GB2104509A

GB2104509A - New synthetic route to optically active 2-penem-3-carboxylic acid derivatives

Info

Publication number: GB2104509A
Application number: GB08218610A
Authority: GB
Inventors: Paolo Lombardi
Original assignee: Farmitalia Carlo Erba SRL
Current assignee: Pfizer Italia SRL
Priority date: 1981-06-30
Filing date: 1982-06-28
Publication date: 1983-03-09
Also published as: DE3224055A1; JPS588085A; IT8221546A0; GB2104509B; IT1190842B

Abstract

Optically active trans-6-substituted-5(R)-2-penem-3-carboxylic acid derivatives of formula <IMAGE> wherein R and R1 are each organic groups and R2 is hydrogen, a cation or a carboxy protecting group, are prepared by a multi-stage process of which the final steps involve reacting a 4(R) mercapto salt of formula <IMAGE> wherein M<n+> is a heavy metal cation of valency n and PHI is an aromatic, heterocyclic or alkyl radical, with a reactive derivative of an acid or thioacid of formula <IMAGE> wherein psi is oxygen or sulphur, and cyclizing the product.

Description

SPECIFICATION New synthetic route to optically active 2-penem-3-carboxylic acid derivatives The present invention relates to a new process for the preparation of optically active trans-fl-substituted- 5(R)-2-penem-3-carboxylic acid derivatives and to new optically active trans-6(S)-substituted-5(R)-2-penem3-carboxylic acid derivatives.

The first object of the invention is a new process for the preparation of optically active trans-fl-substituted- 5(R)-2-penem-3-carboxylic acid derivatives of the general formula (I)

wherein Rand R1 are equal or different organic groups and R2 is hydrogen, a cation or a carboxy protecting group.

The 2-penem-3-carboxylic acid derivatives constitute a known class of synthetic ss-lactam compounds possessing a wide spectrum of antibacterial activity, both against Gram-positive and Gram-negative bacteria, as well as a ss-lactamase inhibiting activity, as reported, for instance, in Acta Pharma. Suec., 14 (Suppl.), 23 (1977) and in J. Am. Chem. Soc., 100, 8214 (1978).

In the above formula (I) each of the organic groups Rand R1 is especially: 1) an acyl group; 2) a free or esterified carboxy group; or 3) agroupofformula -(CH2)Q-Twhereinxiszern x iszero oran integer of 1 to 10; Qisa bond; a saturated or unsaturated, preferably saturated, aliphatic chain, preferably C1-C6 alkylene; an oxygen or sulphur atom; a group -SO- or -SOp-; a group -N=; ora group

wherein Ra is hydrogen or a straight or branched chain C1-C12 alkyl group, preferably C1-C6 alkyl; and wherein T is: a) a branched or straight chain saturated or unsaturated aliphatic hydrocarbon group; b) an aromatic group; c) a cycloaliphatic group; or d) a heterocyclic group; wherin each subsituent a), b), c) and d) may be either unsubstituted or substituted by one or more substituents preferably chosen from the group consisting of halogen; a free or esterified carboxy group; a free or protected amino; a free or protected hydroxy or mercapto group; C1-C6 alkyl; C1-C6 alkoxy; C1-C6 alkyl-mercapto; and a free or protected oxo group.

When R or R1 is an acyl group it is especially C1-C6 alkanoyl, in particular acetyl or propionyl, or benzoyl.

When R or R1 is an esterified carboxy group it is especially a C1-C6 alkoxy-carbonyl group, in particular methoxy-, ethoxy-, or tert-butoxy-carbonyl, or a carboxy group protected by any of the carboxy protecting group usually employed in the chemistry of the peptides which may be, for instance, trichloroethyl, benzyl, p-nitro-benzyl, benzhydryl, acetoxymethyl, acetonyl, pivaloyloxymethyl, trimethylsilyl and similar When R or R1 isa group -(CH2)XQ-TwhereinTisa branched orstraightchain saturated or unsaturated aliphatic hydrocarbon group this is especially C1-C12 alkyl or C2-C12 alkenyl either unsubstituted or substituted as indicated above.

