SE464027B - INTERMEDIATES FOR THE PREPARATION OF NEW 2-SUBSTITUTED AND 2,6-DISUBSTITUTED PENEM SOCIETIES - Google Patents

Description

Thus, according to the present invention, there are provided novel penem compounds of the formula SY 0 CO 2 Z wherein Z is hydrogen or an easily removable ester protecting 9ruPPv X is (a) a group of formula (i) -ORa, wherein Ra is hydrogen, - (ii) -CORb, wherein Rb is hydrogen, hydroxy, optionally substituted lower alkyl or optionally ring-substituted phenyl or heterocyclyl, wherein the substituents on the alkyl group are one or more (preferably 1 or 2) of halogen, hydroxy, oxo, carboxy, carb (lower alkoxy), carbamoyl, lower alkoxy, amino, lower alkylamino, di (lower alkyl) amino, lower alkanoylamino or optionally substituted phenyl or heterocyclyl and wherein the substituents on the phenyl or heterocyclyl rings are one or more (preferably preferably 1 or 2) of hydroxy, lower alkoxy, halogen, lower alkyl, halo (lower alkyl), methanesulfonyl, oxo, lower alkylthio, amino, lower alkylamino, di (lower alkyl) amino, lower alkanoylamino, lower alkanoyl oxy, carboxy, carboxy (lower alkyl), sulf or sulfo (lower alkyl), or (iii) -OCORC, wherein R c is amino, lower alkylamino, di (lower alkyl) amino or optionally substituted lower al- (b) (i) (ii) 3,464,027 alkyl , wherein the substituents have the meanings given in (ii) above, or a substituted lower aliphatic, lower cycloaliphatic or lower cycloaliphatic-lower aliphatic group or a ring-substituted phenyl, phenyl (lower alkyl), heterocyclyl, heterocyclic lower alkyl or heterocyclic thio (lower alkyl) group, wherein the substituents for the above aliphatic, cycloaliphatic, phenyl or heterocyclic groups are NR 1 H -CNR R 3 or -N = C-NR R 3, wherein R 1 is hydrogen, lower 2 Alkyl or phenyl and R 2 and R 3 are independently hydrogen, lower alkyl, phenyl or benzyl, -ORd, wherein Rd is amino, lower alkylamino, di (lower alkyl) amino, substituted lower alkyl, lower alkenyl or optionally ring-substituted phenyl, phenyl- (lower alkyl), heterocyclyl or heterocyclic (lower alkyl, wherein substituent the alkyl, phenyl and heterocyclyl groups have the meanings given in (a) (ii), above, (iii) (iv) (v) (vi) (vii) -O (CH 2) n ORr, wherein n is an integer 1-6 and Rr are optionally substituted lower alkyl or optionally ring-substituted phenyl or heterocyclyl, the substituents on the alkyl, phenyl or heterocyclyl groups having the meanings given in (a) (ii) above, -OCORr ' , wherein R r 'is amino, lower alkylamino, di- (lower alkyl) amino or Rr with the proviso that R 1' may not be unsubstituted lower alkyl, -OSO H; S? -OSOZRI, wherein Rr has the meaning given above under (b) (iii), 464 027 (viii) (ix) (x) (Xi) (xii) O -Og (ORe) (ORr), wherein R is lower alkyl and Rr has the meaning given in (b) (iii) above, -S (O) nRd, wherein n is 0, 1 or 2 and Rd has the meaning given in (b) (ii) above or. §R4 is, in case n = 0, -C-NRSRS, where R4 is hydrogen or lower alkyl and R5 and R6 are independently hydrogen or lower alkyl, with the proviso that Rd may not be unsubstituted phenyl, -CORf, wherein Rf is amino (lower alkyl), (lower alkyl) amino (lower alkyl), di (lower alkyl) amino (lower alkyl), -NHNHT -NRUNRIW -Naonly -O (CH2 ) nA-Re or -NReRg, wherein R17, R1s and Re are lower alkyl, R19 is hydrogen or lower alkyl, A is O, S, NH or NCH3 and n and Rg have those under (b) (iii) and (b ) (viii) the meanings given above, -PO (ORw) 2, wherein RW is hydrogen or lower alkyl, -NHRh, wherein Rh is optionally substituted phenyl, optionally substituted heterocyclyl, -CH = NH, -SO 3 H, -OH, lower alkoxy, amino, lower alkyl- 'S'R17' alkylamino, di (lower alkyl) amino, -NacocH3, -cs2cH3, -sozcns, -soz - <::::> sss uu I 'gun NH - n' c NR 7 R 8, where R 7 and R 8 are independently lower alkyl, phenyl or phenyl (lower alkyl), NH 11 -CR where R 9 is lower alkyl, phenyl or phenyl (lower-91 N lower alkyl) or -C-R 1, where R 1 is amino (lower alkyl), -NH 2, lower alkylamino, di (lower alkyl) amino, -NH% 2>, (xiii) (xiv) (xv) 464,027 0 -NH-g-R 10, wherein R 10 is lower alkyl or optionally substituted phenyl or heterocyclyl, wherein the phenyl and heterocyclyl substituents have the meanings given above under (a) (ii), NH 11 -Nn-c-Nnz, lower Elkexi, -ocaz-Q, - ocazßuoz or -o (cn2) 2s1 (cn3) 3š O II -SC-R11, wherein R11 is lower alkyl, which is substituted by amino, lower alkylamino- or lower alkyl) amino, -NRjRk, wherein R. is lower alkyl and Rk is lower al- 3% lower alkoxy, heterocyclyl, amino or -C-Rif R 1 have the meanings given in (b) (xii) above or wherein R 1 and R k together with nitrogen constitute cooling. wherein then, 0 s <:: llii ~ .I o __ with the proviso that, when R k is amino or -CH 2 CH 2 NH 2, R 2 is methyl and also with the proviso that R 2 and R k can not both be lower alkyl at the same time , -NR. 'Rk', wherein Rj 'is lower alkoxy and Rk' is lower alkyl, heterocyclyl, amino (lower alkyl), (lower alkyl) amino (lower alkyl), di (lower alkyl) amino (lower alkyl) In re alkyl) or -C-R 1, wherein R 1 has the meaning given under (b) and Ö - (xii) above, or wherein R 1 Rk 'together with the nitrogen constitutes 0 0 464 027 (xvi) (xvii) (xviii) (xix) (xx) 6 -NR1RmRn, wherein R1, Rm and Rn are each independently lower alkyl or together with nitrogen - V6 - N / N -CH = CH-Rx, wherein Rx is lower alkyl or optionally ring-substituted phenyl or heterocyclyl, wherein the substituents on the phenyl or heterocyclyl ring have the meanings given in (a) (ii) above, -N = CRxRY, wherein Ry is lower alkyl or optionally ring-substituted phenyl or heterocyclyl, wherein the phenyl and heterocyclyl substituents have the - the (a) (ii) the meanings given above and Rx have the meaning given under (b) (xvii) above, = N-Rp, wherein Rp is hydroxy, lower alkoxy, amino, di- (lower alkyl) amino or 7 or for? 1 -C- (CH 2) n NR 15 R 16, wherein n is an integer 1-6 and R 15 and R 16 are independently hydrogen or lower alkyl, and QY is hydrogen or lower alkyl, optionally substituted with hydroxy, formamido, alkanoyloxy with 1 -6 carbon atoms, alkanoylamino having 1-6 carbon atoms or with phenyl, or Y is dimethyldioxolanyl or 1 * - azido-1 * -ethyl. 464,027 and pharmaceutically acceptable salts thereof, with the proviso that when Y is hydrogen, X is not -CH 2 O 2 Z 2 O 2 B.

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 above-disclosed substituent groups for the 2- and 6-positions of the penetration can be further defined as follows: (a) halogen includes chlorine, bromine, fluorine and iodine; Preferred halogen substituents are chlorine and fluorine; (b) lower alkyl includes both straight and branched chain saturated aliphatic hydrocarbon groups having 1-6 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 particular 1-2 carbon atoms'; (c) lower aliphatic groups include acyclic straight and branched chain, saturated and unsaturated hydrocarbon groups having 1-6 carbon atoms. The unsaturated groups may contain one or more aubble or triple bonds, but preferably contain either a double bond or a triple bond. Examples of lower aliphatic groups are methyl, ethyl, n--propyl, isopropyl, n-butyl, t-butyl, sec-butyl, n-pentyl, isobutyl, vinyl, 1-propenyl, 2-propenyl, isopropenyl, 2 -methyl-2-propenyl, ethynyl and 2-propynyl. The most preferred aliphatic groups are lower alkyl groups as in (b); lower cycloaliphatic groups include alicyclic saturated and unsaturated hydrocarbon groups having 3-8 ring carbon atoms, preferably 3-6 carbon atoms. The unsaturated ring may contain one or more (preferably one) double bond (s). Examples of such groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclopentenyl, 1,3-cyclohexadienyl and cyclohexenyl; lower cycloaliphatic-lower aliphatic groups are cycloaliphatic-aliphatic groups having 3-8 carbon atoms (preferably 3-6) in the cycloaliphatic ring and 1-6 carbon atoms (preferably 1-4 and especially 1-2) in the aliphatic moiety. Examples include cyclopropylmethyl, cyclopropylethyl, cyclopropylpentyl, cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropenylmethyl, cyclopentenylethyl, cyclopropylethenyl, cyclopropylethynyl, etc. The most preferred groups containing this type of cycloalkyl are cycloalkyl alkyl. 3-6 carbon atoms and the alkyl moiety 1-2 carbon atoms; lower alkoxy includes C1-C6 alkoxy groups, the alkyl moiety having the meaning given in (b) above.

Examples are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and n-pentyloxy. Preferred are C1-C4-alkoxy and the most preferred are C1-C2-alkoxy; (q) (h) (i) (j) (k) (1) (m) (n) 9 464 Û27 lower alkylthio comprises C 1 -C 6 alkylthio groups, the alkyl moiety having the meaning given in (b) above. Examples are methylthio, ethylthio and n-butylthio; lower alkylamino includes C 1 -C 6 alkylamino groups, the alkyl moiety having the meaning given above under (b). Examples are methylamino, ethylamino, n-propylamino and n-butylamino; di (lower alkyl) amino is di (C 1 -C 6 alkyl) amino, where each alkyl group has the meaning given above under (b). Examples are dimethylamino and diethylamino; lower alkanoyloxy are groups of the formula lower alkyl-O n -C-O-, where alkyl has the meaning given above under (b); lower alkanoylamino includes groups of the formula \ 1 lower alkyl -C-NH-, where alkyl has the meaning given in (b) above; carb (lower alkoxy) includes groups of the formula O H -C-lower alkoxy, where lower alkoxy has the meaning given in (f) above; halo (lower alkyl) are alkyl groups in which one or more hydrogen atoms have been replaced by a halogen atom; sulfo (lower alkyl) includes groups of the formula - (cH2) nso3n, where n is 1-6; 10,027m) carboxyl (lower alkyl) includes groups of the formula - (CH 2) n COOH, where n is 1-6; (p) phenyl (lower alkyl) includes groups of the formula - (CH 2) n - <, where n is 1-6; (q) (lower alkyl) amino (lower alkyl) includes groups of the formula - (CH 2) n NH-lower alkyl, where n is 1-6 and alkyl has the meaning given in (b) above; (r) di (lower alkyl) amino (lower alkyl) includes lower alkyl groups of the formula - (CH 2) n N '//, where n is 1-6 lower alkyl and each alkyl group has the meaning given above under (b) ; (S) amino (lower alkyl) includes groups of the formula - (cH 2) n NH 2, wherein n is 1-6; - (t) lower alkenyl comprises straight or branched chain, unsaturated aliphatic hydrocarbon groups containing a double bond and having 2-6 carbon atoms, e.g. vinyl, allyl, isopropenyl, 2- or 3-metal or 3-butenyl.

The term "heterocyclic group" or "heterocyclyl" as used herein means heteromonocyclic and heterobicyclic groups of an aromatic nature as well as corresponding partially or fully saturated groups, the heterocyclic groups containing at least one heteroatom consisting of oxygen. sulfur or nitrogen, and is attached to the penem ring carbon atom via a ring carbon atom The preferred heterocyclic groups are either 5- or 6-membered monocyclic groups or fused 6,6- or 5,6-bicyclic groups. gr gives are the following: A LL: Ir Û f; Ü .U f; Üf} I = N so N__u nu \ ”FQ; (1 LN / 'as ___- JN II 464 027 12 Similarly, the terms" heterocyclic lower alkyl "and" heterocyclic thio (OH =) nS-heterocyclic, where n is 1-6 (preferably 1 or 2).

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 5- 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 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), procaine, dibenzylamine, N -benzyl-β-phenethylamine, 1-phenenamine, N, N'-dibenzylethylenediamine, N-alkylpiperidine and other amines which have been used for the preparation of salts of penicillins and cephalospherins. When a basic group is present, the pharmaceutically acceptable acid addition salts are also included, 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 acids, such as trifluoricuronic 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 significance 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, 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-im-methylsilylethyl 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 known in the penicillin and cephalosporin ranges to be readily cleaved in the body to the corresponding acid. Examples of such physiologically cleavable esters include indanyl, phthalidyl, methoxymethyl, glycyloxymethyl, phenylglycyloxymethyl and ac Y wherein Y 'is C 1 -C 4 alkyl or phenyl. Particularly preferred esters of this type are methoxymethyl, acetoxymethyl, pivaloyloxymethyl, phthalidyl and indanyl.

The preferred compounds of formula I are those in which Y is hydrogen or lower alkyl, which is optionally substituted (preferably at the C1 carbon atom) by hydroxy. Particularly preferred compounds belonging to this group are those in which Y is hydrogen, ethyl or Ot-hydroxyethyl. Particularly preferred compounds of formula I are those wherein Y is hydrogen or d-hydroxyethyl. The most preferred compounds are those wherein Y is G1-hydroxyethyl. The present invention relates to novel intermediates of the formula r \ __ T / 5 ¿___N P (Qß 3 '^ coa- III wherein Y is as defined on page 6, Q is phenyl, R (I), in which case X is 1, or M is Hg (II), in which case x is 2. In the intermediates of formula III, R "is preferably p-nitrobenzyl and Y is preferably such substituent groups as above have indicated as preferred in connection with the compounds of formula I. Reactive functional groups, such as amino and hydroxy, in the substituent Y can be protected by conventional blocking groups during the conversion of the intermediates into biologically active end products.

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 at 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 may in turn vary the process for incorporating the desired 2-substituent, i.e. In general, it is preferred to incorporate the substituent Y in an intermediate step of the synthesis and to incorporate the substituent X by acylation of the mercaptide intermediate III, 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. - 464 027 16 Method I (variation 1): Early introduction of the 2-substituent * x oAc 2-ca-ca-oas cs: | - XC-SNI _- 5 ¿_u \ pavå e o B O. ïWn Sålt-X Y g _ ___ è 'M. sc-x ¿__N “fm l soclz o _ \ 8 coza' _ oá-INYOH _ o cozn 'u ° __% ___; / -N Cl bas ___ 'o' 0% N Pøs CÛZR '_ - ccznn I y \ X S' - y / x av1ägsn. “LL s _ arr-N of protective u / x CDZR. group 'of * co a 2 o Ae I CH å- 3- - fö - ca - 65 17 464 B27 Procedure I (variation Zl: Late incorporation of the Z substituent o YN 0A: U y-caæa-om: csz ; I cafét ”ä _ H EM- fi” _-> YW-TSM% -> <| 1H0 soclzï cpzn 'I - 2. kñ / SÄC pø3 “W- SÄC _ MA -> I ___;, - u cl bas '._N Pø bas o' ïJsf '04 3 coza' cozn 'OIY' n "M su _II_ Y '- \ _ sc-x A xc Q Ä-N +"' å o .. 'COZR' C023 '2 \ 5 YI x deviation of "11 5 - / .___- ex / rN' protecting group / o. _- C023 g. Co a 0 ll XCO = acylation medium MA = heavy metal fl saït 464 027 18 Method I (variation 3): Late incorporation of the 2-substituent 2 ï-caæn-oac csr; I øï 'a 0 \ “gy * - scø Yu scø -. A 2 ---> çno soclz oæ-ÄKH C923. Oá-N on _ _ _ coza 'y Y "' H._r scø3 pøa“ x scø3 M - __ b __ b s- 04 N as a cozn 'cnzn' 'I o 2 ¶ 0 I “W- _ su MIL æ * x sc-x ANEI - ___ ¿> 04- Pøa _. O¿__u \ (1> ø3 COZR '' C923 '' Y. “Û ,, .- uox removal of protection group COZR 19 464 Û27 In process I a vinyl ester is converted (Y = H or a group with it in connection with the formula I ova n containing the desired 6-substituent 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 organic solvent, such as diethyl ether, at a temperature of 0 ° C or below. 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-α; thereof, such as the sodium salt). The 4-thioazetidinone is then reacted with a glyoxylate ester O -. The 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 hydrate, in an inert organic solvent (e.g. benzene, toluene, xylene or the like) and preferably at elevated temperature (for example from 50 ° C up to the reflux temperature is preferred) .When a hydrate of the ester is used, the resulting water can be removed azeotropically or with a molecular sieve. 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 , 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, 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 of the solvent system.

At this stage, the process can 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 solvent of the solvent system. flow temperature. 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), logenated hydrocarbons (for example methylene chloride, chloroform, carbon tetrachloride), ethers (diethyl ether, dioxane, tetrahydrofuran, dimethoxyuran, dimethoxyethyl; anna), α 1 -C 1 -C 6 -alkylsulfoxyas (for example dimethylsulfoxide) or a C 1 -C 6 alkanol (for example methanol, ethanol, t-butanol) or a mixture thereof. According to variations 2 and 3, the phosphorane is converted to a heavy metal mercaptide of the formula F Y \ 4 - N n o L 1 :: or v '' \ ßngcoocn: 'I f-N m: o'. Wherein CO is phenyl, x is 1 or 2 and M is Hg (II) when x is 2 or Ag (I) when x is 1. Mercaptide formation is accomplished by reacting the phosphorane with a salt of Hg (II) or Ag (I) or with (methoxycarbonyl) mercury (II) acetate in a methanol-containing solvent and in the presence of an organic or inorganic base such as aniline, pyridine, collidine, 2,6-lutidine A preferred 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) in the heavy metal salt may be any anion which gives a soluble salt in it. selected solvent, for example NO3 ', CH3COO-, BF4-, F-, C104-, NO2, CNO, etc. The mercaptide intermediate is then reacted with an acylating agent capable of introducing the group X-Å-, wherein X is the desired The 2-substituent The acylating agent O 0 (X-ä-@) may be the acid X-ë-OH or a reactive functional derivative thereof, such as m 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 with much better purity than those obtained by the more conventional method of variation 1.

Once the carboxyl-protected penem compound has formed, the protecting group can be removed by conventional unblocking methods (e.g. hydrolysis, hydrogenation or photolysis) to obtain the unblocked penem compound. The removal of the p-nitrobenzyl ester can be accomplished, 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 carbon 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 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 (Process II), the reaction steps are as follows: Process II (variation 1):% oAc cxz-ca-one csri. I i- 4-3 N \ 0 a o sä: x; I clmo ..._. U _, 0 / xx c_o2n o o så-x -T Pø3 ,, ._- 'N cl b ”o _ CO R' _ s _ I X Y. E 'lÉT-ïu bÄS' ° coZR '2 avïägsn. of 'WL r'. protection group _ / x rN o co a OI XC-S fl a pH 7. 0 I, SC-X ä --N OH C02R '\\ --N / fr- * N 0 _ \ __ \ / S / 5 Early introduction of The Z-substituent 464 027 Method II (variation 2): Late introduction of the Z-substituent - CAC cxz-cx-om: cs: 5 I - Acs AA: _ --N. of xa coza 'öæ-N ° H coza' SAc ï / pø SA: MA _ --3-> I __ + ,, - N c: bas / __ N pø bas-- o _ Y. o / 3 C021 * _ coza 'I o SM R sÉ-x x-C- æ -. T Å of Pøï * o / -J - Pøs / s y '_ i x Y' -'s ---> | / f-'N bas / x o.

C023. 0 _ cola 'li Y l ._av1agsn. of WL. s * íïš x protection group ,, _ Å /. _ "0 'co a 464 027 Method II (variation 3): 26 Late introduction of the Z substituent 0A: ø3CSNa cxz-cn-onc csI; _ I 7 5. | 2H0 I 'soc12 "cozn' ¶ ïscø3 Pøa scø3 HA JN cl bas / ï-N Pø bas IZ 3 o Y o coza 'cozn' _, o sn 3 së-x I 'XC- ® PT A.

LN E 'cozn' C023 'I s 4: r1 |: 2'x Yïërs / x' ow _ / r-'N C02 o coziz '- YR _ avTägsn .avë - \ / x Skyddsgr-urpp' l / Qg "/ \ o. cøzn 27 464 027 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 giving the 2-substituted Penem compound. However, it is desired to introduce a 6-substituent 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. method, 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 Any ester inert to the anion chemistry can be used (the reaction involves anion formation with base, followed by reaction). the electrophile with the penem anion), for example lower alkyl such as methyl, ethyl, n-propyl or t-butyl, phenyl, trichlorethyl, methoxymethyl, silyl such as trimethylsilyl or t-butyldimethylsilyl or the like. Phenem 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 non-critical and the usual strong bases; such as sodium hydride, phenyllithium or butyllithium, are suitable. In particular, however, a lithium disilylamide or a lithium dialkylamide is used, such as lithium dicyclohexylamide (LÜCA), lithium diethylamide, lithium dimethylamide or lithium diisopropylamide (LDA).

The electrophile is selected so as to obtain the desired Y-substituent upon reaction with the anion. A particularly preferred electrophile is acetaldehyde, which gives rise to the hydroxyethyl-6-substituent. The introduction of the 6 -substituent by this method is preferably carried out under cooling (for example at a temperature from -80 ° to 0 ° C) in accordance with the general procedure described in the Canadian Journal of Chemistry (19) (1972). ) 3196-3201. After formation of the desired 2,6-penem compound, any ester protecting group can be removed as indicated above to obtain the deprotected product.

The third main reaction process (Process III) is shown in the following reaction scheme: Process III (variations 1 and 2). l: T sCøa - Scøa - - '_79 Å-u 0 ”xä I 0 \ 8 Y * g scø, ->. e, _] _ ba * '° 4 "_' N \ B _ avlägsn. av - M¿ / ba, _ skvddsgrupp 29 \ ._ Tscø3 4" "'N \ S180 CO R' Yw. scø: oä-u ou cozn 'SOCIZ YM. scø3 / ïN Cl CO R' ~ ° \\ removal of protection group --- N OH CO R '-J / SOCIà 464 027 N o IYI ““ - SN w, sÉ-x 04; - N P93 4.-N cl of °° 23 '_ coza' 3 P. ' L xc- Q ll ø:. Pas ~ Q o Y “o_ se-x ä ~ så-X o _ o. - G0 R 'cozn' \ __ \ / 5 Y '\., ____ 1/5 XX 4_l. / _ - \, _ l, / o _- o R_ 'COzR _ _ - C02 avlägsn. av _ ävlägsn- aV skyaasgrupp' skydäserupp Y. s _ y - / X * o // è-no // fl- N °° 2H CO 2 B = blocking group for ring nitrogen The 4-tritylthio-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, dimethylsilyl 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 hydroxyester and conversion of the chlorester to a phosphorane, conversion of the phosphorane to a heavy metal mercaptide, acylation of the mercaptide with X-'Cl-Q, thermal cyclization of the obtained phosphorane to give 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 conversion of the N-protected azetidinone to a heavy metal mercaptide, acylation of the mercaptin, the time with the XCG group 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 obtain 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 do not participate 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 esterification or esterification, mercapto groups by esterification and free carboxyl or sulfo groups for example by esterification including silylation. After the reaction has taken place, these groups can, if desired, be liberated, individually or simultaneously, in a manner known per se.

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. Thus, for example, carbonyl groups can be reduced to alcohol groups, unsaturated aliphatic groups can be halogenated, amino groups can be alkylated or acylated, nitro groups can be converted to hydroxyamino and amino groups, hydroxyl groups can be etherified or esterified, etc.

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 into 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 to the free compounds or by fractional crystallization. from optically active solvents.

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 specified) Celite diatomaceous earth product LAH lithium aluminum hydride n-BuLi n-butyllithium MIBK methyl isobutyl ketone Et c2H5- 'Tr. -C (C6H53 Me CH3-THF tetrahydrofuran Ph phenyl 'DMF dimethylformamide TEA triethylamine PNBG _- p-nitrobenzylglyoxylate THP tetrahydropyranyl TFA trifluoroacetic acid HMPT (or HMPA) hexamethylphosphoric triamide EthOAc 464 027 134 Example gel 1 1- (-Nitrobenzyloxycarbonylmethyltriphenylphosphoranyl) -4- (silver mercaptidyl) -2-azetidinone STIIN 90 ml of a methanol suspension of 13.8 g (0.05 mmol) of triphenylmethyl mercaptan were degassed under 0.5 The mixture was cooled to 09. and 2.4 g (0.05 mol) of sodium hydride in the form of a 50% oil dispersion were added portionwise. The resulting solution was stirred for 5 minutes at room temperature. 7 g (0.059 mol) of 4-acetoxyazetidinone in 5 ml of water were added rapidly, precipitation of 4-triphenylmethylmercaptoaazethinone (2) occurred immediately. The mixture was stirred for 464,027 hours at room temperature. The solid was filtered off, two was 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 89.8% with a melting point of 146.5-147.50.

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.

NMR: δ '(ppm, CDCl 3) 7.60 - 7.10 (15H, m, H-trityl), 4.62 H-4), δ_24 (ln, add, Jgem = 15, J3_4 cis = δ , J3_NH = 1.8, H-ß), 2.81 (111, aaa, Jgem = 15, J3_4 trans = -3, o J3_NH = 1.2, H-3) 'Im w> c = o (cucla ) 1760, -0 NH 3340. sr: ST: šgovua 2 N on 'won wf »° r - PNB' _ 2 | u 'Z 4.54 g (0.02 mol) hydrated p-nitrobenzyl glyoxylate and 6.90 g (0.02 mol) of azetidinone (2) was refluxed for 24 hours in benzene via a Dean-Stark condenser filled with 3A molecular sieves. Additional glyoxylate (2 x 454 mg, 2 mol) 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. 5.9. = 170.5 - 171.5 ° __ man: 5 (ppm, c0c13) 8.07 (zn, a, J = 9, um aramates), 7.45 (part of d, Ho aromatics), 7.40 7.00 (15H, m, trityl), 5.25 (za, s, cn_-1> NB), 4.7s (in, s, Hco), _4.37 '(1u, aa, J3_4 trans 2 3 'J3-4 cis = 4' H-3) '2'83 (1H' dä 'Jgem = 16' J4-3 cis = I 1 464 027 36 4] dä '= 16; J 4-3 = 3, H -4) | 1142 (bnslf in: .g Fo (cnc13) 1770, lnmsxularæpøoa anspunoz 1525 Isomer B: af = o, 7s, sp = 152 - 1s3 ° NMR = <5 (ppm, CDCl3) 8.13 (2H, d, J = 9, Hm aromatics), 7.47 (2H, d, J = 9, Ho aromatics), 7.40 - 7.00 (15H, m, trityl), 5.30 (BH, s, eng-PNB, Hco ), 4.45 (ln, t, J_ = 3.5, H-4), 2.90 - 2.70 (2H, AB part of Aßx, H-4), 1.55 (bs, on). 1R = 1) c = o 150 ml of a cold (-15 °) THF solution (dried over molecular sieves) of 12 g (21.7 mmol) of azetidinone (3) was treated with 1.9 g (24, 1 mmol) 1.94 ml) pyridine and dropwise with 2.86 g (24 mol; 1.88 ml) thionyl chloride under a nitrogen atmosphere. The mixture was stirred for 45 minutes at -15 °. 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.

NMR: δ (ppm, CDCl 3) δ 17 (ZH, d, J = 8, Hm aromatics), 7.67 - 7.00 (17H, m, Ho aromatics, Tr-H), 5.80 (s, HC-Cl), 5.37, - 5.33 (2s, HC-Cl, CH2-PNB), 4.81 (1H, m, H-4), 3.27 - 2.40 g (2H, m , H-3) 1n = 1) c = o (nar-film) 17as, 1770-ONOZ 1525. 37 _ 464 027 sr: ST * Ef ___ u: ___, [j N \ 1/51: J-hn flfi in 0 \ 100 ml of a THF solution (distilled over LAH) of 11.6 g (20.2 mmol) of chlorazetidinone (4) were treated with 7.86 g (30.0 mmol) of triphenylphosphine and 2 ml. 36 g (2, ss ml; 22.0 man 2, s-1utidine. 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 5% aqueous solution of sodium bicarbonate and dried over magnesium sulphate Evaporation of the solvent gave a residue which was purified through a silica gel pad (200 g), the desired phosphane eluted with 30, 40 and 50% ether-benzene , 4 g of product in a yield of 70,4% and with a melting point of 2o1-2o2 ° - Analysis: Ber. for C 49 H 40 N 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. ' IR: -0 ° C (cHc13) 1740, '0 phosphorane (1620, 1610),' Om 1525. '2 Tr. AgNO3 i- x \ ï:? $, ° pyzxain, "\ T%} 43 åï" cozrnn à. The phosphorane (5) having a temperature of 55-60 ° was dissolved in 32 ml of methanol which had been preheated to 55-60 ° 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) of pyridine, the heat bath was then removed immediately The mixture was stirred 464 Û27 33 at room temperature for 2 hours and at 0 ° for 1 hour.

The silver mercaptide 6 was filtered off, washed twice with cold (0 °) methanol and three times with ether. 1.12 g of product were obtained in a yield of 84.5% and with a melting point of 130-1350 (decomposition).

IR: -Q c = ° (CHCl 3) 1795, 1725 (shoulder), 10 phosphorus (1620, 1605). 1) NO. A solution of 1.796 g (3.0 mol) of phosphorane (7) in 3 ml of chloroform was diluted with 90 ml of methanol, cooled to 0 ° under a nitrogen atmosphere and treated in successively with 0.51 g (3.0 mmol) of silver nitrate and 0.33 g (2.4 mmol) of potassium carbonate. The reaction mixture, which was protected from light, was stirred at 0 ° C for 15 minutes, after which the cooling bath was removed and stirring was continued for 3 hours. The reaction mixture was cooled to -10 °, stirred for 1 hour and filtered; the silver mercaptide was washed successively with cold methanol and ether to give 1.91 g of product in a yield of 96% and with a melting point of 138-14S ° (decomposition). I.R ~ (nujol) cm -1: 1748, 1620 and 1605. An analytical sample was obtained by preparative thin layer chromatography (ethyl acetate) and the product showed a melting point of 140-145 ° (decomposition).

Analysis: Ber. for C 30 H 24 N 2 O 5 SPA 2: C 54.31; H 3.65; N 4.22; S 4.83. Found: C 54.11; H 3.48; N 3.92; "S 4.62. 39 464 027 Example gel 3 1- (genitrobenzyloxycarbonylmethyltriphenylphosphoranyl) -4- (sil-mercactidyl) -2-azetidinone A. Use of aniline as base SCOCH ....: ___ L_, N * NCH 'n 0, * x _ \\ -van, - É-: rus COOPNÛ æpNg z 6 .I _ A solution of 1.8 g (3.0 mmol) of phosphorus (7 ) in 4 ml of chloroform was diluted with 90 ml of methanol, cooled to -150 under a nitrogen atmosphere and treated successively with 0.56 g (3.3 mmol) of silver nitrate and 1.5 ml (16.5 mmol) of aniline. The reaction mixture, which was protected from light, was stirred at -15 ° for 0.5 hours, after which the cooling bath was removed and stirring was continued for 24 hours.The reaction mixture was cooled to -10 ° and stirred for 1 hour before being filtered; was washed successively with cold methanol and ether to give 1.55 g of product in a yield of 77.9% and with a melting point of 114-115 ° (decomposition). The product was identical with the compound of Example 2.

B. Use of 4-dimethylaminopyridine (DMAP) as base SCOCR A9 '[:: íf 3. c fl lçlï / caß ', "Yptg - _ ozvua C ° ¿PNF- A solution of 17.96 g (30 mmol) of the above S-acetylphosphane in methanol and dichloromethane (1: 2, 450 ml) through nitrogen (s-10 minutes), refrigerated: it was treated successively with 5.35 g (3l, 5 mmol) of silver nitrate and 3.85 g (3l, 5 mmol) of 4-dimethylaminopyridine. was removed and the solution was refluxed vigorously for 2 hours and then stirred at room temperature for 1 hour.

The colored reaction mixture was treated with charcoal, filtered and evaporated. The residue was redissolved in the smallest possible amount of dichloromethane and added dropwise with stirring to 300 ml of cold methanol. The precipitated silver salt was collected by filtration, washed with ether and dried.

The product was obtained in an amount of 18.1 g in a yield of 91%. m: (cnc13) 1) = 1745 (c = o in ß -lactane and 1607 cnfl max (C = O in ester). ~ '"_ C. Use of diazabicycloundecene (DBU) as base _. 3 AQNQB sAg.

Crude DBÜ: MQOH N pd): PNB 02min 36.0 g (0.060 mol) of the above S-acetylphosphorane was dissolved in 120 ml of methylene chloride. The solvent was evaporated in order to obtain an oil. The resulting oily residue was dissolved in 240 ml of hot (3 °) methanol and treated rapidly with 420 ml of a methanolic solution of silver nitrate (1.068 g; 0.0628 ml). The resulting solution (or suspension) was stirred at room temperature for 5 minutes, cooled (in an ice bath) and a DBU solution (8.96 ml; 0.060 mol) in 20 ml of methanol was added over a period of 5 minutes. The mixture was stirred for 5 minutes. The solid was filtered, washed once with cold (0 °) methanol and ether and dried in vacuo to give 37.0 g of product in 93% yield.

IR: (nujol nai11) fÛ max (c = 0) _och 1600 cm_1 (phosphorane). _ M 4e4 "ñ27 D. Use of pyrrolidine as base '_ SÅQ OCÉ SC 3 Pyrzolidinu | N ÅQNO3 - o N“ ~ c-Pvn 0 “~ c-rvh.' I 3 3 (rooms oovna 'nu en kan (o °) solution of 0.60 g (1.0 nl) of α-acetylethine-1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2'f-acetate) -2-azetidinone in 2 ml of CH 2 Cl solution of AgNo 3 in neon (0.14N; 7.86 mL; 1.1 mmol) and a solution of 0.92 mL (1.1 mmol) of pyrrolidine in 2 mL of MeOH. The cooling bath was removed and the reaction mixture was stirred for 1 h. 75 hours, cooled to -10 °, stirred for 0.25 hours and filtered, the solid was washed with cold MeOH and dried in vacuo to give 0.548 g of product in a yield of 82.4%. and with the melting point 115 °. IR: (nujol) 1) max: 1755 (c = 0) and 150.

Example 4 Mercury (II) - (2'-triphenylphosphoranylidene-2-acetate) -2--azetidinone-4-thiolate acid H9 (Om) 2 2 N c Prha _ _ “ämm _ I S) 2H9 l “Yvrha ~ 'i covua * _ 464 027 1. 4. A solution of 2.4 g (3 mmol) of compound I in 15 ml of dichloromethane was cooled to 5 ° and treated with a solution of 0.525 g (1.65 mmol) of mercury acetate dissolved in 15 ml of methanol. After stirring at 5 ° for 2 hours, the solvent was evaporated and the residue was redissolved in dichloromethane and washed with cold water. After drying over magnesium sulphate and treatment with charcoal, the organic solution was evaporated to give a foam which crystallized on trituration in ether. Yield: 1.73 q (91%). Melting point l23-227 °. nu (cscia) ms an * <-0c_ ° ß-iamam) isoa om * (fenyi).

Example 5 2-Methylpenem-3-p-nitrobenzyl carboxylate (starting from brand time intermediate) 3 '7 §J. Py '* ° *? " "-I: fP": 1-, oavus' - W arna 11 _ ~ xx: A solution of 262 mg (0.2 mmol) of compound II, 35 mg (0.44 mmol) of acetyl chloride and 2 drops of pyridine in 10 ml of dichloromethane was stirred at 5 ° for 1 hour. The precipitated mercury chloride was filtered off and the filtrate was washed successively with cold dilute hydrochloric acid, sodium hydroxide and finally brine. The organic solution was subjected to a stream of hydrogen sulfide for 2 minutes at 5 ° and stirred at this temperature for a further 10 minutes in order to precipitate the last traces of mercury salts.

A small amount of charcoal was added to the black mixture, which was then filtered through a pad of celite. Evaporation of the clear filtrate gave 193 mg (80.7%) of compound III 'as a foamy material. I: (CHCl 3) 1775 (Ün-o / S-lactam) '92 (Oscøcxa) iszo (phenyl). 4§ 464 027 una: ASN ----- Q ca \ 1ø} ° J ° J :: [: %% * _ J COZPNB '2 ha 1 :: ¿: V 75 mg (0, l26 mmol) phosphorane ( III) in 10 ml of toluene was refluxed for 2.5 hours under a nitrogen atmosphere. Evaporation of the solvent and purification of the residue gave 25 mg (63%) of a crystalline compound, the physical data and spectral data of which were in complete agreement with the corresponding data for the title product.

The product IV can, if desired, be subjected to catalytic hydrogenation (30% Pd on celite) in order to produce the corresponding 3-carboxylic acid product.

Example 6 2-Aminomethylpenem-3-carboxylic acid (starting from mercaptide intermediate) yet, o ': cum N _ A9 cunaxn - 2_3 _ ______ L¿ __, _ 0 N - ”\ ommua coovua ._1_r 3.

A solution of 1.25 g (1.99 mmol) of the silver mercaptide 1 in 115 ml of dichloromethane, kept under a nitrogen atmosphere, was cooled to 0 DEG C. and treated dropwise with a 2M solution of azidoacetyl chloride in dichloromethane (1.3 ml; 2). ; 26 mmol) - The reaction was stirred at 0 ° C for 1 hour; the cooling bath was removed 464 027 4, and stirring was continued for 5 hours. The reaction mixture was filtered through a pad of celite and the solid was washed with 35 ml of dichloromethane. The filtrate and washings were combined, washed with sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and concentrated in vacuo to give an orange syrup which was purified by column chromatography (30 g silica gel 60, eluent ether ether-2% ethyl ether 200 ml), ether-6% ethyl acetate (200 ml) and ether-20% ethyl acetate (500 ml), fraction size 10 ml). Combination and evaporation of fractions 49-80 gave a yellow powder in an amount of 0.73 g (60.8%) with a melting point of 61-70 °.

COCHZN: - s ---_-_ o Å I min N 'toluen - Nj- 2 3 WIPM: ° cmhna omæua 2.

A solution of 0.593 g (0.93 mmol) of the phosphorane 2 in 20 ml of toluene was heated at 1050 for 1 hour, cooled to 230 and concentrated to a semi-crystalline compound which was purified by column chromatography (12 g of silica gel 60, eluent). benzene (100 ml), benzene-2% ether (100 ml) and benzene-4% ether; fraction size 10 ml). Combination and evaporation of fractions 18-26 gave a yellow syrup which crystallized on standing to give 0.18 g of product (sense), m.p. 127-128 °. man (cnc13) δ 8.22 (zn, a, JHO 'm = 8.8 Hz, na of p-nitrabenzyl), 7.80 (2H, d, Jnm' Ho = 8.8 Hz, Hm of p- nitrobenzyl), 5.71 (1H, dd, J5'6 cis = 3.6 Hz, J5'6 trans = 2.1 Hz, H-5), 5.33 (ZH, center of ABq, Jaib = 14, 0 Hz, CH2 of p-nitrobenzyl), 4.58 2H, center of ABq, Jalb = 15.0 Hz, CH2on C-2) 3.88 (1H, dd, J6'5 cis = 3.6 Hz, Jgem = 16.5 Hz, H-6 cis) and 3.55 (1H, dd, J6; 5 trans = 2.1 Hz, Jgem = 16.5 Hz, H-6_trans).

IR: (Nujol) cm-1: 2115 and 2090 (N3), 1730 (C = O) B 'lactam) and 1685 (c = 0 in p-nitrobenzyl ester). 45,464,027 An analytical sample was obtained by preparative thin layer chromatography, m.p.

Analysis: Ber. for C 14 H 11 N 5 O 5 S: C 46.54; H 3.07; N 19.37; S 8.87.

Found: C 46.43; H 3.08; N 19.37; S 8.90.

