SE461395B - 4- (2'-AZIDOETOXIACETYLTIO) -1- (2 '-TRIFENYLFOSFORANYLIDEN-2 "-acetate) -2-azetidinones - Google Patents

Description

The novel intermediates of the invention thus provide novel 2,6-disubstituted penem compounds of the formula Y \ 5 / 'min -A- (an:' 2 -Rzo ¿... u O C022 I wherein Y is hydrogen or hydroxyethyl; Z is an easily cleavable ester protecting group; Alk is a C1-alkylene group; Alk 'is a C2-alkylene group; A is oxygen or sulfur; and R20 is an amino group (-NM2), and pharmaceutically acceptable salts thereof.

The compounds of formula I, wherein Z is hydrogen (and their pharmaceutically acceptable salts and physiologically hydrolysed esters), are potent antibacterial agents. Other compounds are useful intermediates for the preparation of the biologically active penem compounds. Since an asymmetric carbon atom is present in the 2-substituted compounds of formula I, such compounds may exist either in the form of racemic mixtures (R, S-form) or as individual right-turning and left-turning (R- and S-form). forms) optical isomers. Preferred compounds are those whose configuration at the S-carbonate corresponds to that of natural penicillin (SR configuration). The substituents in the 6 and 6 positions of the 2,6-disubstituted penem compounds may be in the cis or trans position relative to each other. In case the penem-6 substituent contains an asymmetric carbon atom, the resulting isomers are identified in the following as the isomers A, B, C and'D.

The preferred isomer in compounds of this type is isomer B. Separation of the various optical and geometric isomers can be performed in a conventional manner and by cleavage methods well known to those skilled in the art.

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

The pharmaceutically acceptable salts include non-toxic carboxylic acid salts, for example non-toxic metal salts such as salts of sodium, potassium, calcium, aluminum and magnesium, ammonium salts and salts with non-toxic amines such as trialkylamines (triethylamine), procaine, dibenzylamine, N -benzyl-fi? -phenethylamine, 1-phenenamine, N, N'-dibenzylethylenediamine, N-alkylpiperidine and other amines which have been used for the preparation of salts of penicillins and cephalosporins. When a basic group is present, the present invention also includes the pharmaceutically acceptable acid addition salts, for example salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid and sulfuric acid, or with suitable organic carboxylic acids or sulfonic acids such as trifluorosulfonic acid , maleic acid, acetic acid, citric acid, oxalic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid and malic acid. Compounds which contain an acidic group and an alkaline group may also be present in the form of internal salts, ie. as a zwitterion The preparation of the salts described above can be carried out according to conventional procedures for the preparation of salts of β1-lactam antibiotics, such as penicillins and cephalosporins.

The term "easily 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 can later be removed by other methods to obtain the free carboxylic acid Known ester protecting groups include 2,2,2-trichloroethyl, tertiary alkyl of 4-6 carbon atoms, tertiary alkenyl of 5-7 carbon atoms, tertiary alkynyl with 5-7 carbon atoms, alkoxymethyl, alkanoylmethyl with 2-7 carbon atoms, N-phthalimidomethyl, benzoylmethyl, halobenzoylmethyl, benzyl, p-nitrobenzyl, o-nitrobenzyl, benzhydryl, trityl, trimethylsilyl, triethylsilethyl, β-trimethyl The choice of ester protecting group depends on the subsequent reaction conditions to which the group must be subjected and the conditions which it is desired to use to remove the group. The choice of suitable group is a matter of pure professional skill. 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 β-trimethylsilylethyl ester which can be removed by gene treatment with fluoride ions. Within the framework of easily tinnable ester protecting groups, physiologically cleavable esters also fall, ie. the esters which in the field of penicillin and cephalosporin are known to be easily cleaved in the body to the corresponding acid. Examples of such physiologically cleavable esters include indanyl, phthalidyl, methoxymethyl, glycyloxymethyl, phenylglyoyloxymethyl, thienylglymethyl-o-o-methyloxy-methyl N -cnzc-Y 'wherein Y' is C1-C6-alkyl or phenyl. Particularly preferred esters of this type are methoxymethyl, ethoxymethyl, pivaloyloxymethyl, phthalidyl and indanyl.

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

The preferred compounds of formula I are those wherein Y is C 1-4 hydroxyethyl.

Particularly preferred are the above compounds wherein Z in formula I is hydrogen, pharmaceutically acceptable salts thereof and physiologically cleavable esters thereof, such as acetoxymethyl, methoxymethyl, pivaloyloxymethyl, phthalidyl and indanyl.

The most preferred compounds of the present invention are those wherein Y is C 1 -hydroxyethyl and the 2-substituent is -CH 2 OCH 2 CH 2 NH 2, in particular the free acids, the pharmaceutically acceptable salts thereof and the physiologically cleavable esters thereof. The novel intermediates of the invention may be summarized in the formula Y, wherein C is hydrogen or hydroxyethyl, Q is phenyl, R "is an easily removable ester protecting group. and T is a group of the formula -Qx, aa: x is - (A1x) -A- (A1x ') - xzor I the intermediates of formula II are R "p-nitrobenzyl or trimethylsilylethyl.