When T is an aromatic group it may be mononuclear or polynuclear, preferably mononuclear; it is in particular phenyl or naphthyl, preferably phenyl.

When T is a cycloaliphatic group it is especially a monocycloaliphatic radical, preferably C3-C7 cycloalkyl, in particular cyclohexyl or cyclopentyl, or C5-C7 cycloalkenyl.

When T is an heterocyclic group it is especially a heteromonocyclic group optionally condensed with a benzo moiety or with another heterocyclic ring; in particular it is a heteromonocyclic group such as furyl, thienyl, tetrazolyl, thiadiazolyl, triazolyl, pyridazinyl, triazinyl or a heterobicyclic group formed by a pentatomic heteromonocyclic ring containing at least one hetero atom chosen from N, 0 and Sand by a pentatomic or hexatomic heteromonocyclic ring containing at least one heteroatom chosen from N, 0 and S, in particular, for example, tetrazolo-pyridazinyl and triazolo-pyridazinyl.

When R2 is a cation this is the cation of any pharmaceutically or veterinarily acceptable base, both an inorganic base such as, for instance, an alkali, in particular sodium or potassium, or an alkaline-earth, in particular calcium and magnesium, hydroxide, and an organic base, such as, for example, ammonia or another organic amine, in particular diethylamine, triethylamine, 2-hydroxyethylamine, 1-ethylpiperidine, benzylamine, pyridine, collidine and similar.

When R2 is a carboxy protecting group it is preferably a group which, together with the -COO moiety, forms an esterified carboxy group which may be readily split for example by reduction in hydrogenolysis, by photolysis, by solvolysis, in particular acid hydrolysis or, especially, neutral or basic hydrolysis, or under physiological conditions, or an esterified carboxy group readily convertible into another functionally modified carboxy group.

Examples of carboxy protecting groups R2 are, in particular, optionally halo-substituted lower alkyl groups, especially C,-C6 alkyl, in particular methyl, ethyl and tert-butyl, and trichloroethyl; aralkyl groups, especially benzyl and o- and p-nitrobenzyl; aryloxyalkyl groups, especially aryloxy-C1-C6-alkyl, in particular phenoxy-methyl, phenoxy-ethyl and a-C1-C6 alkyl-a-phenoxy-methyl, for example a-methyl-a-phenoxy- methyl, a-ethyl-a-phenoxy-methyl, a,a-dimethyl-a-phenoxy-methyl; or groups such as benzhydryl, onitrobenzhydryl, acetoxymethyl, acetonyl, pivaloyloxymethyl, trimethylsilyl or dimethyl-tert-butylsilyl and similar.

Protected amino, hydroxy, mercapto and carboxy groups are amino, hydroxy, mercapto and carboxy groups protected by the protecting groups usually employed in the chemistry of penicillins and cephalosporins for this kind of functions.

In particular, protecting groups of the amino, hydroxy and mercapto functions may be, for instance, optionally substituted, especially halo-substituted, acyl groups, preferably acetyl, monochloroacetyl, dichloroacetyl, trifluoroacetyl or benzoyl; triarylmethyl groups, in particulartrityl; silyi groups, in particular trimethylsilyl or dimethyltert-butyl-silyl; or also groups such as tert-butoxycarbonyl orp nitrobenzyloxycarbonyl .

Protecting groups of the carboxy function may be those reported above for the substituent R2 when this represents a carboxy protecting group.

Protected oxo groups are especially oxo groups protected in the form of linear or cyclic acetals, ketals, thioacetals or thioketals.

A number of 2-penem-3-carboxylic acid derivatives are described in the prior art, for instance in J. Am.

Chem. Soc., 101,6296(1979); ibid., 101,6301(1979); ibid., 101,6306(1979); ibid., 102,2039(1980); Tetrahedron Lett., 1978,4059; J.C.S. Chem. Com., 1978,1011; Tetrahedron Lett., 1979,3777,J.Antibiotics 33,453 (1980); J.C.S. Chem. Comm., 1980,70; British patent No. 1,557,559, German Offenlegungsschrift No. 28 19655 and British patent application No.