N 30 \ Pd / ce1it ____, c fl z flfl z __. 2 3 THF: ether; H20 N- _ PNB 3. To a solution of 0.18 g (0.5 mmol) of the penem compound 3 in 6 ml of tetrahydrofuran was added successively 6 ml of ether, 6 ml of water and 0.18 g of 30% palladium on celite. The reaction mixture was hydrogenated under a pressure of 2.07 x 105 Pa at 230 for 2.5 hours and filtered through a pad of celite; the pad was washed with water and the filtrate and washings were combined, washed with a mixture of ether and THF 'and lyophilized to give 30 mg (30%) of compound 4. Water and ether insoluble compound were dissolved in chloroform and the organic solution was washed with water and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave 77 mg (42.8% of the starting material 37. NMR (DMSO d-6) δ: 5.7 (dd, J5-6 cis 3.5 Hz, J _ = 1.5 Hz, H-5). IR: (nujol) cm: 1775 (c = o ip-ïagtšxfânâcn 1515, 1585. uvngå: mp = ('¿= 232o> och 307 (E = 2ss5>.

The title product 4 was also obtained from the intermediate 3 by the following synthesis: S _ _ _ N. u2.Pa/n.:. -, .______-- + ana u 2 3 Tur, eter,. To a solution of 2.4 g (s, s9 mmol) of the penem compound 3 in 165 ml of a 1: 1: 1 mixture of tetrahydrofuran, ether and 464,027 46 water, 4.3 g of 30% -19 palladium was added to diatomaceous earth. The reaction mixture was hydrogenated under a temperature of 3: 1 X 10 Pa at 23 ° for 2.5 hours and filtered over a pad of celite. The filtrate and washings were combined, washed twice with ether, centrifuged and filtered for several hours to give a clear solution, which was lyophilized. 0.622 g in a yield of 45% were obtained. Crystallization of the compound was induced by the addition of 0.3 ml of water. The SUS 'Pe fl SiOD was centrifuged and the water was removed to give an orange solid. This solid was washed twice with water and a light yellow solid were obtained after drying in a gauge of 0: 273'm9 (19.8%) - no - Uv Åmz - 307 (sail) §O). A certain amount of unrestrained starting material (1.2 9; 50%) was recovered. The compound (50 mg) could also be purified by column chromatography (Sephadex G10, column size: 1.6 X 100 cm 3, flow rate: 10 ml / hour, eluent: distilled water: fraction SVO 1 Ym = 1: 5 ml: detector: refractive index). Wagåšè 307 (É- = 3597) OCh 255 (E = 2424).

The stability of the compound in the aqueous solution was checked by UV, the following values being obtained w; 5 h 307 01-3545) '255 (1212773) 21 h 307 (c-3467)' 25§ (: ~ 2411 za h 307 (c-3337) 254 (e-2398) 46 h ao? (C-azss) f '254 lc-zsss) ~ wo h so? (c-SOYS!, _ 94 n slept tu-2842) 170 h 307 (c-1900! at 23? for 3 days, after which A sample of compound 4 was held HO v 2 - so? (6 = 3oss) ooh zss the following UV data were obtained: UV A '(E = zoos). Max' 2 The compound is not converted in the manner described below to two additional 2-penem derivatives. _47 464 027 / s H me) Nauco, some "-N-» H2 / A suspension of 50 mg (0.25 mmol) of compound 4 in 0.5 ml of distilled water was treated with one equivalent. sodium bicarbonate (21 mg), followed by the addition of 1.8 ml (0.024 ml) of ethyl acetate. The reaction mixture was stirred at 23 DEG C. for 20 minutes and lyophilized to give 52 mg of a yellow solid. NMR (D 2 O) δ: 5.7 (m, H-5) and 2.23 (b. nu (Ksncnfå 1772 (c = <> i ß- -laktamL u.v._7l gå: mp =: os (E = 311s) och 253 (6 = 2s2s).

Compound 5 was applied to column (Sephadex G10, column size: 1.6 x 100 cm, eluent: water, detector: IR, fraction size: 1.6 ml) and lyophilization of the appropriate fractions gave 23 mg (45% ) of a light yellow powder. u.v.lL go: mp; 303 (6 = z96o) and 248 (E = 2aas). wmuo, '_fl + mm **: f fa? s, u - o ° Jil-os: cooaaaø. f.

A suspension of 50 mg of 10.25 mol) of compound 4 in 0.5 ml of distilled water was treated with 21 mg (0.25 mmol) of sodium bicarbonate and stirred for 1.5 minutes before the addition (2 minutes) of a mixture of 126 mg (1.5 mmol) of sodium bicarbonate and 154 mg (1.5 mg) of ethyl formimidate hydrochloride. The reaction mixture was stirred for 10 minutes at 23 ° and lyophilization gave an orange powder. nuzo U.v. maxmp: 304 (E_ = 2309). 464 027 48 Example 7 The following Z-penem compounds can be prepared by acylation of 1- (p-nitrobenzyloxycarbonylmethyltriphenylphosphoranyl) -4- - (silver mercaptidyl) -Z-azetidinone with the appropriate acylating agent, followed by cyclization and blocking.

The general reaction scheme is given below: sAq o o 'n __ \ / __) 1. nä-o-cfo-iau Tl / SC ”or J Pin _ -iN - of' YW: 2. acoc-i o YW; I. S -.

A v __ | / R 32/301 Pd / diatuwwacêjorgl -> ,, _ ,, / _. > o. , cozPus / s 'Ä-n / _ o _ co u' prevariation l: RCI> 2H +: LBuCIJCI for variation s: use B21 + PCl5 + RC02H 49 Acylating agent øcnzocouu- (cu2) 4-cozu 1? “= øcnzocoux-cs -C023 (both D and L) É fl zc fi a. øcxzocoux-ca-cozx _fl håde D och L)? “= ~ cn-css øcxzocona-cx-cozu 1. 1 (ßåde D och'ïÖ 9 øcxzocouu-ca-cozn (both D and L)?“ 2ø øcuzoconx-ca- cozx (both-D and L) cxzocxzø-NO2-p øcazocoua-cn-coza (both D and L) ~ cxzcozcxzø-No :-p øCH2ÛCQNH-CH7CÛ2H (both D and L) _ cnzconuz øcxzocouu-ca and E) (EHZCHZSCHB _ øcxzocouu-ca-cozu TE * Qch- L) '(ca2) 4NHco2cx2ø ~ øc fl zocouu-ca-cozx (both D and L).' F33 øcnzoconcxzcøz fl l l.

Method 464 027 Product 2- (4-Aminobutyl) penem-3-carboxyic acid 2- (1-aminoethyl) penem-3-carboxyic acid 2- (1-aminopropyl) penem-3- carboxyic acid 2- (1-amino-2-methylpropyl) -penem-3-carboxylic acid 2- (1-aminobenzyl) penem-3-carboxyic acid 2- (1-amino-2-phenylethyl) -penem - 3-Carboxylic acid 2- (1-amino-2-hydroxyethyl) -penem-3-carboxylic acid 2- (1-amino-2-carboxylic acid) -pen-em-3-carboxylic acid 2- (1-amino -3-methylthiopropyl) -penem-3-carboxylic acid 2- (1,5-diaminopentyl) penem-3-carboxylic acid 2-L-methylamino) ethyl [7-penem-3-carboxylic acid 2- [2- (methylamino) ethyl [7 -penem- -3-carboxylic acid 464 027 y 50 Acylation forging Method Product çxs _ øcxzocoucxzcxzcxazcozx 1 2-Z3- (methylamino) propyl_7-penem- _ -3-carboxylic acid Clliz _ _ 'zczczczc ) 'ïêf fi1'fl ° WWCYY-Pe flfl m' -3-carboxy1 syra fzñs. _ øcx-zzocoucazcoz fl J. Z- fl ethylnom fl toe / DPGHGN '-3-carboxylic acid fzñs øczzzocoucxzcnzcøzx-x 1 2- [2- (ethylamino) ethyl]] penem-3- “_ - -Carboxylic acid. _ 'øcxzocoucxzcxzcxzcoza 1 2- [3- (ethylamino) propyl] -pen- _ em-3-carboxylic acid Ézäs. gçgzoçggqggzcgzcgzcg co 3 1 2- [Ä- (ethylamine] butyl-penem- 2 2 -3-carboxylic acid íø _ _ øcxzocoucxzcozu ', - 1 2 - [(phenylaminomethyl-penem- - -3-carboxylic acid. s? ~ f 1). t 1.7 øcazocouaxæzsxz.cozs_ 1._. Éš fi šibâgšfnglrauüe y -penern f? - _ øcxzoconcxzcnzcxzcozu 1 2- [3- (pheny1amino) propy1_7- '-penem-3-karboxy1 syra * ß øc * zc øc. | -penem- -3- carboxylic acid cxzcouacxzzcozn 1 Z-lacetylaminc fl methyl fl- šaenem--3-carboxylic acid ca3conacazcazcozn '1 2' [2 '(ê <= @ tYïëI fl1'fl0) êtyU-carbox -pen conaca about about co _ '1 Z-I "P fifi ef / FIHHWIIÜPPODYÜ' x 3 2 2 2 2 -peneru-3-carboxylic acid 51 Aczleringsmedeï Mêtßd caaconacxzcnzcnzcxzcoza 1 caascon al cxzcoza 1 csascouxcazcxzcozx 1 csasçonncxzcxzcsåcøz fl 1 cöascouucnzcxzcxzcxzcozx 1 øcnzoconncxzcouacnzcoz f 1 1 _ In øcxzocøuacxzconucnzcuzcozn 1 øcuzfcqux- xcazcouucxzcszcxzcozk J. _ øcxzocouacxzconucazcazcxz-: L cxzcoz fi azucouacnzcozn. 1 nzncouacazcazcozu 1 Hzncouacxzcxzcnzcoza 1 'uzncouzcazcxc7 kt 2- [1- (Acetylamino) butyl] -penem--3-carboxylic acid 2-Libenzoylamino) methyl] -P9 "-em-3-carboxylic acid 2- [2- (benzoylamino) ethyl] -penem-3-carboxylic acid 2-L3- (benzoylamino) propyl_7-penem-3-carboxyic acid 2- [α- (benzoylamino) butyl [7-penem-3-carboxyic acid 2- [Iglycinamido) methyl] -penem-3-carboxyic acid 2- [2- (glycinamido) ethyl] - penem-3-carboxylic acid 2- [3- (glycinamido) propyl [7-penem-3-carboxylic acid 2- [N- (glycinamido) butyl] -penem-3-carboxylic acid 2- (ureidomethyl) penem-3-carboxylic acid 2- (2-ureidoety1) penem-3-carboxylic acid 2- (3-ureidopropyl) penem-3-carboxylic acid 2- (4-ureidobutyï) penem-3-carboxylic 464027 Acxïeringsmedeï CH3NHCONHCH2C02H CH3NHCONHCK2CH2C02B cnauucouxcazcxzcazcqza casnxconacazcnzc fi zcuzcozx øuncouxcnzcozs ønacouacazcazcozn øuuconncazcnzcnzcozn øuucou al cggcxzcnzcnzcozë ca3coNHconacn2co2a ca3cøNaconHca2cx2co2n cx3conaFoNacH2cH2ca2co2n cx3cøusconuczxzcxzcæxzcxxzcozu øCONHC0NHCH2CO2H 52 Method Product 2- (Methylcarbamoylamino) - methylphenem-3-carboxylic acid 2- (2- (methylcarbamoylamino) - methyl] penem-Bk arboxy] acid 2-13- (methylcarbamoylamino) - propyl] penem-3-carboxylic acid 2- [α- (methylcarbamoylamino) -butyl [7penem-3-carboxyic acid 2-Lifenycarbamoylamino) -methyl] penem-3-carboxyamino ) - ethyl penem-3-carboxylic acid 2- [3- (phenycarbamoylamino) -propyl penem-S-carboxylic acid 2- [α-phenylcarbamoylamino) -butyl penem-3-carboxyic acid 2-11-acetylcarbamoylamino) -methyl] -penem-3- carboxylic acid 2- [2- (acetylcarbamoylamino) -ethyl] penem-3-carboxylic acid; 2-13- (acetylcarbamoylamino) - propylene-penem-3-carboxylic acid 2- [α-acetylcarbamoylamino) -butyl] -penem-3-carboxylic acid 2-L1benzoylcarbamoylamino) -methylpene-B-carboxylic acid 53 464 ““ C ° NH ° * 2 ° ** 2 °° g3 1 2- [2- (benzoyï ka rbamoyï ami no) -. ethylene-3-carboxylic acid εCOIIHCONHCH2CH2CH2CO2H J- 2- [3- (benzoyl carbamoylamino) - 'propylenepene-3-carboxylic acid εCONHCONHwZCX-Iztl-IZCHZCOZHB-α-α-β- 2 - [(carbomethoxy carbamoy] -amino) - ca Boconuconzgcszcozx-x 1 'methylpenem-S-carboxylic acid CH aoconacon fl cæizcriz-coza J. 2- [2- (carbomethoxy carbamoyamino) - ethyl] penem-3-carboxy cz-ßoconncougcázcgzçgzgozg 1 2- [3- (ka rbometoxi karbamoy1amino) - _. ' propylene-β-carboxylic acid α-carbonic acid-2-carboxylic acid carbonyl (α-α-α-α-α-α-α-α-α-α-α-α-α-α-α-α-α-α-α-α-α-α-α-α-α-α-α -B- -carboxylic acid (m3) 'asi (c fi zzzocouncouxcaz-1 2- [2- (Z-trimethylisyl] ethyl oxy carb- cmco H ony' | carbamoylamino) -ethyl] penem- * 2 -3-carboxylic acid Z- [B- (Z-trimethylsilyethylethoxy] 'carb- u; CH Co H onylcarbamoyamino) -propyl' |) penenu- 2 2 2 _ ._-B-carboxyic acid, (C33) 3511 (GHz) 2OCONHCONHCH2- 1 464 _027 Acxïeringsmedeï (C33) 3 Si (CH 2) 3 20CONHCONHCH cxzcazcszcozx CH3S2CNHCH2CO2H cx xzszcxxcazcazcozn CH3S2CNHCH2CH2CH2CO2H about 3s2cN1-zcx2c112cx2cx2cø2u cnssoznxcszcoza w- $ CH3 O2NHCH2CH2CO2H CH3SOZNHCEIZCBZCH2COZH Cäasøzxl-ICI Iztl al zcäzciizcozg QSOZNHCH CO H 22_ 2:54 a.m. Method Product 2- [a- (2-trimety1siïyïetyloxi- carbonylcarbamoylamino) -butyl] -penem-3-carboxylic acid 2- [1-methylthiothiocarbonylamino) -methyl] -penem-3-carboxyic acid 2-12- (methylthiotiocarbonylamino) -ethylpenem-3 -carboxylic acid 2- [3- (methylthiothiocarbonylamino) -propyl] -penem-3-carboxylic acid 2- [α- (methylthiothiocarbonylamino) -butyl] -penem-3-carboxylic acid 2-[1-methanesulfonylamino) -methyl-17-phenyl-2-phenyl-3-acid] hetanesulfonylamino) -ethyl] -penem-3-carboxylic acid 2- [3- (methanesulfonylamino) -propyl] -penem-3-carboxylic acid 2- [α- (methanesulfonylamino) -butyl] -penem-3-carboxylic acid 2- [β-benzenesulfonyl ) -methyl7- penem-3-carboxyic acid 55 Acylation Medium Method É uacxucuacxzcazcozx 1 Il uacxnavucazcxzcxzcoza 1 _ "n. xscwacxacazcuzcxzcnzcoza 1 fi øuxcxucxrzcozs 1 N n _ 'ø x-xcxncnzcazcoza 1 É ønxcxäcxazc fi zcæxzcozx “_ 1 3 ønncuacxzczazcxzcnzcoz 1z nn. Il 2 2 2 2 ao ° '_ _: 464 027 Product 2 - [_ 2- (N-methylthiocarbamoylamino) - ethylpenane-3-carboxylic acid Z-LB- (N-methylthiocarbamoylamino) - propylpenem-B-ka carboxylic acid 2- [4- (N-methylthiocarbamoylamino) - butylpenem-B-carboxylic acid Z- [1N-phenylthiocarbamoylamino) - methyl] penem-3-carboxylic acid ZQ- (N- phenylthiocarbamoylamino) - ethylpenem-3-carboxylic acid 2- [3- (1N-phenylthiocarbamoylamino) - propyl] phenem-β-carboxylic acid Z-β1- (N-phenylthiocarbamoylamino) - butylpenem-3-carboxylic acid 2 guanylamino) methyl-penem-3-carboxylic acid 2- [2- (guanylamino) -77-penem--3-carboxylic acid Z-LB- (guanylamino) propyl-pen-em-3 -carboxylic acid 464 027 _Acylating agent BO 2CH2CH2CH2CO2H 0.? jo _ o Lïmx-cxzcoza H3C '-CHZCHZCOZH cxzcn èo H' 'CH 22 2' ° CH2CH2CH2CH2CO2H O Ü | _. n-cnzco cazcoza '-cnzbnzcazcoza' -CH2CH2CH2CH2CO2H 02NCH2CO2H ozucx-xzcxzcoza 02NCB2CH2CH2CH2CO2H Product 2- [α- (guanylamino) butyl] -penem-3-carboxyic acid 2- [Iacetylimino] -acetylimino Ethyl 17-penem-3-carboxyic acid 2-13- (acetamidoylamino) propyl-17-penem-3-carboxyic acid - 2- [α- (acetimidooamino) butyl] -penem-3-carboxyic acid - 2-L1formimidoylamino) methyl17-penem-3-carboxy - [Z- (formimidoylamino) ethyl] - penem-3-carboxylic acid 2- [3- (formimidoyamino) propyl] penem-3-carboxylic acid 2- [α- (formimidoyamino) butyl] -penem-3-carboxyic acid 2- [ Hydroxyamino) methyl7-penem-3-carboxylic acid 2- [2- (hydroxyamino) ethyl] -17-penem--3-carboxylic acid 2- [α- (hydroxyamino) butyl] -penem--3-carboxylic acid 57 Cyclicidation Method? (CH3) 3si (ca fi zocon-cxzccza. lf = ° fl = * s' (C33) 351 (GHz) zocon-cazcxzcozx -; __? “ß (C33) 3si (cuz) 2 ocoucnzcazmzcoza f.? °“ ß (ca s' - '. 35 ucnfzoconcazcxzcnzçnzc 23 f ? “2 (CH3> 3si (cH2) 2ocoNca2co21-x ff 2 YR: (ca3) .3sz (cazhocoucxzcazcgzg. 2 V2: wa -. 3) 3s;. (C¿2) 2oconcxxzcnzcx-xzcuzg y. 2 _ alm : “I _ '\ yæyz (CH3) 3Si (ca2) 2ocoNcn2co2s = 2 ïæyz (CH3) 3SJ. (CH2) 20CO C fl zc fi zcozg _ 1 2 ri fl caäz (C83) si (ca) ocoucx ca ca co x. - 3 2 zzzz 2 2 $ (° H3) z - ca - - 464_Û27 Product -Z- [1-methoxyamine-methyl-penem-Bycarboxylic acid 2- [2- (methoxyamino) ethyl] -7- penem-S-carboxylic acid -ZB- (methoxyamino) propyl - penem-B-carboxylic acid 2-174- (methoxyamino) butyl - penem-3-carboxylic acid 2 - [(hydrazino) methyl] -7penem-3-carboxylic acid Z-LZ- (hydrazino no.) ethyl] 7-phenem--3-carboxylic acid ZB- (hydrazino) propylene-3-carboxylic acid 2'Û ° (hydraz'i now ÜUUÜPEHGN '3-carboxylic acid (2-112,2-dimethylhydrazine) - methylpenem-3-carboxyl acid Z- [Z- (LZ-dimethylhydrazine) - Ethyl] phenene-β-carboxylic acid 2- [3- (2,2-dimethylhydrazine) - propyl] phenene-3-carboxylic acid a Z-ß- (LZ-oimethylhydraz1'n) - -butylpenem-.ii-carboxylic acid 464 027 Aczyme CB3CONHNHCH2CO2H _ CH3CONHNHCH2CH2CO2H CH3CONHNHCH2CH2CH2CO2H2H2H2H2H2H2H2H ° (CH3) 2NCH2CH2CH2CO2H (CH3) 2§cx2ca2cx2cH2co2x Én: _ cxaconcazcoza fas cnacoucæzzcæizcozn ÉH: cxacoscnzczazcazcoza 915 CH3CONCH2çH2CH2CH2CH2CH2CH2H2 Method Product 2 - [(2-Acetylhydrazine) methyl] -7-penem-3-carboxylic acid 2- [2- (2-Acetyl-hydrazine) -ethyl] -Penem-3-carboxylic acid 2- [3- (2-Acetyl-hydrazine) -propyl] -pepem-3 -carboxylic acid 2- [Z- (2-acetylhydrazine) -but-1-yl] -penem-3-carboxylic acid Z- [1-dimethylamino) methyl] -penem-3-carboxyic acid 2- [2- (dimethylamino) ethyl] -pen-em- 3-Carboxylic acid 2- [3- (dimethylamino) propyl [7-penem-3-carboxylic acid 2- [N- (dimethylamino) butyl] -penem-3-carboxyic acid 4 2- [1N-methylacetamido) methyl] -7-penem-3-carboxylic acid 2- [2- (N-methylacetamido) ethyl [7-penem-3-carboxyic acid 2- [3- (N-methylacetamido) propyl [7-penem-3-carboxyic acid 2- [N- (N-methylacetamido) butyl] -7- penem-3-carboxylic Acxleringsmedeï E ::: I ::; $ - cazcazcxzcozn ::: f] ::; h-cazcxzcxzcxzcoza øcxzocou cazcazoc fi fi zcozx øcuzocouncæxzcxazscazcozn azcxzø OC XZOCONHCHZCHZNCHZCOZH 92 øca2oc? uapa2c§2uca2cø2s øcxzocouu- <í :: >> - cazcozx cazcozx _ QWQQNHÖ - øc fl zocoax - <::: >> co2x COH - 2 øcxzoconu - <::: j; - 2 464 027 Product 2-Lifloimido) methylpenemene-3-carboxylic acid 2- [2- (phthalimido) ethyl17-penem-3-carboxylic acid 2-13- (phthalimido) propyl] -penem--3-carboxylic acid 2- [Α- (phthalimido) butyl] -penem-3-carboxylic acid 2- [12-aminoethoxy) methyl] -7-penem--3-carboxylic acid 2 - [(2-aminoethylthio) methyl] -penem--3-carboxylic acid 2-LI2- aminoethylamino) methyl7- -penem-3-carboxylic acid 2- [N- (2-aminoethyl) -N-methylamino] -7-methypenem-3-carboxylic acid 2- (p-aminobenzyl) penem-3-carboxylic acid 2- (o-aminobenzyl) penem-3-carboxylic acid 2- (p-aminophenyl) penem-3-carboxylic acid 2- (m-aminophenyl) penem-3-carboxylic acid 464 027 60 | Aczylating agent Method _ Product I: '_ "c'o'2ïa' _ "" "" '_ "Øcx oconu-% ï :::> 1 2- (o-aminophenyl) penem-3- 2 -carboxylic acid øcxzocouacaz - <:::: >> co2x 1 2- [b- (aminomethyl) Phenyl-17-penem-3,3-carboxylic acid cozoxycocosaconacus - 2-Lh- (aminomethyl) phenyl-3-phenem-3-carboxylic acid C023-oxo-zocouacaz-2-lb-aminomethyl-phenyl - -3-carboxylic acid 61 464 027 Example gel 8 The following 2-penem products can be prepared from the indicated vna starting materials by the following procedure "Saw _ sco (ca2) nc1 | + c1 (cx2) ncoc1 - ¥ -> JI '~ - o J-NYPøB cozvua' °° 2P "B °«. /fg-.N / Q s ~ E;) S e 1; -2-> l ( ca J Cl ---> I <° “2) n'N / \ --N // 2 n NaI // __ 0 co2PNs COZPNB 1 / avblockering llavblockerinq s I 125 æ 'f I i \> ___N // o 0 '6 C023 C02 _ Starting material' Product IS (according to) bl IS (° “2) 'š2 / \> -4 - N // 2“ 4--3 // n "O 0' e COZPNB C02 '\ Exp, A 'n _ m Ao n - l Exp. B n I 2 5- U '2 Exp, C n I 3 cv Ö I 3 Exp. D n I 4 Dß 0 '4 464 027 62 Exem el 9 s D fifi w ~ o f coza + clcocx ca Cl u pg ,. 2 2 _ o “Yés o Y 3. cozine CO 2 PN 3 II 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 was cooled in an ice bath. and treated topically 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 464,027 were 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, 5 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. This was used in subsequent steps without further purification. L 'rn (cxc13) .17ss. 1690 en.

NHR (cocls) 6-_3! 22 (23, d 'JQ Hz), 7755 1453, 111): 5:72 (23: d: _ 3-9 Hz), 5,7 (13, m), so zzn , 2 :), s.ss (za. 2: 1-2-8 (4fl- ml-) 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 sulphate and evaporated in vacuo to give 1.4 g (90%) of compound V as a amorphous solid It was used in subsequent steps without further purification. in 1.ss (is H, m). aa (za, 4.: -9 sz), s.1 (ia. =>. s.1 (za. 2 :). 4.72 (zu, ag J-12 az, J-6 az), "2.6 (4H, m) 2 1.4 <6H. s). 1.29 (en. s) - 464 027 64 VI En A solution of 1.6 g (2.06 mmol) of 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. material and then gave ethylac 620 mg (62%) of compound VI as a white solid, m.p. 83-84 ° upon crystallization from ether.

IR (CHCIB) 1790. 1710 Gl NHR: (CDCIB) δ 8.2 (23. å »UIQ H2), 1.6 (an. A. A-sí-xz) vs (za, s» s.ss un. De. Jam - 4 az .: cis - 2 az), 5.22 (za, 2 :), 4.75 (za. Aq J-12 sz, J-6 az). 3-85 (ml dä] _ KZI _ 4 H25! 315 (ml de! _ Hz '.

J _ - 2 az),: .a-3 .: (za. Nl. 1.4 (an. S). 1-28 (§H. Sl- s _ ß (: 2 / \. 3 «a <>, To a solution of 200 mg (0.4 mol) of compound VI in 8 ml of tetrahydrofuran and 4 ml of ether was added 34 mg (0.4 mmol) of sodium bicarbonate in 4 ml of water and 200 ml of sodium hydroxide. mg 30% Pd / celite, followed by hydrogenation for 2 hours at a pressure of 2.8 x 105 Pa. 65 464 027 The mixture was filtered and the layers were separated. with 1 ml of 1N hydrochloric acid and extracted with 5 x 5 ml of chloroform, the organic extracts were dried over sodium sulfate and evaporated in vacuo to give 76 mg (52%) of compound VII as an oil.

IR (C803) ivso, 1110 = m'f nun (cncis) 6 9.5 (ia. Vs), s.es (1a. Aa.

Jtzans I 43 :, Jcis I 2 Hz), 4.72 (1H, dq -7112-81, JIG Hz), 4.2's.1 (za. Ml, s; 4-4.1 (za, ha, 2.1-2.4 (za , m). 1.as asa ,, s>, 1.25 (öl-X. s).

Exemgel 10 S I in swe N. : H92 o C028 Sàg 9 o +, c13 (cH2) 3P (oc2H5) 2 ---- + Jlf ”P“ o 2 OC H l co rus s \\ u, / (° “2): P (2 s 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 1.5 ml of CH 2 Cl 2 was added dropwise a 1 M solution. of the pyridine in CH 2 Cl 2 (2.2 mL; 2.2 mmol). 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 It was then dried over magnesium sulphate and filtered over celite charcoal, after evaporation to dryness to obtain 0.99 g of a (10% water) Var "oil. obtained 0.5 g of compound 3 (32.8%).

J - - ~ mm 6 (ppm, cncis) 1.o-a.4 (n, lea), 4.e-5.s (an. N), 4-1 (48. q). 3.:-4.z,<2a, a) 2.1 (za. Mh 1.9 czu, az, ice (sn. => - 0.4 g (0.52 mmol) of compound 3 in 35 ml of toluene was refluxed for 4 hours and evaporated to dryness to give an oil containing compounds 3, 4 and ø3P = 0.

This was chromatographed on silica (10% water, 0 ° C 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, una 6 (ppm, coc13). 8.3 (za. 6). 7-67 (251 6); so? (HI qøy (231 d) | 4: 2 q) | (HI q) | 3.4 (H, q), 2.9 (za, mä, 1.9 (ax, m), 1.3 (sa, t). IR (rent) ivso = m'1 (B-iabeam) 111o = m'f «==: =:> a \ S ig”! 'L \% â : / \\ // \\ mmuz ______ * .- ': PNS. s _ - (Cheese) _ i “N -2 CO 23 á A mixture of 0.1 g (0.207 mmol) of the compound 4, 0, lg 30% Pd / celite and 17 mg (0.207 mmol) of sodium bicarbonate in 10 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, extracted with CH 2 Cl 2 and dried over magnesium sulphate, the solution was evaporated to give 48 mg (66.5%) of compound 5. IR spectrum 8 IR90 67. 027 OI: (ß-lacquer tam) 61700 <-C-OHH - Exemgel 11 - (1'R, -5R, 6R) - and (1S; 5S, 6S) = 6- (1'-hydroxy-1'-ethyl) -2-methyl - genem-B-carboxylic acid (isomer D) (illustrates the most preferred process for the introduction of the β-substituent into a middle phase of the synthesis) A. Preparation of 4-trityl-thio -Z-azetidinone intermediates l. 1- (Trimethylsilyl) -4-trityltio-Z-azetidinone 3 A solution of 345 mg (1 mmol) of i-trityltio-Z-azetidinone, 80 mg (0.5 mmol) 1,1,1,3,3,3-hexamethyldisilazane and 55 mg (0.5 nunol) of chlorotrimethylsilane in 20 ml of dichloromethane were refluxed for 18 hours, concentrating the reaction mixture to give the title compound in substantially pure form. _ _ 6 (ppm, cnclah 7.32 cisa, a, arma. -), 4.22 (m, aa, a-4). 2.61 un. AaI a - 4.1. A - 1s_, aa). 2.22 (m, aa. A - 2.:, J _- 16 'H-3) | G03 s; 2.. 1- (t-butyldimethylsilyl) -4-trityltio-Z-azetidinone _ fm ”___, Ef * i' Ii-N Ä 1.62 ml (11, 6 mmol) of triethylamine were added dropwise over 5 minutes; one cooling mmol) of fl i-trityltio-Z-azetidinone and 1.68 g (12.7 mmol) chloro-t-butyldimethylsilane in 35 ml of DMF The reaction mixture was stirred at room temperature for 18 minutes and then diluted with 250 ml of water and 200 ml of ether, the organic phase was washed with 3 x 50 ml of water, dried and concentrated to give 4.33 g of an oil. Crystallization from the pentane gave a total of 4.1 g (89%) of the title compound as a white solid, m.p. 113 DEG-114 DEG-114 DEG. Δ (ppm, CDCl 3 7.45 (153, m, arena.), 4.2 (1H, dd. H-4). 2.63 (1H, dd. J - 4, J - ie, n-3), 2.13 (in, aa , J '2. JI' 16, 14-3), 1.0 (SH, S, t-Bu), 0.35 (GH, S, He). -1 v _ ° 1735 cm. C Anal. Refer to a nossl; c , 73.15, u, 7.24; 2833 N. 3-05: S. 6-97 \ .E \ àu1et: 'c, 73.27; a, 7.32; N, 2.97; s s.94s. 3. 1-methoxymethyl -4-trityltio-2-azetidinone SCÛ skos ----- + »t Jï.f \ o." 2 ° osams A solution of 1.38 g (4.0 mmol) of 4-trityltio-2-azetidinone in 10 ml of THF was added to a well stirred suspension of 200 mg (4.1 mmol) of sodium hydride in the form of a commercial 50% solution (washed with pentane) in 10 ml of THF, which was kept at -150. 12 drops of methanol were added and The mixture was stirred at -15 ° for 0.5 hours, 0.58 g (4.6 mmol) of methoxymethyl bromide were added and the mixture was stirred for 2 hours, diluted with ether, washed with water and brine, dried and concentrated. to give 1.72 g of an oil, crystallization from pentane gave 1.41 g of a white solid, m.p. 2-760. Δ (ppm, CDCl 3): 713 (15H, m, aromat.), 4.4 (3H, m, NCH 2 O and H-4), 3.22 (3H, s, CH 3), 2.76 (2H, m, H -3). 464 027 70 4.

To a suspension of 322 mg (1 mmol) of tetrahutylammonium bromide and 70 mg (1.1 mmol; 85%) of potassium hydroxide in 10 ml of dichloromethane, which was cooled to 5 °. , was added with vigorous stirring - 345 mg (1 mmol) of 4-trityltio-2-azetidinone and 187 mg (1.5 mmol) of methoxyethoxyethyl chloride. The mixture was stirred at room temperature for 2 hours, the solvent was evaporated and the residue partitioned between water and ethyl acetate. The dried organic phase was concentrated to give 415 mg of a viscous oil. Purification by column chromatography on silica gel eluting with 5% ether-dichloromethane gave 206 mg (48%) of the title compound as an oil. u '6 (ppm, CDCl3) § 7-30 (isn. m. amma;). 4.57 (za, “quartet u-gzo). 4-46 O). 3.30 (33. S, 343) »2-75_ (m. Aa. Au. S.sø (an. S. Ogzgaz (23. m, Hf3). 5. 1- (2'-tetrahydropyranyl) -4-trityltio -2-azetidinone - 46 ml 464,027 1.6 ml (1.6M; 2.56 mmol) of n-butyllithium was added dropwise to a solution of 863 mg (2.5 mmol) of 4-trityltio-2-azetidinone in THF After stirring for 1 minute, 560 mg (4.7 mmol) of 2-chlorotetrahydropyran was added and the reaction mixture was allowed to warm to room temperature over 1.5 hours. The reaction solution was diluted with ethyl acetate, washed with salt. solution, dried and concentrated to give 635 mg of an oil Column chromatography on silica gel eluting with dichloromethane-ether gave a mixture of the isomers of the title compound which was contaminated with a small amount of starting material. pm .: man 'ms (fsa. m. aromat.), 4.4 (B, då. 3'4) | 2-9'2-2 (23: Wv- H ° 3h 4-'l ° 3'2 5.0 .. 2.2-O.7 (tetrahydropyranyl) - B. Preparation of 3- (1'-hydroxy-1'-ethyl) -1-methoxymethyl-4-trityltio-2-azetidinones a) (1'S, 3S, 4R- and l ' R, 3R, 4S) -isomer (isomer C) A solution of lithium diisopropylamide was prepared in 5 ml of THF at -78 ° starting from 1.0 ml (1.6M; 1.6 mmol) of n-butyllithium and 0.25 ml ( 1.84 mol) of diisopropylamine.-After 30 minutes, a solution of 491 mg (1.42 mmol) of 1-methoxymethyl-4-trityltio-2-azetidinone in 6 ml of THF was added dropwise, and the solution was stirred for 15 minutes. 3.0 ml of acetaldehyde were added dropwise, and after 20 minutes 30 ml of water were added. The mixture was acidified to pH 3 with 2% hydrochloric acid and extracted with 5 x 20 ml of ethyl acetate. The combined organic phases were washed with brine, dried and concentrated to give an oil which crystallized on trituration with ether in an amount of 440 mg (80%) and with a melting point of 188.5-9 °; _ '* a¿: (cnciai 6 = 1.: - Kisa. a. aramac. a, 4.31 (za. Aaq, ug§2o>. 4. :: (ia. a. J-2, a-4) . 2.11 (an. S. Ocna), a.:z-2.1o (ax, a, as a .. as) o. 1.12 ppm (BIL a, an, ena), fl aißer-.för c26n27uo3s = c moi, 1-1 6.28. U 3.23. S 1.as; F ¥ H fl W% f = c 11.99. H e.o2, n 3.21. S_1-40 \ - b) (1's, 3s, 4R den 1-R, sR, 4s> - and <1'R, ss, 4a and 1'S, 3R, 4S) -isomers (isomers C and B) A solution of 0.482 mmol of lithium diisopropylamide was prepared at -78 ° in 3 ml of dry ether starting from 0.191 ml of a 2 , 52 M solution of butyllithium (0.482 mmol) in hexane and 0.067 ml (0.482 mmol) of diisopropylamine After 20 minutes a solution of 0.171 g (0.439 NO1) (4R OCh 43) -1-methoxymethyl-4- was added dropwise. trityltio-2-azetidinone in a mixture of 1 ml of dry ether and 1 ml of dry THF and the resulting clear solution was stirred for 15 minutes at -780. A solution of 0.96 ml of a 0.5 M solution of tetrabutylammonium fluoride (0 48 mol) of THF was then added, a pale pink precipitate was obtained, after 5 minutes at -780 the reaction b landing with 0.2 ml (excess) of freshly distilled acetaldehyde and stirring was continued for a further 15 minutes. Work-up was carried out by adding to a saturated ammonium chloride solution and extracting with 2 x 25 ml of ethyl acetate. The combined organic phases were washed with brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent in vacuo gave 0.228 g of an oil which was chromatographed on 10 g of silica gel. A 6: 4 mixture of benzene and ethyl acetate gave 0.106 g (62 3 yields) of substrate and a mixture of the two isomeric alcohols, which were separated by chromatography on thin layer plates (same solvent system). The alcohol with the higher Rf value (0.033 g; 17%) was identical with the above isomer (isomer C) and had a melting point of 188.5-189 ° (ether-dichloromethane). The alcohol with the lower Rf value Z (0.030 g, 16%) (isomer B) was obtained as an oil, which crystallized with difficulty from hexane, m.p. 94-9 °. ~ 1 'få (ca ci) v =: soo (om. 1760 cufl (c-cn: * HM (C003) <5 = 6-9 ° 7-5 2 2 max (1514. m. Arcmat), 4.2 ( 2H.Centr =; '8 \ f ABq, J-llá »äz-O-C fl s), 4-23 cin, a, a-2.0, 4-H), a.ss (1a.centr.av en br. sextett, -1 '). 3-3 (13, 55, 33A trans-L5, Jay-ins, 33), 3.15 (3H, s, O-gia). 1.55 (1x.tnnaa ~ =, ou-1- >, xudš (au. a. qfe.s. a-2 '>; gggi. Ber: = för-' c26n27no3s = c 12.ø2, a e.2a, à 1.23. s 7.:s;Fï fl H¶2t = c 71.11 and 6.36.

N 3.l5._ S 7.43%.

C. Preparation of trans-3-acetyl-1-methoxymethyl-4-trityltio-'EEEEÅÉÉEQE Lithium diisopiopylamide is prepared under a nitrogen atmosphere via -780 in the usual manner starting from 0.34 ml (2.4 mol) of diisopropylamine and 1.1 ml of a 2.2M hexane solution of n-butyllithium (2.4 mmol) in 3 mL of THF. A solution of 0.78 g (2 mmol) of 1-methoxymethyl-4-trityltio-2-azetidinone in 3 ml of THF was added dropwise and after stirring for 20 minutes at -78 ° 0.53 g (6 mmol) of ethyl acetate in a portion and stirring was continued for 0.75 hours at -78 °. The reaction mixture was diluted with ether and washed with an ammonium chloride solution, water and brine, dried and concentrated to give 0.7 g of an oil. Purification was accomplished by chromatography on 20 g of silica gel eluting with increasing amounts of ether in benzene. The appropriate fractions in question were concentrated to give the title compound as a colorless oil in an amount of 0.32 g (37%). '' nu (éncls) s =: sf-m usa, name. n. ms un. d. 1-2. 11-4). 4.5 (za, s, u-gga-o), 3.9 (1n, a, J-2. N-3). 3.22 (BH, s. CH 3>, g.o ppm (BH. =. Ens), 1: vm; x = 1110. 1110 = m'1.

D. Preparation of trans-3-acetyl-1- (t-butyldimethylsilyl) -4-trityltio-2-azetidinone. C63 'o LDÅ Jag' 1 i- fi Nx- ß-Bu '3 S1 \ N \ s zt-Eu' ma). 1. 3 2 'Nc fi atz Diisopropylyllithamide was prepared in the usual manner starting from 0.18 ml (1.24 mmol) of diisopropylamine and 0.78 ml of a 1.6M hexane solution of n-butyllithium (1.24 mol) in 8 ml of THF. A solution of 0.46 g (1 mmol) of 1- (t-butyldimethylsilyl) -4-tritylthioia-azetidinone in 8 ml of THF was added dropwise at -78 °. After stirring for 5 minutes, 1 ml of ethyl acetate was added in one portion and the mixture was stirred for 3 hours at -78 °.