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

The reaction steps in Process I are shown in the following reaction scheme: 461 395 8 Process I (variation 1): Early introduction of the Z-substituent 2% 10 oAc y XICI SNa Y-CH-CH-Oàc CSI; "° ao * w së-x - Y '9 ____% M. sc-x I ~; _ axe I soclz of': N \ 8 u _ cozaw oåí-NYOH - Fuzz 'o Y | y 1 * -.' x .. Pøa * N fi så-'X 4 _ é '_ ä bas:. ° 2_.N \ (pø3' C023 'I C023! Y x I OI Y .. | _ g avïagsn. 1-4' / av skydds - u / x ° co a .. øwnp 'of ”2 c cozx f! Ae -_ case- ø - cs - 461 395 Procedure I (variation Zl: Late incorporation of the 2-substituent Y || _ - \ OA: _ Y-cx-ca-oac. Cszs _ I CHSC sm 0 xx '! * N ~ __1, $ A0 .K 1; * ky SAO _____ ¿%> w ¶' _ _ clzao _ I safu: - ° / '- 'xx. cozzv! _ 04-4' ° H cpzn '2 - ü 2. w _ M. sm: Pøa sne .MA _ b. ab oá u cl. * S _ _ 0% N Pø, * P cozn' coza 'o. f »f:« f 2- * N'.

C022 "w 'coza' YS a: Hxhj / x, avïägsn. Av I Wu. S 4 - N / 'škyddsgrupp lix C023' co a ° a ll XC-9 = acyïeringsnledeï MA = tungmeta fl saït 461 595 10 Procedure I (variation 3): Late introduction of the Z substituent - 2 ï ° ^ ° ø cswa. 3 ^ ï-cx-caf-oAg csrs IH _, s ._ _ 'II-_ N \ P, o ° H Y-yk Y f-TSW: ---> Wl / “øß -> QHO soclz of ï-x \ a cozan íï-NYÖH 0021: 'ï" 1 .__ | .scø3 wa ï' * - \ .__ |, scø: m '_.u ~ CJ, bass: .... pø bass. 5 á í n? 3 0. _ o coza 'cozn' u Y O * fl- sa x_¿I__ æ * x sÉ-x A ... u p __ 5 'Gå øa 04 _ YPøs Y \ S y. | x Jvlägsn. av - '° m __ \ / S 4-21 / .protection group N / xo _' 4-5 COZR o cøzia 11 461 595 In process I, a vinyl ester (Y = H or a group with the one indicated in connection with formula I above is converted meaning) containing the desired 6-substituent to the optionally 1-substituted 4-acetoxy-2-azetidinone by a cycloadering reaction with chlorosulfonyl isocyanate (CSI), followed by reduction with an organic reducing agent such as sodium sulfite. The CSI reaction is conveniently carried out in an inert organic solvent, such as diethyl ether, at a temperature of 0 ° C or below. The reduction step can be carried out in an aqueous or aqueous organic reaction mixture at a temperature of 0 ° or below and at a moderate basic pH.

After formation of the 4-acetoxy-2-azetidinone, Process I can be divided into three different routes. According to a synthetic route (variation 1), the azetidinone is reacted with a thiol acid X-g-SH, wherein X has the meaning given above in connection with formula I, or a salt thereof in a suitable solvent (for example aqueous or aqueous organic). Displacement of the acetoxy group results in the incorporation of the desired 2-substituent into the azetidinone at this stage. The displacement reaction is preferably carried out at room temperature or below and at a moderately basic pH value (about 7.5). When Y is 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 O n 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 461 595 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 chlorinating reagent (for example SOCl 2, POCl 3, PCl 5 or the like) in an inert organic solvent (for example tetrahydrofuran, diethyl ether, methylene chloride, dioxane or the like) in the presence or absence of a base , preferably an aliphatic tertiary amine (for example triethylamine) or a heterocyclic tertiary amine (for example pyridine or collidine). The reaction is advantageously carried out at a temperature of from about -10 ° C to room temperature.

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

The phosphorus intermediate is obtained by reacting the chlorester with triphenylphosphine in an inert organic solvent such as dimethylformamide, dimethylsulfoxide, tetrahydrofuran, dimethoxyethane, dioxane or an aliphatic, cycloaliphatic or aromatic hydrocarbon (for example, hexane, bioxene, bioxlo, bioxlo) 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 penem compound by performing a thermal cyclization in an inert organic solvent at a temperature from just above room temperature to the reflux temperature of the solvent system. . The cyclization is most conveniently carried out under reflux conditions. Suitable inert organic solvents include aliphatic, cycloaliphatic and aromatic hydrocarbons (for example benzene, toluene, hexane, cyclohexane), halogenated hydrocarbons (for example methylene chloride, chloroform, carbon tetrachloride), ethers (diethyl ether, dioxane, tetrahydroxyuranamide, dimethoxyhydrouran) for example dimethylformamide), di-C1-C6-alkylsulfoxides (for example dimethylsulfoxide) or a C1-C6-alkanol (for example methanol, ethanol, t-butane-O1) or a mixture thereof.

