AU598832B2 - Bicyclic thiaaza compounds - Google Patents

Description

U

Form COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952-69 COMPLETE SPECIFICATION

(ORIGINAL)

Class Application Number: Lodged: I nt. Class :CcftQtgete Specification Lodged: Pjl*Aity: 0 0 'Related Art: Published: TI s docu ment ct in-4 amoendments madle tun'i. 1, Section 49 arnd is corrcct printing.

0 so 1 9 NWhe of Applicant: Address of Applicant: Actual Inventor: Address for Service: CIBA-GEIGY AG o~tlt Klybeckstrasse 141, 4002 Basle, Switzerland HANS-GEORG CAPRARO, BORIS KOHLER and PETER SCHNEIDER ;)DW WAE- 1 0 8 ,-a-QFE-STRE~MB PN~ASRLA.00 Complete Specification for the invention entitled: BICYCLIC THIAAZA COMPOUNDS The following statement it i full description of this invention, including the best method of performing it known to us 4< .i _1 s i IIII---- 1 4-15992/s t Bicyclic thiaaza compounds The invention relates to 2-penem-3-carboxylic acid compounds of the formula R H H *1

._A-R

I 0 S* R 2 p in which R represents lower alkyl substituted by 7 5 hydroxy or by protected hydroxy, R 2 represents carboxy or functionally modified carboxy, A represents lower alkylene, and R 3 represents an optionally partially unsaturated lactamyl radical or lactonyl radical bonded by way of a ring carbon atom, to optical isomers of compounds of the formula I, to mixtures of these optical

I

I

Ui -I II II~ ~I-L IIII 2 o 0 @000 00a oD a 9* 0 00 0000 06 0.0 00 0 £I 0 isomers, to salts of compounds of the formula I that have a salt-forming group, to processes for the manufacture of compounds of the formula I, to pharmaceutical preparations that contain such compounds, and to their use for the manufacture of pharmaceutical preparations or as pharmacologically active compounds.

Within the scope of this description, the definitions used hereinbefore and hereinafter have the following meanings: Functionally modified carboxy R 2 is especially esterified carboxy cleavable under physiological conditions, or protected carboxy R2 Esterified carboxy groups R 2 cleavable (that is to say metabolisable) under physiological conditions 15 are known from cephalosporin, penicillin and penem chemistry. Suitable groups are especially acyloxymethoxycarbonyl groups in which acyl is, for example, the radical of an organic carboxylic acid, especially an optionally substituted lower alkanecarboxylic acid, or in which acyloxymethyl forms the radical of a lactone. Such groups are, for example, lower alkanoyloxymethoxycarbonyl, amino-lower alkanoyloxymethoxycarbonyl, especially a-amino-lower alkanoyloxymethoxycarbonyl, and 4-crotonolactonyl. Other esterified 25 carboxy groups R 2 cleavable under physiological conditions are, for example, phthalidyloxycarbonyl, 1-lower alkoxycarbonyloxy-lower alkoxycarbonyl, 1-lower alkoxy-lower alkoxycarbonyl, or also 2-oxo-1,3-dioxolen-4-ylmethoxycarbonyl that in the 5-position of the dioxolene ring is optionally substituted by lower alkyl or by phenyl.

An optionally partially unsaturated lactamyl radical or lactonyl radical R 3 bonded by way of a ring carbon atom is especially a monocyclic 4- to 6-membered or lactonyl radical, more especially lactamyl radical or lactonyl radical, more especially 3the corresponding radical of an w-amino- or w-hydroxy-

(C

3

-C

5 )-lower alkanecarboxylic acid, respectively, or of an w-amino- or w-hydroxy-(C 4

-C

5 )-lower alkene- 144 carboxylic acid, respectively, or a bicyclic 5- or 6membered lactamyl radical or lactonyl radical, especially a corresponding benzolactamyl or benzolactonyl radical derived from an w-amino- or w-hydroxy-

(C

4

-C

5 )-lower alkenecarboxylic acid, respectively.

Such radicals R are unsubstituted or may be mono- or poly-substituted, especially mono- or di-substituted, for example, by optionally etherified or esterified a o, hydroxy, for example hydroxy, lower alkoxy, lower *alkanoyloxy or halogen, optionally etherified mercapto, for example mercapto or lower alkylthio, lower alkyl, lower alkyl substituted by hydroxy, esterified hydroxy, r such as halogen or lower alkanoyloxy, amino, lower f alkylamino, di-lower alkylamino, lower alkanoylamino, carboxy, lower alkoxycarbonyl, cyano, carbamoyl or by carbamoyloxy, lower alkenyl, optionally substituted Ij amino, for example amino, lower alkylamino, di-lower alkylamino or acylamino, such as lower alkanoylamino, carboxy, esterified carboxy, such as lower alkoxyi W, carboiyl, cyano and/or by phenyl optionally substituted, for example, by lower alkyl, hydroxy, lower alkoxy, 2 5 halogen and/or by nitro.

tg Preferred radicals R are those of the formula ii H Rq

(CH)

9 (R8-CH) Y 8\p (C C~r(II) i (C L R R R R 4 6 5 7 ii r- i -i fr- 4in which R 4

R

5

R

6 and R 7 independently of one another, each represents hydrogen or one of the radicals mentioned above as substituents of R 3 or in which R 4 together with R 5 represents a bond and Rg and R7, independently of one another, each represents hydrogen or one of the radicals mentioned above as substituents of R 3 or together represent a 1,4-butadien-1,4-ylene radical optionally substituted by hydroxy, lower alkoxy, lower alkyl, halogen and/or by nitro, R 8 and Rg, independently of one another, each represents hydrogen or one of the radicals mentioned above as substituents of R 3 Y represents a radical of the formula or in which R 1 0 represents hydrogen, lower alkyl, one of the substituted lower alkyl radicals 15 5" mentioned above as substituents of R3, especially lower alkyl substituted by amino, hydroxy, carboxy or by cyano, or R 10 represents lower alkenyl, r is 0 or 1, and p and q, independently of one another, each represents an integer of from 0 to 3, with the proviso that when r is 0 the sum of p and q is 1, 2 or 3, or 46. when r is 1 the sum of p and q is 0 or 1, and with the further proviso that the carbon atom adjacent to the lactone ring oxygen atom or to the lactam ring nitrogen atom (-NR 10 as the case may be, does not carry any substituents from the group consisting of optionally etherified or esterified hydroxy, optionally etherified mercapto and optionally substituted amino.

Corresponding monocyclic 5- or 6-membered saturated lactamyl radicals R 3 may also be called i 30 2-oxo-azetidinyl, 2-oxo-pyrrolidinyl and 2-oxo-piperidinyl, and corresponding monocyclic 5- or 6-membered unsaturated radicals accordingly may also be called 2-oxo-dihydropyrrolyl or 2-oxo-tetrahydropyridyl.

Benzo derivatives of such 5- or 6-membered lactamyl radicals are accordingly, for example, 2-oxo-benzo- M4" 5 dihydropyrrolyl or 2-oxo-benzo-tetrahydropyridyl.

Monocyclic 4- to 6-membered saturated lactonyl radicals

R

3 may accordingly also be called 2-oxo-oxetanyl, 2-oxo-tetrahydrofuryl or 2-oxo-tetrahydropyranyl and corresponding 5- or 6-membered unsaturated radicals may also be called 2-oxo-dihyd'ofuryl and 2-oxo-dihydropyranyl respectively. Benzo derivatives of such 5- or 6-membered lactonyl radicals are accordingly, for example, 2-oxo-benzo-dihydrofuryl and 2-oxo-benzodihydropyranyl. In the radicals R 3 that contain a carbon-carbon double bond or a fused benzo ring, the double bond or the benzo ring, as the case may be, is preferably a,6-positioned relative to the lactone- or lactam-carbonyl group, as the case may be.

15 The mentioned radicals are linked to the radical A by way of the ring carbon atom that is in the a-position with respect to the lactam- or lactonecarbonyl group or, especially, by way of the ring carbon atom that is in the a-position with respect to 20 the lactam ring nitrogen atom or the lactone ring oxygen atom and, in the case of 5- and 6-membered lactonyl and lactamyl radicals, further also by way of the corresponding s-positioned ring carbon atom.

In this description, the term "lower" used in connection with definitions of groups and compounds denotes, unless expressly defined otherwise, that the groups and compounds so designated contain from 1 to 7, preferably from 1 to 4, carbon atoms.

t Hydroxy-substituted lower alkyl R, is especially lower alkyl substituted in the a-position to the penem ring structure by hydroxy and is, for example, 1hydroxyprop-1-yl, 2-hydroxyprop-2-yl, 1-hydroxybut-1yl, 2-hydroxybut-2-yl and especially hydroxymethyl and 1-hydroxyethyl.

Lower alkanoyloxymethoxycarbonyl is, for example, 0# 4 4 44* 4 o44~ t *7 4 S 44 .115 .4) 4 44 S 4 4 4 4 4 4 4 ~4t .4 4 I S 114 ~U 4 44 5 4 4~ 14 41 4 4 4 4~44 -6 acetoxymethoxycarbonyl or pivaloyloxymethoxycarbonyl.

a-Amino-lower alkanoyloxymethoxycarbonyl is, for example, glycyloxymethoxycarbonyl, valyloxymethoxycarbonyl or leucyloxymethoxycarbonyl.

1-Lower alkoxycarbonyloxy-lower alkoxycarbonyl is, for example, ethoxycarbonyloxymethoxycarbonyl or 1ethoxycarbonyloxyethoxycarbonyl.

1-Lower alkoxy-lower alkoxycarbonyl is, for example, methoxymethoxycarbonyl or 1-methoxyethoxycarbonyl.

A 2-oxo-1,3-dioxolen-4-ylmethoxy group that in the 5-position of the dioxolene ring is optionally substituted by lower alkyl or by phenyl is especially a phenyl- and more especially a 5-methyl-2-oxo-1 ,3dioxolen-4-ylmethoxy group.

Lower alkoxy is, for example, methoxy or ethoxy, and also n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert.-butoxy, as well as n-pentyloxy, n-hexyloxy or n-heptyloxy.

Lower alkanoyloxy is, for example, formyloxy, acetoxy or propionyloxy.

Halogen is, for example, fluorine, chlorine, bromine or iodine.

Lower alkylthio is, for example, methylthio, ethylthio, n-propvlthio, isopropylthio or n-butylthio.

Lower alkyl is, for example, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl or tert.-butyl, and also n-pentyl, n-hexyl or n-heptyl, and especially methyl or ethyl.

Lower alkylamino is, for example, methylamino, ethylamino, n-propylamino, isopropylamino or n-butylamino, whilst di-lower alkylamino is, for example, dimethylamino, diethylamino, di-n-propylamino or diisopropylamino.

Lower alkanoylamino is, for example, acetylamino Ii ii

-I

C C i 7 1 6 0* 0 0 0 *09 4 1\D 00 9 or propionylamino.

Lower alkoxycarbonyl is, for example, methoxycarbonyl or ethoxycarbonyl.

Lower alkenyl has, for example, from 2 to 4 carbon atoms and is, for example, vinyl or allyl.

Lower alkylene A is straight-chained lower alkylene, for example methylene, 1,2-ethylene, 1,3propylene or 1,4-butylene, or branched lower alkylene, such as straight-chained lower alkylene mono- or disubstituted by lower alkyl, especially methyl or ethyl, for example ethylidene ("methyl-methylene"), 1,2propylene, 1,2-butylene, 1,3-butylene or 2-methyl-1,2propylene.

Preferred as radical RI is hydroxymethyl and especially 1-hydroxyethyl.

Preferred esterified ca.ooxy groups R 2 cleavable under physiological conditions are, for example, lower alkanoyloxymethoxycarbonyl, such as acetoxymethoxycarbonyl or pivaloyloxymethoxycarbonyl, and 1-lower alkoxycarbonyloxy-lower alkoxycarbonyl, for example 1-ethoxycarbonyloxyethoxycarbonyl.

Preferred lactamyl radicals R3 are those of the formula II (Y represents the group -NR 1 0 in which R 10 represents hydrogen or lower alkyl, R 4 and

R

5 each represents hydrogen or together represent a bond, R 6 and R7, independently of one another, each represents hydrogen, lower alkyl, lower alkyl substituted by hydroxy, halogen, lower alkanoyloxy, amino, lower alkylamino, di-lower alkylamino, lower alkanoylamino or by carbamoyloxy, or phenyl optionally substituted by lower alkyl, hydroxy, lower alkoxy and/or by halogen, R 8 and R 9 independently of one another, each represents hydrogen or lower alkyl, r is 0 or 1 and p and q, independently of one another, each represents an integer of from 0 to 3, with the proviso 8 that when r is 0 the sum of p and q is 1, 2 or 3, or when r is 1 the sum of p and q is 0 or 1, and with the further proviso that the carbon atom in radicals of the formula II that is adjacent to the lactam ring nitrogen atom does not carry any substituent from the group consisting of hydroxy, halogen, amino, lower alkylamino, di-lower alkylamino and lower alkanoylamino.

Such lactamyl radicals R 3 are, for example, 4-oxoazetidin-2-yl, 5-oxo-pyrrolidin-2-yl, -3-yl or -4-yl 0 and 6-oxo-piperidin-2-yl or -5-yl, these radicals being unsubstituted, or substituted as indicated above, such as, especially, at the lactam ring nitrogen atom by lower alkyl, for example methyl.

i Preferred lactonyl radicals R 3 are those of the 15 formula II (Y represents the group in which R4 and R5 each represents hydrogen or together represent S. a bond, R 6 and R 7 independently of one another, each represents hydrogen, lower alkyl, lower alkyl substituted by hydroxy, halogen, lower alkanoyloxy, amino, 20 0. lower alkylamino, di-lower alkylamino, lower alkanoylamino or by carbamoyloxy, hydroxy, halogen, amino, lower alkylamino, di-lower alkylamino, lower alkanoylamino, or phenyl optionally substituted by lower alkyl, hydroxy, lower alkoxy and/or by halogen, or R4 and 2 R 5 together represent a bond and R6 and R 7 together j represent a 1,4-butadien-1,4-ylene radical optionally substituted by hydroxy, lower alkoxy, lower alkyl and/or by halogen, R 8 and R 9 independently of one

S

r j another, each represents hydrogen, lower alkyl, amino 0 or hydroxy, r is 0, the sum of p and q is 2 or 3, or r is 1, q is 0 and p is 0 or 1, with the proviso that the carbon atom in the radicals of the formula II that is adjacent to the lactone ring oxygen atom does not carry any substituent from the group consisting of hydroxy, halogen, amino, lower alkylamino, di-lower _Ki "'n..,lllii i i 9 alkylamino and lower alkanoylamfino. Such lactonyl radicals R 3 are especially 5-oxo-tetrahydrofuran-2yl, -3-yl or -4-yl, 2,5-dihydro-5-oxo-furan-2-yl and 3oxo-phthalan-1-yl each unsubstituted or substituted as indicated above.

In preferred compounds of the formula I A represents methylene, ethylene or 1,2-propylene.

Tha functional groups present in the compounds of the formula I, such as hydroxy, carboxy or amino groups, especially the hydroxy group "n the radical R1 and the carboxy group R 2 are optionally protected by protecting groups used in penem, penicillin, cephalo- Co sporin and peptide chemistry. Such protecting groups S0 protect the functional groups concerned from undesired condensation reactions, substitution reactions and the like during the synthesis of the compound of the formula I from its precursors. Such protecting groups s can be removed readily, that is to say without undesirable secondary reactions taking place, for example by solvolysis or reduction.

Protecting groups of this type and the methods by Go which they are introduced and removed are described, for example, in J.F.W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London, New York, 1973, T.W. Greene, "Protective Groups in Organic Synthesis", Wiley, New York, 1981, "The Peptides", Vol. I, Schroeder and Luebke, Academic Press, London, New York, 1965, and Houben-Weyl, "Methoden der Organischen Chemie", Vol. 15/1, Georg Thieme Verlag, Stuttgart, 1974.

In compounds of the formula a hydroxy group 35 in the radical R1 and also a hydroxy group present in r i the radical R 3 may be protected, for example, by acyl radicals. Suitable acyl radicals are, for example, lower alkanoyl optionally substituted by halogen, for example acetyl, dichloroacetyl or trifluoroacetyl, benzoyl optionally substituted by nitro, for example benzoyl, 4-nitrobenzoyl or 2,4-dinitrobenzoyl, lower alkoxycarbonyl optionally substituted by halogen, for example 2-bromoethoxycarbonyl or 2,2,2-trichloroethoxycarbonyl, lower alkenyloxycarbonyl, for example 0 allyloxycarbonyl, lower alkenyloxyoxalyl, for example allyloxyoxalyl, or phenyl-lower alkoxycarbonyl o optionally substituted by nitro, for example benzyloxycarbonyl or 4-nitrobenzyloxycarbonyl. Further *suitable hydroxy-protecting groups are, for example, trisubstituted silyl, such as tri-lower alkylsilyl, for example trimethylsilyl, dimethyl-(2,3-dimethylbut-2-yl)silyl or tert.-butyl-dimethylsilyl, and 2-oxa- or 2thia-cycloalkyl having from 5 to 7 carbon atoms, for S• example 2-tetrahydropyranyl or 2-tetrahydrofuranyl. Tri- 20 lower alkylsilyl, lower alkenyloxyoxalyl and lower alkenyloxycarbonyl are preferred as hydroxy-protecting 0 groups.

A carboxy group R 2 and also a carboxy group present in the radical Rg is customarily protected in 25 25 esterified form, the ester group being readily cleavable under mild conditions, for example under mildly reductive, such as hydrogenolytic, conditions, or under mildly solvolytic, such as acidolytic or especially Sbasic- or neutral-hydrolytic, conditions. Such esterified carboxy groups contain as esterifying groups especially lower alkyl groups that are branched in the 1-position or suitably substituted in the 1- or 2position. Suitable carboxy groups in esterified form are, inter alia, lower alkoxycarbonyl, for example S methoxycarbonyl, ethoxycarbonyl or tert.-butoxycarbonyl,

I

i ~-ra*Y 11 benzyloxycarbonyl optionally substituted by nitro or by lower alkoxy, such as methoxy, for example 4-nitrobenzyloxycarbonyl or 4-methoxybenzyloxycarbonyl, lower alkancylmethoxycarbonyl, such as acetonyloxycarbonyl, benzoylmethoxycarbonyl in which the benzoyl group is optionally substituted, for example, by halogen, such as bromine, for example phenacyloxycarbonyl, halo-lower alkoxycarbonyl, such as 2-halo-lower alkoxycarbonyl, for 'xample 2,2,2-trichloroethoxycarbonyl or 2-bromoethoxycarbonyl, lower alkenyloxycarbonyl, for example Iallyloxycarbonyl, or ethoxycarbonyl substituted in the 4 2-position by lower alkylsulphonyl, cyano or by trisubstituted silyl, such as tri-lower alkylsilyl or *triphenylsilyl, for example 2-methylsulphonylethoxycarbonyl, 2-cyanoethoxycarbonyl, 2-trimnethylsilyli £ethoxycarbonyl or 2-(di-n-butylmethylsilyl)-ethoxycarbonyl. Other protected carboxy groups present in esterified form are corresponding organic silyloxyr carbonyl groups. In these the silicon atom has as substituent(s) preferably lower alkyl, especially d methyl or ethyl, or also lower alkoxy, for example I ~methoxy. Suitable silyl groups are especially trilower alkylsilyl groups, especially trimethylsilyl or dimethyl-tert.-butylsilyl. Preferred protected carboxy S 25 groups are the 4-nitrobenzyloxycarbonyl and lower alkenyloxycarbonyl, especially allyloxycarbonyl, groups, and the ethoxycarbonyl group substituted in the 2-position by tri-lower alkylsilyl, for example trimethylsilyl or di-n-butylmethylsilyl.

A protected amino group in the radical R can be, for example, in the form of a readily cleavable acylamino or silylamino group or in the form of a nitro or azido group. In a corresponding acylamino group, acyl is, for example, the acyl radical of an organic 35 acid having, for example, up to 18 carbon atoms, 25 II 1 I =a o l nrr -12especially an alkanecarboxylic acid optionally substituted, for example, by halogen or phenyl, or especially of a carbonic acid semiester. Such acyl groups are, for example, halo-lower alkanoyl, such as 2-haloacetyl, especially 2,2,2-trifluoro- or 2,2,2-trichloro-acetyl, lower alkenyloxycarbonyl, for example allyloxycarbonyl, lower alkoxycarbonyl optionally substituted in the 1or 2-position, such as lower alkoxycarbonyl, for example tert.-butoxycarbonyl, optionally substituted benzyloxycarbonyl, for example 4-nitrobenzyloxycarbonyl, 2-halo-lower alkoxycarbonyl, for example 2,2,2-trio chloroethoxycarbonyl or 2-bromoethoxycarbonyl, or 2-(trisubstituted silyl)-ethoxycarbonyl, such as 2-trilower alkylsilylethoxycarbonyl, for example 2-trimethylsilylethoxycarbonyl or 2-(di-n-butylmethylsilyl)ethoxycarbonyl. A silylamino group is especially an organic silylamino group in which the silicon atom has as substituent(s) preferably lower alkyl, for example methyl, ethyl, n-butyl or tert.-butyl, or also lower alkoxy, for example methoxy. Corresponding silyl Sgroups are especially tri-lower alkylsilyl, especially I trimethylsilyl, and also dimethyl-tert.-butylsilyl.

Preferred protected amino groups are, for example, azido, nitro, lower alkenyloxycarbonylamino, for example allyloxycarbonylamino, and benzyioxycarbonylamino optionally substituted by nitro.

Salts of compounds according to the invention are especially pharmaceutically acceptable, non-toxic salts S. of compounds of the formula I. Such salts are formed, for example, from the acidic groups present in compounds of the formula I, for example carboxy groups, and are especially metal or ammonium salts, such as alkali metal and alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, and ammonium salts with ammonia or suitable organic

H

il I e II l lca~ 13 amines, such as lower alkylamines, for example triethylamine, hydroxy-lower alkylamines, for example 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tris-(2-hydroxyethyl)-amine, basic aliphatic esters of carboxylic acids, for example 4-aminobenzoic acid 2-diethylaminoethyl ester, lower alkyleneamines, for example 1-ethylpiperidine, cycloalkylamines, for example dicyclohexylamine, or benzylamines, for example N,N'-dibenzylethylenediamine, dibenzylamine or N-benzyl- R-phenethylamine. Compounds of the formula I having a basic group, for example having an amino group, can *form acid addition salts, for example with inorganic acids, such as hydrochloric acid, sulphuric acid or phosphoric acid, or with suitable organic carboxylic or t sulphonic acids, for example acetic acid, succinic I acid, fumaric acid, maleic acid, tartaric acid, oxalic to. acid, citric acid, benzoic acid, mandelic acid, malic acid, ascorbic acid, methanesulphonic acid or 4toluenesulphonic acid. Compounds of the formula I 20 having an acidic group and a basic group can also be in the form of internal salts, that is to say in zwitter- Too ionic form. For the purposes of isolation or purification it is also possible to use pharmaceutically unsuitable salts. Only the pharmaceutically acceptable, c"t* 25 non-toxic salts are used therapeutically, and these are therefore preferred.

The penem compounds of the formula I can have additional chiral centres in the radicals R 1

R

3 and/or A. For example, 1-hydroxyethyl as a substituent Ri can be in the the S- or in the racemic R,S-configuration. In preferred penem compounds of the formula I, a radical RI having an asymmetric carbon atom, especially 1-hydroxyethyl, has the R-configuration.

Further, the carbon atom by which the radical R3 is bonded to the group A is asymmetrically substituted II I I c 14 *9 a 0000 a *a flea 13 11 i 71 a o 6 and can accordingly be in the the S- or the racemic R,S-configuration. Also, a branched lower alkylene radical A can have a chiral centre. The invention accordingly relates to the pure diastereoisomers and mixtures of diastereoisomers of compounds of the formula I that have additional chiral centres in the radicals R 1

R

3 and/or A.

The invention relates especially to compounds of the formula I in which R 1 represents lower alkyl substituted by hydroxy or by protected hydroxy, R 2 represents carboxy, esterified carboxy cleavable under physiological conditions, or protected carboxy R 2

A

represents lower alkylene and R 3 represents, bonded by way of a ring carbon atom, a monocyclic 4- to 6membered lactamyl radical derived from an w-amino-

(C

3

-C

5 )-lower alkanecarboxylic acid or w-amino-(C 4

-C

5 lower alkenecarboxylic acid, a 5- or 6-membered benzolactamyl radical derived from an w-amino-(C 4

-C

5 lower alkenecarboxylic acid, a monocyclic 4- to 6- 20 membered lactonyl radical derived from an w-hydroxy-

(C

3

-C

5 )-lower alkanecarboxylic acid or w-hydroxy-

(C

4

-C

5 )-lower alkenecarboxylic acid, or a 5- or '-membered benzolactonyl radical derived from an whydroxy-(C 4

-C

5 )-lower alkenecarboxylic acid, which radical is unsubstituted or is substituted by hydroxy, lower alkoxy, lower alkanoyloxy, halogen, mercapto, lower alkylthio, lower alkyl, lower alkyl substituted by hydroxy, halogen, lower alkanoyloxy, amino, lower alkylamino, di-lower alkylamino, lower alkanoylamino, carboxy, lower alkoxycarbonyl, cyano, carbamoyl or by carbamoyloxy, lower alkenyl, amino, lower alkylamino, di-lower alkylamino, lower alkanoylamino, carboxy, lower alkoxycarbonyl, cyano and/or by phenyl optionally substituted by lower alkyl, hydroxy, lower alkoxy, halogen and/or by nitro, optical isomers of such il 28 28 compounds of the formula I that have additional chiral centres in the radicals R R 3 and/or A, mixtures of these optical isomers, and salts of compounds of the formula I that contain a salt-forming group.