The mixture was acidified with cold 0.5 N hydrochloric acid to pH 6 and extracted with 2 x 20 ml of ethyl acetate. The combined organic phases were dried and concentrated to give 0.5 g of an oil, which crystallized from pentane in an amount of 200 mg (200%) in total and with a melting point of 122-4 °. 1: vmax = 11so. 1110 = m'1; * ams (coola) 61 a-1.1 cisu. -. azamsc. >. 4-83 <1n. a,: -z.a-4>, 3.38 (ln. a. J-2. a-3). 1.ao (ax. A, cna). 0-92 (SH, S; BU Oo. Os: (en: I; E. Preparation of trans-1- (t-butyldimethylsilyl) -3-formyl--4-trityltio-2-azetidinone U SCQ3 I. H ' To a cooled (-780) solution of 0.34 ml (2.4 mmol) of diisopropylamine in 5 ml of tetrahydrofuran was added dropwise under nitrogen 1.6 to a cooled (D11% If S \ i (C33) 2 t-Bu ml of a 1.5 M solution of n-BuLi (2.4 mmol) After stirring for 30 minutes, a solution of 1.0 g (2.18 mmol) of 1- (t-butyldimethylsilyl) -4- was added dropwise. trityltio-2-azetidinone in 5 ml of tetrahydrofuran and stirring was continued for 30 minutes 0.8 ml (9.9 mmol) of ethyl formate was added and the cooled solution was stirred for 10 minutes, the reaction mixture was washed successively with 5 ml cold 1N hydrochloric acid, 6 ml of 1M sodium bicarbonate, 10 ml of water and brine The organic layer was dried over magnesium sulphate, evaporated and crystallized from pentane to give 810 mg (76%) of the formate as a white solid, m.p. 132 -3 °; in (cHc13) -0 max: neo, 1715 cnfl- lum r (cnc13) 6: 9.0 (m, a, J = 1, zs 112); 1.30 l (15H, m), 4.7 (1H, d, J = 1.5Hz), 3.5 ppm (1H, tf J = 1.5 H2) - NOTE: a) the diisopropylamine was distilled over Ca 2+ and stored 464,027 76, on KOH. a) Tetrahydrofuran was distilled over LAH and stored on 3Å molecular sieves. c) The ethyl formate was stirred at room temperature with K 2 CO 3 and then distilled over PZOS. d) n-BuLi was titrated with 1N hydrochloric acid.

F. Preparation of 1- (t-butyldimethylsilyl) -3- (1'-hydroxy-1'-ethyl) -4-trityltio-2-azetidinones (4 isomer iso-. SCes Cd: 3 a) t-Bu 3 u (He) \ (M °) 3.4 ml of a 1,6M solution of n-butyllithium (5.44 mmol) were added over 5 minutes to a solution of 0.847 ml (6.23 mol) of diisopropylamine in 30 ml of THF, which was maintained at -780. After 0.5 h, a solution of 2.0 g (4.4 mmol) of 1- (t-butyldimethylsilyl) -4-trityltio-2-azetidinone in 20 mL of THF was added; after 15 minutes, 10 ml of acetaldehyde was added in one portion and after another 15 minutes, 100 ml of water were added. The mixture was acidified (pH 5-6) with dilute hydrochloric acid and extracted with 3 x 30 ml of ethyl acetate. The organic phases were washed with brine, dried and concentrated to give an oil, which on thin layer chromatography was found to consist of a mixture of 4 isomers (denoted isomers A, B, C and D in order r of decreasing polarity).

Crystallization of the oily residue in ethyl acetatepentane 77 gave the isomers B and C as a white solid and left the isomers A and B in the mother liquor. The four pure compounds were obtained by preparative chromatography (Waters, 500) of the above solids and mother liquors. The relative proportions have: A 17%, B 32%, _ C 39%, D 12%. If in the above reaction THF was replaced with ether and the reaction was quenched after 1 minute at -78 °, the relative proportions of A, B, C and D became 12.9%, 30.5%, 38.2% and 18.4 %. If the reaction in ether was allowed to proceed to a temperature of 20 ° for 2 hours before quenching, the proportions were 13.4%, 24.6%, 44% and 18%, respectively. If one molar equivalent of anhydrous magnesium bromide was added to the reaction mixture, the proportions were changed to 19.2%, 19.7%, 30%,% and 31%, respectively.

Isomer A: This isomer exhibits cis stereochemistry at C3-C4.

It is a racemic mixture consisting of the (1'S, 3R, 4R) and (1'R, 3S, 4S) enantiomers. The compound hereinafter derived from compound A is designated "isomer A" and is an enantiomeric mixture and has the same configuration at C1, C3 and C4. Compounds derived from compound A via a reaction involving inversion of the configuration are hereinafter referred to as "isomer D" if the inversion takes place at C1 and "isomer C" if the inversion takes place at C3. melting point 152-3 °; * fl mr (cncis) 6 = a.o-s.a (isu, a, examen.), 4.ao (ia, a, J-s.s. a-4). 3.18 (xx. M, H-1 '). 3.10 (in, aa, J-s.s, J-10, a-3). 1.22 (aa, 4. a-a.s, C33). 0.95 (sa, s. Nu). 0.21 (en, u, ana). 5131, 'Ber. for Czounnozsa. c 11.52, a 1.4o, n ma, s: hasmfïlnåêeitc 11.za, a 1.41, n z.4a, s s.19§.

Isomer B: This isomer exhibits trans stereochemistry at C3-C4.

It is a racemic mixture consisting of the (1'R, 3S, 4R) and (1'S, 3R, 4S) enantiomers. Compounds of the same configuration at C1, C3 and C4 are designated "isomer B": 464,027 _ 78 s: (cacza) vu »ms af-'Hc-onnmp. l58-9'CI IR !! (Cxla) Öl 7-60-7-10 (ISK, I; IIOIIZ; h (-02 (Hb å; J-ols H- * II “g 3-300; 3.018) u'3) l 3n5s'3ø15 ( m1 I | H-lnzp 0-88 (lz C v C31 Oo 2-50); Ö-l fi (Ön: 'I C591 Isomer C: This isomer exhibits trans-stereocene at C3-C4.

It is a racemate formed by the (l'S.35.4R) and (l'R.3R.4 $) enantiomers. Compounds with the same configuration at Cl.

C3 and CA are designated "isomer C". Melting point 134-6 °; * m (cncia) s. 1.s0- 1.10 usa, a, nån ...>, 4.32 (m. a, a-naraïo. 2.02 (px, aa. .1-2.1, .1-1.a, az), 2.o-2.s (m, aq, .1-2.1, .1-6, um, 1.02 (su, a, as, ena). 0.95 (sa, n, e-gu), 0.21 (en, a, (my: s: ((19:23) wax: nas m * (co). v Isomer D: This isomer exhibits cis stereochemistry at C3-C4. It is a racemate consisting of (_l'R). , 3R, 4R) - and (1'S, 3S, 4S) -ene fl "thiomers. Compounds of the same configuration for C1, C3 and C4 are designated" isomer D ". Melting point 171-20; m: (cpczz) 1 m0- e.90 (Isa, a, man:), 4.10 (m, a, .1-4.s, nn. 3.02 (m, aa. a-4.s, .1-0.s, 11-3) , - 2.a9 (m. Aq, Jo.s, .1-ss, am, 1.0 (aa, a .1-ss, (ma). 0.91 (en, a, z-nu), 0.22 (an , a, ena). 53 :. Ber, för ca no ssi: c 11.52, a 1.40, n 2.10, s sasufuf fl ßfd c 11.21. 30. 37 2 H 7.43. N 2.51, S 6.318. s šcø, _ JH b) 4 IN / tBu _ \ s1 "\ 5l \ He 2 79 4e4“ ö27 A solution of 1.0 g (2 mmol) of trans-3-acetyl-1- (t-butyldimethylsilyl) -4-trityltio-2- azetidinone in 30 ml of THF was added dropwise under a nitrogen atmosphere to a cooled (0 °) and stirred s suspension of 0.38 g (10 mmol) of sodium borohydride in 120 ml of THF. The ice bath was removed and the mixture was stirred at room temperature for 4 hours. It was poured into ice-cold 1N hydrochloric acid (pH 6), stirred for 15 minutes and extracted with ether three times. The combined ether extracts were dried and concentrated to give 1.04 g of an oil which was crystallized from pentane to give the title compounds as a 70:30 mixture of isomers C and B, m.p. (84% yield).

OH o | CÖB. . A suspension of 4.78 g (15 mmol) of cuprous iodide in 50 ml of ether was cooled to 0 DEG C. and treated with nitrogen with 26 ml of a 1.9 M solution of methyl lithium (50 mmol). The brown solution was stirred at 0 ° for 10 minutes and then cooled to -600 and treated dropwise with 2.43 g (5.0 mmol) of 1- (t-butyldimethylsilyl) -3-formyl-4-trityltio-2-azetidinone in a mixture of 10 ml of tetrahydrofuran and 40 ml of ether. Stirring was continued for 3 hours. The solution was warmed to -400 and treated gently with a 1M solution of ammonium chloride. The mixture was filtered over celite and the organic phase was washed with 3 x 5 ml of a 1M solution of ammonium chloride and then with brine and dried over sodium sulfate. Filtration and evaporation gave the alcohol isomer B, which was crystallized from hot pentane in a yield of 1.6 g (65% and with a melting point of 160 DEG-46 DEG C.).

'H =: ccnczaa 6- 1. :: (isu. Az. 4.os (in, 1). 3.4 (1n, ¿,;.; Fl, 3,25-: .ss (ia. Ni. 1.6 ( in, 1). 0.9 (iza. na o. 0.1 pp. (gu,.;, - §§§¿¿ a) tetrahydrofuran and ether were distilled over LAH, b) methyllithium was titrated with 1N hydrochloric acid, c) copper (I) Iodide was purified by continuous extraction with anhydrous tetrahydrofuran in a Soxhlet extractor for 18 hours and then dried in vacuo in a vacuum desiccator (PZOS) for 18 hours.

. SW; in a . 0.1 ml (0.1 mmol) of methylmagnesium iodide was added dropwise to a cooled (Oo) and stirred solution of 25 mg (0.1 mg). 0.05 mol) trans- -1- (t-butyldimethylsilyl) -3-formyl-4-trityltio-2-azetidinone in 2 ml THF. The solution was stirred for 1.5 hours at 0 °, poured into an ammonium chloride solution, acidified with a 1N hydrochloric acid solution and extracted with ether. Drying and concentrating the organic extracts gave an oil consisting of starting material and a small amount of a mixture of the two title trans compounds, isomer B predominating. F. TV adjustment of (1s, 3s, 4n and 1'n, 3n, 4s) -1- (t-butyld1-methylsilyl) -3- (1'-trimethylsilyloxy-1'-ethyl) -4-tritylthio -2- -azetidinone (isomer C) 81 464 027 A solution of 15 mg (0.3 mmol) (1'S, 3S, 4R and 1'R, 3R, 4S) -1- ((t-butyldimethylsilyl) -3- (1'-hydroxy-1'-ethyl) -4-trityltio-2-azetidinone and 35 mg (0.30 mmol) of azidotrimethylsilane in 6 ml of dry THF were stirred at room temperature until the starting material had disappeared (15 minutes). Purification of the reaction mixture by column chromatography (silica gel, methylene chloride) gave the desired compound as a white solid in an amount of 128 mg (74 .mu.l) with a melting point of 14 DEG-14 DEG.

L? Mr (mr5) 6; n 'ÄIÖNÖtO j' 'dl 07-115) B-4) y 2125-2189 (zul n' “_31 H" 'l') | ° 082-1c ° 7 l | t-êu; a ° 2 ') | f; 913) »“ 0-10 (SH, I, 'O-Siæ fl ya; h ”. (C fl Cls) Vmx: 1736 cin-1 (CIO).

G. Preparation of (1'S, 3R, 4R and 1'R, 3S, 4S) -1 '(t-butyldimethylsilyl) -3- (1'-methoxymethoxy-ether-1'-ethyl) -4-trityl- thio-2-azetidinone (isomer A) Approx. 12.5 ml of a 1,6M hexane solution of n-butyllithium (20 mmol; just enough to obtain a permanent pink color) was added dropwise to a solution of 10.1 g (20 mol) of 11'S, 3R, 4R and 1 ' R, 3S, 4S) -1- (t-butyldimethylsilyl) -3- - (1'-hydroxy-1 "-ethyl) -4-trityltio-2-azetidinone (isomer A) in 100 ml of THF, which was 78 °. After stirring for 15 minutes, a solution of 2 ml (24 mmol) of bromomethoxymethyl ether in 30 ml of THF was added dropwise. The mixture was stirred for 1 hour at -780 and 2 hours at room temperature and poured into 290 ml of an ammonium chloride solution. Extraction with 3 x 200 ml of ethyl acetate, washing with brine, drying over sodium sulphate 464,027 sz and concentration gave the title compound as a crude product which was purified by chromatography on silica gel eluting with increasing amounts of ether in benzene. 10.4 g of product (95%) were obtained. fm (cncia) 6. 1.1-1.s (msn. n. mmm-). 4.41 (m. A. X-4). 4.2: (za. M. A-v. O-èaz-o),: .1-a.4 (21). l- H-B e: H-P). 3.2: (sa, a. O-aaz). 1.37 (aa. A, J-s.s. Css). 0.91 (an. S. Nu), o.2s ppm (an. N. Saa).

H. Preparation of (1's, 3s, 4R and 1'R, 3n, 4s) -1- (t-buts1a1-methylsilyl) -3- (Y-formyloxy-Y-ethyl) -é-trityltio-Z- azeti- dinon (isomer C) cos ~ -.% fcd> 3 _. g n N \ /. A solution of so mg (0.1 mmol) of 1s, 3s, 4R and 1'n, 3n, 4s) -1- (t-butyldimethylsilyl) -3- (1'-hydroxy-1 ' -ethyl) -4-trityltio-2-azetidinone (isomer C), 100 mg (0.4 mmol) of p-bromobenzenesulfonyl chloride and 24 mg (0.2 mmol) of dimethylaminopyridine in 3 ml of DMF and stirred at room temperature until the starting material had disappeared (0.5 hours). Then the reaction mixture was diluted with water and extracted with ether. The organic extracts were washed with brine, dried over magnesium sulfate and evaporated. The title compound was purified by column chromatography. 'ant (cnclg) (S: Lao (ms CHOM 7-2 °' 7- “Ü” - "” m ”y '3.9 ° .4.36 _' a-II). i 'JIz' (m0 S0 HG3) I _: N18 (an. D '3.6.5. 3,20). 1.0 (QR, j, Ü-EÜ) | 0031 (GR: I: 83 464 027 I. Preparation of (1'R, 3S, 4R and 1'S, 3R, 4S) -1 '(t-butyldimethylsilyl) -3-1'-acetoxy-1'-ethyl) -4-trityltio-2-azetidinone isomer B) OAc-O lczO * t N / Wridin I \ * ïÜ '“\ šÉí- \ A solution of 13,85 g (27, s mmo1> 1'RI3s, 4s and 1's sn 4s> =' -1- (t ~ butyldimethylsilyl) - 3- (1'-hydroxy-1'-ethyl) -4- -trityltio-2-azetidinone in 75 ml of pyridine and 50 ml of acetic anhydride (prepared at 00) were stirred for 40 minutes at room temperature. azeotropically with toluene 3 times) to give an almost white solid The crude product was crystallized from an ether-petroleum ether mixture to give the title compound in pure form (97.5%). * mn mange; 7.64-1.0: (Isa. N. A azamae.). 4.60 (IH. I. J-6. B-1 ') - 2-92 119- 4, Jg, a-4 :, 3.55 (in, aa, a-2. J-6, u-3) 1.19 can. ss CH 3 CO> - 0-98 (aa. a. Je.cx3), o.as (sa, 1, z-buzyii. 0.12 (sn. 1. C fl aiz ir 1 tcncia) v_ax = 1715, 174o an '(c-ox J. Preparation of l- (t- butyldimethylsilyl) -3- (1'-paranitrobenzyldioxycarbonyl) -1'-ethyl) -4-tritylthio-2-azetidinone. (4 isomers) 292m sed ", CO 3 3 u" ° 2 u 'tm' 464 027 S, "Isomer C" 8.8 ml of a 1.6 M hexane solution of n-butyllithium (14 mmol; just enough to obtain a permanent pink color) was added dropwise to a solution of 6.55 g (13 mmol) of "isomer C" of 1- (t-butyldimethylsilyl) -3- (1'-hydroxy-1'-ethyl) -4-trityltio-2-azetidinone in 70 ml of THF, as at -78 ° After stirring for 15 minutes, 3.2 g (14.8 mmol) of paranitrobenzyl chloroformate in 30 ml of THF were added dropwise.

The mixture was stirred for 1 hour at -78 ° and poured into 100 ml of an ammonium chloride solution. Extraction with 3 x 100 ml ethyl acetate, washing with brine, drying and concentration gave 11 g of crude product. The title compound in pure form was obtained by chromatography on 220 g of silica gel eluting with increasing amounts of ether in benzene. Yield 93%; melting point 11s-9 ° (et-sr). i '- _ * nu (cnéia) 6: 8.3S-7 (ISK, n, uomat. 1. 5.12 (ZH, a, bcnçyl), 4-.08 (ll-I, d. a-1.a, a-4). 4-axis (za. aq, Js.s, J-2, a-1 '), 2.10 (1u. aa, J-2. a-1.a, n-3). 1.2 ( an, a. a-6.5, caaí. 1.o (sa.;, au) ,. o.:o - ppm (en, 2 :, ma), i: (cacia) vw: 1745 of * (c- on ¿\ _n _ = _ = _ 1_.Ber-. fêêr c38n¿2n2o6s1s = c sa.a3, n_s.2o, u 4.10 .s 4.s9 fl ñ: nmuat: c ss.so.

H 6.26, H 4.11, S 4.59.

Isomer B "Isomer B" of 1- (t-butyldimethylsilyl) -3- (1'-hydroxy-1'-ethyl (-4-trityltio-2-azetidinone), which was treated as described above, gave pure 'isomer B "of 1- (t-butyldimethylsilyl) -3- (1'-paranitrigenbenzyldioxycarbonyl-1'-ethyl) -4-trityltio-2-azetidinone as a foam (95%).' anz (cnc13 ) 6. s.az-a.so cisn. N. Fi zausz. 2. S-1 (mp '| Ånss-Ånzo (mf .p _n-1') | (ml al a-IWSU H_.4) Ü 3 .sa (in. aa. a-1.s, Js.e. a-ax. 1.1 (au, 6. C33). 0-7 (SH. ßä_§ fl7, '0.2 ppm (sn. n. cn3) : 1: (f11np-y_¿x = 1155. 1740 = 1 C = ° - "Isomer A" "Isomer A" of 1- (t-butyldimethylsilyl-3 * (1'-hydroxy-1'-ethyl) -4-trityltio-2-azetidinone, which was treated in the manner described above, gave pure (isomer A) of 1- (t-butyl] imethylsilyl-3- (1'-paranitrobenzyldioxycarbonyl-1'-ethyl) - 4-triethylthio-2-azetidinone as an oil (95%). - lumr (cnc13) α = 8.3-6.7 (19n, m, aromatic), 4.95 (zu, Aßq, benzyl), 4953 (m) -7nsp J-7osp H'1'_ | d; JG; “.4) | (ml aa. Js. A-1.5. A-3), 1.44 (aa, a, Js.s), o.šs ( sn. 1.: any 002 (suf- 2 .; " Isomer D "Similarly," isomer D "of 1- (t-butyldimethylsilyl} -3- (1'-hydroxy-1'-ethyl}) - 4-trityltio-2-azetidinone gave pure" isomer D "of 1- (t-butyldimethylsilyl) -3- (1'-paranitrobenzyldioxycarbonyl-1'-ethyl) -4-trityltio-2-azetidinone (90%). lnmr (cnc13) δ = 8.3-6.7 (len, m, ar @ mat.), 5.20 (za, Aßq, benzyl), 4.72 (1H, d, J = 5, H-4), 3.50 (1H, dq, J = 6.5, J = 0.5, H-1 '), 2.85 (1H, then, J = 0.5, J = 5, H-3), 1.03 (3H, d, J = 6.5, cH3>, 1.0 (sn, S, t-su), 0.35 ppm (sn, S, cn3>; mp 130-2 °.

Analysis: Ber. for C 38 H 42 N 2 O 6 S: C 66.83, H 6.20, N 4.10, S 4.70 Found: C 66.56, H 6.28, N 3.96, S 4.89.

K. Preparation of 1S, 3S, 4R and 1'R, 3R, 4S) -1- (t-butyldimethylsilyl) -3- (1'-methanesulfonyloxy-1'-ethyl) -4-tritylthio- 2-azetidinone (isomer C) _ II 'l ühïl / scøa / äj / “æ ----- 4 - \ ~ 1æa) o" \\ - it 3 2 Si (CH. -Au _ _ \ 92 t- A solution of 2.0 g (4 mmol) of 1 * s; 3s4R and 1'R, 3R, Ås) -1- (t-butyldimethylsilyl) -3- (1'-hydroxy-1'-ethyl) - 4-Tritylthio-2-acetylamine (isomeric c) in ao of 1 ml of chloromethane is treated via s ° with 0.99 g (8.6 mmol) of methanesulfonyl chloride and 0.87 g (8.6 mmol) of triethylamine. After stirring at this temperature under 1 hour under nitrogen, the solution was washed with brine, dried over magnesium sulphate and evaporated to dryness After crystallization from ether-petroleum ether, 1.9 g (8l, 9%) of the mixture with the melting point 120 DEG-122 DEG. cnc13) 5 = 7.13-1.s1 (ISHI I: lrOßlfuöy (m: d: J-zg H-4) | (m: fi y 3.6.5;: p fl'1 '> - 2-96 $ 1fl «' dd - J-2, 2. H-3). 2.84 (aa. a.:netansulfonyl), 1.22 (314, å | JI6.5 | H-Th 0-99 (93, I, §årt ° ßt fl i 0.30 pä (GH, s. sx- (canzn L: va: (cncisn ms (co)). ma, mo J * csoz).

L. Preparation of (1'R, 3S, 4R and 1'S, 3R, 4S) -1- (tubutyldimethylsilyl) -3-4''-methanesulfonyloxy-1'-ethyl) -4-trityltio--2-azetidinone ( isomer B) A solution of 5.03 g (10 mmol) (1'R, 3S, 4R and 1'S, 3R, 4S) -1- (t- - butyldimethylsilyl) -3- (1'-hydroxy-1'- ethyl) -4-trityltio-2-azetidinone (isomer B), 2.52 g (22.0 mmol) of methanesulfonyl chloride and 2.23 g (22.0 mmol) of triethylamine in 200 ml of methyl enchloride were stirred at 5 ° for less than 1 hour. Then the solution was washed with brine, dried over magnesium sulphate and evaporated to give a residue which crystallized as a white solid on trituration in ether. There was obtained 4, 4 g of product (93%) with a melting point of 1274319 'nu ccncia) 5: Lao-Ls: ma, n, nam .. 1, 4.51 un, aq, a-s.o-s.z.

"HP). 4.10 un. A._g-zo, 11-4). A.so (m. Aa._a-so-go aa), 2.0: (axl 'I (sag d; á-6n20 u.2 ') | 0099 I' = 'BÜ, |' (611. a. -Cxan izyzacza) vw: ms and (c-oß .. 81 464 027 M. Preparation of (l'S, 3S, 4R and l "R, 3R , 4S) -3- (1'-p--bromobenzenesulfonyloxy-1'-ethyl) -1- (t-butyldimethylsilyl) -4-trityltio-2-azetidinone (isomer C) λ max 44 l. Os N A solution of 2.5 g (5 mmol) (1'S, 3S, 4R and 1'R, 3R, 4S) -1- (t-butyldimethylsilyl) -3- (1'-hydroxy -1'-ethyl) -4-trityltio-2- '-acetlainone and treated with 2.38 ml (6 mmol) of 2.52M butyllithium in hexane, after 3-4 minutes 1.53 g (6 mmol) were added dropwise. bromobenzenesulfonyl chloride dissolved in THF The solution was stirred at -78 ° for 3 hours and then allowed to warm to room temperature, then the solvent was evaporated and the desired product was purified by column chromatography (silica gel, methylene chloride) to give 3.36 g (94.6%) product with melting point 142-440; 1mE (u1§ à 1.sa (45,;, kxamseruallfomgül, 1.: E-1.so clsn. 1. azuuau) , 4-S9 (ln, _a, J-l.a, a-4), s.sa (ln, aq, J-6.2, a-1 '). 2-99 (1H- dd- 3-1-B:: still H-3) | d; J-6ø2 | H-2 '); .I t-B “) I ° l4 ° Kl '-1 o.aa css. zs. -caszf 1: ccnclaz v __: = 1149 and cc-0). 464 027 88 N. Preparation of (1'S, 3R, 4R and 1'R, 3S, 4S) -3- (1'-methoxymethyl-1'-ethyl) -4-trityltio-2-azetidinone (isomer A) ocazocu3 °° "2 °°" 3 L. fscø, "anno \\ '"' 2 * w A cold (0 °) solution of 11 g (20 mol) of isomer A of 1- (t--butyldimethylsilyl) - 3- (1'-Methoxymethyl-1'-ethyl) -4-trityltio--2-azetidinone in 116 ml of HNPA and 13 ml of water were treated with 2.7 g (42 mmol) of sodium azide. The cooling bath was removed and the mixture was stirred for 30 minutes. It was then poured into 1.3 liters of cold water and dried. The title compound was recrystallized from ethyl acetate-hexane to give 7.2 g (83%) of product as a white solid, mp 173-174 °. 'az (cnc13: 6: 1.10-1. cisu, 1, azanac. 1, 4.95 (za, Aaq¿ J-1.4, cvcnz-o). 4.53 (ln, a.

J-5.2, H-4). 4.42 (ln, a, u-R). 4.15 (la. N. A-1 '). : .s (in. n..a-3). 3.41 (an,;. O-ena), 1.5 (aa, a, Ä-e, ena). Ä: (tar) v __: =: 4oo-asoo in-az, ivso == '1 cc-ox. Preparation of (1'S, 3S, 4R and 1'R, 3R, 4S5-3- (1'-methoxymethyloxy-1'-ethyl) -4: trityltio-2-azetidinone (isomer C) - 464 027 A cold (dry ice-acetone bath) solution of 5.03 g (10 mmol) (1'S, 3S, 4R and 1'R, 3R, 4S) -1- (t-butyldimethylsilyl) -3- (1'- - hydroxy-1'-ethyl) -4-trityltio-2-azetidinone in 50 ml of THF (distilled LAH) was treated dropwise with 1.3 ml of a 1,6M solution of n-butyllithium in hexane until a permanent pink color was obtained. 20 ml of a THF solution of 1.49 g (0.97 ml; 1.19 mmol) of bromomethyl methyl ether were added dropwise, the mixture was stirred at -780 for 30 minutes and at 0 DEG C. for 3 hours. chloride solution and extracted with ether The ether extracts were combined, washed with water, dried, over magnesium sulfate and concentrated to give 5.83 g (100%) (1S, 3S, 4R and 1'R, 3R, 4S). 1- (t-butyldimethylsilyl) -3- (1'-methoxymethyloxy-1'-ethyl) -4-trityltio-2-azetidinone in the form of a crude product, the protecting groups of which were removed as indicated below. one way.

A cold (ice bath) solution of 5.83 g (10 mmol) of the above derivatives in a mixture of 90 ml of HNPA and 10 ml of water was treated with 1.365 g (21 mol) of sodium azide. The cooling bath was removed and the mixture was stirred at room temperature for 2 hours; It was then slowly poured into 900 ml of ice-cold water and stirred for 30 minutes. The resulting precipitate was collected by filtration and redissolved in methylene chloride. The solution was washed with water and brine and W was dried over magnesium sulfate to give 3.0 g (69.3%) of the title compound, m.p. 172-172.50 (ethyl acetate-hexane). _ '_' i: (CHCIB) vmax = 3490 ca-uwj q ivso: mfl (co). 'um: (cncia) a.1.s1-1.12 clsn, JT' u uamu ,.), ': 4.6: (zu, oentnarlaaq, ae. o-czaz-o), 4.49 ua. Mr. u-rn. 4.40 and. a. J-s, a-4). 4.z§-a.ao un, n, am, mas-ms, 'me (43. a + n, CH 84) "- 3} I_ w lcao Pp fi dg J-Gp 464 027 90 P. Preparation of ( 1'R, 3S, 4R and 1'S, 3R, 4S) -3- (1'-formyloxy-1'-ethyl) -4-tritylthio-2-azetidinone (isomer B) osozeaz ccno, J $ C $ 3 '_, J: I :: I, sc0¿ _ 04- "/ \ ,, * sx * ° A solution of (l'S, 3S, 4R and l'R, 3R, 4S) -3- (1 [rp-bromobenzenesulfonyloxy-1 '-ethyne-1- (t-butyl-ethylsily-z-trityltio-z--azetidinone (isomer C) in 3 ml of DMF was heated at 500 for 48 hours and then at 100 ° for 4 hours. The mixture was then diluted with water and extracted with ether, the ether extracts were washed with brine, dried over magnesium sulphate and evaporated, the title compound was obtained as white crystals after purification by column chromatography (silica gel, -c; * umz (gncis) 6: a.ov (la. n, can). 5.24-1.56 cisa. I, aramaz.>. 5.23 (ln, aq, a ~ s.4. 7. aß1 '). 4.38 (in. A J-2.4, a-4), 4.25 (ia, s. Ua), 3.20 (ln. Aa. J-1, 2.4, s-3) 1.4: (as, a, J-6 . 4, a-z '): 1: ccaci> v = mo om, nås (c-o). ms m * (c-o). Preparation of (1'R, 3S, 4R and 1'S, 3R, 4S) -3- (1'-acetoxy-1'-ethyl) -4-trityltio-2-azetidinone (isomer B) W 464 027 5.77 g (10.57 mol) of the pure derivative (1'R, 3S, 4R and 1'S, 3R, 4S) -1- (t-butyldimethylsilyl) -3- (1'-ethyl) -4- trityltio-2-azetidinone was dissolved in a hot mixture of 60 ml of HMPt and 10 ml of water. The solution was cooled to room temperature and 1.2 g of NaN 3 was added. The mixture was stirred for 45 minutes (the course of the reaction could be monitored by thin layer chromatography) and slowly poured with stirring into 800 ml of cold water.

The mixture was stirred for another 20 minutes. The crystalline material was recovered and washed with water.

It was redissolved in methylene chloride, washed with water (two solution and dried over magnesium sulfate as crystallize, 90 g per cent) and salt. Evaporation of the solvent gave a foam, removed from ether-petroleum ether to give 4 cloths: (9s, s%) msa_smä1tpunkten 143-144, s °. ir (cxzcizyvmaxz: ass (Na), _ 1172, 1135 em ° 1 (co). * amz (cncia) 6 = 1.9-ea (isa, m, x nafn-_), 5.12 mncentrurn avdqp-as, 1.5, H- 1'J. 4. :: (ln. D.-J-2-8. H-4). 4.20 (1n. Ns. U-az. 2.11 (la, aea, J3_1.-7.5, J3_4-2- 8. J3_NH-1. S-3), 2.1 (su, a, c fl aco) 1.35 (sa, a, a-as, cn9.

R. Preparation of 3- (1'-hydroxy-1'-ethyl) -4-tritylthio-2-azetidinone. Landing of four isomers) '' OH SC; _ om: scó mê-i fl ffíf 3 l 1 3 o Nxucwz ca3cno \ á -. - 2% w _ * -% 1-cl '°° 3 -ßrff fi arr .m _ 3 sr + A solution_of 0.74 mol lithium diisopropylamide and 1 was prepared at -78 ° in 5 ml dry tetrahydrofuran starting from 0.103 ml (0, 74 mmol) of diisopropylamine and 0.29 ml of a 2.52M solution of BuLi in hexane. After 30 minutes at -78 °, a solution of 0.292 g (6.99 mmol) of (R and S) -1-trimethylsilyl-4-trityltio-2-azetidinone in 2 ml of dry tetrahydrofuran was added dropwise. After 5 minutes, an excess of 0.2 ml of freshly distilled acetaldehyde was added in one portion. After 20 minutes at -78 °, thin layer chromatography indicated complete consumption of the starting materials and the reaction mixture was added to a saturated solution of ammonium chloride. Extraction with 2 x 25 ml of ethyl acetate, followed by washing of the combined organic phases with saturated ammonium chloride, brine and drying over anhydrous magnesium sulphate, gave a yellow oil after evaporation of the solvent. Filtration of this oil on 10 g of silica gel (eluting with a 6: 4 mixture of benzene and ethyl acetate) gave 0.215 g (80%) of an alcohol. This mixture (1Hmr) could not be separated by either high pressure liquid chromatography or thin layer chromatography. a: Acetylation Acetylation of an aliquot of the mixture (0.065 g) with an excess of 1.0 ml of acetic anhydride and 1.4 ml of pyridine gave a mixture of acetates. Analysis by high pressure liquid chromatography showed four components in the following proportions: a) 34.6%, b) 17.4%, c) 30.1%, d) 17.9%. Compound a) was identical to isomer B in direct comparison with high pressure liquid chromatography3. b: t-butyldimethylsilyl derivative 0.121 g (0.34 mmol) of the alcohol mixture was treated with 0.117 g (0.776 mmol) of t-butyldimethylchlorosilane and 0.10 ml (7.14 mmol) of triethylamine in 1 ml of dry dimethylformamide for 36 hours at room temperature. After dilution with ethyl acetate, the solution was washed with saturated ammonium chloride and dried over anhydrous magnesium sulfate. Evaporation gave 0.716 g of an oil which contained four components on analysis by high pressure liquid chromatography. a = 3.7; b = 60.6%; c = 31.1%; d = 4.6% (the identity of each of the components has not been established) 4.

NOTE: Ibutyllithium and lithium hexamethyldisilazane were ineffective in order of increasing polarity. Acetylation of the product obtained from 1-t-butyldimethylsilyl-4-trityltio-2-azetidinone was as follows: 'd = _23.5%; c = 4.1%; b = 33.8%; a = 12.6% 4 conversion of the alcohol mixture obtained from (R 'and S) -1- (t-butyldimethylsilyl) -4-trityltio-2-azetidinone gave the components in the following proportions: a = 5.2%; b = 41.3%; c = 48% rd = 4.6%.

S. Preparation of 1'R, 3S, 4R and 1fS, 3R, 4S) -3- (1'-benzoxy-1'-ethyl) -4-trityltio-2-azetidinone (isomer B) HSO I and l SCOB Q | 55%, ___-___.) _ °: KH _ ° NN; A solution of 35 mg (2 mmol) (1'S, 3S, 4R and 1'R, 3R, 4S) -3- - (1A-methanesulfonyloxy-1'-ethyl) -4-trityltio-2-azetidinone and 432 mg (3 mol) of sodium benzoate in 10 ml of 10% H 2 O-DNF is heated for 7.5 hours at 90 °. The reaction mixture was then diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over magnesium sulfate and evaporated. The residue, which was purified by column chromatography (silica gel, 5% C33 gN-CH2 Cl2), gave the title compound as a white solid in an amount of 108 mg (23.2%), m.p. 464 027 w: w (cociz) e. 1.0: -a.: S (zon. N. Nam.). 5.12 un. dq. .1-s.1. s. a-m. 4.40 (m, a, az.s. Å-o, 4.00 (m. .. um.: _40 (from. -1-9. 2.5. Us). 1.50 (an. A. 0-04. Ar). 1.- 403013; “mf 34 °° (NH). Nas (co). Ms an * cc-o).

T. Preparation of 3- (1'-paranitrobenzyldioxycarbonyl-1'-ethyl) -α-trityltio-2-azetidinone (4 isomers) “0 PNB P33 z. _ ïrscé,% sc03 _----> “\ == <“ ° = N 'tBu “isomer C" a) A solution of 1,3 of “isomer C” of 1- (t-butyldimethylsilyl) -3- (1'-Paranitrobenzyldioxycarbonyl-1 '-ethylI-11-trityltio-Z- -azetidinone in a mixture of 5 ml TFA, 5 ml water, 20 ml dichloromethane and 30 ml methanol was stirred for 2 days at room temperature. The solution was diluted with water and the aqueous phase was extracted with dichloromethane.The combined organic phases were washed with sodium bicarbonate and water, dried and concentrated to give an oil.Crystallization from ether gave 902 mg of the pure title compound, m.p. 78-80 ° . 'rm (cncia) = nas-ens usa. n. amd). .f-.zi un. 4. beÄsyl), 5.05 un, n. nm. 4.40 un. a. »yn). 4.21 un. a, az.a. 14-41. ° 2.31 ua. 00, as.aza us) ochnav ppm (an. a '.': - ss, cash i: (cxcia) vnx: asso (N-az. nes ochn-: s (skhrñrñrai (C-Ooch 4525 u * 0:02). 95 464 027 b) A cold (o °) solution of 9.11 g (13.3 mmol) of "isomer C" of 1- (t-butyldimethylsilyl ) -3- (l'-paranitroben syldioxycarboxyl-1'-ethyl) -4-trityltio-2-azetidinone in a mixture of 90 ml HMPT and 90 ml water was treated with 1.82 g (27.9 mmol) of sodium azide. The cooling bath was removed and the mixture was stirred for 30 minutes. The mixture was then poured into 1 liter of water and extracted with 5 x 200 ml of ether. The ether fractions were combined and washed with 5 x 200 ml of water, brine and dried over magnesium sulphate. Alternatively, since the title compound precipitated on dilution with water, it could be filtered off and recrystallized from ether. The product was obtained in an amount of 7.22 g (89% 1 with a melting point of 78-80 °.

"Isomer B" "Isomer B" of 3- (1'-paranitrobenzyldioxycarbonyl-1'-ethyl) -4-trityltio-2-azetidinone was prepared as described above for "isomer C". The product was obtained in a yield of 92% with the melting point lss, s-lss ° (star). "---" - 'I- = == - _ =' - Ü fam: (cncla) 62 8-25-6-80 (ISK, I, lrømabï), 5.20 (25, I; ÖGIISYI), 4.95 ( m: m: H-1 ') | d 'J-zogp H-4) | (mg S; “-H) | _ ~ (ln, aa, J-lo.a, J-2.9, a-3) ~ 1.40 apa (aa, a. J-1.s, ena), ir (CiiCla) Vax: 3480, 3390 (NH) , 1772, 1750 (CIO), - 1525 cut-l (No2) .lu¶al. I: r1ftn :: caznzeszossl c s1.s9. H 4.96. N 4.93. s 5.64; Éïn fl ïëtc s7.4s, and 4.98. u 4.92, s s.s1.

"Isomer A" "Isomer A" of 3- (1'-paranitrobenzyldioxycarbonyl-1'-ethyl) -4-trityltio-2-azetidinone was prepared as described above for "isomer C". A product with a melting point of 205-22 ° was obtained. - _- = -i ~ *. "* am (cncla) 6: 8.2-6.7.-w; à fi = (lea. a, s: ° a ==. =, s.zz (zu. Asq, bsnzyl), s.s1-4.as ( ln, n.-á-l °), 4.es (la, xa), 4.sø (la, a. Js.s, a-4), 3.65 (ln, aa, 'as.s, lz, JN_a-1, s-3), - 1.52 ppm (gu, 4, J-1.5) 464 027 96 "Isomer D" "Isomer D" of 3- (1'-paranitrobenzyldioxycarbonyl-1'-ethyl) -4 -trityltio-2-azetidinone was prepared as described above for "isomer C" * nar (anal) 63 a.1s-s.vo (lax. u. arømaz. -n, 5.2; (23, Ang, bn = y1), sÅ: o (in. n. a-1 ';. 4.15 cin. un). 4.52 (ia, a, Js.s. a-¿), _ s.42 (ln. J-5.5. 2. H-3 , '1-S ppm (BH- L (J value for H-3 determined by D20 -' ubtyte). D, 316.5, C143 Phenomenon of _ U. (l '.'- R, 3S, 4R and l' -S, 3R, 4S) .- 3- (β-Methanesulfonyloxy-U- -ethyl) -4-tritylthio-2-azetidinone Xisomer B) A solution of 4.95 g (8.5 mmol) of 1'R , 4R and 1'S, 3R, 4S) -1- - (t-butyldimethylsilyl) -3- (1'-methanesulfonyloxy-1'-ethyl) -α- -trityltio-2-azetidinone (isomer B) -OCh 1.11 (10.0 mmol / l) sodium azide in 50 ml of 10% H 2 O-HMPA was stirred for 30 minutes at room temperature. with 250 ml of water and extracted with ether. The organic extracts were washed with brine, dried over magnesium sulphate and evaporated. Crystallization of the residue (ether-petroleum ether) gave 3.33 g (83.8%) of the title compound, m.p. 130-132 °. _ _ '' L * nu (cncis) 6: 7.20-7.62 (153, n, azaat.) _. 4-97 (18. âq. 3-6-4- 6-1. A-1 '). 4.56 (in, a, J-z.a. A-4), 4.22 (ln. N. N-H). 3-27 (IH. Da. A-m. 2.:, U-a),: .o un. .Åman nes (an. E. 1-6-4. Fl_-2 '>: 1: (hajar) valg. Aiss in-az. Ivsa c =' 1 cc-0). 91 464 * ö27 V. Preparation of (1'S, 3S, 4R and 1'R, 3R, 4S) -3- (1'-methanesulfonyloxy-1'-ethyl) 4-trityltio-2-azetidinone (isomer C) Ms SCO k _ O _ f-H fl æu t-Bu A solution of 2.85 i; (4.9 ml) '(1s, 3s, 41z and 1'n, 3n, 4s) -1- (t-butyldimethylsilyl) -3- (1'-methanesulfonyloxy-1'-ethyl) -4-tritylthio- 2-Azetidinone (isomer C) in 25 ml of a 10% aqueous solution of HMPA was treated with 0.65 g (10 mmol) of sodium azide and stirred for 0.5 hours at 25 °. By diluting the solution with 250 ml of water, the reaction product was forced to precipitate. The mecylate product was redissolved in dichloromethane, washed with brine, dried over magnesium sulfate and evaporated. Trituration in ether gave 1.80 g of the title compound as white crystals, m.p. 155-60 °. '/ nr (çnc13) 6: 7.43 (153. m, Äiomac.), 5.02 (ln. aq, J-6.9, 4090 B-1') | I | N-H) | (m | d '3-3: H-4) | then! 3,419! a. u-aa. 1.51 (an, a. A-ea, a-z-n n- vm =: ass m-s). 1168 m * (c-on maLßer. För czšxzsuof. C 64.22. U sas. U Lommmetc 63.93. A 5.39.