2013674 A. The prior art also indicates that the stereochemistry at the 5- carbon atom of the penem nucleus is essential to the development of the pharmacological activity and that, in particular, those penem-isomers which have the R-configuration at C5, that is the same configuration occurring in natural penicillins and cephalosporins, are the more pharmacologically active isomers.

The new process of the present invention allows just to obtain the optically active 5(R)-2-penem-3carboxylic acids of formula (I). According to the present invention the trans-6-substituted-5(R)-2-penem-3carboxylic acid derivatives having the above formula (I) are prepared by the new process herebelow illustrated in the scheme I wherein R, R1 and R2 have the meanings reported above; each of the groups Rs is, independently, hydrogen or C1-C6 alkyl; X represents a halogen atom, in particular chlorine; ,0 represents an aromatic or heterocyclic group, preferably chosen from phenyl, tolyl, a-or ss- naphthyl, pyridyl orthienyl; or a lower alkyl group, preferably C1-C6 alkyl, in particular n-butyl; ly represents an oxygen or sulphur atom; M"+ represents the cation of a heavy metal M in any of its normal oxidation states; M is a heavy metal preferably chosen from Ag, Hg, Au, Cu and Pb; n+ represents the oxidation state of the heavy metal and n is, preferably, an integer from 1 to 4; A represents a residue making the S-A bond particularly labile to the heterolytic action of soluble metal salts or of halogen.

SCHEME I

Preferably A represents an organic group of formula:

wherein X represents a carbon or a silicium atom and wherein, when z is carbon, each of the groups pA, B and pC is, independently, an aromatic or hetero-aromatic group such as for instance, phenyl, a- or ss-naphthyl, biphenyl, thienyl, pyridyl, imidazolyl, thiazolyl, furyl, each unsubstituted or substituted with one or more substituents chosen from CI, F, Br, I, CF3, CCl3r NO2, OR in which R' represents a C1-C6 alkyl group, and, when z is silicium, each of the groups pA, pB and #c is, independently, a straight or branched C1-C12 alkyl group, preferably C1-C6 alkyl; or

wherein Ra is hydrogen or a straight or branched chain C1-C12- alkyl group, preferably C,-C6 alkyl; each of Rb and Rc, which may be the same or different, represents a branched alkyl group, preferably C1-C15, in particular C1 -C4 alkyl, or a straight alkyl group substituted with one or more organic residues especially chosen from the group consisting of: an aryl group, preferably phenyl; an aralkyl group, preferably aryl-C,-C6 alkyl, in particular benzyl; a cycloaliphatic radical, preferably C5-C7 monocycloalkyl, in particular cyclopentyl or cyclohexyl; or a heterocyclic radical, preferably a C5-C7 heteromonocyclic group, in particular tetrahydropyranyl; or Ra and Rb, taken together, or Rb and Re, taken together, form a divalent radical of formula

wherein Y is -O-, -S- or

and each of the groups Rd, Re, Rf and Rg, which may be the same or different, is hydrogen; alkyl, preferably, C1-C6 alkyl; aryl, preferably phenyl; aralkyl, preferably aryl-C,-C6 alkyl, in particular benzvl; a cycloaliphatic group, preferably a C3-C7 cycloalkyl group, in particular cyclopentyl or cyclohexyl; a heterocyclic group, preferably a C5-C7 heteromonocyclic group; or a group (CH2)q0Rh or -(CH2),-S-Rh, wherein Rh has the meanings given above for the groups Rd to Rg, or Rh is an acyl group, preferably C2-C6 alkanoyl, in particular acetyl, or benzoyl; each of m, p and q, which may be the same or different, is zero, 1 or 2; and Q' is oxygen, sulphur, an iminic nitrogen =N- or a group

wherein Ra is as defined above.