The invention relates chiefly to compounds of the formula I in which R 1 represents lower alkyl substituted by hydroxy, R 2 represents carboxy, or esterified carboxy cleavable under physiological conditions, A represents lower alkylene and R 3 represents a radical of the formula H R

(RXCH)

.R

8 P Y (C C) (I R R R R 4 6 5 7 substituted by amino, hydroxy, carboxy or by cyano, or ii lower alkenyl, R and each represents hydrogen or together represent a bond, R 6 and R 7 independently alkoxy, amino, lower alkylamino, dilower alkylamino, lower alkanoylamino or by carbamoyloxy, or phenyl optionally substituted by lower alkyl, hydroxy, lower alkoxy and/or by halogen, Rg and R 9 independently of Sone another, each represents hydrogen or lower alkyl, r is 0 or alkynd substituted by, independently of one anothhydroxy, halogen, lower alkoxy, amino, lower alkylamino, di-lower alkylamino, j 'lower alkanoylamino or by carbamoyloxy, or phenyl i optionally substituted by lower alry hydroxy, lower one another, each represents hydrogen or lower alkyl, is 0 or 1 and h and R, independently of one another, I lw 16 each represents an integer of from 0 to 3, with the proviso that when r is 0 the sum of p and q is 1, 2 or 3, or when r is 1 the sum of p and q is 0 or 1, and with the further proviso that the carbon atom in the radicals of the formula II that is adjacent to the lactam ring nitrogen atom does not carry any substituent from the group consisting of hydroxy, halogen, amino, lower alkylamino, di-lower alkylamino and lower alkanoylamino, optical isomers of such compounds of the formula I that have additional chiral centres in the radicals R R 3 and/or A, mixtures of these optical isomers, and salts of compounds of the formula I that contain a salt-forming group.

The invention also relates chiefly to compounds of the formula I in which R 1 represents lower alkyl substituted by hydroxy, R 2 represents carboxy, or esterified carboxy cleavable under physiological conditions, A represents lower alkylene and R 3 represents a radical of the formula A u~ ,oB 0 0

U

4-.

4 044 #6a #6 SAU4 66.

6 #4 r 0 H R 9 C (CH)q

(R

8 -CH) Y (C C) R R

R

5

R

R4 6 5 7

(II)

in which Y represents the group R 4 and R each represents hydrogen or together represent a bond,

R

6 and R 7 independently of one another, each represents hydrogen, lower alkyl, lower alkyl substituted by hydroxy, halogen, lower alkanoyloxy, amino, lower alkylamino, di-lower alkylamino, lower alkanoylamino or 17by carbamoyloxy, hydroxy, halogen, amino, lower alkylamino, di-lower alkylamino, lower alkanoylamino, or phenyl optionally substituted by lower alkyl, hydroxy, lower alkoxy and/or by halogen, or R 4 and Rg together represent a bond and Rg and R 7 together represent a 1,4-butadien-1,4-ylene radical optionally substituted by hydroxy, lower alkoxy, lower alkyl and/or by halogen,

R

8 and R 9 independently of one another, each represents hydrogen, lower alkyl, amino or hydroxy, r is 0, the sum of p and q is 2 or 3, or r is 1, q is 0 and p is 0 or 1, with the proviso that the carbon atom in the radicals of the formula II that is adjacent to the S lactone ring oxygen atom does not carry any substituent L from the group consisting of hydroxy, halogen, amino, t 15 lower alkylamino, di-lower alkylamino and lower alkanoylamino, optical isomers of such compounds of the formula I that have additional chiral centres in the radicals R 1

R

3 and/or A, mixtures of such optical I\ isomers, and salts of compounds of the formula I that 20 contain a salt-forming group.

The invention relates especially to compounds of S| 4 the formula I in which R 1 represents lower alkyl substituted in the a-position by hydroxy, R 2 represents carboxy, or esterified carboxy cleavable under physio- SL: 25 logical conditions, A represents lower alkylene and

R

3 represents a radical of the formula II in which Y represents the group -NR 1 0 and R 10 represents Shydrogen or lower alkyl, R 8 and R9 each represents hydrogen, r is 0, p is an integer of from 1 to 3 and q is 0 or 1, with the proviso that the sum of p and q is a maximum of 3, optical isomers of such compounds of the formula I that have additional chiral centres in the radicals RI, R 3 and/or A, mixtures of these optical isomers, and salts of compounds of the formula I that contain a salt-forming group.

18 4

I.

L

I S 'fl T t, t *I tL The invention also relates especially to compounds of the formula I in which R 1 represents lower alkyl substituted in the a-position by hydroxy, R 2 represents carboxy, or esterified carboxy cleavable under physiological conditions, A represents lower alkylene and

R

3 represents a radical of the formula II in which Y represents a group r is 1, p and q are 0,

R

4

R

5

R

6 and R7 each represents hydrogen or R4 and Rg together represent a bond and R 6 and R 7 independently of one another, each represents hydrogen, lower alkyl or lower alkyl substituted by halogen, amino, di-lower alkylamino or by lower alkanoylamino, or r is 0, each of p and is 1 and R 8 and R 9 each represents hydrogen, optical isomers of such compounds of the formula I that 15 have additional chiral centres in the radicals R 1

R

3 and/or A, mixtures of such optical isomers, and salts of compounds of the formula I that contain a salt-forming group.

The invention relates preferably to compounds of the formula I in which R 1 represents hydroxymethyl or 1-hydroxyethyl, R 2 represents carboxy, or esterified carboxy cleavable under physiological conditions, A represents methylene or ethylene and R 3 represents oxo-tetrahydrofuran-2-yl, 2,5-dihydro-5-oxo-furan-2- 25 yloptionally substituted by lower alkyl, pyrrolidin-2-yl or 4-oxo-azetidin-2-yl, optical isomers of compounds of the formula I, mixtures of these optical isomers, and salts of compounds of the formula I that have a salt-forming group.

30 The invention relates especially to the compounds of the formula I mentioned in the Examples and to their salts, especially their pharmaceutically acceptable salts.

The compounds of the present invention can be manufactured by processes known per se.

I

I-

-19- The novel compounds are manufactured, for example, as follows: an ylide compound of the formula

Z

R1 H H -I 1 3 N (III),

R

2 i oo in which R A and R3 have the meanings given under Sformula I, R 2 represents a protected carboxy group, 'Z represents oxygen or sulphur and X' represents either a trisubstituted phosphonio group or a diesterified phosphono group together with a cation, is t t Scyclised, or a compound of the formula I t t tI I R H H S1 H H S-C-A--R

C=O

2 (IV), in which R A and R 3 have the meanings given under formula I and R 2 and Z have the meanings given under formula III, is treated with an organic compound of trivalent phosphorus, and, if desired or necessary, in a resulting compound Sof the formula I a protected functional group is converted into the free functional group and/or, if liii.- 84 o 8, 8* 8e 88 8d o 8 8* 0to 8 8 20 desired, in a resulting compound of the formula I a carboxy group R 2 is converted into an esterified carboxy group that can be cleaved under physiological conditions and/or, if desired, in a resulting compound of the formula I a radical R 3 is converted into a different radical R 3 and/or, if desired, a resulting compound having a salt-forming group is converted into a salt, or a resulting salt is converted into the free compound or into a different salt and/or, if desired, a resulting mixture of isomeric compounds is separated into the individual isomers.

In the starting compounds of the formulae III and IV, functional groups, such as a free hydroxy group in the radical R, and other functional groups contained in the radical R 3 are preferably protected by conventional protecting groups, for example by those mentioned above.

Cyclisation of the compound of the formula III The group in a starting material of the formula III is one of the phosphonio or phosphono groups customary in Wittig condensation reactions, especially a triaryl-, for example triphenyl-, or trilower alkyl-, for example tri-n-butyl-, phosphonio group, or a phosphono group diesterified by lower alkyl, for example ethyl, the symbol XO in the case of the phosphono group including in addition the cation of a strong base, especially a suitable metal ion, such as an alkali metal ion, for example a lithium, sodium or potassium ion. Preferred as the group Q is, on the one hand, triphenylphosphonio and, on the other hand, diethylphosphono together with an alkali metal ion, for example a sodium ion.

Cyclisation may take place spontaneously, that is "8 8 Ixc I ~r yI i 1 34 of the formula VI takes place at room temoerature or.

21 to say during the manufacture of the starting materials, or may be effected by heating, for example in a temperature range of approximately from 30 0 C to 160 0

C,

preferably from approximately 50 0 C to approximately 100 0 C. The reaction is preferably carried out in a suitable inert solvent, such as an aliphatic, cycloaliphatic or aromatic hydrocarbon, for example cyclohexane, benzene or toluene, a halogenated hydrocarbon, for example methylene chloride, an ether, for example oo. diethyl ether, a cyclic ether, for example dioxan or tetrahydrofuran, a carboxylic acid amide, for example dimethylformamide, a di-lower alkyl sulphoxide, for example dimethyl sulphoxide, or a lower alkanol, for example ethanol, or in a mixture thereof, and, if necessary, in an inert gas atmosphere, for example a nitrogen atmosphere.

o Cyclisation of the compound of the formula IV S. An organic compound of trivalent phosphorus is derived, for example, from phosphorous acid and is especially an ester thereof with a lower alkanol, for example methanol or ethanol, and/or with an optionally substituted aromatic hydroxy compound, for example phenol or pyrocatechol, or is an amide ester thereof of the formula P(ORa) 2 N(Rb) 2 in which each of Ra and Rb, independently of the other, represents lower alkyl, for example methyl, or aryl, for example phenyl. Preferred S compounds of trivalent phosphorus are tri-lower alkyl j phosphites, for example trimethyl phosphite or triethyl Sphosphite.

The reaction is preferably carried out in an inert solvent, such as an aromatic hydrocarbon, for example benzene or toluene, an ether, for example dioxan or Stetrahydrofuran, or a halogenated hydrocarbon, for 35 which W' represents the radical I; d 22 example methylene chloride or chloroform, at a temperature of approximately from 200 to 140 0

C,

preferably from approximately 200 to approximately 110 0 C, one molar equivalent of a compound of the formula IV being reacted with at least two molar equivalents of the phosphorus compound. Preferably, the compound of the formula IV is placed in an inert solvent and the phosphorus compound, preferably dissolved in the same inert solvent, is added o 10 dropwise thereto.

In a preferred form of the process, the starting S. material of the formula IV is manufactured as a o indicated below and, without being isolated from the reaction mixture, is reacted with the organic compound 15 of trivalent phosphorus, the end products of the formula I being formed.

SCompounds of the formula I obtainable according to S.the process can be converted in a manner known per se into other compounds of the formula I.

S 20 For example, in a resulting compound of the formula I in which one or more functional groups are protected, these groups, for example protected carboxy, hydroxy and/or amino groups, may be freed, optionally 4, in stages or simultaneously, in a manner known per se by means of solvolysis, especially hydrolysis, alcoholysis or acidolysis, or by means of reduction, especially hydrogenolysis or chemical reduction.

In a compound of the formula I obtainable according to the process in which R 2 represents a protected carboxy group and/or in which the radical R3 contains protected carboxy as substituent, the protected carboxy group can be freed in a manner known per se. Thus, tert.-lower alkoxycarbonyl, or lower alkoxycarbonyl substituted in the 2-position by a trisubstituted silyl group, can be converted into free carboxy, for example,

I/

~I

.:1 -4 *s 23 by treatment with a carboxylic acid, such as formic acid or trifluoroacetic acid, optionally with the.

addition of a nucleophilic compound, such as phenol or anisole. Optionally substituted benzyloxycarbonyl can be cleaved, for example, by means of hydrogenolysis, that is to say by treatment with hydrogen in the presence of a metallic hydrogenation catalyst, such as a palladium catalyst. Furthermore, suitably substituted benzyloxycarbonyl, such as 4-nitrobenzyloxy- °10 10 carbonyl, can also be converted into free carboxy by I 0" means of chemical reduction, for example by treatment So with an alkali metal dithionite, for example sodium 0 o4 dithionite, or with a reducing metal, for example tin, customarily in the presence of a hydrogen-yielding agent that together with the metal is capable of producing nascent hydrogen, such as a suitable carboxylic acid, for example a lower alkanecarboxylic 0 0. acid optionally substituted, for example, by hydroxy, for example acetic acid, formic acid or glycolic acid, o 20 o20 or in the presence of an alcohol or thiol, it being preferable to add water. The removal of an allyl protecting group can be effected, for example, by 4O 4I reaction with a palladium compound, for example tetrakis(triphenylphosphine)palladium, optionally in the presence of triphenylphosphine and with the addition of an allyl group acceptor, such as a carboxylic acid, for example 2-ethylhexanoic acid, or a salt thereof, or tributyltin hydride, dimethylbarbituric acid or dimedone. By treatment with a 30 reducing metal or metal salt, as described above, it is Si also possible to convert 2-halo-lower alkoxycarbonyl (optionally after converting a 2-bromo-lower alkoxys ~carbonyl group into a corresponding 2-iodo-lower alkoxycarbonyl group) or benzoylmethoxycarbonyl into free carboxy, it being possible to cleave benzoyl- 37 37 37 shaped bacteria, such as Enterobacteriaceae, Haemophilus -24methoxycarbonyl also by treatment with a nucleophilic, preferably salt-forming, reagent, such as sodium thiophenolate or sodium iodide. Substituted 2-silylethoxycarbonyl can be converted into free carboxy also by treatment with a salt of hydrofluoric acid that yields the fluoride anion, such as an alkali metal fluoride, for example sodium fluoride, in the presence of a macrocyclic polyether ("Crown ether") or with a fluoride of an organic quaternary base, such as tetra- 10 .o lower alkylammonium fluoride, for example tetrabutylammonium fluoride. Carboxy esterified by an organic o t silyl group, such as tri-lower alkylsilyl, can be freed Sin customary manner by solvolysis, for example by t treatment with water or an alcohol. A lower alkoxy- S' *5 carbonyl group substituted in the 2-position by lower alkylsulphonyl or cyano can be converted into free I carboxy, for example, by treatment with a basic agent, such as an alkali metal or alkaline earth metal hydroxide or carbonate, for example sodium or potassium S 20 hydroxide or sodium or potassium carbonate.

As a further possibility, compounds of the formula I in which R 2 represents carboxy can be converted into compounds of the formula I in which R represents an esterified carboxy group that can be cleaved under physiological conditions. Such esters can be manufactured, for example, by reaction of a salt of the acid, which salt is optionally produced in situ, with a reactive ester of a corresponding alcohol W and a strong inorganic acid, such as sulphuric acid, or I 30 31 a strong organic sulphonic acid, such .s 4-toluenesulphonic acid. Also, acid halides, such as chlorides (produced, for example, by treatment with oxalyl chloride), activated esters (formed, for example, with S" N-hydroxynitrogen compounds, such as N-hydroxysuccinimide) or mixed anhydrides (obtained, for example, with i I 25 haloformic acid lower alkyl esters, such as chloroformic acid ethyl ester or chloroformic acid isobutyl ester, or with haloacetic acid halides, such as trichloroacetic acid chloride) can be converted into an esterified carboxy group by reaction with suitable alcohols, optionally in the presence of a base, such as pyridine. Furthermore, in compounds of the formula I that contain a carboxy group protected in esterified form, the carboxy-protecting group can be removed as 10 described above, and a resulting compound of the formula I having a free carboxy group, or a salt thereof, can be converted by reaction with the reactive ester of a corresponding alcohol into a compound of the tv formula I in which R 2 represents an esterified 2

J

carboxy group that can be cleaved under physiological conditions.

In compounds of the formula I obtainable according f V. to the process in which the radical RI and/or optionally the radical R3 contains protected hydroxy as S 20 substituent, the protected hydroxy group can be converted into the free hydroxy group in a manner known per se. For example, a hydroxy group protected by a suitable acyl group or by an organic silyl group is freed in the same manner as a correspondingly protected amino group (see below); a tri-lower alkylsilyl group may, for example, be removed also with tetrabutylammonium fluoride and acetic acid (under these conditions, carboxy groups protected by tri-substituted silylethoxy are not cleaved).

In a compound of the formula I obtainable according to the invention having a protected amino group, this group may be converted into the free amino group in a manner known per se, for example, depending on the nature of the protecting group, preferably by means of solvolysis or reduction. For example, 2-halo- 26lower alkoxycarbonylamino (optionally after converting a 2-bromo-jc er alkoxycarbonylamino group into a 2-iodolower alkoxycarbonylamino group) and 4-nitrobenzyloxycarbonylamino can be cleaved by treatment with a suitable chemical reducing agent, such as zinc in the presence of a suitable carboxylic acid, such as aqueous acetic acid, or by catalysis with hydrogen in the presence of a palladium catalyst, or by treatment with San alkali metal dithionite, for example sodium dithioniCe. Optionally substituted benzyloxycarbonyl- *amino can be cleaved, for example, by means of hydrogenolysis, that is to say by treatment with Sr*' hydrogen in the presence of a suitable hydrogenation catalyst, such as a palladium catalyst, and allyloxycarbonylamino may be cleaved by reaction with a palladium compound, for example tetrakis(triphenylphosphine)palladium, optionally in the presence of triphenylphosphine and in the presence of an allyl group acceptor, such as a carboxylic acid, for example 2-ethylhexanoic acid, or a salt thereof, or tributyltin hydride or dimedone. An amino group protected by an organic silyl group can be freed, for example, by hydrolysis or alcoholysis, and an amino group protected by 2-halo-lower alkanoyl, for example 2-chloroacetyl, can be freed by treatment with thiourea in the presence of a base or with a thiolate salt, such as an alkali metal thiolate, of thiourea and subsequent solvolysis, such as alcoholysis or hydrolysis, of the resulting 3condensation product. An amino group protected by 2-substituted silylethoxycarbonyl can be converted into the free amino group by treatment with a salt of hydrofluoric acid that yields the fluoride anion, such as an alkali metal fluoride, for example sodium fluoride, in *the presence of a macrocyclic polyether ("Crown ether") 35 or with a fluoride of an organic quaternary base, such 27 as tetra-lower alkylammonium fluoride, for example tetraethylammonium fluoride. An amino group protected in the form of an azido or nitro group is converted into free amino, for example, by reduction, for example by catalytic hydrogenation with hydrogen in the presence of a hydrogenation catalyst, such as platinum oxide or palladium, or by treatment with zinc in the presence of an acid, such as acetic acid.

In compounds of the formula I it is also possible *to convert a radical R 3 into a different radical R 3 oto Thus, for example, in compounds of the formula I S.,in which the radical R 3 is substituted by a carboxy group, this carboxy group can be converted according to processes known per se into a functionally modified S 15 carboxy group, such as into an esterified carboxy group. For example, by reacting a compound of the formula I in which the radical R3 is substituted by carboxy with an alcohol, especially a lower alkanol, r there is obtained a compound of the formula I in which R3 is substituted by esterified carboxy, especially lower alkoxycarbonyl, it being preferable to carry out the operation in the presence of a suitable condensatttion agent, for example a carbodiimide, or to remove by azeotropic distillation the water that is formed. On 25 the other hand, carboxy groups in radicals R 3 can also be converted into reactive functional derivatives, such as mixed anhydrides, for example acid halides, or activated esters, and these can be converted by reaction with an alcohol, for example a lower alkanol, into correspondingly esterified carboxy groups, it being preferable when using mixed anhydrides to carry out the operation in the presence of an acid-binding agent, such as an aromatic or tertiary amine or an alkali metal or alkaline earth metal carbonate.

In compounds of the formula I in which the radicdl i -L 28

R

3 is substituted by amino, the amino group can be converted into a substituted amino group, for example a lower alkylamino, di-lower alkylamino or lower alkanoylamino group. The conversion into a lower alkylamino or di-lower alkylamino group is effected, for example, by reaction with a reactive esterified lower alkanol, for example with a lower alkyl halide or sulphonate, in the presence of a basic condensation agent, such as a hydroxide or carbonate of an alkali metal or alkaline 10 earth metal or a heteroaromatic nitrogen base, for example pyridine. In analogous manner, amino can be converted by treatment with the reactive functional y derivative of a lower alkanecarboxylic acid, for I example the corresponding carboxylic acid halide, into 1 15 lower alkanoylamino. Compounds of the formula I having a substitutable ring nitrogen atom in the radical R 3 [Y in the radical of the formula II is can be converted in analogous manner with optionally substituted lower alkyl halides or lower alkenyl halides in the presence of a strong base, for example which the radical R 3 contains a ring nitrogen atom substituted by optionally substituted lower alkyl or lower alkenyl.

Salts of compounds of the formula I having saltforming groups can be manufactured in a manner known per se. Thus, salts of compounds of the formula I having a free carboxy or sulpho group can be formed, for example, by treatment with metal compounds, such as 30 alkali metal salts of suitable organic carboxylic i acids, for example the sodium salt of a-ethylcaproic acid, or with inorganic alkali metal or alkaline earth metal salts, for example sodium hydrogen carbonate, or Swith ammonia or with a suitable organic amine, it being preferable to use stoichiomnetric amounts or only a i I

I~

29 small excess of the salt-forming agent. Acid addition salts of compounds of the formula I are obtained in customary manner, for example by treatment with a suitable acid or a suitable anion exchange reagent.

Internal salts of compounds of the formula I can be formed, for example, by neutralising salts, such as acid addition salts, to the isoelectric point, for example with weak bases, or by treatment with ion exchangers.

Salts can be converted into the free compounds in customary manner; metal and ammonium salts, for example, r ,by treatment with suitable acids, and acid addition salts, for example, by treatment with a suitable basic Sagent.

t r Resulting mixtures of isomeric compounds can be separated into the individual isomers according to methods known per se. For example, a resulting racemate can be reacted with an optically active auxiliary, the resulting mixture of two diastereoisomeric compounds can be separated by suitable physicochemical methods (for example fractional crystallisation, adsorption chromatography), and the individual diastereoisomeric compounds can then be cleaved to form the optically active compounds.

25 In all subsequent conversions of resulting compounds of the formula I, those reactions are preferred which take place under moderately alkaline or, especially, neutral conditions.

The process also includes those forms according to 30 which compounds formed as intermediates are used as starting materials and the remaining process steps are carried out with them, or the process is discontinued at any stage. Furthermore, starting materials can be used in the form of derivatives or can be formed 35 in situ, optionally under the reaction conditions.

;r i j i

Y

;1! 30 The starting compounds of the formulae III and IV can be manufactured as indicated in the following.

reaction scheme I: Reaction scheme I H H W ft ft~ ftftft ft ft ft., ft ft ft ft* ft p ft ft& ft ft ftp ft p PIft ft 'ft ft ft ftftft

LI

lIt tiLl I Li LI I 7 0.

(V)

Sta H H NCHr,X 12-0 Stage 1 ge 3

(VII)

H H 0

(VI)

I Stage 2 H H S-C-A-R 2' (IV) Stage 4

W.

_R

0 D

(III,)

I

44 1-vll-9-t-rinhp nx,nho-,nhoranvlideneacetic! acid allvl L IIC~ 31 Stage 1 Suitable starting compounds of the formula V in which W represents a radical that can readily be exchanged by nucleophilic reaction, for example lower S alkanoyloxy, such as acetoxy, or sulphonyloxy Ro-SO 2 in which R o represents, for example, optionally hydroxy-substituted lower alkyl, such as methyl, tert.butyl or 2-hydroxyethyl, are known, for example, from the published European Patent Application No. 82113, t 10 1German Offenlegungsschrift No. 3 224 055 and German Offenlegungsschrift No. 3 013 997 or can be manufactured in a manner analogous thereto.

In compounds of the formula VI W' represents the radical 3 or triphenylmethylthio or lower 15. alkanoylthio.

A compound that introduces the radical 3 is, for example, an acid of the formula 0 R 3 or especially a salt thereof, for example an alkali metal salt, such as the sodium or potassium 2salt. The substitution may be carried out in an organic solvent, such as in a lower alkanol, a lower alkanecarboxylic acid amide, a cyclic ether, or in a tiff similar inert solvent, at room temperature or at slightly elevated or reduced temperature, for example at from approximately 00 to approximately 40 0

C.

The introduction of a triphenylmethylthio or lower alkanoylthio radical W' is effected in an analogous manner by reaction with an alkali metal salt, for example the sodium salt, of a lower alkanethio- 0 carboxylic acid, for example thioacetic acid, or of Striphenylmethyl mercaptan.

Acids of the formula R 3 and their salts are known from the Literature or can be manufactured in a manner analogous to the processes in the Literature.

described in the Literature.

1 -r :1

-O

i,

Y

i"l~;il 45 alvnwvlir a-cid allvl Pt-Pr t-hvl semiacetal in 100 ml of i i_ u 32 Stage 2 A starting compound of the formula (IV) is obtained by treating an azetidinone of the formula (VI) in which W' represents the radical 3 with an acid of the formula R2'-COOH or especially with a reactive derivative, such as an ester or acid halide, for example the acid chloride, thereof, at a temperature of from -500 to 80 0 C, preferably at from -200 to 0 0 C, in an inert solvent, such as one of those mentioned for the reaction of compounds of the formula (IV) to form compounds of the formula I. When using an acid halide, the operation is preferably carried out in the presence of an acid-binding agent, such as a tertiary aliphatic amine, an aromatic amine or especially an alkali metal or alkaline earth metal carbonate or hydrogen carbonate.