N 3.24s., _ _ W. Preparation of (1'S, 3S, 4R and 1'R, 3R, 4S) -3- (1'-p-bromobenzenesulfonyloxy-1'-ethyl) -4-trityltio-2 -azetidinone (isomer C) 0502082 ozozèaz SC $ 3 # 3 HI 0 N \ \. 464 027 98 A solution of 1.42 g (2 mmol) (1'S, 3S, 4R and 1'R, 3R, 4S) -3- (1'-p-bromobenzenesulfonyloxy-1'-ethyl) -1- ( t-Butyldimethylsilyl) -4-trityltio-2-azetidinone (isomer C) and 0.865 g (6 mmol) of sodium benzoate in 40 ml of a 10% aqueous solution of HMPA were stirred at room temperature for 1 hour. Then the solution was diluted with 100 ml of water and extracted with ether. The ether extracts were washed with brine, dried over magnesium sulfate and evaporated. The title compound as a crystalline crude product was triturated in a small volume of ether and collected by filtration in an amount of 0.92 g (77%), m.p. 125-260. '“« * On xcncisa 6; 1.so (au. 1. b «q; .n- = u1: any1>, 'Lao-ms usa. A, insug a. M; un. Aq, .1-ss 4.0. Hm. 4.so ( n) d; J-zoey 5-4,) 4,040 I; u-H) y då 'JI4UOI zfgl H-3) I 1.so (aa, a, J-s.s, n-2 -); 1 = (case) vn_x =: 4oo = m'i (w-u). 111o = m'1 (CIO).

X. Preparation of (1'R, 3S, 4R and 1'S, 3R, 4SLf3- (1'-hydroxy-1'-ethyl) -4-trityltio-2-azetidinone (isomer B) OSOáQBr, O !! 3 N To a hot solution of 1'S, 3S, 4R and 1'R, 3R, 4S) -3-1'-p--bromobenzenesulfonyloxy-1'-ethyl) -1 - (t-butyldimethylsilyl) -4- -trityltio-2-azetidinone (isomer C) in 5 ml of HMPA was added dropwise to 1 ml of water. The reaction mixture was kept at 90 ° for 20 hours, then diluted with ether and washed 4 times with brine. The organic solution was dried over magnesium sulfate and evaporated and the title compound as a crude product was purified by column chromatography (silica gel, 15% CH 3 CH-CH 2 Cl 2). 122 mg (44.5%) of a white solid, m.p. 187-1890, were obtained. The product was found to be identical to a sample of the title compound which had been prepared by another method.

Y. Preparation of 3- (1'-hydroxy-1'-ethyl) -4-trityltio-2-azetidinone Both isomers, namely (1'S, 3S, 4R and 1'R, 3R, 4S) -3- - ( 1'-hydroxy-1'-ethyl) -4-trityltio2-azetidinone (isomer C) 'and (1'R, 3S, 4R and 1'S, 3R, 4S) -3- (1'-hydroxy-1'-ethyl) -4- -trityltio-2-azetidinone (isomer B) was prepared by the same method. For example, a solution of 1.0 g (2 mol) of (1'S, 3S, 4R and 1'R, 3R, 4S) -1- (t-butyldimethylsilyl) -3- - (1'-hydroxy-1'- ethyl) -4-trityltio-2-azetidinone (isomer C) and 0.865 g (6 mol) of sodium benzoate in 40 ml of a 10% aqueous solution of DMF at room temperature for 18 hours.

Then the reaction mixture was diluted with water and extracted with ether. The organic extracts were washed with brine, dried over magnesium sulphate and evaporated. The title compound as a crude product was crystallized from cold ether to give 0.47 g (61%), mp 134-35 °. '“V s _ * um (cncia) a» 1.12-1.ss usa. n. aromf- h 4-48 (la. a. N-Å). 4.28 (13, a, J-2.9, s = 4). 2-94 (1H. Dq- J-6-5- 6-25.1 u-1 '),' a.o6 cin, aa. J-6.2. 2.a. H-3). 2-18 (1H- = «- ° H1- 1-30 - -1 _ (: x. E, o3ç.s. a-z '> ::: (c fl c13> vmax = a4oo an-sz. Ivso en ( c-OL-464 027 100 'There was thus obtained the compound (1'R, 3S, 4R and 1'S, 3R, 4S) -1- (t-butyldimethylsilyl) -3- (1'-hydroxy-1'-ethyl ) -4-trityl-thio-2-azetidinone (isomer B), mp 190-92 ° C. -F '* aux: cnc131 6: 1.1o11.ss (1su. N, azumae. 1, 4.45 <1a, a, Jz.s. a-4), ¿.ze (1a.l =. ån). 4.10 (ia, aq, a-6.4, s.:. x-1 '). ao§ (1n, aa, Js.a. 2.5; a-az, 1.so c1n. 1, -ena. 1.30 (ax, a. J-6.4, a-z'1: 1z. (Cxc13) vmlxz saoo ta-ua. 11so == 1 (C19) Z. Preparation of (1'S, 3R, 4R- and 1'R, 3S, 4S) -3- (1'-methoxymethyl-1'-ethyl) -1- (paranitrobenzyl-2 '' -hydroxy-zf -acetate--4-trityltio-2-azetidinone (isomer A) A mixture of 7.5 g (17.3 mmol) isomer A of 3- (1'-methoxymethyl-1'-ethyl) -4-trityltiof2-azetidinone, 4.7 g (20.8 mmol) of paranitrobenzyl glyoxylate hydrate and 300 ml of toluene were refluxed for 1 hour in a Dean Starka apparatus filled with 3A molecular sieves, the solution was cooled in ice and 0.24 ml (1 .7 mmol) triethylamine was added dro ppvis. The mixture was stirred for 1 hour, washed with dilute hydrochloric acid, sodium bicarbonate and brine, dried and concentrated to give the title compound as a foam in an amount of 10.5 g (94%). 1m 464 027 'mm (CDCl 3) 6 »8.25-s.a4 (isn. N. Axømac. 2, 5-24 (zu. 1. benzyl), 4.67- 4-83 (BH. N- 0-CH a- 4). 4-34-4-S5 (1H. M. R-2 '). 4.02 (ln. M. A-1'), 2 I 3154 flfl fl ° 3) | I: (B fl, d, JI6.5, i: Vax * 2350 (03). 1770100 B-lahtam), 1735 (C-O ostar), 21605 and '(aroma:.). _ AA. Preparation of (1'S, 3S, 4ROCh 1'R, 3R, 4S) -3- (1'-methoxymethoxy-1'-ethyl) -1- (paranitrobenzyl-2 "-hydroxy-2" -acetate) - -4-trityltio-2-azetidinone (isomer C) OCHZOCHB ° C fi2 ° Ü fl3 çao / J sr: 'J ax covma M ~. 2 A solution of 1.73 g (7.11 mmol) of hydrated paranitrobenzyl glyoxylate was refluxed for 2 hours in 90 ml of toluene using a Dean Strong condenser filled with 3Å molecular sieves To the boiling solution was added 3.0 g (6.93 mmol) (1'S, 3S, 1R and ~ 1'R, 3R, 4S) -3- (1'-methoxymethyloxy) -1'-ethyl) -4-trityltio-2-azetidinone and the mixture was refluxed for a further 2 hours The mixture was cooled to room temperature, 70 mg (97 μl; 0.69 mol) of triethylamine were added and the mixture was stirred under Reaction mixture was washed with a 1% aqueous solution and diluted with ether, aHCO 3, water and HCl, water, a 1% aqueous solution of N brine, dried over magnesium sulfate and concentrated to give 4. 60 g (100%) of the title compound 464 027 1 ° 2 E: (cncza) vmlx =: sao-: zoo (csa). 1165. zvso cc-o), 1s2s == '1: man 'm (enfas) 6: a.2z. a.1s (za. za, Ja, ua Ironic.). 1.61-1.o clvn. 1. a- |: ° m. = - 7. 5.3 (z a. ns, ca: -rus). s.:o-s.o2 (=, ~ a-z ~). 4.as-4.5: (n, a-1 ', _ o-u). 4.Ba. 4.59 (ln, za, J-2, a-4). 4.33. 4.ao (za, 2 censor ~ 2 Anq, J-1, “_ J-1. O-ca: -o). 4.1 - :. s1 (za. N. A-1-1. 3 .: (zu. U-31. 1.1, 3.6 QI3- °) | '(m) d' J-Gøsp, BB. Framstilling av (l R, 3S, 4R and 1S, 3R, 4S) -3- (1'-acetoxy-1'-ethyl) -1- (paranitrobenzyl-2 "-hydroxy-2" -acetat4-trityltio-2-azetidinone OA : - Ho Jim: - is:: Dzliïß "" xírsæz ~. M N 73A NYC !! - 0 H 0 "Isomer B" A solution of 1.82 g (30 mol) of hydrated p-nitrobenzylglyoxylate (triturated with ether ) was refluxed for 2 hours in benzene through a Dean-Stark condenser filled with 3A molecular sieves, then 10.88 g (25.2 mol) were added (1'R, 3S, 4R and 1'S, 3R, 45 ) -3- (1'-acetoxy-1'-ethyl) -4-trityltio-2-azetidinone and the mixture was refluxed for a further 1 hour The solution was cooled to room temperature and 0.35 ml (2.5 mol) of triethylamine was added The mixture was stirred for 2 hours, the course of the reaction being followed by thinning concentrated to give 103,464,027 layer chromatography evaporation of the solvent gave a white foam in quantitative yield (100%, the mixture of epimers). the solution is acidified and washed with a base. ir ccasczz) vmçx = 3520 (ou). ivvs, 1145 = m'1 toilet-oz; Iam: «coc13) 6: a.2. e.1a (za. za, J-å. ao azomat. I. 7.80-6.90 (17H. m. 8-a: omat5 :), 5.28, 5.17 (28, 24, C82-PNB, 4.89 (o.s1u , a. J-1.2, can). 4.ao (cencez m, n-1 '). 4.38 (o.a3 u, 2d. Ja.a.'cno>, 4.22 rn.:au,.a, a4_3 -2.5. N-45, 4.o§ (o.s1a§ a, a4_3- 2.1, u-4), 3.65 (n.e1a. Aa, a3_1, -ss a3_4-2.1, a-ag, 3.41 (o .asH. Öde 33_1, IS.5 J3_4I2.S, Ii-B). 3.33 (0.33ll, d, Jlhš, 98), 3.23 * (0.67H | d. J-1.s, ox), 1.as 1.aa (su, 2 :, c fl acna. 1.10, 1.os kan. Za. Js.8r 6,; mä) CC. Preparation of 3- (1'-paranitrobenzyldioxycarbonyl--1'-ethyl) -1- (paranitrobenzyl-2 "-hydroxy-2" -acetate) 4-tritylthio-2-azetidinone (4 isomers) mmzma. '. GIYHB 2 - 2 than' 55473 * mm "Isomer C" A mixture of 1.70 g (0.3 mol) of "isomer Q; of 3- (1'-paranitrobenzyldioxycarbonyl-1'-ethyl) -4-trityltio-2-azetidinone, 815 mg (3.6 mmol) paranitrobenzyl glyoxylate hydrate and 50 ml of toluene were refluxed for 7 days in a Dean-Stark apparatus filled with 3 A molecular sieves, the cooled solution was washed with hydrochloric acid, sodium bic carbonate and brine, dried and of 2.1 g of the title compound as a mixture of epimers at carbon-2 ". Purification was accomplished by chromatography on silica gel.

Alternatively, the title compound could be prepared using a catalytic amount of triethylamine. Minor polar epimer at C-2 ": * m (cncis) 6: s.zs-s.ao ma. U. .Rum-z.), S.:o, 3.12 14x. 2 :. eensyi J, 4.65 ( in, a, J-9. xz ~>, 4:45 dg __J-2o5 | H-4) | 4045-4110 I | “-1 ') | (my d; J-gf T-OH), 3.28 ( 1H, dd, 312.5, Jl2.5, HB) -, 1.23 ppm (35, d, JI6.5, (133): ir (CBCIB) Wax: 3530 to 3200 (IJ-H), 1765, 1750 (C10 ), 1525 cin-1 (NO2). Lie-r E01- iS-G fi er V- C-2 "=" w (cnczz) s »a.zs-e.ss ma. M. Azomat-), S.2_5 - 5.08 (43, 2 :, benwL), 5.05 (1H, d, .7-7, H-2 "), 4.35 (1H, d, 512.5, H-4), 4.-40 ~ 4.05 (1H , n, H-JJ), 3.42 (1H, 317, ï-OB), I 3.33 (1H, dd, J = 2.5, 2.5, 8-3), 1.23 (38, d, JIG.S, VCH3): (CHCl 3) -1 -1 Wax: 3520 to 3200 (OH), 1755 (C10) I 15.25 cm (NO 2) "Isomer B" A mixture of 1.74 g (7.66 mmol) of hydrated paranitrobenzyl glyoxylate and 3.63 g (6.38 mol) (1'R, 3S, 4R and 1'S, 3R, 4S) -3- (1'-paranitrobenzyldioxycarbonyl-1'-ethyl) -4-triethylthio-2-azetidinone were refluxed in 70 ml of toluene for 3 hours using a Dean-Stark condenser filled with 3A molecular sieves. The solution was cooled to room temperature and 65.4 mg (89 ml; 0.639 mmol) of triethylamine were added. The mixture was then stirred for 4 hours, diluted with ether and washed with a 2% aqueous solution of HCl, water, a 2% aqueous solution of NaHCO 3, water and brine.

The mixture was dried and concentrated to give 5.02 g (100%) of the title compound. Separation of the two epimers was accomplished on a preparative silica gel plate. wß 464 027 Minor polar epimer at C-2 "; 1: (c fl cla) vw:: soc (o-a). m2. 1150 (en) 1525 u * (man 'w (emma) away-mo, - Las-mao.

IN; Is fi matø I; i -: lg h fl åyl fl), m! a-s.s. 6.5. n-m. 4.28 (i.e. J-2-2. Fl-4). 4.2: (m. D. J-en. N-zw. S). 3.29 (ma a-aJ. Om, 1.18 PPM 3.50 (1H, da. 312.2, 6._5. H- 3480 (OH) (33, 4,; .5,5, caapláen fvoLgfunerr- i: (CHCl 3) vw: _ _1 _ 1712, nso (eo) -, -. 1s2s en (nozr. * nya (cncxa) 6. sas-mao ma.) | benayl) | (mp dp JIII-s 'H-2' °) 0 4090- n. Aromatå 4.so un. M. As.sss fl- r). 4.10 (m. Dr # 2- * HN 3-68 m 'då' az. Ss aa). 3.28 (114. a. as.s. ou) f '1-15 vw (ß fl- <1- J'6'5' CHB) I _ "Ismer A" "Isaner A" of 3- (1'-paranitrobenzylrlimdcarbonyl-1'-ethyl) -4-trityl-thio-Z-azetidinone similarly gave a blanix stomach of "ismer A" of 3-paraalkytrolenzensyldioxycarbolyl-1 '-ethyl) -1- (paranitrobenzyl- hyd-hydrcixi- -Z fi acetai fi-é-trityltio-Z -azeticlisxoner. '_ <1'- p.11 (m. b fl ísyle-fl: * am (cnc:) 6: aa-e.1 ma. m.: rum- a g-4, tvâ epinerer) f so un . n. xm, 4.9 and 4.1; un. 24. -1-6. 4.22 ë fl hsas un. 2 :, a-z fi tVå-ePïm-X: _3.sB (m. dd. -1-6. 6. a- szüïh 1.41 than mi. za. ae.s. 0:43. two ePïïfel-'el-Ü- - - "Isomer D" _ "Isomer D" of 3- (1'-paranitrobenzyldioxycarbonyl-1'-ethyl) -4 - -trityltio-Z-iazidine also gave a mixture of "isomer D" of 3- (1'-paranitrobenzylclioxycarbonyl-1'-ethyl) -1- (paranitrobenzyl-2 "-hydroxy-2" -acetate) -4- -trityltio-2-acetidinones. 'umz cçociaz 6: a.:o-e.eo (aan, 1, Äzenae.) .- s.2o (4x. n, ben; y1). 4-83 (ln. 24. Js, x-4), s.so-4.30 (2n._p. 8-1 ', H-2'> - 3-48 (ln. N. H-aa, 3.15 ( la. n, oH), 1.31, 1.30 pre (3fl-26- C fl al- lDD. Preparation of (1'S, 3S, 4R and 1'R, 3R, 4S) -3- (1'-methanesulfonylphonyloxy-1 ' -ethyl) -1- (para-nitrobenzyl-2'-hydroxy-2 "-acetate-4-trityltio-2-azetidinone (isomer C) (epimers at 4§2").

OHS GH: SCÖ Scøs T s N OH M ~ u: - PNB 2 A solution of 10.72 g (42.6 mmol) of paranitrobenzyl glyoxylate hydrate in 350 ml of benzene was refluxed for 2 hours, removing the water azeotropically; in a Dean-Stark trap. To this solution was added 16.62 g (35.5 mmol) (1'S, 3S, 4R and 1'R, 3R, 4S) of 3- (1'-methanesulfonyloxy-1'-ethyl) -4-tritylthio-2 -azetidinone and reflux were maintained for an additional 0.5 hours. Then, the reaction mixture was cooled to room temperature, treated with 0.5 ml (3.5 mmol) of triethylamine and stirred for 3 hours to complete the reaction. Evaporation of the solvent gave a white foam, which was used as such in subsequent steps. a * små (cnci) 6: a.12 (za. a. J-9. a a- umf ..), 7.28 (nu. det av man arma. í-tzityl). 5-28 "'=. S, -caå- gm), se (m5 H' h 3.13), 4,5; (Lsg, j, gz ', ._ 5-0: 4.00 (23, n, 8 -15 _03), 3_15 (15, m, 5-3), 2.73 (314, s, ncsylar), '. 1.30 ppm "" d, J-.S Hz, _ -1 a-2'), :: vmax = as2o to-a). 1115 (c-o) =,! 1765 == (° '° 1- m 464 "E27 EE. Preparation of (1'S, 3R, 4R and 1'R, 3S, 4S) -3- (1-methoxymethyl-1'-ethyl) -1 - (paranitrobenzyl-2 "chloro-2" -acetate) -4- -trityltio-2-azetidinone (isomer A) ocüama-_ oqäqm 3 scåø / \ _ \ _, L \ sem: _ o \ ïfpà -___________ ~ ¿ In a concentration of 1.1 ml (14.2 mmol) of pyridine was added dropwise to a solution of 7 g (1.0.9 mmol) of isomer A of 3- (1'-methoxymethyl-1'-ethyl) -1- (paranitrobenzyl-2 "-hydroxy-2" -acetate) -4-trityl-thio-sz-azetiainone in 356 ml of cold to -1 ° Immediately thereafter, 1.0 ml (1.4.0 mmol) of thionyl chloride was added dropwise and the mixture was stirred for 0.5 hours at -15 DEG C. The precipitate was removed by filtration and washed with benzene.

The combined filtrates were concentrated, the residue was dissolved in fresh benzene and the solution was treated with activated carbon, filtered and concentrated to give 6.5 g (90%) of the title compound as an oil. - 'amr (cncls) 6: s.es-a.ss (193. m, ai-omat: J, 5.24 (28, I, beniyl), 3.43 (38, I. G33), 1-42 ppm (SH d, J-6. CH3).

FF.

Preparation of 1'S, 3S, 4R and oxy-1'-ethyl) -1- (paranitrobenzyl 2 "h 1'R, 3R, 4S) 3- (1'-ethoxymethyl-chloro-2" -acetate) -4- triethylthio-2-azetidinone (isomer C) ff * Wf _ Sxl:'s ST: NY ”. r YCI CO PNB COZPNB U! 1 H II 464 027 mg A cooled (ice-MeOH bath) solution of 4.25 g (6.622 mmol) (1'S, 3S, 4R and 1'R, 3R, 4S) 3- (1'-methoxymethyloxy-1 '-ethyl) -1-paranitrobenzyl 2 "-hydroxy-2" -acetate) -4-tritylthio-2-azetidinone in 60 ml of THF (distilled over LAH) was treated dropwise with 0.1 g / ml (s, s1 moi ) pyriain and o, s3o m1 nyl chloride. The mixture was stirred for 30 minutes at -15 °. The precipitate was collected by filtration and washed with the legs. The THF-benzene solution was concentrated and the residue was redissolved in benzene. The resulting solution was treated with charcoal. Removal of the carbon on a pad of celite and subsequent evaporation of benzene gave the title compound in an amount of 4.86 g (100%). * mn -1 Ii: (cnc13; xäaxz 111o cc ~ c », iszs en (uo2>: (CbCla) 5: 8.15, 8.12 (23. 24, H-aromat. 2, 7.70-7.00 (1714, n, H -arcmat »), s.sz, s.oz (in, 2 :, u-2-3, 5.21 (zx. 1, ca: -Fun). 4.1 (ln. a. H-4). 4.1-3.1 (m, o-caz-o. a-1 '>,: .sz.a (m, a-az, 3.12. s.oa (aa. za, o-caa). Û' 'GG. Preparation of ( 1'RL3S, 4R and 1'S, 3R, 4S) -3- (1'-acetoxy-1'-ethyl) -1- (paranitrobenzyl-2 "-chloro-2" -acetate) -4-trityltio-2 -azetidinone.. _ n / P a, J "° .ii-a -" H5 SOCI "'- 03 Pyridine Cl CÖZPNB" Isomer B "A solution of (1'R, 3S, 4R and 1'S, 3R, 4S) -3- (1'-αC8toxy-1'° -ethyl) -1- (paranitrobenzyl-2 "-hydroxy-2" -acetate) -4-trityl-109,464,027 thio-2-azetidinone (from 10.88 g of NH) in THF (distilled over LAB) was treated at -150 (ice-methanol bath) under a nitrogen atmosphere with 2.19 g (2.24 ml; 27.7 mmol) of pyridine and 3.3 g (2, 02 ml; 27.7 mmol) thionyl chloride The mixture was stirred for 20 minutes at -15 DEG C. The salt was filtered off and washed with benzene Evaporation of the solvent (THF + benzene) gave a residue which was taken up in hot benzene. and treated with charcoal. The suspension was filtered through a pad of celite and evaporation of the solvent gave a foam. lr (cx2cl2> vmax = lvao, 1140 tm'1 fc-o) 'arr (cocls 6: 3-17, 8-21 (23, 26, JI8, Ho arpmatë I 7.76-6.88 (178, I, H-ašomate 1, _ 5-31- S116- S-12, 4-73 (SH. 4 :, CH2-run, cuclz, s.l2-4.ss (la. M; H-l '), 4-35- 4-25 (131 N: H'4): 3-3 ° '3 ~ 45 (15, II, HB) 1.90 (33, l. CHBCO), 1.12 _: '07 J-eosp HH. Preparation of 3- (1'-paranitrobenzyldioxycarbonyl-1'-ethyl) -1- (paranitrobenzyl-2 "-chloro-2" -acetate) -4-tritylthio-2-azetidinones (mixture of epimers at C2 ") 0 ° C 2PNB Q ocozruß SCO3. - 5393 _.: -______ p "Y" n "fm mm corua I 2" Isomer C "58 mg (0.73 mmol) of pyridine was added dropwise to a solution of 470 mg (0.6 mmol) of" isomer C ". "of 3- (1'-paranitrobenzyldioxycarbonyl-1'-ethyl) -1- (paranitrobenzyl 2" -hydroxy-2 "-acetate) -3-trityltio-2-azetidinones (mixture of epimers at C-2" Immediately thereafter, the mixture was cooled to -15 DEG C. Immediately afterwards, 86.5 mg (0.73 mmol) was added dropwise and the mixture was stirred for 0.5 hour at -15 DEG C. The precipitate was removed by filtration and washed with benzene. combi The filtrates were concentrated, the residue was dissolved in fresh benzene and the solution was treated with activated carbon, filtered and concentrated to give the title compound as an oil in an amount of 530 mg (100%). * auf (cncia) 63 a.7-6.3 (233, m, arenan. 7; s.s3 <1n. =. az ~>, s.3o, '5.17 (43, 2 :, benzyl fi), 4.52 (18 , d, JZ, 8-4), 4.20-3.70 (ll-X. n, x-1 '). 3.31 tln. aa. a-3). 1.27 ,, 1.21 ppm fan, sat. J-6.5), 1: (cxcis) vm¿x = 17ao, 17so (c-o) 3, iszs == '1 (nog).

"Isomer B" "Isomer B" of 3- (1-paranitrobenzyldioxycarbonyl-1'-ethyl) -1- (paranitrobenzyl) -2 "-chloro-2" -acetate-4-trityltio-2-azetidinones (mixture of C-2 "epimers) were prepared in the same manner as described above for" isomer C "in quantitative yield. Fam: (cnc13) 5; 3.2: -6.90 (aan. U. Arena. 1. 5.40-so (4x .n, ben; y1 1. 5.40-4.45 (1x; n. u-1 '), 4.32 4.s7 (in. 2 :, s-2 ~), 4.35, 4.31 (in, za, J-2.5. a-41, 3.63 (in, n 'J_2ÛSI 3.605! H-3) l'. (381 26; 11-6050 år (cacia) max: 1780. 17so fc-07. iszs = n'1 (nog).

"Isomer A" "Isomer A" of 3- (1'-paranitrobenzyldioxycarbonyl-1'-ethyl) -1 '- (paranitrobenzyl-2 "-chloro-2" -acetate) -4-trityltio-2--azetidinones ( mixture of C-2 "epimers). ä * amg (cnclz) 6: Q 7" 1.80 (238, m, aromat.), 5.45-4.80 (13, m, x-1 '), 5.18 _ 5.21 (4H , 2 = | benßgl 1. 4-87 (1H, 2d.

H-4), 4.22, 3.87 (1x, 2 :, H-2. 4.05-3.40 "" m. H-3). 1-S7 W 1.50 Qp1 fi (351 25. C53) - H1 464 027 "Isomer D" "Isomer D" of 3- (1 "-paranitrobenzyldioxycarbonyl-1'-ethyl-1 '- (paranitrobenzyl-2" -chloro-2 "acetate) -4-trityltio-2-acetidinones (mixture of C-2" epimers).

IHM (CDCl 3) δ: 8.30-6.70 (238, m, azomat. T), s.sz-s.1o (aa. M, ben = y1.). s.4a, s.ao (1H, 2: H-2 '>, 4-82 (1H, d- .1-5, 3-4), 5_30-5.2o (13, m, H-JJ) , 3.15 (m, m, 3-3) 1.40 I - 1-30 -1 ppm (33, za, J-6.5, ena), 1; cxc13> vmaxs 1780. 1750 (c-0), 1525 cm v (NO2) II Preparation of (1'S, 3S, 4R and 1'R, 3R, 4S) 3- (1'-methane sulfonyloxy-1'-ethyl-1- (paranitrobenzyl-2 "-chloro-2" -acetate ) -4-trityltio-2-acetidinone (isomer C) (epimers at C211.

Tin a can (s °): Solution of 24.0 g (as, s mm ° 1> ~ <1's, 3s, 4R and 1'R, 3R, 4S) 3- (1'-methanesulfonyloxy-1'-ethyl ) -1- (paranitrobenzyl-2 "-hydroxy-2" -acetate) -4-trityltio-2-azetidinone in 350 ml of dry tetrahydrofuran was added 3.65 g (46.2 mol) of pyridine and 5.5 g ( After stirring for 45 minutes, 100 ml of ether were added to precipitate the hydrochloride salt, which was filtered off, the filtrate was evaporated and the residue was redissolved in 200 ml of benzene and treated with charcoal. , which was used as such in subsequent steps 464 0.27, m '' w (conz) 6. 5-13 (23: å: -7-9, Bm other '), 7.72 (178, 1 part G-Yd Ho aromat - Û n I l tzityl). 5.57, 5.12 (IB. S, H-2 "), 5.28 (28, a, -cgzpugh 4_73 un 'm' ku ': '21 (mf nä: 3-3). 2.78 (ät-I, 2 :, msyln-W) '1 21 .r, _ PP ° - <3H- 24- H-6H ,: H-2'>: 1: vmax 1119 =. '? (cfow JJ. Preparation of (1'S, 3R, 4R and 1'R, 3S, 4S) -3- (1'-methoxymethoxy-1'-ethyl) -1- (paranitrobenzyl-2 "-triphenylphosphorus-'' anylidene-2" - acetate) -4-trityltio-2-azetidinone (isomer A) - OCH 2 OCH 3 'OCH 2 OCH 3 see, few, - 1 -N-PNB CO PNB 2 ~ x 2 A mixture of 6.6 g (10 mmol) of isomer A of 3- (1'-methoxy-methoxy-1'-ethyl) -1- (paranitrobenzyl-2 "-chloro-2'-acetate) -4--trityltio-2-azetidinone, 3.3 g (12 1.5 mmol) of triphenylphosphine, 1.3 ml (11 mmol) of 2,6-lutidine and 140 ml of dioxane were refluxed for 2 days. The solution was diluted with ether, washed with 5% HCl, water, dilute sodium bicarbonate solution and brine, dried and concentrated. The residue was purified by chromatography on silica gel eluting with 10% ether in benzene. Concentration of the appropriate fractions in question gave 1.4 g (1.3.7%) of the title compound as a foam. ir (xßry fl ymax: 1750 (c = o) and 1sso-1ssq'c1n'1 (c = c, arena).

H3. 464 027 IKK. Framst. of (1'S, 3S, 4R and 1'R, 3R, 4S) -3- (1'-ethoxy-netyloxy-1'-ethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) - 4-trityltio-2-azetidinone (isomer C) '_ AND ST: N 3' ~. »I ----»: r fl ïçfim g ° f ïfpïïß 2 2 A solution of 4.86 g (e, ás2 mmol ) (1's, 3s, 4n and 1'R, 3R, 4s) -3- (1'-methoxymethyloxy-1'-ethyl) -1- (paranitrobenzyl-2 "-chloro-2" -acetate) -4 -trityltio-2-azetidinone in 100 ml of dioxane (distilled over LAH), 2.60 g (9.93 mmol) of triphenylphosphine and 770 mg (0.837 ml; 7.20 mmol) of 2,6-lutidine were refluxed for 4 hours and kept on a hot bath (100 ° C) for 16 hours.

The mixture was diluted with ether, washed with a 1% aqueous solution of HCl, water, a 10% aqueous solution of NaHCO 3, water and brine, and dried over magnesium sulfate.

The solution was concentrated and the residue was filtered through a pad of silica gel (65 g; 5%, 10% and 20% of ether-benzene) to give 2.8 g (48 g) of the title compound. ir (CHCl 3). Max: 1795 (C = O), 1620 and 1605 (phosphorane) and 1515 cm -1 (NO 2).

LL. Preparation of (1'RI3S, 4R and 1'S, 3R, 4S) -3- (1'-acetoxy-1'-ethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -4 -trityltio-2-azetidinone (isomer B): me _ sr: _ gap ~ il, Cl 2.6-luniain á \ “* \ I / 0 N \ f) ° ~ Ozwa 2 'covn 464 027 H4 A solution of (l R, 3S, 4R and 1'S, 3R, 4S) -3- (1'-acetoxy-1'-ethyl) -1- (paranitrobenzyl-2 "-chloro-2" -acetate) -4-tritylthio- 2-Azetidinone as a crude product in 100 ml of dioxane (freshly distilled over LAH) was treated with 2.97 g (3.23 ml; 27.72 mmol) of 2,6-lutidine and 9.91 g (37.8 g). mmol) triphenylphosphine / The mixture was refluxed (oil bath 130 °) for 18 hours. The solvent was evaporated and the residue was redissolved in methylene chloride. The resulting solution was washed successively with dilute HCl, water, a dilute aqueous solution of NaHCO 3, water and brine. Drying and evaporation of the solvent gave the title compound "as a solid, which was triturated with ether and collected by filtration in an amount of 14.6 g (65.9%). - 1150 (c = 0) and 1620, 1610 mfl (phosphorane) .ir (cnzclz) max.

MM. Preparation of 3- (1'-paranitrobenzyldioxycarbonyl-1'-ethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -4-trityltio-2-azetidinone.

Oüä fl ß 9 'ouamm Sêé 2 cè 3 _ _ 3 __-__-_ í-.y - Cl N p ° * F - ° Y *' Ei-WB copma _ "2 Isomer B A mixture of 4.96 g (6, 22 mol) (1'R, 3S, 4R and 1'S, 3R, 4S) -3- (1'-paranitrobenzyl-dioxycarbonyl-1'-ethyl) -1- - (paranitrobenzyl-2 "-chloro-2" -acetate ) -4-trityltioazetidinone (isomer B; mixture of epimers at C-2 "), 2.47 9 (9.42 mol). Diphenylphosphine and 740 mg (0.80 ml; 6.91 mmol) 2.6-1u The thidin was refluxed in dioxane (freshly distilled over LAH) for 50 hours, the solution was diluted with ether and ethyl acetate, washed with a 5% aqueous solution of hydrochloric acid, water, a 10% aqueous solution of sodium bicarbonate, aqueous and brine and dried over magnesium sulphate ns 464 027 Evaporation of the solvent gave a residue which was passed through a column of silica gel (10 times its weight; 10% ether-benzene, ether and ethyl acetate). a crystalline solid in an amount of 3.1 g (49%) and melting point 1a9-190 ° (ether), ir (cncli) qjmax; 1750 (c = 0), 1620, 1605 (phosphorus) and 1522 cm -1 (NO 2).

Isomer C Isomer C of 3- (1'-paranitrobenzyldioxycarbonyl-1'-ethyl) -1- - (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -4--trityltio-2-azetidinone was prepared as described above for isomer B. ir (cHc13) gmaï: 17 50 (c = o), 1s10, 1620 (front front) and 1520 cm -1 (NO 2); Hmr (CDCl 3) 6: 8.6 = 6.7 (H, aromat.), 5.22 and 4.95 (benzyl), 4.70 (H-4), 2.6 (H-3), 1.19 and 1.07 ppm (CH 3). Isomer D A mixture of 4.598 g (4.45 molar purity 47%) of isomer D (mixture of epimers at C-2 ") of 3- (1'-p-nitrobenzyldioxycarbonyl-1'-ethyl) -1- (p-nitrobenzyl 2" -chloro-2'-acetate) -4-triethyl-thiothio -2-azetidinone, 1.425 g (5.4 mmol) of triphenylphosphine (Aldrich) and 0.63 ml (580 mg; 5.40 mmol) of 2,6-lutidine (Anachemia) in 65 ml of dioxane (distilled over LAH) was refluxed gently for 41 hours under nitrogen, following the course of the reaction by thin layer chromatography (benzene ether = 3: 1).

The dark reaction mixture was cooled, diluted with ethyl acetate and washed successively with 0.1N hydrochloric acid, water, 2% sodium bicarbonate and then brine. Drying over sodium sulfate and evaporation of the solvent gave 4.18 g of a dark oil which was purified by column chromatography (SiO 2, 88 g; eluent 10-25% ether in benzene) to give 1; 108 g ( 1.08 mmol; tubyte 24.3%) of the title compound as a yellow foam. 1 Hmr (CDCl 3) α '= 1.08 (α, J = eHz, 1'-cn 3); ir (pure) fomax. cnfl (s, -C = O) 464 027 H6 NN Preparation of (1'S, 3S, 4R and 1'R, 3R, 4S) 3- (1'-methanesulfonyloxy-1'-ethyl) -14-bananitrobenzyl- 2'-triphenylphosphoranylidene-2 "-acetate) -4-tritylthio-2-azetidinone (isomer C) ae uu, í; ï :: r, scé3 4, s] :: T, sc @ 3 N ci N P6 A solution of 24.7 g (35.5 mmol) (1'S, 3S, 4R and 1'R, 3R, 4S) -3- (1'-methanesulfonyloxy-1'-ethyl) -1 - (paranitrobenzyl 2 "- -chloro-2" -acetate) -4-trityltio-2-azetidinone, 11.2 g (42.7 mmol) of triphenylphosphine and 4.2 g (39.1 mmol) of 2,6-lutidine in 350 ml of dry dioxane was refluxed for 19 hours under nitrogen.

The solvent was evaporated and the crude product was redissolved in ethyl acetate and washed successively with dilute hydrochloric acid, sodium bicarbonate and brine. Purification was by chromatography on a silica gel column (8.5 x 12 cm).

Elution with 1.5 liters of 10% ether-dichloromethane and then 1.5 liters of ether gave the purified phosphorus. 12:36 g (40%). 1 Hmr (CDCl 3) δ: 2.53 and 2.93 ppm (3H, 2s, mesylate); ir '0 max: 1749 and 1620 cnfl (c = o). Preparation of (1'R, 3S, 4R and 1'SL3R, 4SLr3- (1'-hydroxy- - 1'-ethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) - 4-Tricylthio-2-azetidinone (ismer B) OAc 08 in; im COZPNB * - cozvua M7_ 464 Û27 A solution of 4.43 g (5.00 mmol) (1'R, 3S, 4R and 1'S, 3R, 4S ) 3- (1'-acetoxy-1-ethyl) -1- (paranitrobenzyl 2 "-triphenylphosphanylidene-2" -acetate) 4-trityltio-2-azetidinone in a mixture of 10 ml methanol and 60 ml THF was treated at room temperature with a 1% aqueous solution of NaOH (1 equivalent, 200 mg in 20 ml of water). The course of the reaction was monitored by thin layer chromatography (heating the mixture increased the reaction rate), diluting with ether-ethyl acetate. Evaporation of hydrochloric acid, water, an aqueous solution of sodium bicarbonate, water and brine. Evaporation of the solvent gave a residue which was crystallized from benzene-ether to give 3.7 g (87.7%) of product with smaupunkten 169, 5-170, s °. -. _- -1 ir (cn2c12) -J max. 1745 (co) o ch 1620 am (phosphorane) PP. Preparation of 41'S, 3R, 4R and 1'R, 3S, 4S) -Silver-3- - (1'-methoxymethyl-1'-ethyl] -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone-4-thiolate (isomerA) amzuma am2am3 Jjï- (wa. Was _, o "Pa _ N .o> P $ 3 Coša 3 Silver-3- (1'-methoxymethyl-1'-ethyl) -1- (para-nitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -3-tritylthio-2-azetidinone (isomer A0 as described for isomer C of the paranitrobenzyldioxycarbonyl derivative above. Yield: 50% .ir ( pure max: 1145 "cm -1 (c = o>. 464 027 _ H8 QQ. Preparation of (1'S, 3S, 4R and 1'Rf3R, 4S) -silver-2- (1" -methoxymethyloxy-1'- ethyl) -1- (paranitrobenzyl-2 "-triphene-1-phosphoranylidene-2" -acetate) -2-azetidinone-4-thiolate (isomer C) d-oulamaseic acid : '_ O4 PO3 - o „° s co PN' cozvna 007 mg (1.0 mmd1) (1s, 3s, 4R den 1'n, 3n, 4s) -3- (1'-methdxymethyloxy-1; -ethyl) -1- (paranitrobenzyl 2 "-triphenylphosphoranylidene-2" -acetate) -4-trityltio-2-azetidinone was first dissolved in 30 ml of hot (40 °) methanol, treated with 103 mg (0.1 0s ml; 1.3 mmol) pyridine and after cooling with 8.7 ml of a 0.15 M methanol solution of silver nitrate (1.3 mmol). The mixture was stirred for 1 hour at 23 °, cooled (ice bath) and stirred for 20 minutes. The salt was filtered and washed successively with cold methanol and ether (3 times) to give 671 mg (87% of product ir (CHCl 3) q) max: 1745 (c = o>; 1s0s gfdšferam) den 1520 em'1 (§o2).

