturated with cold water. -the raw product was diluted with me d a 5: 1 mixture of benzene and ether and washed with 5 x 20 ml of water. Evaporation of the solvent followed by crystallization from ether hub 18.0 g (77%) of the azide as a white solid. An analytical sample was recrystallized from dichloromethane / ether, mp 174-175 °; Analysis: Ber. for C 23 H 20 N 4 OS: C 68.97, H 5003, N 13.99, found C 68.78, H 5.00, N 14.16; ir (nujol) λ max 2100, 1765 cm-1: fl mr (CDCl 3) δ: 7.35 (15H, m), 4.75 (1H, bs), 4.4 (1H, d J = 2Hz), 3.1-3.7 ppm (3H, m). trans-3-aminomethyl-4-trityltio-2-azetidinone H su / “'l_ [š scoš H x /“ lèf Sw: l 3 ____: .____._._ y 2' O ß NH OL ÄH 67 454 779 Till To a solution of 10.0 g (47.5 mmol) of trans-3-azidomethyl-4-trityltio-2-azetidinone in 500 ml of dry methanol was added 19.0 g of ammonium chloride and 1.0 g of zinc powder and the suspension was stirred for 5 hours. at room temperature. The reaction mixture was filtered and evaporated. The residue was partitioned between 1M hydrochloric acid and benzene. The aqueous layer was alkalized with 1M sodium bicarbonate and extracted with methylene chloride.

The extracts were washed with brine, dried over magnesium sulfate and evaporated in vacuo. The amine crude product was crystallized from ether in an amount of 14.05 g (79%) and with a melting point of 139-9 °; Anal. Calculates for c23n22n2oc1-i / 4 cn2c12 = c 1o.se. a s.1a, N 7_0a, FU flfi ëtt 70.68, H 5.94, N 7.27; ir (cacaf vmax = 1400, 1760 cm'1; 'amr mcøcis) 5: 7.35 (1s fi, m). 5.15 (1a, m), 4.3 (1H, bsä. 2.7-3.5 (sn. M), 1.3 ppm (2H, m) - trans-3-phthalimidomethyl-4-trityltio-2-azetidinone: ~ O A solution of 13.9 g (37.2 mmol) of trans-3-aminomethyl-4-trityl-thio-2-azetidinone and 8 H .3 g (37.9 mmol) of N-carbethoxyphthalimide in 200 ml of benzene were refluxed for 15 hours, the solvent was evaporated in vacuo and the residue was crystallized from ether to give 17.4 g (93% of the title compound, m.p. 30; J funruet 11.92, H 4.e1. A s. <9; ir fcncla) vmax = 1170, 1115 cm'1; Ana ;. Biff foal c _H n_o s = cv: .1a. H 4.19, N s. ss. f-3i24 <* ene 4.1 (BH, m), 3.J - :. 6 ppm (1H, m) 454 779 68 trans-3-phthalimidomethyl-1- (paranitrobenzyl-2'-hydroxy -2'-acetate) -4-trityltio-2-azetidinone Ü. Û ÉS °° = i --- + S °° =, 'ya o fi ïmi ÛZPNE A mixture of 17.4 g (34.52 mmol ) trans-3-phthalimidomethyl-4-trityltio-2-azetidinone, 9.4 g (41, 4 mmol) of paranitrobenzyl glyoxylate hydrate and 4.8 ml (34.5 mmol) of triethylamine in 250 m The tetrahydrofuran was stirred for 20 hours at room temperature.

The reaction mixture was evaporated in vacuo and the residue was treated with charcoal in benzene. Evaporation of the solvent gave g (quantitative yield) of the hydroxy glyoxylate crude product as an amorphous solid. It was used in subsequent steps without further purification. i; (mm1¶ v = 1770 1715 cm -1; * nmr (coci) δ = 8.1 (za. d. J = 9H =) - 7-55 max '3 (au, a, J-ena). 1.3 ( len, m), so-s.4 (za, bsz. 4-2-S-O IIH-N), 2.s-3_s ppm (4x. m1. trans-3-phthalimidomethyl-1- (paranitrobenzyl-2 '-chloro-2'-acetate) - -4-trityltio ~ 2 ~ azetidinone ° o H a 3 rç 9 a. ß fi nw “ß O | 6» -å on' 1 N \ T / o 0 \ ï, c1 cozvsa to a cooled (ice bath, 0 °) solution of 25 g (35 mmol) of trans-3-phthalimidomethyl-1- (paranitrobenzyl-2'-hydroxy-2'-acetate) -4--trityltio-2- azetidinone in 150 ml of tetrahydrofuran was added dropwise 46 ml of a 1M solution of thionyl chloride (46 mmol) in tetrahydrofuran, followed by 46 ml of a 1M solution of pyridine (46 mmol) in tetrahydrofuran. The reaction mixture was stirred at room temperature for 20 minutes. was diluted with 50 ml of petroleum ether and filtered through a bed of celite and carbon dioxide.

The solvent was evaporated in vacuo to give 26 g (quantitative yield) of the chloro-azetidinone as an amorphous solid. It was used in subsequent steps without further purification. 1z (um1¶ vmax = 1115, 1720 = m'1. * Nmr zcnc13> 6 = a.1z (za, 4,: -sn =>. 1.60 (zu, a, J-euza, 1 .: (Lau, m) .s.2s (zu, m), 4.1-s.4 (1x, ->, 4.55 (ll-l. bs), 3.3-4.0 ppm (BH, m) - trans-3-phthalimidomethyl-l- (paranitrobenzyl-2'-triphenylphosphanylidene-2'-acetate) -4-trithylthio-2-azetidinone A mixture of 26 g (35.5 mmol) of trans-3-phthalimidomethyl-1- (paranitrobenzyl-2'-chloro -2'-acetate) -4-trityltio-2-acetidinone, 10.25 g (39.1 mmol) of triphenylphosphine and 4.6 ml (39.1 mmol) of 2,6-lutidine in 200 ml of dioxane were heated The reaction mixture was filtered over celite and evaporated, the residue was chromatographed on a 3509 silica gel column eluting with benzene to benzene / ether (1: 1) to give 219 (62%) of the phosphorane as a white solid. .

Lif vmax = avec,: via = m'1. * amf (cocla) 6: 7.4 (usa. ma, 4.8-s.4 (zu, m). 4.6 zu, m), 3-1 Pen (ÄH bs). Trans-3-phthalamidomethyl-1- (paranitrobenzyl-2'-triphenylphosphanylidene-2'-acetate) -4-trityltio-2-azetidinone 454 779 70 'HB ° "V co - ~ ena / yr:. coz x Exxs En cooled (ice bath) suspension of 18.02 g (18.83 mmol) of trans-3-phthalimidomethyl-1- (paranitrobenzyl-2'-triphenylphosphoranylidene- (-2'-acetate) -4-trityltio-2-azetidinome in 30 ml of tetrahydrofuran, ml of water and 30 ml of acetone were treated dropwise with 4.97 g (20.7 mmol) of sodium sulfide in 30 ml of a 1: 1 mixture of acetone and water and refluxed for 8 hours.The reaction mixture was diluted with water, acidified with 1N hydrochloric acid and extracted with dichloromethane The organic extracts were washed with brine and evaporated in vacuo to give 17.1 g (88%) of the title compound as an amorphous light yellow solid. material. It was used in subsequent steps without further purification. _ 'l ._ ir (pure) GEx = 3150-zeoo, 1150, 1.00 cm;' nmr (cocla) 6: 7: :-( sen, m), 2.2-6.5 ppm l flfl- => - trans-3-phthalisoimidomethyl-1- (paran itrobenzyl-2'-triphenylphosphanylidene-2'-acetate) -4-trityltio-2-azetidinone H Escoa egg s H (OïÅh / ~ __l__ ~ s N / d. 4L_ | A solution of 17.1 g (1.7,54 mmol) of trans-3-phthalimidomethyl-1- (paranitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate) -4 - -trityltio-2-azetidinone in 125 ml of dichloromethane was treated dropwise at room temperature with 3.62 g (17.54 mmol) of N, N'-dicyclohexylcarbodiimide in 30 ml of dichloromethane. The solution was filtered over celite and evaporated to give 18.23 g (quantitative yield) of the title compound as an oil. It was used in subsequent steps without further purification. 1. _ '1. _ ki fl rentqvm. mo, 1155, 1110: m 1 m (cocis) 6. 1.5 (on, m), 4.6-sz (4a, u), 3.9 ppm (za, bax. trans-3-aminomethyl-1- (paranitrobenzyl-2 ') -triphenylphosphoranylidene-2'-acetate) -4-trityltio-2-azetidinone H 5 H Vscø o 1: / 9:03 'WN / y 3: -' -_-_--- v PN 'o NT ÖJ PNB COIPNB A solution of 5.9 g (6.16 mmol) of trans-3-phthalisoimidomethyl-1- (paranitrobenzyl-2'-triphenylphosphoranylidene2'-acetate) -4--trityltio-2-azetidinone in 40 ml of tetrahydrofuran, cooled to -200, was treated dropwise under nitrogen with 0.2 ml (6.16 mmol) of hydrazine and stirring was maintained for 30 minutes, the reaction mixture was acidified with 1N hydrochloric acid and washed with ether; The organic extracts were washed with brine, dried over magnesium sulphate and evaporated, the residue was purified on a 60 g column of silica gel eluting with ether to ethyl acetate to give 3.38 g (66%) of an aminophosphorane as amorphous solid material if (cac13> v = ivso. 1v1o = m '* f' ams (çnci> 6; es-e.1 max 3 3.8-5 .: (ex, m), 0.9-1.9 ppm (zà, m). 454 779 72 trans 3-formamidomethyl-1 - (paranitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate) -4-trityltio-2-azetidinone H 'H SC 2 ° r * 0 PNB 2 min a cooling (ice bath) solution of 5.0 g (s, 4 mmol) trans-α- -aminomethyl-1- (paranitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate) -4-trityltio-2- (azetidinone in 50 ml of dichloromethane was added dropwise under nitrogen a solution of 600 mg .8 mmol) acetic acid formic anhydride in 5 ml dichloromethane, followed by a solution of 1 ml (7 mmol) triethylamine in 2 ml dichloromethane.