Compounds of the formula (VI)-in which W' represents triphenylmethylthio or lower alkanoylthio can be converted into the starting compounds of the formula VI Sin which W' represents the radical 3 by reacting them in the presence of a base, for example pyridine or tri-n-butylamine, in a suitable solvent, r.t? for example diethyl ether or methanol, with a salt of the formula MA in which M represents a transition metal cation, especially the silver cation, and A represents a customary anion that promotes the solubility of the salt MA in the chosen solvent, for example the nitrate, acetate or fluoride anion, and treating the resulting salt of the formula H H R M H M R

(VI')

46 46 d) qi l xur cq I- of 2- f VA q AP A- (1 I -1 '-11 lvlOxv- 33 with an acylating agent that introduces the radical for example with the acid R 3

-A-C(=Z)-OH

or with a reactive functioral derivative, such as an acid halide, for example the chloride or bromide, azide or anhydride, thereof. If a reactive functional derivative of the acid of the formula R 3 for example the acid chloride, is used, the acylation is effected in an inert solvent, such as a chlorinated hydrocarbon, or an ether, at room temperature or while heating or cooling, for example in a temperature range l of from approximately -500 to approximately Si especially at from approximately -300 to approximately +200C.

Acids of the formula R 3 and reactive 15 functional derivatives thereof are known from the Literature or can be manufactured in a manner analogous to the processes described in the Literature.

Stage 3 Compounds of the formula VII in which X o represents a reactive esterified hydroxy group, especially halogen, for example chlorine or bromine, are manufactured by reacting a compound of the formula VI with a glyoxylic acid compound of the formula R2'-CHO or a suitable derivative thereof, such as a hydrate, hemihydrate or hemiacetal, for example a hemiacetal with a lower alkanol, for example methanol or ethanol, and in a resulting compound of the formula VII in which X represents hydroxy, converting the hydroxy group into a 1 30 reactive esterified hydroxy group. The compounds of the formula VII are customarily obtained in the form of a mixture of the two isomers [with respect to the grouping

-CH(R'

2 )MXo].

The addition of the glyoxylic acid ester compound to the nitrogen atom of the lactam ring in the compound 34 of the formula VI takes place at room temperature or, if necessary, while heating. When using the hydrate of the glyoxylic acid compound, water is formed which, if necessary, is removed by distillation, for example azeotropic distillation, or by using a suitable dehydrating agent. The operation is preferably carried out in the presence of a suitable inert solvent or solvent mixture.

The conversion of a hydroxy group X o into a reactive esterified hydroxy group X o in a compound of the formula VII is carried out by treatment with a Sf suitable esterifying agent, for example with a thionyl c halide, for example thionyl chloride, preferably in the i' presence of a basic, especially organic basic, agent, such as an aliphatic tertiary amine, or in the presence of a heterocyclic base of the pyridine type. Preferably, the operation is carried out in the presence of a suitable solvent, for example dioxan or tetrahydrofuran, or a solvent mixture, if necessary while cooling, for example at from approximately -30° to approximately S- 30 0

C.

Stage 4 t t S' The starting material of the formula (III) is obtained by treating a compound of the formula (VII) with a suitable phosphine compound, such as a trilower alkylphosphine, for example tri-n-butylphosphine, or a triarylphosphine, for example triphenylphosphine, i w or with a suitable phosphite compound, such as a trij lower alkyl phosphite, for example triethyl phosphite, or an alkali metal di-lower alkyl phosphite, for example an alkali metal diethyl phosphite, and converting a compound of the formula (III') which may result in which W' represents triphenylmethylthio or lower alkanoylthio into a compound of the formula (III') in which W' represents the radical 3 The reaction with the phosphine or phosphite compound is preferably carried out in a suitable inert solvent, such as a hydrocarbon, or an ether, or in a solvent mixture. Depending on the reactivity, the reaction is carried out while cooling or at elevated temperature, for example from -100 to +100 0 C, preferably at approximately from 200 to 80 0 C. The reaction is customarily carried out in the presence of a basic agent, such as an organic base, for example an amine, eo or "polystyrene HUnig base", or an inorganic base, for oo example an alkali metal carbonate, the initially formed phosphonium compound of the formula *9

S

H H R1 W'

.N

in which X' represents a phosphono group or a phosphonio group together with an anion which, depending on the meaning of the radical Xo (see formula VII) may be, for example, a chloride anion, being converted into the ylide starting material of the formula III.

The introduction of the radical 3 into i compounds of the formula III' in which W' represents lower alkanoylthio or triphenylmethylthio can be effected in a manner analogous to that described in Stage 2.

The process described in Reaction Scheme I for the manufacture of the compounds of the formulae (III), -49- Example 16: (5R,6S)-6-(tert.-butyldimethylsilyloxy- *9 0o o 049 0 9 *4 t t00 V 9

SI

4s I- 44 I c -I c- I- l-LI- 36 (VI) and (VII) and also the processes given for the manufacture of the end products of the formula (I) can also be carried out with optically inactive compounds, and, at any stage of the process, the optically active compounds according to the present invention can be isolated from a resulting diastereoisomeric mixture or racemate in known manner, for example as described above.

The invention relates also to the novel starting 10 compounds, and to novel intermediates obtainable according to the process, such as those of the formulae (III), (IV) and also (VI) and (VII) represents the radical 3 and to the processes given for their manufacture.

The starting compounds used and the reaction conditions chosen are preferably those which result in f a compounds of the formula I described hereinbefore as being especially preferred.

The compounds of the formula I have valuable 20 pharmacological properties or can be used as intermediates for the manufacture of such compounds having valuable pharmacological properties. Compounds of the formula I in which R 1 represents lower alkyl substituted by hydroxy, R 2 represents carboxy, or an esterified carboxy group cleavable under physiological conditions and A and R3 have the meanings given under formula I, and pharmacologically acceptable salts of such compounds having salt-forming groups have antibacterial activity. For example, they are effective in vitro against gram-positive and gram-negative cocci, including enterococci, for example Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pleumoniae and Streptococcus faecalis and Neisseria sp.

in minimum concentrations of from approximately 0.01 to approximately 64 ug/ml, and against gram-negative rod- 37 shaped bacteria, such as Enterobacteriaceae, Haemophilus influenzae and Pseudomonas aeruginosa, in minimumconcentrations of from approximately 0.05 to approximately 128 ug/ml and against anaerobes, such as Bacteroides fragilis or Clostridium sp., in minimum concentrations of from approximately 0.01 to approximately 0.5 ug/ml. In vivo, in the systemic infection of mice, for example by Staphylococcus aureus, Streptococcus pyogenes or Escherichia coli, in the case of 10 subcutaneous administration of compounds according to D no 0 the invention ED 5 0 values of from approximately 2 to oo* approximately 15 mg/kg are obtained.

O '0 The novel compounds can be used as orally or O00 0 1 parenterally administrable antibacterial antibiotics, for example in the form of corresponding pharmaceutical preparations, for the treatment of infections.

Compounds of the formula I in which at least one of the functional groups present is in protected form o. o can be used as intermediates for the manufacture of the above-mentioned pharmacologically active compounds of the formula I.

The pharmacologically acceptable compounds of the present invention can be used, for example, for the manufacture of pharmaceutical preparations that contain a therapeutically effective amount of the active substance together or in admixture with inorganic or organic, solid or liquid, pharmaceutically acceptable carriers that are suitable for oral or for parenteral, Jl that is to say, for example, intramuscular, subcutaneous or intraperitoneal, administration.

For oral administration there are used tablets or gelatine capsules that contain the active ingredient together with diluents, for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, and lubricants, for example silica, talc, stearic acid x r .ir-r -i 38 or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Tablets also contain binders, for example magnesium aluminium silicate, starches, such as corn, wheat, rice or arrowroot starch, gelatine, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and, if desired, disintegrators, for example starches, agar, alginic acid or salts thereof, such as sodium alginate, and/or effervescent mixtures or adsorbents, colourings, flavourings or sweeteners.

For parenteral administration there are suitable especially infusion solutions, preferably isotonic aqueous solutions or suspensions, it being possible to prepare these before use, for example from lyophilised preparations that contain the active substance alone or together with a carrier, for example mannitol. Such preparations may be sterilised and/or may contain adjuncts, for example preservatives, stabilisers, wetting agents and/or emulsifiers, solubilisers, salts for regulating the osmotic pressure and/or buffers.

The present pharmaceutical preparations, which, if desired, may contain other pharmacologically valuable substances, are manufactured in a manner known per se, Si for example by means of conventional mixing, dissolving or lyophilising processes, and contain from approximately 0.1 to 100 especially from approximately 1 to approximately 50 or, in the case of lyophilisates, up to 100 of the active ingredient.

Depending upon the nature of the infection and the I 30 condition of the infected organism, the daily dose (oral or parenteral) used for the treatment of warm-blooded animals (humans and animals) weighing approximately kg is from approximately 100 mg to approximately 2 g.

The following Examples serve to illustrate the invention. Temperatures are given in degrees Celsius.

-52- I 39 Example 1: 2-[(3S,4R)-3-(tert.-butyldimethylsilyloxymethyl)-4-[(2S)-5-oxo-pyrrolidin-2-yl-acetylthio]-2-oxoazetidin-1-yl-2-triphenylphosphoranylideneacetic acid allyl ester 1.32 g (8.2 mmol) of (2S)-5-oxo-pyrrolidin-2-ylacetyl chloride (prepared from the acid with SOC1 2 is slowly added dropwise, while stirring, to a solution of 4.0 g (5.6 mmol) of the silver salt of 2-[(3S,4R)-3- 0 (tert.-butyldimethylsilyloxymethyl)-4-mercapto-2-oxoe 10 azetidin-1-yll-2-triphenylphosphoranylideneacetic acid allyl ester (European Patent Application No. 125207) and 0.85 ml (10.6 mmol) of pyridine in 70 ml of CH 2 Cl 2C2 (00 under N 2 When the dropwise addition is complete, Sthe whole is stirred for a further h hour at 00. The precipitate is filtered off with suction over Hyflo and the filtrate is washed twice with saturated NaHC03 solution and twice with saturated sodium chloride solution, dried with Na 2

SO

4 and concentrated by evaporation. The crude product is purified by flash chromatography (silica gel Merck 70-230 mesh ASTM; ethyl acetate) aD (1.12 ethanol) 25.60; S; IR (3 CH 2 C1 2 3420, 2860-3500, 1756, 1702, 1641, 1438, 1241, 1104, 838 cm-1'.

Example 2: (5R,6S)-6-(tert.-butyldimethylsilyloxymethyl)-2-[(2S)-5-oxo-pyrrolidin-2-ylmethyll-2-penem-3carboxylic acid allyl ester 1.7 g of 2-[(3S,4R)-3-(tert.-butyldimethylsilyloxymethyl)-4-[(2S)-5-oxo-pyrolidin-2-acetylthiol-2-oxoazetidin-1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester are dissolved in 500 ml of toluene and the solution is stirred under reflux for 1.5 hours under nitrogen. Concentration of the solution by evaporation 53 I- 1 II e 1% n A f% -1 If A A 1 -7 if '1 0 '3 a 1 ii El

I

iJ

I

ii 1.1 1 11 Li 40 and flash chromatography (silica gel Merck 70-230 mesh ASTM; toluene/ethyl acetate 1:1) yield the pure end product.

aD (1 .02 ethanol) 1 12. IR (3 CH 2 Cl 2 3420, 2820-3460, 1789, 1702, 1651, 1581 1314, 1122, 837 cm1 1.

1 H-NMR (CDCl 3 8 5.96 5.86 5.57 (d,1, 5.39 (dd,I, J=1.3 and 17.4), 5.25 (dd,1, J=1.3 and 10.5), 4.72 (ddd,l, J=1.0, 5.0 and 13.0), 3.96 (dd,1, J=4.5 and 11.0), 3.92 (dd,1, J=3.9 and 11.0), 15 3.90 3.86 3.33 (dd,1, J=5.3 and 13.9), 2.71 (dd,1, J=5.7 and 13.9), 2.35 (mn,2) 2.30 1 .87 0.88 0.08 ppm.

Example 3: (5R,6S)-6-hydroxymethyl-2-[(2S)-5-oxo- 20 pyrrolidin-2-ylmethyl]-2-penem-3-carboxylic acid allyl ester 770 mg (1.70 mmol) of (5R,6S)-6-(tert.-butyldii-ethylsilyloxymethyl)-2-[ (2S)-5-oxo-pyrrolidin-2ylmethyl]-2--penem-3-carboxylic acid allyl ester are 25 dissolved in 35 ml of dried tetrahydrofuran and, under an argon atmosphere, after the solution has been cooled to -780, 0.67 ml (11.71 mmol) of acetic acid is added.

3.76 ml (3.76 mmol) of a 1M tetrabutylammonium fluoridp solution in tetrahydrofuran are then added dropwise and 30 the mixture is allowed to come up to room temperature and is stirred for 4.5 hours at that temperature.

less The white product slowly precipitate8s and is washed with cold dried tetrahydrofuran and then with ether.

M.p. 134-1380.

ah (1,00 ethanol) 1 3 4 0 o; IR (3 CH 2 Cl 2 3615, 3420, 2820-3700, 1790, 1705, 1653, 1580, 1315 cm-1; 1 H-NMR (CDCl 3 6.12 5.95 5.65 (d,1, J=14), 5.41 (dd,1, J=1.3 and 17.4), 5.28 (dd,1, J=1.3 41 and 10.5), 4.78 (ddd,1, J=1.0, 5.0 and 13.0), 4.66 (ddd,1, J=1.0, 5.0 and 13.0), 4.01 3,*if6 3.92 3.30 (dd,1, J=5.3 and 13.9), 2.75 (dd,1, J=5.7 and 13.9), 2.42 2.34 2.30 1.87 ppm.

Example 4: Sodium salt of (5R,6S)-6-hydroxymethyl-2- (2S)-5-oxo-pyrrolidin-2-ylmethyl1-2-peflem-3-carboxylic acid 390 mg (1.16 mmol) of (5R,6S)-6-hydroxymethyl-2- -5-oxo-pyrrol id in-2-ylmethyl] -2-penem-3-carboxyl ic acid allyl ester and 163 mg (1.16 mmoi) of dimedone are dissolved in 150 ml of ethanol at 350 under a nitrogen atmosphere. After the addition of 183 mg (0.16 mmol) of palladium-tetrakis (triphenylphosphine), 0 the reaction mixture is stirred for 2.5 hours at the same temperature in the dark. The white suspension is *o filtered and washed with cold ethanol, ethyl acetate and ether. The product is filtered over XAD-2 in the form of a sodium salt at a pH of 7.1 using sodium bicarbonate solution and subsequently lyophilised.

aD (0.38

H

2 104.50; UV (H 2 -L max 260, 305 nm; IR (DMSO-d 6 2700-3680, 1770, 1690, 1610, 1581, 1367 cm's 1 H-NMR (D 2 0) &5.61 1, J=1 4. 03 1) 3. 99 3.94 3.12 (dd, J=5.5 and 14.3), 3.03 (dd,1, J=5.5 and 14.3), 2.40 2.31 1.91 Example 5: (3S,4R)-3-(tert.-butyldimethylsilyloxy-_ methyl)-4-1 (2R)-5-oxo-pyrrolidin-2-ylacetylthio]-2oxoazetidin-1 -yl] -2-triphenylphosphoranylideneacetic acid allyl ester T-'e title compound is manufactured analogously to -42 Example 1 from the silver salt of 2-[(3S,4R)-3-(tert.butyldimethylsilyloxymethyl) -4-mercapto-2-oxo-azetid in- 1-yl] -2-triphenyiphosphoranylideneacetic acid allyl ester and (2R)-5-oxo-pyrrolidin-2-ylacetyl chloride (prepared from the acid with SOC1 2 aD(0.99 ethanol) 32.30; IR (3 CH 2 l) aD21) 3420, 2835-3470, 1756, 1704, 1620, 1437, 1242, 1104, 838 cm- 1 Example 6: (5R,6S)-6-(tert.-butyldimethylsilyloxymethyl)-2-[ (2R)-5-oxo-pyrrolidin-2-ylmethyl]-2-penem-3carboxylic acid allyl ester (3S,4R)-3-(tert.-butyldimethylsilyloxymethyl)- 4- -5-oxo-pyrrolidin-2-ylacetylthio] -2-oxo-azetidin- ,15 1-yl]-2-triphenylphosphoranylideneacetic acid allyl analogous to that described in Example 2.

M.P. 99-1010.

aD (0.98 ethanol) 85.00; IR (3 CH 2 Cl 2 3420, 2770-3470, 1789, 1704, 1581, 1315, 1121, 837 cm- 1 ~c 1 H-NMR (CDCl 3 6 5.77 60 (d,1, 5.43 (dd,1, J=1.3 and 17.4), 5.25 (dd,1, J=1.3 and 11.0), 4.72 (ddd,1, J=1.0, 5.0 and 13.7), 4.59 S 25 (ddd,1, J=1.0, 5.0 and 13.7), 3.97 (dd,1, J=5.0 and 10.8), 3.92 (dd,1, J=4.0 and 10.8), 3.90 3.85 3.14 (dd,1, J=6.3 and 14.1), 2.92 (dd,1, and 14.1), 2.37 2.29 1.87 0.89 0.08 ppm.

Example 7: (5R,6S)-6-hydroxymethyl-2-[ pyrrolidin-2-ylrhethyl]-2-penem-3-carboxylic acid allyl ester The title compound is obtained analogously to Example 3 starting from (5R,6S)-6-(tert.-butyldimethyl- -56- Al 1 X,l cc!4- e ii I; I u~~ Qa o a p 0 *a a a a a se a a 43 silyloxymethyl)-2-[(2R)-5-oxo-pyrrolidin-2-ylmethyl]-2penem-3-carboxylic acid allyl ester.

aD (1.04 ethanol) 93.40; IR (3 CH 2 Cl 2 3603, 3419, 2750-3700, 1737, 1703, 1578, 1315 cm1 1 H-NMR (CDCl 3 6 G.50 5.93 (m,1)1 5.67 5.43 (dd,1, J=1.3 and 17.4), 5.28 (dd,1, J=1.3 and 11.0), 4.77 (dd,1, J=5.0 and 13.7), 4.66 (dd,1, J=5.0 and 13.7), 4.00 3.94 3.24 (dd,1, J=6.3 and 14.2), 2.83 (dd,1, J=4.8 and 14.2), 2.82 2.38 2.31 1.87 ppm.

Example 8: Sodium salt of (5R,6S)-6-hydroxymethyl-2- [(2R)-5-oxo-pyrrolidin-2-ylmethyl-2-penem-3-carboxylic acid The title compound is obtained in a manner analogous to that described in Example 4 starting from (5R,6S)-6-hydroxymethyl-2-[(2R)-5-oxo-pyrrolidin-2ylmethyl]-2-penem-3-carboxylic acid allyl ester.

aD (0.28 H 2 0) 169.40; UV (H 2 0) Xmax 259, 305 nm; IR (DMSO-d 6 2700-3650, 1769, 1690, 1610, 1582, 1367 cm- 1 1 H-NMR (D 2 5.61 (d,1 4.03 4.00 3.95 3.38 (dd,1, J=6.2 and 14.3), 2.69 (dd,1, J=4.8 and 14.3), 2.44 2.38 2.31 1.90 ppm.

Example 9: -allyloxycarbonyloxyethyl] (2S)-5-oxo-pyrrolidin-2-ylacetylthioll-2-oxoazetidin-1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester The title compound is manufactured analogously to Example 1 from the silver salt of 1'-allyloxycarbonyloxyethyl-4-mercapto-2-oxo-azetidina~ a, 4 44 4' a ,4 y1;4~ I I 57 IR (5 CH 2 C1 2 2800-3200, 1760, 1687, 1620, 1110 cm-1 -44 ester and (2S)-5-oxo-pyrrolidin-2-ylacetyl chloride (preparedtrom he fo~reenacid~naei acid allyl) IR (3 CH 2 Cl1 2 34 2 0, 2 86 0-35 0 0, 175 6, 1701 cmI The starting compound can be manufactured as follows: I a) Iallyloxycarbonyloxyethyl.4tr iphenylmethylthio-azetidin- 2 -one 7.22 g of triphenylmethylmercaptan are suspended I in 40 ml of methanol at 00 and a total of 1.29 g of a 155 sodium hydride suspension in oil is added in portions over a period of 10 minutes. Subsequently, an emulsion of 6.95 g of (1 '-allyloxycarbonyloxyethyl]-4-tert.-butylsulphonylaze-tidin- 2 one (European Patent Application N o. 126709) in 40 ml I acetone and 40 ml of water are added dropwise over a I period of 30 minutes. After stirring for 30 minutes at 00 and for 1 hour at room temperature, the reaction mixture is concentrated in a rotary evaporator, 4 methylene chloride is added, and the aqueous phase is separated off. The organic solution is washed with brine and dried over sodium sulphate. After concentration, the crude title compound is purified by chromatography on silica gel (eluant toluene/ethyl acetate 2:3).

TLC (toluene/ethyl acetate R 0.59; IR (CH 2 Cl 2 3390, 1760 cm.

b) (I '-allyloxycarbonyloxyethyl]- 4-triphenylmethylthio-2-oxo-azetidin-1 -yl] -2-hydroxyacetic acid allyl ester g of molecular sieve (dR) are added to 7.95 g of '-allyloxycarbonyloxyethyl]-4triphenylmethylthio-azetidin-2-one and 4.03 g of -58a. rn Aor n'mn-~lrn 17Qn-l 1741;- 1705.

r r- i--ll-u 45 glyoxylic acid allyl ester ethyl semiacetal in 100 ml of absolute toluene and the whole is stirred for 94 hours at 600. After filtration and concentration in a rotary evaporator under reduced pressure, the crude product is purified by chromatography on silica gel (eluant toluene/ethyl acetate TLC (silica gel, toluene/ethyl acetate Rf 0.22 and 0.16; IR (CH 2 Cl 2 3521, 1760, 1745 cm 1 c) 2-[(3S,4R)-3-[(1'R)-1'-allyloxycarbonyloxyethyl]- 4-triphenylmethylthio-2-oxo-azetidin-1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester 182 ul of thionyl chloride and 206 ul of pyridine are added in succession within a period of 5 minutes, at -15° while stirring, to a solution of 1.0 g of 2-[(3S,4R)-3-[(1'R)-1'-allyloxycarboyloxyethyl]-4-tri- S* phenylmethylthio-2-oxo-azetidin-1-yl]-2-hydroxyacetic acid allyl ester in 10 ml of tetrahydrofuran. The white suspension is subsequently stirred for 1 hour at -100 and filtered over Hyflo. The residue is washed with toluene and then concentrated in a rotary evaporator. The residue is dissolved in 10 ml of dioxan, 624 mg of triphenylphosphine and 0.257 ml of 2,6-lutidine are added and the whole is stirred at 800 bath temperature for 46 hours. The mixture is filtered over Hyflo and this residue is subsequently washed with toluene. The combined filtrates are CE' concentrated by evaporation. Chromatography of the residue on silica gel yields the pure product (eluant toluene/ethyl acetate TLC (silica gel, toluene/ethyl acetate Rf 0.20; IR (CH 2 C1 2 1745, 1605 cm 1 :4 .ilrr~L 1 i 46 d) Silver salt of 2-[(3S,4R)-3-[(1'R)-1'-allyloxycarbonyloxyethyl-4-mercapto-2-oxo-azetidin-1-yl]-2 triphenylphosphoranylideneacetic acid allyl ester 5.31 g of '-allyloxycarbonyloxyethyl]-4-triphenylmethylthio-2-oxo-azetidin-1-yl]-2triphenylphosphoranylideneacetic acid allyl ester are placed in 63 ml of ether and, at room temperature, ml of a 0.5M aqueous silver nitrate solution are added. Subsequently, 14.7 ml of a mixture of 3.6 ml of tributylamine, 0.18 ml of trifluoroacetic acid and ml of ether are added dropwise thereto and the reaction mixture is stirred for a further 20 minutes.

The solid material is then filtered off with suction and washed with ether, water and again with ether. The solid material is, for the purpose of purification, made into a paste in 40 ml of ether and 40 ml of water, filtered with suction and dried.

IR (CH 2 C1 2 1760, 1621 cm- 1 Example 10: '-allyloxycarbonyloxyethyl]-2-[(2S)-5-oxo-pyrrolidin-2-ylmethyl]-2-penem-3carboxylic acid allyl ester N4 9 4 a* 4.

at,, 4.I 2-[(3S,4R)-3-[(1'R)-1'-allyloxycarbonyloxyethyl] -4- 94 [(2S)-5-oxo-pyrrolidin-2-ylacetylthio]-2-oxo-azetidin- 1-yl]-1-triphenylphosphoranylideneacetic acid allyl ester is converted into the title compound in a manner analogous to that described in Example 2.

IR CH 2 C12): 3420, 2820-3460, 1791, 1701 cm-1 1 H-NMR (CDC1 3 6 5.92 5.91 5.60 (d,1, H-NMR(CP 3) 5.41 (dd,1, J=1.3 and 14.2), 5.36 (dd,1, J=1.3 and 14.2), 5.29 (dd,1, J=1.3 and 5.26 (dd,1, J=1.3 and 5.12 4.78 (ddd,1, J=1.0, 5.0 and 11.2), 4.68 (ddd,1, J=1.0, 5.0 and 11.2), 4.64 (dd,2, and 11.2), 3.89 3.88 (dd,1, J=1.5 and 3.31 (dd,1, J=5.5 and 14.5), 2.72 (dd,1, J=6.2 and 161 -47 14.5), 2.35 2.33 1.86 1.46 (d,3, J=6.4).

Example 11: Sodium salt of (5R,6S)-6-[(1'R)-1'-hydroxyethyl]-2-[ (2S)-5-oxo-pyrrolidin-2-ylmethyl]-2-penem-3carboxylic acid The title compound is obtained analogously to Example 4 starting from '-allyloxycarbonyloxyethyl)-2-[ (2S)-5-oxo--pyrrolidin-2-ylmethyll- 2-penem-3-carboxylic acid allyl ester.

aD (0.164 H 2 0 100.70; UV (10-4 H0)Lma 261 305 nm; IR (3 DMSO-d 6 2800-3650, 1770, 1690, 1611, 1581, 1365R 6 5.63 4.24 4.03 3.86 (dd,1, J=1.5 and 3.09 (dd,1, J=6.3 and 14.2) 3.03 (dd,1, J=5.8 and 14.2) 2.39 (m,2) 2.34 1.92 1.31 J=6.4).