According to Variations 2 and 3, the phosphorane is converted to a heavy metal mercaptide of the formula ewa, C fi šß '.III or HQCOOCH3 -v whom, and CO23 "III; wherein Q is phenyl, x is 1 or 2 and M is Cu (II), Pbuï) or Hg (II) when x is 2 or Ag (I) when x is 1. The mercaptide formation is effected 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 methanol-containing solvent and in the presence of an organic or inorganic base, such as aniline, pyridine, collidine, 2,6-lutidine, an alkali metal carbonate or the like. The reaction can be carried out at room temperature or, if desired, under moderate cooling or heating. The anion (A) in the heavy metal salt can be any anion which gives a soluble salt in the chosen solvent, for example NO 3 ", CH 3 COO- , BF4-, F-, C104-, NO2, CND etc. The mercaptide intermediate is then reacted 0. I with an acylating agent capable of introducing the group X- (lk, wherein X is the desired penem-2 substituent. The acylating agent O 0 (X-3-CD) may be the acid X-3-OH or a reactive functional derivatives thereof, such as an acid halide (preferably acid chloride), acid azide, acid anhydride, mixed acid anhydride, active ester, active thioester, etc. The acylation is carried out in an inert solvent (for example a halogenated hydrocarbon such as methylene chloride, or an ether , such as dioxane, tetrahydrofuran or diethyl ether) and, when an acid derivative is used, in the presence of an acid acceptor, such as a tri (lower alkyl) amine (for example triethylamine) or a tertiary organic base, such as pyridine, collidine or 2,6-lutidine. When the free acid is used, the acylation is carried out in the presence of a suitable condensing agent, for example a carbodiimide such as N, N'-dicyclohexylcarbodiimide.

The acylation of the mercaptide can be carried out within a wide temperature range but is preferably carried out at a temperature of from about -20 ° to + 25 ° C. After the acylation, the resulting phosphorane is cyclized, as described above, to obtain the desired penem ester. . - The formation of the phosphorane via the mercaptide intermediate (variations 2 and 3) has been shown 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 (e.g. hydrolysis; hydration or photolysis) to obtain the unblocked penem compound. The removal of the p-nitrobenzyl ester can be effected, for example, by catalytic hydrogenation in the presence of a noble metal catalyst such as palladium or rhodium comprising derivatives thereof such as oxides, byroxides 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 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: '461 395 1 @ L Process II (variation 1): Early introduction of the Z-substituent if: u cxz-ca-oac .csxi | XC-SNH E xff: _: I / sc * ___.> Jsc-x H - HW 'I som: of xx cozn' øf-N OH 0 o _, së x Ä- i b. '- I à C fi z fl' cozau I C023 'Q' coin '.. 2' 'avïagsn. av R / S skyddsgrupëp 'l / x _ o co a 17 461 395 För-farande II (variation'2): Sent ínför-Hvande av Z-substituenten OAc _ cxfg-cz-x-OA: ___ cä>, | . ~ 4 - M \ P I O g - M 'sm' * få _ -> -:> w 'v f ”I soclz i.. i cola 'I 3 ä * r MA â§u ° b flfi') __ N Pø basr i 'cozn' cozn '0' i C023 'COZR ”S 2' | / xr "1- sx .__- u 64 ba§ N / I .l '_ o R' CQ2 y. s avïägsn. av 3% - * -_> x skyddsgrupp '4__N / _' 0 C92? 4161 595 18 Method II (variation-ä: Late 'introduction of the Z-substituent ca -cx-oae- csz; if øBCSNa š 2' pH 7.5 0 K 3 -_ | / scø3 ___; -scøa IN 'fm TN' soc12 o xx cozn '04 * OH cozn' _r scøa P-øa. __ |, scøB m cf-NYCL bas oá_.l ~ l \ (pø3 bas i 00212 'cozn' oo ._TSM x_å_ Q 53-1 A 'oâi-u Pø: s / __ u Pøa s 0 / __. | / s' __ ”/ X _ y yy-'Lírs x ba: n '“ C02 Q av1 ägsn .av-é protection group' 19 461 395 As can be seen, procedure II is essentially the same as process I (except that Y must be hydrogen) up to the thermal cyclization step giving the 2-substituted penem compound, however, if desired, a 6-substituent is now introduced at this stage by reacting 2-penem the compound with a suitable electrophile in an inert solvent (for example tetrahydrofuran, diethyl ether, dimethoxyethane or the like) and in the presence of a strong base. The reaction is reacted in the form of the free acid (obtained by deblocking as described above) in the presence of about two equivalents of base or alternatively a suitable 2-penem ester can be used in the presence of about one equivalent of base. An ester is used which is inert with respect to the anion chemistry (the reaction involves anion formation with base, followed by reaction of the electrophile with the penem anion), i.e. trimethylsilyl. Penem esters with activated methylene groups, such as p-nitrobenzyl, are not suitable, and if the 2-penem ester is of this type, it must first be unblocked and either used as the free acid or converted to a suitable ester.

The particular base used is non-critical and the usual strong bases, such as sodium hydride, phenyllithium or butyllithium, are suitable. However, a lithium disilydamide or a lithium dialkylamide in particular is used, such as lithium dicyclohexylamide (LDCA), lithium diethylamide, lithium dimethylmamide or lithium diisopropylamide (LDA).

The electrophile is selected to give the desired Y-substituent upon reaction with the anion and is, for example, acetaldehyde, which gives rise to the hydroxyethyl-6-substituent. The introduction of the 6-substituent by this method is preferably carried out under cooling (for example at a temperature from -800 to 0 ° C) in accordance with the general procedure described in Canadian Journal of Chemistry and (19) (1972) 3196-3201. 461 595 N 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 protecting groups.