Stirring was continued for 30 minutes. The solution was washed successively with 1M hydrochloric acid, water, 1M sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate and evaporated and the residue was chromatographed on SO g of silica gel column. Elution with ether to ethyl acetate gave 2.0 g (39%) of the formamide as an amorphous solid. l -1 i: (C fi Cl) v: 1740, 1685, 1620 cm.- Hm: 3 max (cac13> 5; es-az (ass, m), 2.5-5.3 ppm (va. ml. trans silver-3- formamidomethyl 1- (paranitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate) -2-azetidinone-4-thiolate _ n E iis, f »ï__É'5C ° 3 ngn / 'wí% 45 * 9 n .- y H 1 a --- ~ * L rf-'Nvwg 0 NYW: (0 phg LO FNB 1 2 A solution of 550 mg (0.64 mmol) 3-formamidomethyl-1- (parani trobenzyl-2 '- tri-phenylphosphoranylidene-2 '-acetate) -4-triethylthio-2-azetidinone in 10 ml of dichloromethane was evaporated to dryness and diluted with 20 ml of hot methanol, the solution was stirred at 600 and treated with 7 ml of a preheated (600) 0.15 M silver nitrate solution (0.86 mmol) in methanol, followed by 0.57 ml of a 1,5 M pyridine solution (0.86 mmol) in methanol. The mixture was filtered for 30 minutes at room temperature and then for 2 hours in an ice bath The solid was filtered, washed with cold methanol and ether and dried to give 300 mg (65%) of the silver salt as a beige dye. st material. It was used in subsequent steps without further purification. trans-4-acetylthio-3-formamidomethyl-1- (paranitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate) -2-azetidinone f HB sn â, / H § A i 9 __ -., c HtN '/ 3' HN 6 ----- + n. to Q 2 (; 3 OY 3 Cozpxg COIPNB To a cooled (ice bath) solution of 800 mg (1.1 mmol) of trans- -silver-3-formamidomethyl-1- (paranitrobenzyl-2'-triphenylphosphoranylidene-2'- acetate) -2-azetidinone-4-thiolate in 10 ml of dichloromethane was added dropwise under nitrogen 1.33 ml of a 1M acetyl chloride solution (1.33 mmol) in dichloromethane, followed by 1.33 ml of a 1M solution of pyridine (1, 33 mmol) in dichloromethane, the solution was stirred in a cooling bath for 1 hour and then filtered over celite. The filtrate was washed successively with 1M hydrochloric acid, water, 1M sodium bicarbonate and brine and the organic layer was dried over magnesium sulphate and evaporated. was purified on a .0 g silica gel column and eluted with ethyl acetate to% methanol in ethyl acetate to give 450 mg (62%) of the title compound: 1: 3 max county,, c, C13, ¿, 8_¿8 ( ; H, 5,; = 9H,), 1.oe.o lzsa. M), 6.15 (zu, c. _; = 9 51), 6.3 (11-4, m), 5.5 (ll-I , m), 5.2 (25. ace), 4.9 (1H, bs), 3.6 (1H, m), 3.0 (1H, m), 2.2 ppm (JH, CW S ). 454 779 74 Paranitrobenzyl 6-formamidomethyl-2-methylpenem-3-carboxylate Hzwf * '* ___...

H PQB o \ f * CO2PNB A solution of 450 mg (0.68 mmol) of trans-4-acetylthio-3-form-amidomethyl-1- (paranitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate) -2-azetidinone in 10 ml of toluene was refluxed for 12 hours. Concentration and purification on a silica gel column eluting with ether to 10% methanol in ether gave 100 mg (39%) of the penem compound as an amorphous solid. (IRCl 3) vmax = 1780, 1690 cm -1; 'Hmm (cnclz) 6: s.2 (za, a, a = 9uz). a.2 (ln, 5). 1.6 (zu. A .: = 9nz). s.9 (ln. ml. s.ss (1H, S), s.:s (za. 25), 3.3-4.1 (JH, m) - 2.33 ppm (BH, S) - 16-formamidomethyl -2-methylpenem-3-carboxylic acid, sodium and potassium salts s HI ¥ S a3v ”'” ~ g _ HSN' / Ä "3“ _ ca) ----- + HN C fl3 O ”° ogß COZPNB and En blending of 80 mg (0.2l mmol) of paranitrobenzyl 6-formidomethyl-2-methylpenem-3-carboxylate, 100 mg of 30% palladium on celite, 10 ml of tetrahydrofuran, 25 ml of ether and 4.46 ml of a 0.05M Buffer solution ÉH 7 (0.223 mmol) was hydrogenated for 3 hours in a Parr shaker at an initial hydrogen pressure of 3.1 x 10 5 Pa. The catalyst was removed by filtration on celite and washed with water. The filtrate and washings were combined and the phases were separated. The solid crude product was purified by high pressure liquid chromatography to give 18 mg of a mixture of the sodium and potassium salts 75 454 779 uv (H 2 O) Amaxz 299 (c 4933). (c 4094); 1: ínujoii -1 vmax = 3100-3650, _. 1755 cm: * umz (020) 6: 0.15 (ia, 1), 5.53 (ln, a, 7-1-432), 4-0 (1H, m), 3.74 (1H, d, J-SHZ), 3,254.3 (15, m), 2.27 ppm (3H- s).

Example Gel 13 (4 ', 5R, 6S and 4'S, 5S, 6R) -6- (2', 2'-dimethyl-1 ', 3'-dioxolan--4'-yl) -2-methylpenem-3-carboxylic acid (isomer C) PREPARATION OF IN ST:. S71 'É-MJ: hf \ l / OCh 0 N \ o 5¿ S1 /> </ X (4'R, 3S, 4R and 4'S, 3R, 4S) -and (4'S, 3S, 4R and 4'R , 3R, 4S) -1- (t-butyldimethylsilyl) -3- (2 ', 2'-dimethyl-1', 3'-dioxolan-4'-yl) -4-trityltio-2-azetidinone ("isomer C "and" isomer B ") Ethyl O- (2-methoxy-2-propylglycolatel) HC / Ä GE ë-ÉMÉ k] kB t.

POCÄ. To a solution of 15.6 g (0.150 mol; freshly distilled) of ethyl glycolate and 16.4 g (0.216 mol; 95% pure) of 2-methoxypropylene2) in 150 ml of dichloromethane was added at 0 DEG-50 DEG. drops (35 mg; 0.23 mmol) of phosphorus oxychloride and the mixture was stirred for 15 minutes 454 779 vs at 0-50 and at room temperature for 1.5 hours. The mixture was then added with 30 drops of pyridine and stirred for 45 minutes, after which the solvent was evaporated. The residue was diluted with 150 ml of pentane, dried over potassium carbonate. After filtration, the solvent was evaporated, yielding 27.89 g (0.18 mol, 100%; 94.9% pure) of the title compound as a colorless oil. 'nar. 3.1: (sn, s. -Ocs3). 3.88 (za. S. -Ocnzco-3, 4-10 (2H. Q. J-7H =. -§G2CH3): 1z (1 "ent) vmax; ivso, 1135 = m'l fester). 1); _ naínwaia er az., Rat. Letš., 4321 (1975) 2) 24.5. Newman and M.C. Vanda: Zwan, J. Org. Chenqlq, 2910 (1973). (3S, 4R and 3R, 4S) -1- (t-butyldimethylsilyl) -3- (1'-keto-2'- (2 "-methoxy-2" -isopropyloxy) -1'-ethyl) -4- trityltio-2--azetidinone ßsr: 1) LDA / 'raf s-rr N \ s¿ / 2) ME: OCH3 J: N | \ Si / / X ÛHE / X To a stirred solution of 18.5 ml (0 134 mol) diisopropylamine in 400 ml of THF (freshly distilled from LAH) at -780 was added 90 ml of 1,6N n-butyllithium (0.144 mol) in hexane under a nitrogen atmosphere. After 30 minutes, a solution of 50.0 g (1.09 mol) of 1- (t-butyldimethylsilyl) -4-trityltio-2-azetidinone in 100 ml of THF was added dropwise over 10 minutes and the mixture was stirred for 5 minutes. To this pink solution was added 23.94 g (0.136 mol) of ethyl O- (2-methoxy-2-propyl) glycolate, and the mixture was stirred for 1 hour. After removing the dry ice bath, 200 ml of saturated ammonium chloride solution was added, followed by 100 ml of brine. The aqueous phase was extracted with 3 x 100 ml Et 2 O. The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated to give 60.95 g (1.03 mol; crude yield 454 779 - 77 94.6%). ) of the title compound as an orange oil. This crude product was used in subsequent steps.

A pure sample was obtained by column chromatography (S102, eluent: 2% 31:20 in benzene); * Hmx (cncxg) 6 = 0-30 (GH. S. Si-css). o.9s (sa. 1. = -au), 1.12 (sn, 5, CH). 1.15 (JH. S. CH). 2.15 (au, a, ocn), 3.51 (1n, A av As. A - 3 3 3 gem HM). 3-77 (1H, d, J-1-é fl z, 11-3). 3.97 (m. Hav As, agem-nnz), 4.83 (1H, d, Jnl.6'riz, 8-4), 7.l-7.6 (1SH, m, aromag), Hs): ir (ytgnt) vmax : nso. ms. nine en * (c-ø), ne, of o.s: (benzene; mao-au), RI 0.61 (hexane z EtOAC I 221). (2S, 4R and 3R, 4S) -1- (t-butyldimethylsilyl) -3- (1'-hydroxy-2'- -methoxyisopropyloxyethyl) -4-trityltio-2-azetidinone (mixture of epimers at C-1 ') o JH ST sf _ r Y Naszu X0., ocn: h' _ “'“ "' 'ocHB o / \ ../ X \ si / A solution of 60,95 g (0, l03 mol) oren l - (t-butyldimethylsilyl) -3- (1'-keto-2 '- (2 "-methoxy-2" -isopropyloxy-1'-ethyl) -4-trityltio-2-azetidinone in 100 ml THF was diluted with 350 ml of absolute ethanol and to this solution was added at 0 DEG C. 4.88 g (0.66 mol) of NaBH4 The mixture was stirred at room temperature for 2 hours and slowly added with 280 ml of brine The mixture was extracted with 3 x 150 g Et 2 O and the extracts were washed with brine, dried over sodium sulfate and evaporated to give a yellow residue which was redissolved in 500 ml of dichloromethane, the solution was again dried over sodium sulfate and evaporated to give 57.1 g (0.0966 mol crude yield 93.8%) of the title compound as a crude yellow foam 454 779 78 'xmx (cvc1¿) 6. 0.11 L »(I, S1CH3), 0.80, 0.87 (22, Si-Cß fl n 1.22. 1-25 (21, C113), 3.03 (S, OCHB), 4.12 (a, a-zxz, sm), 7.ov.1 (m, uamy- ns), sdfe fl ï fi vmax 3460 (om, 1745 (CO), 1595 (aromag-JI R! 0.47 '' 0.42 (hexane, z EtOAc-Zzl) This crude material was used in subsequent steps without purification. (4'S, 3S, 4R and 4'S, 3R, 4S) -and (4'S, 3S, 4R and 4'R, 3R, 4S) -1- -t-butyldimethylsilyl) -3- (2 ', 2'-dimethyl-1', 3'-dioxolan-4'-yl) -4-trityltio-2-azetidinone (isomer C and isomer B) H v I: Tr p-'rso fl- Hzb yfr He. e _ x N o ”\\ _ /> Cm * si S1 OH /> <.