Example 12: (35 '-allyloxycarbonyloxyethyll -5-oxo-pyrrolidin-2-ylacetylthio] -2-oxoazetidii.--yl]-2-triphenylphosphoranylideneacetic acid allyl ester The title compound is manufactured analogously to Example 1 from the silver salt of 1 '-allyloxycarbonyloxyethyl]-4-mercapto-2-oxo-azetidin- 1 -ylI-2-triphenylphosphoranylideneacetic acid allyl ester and (2R)-5-oxo-pyrrolidin-2-ylacetyl chloride (prepared from the free acid with SOC1 2 IR (3 CH 2 Cl 2 3420 2850-3650 1752 1702 cm1 Example 13: '-allyloxycarbonyloxyethyl] -2-f (2R) -5-oxo-pyrrolidin-2-ylmethyl] -2-penem-3carboxylic acid allyl ester 2- '-allyloxycarbonyloxyethyl]-4- -48 [(2R)-5-oxo-pyrrolidin-2--ylacetylthio]-2-oxo- azetidin- 1-yll-1-triphenylphosphoranylideneacetic acid allyl ester is converted into the title compound in the manner described in Example 2.

IR (3 CH 2 Cl 2 34,20, 2800-3500 1790 1702 cm'.

Example 14: Sodium salt of (5R,6S)-6-[(1'R)-'-hydroxy-.

too*o ethyl] (2R)-5-oxo--pyrrolidin-2-ylmethyl]-2-penem-3carboxylic acid The title compound is obtained analogously to Example 4 by removing all protecting groups from Vo(5R,6S)-6- '-allyloxycarbonyloxyethyl] oxo-pyrrol idin-2-ylmethyl] -2-penem-3-carboxylic acid allyl ester.

aD (0.199 H 2 0) 163.50; (10-4 H 2 )ma 261, 305 nm; IR (3 DMSO-d 6 2800-3650, 1769, 1690, 1610, 1581, 1367 cm- 1 0 ties H-NMR (D 2 0) 6 5. 62 1, J=1 4. 25 1) 4. 03 3.87 (dd,1, J=1.4 and 3.37 (dd,1, J=6.8 and 14.4), 2.71 (dd,1, J=5.3 and 14.4), 2.38 2.34 (m,1 1.91 1.31 Example 15: 2--[(3S,4R)-3-(tert.-butyldimethylsilyloxymethyl)-4-[ (2S)-1-methyl-5-oxo-pyrrolidin-2-ylacetylthio]-2-oxo-azetidin-1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester The title compound is manufactured analogously to Example 1 from the silver salt of 2-[(3S,4R)-3-(tert.butyldimethylsilyloxymethyl)-4-mercapto-2-oxo-azetidin- 1 -yl]-2-triphenylphosphoranylideneacetic acid allyl ester and (2S)-l-methyl-5-oxo-pyrrolidin-2-ylacetyl chloride (prepared from the acid with SOC1 2 IR (3 CH Cl):25-50 176 10, 838 cm-1 -62 carboxylic acid allyl ester,

I

I

49

I

I,.

I

114' It 4' r II 4' 4' 4' 114' 14' 4' I 4' 4'

I

4' Ii 4' I 4' *4' 1-4' 4' 1 4' '14' 4'tIl 4' 11 Example 16: (5R,6S)-6- (tert.-butyldimethylsilyloxymethyl)-2-[ (2S)-l-methyl--5-oxo-pyrrolidin-2-ylmethyl]- 2-penem-3-carboxylic acid allyl ester Analogously to Example 2, 2-[(3S,4R)-3-(tert.butyldimethylsilyloxymethyl)-4-[(2S)-l-methyl-5-oxopyrrol id in-2-ylacetylthio] -2-oxo-azetidin-1 -yl] -2triphenylphosphoranylideneacetic acid allyl ester is cyclised to the title compound.

IR (3 CH 2 Cl 2 2820-3550, 1795, 1710, 838 cm- Example 17: (5R,6S)-6-hydroxymethyl-2-[ (2S)-l-methyl- 5-oxo-pyrrolidin-2-ylmethyl]-2-penem-3-carboxylic acid allyl ester (5R,6S)-6-(tert.-butyldimethylsilyloxymethyl)-2- 15 (2S) -1-methyl-5-oxo-pyrrol id in-2-ylmethyl] -2--penem-3carboxylic acid allyl ester is reacted analogously to Example 3 to form the title compound.

IR (3 CH 2 C1 2 2750-3550, 1795, 1710, 1685 cm-1 Example 18: Sodium salt of (5R,6S)-6-hydroxymethyl-2- (2S)-l-methyl-5-oxo-pyrrolidin-2-ylmethyl-2-pelem-3carboxylic acid The title compound is obtained analogously to Example 4 from (5R,6S)-6-hydroxymethyl-2-[(2S)-1-methyl- 5-oxo-pyrrol id in-2-ylmethyl] -2--penem-3-carboxylic acid allyl ester.

UV (10-4 H 2 "X 260, 305 nm; 2 m-1 IR (3 DMSO-d 6 2800-3650, 1769, 1680 cm-1 Example~ 19: 2-[(3S,4R)-3-(tert.-butyldimethylsilyloxymethyl)-4-t (2R)-l-methyl-5-oxo-pyrrolidin-2-ylacetylthio] -2-oxo-azetidin-I -yll -2-triphenylphosphoranylideneacetic acid allyl ester The title compound is manufactured analogously to Example 1 from th~e silver salt of 2-[(3S,4R)-3-(tert.- 09

I

994 9 #99w S *9g ~t9 9 99 4 9 999 *4 949 .9 9 I 99 1 4 9 94 us 9 9 99~ S9*~ 4 50 butyld imethylsilyloxymethyl) -4-mercapto-2-oxo-azetid in- 1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester and (2R)-l-methyl-5-oxo-pyrrolidin-2-ylacetyl chloride (prepared from the free acid with SOC1 2 IR (3 CH 2 1 2 2800-3550 1760 1685 837 cmfl Example 20: (5R,6S)-6- (tert.-butyldimethylsilyloxymethyl)-2-[(2R)-l-methyl-5-oxo-pyrrolidin-2-ylmethyl]- 2-penem-3-carboxylic acid allyl ester 10 Analogously to Example 2, 2-[(3S,4R)-3-(tert.butyldimethylsilyloxymethyl)-4-[ pyrrolidin-2-ylacetylthio]-2-oxo-azetidin-1 -yl]-2triphenylphosphoranylideneacetic acid allyl ester is cyclised to the title compound.

15 IR (3 CH 2 Cl 2 2750-3600, 1790, 1706, 837 cmf 1 Example 21: (5R,6S)-6-hydroxymethyl-2-( (2R)-1-methyl-5oxo-pyrrolidin-2-ylmethylj-2-penem-3-carboxylic acid allyl ester Analogously to Example 3, (5R,6S)-6-(tert.,-butyld imethylsilyloxymethyl) idin-2--ylmethyl]-2-penem-3-carboxylic acid allyl ester is converted into the title compound.

IR (3 CH 2 Cl 2 2750-3600 1790 1685 cnf'.

Example 22: Sodium salt of (5R,6S)-6-hydroxymethyl-2- [(2R)-l-methyl-5-oxo-pyrrolidin-2-ylmethyll-2-penem-3carboxylic acid The title compound is obtained analogously to Example 4 from (5R,6S)-6-hydroxymethyl-2-[(2R)-l-methyl- 5-oxo-pyrrolidin-2-ylmethyl]-2-penem-3-carboxylic acid allyl ester.

UV (10-4 H 2 0) Xmax 262, 303 nm; IR (3 DMSO-d 6 2800-3650, 1790, 1680 cm- 1 51 Example 23: The following compounds are manufactured analogously to Example 1: from the silver salt of 24-I(3S,4R)-3-[(1 '-allyloxycarbonyloxyethyl) -4-mercapto-2-oxo-azetid in-i -yll-2- 000 triphenyiphosphoranylideneacetic acid allyl ester and 0 (2S)-1-methyl-5-oxo-pyrrolidin-2-ylacetyl chloride (prepared from the acid with SOCl 2 000 2-[(3S,4R)-3-E(1 -allyloxycarbonyloxyethylll-4- (2S) -1-methyl-5-oxo-pyrrol id in-2-ylacetylthiol -2-oxo- 00 azetidin-1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester, IR (4 CH 2 Cl 2 3670, 2800-3550, 1755, 1688, 1620, o1242, IUS9, 1000, 825 cfrom the silver salt of 2-[(3S,4R)-3-[(1'R)-1'-allyloxy- '000 carbonyloxyethyl]-4-mercapto-2-oxo--azetidin-1 -ylII- 2 triphenylphosphoranylideneacetic acid allyl ester and (2R) -1-methyl-5-oxo-pyrrol idin-2-ylacetyl chloride 0(prepared from the free acid with SOCl 2 2-t(3S,4R)- 3-[l 1'R)-1 '-allyloxycarbonyloxyethyll (2R)-1 -methyl- 5-oxo-pyrrolidin-2-ylacetylthio]-2-oxo-azetidin-1-yl]-2triphenylphosphoranylid.m eacetic acid allyl ester, IR (3 CH 2 C 1 2 3 680 2 80 0-36 0 0, 176 0, 175 0, 16 85 1620, 1435, 1250, 1110, 685 cfrom the silver salt of 2-[(3S,4R)-3-(tert.-butyl- .1 dimethylsilyloxymethyl)-4-mercapto-2-oxo-azetidin-1-yll- 2-triphenylphosphoranylideneacetic acid allyl ester and (2S)-6-oxo-piperidin-2-ylacetyl chloride: 2-[(3S,4R)-3- (tert.-butyldimethylsilyloxynethyl)-4-[ (2S)-6-oxopiper id in-2-ylacetyl thiol -2-oxo-azetid in-i -yl] -2-tr iphenylphosphoranylideneacetic acid allyl ester, IR C 2 C1 2 3422, 2820-3100, 1756, 1680, 839 -52from the silver salt of 2-[(3S,4R)-3-(tert.-butyld imethylsilyloxymethyl) -4-mercapto-2-oxo-azetid in-i -yl] 2-triphenylphosphoranylideneacetic acid allyl ester and (2R)-6-oxo-piperidin-2-ylacetyl chloride: 2-[(3S,4R)-3- (tert.-butyldimethylsilyloxynethyl)-4-[ (2R)-6-oxopiperidin-2-ylacetylthio]-2-oxo-azetidin-1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester, IR (3 CH 2 1 2 3421, 2850-3450, 1756, 1681 837 c- 42C12): from the silver salt of '-allyloxy- 4; 4 carbonyloxyethyll -4-mercapto-2--oxo-azetid in-i -yl] -2triphenylphosphoranylideneacetic acid allyl ester and Ito,(2S)-6-oxo-piperidin-2-ylacetyl chloride: (3S,4R)-3- '-allyloxycarbonyloxyethyll-4-[(2S)-6-oxopiper idin-2-ylacetylthio) -2-oxo-azetid in-i -yl] 2-tr i- *'~,phenylphosphoranylideneacetic acid allyl ester, IR (3 CH 2 Cl 2 33 81 2 85 0-3 200 175 7, 16 60 12 40 III1110, 950 c from the silver salt of '-allyloxycarbonyloxyethylll-4-mercapto-2-oxo-azetidin-1-ylj-2triphenylphosphoranylideneacetic acid allyl ester and (2R)-6-oxo-piperidin-2-ylacetyl chloride: 2-t (3S9,4R)-3- '-allyloxycarbonyloxyethyl]-4-[(2R)-6-oxopiperidin-2-ylacetylthiol-2-oxo-aztidinyl] 2 triphenylphosphoranylideneacetic acid allyl ester,

I(C

2

C

2 3422, 2890-3420, 1756, 1681 m1 from the silver salt of 2-[(3S,.4R)-3-(tert.-butyldimethylsilyoxymethyl)-4-mercapto-2-oxo-azetidifl-1-yl]- 2-triphenylphosphoranylideneacetic acid allyl ester and (2S)-4-oxo-azetidin-2-ylacetyl chloride: (3S,4R)-3- (tert.-butyldimethylsilyloxymethyl)-4-[(2S)-4-oxoazetidin-2-ylacetylthio] -2-oxo-azetidin-1 -yl] -2-tr iphenylphosphoranylideneacetic acid allyl ester, -44 -53- IR (3 CH 2 Cl 2 3620, 2800-3600, 1762, 839 cfrom the siver salt of 2-[(3S,4R)-3-(tert.-butyld imethylsilyloxymethyl) -4-mercapto-2-oxo-azetid in-i -yl] 2-triphenylphosphorz~nylideneacetic acid allyl ester and (2R)-4-oxo-azetidin-2-ylacetyl chloride: 2-[(3S,4R)-3- (tert.-butyldimethylsilyloxymethyl)-4-[ (2R)-4-oxoazetidin-2-ylacetylthio] -2-oxo-azetid in-i -yl] -2-tr ift a phenylphosphoranylideneacetic acid allyl ester, IR (3 CH 2 Cl 2 3620, 2830-3580, 1756, 840 c- ;r from the silver salt of '-allyloxycarbonyloxyethyl] -4-mercapto-2-oxo-azetid in-i -yl] -2tr iphenylphosphoranyl ideneacetic acid allyl ester and (2S)-4-oxo-azetidin-2-ylacetyl chloride: 2-[(3S,4R)-3- '-allyloxycarbonyloxyethyl]-4-[ (2S)-4-oxoazetidin2ylacetylthio]-2oxo-azetidinyl]- 2 triphenylphosphoranylideneacetic acid allyl ester, IR (3 CH 2 Cl 2 3620 2800-3600 1762 1679, 1621 1439, 1375, 1245, 1110, 630 cfrom the silver salt of '-allyloxycarbonyloxyethyl] -4-mercapto-2-ox o-azetid in-i -yl] -2triphenylphosphoranylideneac~iic acid allyl ester and (2R)-4-oxo-azetidin-2-Ylacetyl chloride: (3S,4R)-3- I-allyloxycarbonyloxyethyl-4-[(2R)- 4 -oxo azetidin-2-ylacetYlthliol-2-oxo-azetid in-i -yl] -2-tr iphenylphosphoranylidefleacetic acid allyl 6ster, IR (3 CH 2 Cl 2 3620, 2800-3600, 1756, 842 cmfrom the silver salt of 2-[(3S,4R)-3-(tert.-butyld imethylsilyloxymethyl) -4-mercapto-2-oxo-azetidin-1 -yll 2-triphenylphosphoranylidefleacetic acid allyl ester and (2S)-5-oxo-pyrrolidin-2-ylI-propionyl chloride: 2-' [(3S,4R)-3-(tert.-butyldimethylsilyloxymethyl)-4-t3- -54 [(2S)-5-oxo-pyrrolidin-2-ylI-propionylthiol-2-oxoaztdn1yl2tihnlhshrnldnaei acid allyl est;er, IR (3 CH 2 Cl 2 3421, 2850-3510, 1756, 1695, 838 cm- 1 Dfrom the silver salt of '-allyloxycarbonyloxyethylj -4-mercapto-2-oxo-azetid in-i -y'll-2-tr iphenylphosphoranylideneacetic acid allyl ester and 3- [(2S)-5-oxo-pyrrolidin-2-yl-propionyl chloride: 2- '-allyloxycarbonyloxyethyl]-4-[3- [(2S)-5-oxo-pyrrolidin-2-yl]-propionylthiol-2-oxoazetidin-1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester, IR (3 CH 2 Cl 2 3420, 2800-3500, 1755, 1695, 1620, 14738, 1245, 1110 cfrom the silver salt of 2-[(3S,4R)-3-(tert.-butyldimethylsilyloxymethyl)-4-mercapto-2-oxo-azetid in-i -yl]- 2-triphenylphosphoranylideneacetic acid allyl ester and (3S)-2-oxo-pyrrolidin-3-ylacetyl chloride: 2-U(3S,4R)- 3-(tert.-butyldimethylsilyloxymethyl)-4-, 3S)-2-oxopyrrol id in-3-ylacetylthiol-2-oxo-azetid in-i -yl] -2-tr i- I phenylphosphoranylideneacetic acid allyl ester, IR (3 CH 2 Cl 2 3421 2860-3520 1756 1704, 840 cfrom the silver salt of '-allyloxycarbonyloxyethyl] -4-mercapto-2-oxo-azetidin-1 -yl]I-2triphenylphosphoranylideneacetic acid allyl ester and (3S)-2-oxo-pyrrolidin-3-ylacetyl chloride: 2-II(3S,4R)- '-allyloxycarbonyloxyethyll-4-I (3S)-2-oxopyrrolidin-3-ylacetylthio]-2-oxo-azetidin-1-yl]-2triphenylphosphoranylideneacetic acid allyl ester, IR (3 CH 2 Cl 2 3418, 2850-3505, 1756, 170,4 crrr 1 from the silver salt of 2-t(3S,4R)-3-(tert.-butyldimethylsilyloxymethyl) -4-mercapto-2-oxo-azetidin-1 -yl] 2-triLphenyiphosp'horanylideneacetic acid allyl ester and (4S)-2-oxo-pyrrolidin-4-ylacetyl chloride: 2-[(3S,4R)- 3-(tert.-butyldimethylsilyloxymethyl)-4-[ (4S)-2-oxopyrrolidin-4-ylacetylthio]-2-oxo-azetidin-1-yl]-2triphenyiphosphoranylideneacetic acid allyl ester, IR (3 CH 2 Cl 2 3420, 2855-351 5, 1754, 1700, 838 c- 9 tfrom the silver salt of allyloxycarbonyloxyethyll-4-mercapto-2-oxo-azetidin-lyl]-2--triphenylphosphoranylideneacetic acid allyL ester tc and (4S)-2-oxo-pyrrolidin-4-ylacetyl chloride: 2-[(3S, 'R)-l'-allyloxycarbonyloxyethyl]-4-'(4S)-2oxo-pyrrolidin-4-ylacetylthio]-2-oxo-azetidin-1-yl]-2triphenylphosphoranylideneacetic acid allyl ester, fi IR (3 %CHt 2R( C 2 342 2, 2860 -3 490 175 8, 170 4cm from the silver salt of ticallyloxycarbonyloxyethyl] -4 -mercapto-2-oxo-azetid in-i yl]-2-triphenylphosphoranylideneacetic acid allyl ester actand (2S) -1-allyl-5-oxo-pyrrol id in-2-ylacetyl chloride: '-allyloxycarbonyloxyethyl]-4- (2S)-l-allyl-5--oxo-pyrrolidin-2-ylacetylthio]-2-oxoazetid in-i -yl]-2-triphenylphosphoranylideneacetic acid allyl ester, IR (4 CH 2 C1 2 2800-3140 1760 1689 1620 1440 1245, 1110, 1000 m1 from the silver salt of allyloxycarbonyloxyethyl] -4-mercapto-2-oxo-azetidin-1 yl]-2-triphenylphosphoranylideneacetic acid allyl ester and (2S)-2,5-dihydro-5-oxo-pyrrol-2-ylacetyl chloride: '-allyloxycarbonyloxyethyl]-4- [(2S)-2,5-dihydro-5-oxo-pyrrol-2-ylacetylthio]-2-oxoazetidin-1-yl]-2-triphenylphosphoranylideneacetic acid -56 allyl ester, IR (5 C1 2 l) 44, 2820-3550, 1758, 171 5, 1110 cfrom the silver salt of 'R)1 allyloxycarbonyloxyethyll -4-mercapto-2-oxo-azetid in-i yl]-2-triphenylphosphoranylideneacetic acid allyl ester 4and (S--2allxcroyehl--x-yrldn2 4 ylacetyl chloride: '-allyloxy- 4 carbonyloxyethyll-4-[(2S)-l-(2-allyloxycarbonylethyl)- 4 5-oxo-pyrrol id in-2-ylacetylthio] -2-oxo-azetid in-i -ylI- 4 *:10 2 -triphenylphosphoranylideneacetic acid allyl ester, 4 IR (3 CH 2 Cl 2 2800-3150, 1760, 1740, 1685, 1620, 41445, 1370, 1240, 1110, 1000 cfrom the silver salt of '-allyloxycarbonyloxyethyl]-4-mercapto-2-oxo-azetidin-1-yl]-2aci 360,50 160 ester and (2S)-l-(2-allyloxycarbonylaminoethyl)-5-oxo-pyrrolidin- 2-ylcetl clorde:2-[(3S,4R)-3-[(1 '-allyloxycarbnylxyetyl]4-[(S)--(2-allyloxycarbonylaninoethyl)-5-oxo-pyrrolidin-2-ylacetylthio]-2-oxo-azetidin- 1-yl-2-ripenyphophoanyideeacticacid allyl IR H 350 ,2BO-3 50 170 ,1686 1620 41110, 1000cm from the silver salt of 2-[(3S,4R)-3--[(1'R)-1'-allyloxycarbonyloxyethyl] -4-mercapto-2-oxo-azetidin-1 -yll -2triphenylphosphoranylideneacetic acid allyl ester and (2-allyloxycarbonyloxyethyl)-5-oxo-pyrrolidin-2ylacetyl chloride: '-allyloxycarbonyloxyethyll-4-t (2S)-1-(2-allyloxycarbonyloxyethyl)-5-oxo-pyrrolidin-2-ylacetylthio]-2-oxo-azetidin- 1 -yll-2-triphenylphosphoranylideneacetic acid allyl ester, ft t

I-

.t t t .1 57 IR (5 CH 2

CG

2 2800-3200, 1760, 1687, 1620, 1110 cmv; f rom the silver salt of 2- 1 allyloxycarbonyloxyethyl] -4-mercapto-2-oxo-azetid in-i yljl-2-tripihenylphosphoranylideneacetic acid allyl ester and (2S)-i-(2-cyanoethyl)-5-oxo-pyrrolidin-2-ylacetyl chloride: 2-[(3S,4R)-3-[(l'R)-1'-allyloxycarbonyloxyethyl]-4-[ (2S)-i-(2-cyanoethyl)-5-oxo-pyrrolidin-2ylacetylthiol -2-oxo-azetid in-i -yl] -2-tr iphenylphosphoranylideneacetic acid allyl ester, IR (3 CH 2 Cl 2 2800-31 80, 2252 1761 1685 1620 1110 cm- 1 Example 24: The following compounds are manufactured analogously to Example 2: from '-allyloxycarbony:Loxyethyl]- 4-1 (2S)-l-methyl-5-oxo-pyrrolidin-2-ylacetylthio]-2oxo-azetidin-1-yl]-2-triphenylphosphoraflylideneacetic acid allyl ester: '-allyloxycarbonyloxyethyli -methyl-5-oxo-pyrrolidin-2ylmethyl]-2-penem-3-carboxylic acid allyl ester, aD (0.464 ethanol): 48.90; IR (4 CH 2 Cl 2 3680, 2800-3550, 1795, 1740, 1710, 1685, 1580, 1375, 1330, 1245 cm-1 from '-allyloxycarbonyloxyethyll- (2R)-1-methyl-5-oxo-pyrrolidin-2-ylacetylthio]-2oxo-azetid in-i -yl]-2-triphenylphosphoranylideneacetic acid allyl ester: (5R,6S)-6[(1'R)-l'allyloxycarbonyloxyethylll-2-[ (2R)-1-methyl-5-oxo-pyrrolidin-2-ylmethyl]- 2-penem-3-carboxylic acid allyl ester, aD (0.755 ethanol): 157.40; t tt f -58- IR (3 CH 2 C1 2 3680, 2750-3600, 1790, 1745, 1705, 1685, 1310, 1245 cm- 1 from 2-[(3S,4R)-3-(tert.-butyldimethylsilyloxymethyl)-4- [(2S)-6-oxo-piperidin-2-ylacetylthio] -2-oxo-azetidin-1 ylI-2-triphenylphosphoranylideneacetic acid allyl ester: (5R,6S),-6-(tert.-butyldimethylsilyloxymethyl)-2- (2S)-6-oxo-piperidin-2-ylmethyl]-2--penem-3-carboxylic acid allyl ester, 1 3% HC IR 3 C 2

C

2 3680, 2800-3550, 1795, 1740, 1685 cfrom 2-[(3S,4R)-3-tert.-butyldimethylsilyloxymethyl)-4- [I(2R) -6-oxo-piper id in-2-ylacetylthio] -2-oxo-azetidin-1 yll-2-triphenylphosphoranylideneacetic acid allyl ester: (5R,6S)-6-(tert.-butyldimethyJ.silyloxymethyl)-2- [(2R)-6-oxo-piperidin-2-ylmethyl]-2-penem-3-carboxylic acid allyl ester, IR (3 CH 2

C'

2 3680, 2750-3600, 1789, 1685, 836 cm- 1 from 2-[(3S,4R)-3-E(1 '-allyloxycarbonyloxyethyl]- 4- [(2S)-6-oxo-piper idin-2-ylacetylthio] -2-oxo-azetidin- 1 -ylI -2-triphenylphosphoranylideneacetic acid allyl ester: '-allyloxycarbonyloxyethylil-2- (2S)-6-oxo-piperdin-2-ylmethyl]-2-penem-3-carboxylic acid allyl ester, IR (3 CH 2 C1 2 3381, 2850-3400, 1790, 1755, 1710, 1580, 1310, 1250, 1175, 790 cm- 1 from 2-t(3S,4R)-3-[(1 '-allyloxycarbonyloxyethyl]- 4- E(2R) -6-oxo-pip-r idin-2-ylacetylthio] -2-oxo-azetid in- 1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester: '-allyloxycarbonyloxyethyll- 2-f (2R)-6-oxo-piper id in-2-ylmethyl] -2-penem-3carboxylic acid allyl ester, IR (3 CH 2