The third main reaction process (Process III) is shown in the following reaction schemes: Process III (variations 1 and 2). , scø3 n scøa w 0 "'x crf-K, Y * N scø, ->' I h.. nïn \ B avlägsn. av MA / ba. ßkyöêßgruvp * -_;], scø, w“ ~ sE_x j _ J Ü '. | O ____ N \ 2! 4 6 1 3 9 5 FIX., Scø3 * x, su (__- tkr: _' o NN; Ho '- o ïøzn' - i x-ë- ® V - N oz: i - '0 B cozn' avlägsn. Av k dd V goçlz 5 Y .__ 59I'UPP vi '?' \ - \ .__ TSCø3 Y \ _T5C.X 4 1 _ O, '. Ä \ vøa -. B ". 'm av yï fi scøf * Yu' AE xo / oå-u ou CO R '2 - ° cogn- 461 595 22 * R sa ä. së-x --N ø I i --a ci 054 3. da coza 'C023. I, x-É- 9 I l / šíí o * R så-x ya., S -x ..; N - ø _-. N 0032-' cozn 'I x I xoa' - «on ' C02 _ C02 _. Removal of _ Wlääs fi- of _ protection group SKYWSEINPP Y 2.

R x 511- I x 4_-a ¿fl- ll 0. . g man C023 B = blocking group for ring nitrogen The 4-trityltio-Z-aretidinone in process III is formed in the manner described according to process II (variation 3).

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

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

In one way, the N-substituted intermediate is unblocked by conventional methods (e.g. acid hydrolysis) and then converted to the 2,6-penem compound via aster formation, chlorination of the hydroxyester ern 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 obtained phosphorane to obtain the 2,6-penem ester and removal of the carboxyl protecting group. The reaction conditions for these steps are those revealed in connection with process II ( variation 3).

An alternative route involves conversion of the N-protected azetidinone to a heavy metal mercaptide, acylation of the mercaptide with the group X-CI-Q removal of the N-protecting group, reaction of the azetidinone liberated from the protecting group with the glyoxylate ester, chlorination , reaction of the chloroester with phosphine to obtain the phosphorane, cyclization of the phosphorane to obtain the penem ester and removal of the carboxyl protecting group to obtain the 2,6-penem compound. The reaction conditions for these steps have been revealed above. The Penem compounds in the form of the free acids can be converted into pharmaceutically acceptable salts thereof or into readily removable esters thereof (especially physiologically cleavable esters). Salts can be prepared by reacting the free acid with a stoichiometric amount of a suitable non-toxic acid or base in an inert solvent, followed by recovery of the desired salt, for example by lyophilization or precipitation. Esters (especially physiologically cleavable esters) can be prepared in a manner analogous to the preparation of the corresponding esters of penicillins and ophalosporins. 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 optical active solvents.

Accordingly, the novel intermediates of the invention can be used in a process for the preparation of compounds of formula I, which process cyclizes a compound of formula I in an inert organic solvent at a temperature just above room temperature to the reflux temperature of the solvent. Wherein Q is phenY11 R11 is an easily removable ester group and X is - (Alk) -A- (Alk ') ~ R201 measured by methods known per se. 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 bass.

The penem compounds in the form of the free acids provided by the present invention and the pharmaceutically acceptable salts and physiologically cleavable esters of said acids have been found to be potent broad spectrum antibacterial agents useful in the treatment of infectious diseases of 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 (ie, compounds of general formula I, wherein Y ~ H) exhibit antibacterial activity per se and are also useful. intermediates (preferably in the carboxyl-protected form) for the preparation of the 2,6-disubstituted penem compounds I via anion formation and reaction with an electrophile. 461 595 26 The invention is further illustrated by the following exemplary embodiments, in which the temperature indications refer to degrees Celsius. For convenience, some abbreviations are used in the examples.

Below is an explanation of the meaning of less obvious abbreviations: csI “'pet. ether k.p.

NMR ether Celite LAB n-BuLi MIBK Et Tr Me THF 'Ph DMF TEA PNBG TH? TFA HMPT (or HMPA) EtOAC DMSO Ac M8 DMAP PY _ LDA chlorosulphenyl isocyanate petroleum ether boiling point 'nuclear magnetic triane diethyl ether (unless otherwise specified) diatomaceous earth product lithium aluminum hydride n-butyllithium methyl isobutyl ketone C2H5-ct-csïa. tetrahydrofur phenyl dimethylformamide triethylamine p-nitrobenayyl glyoxylate tetrahydropyranyl trifluoroacetic acid hexamethylfoefortriamide ethyl acetate dimethyl sulfoxide ca3co- 'CH 3 SO 2 -4-dimethylaminopyridine pyridine lithium isopropylam ) -2- (2-aminoethoxymethyl) penem-3-carboxylic acid (isomer É) OH - Ås. (1'R, 3S, 4R and 1'S, 3R, 4S) -4- (2-azidoethoxy) acetylthio-3- (1'-hydroxyethyl) -1- (p-nitrobenzyl-2 "- triphenylphosphoranylidene-2 "-acetate) -2-azetidinone (isomer B) OH cl mi 'QB IJ She ueasicigsesu I; ssinea 19 ï] ¶ '\\ o * ”\ *' N3 _¿LM _, \\ ,, N3 En 'M3 WWF a If n: g' rn 'o 4.3 Ézm -“ Own ÉPNB To a stirred solution of 820 mg (1.6 mmol) (1'R, 3S, 4R and 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 -15 ° (methanol-ice bath) under a nitrogen atmosphere in order 0.164 ml (4.66 mmol; 4.02 equivalents) of triethylamine, 0.589 ml (4.64 mmol; 4.00 equivalents) of 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 -1 ° -1 °. To the mixture was added 0.220 ml (2.72 mmol) of pyridine and then a solution 1 of 372 mg (2.27 mol; 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 = 1zl) to give 538 mg (0.739 mmol; yield 63.7%) of the title compound as a yellowish oil: * nu (cucis) s » 1.2: (a. A-eaz. GiB-w- SG (2fi- * H1 ocg 7_3.g_4 ppm (arena: ast; 1: (rent) umax = 3420 (ou). Zioo (-ua). Nso (c -oaoeh mo m * (ua-stan a: 0.20 (cazczmom mn. (1'R, 5R, 6S and 1'S, 5S, 6R) -p-nitrobenzyl-6- (1'-hydroxyethyl) -2- (2- azidoethoxymethyl) penem-3-carboxylate (isomer B) a, ._ - n fm) ~. s 3 J * lïíi 6 __EEEE__. N \%? '° ä “mšmä5 0 n On, _ Å - dust 2 V A solution of 490 mg (0.673 mmol) (1'R, 3S, 4R and 1'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 average 5-10% EtOAc in CH 2 Cl 2), followed by crystallization from the CH 2 Cl 2 to give 202 mg (0.449 mmol; yield 66.8%) of the title compound as pale yellow crystals.

