SE448995B - 2-SUBSTITUTED AND 2,6-DISUBSTITUTED PENEM SOCIETIES AND PROCEDURES FOR PREPARING THEREOF - Google Patents

Description

. nun, 448 995. ,,,,,,,, ... ~ w4 u _. . . each is an alkylene group having 1 to 2 carbon atoms; é is O, S or SO; Aik 'is an alkylene group having 2 to 4 carbon atoms; and X is hydrogen or lower alkyl having 1 to 6 carbon atoms, optionally substituted with hydroxy; and pharmaceutically acceptable salts thereof.

The term "lower alkyl" includes both straight and branched chain saturated aliphatic hydrocarbon groups having 1 to 6 carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, etc.

Preferred lower alkyl substituents have 1-4 carbon atoms and especially 1-2 carbon atoms. 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 black units (R, S-form) or as individual right-turning and left-turning (R: and S-forms) optical isomers. Preferred compounds f 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 below as isomers A, B, C and D (see Example 58 for stereochemistry). The preferred isomer in compounds of this type is isomer B. Separation of the various optical and geometric isomers can be carried out in a conventional manner and by cleavage methods well known to those skilled in the art.

The present invention includes the compounds of formula I in the form of isomer mixtures and also in the form of the individual separated and cleaved isomers. fy. 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-benzylamine -phenethylamine, 1-ephenamine, N, N '-dibenzylethylenediamine, N-alkyl-piperidine and other amines which have been used for the preparation of salts of penicillins and cephalosporins. When a basic group is present, the present invention includes the pharmaceutically acceptable acid addition salts, for example salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid and sulfuric acid, or with suitable organic carboxylic acids or sulfonic acids such as trifluoroacetic acid, sulfonic 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 "readily cleavable ester protecting group" refers to such a group which has acquired a very special meaning in the field of β-lactam and peptide. Many such groups are known which are used to protect the carboxyl group during subsequent chemical reactions and which may later 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--7 carbon atoms, alkoxymethyl, alkanyl polymers having 2-7 carbon atoms, N-phthalimidomethyl, benzoylmethyl, halobenzoylmethyl, benzyl, p-nitrobenzyl, o-nitrobenzyl, benzhydryl, trityl, trimethylsilyl, triethylsilyl, β-trimethylsilylethyl and the like. depending 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. action. 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 trimethylsilylethyl ester which can be removed by treatment with fluoride ions. Within the framework of easily cleavable ester protecting groups, physiologically cleavable esters also fall, ie. the esters which in the field of penicillin and cephalosporin are known to be easily broken down in the body to the corresponding acid. Examples of such physiologically cleavable esters include indanyl, phthalidyl, methoxymethyl, glycyloxymethyl, phenylglycyloxymethyl, thienylglycyloxymethyl and acyloxymethyl of formula F? C 1 -C 4 -Y 'wherein Y' is C 1 -C 4 alkyl or phenyl. Particularly preferred esters of this type are methoxymethyl, acetoxymethyl, pivaloyloxymethyl, phthalidyl and indanyl.

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

The preferred compounds of formula I are those wherein Y is hydrogen, ethyl or c2-hydroxyethyl. Particularly preferred compounds of formula I are those wherein Y is hydrogen or α-hydroxyethyl. The most preferred compounds are those wherein Y is α-hydroxyethyl. A preferred embodiment of the present invention relates to compounds of formula I, wherein the 2-substituent is - (Alk) -O- (Alk ') - NH 2 Examples of substituents falling within this class , includes -CH 2 OCH 2 CH 2 NH 2, -CH 2 CH 2 OCH 2 CH 2 NH 2, -CH 2 OCH 2 CH 2 CH 2 NH 2, -CH 2 OCH 2 CH 2 CH 2 CH 2 NH 2, -CH 2 CH 2 OCH 2 CH 2 CH 2 NH 2, and -CH 2 .H ~ OCH 2 CH 2 NH 2.

CH 3 Within this class of compounds are preferred, wherein Y is hydrogen, ethyl or 2-hydroxyethyl. Particularly preferred compounds are those in which Y is hydrogen or α-hydroxyethyl and the most preferred compounds are those in which Y is α-hydroxyethyl.

Another preferred embodiment of the present invention relates to compounds of formula I, wherein the 2-substituent has the formula - (Alk) -S- (Alk ') - NH 2 Examples of substituents within this class include -CH 2 SH 2 CH 2 NH 2, -CH 2 CH 2 CH 2 CH 2 NH 2, -CH 2 SH 2 CH 2 CH 2 NH 2, -CH 2 SCH 2 CH 2 CH 2 CH 2 NH 2, -CH 2 CH 2 SCH 2 CH 2 CH 2 NH 2, -CH CH 2 SCH CH NH and -CH CHSCH CH NH. 2 2 2 2 2 '2 2 2 CH 3 Within this class of compounds, the preferred ones are those wherein Y is hydrogen, ethyl or α-hydroxyethyl. Particularly preferred compounds are those wherein Y is hydrogen or α-hydroxyethyl and the most preferred compounds are those wherein Y is α-hydroxyethyl. a. 1 ...-. __ .. ..-... i ...-......

An especially preferred embodiment of the present invention relates to the following compounds which fall under formula I: (a) Y = H; 2-CH 2 CH 2 NH 2 2 2; (b) 'Y = 2 2 2 2; (C) Y = H; 2-cnzscnzcn NH 2 2 '(d) Y = (e) ¥ = H; 2-CH ECH CH NH and 2 2 2 2 9 (f) Y = <: - hydroxyethyl; 2-CH2šCH2CH2NH2.

Particularly preferred are those of the above compounds wherein Z in formula I are physiologically cleavable 3 'esters thereof, such as acetoxymethyl, methoxymethyl, pivaloyloxymethyl, phthalidyl and indanyl.

The most preferred compounds of the present invention are those in which Y is hydrogen or in particular α-hydroxyethyl and the 2-substituent is -CH AND CH NH 2 2 2 2 'in particular the free acids, pharmaceutically acceptable in the salts thereof and pharmaceutically acceptable. the esters thereof.

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 I ~ depending on the stage in which the 6-substituent, i.e.

Y, incorporated. Thus, in Process I, the 6-substituent is incorporated into the starting material; in process II Y is incorporated at the end of the synthesis and in process III the substituent Y is incorporated in an intermediate step of the synthesis. Each of the three main processes can in turn vary the process for incorporating the desired 2-substituent, 448,995 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 or IIIa, as shown below, as these methods have been found to be most commonly used.

The reaction steps of Process I are shown in the following reaction scheme: -u fl. ,. ..._, L ..-.> ... 1 ... ,,,, ... _. V n ...- .. 448 995 Method I (variation 1): Early incorporation of the Z substituent. y 0 om: n y-ca-ca-oac csr; XC'5N “å 'N pH 7.5 0 \' H o * w 'Sg-X' '* m so x b. f-è '. ___-_; - 'v (1130 í i soclz z-'ïß _ I »nun-N o ~ _ * a °° 2R. 04.

C02R "o _ i Y sg-x 'Pø Y scÉ-x' A _ 3 _ avel ba; _ N èøa 5 Y“ xk S yi _ x êvïägsn. Whíl / s _4 - N / av protection-s- / x °. own »'” _ ”COZR Q C028 O ü Ac -_ CiíaC-' - ø l CH n I ss - X = - ~ '-A - NH2 (V1 Procedure I (variation Ä: 2 _ om; ll: z-cx-cx-ozxc csr; CHBC sm _ - N \ PH 7,5 l- o H .YR _ M - ._ YR SAc L _ çH ° _ soclz- _ fi * I n vl-N ÛK o __ \ H _ _ C023 04, ç92R 'Y' Y. saa - Pø3 ““ _ sA = _MÅ --9 N cl _ bas '/ ___ N pøa ba! oo / coza' cozn 'Y o' g ¿“M sm x ä ® YR sc-x A \ J * Q .- 'COZR' i COZR "Y s Y ix removed by _ ¶ 5 F - à x 'N * protection group o ï * / C023' Q, co a H XCQ = acyïeringsmedeï MA = tungmetaïisaït 448 995 ------.-...-.- .. ___... - .. Mu-qi Sent íförlivande av Z-substituenten 448 995.

Method I (variation 3): Late introduction of the Z-substituent y n: c c- cx if: cs: if øïcsua -> "ïífš" ._. _ N _ n _ _;. 0 \ H.

Y u., Scø3 '1. .. __N os: o \ B coza _ 04 Y ooza "x v 'K scøa Pøa scø3 --T'> N Cl bas N 12953 o» o coza "coza 'I. o y sn 3 fi Y '\ - \ _ så-x x-c- G)' __ o N Pø: o / -fN Pøs COZR 'cozn ". Y.

X S Y I x avïägsn. av “Líl / S ----> x / J-N / protection group / o _ ,, .-- N COZR '- 0 soc; Base MMA * 448 995 In process I, a vinyl ester (Y = H or a group having the meaning given in formula I above) containing the desired 6-substituent is converted to the optionally 1-substituted 4-acetoxy-2- the 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 can be performed in an aqueous or aqueous organic reaction mixture at a temperature of 0 DEG C. or below and at a moderate basic pH value.

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 is the desired 2-substituent, 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-azetidinone to the 4-acetylthio-2-azetidinone and 4-trityltio-2-azetidinone products, respectively, by nucleophilic displacement with thioacetic acid and triphenylmethyl mercaptan (or a salt thereof, respectively). such as the sodium salt). The 4-thioazetidinone is then reacted with a glyoxylate ester 0 u HC-CO 2 R ", wherein R" is an easily removable ester protecting group, such as p-nitrobenzyl or trimethylsilylethyl, or a reactive oxo derivative thereof, such as a hydrate, in a 448,995 12 inert organic solvent (for example benzene, toluene, xylene or the like) and preferably at elevated temperature (for example from 50 ° C up to reflux temperature is preferred). When a hydrate of the ester is used, the resulting water can be removed azeotropically or with a molecular sieve. The hydroxy ester product is formed as a mixture of epimers, which may optionally be purified by chromatography or used directly in subsequent steps. Conversion of the hydroxy ester to the corresponding chlorine ester is achieved by reaction with a chlorination reagent (for example SOCl 2, POCl 3, PCl 5 or the like) in an inert organic solvent (for example tetrahydrofuran, diethyl ether, methylene chloride, dioxane or the like) in the presence or absence of a base, preferably an aliphatic tertiary amine (for example triethylamine) or a heterocyclic tertiary amine (for example pyridine or collidine). The reaction is advantageously carried out at a temperature of from about 10 ° C to room temperature.

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

The phosphorus intermediate can be obtained by reacting the chloroester with a suitable phosphine (preferably triphenylphosphine or a tri (lower alkyl) phosphine such as triethylphosphine or tri-n-butylphosphine) in an inert organic solvent such as dimethylformamide, dimethylsulfoxide, tetrahydrofuran, 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 once again take two pathways. According to variation I (where the 2-substituent has already been incorporated), the phosphorus intermediate is converted to the desired penemene compound by performing a thermal cyclization in an inert organic solvent at a temperature of just above room temperature. to the reflux temperature of the solvent system. The cyclization is most conveniently performed under reflux conditions. Suitable inert organic solvents include aliphatic, cycloaliphatic and aromatic hydrocarbons (for example benzene, toluene, hexane, cyclohexane), halogenated hydrocarbons (for example methylene chloride, chloroform, carbon tetrachloride), ethers (diethyl ether, dioxane, carethoxyethrofuran), dimethylformamide), di-C 1 -C 6 alkylsulfoxides (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 amy "CO 2 R" (m 3 .III or HQCOOCH 3 71 mm 3 COQR "4 - N IIIa wherein Q is preferably phenyl" or lower alkyl, x is 1 or 2 and M is Cu (II), Pb (II) or Hg (II) when x is 2 or Ag (I) when x is 1. The mercaptide formation is accomplished by reacting the phosphorane with a salt of Hg (II), Pb (II), Cu (II) or Ag (I) or with (methoxycarbonyl) mercury (II) acetate in a methanolic solvent and in the presence of »- ... un-hnn- fl m. U ... 448 995 _ .. ... An organic or inorganic base such as aniline, pyridine, collidine, 2,6-lutidine, an alkali metal carbonate or the like. A preferred base is pyridine. 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 the chosen solvent, for example NO 3 ", CH 3 CO -, N02, CNO etc. Merkaptidm the intermediate product is then converted to 0. with an acetylating agent capable of introducing the group X-Å-, wherein X is the desired penem-2 substituent. The acylating agent OO (X-3- (3) may be the acid X-8-OH or a reactive functional derivative thereof, such as an acid halide (preferably acid chloride), acid azide, acid anhydride, mixed anhydride, active ester, active thioester etc. The acylation is carried out in an inert solvent (for example a halogenated hydrocarbon such as methylene chloride, or an ether such as dioxane, tetrahydrofuran or diethyl ether) and, when an acid derivative is used, in the presence of an acid acceptor such as a tri (lower alkyl) amine (for example -1 "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 of from about -20 ° to + 2S ° 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 been formed, the protecting group can be removed by conventional unblocking methods (eg hydrolysis, hydrogenation or photolysis) to give the unblocked penem compound. The removal of the p-nitrobenzyl ester can be 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 coal or diatomaceous earth. A non-reducible aqueous or anhydrous inert solvent is used, such as water, ethanol, methanol, ethyl acetate, tetrahydrofuran, diethyl ether or dioxane. The hydrogenation can be carried out at atmospheric pressure or elevated pressure and preferably 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: d.-. ___- l 448 995 16 Process II (variation 1): Early introduction of the 2-substituent 'I' Q 0A u cx -cx-oae cs: i I c * Ws fl a 2 * T-ä>. 3 2 N \ PH 7.5. 0 H. - ä ”g __l, sc-x sc-x I .q ° | ** ° 'soclz - __ * - --N oo xx coza 04 H _ _ cozn' o I 1 sè-xz \ (h K 3 ' PC KZX coz fi '0 COIR ”.. Y' avïagsn. Av 5 ----->. Skyddsgrupp _N \\ ~%;» - X | o CO HV .........- ~ .wx. r..f ...> ____. = ..--. - ... u. .., -... \ ........ ~. ,,,,,,, 17 Procedure II (variation'2): 448 995 I 'om: _ caf-.cx-oaa csr; _ ÅCSNa å _ ¿N pH 7,5.' 0 \ H.

KC 'SAc I' cxo I, in I v-ï or xx coza 04 N ° H cbzn 'SAc Pøa 5A; : E 1 ba: N N c _... Pø o. 04 3 C023 'COIR "I' o su 3 së-x X-C- Q \. __N 00211 'cola" s y' | X Y '~ Lu ___ T /' S ____._ .. è. / ß-'N / bas / x 0 u 'C023 Q _ COZR Y. avïägsn. av “L ___ (5 ----> x protecting group - / lr fl- * N ff ~ o co a Late introduction of the Z substituent ..... ........... '|.:. «...__..._..-» nur-nn nu w L n-wh ". 1 _ .., ... 4, 448 995 18 Procedure II (variation-Ü: Sent 'ínförïívande av Z- the substituent 'Om: _ ø csNa cxz-cn-oac cs: E _ 3 à N pH 7. S' fo \ H scø: ____> scøa I cxo I socl 42'-N '-, Ä N on 2 o \ H COZR O / '__ çozx "SCø3 Pøs scøa MA ¶ ---%> N Cl bas N PøB bas Ä Y" ° Y co2R' 1 co2R "¶ 'o sn 3“ -_T x_c_ e sc-x b, _ - --- é> ---%> ¿øL-N Pø3 ... N Pø.

° * K% - f ß v C023 'cozn' S Y X Y R s i _ É 414 * / bas / x Q / IP-N COZR "Q _ co R" av1ägsn.av; protecting group fi YR s, X 0.

C025 .__-.__., _ ,, '. <. Mvv ... _ 19 448 995 as can be seen, process II is essentially the same as process I (except that Y must be hydrogen) up to the thermal cyclization step which gives the 2-substituted penem compound. However, if desired, a 6-substituent is now introduced at this stage by reacting the 2-penem compound with a suitable electrophile in an inert solvent (for example tetrahydrofuran, dieqdeuz, dimethoxyethane or the like) and in the presence of a strong base. In this process, the 2-penem compound can be reacted in the form of the free acid (obtained by deblocking as described above) in the presence of about two equivalents of base or alternatively a suitable 2-penem ester can be used in the presence of about one equivalent bass. One can use any ester which is inert with respect to the anion chemistry (the reaction involves base anion formation, followed by reaction of the electrophile with the penem anion), for example lower alkyl such as methyl, ethyl, n-propyl or t butyl, phenyl, trichloroethyl, methoxymethyl, silyl such as trimethylsilyl or t-butyldimethylsilyl or the like. 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 not critical and the usual strong bases, such as sodium hydride, phenyllithium or butyllithium, are suitable. However, in particular, a lithium disilylamide or a lithium dialkylamide, such as lithium dicyclohexylamide (LDCA), lithium diethylamide, lithium dimethylamide or lithium diisopropylamide (LDA), is used.

The electrophile is selected 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 6- - a-w »- <-.-.-.__.__. M.-_-. The 448,995 substituent by this process is preferably carried out under cooling (for example at a temperature from -800 to 0 ° C) according to the general procedure described in Canadian Journal of Chemistry QQ (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 product liberated from acydic groups. The third main reaction procedure (Method III) is shown in the following reaction scheme: Method III (variations 1 and 2). scøa scøa _ ° Rs' ° à NN: Y Y ~; scøa --é> I bas ~ 04 - N \ B avlägsn. of Skyê fi group MIX / bass * '-._____ \, scø3 HO COZR' ha. scø3 o4-u ox cozn 'SOCIZ x wa á fi- N l C022. ba: I N Pø; 21 448 995 V], su N o * a 'ï x-c- G o mf'- sä-x' I_T ._. N \\ B avlägsn. of protection group \\. ~ -._...,. - »~.«.-........- ~. ~ Ym 448 995 22 o Y \\ -__ TSH sc-x. ° ¿~ "N \ (Pø3. U cl CÛZR 'cozaw 3» ø. I' wc 'Q l / b 3 - _ - _nr' å 2 SC ~ XY 5â.xx I x 4-12; f '\ \ / f- fl- N lo II o RI 'co2R, C02 ¶.removal of _removal of protection group' SKYÖÜBQÉUPP Y ly. hLL-írs x Rís X 4 * “*“ I / 4L-N // ° i - - 2 ° coza B = blocking group for ring nitrogen The 4-trityltio-2-azetidinone in process III is formed in the manner described according to process II (variation 3).

The ring nitrogen in the azetidinone is then protected by a conventional, easily removable blocking group, such as triorganosilyl (for example trimethylsilyl or t-butyldimethyl-vx-J-.w-ví _ .i _..._., .... _.... ... u-_ innan-vu .. ..-. w-_a _.....-_ 'aaa-u - .. ui_n_.iaaï 448 995 23 silyl), methoxymethyl, methoxyethoxymethyl , tetrahydropyranyl or the like. The introduction of the desired Y substituent into the 1-position of the azetidinone is then effected by reacting a suitable electrophile with the N-protected azetidinone in the presence of a strong base (the reaction conditions are those described above in connection with process II ).

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

In one way, the N-protected intermediate is unblocked by conventional methods (e.g. acid hydrolysis) and then converted to the 2,6-penem compound via ester formation, chlorination of the hydroxy ester} conversion of the chlorester to a phosphorane, conversion of the phosphorane to a heavy metal mercaptide, acylation of the mercaptide with O XgQ, thermal cyclization of the resulting hub 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 converting the N-protected azetidinone to a heavy metal mercaptide, acylating the mercaptide with the group X-á-C) removing the N-protecting group, reacting 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.

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 Q manner analogous to the preparation of the corresponding esters of penicillins and cephalosporins. The resulting isomer mixtures can be cleaved into the separate isomers according to known methods. Mixtures of diastereomeric isomers can be separated, for example, by fractional crystallization, adsorption chromatography (column or thin layer chromatography) or other suitable separation methods. The resulting racemates can be cleaved in the antipodes in the usual manner, for example by preparing a mixture of diastereomeric salts with optically active salt-forming reagents, separating the diastereomeric salts and converting the salts to the free compounds or by fractional crystallization from optically active solvents. . Accordingly, the present invention also provides a process for the preparation of compounds of formula I, which process cyclizes a compound of formula Y in an inert organic solvent at a temperature just above room temperature to the reflux temperature of the solvent. wherein R is phenyl or lower alkyl, R 11 is an easily removable ester group Pf T is -COX, where X = 7 (Alk) -A- (Alk ') - NH m fl a fl mgr, optionally substituted with hydroxy, by 2, a Y is hydrogen or lower alkyl by 1-6 per se known methods, removes the removable ester group and optionally converts a compound of formula I, wherein Y is hydrogen, to a compound, where Y is a substituent, by treating said product with a corresponding electrophile in an inert organic solvent in the presence of a Strong base. The penem compounds in the form of the free acids provided by the present invention and the pharmaceutically acceptable the salts and physiologically cleavable esters flfl - way.- "...,. _, __ _ __.-.._.... '.;. = ._' ..:.: .'.'...'_.__ ;; _ 448 995 26 ..., -. .-...-._..... ..._- J- ............, of said acids have been found to be potent broad-spectrum antibacterial agents which are useful in the treatment of infectious diseases in animals, including humans, caused by both gram-negative and gram-positive organisms.