CL

2 3421, 2850-3400, 1788, 1680 m1 -59 from 2-[(3S,4R)-3-(tert.-butyldimethylsilyloxymethyl)- 4-[(2S)-4-oxo-azetidin-2-ylacetylthio]-2-oxo-azetidin- 1 -yl] triphenyiphosphoranyl ideneacetic acid allyl ester: (5R,6)-6-(tert.-butyldimethylsilyloxymethyl)-2- [i(2S) -4-oxo-azetid in-2-ylmethyl]l-2-penem-3--carboxyl ic acid allyl ester IR (3 CH 2 C1 2 3500, 2830-3500, 1789, 1750, 839 cm- 1 from 2-[(3S,4R)-3-(tert.-butyldimethylsilyloxymethyl)- 4- -4-oxo-azetidin-2-ylacetylthiol -2-oxo-azetid in- "#too,1-ylII-2-triphenylphosphoranylideneacetic acid allyl 0 (2R) -4-oxo-azetid in-2-ylmethyl] -2-penem-3-carboxyl ic acid allyl ester, 001 too IR (3 CH 2 C1 2 3500, 2830-3500f 1790, 1753, 840 m from '-allyloxycarbonyloxyethyl]- 4- [(2S)-4-oxo-azetidin-2-ylacetylthio]l-2-oxo-azetidin- 1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester: (5R,6S)-6- '-allyloxycarbonyloxyethyll -2- (2S)-4-oxo-azetidin-2-ylmethyl]-2-penem-3-carboxylic acid allyl ester, IR (5 CH 2 C1 2 3500, 2830, 1790, 1768, 1750, 1710, 1680, 1365, 1315, 1245 cfrom '-allyloxycarbonyloxyethyl)- 4- -4-oxo-azetid in-2-ylacetylthiol -2-oxo-azetid in- 1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester: (5R,6S)-6-E '-allyloxycarbonyloxyethyi]- 2- [(2R)-4-oxo-azetidin-2-ylmethyll -2-penem-3-carboxylic acid allyl ester, IR (3 CH 2 C1 2 3500, 2830-3500, 1787, 1755, 839 cm 1.

from 2-I (3S,4R)-3-(tert.-butyldimethylsilyloxymethyl)- 4-[3-I (2S)-5-oxo-pyrrolidin-2-yl] -propionylthio] -2-oxo-

I'

t S S 51 I (S S I I S g<t S S St S S 5(5 5 It I I I lIZ It S I S III S 55 S S S I It $1 S 5.55 60 azetidin-1--Yl]-2-triphenylphosphoranylideneacetic acid allyl ester: (5R,6S)-6-(tert.-butyldimethylsilyloxymethyl) (2S )-5-oxo-pyrrol idin-2-yl] -ethyl] -2penem-3-carboxylic acid allyl ester, IR (3 CH 2 Cl 2 3421 2820-3310, 1790 1705 cm- 1 from 'R)-1'-allyloxycarbonyloxyethyl]- (2S)-5-oxo-pyrrolidin-2-yl]-propionylthio] -2-oxoazetidin-1 -yl]-2--triphenylphosphoranylideneacetic acid allyl ester: '-allyloxycarbonyloxyethyl]1 (2S) -5-oxo-pyrrolidin-2-yl I-ethyl]1 -2penem-3-carboxylic acid allyl ester, IR (5 CH 2 Cl 2 3415, 2800-3300, 1790, 1749, 1700, 1650, 1580, 1375, 1315, 1248 cfrom 2-[(3S,4R)-3-(tert.-butyldimethylsilyloxymethyl)- (3S)-2-oxo-pyrrolidin-3-ylacetylthiol-2-oxoazetidin-1-yll-2-triphenylphosphoranylideneacetic acid allyl ester: (5R,6S)-6-(tert..-butyldimethylsilyloxymethyl) -2-1(3S)-2-oxo-pyrrolidin-3-.ylmethyl] -2--penemn-3carboxylic acid allyl ester, IR (3 CH 2 Cl 2 3420, 2820-3315, 1790, 836 cm 1.

from '-allyloxycarbonyloxyethyl]- 4-[(3S)-2-oxo-pyrrolidin-3-ylacetylthio]-2-oxo-azetidin- 1-yll-2-triphenylphosphoranylideneacetic acid allyl ester: -allyloxycarbonyloxyethyl]-2- (3S)-2-oxo-pyrrolidin-3-ylmethyl]-2-penem-3-carboxylic acid allyl ester, IR (3 CH 2 Cl 2 3422, 2815-3250, 1791, 1705 cfrom 2-[(3S-4R)-3-(tert.-butyldimethylsilyloxymethyl)- (4S)-2-oxo-pyrrolidin--4-ylacetylthio]-2-oxoazetidin-1 -yll-2-triphenylphosphoranylideneacetic acid allyl ester: (5R,6S)-6-(tert.-butyldimethylsilyloxy- -61methyl)-2-[(4S)-2-oxo-pyrrolidin-4-ylmethyll-2-penem-3carboxylic acid allyl ester, IR~~ (%CH1 2 3410, 2820-3300, 1787, 1707, 836 cmf from '-allyloxycarbonyloxyethyll- 4 -(4S)-2-oxo-pyrrolidin--4-ylacetylthio]-2-oxo-azetidinl-ylI-2-triphenylphosphoranylideneacetic acid allyl ester: '-allyloxycarbonyloxyethyl] -2- 4 S)-2-oxo-pyrrolidin-4-ylmethyl]-2-penem-3carboxylic acid allyl ester, IR (3 CH 2 C1 2 3415, 2820-3315, 1788, 1705 c from '-allyloxycarbonyloxyethyl]-4- (2S) -1-allyl-5-oxo-pyrrolidin-2-ylacetylthio] -2-oxoazetidin-l--vli-2-triphenylphosphoranylideneacetic acid allyl ester: (5R,6S)-6-[1 '-allyloxycarbonyloxyethyl]-2-[(2S)-l-allyl-5-oxo-pyrrolidin-2-ylmethyl]-2penem-3-carboxylic acid allyl ester, IR H 2

C

2 2800-3140, 1790, 1745, 1710, 1690, 1650, 1580, 1370, 1315, 1245, 1175, 940 cfrom '-allyloxycarbonyloxyethyll- 4-I (2S)-2,5-dihydro-5-oxo-pyrrol-2-ylacetylthio]-2oxo-azetidin-1-yl]-2-triphenylphosphoranylideneacetic IR (5 CH 2 1) 32,80-3550, 1789, 1715, 1170 cm- 1 f roi 2- 4R) -3-1 I'R) -1 '-a11yloxycarb.nryoxyethy1) (2-allyloxycarbonylethyl) -5-oxo-pyrrol idin-2ylacetylthio] -2-oxo-azetidin-1 -yl] -2-triphenyiphosphoranylideneacetic acid allyl e'ster: allyloxycarbonyloxyethyl]-2-[ (2-allyloxycarbonylethyl) -5--oxo-pyrrolidin-2-ylmethyl] -2-penem-3- -62carboxylic acid allyl ester, IR (3 CH 2 C1 2 2800-3150, 1790, 1740, 1700, 1685, 1575, 1445, 1365, 1310, 1240, 1200, 1170 cm 1 from 'R)-1'-allyloxycarbonyloxyethyl]- (2S)-l-(2-a11y1oxycarboflamifloethyl)-5-oxopyrrolidin2yacetythio]2oxoazetidif--ll- 2 triphenylphosphoranylideleacetic acid allyl ester: '-allyloxycarbonyloxyethyl]-2-[(2S)- 1- (2-allyloxycarbonylamiloethYl) -5-oxo-pyrrolidin-2-yl- 10 methyl]-2-penem--3-carboxylic acid allyl ester, o IR (5 CH 2

C'

2 3650, 2800-3140, 1790, 1743, 1705, 0: 1690, 1173 cm 1 from '-allyloxycarbonyloxyethyl]- (2S)-1-(2-allyloxycarbofylloxyethyl)5-oxo pyrrolidin-2-yaceythio]-2oxoazetidif1yl> 2 triphenylphosphoranyJlideneacetic acid allyl ester: it '-allyloxycarbonyloxyethyl]-2-[(2S)- 1- (2-allyloxycarbonyloxyethyl)-5-oxo-pyrrolidif--l2Y methyl]-2-penem-3-carboxylic acid allyl ester, t titIR (4 CH 2 C1 2 2800-3180, 1790, 1742, 1705, 1690, 1172 m1 from 'R)-1'-allyloxycarboflyloxyethyl]- (2S)-l-(2-cyanoethyl)-5-oxo-pyrrolidil-2-ylacetylthio]-2-oxo-azetidin-1-yl]-2-triphelylphosphoralideneacetic acid a].lyl ester: allyloxycarbonyloxyethyli-2-[ (2S)-1-(2-cyanoethyl) oxo-pyrrolidin-2-ylmethyl] -2-penem-3-carboxylic acid allyl ester, IR (5 CH 2 C1 2 2800-3150, 2250, 1790, 1742, 1701, 1685, 1620, 1110 cm- 1 -63 Example 25: The following compounds are manufactured A analogously to Example 3: from (SR,6S)-6-(tert.-butyldimethylsilyloxymethyl)-2- -6-oxo-piperidin-2-ylmethyl] -2-penem--3-carboxylic acid allyl ester: (5R,6S)-6-hydroxymethyl-2-[(2S)-6- 0 oxo-piperidin-2--ylmethyl]-2-penem-3-carboxylic acid 4allyl ester, IR (%CHl 2 2750-3600, 1780, 1685 J~ 10 from (5R,6S)-6-(tert.-butyldimethylsilyloxymethyl)-2 t [(2R)-6-oxo-piperidin-2-ylmethyl--2-penem-3--carboxylic t ts acid allyl ester: (5R,6S)-6-hydroxymethyl-2-[(2R)-6oxo-piperidin-2-ylmethyl]-2-penem-3-carboxylic acid allyl ester, IR (3 CH- 2 C1 2 2800-3550, 1778, 1680 cfrom (5R,6S)-6-(tert.-butyldimethylsilyloxymethyl)-2- [(2S)-4-oxo-azetidin--2-ylmethyl]-2-penem-3-carboxylic acid allyl ester: (5R,6S)-6-hydroxymethyl-2-[(2S)-4oxo-azetidin-2-ylmethyL]-2-penem-3-carboxylic acid allyl ester, IR (3 CH 2 C1 2 2750-3550, 1790, 1750 cm from (5R,6S)-6-(tert.--butyldimethylsilyloxymethyl)-2acid allyl ester: (5R,6S)-6-hydroxymethyl-2-[ (2R)-4oxo-azetidin-2-ylmethyl] -2-penem-3-carboxylic acid allyl ester, IR (3 CH 2 Cl 2 2755-3580, 1787, 1755 cfrom (5R,6S)-6-(tert.-butyldimethylsi'Lyloxymethyl)-2- (2S)-5-oxo-pyrrolidin-2-yl]-ethyll-2-penem-3carboxylic acid allyl ester: (5R,6S)-6-hydroxymethyl- 2-112-[ (2S)-5-oxo-pyrrolidin-2-yl]-ethyll-2-penem-3- -64 carboxylic acid allyl ester, IR (3 CHCl) 3415, 2800-3300, 1790, 1697cm from (5R,6S)-6-(tert.-butyldimethylsilyloxymethyl)-2- [(3S)-2-oxo-pyrrolidin-3-ylmethyl]-2-penem-3-carboxylic acid allyl ester: (5R,6S)-6-hydroxymethyl-2-[(3S)-2oxo-pyrrolidin-3-ylmethyl] -2-penem-3-carboxylic acid allyl ester, IR (3 CH 2 Cl 2 2760-3540, 1780, 1700 c from (5R,6S)-6-(tert.-butyldimethylsilyloxymethyl)-2- U [(4S)-2-oxo-pyrrolidin-4-ylmethylj-2-penem-3-carboxylic acid allyl ester: (5R,6S)-6-hydroxymethyl-2-[(4S)-2oxo-pyrrolidin-4-ylmethyllj-2-penem-3-carboxylic acid allyl ester, I(3%C 2 Cl 2 2750-3610, 1777, 1688 cm Example 26: The following penem-3-carboxylic acids are prepared as sodium salts analogously to Example 4: U from '-allyloxycarbonyloxyethyl]-2- [(2S)-1-methyl-5-oxo-pyrrolidin-2-ylmethyl]-2-penem-3carboxylic acid allyl ester: (1 tellhydroxyethyl]-2-[ (2S)-l-methyl-5-oxo-pyrrolidin-2-ylmethyl] -2-penem-3-carboxylic acid, aD(0.597 H 2 0):+3.0 UV(0 H 0) )max =260; 305 nm; IR (3 DMSO-d 6 3100-3650, 2800-3050, 1769, 1680, 1610, 1360, 990 c- 1 H-NMR (D 2 5.62 1, J 4.25 (dt, 1, J 6.5 and 3.99 3.87 (dd, 1, J 1.5 and 3.32 (dd, 1, J 4.5 and 14.0), 3.06 (dd, 1, 1 and 14.0), 2.83 2.44 (in, 2.35 (mn, 1), 2.22 (in, 1.90 (in, 1.30 3, J d from '-allyloxycarbonyloxyethyl]-2- [(2R)-1-methyl-5-oxo-pyrrolidin-2-ylmethyl--2-penem-3carboxylic acid allyl ester: hydroxyethylll-2-[ (2R)-l-methyl-5-oxo-pyrrolidin-2-ylmethyl]-2-penem-3-carboxylic acid, aD (0.646 820): +219.80; UV (10-4 H2)Xa 261; 305 nm; IR (3 DMSO-d 6 3100-3650, 2800-3050, 1770, 1680, 1610, 1360, 985 cm1 1 H-NMR (D 2 5.61 1, 1 4.24 1, J 3.99 (mn, 3.86 (dd, 1, J 1.4 and 5.9), 3.59 (dd, 1, J 4.8 and 15.1), 2.85 2.73 (dd, 1, J 5.5 and 15.1), 2.52 (in, 2.39 (in, 2.25 (in, 1.87 (mn, 1.30 1, J from (5R,6S)-6-hydroxymethyl-2-[ (2S)-6-oxo-piperidin- 2-ylmethyl]-2-penem-3-carboxylic acid allyl ester: It (5R-6S)-6-hydroxymethyl-2-[ (2S)-6-oxo-piperidin-2ylmethyl]-2-penein-3-carboxylic acid, lj UV (10-4 H20) Xmax =258; 303 n; IIR (3 DMSO-d 6 2800-3700, 1774, 1675 cij from (5R,6S)-6-hydroxyinethyl-2-[ (2R)-6-oxo-piperidin- 2-ylmethyl]-2-penem-3-carboxylic acid allyl ester: (5R,6S)-6-hydroxymethyl-2-[(2R)-6-oxo-piperidin-2- II ylmethyll-2-penem-3-carboxylic acid, UV (10~ H20) Xmx 261; 302 nm; IR (3 DMSO-d 6 2800-3700, 1773, 1675 cm 1 from '-allyloxycarbonyloxyethyl]-2- -6-oxo-piperidin-2-ylmethyl] -2-penem-3-carboxylic acid allyl ester: '-hydroxyethyl]-2- [i(2S) -6-oxo-piperidin-2-ylmethyl] -2-penem-3-carboxylic acid, UV (10- 820) Amax =259; 304 n; -66- IR DSO- 6 2750-3710, 1772, 1660 c aD (0.12 H 2 +56.40; from '-allyloxycarbonyloxyethyl]-2- [(2R)-6-oxo-piperidin-2-ylmethyl]-2-penem-3-carboxylic acid allyl ester: (5R,6S)-6-[(1'R)-1'-hydroxyethyl]-2- [(2R)-6-oxo-piperidin-2-ylmethyl]-2-penem-3-carboxylic acid, UV (10-4 H2 X max 262; 302 nm; IR (3 DMSO-d 6 2B10-3690, 1772, 1675 c from (5R,6S)-6-hydroxymethyl-2-[(2S)-4-oxo-azetidin- 2-ylmethyl]-2-penem-3-carboxylic acid allyl ester: I" j (5R,6S)-6-hydroxymethylt-2-[ (2S)-4-oxo-azetidin-2-ylmethyll-2-penem-3-carboxylic acid, UV(10~% H 2 0) Xmax 260; 305 nm; IR (3 DMSO-d 6 2800-3600, 1760, 1745 cm1 from (5R,6S)-6-hydroxymethyl-2-[ (2R)-4-oxo-azetidin- 2-ylmethyl]-2-penem-3-carboxylic acid allyl esk,-o: (5R,6S)-6-hydroxymethyl-2-[ (2R)-4-oxo-azetidin-'-ylmethyl]-2-penem-3-carboxylic acid, UV (10-4 H 2 0) Xmax 260; 306 nm; IR (3 DMSO-d 6 2800-3600, 1765, 1751 cfrom (5R,6S)-6-[(1'R)-1'-allyloxycarbonvloxyethyl]-2- [(2S)-4-oxo-azetidin-2-ylmethyl]-2-penem-3-carboxylic acid allyl ester: (5R,6S)-6-[(1'R)-1'-hydroxyethyl]-2- -4-oxo-azetidin-2-ylmethyl] -2-penem-3-carboxylic acid, aD (0.619 H 2 +132.90; UV (10-4 H 2 0) Xmax 260; 304 nm; IR (3 DMSO-d 6 2800-3600, 1760, 1745, 1610, 1591, 1362, 990 cm- 1 H-NMR (D 2 65.7 1, J 4.25 (dt, 1, -67 J 5 5.4 a nd 4.00 (d d,1 J 1 15 a nd 5.5) 3.3 0 (dd, 1, J 5.7 and 15.0), 3.14 (in, 2.77 (dd, 1, J 2.2 and 15.0), 1.30 3, J 6.4); from '-allyloxycarbonyloxyethyl--2- [(2R)-4-oxo-azetidin-2-ylmethyl]-2-penem-3--carboxylic acid allyl ester: (5R,6S)-6-[(1'R)-1'-hydroxyethyl]-2- -4-oxo-azetidin-2-ylnethyl] -2-penem-3-carboxylic acid, UV (10-4 H 2 0) Xinx=20 0 nm; ~iU I (3 %DMSO- 6 2800-3600, 1762, 1750 cm' frm(5R,6S)-6-hydroxymethyl-2-[2-[(2S)-5-oxo-pyrrolidin-2-ylJ-ethyl]-2-penem-3-carboxylic acid ally1 ester: (5R,6S)-6-hydroxymethyl-2-[2-[ idin-2-yl]-ethyljj-2-penem-3-carboxylic acid, UV (10-4H 2 0) Xmx 257; 302 nm; IR (3 DMSO-d 6 2600-3650, 1770, 1691 c from '-allyloxycarbonyloxyethyl]-2- (2S)-5-oxo-pyrrolidin-2-yl]-ethyl]-2-penem-3carboxylic aciLd allyl ester: hydroxyethyl]-2-[2-[(2S)-5-oxo-pyrrolidin--2-yl]-ethyl]- 2-penem-3-carboxylic acid, B ~a (0.108 H 2 +194.50; UV(10~% H 2 0) Xmax 259; 302 nin; IR (3 DMSO-d): 2600-3650, 1770, 1690, 1610, 1588, 1365 cm- 1 4-, 1 H-NMR (D 2 65.63 1, J 4.24 1, J 3.84 (dd, 1, J 1.4 and 3.78 (in, 1), 2.87 2, J 2.39 (mn, 2.30 (in, 1.82 (in, 1) 1.80 (in, 2) 1 .31 1 J from '-allyloxycarbonyloxyethyll-2- -2-oxo-pyrrolidin-3-ylnethyl] -2-penem-3-carboxylic -68 acid allyl ester: (5R,6S)-6-[(1'R)-1'-hydroxyethyl]-2- [(3S)-2-oxo-pyrrolidin-3-ylmethyll-2-penem-3-carboxylic acid, UV (10-4 H 2 0) X~max 262; 303 nm; IR (3 DMSO-d 6 2780-3700, 1768, 1691 cm1 from (5R,6S)-6-hydroxymethyl-2-[ (3S)-2-oxo-pyrrolidin- 3-ylmethyll-2-periem-3-carboxylic acid allyl ester: (5R,6S)-6-hydroxymethyl-2-[ (3S)-2-oxo-pyrrolidin-3-yJmethyll-2-penem-3-carboxylic acid, UV (10-4 H 2 0) Xma4 262; 303 nm; t4VIR (3%DS- 6 2800-3700, 1772, 1690 cm t from (5R,6S)-6-hydroxymethyl-2-[(4S)-2-oxo-pyrrolidin- 4-ylmethyl]-2-penem-3-carboxylic acid allyl ester: (5R,6S)-6-hydroxymethyl-2-[ (4S)-2-oxo-pyrrolidin-4-ylmethyllj-2-pertem-3-carboxylic acid, UV (10-4 H 2 0) Xmax 257; 302 nm; IR (3 DMSO-d 6 2800-3700, 1775, 1691 cm from '-allyloxycarbonyloxyethyll-2- [(4S)-2-oxo-pyrrolidin-4-ylmethyl]-2-penem-3-carboxylic acid allyl ester: (5R,6S)-6-rL(1'R)-l'-hydroxyethyl1-2- [(4S)-2-oxo-pyrrolidin-'4-ylmethy1]-2-penem-3-carboxylic C C acid, UV ('10-4 H 2 0) ",max 258; 302 nm; IR (3 DMSO-d 6 2800-3700, 1776, 1691 cmfrom '-allyloxycarbonyloxyethyl] -2- [I(2S)-1-ally1-5-oxo-pyrrolidin-2-ylmethyl1-2-penem-3carboxylic acid allyl ester: hydroxyethyl]-2-[ (2S)-1-allyl-5-oxo-pyrrolidin-2-ylmethyll-2-penem-3-carboxylic acid, aD (0.616 H 2 0) +101.70; UV (10- H 2 0) X max 260, 304 rim; L1I~~ ii 69 IR (3 DMSO-d 6 2800-3140, 1770, 1680, 1610, 1580, 1415, 1365 cm'1 H-NMR (D 2 5.79 5.62 1, J 1.4), 5.23 (dd, 1, J 1.4 and 5.19 (dd, 1, J 1.5 and 13.8), 4.24 1, J 4.14 (ddi, 1, J 4.5 and 16.2), 4.06 (Im, 3.85 (dd, 1, J 1.4 and 3.73 (dd, 1, J 5.9 and 16.2), 3.22 (dd, 1, J 4.4 and 14.3), 3.09 (dd, 1, J 7.4 and 14.3), 2.50 1), 2.43 (in, 2.27 1.92 1.30 1, J from (5R,6S)-6-[(1'R)-'-allyloxycarbonyloxyethyl]-4- -2,5-dihydro-5-oxo-pyrrol-2-ylImethyl-2-penem-3carboxylic acid allyl ester: hydroxyethyl]-2-[(2S)-5-oxo-2,5-dihydropyrrol-2-yliethyl]-2-penei-3-carboxylic acid, UV (10- H 2 0) Xmax 260, 305 nm; IR (3 DMSO-d 6 2700-3700, 1770, 1700, 1610 cm-1 LU from (1 'R)--allyloxycarbonyloxyethyl]-2- [(2S)-l-(2-allyloxycarbonylethyl)-5-oxo-pyrrolidin- 2-yliethyl]-2-penem-3-carboxylic acid allyl ester: (sR,6S)-6-[(1'R)-1-hydroxyethyl]-2-(2S)-l-(2-carboxyethyl)-5-oxo-pyrrolidin-2-yliethyll-2-penei-3carboxylic acid (disodium salt), UV (104 H 2 0) Xmax 257, 305 n; IR (3 in DMSO-d 6 2700-3700, 1770, 1670, 1610, 1583, 1370, 990 cm- 1 1 H-NMR (D 2 6 5.63 1, J 4.23 1, J 4.09 3.87 (dd, 1, J 1.5 and 3.78 3.28 3.25 3.11 (dd, 1, J 6.5 and 14.2), 2.39 2.18 1.90 (m, 1.28 1, J 6.2); ;:v 707 from '-allyloxycarbonyloxyethyl]-2- 2 S)-1-(2-allyloxycarbonylaminoethyl)-5-oxo-pyrrolidin- 2 -ylmethyll-2-penem-3-carboxylic acid allyl ester: (5R,6S)-6-[(1'R)-1'-hydroxyethyl]-2-[(2S)-l-(2-aminoethyl) -5-oxo-pyrrolidin-2-ylmethyl] -2-penem-3carboxylic acid (free acid), UV (10U %H0) ~~Ax 259, 305 nm; IR DSO- 6 2800-3650, 1770, 1675, 1610, 1582, 1370 cm' from '-allyloxycarbonyloxyethyl]-2- 2 2-ylmethyl]-2-penem-3-carboxylic acid allyl ester: (5R,6S)-6-[(1'R)-l'-hydroxyethyl]-2-[(2S)-l-(2-hydroxyethyl) -5-oxo-pyrrolidin-2-ylmethyl] -2-penem-3carboxylic acid, UV 10~% 2 0 Xmax =256, 304 nm; IR (3 DMSO-d 6 2800-3650, 1771, 1672, 1610, 1583 c It from 'R)-1'-allyloxycarbonyioxyethyl]-2- V [(2S)-l-(2-cyanoethyl)-5--oxo-pyrrolidin-2-ylmethyl]-2penem-3-carboxylic acid allyl ester: 1 '-hydrox~tethyl]-2-[(2S)-l-(2-cyanoethyl)-5-oxopyrrolidin-2-ylmethiyll-2-penem-3-carboxylic acid, UV (10-4%H 2 0) Xmax =256, 305 nrn; IR (3 DMSO-d 6 2800-3150, 2250, 1770, 1671, 1610 cm- 1 Example 27: (5R,6S)-6-[(1'R)-l'-hydroxyethyl]-2-[(2S)- 5-oxo-pyrrolidin-2-ylmethyl] -2-penem-3-,carboxylic acid pivaloyloxymethyl ester 0.75 g (5 mmol) of sodium iodide are dissolved in 3 ml of acetone and 0.19 ml (1.3 mmol) of pivalic acid chloromethyl ester is added. The mixture is stirred at 71 room temperature for 3 hours and then added dropwise to 9 ml of methylene chloride. The precipitated inorganic salts are filtered off. The methylene chloride solution is concentrated to approximately 1 ml and, at 00, added to a solution of 167 mg (0.5 mmol) of 1'-hydroxyethyl]-2-[(2S)-5-oxo-pyrrolidin-2-ylmethyl]-2penem-3-carboxylic acid (sodium salt) in 5 ml of absolute DMF and 0.5 ml of DMSO. After stirring for minutes at 00 and for a further 30 minutes at room temperature, the reaction mixture is taken up in ethyl jr acetate and washed with brine. After drying over e" 1 sodium sulphate and concentration in a rotary evaporator, the crude product is purified on silica gel (eluant toluene/ethyl acetate).