A solution of 57.1 g (0.0966 mol; crude product) (3S, 4R and 4R, 4S) of 1- (t-butyldimethylsilyl) -3- (1'-hydroxy-2'-methoxyisopropyloxyethyl) -4- trityltio-2-azetidinone (mixture of diastereomers at C-1 ') in 500 ml of dichloromethane was treated at room temperature with 200 mg of p-toluenesulfonic acid monohydrate and ml of 2,2-dimethoxypropane and then stirred for 1 hour.

The mixture was washed with a saturated sodium bicarbonate solution and then brine, dried over sodium sulfate and evaporated to give 49.64 g (0.0888 mol; crude yield 91.9%) of a mixture of the title compounds. (isomer B and isomer C) as a yellowish foam.

This was purified by high pressure liquid chromatography (Waters 500 silica gel; eluent: hexane-ethyl acetate = 9: 1) and by crystallization to give 14.28 g (25.5 mmol; 26.4%) of isomer C as white crystals with white crystals. mp 146-7 ° (pentane) lnmr (cc1,> 5 = 0.27, 0.95 (an, S, si-ten), l.l5 6H, s, di-Me), 2.5 ~ 2.9 (1H, m, H ~ 4 '), 2.97 (1H, t, J = 1.8 Hz, H-3), 3.25 ~ 3.9 (ZH, m, H-S'), 4.27 (1H, d, J = 1.8Hz, W 454 779 H-4), 7.1-7.6 (15B, m, aromat. Hs); ir (nujol) 1) max: ivso, ises cm'1 (aroma :.); of 14.4s (hexane = EtOAc = 4: 1) and 14.50 g (25.9 mmol; yield 2S, 9%) of isomer B as white crystals, m.p. 144-5 ° (Et 2 O-pentane) nmz (cc14) 6: o.o2 (en, s. swe), 0.21: (en, s, si-esm, 1.13, ma (an, n. aina). 2.5-2.8 (ll-I, m, HU ILS-LI (1H, m, H-5 '), 3.48 (13, then, J ILSHz, 3.4 J3_4, -S.0Hz, 3-3), 3.93 (IR, d, .74_3-1.5Hz, Hd), 7.l-7.7 (155, m, aromat. Iis), - iz (nujol) vmax: 1650 (CIO), 1595 coq '(axomat.); Ar o.:1. Anal ßer.för c] 3a41no3ss1 = c 1o.ao, x 7.ae, N 2.so, s s.1a; funïletzzsomer c) c 10.23. H 7.10, u 1.3-, .H N 2.41, S 5.53 and (Isomer B) C 70.52, H 7.31, N 2.40, S 5.05.

Preparation of (4'R, 3S, 4R and 4'S, 3R, 4S) -3- (2 ', 2'-dimethyl-1', 3'-dioxolan-4'-yl) -4-trityltio-2 -azetidinone (isomer C) To a stirred solution of 14.3 g (25.6 mmol) (4'R, 3S, 4R and 4'S, 3R, 45} ° 1- (t-butyl-dimethylsilyl) -3- ( 2 ', 2'-dimethyl-1', 3'-dioxolan-4'-yl) -4-trityltio-2-azetidinone (isomer C) in 230.4 ml of hexamethylphosphoric acid triamide was slowly added (under 20 minutes) at O-50 a solution of 2.50 g (38.4 mmol; 1.5 equivalents) of sodium azide in 25.6 ml of water, the mixture was stirred for 2 hours at room temperature and poured into 2.5 liters of cold water. obtained was washed, washed with water and dried to give 454 779 90 - 11.26 g (25.3 mmol; crude yield 98.8%) of the title compound as a white solid. pure material was obtained by crystallization from CH 2 Cl 2 -Et 2 O; melting point 192-30 (decomposition); _'mu (cnc13.16; 1.: 3, 1.37 (an, 2: -. di-ne). 3.27 ( m, c. s-anz. ns), Ls - m (JH: mn H'4 | l _ fi- sqr 4-40 (IH: d! J-: Hzi a-4ll 4'47 (nlh bg 'NH' D20 switched), .1.1-1.1 ppm (lsu. m. ar ° m = t- H => = ir! nvi ° 1) vmax = -1 _ 3220 (mi), 1759 (ç-qh, 1950 cm (azomat..) .- Rf 0.31 (hexane- - EtOAc In 3: 2). (4'R, 3S, 4R and 4'S, 3R, 4S) -3- (2 ', 2'-dimethyl-1', 3'-dioxolan--4'-yl) -1- (p-nitrobenzyl 2 "-hydroxy-2" -acetate) -4-trityltio--2-azetidinone (mixture of epimers at C-2 ") (isomer C) Z * - STI 'o Q Fflëua * r NH Å. A suspension of 6.57 g (28.95 mmol; 1.15 equivalents) of p-nitrobenzylglyoxylate hydrate in 500 ml of benzene was refluxed for 2 hours at a Dean-Stark trap. The mixture gave p-nitrobenzyl glyoxylate as an oil, a mixture of this oil and 11.2 g (25.2 mmol) (4 ', 3S, 4R and 4'S, 3R, 4S) of 3- (2'-dimethyl-1'- 3'-dioxolan-4'-yl) -4-tritylthio-2-azetidinone (isomer C) in 350 ml of THF (distilled from LAB) was treated with 289 mg (2.86 mmol) of triethylamine at room temperature 18 hours (overnight) After evaporation of the solvent, the residue, which had been diluted with 200 ml of dichloromethane, was washed successively with brine containing 2.9 ml of 1N hydrochloric acid, saturated sodium bicarbonate solution and brine, dried over sodium sulfate and evaporated after the addition of 30 ml of Et 2 O to give 17.2 g (26.3 mmol; crude yield 100%; purity 95.8%) of the title compound as a white foam; Rf 0.40 and 0.30 (benzene: Et 2 O = 3: 2). Each isomer was separated by high pressure liquid chromatography (SiO 2; eluent: benzene: Et 2 O = 3: 2) and purified by crystallization from CH 2 Cl 2 -Et 2 O. xsomer z = of o.4o tbensen = stzo-1:21; mp 15: -4'c; * amf (cnclsl 6: 1.20 (ex, 1, ai-new. 1.1 (za, m.

H-3, - OH). 3.5-4.2 (an, m. R-4;. A- $ '), 4.55 (in, d, J = znz, n-4), .17 (1H, bt. R-2 "), 5.30 (ZH , 5,0CH2ArL 7.1-8.3 ppm (19H, m.

."'HRS ;' . - aroma: s) ir (nujol) vmax. 3370 (OH), 1775 (3-1at¿¿m, l 1745 Cm 1 (c); A 1.BeF.för. _ _ ° s ef _23. Cje fl aáuzoss. C es.o4, h 5.23, N 4.za Found: C 55-551 H 5.64, N 4.11 Isomez II: Rf 0.30 (benzene: E fl2 O = 3; 2); amp 164-5'C; 1 fi mz KCDCI3) 6: 1.17 (GH, s, di-Me ), ~ J.2 (2H, m, ~ HJ / gg), 3.4-4.0 (ax, m, a-4; Hs ~), 4.51 <1x, 4, a = zn =, H-az, sz: «1n, sr,, 2 ~) f 5.27 (23, s, -OCH2Ax), 7.1-8.3 ppm (19H, m, aromat. Hg), ir (nuà ° l> vmax: ssao cos), 1165 cs-zlatan ), = 1740 Cm'1 (e $ = e,), - è fi il- BE * -füfï C35H34N2o8s = c ss.o4, H s.2 :, N 4.áa, s 4.90. fi unnet: c ss.o1, H s.:4, N 4.zs, s 4.vs. (4'R, 3S, 4R and 3'S, 3R, 4S) -3- (2 ', 2'-dimethyl-1', 3'-dioxolan--4'-yl) -1- (p-nitrobenzyl 2 " -chloro-2 "-acetate) -4-triethylthio-2--azetidinone (mixture of epimers at C-2") (isomer C) To a stirred solution of 17.13 g (25.07 mmol) (3 'R, 3S, 4R and 4'S, 3R, 4S) 3- (2', 2'-dimethyl-1 ', 3'-dioxolan-4'-yl) -1- 454 779 82 - (p-nitrobenzyl ° 2 "-hydroxy-2" -acetate) -4-trityltio-2-azetidinone (isomer C) (mixtures of epimers at C-2 ") in 250 ml Tar was added via -1s ° under nitrogen 2.84 ml1 <3s , 1 mm ° 1> pyridine and immediately thereafter 2.20 ml (30.1 mmol; Anachemia) thionyl chloride. The mixture was stirred for 20 minutes at -150 and then the white precipitate was filtered off. After washing with benzene, the filtrates and washings were combined and concentrated. The residue, which was dissolved in 250 ml of benzene, was treated with activated carbon, filtered and evaporated to give 17.94 g (26.65 mmol; crude yield 100%; purity 94.1%) of the title compound. the compound as a crude product in the form of a white foam; Rf 0.76 (benzene: Et 2 O = 3 = 2); Hmr cnc13) 5 '=' 1-20 (SH. S. Dine). 3.17 (ia. M. H-3), 3.4-3.9 (au, m. X-4 '* fC'f n-s'), 4-67- 4-72 (1H, 2d. J-2.5 Hz. H-4). s.:o (za, S. ocxzaza, s.ea <=, n-2 ") gçh 7.1-8.3 ppm» (19 H. m. ammar Rs), i: (fíentkamax: 1770 cm-l (B- -lactam and ester) ~ This material was used in subsequent steps without purification (4'R, 3S, 4R and 4'S, 3R, 4S) -3- (2 ', 2'-dimethyl-1', 3'-dioxolane - -4'-yl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -4-tritylthio-2-azetidinone (isomer C) 0, J ~, lsrf 3 Ä \ » Sr: 4, __ N \\ T ,, c1 åi ° X- aJ ::: í! Po: üiblanàüng ær 17.87 g (25.0 mmol; purity 94, 1%; mixture of epimers at C- 2 ") (4'S, 3S, 4R and 4'S, 3R, 4S) -3- (2'-dimethyl-1 ', 3'-dioxolan-4'-yl) -1- (p-nitrobenzyl-2" -chloro-2 "-acetate) -4-trityltio-2-azetidinone (isomer C), 7.27 g (27.5 mmol 'ax qu 83 454 77_9 (triphenylphosphine and 3.19 ml (27.5 mmol) ) 2,6-lutidine in 350 ml of dioxane (distilled from LAB) was refluxed for 40 hours under nitrogen Evaporation of the solvent in vacuo gave 29.5 g of a dark oil which was purified by column chromatography (SiO 2 330 9; eluent 20-50% Et 2 O in benzene) to give 10.5 g of a yellowish solid rial.