RR. Preparation of silver 3- (1'-paranitrobenzyldioxycarbonyl-1'-ethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone-4-thiolate - 9 464 027 "Isomer B" 1.02 g (1 mmol) (1'R, 3S, 4R and 1'S, 3R, 4S) 3- (1'-paranitrobenzylcarbonyldioxy-1'-ethyl) -1- (paranitrobenzyl-2 " -triphenylphosphananylidene-2 "-acetate) -4-trithio-2-azetidinone was first dissolved in 3 ml of dichloromethane and diluted with 20 ml of hot (ss °) meon.

The hot solution was first treated with 120 ml (117 mg; 1.48 mmol) and 8 ml of a hot (55 °) 0.5M methanol solution of silver nitrate (1.2 mmol). The mixture was stirred at room temperature for 15 minutes and then at 0 ° for 2 hours.

It was concentrated to a 10% solution on a rotary evaporator (no bath). The mercaptide was filtered off and washed twice with cold (-13 °) methanol and 3 times with ether. 917 mg (100%) of product were obtained. ir (nujol mull) Omax: 1745 (c = o), isoø (phosphorane> ochqlslv cm'1 (NO2).

Isomer C "Silver 3- (1'-paranitrobenzyldioicarbonyl-1'-ethyl) -1- (paranitrobenzyl 2" -triphenylphosphoranylidene-2 "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone-4- thiolate, "isomer C" was prepared as described above for "isomer B"; ir (nujol) 4) max: 1745 (c = o) and 1600 cm -1 (phosphorus).

"Isomer D" A solution of 145 mg (0.142 mmol) of isomer D of 3- (1'-nitrobenzylcarbonyldical-1'-ethyl) -1- (p-nitrobenzyl 2 "-triphenyl- phosphoranylidene-2" -acetate) -4: trityltio-2-azetidinone was prepared by first dissolving it in 5 ml of dichloromethane, removing the dichloromethane at 55-60 ° and adding 4 ml of MeOH. To the above solution was added 1.14 ml of a warm 0.1 M solution of silver nitrate 1 neon (0.1 moi; 1.2 equivalents), followed by 14 ul (D17 mol; 1.2 equivalents) of pyridine, and the silver mercaptide began to precipitate immediately. 2 hours at room temperature and 1 hour at 00. The mercaptide was collected by filtration and washed 464,027 m, with ice-cooled MeOH and ether to give 99 mg (0.1 mmol; 78%) of the title compound as a brownish solid. (ir (nujol) 1) nmx: 1750 cm-1 (s, C = 0).

SS. Preparation of (1'R, 3S, 4R and 1'S, 3R, 4S) -Silver'3-1 "% N-hydroxy-1'-ethyl) -1-paranitrobenzyl-2" -triphenylphosphoranylidene-2 "-acetate) -2 -azetidinone-4-thiolate (isomer B) 04 3 CHN Y 55 O - 2? 7ï. A solution (the crystalline material was first dissolved in dichloromethane) of 1 g (1.19 mmol) (1'R, 3S, 4R and 1'S, 3R, 4S) 3- - (1'-hydroxy-1'- ethyl) -1- (paranitrobenzyl-2'-triphenylphosphoranylidene-2 "-acetate) -4-trityltio-2-azetidinone in 10 ml MeOH was treated with 124 μl (12l, 3 mg; 1.53 mmol) pyridine and at 100 with 15 ml of a 0.5 M solution of silver nitrate (2.25 ml) in MeOH or with such a large volume that no precipitation of silver mercaptide was obtained anymore. The mixture was stirred for 1 hour and concentrated on a rotary evaporator (no bath). ) to a concentration of about 10% The solvent was evaporated The filter cake was washed once with MeOH and 3 times with ether and pumped under high vacuum to give 954 mg (100%) of product ir (nujol soil) 1) max: 3500 -3400 (oH), 1752 (c = o) 1595 (phosphorane) to 1525 cm -1 (NO 2).

TT. Preparation of <1'n, 3n, 4R and 1s, 3s, 4s> -4-acetylthio--3- (1'-p-nitrobenzyldioxycarbonyl-1'-ethyl) -1- (p-nitrobenzyl-2 (-Triphenylphosphoranylidene-2 (-acetate) -2-azetidinone (isomer D) amine OCOZPNB 5A; S09 aacunfnß _ 3 * å N PQB aæciz _ o \ f? N 2 "of co yèß cozvua CO? NB, 2 I 1m 464 027 To a stirred solution of 85 mg (0.095 mmol) of silver-3- - (1'-paranitrobenzyl-2" -triphenylphosphoranylidene-2 "-acetate) -2- azetidinone-4-thiolate (isomer D) in 5 ml of dichloromethane containing 30 μl (about 0.37 mmol; Fisher) pyridine was added at os ° zo ul (0.2 mmol) cH 3 col and the mixture was stirred for 30 minutes at 0-5 The precipitate which formed was filtered off and washed with dichloromethane, the filtrate and washings were combined and washed successively with brine, dilute hydrochloric acid, saturated sodium bicarbonate and then brine, dried over sodium sulphate and evaporated to give 75 mg ( yield 95%) of the title compound as a syrup. 1 mr (CDCl 3) 2 §: 2.33 (s, -SOCOCH 3): ir (pure) - \) mx: 1750 (β-lactam, ester), 1695 (thiaesterl 1520 and 1350 cm -1 (-NO 2).

Preparation of (1'R, 5R, 6R and 1'S, 5S, 6S) -cis-p-nitro-benzyldioxycarbonylmethyl-penem-3-carboxylate (isomer D) 0 11811 I EV "- ~" year u P9 6 N - A solution of 74 mg (0.09 mmol) of the above acetylthioacetidinone in 30 ml of toluene was refluxed under a nitrogen atmosphere for 7 hours. After evaporation of the solvent, the residue was purified by high performance liquid chromatography (SiO 2; eluent benzene: ether = 3: 1) to give 24 mg (0.044 mmol; 49% yield) of the penem ester as a syrup. (Note: this oil could be crystallized from THF ether or dichloromethane ether). 464 027 122 'Hur \ CDCJ.3) d: 1.140 (an. A. A-e.s az. V-cas). 2.38 (an. N. Z-cxa). 4.01 un. aa, asus-un. safari-z. s-m. s.os-s.:o-s.s4-s.ss (zu. As ny? - a-cozgz-u). s.ao un. a. r-ocoz-gz-un. s.1-s.s name. v-a). s.sa (ma: SIS-ana sm. 1.49-1.s4-a.1a-s.:a (an. Azuazn rïumz. m. Lsa-Lsa-ans- 8.33. (43, A2'B2 ', B -aromata 'Hsh i: (rtn fi) Vux: H80 (B-lahtam), 1750 (-0 <: 0 ._, -). 1110 man),: szo, ~'. iaso m * (4102). vv. preparation of (1'n.sR, sR and f's, ss, ss) = potassium and sodium δ- (1 '-hydroxyethyl-Z-methylpenem-B-carboylate (isomer D) - ocozm' on / Ürr S nz / pa-çnir 0 N \ ¿? _mÉ '¶HP% & e fi% EQ 0 n \ ¿> 4m3 cozvua - co fi ß, »S9 A solution of 24 mg (0.044 mol) of the above-mentioned penem ester in 5 ml of TH was mixed with 10 ml of ether, 5 ml of water, 1.00 ml of phosphate buffer (0.05 molar; pH 7.00; Fisher) and 50 mg of 30% Pd-celite (Engelhard) The mixture was hydrogenated at a pressure of 2.4 x 105 On for 21.5 hours at room temperature.

After removal of the catalyst (over celite), the separated aqueous layer was washed with ether and lyophilized to give 12 mg of the title mixture of sodium and potassium salt as a white powder. * se (nzo) 591.2: (an. a. J-enz. rag- 2-21 UH- = - z-cas). Las un. aa. usla-ana. awfsnz. 61m- 4-2 (13-3- WH): s.ss ppm (m. A. As' 6-4111. S-m: i: mu fi beer) va; 1755 (PIIHW f -x-suc). : se 1s1o ef * x-cozaz; w tagen-a; 297 (ß 23 °° - u: 1900.. X-su flfi '_ 123. 464 027 This material was identical with a sample of the title compound prepared by aldol condensation of acetaldehyde with the dianion of' 2- methylpenem-3-carboxylic acid.

Example Gel 12 (1'S, 5R, 6S and 1'R, 5S, 6R) 6-1'-hydroxy-1'-ethyl) -2-methylpenem--3-carboxylic acid (ismer C) Method A: CO CONN CO PNB - COZH occzmm 'O? NB ozpna OH sn 2. 9 sAe '- s ___... § .__- ip 3 :? H3 u N o \: ïw3 "xfßåg lo“ o: PNB 2 2 Methød B: OCO PNB Ålem ... _-NO, \ si & ozpns * ljïnzrn sne. 5 ,, o uYou of-uïvøa CO 335 _ O PNB 464 Method A 1) (1'S, 3S, 4R and 1'R, 3R, 4S) -4-Acetylthio-3- (1'-paranitrobenzyldioxycarbonyl-1'-ethyl) -1- (paranitrobenzyl-2 "- triphenylphosphoranylidene-Z "-acetate) -Z-azetidinone (isomer C) ocozma '/ f fl f fi l sa ÄTD / ° waves: ~ f” 0 “> \ f? P ° 3 c5H5N.“ \ 74? ° 7 ~. co A cold (ice-methanol bath) solution of 1.14 g (1.30 mmol) of 1'S, 3S, 4R and 1'R, 3R, 4S) -Silver 3- (1'-paranitrobenzyl-dioxycarbon - yl-1'-ethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone-4-thiolate (isomer_C) in 60 ml of dichloromethane was treated with 0.6 ml (0 , 74 mmol) pyridine and dropwise with 236 mg (0.2l3 ml; 3.00 mmol) acetyl chloride. The reaction mixture was stirred for 1 hour at -15 °. The precipitate was filtered off and washed with ether. The filtrate was washed with a 2% aqueous solution of hydrochloric acid, water, a 2% aqueous solution of sodium bicarbonate, water and brine, and dried over magnesium sulfate. The residue was triturated by evaporation of the solvent in ether to give F "'aq" K83.7%) product with a melting point l84-1850 (decomposition, i: (CHCl3) vw: ns; im .co ). xszo ochïeos m'l (f0Sf0r - '= 1n) -' m1. Ber- fcr C425 se '3:11 H 4.49, N 4.88, S 4.26.: sn c enas, a 4.42, u 5.11, s aan; Found: _C 61.26, 125 464iU27 2) (1'S, 5R, 6S and 1'R, SS, 6R) -paranitrobenzyl-2-methyl-6- (1'-paranitrobenzyldioxycarbonyl-1'-ethyl) -penem-3 -carboxylate (isomer C) OCOZPNB;. _ ocg pga _ 2 SA: J: -M * f ïläås - RW; Û PNB COzptqa 2 Ern solution of ass mg- (Lo-í moi) <'s, 3s, 4n and 1'n, 3R, 4s) -4- -acetylthio-3- (1'-paranitrobenzyldioxycarbonyl-1'-ethyl) -1- - (paranitrobenzyl 2 "-triphenylphosphoranylidene-2" -acetate) -2- -azetidinone ( isomer C) in 60 ml of toluene was refluxed for 4.5 hours After concentrating the solution, the residue was passed through a silica gel column (10 g; 1% ether in benzene) to give 3939 mg (69.6%) of the the title compound in pure form, m.p. 157 DEG-158 DEG (CHCl3 ether) . 1: (cxcia) vmax = ivas, 114s. 1110 (c-oz, iszs = m'1 (nog), * amg (CDCl3) 6: 8.30-7.2 (an, m, H-arena. 1 5.46 (13, 4, J-1,3, 3-5 ), $ .40-5.0 (SH. M. Z CI-Iz-PNB ', HP), 3.95 (13, then, J = 1_3, 34.4,, __ \ H-6), 2.35 (an. S .CHBI, 1-43 ppm (SH. D. Js.4. C fi ai: Ana1.Ber.a for c24n? 1n3o1 ° s «c 53.04, H 3.99, u'7.7a; Euærnat; 52.75, H 3, 86, N 7.69. (F 3) (1'S, 5R, 6S and 1'R, SS, 6R) -6311'-hydroxy-1'-ethyl) -2-meth-1-phenem-3-carboxylic acid (isomer C ) ïdämæ JT \ s' 0 s CH ---- + Q 2 _ _.: Qüß noi: PNB _ CO2H 464 02? 126 A mixture of 206 mg (0.379 mmol) (l'S, 5R, 6S and l'R, 5S, 6R) - paranitrobenzyl 2-methyl-6- (1'-paranitrobenzyldioxycarbonyl-1'-ethyl) -penem-3-carboxylate, 30 ml THF, 40 ml ether, 20 ml water, 7.64 ml of a 0.05M buffer solution pH 7 (0.382 mmol) and 500 mg of 30% Pd on celite were hydrogenated at a hydrogen pressure of 2.9 x 105 Pa in a Parr shaker for 16 hours, the catalyst was filtered and washed with water. times with ether, was acidified portionwise with a cold 1% aqueous solution of hydrochloric acid a to pH 2.5 and extracted with 15 x 20 ml of ethyl acetate between each hydrochloric acid addition. The ethyl acetate extracts were combined and washed with x 30 ml brine. Evaporation of the solvent and trituration of the residue with ether gave 57 mg (65.6%) of the title compound. i: (mr) vw: asaeüwo (æm, .H55: I isen = m'1 cc-2; uv (szouz ina: 311 (e eszaw.: sz (e asvzzf * fl mz (DMSO-da)): 5.57 ( IH, d, 311.7, 3-5), 4.02 (IH, i, HJ-'h 3-75 (13, ¿¿,; .1_1, 3.3.5, a-sz, 2.2: (an. S. Ens 1.2: ppm (BH: df I METHOD B l1 Silver- (1'S, 3S, 4R and 1'R, 3R, 4S) -1- (t-butyldimethylsilyl) -3- (1'-paranitrobenzyldioxycarbonyl-1 '-ethyl) -2-azetidinone-4-thiolate (isomer C) ocozpnß "\ 0CO2PNB el:, scç3 sne ----- + H. 0 § \ sf'e2 o \ É¿) h2 _ \ = 3 g (143 mol) of isomer C of 1 '- (t-butyldimethylsilyl) -3- - (1H-paranitrobenzyldioxycarbonyl-1'-ethyl) -4-trityltio-2-azetidinone was dissolved by stirring. in 12 ml of hot (400) methanol A solution of 0.59 g of silver nitrate in 12 ml of methanol was added followed by 0.13 ml of pyridine, the mixture was stirred vigorously for 1 hour at room temperature and for 2 hours. The solid silver mercaptide was collected by filtration and washed with ether to give 352 mg (46%) of ir-1) max = 1135 cm -1 (c = 0). 2) (1'S, 3S, 4R and 1'R, 3R, 4S) -4- [cetylthio-1- (t-butyldimethylsilyl-3- (1'-paranitrobenzyldioxycarbonyl-1'-ethyl) -2-azetidinone (isomer C) CO 2 PNB ocozpug 5A? SAc .... + .__; N 2 Me o -3 \ sfn2 0 N \ gf / 2 \ & \ få ": su To a solution of 880 mg of isomer C of silver-1- (t-butyl-dimethylsilyl) -3- (1'- paranitrobenzyldioxycarbonyl-1'-ethyl) -2-azetidinone-4-thiolate in 40 ml of dichloromethane stirred at 0 ° was added 0.57 ml of pyridine followed by a dropwise addition of 0.49 ml of acetylchloria. °, the solid was removed by filtration and the filtrate was diluted with ether, dried over a 2% aqueous solution of hydrochloric acid, water, a 2% aqueous solution of sodium bicarbonate and brine, dried and concentrated to give 610 mg of the title material such as an oil. I1m “¿ux%; ¿, g¿ 7.48 (48, 2d, aromata), 5.40 (IH. d. -7-2-2, 11-410 5-2 (zu. s . bensviz, s.:-4.9 (la. Ä. H-1 '). 3242 (IH. dd. 1-2- 3-31- 2.32 (sa, S. cx3>, 1.40 (sn, a, J- 6.5, css). 0-95 (9H- I- = ~ B «>, olä ppm (en, css). 464 027 128 3) (1,3S, 4R and 1'R, 3R, 4S) -4- Acetylthio-3- (1'-paranitroben-oxycarbonyl-1'-ethyl) -2-azetidinone (isomer C) UI amphma _ g ß S A: SRC ----: -> M. N o \ sk 2 O \ 3 1, 4 g isomer C of the above S-acetyl-Nt-butylmethyl--silga-azetidinone derivative was dissolved in a mixture of 0, 5 ml TFA, 5 ml water, 3 ml methanol and 2 ml dichloromethane and stir; 48 hours at room temperature. The solution was diluted with 100 n of water and extracted with 4 x 20 ml of dichloromethane. The combined organic extracts were washed with a 2% sodium bicarbonate solution and brine, dried and concentrated to give the title compound as an crude oil. Purification was accomplished by chromatography on 30 g of silica gel eluting with ether in benzene to give 650 mg of product.

Crystallization from benzene gave a white solid. * nur (cncia) 6: s.1s, 1.45 (aa, za, azomsa.>. 6.18 (18, NH), 5.19 (28, S, bansyl), 5-05 (28, I, H-4 1 E -l fl),: oss (mg då; 3.205; 4051 a-3) | (æy s 'I PPI .sx, a. Js.s, cn3); 1: vu¿: = ivso, 1150, isss = -' 1 (c-oz.

4), 3S, 4R and 1'R, 3R, 4S) -4-acetylthio-3- (1,4-paranitroben-oxycarbonyl-1'-ethyl) -1- (paranitrobenzyl-2 "-hydroxy- -acetate) -2-azetidinones (epimers at Cf2 '). (isomer C) ocozpna OCO2PNB said: _ SÄ = ---- + ° i "” f ”ß \ H _ _ _ o u9 464 02? A mixture of 750 mg of isomer C of 4-acetylthio-3- (1 '- -paranitrobenzyldioxycarbonyl-1'-ethyl) -2-azetidinone, S25 mg paranitrobenzyl glyoxylate hydrate and 50 ml of benzene were refluxed for 3 days in a Dean-Stark apparatus filled with BA molecule sieves. and refluxing was continued for another 2 days.

The mixture was diluted with ether, washed with 2% hydrochloric acid, water, 2% sodium bicarbonate and water, dried and concentrated to give 975 mg of an oily residue. Chromatography on silica gel eluting with 85:15 benzene ether gave the title compounds in pure form. - 'mn (CDCIB) 6: a.2s-6.75 (as. m. azamau.', _s.: o, s.12 (an. 2 :. bensyi-), s.os-4.10 (in, H- 2->, 4.45-4.35 (la. Za. A-4), 4.so-4.10 (130 m; 8-1 ') | m; 3-2 l: dy 5) (1'S, 3S, 4R and 1 'R, 3R, 4S) -4-Acetylthio-3- (1'-paranitrobenzyldioxycarbonyl-1'-ethyl) -1- (paranitrobenzyl-2 "- triphenylphosphoranylidene (2" acetate) 2-azetidinone (isomer C) Ocovus G ° PNB OPNB 2 SÄC 2 'SÅC Ö P 2 SÃC SOCI: 3 _ NÉOH “than N X1 / w3 CO PNB: mm: mm 2 _ 577 mg (1 mmol) of isomer C of 4-acetylthio-3- (l '-paranitro-benzyldioxycarbonyl-1'-ethyl) -1- (paranitrobenzyl 2 "-hydroxy-2" -acetate) -2-azetidinone was dissolved in 10 ml of anhydrous THF and 95 mg (1.2 mmol) of pyridine were added The solution was cooled to 0 ° and 143 mg (1.2 mmol) of thionyl chloride was added slowly, the mixture was stirred for 30 minutes at 0 DEG C. and diluted with a small amount of ether and the insoluble salts were removed by filtration and washed with ether.

The combined filtrates were concentrated to give a crude mixture of the epimers of the C-2 "chlorine compound.

It was dissolved in 20 ml of THF and 314 mg (1.2 mmol) of triphenylphosphine and 129 mg (1.2 mmol) of 2,6-lutidine were added and the solution was stirred at 45 ° for 4 days. The solid was removed by filtration and washed with benzene and the combined filtrates were concentrated to give an oil whose spectral characteristics and thin layer chromatography properties were identical with the corresponding properties of a sample of the title compound prepared by acylation of the corresponding silver thiolate.

The desired penem product can be prepared by reacting the title compound by the method 'according to steps 2 and 3 in Example 12 (Method A).

Example 13 (1 'R, SR, 6S and 1' S, 5S, 6R) -6- (1'-hydroxy-1 '-ethyl) -Z-methyl-penem-3-carboxylic acid (isomer B).

- METHOD A _ 0602M43 222m ocošrwa ° "- __, _ __; a - + C * sad Ae / Lrfs o" s o Ywï 'N 3 o N_% “B. - o a ~ PNB “co vx: 2 2 3 2 METHOD B on I. OH. . or EAT; _ iams / 'rza sn _ & \ / H / ïj / s n. ° “" fi * * z fififi i fi ïlw fl f ”°"' s? in method 31x30 * 'mama fw' _ ° z "'131 464 027 METHOD A 1) (1'R, 3S, 4R and 1'S, 3R, 4S) -4-acetylthio-3- (1'-paranitrobenzyl) dioxycarbonyl-1'-ethyl) -1- (paranitrobenzyl-2 "- -triphenylphosphoranylidene-2" -acetate) -2-azetidinone (isomer B) uuU FNB J * 2 SM _ ocozrua SÅ lïí / aan »Än ° i-íï -y ° "Ywß ° s" s ". A solution of 917 mg (1.03 mmol) (1'R, 3S, 4R and 1'S, 3R, 4S) -Silver-3- (1'-paranitrobenzyldioxycarbonyl-1'- ethyl) -1'-paranitrobenzyl 2 "-triphenylphosphoranylidene-2" -acetate) -2--azetidinone-4-thiolate (isomer B) in 20 ml of dichloromethane was treated at -15 ° (ice-methanol bath) with 242 μl ( 247 mg; 3.3 mol) of pyridine and dropwise with 142 μl (157 mg; 2.0 mmol) of acetylclene. Biananingen stated; 15 minutes at -1 ° C and the solid was filtered off and washed with ether. The organic solution was washed with a 2% aqueous solution of hydrochloric acid, water, a 2% aqueous solution of sodium bicarbonate, water and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was crystallized from ether to give 710 mg (80%) of product having the anal point 1s3-1ss °; i: (cnc13) -g ax = 1775, 1695 _ (c = o), 1620, 1sos (phosphorane) and 1625 cm fl (NO2). 2) (1'R, 5R, 6S and 1'S, 5R, 6R) -Paranitrobenzyl-2-methyl-6- (1'-paranitrobenzyldioxycarbonyl-1'-ethyl) 'peem "3'carb' oxylate (isomer B) OCOZPNB - 2 sne. '_ J, 5 -_ u, u. CH 3 o N Po 3 A -' u ä 'PNB. _ ° 2PNB 2 _ 464 027 u 132 A solution of 650 mg (0.79l mmol) ( 1'R, 3S, 4R and 1'S, 3R, 48) 4-Acetylthio-3- (1'-paranitrobenzyldioxycarbonyl-1'-ethyl) -1- (paranitrobenzyl 2 "-triphenylphosphoranylidene-2" -acetate) -2- - azetidinone was refluxed for 7 hours in toluene, after evaporation of the solvent the concentrated solution was passed through a silica gel column (10 times its weight) and the title compound (0.5% ether-benzene to 2% ether-benzene). was obtained as a white solid in an amount of 329 mg (77%) m.p. 134-1350 (CH 2 Cl 2 --ether); ir (cnci?) 'vmax = ivss, 1145, 17os' (co), iszs = m' 1 (uo2); * nmx (coola) 6: 8.20 (211. d, Ho azomat.), 7.60 (23, d, Hm aromat.), 5.55 (1H, d, J-LS, nS), ss-4 .§S (sn, n, zcnz-run, n-1 '). A.as (in. Aa, J-1.a. J-1.5, a-6).' 1.so ppm (sn, a .J-6.3, ca3): ¿g3¿.Ber. for 2.38 (35, s, C33) I C24H2IN3O1OS: C 53.04, H 3.89, N 7.73, S SJWFKJIIIIGÉZC 53.05; H 3.98, N 7.63, S 6.02. 3) (1'R, 5R, 6S and 1'S, 5S, 6R) -6- (1'-hydroxy-1'-ethyl) -2-methyl-penem-3-carboxylic acid (isomer B) OCO2PNB _ g In. s 'H2 j' 5 I I Q; ----- + II ca 3 3 m> nm 2 "A mixture of 65 mg (0.2 mol) (1'R, 5R, 6S and 1'S, 5S, 6R) - -paranitrobenzyl-2-methyl-6 - (1'-Paranitrobenzyldiolacarbonyl-ethyl) -penem-3-carboxylate (isomer B), a 0.05 N buffer solution pH 7 (1.06 equivalents), 10 ml of water, 10 ml of THF and 25 ml of ether were shaken in a Parr hydrogenator for 16 hours at a hydrogen pressure of 3.4 x 105 Pa using 200 mg of 30% Pd on celite. The catalyst was filtered off and washed with small volumes of water. The aqueous layer was washed with 3 times ether, acidified portionwise with a cold 1% aqueous solution ns 464,027 of hydrochloric acid, extracted with ethyl acetate between each addition of hydrochloric acid and saturated with brine and carefully extracted with ethyl acetate. a solid residue which was triturated with methylene chloride to give 19.4 mg of product (71%). i: (nujan vm = asoo (o-na. n as. : en an * (c-on w (seem Ämax: ZGÖ (E 3450), 309 (C 6400)! IHJ !!! (DHSO G6) Ö: 5.54 (l fl q d: J-losf a-5) | m; H-l ') | 402-315 bs; då! J-6.5. A-1.s, ae). 2.28 (aa. S. ena)., 1.15 ppm (aa. D. J-6. CH3>.

METHOD B 1) (1'R, 3s, 4R and 1's, 3R, 4s) 4-Acetylthio-3- (1H-trimethylsilyloxy-1'-ethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranyl-'idene-2 "Acetate) -2-azetidinone (isomer B) UTMS o cozguæ cozina A suspension of 505 mg (0.715 mmol) (1'R, 3S, 4R and 1'S, 3R, 4S) -Silver-3- (1 ' -hydroxy-1'-ethyl) -1- (paranitrobenzyl'2 "- -triphenylphosphoranylidene-2" -acetate) -2-azetidinone-4-thiolate in zs m1 'marcylated to -1s ° (is-methanol baa), was treated dropwise with 289 mg (398 μl 52.86 mmol) of triethylamine, 310 mg (262 μl; 2.85 mmol) of trimethylchlorosilane and finally with 50 mg (0.734 mmol) of imidazole and stirred for 3 hours at -15 ° = and at room temperature for 16 hours (IR with respect to an aliquot showed absence of hydroxyl group.) The mixture was cooled to -15 °, diluted with 20 ml of dichloromethane, treated with 226 mg (231 μl; 2.86 mmol) of pyridine and 168 mg of B i «^ 9 rnsci Acci ~ 'L ~ s ^ °' ______ ¿'--- Q à _ \ 1,, P03 man csusu 1- ~ \ fa? 3 464 027 134 (152 u1; 2, l4 mmol) acetylchloride , stirred for 0.5 hours, diluted with ether , was washed with a dilute aqueous solution of hydrochloric acid, water, a 5% aqueous solution of sodium bicarbonate, water and brine and dried.

The solvent was removed on a rotary evaporator and the residue was purified by filtration through a silica gel column (ratio 1:10, 3-10 ether in benzene) to give 360 mg (84.2%) of the title compound mixed with 30 mg. (7.8%) of the desilylated derivative. ir (liquid fi elm) 1) max. 1750, 1790 (C = O), 1620 (phosphorus) and 1518 cm (NO 2). - 2) (1'R, 3S, 4R and 1'S, 3R, 4S) -4-acetylthio-3- (1'-hydroxy-1'-ethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" - acetate) -2-azetidinone (isomer B) OH - Jim 5A; .uaß SAc dJ :: 1 / P ° 3. PQ3 fm fam 2 A solution of 360 mg (0.504 mmol) (1'R, 3S, 4R and 1'S, 3R, 4S) - 4-acetylthio-3-1'-trimethylsilyloxy-1'-ethyl) -1 (paranitrobenzyl- 2 "-Triphenylphosphoranylidene-2" -acetate) -2-azetidinone was treated with 3 drops of TFA and stirred for 18 hours at room temperature. The mixture was diluted with ethyl acetate, washed with water, a dilute aqueous solution of sodium bicarbonate, water and brine, and dried over magnesium sulfate. Evaporation of the solvent gave 334 mg (100%) of the title compound; ir (CHCl 3) dmæf 1755, 1590 (c = o), 1620, isos (phosphorarnocn 1520 an * (Hoz). 135 _ 464 '6127 3) (l'R, 5R, 6S och l'S, SS, 6R) -paranitrobenzyl -2-methyl-6- (1'-hydroxy-1'-ethyl) -penem-3-carboxylate (isomer B) 01-1. . _ / Lx sac Ä 2 / Å H N P93. o 7: covua mm 2 2 A solution of 410 mg (m.p. c1'1z, 3s, 4n And 1's, 31z, 4s> - '4-acetylthio-3- (1'-hydroxy-1' ¥ ethyl) - 1- (Paranitrobenzyl 2 "-triphenylphosphoranylidene-2" -acetate) -2-agetidinone in 40 ml of toluene was refluxed for 7 hours. The toluene was partially evaporated.

The residue was passed through a silica gel column (ratio 1:12; 3%, 4% and 5% ether in benzene) to give 151 mg (65%) of the title compound as a white solid, m.p. 161-161.5 °. . 1: (cnc13> vmax = ssoo, asoo-aaoø (ou). Lvao, lsoa (eo), 1525 = m ° 1 (nog), * nar 6 »s.zo (za, 4. J-1, ao arenan .>, 1.60 (zu. A axøxnat. H 5.57 (1H. D, 3-2, 8-5), 5.29 (ZH, center av Aßq, 51-15, mia-yxa), 4.2 (m, dq,. 7-7, 3-6, HP). 3.61 (18. dd, .7-7, J-2. 5-6). 2.33 (an. S, ena),. 1. :: ppi: (an, a, .zs. 1113): ¿\ _n = _1.Ber. för. 16 16 2 6 N 7.71, s 8.96. 4) (l'R, 5R, 6S och l'S, 5S, 6R) ~ 6- (l '-hydroxy-1'-ethyl) -2-methyl-c HN os = c 52.74, H 4.43, N 7.69, s s.ao; Phinyl fl: c 52.67. u 4.41. penem-3-carboxylic acid (isomer B) OH A mixture of 89 mg (0.24 Å mmol) (1 ', 5R, 6S and 1'S, 5S, 6R) - - 464 027 136 -paranitrobenzyl -6- (1'-hydroxy-1'-ethyl) -2-methylpenem-3-carboxylate, 15 ml THF, 10 ml water, 30 ml ether, 5.06 ml of a 0.05 N buffer solution pH 7 ( 0.253 mmol) and 250 mg of 30% Pd on celite were shaken in a Parr hydrogenator for 3.5 hours at a hydrogen pressure of 3.1 x 10 5 Pa. Workup in the same manner as described above gave 32 mg (57%) of the for specified in the heading the purification.

Example Gel 14 (1'S, 5R, 6R and 1'R, 5S, 6S) -6- (1'-hydroxy-1'-ethyl) -2-methyl-penem-3-carboxylic acid (isomer A) 1) (1'S , 3R, 4R and 1'R, 3S, 4Si-4-acetylthio-3- (1'-methoxymethoxy-1'-ethyl); 1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -2 -azetidinone (isomer A) KH AND 2 3 _, z fi 3 Ag SAC CO PNB "-f COZPNB Isomer A of 4-acetylthio-3- (1'-methoxymethoxy-1'-ethyl) -11 (paranitrobenzyl-2" -triphenylphosphoranylidene-2'-acetate) -2-azetidinone was prepared as described above for isomer C of paranitrobenzyldioxycarbonyl derivative in a yield of ssæ 1: (pure) Q max: nso and 1690 cm -1 (c = o). 137 464 G27 2) (1'S, 3R, 4S and 1'R, 3S, 4S) 4-acetylthio-3- (1'-hydroxy-1'-ethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene 2 "-acetate) -2-azetidinone, (isomer A): mama OH M n fa: P63 \ (F $ ° Y ° ß OPNB 'CDPNB 500 mg (0.68 mmol) of isomer A of 4-acetylthio- 3- (1'-Methoxy-methoxy-1'-ethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate-2-azetidinone was added to a cooled (Oo) solution of 50 ml of trifluoroacetic acid oc h 10 ml of water and stirred for 15 minutes in ice and 3 hours at room temperature. The reaction mixture was concentrated, dichloromethane was added and the solution was washed with sodium bicarbonate, water and brine, dried and concentrated to give 450 mg (96%) of the title compound. ir (rent) -J max. 3400 (om, 1745 and 1690 mfl (c = o>. '3) (1'S, 5R, 6R and 1'R, 5S; 6S) -paranitrobenzyl-6- (1'-hydroxy-1'-ethyl) - 2-methylpenem-3-carboxylate (isomer A) 'ma' i ', J \ s ^ ° _ / l: E: IfS -1 ~ ß ß The title compound was prepared as described for isomer C of paranitrobenzyldioxycarbonyl the derivative 464 027 138 in a yield of 45%.: w (conz, 45, 733 (4R. Aßq, azamsa.>. s.ea (la. a. J-4.0. H-5). 5.33 (23. Anq. Ben fi vll '4.3 (m, n. Ar), 3.8 un, aa. J-4.o, as). 2-41 (BH. S. C fl a). 2-31 (IH. S, OH), 1.42 ppm (BH, d, JIG. (333): i: (üiCla) Wax: 3100- asoo (ou). 1780,. 1710 cm'1 (co). 4) (l'S, 5R, 6R and l'R, 5S, 6S) -6- (1'-hydroxy-1'-ethyl) -Z-methyl-penem: 3-carboxylic acid (isomer A) I. I m ca -----> cs 3 3 ø N “* A mixture of 82 mg (0.2 mmol) of isomer A of paranitrobenzyl 6- (P-hydroxy-P-ethyl) -Z-methylpenem-B- carboxylate 400 mg of 30% palladium on celite, 10 ml of THF, 25 ml of ether, 10 ml of water and 4 mol of a 0.05 M buffer solution pH 7 (Fisher = SO-B-108) were hydrogenated for 4 hours. n Parr shaker at an initial hydrogen pressure of 3.1 x 105 Pa. The catalyst was removed by filtration on celite and washed with water. The filtrates were washed with ether and the aqueous layer was acidified with 0.25 M cold hydrochloric acid and extracted with 5 x 10 ml of ethyl acetate.

The combined organic extracts were washed with brine, dried and concentrated. The skunupic solid was triturated in ether to give 20 mg (44%) of a white solid. ir (nujol) Qmax: 3500 (OH), 1765 and 1665 cm -1 (c = o>; uv (ston) Lmax: 301 (z 5922). 260 (z 4280). 139 464 Û27 Example '1 5 (l' R, 5R, 6S and 1'S, SS, 6R) -2-aminomethyl-6- (1'-hydroxy-1'-ethyl) -penem-3-carboxylic acid (isomer B) (1'R, 3S, 4R and 1'S, 3R, 4S) -4-azidoacetylthio-3- (1'-hydroxy-1'-ethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone (isomer B) 01 -1 OH sm 'rnsCl A Ciqocgzgsh. I ß L Ä fi cæ fl zna o NYPQB TEA ~ _ * Yçs COZPNB cozpn-B A cold (ice-methanol bath) suspension of 970 mg (1.37 mmol; of 1 mol of the corresponding trityl compound) (1 R, 3S, 1R and 1'S, 3R, 46) silver 3- (1'-hydroxy-1'-ethyl) -1- (paranitrobenzyl 2 "-tri-phenylphosphoranylidene-2" -acetate) -2-azetidinone- 4-Thiolate in 40 mL of THF was treated dropwise with 0.695 mL (595 mg; 5.48 mmol) of trimethylchlorosilane 0.765 mL (555 mg; 5.49 mmol) of triethylamine and 50 mg (0} 734 mmol) of imidazole. under nitrogen and then cooled to -15 ° (ice-methanol), after which 406 mg (3.40 mmol) of azidoacetyl chloride were added. the breath was stirred for 30 minutes (the course of the reaction was followed by thin layer chromatography). The solid was filtered off and washed with ether. The filtrate was diluted with additional ether, washed with a 1% aqueous solution of hydrochloric acid, water, a 1% aqueous solution of sodium bicarbonate, water and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was taken up in 50 ml of moist dichloromethane and treated with 3 drops of TFA (cleavage of TMS ether was followed by thin layer chromatography). The methylene chloride solution was then washed with a 1% aqueous solution of sodium bicarbonate, water and brine and dried over magnesium sulfate. The residue was passed through a silica gel column (8 times its weight of benzene ether 1: 1, ether and ethyl acetate 1: 1) to give 565 mg (69.8%) of the title compound; ir (film) Omax: 3500-3200 (O-H), 2100 (fi), 1755, 1609 (C = O), 1620-1605 (phosphorane) and 1518 cm (NO 2). (1'R, 5R, 6S and 1'S, 5S, GR) -paranitrobenzyl-2-azidomethyl- 6- (1- '1-hydroxy-1'-ethyl) penem-3-carboxylate (isomer B) ox skmm u / ïL -Q / 2 3 'roluen Äng / SN ---_- “* 2: o“ \ íf ° 3 §. 2PNB 2 A solution of 500 mg (0.73l mmol) (1'R, 3S, 4R and 1'S, 3R, 4S) - 4-azidoacetylthio-3- (1'-hydroxy -1'-ethyl) -1- (Paranenitrobenzyl) 2 "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone in 100 ml of toluene was refluxed for 30 minutes under nitrogen. The solution was concentrated in vacuo and the residue was passed through a silica gel column (5 3.5-4% ether-benzene) to give 193 mg (65.1%) of the title compound as a yellowish solid. Sn * (Cbdla) 6: 8.13 (28, d , Ho aromat. H 7.52 (23, d. En aromat-), s.ss (ln. A. J-1.8. A-5). 5.21 (zu. Center - ABs- J'l3-S- CH, - PN§): 4_50 (23, cenggr_ i 'm, CHZ-Nz), 4-15 (l fl ø I: H'1') | 3-73 (ia, aa, Js.:, J-1.:. H -sm. 1.92 (1H. d. J-4 .0-H), 1-22 »PN (ax, 4, J-5,3 enar; 1: ccncza) vu.x = z11o '(n3). ivss xvos (c ~ o) lszo = n'l ~ (uo2L 141 464 027 (1'R, 5R, 6S and 1'S, SS, 6R) -2-aminomethyl-6- (1'-hydroxy-1'- - ethyl) -penem-3-carboxylic acid (isomer B) on _ ou: 2 /: 5 __. f2__. _ mf: CO PNB C023 A solution of zs mg (o, os2 moi) u'n, sn , ss and is, ss, en) - - '' Paranitrobenzyl-2-azidomethyl-6- (1'-hydroxy-1'-ethyl) -penem-3-carboxylate in a mixture of 6 ml of THF, 6 ml and ml of water was shaken in a Parr hydrogenator É, 5 hours at a hydrogen pressure of 2.8 x 105 Pa using 100 mg of 10% Pd on carbon. The catalyst was filtered off and washed with small volumes of water. The aqueous layer was washed with ether 3 times and lyophilized to give 11 mg (73%) of the title compound. * auf (nio) 5 »s.vs (ia. 4, a-2. u-5), 4.:o Win, == n ==:». J-s.s.

H'l ') | (m1 då; J-óosp J-z; I d: 3.605: css), LÉ cnujai null) vm¿x = asso-z4so co-H, u-na. lvss (c-o>, 1600 can-1 (C09: IW (B20), ÄN; 309 (E 3650), 255 (t 2815).