.: (Cans) 5, L ”(33, 5,; .5_5g¿, 533.13), 2.18 (IH, br. Om; 3.2-3.9 (sn n -ca - oe fi uësz. 3.9-4.5 (ln. N. H-1 '>. 4-45-4-12-4-75-5-02 (IH- 0 I 2 An-typ, ca -za. S.oz-s.:ss.:ss.s7 (za AB type --CH2A => - S-62 KIK- z aa1n =. A-sz and 1.42-1.55-a.1a-a.za ppm <4Hf Ä2'B2 '«* f °“ “'“ “) '-1 1: (nujaia vm_x = _a4so (-on). 211fl <-N3> - 1755 * ß'1ëF ==” * °° h 15 °° ° “(enter).' 29 ~ 461 395 Ett analytical sample was obtained by further crystallization with the melting point 1o7-1oe ° (cnzclz-e fi er). “v (Own) xmu: 264 (a 12000) and 323: nu u: 920m: n: se:: cazcif mom-mn Anu calcd. get: cmannsgs: c 43.10, g 4.35, n 15.33, s 7.13, fvn fl â: C 47.81, H 4.181 !! 15.00, S 7.1.6 (l'R, 5R, 6S and 1'S, 5S, 6R) -6-1'-hydroxyethyl) -2- (2-azidoethoxymethyl) penemr3-carboxylic acid (isomer B) ox - ou JH. S JM 5 _ II 2- c fl zocx-xzcazua ___- p A solution of 180 mg (0.400 mmol) of (1'R, 5R, 6S and 1'S, 5S, 6R) -p-nitrobenzyl-6- (1'-hydroxyethyl) -2- (1'-hydroxyethyl). 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 105 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 (0.293 mmol; crude yield 73.2%) of the title compound as a yellowish powder as a crude powder. proaukt. uv (H 2 O) Å, max = 305.5 (84800) and 255 mu (63000).

The powder was purified by high pressure liquid chromatography (Water C18 Micro Bondapack Reverse Phase 30 cm x 10 m; 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. 'am (D20) 6: 1.34 (BH. d. J-6.4 az, ena-1'), 3.26 (za, m, -enas), 3.02 (za, n. -oggacnz 1'.6a2Hz | Hz '" "6) | 402-404 (my m 'H' 1 ', | 4052-' d 'Hz,') | 3.94 (ia. Aa, J6_ 1: cxaz-disk) vmax = 3420 (ox), 3000-2000 (br. cozaa. 1105 (s-13k; am; and 1s1s = u'1 c-0025): av (ago) Am.x = 306 (e 5300) and: sa mp (e; 50q ;, 461 395 3 Example 2 2- (2-aminoethoxymethyl) penem-3-carboxylic acid (via mercaptide intermediate) s I: ulacazimase to ethyl 2-chloroethoxyacetate room 30 01 clwäæfa * "" I; iso-wow '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 were heated for 6 hours in a bomb at 150 DEG-160 DEG C. After cooling, the reaction mixture was distilled under reducing pressure. vervia merernön 6.66 g (s4.4 ml; 27.2%) ethyl chloroacetate with a boiling point of 22-24 ° (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 49-53 ° (0.1 mm Hg); * mr (mia: 6: 1. :: hu. =. -1-m.-ca,>.: .s-4.0 (fn, n. A222.-ca acnz-cl), 4.15 (zu, s, -cocnzo-3. 4.26 ppi (Zl-I, q, Jf / Bm-Olz fl sh lrflfent) V-u: 1740 fl- l (CIO ostar).

Procedure according to D. Klamann et al, Jastus Liebig Ann. Zlg (l967) 59 (Rapp: yield 42%, bp S5.5 ° / 0.35 mm Hg).