This solid was washed with Et 2 O to give 7.49 g (8.33 mmol; yield 33.3%) of the title compound as pale yellow crystals; 1 mr (CDCl 3): 1.07 (s, di-Me) and 7.1-8.2 ppm (m, aromatic, Hs); ir (nujol) \) max: 1760 cm-1 crystallization from CH 2 Cl 2 -Et 2 O with melting point 231-2 Anal .: Ber. for C 54 H 47 N 2 O 7 PS: C 72.14 H 5.27 N3.12 S 3.57; Found: C 72.18 H 5.43 N 2.98 S 3.41; Rf 0.17 (benzene: Et 2 O = 1: 1).

(C = O). An analytical sample was obtained by On I (4'R, 3S, 4R and 4'S, 3R, 4S) -Silver-3- (2 ', 2'-dimethyl-1', 3'-dioxolan-4'-yl ) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone-4-thiolate (isomer C) z AgNoa-Pyrol :: lñ: T??; ç3 neon «P43 A solution of 319 mg (0.355 mmol) (4 ', 3S, 4R and 4'S, 3R, 4S) - 3- (2', 2'-dimethyl-1 ', 3'-dioxolan-4'-yl) -1- ( p-Nitrobenzyl-2 "--triphenylphosphoranylidene-2" -acetate) -4-trityltio-2-azetidinone (isomer C) in 10 ml of dichloromethane was evaporated to give an oily residue, which was redissolved in 8 ml of hot (600) methyl To this solution was added 4.0 ml of a warm (600) 0.5M solution of silver nitrate (0.60 mmol) in methanol and then 29 μl (0.36 mmol) of pyridine, the mixture was stirred for 5 hours at room temperature and 1 The precipitate was collected and washed with ice-cold methanol and then with cold 454 779 M Et 2 O to give 255 mg (0.334 mmol; yield 94.1% of the title compound as a brownish solid; ir ( nujol) \, max: 1750 cm-1 (s, C = O), (4'R, 3S, 4R and 4'S, 3R, 4S) -3- (2 ', 2'-dimethyl-1', 3'-dioxolane-4'- yl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -4-acetylthio-2-azetidinone (isomer C) + *: ï: eTI5Å9 cxacocl / pyz «" _____________ + II o N YPO: CH 2 Cl 2 or P 4 * To a solution of 254 mg (0.333 mmol) (4'R, 3S, 4R and 4'S, 3R, 4S) -silver-3- (2 ', 2'-dimethyl-1', 3 '-dioxolan-4'-yl) -1- - (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate-2-azetidinone-4-thiolate (isomer C) in 15 ml of dichloromethane containing 100 μl (1.24 mmol; 3.72 equivalents) of pyridine was added at 0-50 71 μl (1.0 mmol; 3.0 equivalents) of acetyl chloride.

The mixture was stirred for 40 minutes at 0-50. After filtering the precipitate over celite, the filtrate was washed successively with brine containing 1.25 ml of 1N hydrochloric acid, a saturated sodium bicarbonate solution and then brine, dried over sodium sulfate and evaporated to give 200 mg of an oil which was crystallized from Et 2 O to give 155 mg (0.222 mmol; yield 66.7%) of the title compound as white crystals; lnmr (cncly å = 1.23 (s, ai-Me), 2.20, 2.33 (25, -sAc) and 7.2-8.3 ppm (m, aromatic. Hs): ir (nujol) 'Û max: 1750 (-lactam and ester) and 1690 cm -1 (thioester) An analytical sample with a melting point of 177-80 was obtained by crystallization from CH 2 Cl 2 -Et 2 O. Anal Calcd for C 37 H 35 N 2 O 8 PS: C 63.63, H 5.05, N 4.01, S 4.59; Found: C 63.34 , H 5.32, N 3.83, S 4.31; Rf 0.62 (EtOAC) .85 454 779 (MR, SR, 65 and 4 'S, 4S, SIU-p-nitrobenzyl-δ- (Z', 2'-dimethyl- 1 ', 3'-dioxolan-4'-yl) -2-methylpenem-3-carboxylate (isomer C) α-: I / SAC column 5-Ocrylic acid: 0: PNB A suspension of 443 mg (0.634 mmol) (4'R, 3S, 4R and 4'S, 3R, 4S) -3- (2 ', 2'-dimethyl-1', 3'-dioxolan-4'-yl) -1- (p-nitrobenzyl) 2 "-Triphenylphosphoranylidene-2" -acetate) -4-acetylthio-2-azetidinone (isomer C) in 70 ml of toluene was refluxed for 6 hours under nitrogen. Evaporation of the solvent gave a white solid which was purified by column chromatography ( S102 10 g; eluent 10% Et 2 O in benzene) to give 247 mg (0.57 mmol; yield 92.7%) of the title compound as a white solid; * Hm (cøcig) s = 1.42 (an, s, as-ne), ma un, s. Z-CHB). 3-8-4-5 MH, m, H-s. 11-43 n-sw, s.o2-s.2s-s.:as.s7 (za. Na: yp. -Ocaziry, s.s1 (15, a, J-1.a az. H-sl, 7-52-7-67-8-12'5-27 PP "(4H, A2'B2 ', azomamophysrh in: (nujol) VN; 1750 (afïabtam fi __ 1700 cm-1 (eszer) An analytical sample with melting point 167 -80 was obtained by crystallization from CH2Cl2-Et2O; w (atom xmax =: ss (z ia.oco> and na nu -9 »c0> - Aa = Ber f-for ca N os = c 54.28, H 4.79, N 6.66 , s 1.63; (* '°':>: ^ ^ 192027 found: 54.15, H 4.78, N e.s4, s 7.64; n: 0.62 Benzen-nzo fl u). (4'R, 5R, 6S and 4'S, 5S 6R) -6- (2 ', 2'-dimethyl-1', 3'-dioxolan--4'-yl) -2-methylpenem-3-carboxylic acid (isomer C) 741: .5 CF a I / aa-c ns i I 0%; / 3 i vi * Allow CO Prra 454 779 ae A solution of 195 mg (0.464 mmol) (4'R, 5R, 6S and 4'S, 5S, 6R) p-Nitrobenzyl 6- (2 ', 2'-dimethyl-1', 3'-dioxolan-4-yl) -2-methylpenem-3-carboxylate (isomer C) in 20 ml THF was mixed with ml Et2O , 20 ml of water, 39 mg (0.46 mmol) of sodium bicarbonate and 200 mg of 10% Pd-C (Engelhard) The mixture was hydrogenated for 4 hours at room temperature at a pressure of 2.4 x 105 Pa. After removal of the catalyst (over celite), the aqueous layer was washed twice with ethyl acetate, saturated with sodium chloride, acidified with 0.47 ml of 1N hydrochloric acid and then immediately extracted with 3 x 20 ml of ethyl acetate.

The extracts were washed with brine and dried over sodium sulfate and evaporated to give 94 mg of a yellowish solid which was rinsed with pentane to give 89 mg (0.3l mmol; yield 67%) of the title compound. as a yellowish solid with a melting point of 132 ~ 3 °; Rf 0.60 (acetone: HOAc = 5: 0.7); 7 'mw (cx1§ &; 1.: 1, 1.4: (su, 25, ai-ne), 2.36 (an, 5, 2-ca3>. 3.9-4.6 (au, m. H-6, H- 4 ', a-s') 5.59 ppm (la. A. J-1.7 Hz, H-51: ir (nujoll v¶ax 1 l 1760 (ß-labtam), 1660 cm- ((2023): UV (EtOH ) Ämax: 309 (E 6300), 263: nu (z 21800).

Example Gel 14 (4'S, 5R, 6S and 4'R, 5S, 6R) -6- (2 ', 2' - dimethyl-1 ', 3'-dioxolan--4'-yl) -methylpenem-3-carboxylic acid ( isomer B) 87 454 719 (4'S, 35.4R and 4'R, 3R, 4S) -3- (2 ', 2' - dimethyl-1 ', 3'-dioxolan--4'-yl) -4- trityltio-2-azetidinone (isomer B) The title compound was prepared as described in Example 13 for "isomer C" starting from 14.4 g (25.8 mmol) (4'S, 3S, 4R and 1'R, 3R, 4S) -1- (t-butyldimethylsilyl) -3- - (2 ', 2'-dimethyl-1', 3'-dioxolan-3'-yl) -4-trityltio-2-azetidinone (isomer B) m.p. 1550 (CH 2 Cl 2 -Et 2 O) in a yield of 10.8 g (24.3 mmol; 94.1%); Rf 0.24 (hexane: ethyl acetate = 2: 1); (cocls) = 1.37, 1.40 (sn. 25, ai-Mex, 2.23 (1H, (id, J3-4 = 2.S H2, ISHZ, H-3), 3.7-4.5 MH. m. H-4 ' , H-5'.NH).