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

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

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

According to the present invention there is also provided a method of combating bacterial infections in animals, in particular warm-blooded animals, which method involves administering an acid of formula I or a physiologically cleavable ester 448 995? W 3 thereof or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for an infected host animal in an amount sufficient to combat such an infection.

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

Below is an explanation of the importance of less obvious abbreviations: CSI pet. ether k.p.

NMR ether Celite LAH n-BuLi MIBK Et Tr Me THF Ph DMF TEA PNBG THP TFA HMPT (or HMPA) EtOAC DMSO Ac MS DMAP Py LDA chlorosulfonyl isocyanate boiling point nuclear magnetic resonance diethyl ether (unless otherwise stated) diatomaceous earth lithium hydride methylalium - -C (C 6 H CH 3 -tetrahydrofuran '9 phenyl acid dimethylformamide triethylamine p-nitrobenzylglyoxylate tetrahydropyranyl trifluoroacetic acid hexamethylphosphoric triamide ethyl acetate dimethylsulfoxide CH CO 3 -n3so 1- (Trimethylsilyl) -4-trityltio-2-azetidinone cès SCÖB 0 N. N \ ¶x A solution of 345 mg (1 mmol) of 4-trityltio-2-azetidinone, 80 mg (0.5 mmol) 1, 1,1,3,3,3-hexamethyldisilazane and 55 mg (0.5 mmol) 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. (p pm. cDc13) = 7.32 (15H, m, aroman. -1, 4.22 (13, ¿¿, 3_4), 2-67 (lä. dd, J = 4-1, J ~ 16, H-3), 2.22 (ln , ad, J - 2.2, J 'I 16, 8-3), 0.3 (95, s, CHJ) 2. 1- (t-butyldimethylsilyl) -4-trityltio-2-azetidinone: 1/3 Cm; - N CH ON o N Sif exile: C (CH3) 3 l, 62 ml (11, 6 mmol) triethylamine was added dropwise over 5 minutes to a cold (o °) and Stir solution of 3.5 g <10, 1 mmol) of 4-trityltio-2-azetidinone and 1.68 g (12.7 mmol) of chloro-t-butyldimethylsilane in 35 ml of DMF. The reaction mixture was stirred at room temperature for 18 hours 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 pen intermediates ... n-www 14 u: 448 995 29 .__ ,, ._ M ,, ..,. Wa .. _....._.......... The mixture gave a total of 4.1 g (89%) of the title compound as a white solid, m.p. 113 DEG-114 DEG-114 DEG. '6_ (1H, dd. H-4). 2-63 (1H, dd. J - 4. J - 16, H-3), 2.1: (ia, aa, J - 2. J - 16, 5-3), 1.0 (95, S, c-au ), o.3s (sa, s, ne). -1 _ u va ”1735 am. anal. Ber.fcr cza fl sanoggi, c, 73._1S; n, 7.24, - N. 3.05; s, 6.97 \ .Eïnu¶et: 'c, 73.27; u, 7.32, N, 2.97, s s.94s. 1. 1-Methoxymethyl-4-trityltio-2-azetidinone 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 -150 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. 72-760. Δ (ppm, CDCl 3): 7.3 (15H, m, aromat.), 4.4 (3H, m, NCH 2 O and H-4), 3.22 (3H, s, CH 3), 2.76 (ZH, m, H -3). 448 995 4. 1- (Methoxyethoxymethyl) -4-trityltio-2-azetidinone ........,. ,, ...., ~ .. n.-. To a suspension of 322 mg (1 mmol) of tetrabutylammonium bromine and 70 mg (1.1 mmol / l; ss%). Potassium Newaroxia In 10 ml of dichloroethane, which was cooled to 50 DEG C., 345 mg (1 mmol) of 4-trityltio-2-azetidinone and 187 mg (1.5 mmol) of methoxyethoxyethyl chloride were added with vigorous stirring. The mixture was stirred at room temperature for 2 hours, the solvent was evaporated and the residue was 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 g (48%) of the title compound as an oil. 6 (ppm. CDc13) ¶ 7.30 usn, m, azamaq. ), 4.57 (zu. Mkvartcü: N-_c1_ «2o>, 4.46 (m, aa, ma).: .So (an, n, ogzgazo). 3.30 (aa. N, ena).: As (za, m , H-3). - '. L- (2' ~ tetrahydropyranyl) -4-trityltio-2-azetidinone scø: __ (/ month * Û O H- \ In _______-__-_ _ 31 448 995 § 1, 6 ml (1.6M; 2.56 mmol) of n-bu-yllithium was added dropwise to a solution of 863 mg (2.5 mmol) of 4-trityltio-2-azetidinone in THF, which was kept at -7 ° C after stirring for 15 minutes. 560 mg (4.7 mmol) of 2-chlorotetrahydropyran were 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 brine, dried and concentrated to give 635 mg of a 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.

. Q 6 (ppm, CDCl 3 7.28 (1524, m, aromat.), 4.4 (ä, äd, fl r4), 2-94-7 (25: m: ''31 4'1 "3'2 ~ IW_O.- 2.2 -0.7 (tecrahydtopyranyl) - .d_- .ha-equ 448 995 32 6. Preparation of 4-trityltio-1- (p-nitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate) -2-azetidinone scé É : fw O 3 P.

CO 2 NB 1- (1'-carboxy-1'-hydroxymethyl) -4-trityltio-2-azetidinone-triethylamine salt ST: STI CH0 - TEA l mao _----- r * ._ '*' 'N OH díïjš ; To a solution of 3.5 g (10.5 mmol) of 4-trityltio-2-azetidinone in 8 ml of tetrahydrofuran was added 1.42 ml (10.5 mmol) of triethylamine and 1.02 g (10.5 mmol) of glyoxylic acid hydrate. The mixture was stirred at room temperature for 1 hour with 4 Å molecular sieves (these were dried at 150 DEG C. for 18 hours) in a volume of 8 ml and allowed to stand at room temperature overnight. The solid mixture was diluted with methylene chloride and filtered; the filtrate was evaporated and the residue was crystallized from pentane to give 5.18 g (98%) of the title compound as a white solid, m.p. ir v = 3100-3600, màX ochnss efl; Um ccnc131 - 4.50 (in, aa, J-aaz, J-auz), 3.0 (1H, ad. J-1SHz. J = 7Hz). 3-1 (GH. Q.

J = 1H =), 2.70 (ln, da, a = 1sHz, J = 3 fl z), 2.0-3.5 (za, m) or 1.2l ppm (sa, c, J = 1xz). 1- (1'-carboxy-1'-chloromethyl) -4-trimethylthio-2-azetidinone ST: ST: ---- + OH + SOCl2 _, cazclz ¿í: jI: ïHJc1 0 0 \\ rf .TEA CO28 CO H 448 995 33 A cooled (ice bath) solution of 1.04 g (2.0 mmol) of triethylamine the salt of 1- (1'-carboxy-1'-hydroxymethyl) -4-trityltio-2-azetidinone in 5 ml of methylene chloride was treated dropwise under nitrogen with 0.16 ml (2.2 mmol) of thionyl chloride in 2 ml of methylene chloride. The solution was stirred at room temperature for 20 minutes and concentrated. The residue was diluted with benzene and filtered through a bed of celite and charcoal. The filtrate was evaporated in vacuo to give 870 mg (quantitative yield) of the title compound as an amorphous solid. It was used in subsequent steps without further purification. _ = lvvs em'1 i; u; * Hz-nr (CDCl3) <5 = max 9.22 (m, hä), 7.27 (ISH, m), 5.3 and 5.2 (ll-i, Id, .ï-I fl z), 4.6 (1H, m) 0ch2.8 ppm (28. m). ,. 1- (1'-carbo-p-nitrobenzyloxy-1'-chloromethyl) -4-trityltio-2-azetidinone Cl n., (Lisää + FNs-ox ____2________, N \ ï / pl cHc13 01 I G1 1M pyridine / THI To a cooling (ice bath) solution or 0.17 ml (2.2 mmol) in 4.4 ml of chloroform (the chloroform was allowed to stand in contact with 3Å molecular sieves for 18 hours before the reaction in order to remove any traces of alcohol 0.19 ml (2.2 mmol) of oxalyl chloride were added dropwise, the mixture was stirred for 5 minutes in ice and then for minutes at room temperature, the solution was cooled in an ice bath and treated dropwise with 854 mg (2 mmol) of 1- (1'-carboxy). 1'-chloromethyl) -4-trityltio-2-azetidinone in 2 ml of chloroform, followed by 2.2 ml of a 1M solution of pyridine (2.2 mmol) in tetrahydrofuran, the solution was stirred for 30 minutes at room temperature, cooled. The mixture was treated with 370 mg (2.2 mmol) of paranitrobenzyl alcohol in 2 ml of a 1: 1 mixture of tetrahydrofuran and chloroform and with 0.31 ml (2.2 mmol) of triethylamine.

The solution was stirred at room temperature for 30 minutes and then evaporated. The residue was diluted with benzene and filtered over a bed of celite and charcoal and the filtrate was evaporated in vacuo. The chlorester ester product was purified on a silica gel pad (5 g) and eluted with methylene chloride to give 448 995 34 _ ... ... t, .__. held 790n @ @ (70%) of the title compound as a beige powder. Trituration in ether gave a white solid, mp 168-1690. ir V ma 3 J-9H =>. 1.49 (2H, d, J = snz). 1.3 <1sH. m). s.vs and š.3s (LH. 2s). .3 (21-1, s), 4.55 (1H, m), 2.8 (2H, m).

X, ivao. 1760 = m'l; * fi mf (cncl 3 6: a.1s (zu, a, This compound was identical to an authentic sample, which had been prepared by reacting 4-trityltio-2-azetidinone with p-nitrobenzyl glyoxylate, followed by treatment with thionyl chloride.

Example 1 1- (p-nitrobenzyloxycarbonylmethyltriphenylphosphoranyl) -4- (silver mercaptidyl) -2-azetidinone J 2 / PO 3 W ° cozyua ST: ° ^ ° 'usa p if far -_ * “H Na. [w IN 90 ml of a methanol suspension of 13.8 g (0.05 mmol) of triphenylmethyl mercaptan was degassed for 0.5 hours with a stream of nitrogen. The mixture was cooled to 0 DEG C. 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 and 7.7 g (0.059 mol) of 4-acetoxyazetidinone in 55 ml of water were added rapidly. Precipitation of 4-triphenylmethylmercaptoaazethidinone (2) occurred immediately. The mixture was stirred for 4 hours at room temperature for 4 hours. The solid was filtered off, washed with water and dissolved in methylene chloride. The methylene chloride solution was washed with dilute HCl, water, aqueous sodium bicarbonate solution, water and brine and dried over magnesium sulfate. The product was obtained in a yield of 89.8% with a melting point of 146.5-147.50.

Ana1ys = ser. for c22H19Nos = c 76.49 H s, s4; N 4.05; s 9.28 Found: C 7.54; H 5.60; N 4.00; S 9.36.

NMR: δ (ppm, cDc13) - 7.60 - 7.10 (1511, m, H-trityl), 4.62 (1n, bg, NH), 4.40 (in, aa, J4_3trans = 3.0 J4_3 cis = s, H-4), 3.24 (1H, aaa, Jgem = 1s, J3_4 cis = s, J3_NH = 1, s, _ H-3), 2.81 (1H, add, Jgem = 15 , J3_4 trans = 3.0 J3_NH = 1.2, H-3) m. 00 (cnc13) 1760, ONE 3340.

T sr: "ST 'ê: oPNa Z __.._ L .__ .. f ~ N ou * won _ N \ H. O - 0 0 _2- r [u 4,54 g (0.02 mol) hydrated p nitrobenzyl glyoxylate and 6.90 g (0.02 mol) of azetidinone (2) were refluxed for 24 hours in benzene via a Dean-Stark condenser filled with 3A molecular sieves, additional glyoxylate (2 x 454 mg, 2 mmol) was added with reflux (18 hours) after each addition.

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

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

Isomer A: Rf = 0.87 m.p. = 170.5 - 171, s NMR = δ (ppm, coc13) 8.07 (za, a, J = 9, Hm aromatics>, 7.45 (part of d, Ho aromatics), 7.40-7 .00 (15H, m, trityl), 5.25 f (2H, s, CH 2 -PNB), 4.75 (1H, s, HC-O), 4.37 (1H, dd, J 3, J 3 -4 cis = 4, H-3), 2.83 (1H, dä, Jgem = 16, 3-4 trans = J. = 4-3 cis 448 995 36 4, 11-4), 2.10 (111, aa, Jgem = 16, 1.42 (bs, om.

IR; 1) 0: 0 (cnc13) 1770, 176o (s1 J 4-3 trans = 3 'H_4)' ISOIUEI 'B; Rf = 0.75, 5.15. = 152 - 153 ° Nmm 6 (ppm, cnc13) 8.13 (214, a, J = 9, Hm aromatics), 7.47 (28, d, J = 9, Ho aromatics), 7.40 - 7, 00 (15H, m, trityl),, 30 (snfs, caz-Pma, nco), 4.45 (114, t, J = 3.5, 14-4), 2.90 - 2.70 (2H, AB part of ABX, H-4), 1.55 (bs, OH).

IR = JC = O (cac13) 1767, 1755 (shoulder), 1) 1525, ^ J 3500.

N02 OH ST! ST SOCJ. r - 2 N OH pyridine 'N Cl YOZPNB i: PNB 2 2 A 150 ml of a cold (r15 °) 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 mmol; 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 94% yield on crystallization from chloroform. 11mm δ (ppm, cnc13) 8.17 (211, a, J = s, Hm aromatics), 7.67 - 7.00 (17H, m, Ho aromatics, Tr-H), 5.80 (s, HC ~ Cl), 5.37,, 33 (2s, HC-Cl, CH2-PNB), 4.81 (1H, m, H-4), 3.27 - 2.40 (ZH, m, H-3 ) Imàczo (Kax-film) 1785, 177o0NO2 1525. v-UWM 448 995 37 o - QZPNB. cozpns sw: U »S72 øav Eïï \ 1J, c1 2,6-lutidi fl _ \ ï,» P ° 3 ¿, å 100 ml of a THF solution (distilled over LAH) of 11.6 g (20.2 mmol chlorazetidinone (4) was treated with 7.86 g (30.0 mmol) of triphenylphosphine and 2.36 g (2.6 ml; 22.0 mmol) of 2,6-lutidine. The mixture was refluxed for 72 hours. The precipitate was filtered off and washed with ether. The organic solution was washed with a 2% aqueous solution of HCl and a%% aqueous solution of sodium bicarbonate and dried over magnesium sulfate. Evaporation of the solvent gave a residue which was purified through a silica gel pad (200 g). The desired phosphorus was eluted with 30, 40 and 50% ether-benzene to give 1.4 g of product in a yield of 70.4% and with a melting point of 201-22 °.

AnalyS: 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: -Q c = o (CHCl 3) 1740, 'Û phosphorane (1620, 1610), 1) N02 1525. ~ z T', Aguoa SA9 É _ N \\: ¿? 03 - ° vy: §a1nY N_ \ T ?? v, 'oàvua cozvua 3 á 1.6 g (2 mmol) 4-tritylmercaptoazetidinone was dissolved in 20 ml CH 2 Cl 2 and the solvent was evaporated at 55-600. The phosphorane (5) with the temperature 55-600 was dissolved in 32 ml of methanol, which had been preheated to 55-600 Immediately after obtaining a methanol solution of compound 6, it was treated with a preheated (55-600) mixture of 16 ml of methanolic 0.15 M silver nitrate solution (1 , 2 equivalents) and 174 mg (178 μl; 2.2 mmol; 1.1 equivalents) of pyridine. The heat bath was then removed immediately. The mixture was stirred. @ u1 _- = r.;. x _-..., __z. ~ ~ 448 995 38 at room temperature for 2 hours and at 00 for 1 hour.

The silver mercaptide 6 was filtered off, washed twice with cold (00) 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). . ' In; -0 czo (cHcl3) 1795, 1725 1605), - Q NO2 1530.

Exemgel É § 1- (p-nitrobenzyloxycarbonylmethyltriphenylphosphoranyl) -4- (silver mercaptidyl) -2-azetidinone Z- scmm - I J 5 ^ 9 dïïïí / '. x co3.Ag ~ o3 áíïlíf neon N _ 0 \\ ï-ppb; A solution of 1.796 g (3.0 mmol) 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 turn. 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 -100, 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 l§8-1450 (decomposition). I.R. (nujol) cm'l = 1748, lszo and leos. An analytical sample was obtained by preparative thin layer chromatography (ethyl acetate) and the product showed a melting point of 140-1450 (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. 39 448 995 Example gel 3 1- (p-nitrobenzyloxycarbonylmethyltriphenylphosphoranyl) -4- (silver mercaptidyl) -2-azetidinone A. Use of aniline as base SCOCH. ': r 3 Aniline, AgNo saw _ _ ______..__. l .._ ¿N. neon - 'N o ~ \ I ~ \, c vina o: _PPh3 CÖOPNÉ OOpNB l 6.

A solution of 1.8 g (3.0 mmol) of phosphorane (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 -150 for 0.5 hours, after which the cooling bath was removed and stirring was continued for 24 hours. The reaction mixture was cooled to -100 and stirred for 1 hour before being filtered; The silver mercaptide was washed successively with cold methanol and ether to give 1.5 g of product in a yield of 77.9% and with a melting point of 114-11 ° (sonar). The product was identical to the compound of Example 2.

B. Use of 4-dimethylaminopyridine (DMAP) as the base scocn SA H 3 ÅgNO / DMÅP \ fi 9 ca cl / en os o xfw; A solution of 17.96 g (30 mmol) of the above S-acetylphosphane in methanol and dichloromethane (1: 2, 450 ml) was purged with nitrogen (5-10 minutes). ), cooled to 5 ° and treated in a ... få '....._..._......., ..-. - _..., -, -.- wq 5.8.8 g (3l, 5 mmol) of silver nitrate and 3.85 g (3l, 5 mmol) of 4-dimethylaminopyridine. 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 least 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%.

IR; (cHc13) Qmax: 1745 - (c = o i / ß -1actam) to 1607 cnfl (C = O i ester).

C. Use of the diazabicycloundecene (DBU) as the base scoc "" Agnoj s "9 ___..________.___ 1, åa ÛBU. MIOH o N péa OZPNB fi pNB 2 36.0 g (0.060 mol) of the above S-acetylphosphorane dissolved in 120 ml of methylene chloride The solvent was evaporated to give an oil The resulting oily residue was dissolved in 240 ml of hot (350) methanol and treated rapidly with 420 ml of a methanolic solution of silver nitrate (10.68 g; 0.0628 mol 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 solid was filtered, washed once with cold (Oo) methanol and ether and dried in vacuo to give 37.0 g of product in 93% yield.

IR: (nujol naill) f fl max (c = 0) and 1600 cm_l (phosphorus). «4, _ 448 995 D. Use of pyrrolidine as base SAg a [: T" Scoc 3 Pyrrolidine _ N 59 "° 3 - o N * \ c-Pvh 0“ * c- »Ph. I 3 3 mmmm mwua ' To a cold (00) solution of 0.60 g (1.0 mmol) of 4-acetylthio-1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone in 2 ml of CH 2 Cl 2 was added 4 ml MeOH, a solution of AgNO 3 in MeOH (0.4N; 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 1.75 hours, cooling to -10 °, stirring for 0.25 hours and filtering, the solid was washed with cold MeOH and dried in vacuo to give 0.548 g of product in a yield of 82 ° C. , 4% and with melting point 1150: IR: (nujol) 1) max: 1755 (c = o) cch lsoo cnfl (arcmatcr).

Example 4 Mercury (II) - (2 "-triphenylphosphoranylidene-acetate) -2- -azetidinone-4-thiolate sr: 3 N \ - h L" ß zwæ 1 s) f @ l "YPPÜS" Covm \ ..._ ... aww fi-. u-fø-c mm ... _. 448 995 42 A solution of 2.4 g (3 mmol) of compound I in 15 ml of dichloromethane was cooled to 50 and treated with a solution of 0.525 (1.65 mmol) of mercury acetate dissolved in 15 ml of methanol. After stirring at 50 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 g (91%). Melting point 123-1270.