Example gel 16 (1'R, 5R, 6S and 1'S, 5S, 6R) -2- (4-aminobutyl) -6- (1'-hydroxyethyl) penem-3-carboxylic acid (isomer B) OH JW sp I! _; 2 »-um§4m5 COOH 464 027 1,2 (l'n, as, sa ooh 1's, 3n, 4s) -4- (8-ozidohntenoyleim-s- - (1'-hydroxyethyl) -1- ( paranitrobenzyl-2'-triphenylphosphoranylidene-2 "-acetate) -2-azetidinone. W / ÉfJ-: fsåg -rascl g 2130: 42) Åcocl _ a * je '' gæ fl zws N rea, In. 'can Hgod” “ ~ f-rrh 5 5 N \ ~ CÉPNB OOPNÉ A solution "of 3.03 g- (4,2s nnnol) (1'n, 3s, 4n ooh l's, 3lz, '4s) silver-3- (l'- hydroxyethyl) -1- (paranitrobenzyl-2 "-triphenyl-phosphoranylidene-2" -acetate) -2-azetidinone-4-thiolate in 55 ml of dry THF, which was stored under a nitrogen atmosphere, cooled to -2 ° and treated in Order 2.39 ml (17.1 mmol) of triethylamine, 2.18 ml (17.1 mmol) of trimethylchlorosilane and 0.10 g (1.47 mol of imidazole). The reaction mixture was stirred at -25 DEG C. for 0.25 g. hours, the cooling bath was removed and stirring was continued for 16 hours. The reaction mixture was cooled to 0 ° C and diluted with ss nl dichloromethane; after successively with 0.73 ml (9.0 mmol) of pyridine and with a solution of 1.36 g (8.56 mmol) of 4-aminobutanoyl chloride in 10 ml of dichloromethane. The reaction mixture was stirred at 0 DEG C. for 1 hour and filtered through a pad of celite. The pad was washed with 25 ml of dichloromethane; The filtrate and washings were combined and diluted with 300 ml of ethyl acetate. The organic solution was washed with 1N hydrochloric acid, water, a saturated sodium bicarbonate solution and water, dried over anhydrous magnesium sulfate and concentrated on a rotary evaporator to an orange syrup. . The syrup was dissolved in 75 ml of dichloromethane and 4 ml of water and 0.2 ml of TFA were added; the reaction mixture was stirred at 23 ° for 1.5 hours, washed with sodium bicarbonate and water, dried over anhydrous sodium sulfate and concentrated to an orange syrup (3.4 g). Purification of the syrup was accomplished by column chromatography (silica gel G60, 80 g; eluent: Et 6 Ac in CH 2 Cl 2 ma 464 027 10% -75%). Evaporation of the appropriate fractions in question gave 2.14 g (67.7%) of an oil. Analysis: Ber. for C 37 H 36 N 5 O 7 SP: C 61.23, H 5.00, N 9.65, S 4.42; found: C 61.17, H 5.10, N 10.02, S 3.71. 1'R, 5R, 6S and 1'S, 5S, 6R) -paranitrobenzyl Z- (δ-azidobutyl) -6- (1'-hydroxyethyl) -penem-3-carboxylate OH 'OH S Ä-'Ugm a:' AJ.

N TOÅMGIII ^ n 4.13 _ 0, * \ _PPh _ o - ïoopNš g OOPNB A solution of 2.04 g (2.81 mmol) (l'R, 3S, 4R and l'S, 3R, 4S) 4- ( -azidobutanoylthio) -3- (1'-hydroxy-1'-ethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone in 310 ml of a 30: 1 mixture of toluene and dichloromethane were refluxed for 9 hours under a nitrogen atmosphere (dichloromethane melt) ss °. Analysis: Calc. for the c19H¿ln5o6 the titanium was removed at the beginning of the reflux). The reaction mixture was cooled to 230 and the toluene was removed in a vacuum. obtained an orange residue which was purified by column chromatography (silica gel 60, 45 g; eluent: ether in petroleum ether 1: 1 - 9: 1) The appropriate combinations were combined and concentrated to a syrup which was crystallized from a mixture of ether and petroleum ether to give 0.443 g (35.2%) of product having a s = 51.5, H 4.73, N 15.65, S 7.17; Found: C 51.05, H 4.86, N 15.86, S 7.19 The fractions corresponding to unreacted ed vapor material was cyclized in the manner indicated above to give an additional 0.276 mg (2.1%) of the title compound. 464 027 144 -lv, 2100 ma), 1779 (ç-Q, ßqghzm) I 1705 cm (C10, PNB esteth uv (H20 za-c; xm =: se (e msn. Ne (esazs). 'Am- 6) : 1.26 (d- J fl "2" 4 Høl ~ -6 ~ 3 al: 3H | MBÜ '1n52'1.77 (av ÅHU H-: Il H'3') | 2 ° 57-3 '°° (m, za, H-4 '>, 3.00-3.42 cm, za, H-1'). 3.12 (da, JH_6_H_5-1.6 Hz.

JH.G-H-I'IG_Å Hzl 'H fl6) | 4902-4042 En 'm' a fi ll-) l Ja-b fl lahs Hz! .las Hz; 1H | H'5) I (d '' Im-HQ IR, CH _ 'PNB Qâttll: 5-50 (ål JH-5-H-5 2 -ea az, za. um »ua escez) -,' 8.21 Pp fl 53- J3 ° _H '° -B H2- 23' “° PNB cheeses). (1'R, 5R, 6S and 1'S, 5S, 6R) -2- (4-aminobutyl) -6- (1'-hydroxyethyl) -penem-3-carbogyl acid on OH, »1 ~ 10: Pa / c 'J "' S 'mm) u -4 ----- (aï fl mß 2 4 3 ons: ergo. Hzo 0 o am. Anna To a solution of 0.54 g (1.2l mmol) (l R, 5R, 6S and 1'S, 5S, GR) -paranitrobenzyl 2- (-azidobutyl) -6- (1'-hydroxyethyl) -penem-3-carboxylate in 50 ml of dimethoxyethane were added 50 ml of ether, 50 ml of water and 0.54 g of 10% palladium on charcoal The reaction mixture was hydrogenated for 3 hours at 230 under a hydrogen pressure of 3.1 x 10 5 Pa. The reaction mixture was filtered over a pad of celite and the filtrate was diluted with ether. The aqueous phase was separated with ether. The title compound was obtained as a crude product and purified by high performance liquid chromatography in: (KBr) vmx: 1760 (C10, B-labtam), 651565 cm-1 (CO, barboxylate): 1811:; (D20) : * '32 (d 'Jen: -H-1 - s.4 az, aa, css). 1.45-1.as (n. 4n. A ¥ 1'.x-a'), (ng 43; a-gi: a-4 ') | (adp Ja-Ga-lg-Gil Hz! _1I4 Hz; l-Hp 8-6) | (m1 in; Hl-'Q (al JH_s-H_6 -1.4 az, 1 3, H-5;, _ uv (azel 1mlx =: eo (e 4240),: oz (c saeoy. 404 027 UN 14 Example 17 (1 "R, 5R, 6S and 1'S, 5S, 6R) -2- (trans-3'-amino-1'-cyclobutyl) -6- (1" -hydroxy-1 "- ethyl) penene-3-carboxylic acid (isomer B) (1 "R, 3S, 4R and 1" S, 3R, 4S) -4- (trans-3'-azidocyclobutanoylthio) -3- (1 "-hydroxy- 1 "-ethyl) -1- (paranitrobenzyl-2" -triphenyl-phosphoranylidene-2 "-acetate) -2-azetidinone j" si., A., Ïïís fi- o - g 'w ¶ :: T nßcl __3_ * N Al 32 * -c-Prha - coovua now 1 "m CH 2 -Ph 3 cm 3 A solution of 1.01 g (1.43 mmol) (1'R, 3S, 4R and 1'S, 3R, 4S) silver 3- (1'-hydroxyethyl) -1- (paranitrobenzyl 2 "-triphenylphosphoranylidene-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 0.109 (1,47-mol) of imidazole, the reaction mixture was heated to -15 ° and stirred under 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 2 ml of chloromethane; was then partitioned between 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-3-azidocyclobutanoyl chloride. The reaction mixture was stirred for 1 hour at 23 ° and filtered through a pad of celite. The filtrate was diluted with 100 ml of ethyl acetate and washed with 1N hydrochloric acid, water, a saturated sodium bicarbonate solution and water, dried over anhydrous magnesium sulfate 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 (1.19). Purification of the syrup was accomplished by column chromatography (silica gel-60, 20 g; eluent: EtOAc ether 35% -70%). Evaporation of the appropriate fractions in question gave 0.77 g (74.4%) of the title compound as an oil. ir (rent) 1) ma-x: 3440 (on), 2100 (M3), 1755 (c = o β-lactam), 1735 (c = o). 1680 (c = o> and 1625 cnfl (aromae). (1 "R, 5R, 6S and 1" S, 5S, 6R) -paranitrobenzyl-2- (trans-3'-azidocyclobutyl) 6- (1 "- hydroxy-1 "ethyl) penem-3-carboxylate ox I / Y * / L s 83 A" w ----- + 30 0 - n; s mm A solution of 2.27 g (3,14) mol) (1'R, 3S, 4R and 1 "S, 3R, 4S) 4- (trans-3'-azidocyclobutanoylthio) -3- (1" -hydroxy-1'4ethyl) -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 3 + toluene) was removed with a Dean-Stark The reaction mixture was cooled to 230 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 M7. 464,027 0-6%). Evaporation of the appropriate fractions gave 0.38 g (27.3% of the title compound, m.p. 134-135 °. Analysis: Calcd for C 19 H 19 N 5 O 6 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; 1 _ 1: (Kax) vmax. 2110 (Na), 1165 c-o 8-labznm). isso (c-o rus @ == e:>. islo (Nog), lass = m'1 cno2> »'umr ccnciaz 6. 1.as <4. _: ca _H_1, -6.3 Hz. ax, C33). 2.0-2.75 (m. 43, a-2 ', fl ~ ¶'). 3.67 (dd. 3 Ja-sa-s'1'5 Hz 'Ja-eH-1' _. N-1'-, s.ao (Aag, aa_b-13.6 az. Za, eg: -vn-ung) . 5.60 td. JH_5_H_6 '.ens Hz!: BI a-6) I 308-4155 (ml 381 Hl "H-aç 1.5 az. Ia, a-sa, 1.59 za, aH ° _“ ma.a az, za ; am vas), 8-20 (d. JHm_H ° -ea az, zu, ao az rus). uv ccacis. 22 ° =>. Amax = 266 (2 120502, 322 ppm (E 10008).

The unreacted phosphorane was recovered mixed with Ph 3 P-O and cyclized as 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, 5S, 6R) -2- (trans-3 "-cyclobutyl (6- (1" - _-hydroxyethyl) penem-1-carboxylic acid - SN: os va / c ü = 'a-Mmferïï * WW;' mmæ ~ - cam To a solution of 0.33 g (0.74 mmol) (1 "n, sn, es 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 105 Pa and filtered through a pad of celite. The pad 464 027 -148 was washed with water and the filtrate and washings were combined and diluted with ether. The aqueous phase was separated, washed with ether and lyophilized to give 0.20. g (95%) of product (H 2 O, 23 ° C>, 1, max: zss (¿ï 2725) and 306 (¿$ 3613) The crude product was triturated with water and the white solid was filtered and dried over P 2 O 5 in high vacuum for 5 hours, yielding Prøducto Iam: å: (d, Ju-2 - H_1'.6_3 Hz, ax. ß-2'-, 2.:-2.7 cm, 4H, a-2 '. H-4'). 2-90 (dd. JH_6_H_5-ls az, JH_6_H_1. 4.1 3:, m, u-G), 5.68 (d, JH_s_H_6-! 1.5 Hz, 1H, H-SH uv (E20: 23-6) Ä v: 258 (C 473B), - 306 (E 6319).

The filtrate was purified by high performance liquid chromatography to give about 1 mg of product; uv (nzo, 23 ° c> ß. max = _2s1 (E asso) ooh: os (E soss).

Example Gel 13 Following the general procedure of Example 11, the following 2,6-disubstituted penem compounds can be prepared using the indicated electrophiles.

Electrophil - g Product _ s' I CH J-N / -ß - 0. 002: -: R I G13; C33- cacmcßo / \ t aa azcn 3 2 2 3 3 2 'c1 ~ 13cx2cs2oso2 © o <3 cxgcazcuz- ca: -ca-ca: -az' ca2-cacu2- i "xcsc-cxzaz xczccxz l> - \ '“ l> - \ Br Electrophile 0SO2 Q¶3 ° fl ï§: øClizCâzCl-I 0502 / \ øüh fi æ fl ßr ECC !! 3! ~ 4- a can be oxidized to CH3SCH2- and CH 149 464 027 S m, - C83 T SCH2- ß - _ b can be oxidized to CH3SCH2CH2f and CH3SO2CH2CH2- O - H c OH protected via -C-OPNB 464 027 Göê) ßßß 1 50 Elektrøfil R. _ on ca ca cao i '57 3 2 - cgoäæ-_ - _ @ Å_ _' "Æ fl zcazf?" _ @ / §? D a5æ «m2_ 5. _ @ @ Ä “S fl äfëëz S d? ': saa-ca - Ö f * _ v. OH Q ”O <øoca2c1 øocxz- øcu2oca2c1 I øcazocaz- øocazcxzcz øocazcaz- øcxzoczagcz-: zcz ~ øcazocxzcsz- _; øscazcz. øscaz _ '- _® øclízsCl-Izcl ÜCHZSCHZ øscnzcxzci øscazcxz- _ _ _® øcs2scs2ch2c1 _ øcxazscuzcsz ml SH protected -C-0-PNB can OG _ ø-l \, Q <:> can_ßCHider- to ØCH2 CH2CH and øS02CH2CH2- -'- _ cH3? N-cH¿- ° _ _ 2 1 can be oxidized to -'- øscuz and øsøzcnz- ~ 2 9_ _ ”øcnzscnzcnz- and _-_ _ øcnzscnz- and øcnzsozc fi åf] øc] Electrophile s øf ÖCHZCHO ° øCH-Gi-CHO CHBGIZCOZCBB @ can_oxidize to ø "\ j, / ^ \ S038 464 027 464 027 Electrophilic øcx-czacozcaa _ øCEC-CHO øCEC-COZCH: øCi-ls ø / \ /, CI ~ °, / \ / co2cn3 9 / Lx / c: "LEV" _ _ ln: s “_ I 152 ~ z / \ / ° \ ø \ 'ï“ øCac-CH- © o Il øCEC-C-, sa ø / \ @ 153 Elektrofil UV ÜVV ”> NI / I> X \ _, B = \\ _ o IN? Br \ ”š H 9 Cz fi sOC-Cl“ R CZHSOCCHZBI mac-cnzcl _ 4e4 "ö27 464 027 154 Elektrofil R = '__-__ o rcazcxzcozcsa r / \ / \ øzn-cxzcl _. Somæ / \' S \ s / \ _ ° / \ ocnzcl. ___! O (PNB-o) 22 H2 ° 3P _ _ mx - '2 _ ¶ ca3cao / \ q) @ @ on OMS “3 Vlä _ -> -> š Ö? __ & \ s / Ü Ö; _ 154. B _ nnco PNB m, _. / K 2 CH sàxmzíexagel - '_ _ 0 m; 92 NH N-co PNB 2. Ca 2 3 _ ® også. / K Å Ä' -> -> . ~ 6 '_ ä o ”eller 155 _ 464 027 NH 2 jïnyz I away," _ ca: 04 -A _ - _ ON ° co a 2 eller J ___; _ - '__; .__ \. * 2-: 113 _ _ __ N zf - ° _ _ 0 '_' _ o cozu ellër JE / NÜONHR _ N fi coxaa "-å" å => '- ** _ N 94' 04 ~ ° coza 'R' Ho C53: 'eller C fl gw' "___ ¿... ä _ ..> CH3 N zf 'oh' 0 / _ cozx 464 027 OH OH 156 eller JMS °«. Üfw ÜV 464 027 šlektrofil a - 'ø NER' Rp R 'I H1 øCl-IZCHO' w @ c / q ø a ø nv R 'RI IH' RR'N Q ® Q-Zaæl C830- Exemgel 19 (l'S, 5R, 6S och l'R, 5S, 6R) '5 trimethylsilylethyl-6 (1'-acetoxy-1'-ethyl) -2-methylgenem-3-carboxylate (isomer C) / ki-1 'I: FL '-hydroxy-1' -ethyl) -1- (β-trimethylsilylethyl-2 "-triphenyl-phosphoranylidene-2" acetate) -4-trityltio-2-azetidinone _ H STI 'TI If 1) m; n. _ PPh To a solution of 185 mg (1.84 mmol) of diisopropylamine in 5 ml of tetrahydrofuran at -78 ° was added 1.3 ml (2.0 mol) of n-but. After 5 minutes, a solution of 1.27 g of 11.67 mmol) of 1- (-trimethylsilylethyl 2 "-triphenylphosphoranylidene-2" acetate) -4-trityl: Wo-2-azetidinone in 15 nl tetrahydrofuran dropwise over 20 minutes and u 464 027 158 stirring stirring. After 2 minutes, 1 ml of freshly distilled acetaldehyde was added and the solution was stirred for 5 minutes. 12.6 ml of 0.3M hydrochloric acid were added and the mixture was allowed to warm to 23 °. 20 ml of water and 20 ml of ethyl acetate were added, the mixture was shaken and the layers separated. The organic phase was washed with water and saturated sodium chloride (20 ml each) and dried, and the solvent was evaporated in vacuo to give 1.37 g of crude product. The product was absorbed from methylene chloride on 7 g of silica gel and applied (dry) to a 28 g silica gel column. The column was eluted with 100 ml of ether and then with 50 ml of a 1: 1 mixture of ether and ethyl acetate. The first 20 ml fractions were discarded. The remaining fractions were combined and the solvent was evaporated in vacuo to give 1.03 g of product. This product was adsorbed from ether on a 50 g silica gel column (wet). The column was eluted with 680 ml of ether and then with 200 ml of ethyl acetate. Later fractions were combined (major-low Rf value on thin layer chromatography) and the solvent was evaporated in vacuo to give 440 mg (33%) of the title compound in partially purified form; ir 'Ûmaf 3400 (OH) and 1750 cm-1 (low-lactam and ester); 1 Hmr (CHCl 3) δ; too poor resolution to allow peak determinations other than aromatics and trimethylsilyl. Silver 3- (1'-hydroxy-1'-ethyl) -1-β-trimethylsilylethyl-2 "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone-4-thiolate OH w.

N Ph N P25 3 m I \ K 3. 2 A; 3. . A solution of 425 mg (2.5 mol) of nitrate nitrate, 79 mg of 11.0 mmol) of pyridine and 10 ml of water was added to a solution of 403 mg of 10.0 (SO mmol) of the above compound. in 10 ml of ether. The mixture was stirred vigorously for 1 hour. The precipitate was collected by filtration and washed with water and ether to give 267 mg (80%) of the title mercaptide. ir fl max: 3400 (OH) and 1750 cm-1 (ß- -lactam and ester). 4-Acetylthio-3- (1'-acetoxy-1'-ethyl) -1- (trimethylsilylethyl-2 "-triphenylphosphoranylidene-2" -acetate) -Z-azetidinone 01-1 OAc, NJ _ SAc Agt1 / pyridine 5 , PPha PPhB i A / smeß _ _ Y / \ / sm ° 3 02.

A solution of 70 mg (0.88 mmol) of acetyl chloride in 1 ml of methylene chloride was added dropwise to a solution of 267 mg (0.40 mmol) of the above silver mercaptide and 70 mg (0.88 mmol) of pyridine in 5 ml. ml of methylene chloride at 00. The mixture was stirred at 00 for 1.5 hours and then at 230 for 15 minutes.

The precipitate was filtered off and the solution was washed with 0.1 M hydrochloric acid and 0.1 M sodium bicarbonate (10 ml each).

The solvent was evaporated in vacuo to give 153 mg (59%) of the title compound; i, vmx, a-: so (om, 1150 (s-lactem QÃE-iiåâ-'f-É) m4 lsso m ' l (fi0estêfg * am (cnc13) .. s = '1.sa.z (m. isa. m, s.as (br, ma, un. so-so (wPPlÖSU-i ÅH, x fl; Ûc fl z; H') 3) | 2- °° 2-Ö (3 .Gao ÛÅCO 5Å =) | ° ~ 9 ° 1 ~ 7 (lv SHI ena, cuzsl) °. ° h 0.20 ppm (s, sa, six-ma). ( 1's, sn, ss and 1 ', ss, s1u-p-zaimet-silylethyl-s- (1' -acetoxy-1'-ethyl) -2-methylpenem-3-carboxylate (isomer C) OA: OA : 'SAc - HH s He si) n! En »P11' 4 n ° 3 Sina _ / \ / 3 ¶2 / \ / Sillen 2 464 Û27 '1w A solution of 150 mg (0.23 mmol) of the above The phosphorus in 15 ml of toluene was refluxed for 2 hours. The solution was mixed with 1 g of silica gel and the solvent was evaporated in vacuo. The silica gel was applied to a 4 g silica gel column (dry) and eluted with ether. The first 5 ml fraction (a single high) Rf value on thin layer chromatography) after evaporation of the solvent gave 65 mg (76%) of the title as a waxy solid material. 1: v 1 1190 (Bi; b = am>. 1740 (-seuzn [EX - v 'I ivoo ef * (om, * nu (cncis)) s: (a. -R-znz. M. N-sa .s. ((m, m.

H-1 ') v Å-a (I: 25: xgzï: 3-9Û (qi JUÛBZ: -A fl zf la: H' ° 7) I: '37 (s'_ 3 "'2_ca3)' 2.11 äs' 33 'OÄCJ' 1_42 (¿'Jn§: §, al': Hp 2'fl C fl3) r 111 (m:: Kr C851), 0.05 çpm (s, 93. Silica) - The product was found to be a single isomer.

Example Gel 20 (1'R, 5R, 6S and 1'S, 5S, 6R) -6-1'-amino-1'-ethyl) -2-methylpenem-3-carboxylic acid Method A (1'R, 3S, 4R and 1'S; 3R, 4S) 3- (1'-azido-1'-ethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -4-trityltio-2-azetidinone (isomer, B ) H 'scø 3 CO n P93' '3 63' CO PNB COZPNB W1 _ 464 027 A solution of 12.36 9 (13.4 mmol) (1'S, 3S, 4R and 1'R, 3R, 4S) - - (1-Methanesulfonyloxy-1'-ethyl) -1- (paranitrobenzyl 2 "-triphenylphosphoranylidene-2" -acetate) -4-trityltio-2-azetidinone (isomer C) in 135 ml of a 10% aqueous solution of HMPA was heated for 7 hours at 85 ° in the presence of 1.75 g (27.0 mmol) of sodium azide, the solution was then poured into 1 liter of cold water and the crystallized reaction product was recovered by filtration. Reconstitution in dichloromethane, washing with brine and drying over magnesium sulphate gave 11.5 g (98.9%) of the azidophosphorane as a yellow foam after evaporation of the solvent. The product was used as such in subsequent steps. Tr {) (CHCl 3 ): 2100 (N3), 1740 and 1. max -1 (1'R, 3S, 4R and 1'S, 3R, 4S) 4-Acetylthio-3- (1'-azido-1'-ethyl) -1- (paranitrobenzyl) -2-triphenylphosphoranylidene-2 "-acetate) - -2-azetidinone (isomer B) - NN 'N 3 ce: 3 S, 2Hg I / Li scocaa' N q »'uio ¿_.w | Po g 7 q 3 of 3 0 Y 3 O' - o mm n.-f A cold (SO) solution of 8.9 g (10.25 mmol) (1'R, 3S, 4R and 1'S, 3R, 4S) 3- (1'-azido-1'-ethyl) - 1- (Paranitrobenzyl 2 "-triphenylphosphoranylidene-2" -acetate) -4-trityltio-2-azetidinone in 30 ml of dichloromethane was mixed with a solution of 2.12 g (6.66 mmol) of mercury acetate in 30 ml of methanol. stirring for 0.5 hours at 5 ° and for 1.5 hours at room temperature, the solvent was evaporated and the mercury salt in the form of a crude product was redissolved in dichloromethane and washed with saturated sodium bicarbonate solution and brine. to 5 ° and treated directly with 1.66 g (21 mmol) of pyridine and dropwise with 1.65 g (21 mmol) of acetyl chloride.The reaction mixture was stirred at the mercury chloride was filtered off and the filtrate was washed successively with dilute hydrochloric acid, sodium bicarbonate and brine. Thereafter, the organic solution was saturated at 5 ° with hydrogen sulfide in order to precipitate residual mercury impurities such as mercury sulfide. The thioester crude product obtained after evaporation of the solvent was purified on a silica gel column (8.5 x 9 cm), eluting with 500 ml of dichloromethane and 15% acetonitrile-dichloromethane.

5.1 g (74.6%) of product were obtained. 1fl g (qx19 a Lvo (ia, a, H-1'S, 2.98 (xx. M, a-3), 2. :: and 2.20 (sal 2 :. ace = Y1>. 1-28 (33, d,; .6 ,; H., H-2 ~), 1: »max (cac13) = 2115 (ua), lvsa. 1693; '1620 can-1 (CIO) (1'R, 5R, 6S and 1'S, 5S , 6R) paranitrobenzyl 6- (1'-azido-1'-ethyl) -2-methyl-penem-3-carboxylate (isomer B) A solution of 5.19 (13.1 mmol) (1'R , 5R, 6S and 1'S, 5S, 6R) 4- -acetylthio-2- (1'-azido-1'-ethyl) -1-paranitrobenzyl 2'-triphenylphosphoranylidene-2 "-acetate) -2-azetidinone in 100 ml of toluene were refluxed for 2 hours under nitrogen, the solvent was evaporated and the reaction mixture was purified by chromatography on a silica gel column (7-x 5 cm) The azidopenem compound was eluted with dichloromethane (further elution with 10% ether-dichloromethane allowed 82 g unreacted phosphorus).

1.21 g (40.6% of product with melting point 132-340. 163 464 007127 'HSM (CDCl 3) 6: 8.21 (Zl-1, d, Hm azomat.), 7.60 (28, d, Ho aromatic) were obtained. J, 5.51 (II-I, d, Jil-S Hz, 8-5), 5.33 (ZH, ABq, H-benzyl), 3.92 (1H, dq, JIB. 6.4 Hz. HU), 3.67 (1H, then , Jil-S, 8 Hz, HG), 2.37 (JH, s, C83) - i 1.46 (BH, d, JIGJ Hz, fl "2 ') li! Vau (CDClsh 2123 013); 1788, 1712 m * ( (1'R, 5R, 6S and 1'S, 5S, 6R) 6- (1'-amino-1'-ethyl) -2-methylpenem-3-carboxylic acid (isomer B) N = '3.

S '2 ---- + “wa N ens 0 CÛ2PNÉ o A solution of 440 mg (1.13 mmol) (1'R, 5R | 55 0Ch 1'S, 5S, 6R) - paranitrobenzyl-6- (1'- azido-1'-ethyl) -2-methyl penem-3-carboxylate in 120 ml of a 1: 1: 1 mixture of THF, ether and water were hydrogenated at a pressure of 3.4 x 105 Pa under 1 hour in the presence of 440 mg of 10% Pd-C. The catalyst was filtered off, the filtrate was extracted with ether and the aqueous phase was lyophilized. The amino acid crude product (100 mg) was purified by high performance liquid chromatography to give 19.5 mg. * auf (nzoa 6 »s.s9 (la, a, Jo.e Hz. H-sn. 3.94 (2H. = .- aa, H-1 '). 2.2s (ax. s, ens). 1.50 ( an. a. J-6.4 Ha. H-2 '): 1: valx (Nui ° 1> = 1161. 1s1s cm'1 cc-oz, av (H20) àmax =: oo nu (esßz fi x Förfårande B (1' R, 3s, 4s and 1s, 3R, 4s) -3- (r-azido-r-ethyl) -4-trityltio--2-azetidinone (isomer B) ma 3 co3 464 027 164 A solution of 1.75 g (3 mol) (1'S, 3S, 4R and 1'R, 3R, 4S) 1- - (t-butyldimethylsilyl) -3- (1'-methanesulfonyloxy-1'-ethyl) -4-trityltio-2-azetidinone (isomer C) and 0.39 g (6 mmol) of sodium azide in 15 ml of a 10% aqueous solution of HMPA were heated under nitrogen at 75-80 ° for 3 hours, then the reaction mixture was diluted with ethyl acetate and washed several times. The organic phase was dried over magnesium sulphate and evaporated to give an oil which crystallized spontaneously.Trituration in ether and filtration gave 95l mg (76.5%) of the azido compound as a white solid, m.p. 900 (decomposition). "* Mm mmn3) 6; 1.zs¿1.1s (isx. M, azomat. X, 4.43 (zu. a. J-a. a-4). 4.31 (la. S, n-az. S.as (mn, aq, a-1, ss, xf1 '>. 3.16 <1a. Aa. A-1, 3, a-sa.: Iso (SH, d , J-6.S, H-2 '): i: wax (Cx-iclzh 3410 (n-Bi-2123 (N3),' 1165 = m'1 (co). (1'R, 3S, 4R and 1'S, 3R, 4S) -3- (1'-ethyl) -4-trityltio-2-azetidinone (isomer B) A suspension of 1.0 g (2.41 mol) (1'R, 3S, 4R and 1'S , 3R, 4S) 3- (1'-azido-1'-ethyl) -4-trityltio-2-azetidinone (ismer B) and 100 mg of platinum oxide in 100 ml of ethyl acetate were hydrogenated for 1 hour at a pressure of 3.4 x 105 Since the reaction was not complete, 200 mg of platinum oxide was added and the mixture was hydrogenated for a further 1 hour, finally 200 mg of platinum oxide were added again and the reaction was allowed to continue for 2.5 hours. Total amount of catalyst: 500 mg Total time: 4 The catalyst was then filtered off and the solvent was evaporated. The amine crude product crystallized from ether in an amount of 700 mg (80%) and with a melting point WS 464 DEG-274 DEG-30 DEG. , 53 (153, m, aromatc), 4-40 (m, d '_, _ ¿_5,' Hmm Mm umbred, un, 3.10 qx. Aq. .1-s. 1. 6.:. a-w. 3.0: (m. Aa. .1-s.1. 2.s. x-sï. 1-20 (ß fl- fl «“ W- ”q” - 1.o-1.ao ppm (an. Bred, MHz) - (1'n, 3s, 4R and 1's, 3R, 4s> 3- <1'-o-hydroxys11ox ety -etyD- fl i-urityltio-Z-azetidirone (isaner B) - NH: .HNCO2PNB JÜÉTSM A solution of 1.00 g (2.57 nmol) (1'R, 3S, 4R and 1'S, 3R, 4S) 3- (1'-amim-1 Ethyl) -4-tritylthio-2-azetidinyl (isomer B) in 100 ml of dichloronexethane was cooled to 25 DEG C. and treated with 0.61 g (2.8 mmol) of p-hif-polysylchlorophenic acid and 0.22 g (2.8 .mu.m.) After stirring at 45 DEG C. for 45 minutes at room temperature below 2.25 .mu.m, the reaction mixture was washed with dilute hydrochloric acid and bile solution, dried over sodium sulfate and evaporated to dryness. The product crystallized from ether in an amount of 1.03 g (70.5%) and with .. n snaltpanlctexz 147 50. m "(conz) ö: 1. - I 7.10-8.33 (19H, m, aromat.) , 5.23 (23, s. Benzyl), 5.08 (1H, N'H) 4.40 (1n, c, à-x), 4.29 (za, a. A-2.2, a-45, 4.1o (la. Dq Yes. 6. a-1 '>. 3.18 (1H, then, JIZ-Z, B, H-É), 1.23 PPIVÜH: d! 5-60 H ° 2ÜI if “max (chc13) ¿: ass tu-H). 1165, 1124 ch ° 1 te-oz. - "i (1'R, 5R, 6S od: 1'S, 5S, 6R) p-Nitriddenyl-Z-retyl-G- (Pp-nitrobenz-o-: carbonylazrano-P-ei-.ylk penan-B-carbonylate (isaner B) m-zco PN: - "HWfNB 2 scøa S / tïïl,, -" f'¿ "*} l: EQ *" = 464 027 - 166 The title product was prepared from (l'R, 5R, 6S and 1'S, 5S, 6R) 3- (1'-Penitrobenzyloxycarbonylamino-1'-ethyl) -4-trityltio-2-azetidinone (isomer B) by standard procedure Melting point 108-110 °. 1 l mr (CDCl 3) Δ: 7.50-8.40 (8H, m, aromat.), 5.58 (1H, d, J = 1.20, H-5), 5.35 (2H, ABq, benzyl ester), 5.20 (2H, s, benzyl carbamate ), 4.90 (1H, broad NH), 4.20 (1H, dq, J = 6.8, H-1 '), 3.80 (1H, dd, J = 1.2, 8.0, H-6), 2.40 (3H , s, (C33), 1.40 (BH, d, J = 6, CH3); 1: Q max; 3435 (now), 1777 and 1717 cm * (c = o) The p-nitrobenzyl ester can be subjected to catalytic hydrogenation according to with the procedure of Example 20 (Method A) to give the corresponding carboxylic acid.

Example 21 Silver 1- (β-trimethylsilylethyl-Z '-triphenylphosphoranylidene-Z' -acetate) -2-azetidinone-4-thiolate S59 '- OI N% PQ3 "but co ca ca s -ca, 222: C33 di - ß -trimethylsilylethyl fumarate _ - o - '-: ways ca Hd / ~. / Siægfs pyzidin 3 wv' 464 027 To 20 ml of a cold (-100) ether solution of 4.73 g (0.04 mmol) 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 -10 ° and 10 minutes at room temperature, charcoal was added and the reaction mixture was filtered on a pad of celite, the filtrate was washed with 150 ml of a 1: 1 mixture of 1% sodium bicarbonate and brine. The ether solutions were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a brown solid. was purified on a silica gel pad (30 g, 4 x 5 cm) eluting with 300 ml of benzene to give 4.855 g (77%) of an oil which was allowed to stand. melting point saa-PE, hu, fa, 31432804512: c 53.12, H Såhfunnet: C 53.35, H 8.91. Hm (CDCl 3) δ: e.1a (za, s, c-ca). 4.26 (4H, m, CH, - °) - 1-03 (4H, m, CH i: (CHCl 3) Vax: 1710 (C10 f ester), -1 1643 (c-c). 1261. izsa. sszf B40 == (S1 '°) - Trimethylsilylethylglyoxylate hydrate. . o _ sicca) 33 n o amm.

§3 (ma) as: z »(single phase °; A solution of 37 g (0,11 mmol) of di- '-trimethylsilylethyl fumarate in 1.1 liters of methylene chloride was ozonized at -78 ° until a residual blue color was obtained, the excess ozone was evaporated off with nitrogen and 2.57 ml (0.351 mol) of dimethyl sulphide were added, the solution was gradually allowed to warm to 23 DEG C. The reaction mixture was diluted with carbon tetra chloride 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 25 °) to dryness to give 43.9 g. g 464 027 ° 168 (97%) of the title compound. ir (pure) Omax: 34 50 (-om, 1740 (ester, 1255, eso and 840 cm -1 (Si-C)). trinxethylsilylethyl (2'-hydroxy-Z '-acetate) -4-trityltio-2-azetidinone-3' 1H (OCT: sig * 3 NN10 N YO CO 2 HA / sucuns 4,000 g (11, 6 mmol) trimethylsilylethyl glyoxylate- hydrate and 4.8 g (24.96 mmol) of 4-trityltio-2-azetidinone were refluxed in 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. * aux (cnc13) 6 = v.ao - s.1o (isx. m. ezicyi), 5.23, Leo (in, 2 :. a-c-O). .4-50 - 4-10 (BH- H- 34: - ° '° ** 27- 2.60 (m, a, u-: nfo-es un. N. Caz-si) .- ° -1 vw ß fl - = - Si-C fl y * i: (mala) v, 3520 (45), 1755 (co B-lattam). 1740 (Qo I !!!. - -1.. ===:>,: ses (cu . axowøt- 2- 1251- 860. - 840 = fl <° '$ i> 1- (ß-trimethylsilylethyl T-chloro-T-acetate) -4-trityltio-2--azetidinone STI __ Sælz STI' _ n 0 Pïfi fi i "0: 1 / ci si in COA / (cH3) 3_ïA / sirc fi al: 2 2 w9 464 Û27 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 (1.08 mmol) pyridine and 40 ml of dry THF at -15 ° under a nitrogen atmosphere.

The mixture was stirred for 2 hours at -15 °. The precipitate was removed by filtration on a pad of celite and washed with 50 ml of benzene. The filtrate was evaporated in vacuo at 30 °. 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.

'Her (§DC13) 6: 1.ao xisa, m, azømau. -a), 5.11 - 5.43 (in, 25, en-cl). 4.7 - 4.2 (aa, m. A-4,. Ca: -oz. Z.as - z.su (zu, m. A-2). 1.15 c2H._m, ca: -s1> ,. - o. oe ppm (sn. =, sx-cnsia ir (reurt) 1 v, nx = 1160 (c-oi. aeo, - a4o cm '(c-si). 1- (ê -trimegylsilylethyl-Z' -triphenylphosphoranylidene-Z Acetate) -4-tritylthio-2-azetidinone aziphysulphazazine 20 ml of a dioxane solution of 4.12 g (7.568 moles) of the above-mentioned chloroacetaninane was benzane with 2,209; (8424 mmol) triphenylphosphine and 0.98 ml (8.424 mmol) of 2,6-lutidine, 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. was purified on a silica gel column (200 g, 4 x 35 cm) using ethyl acetate-hexane (3: 7, 1 liter; 7: 3, 1 liter) to give 4.836 (83%) of the title phosphorane. . 1: (film) vmax = 1155 (c-or. 1s1s (fi OSfOI-'anh - as: mh aso nä. (Sa-c). GLuJaer. For cx no vssxf c 1s.es. u s.o1, Q 1.a1, FW1 fl HKï fi = c 1z.1q. A s.os. (7 46 3 N 1.83 \ Silver 1- (β-Trimethylsilylethyl-2'-triphenylphosphoranylidene-2'-acetate) -2-azetidinone-4-thiclate La .. ..- .na Q 7.64 g (10 mmol) 1- (β -trimethylsilylethyl-Z'-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 landing 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 10 minutes and pump GÉ min.) To give 6.42 g of the title compound. ir (cnc13r0m ax: 1862 (c = 0, '1s3o (phosphorane). 860 and 840 CH-1 (SI-C). 171 464 027 Example 22 6-formamidomethyl-2-methylpenem-3-carboxylic acid, sodium and § H-CH 3 ° other than potassium salts Q. trans-1- (t-Butyldimethylsilyl) -3-methanesulfonyloxymethyl-4-triethylthio-2-azetidinone H ou HR Cd 9 09 "" 3: ao /: : Ié 3 .______..._ § \ s1mn§2 \ s1 (cn3) 2 t-au t-BÜ A solution of 8.0 g (16.36 mmol) of trans-1- (t-butyldimethylsilyl) -3-Hydroxymethyl-4-trityltio-2-azetidinone in 50 ml of dichloromethane was treated at s ° with 1.4 ml of methanesulfonyl chloride in 10 ml of dichloromethane and 2.5 ml (18 mmol) of triethylamine. The solution was then washed for 1 hour under nitrogen, then washed successively with cold 1M hydrochloric acid, 1M sodium bicarbonate solution and brine, dried over magnesium sulphate and evaporated in vacuo. The residue (mixture of the hydroxy and mesylate compounds) was treated. a second time as before to obtain 90 g (97%) of the mesylate as an amorphous solid. et was used as such in subsequent steps without further purification. An analytical sample was recrystallized at melting point 167-11 ° from methylene chloride; .k (raw-Z) V: 1755; (fl-ll IHM! (CDCÉJ) 5 '7-3 (153: 5)! (J un; d' J'2H fl 'och IIIX _ a.§ (ia. aa, a-aaz, 4a =). 1 -2 tz ba. Ba) 2-8 (= Hf 2) - Q; 95 KPH- fl ° -3Pw fl 16H, §- 464 027 172 Trans-3-methanesulfonyloxymethyl-4-trityltio-2-azetidinone and trans-3-azidomethyl -4-trity1thio-2-azetidinone HH 'see "H _ Håfï, 3 HSO. N / fl: SCQJ N" "“ ““ “* --- + 3 I i H, \ ~ u? 4m5> 2 _ 0 A solution of 21.0 g (37.0 mmol) of trans-1- (t-butyldimethylsilyl) -3-methanesulfonylmethyl-4-trityltio-2-azetidinone in 90 ml / ml: The PA cooling on the bed was 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 The trans-3-methanesulfonyloxymethyl-4-trityltio-2-azetidinone was diluted with 90 ml of HMA, treated at rest with 2.7 g (41.2 mol) of sodium azide in 10 ml of water, heated at 60 ml. ° for 2 hours and triturated with cold water.The azide crude product was diluted with 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 gave 18.0 g (77%) of the azide as a white solid. An analytical sample was recrystallized from dichloromethane / ether and had a melting point of 174-1750; _ Analysis: Ber. for C 23 H 20 N 4 OS: C 68.97, H 5003, N 13.99, found cans, n 5.10, N 14.16; ir (mujel) Q max 21oo, '1155 em'1 = lnmr (cnc13) δ = 7.35 (1511, m), 4.75 (1a, _be), 4.4 (1H, d J = 2Hz), 3.1-3.7 ppm (3H , m). Trans-3-aminomethyl-4-trityltio-2-azetidinone aa 3 a ara / w S003 Ä uzz / * trscås n 0 u fl - H W. I 464 027 To a solution of 10.0 g (47.5 mmol) 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 inhaled 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 °; _ I. , _ .se, H 5.13, Anal. Ber.för ~ c23n22n2ocl 1/1 cazclz c 1o u 1.09: FUmW-'tb 1o.ss, u 5.94. n 1.21; i: (cacla) vmx: 3400, 1160 = n'l; 'ann (cocl3) 6: 1.as 2.1-3.5 (au, nl, l.3 ppm (2H. ml. trans-3-phthalimidomethyl-4-trityltio-2-azetidinone>: - O' un ”'3 Û N 'H 3 fl zn / m .__.__--- § I. Oil; 0 _ H; u H.