The group A may be, for instance, represented by one of the following structures:

The use of certain groups A in the preparation of racemic penems is known [Tetrahedron Lett. 22. 355 (1981)].

The preparation of penems, including optically active 5(R)-penems of formula (I), by an intramolecular Wittig reaction on 4-acylthioazetidinyl phosphoranes, including the 4(R)-isomers (VIII), is known from the prior art to be the most efficient way to prepare this class of B-lactam compounds [J. Am. Chem. Soc., 101, 6296 (1979); ibid., 101,6301(1979); ibid. 101,6306 (1979); ibid., 102, 2039 (1980); British Patent No.

1,557,559, German Offenlegungsschrift No.28 19 655, British Patent applications No. 2013674A and No.

80.05476].

According to those methods which involve a total synthetic approach to penems, a racemic or optically active intermediate (VIII) is obtained by a multi-step synthetic intermediate (VIII) is obtained by a multi-step synthetic sequence which requires, at an early stage, the essential step of displacing a nucleofuge leaving group Leitherin a reacemiccompound of the formula (IX)

wherein R is defined as above, or in a previously resolved 4(R)-compound of the formula (IXa)

wherein R is defined as above, by a thiolacid or by a dithioacid, to give, respectively, a racemic compound of general formula (X)

wherein R, R1 and 9 are as defined above, or an optically active 4(R)-compound of formula (Xa)

wherein R, R1 and 9 are as defined above.

According to the said known processes the compounds (X) or (Xa) are then submitted to further subsequent steps having the scope to introduce in the 1-position of the azetidine ring the unit

characterizing the compounds (VIII).

On the other hand, according to certain known alternative methods which prepare the penem-derivatives starting from natural 6-amino-penicillanic acid or penicillins, the intermediate (VIII) is obtained (see published British pat. application No. 80.05476) by a multi-step synthetic sequence which requires, at an early stage, both the essential step of introducing the grouping R into the penam nucleus to give a compound of formula (Xl)

wherein R is as defined above, and the not less essential step of introducing the grouping R1 by the opening of the thiazoline ring in the presence of an alkyne of the type

wherein R1 has meaning given above.

According to the said known process the obtained optically active compound of formula (XII)

wherein R and R1 are as defined above, is then submitted to further subsequent steps having the scope to replace the substituent in the 1-position of the azetidine ring by the unit

and to restore the acylthio functionality characterizing the compounds (Vill).

In the previous methods, therefore, the 2-substituent R1 and the 6-substituent R of the penem nucleus are entered, in practice, at the beginning of the synthetic pathway.

This implies that to prepare, according to the known methods, the 4(R)-compounds (VIII), and finally, the 5(R)-penems (I), for each substituent R1 and R to be introduced in the final product, repetition of the whole sequence is required.

Furthermore the above displacement reaction to obtain compounds (X) or (Xa) from compounds (IX) or (IXa), when performed directly by the appropriate thiolacid or dithioacid, proceeds frequently with poor yields and/or, in many instances, with difficulties depending on the preparation and/or on the availability of the properthiol acid or dithioacid. Similarly when the same displacement reaction is performed by a thioenol through an intermediate thioenolether, e.g. according to J. Am. Chem.Soc., 101; 6306(1979); ibid, 102,2039 (1980); or Tetrahedron Lett., 1979,3777, the advantage of obtaining in high yields the intermediate azetidinylthioenolether of formula (Xb)

wherein R and R1 are as defined above and ' is an optionally substituted methylene group, either in a racemic or in an optically active form, is strongly limited by the availability of the correct thioenol and by the further oxidative cleavage of the olefinic bond C = ' required to restore the acylthio functionality characterizing the compounds (VIII).

Moreover, in this case, the presence of base labile and/or oxidation sensitive moieties in the grouping R1 creates often additional problems.

From the above it appears evident that the known sequences for obtaining the intermediate (VIII), that is the penultimate intermediates to the synthesis of 2-penem derivatives (I), suffer two main disadvantages which are "lack of flexibility" and "lack of productivity".

With the new process of the invention both these disadvantages are eliminated.