IR; (cHCl3) 1745 cm -1 (1) c = o / 9-laccam) isos cm -1 Example 5 A. Preparation of 3- (1'-hydroxy-1'-ethyl) -1-methoxymethyl-4-tritylthio -2-azetidinones a) (1'S, 3S, 4R- and 1'R, 3R, 4S) -isomer (isomer C) A solution of lithium diisopropylamide was prepared in 5 ml of THF at -1a ° starting from 1.0 ml (1, 1.6 mmol) (n-butyl lithium and 0.25 ml (1.84 mmol) 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 9 -fl- nømv-w-v- ...- r ... w-_ 448 995 43-_ ~ i 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 melting point sm 1s, 5-9 °; '* 1uR:' (cnc13; 6.7.3- txsn. M, -zomrc. A, 4.31 (zx, Aag, N-5520), 4.32 (ia, a, J-2. U-4). 3.17 '( 331 I, OCHS), 3.32-2.70 (23, m, 3-3 O .. 21-5) 0- -1.12 PPI! (35: a, a-1, ena), Ana1.Iär.iR fi: c26a17no3s «c 11.02, n e.za, u a.2a, s 7.:s,Fï flfl N @ fi ä: 11.99, a e.o2, N 3.21, s 7.4os. b) (l'S, 3S, 4R and l ' R, 3R, 4S) - and (1'R, 3S, 4R and 1'S, 3R, 4S) -isomers (isomers C and B) A solution of 0.482 mmol of lithium diisopropylamide was prepared at -786 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 0.71 g (0.439 mmol) of (4R and 45) -1-methoxymethyl-4-trityltio-2-azetidinone in a mixture of 1 ml of dry ether and 1 ml of dry THF and the resulting the clear solution was stirred for 15 minutes at -78 °. A 0.96 mL solution of a 0.5 M solution of tetrabutylammonium fluoride (0.48 mmol) in THF was then added. A faint pink precipitate was obtained. After 5 minutes at -780, the reaction mixture was added 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% yield) 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 to the above isomer (isomer C) and had a melting point of 188.5-1a9 ° (ether-chloromethane>. The alcohol with lower Rf The value (0.030 g, 16%) (isomer B) was obtained as an oil, which crystallized with difficulty from hexane, m.p. 94 DEG-95 DEG. (cuzciz: vw. saoo (om. neo and others) (c-on (coola) maa-Ls (isx, m, _. = ° mar),, 4.2 (lx. 4. J-1.0. 4-a). 3.65 (1H, cæa1tr.enr_e fl i In: .se§d: stt, -l '). 3-3 (m, m, Ja ", trans-LS, J3ll_-5.5, H3). 3.15 (an, u, o-gga). 1.55 41a, tnnd' 1. ou-1 ') , 1.os (ax, a, Je.s, x-2 ') »Anal. Ekan. Fin: cu no s = c 12.02. X a.za, ü 1.13, s 7.a91FïHU¶2t = c 11.77, H 6.36, 2621 3 u 1.15, s 7.4: \.

B. Preparation of trans-3-acetyl-1-methoxymethyl-4-tritylthio- -azetidinone o Céi LDA: KN C93 N, -ÉEÉITTÉ 3 N 0 \ / ° \ 0 \ / 0 \ Lithium diisopropylamide was prepared under a nitrogen atmosphere at -780 on customary starting from 0.34 ml (2.4 mmol) 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 -780 0.53 g (6 mmol) of ethyl acetate were added in one portion and stirring was continued for 0.75 hours at -780. The reaction mixture was diluted with ether and washed with an ammonium chloride solution, water and brine, dried and concentrated. ... w .....-.....- .. _ ... sun-www ï-If '448 995 45 was obtained to obtain 0.7 g of an oil. Purification was accomplished by chromatography on 20 g of silica gel eluting with 2 increasing amounts of ether in benzene. The appropriate fractions E in question were concentrated to give the title compound as a colorless oil in an amount of 0.32 g (37%). 'nmr (cnc13> 6.1.7-es (isa. azomat.>, 4.es (ia, 4. a¿2, n-4). 4.s (zu, .. u-gg: -0). 3.9 (ik, a, J-2, n-ax. 1.22 (an. -. Ena), -1 I 2.0 ppm (sa, a, cx3) | 1: vmax. 1110. 1110 am. T C. Preparation of trans-3-acetyl-1- (t-butyldimethylsilyl) -4-tritylthio-2-azetidinone S.Mn§2. C93 '0 LDA cH, 1M skøa 3 \ / gkgu E tOàc' 3 in N 'Diisopropylthyllamide was prepared 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 mmol) in 8 ml of THF. A solution of 0.46 g (1 mmol) of 1- (t-butyldimethylsilyl) -4-trityltio-2-azetidinone in 8 ml of THF was added dropwise at -780. After stirring for 5 minutes, 1 ml of ethyl acetate was added in one portion and the mixture was stirred for 3 hours at 7878 ° .

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 a mixture. _.._-:.-.._ ~ -............. ~ __; 448 995 46. ...._......_...- ... s-q-.w-u-w-vq amount of 200 mg in total (40%) and with a melting point 122-4 °. 1: umax «17so, 1110 = m'1, * am = (coc13) 6- e-1.1 (isa, m, azumsç ..), 'i 4.a: (ia, a, J-2, x- 4). 3.38 (ln, a, J-2, u-3). 1.ao (ax, n, ena), 0.92 (9H, i, Bu 5.2 0.3 ppm (GH, I, C143).

D. Preparation of trans-1- (t-butyldimethylsilyl) -3-formyl--4-trityltio-2-azetidinone furnace-p ... ~ sC $ 3 H, í; 1 :: fi, sc®3 \. 0, (çg:) 2 _ s: (Cu3) 2 2-8 !! In a t-Bu nv- To a cooled (-7s °> solution of 0.34 ml (2.4 mmol) of diisopropylamine in 5 ml of tetrahydrofuran was added dropwise under nitrogen 1.6 ml of a 1.5 M solution of n -BuLi (2.4 mmol) After stirring for 0 minutes, a solution of 1.0 g (2.1 mmol) of 1- (t-butyldimethylsilyl) -4-trityltio-2-azetidinone was added dropwise over 5 minutes. 0.8 ml (9.9 mmol) of ethyl formate were added and the cooled solution was stirred for 10 minutes, the reaction mixture was washed successively with 5 ml of 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. 132-30; IR (CHCl3) : 1760, 1715 cm -1; lnmr (cnc13) á '= 9.0 (ln, d, J = 1.2s Hz), 7.30 δ (1sH, m), 4.7 (la, d, J = 1.sHz ), 3.5 ppm (ln, t, J = 1, s Hz).

NOTE: a) the diisopropylamine was distilled over CaH and stored ,,,,,,,,,. _ .. w -........... .- .448 995 47 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 then distilled over P 2 O 5.

ZCO3 and d) n-BuLi were titrated with 1N hydrochloric acid.

E. Preparation of 1- (t-butyldimethylsilyl) -3- (1'-hydroxy-1'-ethyl) -4-trityltio-2-azetidinones (4 isomers) OH. 5CÉ> 3 CÖJ 1) '3 I I u-au *' ”" "" "'N N \ Si /' \ si / tßu. (HQ) 2 \ (H0) 2 3.4 ml of a 1,6M solution of n-butyllithium (5.44 mmol) was added over 5 minutes to a solution of 0.847 ml (6.23 mmol) of diisopropylamine in 30 ml of THF, which was kept at -78 °. After 0.5 hours, 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 respectively in order of decreasing polarity).

Crystallization of the oily residue in ethyl acetate-pentane vn .. __... ... wñæf-ghM ... _ .. ..-__..- »w- '448 995 48 gave the isomers B and C as a white solids and left 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 -780, the relative proportions of A, B, C and D became 12.9%, 30.5%, 38.2% and 18.4%, respectively. . 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%, 30.1% 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 which in the following derives from compound A denotes "isomer A" and consists of 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. 7 in Melting point 152-30; * m (cvcla) 6- e.o-s.e usa, m, “cm-> .. 4.ao un, a, .z-s.s, x-n. 3.78 (la, m, H-1 '), 3.10 (la, da, J-5.5, J-10, R-3), 1.22 (35, 5, -J- fi- s, ena). 0.95 (en, a, m, 0.27 (sa, n, ana). _A_f¿ ;. Ber. För Cm fi nuozsx: c 71.52, n 1.4o, N 23: e, s saemFun fl etc mas, H 7-41, N 2.49. s p.19s.

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, 45) enantiomers. Compounds of the same configuration at C1, C3 'and C4 are designated "isomer B": Isomer C: This isomer exhibits trans stereochemistry at C. \ .. \., .... w »~ u 448 995 49 1: (cxcla) vmax» 1745 cm'1 (c-0): amp. lsa-sc, * amz (coola) 6 »1.60-1.1o (xsa. m. azomac. 1, 4.02 (la. a, .1-oa 14-4), 3. :: uauaa, .1-3. o, ao.e. as),: nas-mms mi. m. a-w, o.ee (nu, ca] a? - c-au), 0.16 (sa. 1, ena), 3- (34.

It is a racemate formed by the (1'S, 3S, 4R) and (1'R, 3R, 4S) enantiomers. Compounds with the same configuration at Cl.

C3 and CA are designated "isomer C". Melting point 134-60;, 'nmz (coclaz 6 «7.so- 7.10 (153. m; aroma: -.), 4.32 (lä. D. J-Lâ, Hed), 3.02 (1H, dd, J-2.'I. J-LB, H ~ 3), ILO-LS (1H, dq, J-2.7, .7-6, H * 1 '), 1.02 (BH, d , J-6, cua), 0.95 (95. 1, c-au), 0.27 (en, n, cH3): 1: (c fl cla) J.

Nim-xx 1735 cm. (CIO). _! Isomer D: This isomer exhibits cis stereochemistry at C3-C4. It is a racemate consisting of the (1'R, 3R, 4R) and (1'S, 3S, 4S) enantiomers. Compounds of the same configuration at C1, C3 and C4 are designated "isomer D". Melting point 171-2 °; '_ fw (cpcxa) 1 mao- e.so usa, m, .famn y, 4.10 (m. a, .1-4.s. a-ø). : (02 (m, 44).

J-4.5, J-0.5. H-3) «§.a9 (1H, dq, J-o.s, J-6.5, u-1 '), 1.0 (JH, a, J ~ 6.5. CH3). 0.97 (914, I, trim), 0.32 (SH, I, C143). §_N_a _] _._. Ber, for c3 ° a37uo2ssL = c 11.52, H 7.40; s 2.78, s s.as \ .fUIH * 2t = C 71-27.

H 1.43, N: .s1, s s.a1 \.

OH s šcø; BH _ 'Å g am, b) 3 g' Nxiq-'F-B fl 0 N \ si / t_au. 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 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. 119-121 °. (in exchange).

OH; CÖ3 - '. ¶; l§ 1 5c $ 3 ----- 4! NN Å: (oss) 2 μl (ma) z -Eu -Eu Ilomer B A suspension of 4.78 g (15 mmol) of cuprous iodide in 50 ml of ether was cooled to 0 DEG C. and treated under nitrogen with 26 ml of a 1.9 g 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. one was continued for 3 hours.

Stirring- The solution was warmed to -400 and carefully treated 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 crystallized from hot pentane in a yield of 1.6 g (65%) and with a melting point of 160 DEG-10 DEG. 43 "'.. .... ..... ~ _...... H“ Vf 448 995 51 ... n-ßw-a-wvea- .- 1: (cncla) vmaxi 1130 cm' 1, m: 4-05 (1H, I), 3.4 (1H, d, J-g fl z, 3.35. 3-55 KIK- ni, 1-6 (1H, -J, o.9 czza, dm (cncia) pp. 1. :: usa, I) O. 041 ppm (GH, I).

NOTE: a) tetrahydrofuran and ether were distilled over LAH, b) methyl lithium was titrated with 1N hydrochloric acid, c) copper (I) iodide was purified by continuous extraction with anhydrous tatrahydrofuran in a Soxhlet extractor É for 18 hours and then dried in vacuo in a vacuum desiccator (PZOS) for 18 hours. 0.1 ml (0.1 mmol) of methylmagnesium iodide was added dropwise to a cooled (00) and stirred solution of 25 mg (0.05 mmol) of trans- -1- (t-butyldimethylsilyl) -3-formyl-4- trityltio-2-azetidinone in 2 ml of 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 concentration of the organic extracts gave an oil which consisted of starting material and a small amount of a mixture of the two title trans compounds, with isomer B predominating. an-.

F. Preparation of (1'S, 3S, 4R and 1'R, 3R, 4S) -1- (t-butyldimethylsilyl) -3- (1'-trimethylsilyloxy-1'-ethyl) -4-trityltio-2- A -azetidinone (isomer C) 448 995 52 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%) and melting point 14g-60.

Uwe '(coola) 6. 7.10-7.60 (1521, m, aromat; 2, 4.30 (1H, (d, Jl.5, Hd), 2.2S-2.69 (1H, m, 3-3, H-J fl) , 0.82-l.07 (128, m, t-§u, HT), 0.27 (GH, I, ena). -O.1o (sa, s, -o-sucaah, 1: - (cacis) vw. 11: em * mo).

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) OH KZÛCH 3 54.3. SCIÖ: IN \ si (M 2 o N \ 5i / (Men. I ° 2 "* c-nu '5 t-Bu ~ About 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 mmol) (1'S, 3R, 4R and 1'R, 3S, 4S) -1- (t-butyldimethylsilyl) - (1'-hydroxy-1'-ethyl) -4-trityltio-2-azetidinone (isomer A) in 10 ml of THF, kept at -7 ° C. After stirring for 15 minutes, a solution was added dropwise. of 2 ml (24 mmol) of bromomethoxymethyl ether in 30 ml of THF The mixture was stirred for 1 hour at -780 and 2 hours at room temperature and poured into 200 ml of an ammonium chloride solution.Extraction with 3 x 200 ml of ethyl acetate, washing with brine , drying over sodium sulfate 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 to give 10.4 g of product (95%). ). ñ fl mr (cncla) 6: 7.1-7.5 (lsav m, .r ° m. =.), 4.41 (in, d. H-4). 4-23 (za, aaq. A-7, o-ån: -oz, 3.1-3.4 (za, m. R-3 from H-iv), 3.23 (ß fl. 1.0-CH3). 1.37 (33 , 4, gg, 5, g33), _ 0.97 (9H, n, Du), 0.25 ppm (GH, 21, cyl).

H. Preparation of (1'S, 3S, 4R and 1'R, 3R, 4S) -1- (t-butyldimethylsilyl) -3- (1'-formyloxy-1'-ethyl) -4-trityltio-2- azetidinone (isomer C) HO A solution of SO mg (0.1 mmol) 1'S, 3S, 4R and 1'R, 3R, 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 ml) of amphetylaminopyridine in 3 ml Dm 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. n fl mx ¿cDC13) 5, 1.30 (in, 1. cuo), 1.20-1.66 (LSE. m- = r ° m ° = -) «: Ao-me (mm um. 4.01 un. d, -1-2- HY- 3-22 m 'med "” ü ”1.19 (an. 4, Je.s, _a-2'>. 1.0 (au. =. = -B“> - ° -11 iö fl f "¿* '°“ 3) - 448 995 54 I. Preparation of (1'R, 3S, 4R and 1'S, 3R, 4S) -1 '(t-butyldimethylsilyl) -3-1'-acetoxy-1'-ethyl) -4-trityltio-2-azetidinone Kisomer B). on J * ST: Aâgt) / lçcc fi rf '1 :; _ / _EEZEF___ ”é * y .t. "\ E, / {\ ej-. - ~ un;. .....-.

A solution of 13.85 g (27.5 mmol) of 1'R, 3S, 4S and 1'S BR 45) -1- (t-butyldimethylsilyl) -3- (1'-hydroxy-1'-ethyl) ~ 4 - -trityltio-2-azetidinone in 75 ml of pyridine and SO ml of acetic anhydride (prepared at 0 DEG C.) was stirred for 40 minutes at room temperature. The reagent was evaporated (the last traces were azeotroped with toluene 3 times) to give ...-........ ._.-.....-......_ .. ...__............ »...... W) _ an almost white solid material. The crude product was crystallized from an ether-petroleum ether mixture to give the title compound in pure form (97.5%). 'm (cum: 6.

'Lea-Los usa, n, x aromt. J. 4.60 (1H, m -7-6, HU), 3.92 (1H, a. Jg, x-4), 3.55 (ln, da. A-2. J-2. H-3), 1.19 ( an, 1, caaco), o.9e (33, d, J-6, CH3), 0.88 (93, s, c-butyl), 0.12 (GH, I, 633); i: (enas) vmx, ms, mo m * (co) J. Preparation of 1- (t-butyldimethylsilyl) -3- (1'-paranitrobenzyldioxycarbonyl) -1'-ethyl) -LI-trityltio-Z- azetidinone. (4 isomers) 448 995 55 - - «--_-.._...-...._.... ...__- vn" 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 -780. After stirring for 15 minutes, 3.2 g (14.8 mmol) of paranitrobenzyl chloroformate in 20 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%; mp 118-90 (ether).

'Hmr (CDCIB) 6- a.:s-7 (msn, m, .roman _ /. 5.12 (zu, =, b-n; y1>, Äïoa (ia, a.

J-1.e, u-4). 4 - :. s (ia, aq, J-6.5, J-2. N-1 '), 2.10 (in. Ad, a-2, J-1.e. H-2). 1.2 (aa. A, Je.s, ena), 1.0 (sa,., Au), o.so _ s ppm (en, n, cash L: (cncia) vmx «1145 m * (c-on ggßer. fišr c3au42N2o6s1s. c se.a :, n, s.zo, u 4.io, s 4.e9.F \ nu¶et: c 66.90, H 6.26, N 4.11, S 5359.

"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'-paranitrobenzyldioxycarbonyl-1'-ethyl) -4-trityltio-2-azetidinone as a foam (95%). cnc13> 61 s.az-s.so <19u, m, aromqc.), s.1 un, -. bmsyn, tes-mao un, m. xm,: _91 un. a, .v-Ls. un, s.sa (m, aa, a-1.s, .rs.e. sin). 1.1 (an. d. C113). 0.1 (se. u; nu),. ° _2 ppm (GH, ,, C33 ), 1, (film) vmaxs 1755. 1740 em ~} co.

"Isomer A" "Isomer A" of 1- (t-butyldimethylsilyl-3- (1'-hydroxy-1'-ethyl) -4-tritylthio-2-azetidinone, which was treated in the manner described above , gave pure (isomer A) of 1- (t-butyldimethylsilyl-3- (1'-paranitrobenzyldioxycarbonyl-1'-ethyl) -4-triethylthio-2-azetidinone as an oil (95%). CDCl 3) δ: 8.3-6.7 (19H, m, aromatic), 4.95 (2H, ABq, benzyl), 4.5: (ln, p, J-1.5, J-7.5, u-1 {_. 4.31 (la, a , a-6. u-4), 3.32 (ln. aa, aa, J-1.5, H-3). 1.44 (ax, a, Js.s), o.9s (eu, 1.: sub '0 .: ppm (eu, 2., ena). n '"Isomer D" Similarly, "isomer D" of 1- (t-butyldimethylsilyl-3- (1'-hydroxy-1'-ethyl) - 4-trityltio-2-azetidinone pure "isomer D" of 1- (t-butyldimethylsilyl) -3- (1'-paranitrobenzyldioxycarbonyl-1'-ethyl) -4-trityltio-2-azetidinone (90%). Lumr (cnc13) δ = 8.3-6.7 <19H, m, aromat.), 5.20 (za, Asq, 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 (9H , s, t-su), 0.35 ppm (en, s, cH3); mp 13o-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 1SS, 3S, 4R and 1'R, 3R, 4S) -1- (t-butyldimethylsilyl) -3- (1'-methanesulfonyloxy-1'-ethyl) -4-trityltio--2 -azetidinone (isomer C) 1 OH I. .. OM / ïTSCdIB / | í __ (sc4> 3 N \\ .KN _ §§_§: 3) 2 0 \\ §§ (cn3) 2 t-Eu A solution of 2.0 g (4 mmol) l'S , 3S4R and 1'R, 3R, 4S) -1- (t-butyldimethylsilyl) -3- (1'-hydroxy-1'-ethyl) -4-trityltio-2-azetidinone (isomer C) in 80 ml of dichloromethane were treated at 50 with 0.99 g (8.6 mmol) of methanesulfonyl chloride and 0.87 g (8.6 mmol) of triethylanine. After stirring at this temperature for 1 hour under nitrogen, the solution was washed with brine, dried over magnesium sulfate and evaporated to dryness. After crystallization from ether-petroleum ether, 1.9 g (81.9%) of the mesylate, m.p. 120-1220, were obtained; lñmr (CDCl 3) 6: 7.l3-7.61 (1SH, m. nr ° maç.§,. 4-50 (1H. d, J-2. H-4). 3.6: (za, aq, J-6.5 , 2. a_l ') l 2096 slav då! J-zr 2: H "3J | 2:94 (JH: É | TíÉtaIlSulfOnYl), 1.32 (au, a, J-6.5, H-1- ;, 0.99 (sn , a, gl - = - sub ”o.ao ppm (eu, 1. si- (cx3),) 1 1; val *. 1146 (co), 1341, zzeo = m'1 L. Preparation of (l” R, 3S, 4R and 1'S, 3R, 4S) -1- (tubutyldimethylsilyl) -3- (1 "-methanesulfonyloxy-1'-ethyl) -4-trityltio--2-azetidinone (isomer B) OH II SO SCÖS scüg ... ï-.íy NN / '\ s¿ 0 \ ~ / .- Ö' SÅ * A solution of 5.03 g (10 mmol) (l'R, 3S, 4R and l'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 methylene chloride were stirred at 50 for 1 hour, then the solution was washed with brine, dried over magnesium sulfate and evaporated to give a residue which crystallized as a white solid. material by trituration in ether 5.40 g of product (93%) with melting point were obtained 1274310. lumx (cncla) 61 7.2o-7.6: glsa, m. Azomau. ~). 4.51 (ln. Ag, as.oe.z, H-1 '), 4.10 (IJ-I, d, J ~ 2.0, XÉI-d), 3.60 (IH, dä,' JS-Ü-ZIO, IlJ) , 2.03 (BH, I. -ena). f.o1 (an. a. J-6.2. a-2'J. 0.90 (sa,., e-au), 0.1: (en, f. -css), 1; vmlx | 1145 = m'1 ( co., 448 995 see M. Preparation of (1'S, 3S, 4R and 1'R, 3R, 4S) -3- (1'-p--bromobenzenesulfonyloxy-1'-ethyl) -1- (t-butyldimethylsilyl ) - -4-tritylthio-2-azetidinone (isomer C) ac§a. 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-azetidinone (isomer C) in 100 ml dry THF was cooled to -780 and treated with 2.38 ml (6 mmol) of 2.5 M butyllithium in hexane After 3-4 minutes, 1.53 g (6 mmol) of p-bromobenzenesulfonyl chloride dissolved in THF were added dropwise. 780 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%) of product, m.p. 142-44 °. ; »Hm (mig, ö, 1.69 (4u,., Hxaasensuliüonydi, 1.za-7.60 (xsn, m, nromaq), 4.59 (1fl._ a. J-1.a, n-4) , 3.se (in, aq, J-6.2, a-1 '), 2.99 (ln. dd, J-1-8. 2.0, a-3), 1.1a (sa, a, a-s.z, x ~ 2 '), 1.09 (en. E, c-au). 0.40u, - 0.38 (GH: 25; 'CI-lgh i! (CHCl 3) Vm-xl 1749 cm-1 (C43) -' rr ..., _,.-.......... ....- munnen-Vw !! ,,., ....- _. m.-. .....-.......... ...-m _-.-. L-- 448 995 59 ...__ .._--. W.- ~ .-- .. .w -... mv -... w-un N. Preparation of (l'S, 3R, 4R and 1'R, 3S, 4S) -3- (1'-methoxymethyl-1'-ethyl) -4-trityltio-2-azetidinone (isomer A) FUN 4 - 3 'o \ s¿ * m: “Na tïlu in A cold (Oo) solution of 11 g (20 mmol) of isomer A of 1- (t- -butyldimethylsilyh -3- (1'-methoxymethyl- 1'-ethyl) -4-trityltio--2-azetidinone in 16 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, then poured into 1 g of 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, m.p. 173-1740. (cocia) 61 1.m-1.