Ja-4 '4.50 (1H, d, JILSHá, H-á), 7.l-7.6 ppm (155, m, arcmat. H5), - ir 3110 (Na), 1745 = m'1 C 72.78, P1 Öfll , N 3.14, S 7.20: fUnn-C 72.16, H 6.11. N 3.14, S 7.17. (4'S, 3S, 4R and 4'R, 3R, 4S) -3- (2 ', 2'-dimethyl-1', 3'-dioxolan--4'-yl) -1- (p-nitrobenzyl * 2 "-hydroxy-2" -acetate) -4-trityltio- -Z-azetidinone (mixture of epimers at C-2 ") (isomer B) 454 779 e 88 The title compound was prepared as described in Example 13 for "isomer C" starting from 10.8 g (24.3 mmol) = 'S, 3S, 4R and 4'R, 3R, 4S) 3- (2', 2'-dimethyl-1 ', 3'-dioxolane -4'-yl) -4-trityltio-2-azetidinone (isomer B) 15.8 g of product (24.1 mmol; 99.3%) were obtained in a yellowish foam farm: Rf 0.29 and 0.22 (benzene: Et 2 O + 1: 1); V »'umz tcucll) 6 = 1.28, 1.34 (zs, di-Me) 3.4-4.4 (m, R-3. H-4', n-s ', H-2 ", oH). 4.39, 4.5: (2d, J-2Hz. 8-11) - 5.15, 5.25 (2s, OCH2Ar), 7.1-B.3 ppm (m, aromaz. As), 1: (pure) vmax = 3440 (br, ou), 1760 (c-ox, 1s2o, 1:50 cm-1 (NO2). ~ (4'S, 3S, 4R and 4'R, 3S, 4S) -3-2 ', 2'-dimethyl-1' (3'-dioxolan--4'-yl) -1-nitrobenzyl-2 "-chloro-2" -acetate) -4-trityltio-2-azetidinone (mixture of epimers at C-2 ") (isomer B) THF The compound of the title compound was prepared as described in Example 13 for "isomer C) starting from 14 ° C .pyr 571'pyr 571 '__.___ 2 _.___, 51- N on ON \ v / cl IC ° 2?" B cozvua 9 g (22.8 mmol) (4'S, 3S, 4R and 4'R, 3R, 4S) -3- (2 ', 2'-dimethyl-1', 3'-1 ', 3'-dioxolane d'-yl) -1- (p-nitrobenzyl-2 "-hydroxy-2" -acetate-4-trityltio-2-azetidinone (isomer B) (mixture of epimers at C-2 "). obtained 14.1 g of product (20.9 mmol; 919%) as a yellowish foam; Rf 0.53 (benzene: Et 2 O = 3: 2); m 'amz (cvc13> 5; 1.3s. 3.29) .ss. di-Me), 3.4- ~ '.. s (m, m, 2-1-3, ä-fx flfl- SW. 4.57 (in, d, 5 = 3'r:. ~., 3- 43, .13 (s. 3-3), 5.27 (s, OCHZM), 7.143.3 ppm (LSE, s. A: c:. ~ A :. í-Isä: lar (vènt ) vmax: 1780 cm-1 (S-labtam. escer). 89 454 779 (4'S, 3S, 4R and 4'R, 3R, 4S) -3- (2 ', 2'-dimethyl-1', 3'-dioxolan--4'-yl) -1- (p- nitrobenzyl-2 "-triphenylphosphoranilide-2" -acetate) -4-trityltio-2-azetidinone (isomer B) cozvo CO PNB The title compound was prepared as described in Example 13 for "isomer C" starting from 14 0 g (20.8 mmol) (4'S, 3S, 4R and 3'R, 3R, 4S) -3 ~ (2 ', 2'-dimethyl-1', 3'-dioxolan-4'-yl ) -1- (p-nitrobenzyl-2 "-chloro-2" -acetate-4-trityl-thio-2-azetidinone (isomer B) (mixture of epimers at C-2 ").

4.64 g of product (5.16 mmol; 24.8%) were obtained, m.p. 190 DEG-95 DEG (sonication; cn2c12-st2o); * amf a = 1.12, 1.20, 1.27. 1.35 (as, ai-ne), 1 »~ 7.0-8.l ppm (m, aromat. Hs): i! lCš-šzClz) Vmax: 1750 cm- (g-labtam es: er>; Anal. Calc. for ^ c54n47N2o7Ps = c 72.14, H 5.27, x 3.12, s 3.57; fU flfl @ t1c 71.90, H s.sv, N 3.01 , s 3.56; af o.21 (ben5en) s; 2o = 1 = 1). 1'S, 3S, 4R and 4'R, 3S, 4R) -Silver-3- (2 ', 2'-dimethyl-1', 3'- -dioxolan-4'-yl) -1- (p -nitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone-4-thiolate (isomer B) 7Lr S71: Ü: A0 q \; l 1 Agso_-py: '“--T / _' 0 / -N \ ï7P $ 3 neon _ 0 u \ T? Pó3 CO2FÄÉ »CO p- * B The title angina compound was prepared as described in Example 13 for" isomer C "starting from 1.00 g (1.2) 45 mmol (4'S, 3S, 4R and 4'R, 3S, 4R) 3- (2 ', 2'-dimethyl-1', 3'-dioxolan-4'-yl) -1- ( p-nitrobenzyl) -2 "triphenylphosphoranylidene-2" -acetate) -4-trityltio-2-azetidinone (isomer B). 580 mg of product (0; 760 mmol); 67.8%) with a melting point of 129-1350 ( The solubility is (nujoi) J max = 1745 if * (β-mcfam, β-ester). (4'S, 3S, 4R and 4'R, 3R, 4S) -3- (2 ', 2'-dimethyl-1' , 3'-dioxolan-4'-yl) -1 - (- nitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -4-acetylthio-2-azetidinone (isomer B) 3 in SAg Såc ____ 1 _________ + CH COCl The compound of the title compound was prepared as described in Example 1: P 2 O 2 CO 2 PNB PNB or 13 for "isomer C" starting from 2.46 g (3.22 mmol) (4'S, 3S, 4R and 4'R, 3R, 4S) of silver 3- (2 ', 2'-dimethyl-1', - 3'-dioxolan-4'-yl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone-4-thiolate (isomer B). The product was purified by column chromatography (SiO 2, 32 g; eluent 10% -50% ethyl acetate in dichloromethane = 1: 1); * amx (coc13> ó = 1.23, 1.27. 1.30 (Bs, di-He), 2.22, 2.33 (25, SAcDI LZ-B.) ppm (m, arcmat. 55): ir (Moi) vmx 1755 (B- lactam, escer), 1695 cm-1 (6 ioester). (4'S, 5R, 6S and 4'R5S, 6R) β-nitrobenzyl-6- (2 ', 2'-dimethyl-1', 3'-dioxolane -4'-yl) -2-methylpenem-3-carboxylate (isomer B) &quot; for "isomer C" starting from 200 mg (0.286 mmol) (4'S, 3S, 4R and 4'R, 3R, 4S) 3- (2 ', 2'-dimethyl-1'-3'-dioxolane-4 '-yl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -4-acetylthio-2-azetidinone (isomer B) 64 mg of product (0.5 mmol) were obtained; 53%) with melting point 1s1-2 ° (cnzciz / Etzon af o.ev (benzene = 2: 20-1 = 1); 'amz (cnc13) 6: 1.29, 1.38 (sa, 25, ai-new, 2.30 (an, S, 2-cx3), fl :. e-4.4 (ax, m, ns. N-4'.n-š '>, s.oo-s.1e-s.2a-5.46 <4u , Aaq, -OCrízltrL 5.47 (1H, d, J-LSHz, HS), E7.42-7.5S-8.05 ~ BJS ppm (48, ll A 's'. .F ° mi =. Ns). 1: ( rent) vmax = ives cm '<8-1ae: = m), 1110 cm' 2 2 (e see:); av (ston) Amax:: se (: 13,300) 314 nu fc 9.700): Anal. Bg, -_ f_ CIQKZON2O7S: C 54.281 51 4.79, N 6.66, S 7.63rfUp fl ef; C 54.00. H 4.75, N 6.63, S 7.61. (4'S, 5R, 6S and 4'R, 5S, 6R) -6- (2 ', 2'-dimethyl-1', 3 '-dioxolan--4'-yl) 2-methylpenem-3-carboxylic acid (isomer B) CH H z / Pd-C H 3 -_ ~ * - * - “- * N 3 COZHÉB CO2H The title compound was prepared as described in Example 13 for" isomer C "starting from 79 mg ( 0.9 mmol) (4'S, 5R, 6S and 4'R, 5S, 6R) -p-nitrobenzyl-6- (2 ', 2'-dimethyl-1', 3'-dioxolan-4'-yl ) -2-methylpenem-3-carboxylate (isomer B). After recrystallization from dichloromethane-pentane, 9 mg (0.032 mmol; 17%) of product were obtained. of o.s:; 'amr (cac13> § = 1.35, 1.44 (sn, 25, di-nen, 2.21 -ss. S, 2-cn3>. 3.5-4.5 (415, m, HG, H-4', H-5 '), 5.56 ppm (li-l, brs, 5-51: rr (fênt) Vmax: vas = m ° * <5-; ar == m); uv <: = o fi) Añax: sov 4: azccwl. 454 779 92 Exemgel 15 (1'R, 5R, 6S and 1'S, 5S, 6R) -6- (1'-hydroxy-2'-methoxymethoxy-2'-ethyl ) -2-ethyl) -2-methylpenem ¥ 3-carboxylic acid (isomer C) 98 N VW. st * O: H (1'R, 3S, 4R and 1'S, 3R, 4S) -3- (1 ', 2'-dihydroxyethyl) -1-p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -4-acetylthio-2-azetidinone (isomer C) gu ~ _ A: __ FIK / t., SAC Q »/}; l :: T” § TFA-nzo lïïr N 6 N P4 0 \ fi% 2 3. A solution of 472 mg (0.676 mmol) (4'R, 3S, 4R and 4'S, 3R, 45) * 3- (2 ', 2'-dimethyl-1', 3'- dioxolan-4'-yl) -l (p-nitrobenzyl-2 "- -triphenylphosphoranylidene-2" -acetate) -4-acetylthio-2-azetidinone (siomer C) in 1.0 ml of trifluoroacetic acid and 0.1 ml of water were obtained stand 30 minutes at room temperature. The mixture was added dropwise to a cold solution of 2.5 g of sodium bicarbonate in 50 ml of water and extracted with 3 x 20 ml of dichloromethane. The extracts were washed with a saturated sodium bicarbonate solution and then brine, dried over sodium sulfate and evaporated to give 458 mg (0.695 mmol; 100% crude yield; 97.3% purity) of the title compound as a crude product. form of a yellowish foam; * amz (cnc13) 5: 2.zo. 2.22 (25. saa), '1 2-a 3 = ~ a am araaat. H51; . :( çent) v = ez4zo'fo fi ;. 1145 '' J '' max (3-: a == am, @ S = e: H isen = m'1 (ïí08St8F) af o.1s e = c¿ = \. U; 'I m ss 454 779 ( 1'R, 3S, 4R and 1'S, 3R, 4S) -3- (1'-hydroxy-2'-methoxymethoxy-1'-ethyl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" - -acetate) -4-acetylthio-2-azetidinone (isomer C) no 9 "ga i SÅ / O \ / Ö ^ / -, -e /:; I: jT¿ C 5; cx2ocH3-dine: ylanilin ç [: ïrnSA: N P93 cuzcxz 0 n \\ ¿; @ 3 Y f 'i' to mm oamm 55 r- 2 To a solution of 291 mg (0.430 mmol; purity 97.3% (1'R, 3S, 4R) and 1'S, 3R, 4S) -3- (1 ', 2'-dihydroxyethyl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -4-acetylthio--2-azetidinone (isomer C) and 55.2 mg (0.442 mmol; 4 drops) of bromomethyl methyl ether in 8 ml of dichloromethane were added at 0 DEG to 58.8 mg (0.483 mmol; 5 drops) of N, N'-dimethylaniline and the mixture was stirred for 20 hours at room temperature. a further 2 drops of bromomethyl methyl ether and 2 drops of N, N'-dimethylaniline were added and the mixture was stirred for a further 4 hours, it was then diluted with dichloromethane and washed successively with 1N hydrochloric acid, one m saturated sodium bicarbonate solution and brine, dried over sodium sulfate and evaporated. The obtained crude product was purified by high pressure liquid chromatography (SiO 2, eluent ethyl acetate) to give 31 mg (0.186 mmol; yield 42.2%) of the title compound as an oil; of 0.24 G: oA @); * fi m1 '3.30 (5th and). 4.52 (s.-OCH20-L 0Ch 7-4-9-3 PP "lm '° f °" a “- = 557; if re .. _ - 4 (ntkmax: 3420 (GH), 1755 lar, S- lactam and ester) OCh -590 CT "(thioester) 454 779 94 1 '(1'R, SR, 6S and 1'S, SS, 6R) -p-nitrobenzyl-6- (1'-hydroxy-2'-methoxymethoxy -2'-ethyl) -2-methylggnem-3-carboxylate gu 9 "sn / ° 5,) l \, P \ _ / ~. | Ca, toluene | N 3" Y "° = ~ ^ ° 0 2 COZPNB A solution of 167 mg (0.238 mmol) (1'R, 3S, 4R and 1'S, 3R, 4S) - 3- (1'-hydroxy-2'-methoxymethoxy-1'-ethyl) -1- (p-nitrobenzyl-2 "- -triphenylphosphoranylidene-2" -acetate) -4-acetylthio-2-azetidinone (isomer C) in 30 ml of toluene was refluxed for 8 hours under nitrogen. Evaporation of the solvent in vacuo gave an oily residue which was purified by high performance liquid chromatography (SiO ethyl acetate) to give 68 mg (D, 16 mmol; yield 67) of the title compound as an oil. of o.s1 æ = oAc1. o.1s abensen, a: 2o = 1 = z); * nmz (cnc1š) n6 = 2.38 (an. s. 2-cxsw,: .as (in, bf, o fi ;, 1.40 (sa. S, ocnap, 3.6-3.8 (28, m, H-2 '), 3.90 (IE, then, J, - _5 = 2H :, J 6_1, -452. A-5) . 4.1e (la, m, H-1 '), 4.67 (za, 5, -ccazo-). 5.0: -š.z7-s .: as.e2 (zu, Aag. Ocnzafy, .65 (lä, d, J = 2Hz, H-5), 7.55-7.70-8.15-8.30 ppm (GH, A 'B ', azomat. 2 2 ns>; 1: (Fent) vmax = saso (cs).: vas as-zaezamm. 1v1o <@sta:>, xszo = m “ï, 11: nu (c e1oæ>; Ana; Calculates for cl5x2 ° u2o8s = c 50.94. A 4.75, s s.so; F3H1 fl Gï c s1.1 :, a 4.71, x a.za. (1'R, 5R, 6S and 1'S, 5S, 6R) - 6-1'-hydroxy-2'-methoxymethoxy-2'-ethyl) -2-methylpenem-3-carboxylic acid (isomer C) OH and / K / ° / = ~ -. H 7,? EC or Al_h. 3 ___ = ________ + N -3 O2? NB CO25 A solution of 51 mg (0.12 mal) <1'R, sR, 6s and 1's, 5s, sR) -p- lv 454 779 95 -nitrobenzyl-6- (1'-hydroxy-2'-methoxymethoxy-2'-ethyl) -2-methyl-penempenem-3-carboxylate (isomer C) in 10 ml of THF was mixed with 10 ml of Et 2 O, 10 ml of water, 10 mg (0.2 mmol) sodium bicarbonate and 50 mg 10% Pd-C (Engelhard) It was hydrogenated at room temperature for 3 hours at a pressure of 2.2 x 105 Pa.