IR (methylene chloride): 3590, 1770, 1690 cm-1.

Example 28: (5R,6S)-6-[(1'R)-1'-hydroxyethyl]-2-[(2S)- 5-oxo-pyrrolidin-2-ylmethyl]-2-penem-3-carboxylic acid Sacetoxymethyl ester 133 mg (0.398 mmol) of (5R,6S)-6-[(1'R)-1'-hydroxyethyl]-2-[(2S)-5-oxo-pyrrolidin-2-ylmethyl]-2-penem-3carboxylic acid (sodium salt) are dissolved in 5 ml of absolute DMF and 0.5 ml of absolute DMSO and, at 00 a solution of 70 mg '(0.46 mmol) of acetoxybromomethane in 0.5 ml of absolute DMF is added dropwise thereto.

After stirring for 30 minutes at 00 and then for a further 30 minutes at room temperature, the reaction Smixture is taken up in ethyl acetate and washed with brine. After drying the organic phase over sodium sulphate and concentration in a rotary evaporator, the crude product is purified on silica gel (eluant toluene/ethyl acetate).

IR (methylene chloride): 3580, 1770, 1690 cm 1 -72 Example 29: (5R,6S)-6-[(1'R)-1'-hydroxyethyll-2-[(2S)- 5-oxo-pyrrolidin-2-ylmethyll-2-penem-3-carboxylic acid ethoxycarbonyloxyethyl ester 0.6 g (4 mmol) of sodium iodide is dissolved in 2 ml of acetone and 0.14 ml of ethyl-1-chloroethyl carbonate is added. The mixture is stirred at room temperature for 3 hours, added dropwise to 8 ml of methylene chloride and the precipitated inorganic salts are filtered off. The methylene chloride solution is concentrated to approximately 1 ml and, at added to a solution of 167 mg (0.5 mmol) of t n 1 '-hydroxyethyl]-2-[(2S)-5-oxo-pyrrolidin-2-ylmethyl]- 2-penem-3-carboxylic acid (sodium salt) in 3 ml of DMF.

After stirring for 3 hours at the reaction mixture is taken up in ethyl acetate and the organic phase is washed with water. After drying over sodium sulphate and concentration in a rotary evaporator, the crude product is purified on silica gel (eluant: toluene/ethyl acetate).

IR (methylene chloride): 3585, 1770, 1690 cm 1 4 t Example 30: (5R,6S)-6-[(1'R)-1'-allyloxycarbonyloxyethyl]-2-[(2S)-5-oxo-pyrrolidin-2-ylmethyl]-2-penem-3carboxylic acid allyl ester 2 g (4.26 mmol) of 2-[(3S,4R)-3-[(1'R)-1'-allyloxycarbonyloxyethyl]-4-[(2S)-5-oxo-pyrrolidin-2-ylacetylthio]-2-oxo-azetidin-l-yl]-2-oxoacetic acid allyl ester and 1.78 ml (10.5 mmol) of triethyl phosphite in 200 ml of toluene are stirred for 2 hours at 1050 under an argon atmosphere. The working up is carried out in the manner described in Example 2.

IR (3 CH 2 C1 2 3420, 2820-3460, 1791, 1701 cm 1 SThe compound is identical to the compound described in Example

I

73 The starting material can be manufactured as follows: a. (3S,4R)-3-[(1'R)-1'-allyloxycarbonyloxyethyl]-4- [(2S)-5-oxo-pyrrolidin-2-ylacetylthio]-2-oxo-azetidine 16 ml (16 mmol) of IN NaOH and 2.23 g (14 mmol) of (2S)-5-oxo-pyrrolidin-2-thiocarboxylic acid are slowly added, at to a solution of 2.57 g (10 mmol) of (3S,4R)-3-[(1'R)-1'-allyloxycarbonyloxyethyl]-4-acetoxy- 2-oxo-azetidine (cf. European Patent Application S No. 126709) in 25 ml of acetone. The whole is stirred El. for 30 minutes, then the acetone is removed by concentration by evaporation and the aqueous residue is extracted three times with 25 ml of ethyl acetate each Stime. The combined extracts are washed with 25 ml of NaHCO 3 solution and then with 25 ml of concentrated NaC1 solution, dried over Na 2

SO

4 and concentrated by evaporation. The residue is purified by chromatography con silica gel (eluant toluene/ethyl acetate).

.IR (4 CH 2 C1 2 3410, 2800-3650, 1775, 1720, 1500, -1 1220, 840 cm 1 b. 2-[(3S,4R)-3-[(1'R)-1'-allyloxycarbonyloxyethyl]- 4-[(2S)-5-oxo-pyrrolidin-2-ylacetylthio]-2-oxo-azetidin- 1-yl]-2-oxo-acetic acid allyl ester 0.84 ml (7.5 mmol) of allyloxyoxalyl chloride and 1.27 ml (7.5 mmol) of Hinig base are added dropwise to a solution of 1.78 g (50 mmol) of allyloxycarbonyloxyethyl]-4-[(2S)-5-oxo-pyrrolidin-2ylacetylthio]-2-oxo-azetidine in 25 ml of CH 2 C12 at -150 under an argon atmosphere. The mixture is stirred for 1 hour at the same temperature, washed in succession with 25 ml of 0.1N HC1, twice each with 25 ml of NaHCO 3 solution and 25 ml of concentrated NaCl solution, dried over Na 2

SO

4 and concentrated by evaporation. The crude 74 product is reacted further without any additional purification.

IR (5 CH 2 Cl 2 3410, 2800-3700, 1815, 1720, 1210 cm- The (5R,6S)-6-[(1'R)-1'-allyloxycarbonyloxyethyl]- 2-[(2S)-5-oxo-pyrrolidin-2-ylmethyl]-2-penem-3carboxylic acid allyl ester is converted in a manner analogous to that described in Example 11 or 4 into the sodium salt of (5R,6S)-6-[(1'R)-1'-hydroxyethyl]-2- [(2S)-5-oxo-pyrrolidin-2-ylmethyl]-2-penem-3-carboxylic acid.

All of the penem compounds mentioned in the preceding Examples can be manufactured in a manner analogous to that described in Example Example 31: 2-[(3S,4R)-3-(tert.-butyldimethylsilyloxymethyl)-4-(5-oxo-tetrahydrofuran-2-acetylthio)-2-oxoazetidin-1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester (diastereoisomers A and B) S A mixture consisting of 10.23 g of the silver salt 2x f of 2-[(3S,4R)-3-(tert.-butyldimethylsilyoxymethyl)-4mercapto-2-oxo-azetidin-1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester (European Patent Application No. 125207), 2.18 ml of pyridine and 50 ml of methylene chloride is added dropwise to a solution of 4.2 g of r. racemic 5-oxo-tetrahydrofuran-2-acetyl chloride [prepared from the acid according to R.D. Allan et al., Austr. J. Chem. 36, 977 (1983)] in 100 ml of

CH

2 Cl 2 at 00 while stirring. When the dropwise addition is complete, the cooling bath is removed and the whole is then further stirred for 1 hour at room temperature. The precipitate that forms is filtered with suction over Hyflo and the filtrate is washed once with saturated NaHCO 3 solution and once with saturated sodium chloride solution, dried with Na 2

SO

4 and concentrated by evaporation. The crude mixture is t separated into the diastereoisomers by chromatography on silica gel (eluant: hexane/ethyl acetate 1:1).

(3S,4R)-3-(tert.-butyldimethylSilyloxymethyl)-4- [(2R -5--oxo-tetrahydrofurari-2-acetylthio] -2-oxoazetidin-1-yl]-2-triphenylphosphoraflylideneacetic acid allyl ester (diastereoisomer A) TLC (silica gel): hexane/ethyl acetate Rf 0.22.

IR (methylene chloride): 5.64, 5.68, 5.93 mmn.

(3S,4R)-3-(tert.-butyldimethylsi'lyloxymethyl)-4- [(2S ?)-5-oxo-tetrahydrofuran-2-acetylthiol-2-oxoazetidin-1-yl]-2-triphenylphosphoranylideneacetic acid 41tt 4allyl ester (diastereoisomer B) 1 .0 TLC (silica gel): hexane/ethyl acetate 1:1 Rf 0.16.

IR (methylene chloride): 5.63, 5.71, 5.79, 5.91 Urn.

S Example 32: (5R,6S)-6 1,";ert.-butyldirnethylsilyloxymethyl)-2-[ (2R ?)-5-oxo-tetrahydrofuran-2-ylmethyl]-2-_ penem-3-carboxylic acid allyl ester (diastereoisomer A) t 730 mg of 2-[(3S,4R)-3-(tert.-butyldimethylSilyltil 20 oxyrethyl)-4-[(2R ?)-5-oxo-tetrahydrofuran-2-acetylthiol- 2-x-ztdn1yl2tihnlhshrnldnaei acid allyl ester (diastereoisomer A) are dissolved in 100 ml of toluene, a few crystals of 2,6-di-tert.-butylp-cresol (BHT) are added, and the whole is stirred for 7.5 hours at 900 under a nitrogen atmosphere.

Concentration by evaporation of the solvent and chromatography of the residue on silica gel with the eluant ether/hexane yields the pure product.

12~. 88-900.

30 IR (methylene chloride): 5.63, 5.87, 6.34 urn.

Example 33: (5R,6S)-6-(tert.-butyldimethylsilyloxyrnethyl)-2-[ (2S ?)-5-oxo-tetrahydrofuran-2-ylmethyl]-2penem-3-carboxylic acid allyl ester (diastereoisomer B) The title compound is obtained analogously to -76- Example 32 starting from 690 mg of 2-[(3S,4R)-3-(tert.butyldimethylsilyloxymethyl)-4-[(2S furan-2-acetylthio]- 2 -oxo-azetidin-l-yl]-2-triphenylphosphoranylideneacetic acid allyl ester (diastereoisomer B).

M.p. 105-1080.

IR (methylene chloride): 5.64, 5.88, 6.34 um.

Example 34: (5R,6S)-6-hydroxymethyl-2-[(2R tetrahydrofuran-2-ylmethyl]-2-penem-3-carboxylic acid i f allyl ester (diastereoisomer A) 327 mg of (5R,6S)-6-(tert.-butyldimethylsilyloxyl methyl-2-[(2R ?)-5-oxo-tetrahydrofuran-2-ylmethyl]-2- S*penem-3-carboxylic acid allyl ester (diastereoisomer A) are dissolved in 6 ml of absolute tetrahydrofuran (THF) and, under an argon atmosphere, after the solution has been cooled to -800, 0.495 ml of acetic acid is added.

18 ml of a 0.2M tetrabutylammonium fluoride solution in THF are then added dropwise and the mixture is allowed to warm to room temperature and stirred for 3 hours at that temperature. The reaction mixture is concentrated to 5 ml in a rotary evaporator and the residue is taken up in 50 ml of ethyl acetate. The organic phase is washed once with saturated NaHCO 3 solution and once c with saturated sodium chloride solution, dried over sodium sulphate and concentrated. Concentration by evaporation in a rotary evaporator yields the crude "M product, which is purified on silica gel with hexane/ethyl acetate NMR (CDC1 3 6 5.66 3.36 3.11 (dd) ppm.

UV (ethanol): Xmax 319, 248 nm.

77 Example 35: (5R,6S)-6-hydroxvmethyl-2-[(2S tetrahydrofuran-2-ylmethyl]-2-penem-3-carboxylic acid allyl ester (diastereoisomer B) The title compound is obtained analogously to Example 34 starting from 300 mg of (5R,6S)-6-(tert.butyldimethylsilyloxymethyl)-2-[(2S tetrahydrofuran-2-ylmethyl]-2-penem-3-carboxylic acid allyl ester (diastereoisomer B) NMR (CDCl 3 6 5.64 3.43 3.07 (dd) ppm.

UV (ethanol): Xmax: 320, 245 nm.

rmax n Example 36: Sodium salt of (5R,6S)-6-hydroxymethyl- V ?)-5-oxo-tetrahydrofuran-2-ylmethyl]-2-penem-3carboxylic acid (diastereoisomer A) A367 mg of (5R,6S)-6-hydroxymethyl-2-[(2R tetrahydrofuran-2-ylmethyl] -2-penem-3-carboxylic acid allyl ester (diastereoisomer A) are dissolved in 8 ml of absolute THF and cooled to 0O. After the addition of 15 mg of palladium-tetrakis(triphenylphosphine) and 0.86 ml of tributyltin hydride, the reaction mixture is allowed to warm to room temperature and is stirred for hours. Then, 0.19 ml of acetic acid is added and the whole is stirred at room temperature for a further minutes. Subsequently, the reaction mixture is poured onto ethyl acetate and the product is extracted with saturated NaHCO 3 solution. Purification is effected by chromatography on XAD-2 (eluant: water) NMR (D 2 0) 6 5.62 3.50 2.97 (dd) ppm.

UV (H20) Xmax: 303, 258 nm.

Example 37: Sodium salt of (5R,6S)-6-hydroxymethyl-2- [(2S ?)-5-oxo-tetrahydrofuran-2-ylmethyl]-2-penem-3carboxylic acid (diastereoisomer B) The title compound is obtained analogously to Example 36 starting from 83 mg of (5R,6S)-6-hydroxy- 78 methyl-2-[(2S ?)-5-oxo-tetrahydrofuran-2-ylmethyl]-2penem-3-carboxylic acid allyl ester (diastereoisomer B).

NMR (D 2 0 5 5.63, 3.31, 3.23 ppm.

UV (H 2 Xmax: 300, 263 nm.

Example 38: 2-[(3S,4R)-3-[(1'R)-1'-allyloxycarbonyloxyethyl]-4-(5-oxo-tetrahydrofuran-2-acetylthio)-2-oxoazetidin-1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester A solution of 2.8 g of racemic 'furan-2-ylacetyl chloride [prepared from the acid in rt,. accordance with R.D. Allan et al., Austr. J. Chem. 36, 977 (1983)] in 30 ml of CH 2 Cl 2 is cooled to 00 and there is added dropwise thereto a mixture consisting of g of the silver salt of allyloxycarbonyloxyethyl]-4-mercapto-2-oxo-azetidin- 1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester (see Example 17), 1.4 ml of pyridine and 30 ml of

CH

2 Cl 2 When the dropwise addition is complete, the cooling bath is removed and the whole is then stirred I for 1 hour at room temperature. The precipitate that has formed is filtered off with suction over Hyflo and the filtrate is washed once with saturated NaHCO 3 solution and once with saturated NaCl solution, dried with Na 2

SO

4 and concentrated by evaporation, After repeated purification on silica gel (eluant toluene/ethyl acetate 1:1 and hexane/ethyl acetate 2-[(3S,4R)-3- [(1'R)-1'-allyloxycarbonyloxyethyl]-4-(5-oxo-tetrahydrofurlfuran-2-acetylthio)-2-oxo-azetidin-1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester (diastereoisomeric mixture) is obtained in the form of a colourless oil which, on drying, solidifies to a foam.

IR (methylene chloride): 5.68, 5.90, 6.47 um.

There are obtained in an analogous manner starting from optically active and X; 1 -79 furan-2-ylacetyl chloride and the silver salt of 2- '-allyloxycarbonyloxyethyll-4mercapto-2-oxo-azetidin-1-yl]-2-triphelylphosphoralylideneacetic acid allyl ester the diastereoisomeric phosphoranes '-allyloxycarbonyloxyethyl]-4-[ (2R)-5-oxo-tetrahydrofuran-2-acetylthio]- 2 oxo-azetidin-1--yl]-2-triphenylphosphoranylideneacetic acid allyl ester: IR (methylene chloride): 5.67, 5.90, 6.17 jirn; and -allyloxycarbonyloxyethyll- *0 4-[l(2S)-5-oxo-tetrahydrofuran-2-acetylthio]-2-oxoazetidin-1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester: IR (methylene chloride): 5.76, 5.89, 6.11 wmn, respectively.

Example 39: '-allyloxycarbonyloxyethyll (5-oxo-tetrahydrofuran-2-ylmethyl) -2-penem-3carboxylic acid allyl ester (diastereoisomeric mixture) oxo-tetrahydrofuran-2-acetylthio) -2--oxo-azetidin-1 -yll 2-triphenylphosphoranylideneacetic acid allyl ester (diastereoisorneric mixture, 212 mg) is dissolved in ml of absolute toluene, a few crystals of 2,6-ditert.-butyl-p-cresol (BHT) are added and the whole is stirred for 24 hours at 90 0 under a nitrogen atmosphere.

Concentration by evaporation of the solvent a2nd chromatography of the residue on silica gel with the eluant toluene/ethyl acetate yields the pure product in the form of a viscous oil.

IR (methylene chloride): 5.61, 5.72, 5.84 un I S I III I 80 Example 40: Diastereoisomers of (5R,6S)-6-[(l'RV1l'allyloxycarbonyloxyethyl] (5-oxo-tetrahydrofurafl2ylmethyl)-2-penem-3-carboxylic acid allyl ester Analogously to Example 39 there are obtained from 290 mg of '-allyloxycarbonyloxyethyl]-4--E (2R)-5-oxo-tetrahydrofuran-2-acetYlthio]- 2 oxo-azetidin-1-yl] -2-triphenylphosphoranylideleacetic acid allyl ester and from 290 mg of 1 '-allyloxycarbonyloxyethyll-4-[ furan-2-acetylthio] -2-oxo-azetidin-1-yl] -2-triphenylphosphoranylideneacetic acid allyl ester, respectively, after purification on silica gel (eluant: toluene/ethyl acetate the diastereoisomeric penem esters 'R)-l'-allyloxycarbonyloxyethyl]-2-I(2R)-5oxoi-tetrahydrofuran-2-ylmethyl] -2-penem-3-carboxylic acid allyl ester, IR (methylene chloride) 5.62, 5.73, 5.85 urn; and '-al.yloxycarbonyloxyethyl]-2-[(2S)- 5-oxo-tetrahydrofuran-2-ylmethyl] -2-penem-3-carboxylic acid allyl ester, IR (methylene chloride): 5.61, 5.73, 5.88 p'm, respectively.

Example 41: Sodium salt of hydroxyethyl] -2-(5-oxo-tetrahydrofuran-2-ylmethyl) -2penem-3-carboxylic acid (diastereoisomer ic mixture) 260 mg of '-allyloxycarbonyloxyethyll (5-oxo-tetrahydrofuran-2-ylmethyl) -2-penem- 3-carboxylic acid allyl ester (diastereoisomeric mixtCure) are dissolved at 00, under argon, in 10 ml of absolute THF and 20 mg of palladiumtetrakis-(triphenylphosphine) are added. 630 ul of tributyltin hydride are added dropwise using a syringe. The cooling bath is then removed and the reaction mixture is subsequently 81 stirred for 1.5 hours at room temperature. After the addition of 139 ul of acetic acid the whole is stirred for a further 30 minutes at room temperature, then the reaction mixture is diluted with ethyl acetate and the solution is extracted twice with soda solution (0.9 g of soda in 50 ml) and four times with saturated NaHCO 3 solution. The pH of the inorganic phase is adjusted to with acetic acid, and the mixture is concentrated in a rotary evaporator and purified on XAD-2. The title compound is obtained in the form of a colourless lyophilisate.

IR (DMSO-d 6 5.66, 6.19, 6.32 lim.

UV (H 2 max 304, 258 nm.

SExample 42: Diastereoisomers of the sodium salt of a7 I oftfuran-2-ylmethyl)-2-penem-3-carboxylic acid In a manner analogous to that described in Example 41, 150 mg of '-allyloxycarbonyloxyre ethyl]-2-[ (2R)-5-oxo-tetrahydrofuran-2-ylmethylJ-2penem-3-carboxylic acid allyl ester, and 150 mg of (5R,6S)-6-[1 '-allyloxycarbonyloxyethyl]-2-[(2S)- 5-oxo-tetrahydrofuran-2-ylmethylj-2-penem-3-carboxylic acid allyl ester are each respectively reacted to form the following diastereoisomeric penems, which are purified over an XAD-2 column: sodium salt of '-hydroxyethyl]-2- [(2R)-5-rxo-tetrahydrofuran-2-vlmethyl]-2-penem-3z carboxylic acid UV (H20): Xmax 304, 260 nm; sodium salt of 'R)-1'-hydroxyethyl]-2- [(2S)-5-oxo-tetrahydrofuran-2-ylmethyll -2-penem-3carboxylic acid, UV (H 2 max: 304, 260 nm.

4 Example 43: Diastereoisomers of 2-[(3S,4R)-3-(tert.butyldimethylsilyloxymethyl)-4-(3-oxo-phthalal-acetyltho--x-ztdn1y]2-rpeypopoayiee acetic acid allyl ester A mixture consisting of 8.6 g of the silver salt of (3S,4R)-3-(tert.-butyldimethylsilyloxymethyl)- 4 mercapto-2-oxo-azetidin-1-yl] -2-triphenylphosphoralylideneacetic acid allyl ester, 1.28 ml of pyridine and fro o100 ml of methylene chloride is added dropwise to a $699*solution of 3.28 g of 3-oxo-phthalan-1-acetyl chloride (prepared from the free acid with SOd 2 in 150 ml of fit Q0 methylene chloride at 0 while stirring. When the dropwise addition is complete the cooling bath is f 4 removed and the whole is further stirred at room temperature for 1 hour. The precipitate that has formed is filtered with suction over Hyflo and the filtrate is washed once with saturated NaHCO 3 solution and once with saturated sodium chloride solution, dried with NA so 4 and concentrated by evaporation. The crude mixture is filtered over silica gel (eluant hexane/ethyl acetate 1:1) and separated into the diastereoisomers on a Merck ready-prepared column (eluant hexane/ethyl acetate 2:1 and 1:1): 2-[(3S,4R)-3-(tert.-butyldimethylsilyloxymethyl)-4- [(iS ?)-3-oxo--phthalan-l-acetylthiol-2-oxo-azetidin-lyl]-2-triphenylphosphoranylideneacetic acid allyl ester (diastereoisomer A): TLC (silica gel, hexane/ethyl acetate Rf =0.19; IR (methylene chloride): 5.68, 5.93, 6.18 pm; (3S,4R)-3-(tert.-butyldimethylsilyloxymethyl)-4- [(1R ?)-3-oxo-phthalan-1-acetylthio]-2-oxo-azetidin-1yl] -2-triphenylphosphoranylideneacetic acid allyl ester (diastereoisomer B): TLC (silica gel, hexane/ethyl acetate Rf =0.148; IR (methylene chloride): 5.66, 5.91, 6.18 um.

83 (p *A *p 04 o p o p *0 o *p 09 e Example 44: (5R,6S)-6-(tert.-butyldimethylsilyloxymethyl)-2-[(is ?)-3-oxo-phthalan-1-ylmethyll-2-penem-3carboxylic acid allyl ester (diastereoisoner A) 915 mg of 2-[(3S,4R)-3-(tert.-butyldimethylsilyloxymethyl)-4-[ (IS ?)-3-oxo-phthalan-l-acetylthio]-2-oxoazetidin-1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester (diastereoisomer A) are dissolved in 100 ml of toluene, a few crystals of 2,6-di-tert.-butyl-pcresol (BHT) are added and the whole is stirred for 4 hours at 1000 under a nitrogen atmosphere.

Concentration by evaporation of the solvent and chromatography of the residue on silica gel with the eluant toluene/ethyl acetate yields the pure product.

TLC (silica gel, toluene/ethyl acEtate Rf 0.75; IR (methylene chloride): 5.59, 5.65, 5.86, 6.32 Urm; NMR (CDCl 3 6 =5.49 3.52 3.45 (dd) ppm.

Example 45: (5R,6S)-6-(tert.-butyldimethylsilyloxymethyl)-2-[(iR ?)-3-oxo-phthalan-1-ylmethyll-2-penem-3carboxylic acid allyl ester (diastereoisomer B) The pure title compound is obtained analogously to Example 44, starting from 810 mg of 2-[(3S,4R)-3-(tert.butyldimethylsilyloxymethyl)-4-[(lR ?)-3-oxo-phthalan-1acetylthio]-2-oxo-azetidin-1-yll-2-triphenylphosphoranylideneacetic acid allyl ester (diastereoisomer B) after 2 hours' heating at 100 M.p. 124-125 IR (methylene chloride): 5.58, 5.65, 5.66, 6.32 um; NMR (CDCl 3 6 5.57 3.75 3.24 (dd) ppm.

Example 46: (5R,6S)-6-hydroxymethyl-2-[(1S ?)-3-oxophthalan-1-ylmethyl]-2-penem-3-carboxylic acid allyl ester (diastereoisomer A) 590 mg of (5R,6S)-6-(tert.-butyldimethylsilyloxymethyl)-2-[(IS ?)-3-oxo-phthalan-1-ylmethyl-2-penem-3-

U

84 carboxylic acid allyl ester (diastereoisomer A) are dissolved in 15 ml of absolute tetrahydrofuran and, under an argon atmosphere, after the solution has been cooled to -800, 0.81 ml of acetic acid is added.