(ISK, n. Aromat- H 4.85 (1H, ABq, 3-74, Q-CHI-O). 4.53 (1H, d, .1-s.2, 11-4), 4.42 (ux, u, rie -u) 4.15 (in, m, ur). 3.5 (in, m, 11-3), 3.41 (an, e, o-caa). 1.5 (an. a, 21-6, m3). i: man vmx: 3400-3500 (u-zn, iveo an * (co). .- O. Preparation of (1'S, 3S, 4R and 1'R, 3R, 4S) -3- (1'-methoxy-methyloxy- l '-ethyl) -flitrityltio-Z-azetidinone (isomer C) 1 Qçgzoçgz I. OCNZOCH: J: ST: Ja, Tr J. "ST * azcx ocn" NaN "2 s, ._...__ 2._. A cold (dry ice-acetone bath) solution of 5.03 g (10 mmol) (1'S, 3S, 4R and 1'R). , 3R, 48) -1- (t-butyldimethylsilyl) -3- (1'-hydroxy-1'-ethyl) -4-trityltio-2-azetidinone in 50 ml of THF (distilled LAH) was treated dropwise with 13.0 20 ml of a 1,6 M 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 -78 ° for 30 minutes and at 0 DEG C. for 3 hours, poured into an ice-cold ammonium 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%) (1'S, 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 described below.

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 mmol) 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 dried over magnesium sulfate to give 3.0 g (69.3%) of the title compound, m.p. 172-17z, s ° (ethyl acetate-hexane). ir (CHCl 3) vmax = 2490 (ux> J ivao cm -1 (c-ø;, * um: x «r ° ma¿.); = 4.63 (zu, cxa1tr.aJ $ nq, Ja, o-ca: -0). 4.49 (la, |. Nn). 14.40 (in. 4, J-3, n-4>, 4.: §-3.90 (la, m, a-1 '). 3.35-1.15': .2s (43. n + m, caaß í H-sä, 1.30 ppm (an, a, J-6, caa) a -4 44ag99s 61 .... ....-,., ...- ~ ...- -.... ~. ~. -.-.-__.-_ H P. Preparation of (l'R, 3S, 4R and l¿S, 3R, 4S) -3- (l ' -formyl-oxy-1'-ethyl) -4-tritylthio-2-azetidinone (isomer B) osozez and oxo CO 3 «scos N / '° \ $ ï fi- _ ° \ x A 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 3 ml DMF The reaction mixture was then diluted with brine for 48 hours and then at 1000 for 4 hours. The reaction mixture was then diluted with water and extracted with ether. The ether extracts were washed with brine, dried over magnesium sulfate and evaporated to give the title compound as white crystals after purification by column chromatography. (silica gel, s \ cncwæx¿u2) s * uni (anal) 6. a.ov (L u. 1, cxo), 5.24-1.ss (isu, m, a = ° m @ =.>. S.2a (in, aq. J-6.4. 7, H-1 ';, 4.aa (ln, dm J-2.4. H-4) 4.25 (1H, 1.un), 3.29 (in, aa, J-1, 2.4, R-3), 1.43 (BH, d, J-6.4. R-2 ' ): ir 2 (anal) vmax- a4oo (ua) .zves (co), 1125 = a ° 1 Q Preparation of (1'RL3S, 4R and 1'S, 3R, 4S) ~ 3- (1'-acetoxy- - 1'-ethyl) -4-trityltio-2-azetidinone (isomer B) QAC ... OOC 448 995 6 2 'å, 77 g (10.57 mmol) 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 HMPt and ml water, the solution was cooled to room temperature and 1 .2 g of NaN3 were 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 (twice) and brine, and dried over magnesium sulfate.

Evaporation of the solvent gave a foam which crystallized from ether-petroleum ether to give 4.90 g of product (96%), m.p. 143-144 ° C. .. “1 1 1; (cn2c12) vmax | 3395 (N nä, 1772, 1738 cm (C-0). Nmr (cncza) 6 1 1.9-ae (isa, m. H .r ° ma: f), 5.12 (1u, cea1tJnnn aurékgp-es, 7.s , H-IW- 4-22 (1H- d. -1-2-8, HM. Mao (m, hu. W-zn, 3.11 (m. Add, F J3_1.-7.5. J3_4-2.8. J3_NK- 1. nJ). 2.1 (ax,., Casco), 1.35 (33, ¿, J-6.5, C33).

R. Preparation of 3- (1'-hydroxy-1'-ethyl) -4-trityltio-2-azetidinone. Mixture of four isomers) OAc. or ¿. “SC scó D m CH- 3“ __ "= --_" * ° - pyridin 'N cd cho _ _, o * sncn) 3 \ ** c: \ “33 I §L + si-cl °°; DM? -N (a =) 3% A solution of 0.74 mmol of lithium diisopropylamide and 1 was prepared at -78 ° in 5 ml of dry tetrahydrofuran starting from 0.103 ml (0.74 mmol) of diisopropylamine and 29 ml of a 2.52M solution 448 995 63 .M -... o fl ma -... n-.a ... um-Many ning of BuLi in hexane. After 30 minutes at -780, 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 -780, 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 sulfate, 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 mixture. This mixture (lñmr) could not be separated by either high pressure liquid chromatography or thin layer chromatography. az 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 0.11 g (0.34 mmol) of the alcohol mixture was treated with 0.117 g (0.776 mmol) of t-butyldimethylchlorosilane and 0.1 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 V of an oil, which contained four components when analyzed by § »y. 448 995 64 ... www »w -... m- 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 determined) 4.

NOTE Butbutyllithium and lithium hexamethyldisilazane were ineffective in order of increasing polarity acetylation of the product obtained from 1-t-butyldimethylsilyl-4-trityltio-2-azetidinone were the following proportions: 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%: d = 4.6%.

S. Preparation of 1'R, 3S, 4R and 1'S, 3R, 4S) -3- (1'-benzoxy-1'-ethyl) -4-trityltio-2-azetidinone (isomer B) H50 Qccc. fl. 55473 - scó3 ~ _ o “feg Q N \ ¶ J.

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 mmol) of sodium benzoate in 10 ml of 10% H 2 O-DMF were heated for 7.5 hours at 900. Then the reaction mixture was diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, magnesium sulfate and evaporated. dried over the residue, which was purified by column chromatography (silica gel, 5 g CH 3 CN_CH 2 Cl 2) to give the title compound as a white solid in an amount of 108 mg (23.2%), m.p. 448 995 ... m 1 .., ........ ___-_ .. .m -... a- »auygw 'Hmz (cnc13) 6: 7.0: -a.2s (zon. M , granar. J, s.a2 (xx, .g. dq, J-6.1, 9, H-1 '), 4.40 (IK, d, J-2,5, Å-Q' 4_3Q (m, h 193 ) '3-40 (U fl lååf 3-9, 2.5, 3-3), 1,50 (33, d, J-5,1, g-yhíx- (c fl cla) vmlxf 2400 (NH). 17ss (co), 1715 = m'1 (C-O), T. Preparation of 3- (1'-paranitrobenzyldioxycarbonyl-1'-1-ethyl) -4-trityltio-2-azetidinone (4 isomers) VE 0 PNB 'or PNB 2.

SCÖ3 2 sea: N 'ñ \ s./M°2 N \ H tBu E "isomer C" a) A solution of 1,3 of "isomer C" of 1- (t-butyldimethylsilyl) -3- (1 Paranitrobenzyldioxycarbonyl-1'-ethyl-4-trityltio-2-azetidinone in a mixture of 5 ml of TFA, 5 ml of water, 20 ml of dichloromethane and 30 ml of methanol was stirred for 2 days at room temperature, the solution was diluted with water and the aqueous phase 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. 78-800.

Igmr (CDCl 3) z 8.25-6.7S (ISK, m, aroma: n: 5.21 (23, 1, belitsyl), ia -05 (IK, m, K "1 '), 4-40 (IR, 8, NH), 4.27 (1H, å, Jl2.a, H-Å), 3.17 (ln, dd. J-5.:. 2.8, a-3: Cx fi, 1.37 ppm (ga. A, Js.s, cua ), 1: (cuc13) \ ¿_x «aa9o (NH). 1765 çx fl1174 s üamuüàpaj (co and 'Lszs and (NO2). 448 995 66 b) A cold (09) solution of 9.11 g (l3.3 mmol ) of "isomer C" of 1- (t-butyldimethylsilyl) -3- (1'-paranitrobenzyldioxycarboxyl-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 atidide, 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, since the title compound precipitated on dilution with water, it could alternatively be filtered off and recrystallized from ether, the product was obtained in an amount of 7.22. g (89%) with a melting point of 78-800.

"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 a melting point of 155.5-1560 (ether). v-. (cocia) 6: 6.2S-_6.B0 (193, m, nzomatw.), 5.20 (ZH, u, bcnsyl), 4.95 (la, m, x-1 '), 4.35 (ln , 4, J-2.9, H-4). 4.11 (zu, 1. N-H), 3.20 (la, aa, J-1o.e, a-2.9, H-J) - 1.40 pp; (su, a, J-1.5, cnalx 1: acucis) vmlx. a4ao, asso (N-a), 1112, ivso (c-o). . iszs cm ° 1 Knoziflumal. Iër fi iïir: caznzsuzoösz c 61.59, H 4.96, N 4.93. s s.e4; Éï fl u fl štc 67.49. a 4.sa, N 4.92, š s.ev.

"Isomer A" "Isomer A" of 3- (1'-paranitrobenzyldioxycarbonyl-1'-ethyl) -4-trityltio-2-azetidinone was prepared as described above for "isomer C". A product was obtained, m.p. -2os °. '-v- _... ._i, = ----- ï. * umx (cnc13> 61 e.2-6.1 (193, m, azomat. \, 5.22 (25, ABq, bannyl), S.57-4.95 (ll-x, m, H-IU), 4.65 (in, NH), 4.so (in, a. Js.s, x-45, a.es (in, aa, J-6.5. 12, aN _ “- 1, n-2), - 1.s: ppm ( au, 4, a ~ vn).., me., 448 995 67 "Isomer D". ..._ ..- mA-nun "Isomer D" of 3- (1'-paranitrobenzyldioxycarbonyl-1'-ethyl) ~ -4-trityltio-2-azetidinone was prepared as described above for "isomer C" u 'umx (cool) 61 e.1s-s.1o (len, m, chromau. F). S.:a (za, Aaq , b fi nsylz. s.zo (in. m. H-1 ';, 4.1s (ln. NH). 4-52 (ia. 4. Js.s. xg), _ a.4: (in, as.s , 3. xa, ^ 1.s ppm (BH. A, a-ms.m5). (The value of H-3 determined after D 'ubtyte). "Ñæmsü fl lnüg of U. (lWL3S, 4R and l'- S, 3R, 4S) -3- (1'-methanesulfonyloxy-1'-ethyl) -4-tritylthio-2-azetidinone (isomer B) zg '0 G- u: ï fi í O u .w A solution of 4, 95 g (8.5 mmol) 1'R, 3S, 4R and 1'S, 3R, 4S) -1- (t-butyldimethylsilyl) -3- (1'-methanesulfonyloxy-1'-ethyl) -4--tritylthio 2-azetidinone (isomer B) and 1.1 g (7.0 mmol) of sodium azide in 50 ml of 10% H 2 O-HMPA were stirred for 30 minutes at room temperature. r. The solution was then diluted with 250 ml of water and extracted with ether. The organic extracts were washed with brine, dried over magnesium sulfate and evaporated. Crystallization of the residue (ether-petroleum ether) gave 3.33 g (83.8%) of the title compound, m.p. 130-131 °. '' 2 Hmm (CDCIB) å: 7.20-7.62 (ISH, m, Aromat-) _ | 4.97 (1H: dCl: CWG-α: 5-1: HP), 4.56 (UU d, 312.8, TV4), 4.22 (1H, m, N-FU; 3-27 (1H, then, WIS-1. 2.8 , PPI), 3-0 (331 I, -CHSUI 1.63 (JH, d, 316.4, FPZÜJ ir (nujolz vmax-: las (nH). Zvsa cm'l (co). 448 995 68 V. Preparation of (l'S , 3S, 4R and 1'R, 3R, 4S) -3- (1'-methanesulfonyloxy-1'-ethyl) 4-trityltio-2-azetidinone (isomer C) OHS SCO ° N \ * Fi (ca3) 2 t-Bu A solution of 2.85 g (4.9 mmol) (1'S, 3S, 4R and 1'R, 3R, 4S) - 1- (t-butyldimethylsilyl) -3- (1'-methanesulfonyloxy-1 Ethyl) -4-trityltio-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 250. By diluting the solution with 250 ml of water, the reaction product was forced to precipitate, the mecylate crude product was redissolved in dichloromethane, washed with brine, dried over magnesium sulphate and evaporated.Trituration in ether gave 1.80 g of the title compound as white crystals with melting point 155 DEG-60 DEG C. b / llmt (CbCl2) 61 7.43 (1SH, m, n-'zoxnnt- I, 5.02 (III, dq. J-IL9, 4.9. H-1 '), f.ss (1n. 1, N-H). 4.95 (la, a, J-3, u ~ 4). 3.33 (ln, ad, a-4.9, a, u-za, É.s1 (aa. A, as.s, x-z ') | 1: vmax »: ass (N-am. Ivsa = m'1 (co>: ¿¿¿.Ber- íïäf c wa no s. c 64.22. a s.s9, u: .oo, fï fl “* 2 t-c ea.ss. H 5.39, 25 4 N 3'24 \ ¶ W. Preparation of (1'S, 3S, 4R and 1'R, 3R, 4S) -3- (1'-p-bromo-benzenesulfonyloxy-1'-ethyl) -4-tritylthio-2-azetidinone (isomer C) OSOIQBL 'Qsozéßr SC $ JC $ 3. I ----- »N / u' 0 N ~ \ H 448 995 A solution of 1,42 g (2 mmol) (1'S, 3S, 4R and l'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 sulphate and evaporated. in the form of a crystalline crude product was triturated in a small volume of ether and recovered by filtration in an amount of 0.92 g (77%) with the melting point 125-260.

'"' 'Knut (CDCIB) ö: 7.80 (43, n, bonlsenënulfonyl), 1.30-1} ss <1sa, m, ¿= ° ma; .Ä o, s.is (in, aq, Je.s, 4.0, x-1 '), 4.so (in, a, J-2.9, a-4), 4:40 (ia,., U ~ a) 3.40 (ia. Aa. A-4.0. 2.9. a-aa. _ '-1 1.so (ax, a, Ja.s, H-2'); 1: (C-OJ.

X. Preparation of (1'R, 3S, 4R and 1'S, 3R, 4S) [3- (1'-hydroxy-1'-ethyl) -4-trityltio-2-azetidinone (isomer B) 4 OSD 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 with 1 ml of water. The reaction mixture was kept at 900 for hours, then diluted with ether and washed 4 times with brine. The organic solution was dried over magnesium sulphate 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 with a melting point of 187-189 ° 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 H H scc. Both isomers, namely (1'S, 3S, 4R and 1'R, 3R, 4S) -3- - (1'-hydroxy-1 '). -ethyl) -4-tritylthio2-azetidinone (isomer C) and (1'R, 3s, 4R and 1s, 3R, 4s) β- (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 mmol) (1'S, 3S, 4R and 1'R, 3R, 4S) -1- (t-butyldimethylsilyl) was stirred. 3- - (1'-hydroxy-1'-ethyl) -4-trityltio-2-azetidinone (isomer C) and 0.865 g (6 mmol) of sodium benzoate in 40 ml of a 10% aqueous solution of DMF at room temperature below 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 as a crude product was crystallized from cold ether to give 0.47 g (61%), m.p. 134-350.

* Hm (cocxs) a. Mz-mse usa. m. aroma »a. 4.48 (in, -, NH), 4.2a (15, d, J-2.a, H * 4), 2.94 (1H. dq, J-6-5. 6-2. no. ),: Los (m, aa. A-az, ze, x-az. 2.18 un. N. -Orm 1-30 -1 (an, <1, ages, uz-nn- (anala) vmx:: wo (n-zn. 1160 m << = - °> - 6. n H 448 995 In the same way the compound (1'R, 3S, 4R and 1'S, 3R, 4SY- -1- (t-butyldimethylsily1) -3 - (1'-hydroxy-1'-ethyl) -4-tritylthio-z-azetidinone (isomer B), mp 190 DEG-92 DEG C. * amrococa) 6: 7.10-7.55 (isa. M, azamac .), 4.45 (ia, 4, Jz.s, a-4). Ä.2a (zu, n, uu). 4.10 (ia, aq, J-6.4, sa, a-1 '), so§ ( ln, da, J-5.3, 2.5. HJ). 1.50 (ia, 1, -on), _1.ao can. 4. as.4, a-2 °> »¿:, (cac13) vm_x.: acc cu-u). iveo = '' 1 (CO) 'Z. Preparation of (1'S, 3R, 4R and 1'R, 3S, 4S) -3- (1'-methoxy-methyl-1'-ethyl) - 1- (Paranitrobenzyl-2 '' -hydroxy-2H-acetate) -4-tritylthio-2-azetidinone (isomer A) r AND AND 2 3 oczoculphs iii ii: Dm _ N \ 5 l YO "COZPNB En mixture of 7.5 g (17.3 mmol) of isomer A of 3- (1'-methoxymethyl-1'-ethyl) -4-trityltio-2-azetidinone, 4.7 g (20.8 mmol) of paranitrobenzyl glyoxylate -hydrate and 300 ml of toluene were refluxed for 1 hour in a Dean Stark apparatus filled with 3Å molecular sieves. The solution was cooled in ice and 0.24 ml (1.7 mmol) of triethylamine was added dropwise. The mixture was stirred for 1 hour, washed with saturated 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%). 448 995 72 * mm (CDCIB) δ: 8.2S 6. 6.84 (1914, m, aromac.), 5.24 (1H, n, benzyl), 4.57- 4.83 (JH, m, 0-CH 2, α-4 ), 4.34-4.55 (ln, m, u-2 "). 4.02 (la. M, u-i '), 3.54 (1H, .m,' 11-3), 3.40 (Ja, a, G-Cfis ), 1.38 (an, d. Je.5, ma), ir (Kax) Vmax '3360 (OH). I710' (arom-st. - :).