A solution of 13.9 g (31.2 mmol) of trans-3-aminomethyl-4-tritylthio-2-azetidinone and 8.3 g (37.9 mmol) of N-carbethoxyphthalimide in 200 ml of benzene was 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. 172-3 DEG.): BGIL-HFOSCNAUZOAS: c.13.19. .l found: 13.92, x 4.91, n 5.49; i: (cxcla) vw. l-11o, ms en '1' anx (coola) 6. 1.8 (an. nl, 1 .: (lsa. m). 1.45 (13.19. J-zazz. 2-2- 401 3I: "4ø6 (m) -) n trans-3-phthalimidomethyl-1- (paranitrobenzyl-2'-hydroxy-2'-acetate) -4-trityltio-2 -azetidinone na _ __ * 3 sces \ scoa ua 'o YO !! ofmn A mixture of 17.4 g (34.52 mmol) of trans-3-phthalimidomethyl-4-trityltio-2-azetidinone, 9.4 g (4l .4 mmol) of paranitrobenzyl glyoxylate hydrate and 4.8 ml (34.5 mmol) of triethylamine in 250 ml of tetrahydrofuran were 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 25 g (quantitative yield) of the hydroxy glyoxylate crude product as an amorphous solid. It was used in subsequent steps without further purification. 1z (om1§ v = 1170, 1115 = m'1 = lan: - 7-S5 ma: 3 (as. E, J-saa). 7 .: cisa, 1), so-s.4 (za. Rs ). 4-2-5-0 fi fl- => / 2.8-3.8 ppm MH, m). trans-3-phthalimidomethyl-1- (paranitrobenzyl-2'-chloro-2'-acetate) -4-trityltio-2-azetidinone H g SC * U 9. 1 :: ° - »tf, m _. To a cold (1sbaa, o °) solution of 25 g (35 ml) of trans-3-phthalimidomethyl-1- (paranitrobenzyl-2'-hydroxy-2 ') -acetate) -4-. = -trityltio-2-azetidinone in 1 ml of tetrahydrofuran was added dropwise 46 ml of a 1M solution of thionyl chloride (46 mmol) in tetrahydrofuran, followed by 16 ml of a 1M solution of pyridine (46 mmol) and tetrahydrbfuran. The reaction mixture was stirred at room temperature for 20 minutes, diluted with 50 ml of petroleum ether and filtered through a bed of celite and bicarbonate.

The solvent was evaporated in vacuo to give 26 g (quantitative yield) of the chloroacetidinone as one. amorphous solid material. It was used in subsequent steps without further purification. -n- (cucia) v = 1115. 1720 = m'1. lan: icnciz) 6: s.12 (za, a, J-saa). 7-60 flfl x (23, å; JIQHZ), 7.3 (1911, m), 5.25 (25, Bh 4.7 '$. 4_ (130 l) | 4-55 (Ing bf). I soa-4co m) c trans -3-Phthalimidomethyl-1- (paranitrobenzyl-2'-triphenylphosphanylidene-2'-acetate) -4-trithylthio-2-azetidinone A mixture of 26 g (35.5 mol) of trans-3-phthalimidomethyl-1- (paranitrobenzyl-2'-chloro-2'-acetate) -4-tritylthio-2-acetiaminone, 10.25 g <39.1 mm 2) triphenylphosphine and ¿) s m1 (39.1 mm ° 1> 2, The reaction mixture was filtered over celite and evaporated, the residue was chromatographed on a 350 g silica gel column eluting with benzene to give 1 g (1: 1) to give 219 (62%). of the phosphorane as a white solid.

L_§: (cuc13), v “lx = ivso, ivio = m'1. 'fl mz (cncxa) 6: 1.4- (aan, ma, 4.es.4 (au. az. 4.6 (za, g), 3.1 ppm' - unyn. trans-3-phthalamidomethyl-1- (paranitrobenzyl-2 ') -triphenylphosphananylidene-2'-acetate) -4-tritylthio-2-azetidinone 464 027 176: Na; Men - P; A cooled (ice bath) suspension of 18.02 g (18.83 mmol ) trans-3-Phthalimidomethyl-1- (paranitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate) -4-trityltio-2-azetidinone in 30 ml of tetrahydrofuran, 30 ml of water and 30 ml of acetone were treated dropwise with 4.97 9 (20.7 mmol) of sodium sulphide 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 mixture was washed with brine and evaporated in vacuo to give 17.1 g (88%) of the title compound as an amorphous light yellow solid, which was used in the subsequent steps without further purification. rentym: aiso-asoo. 1750. 1700 fl flß 'HM (cncia) 8; 7: :-( saa. nl, 3.3-S -5 ppm (I f I) - trans-3-phthalisoimidomethyl-1- (paranitrobenzyl-2'-triphenylphosphanylidene-2'-acetate) -4-trityltio-2-azetidinone HH 'g Û aha-r iii *, C025 O fl A solution of 17.1 g (17.54 mmol) of trans-3-phthalimidomethyl-1- (paranitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate) -4- -tritylthio- 2-azetidinone in 12 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. rn ~. _ _1 än (rent) vw: zim. ivss, nice », 'am -_- (cucia) 6 = 7.5 (383: mh 4-6-5-3 (43, u), 3.9 ppm (211, bi). trans-3-aminomethyl-1- ( paranitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate) -4-trityltio-2-azetidinone HHHH _ a scø ', »! SC * o N / 3 _ RZN w. 3 N A solution of 5.9 g (6.16 mmol) of trans-3-phthalisoimidomethyl-1- (paranitrobenzyl-2'-triphenylphosphoranylidene2'-acetate) -4--trityltio-2-agetidinone in 40 ml 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 aqueous phase was alkalized with 1M sodium bicarbonate The organic extracts were washed with brine, dried over magnesium sulphate and evaporated to give 60 g of silica gel column eluting with ether to ethyl acetate to give 3.38 g (66%) of the aminophosphorane as an amorphous solid. material 1: (cnciš) vmax = 1129, 1110 = m '*, * amz (çnciai 6; s.s-e.1 ca4n, I). a.a-5 ,: fen. u), - os-1.9 ppm (za. mi. 178 464 027 trans 3-formamidomethyl-1- (paranitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate) -4-trityltio-2-azetidinone HH To a cooled (ice bath) solution of 5.0 g of (-aminomethyl-1-2'-acetate) -4-trityltio-2- (azetidinone) was added dropwise under nitrogen a solution I ngN / fi scø, nr N ø _ f = '2 "" - 6.04 mmol) trans-3- (paranitrobenzyl-2'-triphenylphosphoranylidene - 50 ml dichloromethane of 600 mg (6.8-mmol) acetic acid anhydride in 5 ml of dichloromethane, followed by a solution of 1 ml (7 mmol) of triethylamine in Stirring was continued for 30 minutes 2 ml of dichloromethane.

The solution was washed successively with 1M hydrochloric acid, Water, 1M sodium bicarbonate and brine. It was concentrated over magnesium sulfate, chromatographed on 50 g of silica gel collo ether to ethyl acetate to give 2.0 g (39%) of an amorphous solid. year (C1-1C18) Wax: 1740, 1685, (CDCl3) δ: 6.6-8.2 (BSH. mh trans silver-3-formamidomethyl-1- (paranylphenylphosphoranylidene-2'-acetate) -2-azetide HE HXN / A solution of 550 mg (0.64 mmol) of 3-form-nitrobenzyl-2'-triphenylphosphoranylidene-2-thio-z-azetidinone in 10 ml of the cyclamethane organic layer is dried. and evaporated and the residue eluted with the formamide such as 1620 and: Hsu 215-513 (m0 m): trobenzyl-2'-triinone-4-thiolate Egg / ma * ä 559 Ål? n: f PNB Amidomethyl 1- (para '-acetate) -4-trityl was evaporated to dryness and diluted with 20 ml of hot methanol, the solution was stirred at 60 ° and treated with 5.7 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 stirred solution was stirred for 30 minutes at room temperature and then 2 hours in an ice bath, the solid material was filtered, washed with cold methanol and ether and dried to give 300 g mg (65%) of the silver salt as a beige solid It was used in subsequent steps without further purification. trans-4-acetylthio-3-formamidomethyl-1-zparanitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate) -2-azetidinone H3; / mjíjr SAg aZä / Ac i '° = "V2" o "' N çgzpm 'COZPNB To a cooled (ice bath) solution of 800 mg (l, 11 mmol) 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 sulfate and evaporated. The residue was purified on a 5.0 g silica gel column and eluted with ethyl acetate to 10% methanol in ethyl acetate to give 450 mg (62%) of the title compound; _r ¿, (CHCl3) vm.x = 1155, less, iszo = n ° * »x fl mf 62 (m: å: _J-9HZ) | 700-800 mf (zxg d! J-9 az), 6 .: (in, m), ss (ia. N), 5.2 (z fl. Biï- 4-9 (1H- bf), 3-6 un, mp Lo ua, my 2.2ppn 464 027 180 Paranitrobenzyl 6-formamidomethyl-2-methylpenem-3-carboxylate HH s "gu / s § ^ ° _ nggß 'L en, -" _ "' a H Po 0 * o É A solution of 450 mg (0.668 mol) of trans-4-acetylthio-3-formamidomethyl-1- (paranitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate) -2-azetidinone in 10 ml of toluene was refluxed 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. 1: (cac13> vmax = 11ao, isso = m'1; * nar (cncisz az a.2 (za. 4. J-snzi. ez (ln. s). 7.s (za. d. J-sazx. 6.9 (in. g), s.ss (la. sl. S-JS <2H. 2 :). 3-3- 4.1- (aa. mr,. 2.33 pm (au. sn. 6-formamidomethyl-2-methylpenem-3-carboxylic acid) sodium-And potassium salts \ A mixture of 80 mg (0.2 .mu.l) of paranitrobenzyl-6-formido-methyl-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 @H 7 (0.223 mmol) were hydrogenated for 3 hours in a Parr shaker at an initial hydrogen pressure of 3.1 x 105 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 aqueous phase was washed with 3 x 15 ml of ether and lyophilized. The solid crude product was purified by high pressure liquid chromatography to give 18 mg of a mixture of the sodium and potassium salts. _ -_ _ 'uv (H20) Åmaxx 299 (C 4933), 259 (8 4094): ir tnujol) vmaxl: zoo-asso,. 1155 = m'1; * amx (ago) 61 a.1s (zu, |), 's.s: (ln. a.

J-1u4Hz) | 400 =) I (ml d! J-5Hz) | 2.27 ppm (3H, g), Exemgel 23 (1'S, 5R, 6S and 1'R, 5S, 6R) -6- (1'-hydroxy-1'-propyl) -2-methyl- -penem-3-carboxylic acid, sodium salt (isomer C) Et fH_ _ _.- Bokia »_ 5 NQ-gg 30 0 CO2Nn trans-1t-butyldimethylsilyl-3-propionyl-4-trityltio-2-azetidinones' o 2 _ \ In: 37.50 ml of a 1.6M hexane solution of n-BuLi (60 mmol) was added dropwise under nitrogen. to a cooled (dry ice-acetone bath) and stirred solution of 8.50 ml (60 mmol) of diisopropylamine in 200 ml of dry THF. The mixture was stirred in cold and 22.9 g of 150 mmol) of 1-t-butylanethylethynyl: tritylua-z-acetylamino 1100 ml of dry THF were added. After 15 minutes, 40 ml (excess) of methyl propionate was added and the reaction mixture was kept at -8 ° for 4 hours. Then the cooling bath was removed and the internal temperature rose to 0 ° (about 40 minutes). The mixture was poured over 464,027,182 ice-hydrochloric acid (pH about 6) and extracted with ether. The layers were separated and the aqueous layer was extracted with ether.

The combined ether solutions were washed with water and brine and dried over sodium sulfate. The solution was evaporated in vacuo to give an oil in quantitative yield. This contained a mixture of starting material and the title compound and was used as such and purified in subsequent steps. ir (rent) 1) nwx: 1710 0 u _ (-c-), 17so cm 1 (ß -laktam). lt-butyldimethylsilyl-3 - ((1'-hydroxy-1 '-propyl) -fi-trityltio-Z-azetidinones' 'ma sm \ vJÄ T:' + \ v} \ '2 _ NIBH4 __': A solution of 26 g (50 mmol) of 1-t-butyldimethylsilyl-3-propionyl-4-trityltio-2-azetidinone and 7.6 g (200 mmol) sodium borohydride in 400 ml THF was stirred for 18 hours at room temperature.

- It was poured onto ice-1N HQI (pH 6) and extracted with ether.

The acidic phase was extracted several times with ether and the combined ether solutions were washed with brine, dried over sodium sulphate and evaporated to give 25.0 g of an amorphous solid. This crude product was chromatographed on SiO 2 (ACT.1,400 g) “and was first eluted with dichloromethane to give 10.8 g of 1-t-butyldimethylsilyl-4-trityltio-2-azetidinone. Elution with 20% ether in dichloromethane gave 10.3 g of the title compound as a mixture of two isomeric trans alcohols. These were separated by high pressure liquid chromatography (Water Associates, System S00) and using 10% ethyl. ; that in dichloromethane as an eluent. Isomer C, white solid, 3.8 g; m.p. (pet.ether) 134-36 ° C. lnmr (cnc13) J; 7.1-7.s (1511, m, six). .__ a), 3.1 (H, wß, 464,027 dd), 2.5 (H, m), 0.7-1.7 (SH, m), 0.97 (9H, s) and 0.25 ppm (6H, s). Anal! : ber. for C 31 H 39 NO 2 SSi: C 71.91, H 7.59, N 2.71; found: C 71.51, H 7.60, N 2.96. Isomer B. white solid, 5.4 g; m.p. (pentane-pet.ether) 97-99 ° C. d lnmr (cnc13) 'å' - = 7.1-1.s (lsu, m, s-rr), 4.15 (u, d), 3.4 (H, dd), 3.2 (H, m), 0.7-1.7 ( SH, m), 0.85 (SH, s) and 0.1 ppm (en, s). 97-9 ° C. lnmr (cnc13) = 7.1-7.s (isa, m, sfrr), 4.15 (H, d), 3.4 (H, then), 3.2 (H, m), 0.7-1.7 (SH, m) Û.85 (9H, s) and 0.1 ppm (6H, s). The total yield of these two alcohols (calculated on recycled starting material) was 67.5%. (1'S, 3S, 4R and 1'R, 3R, 4S) -1-butyldimethylsilyl-3- (1'-paranitrobenzyldioxycarbonyl-1'-propyl) -4-tritylthio-2-azetidinone (isomer C) 0 PNB OH a 2 sr - \ ~ / ii. ST 'V * - I + clcozPtm n-BuLi - H u \ * s1na2 0 \\ 5i "° 2 To a cooled (dry ice-acetone bath) solution of 3.1 g (6 mmol) 1'S, 3S, 4R and 1' R, 3R, 4S) -1-t-butyldimethylsilyl-3- (1,4-hydroxy-1'-propyl) -4-trityltio-2-azetidinone (isomer C) in 20 ml of dry THF was added dropwise under nitrogen 4, 88 ml of a 1.6M hexane solution of BuLi (7.8 mol), stirred at -78 ° for 25 minutes, then 1.56 g (7.2 mol) of paranitrobezyl chloroformate in 10 ml of dry THF are added dropwise and the resulting mixture is stirred. It was diluted with ether and washed with ammonium chloride solution and brine, the organic phase was dried over sodium sulfate and evaporated to dryness to give 4.2 g (quantitative yield) of the title compound. 'm- (cnc13) saz (za, a), 1.o-1.7 (nu, m), s.1: (m. a). 4.05 (HI d). 3.15 (xp ° os5-1n8 l, l o., (sal.) '(GH, d) 464 027 184 (1'S, 3S, 4R and 1'R, 3R, 4S) -3- (1'-paranitrobenzyldioxycarbonyl-1'-propyl) -4 -trityltio-2-azetidinone (isomer C) ~ t / íxï? P; ïsT ~ \, §c ° 2PN B - z '' m ”ST: '_ °) __" + mæw + ms --- »I Å _ \ s¿m2 (IN H20) \ H _ To a cooled (ice bath) solution of 4.2 g ( 6 mmol) (1'S, 3S, 4R 'and 1'R, 3R, 4S) 1t-butyldimethylsilyl-3- (1'-paranitrobenzyldioxycarbonyl-1'-propyl) -4-tritylthio-2-azetidinone (isomer _C) To 40 ml of HMPT containing 10% water was added 0.78 g (12 mmol) of sodium azide. The mixture was stirred for 1 hour at room temperature. It was diluted with 100 ml of water and extracted with 4 x 15 ml of a 1: 1 mixture of benzene and petroleum ether. The organic phase was washed with 6 x 30 ml of water and brine. It was dried over sodium sulfate and evaporated to dryness to give 3.5 g (quantitative yield) of a solid which was treated with pentane and filtered to give 3.4 g of a pale yellow solid, m.p. 84-86 °. _ * Eu ccncia) 6; a.2 (zu. aa, 1-1.1 (lvs. nl. sz za. s). 4.95 (H. dt), '4.4 (ua). 4.25 ca, ai, 3.4 (5, aa), 1-7 (28. n), 0.95 ppm (330 t) 1.- (1'S, 3S, 4R and 1'R, 3R, 4S) -3- (1'-paranitrobenzyldioxycarbonyl-1'-propyl) -1- (paranitrobenzyl-2 "-hydroxy-2'-hydroxy-2" -acetate) -4-tritylthio-2-azetidinone (isomer C) 'PNB-4' / fco2Pus sf: I - ~, _ STI 'TH N + PNQ glyoxalate c "__-tim" VB wß ß 464 027 To a solution of 3.2 g (5.5 mmol) (1'S, 3S, 4R and 1'R, 3R, 4S) - 3 - (1'-Paranitrobenzyldioxycarbonyl-1'-propyl) -4-trityltio-2-azetidinone (isomer C) and 1,362 g (6 mmol) of paranitrobenzyl glyoxylate hydrate in 50 ml of dry THF were added a catalytic amount (4 drops of TEA and sodium sulphate (to absorb water formed). The mixture was filtered and evaporated to dryness to give 4.35 g (quantitative yield) of an amorphous solid. -Limr (CDCl 3) 5: 8.25 QHH, then), -7-7.9 (193, III) - s-zs (Zay I) | S-IÅÛR; 8): 4-8 (u: d, l 4-4 (av dd) | 4-1 (Hr dt) l 3.4 (af my. 1.1-1.e (za, az, 0.9 ppm (au. Zï. - - (1'S.3S.4R and 1'R, 3R.4S) -3- (1'-uranitrobenzyldioxycarbonyl-1'-propyl) -1- (paranitrobenzyl 2 "-chloro-2" -acetate) 4-trityl - thio-2-azetidinone (isomer C) ocozrua '° C ° ¿PNH vx ST: \) \ ST: PY / Ti fi' _ ___- ii * _ NHN _ Y soclz / 'nw (C Yu ° 2P “cogvna Till To a cooled (ice-salt bath) solution of 4.35 g (5.5 mmol) of the above glyoxylate in 30 ml of THF was added 7 ml of 1N pyridine (7 mmol) in THF followed by a dropwise addition of 7 ml of 1N SOCl mmol) and THF. The resulting mixture was stirred for 1 hour at the above temperature and diluted with 30 ml of benzene, stirred in quenched (ice-water bath) for 30 minutes and filtered over celite charcoal. The filtrate was evaporated to dryness to give 3.8 g (85.3% /% of an amorphous solid; mm (anal) 5, 5_15 (45, d), 6.75-7.7 (195. 11); 5-55 4 §_ (a, g), 2.85 (Ü, l): 3-4 _: (a ,; »az u fl. Sn LI RH-IH (H, m). 1.25-2.0 (za. N), = o 9 ppm (3H- * 1- 464 027 1% (1'S, 3S, 4R and 1'R, 3R, 4S) -3-K1'-garanitroenosyldioxycarbonyl-1'-propyl) -1- (parani trobenzyl- N-triphenylphosphoranyl-idene-Z "-acetate) -11-trityltio-Z-azetidinone (isomer C) oco m: _ ocozmæ sr: Å \ J \ 03?

------ +. To a solution of 3.7 g (4.568 moles) of the above chloro compound in 35 ml of dioxane was added 1.197 g (5 mmol) of triphenylphosphine and 0.54 g (5 mmol) lutidine. The mixture was heated in an oil bath at 1000 for 3 days. It was cooled, diluted with ether and washed successively with 1N hydrochloric acid, 1M sodium bicarbonate and brine. It was dried over sodium sulfate and filtered over celite charcoal. The filtrate was evaporated to dryness to give 3.6 g of an oil. This was chromatographed on 120 g of SiO 2 and eluted with benzene and benzene ether to give 1.45 g (31%) of the title compound as an amorphous - rvso and others (broad). solid material; ir (rent) J max. (1'S, 3S, 4R and 1'R, 3R, 4S) -4-acetylthio-3- (1'-paranitrobenzyldioxycarbonyl-1'-propyl) -1- (paranitrobenzyl-2'-triphenylphosphoranylidene-2? -acetate) -2-azetidinone (isomer C) oco Pma Ja: m 060 PNB 3 2 2 sA * __- r ST! Aguoz If SÄQ c33gc1 va, C u, __, .___- å .Ja-Vä vy / moa on: PY / MOH P03 dust '\ z; mm \: ånm' I To a warm (600) solution of 1.4 g (1.35 mmol) of the above phosphorane in 40 ml of methanol was added with stirring a warm solution of 0.3 g (1.76 mmol) of silver nitrate in 10 ml of methanol, followed by 0.107 g (0, 11 ml; 1.76 mmol) pyridine. The silver market period began to fall immediately. The mixture was stirred for 15 minutes at room temperature and 2 hours at 0 °. It was filtered and the solid was washed well with cold methanol and ether to give 1.2 g of product in quantitative yield, m.p. 113 DEG-115 DEG C. (dec.); ir (nujol) q) næx: 1740-1760 cm-1 (wide). This material was used as such. To a cooled (ice bath) solution of 1.2 g (1.35 mmol) of the above mercaptide in 15 ml of dichloromethane was added 0.118 g (0.17 ml); 1, of acetynuaphia in 2 ml of aliquot, phase of 0.119 g g (0.2 ml; 1.5 mol) pyridine 1 2 ml dichloromethane The mixture was stirred for 30 minutes at 0 ° C.

It was filtered over celite to remove the silver salt and the filtrate was washed successively with 0.5 N hydrochloric acid, water, 0.5 M sodium bicarbonate and brine. The dichloromethane solution was dried over magnesium sulphate and evaporated to dryness to give 0.94 g (83.4%) of the title compound as an amorphous solid. ir (rent) Ümax: 1750 cm-l (wide). (1'S, 5R, 6S and 1'R, 5S, 6R) -paranitrobenzyl-6-Ä'-paranitrobenzyl dioxylcarbonyl-1'-propyl) -2-methylpenem-3-carboxylate (isomer C) COCO2PNB OZPNB n II x 3 g P63 ß pug 'CO 2 PNB 2 A solution of 034 g (1.07 mmol) of the above phosphorus in 35 ml of toluene was greased to reflux and 5 ml of toluene was distilled off.The yellow solution was refluxed for 7.5 hours . It was evaporated to dryness to give 0.76 g of a thick oil which was chromatographed on SiQ2 (ACT 1.309) and eluted with benzene and in benzene in ether to give 0.32 g (53 .mu.l). 4%) of the title compound) 464,027 wa as a solid with a melting point (pentane) 160-1e2 °.

(Kv-Lt (CbCl2) δ: 7.3 ° 8.4 (811. n, aromatics), 5.4 ((4.4), 5-3 NH, benSyl, I), 5.0 (H, da), 4.0 ( B, dd), 2.35 (GH, s), - 0-5 (271, αq), 1.0 ppm (JH, t). (1'S, 5R, 6S and 1R, 5S, 6R) -6% i ' -hydroxy-1'-propyl) -2-methyl-penem-β-carboxylic acid (isomer C), sodium salt - oco2PNa "I / r '\ o) ws' es CH' Bz / Pñ-Celite-HD CH III 3 - --- 4- ~ I 1 3 N f osf a tbuf - 0 "3 fert coz 'm * A mixture of 48 mg (0.086 mmol) of the above ester and 100 mg of 30% Pd / celite in 10 ml of THF, 20 ml of Et 2 O, 10 ml of water and 2 ml of phosphate buffer pH 7 were hydrogenated for 23 hours at a dilution pressure of 3.4 x 105 Pa. It was filtered over celite and the layers were separated. The organic layer was washed with 2 x 5 ml of water and the combined aqueous layers were washed with 2 x 10 ml of ethyl acetate. The aqueous layer was then lyophilized to give 30 mg of the title compound as a white salt; ir (KBr) 1) max: 1750 (ß-lak- ram), 1600-1650 qnfl (bred, -cofn uv Ašwx: zsa (61105), sos (6 1244). '_ Exemge 1 2 4' (l ' R, 5R, 6S and 1'S, 5S, 6R) -6- (β-hydroxy-β-propyl) -Z-methyl-penem-3-carboxylic acid, sodium and potassium salts (isomer B) 1a9 464 027 (1 1R, 3S, 4R and 1'S, 3R, 4S) 4-t'-butyldimethylsilyl-3- (1'-form-yloxypropyl) -4-trityltio-2-azetidinone (isomer B) '3 \ ~ / l: I: T1ø {sT' DMAP, Aezo \ ~, Åc T's _ I: T o \ ~ - ° “2 ° 12 N s *" ° 2 ° \ * s1n «2 4- dimethylaminopyridine (DMAP) was prepared according to a) HC

Brown et al. Org. Synth. Collect. Vol. 5 (1973) vol. 5 977 and b) Helmut Vorbrüggen et al. Angew. Chem. Int. Oath. 11 (1978) 569.

Tin a cold (o °) solution of 3.612 g <7 man <1'R, ss, 4n and 1'S, 3R, 4S) lt-butyldimethylsilyl-3 (1'-hydroxy-1'-hydroxy-1'-propyl -4-Trityltio-2-azetidinone (isomer B) in 50 ml of dichloromethane was added 4.48 ml (35 mmol) of Et 3 N, 0.63 ml (16.8 mmol / l) of HCO 2 H and 0.854 g (7 mmol) of DMAP, followed by of the dropwise addition of 7.14 g (70 mmol) of acetic anhydride, the clear yellow solution was stirred at -40 ° and poured onto ice-1N hydrochloric acid (pH 6), after which the layers were separated, the dichloromethane solution was washed with 1M sodium bicarbonate and brine. It was dried over sodium sulfate and evaporated to dryness to give 3.8 g of a solid residue, which was treated with pentane and filtered to give 3.7 g (96.8%) of a white solid, m.p. -27 °; _ I i; (rïëíñbm: 1120 (a-ê-ø, 1750 ml (Baàktbæl: Iam; (Cans) 5; 7,1 (n, s, B-x fi 6.8-'I.7)) mh 53 (E, m), 4_ ° 5 m, d, J-LS), 3.7 (E, nfJ-1S, 31-71: 1.4 (23. mh 0.95 (en. s). oe (an. t ) ° Éh 0-1 Pm (ß fl- * N è fl šißef-fbr! Cgg fl ggmass ”c 10 .42: H 1.20: N 2.s1: f fl0 "9 t = C 70-201 H 7-33-“ 2-73- 464 027 _ Ä wo (1'R, 3S, 4R and 1'S, 3R, 4S) - 3- (1'-formyloxy-1'-propyl) -4-triethylthio-2-azetidinone (isomer B) OCHO 0530 - Jm ST: Je, Tr - find 'N + NaN: * ïí-ï _ 0 - 51x62: os uzo N \\ To a cooled (ice bath) solution of 3.7 g (6.77 mmol) of the above azetidinone in 40 ml of HMPT containing 10% water was added 0.91 g (14 mmol) NaN3. The mixture was stirred for 1.5 hours at room temperature. It was poured onto 200 ml of ice water and extracted with 4 x 40 ml of ether. The ether solution was diluted with petroleum ether and washed thoroughly with water and brine to remove HMPT. It was dried over sodium sulfate and evaporated to dryness to give 2.92 g (quantitative yield) of a thick colorless oil. 'amz (coola) 6: 8.1 (H. HE-.s), 1.1-1.1 (lsn, m. -grrh 5_23 m' I. J, 7) '438 (H, a' J.2_s) * 'M3 (H, -NHI- 3.35 (H, dd: J = 2.5, Js7), 1.75 (28, n), 1.0 ppm (BH, -23- (1'R, 3S, 4R and 1'S, 3R, 4S) -3 - (1'-formyloxy-1'-ethyl) -1- (para-nitrobenzyl-2 "-hydroxy-2" -acetate) -4-tritylthio-2-azetidinone (isomer B) and OCHO II * ST, / sr: '1 I mm-mxmumu II d „\ ~ E ~ szsn / var o \ ï, f ° fi *' mamm 2, A mixture of 2.9 g (6.77 mol) 3- (1'-formyloxy -1'-propyl) -4-tritylthio-2-azetidinone (isomer B), 1.59 g (7 mm 2> PNB - _4 1% _ 4e4 "2727 -glyoxylate, 5 drops of Et3N and 5.0 g of anhydrous sodium sulphate in 50 ml of THF was stirred for 18 hours at room temperature The mixture was filtered and evaporated to dryness to give 4.33 g (quantitative yield) of an amorphous solid. * nmz (zu) 6); (H | m) | 403 m0 ß | fl) 443 H; I)] | 4.2-4 .: (n, a.'1 / 2 x se 4.2, 1/2 H az 4.3), a.ss (H , -), 1.4 (za, m), "0.8 ppm (JH, t). (1'R, 3S, 4R and 1'S, 3R, 4S) -3- (1'-formyloxy-1'-propyl) -1- (paranitrobenzyl-2 "-chloro-2" -acetate) -4- trityltio-2-azetidinone (isomer B) OCHO áCï-IO, 1% sm: 'Pwwml \ «J \ än Ål! To a cooled (ice-salt bath) solution of 4.3 g (6.77 mmol) of the above glyoxylate and 8 ml of a 1M solution of pyridine (8 mmol) in THF in 30 ml of THF was added dropwise 8 ml of one mM solution of SOCl 2 (8 mmol) in THF. The resulting solid mixture was stirred for 1 hour at the above temperature. It was diluted with 30 ml of benzene and stirring was continued for 20 minutes. The mixture was filtered over celite charcoal and the filtrate was evaporated to dryness to give 4.0 g of 92 '. (%) of an amorphous solid in: (rem) vw: 1720 m _), 1,50 -I _ g, 2 7.8 (1-Qpm), 1780 cm (B-lahtam). IHM (ewa-g) 5 8 25 (fb '2->. 1-v.1s <11H. W>. S-25 <2H- dl' 5- ° * “'.“' 2 0.9 pin-LW- Ü- 406 (BI 5)! (A: 'I E- «4 m, a) .3.1 (B.mh IJ WH-Ib 464 027 192 (1'R, 3 $, 4R and 1'S, 3R, 4S) -3- (1'-formyloxy-1'-propyl} -1- - (paranitrobenzyl-2 "-triphenylphosphoranylidene-2'-acetate) -4--trityltio-2-azetidinone (isomer B) OCHO ST '- ~ \, jfa ° sr: 03? Aiaxin oàïïrl' 0 ~ \ r / 01 1u = 1a1n ~ ~> f, P °, cozrun COQPNB A mixture of 4.0 g (6.07 mmol) of the above chlorine compound, 1.834 g (7 mmol) of triphenylphosphine and 0.749 g (7 mmol) of lutidine in 40 ml of dioxane were heated for 2 days at 100 ° (oil bath).

The mixture was cooled, diluted with ether and washed successively with a cold solution of 1N hydrochloric acid, 1M sodium bicarbonate and brine. The organic solution was dried over sodium sulfate and filtered through celite charcoal.

It was evaporated to dryness to give an oil which was chromatographed on SiO 2 (ACT.1200 g) and eluted with benzene and benzene ether to give 2.60 g (48.45%) of the title compound as an amorphous solid 2 1720 (HC-O-) and 1750-1760 material; ir (pure) 4) max: cm-1 (-CO2PNB and β-lactam). (1'R, 3S, 4R and h''S, 3R, 4S) -4-Acetylthio-3- (1'-formyloxy-1'-propyl) -1- (paranitrobenzyl-2'-triphenylphosphoranylidene-2 "- -acetate) -2-azetidinone (isomer B) \ / fi? ° 9 * \ vjqm s íylßés: DE / Mä C02PNB o! A hot (600) solution of 8.7 ml of a 0.5 M solution of silver nitrate (1.3 mol) in CH 3 OH was added to a mixture of 0.88 ml. g (1 mmol) of the above phosphorane and 0.103 g (1.3 w3 464 027 mmol) of pyridine in 5 ml of methanol, which had been heated to 60 °.

The mixture was stirred at room temperature for 15 minutes and at 0 ° for 2 hours. It was filtered and washed with cold methanol to give 0.53 g (71%) of the silver mercaptide as a yellow solid, which was used as such. To a cooled (ice bath) mixture of 0.53 g (0.71 mmol) of the above mercaptide and 0.079 g (1 mmol) of pyridine in 10 ml of dichloromethane was added dropwise 0.079 g (1 mmol) of cn After stirring for 1 hour at 0 °, the mixture was filtered. The filtrate was washed well with a cold solution of 0.5M hydrochloric acid, 0.5M sodium bicarbonate and brine. The filtrate was dried over sodium dilphate and evaporated to dryness to give 0.43 g (63% of an oil. Ir (pure) q) max: 1700-1760 cm -1 (wide β-ε and β-lactam). . (1'R, 3S, 4R and 1'S, 3R, 4S) and acetylthio-3- (1'-hydroxy-1'H -propyl-1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -2 -aaetidinone (isomer B Jim) SAc "\ JH 5A; ß Hcl / neon _ _ xf-wß _ o was: treated at room temperature with 10 ml HCl / MeOH (prepared from 2 ml concentrated HCl and diluted with MeOH to a volume of 24 ml) The mixture was kept at room temperature for 0.5 h. It was alkalized with 1M sodium bicarbonate, extracted was washed with ethyl acetate solution, washed with brine and dried over sodium sulfate, evaporated to give 0.9 g of the title compound as a crude product, chromatographed on S102 eluting with ether and a 1: 1 mixture of ether and ethyl acetate to give 0.64 g (62.5% of the title compound in pure form as an amorphous solid; 5m, ¿qx¿9 M 525 (23, d) , 7.154.1 (1711, n, armat-), 5.6 (H, n), 5-2 (25 31 4-9 m, 4.4 (a. n), 2 .: (an. sm, 1.5 (an. n, 0.9 ppm 'UH-fl- (1'R, 5R, 6S and 1'S, 5S, 6R) -paranitrobenzyl-6- (1'-hydroxy- 1'-; propyl) -2-methylpenem-3-carboxylic acid (isomer B) ma = '_ H' 00% AC ä »___- ii * HP 3 for * o PNB 02PNB 2 0.2 g (0.3 mmol ) of the above phosphorane in 45 ml of toluene was heated to reflux and 5 ml of toluene was distilled off, the resulting solution was refluxed for 6 hours, cooled and evaporated to dryness to give 0.2 g of an oil, which was chromatographed on S102 and eluted with ether to give 0.1 g (87%) of the title compound as a white solid, m.p. 133-1350 (pentane); 5wr (GN 6 6: 8: 3 756 d) | 506 (RI 6)! D) l (af.) 'Los' _ 308 (H | -) | 2-4 I | 2: 2 (a) w) l 117 II PPI! (331 t). (1'R, 5R, 6S and 1'S, 5S, 6R) 6-Q'-hydroxy-1'-propyl) -2-methyl-penem-3-carboxylic acid (isomer B), mixed K and Na salts 195 A mixture of 0.07 g (0.68 mmol) of the above ester, 150 mg of 30% Pd celite and 4 ml of buffer solution pH 7 in 15 ml of THF, 25 ml of Et 2 O and 15 ml of deionized water were hydrogenated for 4 hours at an initial pressure of 3.3 x 105 Pa. The mixture was filtered over celite and the layers were separated. The aqueous layer was washed with ethyl acetate and then lyophilized to give 91 mg of a solid; ir (KBr) _ .J - 1780 (p-mktam) och 1650 cm * (bred, -cø2 '>; uv max' H20 fl, max: 255 (6 983) øcn soo (6 1092).

Example Gel 25 (1'R, 5R, 6S and 1'S, 5S, 6R) -6- (1'-hydroxy-2'-phenylethyl) -2-methylpenem-3-carboxylic acid (isomer B) M fi yr fl, CO trans-1- (tebutyldimethylsilyl) -3-phenylacetyl-4-trityltib-2-azetidinone TI 0 s? _ _ + LDA + QG * co: t ÖVW: z _ I -É fl íl, 2 2 '' 18.32 g (40 mmdl) 1-t-butyldimethylsilyl-4-tritylethio-2-aze4_tidinone in 100 ml of THF was added dropwise under nitrogen to a cooled 464 G27 - 196 (-780) LDA solution (prepared under nitrogen at -78 ° by dropwise addition of 101.25 ml of 1.6M n-BuLi (162 mmol) to 22.95 ml (162 mmol) diisopropylamine in 150 ml of THF and stirred for 30 minutes at -78 ° The mixture was stirred for 30 minutes at -78 ° and then 15.66 g (15.1 ml; 93.6 mmol) of ethylphenyl acetate in 50 ml of THF were added and the reaction mixture was stirred. - 2 hours at -78 ° C. It was poured on ice-1N hydrochloric acid (pH 5-6) and extracted with ether several times, the ether solution was washed with brine and dried over sodium sulfate.

It was evaporated to dryness to give 33.7 g of a solid crude product. This was dissolved in 10 ml of ether and triturated with 200 ml of pentane. The solid was filtered and washed several times with pentane to give 13.3 g (79.6%) of a white solid, m.p. 141-143 °. > Jm (cm: e = 4 700 _ 7: 6 fl) | 4: 8 (ag 6); 3: 7 (al ó, l ')' (HI I) lus (930 ') | from 1-10 1- (t-butyldimethylsilyl-3- (1'-hydroxy-2'-phenylethyl) -4-trityl-thio-2-azetidinone (2 trans-diastereomeric OH q fi-: šz "fa gvlêil ~ 28, 8 g (50 mmol) of trans-1- (t-butyldimethylsilyl) -3-phenylacetyl-1-la-trityltio-z-glycetioninone 0.5 g (0.2s ml) of Nasn4 in zoo-ml of THF were stirred for 18 hours at The mixture was poured onto ice-1N hydrochloric acid and extracted with dichloromethane. The dichloromethane solution was washed with brine and dried over sodium sulfate. It was evaporated to give 27.7 g of an amorphous solid. A portion of the wv 464,027 solid the material (23.0 g) was chromatographed on S10 2 and eluted with hexane-ether to give 14.4 g of an off-white solid which was found to be a mixture of (1'R, 3S, 4R and 1'S, 3R). 4S) - and (1'S, 3S, 4R and 1'R, 3R, 4S) -isomers in a ratio of 1: 1 (60%). 'Ann (cocia) 6: 1-1.1 (zone m). 4-31 (1 / za, 4), 4.1a (1 / za. Az, 3.3-a.ä (H. n). 3.45 (1/28. Dö), 3-I (1 / zu, aa) , 2.7 (za. Ny. O.s7 (sa. D), 0.25 ppm (GH. S) - 1- (t -butylainethylsilyl) -3- (1'-fornyloxy-2'-phenylethyl) -41-trityltio-2-azetidinone or 'O ¿\ vJ HM rm fl & ¿T * a sr: ~ ”sr: w-' * II sun --sun N-in ° 1- 2 _ ° .F 2 o ° 2 150m !! To a cooled (-40 °) solution of 14.4 g (24.9 mmol) of the above mixture of alcohols in 250 ml of dichloromethane was added 15.93 ml (125 mmol) of Et 3 N, 2.24 ml (59 , 76 mmol) HCO 2 H and 3.04 g (24.9 mmol) DMAP. After stirring for 5 minutes, 2.35 ml (249 mmol) of acetic anhydride were added dropwise. The clear solution was stirred at -40 ° for 15 minutes, then turning into a white cloudy mixture. It is stored at -4 ° for a further 45 minutes (total time 1 hour. The mixture is poured on ice-1N hydrochloric acid and the layers are separated. The dichloromethane solution is washed well with cold 1N hydrochloric acid, water, 1N sodium bicarbonate and brine. It was dried over magnesium sulfate. and evaporated to give 14.0 g of an amorphous solid, the mixture was separated by high pressure liquid chromatography (Water Associates, System 500) to give 6.0 g of "isomer B", m.p. 172-73 ° and 6.0 g 'isomer C ", m.p. 188-890.