After filtering the catalyst over celite, the separated aqueous layer was washed 3 times with Et 2 O and saturated with sodium chloride. The aqueous phase was acidified at 0 DEG C. with 1.2 ml of 0.1N hydrochloric acid and extracted immediately afterwards with 3 x 15 ml of ethyl acetate. The extracts were washed with brine, dried over sodium sulfate and evaporated to give 22 mg of a yellowish solid, which was rinsed with a small amount of Et 2 O to give 20 mg (0.069 mmol (yield 58%)) of the title the compound as a light yellow solid with a melting point 137 ~ 8 ° (decomposition). * umr (nnso-ae) 6: 2.25 (aa. s, 2-cnai. 2.27 (BH, s, OCH 3). a.4a12n, a, J = e.2H =, 2'-H). a.e1 cin, aa. as 5-1.vn =, J6_1 .-:.: Hz. sH), «.se (IH, s. - OCHZO-L '5.55 ppm (1H, d. J = 1-7 Hz. S-Hh i: (KBr) Vmax = 3410 (on), 1755 (β-lattam), 1655 cm -1 (CO 2 H); uv ( Enea) Amax =: os (c saoo) and 262 mu (e 4200), Exemgel 16 (1'S, 5R, 6S and 1'R, 5S, 6R) * 6 ~ (1'-hydroxy-2'-methoxymethoxy-2 '- -ethyl) -2-methylpenem-3-carboxylic acid (isomer B) OH (N 2 O 2 N 2 O 2 O 2 N 2 O 2 O 2) 2525 96 (1'S, 3S, 4R and 1'R, 3R, 4S) -3- (1 ', 2'-dihydroxyethyl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" acetate) -4-acetylthio-2-azetidinone (isomer B) The title compound was prepared as described in vits in Example 15 for "isomer C" starting from 1.03 g (1.47 mmol) (4'S, 3S, 4R and 4'R, 3R, 4S) 3- (2 ', 2'-dimethyl-1', 3 '-dioxolan-4'-yl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -4-acetylthio-2-azetidinone (isomer B). 970 mg (1.47 mmol; 100%) of product were obtained as a yellowish foam; _ ~ [mm mm1n6 = 2.20, 2.32 (25, -sne »7.3-8-2 Ppm (m- = f ° fi af- HS) # if (fe fl t) ï '-1 lv = z <1o (on), 1150 (S-lactam, eszeryl .sso = m (thioester). Λ max of 0.16 (Emm) - (1'S, 3S, 4R and 1'R, 3R, 4S) -3- (1'-hydroxy-2'-methoxymethoxy- 1'- -1'-ethyl) -1- (p-nitrobenzyl'2 "-triphenylphosphoranylidene-2" -acetate) -4-acetylthio-2-azetidinone (isomer B) BOJ. SAC N: AC '"" The title compound was prepared as described in Example 15 for "isomer C" starting from 485 mg (0.736 mmol) (1'S, 3S, 4R and 1). R, 3R, 4S) 3- (1 ', 2'-dihydroxyethyl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -4-acetylthio-2-azetidinone (isomer B 205 mg (0.292 mmol; 39.6%) of product were obtained in the form of an oil; m '97 454 779 * nmr (cnc13> 6: 2.22, 2.33 (25, sA =>. 3.32 (s, ocus)) , 4.57 (;, »ocu2o -> / 1.2-a .: ppm (m. =: ° ma =,) ir (ren¶) u¿ax = sazo (on), ivss ts-1ak @ am, eszezb 1690 tioester Eph 0.32 (EtOACJ. (1'S, 5R, 6S and 1'R, 5S, 6R) -p-nitrobenzyl-6- (1'-hydroxy-1'-methoxymethoxy-2'-ethyl) -2-methylpenem -3 -carboxylate OH H 5A: / D __., toluene -HQ '---- + 0 N f P $ 3 Å CHB o -' ozmæ PNB 2 The title compound was prepared as described in Example 15 for "isomer C starting from 205 mg (0.292 mmol) (1'S, 3S, 4R and 1'R, 3R, 4S) 3- (1'-hydroxy-2'-methoxymethoxy-1'-ethyl) -1- (p -nitrobenzyl-2 "-triphenylphosphanylidene-2" -acetate) -4-acetylthio-2-azetidinone (isomer B) and 10 mg (0.09 mmol) of hydroquinone. 38 mg (0.090 mmol; 31%) of product, m.p. 152-40; R: 0.2: (benzene = z: 20 = 1 = 1); Amr zcsc13> 5: 2_37 (35, 5, 2- (253), 3.40 (BH. S. GCI-la), 3.4-3.9 (BH, m. 3-6, Hg-qf 4.15 (La, m, H-1 '). 4.e7 (za. S. -Ccazo-). S.; O-5.27-s.: 9-s.sa H) - m (ZZ-i, ABq, -CCHZÅIL 5.67 (1H , d, J = l.5 H2 .. HS), 5.55-5.1 a.2v »Dm (sä) A 'a_', af ° ma = .- a); 1: ica cl muiz) v = 3:10 ica). "i 3 2 2 max 2 ives (5-zahuam), 1700 cm ° * (es; e :); uv ars: -z = ca-1 = 1> x =: ss NEX (E IOÅÛO), 31-1 mU (E 7800) 454 779 98 (1'S, 5R, 6S and 1'R, 5S, 6R) -6- (β-hydroxy-Z'-methoxymethoxy-ZH-ethyl) -2-methylpenem-3-carboxylic acid ( isomer B) OH CH ßvx / L. s H "M ßvk / L. s WB ____ 2 ..__: -:> n3 OZPNE CO 2 The title compound was prepared as described in Example 15 for "isomer C" starting from 36 mg (0.08S mmol) (1'S, 5R, 6S and 1 R, 5S, 6R) - "p-Nitrobenzyl-6- (P-hydroxy-2'-methoxymethoxy-Z '-ethyl) -Z-methylpenem-B-carboxylate (isomer B) (36 mg, 0.085 mmol 7.5 mg (0.026 mmol;%) of product were obtained in the form of yellowish crystals. * Mu- (cncia) 6: 2.36 (an. S. Z-c fi3). 3.39 (BH. S. OCHS), 3 -6-3-9 (1H. M. Xa. H-2 '), 4.15 (m, m, fi- r), 4.55 fï fl- S- 0CH 2 OH ~ 5-67 ppm (1H. D. J = 1-4 Hz, H-5): ir (CR Cl) v 2 2 max J. nas (s-iabcam), xsvs en 'ccozm; uv mom xmax =: os u: zsoo), 263 m fl (E2900).