AA. Preparation of (1'S, 3S, 4R and 1'R, 3R, 4S) -3 - (1'-methoxy-methoxy-1'-ethyl) -1- (paranitrobenzyl-2 "-hydroxy-2" -acetate) - -4-trityltio-2-azetidinone (isomer C) 3 _ ç fi o ST: / J ST: co PNB / Jílïïïí ”___..---- + OH æ fi 2 0 _ are _ A solution of 1.73 g (7 11 μl) hydrated paranitrobenzyl glyoxylate was refluxed for 2 hours in 90 ml of toluene using a Dean Stark condenser filled with 3Å molecular sieves. To the boiling solution was added 3.0 g (6.93 mmol) (1'S, 3S, #R 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 mmol) of triethylamine were added and the mixture was stirred for 2 hours. The reaction mixture was diluted with ether, washed with a 1% aqueous solution of HCl, water, a 1% aqueous solution of NaHCO 3, water and brine, dried over magnesium sulfate and concentrated to give 4.60 g (100 g). %) of the title compound.f '-1 n, 448 995' I J3 E: (anal) vmax | as: o-3100 (0-H). 1765. 1150 tc-0), 151525 cm -1 (NO 2), * ant (CQCl 3) 61 a.22, 8.18 (za, za, Ja, Hm aromat-). 7.67-7.0 (17H, m, n- aromac. 7, .3 (za, ba. ca: -PNB), 5.30-s.o2 (m, -H-2 "). 4.89-4.52 ån, n-1 ',. on), 4.63, 4.59 ( ln. Id. J-2. H-4), 4.33, 4.30 (za, 2 center -1 2 Asq. J-7, J-7. 0 ~ cH2-o), 4.1 ~ 3.67 (la. m. H -1 '), 3.2 (1H, H-3), q.1, 3.6 (3u, .2n, CH3-01. - 1.15 ppm (an. D. Ja.s, ena).

BB. Preparation of (1'R, 3S, 4R and 1S, 3R, 4S) -3- (1'-acetoxy-1'-ethyl) -1- (paranitrobenzyl-2 "-hydroxy-2" -acetate) 4- trityltio-2-azetidinone Ohc 'AC ¿J ". ST: HO n Äï ST:.' 2, N 753 N OH COzPNß" Isomer B "A solution of 1.82 g (30 mol) of hydrated p-nitrobenzyl glyoxylate ( triturated with ether) was refluxed for 2 hours in benzene through a Dean-Stark condenser filled with 3Å molecular sieves, then 10.88 g (25.2 mmol) (1'R, 3S, 4R and 1'S, 3R were added , 4S) -3- (1'-acetoxy-1'-ethyl) -4-trityltio-2-acetidinone and the mixture was refluxed for a further 1 hour The solution was cooled to room temperature and 0.35 ml (2.5 mmol) The mixture was stirred for 2 hours, the reaction followed by thin layer chromatography. Evaporation of the solvent gave a white foam in quantitative yield (100%, the mixture of epimers). bas. ir (cnaczzß vmax = 3520 (ou). 1775. 1745 = a'l ñc-0); * amr (cocisz ¿= e. g. a.1a (zu, za, Ja. ua azomt. -), 7.8G-6.90 (1721, m, Ii-aromacåz), 5.28, 5.17 (1H, 24, GHz-PNB, Ä.aa (o.s7a, 6. J-7.2, cno), Ä.B0 (cancer f m. H-1'J. 4.30 (o.33 u, za, Ja.a.'cao>. 4.22 g.1, u-qi.: .ss (n.s7n. aa, a3_l, -sa,: 3_4-2-1. H-3;. 3.47 (o.3åx, aa, z3_1, -515 J3_4-2.5. u-3). 3.33 (o .33n. A, as.e, pa). 3.23 (o.e7u. A. J-7.5. Ou), 1.as¿ 1.se (sa, 2 :, caacn), 1.10, 1.06 (su. Za Preparation of 3- (1'-paranitrobenzyldioxycarbonyl-1'-ethyl) -1- (paranitrobenzyl-2 '-hydroxy-2h-acetate) 4--trityltio-2-azetidinone (4 isomers) ocozvna. _ Vw 'PNB SKÖJ "\ scéfi \"' ° NY "'ovm" Isomer C "A mixture of 1.70 g (0.3 mmol) of" isomer C "of 3- (1' paranitrobenzyldioxycarbonyl-1'-ethyl) -4-trityltio-2-azetidinone, 815 mg (3.6 mmol) of paranitrobenzyl glyoxylate hydrate and 50 ml of toluene were refluxed for 7 days in a Dean-Stark apparatus filled with 3 Å molecular sieves. The cooled solution was washed with hydrochloric acid, sodium bicarbonate and brine, dried and concentrated to give 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 (cvczs) <5- a.2s-a.ao ma, m. Other.->, s.:o, _ :. 1z (m, 2 :, 'benzyl J,: ms un, a, as, um, 4.45 (in, a, _g-2.5. U-4), 4.45-4.10 (ia, m. A-1 '), a.so (in, a. A -9, 2 "-ox), 3.29 (LH, aa, Jz.s, J-2.5, a-3).,: 1.2: ppm (au, d. J-6.5, caaa, 1: (cucia) vmax = asso eo azoo (D-az. ivss, ivso (c-os, iszs = m'1. (NO2) .I4er jggl. iscrmsr v. (E-2 ": 'Hm; (cncia) 5. a.2s -a.as azama =.). s.:s, s.oe (ax, za. ben fl yirå, s.os (in, a, J-1, a-2 "), 4.25 (ln, a. J- 2.5. X-4), 4.40-4.os (ia, m. A-1 '), 3.42 (in, a ~ 1, 2 "-ån), 3.33 (ln, da, J-2.5, 2.s , H-3). 1. :: (au, a, as.s, taga: 1: ccucia). <1.

Vmaxx 3520 to 3200 (O-H), 1755 (C10) /. 15725 cm (NO 2) "Isomer B" A mixture of 1.74 g (7.66 mmol) of hydrated paranitrobenzyl glyoxylate and 3.63 g (6.38 mmol) (1'R, 3S, 4R and 1'S, 3R, 4S) -3- (1'-Paranitrobenzyldioxycarbonyl-1'-ethyl) -4-triethylthio-2-azetidinone was 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 .02 g (100%) of the title pure compound. Separation of the two epimers was accomplished on a preparative silica gel plate. .n 448 995 76 'Minor polar epimer at C-2 ": ir (CHCl 3) vmax fl 3500 (OH). 1772. 1750 (cO) 1525 mfl (uozn * mr (00613)« S «e.3 <_J-ao -, 'Les-mao, (235, m, amma ...), 5.27,. 5.1.3 (43, 2 :, benzylr), 4.71 (1H, m; .1-es, 6.5, 14-11) , 4.2a (m, a, .1-2.2, x-4), 4.23 (ln. A. J-en, a-2 “). 3.sø_ (1z-z, aa, J-Lz, e. _s.1-1-3), 2.23 (11-1, a, a-aJ, oH), 1.18 ppm (an, a. as.s, cxanMer mlggxner: L: (cucls) vmax: s4ao (oa) 1172 , nso (co) ~, - .. zszs affluæozr. * rgnr (cncla) 6- sas-saa (nu. m, axon-gu; d, 5.15 (an, bannyl 1. 4.72 (ln. a, J-7 .s, a-2 "0) .4.90- 4.50 (m, m, Js.5, 6.5, fl- r), 4.10 (m, a, Jz, u-4). 3.62: (m. dm -2 , ehsfn-a), 3.22; (13, a, Je.s, ox), _ ~ 1.15 ppm (BH: d 'J "6'5' C fl a).

"Isdner A" - (in "Isana" A "of 3- (1 '- @ anitrobansylcycycarbonyl-1'-ethyl) -4-tritylthio-Z-azetidinone similarly gave a mixture of" isomer A "of 3 - (1'- -pataritrobenzyldioxilzarbonyl-1'-ethyl) -1- (paranitoxynberxyl-Z "-hydroxy--2" -acetate) -fl-trityltio-Z-azetidiaxones .m (cc-clan ö »(aa- ex: (nu. m, .romae- 5.17 (zu. bGHSYJ-e-Ü: so (m, m. x-qs. 4.9 601144; (m. za. Js. fl- mfvå ePï-Tfšfef fl (J: óchass (m. 2 :. H-rufïvå ePïm-Xf a-se (m. aa. -re. s, x-: uæh-Ln pga (ag, za. J-ehs, caa. two epímefer) - "Isomer D "Isomer D" of 3- (1'-paranitrobenzyldioxycarbonyl-1'-ethyl) -4-trityltio-Z-azetidinone also gave a mixture of "isomer D" of 3- (1'-paranitrobenzyldioxycarbonyl-1'-ethyl). '-ethyl) -1- (paranitrobenzyl-2 "-hydroxy-2" -acetate) -4-tritylthio-2-acetidinones .m (encia) <5 »a.so-s. so ma, m. Äzomau.), s.2o un; m, bangyl J. 4.93 (in. za, Js, H-4), s.so-4.30 (za, m, H-1 'H-2 " 3.48 l (1H, E, HJ), 3.15 (1H, m, OH), 1.37 in 1.30 ppm (JH, C53) - DD. Preparation of (1'S, 3 S, 4R and 1'R, 3R, 4S) -3- (1'-methanesulfonyloxy-1'-ethyl) -1- (garanitrobenzyl-2 "-hydroxy-2" -acetacin-4-trityltio-2- azetidinone (isomer C) (epimers at C11). n A solution of 10.72 g (42.6 mmol) of paranitrobenzyl glyoxylate hydrate in 350 ml of benzene was refluxed for 2 hours, azeotropically removing the water 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. The reaction mixture was then 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. * nmr (cnc13) 61 a.12 (zu, a, J-9. nn aromacf), 1.28 (ma, doJ. av 4,140 arenan., crityl), 5.28 (za, u, -cnzí ana), 4.89 (os n. 5, n-1 "), 4.62 (1.sn. n. a-2",. H-4), 4.oo (2H. m. H-l '. -on), 3.15 (in. m, n-3). 2.1: (sn, s, mesyxat), 1 1.30 ppm (an, a, ans nn, H-Ph i: vuuxxsszo 'xo-n), 1775 (co) 1 ,: 1765: mfl (c-OL 448 995 78 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) is called '_.' Oc oc zocxxa ÄD / 3 _ x scça ox * rv 0 'Cl \ :: P' 4 ~ 2 Na cozine 1.1 ml (14.2 mmol) 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-tritylthio-2-azetidinone in 350 ml of THF cooled to -150. 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 -150. 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. * amz (cocls) 6, s.es-a.as <19H. m, aromacfn 1. 5.24 (zu, n, bqnsyl), 3.43 (aa,;, qcxa), 1-42 ppm (ax, a, J-s, cxa).

FF.

Preparation of 1'S, 3S, 4R and 1'R, 3R, 4S) 3- (1'-ethoxymethyloxy-1'-ethyl) -1- (paranitrobenzyl 2 "-chloro-2" -acetate) -4-tri - tylthio-2-azetidinone (isomer C) name i 2 3 ocuzocna sr: / JN .. STI: g sauz, _ _ ---______._ y \ TÄm - C OIPNB Cl C O2PNB -v- 448 995 79 En kyld (is-MeOH-bath) solution of 4.25 g (6.662 mmol) (1'S, 3S, 4R and 1'R, 3R, 4S) 3- (1'-methoxymethyloxy-1'-ethyl) -1-paranitro- benzyl 2 "-hydroxy-2" -acetate) -4-triphylthio-2-azetidinone in 60 ml of THF (distilled over LAH) was treated dropwise with 0.696 ml (8.6l mmol) of pyridine and 0.530 ml (8.6l mmol) of thio - nvlchloride. The mixture was stirred for 30 minutes at -150. 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 4.36 g (100%). '1 mon: hm: 11: (cxcia) v¿ax = 1770 (co), iszs cm' (CDCl 3) 5: 8.1.5, 8.12 (211, 2d, H-azomat- I, 7.70-7.00 (1714, m, H-aromat- h s.s2, s.oz <1a, zs, x-2 ~>, s.z1 (an, 0, ca: -Pas), 4.1 (in, a, afqn, 4.1-3.1 (m, o-ex: -o, x-1 ~), as-za (m, n-aa, 1.12,: .oe (aa, za, o-ena). 1-30-0-96 PPN ( BH, m, C33).

GG. Preparation of (1'R, 3S, 4R and 1'S, 3R, 4S) -3- (1'-acetoxy-1'-ethyl) -1- (paranitrobenzyl-2 "-chloro-2" -acetate) - 4- trityltio-2-azetidinone. i AC í-, s * TI - socl? i .. STI O _ \ 1J, 9H ryrxain * T - 0 J: 1 cl cozvna ~ \ ï3; pNB "Isomer B" A solution of (1'R, 3S, 4R and 1'S, 3R, 4S) -3- (1'-acetoxy-1'-ethyl) -1- (paranitrobenzyl-2 "-hydroxy-2" -acetate) -4-trityl-thio-2-azetidinone (from 10.88 g of NH) in THF (distilled over LAH) 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 The mixture was stirred for minutes at -1 °, 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. filtered through a pad of celite and evaporation of the solvent gave a foam ir (CH 2 Cl 2) vmax = lvao, 1140 tm'l (co) 'umr (cncla 6: 8.17, 6.21 (ZH, Id, JB, Ho arpnxatš ä 7.76- 6.B8 (173, m, H-aromat ”. 3, s.al, szls, s.l2, 4.1: (sa, 4e¿ ca: -PNB, cucl), s.lz-4.ss (ln, m. H-1 '), 4.35-4.25 (ln, m, u-al, 3.80-3.45 (luv m, H-: J 1.90 (an, -. cxaco), 1.12 1.07 (3H, _J ~ 6.5, C53 ) .

HH. Preparation of 3- (1'-paranitrobenzyldioxycarbonyl-1'-ethyl) -1- (paranitrobenzyl-2 "-chloro-2" -acetate) -4-tritylthio-2-azetidinones (mixture of epimers at C2 ") OCOZPNB 0 PNB æo 2 s '' scwa 0 Y NY Cl 0 PNB QZPNE "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 ") in ls ml of THF cooled to -1 °. immediately thereafter, 86.5 mg (0.73 mmol) was added dropwise and the mixture was stirred for 0.5 hours at -150. 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 the title compound as an oil in an amount of 530 mg (100%). 1 mr (CDCl 3) δ 8.7-6.8 (233, m, aromat.!); 5.53 (1H, 1, H-2 "), 5.30, 5.17 (45, 29, benzyl), 4.52 (1H, d, J-2, H-4), 4.20-3.70 (1H, m, H-1 '), 3.31 (1H, dd, H-3), 1.27 -¿ .1.21 ppm (3H, Zd, J-6.5) | L! (CHCl 3) -1 vmax. Ivao, ivso "Isomer B" "Isomer B" of 3- (1-paranitrobenzyldioxycarbonyl-1'-ethyl) -, 1 '(Paranitrobenzyl) -2 "-chloro-2" -acetate-4-trityltio-2-: E -azetidinones (mixture of C-2 "-pimers ) was prepared in the same manner as described above for "isomer C" in quantitative yield. * xmz (anal) ¿¿a.zs-6.90 (aan, m, aromat.), 5.40-5.0 (43, m, benxyl.), 5.40-4.45 (1H; m, Hf1 '), 4.82 4.57 (xx, za, x-2 "), 4.36, 4.31 (ln. za, J-2.5. n-4). 3.63 (in, m. J-2.5, Js.s, x-3), 1.zs, 1.1a ppm (ax,: a, _J-ss, cua), ir (caciai max. iyao, lvso mc-o), 1szs cm'1 (non).

Isomer A "Isomer Å" of 3- (1'-paranitrobenzyldioxycarbonyl-1'-ethyl) -1 '- (paranitrobenzyl-2-chloro-2 "-acetate) -4-trityltio-2-azetidinones ( mixture of C-2 "epimers). ~ | * umf ccncig) 6- a.ao-e.eo (aan, m, aromac.>, .45-4.80 (1H, m, H-1 '), 5.18 _ 5.21 (4H, 20, benxyl), 4.87 ( 1H, Zd, H-4). 4.22., .3.87 (LH. 2 :, H-2 "). 4.05-3.40 (LH, m, H-3), '17.5 W 1.50 ppm (BH, Éd , CHJ). 448 995 82 "Isomer D" "Isomer D" of 3- (1 "-paranitrobenzyldioxycarbonyl-1'-ethyl-1 '- (paranitrobenzyl-2" -chloro-acetate) -4-trityltio-2 -azet- idinones (mixture of C-2 "-epimers). * fl mx (cncia) 6 = a.:os.7o (zax, m, arena; 3),. :: - s.1o (4x, m, r @ n5y1.), - s.4a, 1 5.30 (in, za, H-25). 4.e2 (la, d.

J-5, x-4). 5.30-s¿2o (ln. M, R-l '). 3-15 (1H, m, H-3), 1.40, 1.30 -1 ppm (33, za, J-6.5, cn3); 1: c fi cls) vm¿x | 1780. 1750 (C-0), 1525 cm -1 (NO 2) 2. Preparation of (1'S, 3S, 4R and 1'R, 3R, 4S) 3- (1'-methane sulfonyloxy-1'-ethyl-1- (paranitrobenzyl-2 "-chloro-2" -acetate) -4-tritylthio -2-acetidinone (isomer C) (epimers at Czil.

To a cold (s °) solution of 24.0 g 05.5 mmol) <1s, 3s, 4R and 1'R, 3R, 4S) 3- (1'-methanesulfonyloxy-15-ethyl) -1- (paranitro benzyl 2 "-hydroxy-2 - (acetate) -4-trityltio-2-azetidinone in 350 ml of dry tetrahydrofuran were added 3.65 g (46.2 mmol) of pyridine and 5.5 g (46.2 mmol) of thionyl chloride 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, evaporation of the solvent steg. 448 995 83 'Hmr (anna) a. 8.19 (23 4 J.' vv 9, Hm aromat ..), 7.72 (175, m, deL owm Hc aroma "_ 'tritylu 5.57., - 5.12 (LH, n, H-2 "), 5.28 (ZH, s, -cxzpgqgh 4_73 '' 1" f “'-“ °' "'3-21 <1H« 2dq, Hs).: na (an. 2 .. amanie -M '1.21 3, - _ 1 „l PPM (30: d H GRZ; H 2) | ir Unix 1779 cm (co) JJ. Preparation of (1'S, 3R, 4R and 1'R, 3S, 4S) - 3- (1'-methoxymethoxy-1'-ethyl) -1- (paranitrobenzyl-2 "- triphenylphosphoranylidene 2 "-acetate) -4-tritylthio-2-azetidinone (isomer A) OCH 2 OCH 3 OCl 2 OCH 3 scos _ coa __,,. ~ N o Cl. _ Y? A mixture of 6.6 g (10 mmol) of isomer A of 3- (1'-methoxy-methoxy-1'-ethyl) -1- (paranitrobenzyl-2 "-chlor -2 "-acetate) -4- -trityltio-2-azetidinone, 3.3 g (1.2 mmol) of triphenylphosphine, 1.3 ml (11 mmol) of 2,6-lutidine and 140 ml of dioxane were refluxed for 2 day. The solution was diluted with ether, washed with% 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 cxnnqymax = 1750 448 995 84 KK. Eramst. of (1'S, 3S, 4R and 1'R, 3R, 4S) -3- (1'-methoxy-methyloxy-1'-ethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate ) -4-trityltio-2-azetidinone (isomer C) OCHZOCR:. øcuzoc fl: _ l, L ~ sr: ro:: l :: IfST 'I olïïl / ci -' \ ¶ff? s. A solution of 4.86 g (6.662 mmol) (1'S, 3S, 4R 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 7.20 mmol) of 2,6-lutidine was refluxed for 4 hours and kept on a hot bath (1000) 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 filtered through a silica gel column (65 g 5%, 10% and 20% ether-benz-J) to give 2.8 g (48%) of the title compound ir (CHCl 2). {Max: 1795 (C = O), 1620 and 1605 (phosphorus) and 1515 om '(NO 2).

LL. Preparation of (1'R, 3S, 4R and 1'S, 3R, 4S) -3- (1'-acetoxy-1'-ethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -4-trityltio-2-azetidinone (isomer B) STI da? A solution of (1'R, 3S, 4R and 1'S, 3R, 4S) -3- (1 ') is a solution of (1'R, 3S, 4R and 1'S, 3R, 4S). -acetoxy-1'-ethyl) -1- (paranitrobenzyl-2 "-chloro-2" -acetate) -4-trityltio--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 mmol) of triphenylphosphine. The mixture was refluxed (oil bath 1300) 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%). ir (cazciz) max: ivso (c = o) and 1620, 1e1o cm'1 (phosphorane).