13.24 ml of a 0.44M tetrabutylammonium fluoride solution in THF are then added dropwise and the mixture is allowed to come to room temperature and is then stirred for 3 hours at that temperature. The reaction J mixture is concentrated in a rotary evaporator and the S.residue is taken up in 50 ml of ethyl acetate. The organic phase is washed once with saturated NaHCO 3 solution and once with saturated sodium chloride solution, dried over sodium sulphate and concentrated.

Concentration by evaporation in a rotary evaporator yields the crude product, which is purified on silica gel with toluene/ethyl acetate 1:1.

IR (methylene chloride): 5.59, 5.65, 5.86, 6.33 um.

NMR (CDC1 3 6 5.51 3.60 3.46 (dd) ppm.

Example 47: (5R,6S)-6-hydroxymethyl-2-[(1R ?)-3-oxophthalan-1-ylmethyl]-2-penem-3-carboxylic acid allyl ester (diastereoisomer B) The title compound is obtained analogously to Example 46 starting from 485 mg of (5R,6S)-6-(tert.butyldimethylsilyloxymethyl)-2-[(1R ?)-3-oxo-phthalan- 1-ylmethyl]-2-penem-3-carboxylic acid allyl ester (diastereoisomer B).

S, IR (methylene chloride): 5.59, 5.65, 5.86, 6.33 um.

SNMR (CDC1 3 6 5.62 3.76 3.28 (dd) ppm.

Example 48: Sodium salt of (5R,6S)-6-hydroxymethyl-2- [(IS ?)-3-oxo-phthalan-1-ylmethyl]-2-penem-3-carboxylic acid (diastereoisomer A) 172 mg of (5R,6S)-6-hydroxymethyl-2-[(1S ?)-3-oxophthalan-1-ylmethyl]-2-penem-3-carboxylic acid allyl _hp 85 ester (diastereoisomer A) are dissolved in 5 ml of absolute THF and cooled to After the addition of mg of palladium-tetrakis-(triphenylphosphine) and 353 ul of tributyltin hydride, the reaction mixture is allowed to warm to room temperature and is stirred for 1 hour. Subsequently, 79 pl of acetic acid are added and the whole is stirred for a further 30 minutes at room temperature. The reaction mixture is poured onto ethyl acetate and extracted once with 10 ml of Na 3

CO

3 solution (0.9 g/50 ml H 2 0) and three times, with 10 ml each time, with saturated NaHCO 3 solution. The combined aqueous phases are washed once K with ethyl acetate. Purification is carried out by chromatography on XAD-2 (eluant: water and water/isopropanol 9:1).

NMR (D 2 6 5.22 4.05 3.26 (dd) ppm; SoUV (H 2 Xmax 305, 284, 275, 231 nm.

0 oo Example 49: Sodium salt of (5R,6S)-6-hydroxymethyl-2- :o [(1R ?)-3-oxo-phthalan-1-ylmethyl]-2-penem-3-carboxylic acid (diastereoisomer B) The title compound is obtained in a manner analogous to that described in Example 48 starting from (5R,6S)-6-hydroxymethyl-2-[(1R ?)-3-oxo-phthalan-1ylmethyl]-2-penem-3-carboxylic acid allyl ester (diastereoisomer B).

NMR (D 2 6 5.43 4.09 3.48 (dd) ppm; UV (H 2 Xmax 304, 284, 275, 231 nm.

Example 50: Sodium salt of hydroxyethyl]-2-(3-oxo-phthalan-1-ylmethyl)-2-penem-3carboxylic acid (diastereoisomers A and B) In a manner analogous to that described in Examples 43-49 there are obtained, starting from the silver salt of 'R)-1'-allyloxycarbonyl- I 86 oxyethyl]-4-mercapto-2-oxo-azetidin-1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester and 3-oxophthalan-l-acetyl chloride, the following diastereoisomeric penems: the sodium salt of (5R,6S)-6-[(1'R)-1'-hydroxyethyl]-2- [(IS ?)-3-oxo-phthalan-1-ylmethyl]-2-penem-3-carboxylic acid (diastereoisomer A) [UV (H20): Amax 305, 285, 274, 231 nm] 0 and the sodium salt of (5R,6S)-6-[(1'R)-1'-hydroxyethyl]-2-[(1R ?)-3-oxo-phthalan-1-ylmethyl]-2-penem-3o*« carboxylic acid (diastereoisomer B) [UV (H 2 Xmax 304, 283, 275, 230 nm].

Example 51: (5R,6S)-6-hydroxymethyl-2-[(2S tetrahydrofuran-2-ylmethyl]-2-penem-3-carboxylic acid pivaloyloxymethyl ester 0.75 g (5 mmol) of sodium iodide are dissolved in 3 ml of acetone and 0.19 ml (1.3 mmol) of pivalic acid chloromethyl ester is added. The mixture is stirred at room temperature for 3 hours and then added dropwise to 9 ml of methylene chloride. The precipitated inorganic S^ salts are filtered off. The methylene chloride S" solution is concentrated to approximately 1 ml and, at 00, added to a solution of 160 mg (0.5 mmol) of the sodium salt of (5R,6S)-6-hydroxymethyl-2-[(2S tetrahydrofuran-2-yl)nethyl]-2-penem-3-carboxylic acid (diastereoisomer B) in 5 ml of absolute DMF and 0.5 ml of DMSO. After stirring for 30 minutes at 0° and a further 30 minutes at room temperature, the reaction mixture is taken up in ethyl acetate and washed with brine. After drying over sodium sulphate and concentration in a rotary evaporator the crude product is purified on silica gel (eluant toluene/ethyl acetate).

IR (methylene chloride): 2.79, 5.63, 5.89 um.

87 Example 52: (5R,6S)-6-hydroxymethyl-2-[(2R tetrahydrofuran-2-ylmethyl]-2-penem-3-carboxylic acid acetoxymethyl ester 128 mg (0.398 mmol) of the sodium salt of (5R,6S)- 6-hydroxymethyl-2-[(2R ?)-5-oxo-tetrahydrofuran-2ylmethyl]-2-penem-3-carboxylic acid (diastereoisomer A) are dissolved in 5 ml of absolute DMF and 0.5 ml of absolute DMSO and, at 00, a solution of 70 mg (0.46 mmol) of acetoxybromomethane in 0.5 ml of absolute DMF *n is added dropwise. After stirring for 30 minutes at add.00 and then for a further 30 minutes at room temperature, the reaction mixture is taken up in ethyl acetate and washed with brine. After drying the organic phase over sodium sulphate and concentration in *0 a rotary evaporator, the crude product is purified on silica gel (eluant toluene/ethyl acetate) IR (methylene chloride): 2.79, 5.62, 5.88 um.

Example 53: '-allyloxycarbonyloxyethyl]-4- [3-(2-oxo-tetrahydrofuran-4-yl)-propionylthio ]-2-oxo-azetidin-1-ylJ-2-triphenylphosphoranylideneacetic acid allyl ester (diastereoisomeric mixture) 293 mg of the silver salt of 1'-allyloxycarbonyloxyethyl]-4-mercapto-2-oxo-azetidin- 1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester and 47 ul of pyridine are dissolved in 2 ml of

CH

2 Cl 2 and, at 00 under argon, 111 mg of racemic 3-(2-oxo-tetrahydrofuran-4-yl)-propionyl chloride (obtained in customary manner with SOC1 2 from the corresponding acid manufactured in accordance with O.

Ceder et al., Acta Chem. Scand. 24, 2693 (1970)) are added dropwise. After stirring for 75 minutes at room temperature, the resulting precipitate is filtered with suction over Hyflo and the filtrate is concentrated by evaporation. The residue is taken up e-A 7 88 in ethyl acetate, and washed twice with saturated NaHCO 3 solution and twice with saturated NaC1 solution. After drying over Na 2

SO

4 the organic phase is concentrated and the residue is purified on silica gel (eluant toluene/ethyl acetate The title compound is obtained in the form of a viscous oil which, on drying, soldifies to a foam.

IR (CH 2 C1 2 5.68, 5.91, 6.18 um.

Example 54: (5R,6S)-6-[(1'R)-1'-allyloxycarbonyloxyethyl] [2-(2-oxo-tetrahydrofuran-4-yl)-ethyl]-2penem-3-carboxylic acid allyl ester (diastereoisomeric #t, mixture) The title compound is obtained in the form of a yellowish resin analogously to the process described in Example 39 starting from 3.1 g of S1 '-allyloxycarbonyloxyethyll-4-[3-(2-oxo-tetrahydro- ~furan-4-yl)-propionylthio] -2-oxo-azetidin-1-yl] -2triphenylphosphoranylideneacetic acid allyl ester (diastereoisomeric mixture) after stirring for 5 hours on an oil bath at a bath temperature of 1100 and subsequent chromatographic purification on silica gel (eluant: hexane/ethyl acetate 1:1).

IR (CH 2 Cl 2 5.60, 5.72, 5.85, 6.32 um.

Example 55: Sodium salt of hydroxyethyl]-2-[2-(2-oxo-tetrahydrofuran-4-yl)ethyl] -2-penem-3-carboxylic acid '(diastereoisomeric mixture) Under argon, 140 mg of allyloxycarbonyloxyethyl]-2-[2-(2-oxo-tetrahydrofuran- 4-yl)-ethyl]-2--penem-3-carboxylic acid allyl ester (diastereoisomeric mixture) are dissolved in 1.5 ml of absolute tetrahydrofuran and 20 mg of palladiumtetrakis-(triphenylphosphine) are added. 63 o1 of 7.

89 acetylacetone are added dropwise to this mixture and the whole is then stirred for 3 hours at room temperature. The reaction mixture is then concentrated in a rotary evaporator, 0.82 ml of saturated NaHCO 3 solution is added and the whole is directly filtered over an XAD-2 column. The product-containing fractions are concentrated and purified again on Opti-up silica gel (eluant in both cases is water). The title compound is obtained in the form of a colourless lyophilisate.

09 IR (DMSO-d 6 5.66, 6.20, 6.32 im.

2UV (H 2 max 303, 260 nm.

o9 Example 56: 2-[(3S,4R)-3-(tert.-butyldimethylsilyl- 0 oxymethyl) (2,5-dihydro-5-oxo-furan-2-ylacetylthio) 2-oxo-azetidin-l-yl]-2-triphenylphosphoranylideneacetic 09 acid allyl ester (diastereoisomeric mixture) 580 mg of 2,5-dihydro-5-oxo-furan-2-ylacetyl chloride (obtainable with SOC1 2 from the corresponding acid manufactured in accordance with the method of J. A. Elridge et al., J. Chem. Soc. (1950) 2228) are dissolved in 25 ml of CH 2 C1 2 and, at 00, a solution of 1.71 g of the silver salt of 2-[(3S,4R)- 3-(tert.-butyldimethylsilyloxymethyl)-4-mercapto-2-oxoazetidin-1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester and 285 mg of pyridine in 25 ml of

CH

2 C12 are slowly added. When the dropwise addition is complete, the cooling bath is removed and the whole is then stirred for a further hour at room temperature. Working up is carried out analogously to the method described in Example 38. Purification of the phosphorane (diastereoisomeric mixture) is effected by chromatography on silica gel (eluent hexane/ethyl Sacetate 1:1).

IR (CH 2 Cl 2 5.67, 5.89, 6.17 um.

'i Vt t 90 Example 57: (5R,6S)-6-(tert.-butyldimethylsilyloxythyl)-2-(2,5-dihydro-5-oxo-furan-2-ylmethyl)-2-pene- 3-carboxylic acid allyl ester (diastereoisomeric mixture) 645 mg of 2-[(3S,4R)-3-(tert.-butyldimethylsilyloxymethyl)-4-(2,5-dihydro-5-oxo-furan-2-ylacetylthio)- 2-oxo-azetidin-1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester (diastereoisomeric mixture) are dissolved in 50 ml of absolute toluene, a few crystals t of BHT are added and the whole is stirred for 3 hours at an oil bath temperature of 95-1000 under a nitrogen atmosphere. Concentration by evaporation of the solvent and chromatography of the residue on silica gel in hexane/ethyl acetate yields the pure product.

IR (CH 2 C1 2 5.58, 5.67, 5.85 im.

Example 58: (5R,6S)-2-hydroxymethyl-2-(2,5-dihydro-5oxo-furan-2-ylmethyl)-2-penem-3-carboxylic acid allyl ester (diastereoisomeric mixture) 190 mg of (5R,6S)-6-(tert.-butyldimethylsilyloxymethyl)-2-(2,5-dihydro-5-oxo-furan-2-ylmethyl)-2-penem- 3-carboxylic acid allyl ester (diastereoisomeric mixture) are dissolved in 5 ml of absolute tetrahydrofuran and cooled to -780. There are added dropwise to this solution, using a syringe, 228 ul of acetic acid followed by 2.1 ml of a IM tetrabutylammonium fluoride solution in THF. When the dropwise addition is complete, the cooling bath is removed and the whole is stirred for a further 1.5 hours. The reaction mixture is taken up in ethyl acetate and washed until neutral with saturated NaHCO 3 solution and saturated NaC1 solution. After drying over Na 2

SO

4 the solution is concentrated and the residue is chromato- -91 graphed on silica gel (eluant: hexane/ethyl acetate 1:1).

IR (CH 2 Cl 2 5.58, 5.66, 6.31 urn.

Example 59: Sodium salt of (5R,6S)-6-hydroxymethyl- 2- (2 ,5-dihydro-5-oxo-furan-2-ylmethyl) -2-penem-3carboxylic acid (diastereoisomeric mixture) The title compound is obtained in the form of a colourless lyophilisate analogously to the process described in Example 41 starting from 50 mg of (5R,6S)-6-hydroxymethyl-2-(2,5-dihydro-5-oxofuran-2-ylmethyl)-2-penem-3--carboxylic acid allyl ester (diastereoisomeric mixture) and after purification on XAD-2.

IR (KBr): 5.71 urn; UV (H 2 X~max =305, 257 nm.

Example 60: Diastereoisomers of 2-II(3S,4R)-3-(tert.butyldimethylsilyloxymethyl)-4-(2,5-dihydro-5-oxofuran-2-ylacetylthio)-2-oxo-azetidin-1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester The diastereoisomeric mixture obtainable in accordance with Example 56 is separated by repeated chromatography on silica gel (eluant hexane/ethyl acetate 2.5:1) into the individual diastereoisomers: (3S,4R)-3--(tert.-butyldimethylsilyloxymethyl)-4- [(2S)-2,5-dihydro-5-oxo-furan--2-ylacetylthio]-2-oxoazetidin-1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester: IR (CH 2 Cl 2 5.68, 5.89, 6.17 urn; (3S,4R)-3-(tert.-butyldimethylsilyloxymethyl)-4- 5-dihydro-5-oxo-furan-2-ylacetylthio] -2-oxoazetidin-1-ylI -2-triphenylphosphoranylideneacetic acid allyl ester IR (CH 2 Cl 2 5.68, 5.91, 6.18 un 92 Example 61: (5R,6S)-6-(tert.-butyldimethylsilyloxymethyl)-2-[ (2S)-2,5-dihydro-5-oxo-furan-2-ylmethyl]-2penem-3-carboxylic acid allyl ester The title compound is obtained in crystalline form analogously to the process described in Example 57 starting from 744 mg of 2-[(3S,4R)-3-(tert.-butyldimethylsilyloxymethyl)-4-[ (2S)-2,5-dihydro-5-oxofuran-2-ylacetylthio]-2-oxo-azetidin-1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester.

IR (CH Cl 2 5.58, 5.67, 5.85. 6.32 tim.

Example 62: (5R,6S)-6-hydroxymethyl-2-[ (2S)-2,5dihydro-5-oxo--furan-2-ylmethyl] -2-penem--3-carboxylic acid allyl ester The title compound is obtained in the form of a viscous oil analogously to the process described in Example 58 starting from 315 mg of (5R,6S)-6-(tert.butyldimethylsilyloxymethyl)-2-[ (2S)-2,5-dihydro-5oxo-furan-2-ylmethyl]-2-penem-3-carboxylic acid allyl ester after chroma~tographic purification on silica gel.

IR (CH 2 Cl 2 2.84, 5.59, 5.83, 5.85, 6.32 uim.

Example 63: Sodium salt of (5R,6S)-6-hydroxymethyl-2- [(2S)-2,5-dihydro-5-oxo-furan-2-ylmethylll-2-penem-3carboxylic acid The title compound is obtained in the form of a colourless lyophilisate analogously to the process described in Example 59 starting from 170 mg of (5R,6S)-6-hydroxymethyl-2-[ (2S)-2,5--dihydro-5-oxofuran-2-ylmethyl]-2-penem-3-ca 'joxylic acid allyl ester and after purification on XAD-2 and lyophilisation.

IR (DMSO-d 6 5.71, 6.19, 6.31 urn; UV (H 2 Xmax =306, 259 nm.

-93- IiExample 64: (5R,6S)-6-(tert.--butyldimethylsilyloxymethyl)-2-( (2R)-2,5-dihydro-5-oxo-furan-2-ylmethyl]-2d penem-3-carboxylic acid allyl ester The title compound is obtained in crystalline form n analogously to the process described in Example 57 starting from 702 mg of 2-[(3S,4R)-3-(tert.-butyldimethylsilyloxymethyl)-4-[ (2R)-2,5-dihydro-5-oxofuran-2-ylacetylthi-o] -2-oxo-azetidin-1 -yll -2-triphenylphosphoranylideneacetic acid allyl ester and after chromatographic purification on silica gel (eluant hexane/ethyl acetate 2.5:1).

IR (CH 2 Cl 2 5.58, 5.67, 5.85, 6.32 ium.

The compound was subjected to X-ray structural analysis, which confirmed the absolute configuration indicated.

Example 65: (5R,6S)-6-hydroxymethyl-2-[(2R)-2,5dihydro-5-oxo-furan-2-ylmethyl]-2-penem-3 carboxylic acid allyl ester The title compound is obtained in the form of a colourless crystalline compound analogously to the process described in Example 58 starting from 193 mg of (5R,6S)-6-(tert.-butyldimethylsilyloxymethyl)-2-[ (2R)- 2,5-dihydro-5-oxo-furan-2-ylmethyl] -2-penem-3carboxylic acid allyl ester and after chromatographic purification on silica gel.

IR (C9 2 C1 2 5.58, 5.67, 5.85, 6.32 jm Example 66: Sodium salt of (5R 1 55)-6-hydroxymethyI- (2R)-2,5-dihydro-5--oxo-furan-2-ylmethylJ-2-penem-3carboxylic acid The title compound is obtained in the form of a colourless lyophilisate analogously to the process described in Example 59 starting from 357 mg of 6S) -6-hydroxymethyl-2- -94 furan-2-ylmethyl]-2-penem-3-carboxylic acid allyl ester and after purification on xAD-2 and lyophilisation.

17t '(DO-d 6 5.65, 5.71, 6.19 11m; ~a 305, 256 nm.

Example 67: 2-[(3S,4R)-3-[(1'R)-1'-allyloxycarbolyloxyethyl] (2 ,5-dihydro-5-oxo-furan-2-ylacetylthio) -2oxo-azetidin-1 -yl -2-triphenylphosphoranylideneacetic acid allyl ester (diastereoisomeric mixture) The title compound is obtained analogously to the process described in Example 38 starting from 1.3 g of racemic 2,5-dihydro-5-oxo-furan-2-ylacetyl chloride, 3.8 g of the silver salt of allyloxycarbonyloxyethyll -4-mercapto-2-oxo-azetidin-lyl]-2-triphenylphosphoranylideneacetic acid allyl ester and 676 wl of pyridine and after purification on silica gel; on drying the title compound solidifies to a foam.

IR (CH 2 Cl 2 5.68, 5.91, 6.16 um.

Example 68: '-allyloxycarbonyloxyethyl] (2,5-dihydro-5-oxo-furan-2-ylmethyl)-2-penem- 3-carboxylic acid allyl ester (diastereoisomeric mixture) The title compound is obtained in the form of a viscous oil analogously to the process described in Example 39 starting from 1.97 g of 1 '-allyloxycarbonyloxyethyll-4-(2,5-dihydro-5-oxofuran-2-ylacetylthio)-2-oxo-azetidin-1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester (diastereoisomeric mixture).

IR (CH 2 C1 2 5.57, 5.68, 5.84, 6.31 "m.

.16.

Example 69: Sodium salt of hydroxyethyl] (2 ,5-dih ydro-5-oxo-furafl-2-Ylmethyl) 2-penem-3-carboxyl ic ac7id (diastereoisomer ic mixture) The title compound is obtained analogously to the process described in Example 55 starting from 962 mg of dihydro-5-oxo-furan-2-YlmethYl) -2-penem-3-carboxylic acid allyl ester (diastereoisomeric mixture) and after purification over an XAD-2 column.

IR (DMSO-d 6 5.63, 5.70, 6.19, 6.31 urn; UV (H 2 306, 259 nm.

Example 70:_ Diastereoisomers of 1 '-allyloxycarbonyloxyet hyll (2 ,5-dihydro3methyls5oxo-furan-2-ylacetylthio) -2-oxo-azetid in-i -yll -2triphenyiphosphoranylideneacetic acid allyl ester A mixture of the diastereoisomeric phosphoranes is obtained analogously to the process described in Example 38 starting from 3.02 g of racemic 3-methyl-5-oxo-furan-2-ylacetyl chloride (obtainable with SOC1 2 from the corresponding acid prepared in accordance with the method of J.A. Elridge et al., J. Chem. Soc. (1950) 2228). The diastereoisomeric phosphoranes can be separated by repeated chromatography on silica gel (eluant toluene/ethyl acetate 1:1 and hexane/ethyl acetate 1:1).

2-[(3S,4R)-3-L (l'R)-1'-allyloxycarbonyloxyethylP 4 2 5 dihydro-3-methyl-5-oxo-furan-2-ylacetylthio) -2-oxoazetidin-1 -yl] -2-triphenyiphosphoranylideneacetic acid allyl ester (diastereoisomer A): IR (CHE Cl 5.68, 5.91, 6.17 gm.

(l'R)-l'-allyloxycarbofyloxyethyl] 4 1.

2 5 dihydro-3-methyl5-oxofural2ylacethylthio) -2-oxoazetidin-1-y11 -2-triphenylphosphoranylidefleacetic acid allyl ester (diastereoisomer B): 96 IR (CH 2 Cl 2 5.67, 5.89, 6.16 Jim.

Example 71: (1 R)-1 '-allyloxycarbonyloxyethyl] ,5-dihydro-3-methyl-5-oxo-furan-2-ylmethyl) 2-penem-3-carboxylic acid allyl ester (diastereoisomer

S

4, :441 r

I

r r t I It, The title compound is obtained analogously to the process described in Example 39 starting from 878 mg of 2-[(3S,4R)-3-[(l'R)-1'-allyloxycarbonyloxyethyl]-4-(2,5dihydro-3-rnethyl-5-oxo-furan-2-ylacetylthio) -2-oxoazetidin-l-yl]-2-triphenylphosphoranylideneacetic acid allyl ester (diastereoisomer A) and after purification on silica gel (eluant hexane/ethyl acetate 1:1).

IR (CH 2 Cl 2 5.58, 5.66, 5.71, 5.85, 6.07, 6.33 urn.

Example 72: Sodium salt of hydroxyethyll-2-(2,5-dihydro-3-methyl-5-oxo-furan-2ylmethyl)-2-penem-3-carboxylic acid (diastereoisomer A) The title compound is obtained in the form of a colourless lyophilisate analogously to the process described in Example 55 starting from 119 mg of 'R)-1'-allyloxycarbonyloxyethyl]-2-(2,5di'hydro-3-methyl-5-oxo-furan-2-ylmethyl) -2-penem-3carboxylic acid allyl ester (diastereoisomer A) and after purification over XAD-2 and lyophilisation.

IR (DMSO-d 6 5.65, 5.70, 6.09, 6.19, 6.32 urn.

UV (H 2 )Lmax: 307, 258 nm.

Example 73: '-allyloxycarbonyloxyethyl] (2 ,5-dihydro-3-methyl-5-oxo-furan-2-ylmethyl) 2-penem-3-carboxylic acid allyl ester (diastereoisomer

B)

The title compound is obtained analogously to the process described in Example 39 starting from 626 mg of 2- 4R) -3-1(1 -1'-allyloxycarbonyloxyethyl] 4 71 ii if e t it

C-

97 dihydro-3-methyl-5-oxo-furan-2-ylacetylthio) -2-oxoazetidin-1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester (diastereoisomer B) and after purification on silica gel (eluant hexane/ethyl acetate 2.5:1).

IR (CH 2 Cl 2 5.58, 5.67, 5.71, 5.85, 6.07, 6.32 umn.

Example 74: Sodium salt of hydroxyethyl] (2 ,5-dihydro-3-methyl-5-oxo-furan-2ylmethyl)-2-penem-3-carboxylic acid (diastereoisomer B The title compound is obtained in the form of a colourless lyophilisate analogously to the process described in Example 55 starting from 558 mg of '-allyloxycarbonyloxyethyl]-2- (2,5-dihydro-3-mnethyl-5--oxo-furan-2-ylmethyl) -2-penem- 3-carboxylic acid allyl estier (diastereoisomer B) and after purification on XAD-2 and lyophilisation.

IR (DMSO-d 6 5.65, 5.69, 6.08, 6.19, 6.32 um.

UV (H 2 Xmax 305, 258 nm.

Example 75: R)-1 '-allyloxycarbonyloxyethyl] (5-oxo-tetrahydrofuran-2-yl)-propionylthiol -2-oxo-azetid in-i -yl] -2-tr iphenylphosphoranylideneacetic acid allyl ester (diastereoisomeric mixture) The title compound is obtained in the form of a diastereoisomeric mixture analogously to the process described in Example 38 starting from 380 mg of racemic 3- (5-oxo-tetrahydrofuran-2-yl) -propionyl chloride.