As appears from scheme I, the new process of the invention allows to prepare by a unique synthetic sequence, which is independent from the meaning of the 2-substituent R1 in the final product, a common intermediate, namely the compound (VII), from which, by a sole step involving the coupling with any desired

unit, any desired intermediate (VIII) can be obtained.

Since, as already said, the synthetic sequence to prepare the common intermediate (VII) is independent from the R1 value, no repetition of the whole sequence is required for each substituent R1 to be entered in the penem (I) contrary to what occurs in the previously known methods.

This confers very high flexibility to the new process of the invention which allows to obtain easily a wide choice of 5(R)-2-penem-3-ca rboxylic acid derivatives.

Furthermore, in the known methods of the prior art, the introduction of the

moiety characterizing the compound (VIII) which, as already said, is performed at an early stage of the synthesis, constitutes a very critical step which usually proceeds with poor yields and/or difficulties.

Obviously, the presence of such a critical step has serious negative consequence on the yield, i.e. on the productivity, of the whole process and, in addition, this negative effect is further increased by the fact that the critical step is performed at a very early stage of the synthesis.

According to the new process of the invention, on the contrary, the introduction of the

moiety is carried out, as is evident from scheme 1, at a later stage (penultimate step) of the sequence and therefore its influence on the productivity of the whole process is slighter. Moreover, this step does no longer constitute a critical point of the synthesis. The trick of employing the mercapto salt (VII) as nucleophilic agent allows indeed to use an acid or thioacid, or a reactive derivative thereof, in the displacement reaction, instead of the thiolacid or dithioacid orthioenol or alkyne derivatives used in the previous methods.

Since acids and thioacids are both more easily prepared and more easily available than thiolacids, dithioacids, thioenols and alkynes their use contributes to increase the flexibility and the productivity of the new synthetic process of the invention.

In addition, in view of the very high nucleophilic properties of the mercapto salt (VII), the displacement reaction proceeds with better yields than in the previous methods and this further contributes to the productivity of the synthesis. From the above it follows that the most relevant and original aspect of the present invention resides in the possibility to obtain optically active penem derivatives having the 5(R) configuration by a process not suffering of the disadvantages of the previous methods, that is a process characterized by having very high flexibility and very high productivty.The possibility of obtaining optically active trans-6-substituted 5(R) molecules is achieved in the present invention starting from the chiral compound (II), which is a particularly suitable intermediate for the displacement reaction with the thiol A-SH In accordance with the above reported scheme I the new process of the invention comprises: a) reacting an optically active azetidine 2-one derivative of formula (II)

wherein R and R3 are as defined above with a thiol of formula A-SH wherein A is as defined above, or a salt thereof, so obtaining the optically active 4(R)-thioderivative having the formula (Ill)

wherein R and A are as defined above; b) reacting a 4(R)-compound (III), with a glyoxylic acid derivative of formula OHC-COOR2 wherein R2 is as defined above, so obtaining a 4(R)-derivative of formula (IV)

wherein R, A and R2 are as defined above; c) halogenating a 4(R)-carbinol (IV), so obtaining a 4(R)-derivative of formula (V)

wherein R, A and R2 are as defined above and X is a halogen atom; d) reacting a 4(R)-compound (V), with a phosphine derivative of formula P03 wherein 0 is as defined above, so obtaining a 4(R)-phosphorane of formula (VI)

wherein R, A, R2 and 0 are as defined above; e) reacting a 4(R)-phosphorane of formula (Vl),with a solution of a heavy metal salt of formula Mn±ynwherein M and n are as defined above and Y is the anionic residue of the salt, so obtaining a 4(R)-mercapto salt of formula (VII)

wherein R, R2,0, M and n are as defined above;; f) reacting a 4(R)-mercapto salt of formula (VII), with a reactive derivative of an acid orthioacid of formula

wherein R, and 9 are as defined above, so obtaining a 4(R)-derivative of formula (VIII)

wherein R, R" R2, 9 and p are as defined above; g) cyclizing a 4(R)-compound of formula (VIII), so obtaining a 5(R)-penem derivative of formula (I)

wherein R, R, and R2 are as defined above and, if desired, salifying a compound of formula (I) wherein R2 is hydrogen and/or, if desired, esterifying a compound of formula (I) wherein R2 is hydrogen or a cation, and/or, if desired, obtaining a compound of formula (I), wherein R2 is hydrogen or a cation from one in which R2 is a carboxy protecting group and/or, if desired, converting a compound of formula (I) into another compound of formula (I).