MM. Preparation of 3- (1'-paranitrobenzyldioxycarbonyl-1'-ethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -4-trityltio2-azetidinone. .W ° C ° 2PNB oco PNB 2 SCO3 scé Cl 0 o N Pég xïönua '\ Tá .. 2 - CO PNB ISOITIGI B A mixture of 4.96 g (6.22 mmol) (l'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 g (9.42 mmol) of diphenylphosphine and 740 mg (0.80 ml; 6.91 mmol) of 2,6-lutidine were refluxed in dioxane (freshly distilled over LAH) for 30 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, water and brine, and dried over magnesium sulfate. ....___...._. ... _.-_._ ...-..,.. 448 395 86 Evaporation of the solvent gave a residue which was allowed to pass through a silica gel column (10 times its 10% ether-benzene, ether and ethyl acetate) The title compound was obtained as a crystalline solid in an amount of 3.1 g (49%) and melting point 189-1900 (ether); ir (CHCl 3) q] nmx: 1750 (C = O), 1620, 1605 (phosphorane) and 1522 cm -1 (NO 2).

Isomer C Isomer O 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 (CHCl 3) -O mai: 1750 (C = O), 1610, 1620 (phosphano) Qcn 1520 cm -1 (Nozn Hmr (cDc13> ö: ae = 6.7 (n, 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 mmol; 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-triethylthio-2-azetidinone, 1,425 g (5.4 mmol) of triphenylphosphine (Aldrich) and 0.63 ml (580 mg; 5.40 mmol) 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 10; 88 g (1 g). .08 mmol (tuby yield 24.3%) of the title compound as a yellow foam. a '= 1.08 (a, J = enz, i'-cu3>; ir (rent) / Qma C = 0). 1 Hmr (CDCl 3): 1745 cm -1 / x (s' 448 995 87 NN. Preparation of (1'S, 3S, 4R and 1'R, 3R, 4S) 3- (1'-methanesulfonyloxy-1'-ethyl) -1 % @ ananitrobenzyl-2 "-triphenyl- phosphoragylidene-2" -acetate) -4-trityltio-2-azetidinone (isomer C) 10 Ms scøa M "scég _-_-___-_ §" cl N \ ffó ïízma CO2PNB En 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-tritylthio-2-acetethinone, 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 were refluxed. hours under nitrogen. The solvent was evaporated and the crude product was redissolved in ethyl acetate and washed successively with dilute chlorine> 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 phosphorane. 12.36 g (40%). 1 Hmr (CDCl 3) δ: 2.53 and 2.93 ppm (3H, 2s, mesylate); ir 'O max: 1749 and 1620 cm * (c = o).

OO. Preparation of (1'R, 3S, 4R and 1'S, 3R, 4S) -3- (1'-hydroxy-1'-ethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -4-trityltio-2-azetidinone (isomer B) 0Ac OH (L. ST: Ä., TL 'ïf- mon o N ~ \ føP ° 3' 0 N Póa C °; PN3 "COIPNB 448 99,5 'En 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 of methanol and 60 ml of THF was treated at room temperature with a 1% aqueous solution of NaOH (1 equivalent, 200 mg in 20 ml The reaction was monitored by thin layer chromatography (heating the mixture increased the reaction rate). The mixture was diluted with ether-ethyl acetate and washed with hydrochloric acid, water, aqueous sodium bicarbonate, water and brine. residue, which was crystallized from benzene ether to give 3.7 g (87.7%) of product, m.p. 169.5-170 ° C (cnzclz) 0 max = 1745 (c = o) and 1620 cm * (phosphorus) PP. Preparation of (1'S, 3R, 4R and 1'R, 3S, 4S) -Silver-3- - (1'-methoxymethyl-1-ethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate ) -2-azetidinone-4-thiolate (isomer A) 0cH 2 OCH 3 Ocu2ocH3 C .__ SAg “If °° ___» ”if i N 0%>“ P ° s OP ° 3 COZPNH Silver 3- (1'-methoxymethyl) was prepared -1'-ethyl) -1- (para-nitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -3-tritylthio-2-azetidinone (isomer A) as described for isomer C of the paranitrobenzyldioxycarbonyl derivative above. Yield: 50%. ir (rent) fgmax: 1745 cnfl (c = o). 448 995 89 4 QQ. Preparation of (1's, 3s, 4R and 1'R, 3R, 4s) -silver-2- (1'- -methoxymethyloxy-1'-ethyl) -1- (paranitrobenzyl-2 "-triphenyl] -phosphoranylidene-2" - acetate) -2-azetidinone-4-thiolate (ïsomer C) AND AND mmämæs 2 3 ÄN swr _ D AgNo 5 "? ._.___ 2 ____ + _ * l OÉYPQ; - '' ° ON Yjw] cozrxa, '_ 1 C 2P "B 887 mg (1.0 mmol) (1'S, 3S, 4R and 1'R, 3R, 4S) 3- (1'-methoxymethyloxy-1'-ethyl) -1- (paranitrobenzyl 2" - triphenylphosphoranylidene-2 "-acetate) -4-trityltio-2-azetidinone was first dissolved in 30 ml of hot (400) methanol, treated with 103 mg (0.65 ml; 1.3 mmol) of 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 230, 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)) 1) max: 1745 (c = o), leos gføšforan) and 1520 cm -1 (NO 2).

RR.

Preparation of silver 3- (1'-paranitrobenzyldioxycarbonyl-1'-ethyl) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone-4-thiolate-ocovua ñ 5C @ COZPNB N On '- ° 1: 3 M: rus 3 O PNB 448 995 90 "Isomer B" 1.02 g (1 mmol) (1'R, 3S, 4R and 1'S, 3R, 4S) 3- (1'-paranitroben sylcarbonyldioxy-1'-ethyl) -1- (paranitrobenzyl-2 "-triphenylphosphanylidene-2" -acetate) -4-trithio-2-azetidinone was dissolved in 3 ml of dichloromethane and diluted with 20 ml of hot (550) MeOH.

The hot solution was first treated with 120 ml (117 mg; 1.48 mmol) and 8 ml of a warm (550) 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 (-130) methanol and 3 times with ether. 917 mg (loos) of product were obtained. ir (nujol null) {> maX = 1745, ieoo (phosphorus) and 1511 cm'l.

"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) a) max: 1745 (c = o) pch 1600 cm -1 (phosphorane).

Isomer D "A solution of 144 mg (0.442 mmol) of isomer D of 3- (1'-nitrobenzylcarbonyldioxy-1'-ethyl) -1- (p-nitrobenzyl 2" -triphenylphosphoranylidene-2 Acetate) -4-trityltio-2-azetidinone was prepared by first dissolving it in 5 ml of dichloromecane, removing the chloromethane at ss-50 ° and adding 4 ml of MeOH. To the above solution was added 1.14 ml of a hot 0.15 M solution of silver nitrate in MeOH (0.1 mmol; 1.2 equivalents), followed by 14 μl (0.1 mmol; 1.2 equivalents) of pyridine, and the silver mercaptide began to precipitate immediately. The mixture was stirred for 2 hours at room temperature and 1 hour at 0 DEG C. The mercaptide time was collected by filtration and washed ..._-_.._..., ..............-,., with ice-cooled MeOH and ether to give 99 mg (0.1 mmol; 78%) of the title compound as a brownish solid; (nujol) 1) nmx: 1750 cm -1 (s, C = O).

SS. Preparation of (1'R, 3S, 4R and 1'S, 3R, 4S) -Silver 3- [4'-coxy- - 1'-ethyl) -1-Caranitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) - 2-azetidinone-4-thiolate (isomer B) ox _ OH / lri / ST: Aqua Ä. SA? ______i__, Lïí N P9, c HN o xfø 3 55 Q r% C02PNB C021; NB A solution (the crystalline material was first dissolved in di-chloromethane) of 19 (1,9 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 1224 μl (12l, 3 mg; 1.53 mmol) pyridine and at 100 with 15 ml of a 0.1 M solution of silver nitrate (2.25 mmol) in MeOH or with such a large volume that no precipitation of silver mercaptide was obtained. The mixture was stirred for 1 hour and concentrated on a rotary evaporator. 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 448 995 92 Example 6 (1'R, 5R, 6S and 1'S, 5S, 6R) -6- (1'hydroxyethyl) -2- (2-aminoethoxymethyl ) penem-3-carboxylic acid (isomer B) one / L »s I Zocyncazunz o man (1'R, 3S, 4R and 1'S, 3R, 4S) -4- (2-azidoethoxy) acetylthi o-3- (1'-hydroxyethyl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone (isomer B), in addition to a hydroxypene 2) TFA ** _ 'Oøfl , \ §: D CO2PNB COZPNB OH using, Cl 3 / Py: OH SO '. 1. / la 9 u = 3sic1 (zr3N '15 ssrnes 7 \ ï§ / \ * 0 / ”\“ / N Å s, / ~ \, »“ 3 Nfgó 3 ÛZPNB To a stirred solution of 820 mg (l, l6 mmol ) (1'R, 3S, 4R and rn 1'S, 3R, 4S) silver-3- (1'-hydroxyethyl) -1- (p-trobenzyl-2 "- triphenylphosphoranylidene-2" -acetate) -2-azetidinone-4- thiolate (isomer B) in 20 mL of THF was added at -150 (methanol-ice bath) under a nitrogen atmosphere successively 0.168 mL (4.66 mmol; 4.02 equivalents) of triethylamine, 0.589 mL (4.64 mmol; 4 .00 equivalents) chlorotrimethylsilane and 81.2 mg (1.2 mmol) of imidazole.

The mixture was stirred for 18 hours (overnight) at room temperature and then cooled to -10 - -1s °. To the mixture was added 0.220 ml (2.72 mmol) of pyridine and then a solution of 372 mg (2.27 mmol; 1.96 equivalents) of 2-azidoethoxyacetyl chloride in 20 ml of CH 2 Cl 2. The mixture was stirred for 1 hour at room temperature. After filtering the precipitate, the filtrate, diluted with ethyl acetate, was washed successively with 1N hydrochloric acid, brine, saturated sodium bicarbonate solution and brine, dried over sodium sulfate and evaporated to give 748 mg of an oil. This oil dissolved in moist CH 2 Cl 2 (20 mL with 3 drops of water) was treated with 2 drops of trichloroacetic acid at room temperature for 30 minutes. The mixture was washed with saturated sodium bicarbinate solution and then brine, dried over sodium sulfate and evaporated to give 695 mg of an oil as a crude product. The oil was purified by column chromatography (15 g SiO 2; eluent EtOAC: CH 2 Cl 2 = 1: 1) to give 538 mg (0.739 mmol; yield 63.7%) of the title compound as a yellowish oil: (cpcisy 6; 1.22 (a, a = eaz. cn3-1 '). S-6 (26. H-4) gçh 7.; - 8.4 ppm (aromat Hs): ir (rent) Vmax: 3420 (0H) «2100 (-H3). 1 1150 (c ~ o) and 1690 em '(z1 ° e = cez); af 0.20 (cn2c12 = s: oAe -1 = 1L (l'R, 5R, 6S Och l'S, 5S , 6R) -p-nitrobenzyl-6- (1'-hydroxyethyl) -2- (2-azidoethoxymethyl) penem-3-carboxylate (isomer B) «on oa".

/ I S> ~ / ”\ w» / * \ / ”NB flw. 5 W 6 .__ É2É fl L__i N “2 ° c" 2CH2 "3 N pç Å 0 0 Y 3 cozmna ozvwa A solution of 490 mg (0.673 mmol) (l'R, 3S, 4R and l'S, 3R, 4S) - 4 ~ (azidoethoxy) -acetylthio-3- (1'-hydroxyethyl) -1- (p-nitrobenzyl-2 "-triphenyl-phosphoranylidene-2" -acetate) -2-azetidinone (isomer B) in 80 ml of toluene was carefully refluxed for 3 hours. Evaporation of the solvent in vacuo of an oily residue, which was purified by column chromatography (10 g SiOH 2; eluent 5-10% EtOAc in CH 2 Cl 2), followed by crystallization from CH 2 Cl 2 ether to give 202 mg (0.449 mmol; yield 66.8%) of the title compound as pale yellow crystals. 'nu (amg: (SH m _cH _ and 3-6), 3_g-4_5 (lg, m, x-1'), 4.45-4.72-4.15-s.o2 (za.

II 2 AB-typ,: az-2), s.oz-s.2s-s.as-s.s7 (za, AB-typ.-C fl znr), S-62 (1H- a, a = 1uz, Hs) and 7.42-7.65-a.1: -e.2a ppm (4H- ^ 2'B2'1 a = ° ma '“$> * -1 _. _ _ _ -1 h 1660 lr (zero,“ max_ 3460 (Og), 2110 (NB), 1165 (B gknam) oc cm (ester) 448 995 94 An analytical sample was obtained by further crystallization with melting point 1o7-10a ° (cnzclz-ether) _ uv (scene) A = 264 (e 12ooo) and 323 now max __ lnu O (e 9200); n: ssz (cazcizumøx-Li), Anal. Bar. For claalguso7s.

C 48.10, H 4.26, N 15.88, S 7.13: fÜ flfl S: C 47.81, H 4-15; N 15.00. S 7.16 (1'R, 5R, 6S and 1'S, 5S, 6R) -6-1'-hydroxyethyl) -2- (2-azidoethoxymethyl) penem-3-carboxylic acid (isomer B) OH - ox J., s j., s cncnxcan! I c 2 2 2 3 ----_; N Solution of 180 mg (0.400 mmol) (1'R, 5R, 6S and 1'S, 5S, 6R) - p-nitrobenzyl-6- (1'-hydroxyethyl) -2- (2-azidoethoxymethyl ) penem-3-carboxylate (isomer B) in 18 ml of THF was mixed with 19 ml of ether, 18 ml of water and 180 mg of 10% Pd-C. The mixture was hydrogenated (H 2, 3.8 x 10 Pa) for 2.5 hours at room temperature. After filtering off the catalyst, the aqueous filtrate was washed with ethyl acetate and lyophilized to give 84.4 mg (0.229 mmol; crude yield 73.2%) of the title compound as a yellowish powder as a yellow powder. raw proaukt. uv (nzmhmax: 305.5 (64800) and zss mu (83800).

The powder was purified by high pressure liquid chromatography (Water C18 Micro Bondapack Reverse Phase 30 cm x 10 mm; eluent 1% CH 3 CN in H 2 O) to give 44.7 mg (0.155 mmol; yield 38.8%) of the title. the compound as a white powder. '* Hmr (D 2 O) δ = 1.34 (BK, d. J-5.4 az, cxa-1-). 3.26 (2H, m, -cazu), 3.92 (gu, m, -ggëæc fl 3.94 (la, aa, J6_1, = s.2H =, J 2% '6_5 = 1.4 Hz, HG), 4.2-4.4 ( ln, m, H-1 '), 4.52- 4.7o-4.s4-5.o2 (2H, As-: yp, cH2 ~ 2) and 5.71 ppm (13, ¿, J = 1_3 Hz, 3-5 ), ir (Ka: -disk) vmax: 3420 (on), 3000-2600 (br, cozn), 1765 (ß_1actam) and -1 1575 cn (4028)) uv (H20) Ämax: 306 (G 5300) and 258 mp (c 3600). 448 995 95 Example 7 7 2- (2-aminoethoxymethyl) penem-3-carboxylic acid (via mercaptide intermediate) Ethyl 2-chloroethoxyacetate now C; clca co 2: + ¶; 7 -Éï fi å --- + q \ ¶ / ^ \ U / ^ \ «” 2 2 1so-1so ~ c 0. ' A mixture of 24.5 g (0.200 mol of ethyl chloroacetate, 8.80 g (0.300 mol) of ethylene oxide and 0.40 g (1.9 mmol; dried in vacuo) of tetraethylammonium bromide was heated for 6 hours in a bomb at 150-1600. The reaction mixture was distilled under reduced pressure to give 6.66 g (54.4 mmol; 27.2%) of ethyl chloroacetate, b.p. 22-240 (0.5 mm Hg) and 8.39 g (50.4 mmol; 25. 2%) ethyl 2-chloroethoxyacetate as a colorless oil having a boiling point of 49-3 ° (0.1 mm ng), * kmr (cncis) 6: 1.2a νan, c, J-vxz, -cna), 3.5-4.0 (fn, m, Azaz, -cnzcxz-cl). 4.15 (za. 8, -cocnzo-), 4.25 ppm (in, q, a-vaL-oggzcusn i: (remgvmax: 1140 en * (c-o esta).

Procedure according to D. Klamann et al, Jastus Liebig Ann. Zlg (1967) 59 (Rapp = yield 42%, bp ss, s ° / 0.35 mm ng).

Ethyl 2-azidoethoxyacetate cl N N: co zu: 63. A mixture of 7.71 g (36.3 mmol) of ethyl 2-chloroethoxyacetate and 3.31 g (50.9 mmol) of sodium azide in 100 ml of DNF was heated for 3.5 hours at 80-900, after which time thin layer chromatography (hexane ether 1: 1) indicated that the reaction was complete.

The cooled mixture was poured into 1 liter of water and extracted with 3 x 250 ml of ether. The extracts were washed with water twice and brine, dried over magnesium sulfate and evaporated to give 7.16 g (41.4 mmol; 89.4%) of ethyl 2-azidoethoxyacetate as a yellowish oil; (cncla) 6: 1530 (aa, c, J-v fl z. -ocnzggg). 3.3-4.0 (4H. M. -OCHZ H cxzna), 4.13 (zu. S,> cocn2o->. 4.22 ppm (zu. Q, v ~ 7H =, - ° Eë2CH3 “ir (rent) vmax = 2100 (NJ ) and 1750 cm-1 (C-0 escer).