Ethyl 2-azidoethoxyacetate wa: _6733 etc. A mixture of 7.71 g (36.3 mol) of ethyl 2-chloroethoxyacetate and 3.31 g (50.9 mmol) of sodium azide in 100 ml DMF 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; % „'(Axla) 5, 1:39 (33, t, 3.733, -OCl-lzg fl ah 3.3-4.0 MH» u. -OCHZ ca2u3). 4.1: (za. =. -Cocnzo-). 4-22 PP »(1H, q. J-vnz. - ° Eë; ° H39 '1: (pure) v = 2100 (Na) and ivsu e =' 1 (c-0 asteri- NIX This material was used in the following step without further purification. 2-azidoethoxyacetic acid see u Neon Ho \\ r), \\\ n ----- »3 Q \ I / ^ \\ aø” \ ~ // 3 Hoqumi 0 G / ”\ ~ / To a solution of 6.56 g (37.9 mol) 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 overnight (17 hours). 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 sulphate and evaporated to give 4.25 g (29.3 mmol; 77.3%) of 2-azidoethoxyacetic acid as a colorless solution (cnciaa-á: a.:-4.o (nu, n. - ocazczaznan 4.22 (28. S. -Cbczizo-L 9.52 ppm (ms -cozm alternated with 020): i: (pure fi vm: zsoo-asoo (bn- conz) 21oo (un) and 111m an * c «» a5m. | This material was used in subsequent steps without further purification. 2-Azidoethoxyacetyl chloride A solution of 2.09 g (14.4 mmol) of 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; H „'(° 1¶ & & 43 (2m hc.:, J-suz, -cazo-1 3.78 (za. Br.:. J-snz. -Ca2u3> och 4.50 pp us. S, -cocuzo-y, uu-enc) vw:: zoo (un) mer, xaoo m * c-cocn.

This material was used in subsequent steps without further purification. 4- (2 * -Azidoethoxyacetylthio) -1- (paranitrobenzyl-2 "-triphenylphosphanylidene-2" -acetate) -2-azetidinone COZPNB "a To a stirred solution of 7.96 g (1.2.0 mmol) of silver -1- (para-nitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone-4-thiolate in 100 ml of dichloromethane containing 1.94 ml (2.0 mol) of pyridine was added at 0-5 ° under a nitrogen atmosphere a solution of 2.23 g (13.6 mol) of 2-azidoethoxyacetyl chloride in 20 ml of dichloromethane and the mixture was stirred for 2 hours at room temperature. After filtering the precipitate, the filtrate was evaporated and the residual oil was purified by column chromatography (S102, solution; eluent EtOAc: CH2Cl2 = 1zl). 4.216 g (6.17 mol; S1.4%) of the title phosphorane were obtained as a yellowish foam. This foam was used in subsequent steps. An analytical sample was obtained by crystallization from a 1: 9 mixture of dichloromethane and ether, m.p. 128-1290 (dec.); 1: (nujaix vm_x = zoso (-ua). 1155 (B-1-crane) and lsso: -71 (annah Anu .. benför cuazonso7vsz c 59.74. U 4.42, n 1o.zs.

S Solution: C 59.33, B 4.49, N 9.69, S 5.19: tlc (EtOAc) nf-m55, 33 461 595 p-nitrobenzyl 2- (2-azidoethoxy) methyl-penem-3-carboxylate S% NNS s 1 Ef M __ =. U =. = 2__. : IH m, m, N Å 2223 J 3 ä i: m: - co rus z _ - 2 A solution (cloudy) of 4.13 9 (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 matter, the solvent was evaporated in vacuo and the residual oil was purified by column chromatography (SiO 2, 80 g; eluent 5% ether in benzene). 2.44 g (6.02 mmol; 99.6%) of the title compound were obtained 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; 'xm- (cncia) 6: 3.35 (za, u. a-sazfoczzz-L trans _ 3.85 (1H, then, Jga-löiiz, Jds-BJS Hz, CG-il), 4.73 (Zl-1, ABq, JIIG , 19 3947 (m) “g J c6-H) | (m) t! Cz-csz). s.ao (zu. ang, a-1: .s, 9, -ocszazå. s.sa (1x, aa,: trans- zaz., ac-ilqis az. cs-nz. 1.so-1.sa -a.1z-a.z1 pp »un, Azuazu Hsh i: (nujol) Vau: 2100 (413), _1785 (B-lalctwu) och 1695 cm-l (nur) w (annu) Alu:: sa nu ( eizooo). 320.5 nu (essoo) u: (benzene fi) etherl fl.) lit-msn. 2- (2-aminoethoxy) methyl-penem-3-carboxylic acid and OCH CH Hz / Pd-C Él / S o qf "2 2 OH OH CO PNB 2 A solution of 1.62 g (4.00 mol) of the above azido ester in 50 ml of dimethoxyethane was mixed with 50 ml of ether, 50 water and 1.62 g of 10% Pd-C (Engelhard) and hydrogenated. .5 hours at 461 395 34 room temperature (hydrogen pressure 3.8 x 105 Pa) After filtration of the catalyst, the aqueous layer was washed with 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 (Hzm fl max: 304 mu (55000) This material was purified by high pressure 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 title amino acid as a white powder; Than (D20) is 3-19-3-'9 (4Hp n; (mg then; ap Jqm'-1a9 Hz 'c6- fl) | 3.88 (18, then, 39-1163 Hz, Jäs-SJ Hz , (Is-H), 4.52-4.70-4.83-5.01 (211, AB typ, 62418204 och 5.77 pp (18, då. Jah-LG flm -Tumfl-S Cs-Hh i: (nr-skiva vw: 1779 ( B-lactu) and 1,580 and hcoz fi h w (H20) Ä- “t 304 I !! (25400), 256 now (23100).