IR (CH 2 Cl 2 5.66, 5.89, 6.17 um.

Example 76: '-allyloxycarbonyloxyethyl] t2- (5-oxo-tetrahydrofuran-2-yl)_-ethyl] -2penem-3-carboxylic acid allyl ester (diastereoisoneric mixture) The title compound is obtained analogously to the 98 process described in Example 39 starting from 418 mg of '-allyloxycarbonyloxyethyl]-4-[3- (5-oxo-tetrahydrofuran-2-yl) -propionyithiol -2--oxoazetid in-i -ylJ -2-triphenyiphosphoranylideneacetic acid allyl ester (diastereoisomeric mixture) and after purification on silica gel (eluant hexane/ethyl acetate 1:1).

IR (CH Cl 2 5.58, 5.72, 5.84, 6.32 ism.

Example 77: Sodium salt of hydroxyethylI-.2-[2-(5-oxo-tetrahydrofuran-2-yl)-etnyl]- 2-penem-3-carboxyl ic acid (d iastereoisomer ic mixture) The title compound is obtained in the form of a colourless lyophilisate analogously to the process tot described in Example 55 starting from 149 mg of '-allyloxycarbonyloxyethyl-2-[2- (5-oxo-tetrahydrofuran-2-yl) -ethyl] -2-penem-3carboxylic acid allyl ester (diastereoisomeric mixture) and after purification over XAD-2 and lyophilisation.

IR (DMSO-d 6 5.65, 6.19, 6.30 jim.

UV (H 2 Xmax 302, 259 nm.

Example 78: In a manner analogous to that described in Examples 43-49, starting from the silver salt of 2- [(3S,4R)-3-(tert.-butyldimethylsilyloxymethyl)-4mercapto-2-oo-azetidin-1-yl] -2-triphenylphosphoranylideneacetic acid allyl ester and racemic 5-methoxy-3-oxo-phthalan- 1-ylacetyl chloride (obtainable from the free acid with SOC1 2 the following diastereoisomeric penems are obtained: sodium salt of (5R,6S)-6-hydroxymethyl-2-(5-methoxy- 3-oxo-phthalan-1-ylmethyl) -2-penem-3-carboxylic acid, diastereoisomer A: UIV (1120): )Lmax =302, 229 (shoulder) 212 nm; 'Al 13. (5 ,S -y roy ty ]2 [2 )4o o 99 diastereoisomer B: UV (Ii 2 Xrax (shoulder), 212 nm.

=303, 230 9 CC 0 p 0 eq.,, 8 0 QqCq p pq 0 p P.C 9 o 9~ 0 0 pqq p .9 00 0 904 *00 i. 90 9* Example 79: In a manner analogous to that described in Examples 31-78, starting respectively from the silver salt of 2-[(3S,4R)-3-(tert.-butyldimethylsilyloxymethyl) -4-mercapto-2-oxo-azetid in-i -yl] -2-tr iphenylphosphoranylideneacetic acid allyl ester and from the silver salt of 'R)-l'-allyloxycarbonyloxyethiyl] -4-mercapto-2-oxo-azetid in-i -2-triphenylphosphoranylideneacetic acid allyl ester with and (4S)-3-(2-oxo-tetrahydrofuran-4-yl)-propionyl chloride, respectively, (each produced from the free acid with SOd1 2 the following are obtained: sodium salt of (5R,6S)-6-hydroxymethyl-2-[ (4R)-2-(2-oxotetrahydrofuran-4-yl) -ethyl] -2-penem-3-carboxylic acid, UV (H 2 Xmax =302, 257 nm; sodium salt of (5R,6S)-6-hydroxymethyl-2-( (4S)-2-(2-oxotetrahydrofuran-4-yl) -ethyl] -2-penem-3-carboxylic acid, UV (H 2 Xmax 303, 257 nm; and sodium salt of '-hydroxyethyl]-2- [(R--2oottayrfra--l-ty12pnm3 carboxylic acid, UV (H 2 Xma 301, 256 nm; sodium salt of -hydroxyethyll-2- [(4S)-2-(2-oxo-tetrahydrofuran-4-yl)-ethyl]-2-penem- 3 carboxylic acid UV (H 2 Xmax 302, 258 nm, respectively.

Example 80 In a manner analogous to that described in Examples 31-78, starting respectively from the 00 *0 0 Ki 100 silver salt of (3S,4R)-3-(tert.-butyldimethylsilyloxymethyl) -4-mercapto-2-oxo-azetidin-1-yl] -2-triphenylphosphoranylideneacetic acid allyl ester and from the silver salt of '-allyloxycarbonyloxyethyl]-4--mercapto-2-oxo--azetidin-1-yl]-2-triphenylj phosphoranylideneacetic acid allyl ester and racemic or optically active or 2,5-dihydro-5-oxo-furan- 2-yl-acetyl chloride, 2,5-dihydro-3-methyl-5-oxo-furan- II 2-ylacetyl chloride and 2,5-dihydro-3,4-dimethyl-5-oxofuran-2--ylacetyl chloride (each prepared from the free acid with SoC 2 the following penems are produced: sodium salt of (5R,6S)-6-U1l'R)-1'-hydroxyethyll-2- (2,5-dihydro-5-oxo-furan-2-ylmethyl) -2-penem-3carboxylic acid, diastereoisomer A: UV (H2) =ma 302, 257 nm, diastereoisomer B: UV (H 2 Xmx 3,25n; sodium salt of (5R,6S)-6-hydroxymethyl-2-(2,5--dihydro- 3-rethyl-5-oxo-furan-2-ylmethyl) -2-penem-3-carboxylic acid, diastereoisomer A: UV (H20): Xma 305, 258 nm, diastereoisomer B: UV (820): )Lmax =304, 258 nm; sodium salt of (5R,6S)-6-hydroxymethyl-2-(2,5-dihydro- 3, 4-dimethyl-5-oxo-furan-2-ylmethyl) -2-penem-3carboxylic acid, diastereoisomer A: UV (H2) =ma 304, 258 nm, diastereoisomer B: UV (H20): Arnax 305, 258 nm; sodium salt of (5R,6S)-6-t(1'R)-1'-hydroxyethyl]-2- 5-dihydro-3 ,4-dimethyl-5-oxo-furan-2-ylmethyl) -2penem-3-carboxylic acid, diastereolsomer A: UV (H20): )Lmax 304, 259 nml, diastereoisomer B: UV (820): Ama 306, 257 nm.

101 Example 81: The sodium salt of hydroxyethyl]-2-[3-(5-oxo-tetrahydrofuran-2-yl)propyl]-2-penem-3-carboxylic acid is obtained analogously to the process described in Example starting from 358 mg of (5R,6S)-6-[(1'R)-1'-allyloxycarbonyloxyethyl]-2-[3-(5-oxo-tetrahydrofuran-2-yl)propyl]-2-penem-3-carboxylic acid allyl ester.

UV (water): Xmax 302, 260 nm.

The starting material can be manufactured as S follows: S a) 1-pyrrolidinocyclopentane I F 84.1 g of cyclopentanone and 106.7 g of pyrrolidine are placed in 300 ml of benzene and boiled r overnight in a water separator. After the solvent and excess reagent have been removed the enamine is further reacted without being further purified.

b) 3-(2-oxo-cyclopent-1-yl)-propionic acid ethyl ester g of enamine (see Example 81a) and 43.8 g of ethyl acrylate are heated at the boil for 4 hours in 300 ml of dioxan. 25 ml of water are then added to the reaction mixture, which is heated under reflux for a further 30 minutes. The solution is concentrated, washed with IN HC1 and saturated NaHCO 3 solution and dried with Na 2

SO

4 After the solvent has been removed, the residue is distilled 71 0 C/200 Pa). The product, in the form of a colourless I liquid, remains.

IR (CH 2 Cl 2 5.78 um.

c) 3-(6-oxo-tetrahydropyran-2-yl)-propionic acid ethyl ester 1.3 g of m-chloroperbenzoic acid and 0.5 g of t

,I

r .f

I

102 NaHCO 3 are added to 1 g of the ester from Example 81b in 10 ml of CH 2 Cl 2 and the whole is stirred for hours at approximately The reaction mixture is filtered with suction over a frit, washed with saturated NaHCO 3 solution, IN sodium hydroxide solution and again with saturated NaHCO 3 solution, dried over Na 2

SO

4 and concentrated. Filtration on silica gel in diethyl ether/hexane and distillation in a bulb tube (1150/200 Pa) yields the

IT

title compound.

IR (CH 2 C1 2 5.78 um.

d) 4-(5-oxo-tetrahydrofuran-2-yl)-butyric acid g of the ester from Example 81c are stirred at 0° overnight in 27 ml of 2N HC1 and 30 ml of THF.

The reaction mixture is then heated for one hour at 500 and diluted with 100 ml of water and the solution St, is saturated with sodium chloride. This solution is extracted for 15 hours with diethyl ether. Purification of the resulting substance on silica gel in

CH

2 Cl 2 /methanol (98:2) yields the title compound.

IR (CH 2 C1 2 5.64, 5.84 urn.

The 4-(5-oxo-tetrahydrofuran-2-yl)-butyric acid is converted in customary manner with thionyl chloride into the acid chloride, which is converted in an analogous manner to that described in Examples 56 and 57 into the starting compound.

-i Example 82: 2-[(3S,4R)-3-[(1'R)-1'-allyloxycarbonyloxyethyl]-4-[(2S)-T-methoxycarbonylmethyl-5-oxopyrrolidin-2-ylacetylthio]-2-oxo-azetidin-1-yl]-2triphenylphosphoranylideneacetic acid allyl ester The title compound is mnaufactured analogously to Example 1 from the silver salt of 1'-allyloxycarbonyloxyethyl]-4-mercapto-2-oxo-azetidin- 103 *8 99 9 999 9999 8 9 99 9~9 8 99 9 9 899 9 9 99 999 8 99 9 9*9 99 898 98 i 9 I 88 8 9~t l-yl] -2-triphenyiphosphoranylideneacetic acid allyl ester and pyrrolidin-2-ylacetyl chloride (prepared from the acid with SOC1 2 IR CH 2 Cl 2 1750, 1690, 1620 cmf 1 TLC (silica gel, ethyl acetate), Rf =0.45.

Example 83: '-allyloxycarbonyloxyethyl]-2-[ pyrrolidin-2-ylmethyl] -2-penem-3-carboxylic acid alJlyl ester The '-allyloxycarbonyloxyethyl] (2S) pyrrolidin-2-ylacetylthio-2-oxo-azetidin-1-yl] -2triphenylphosphoranylideneacetic acid allyl ester is reacted analogously to Example 2 to form the title compound.

IR (3 CH 2 Cl 2 1785, 1745, 1695, 1580 cm- 1 TLC (silica gel, ethyl acetate) Rf 0.52.

Example 84: ScOium salt of hydroxyethyll-2-[ pyrrolidin-2-ylmethyl] -2-penem-3-carboxylic acid 230 mg (0.45 mmol) of allyloxycarbonyloxyethyl] -1-methoxycarbonylmethyl-5-oxo-pyrrolidin-2-ylmethyl] -2-penem-3carboxylic acid allyl ester and 155 mg (0.99 mmol) of dimethylbarbituric acid are dissolved in 5 ml of tetrahydrofuran at room temperature under a nitrogen atmosphere. After the addition of 61 mg of palladiumtetrakis-(triphenylphosphine) the reaction mixture is stirred for 45 minutes at room temperature. The product is filtered in the form of a sodium salt at a pA of 7.1 over XAD-2 and then lyophilised.

UV (water): X max 305 nm.

I i -^i.ru IIX-.---CIC-i 104 IR (3 DMSO-d 6 1769, 1687, 1612 cm 1 TLC (UPC 12 water), Rf 0.3.

Example 85: Dry ampoules or phials, each containing g of the sodium salt of hydroxyethyl]-2-[( 2 S)-5-oxo-pyrrolidin-2-ylmethyl]-2penem-3-carboxylic acid as active substance, are manufactured as follows: 4i it Composition (for 1 ampoule or phial): active substance mannitol 0.5 g 0.5 g A sterile aqueous solution of the active substance and the mannitol is subjected to freeze-drying under aseptic conditions in 5 ml ampoules or 5 ml phials and the ampoules or phials are sealed and checked.

Instead of the above-mentioned active ingredient it is also possible to use the same amount of a different active ingredient from the preceding Examples.

i

Claims (21)

1. Compounds of the formula R H H 1 A-R (I) 0 Sro 00 P$ R2 in which R 1 represents lower alkyl substituted by 0 hydroxy or by protected hydroxy, R represents carboxy, esterified carboxy cleavable un.er physiolo(ica.l conditions, or protected carboxy R 2 1 A represents lower alkylene and R 3 represents, bonded by way of a ring carbon atom, a monocyclic 4- to 6-membered lactamyl radical derived from an w-amino-(C 3 -C 5 S lower alkanecarboxylic acid or w-amino-(C 4 -C 5 lower alkenecarboxylic acid, a 5- or 6-membered benzo- lactamyl radical derived from an w-amino-(C 4 -C 5 lower alkenecarboxylic acid, a monocyclic 4- to 6- membered lactonyl radical derived from an w-hydroxy- (C 3 -C 5 )-lower alkanecarboxylic acid or w-hydroxy- (C 4 -C 5 )-lower alkenecarboxylic acid, or a 5- or 6- membered benzolactonyl radical derived from an w- hydroxy-(C 4 -C 5 )-lower alkenecarboxylic acid, which radical is unsubstituted or is substituted by hydroxy, lower alkoxy, lower alkanoyloxy, halogen, mercapto, lower alkylthio, lower alkyl, lower alkyl substituted by hydroxy, halogen, lower alkanoyloxy, amino, lower 106 alkylamino, di-lower alkylamino, lower alkanoylamino, carboxy, lower alkoxycarbonyl, cyano, carbamoyl or by carbamoyloxy, lower alkenyl, amino, lower alkylamino, di-lower alkylamino, lower alkanoylamino, carboxy, lower alkoxycarbonyl, cyano and/or by phenyl optionally substituted by lower alkyl, hydroxy, lower alkoxy, halogen and/or by nitro, optical isomers of such compounds of the formula I that have additional chiral centres in the radicals RI, R 3 and/or A, mixtures of these optical isomers, and salts of compounds of the formula I that contain a salt-forming group. r*t St t

2. Compounds of the formula I according to claim 1 in which R 1 represents lower alkyl substituted by hydroxy, R 2 represents carboxy, or esterified carboxy cleavable S* under physiological conditions, A represents lower alkylene and R 3 represents a radical of the formula H R C (CH) S(R -CH) Y 8 p (II) -r c R4 R R5 R7 in which Y represents the group -NRI 1 and R 10 represents hydrogen, lower alkenyl, or lower alkyl optionally substituted by amino, hydroxy, carboxy or by cyano, R 4 and R5 each represents hydrogen or together represent a bond, Rg and R 7 independently of one another, each represents hydrogen, lower alkyl, lower alkyl substituted by hydroxy, halogen, lower alkoxy, amino, lower alkylamino, di-lower alkylamino, lower alkanoylamino or by carbamoyloxy, or phenyl optionally I, .Y 107 substituted by lower alkyl, hydroxy, lower alkoxy and/or by halogen, R 8 and R 9 independently of one another, each represents hydrogen or lower alkyl, r is 0 or 1 and p and q, independently of one another, each represents an integer of from 0 to 3, with the proviso that when r is 0 the sum of p and q is 1, 2 or 3, or when r is 1 the sum of p and q is 0 or 1, and with the further proviso that the carbon atom in the radicals of the formula II that is adjacent to the lactam ring nitrogen atom does not carry any substituent from the group consisting of hydroxy, halogen, amino, lower alkylamino, di-lower alkylamino and lower alkanoylamino, optical isomers of such compounds of the formula I that have additional chiral centres in the radicals R,, S R 3 and/or A, mixtures of these optical isomers, and salts of compounds of the formula I that contain a salt- forming group.

3. Compounds of the formula I according to claim 1 in which R 1 represents lower alkyl substituted by hydroxy, R 2 represents carboxy, or esterified carboxy cleavable under physiological conditions, A represents lower alkylene and R 3 represents a radical of the formula H R S( Y (II) R R R R 4 6 5 7 in which Y represents the group R 4 and R each represents hydrogen or together represent a bond, NT O 108 R 6 and R 7 independently of one another, each represents hydrogen, lower alkyl, lower alkyl substituted by hydroxy, halogen, lower alkanoyloxy, amino, lower alkylamino, di-lower alkylamino, lower alkanoylamino or by carbamoyloxy, hydroxy, halogen, amino, lower alkyl- amino, di-lower alkylamino, lower alkanoylamino, or phenyl optionally substituted by lower alkyl, hydroxy, lower alkoxy and/or by halogen, or R4 and R 5 together represent a bond and Rg and R 7 together represent a 1,4-butadien-1,4-ylene radical optionally substituted by hydroxy, lower alkoxy, lower alkyl and/or by halogen, Rg and R 9 independently of one another, each represents hydrogen, lower alkyl, amino or hydroxy, r is 0, the sum of p and is 2 or 3, or r is 1, (1 is 0 and p is S 0 or 1, with the proviso that the carbon atom in the radicals of the formula II that is adjacent to the lactone ring oxygen atom does not carry any substituent from the group consisting of hydroxy, halogen, amino, lower alkylamino, di-lower alkylamino and lower alkanoylamino, optical isomers of such compounds of the formula I that have additional chiral centres in the radicals R 1 R 3 and/or A, mixtures of such optical S isomers, and salts of compounds of the formula I that Scontain a salt-forming group.

4. Compounds of the formula I according to claim 1 in which Ri represents lower alkyl substituted in the a-position by hydroxy, R 2 represents carboxy, or esterified carboxy cleavable under physiological conditions, A represents lower alkylene and R 3 represents a radical of the formula II in which Y represents the group -NR 10 and R 10 represents hydrogen or lower alkyl, R 8 and R 9 each represents hydrogen, r is 0, p is an integer of from 1 to 3 and q -s 0 or 1, with the proviso that the sum of p 109 and q is a maximum of 3, optical isomers of such compounds of the formula I that have additional chiral centres in the radicals R 1 R 3 and/or A, mixtures of these optical isomers, and salts of compounds of the formula I that contain a salt-forming group. Compounds of the formula I according to claim 1 in which RI represents lower alkyl substituted in the a-position by hydroxy, R 2 represents carboxy, or esterified carboxy cleavable under physiological condi- tions, A represents lower alkylene and R 3 represents a radical of the formula II in which Y represents a group r is 1, p and q are 0, R 4 R 5 R 6 t and R7 each represents hydrogen or R4 and R Stogether represent a bond and Rg and R 7 independently of one another, each represents hydrogen, lower alkyl or lower alkyl substituted by halogen, amino, di-lower alkylamino or by lower alkanoylamino, or r is 0, each of p and q is 1 and R 8 and R 9 each represents hydrogen, optical isomers of such compounds of the formula I that have additional chiral centres in the radicals RI, R 3 and/or A, mixtures of such optical isomers, and salts of compounds of the formula I that contain a salt- forming group. S 6. Compounds of the formula I according to claim 1 in C C t (c which R 1 represents hydroxymethyl or 1-hydroxyethyl, SR 2 represents carboxy, or esterified carboxy cleavable under physiological conditions, A represents methylene or ethylene and R 3 represents 5-oxo-tetrahydrofuran-2- yl, 2,5-dihydro-5-oxo-furan-2-yl optionally substituted by lower alkyl, 5-oxo-pyrrolidin-2-yl or 4-oxo-azetidin- 2 -yl optical isomers of compounds of the formula I, mixtures of these optical isomers, and salts R 1 represents (R)-l-hydroxyethyl and R 2 R 3 and A have the meanings given in claim 1.

8. The pharmaceutically acceptable salts of compounds of the formula I according to claim 1.

9. (5R,6S)-6-hydroxymethyl-2-(5-oxo-pyrrolidin-2-yl- methyl)-2-penem-3-carboxylic acid, the pure diastereo- isomers thereof and mixtures of these diastereoisomers, and pharmaceutically acceptable salts thereof according to claim 1. (5R,6S)-6-R)-l'-hydroxyethyl]-2-(5-oxo- pyrrolidin-2-ylmethyl)-2-penem-3-carboxylic acid, the pure diastereoisomers thereof and mixtures of these diastereoisomers, and pharmaceutically acceptable salts thereof according to claim 1.

11. l'-hydroxyethyl]-2-[(2S)-5-oxo- pyrrolidin-2 -ylmethyl]-2-penem-3-carboxylic acid and pharmaceutically acceptable salts thereof according to claim 11. ,41' 12. (5R,6S)-6-[(l'R)-1'-hydroxyethyl]-2-(4-oxo- azetidin-2-ylmethyl)-2-penem-3-carboxylic acid, the pure diastereoisomers thereof and mixtures of these diastereoisomers, and pharmaceutically acceptable salts thereof according to claim 1.

13. 5R,6 -hy r111 2 [2S -o o azetidin-2-ylmethyl] -2-penem--3-carboxylic acid and pharmaceutically acceptable salts thereof according to claim 12.

14. (5R,6S)-6-[(l'R)-l'-hvdroxyethyl]-2-[(2S)-l-methyl- 5-oxo-pyrrolidin-2-ylmethyl]-2-penem-3-carboxylic acid, the pure diastereoisomers thereof and mixtures of these diastereoisomers and pharmaceutically acceptable salts thereof according to claim 1. 0a015. (5R, GS) -6-hydroxymethyl-2-(5-oxo-tetrahydrofuran- 2-ylmethyl)-2-penem-3-carboxylic acid, the pure diastereoisomers thereof and mixtures of these Ono0 0 0diastereoisomers and pharmaceutically acceptable salts thereof according to claim 1. 0a

16. (5R,6S)-6-[(l'R)-l'-hydroxyethyll-2-(5-oxo-tetra- hydrofuran-2-ylmethyl)-2-penem--3-carboxylic acid, the OOpure diastereoisomers thereof and mixtures of these Sdiastereoisomers and pharmaceutically acceptable salts thereof according to claim 1. 0

17. (5R,6S)-6-[(l'R)-l'-hydroxyethyl]-2-[(2S)-5-oxo- tetrahydrofuran-2-ylmethyll -2-penem-3-carboxylic acid and pharmaceutically acceptable salts thereof according A claim 16.

18. (5R,6S)-6-[(l'R)-l'-hydroxyethyl}-2-[(2R)-5-oxo- tetrahydrofuran-2-ylmethyl] -2-penem-3-carboxylic acid and pharmaceutically acceptable salts thereof according to claim 16. 112

19. (5R,6S)-6-[(1'R)-l'-hydroxyethyl]-2-(2,5-dihydro-3- methyl-5-oxo-furan-2-ylmethyl)-2-penem-3-carboxylic acid, the pure diastereoisomers thereof and mixtures of these diastereoisomers and pharmaceutically acceptable salts thereof according to claim 1. (5R,6S)-6-[(l'R)-l'-hydroxyehyyl]-2-[2-(2-oxo- tetrahydrofuran-4-yl)-ethyl]-2-penem-3-carboxylic acid, the pure diastereoisomers thereof and mixtures of these diastereoisomers and pharmaceutically acceptable salts thereof according to claim 1.

21. (5R,6S)-6-[(l'R)-l'-hydroxyethyl]-2-[2-(5-oxo- tetrahydrofuran-2-yl)-ethyl]-2-penem-3-carboxylic acid, af the pure diastereoisomers thereof and mixtures of these diastereoisomers and pharmaceutically acceptable salts S thereof according to claim 1.

22. (5R,6S)6-R)6- 'R)-'-hydroxyethyl]-2-(2,5-dihydro-5- oxo-furan-2-ylmethyl)-2-penem-3-carboxylic acid, the pure diastereoisomers thereof and mixtures of these diastereoisomers and pharmaceutically acceptable salts f thereof according to claim 1.

23. Pharmaceutical preparation containing a compound of the formula I according to claim 1 or a pharmaceutically acceptable salt of such a compound together with a pharma- ceutically acceptable carrier or diluent.

24. A method for the therapeutic treatment of a human or animal body for bacterial infection comprising admini- stering to said human or animal an antibacterially effective amount of a compound in accordance with claim 1. r i 113 Process for the manufacture of compounds of the formula I according to claim 1, characterised in that an ylide compound of the formula Z H H zI K 1 "S-C-A--R (III), OX R 2 1 in which R 1 A and R 3 have the meanings given under 4 formula I, R 2 represents a protected carboxy group, Z represents oxygen or sulphur and XJ represents either a trisubstituted phosphonio grou l or a diesterified phosphono group together with a cation, is cyclised, or a compound of the formula (i H H SS-C--A-R o C=0 (IV), 21 in which R 1 A and R3 have the meanings given under formula I and R 2 and Z have the meanings given under formula III, is treated with an organic compound of trivalent phosphorus, and, if desired or necessary, in a resulting compound of the formula I a protected functional group is L/^ 114 converted into the free functional group and/or, if desired, in a resulting compound of the formula I a carboxy group R 2 is converted into an esterified carboxy group that can be cleaved under physiological conditions and/or, if desired, in a resulting compound of the formula I a radical R3 is converted into a different radical R 3 and/or, if desired, a resulting compound having a salt-forming group is converted into a salt, or a resulting salt is converted into the free compound or into a different salt and/or, if desired, a resulting mixture of isomeric compounds is separated into the individual isomers.

26. The compounds of the formula I obtainable in accordance with the process according to claim

27. A compound of the formula I substantially as described in the examples.

28. A method for the manufacture of a compound of the formula I substantially as described in the examples.

29. A pharmaceutical preparation comprising a compound of the formula I substantially as described in the examples. DATED this 10th day of April, 1990. CIBA-GEIGY AG By Its Patent Attorneys, ARIHUR S. CAVE CO. i I 2> .4