Total yield of pure compound 12.0 g (73.2%) - 464 027 198 nam- e. 'M ccnua: s: s.s-7.7 ma. n). 5.05 m, 7th. Las (ca. a) 3.55 and 3.75 (mtvå dubln). 2.7-z.9 (za, a), o.ae (en, n and oz ppm (eu, sz. Isene: ax * amg ccncla) 61 7.75 (u. 5), 5.9-7.5 (zon. N). 4.3 (H, 4 :). 5.95 ca, az. A.a7 ta, ¿a). 2.95 (H, 5). 2.a5 (out 8); ons (SH: I) -PPH I) ø 3- (1'-formyloxy-2'-phenylethyl) -4-trityltio-2-azetidinone (1'R, 3S, 4R and 1'S, ÉR, 4S enantiomers) QÉ: ?, pcxo S73 _ ¿\ É; ¿f: 3 ° sr: m-sun 0 “i" Jïf lïf _ + = * f Isomex-B To a cooled (ice bath) solution of 5.9 g (9.375 mmol) of 1.3 g (20 mmol) of NaN 3 were added to the above formate in 50 ml of HMPT containing 10% water, the mixture was stirred for 1.5 hours at room temperature, it was poured onto 300 ml of ice water and extracted with 3 x 100 ml of ether. The ether solution was washed well with water and brine, dried over sodium sulfate and evaporated to give a solid residue.

This was treated with petroleum ether and filtered to give 4.4 g (92%) of a white solid, mp 1-9-71 °. : nn fl nop c vß-ß- ß M1- »2,94, fänn1, = c 7š:; 4,: k 5.54, n 2.75. * aux tcncla) 5 = 7-9 tu. 5), 7.iÄ7.s (29, n). 5.4 in. n). 4-6 (H, RHD- 4-2 (H- 4) -: .a (x, 457. 2.15 ca. s) f '3-0 (H- ß) - 199 _ 464 027 3- (l' -formyloxy-2'-phenylethyl) -1- (paranitrobenzyl 2 "-hydroxy-2" -acetateH-trityltio-Z-azetidixine (1'R, 3S, 4R and 1'S, 3R, 4S-enantiomers) .Bër. För: _ Ånßl C3IH27NÛ3SI C 7S | ÅJ | H 5.510 n man fmfßtrc 15.011. As.e4, n ma. * Nu (cncis) 6. 1.9 <3;.) | Val-vas (zpap m) | 5 : 4 (Hg fl) | 4.6 (H, mi '4.2 (u, d), a., (H0: oz-s (Hp I), 300 (H0 I) o 3- (1'-formyloxy-Z' -phenylethyl-1- (paranitrobenzyl 2 "-hydroxy-Z" -acetate) 11-trityltio-Z-atetidinone (1 'R, 3S, 4S-enentiomers)' H OCHO - ---_-: - CO 2 PNB A suspension of 2.37 g (10, 16 mmol) of PNB glyoxylate in 100 ml of dry benzene was refluxed in a Dean Stark apparatus (packed with 3A molecular sieves) for 2 hours. 4.2 g (8.537 mol) of the above NH compound were added and the refluxing was continued for a further 1 hour, the mixture was cooled to room temperature and 0.12 ml (0.85 mmol) of Et N were added and the mixture was stirred for 1.5 hours at r ums- 3 temperature. It was evaporated to dryness to give the title compound in quantitative yield as a mixture of two isomeric alcohols. ., __ * am- (çncls) a: eo-s.3 (214. two düßbl ».) .-, __ 1.6 (n. two sing1.) _, '1.o-1.4 (zone, m), s.zs (an. ar. 4.35 ni, two dubb1.) ", ':. s-4.s (un bred), 7.5, 4.901. om, 4.25, s.1-as m. m, 2.9 ppm un 464 2727,200 3- (1'-formyloxy-2'-phenylethyl) -1- (paranitrobenzyl 2'-chloro-2 "-acetate) -4-trityltio-2-azetidinone (1'R, 3S and l'S, 3R, 4S- -enantiomers H amo - 5 amo «\: * f / 57 '_ Ö% ~~. ST' Jin OH - N Cl Coz fi m Cßz fl ß To a cold (ice-salted solution of 6.0 g (8.537 mmol) of the above glyoxylate in 30 ml of dry THF was added 10 ml of a 1M solution of pyridine (10 mmol) in THF, followed by dropwise addition of 10 ml of a 1N solution of thionyl chloride (10 mol) in THF. For one hour at the above temperature, the mixture was diluted with 30 ml of benzene and stirring was continued for 30 minutes in the cold, it was filtered over celite charcoal and evaporated to dryness to give 6.0 g (98%) of an amorphous solid. '' 'az (cncia) 6: a.2 (ax. n). 1-1-7 <2aa. n). sa cs. ul. 5.25 (za. =>, 4.35 Ku. 4). 3-5 -4- ° CH- fi l- ßfß (H: IW. 2-9 PP ”(an. An; .- 3- (1'-formyloxy-2'-phenylethyl) -1- (paranitrobenzyl 2" -triphenylphosphoranylidene-2'-acetate) -4-trityltio-2-azetidinone (l'R, 3S- 4R and 18, 3R, 48-enantiomers) °: E>, uuw ST: _ 'çjjxäxmo st:' 0 _ “\ Tr ° 1 -_ o" \ f) ° a çgzlmg C02PNB 20 A mixture of 6.0 g (8.333 mmol) of the above chloro compound, 2.489 g (0.5 mmol) of triphenylphosphine and 1.065 g (1.1 ml; 9.5 mmol) of lutidine in 50 ml of dioxane was heated for 18 hours at 110 °. The mixture was cooled and filtered over celite. The filtrate was diluted with ethyl acetate and washed with cold 1N hydrochloric acid, water, 1M sodium bicarbonate and brine. The mixture was dried over sodium sulfate and evaporated to give 8.0 g of crude product. This was chromatographed on SiO 2 and eluted with a 1: 1 mixture of ether and hexane and ether to give 4.0 g (51%) of the title compound, m.p. 235-37 ° ( ). ir '(film) (tmax: 1120, 1750 mph. 4-acetylthio-3- (1'-formyloxy-2'-phenylethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -2 -azetidinone (1'R, 3S, 4R and 1'S, 3R, 4S-enantiomers) amo H ocno H ocno sa: - + --wo _ \ (F ° 3 _ 0 Ngfpøa 'Oflïgv: c ° PNB ° PNB co To a refluxing solution of 3.6 g (3.8 mmol) of the above phosphorus and 0.33 g (4.2 mmol) of pyridine in 30 ml of dichloromethane and 30 ml of methanol were added dropwise 28 ml of a 0.5 M methanol solution of silver nitrate (4.2 mmol) The mixture was stirred for 2.15 hours at room temperature, concentrated to a small volume (about 10 ml), cooled and filtered to give 2 ml. 3 g (77%) of the silver mercaptide as a yellow solid This mercaptide and 0.277 g (3.5 mmol) of pyridine in 20 ml of ice-cooled dichloromethane were treated dropwise with 0.27 g (3.5 mmol) of CH 3 COCl in 5 ml. The mixture was stirred for 3 hours at room temperature, filtered over celite and the filtrate was washed with cold 1N hydrochloric acid, water, 1N sodium bicarbonate and brine. The mixture was dried over 464,027 m, magnesium sulfate and evaporated to dryness to give 1.0 g (89.8%) of an amorphous solid. * anu- (Cbcia) 6ÄB-2 (gg, 4), 1.0-aja (aan, n), 4.5-5.1 (an, na. 2.6 - :. i _ ;: a, aa. 2-3 ppm (28. d; SAG) 1,4-acetylthio-3- (1'-hydroxy-2'-phenylethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene 2" -acetate) -2-azetidinone (1'R, 3S, 4R- and 1'S, 3R, 4S-Enentiomers) H OCHO - KX ~ FKSÅ ° - 432m saa _. Ä-NYPQ - (Ü wa Cßzrna _ 2 \ I:; Pna A solution of 1.8 g (2.4l6 mmol) of the above phosphorus in 10 ml of THF was treated with 10 ml of 1N HCl / MeOH and the mixture was stirred for 4 hours at room temperature, it was concentrated to remove methanol, diluted with cold water, alkalized with 1N sodium bicarbonate and extracted with CHCl 3. The solution was dried over magnesium sulphate and evaporated to give 1.65 g of an amorphous solid, which was chromatographed on SiO 2 and eluted with ether ethyl acetate to give 1.30 g (75%) of the title compound. . 1mm¿an%, ¿, s¿ u5¿¿h '\ 6.1-eo tzzn. N). 4.0-6.0 (sn, n). 2.5-3,5 (38. n),' 2-2 PP * (aa fi u. paranitrobenzyl-6- (1'-hydrox (2'-phenylethyl) -2-methylpenem-3-carboxylate (1'R, 5R, 6S and 1'S, 5S, 6R-enantiomers) ma, f &) gfm¶ sne A _ *: ë> ñí: jr » s II .__------ +? “f fi. ° N \ fåÄc _ '0 N aan; . A solution of 1.2 g (1.67 mmol) of the above phosphorus in 80 ml of toluene was refluxed (10 ml was distilled off to remove moisture and low boiling solvent present) for 6 hours. The solution was evaporated to dryness and the crude product was chromatographed on S102. The title compound was obtained by eluting the column with ether to give 0.65 g (89%) of amorphous solid. 1 Hmr (CDCl 3) δ: 8.2 (28, d), 7.6 (Zl-I, d), 5.4 (H, d), C 2-5.4 (23, 6): ILO-ILS (H, Xp), 3.7 -4.0 (H, then), 3.0 (23, d), 2.3 ppm (330 L) - 6- (1'-hydroxy-2'-phenylethyl) -2-methylpenem-3-carboxylic acid (1'R, 5R , 6S and 1'S, 5S, 6R enantiomers) n ou ik * OH W.

° \ / '- S si; A mixture of 0.33 g (0.75 mmol) of the paranitrobenzyl ester, 17.4 ml of 0.05 M buffer solution pH 7, 30 ml THF, 30 ml Et 2 O, 60 ml distilled water and 0.69 g of 30% Pd / celite were hydrogenated for 24 hours at an initial pressure of 3.4 x 10 Pa. The mixture was filtered over celite and the organic The combined aqueous layers were isolated and the layer was washed with water. was washed several times with ethyl acetate and lyophilized for 18 hours to give the title compound as a yellow solid salt. This was treated with a small amount of water, acidified with cold 1N hydrochloric acid and extracted well with CHCl 3. The solution was dried over magnesium sulfate and evaporated to give a solid residue. This was treated with ether and filtered to give 30 mg (1.3%) of a white solid, m.p. ir (nujol O „m5 3580 (on, sharp), 1660 and 1760 mfl; uv (meon) IL max = 310 (2 5490 and 254 (C 4880). 464 027 zm Exemgel 26 (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: - ST : - 1L / \ / and o N \ ° si 4 / / '74 / '74 (4'R, 3S, 4R and 4'S, 3R, 4S) -and (4'S, 3S, 4R and 4'R, 3R, 4s) -1- (t4butylamecylsilyl) -3- <2 ', ze-amethyl-1'.3'-dioxolan-4'-yl) -4-trityltio-2-azetidinone ("isomer C" and' isomer B ') Ethyl O- (2-methoxy-2-propyl glycolate) HQ \ «ÅÄ \ wE: -lÉ: ï:" “' '' ', š; f \" / x \\ m:'? OC13 T111 en solution of 15.6 g (0.150 ml: freshly distilled) of ethyl glycolate and 16.4 g (0.216 mol; 95% pure) of 2-methoxypropylene - in 150 ml of dichloromethane were added at 0 DEG-3 DEG (3 drops) ( 35 mg; 0.23 mmol) of phosphorus oxychloride and the mixture was stirred for 15 minutes at 0-5 ° 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 off. 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. * ams (cc14) 6: 1.25 (zu. z. J-vn: -cazggaf. 1.2a (sn.;. nezy, 3.12 (a fl, S, '° CH3) p 3.88 (zaç I;' $ H2c ° “ ) | 4-10 (230 q: J-7H2ø 'ç_H_2cH:) ¶ \ iz (l ”ênt) Vmx: 1760, 1735 ml (ester). 1) a. Ueinwam a: u., Ut. Utè .. mv um) '_ 2) MS Newman and MJZ. Vanda: Zwan, J. Org. Che1h, _3_8_, 2910 (1973). (3S, 4R and 3R, 4S) -1- (t-butyldimethylsilyl) -3- (1'-keto-2'- - (2 "-methoxy-2" -isopropyloxy) -1'-ethyl) -4- trityltio-2--azetidinone a _ STI 1) LUÄ / THF can I l \ \ 21 M: m: ß / si "“ s1 /> </ X OMQ To a stirred solution of 18.5 ml (0.134 mol) diisopropylamine in 400 ml of THF (freshly distilled from LAB) 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 (0 | 10 3 mol / l Yield 464 027 206 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% Et 2 O in benzene); IHM! (Cxla) 58 0-30 (GH, S, Si-CHBJ, 0-95 (SH, I, t-Bu), 1.12 (SH, 3, CH 1, 1.15 (33. I. CH), 3.15 (SH , s, OCH), 3.57 (1H, AaV 53, J n 3 3 3 qgm mm. 3-77 (1H, d. J-Lsxz. xa), 3.91 (m, nav As, agwqmz), 4.93 ( ll-l, d, 311.682. H-4), 7.l-'I.6 (1SH, m, arouut -_), Hs); ir (ragg-_) vmx: 1150. 1125, 1110 = a ' 1 (co), rie. Ar o.ss (benzene; asgo-411).

R! 0.61 (hexane z EtOAc I Mil-1 ° (2S, 4R and 3R, 4S) -1- (t-butyldimethylsilyl) -3- (1'-hydroxy-2'-methoxyisopropyloxyethyl) -4-trityltio-2-azetidinone (mixture of egimers at C-1 ') i than S "vasa, s" 3 1: 1 "ms vtïx o_ /' * \ sf /. /> </ '> (* si A solution of 60.95 g (1.03 mol) of pure 1- (t-butyldimethylsilyl) -3- (1'-keto-2 '- (2 "-methoxy-2" -isopropyloxy-1'-ethyl) -4- trityltio-2-azetidinone in 100 ml of THF was diluted with 350 ml of absolute ethanol and to this solution was added at 0 ° 4.88 g (0.66 mol) of NaBH 4 The mixture was stirred at room temperature for 2 hours and slowly added 280 ml of The mixture was extracted with 3 x 150 ml Et 2 O and the extracts were washed with brine, dried over sodium sulphate and evaporated to give a yellow residue which was redissolved in 500 ml of dichloromethane: The solution was again dried over sodium sulphate and evaporated. obtained 57.1 g (0.0966 mol; crude yield 93.8%) of the title compound as an impure foam (J = 10 Hz, m, H-SI) | '464 027 207' unz (c9c1¿) 6- o.11 L- (=, s1cn3>, o.au. o.a1 (25, si-tag). 1.22. 1.25 (25. saa), a.oa (5. eca3>, 4. :: (a. A-zxz, u-4). 1.0-1.1 (n, azgnny- ng), 1; (rent) vmax 1460 (ou), 1145 (co), 1595 (n: nnng.): az o.41 * = ~ lo.4z (ngxån, 1 zzoA = -z = 1> This raw 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 _ I Sh * P ~ T = ° "'" á2 ° ör "M fi 9, o" \ s ¿/ X m: N * sl / /> <8 A solution of 57.1 g (moss moi; rapeseed) (3s.4n through 4R, 4S) 1- (t-butyldimethylsilyl) -3- (1'-hydroxy -2'-methoxyisopropyloxyethyl) -4-tritylthio-2-azetidinone (mixture of diastereomers at C-1 ') in 500 ml of dichloromethane was treated at room temperature with ZOO mg p-toluenesulfonic acid monohydrate 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 (o, osas flour: 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 performance liquid chromatography (Waters 500 silica gel; eluent: hexane-ethyl acetate = 9: 1) and 98 'after crystallization to give 14.28 g (25.5 mmol, 26.4%) of isomer C as white crystals, m.p. 146-7 ° (pentane) lan: (cc14) S: 0.27 (sH, s, s1-cn3>, 0.95 (sn, s, si-tßu), 1.15 sn, S, ailme), 2.5-2.9 (ln, , H-4 '), 2.97 (ln, t, J = 1.8Hz, 454 027 2% H-4),' 7.1-7.6 (lsn, In, aromat. As), 1: (nujol) 19 max: 17so (c = o), 1s9s cm'1 (ar ° ma :.); of o.4s (nexane = EtOAc = 4: 1) and 14.50 g (25.9 mmol; yield 25.9%) of isomer B as white crystals, m.p. 144-50 (Et 2 O-pentane) - nu (een) 6: o.o2 (ex. S. sine). o.a :: (ex, 1. si-enn). 1-13. 1.16 (GH. 2: dine). 3.4 ILSHz, 3-4), 7.1-'I_.7 (158, m, 2.5-2.8 (1H, m HU), 3.3-4.1 (23, I: H ° 5 ') v 3-43 (131 Go: J '' l-SRZ:; 3_4, -5.on =. H-3). 3.9: (1x, a.: 4_3 'aromat. Hsh i: (nuåol) wax: 1650 (CIO), 1595 url (else, H ns 0.31 (nexan - = 2: oA = -4 = 1) f Anal §er.for ~ c33 fl¿1 no3ss1 = c 1o.so.

H 7.38, u z.so, s 5.73; fU flfl @ f (: = ° m =: c) c 10.23. at 1.30. a 1.:-, _ _ ,, - N 2.41, S 5.53 and (Isene: B) C 70.52, H 7.31, N 2.40, 5 5.05.

Preparation of (4'R, 3S, 4R and 4'S, 3R, 4S) -3- (2 ', 2'-dimethyl-1', 3'-dioxolan-4'-yl) -4-tritylthio- 2-azetidinone (isomer C) O - ST: '. ST: ¶ "1 'un« \ / * ~ al-' -maäšïr - “'* N“ wa ~ «To a stirred solution of 14.3 9 (25.6 mmol) (4'R, 3S, 4R and 4'S, 3R, 4S) -1- (t-butyl-dimethylsilyl) -3- (2 ', 2'-dimethyl--1', 3'-dioxolan-4'-yl) -4-trityltio-2-azetidinone (isomer C) in 250.4 ml of hexamethylphosphoric acid triamide was slowly (at 20 minutes) added at 0-50 a solution of 2.50 g (38.4 mol; 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, the white precipitate obtained was collected, washed with water and dried to give 11.26 g (25.3 mol). crude yield 98.8%) of the title compound as a white solid, a pure material was obtained by crystallization from CH 2 Cl 2 -Et 2 O, mp 192-3 ° (dec. * wu 2, M ') 0 (m0 t! J'3Hz | H-3) | 318-404 (an. N. 11-42' B-Sm 4.40 (IH. M -I-ß fl z. 11-0- 4-47 UH - bf »W 'D20 växlade),' .1.1-1.7 ppm (isn. n..; ° m; r .. fl sn; 1: xnuißll Vmax * azzo (nun. iveo (co), - ieso = m'1laramae; _11 az o.a1 (n = x = n- = EtOAc ~ 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-tritylthio--2-azetidinone (mixture of epimers at C-2 ") (isomer C) ST: 0 q V E fi zm if * N ------ +. 3 A suspension of 6.57 g (28.95 mmol; 1.5 equivalents) of p-nitrobenzyl glyoxylate hydrate in 500 ml of benzene was refluxed for 2 hours at a Dean-Stark trap. 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'-dioxolane -4'-yl) -4-trityltio-2-azetidinone (isomer C) in 350 ml of THF (distilled from LAB) was treated with 289 mg (2.86 mol) of triethylamine at room temperature for 18 hours (overnight) under nitrogen. 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, a saturated sodium bicarbonate solution and brine, dried over sodium sulfate and evaporated. addition of 30 ml of Et 2 O to give 17.2 g (26.3 mmol; 100% crude yield; 95.8% purity) 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 performance liquid chromatography (SiO 2; eluent: benzene: Et 2 O = 3: 2) and purified by crystallization from CH 2 Cl 2 -Et 2 O-Isom 2 I: R 0.40 (bensen z 5: 20-a = 2>: mp 15: -4-0; * auf (cnc13> 6 »1.20 (su, |, .41-ne), 1.1 (zu. N. 3-3 ' 4 305-402 (sal .I H-da 0 a-S ', I d' J-znz; H-4J! S.1â (1x. Br. H-21). S.s0 (za, 1, ocuznzy ~ 1.1-ea gp »(190, m. Azamazi = u = ;: 1: (nuj ° 1) vm¿x = 3:10 (cat. 1115 (B-laeeamr, 1145 am'1 (este:) r gggg , 39? -F0T c36n3¿n2o8s = c 56.04, H 5.23, N 4.28, found: c as.as. n s.s4, u 4.11. Zßomez 11. nr 0.30 (b = ns0n. = 0: 20-z = 2); mp 164-s ° c; * aux (cnc13) 6: 1.11 (su. 1, ai-na), -1.2 (za, n. H-1,: ou), 3.4-4.0 (aa. N , B-41, a-s '). 4.51 (1x, 4. a-zaz. X-4), 5.23 (1s, 0:. -2') - S-27 t2H. S. - ° cs2A:> , '1.1-0 .: ppm <1sa. 1,. = ° m ==. Usa »1: (nujai) vmax. 3340 (ou). 1165 (B-1; e: = n), 2 1140 = m ° 1 (.s =. =), 363428 gg, Bmvñnc anus.csmM.uan.N «à.s« w.ümwü _ * Ü- c 66.01. H 5.24. U 4.:a. S 4.1s. ' '(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-trityltio-2-azetidinone (mixture of epimers at C-2") (isomer C) ëjr: as dy: 1 - ÜMÜST: u' u \ fpH reach \ 0 \ x: ï; a 'COPNB To a stirred solution of 17.13 g (25.07 mmol) (3'R, 3Sf4R - and 4's, 3R, 4s) 3- <2 ', 2'-amethyl1-1.', 3'-di ° > <° lan-4'-Yl) -1- 464 027 211 - (p-nitrobenzyl-2 "-hydroxy-2" -acetate) -4-tritylthio-2-azetidinone (isomer C) (mixtures of epimers at C-2 ") in 250 mL of THF was added at -15 ° under nitrogen 2.84 mL (35.1 mmol) of pyridine and immediately thereafter 2.20 mL (30.1 mmol); Anachemia) thionyl chloride. The mixture was stirred for 20 minutes at -15 ° 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) 6 '= J-2 ° f fifl f = - fi i flfl l- 2-1? (IH. M. H-3), 3.4-3.9 (sa. M. N-4 '* "="' a-s'>. _ 4-67. 4.72 (13. za. J-2.5 az, H -4), 5.30 (za, s, oc fl znz), s.sa (s, n-2 ") OCh 7-1-9-3 PPM- (19 H, n. Uomaf Hsh i: (Hen fl vmx: 1770 and ( B-actam and cheeses) This material was used in subsequent steps without purification (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-trityltio-2-azetidinone (isomer C) I-Nrï / c; diox. 903 Eriblanzinizxg of 17.87 g (25.0 mmol; purity 94.1%; mixture of isimers at c-z fl) (4's, 3s, 41z and 4's, 3n, 4s) -3- (2'-a1- 'methyl-1', 3'-dioxolan-4'-yl) -1- (p-nitrobenzyl-2 "-chloro-2" -acetate-4-trityltio-2 -azetidinone (isomer C), 7.27 9 (27.5 moles 464,027 212 (triphenylphosphine and 3.19 ml (27.5 moles) of 2,6-lutidine in 350 ml of dioxane (distilled from LAB)) were refluxed for 40 hours. Evaporation of the solvent in vacuo gave 29.5 g of a dark oil, which was purified by column chromatography Ksioz 330 g; 1 benzene) to give 10.5 g of a yellowish solid.

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 (C = O). An analytical sample was obtained by crystallization from CH 2 Cl 2 -Et 2 O with a melting point of 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.l7 (benzene: Et2O = lsl). (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) .mu.l Agm: -nu; [: I "ys EQOH - A solution of 319 mg (0.3s mnol) (4 ', ss, 4R and 4's, 3n, 4s) - É- (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 (60 °) methanol. To this solution were added 4 .0 ml of a warm (60 °) 0.5 M 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 hour at 0 °. - was taken and washed with ice-cold methanol and then with cold 464 027 213 Et 2 O to give 255 mg (0.334 mmol; yield 94.1% of the title compound as a brownish solid; ir (nujol) λmax: 1750 cm -1 (s, C = 0). (4'R, 3s, 4n beh 4s, 3R, 4s) -3- (2'm-aminegl-1'-r-dioxolan--4'-yl) = 1-ip-nitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -4-acetylthio-2-azetidinone (isomer C) \ - *: [: Tr's ^ 9 c fl scocl / pyr t. 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 mol; 3.72 equivalents) Pyridine was added at 0-50 71 μl (1.0 mol; 3.0 equivalents) of acetyl chloride.

The mixture was stirred for 40 minutes at 0-5 °. 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 (cnc13) ä = 1.23 (s, ai-Me), 2.20, 2.33 (zs, -sAcLocn 7.2-8.3 pp_m (m, aromat. 'Hs): ir (nujol)' Ûmaxz 1750 (-lak- tam och ester) and 1690 cm-1 (thioester) An analytical sample with a melting point of 177-8 ° was obtained by crystallization from CH 2 Cl 2 - -Et 2 O. Ana 1 Calculated for c 37 H 35 N 2 O 8 Ps = c 63.60, 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). - 464 2727 'm4' É (4'R, 5R, 6S and '4'S, 48, SRJ-p-nitrobenzyl-6- ( 2 ', 2'-Phetyl-1', 3'-dioxolan-4'-yl) -2-methylpenem-3-carboxylate (r more C) toludene 0 K get? 0.634 mmol) (4'R, 3S, 4R and S, 3R, 45) -3- (2 ', 2'-methyl-1', 3'-dioxolan-4'-yl) -1- (p- The benzyl-2 "-triphenylphosphoranylidene-2" -acetate) -4-acetylthio-2ethidinone (isomer C) in 70 ml of toluene was refluxed for 6+ years under nitrogen. Evaporation of the solvent gave a vi East material, which was purified by column chromatography over 10 g (eluent 10% Et 2 O in benzene) to give 247 mg (0.587 mmol; yield 92.7%) of the title compound. one as a white solid; - * nar ccaczs) 3- °° 4-S- & 4H. I. H-G. n-4; as °), s.o2-s.zs-s.aa-s.s1 (za. A2 - -ocn2Ar>, s.s1 (la. a. a-1.a sz. a-sa, _ v. sz-1.61-a.1z-s.z7 ppr MH. Aäazh-azoman flfl slh i: (nujol) Vau; 1750 (Bdabtmlr '1100 cm ° 1 u; (estez) An analytical sample with melting point 167-80 obtained by crystallization from CH 2 Cl 2 -Et20; "_- -øl uv (ston) Amax = 265 (e 14, ooo) ^ fh 114 nu (e 1o, ooo); Ana1.Bef f-for c H uo sz c s4.2a, n 4.79. uss 7.63: lszoz 1 found: 54.15. x 4.18. u 6.54. s 1.64: af 0-62 5915911422- “- (4'R, sR; ¿š gen 4's, ss, 6R) -6- (2 ', 2 '-dimethyl-1', 3'-α 'alan--4'-yl) -2-methylpenem-3-carboxylic acid (isomer C) is -sg II / Pd-C - o NOH COZPNB 2 464 027 215 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'-dioxolane-4- yl) -2-methylpenem-3-carboxylate (isomer C) in 20 ml of THF was mixed with 20 ml of Et 2 O, 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 10 5 Pa. (celite), the aqueous layer was washed twice with ethyl acetate, saturated with sodium chloride, acidified with 0.47 ml of 1N hydrochloric acid and extracted immediately afterwards 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); I '' m (cncza) a »11371 25; di'H fl) 1 'y 319-416 m! a-öl H- (3 a-s'), s.s9 ppm (ia, 4. J-1.1 az, n-sw: 1: vmax: xvso (s-zauzam), isso = m'1, uv < : = oa; xm¿x =: os (c saoox, 263 HU (E 3800).

Example Gel 27 (4'S, 5R, 6S and 4'R, 5S, 6R) -6- (2 ', 2'-dimethyl-1', 3'-dioxolan--4'-yl) -methylpenem-3-carboxylic acid ( isomer B) - ti, s _ - N an: 0 'or 464 027 I 216 (4' 4'Ry3R. | (2 '] 2'-dimethyl-1' 13 -4 '-yl) -4-tritylthio- 2-azetidinone (isomer B).

(Yes) The title compound was prepared as described in Example 51 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) -11-trityltio-Z-azetidinone (isomer B), m.p. ° (Cl 2 Cl 2 -EtzO) in a yield of 10.8 g (24.3 mmol; 94.1%); Rf 0.24 (hexane-ethyl acetate = 2: 1); = 1.31. 1.40 (an. N, ai-m. 3.2: (ll-1, dd, JB-kLS Hz, J ISHz, 3-3), 3.7-4.5 (ÄH, I, H- * IHH-SHN- H), 3-4 '4.50 un, a. A-Lsná, 11-4), 7.1-1.s ppm usa. N, arma. M; i: (nujnn mo (un), äns m * (c- on Annßernför. c27a27uo3s = c 12.18. a 6.11, 111.14, s 1.20; fUHII-C 72.16. H 6-11. N 3-14. S 7-11- (4 'S, 3S, 4R och 4'R, 3R , 4S) - 3- (2 ', 2'-dimethyl-1', 3'-dioxolane--4 '-1l) -1- (p-nitrobenzyl-Z "-hydroxy-2" -acetate) -4- trityltio--2-azetidinone (mixture of epimers at C-2 ") (isomer B) J b, 'sr: ° ma on» sr: _ - 2 IS: usa / mr. the indicated compound was thus prepared described in Example 51 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'-dioxolan--4'-yl) -4-trityltio-2-azetidinone (isomer B). 15.8 g of product (24, 1 mmol; 9§, 3%) were obtained in the form of a yellowish foam; kf 0.29 and 0.22 (benzene = Et 2 O + 1 = 1); 1 '' amr (cocia) 6 »1.29. 1.34 (zs, ai-nr), 3.4-4.4 (m, x-9, H-4 ', n-s'. H-2 „.oH). 4-39. 4.52 (261 3.232; n-4) | 50159 (231 7 | 1 ° Bo3 ppm (mg _. | Aromr. An; i: (renthm.: Ua (br. Om. Nso (co). 1920. 1350 ena-l (N05). _ ~ (4'S, 3S, 4R and 4'R, 3S, ES) -3-2 ', 2'-dimethyl-1', 3'-dioxolan--4'-yl) -1-nitrobenzyl-2 "-chloro-2" - acetate) -4-tritylthio-2-azetidinone (mixture of epimers at C-2 ") (isomer B) Od OH 7L ° ~ I STI 'O: Lo srr" j from; CO PNB cozvus The title compound was prepared as described in Example 51 for isomer C) starting from 14.9'g (22, a mmol) (4's; 3s, 4a then 4'R, 3n, 4s) -3- <2 ', 2'- aimeryl-1 ', 3'-1', 3'-dioxolan-d'-yl) -1- (p-nitrobenzyl-2 "-hydroxy-2" -acetate-4-trityltio-2-azetidinone (isomer B) (mixture of epimers at c-2 "). 14.1 g of product (20.9 mg / l; 919%) were obtained in the form of a yellowish foam; Rf 0.53 (benzene: Et 2 O = 3 = 2); .l flfl f 6: Inn: 2 ,:: li-He), 3.4-4.s (411, m, nga, x-4 ', a-5'), 4.57 (nl. d. J-B fl z. 8- 4). 5.13 (s. H-Tï), 5.27 (s, Oman), 7.l-8.3 ppm (1911. m. Arom-ut. 55): ir vax: 1780 end (B-lahtarfn ostar). 464 027 'zw. (4's, 3s, 4R and 4'n, 3R, 4s) -3- <2', 2'-dimethyl-1'.3'-di ° X ° 1ß n- -4 '-yl) -1- (p-nitrobenzyl-2'-triphenylphosphoranilidene-2 "-acetate) -fi-trityltio-Z-azetidinone (isomer B) to» S "' _ Pø -fq ' The title compound was prepared as described in Example 51 for "isomer C" starting from 14.0 g (20 g). , 8 mol) (4'S, 3S, 4R and 31R, 3R, 4S) -3- (2 ', 2'-dimethyl-1', 3'-dioxolan-4'-yl) -1- (p- nitrobenzyl-Z "-chloro-2" -acetate-4-trityl-thio-Z-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 (decomp. CH2 Cl2-Et2 O) 3 * au (cncis) 63 1.12. 1.20, 1.21. 1.35 us. 131-315),. 7.0-B.l pp; (n. coast. "85): i: (CäzClz) Vuxf 1750 621.1 (34-0591” .nun _x _ = _ u¿ _._ Ber-l 'för cännxzogs: c 12.14. a 5.27. u 3.12, s 3.51: fun fl etïc 11.90. u 5.57. x 3.01, s 3.55; n: oaíwengen) mao-nn. 0 n .. 's- (4's, 3s, 4n 0 = n_4'R, 3s, 4n> -silver-3-kz' , z '-methyl-1'-3'-dioxolan-4'-yl) -1- (p-nitrobenzyl-Z "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone-4-thiolate (isomer B) i: s »~ i ö.» G rf ------ ^ 1 “° '” = io YP ° 3 ~ coznæ cözvus The title angina compound was prepared as described in Example 51 for isomer C starting from 1.00 Q (1112 with 464 627 mmol) (4'S, 3S, 4R and 4'R, 3S, 4R) 3- (2 ', 2'-dimethyl-1', 3'-di-OX 4'-yl) -1- (p-nitrobenzyl) -2 "-triphenylphosphoranylidene-2" -acetate) -4-trityltio-2-azetidinone (isomer B). Sso mg product (o fl so mmonçmaæ) was obtained with a melting point of 129-13s ° (decomposition ir (nujoi) Q max: 1745 om * (p-1actam, ester). '- (4' s '35 y 4 'Rp 3R | - 3- 'p 2 I' 13 I -4 '3/1) -1- (-nitrobenzyl-2 "-triphenylphosphoranylidene-Z" -acetate) -4-acetylthio-Z-azetidinone (isomer B) Ung "_ The compound of the title compound was prepared as described in Example 51 for "isomer C" starting from 2.46 g (3.22 g). mmol) (4'S, 3S, 4R and 4'R, 3R, 4S) silver 3- (2 ', 2'-dimethyl-1', - 3'-dioxolan-4'-yl) -1- (p-nitrobenzyl -2 "-Triphenylphosphoranylidene-2" -acetate) -Z-azetidinone- (i-thiolate (isomer B). The product was purified by column chromatography (S102, 32 g; eluent 10% -50% ethyl acetate in dichloromethane = 1 : l); 'nu (cncia) 6: 1.23. 1.21, 1.30 (an. (ai-m), 2.22, 2. :: (za, sne),' La-aa ppm (m. aroma: - Hm 1 : (rent) vw ivss tß-liem, àescez), -. less ef * (e.1 ° == 1; u). (4'S, 5R, 6S och 4'R5S, Gm-p-nitrobenzyl-G- ( 2 ', 2'-dimethyl-1', 3'-dioxolan-4'-yl) - 2-Methylpenem-3-carboxylate (isomer B) in Å: PNB va: 464 G27 220 The title compound was prepared as described in Example 51 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'-dioxolan-4'-yl) -1- (p-nitrobenzyl-2 "-triphene- ylphosphoranylidene-2 "-acetate) -4-acetylthio-2-azetidinone (isomer B). 64 mg of product (0.5 mmol; 53%) with a melting point of 151-2 ° (CH 2 Cl 2 / Et 2 O) were obtained; .if 0.67 (benzene 1: ego-um * m- (cocia) s. 1.29. 1.38 (en. ae. ai-ue), z.ao (an. n. 2-CH3).,:. e-4.4 (ou. e, a-6. n-4 °, n-š '). s.oo-s.1a-s.2a-s.4s (on, Aag, -oèazaza, 5.41 xin, a, a- 1.sâ =. A-5), 1 7.42-1.ss-a.os-a.1s ppm con, Aäazf, uooec. Ash 1: (Ten fl vmx: nlas en * cß-lebm), 1110 ef * (es : e :); uv (neon) Xmax =: ss (a 13,300) 314 nu (e 9; 1oo): Anal. Ber_f, CIQH2ONZO7S: C 54.28. B 4.79, N 6.66-, S 7.63: fURnEt: C 54.00: N 4.75, N 6.68, 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) and K 2 S WC o .. s: ro-e f * me COZHG 2 - The title compound was prepared as described in Example 51 for mg (0.19 mmol) (4'S, 5R, 6S and 4'R, 5S, 6R) -p-nitrobenzyl-6- (2 ', 2'-dimethyl-1', 3'-dioxolane-4 ' -yl) -2-methylpenem-3-carboxylate (isomer B) After recrystallization from dichloromethane-pentane 9 mg (0.032 mmol; 17%) of product were obtained. P - 0.54 (Acetone: HOAc-Szm fi l; 'ain- (coc13> s. 1.35. 1.44 (en, a, 41-1 4.), 2.31 ua. s, z-cna), ss-4.s - (og, m, ~: 2. a-4 ', a-s'1, s.ss; u »(ia. bre. x-sa; 1: - (fsššëå vmax = nos ef * (as-name w xšeom lux: sov ge mo),.: sz nu u: mo). 221 464 027 Example 28 2-Benzimidqylaminomethylpenem-3-carboxylic acid S m: _ _ n '° To a suspension of 0.38 g (0.0015 mol) of sodium 3-benzyl-1, (3f '°' ° “2. Coon I 'I __ mr (I)' (II) 464 027 222 2,4-Oxadiazol-5-one-4-acetate (I; K. Takâcs and K. Harsânyi, ggr. Lgâ (1970) 2330) in 10 ml of methyl chloride containing 2 drops of DMF was added at room temperature 0.13 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. . s. (II) + 3 / 5- * 8 2232012 II Wgww-Câ OÄ pwumm ° æ <I 2 _ 3 oN 'enn ä? 2PNB (III)' 2 (IV) A solution of 1.0 g (0 .0015 mol) of compound III and 0.12 ml (0.05 mol) of pyridine in 10 ml of methylene chloride under a nitrogen atmosphere was cooled to 4 °. The solution of the acid chloride II was added in one portion to the solution of the compound III and the reaction mixture was stirred for 5 minutes at 4 ° 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 0.111 hydrochloric acid, such as 1 ml of sodium microcarbon: and one 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 SilicAR CC-7 silica gel using chloroform such 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. - 223 1164 027. () 5 C IV HÉEEL-> /%? ¶ 0% - <í ::> again ¥% PS'o4 ma: H kdcung (emm (v) 'A solution of 0.4 g (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 5% ethyl acetate in methylene chloride as eluent to give 0.15 g (66%). Infrared and nuclear magnetic resonance spectra were consistent with the structure of compound V. Anal. Calcd for C 23 H 18 N 4 O 1 S: C 55.86; H 3.67; N 11.33 .

Found: C 56.17; H 3.76; N 11.23. A solution of 0.135 g (0.00027 mol) of compound V in 40 ml of tetrahydrofuran and 40 ml of anhydrous diethyl ether was added to a catalyst consisting of: v- ~ -m o. 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 10 5 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 medudiethyl 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 penemic acid, m.p. 156-173 ° (dec.). Infrared and nuclear magnetic resonance spectra were 1 in accordance with the structure of the desired product.- Anal. looks. for clsulsrgoas-snzo: c 52.31; and 5.27; N-lznzo.

Found: C 51.64; H 4.95; N l2¿3l.

Claims (1)

Compounds of the formula v \ S '1..u? (Q) -O' Y 3 H CO23 '8 wherein Y is hydrogen or lower alkyl, optionally substituted by hydroxy, formamido, alkanoyloxy having 1-6 carbon atoms , alkanoylamino having 1-6 carbon atoms or with phenyl, or Y is dimethyldioxolanyl or 1'-azido-1'-ethyl. M is A9 (I), in which case x is 1, or M is Hg (II), in which case x is 2; Q is phenyl; and R "is an easily removable ester protecting group.