Example g Z- (Z-aminoethylation 1) nem-B-carbols (via mercaptom intermediate) I: Q "zsmzæzmz, \ Cß fl Z-azidoethylmethanesulfonate Br fi izc fi zu-l ___... uaqizçgaqg A solution of 7.5 g (60 g .0 mmol) of bromethanol and 5.0 9 (76.9 mmol) of natrimazide in 30 ml of HMPT were heated for 2.5 hours at 1150.

The reaction mixture was cooled to 23 ° 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 ° and treated with 3.57 ml (72.0 mmol) of mesyl chloride and 10, respectively. 0 ml (72, mmol) of triethylamine. The reaction mixture was stirred for 1 hour at 0 ° and then for 6 hours at 230 ° C and poured into 300 ml of water. The aqueous solution was extracted with 1 x 200 ml '(0.3 torr); 5.8 g, 58.5%; 461,395 and 4 x 100 ml of ether; the ether extracts were combined, washed with 1N hydrochloric acid, water, saturated sodium bicarbonate solution and water, dried over anhydrous magnesium sulphate and concentrated on a rotary evaporator to an orange liquid which was distilled in a high vacuum; boiling point 95-1000 in: (pure fi vmx: 2005 1. 'm (me) a: (a. us), 1:45 (s. sug-o), ms m. sag-o) an' 3.03 (s. BH , 0633), 11.43-21.76 (m. 28, H-2) 0ch 4.2-4.46 ppm (I:: of H-JJ-2'-azidoethylthioglycolic acid Å zuuzaamu + _______, 3 2 2 Nascazcoona 2- H * uacazcazscnzcoon 3, 14 g (34.1 mol) of thioglycolic acid were treated with 68 ml (68.0 mmol) of a 1N sodium hydroxide solution and the resulting solution was stirred for 0.5 h at 230 and treated with .3 g (32.1 mmol) of 2'-azidoethyl methanesulfonate in 50 ml of dimethoxyethane The reaction mixture was stirred at 45 ° for 22 hours, cooled to 230, washed with 3 x 20 ml of dichloromethane, 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 to an oil which was distilled in high vacuum at a boiling point of 117-122 ° (0.27 torr); 4.2 g, 81.2%; J. p: (i-e'nt ) vm = zioo (s, ua), 11oa (s. co) m '.' nu (cncia) 6: 2.1-3.01 (n. za. a-1 '), 2. 35 (s, 28. H-1) »3-30-3-73 šß- 2H« H-2 ') -uch11.B1 ppm (s. 1H, C008). 2'-azidoethylthioacetyl chloride (coci) 2 ï-C The reaction mixture was stirred at 230 for 1.5 hours and the solvent was removed on a rotary evaporator to give a yellow liquid. ir (rent) v__x = 2100 ca. aa). 11es (ba. C-0). inn: (cncia) 6: 2.6-a.o '(n. zu, s-1 ~), 3.37-3.13 un. zu. α -: acetidinone I - 9 ages sea ca u gwzsmzmfs L '2 2 2 3 m' _ O, \ F.PPh3 nw fl PPhs gummi '' mums: A solution of 15.7 mmol of silver-1- -1'-acetate) -2-azetidinone-4-thiolate and 1.6 ml (19.8 mmol) of pyridine in 200 ml of dichloromethane were 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 reaction mixture was stirred for 1.5 hours at 23 ° and filtered and the solid was washed with dichloromethane. , a saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and concentrated in a rotary evaporator to an orange syrup Column chromatography (300 g silica gel G-60; eluent ethyl acetate in dichloromethane, 0-40%) of the crude 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 DEG-151 DEG (decomposition) was obtained. fl pbëš. for cuxsousosszv: c saas, a 4.32, u 10.01. s 9.17: funnecc ss.s4, H 4.36. at 10.03. s 9.25. i =. (xs :) vm.:= 21oo ts. us), 11so (S, 'C-Oav B-lakcam), 1675 (s, c-o). 1sss fn. c-o), 1610 (s, ammo-y and 144o: fl- n. r-rn). 37 461 395 Paranitrobenzyl 2-aminoethylthiomethylpenem-3-carboxylate ECH2SCH2CH2N3 S: ïA -... q ß »\ 2_CHZSCHZCH2N3 ) 4- (2'-azidoethylthioacetylthio) -1- (paranitrobenzyl-2 "-triphenylphosphoranylidenylacetate) -2-azetidinone in 375 ml of toluene was stirred for 2.25 hours at 110 ° under a nitrogen atmosphere. The reaction mixture was cooled to 23 ° and evaporated. of the solvent in a rotary evaporator gave an orange syrup Purification of the crude material was carried out 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%' iz- (rent) vw: zioo (s. ns). 17as tu. co av B-1¿É: am) 5_17os = n'l is, co av rusa; 'ams icncis ) 6: 2.53-2.90 (n. Zu, a-1 "), 3.30-3.67 (m. An, uoz ', ns ezansa, 3.9: znaq, ä__b-14.am = n za, n-1'a, 5.32 (nsq, -Phnozi. 5.66. (Dd,: a_5, a_6 ei, -3.6 az. 2 las Hzp 1.3) 5-5, '(d) JRïH-suan: |: Hg HQ: vb-ia. Om, za, gu; J "- HS .8-6 trans PNB, OCh. aula Ppm (Üg 38-8 32:: of HI PNB) o: Hm-Ho 2-aminoethylthiomethylpenem-3-carboxylic acid - s' f, Ll _% 'm2s °' 2 ° 82 "s 2 2 2 3 0 - amma ~" äs To a solution of 45 mg (0.1 mmol) of p-nitrobenzyl 2-azidoethylthiomethylpenem-3-carboxylate in 5 ml of dimethoxyethane were added 5 ml of ether, 5 ml of water and 45 mg (0.1 mmol) of 10% Pd-C. The reaction mixture was hydrogenated for 3.0 hours at 23 ° 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 crude liquid chromate compound (20 mg) was purified by high pressure printing to give 5 mg (18%) of product; Lxïltlr) v- “s 1165 (c-o), zsoo = n'1 (b. Coo '); * unz (ago) 6 »: ¿vo - :. oo (n. za. a-1-3, 3.15-3.45 In. za, u-2"), 3.49 (da, så'-16.a fl :. J6,5 gta ".- 1.7as.