This material was used in subsequent steps without further purification. 2-azidoethoxyacetic acid Et N NaOI-I HN 3 ----- ~ 3 Q \\ g // \\ * o /// \\ “” / I u2o ~ Meox c \\ ¶ / y ^ \\\ o To a solution of 6.56 g (37.9 mmol) of ethyl 2-azidoethoxyacetate in 80 ml of methanol was added 80 ml of a 1N aqueous solution of sodium hydroxide and the mixture was stirred at room temperature over night (17 hours). After removal of insoluble matter, the methanol was evaporated in vacuo and the residue was saturated with sodium chloride and washed with 3 x 30 ml of ether. The aqueous layer was acidified with 30 ml of 3N hydrochloric acid and extracted with 4 x 40 ml of ether. The ether extracts were washed with brine, dried over magnesium sulfate and evaporated to give 4.25 g (29.3 mmol; 77.3%) of 2-azidoethoxyacetic acid as a colorless oil; * Hmr (cocla) -6: 3.3-4.0 (45, m, -ocnzcnzua), 4.22 (za. S, -cocuzo-), 9.52 ppm (ln, S, -coz fl. Switched with 020): ir (pure) vm¿x = zeoo-: soc (br.-coza) 2100 (asia and 1740 cm-1 C = O-CO2H). This material was used in subsequent steps without further purification. 2-azidoethoxyacetyl chloride 3 SOCl Cl N m \\ E / \\ o // \\ // N ______ ¿__ * ° // \\ // 3 448 995 97 A solution of 2.09 g (14.4 mmol) 2-Azidoethoxyacetic acid in 5 ml of thionyl chloride was stirred for 4 hours at room temperature. The excess thionyl chloride was removed in a water suction vacuum and the residue, which was dissolved in 10 ml of benzene (dried over molecular sieves), was evaporated in vacuo. The oil thus obtained was dried in vacuo (water pump) over sodium hydroxide for 1 hour to give 2.23 g (1.3.6 mmol; 94.4%) of 2-azidoethoxyacetyl chloride as a colorless oil; lm "m" ni'5 * 3 “3 (2m bf. z, J-sxz. ~ cn2o-1 3.78 (zu. br.-z. J-saz. -cuzua) och 4.50 ppm ums; ææ% æn1dæm3¿ w¿zmouummw mwaflpwun _ This material was used in the subsequent steps without further purification 4- (2 * -azidoethoxyacetylthio) -1- (paranitrobenzyl-2 "-triphenylphosphananylidene-2" -acetate) -2-azetidinone say Py: / cn cl S, / ^ \\, / 'N3 Ch \ ¶ / f \\ C / f \\ // M3 + -_____ ÄLÄí + \ ï / \\ ° J [: N Ö P o' \ fi4} 3 éa cozpua COZPNB To a stirred solution of 7.96 g (1.2 mmol) of silver 1- (paranitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone-4-thiolate in 100 ml of dichloromethane containing 1, 94 ml (24.0 mmol) of pyridine were added at 0-50 under a nitrogen atmosphere to a solution of 2.23 g (1.3.6 mmol) of 2-azidoethoxyacetyl chloride in 20 ml of dichloromethane and the mixture was stirred for 2 hours at room temperature After filtration of the precipitate the filtrate was evaporated and the residue (160 g; eluent (EtOAc: CH 2 Cl = 1: 1). 4.216 g (6.7 mmol / l; 51.4%) of the title phosphorane were obtained as a tartaric oil purified by column chromatography (SiO4 yellowish foam. This foam was used in the subsequent step. An analytical sample was obtained by crystallization from a : 9-mixture of dichloromethane and ether with a melting point of 128-129 ° (decomposition); ir vmax = 2090 (-NS) .11ss (B-1acram) and 1690 = m'1 (ci ° escer); Anal . ber-.för co vs. c 59.74, n 4.42, N 10.26, 34 "3oNs 7 s 4.e9; found = C 59.33. H 4.49. N 9.69, s 5.19; tic Gm0Ac) af-o.ss. 448 995 98 Q-Nitrobenzyl-2- (2-azidoethoxy) methyl-penem-3-carboxylate \ E / ”> \ o /” \\ / ”RJ 'S toluene -: _ - _-_- + (f ífws A "z °°" 2 ° "2" 3 cozrns cozpug A solution (cloudy) of 4.13 g (6.04 mmol) of the above phosphorus in 200 ml of toluene was refluxed for 1.5 hours under a nitrogen atmosphere. After removal of insoluble material was evaporated the solvent in vacuo and the residual oil was purified by column chromatography (SiO 2, 80 g; eluent 5% ether in benzene) to give 2.44 g (6, 02 mmol; 99.6%) of the title compound as a yellowish oil. This oil was used in subsequent steps. Crystallization from a 1: 9 mixture of dichloromethane and ether gave an analytical sample, m.p. 88-89.50; * nmz (coola) 6 = 3.35 (zu. u. J = sxz, -ocnz-), 3.47 (la, aa. Jgem-lsxz, Jtrans-zuz. ce-u), 3.67 (zu, c, J = sn =, - CHZN3), 3.85 (1H, dd, Jgem ~ 16Hz, Jcis-ï_5 Hz, Cs-n), 4.73 (23, Agq, J-15, 19 C2 ~ CH2), 5.30 (2H. Aag, J-13.5, 9, -ocuzaz), 5.63 (1H, da, J trans- znz, aqis-3.5 Hz. Cs-H). v.so-7.63-a.12-a.21 ppm (aa, A2'a2 °, 'aroma: un; 1: (nujai) om;: mo (ma), nas (ß-iakm) and mas m3 ( esceza uv (ston) xmÄx = 2s3 mu (e1zooo>, s2o.s mp (essoo): ia (benzene) e: er = 1 = 1) nf-o.so 2- (2-aminoethoxy) methyl-penem ~ 3 -carboxylic acid ca ocn en N H2 / Pd-C S ---- + o “ß 2 2 3. CHZOCHZCH2NR2 j of co gull 2 A solution of 1.62 g (4.00 mmol) of the above azidoester in 50 ml dimethoxyethane was mixed with 50 ml of ether, 50 water and 1.62 g of 10% Pd-C (Engelhard) and hydrogenated for 2.5 hours at 448,995,999 room temperature (hydrogen pressure 3.8 x 105 Pa). After filtration of the catalyst, the aqueous layer was washed 2 x 50 ml of ether and then with 50 ml of ethyl acetate The aqueous solution was lyophilized to give 817 mg (3.34 mmol; 83.6%) of the title amino acid as a yellowish powder; uv (Hzmaxmax: 304 mu (ÛSOOO)). This material was purified by high performance liquid chromatography (Waters, C18 Micro Bondapak Reverse Phase 30 cm x mm; eluent 1% CH 3 CN in H 2 O) to give 432 mg (1.77 mmol; 44.2%) of the n the title amino acid as a white powder; 5wæ (Dfn & 3Jß-X9 (43, m, -OCH CH NH), 3.54 (18, dd, Jgem-16-9 Hz, J 2 2 2 ns-1.9 Hz. C6_ fl). Tra 3.88 (ln, ad, J -16.a Hz, J _ -3.7 az, c -H), 4.52-4.70-4.aa-5.01 (zu, gem cis 6 As type, cz-cxzo-) and 5.77 ppm (1H, da, Jcis -3.6 Hz, Jtxans-1.9 cs-H) | ir (xsrw fl ríva vmax = 1770 (ß-lakcam) and 1580 cm'1 (-coz fi a; uv (H20) Ämax: 304 my (ES400), 256 mn (EBIOO).

Example 8 2- (2-Aminoethylthiomethyl) penem-3-carboxylic acid (via mercaptom intermediate) 1 S-Cyclic acid-2-azidoethylmethanesulfonate ----> BXCH: CH 20k! N 3CH 2 CH 2 OMS A solution of 7.5 g (60.0 mmol) of bromethanol and 5.0 g (76.9 mmol) of natrimazide in 30 ml of HMPT was heated for 2.5 hours at 115 °.

The reaction mixture was cooled to 230 and diluted with 100 ml of dichloromethane. The solid was removed by filtration and then the dichloromethane was evaporated on a rotary evaporator to give a yellowish liquid which was cooled to 0 DEG C. and treated successively with 5.57 ml (72.0 mmol) of mesyl chloride and 10.0 g. ml (72, mmol) of triethylamine. The reaction mixture was stirred for 1 hour at 0 DEG and then for 6 hours at 230 DEG C. and poured into 300 ml of water. The aqueous solution was extracted with 1 x 200 ml of 448 995 100 and 4 x 100 ml of ether; the ether extracts were combined, 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 liquid, which was distilled in high vacuum; boiling point 95-1000 (0.3 torr), 5.8 g, 58.5%; ._ i! (rgnt) Vmax: 2005 cs, M3), 1:45 (S, so: -a). 1175 (m, so: -oz cm'1. 'Umx (cncla) 6; 3.oa (s, an. Ocas), 3.4: -3.76 (m. 2H, H-2) and 4.2-4.46 ppm (m , 28, 3-1). 2'-azidoethylthioglycolic acid 1. A n cn cs ons + N scn coon ---_____ + 3 2 2 H 2 a + N ml (68.0 mmol) of a 1N sodium hydroxide solution and the resulting solution was stirred for 0.5 hours at 230 and treated with .3 g (32, 1 mmol) of 2'-azidoethylmethanesulfonate in 50 ml of dimethoxyethane. 22 hours, cooled to 23 °, washed with 3 x 2 ml of dichloromecane, acidified with a 6N hydrochloric acid solution and extracted with 7 x 40 ml of dichloromethane, the dichloromethane extracts were combined, dried over anhydrous sodium sulfate and concentrated on a rotary evaporator, distilled to an oil in a high vacuum with a boiling point of 117-122 ° (0.27 torr); 4.2 g, 81.2%;,., -1 i; (pure) \) max2 2100 (S, 113); 1708 (S, C flfi) GB. 'ma 2.7-3.07 (m, 2H, H-1 '), 3.35 (S, 23. H-1), 3-30-3-73 (N, ZH, H-2') -and 11.81 ppm (S ll-1, COOH). To a solution of 3.33 g (20.7 mmol) of 2-azidoethylthioglycolic acid 448 995 101 in 50 ml of dichloromethane was added 3.9 ml of oxalyl chloride and 1 g of 2'-azidoethylthioacetyl chloride. The reaction mixture was stirred at 230 for 1.5 hours and the solvent was removed in a rotary evaporator to give a yellow liquid. (Pure) NJ: zoo (s. N31. Ms (ns. Co>. * Hm (emma) s): ia-m '(m, za, H-1'¶. 3.37-3.73 (m, zu, a-2'), and 3.92 ppm (S, za, n-1), 4- (2'-azidoethylthioacetylthio) -1- (paranitrobenzyl-2 "-triphenyl- phosphoranylidene-2" -acetate) -2-acetidinone SA '&; âïïjr' 9 clgc fl sca and N “2scH2CH2N3 _____ l__l_lJ ____ + NN ~ \ 0 53:13:53 A solution of 15.7 mmol of silver-1- (paranitrobenzyl-1'-triphenylphosphoranylidene-1'-acetate) -2-azetidinone-4-thiolate and 1.6 ml of M (19.8 mmol) pyridine in 200 ml of dichloromethane was treated dropwise (0.25 hours) with a solution of 3.64 g (20.3 mmol) of 2'-azidoethylthioacetyl chloride in 50 ml of dichloromethane. The mixture was stirred for 1.5 hours at 230 DEG C. and filtered and the solid was washed with dichloromethane. The filtrate and washings were combined and washed with a 0.1N hydrochloric acid solution, water, saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to an orange syrup. Column chromatography (300 g of silica gel G-60; eluent ethyl acetate in dichloromethane, 0-40%) of the crude product gave, after evaporation of the solvent, 7.7 g (70%) of a white powder. After recrystallization from dichloromethane-ether-petroleum ether, an analytical sample with a melting point of 150-1510 (decomposition) was obtained. 13131. bes. for C 34 H 30 N 5 O 6 S 2 P = c se.3s, H 4.32, N 10.01. s 9.17; fi lnnetzc sa.s4, H 4.36, N 10.03, s 9.25. 1; (xsr) vmax = 2100 (s. NB), 1750 (s, 'C-0 of β-lactam), 16SS (s, C-0), 1655 μg, C-0), 1510 (S, a, ° m¿;) ¿- and 1440 = m'l- (S, P-Ph). 448 _995 102 Paranitrobenzyl 2-aminoethylthiomethylpenem-3-carboxylate SgCl-1 SCH 2 CHN f 2 2: r'S N _____ ê ____, 4 [: j; A suspension of 4.5 g (6.43 mmol) of 4- (2'-azidoethylthioacetylthio) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidenyl acetate) -2-aze-I thidinone in 375 ml of toluene was stirred for 2.25 hours at 1100 under a nitrogen atmosphere. The reaction mixture was cooled to 230 and evaporation of the solvent in a rotary evaporator gave an orange syrup. Purification of the crude material was performed on a silica gel column (90 g of silica gel G-60; eluent ether-petroleum ether 1: 1-3-3: 2); the pure material was obtained as a yellow syrup 2.2 g, 81%. 'ir (rent) vmax: z1oø (S, u3), 11es (S, co of e-1a <: am) ¿_17os = n "l (S, c = o of PNB),' nmr 6 = z.sa -2.90 (N, zn, x-1 "), 3.30-3.67 (m, au, Hoz". H-6 crans), 3.98 (Aag, ha_h-14.eai; zu, u-1 '), s. : 2 (Asq, Ja_b-13.0Hz, 21-1, Eäz-PMOZ), 5.66_ (dd, J ~ 3.5 Hz, HS .H-á cis aH_S'H_6 trans-1.9 az, 1-H, xs), 1.sa (d, JH ° -um-a.aaz, zu; no Pußloclx 8.19 ppm (d. JHm_H ° -a.eHz, za, am PNB). To a solution of 45 mg (0.1 mmol) of p-nitrobenzyl-2-azidoethylthiomethylpenem-3-carboxylate in 5 ml of dimethoxyethane was added 5 ml of ether. 5 ml water and 45 mg (0.1 mmol) 10% Pd-C. The reaction mixture was hydrogenated for 3.0 hours at 230 under hydrogen pressure of 3.1 x 10 5 Pa and filtered through a pad of celite. The pad was washed with ether and the filtrate and washings were combined and diluted with ether. The aqueous phase was separated and washed with ether and lyophilized. The compound obtained as a crude product (20 mg) was purified by high pressure liquid chromatography to obtain 5 mg (18%) of product; ir (Kax) v z 1765 (c = o), NEX leon = m'1 (b, coo '); * amz 3.15-3.45 'for - - _ - _. cm,. a 2), 3 49 (da, agem is eaz. J6, s trans 1.1n =, H-6 =: anš>.: _85 (ad. Igen-1s.ea =. J -z.4u =, a- 6 C151.6-Scis 4.05 (Aaq, Ja_b-14.6Hz. Za. H-1) and 5.74 ppm (da. J5_6 cis-3.¿Hz, -J5_6 trans-Lv fl z. M, xx-Sh w AMX: 301 (e 4330), zso (e 3282).

Example 9 2- (2-Aminylsulfonylmethyl) penem-3-carboxylic acid 1 IS 3 N 2% - cx42 cx-x-sulfonyl fl mm para-nitrobenzyl-2- (2-azidoethylsulfonylmethyl) penem-3-carboxylate s ~ ncPaA i 'ca¿scH2cH2N3 --------- + C "g3c" 2C "2" 3 0 N. cuzclz 0 ~ OOPNB OOPNB A solution of 0.36 g (0.85 mmol) of p-nitrobenzyl-2- azidoethylthiomethylpenem-3-carboxylate in 30 ml of dichloromethane was cooled to -200 under a nitrogen atmosphere and treated dropwise (2 hours) with a solution of 0.147 g (0.85 mmol) of m-chloroperbenzoic acid in 90 ml of dichloromethane. The reaction mixture was stirred for 0.5 hours at -200, warmed to room temperature and washed with a saturated sodium bicarbonate solution and water, the organic solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to an orange residue, chromatographed on silica gel (silica gel G-60, 9 g; eluent 25). % ethyl acetate in dichloromethane, fraction size: 7 ml) 1. g 448 995 104 Concentration of the appropriate fractions in question gave 0.27 g (72.6%) of a tt white solid with melting point l28 ~ l3l °.

Recrystallization from acetone-ether-petroleum ether gave an analytical sample, m.p. 1420 (dec.); Analysis. ber. for cl6N5o6s2 = c 43.93, H 3.46. u 16.01. s 14.66; found = c 43.19. H 3.44. N 16.02, s 14.63. ir (Kax) vmax = 2110 (CIO a] β-lactam fi 1690 (CIO of PNB ester), 1600, 1560 (C = 'C), 1520, 1 CHCl a-. I! 1.355 cm 0102), - uv Ämax 3: 265 (E 12884), 333 (E 8764). Kim: (CDCl 3) δ: 2.95 (1H, m ', CH CH NS), 3.58 (dd, JH -2.0Hz, J = 16.6Hz, 212' JG-m -GHS trans 14-6 trans), 4.33 ( centeräv ABq, Ja b = 13.4 Hz, H-l '), 4-32 (Cê fl f-Er EV' f Aag, JLb-IBJHz, H-l '), 5.33 (center av ABq, Ja'b ~ l3.7I -lz, ZH. CH: of PNB ester), 5.75 (dd, J -3-61-12, -: JH HSu-6 cis Z 'JH-SHG trans 11-1, 3-5), 7.60 (d , JH ° _Hm = 8.8I-iz, Z fl, Ho of PNB ester) and 8.22 (d, JHm_H ° -'8.8Hz, 21-1, Hm EVPNB esterh, 2- (2-aminoethylsulfonylmethyl) -penem-3 -carboxylic acid s S 3 lot Fd / C ____, CH gen cn Nu H2 cH2CH2N3 DMs, E: o, H 0 2 2 2 2 0 N 2 2 oowæ C005 To a solution of 57 mg (0.13 mmol) paranitrobenzyl-2 - (2-Ethylsulfonylmethyl) -penem-3-carboxylate in 20 ml of dimethoxyethane was successively added 10 ml of Et 2 O, 10 ml of water and 10% Pd to charcoal (57 mg) The reaction mixture was hydrogenated for 1.25 hours under a hydrogen pressure of 3 .8 X 105 Pa and filtered over a pad of celite The filtrate was diluted with Et 2 O, the organic phase was separated and the aqueous solution was washed twice with Et 2 O and lyophilized. a crude orange powder (30 mg) was purified by high performance liquid chromatography; lyophilization of the appropriate fractions gave 10.4 mg (29%) of the title compound as a white powder; ao of Am: x = 313 (p. 4911); ir (nar) vmax = 1720 (c-o of s-13kcam and also dsarboxyxac); * amg (020) 6: 3.0-2.1 + (su. H-6 trans. cgiggzuxa), 3.90 (ad, a “_6_a_5 cis l fl. H-6 cis), 5.45 (centerav Aßq, Ja b-13-GHz» H'1 '), 4-50 (Ce ï ïef O -3.6Hz, J ~ 16.9Hz. Av av of As, J -13.6 Hz, H-1') and 5.9 (m, in, HS). qa, b- Exemgel 10 Silver 1- (ß-trimethylsilylethyl-Z '-triphenylphosphoranylidene-2'-acetate) -2-azetidinone-4-thiolate SAg EN På Q 3 \\ í: ca cs sí / cëâ 2 2 2 \ CH3, 3 Di- ß -trimethyls in lylethyl fumarate ~ \ O í (CH3) 3 ~ qr fl JL \ Cl Hg / ^ \ / ”s1 (C“ 3) 3. pyridine To 20 ml of a cold (-1010) ether solution of 4.73 g (0.04 mmol) of 2-trimethylsilylethanol (H. Gerlach Helv. Chim. Acta QQ (1977)). ) 3039) and 5.56 ml (0.07 mol) of pyridine were added dropwise (15 minutes) under nitrogen 3.78 ml (0.035 mol) of fumaryl chloride dissolved in ml of ether. The black mixture was stirred for 5 minutes at -100 and 10 minutes at room temperature. Charcoal was added and the reaction mixture was filtered on a pad of celite. The filtrate was washed with 150 ml of a 1zl mixture of 1% sodium bicarbonate and brine. The aqueous phase was re-extracted with ml of ether. The ether solutions were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a brown solid. This compound was purified on a silica gel pad (30 g, 4 x 5 cm) with 300 ml of benzene as eluent to give 4.855 g (77%) of an oil which solidified on standing. melting point 33-34 °; ...._ _l ._... f _....__.- .. 448 995 106 Anal. ber. for Cn fi zaoqsi =; - c 53.12, H 8.91, - funneczc 53.35, n 8.91. 'mur (cDc13) 6; 6.78 (zx, s, c.cH). 4.26 (an, m, ca: -0), 1.03 tß fl, m, cuz-si) and 0.06 ppm (len, s, (CH 3) 3 Si); ir (CHCl 3) vmax = 1710 (cmoav ascer). 164: (c-c), 1261, izsa, se: och aao an * (si-c), Trimethylsilylethylglyoxylate hydrate Û sucu; 3 3 1) o Hwm2 ima) (cn3) 3si 2) (cH3) 2s 05 / ~ \, »5 3 3 A solution of 37 g (0,117 mmol) of di-IB-trimethylsilylethyl fumarate 1, 1 liter of methylene chloride was ozonized at -780 until a residual blue color was obtained. Excess ozone was evaporated with nitrogen and 2.57 ml (0.5l mol) of dimethyl sulfide was added. The solution was allowed to gradually assume a temperature of 230 DEG.

The reaction mixture was diluted with carbon tetrachloride to 2 liters. and washed with 500 ml of a 1% aqueous solution of sodium carbonate. The organic phase was dried over sodium sulfate, filtered on cents and evaporated (about 2 ° C) to dryness to give 43.9 g (97%) of the title compound; ir (rentianmxz 3450 (-OH), 1740 (ester, 1255, 860 and 50 cm 3 * (si-c) -1- (ÅS-trimethylsilylethyl-2 '-hydroxy-2'-acetate) -4-trityltio-2- aaetidinone Tr (on), 5Tf Å 2. i: /, \ v / sicus __________ + N 2, Ö N OI-L 0 \ fl 'o \ f, / f \ / §iæH fl3 4,000 g (ll, 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. (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 left the column (about 1.5 liters) and then with 2 liters 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 the title compound. 6.10 usa, m. Enryn. 5.23 and 4.90 (ln. 25, aco), 4.50 co 4.10 (aa. m. H-3 and o-cnz), z.eo (za, m, H-2), 0.95 (za, m, ca -sioch 0.1 ppm (eu, S, si-cn3); 2 ir (cxcisz vma = aszo (-on), 1765 (c-oav * 8-lqkcam). 1740 (c = o or X -1,. ester), 1595 (CH, aromat), 1257. 860 OCh 840 cm (C-Si) 1- (β-dimethylsilylethyl-2'-chloro-2'-acetate) -4-trityltio-2-azetidinone STI Ha 0 "\ r '/, \\ // si (cn3) 3 co 2 2 STr SOCIZ íl / A solution of 0.74 ml (10.37 mmol) of thionyl chloride in 9 ml of THF was added dropwise with stirring to a solution of 4.9 g (9.37 mmol). 1- (β-trimethylsilylethyl-2'-hydroxy-2'-acetate) - 4-trityltio-2-azetidinone, 0.84 ml (10.38 mmol) of pyridine and 40 ml of dry THF at -150 under a nitrogen atmosphere. The mixture was stirred for 2 hours at -15 DEG C. 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 300. The residue was dissolved in 100 ml of benzene, treated with charcoal and filtered through a pad of celite. Evaporation of the solvent gave a residue which was purified through a silica gel pad (100 g, 4.7 x 11 cm; 1zl hexane-benzene, 400 ml; 1: 19 ether-benzene, 1 liter). Indunst- Y STI SAg * + AgN0 + (nBu) N-l-CFCOH --_--- + .øl :: ï / å 3 3 3 2 ecer / H20 N p @ 3 _. o _ ..,. - ._-. u ... r. = -.: __ ».._____, _. _. . 448,995 108 of the appropriate fractions in question gave 4.64 g (92%) of the title compound. 1) nam: (cocls) ¿. 1_30 (153, m, aroma: -H). 5.77 oeh š.43 (1H, 2s, gg-cl), 4.7 - 4.2 (au, m, H-4 and ca: -o), 2.as - 2.50 (zu. M, _ H_3 ,. 1_15 (23 , m, C32-51) and 0.05 ppm (9H, s. Si-cH3): ir (pure) v = 1760 (š-o), B60 and aao and others (c-sx).