Example 17, Z-Benzimidoylaminomethylpenexene-3-carboxylic acid Ü ”-rff NJ G12 -nta- c - m2 G \ C005 A. wßöf-r-cäzcošxa * + (c0c1) 2 (men: * a __ :: -: man - f / k av: = 2 // -'- '\ I' \ (I) (31) 99 454 779 To a suspension of 0.38 g (0.0015 mol) of sodium 3-benzyl-1,2 , 4-oxadiazol-5-one-4-acetate (I; K. Takács and K. Harsänyi, ëeš. Lgå (1970) 2330) in 10 ml of methyl chloride containing 2 drops of DMF was added at room temperature 0.13 ml (0.0015 mol) of oxalyl chloride, which caused the mixture to foam, The reaction mixture was stirred for 1 hour at room temperature, the sodium chloride formed was removed by filtration and the filter cake was washed with several small portions of methylene chloride, the solution of the acid chloride (II) was used directly.

B '(II) Saw a cl s \\ E // QHä \\ 2 2 fk \ _ +41 »OH a ß <eQ I XF 3 vil: ozr fl a OEPNB (III) (IV) A solution of 1.0 g (0.0015 mol) of compound III and 0.12 ml (0.065 mol) of pyridine in 10 ml of methylene chloride under a nitrogen atmosphere were cooled to 40. The solution of acid chloride II was added in one portion to the solution of compound III and the reaction mixture stirred for 5 minutes at 40 and then 1.5 hours at room temperature. A thick precipitate formed in the reaction mixture. The mixture was filtered and the filtrate was diluted with methylene chloride to a volume of 70-90 ml. The organic phase was then washed successively with 70 ml of 0.1N hydrochloric acid, 80 ml of 1% sodium bicarbonate and 80 ml of water. The methylene chloride phase was dried over magnesium sulfate.

The solvent was removed under reduced pressure, and the residual oil was chromatographed on Mallinckrodt Silica CC-7 silica gel using chloroform as eluent to give 0.4 g (30.5%) of compound IV as an oil. Infrared and nuclear magnetic resonance spectra were consistent with the structure of compound IV. 4s4i779g IW c. (Iv) S 22leai_i / H5 \ fl -._. C fl2 / V \\ âterkxps- 0 = <i __ M fl n fi w ozrns (V) A solution of 0.4 9 (0.00045 mol) of compound IV in 50 ml of toluene was refluxed for 4 hours. The solvent was removed under reduced pressure and the residue was chromatographed on Mallinckrodt SilicaAR CC-7 silica gel using% ethyl acetate in methylene chloride as eluent to give 0.15 g (66.6%) of compound V as an oil which solidified. . Infrared and nuclear magnetic resonance spectra were consistent with the structure of compound V.

Anal. Ber. for C H N O S: C 55.86; H 3.67; N 11.33. Found: C 56.17; H 3.76; N ll, 23. xx 'H cx 2 å \\ iï / hxæ io: Pa / c: ácí /' “H2®% H D. 4v) A solution of 0.135 g (0.00027 mol) of compound V in 40 ml of tetrahydrofuran and 40 ml anhydrous diethyl ether was added to a catalyst consisting of a slurry of 10% palladium on carbon in 40 ml of water under a nitrogen atmosphere. The resulting mixture was hydrogenated for 3.5 hours in a Parr hydrator at room temperature at an initial hydrogen pressure of 3.6 x 105 Pa. Hydrogen uptake was 3.1 x 104 Pa. The catalyst was removed by filtration and the filter cake was washed well with water. Additional diethyl ether was added to the filtrate and the phases were separated. The aqueous phase was extracted 3 times with diethyl ether. Thereafter, the aqueous phase was concentrated to dryness under reduced pressure. The residue was chromatographed using high pressure liquid chromatography to give 0.050 g (58%) of the title penic acid, m.p. 156 DEG-173 DEG (decomposition). Infrared and nuclear magnetic resonance spectra were consistent with the structure of the desired product.

Anal. Ber. for C 15 H 15 N 3 O 3 S-5H 2 O: C 52.31; H 5.27; N 12.20.

Found: C 51.64; H 4.95; N 12.31.