H-G tzanlh 3.05 (then, J fl- 'l fi dllm J6_scu'3.4li :, 3-6 ett). 4.05 (ang. J., b-14.6u :, 23, R-1) ° ch'5.14 gp: (aa, a5_6 ° ¿'.; _ 4H ,,' J, _6 ,, _ n, -1-V fl z. IB, H-sä: uv A__x =: cv 1: 4:30). : so (e szazs.

Example gel 4 (1'R, 5R, 6S and 1'S, 5S, 6R) -6- (1'-hydroxyethyl) -2- (2-aminoethoxymethyl) -penem-3-carboxylic acid (isomer B] - alternative procedure " (Isomer B) 3 "461 595 (1'R, 3S, 4R and 1'S, 3R, 4S) -4- (2-azidoethoxyacetylthio) -3- (1'-hydroxyethyl) -1- (β -trimethylsilylethyl-Z 'triphenylphosphorant liden-2 "-acetate) -2-azetidinone IHA ííà °" Ywa o N ° = z .I .- _ ee2 / \ / ~ °' * {"-: mA / six 1 54 ml (11, 8 mmol) of trimethylsilyl chloride was added to a stirred slurry of 2.48 g (3.34 mmol) of silver-3- (1'-hydroxy-ef-Yl) -1- (β -trimethylsilylethyl) -Z "-triphenylphosphoranylidene-Z" -acetate) -2-azetidinone-4-thiolate (isomer B), 136 mg (2.0 mmol) of imidazole and 1.64 ml (11.8 mol) of triethylamine in 60 ml of THF at 00. The mixture was stirred for 18 hours at 230. 60 ml of methylene chloride were added, the mixture was cooled: 111 -1s °, 1.32 ml (16.4 mol) of pyridine and 1.43 g (8.70 mmol) of β-azidoethoxy Acetyl chloride was added and the mixture was stirred for 0.5 hours at -15 DEG C. 60 ml of ether, 60 ml of ethyl acetate and 20 ml of 1M hydrochloric acid were added. the recipient 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 17 max: 1755 een 1695 enfl. (1'R, s1z, ss a 1's, ss, sn) -§ -trimethylilylethyl-z-ß-eziae-ethoxymethyl-6- (1'-hydroxyethyl) -penem-3-carboxylate (isomer B) ai OH scocazoc fl zcnzna S o YM: ___., o \ 2-ca2oca2 <: n2u3. A solution of 1.3 g of the above phosphorus in 200 ml of toluene was refluxed for 3 hours. Concentration of the solvent on a rotary evaporator 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%). irqzmax: 1760 and 1700 cm-1; 1Hmr indicated contamination with a second isomer. (1'R, 5R, 6S and 1'S, 5S, 6R) -2-α-Azidoethoxymethyl-6- (1'-hydroxyethyl) -penem-3-carboxylic acid (isomer B) A solution of 3 ml (1 .5 mmol) of anhydrous tetrabutylanuonium 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 °. After 15 minutes at 0 ° C, 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%). 1: v;.: = Asoo, ivas, 1610 = - 'I,' u- (cuu3) 6 = 1.u> (an 4. a-e.s, ena-r). 2.2: (m. Om. A.1-as (sa, n. Ca: undan-s),: .s-'4.4 (mg I 'n-l') | scen (ml d; 3-1; ( 1'R, 5R, 6S and 1'S, 5S, 6R) -6- (1'-hydroxyethyl) -2- (2-aminoethoxymethyl) -penem-3-carboxylic acid (isomer B) s aouaoamea. A solution of 150 mg of the above azido compound in 15 ml of THF, 1.5 ml of ether and 1.5 ml of water was hydrogenated in a Parrskak apparatus in the presence of 150 ml. mg 10% Pd / C at an initial hydrogen pressure of 4.1 x 105 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. by means of high pressure liquid chromatography (Waters, C18 Micro Bondpack Reverse Phase) gave 46.7 mg of the title compound in pure form.The compound was identical to a previously prepared sample obtained by hydrogenation / hydrogenolysis of the corresponding azido-p -nitrobenzyl derivative.

Claims (4)

461 395 42 2. BAIENIKEEE The compounds 4- (2'-azidoethoxyacetylthio) -3- (1'-hydroxyethyl) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone; 4- (2'-azidoethoxyacetylthio) -1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2" -acetate) -2-azetidinone: 4- (2'-azidoethylthioacetylthio) -1Å (p-nitrobenzyl-2 " -triphenyl- phosphoranylidene-2 "-acetate) -2-azetidinone: and 4. - (2'-azidoethoxyacetylthio) -3- (1'-hydroxyethyl) -1- (-trimethylsilylethyl-2 "-triphenylphosphoranylidene-2" -acetate) -2-acetidinone.