NEX L- (Q-trimethylsilylethyl-2'-triphenylphosphoranylidene-2'-acetate) - 4-trityltio-2-azetidinone '' rr 3. QP STI 3 N Cl 2,6-lut: idin N P4, 'S' ( CH) ïšê / SJJCHIQS KÖ / l 3 3 2 ml of a dioxane solution of 4.12 g (7.568 mmol) of the above chlorazetidinone were treated with 2.209 g (8.424 mmol) of 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. The residue was purified on a silica gel column (200 g, 4 x 31 cm) using ethyl acetate-hexane (3: 7, 1 liter; 7: 3, 1 liter) to give 4.836 g (83%) of the title the phosphorane. ir (film) vmax: 1755 (C = O), _1615 (phosphorane), aso and aao and (si-c). Anal. ber. for c47n46no3Pssi = c 73.99, H 6.07, N 1.ß1; found: c 12.18, H 6.08.

Name: * Silver-L-QS-trimethylsilylethyl-2'-triphenylphosphoranylidene-2'-acetate) -2-azetidinone-4-thiolate (10 mmol) 1 - ([.beta.-trimethylsilylethyl-2'-triphenylphosphoranylidene-2'-acetate) -2-azetidinone was dissolved in 60 ml of ether. 80 ml of a 0.5 M aqueous solution of silver nitrate (40 mmol) was added followed by rapid addition (1 minute) of a solution of 3 ml (12, 58 mmol) of tributylamine and 0.154 ml (0.2 mmol) of trifluoroacetic acid in 20 ml. ml of ether. The mixture was stirred mechanically for 19 minutes. The precipitate was filtered, 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 (suction for 10 minutes and pump for 65 minutes) to give 6.42 g of the title compound. Example 1 Silver-3- (1'-hydroxy-1'-ethyl) -1- (β-% dimethylsiloethyl-2 "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone-4-thiolate P OH SAg Me N 'Ph o \ (? / L / sine: Trans-3-acetyl-1- (β-trimethylsilylethyl-Z' -triphenylphosphoranylidene-2'-acetate) -4-trityltio-2- azetodinone .. o ST: T ”1. Lun ne __.__ í -_-- + PH, 2. mom: N PPnJ _ 3. 0 SiMe o YA / smes - 0 / \ / V3 o: - 2 Till en lösning of 0.80 ml (5.5 mmol) of diisopropylamine in 25 ml of tetrahyarofuran at -78 DEG C., 4.0 ml (6.0 mmol) of n-butyllithium were added with stirring, and after 3 minutes a solution of 3.82 g was added. (5.00 mmol) 1 - ([N-trimethylsilylethyl-2'-triphenylphosphanylidene-2'-acetate) -4-trityltio-2-azetidinone in 40 ml of tetra-hydrofuran dropwise for 20 minutes with stirring. For 2 minutes, 2.5 ml (25 mmol) of ethyl acetate were added and the solution was stirred for 10 minutes, the cooling bath was removed and 58 ml of 0.2 M hydrochloric acid were added with vigorous stirring. Water and ethyl acetate were added (65 ml each), the mixture was shaken and separated es. The organic phase was washed with water and saturated sodium chloride (60 ml each) and dried, and the solvent was evaporated in vacuo to give 4.1 g of crude product. The product was absorbed from methylene chloride on 20 g of silica gel and applied (dry) to a 120 g silica gel column. the column was eluted with 200 ml of a 1: 1 mixture of ether and hexane and then with 500 ml of ether. Evaporation of the solvent from the appropriate fractions gave 2.17 g (53%) of the title compound in a partially pure state; ir¿) maX = 1755 (-lactam and ester) and 1710 cm -1 10 Hm: (CDCl 3) 5 '= 1.67 and 1.87 peaks for cn3c-, trimethylsilyl and aromatic peaks; the residue is poorly dissolved. ( ketone); 1 3- (1'-hydroxy-1'-ethyl) -1- (β-trimethylsilylethyl-2 "-triphenyl-phosphoranylidene-2" -acetate) -4-tritylthio-2-azetidinone o OH STI 'T ! Mejïv / 'Nam-Il; _ M, ------ + N Ph N PPha O 3 SiMe Y SiMe cošfxv / 3 CO 2, / * \ / f 3 A solution of 2.10 g (2.60 mmol) of the above compound in ml of tetrahydrofuran was added to a slurry of 160 mg (4.3 mmol) of sodium borohydride in 10 ml of tetrahydrofuran. The mixture was stirred for 4 hours at 230. 30 ml of water were added followed by a slow addition of 1M hydrochloric acid until the pH became 3. The mixture was extracted with 50 ml of ethyl acetate. The organic phase was washed with 50 ml each of 0.1 M sodium bicarbonate solution, dilute sodium chloride and 448,995 μl saturated sodium chloride and then dried, after which the solvent was evaporated in vacuo to give 2.22 g of shrimp product.

The product was absorbed from methylene chloride on 11 g of silica gel and applied (dry) to a 44 g silica gel column. The column was eluted with ether. Evaporation of the solvent from the appropriate fractions gave 1.43 g (68%) of the title compound in the partially pure state; 1Hmr (CDCl 3): oH _ peaks around É; 1 for CH 3 OH-, trimethylsilyl and aromatic peaks; the residue poorly dissolved.

Silver 3- (1'-hydroxy-1'-ethyl) -1- (β-trimethylsilylethyl-2 "-phenylphosphoranylidene-2" -acetate) -2-azetidinone-4-thiolate H OH 'SAg Me ___--- A solution of 1.43 g (8.4 mmol) of silver nitrate in 40 ml of water and a solution of 0,27 ml (3.35 mmol) pyridine and 1.35 g (1.67 mmol) of the above phosphorane in 40 ml of ether were stirred vigorously for 1 hour at 230. The precipitate was collected by filtration, washed with water and ether and dried to give 1.24 g (100% ) of the title compound as crude product; ir fi) max: 3420 (OH) and 1750 cm_l (ß-lactam and ester).

Example gel 12 (1'R, 5R, 6S and 1'S, 5S, 6R) -6- (1'-hydroxyethyl) -2- (2-aminoethoxymethyl) -penem-3-carboxylic acid (isomer B) - alternatively procedure as N 2 -Cazocuscu: m 2 O CO 23 (Isomer B) 448 995 112 (1'R, 3S, 4R and 1'S, 3R, 4S) -4- (2-azidoethoxyacetylthio) -3- (1'-hydroxyethyl) -1- (β-dimethylsilylethyl-2 "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone 1H / ul :: 1, 5Åg. scocuzocinzcazus _ N pç - N 03 3 / O l / s'- _ 1- _ ~ 1.54 ml (11, 8 mmol) trimethylsilyl chloride was added to a stirred slurry of 2.48 g (3.34 mmol) silver -3- (1'-hydroxyethyl) -1- (β-trimethylsilylethyl-Z "-triphenylphosphoranylidene-Z" -acetate) -2-azetidinone-4-thiolate (isomer B), 136 mg (2.0 mmol imidazole and 1.64 ml (11, 8 mmol) of triethylamine in 60 ml of THF at 00. The mixture was stirred for 18 hours at 23 °. 60 ml of methylene chloride were added, the mixture was cooled to -150, 1.32 ml (16.4 mmol) of pyridine and 1.43 g (8.7 mmol) of β-azidoethoxyacetyl chloride were added and the mixture was stirred for 0.5 hours at -150. 60 ml of ether, 60 ml of ethyl acetate and 20 ml of 1M hydrochloric acid were added. The precipitate was removed by filtration and the organic phase was washed with 100 ml of 0.1 M hydrochloric acid, 100 ml of 1% sodium bicarbonate and saturated sodium chloride.

Concentration of the dried solution gave the title compound as a crude product as an oil in 85% yield. ir 1) max: 1755 and 1695 cnfl. (1'R, 5R, 6S and 1'S, 5S, 6R) -15-trimethylsilylethyl-2 -} 3-azidoethoxymethyl-6- (1'-hydroxyethyl) -penem-3-carboxylate (isomer B) OH m scocxzoc oc zc fl zng S o näs / ___-_; - 0 ß- CHZOCHÉCLRZN: CO 2 / "\« / sä: _ I CO 2 '/ \ "/ Sä: _ A solution of 1.3 g of the above phosphorus in 200 ml of toluene was refluxed 3 hours. Concentration of the solvent on a rotary evaporator now gave the title compound as a crude product. Chromatography on 40 g of silica gel eluting with increasing proportions of ether in hexane gave the title compound in crystalline form (65%). ir17 1760 max: and 1700 cm 1; 1Hmr indicated contamination with a second isomer. (1'R, SR, 6S and 1'S, SS, 6R) -2 -? - azidoethoxymethyl-6- (1'-hydroxyethyl) -penem-3-carboxylic acid (isomer B) O . _ ïs _ nam man ---- + 2 2 2: N x2ocu2cs¿u3 0 N ° / ou '' 2 oz / ^ ~ / sïf A solution of 3.ml (1.5 mmol) of anhydrous tetrabutylammonium fluoride in THF was added to a solution of 155 mg (0.37 mmol) of the above ester in 2 mL of THF at 0 ° C. After 15 minutes at 0 DEG, 10 ml of water and 10 ml of ethyl acetate were added, the mixture was acidified to pH 3 with 1M hydrochloric acid and the phases were separated. The organic phase was extracted with 0.05M sodium bicarbonate, the aqueous extracts were acidified to pH 3 with hydrochloric acid and extracted with ethyl acetate. The organic extracts were washed with saturated sodium chloride, dried, concentrated on a rotary evaporator and the residue triturated in ether to give 27 mg of the title compound as a crude product (28%). l ir vmax = ssoo, 11ss, 1670 au ', * nmr (cncla) 6; 1.30 (an. A, J-6.5, cn3-1 '), 2.22 (in, on), 3.1-3.9 (sa. M. Cnz ocha-e) - a.9J4.4 (la, m, 5-1 '), 5.60 (ln, d, J-1, u-5). (1'R, 5R, 6S and 1'S, 5S, 6R) -6- (1'-hydroxyethyl) -2- (2-aminoethoxymethyl) -penem-3-carboxylic acid (isomer B) HH s' scn uzocu cazua . , l _________- + N H2 °° 2 2N “2. N 2 0 cozn ~. C ° 2 "448 995 114 A solution of 150 mg of the above azido compound in 15 ml of THF, 15 ml of ether and 15 ml of water was hydrogenated in a Parrskak apparatus in the presence of 150 mg of 10% Pd / C at an initial hydrogen pressure of 4.1 x 10 5 Pa. After 3 hours, the catalyst was removed by filtration over celite and the aqueous phase was washed with ethyl acetate and lyophilized to give the title compound as a crude product.Cleaning by high pressure liquid chromatography (Waters, C18 Micro Bondpack Reverse Phase) gave 46.7 mg of the title compound in pure form, the compound being identical to a previously prepared sample obtained by hydrogenation / hydrogenolysis of the corresponding azido-p-nitrobenzyl derivative.

Example 13 6-Ethyl-2- (2-aminoethoxymethyl) penem-3-carboxylic acid c2u5 \ SI cx oc fl CH NH á__N \\ J> * 2 2 2 2 0 \ CO 2 HI / ~ _ ORC one '// ^ \ »4f ° Ac__JEE ___ q el I, NH 'NH Nat-ICO: I 0 Nazsoa 1 II III 1-butenyl acetate (about 1: 1 mixture of the cis and trans isomers) was prepared according to PZ Bedoukian, J. Am.

Chem. Soc. ÉÉ (1944) 1325.

To 50 ml of the cooled (-150) compound I was added dropwise ml (11 g; 78 mmol) of CSI. The mixture was gradually heated: iii o ° unaer 30 minutes. It is cooled to -20 ° C and carefully ground to a mixture of 8 ml of water, 35 g of ice, 18.4 g of sodium bicarbonate and 6.4 g of sodium sulfite. The mixture was stirred vigorously for 30 minutes at 00, treated with 250 ml of petroleum meter and cooled to -400. The solvent was decanted off and the residue was treated with an additional 100 ml of petroleum ether in the same manner. The combined petroleum ether extracts were washed with 30 ml of water and dried over sodium sulfate to recycle compound I.

The aqueous phases were combined and extracted with 5 x 40 ml of ethyl acetate. The extract was dried over sodium sulfate and concentrated in vacuo to give 7.0 g (57%) of a mixture of 28% of compound II and 72% of compound III. 'pp- 82-8S'C (0-01 mmu; nm = .6 (pam, cnc13) 7 .: <1a, ua) 5.92 (o.72 H. d, J - 4.4, Iz-H-3 ), 3.3 (o.2s H, d, J - 1.4,: Iz-u-4>,:.: (IH. M. Ua). 2.24 (aa, s), 2.12 (zzncvå q, a - 1) , 1.1 (auptvå c, _; .. 7, _ u 1115. ivss ca'l Anal. Ber. För c H no cs: .49, H 1.os, N a.9i. Co - 7 ll 3 Funnec c á: .iz. u 6.92. u a.as.

0.8 ml (850 mg; ll, 2 mmol) of sodium thioacetate was prepared by adding thioacetic acid to ll, 2. ml of a cooled (ice-bath) 1N sodium hydroxide solution under nitrogen, which was added to a cooled solution of 1.57 g (10 mmol) of compounds II and III in 5 ml of water under nitrogen, the mixture was stirred for 1 hour at room temperature. oil was separated, 9 ml of acetone were added and stirring was continued for 1.5 hours, the mixture was concentrated in vacuo to remove acetone and then extracted with methylene chloride.The extract was dried and concentrated in vacuo to give 1.65 g (95%) of a crude mixture of 85% trans-IV and 15% cis-IV with boiling point 10 ° -10 ° (0, o 2 man; 448 995 116 7.1 (1HJIH) 5.53 (o.241-1, d, g = 4_5, cis -H-4). 5.12 (o.en, d. J - 2.4 == ans -a-41: _34 (15, two t, J _ 7, 2.48 (ax) 1.9 (in, two q, J_- 7 , 1_l5 ¿3H'tV¿ t '¿=, _ v C = O 170' o, 17es cm nu c 4a.sa, u 6.40. N 8.07. L - Anal. Benför C73 v; Fu flflflfl C 48-1 8. x 6.47, u 7.77 than 50x83 0 N - @ 'CH -co CH (OH) AC 2 2 2 2 NH N - 0 \\ aw fl CO2PNB IV V A mixture of 1.25 g (7.2 mmol) of compound IV and 1.6 g (7.5 mmol) of p-nitrobenzyl glyoxylate in 80 ml of benzene were refluxed for 20 hours under a Dean Stark water trap followed by concentration in vacuo to give 3.01 g of crude product.

This was filtered over a small amount of silica in chloroform to give 2.8 g (quantitative yield) of the light yellow oil V containing a certain amount of solvent: 7.9 (411, m) 5.3 (411, m) 4.8 (m, on) 3.2 (in, m) 3.37 and '3.33 (an, two s)' 1, s' <2n, m) 1.05 (an, m) -Oczd 1765, 1700 cm-. This product was used in subsequent steps without further purification. 67.9 (4H, m) s.3 (Mnm) 4.8 (in, on) 3.2 (in, m) 3.37 and 3.3: (3a.rvå s) 1.a (za. M) 1.65 (an. M) v fl m 17ss , '17oo afl.

,, H: l :: 1 / fscocxa socl 'cocua NN o \ f fl oa o \ íac1 o Pa cozvus V 2 N V1 To a cooled (ice bath) stirred solution of 2.1 g (5.5 mmol) of the compound V i 10 ml of dry benzene were added, 3 ml of thionyl chloride, and the mixture was kept at 50 for 2 hours, after which it was evaporated in vacuo at room temperature. The excess thionyl chloride was removed by repeated addition and evaporation of benzene and the product was purified by filtering the benzene solution over a small amount of silica gel to give, after concentration in vacuo, 1.7 g (77%) of the light yellow oil. H7 448 995 VI as crude product: 7 9 (43, m) 5.0 (15, S) 5.3 (33, m) 3.3 (1H. M) ë.7 and 2.3 (3H.two s) I -l 1.75 (33, m m) 1.0 (33, m) vego 1700, 1775 cm. .

The product was used in subsequent steps without further purification. ,, e \ __ 1, s-cocna Pçs - -coca: N. . IN \ lutidxn GíCl \\ ?, P¿3 s co cozvua I ': PNB VT vx: A mixture of breeding, 7 g (4.2 mmol) of compound VI, 1.57 g (6.0 mmol) of triphenylphosphine and 5 g 35 mg (5 mmol) of 2.6-lutidine in 20 ml of dry dioxane were heated for 19 hours at 350, followed by. concentration in vacuo. The dark red residue was chromatographed on a 35 g silica gel column. Elution with benzene ether gave 2.3 g (87%) of crude product VII as a light red oil, which was used in the subsequent step without further purification. sA 3: 1 / s-cocua Agno3 fx. ß ---> I I N 'bas V o? PøB o. Y Pøs comm 2 COQPNB VII v11: The mercaptide VIII was prepared starting from the compound VII by the general procedure of Example 3. llf: 448 995 118 Cl N / Fyr SAÉ 1) \\ ä / ^ \ ¶, f \\, / 3 0 "YPQ 2) TFA - coamæ vIII '/ 3 § \\ f / \\ o / ^ \ ~ () EN ° ^ 0 * \ F? Ø3 ___--- Q) cogma. -" IX / 4; S H2 / Pa-c;> K oc fi cx N ^ __ "__ '“ _ š> O [NI \ _ / _ ° 2 2 a 3 \ co2PNB' xs gnzocxzcazuuz 0 COZH XI Reaction of mercaptide VIII with 2-azidoethoxyacetyl chloride according to the procedure according to Example 6 gives the intermediate IX, which can be cyclized and reduced as in Example 6 to obtain the title product.

Biological Data Representative compounds of the present invention were evaluated as in vitro antibiotics for a variety of microorganisms. After dissolving in water and diluting with nutrient broth, samples of the indicated compounds were found to show the following minimum inhibitory concentrations (MIC) in micrograms / ml with respect to the indicated microorganisms when determined after overnight incubation at 370 by the tube dilution method. (V MIC of EE organism Streptococcus pçeumoníae A9S8S Streptococcus.pyogenes A9604 'Staphylococcus aureus A953? Scaph aureus + S0 \ Serum A953? Staphylococcus aureus A9606 Staphylococcus aureus AISO97 Sçreptococcus faecalis A20688 Al5ll9 Escherichia coli Escherichia coli A2034l-l Xlebsíella AlSl30 pneumoniae, Klebsiella species, Proteus A20468 mirabilis A990O Proteus vulgaris A2l559 Proteus morganii Al5l53 Proteus rettgeri A2l203 Sezratía marcescens A200l9 Enterobacter cloacae A96s9 'Enterobacter cloacae A96S6 Pseudomonas aeruginosa L9843Å Pseudomonas aeruginosa A2l2l3 Hemophilus influenzae A9833 Haemophilus influenzae A2l522 Bacteroides fragilis A2093l Bacteroides fragilis A20929 448995 Prior al IN (eczema electricity No) _§_ _l_ _å_ _2_ .03 .l3 -13 .5 .os .ia .la .s .06 .l3 .l3 .5 s; .s 4 .25 32 15 4 I 125 ”16 63 4 32 63> 63 .S 2 4 8 .SB 16 32 2 4 8 32 2,> 12s 253> s3 l 2 4 8 l B 16 l6 4 8 8 16 2 2 8 16 2 .2 3 32 8 8 32 32 2 4 32 63 16 63 53 63 3 125> 63 63

Claims (5)

10 15 20 25 30 .ß -ïb- OO \ .O \ O (Il / 120 Patentkrav Compounds of the formula y \ __ | / s (Alm -A- (Al , S or SO; Alk 'is an alkylene group having 2 to 4 carbon atoms, and IR 1 is hydrogen or lower alkyl having 1 to 6 carbon atoms, optionally substituted with hydroxy, and pharmaceutically acceptable salts thereof. Compounds according to claim 1, wherein Y is hydrogen, ë fi yl or vi -hydroxyethyl. Compounds according to claim 1 or 2, characterized in that Alk is alkylene having 1 carbon atoms and Alk 'is alkylene having 2 carbon atoms. 4. A process for the preparation of a compound according to any one of claims 1 to 3, characterized in that in a inert organic solvent at a temperature just above room temperature up to the reflux temperature of the solvent a compound of the formula Y SJT COZR "15, 2} 448 995 wherein Q is phenyl or lower alkyl, R11 is an easily removable ester group, T is -COX, where X is - (Alk) -A- (Alk ') - NH and Y is hydrogen or lower alkyl of 1 to 6 carbon atoms, optionally substituted with hydroxy, removes the removable ester group by conventional methods and optionally converts a compound of formula I, wherein Y is hydrogen, to a compound wherein Y is a substituent, by treating the product with a corresponding electrophile in an inert organic solvent in the presence of a strong base. Pharmaceutical composition having antibacterial action, characterized in that it comprises as active ingredient a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt or physiologically cleavable ester thereof and a pharmaceutically acceptable carrier or diluent.