Biological Data Representative compounds of the present invention were tested for in vitro antibiotic activity against a variety of microorganisms. After dissolving in water the compounds listed in the table below and diluting with nutrient broth, the activity was measured by determining the minimum inhibitory concentration (MIK) in ug / ml with respect to the indicated microorganisms by overnight incubation at 370 using the tube dilution method. . The following results were obtained. 454 779 102 MIK in EE / ml Compound (Example no.) Organlsm 1 Streptococcus pneumoniae 125 A958S I Streptococcus pyogenes, l25 A9604 “Staphylocbccus aureus 1 A9537 Staph aureus +50 \ 3 Serum A9S37> Staphylococcus aurecous' A4 32 faecalis 125 A20688 Escherichia coli 3 Al5ll9 Escherichia coli 2 Å2034l ° l Klebsiella pneumoniae 125 Al5l30 Xlebsíella species 4 A20468 Proteus mirabílis 3 A9900 Proteus nirabim 63 A97l6 Proteus morganii 53 AISISB 'AoteIS maracacea39 Pseudomonas aeruginosa 125 A9S43A Pseudomonas aeruginosa> L25 A2l2l3 Hemophilus influenzae - Å9833 Haemophilus influenzae - A2lS22 Bacteroides fragílís - A2093l Bacteroides fragilis Å20929 M u: vx 103 MIK i Gg9gmml (45 A953? Staph aureus +50! Serum A953? Staphylococcus aureus A9606 Staphylococcus aureus AISO97 Streptococcus faecalis A20688 Escherichia coli Al51l9 Escherichia coli A2034l-1 Klebsiella pneumoniae Al5l30 Klebsiella species A20468 Proteus mirabilis A9900 Proteus vulgaris A97l6 Proteus morganii Al5l53 Proteus rettgeri A2l203 Serratia marcescens A200l9 Enterobacter cloacae ABSS9 Enterobacter cloacae A96S6 Pseuåomonas aeruginosa A9843A Pseudomonas aeruginosa A2l2l3 Eemcphílus influenzae 59833 Haemophilus influenzae A2lS22 Bacteroides fragilis A2093l Bäcteroides fragilis A20929 _: - 125 63 63> l25 125 125 .0l6 .06 .li Is 454% 779 104 MIK i Eg / ml Organism streptococcus pneumoniae A95895 " aureus +50! Serum A953? Staphylococcus auzeus A9606 Staphylococcus aureus AlS097 Streptococcus faecalis A20688 Escheríchia coli Al51l9 Escherichia coli A2D34l-l Klebsiella pneumoníae Al5130 Klebsiella-species A2046B ? R0teuS: ettgeri A2l203 Serratia marcescens A200l9 Enterøbaccer cloacae Enterobacter cloacae A9659 ASSSG Pseudomonas aeruginosa aerugíncsa Ä9843Å Pseuöomonas A2l2l3 Hemophilus influenzae A983] Haemophilus influenzae Å2l522 A2093l Bacteroides fragilis Bacteroides fragilis A20929 compound (Example No.) '; Lf25 "í_T9l6 8 .ZS 8 .03 32 63 16 16 en> 1äs> l2S 16 63 63> l2S> 125 125> l2S> l2S> 125 I 63 32 1125 _ 125 gg 63 _ 63 15 125> l2E 125 125 125> 125 125, ¿25 m 105 MIX i Eg / ml Compound Oruanísm Pseudomonas aeruginosa AZOS99 Pseudomonas aeruginosa A992S "Pseudomonas aeruqinosa A20229 Proteus specíes A20543? roteus mirabilis A9715 Providencia atuartii A21205 454 779 (example no.) 7 n Eg / m 16 Streptococcus pneumoníae Å958S Streptococcus pycgenes 16 A9604 Scaphylococcus aureus 32 A9537 Staph aureus +50 \: G3 Serum A953? Staphylccoccus aureus> 125 A9606 Scaphylococcus auzeus> 125 _ Al5097 Screpcococcus faecalis Å20688 Escherichia coli Al5ll9 Escherichia coli A2034l-1 Klebsiella pneumoniae AlSl3D Klebsiella species A20468 Proteus mirabilis Ä9900 ~ Proteus vulgaris - A97l6 Proteus morganii 125 AlSlS3 Proteus rettgeri 125 A212o3 Serratia marcescens> l25 A200l9 Encerobacter clcacae> l2S A9659 Ente: cbacter cloacae> 12S A96S6 Pseuéomonas aeruginosa Å9E43A _5. 2 125 63> l25> l25> l2S 63 Pseuócmcnas aerugínosa A2l2l3 Hamcphilus influenzae A9833 Haemophilus influenzae, A2lS22 Baczeroides fragilís A2093l Bacteroíáes Eragílis A20929 w fm .1 107 MIK i A299A P2A9202 Proteus mirabilis A97l6 Proteus mirabilis A9S55 Compound .å 63 454 779 (example no.) 779 108 (example no.) MIK in Eg / ml Compound Organism Streptococcus pneumoníae A9585 Streptococcus pyogenes A9604 .âtaphylococcus aureus A9537! Scaph aureus + Serum A9S37 Staphylococcus aureus A9606 Staphylococcus aureus Al5097 Streptococcus faecalis A20688 Escherichia coli Al5ll9 Escherichia coli A2034l-l Klebsiella pneumoniae Al5l30 Klebsiella spacies A2D468 Proteus mirabilis A9900 Proteus vulgaris' A955S Proteus morganii AlSlS3 Proteus rectgeri Å2l203 Serratia marcescens A200l9 Enterobacter cloacae A9659 Enterobacter cloacae A9656 Pseudomonas aeruginosa A9B43A Pseušomonas aerugíncsa A2l2l3 Hemophilus influenzae A9833 Haemophilus influenzae A2l522 Bacteroídes fragílis A2093l Bacteroídes fragílís A20929 6 63 125 32 32> l25 63 63 63 32> l2S 63 125> l25 125 125 125 32 32 '\ St \ Acco \ \ \ pyogenes _A9604 'Staphylococcus aureus A953? Snaph aureus + S0i Serum A9537 Staphylococcus aureus A9606 Staphylococcus aureus AISO97 Screptococcus faecalis A20688 Escherichia èoli Al5ll9 Escherichia coli A2034l-l Klebsiella pneumoniae AlSl30 Xlebsíella species A20468 Proteus mirabilis A9900 e Proteus vulgaris A9555 Proteuszmorganíi Al5lS3 Proteus rettgeri A212o3 Serratia marcescens A200l9 Enterobacter cloacae A9659 Enterobacter cloacae A9656 ? seudomonas aerugínosa à9843A Pseudomonas aeruginøsa A212l3 äemophílus influenzae Å9833 Haemophilus influenzae Å2l522 Bacteroídes fragílis A2093l Bacteroides fragílís A20929 454 779 ml Föfe fl i fi (exem l25 el 125 16 16 M M exem el nr) Organlsm Å Streptococcus pneumoníae _504 ABSBS .008 Streptococcus pyogenes _0D4 _Å9604 'cos Staphylococcus aureus _008 Ä9537 _0gg Staph aureus + 50 $ _05 Serum A953? _95 Staphylococcus aureus _05 ÄÉSOG V _05 Staphylococcus aureus .06 AlS097 .25 Streptococcus faecalís _5 A20688 _5 Escherichia coli _13 AlSll9 _25 Eschezíchía coli <.2S A2034l ~ l .l3 Klebsiella p5. <.25 A9900 -25 Proteus vulgaris <.25 A2l559. .25 Protéus morganii l AlSlS3 1 Proteus rettgeri <_35 A2l203 .S Serratia marcescens .S Azools -5 Enterobacter cloacae 4 Asess 2 Enterobacter cloacae _5 A96S5 .S Pseudomonas aerugínosa 15 A9a43A 16 Pseuöomonas aerugínosa 53 A21298 A21298 A21298 'Bacteroídes fragilís A209 31 Bacteroiöes fragilís A20929 m; 454 779 (exemgel nr) lll MIK i H9 / ml Förening Or anísm streptococcus pneumonía A9S8S Streptococcus pyoganes A9604 fl scaphylococcus aureus A9537 Staph aureus +50 \ Serum A953? Staphylococcus aureus A9606 Staphylococcus aureus A1S097 Streptococcus faecalis A20688 Escherichia coli Al5ll9 Escherichia coli A2034l-I Klebsiella pneumoniae AlSl30 Klebsiella species A20468 Proteus mirabilis A9900 Proteus vulgaris A2l559 Proteus morganii A1Sl53 PIOt2US rettgeri A21203 Serratia marcescens Å200l9 Enterobacte: cloacae A9659 Enterobacter cloacae A96S6 Pseudomonas aeruginosa Å9343Å Pseudomonas aeruginosa A2l2l3 Hamophílus influenzae A9833 Haemophilus influenzae Å21S22 Bacteroiöes fzagílís A2093l Bacteroiócs fragílís A20929 2 16 32 63 32> 63 16 63> 63 454 779 m 'MIK i Eg / ml Organísm Streptococcus pneumoniae ABSScous4Sus Pus Staph aureus +50! $ Erum'Å9537 Staphylococcus aureus A9606 Staphylococcus aureus, Streptococcus faecalis A20688 AISOS7 Escherichia coli Escherichia coli AlSll9 A2034l-l Klebsiella pneumoniae A20468 AlSl30 Klebsiella species Proteus mirabilis Proteus vulgaris A9900 A2l559 Proteus_morganíi Al5lS3 - Proteus rettgeri Serratia marcescens A2l203 AZOOI? Enterobacter cloacae A9659 Enterobacte: cloacae AQSSS Pseuöomonas aerugíncsa A9B43Å Pseuöomonas aerugínosa A212l3 Hemophílus influenzae A9833 Haemophilus influenzae AZISZ2 Bacteroides fragílís A2093l A3293l Bacteroí29 32 63 63 32 32 63 63 32 ~ am ll3 Organism streptococcus pneumoniae A9585 Streptococcus pyogenes A9604 .Staphy1ococcus aureus A953? staph aureus + 50t Serum A953? scaphylococcus A96D6 aureus Staphylococcus aureus, Streptococcus faecalis A20688 Al5097 Escherichia coli AlSll9 Escherichia coli A20341-1 Xlebsiella pneumoniae Al5l30 K1ebsiella'specíes Å20468 Proteus mirabilis Proteus vulgaris A9900 A2l559 Proteus morganii Proteus rettgeri Ål5lS3 A2l203 Serratia marcescens A200l9 Å9659 Enterobacter cloacae Enterobacter cloacae A96S6 Pseudomonas aeruginosa Pseudomonas aeruginosa A9843A Å2l2l3 Hemophílus ínfïuenzae A9833 Haemophilus influenzae A2lS22 Bacteroides fragilís A2093l Bacteroidcs fragilís A20929 454 779 MIX i ml Förening (example no.) 12. _l_š l_5_ 16 sa 16 4 ïï sa 32 '4 32> s: sa> s> 32 > 32> 63 sa 63> e3> sa ss> s:> ss> sa 63> e3> s:> s3> ea 63 63> s3> s3 sa es> s3> s3 sa> s3> es> s3> s3> s3 es> e3> e: sa> s:> ss> ea> s3> 63> 63> 63> 63> ea es 32 sa> e3> ss> ea es> 63> 63 63> 63> e3 '> ez ss ss sa sz sz sa ss es es sa sa 454 779 1 ”MIK i Eg / ml or anísm Förening (example no.) Screptocoecus pneumoníae - y A9S85 * .S Streptocoocus pyogenes . _A9604 .5 staphylococcus aureul A953? .S Staph auxeus + S0 \ Serum A9S37 15 Staphylococcus aureus Å960G 32 Staphylococcus aureus AISOS7> 63 Snreptococcus faecalís _, A20688> 63 Escheríchia coli AlSll9 63 Escheríchia coli A2034l-I> 53 Aleílíella> 53 AlleSiella pneumonia 63 Proteus vulgaris A2l559 63 P: oceus'morganii Al5153 63 Proteus rettgeri A2l203 63 Serratia marcascens A20019 63 Entarobacter cloacae A9659> 63 Enterobacte: cloacae - A9656 63 Pseudomonas aeruginosa A9843A 63 Pseudomonas Aceail2. 'Haemophilus influenzae A2l522 - Bacteroíöes fragílís A2093l ° Bacteroídcs fragilis Å20929 ll-P 4! A representative compound of the present invention was also tested in vivo on mice and the PD value (the dose of the compound in mg / kg required to protect 50% of the treated mouse against an otherwise lethal infection of a microorganism) is given below. .

S. aureus A 9537 Ant.infecting Number of Be- organisms of be- hand- PD50 S. aureus handl. Compound A 9537 method (mg / kg / treatment) Compound 5 according to ex. 7.8 x 10 2 lM 0.12 The blood levels of mice after intramuscular administration of a representative compound of the present invention were determined and are set forth in the table below.

Blood levels in mice * in pg / ml after intramuscular administration of 40 mg / kg body weight Compound Minutes after administration lo 20 so 45 eo 90 120 Compound en1.e> <. 9 44.7 34.4 23.7 17.6 9.8 3.6 l * Mean value for 6 mice

Claims (3)

454 779 Mg, _ BATENTKRAV Ü? Compounds of formula Y IW X wherein Z is hydrogen or an easily removable ester protecting group and Y is (a) methoxymethoxyhydroxyethyl, in which case X is methyl; (b) formamidomethyl or 2,2-dimethyl-1,3-dioxolanyl, in which case X is alkyl of 1-6 carbon atoms; (c) hydroxy-substituted alkyl having 1 to 6 carbon atoms, in which case X is aminocyclobutyl or (d) hydrogen, in which case X is (i) - (CH 2) PO (O-alkyl) 2, where Q is an integer 1-6 n and alkyl is lower alkyl of 1-6 carbon atoms; ~. ml * vi (ii) - (CH 2) NHOH, where Q is an integer 1-6; n .L ”1 454 779 (iii) - (CH2) n- I wherein Q is an integer 1 - 6; A is B (iv) - (CH 2) OCO (CH 2) NR R, where Q and Q independently of which m A B others are 1 or 2 and R and R are independently hydrogen or alkyl of 1 to 6 carbon atoms; is alkyl having 1 to 6 carbon atoms, phenyl or - (CH) - <§: Ü> where Q is 1 or 2 or 2 m (Vi) (V) - (cnz) NHc (R °) = Nn, where n is a nnal 1 - 6 and Rc a 3 -ca -c - 2 -OCH N 3 and pharmaceutically acceptable salts thereof. 454 779 41% Process for the preparation of a compound according to claim 1, characterized in that in a inert organic solvent at a temperature from just above room temperature to the reflux temperature of the solvent a compound of the formula OY ___ ax NP (Q1 O 3 COZR is cyclized wherein Q is phenyl or lower alkyl, R "is an easily removable ester group and X and Y have the meanings given in claim 1, by methods known per se remove the removable ester group and optionally other protecting groups and if Y is hydrogen converts the product to another desired product, where Y is not hydrogen, by treating said product with a corresponding electrophile in an inert solvent in the presence of a strong base. 3. A pharmaceutical composition having an antibacterial action, characterized in that it comprises as active ingredient a compound according to claim 1 or a pharmaceutically acceptable salt or physiologically cleavable ester thereof, together with a pharmaceutically acceptable carrier or diluent. M