The reaction of the azetidin-2-one of formula (II) with the thiol of formula ASH or a salt thereof, which is preferably an alkaline, sodium or potassium in particular, salt, may be performed at a temperature varying approximately between 0 C and the room temperature in a suitable solvent which may be, for instance, water, acetone, tetrahydrofurane, dimethylformamide, methylene chloride, trichloromethane, acetonitrile or their mixtures. Optionally, the salt of the thiol of formula ASH may be obtained in situ performing the reaction in the presence of a base such as, for example, sodium or potassium hydroxide or sodium or potassium hydride, sodium or potassium carbonate or organic bases.

The condensation reaction between a 4(R)-compound of formula (Ill), and a glyoxylic acid derivative of formula CHO-COOR2 is preferably carried out in an inert solvent, such as, for instance, tetrahydrofurane, dimethylformamide, dioxane, methylene chloride, trichloromethane, acetonitrile or a mixture of these solvents, in the presence of a base which may be for example, triethylamine, piperidine or similar. The reaction temperature may range from about 0 C to the reflux temperature of the used solvent, but the room temperature is preferred.

The subsequent halogenation of a 4(R)-carbinol of formula (IV), to give a 4(R)-compound of formula (V), may be carried out by means of an appropriate halogenation agent. Preferably it is desired to obtain a compound (V), wherein X is chorine. Therefore a chlorination is preferably performed using thiony chloride as chlorinating agent and operating both in the absence of solvent or in the presence of an anhydous inert organic solvent such as, for example, tetrahydrofurane or benzene ortoluene. The reaction is carried out in the presence of a base, pyridine for instance, at a very low temperature, preferably varying from about -70"C to about 0 C, more preferably from -30"C to 0 C. The conversion of a 4(R)-compound of formula (V), into a 4(R)-phosphorane derivative of formula (VI), by reaction with a phospine of formula Pp3is preferably performed in an anhydrous inert solvent such as, for instance, methylene chloride, benzene, toluene, tetrahydrofurane, in the presence of a base which may be, for example, pyridine or 2,6-lutidine, at a temperature varying preferably between about 0 C and about 60"C, more preferably between 25"C and 50"C.

A heavy metal salt of formula M"±Y"- may be a salt of an inorganic or organic, preferably inorganic, acid, such as, for example, in particular, sulphuric, nitric, hydrochloric, formic or acetic acid.

As already said, the heavy metal M is preferably a metal chosen from the group consisting of Ag, Hg, Cu, Au and Pb. Preferred salts of formula M"' -Y"- are AgNO3 or Hg(OCOCH3)2. The reaction of a 4(R)-phosphorane of formula (Vl), with a heavy metal salt of formula M"+ -Y"- is preferably carried out by using a solution of an equivalent amount of the salt in a suitable polar solvent such as, for instance, water, an aliphatic alcohol, preferably a C1-C6 aliphatic alcohol, in particular methanol or ethanol, or a mixture of these solvents. The reaction usually proceeds with almost quantitative yields at temperatures varying from about 00C to the reflux temperature, preferably at room temperature. A reaction derivative of the acid or thioacid of formula

preferably is an halide, in particular the chloride, or an anhydride or mixed anhydride. The reaction between a 4(R)-mercapto salt of formula (VII), and a reactive derivative of the compound of formula

is preferably carried out using an excess of the latter reagent in an inert, anhydrous organic solvent such as, for instance, acetonitrile, benzene, toluene, dimethylformamide, methylene chloride, chloroform and similar, at a temperature varying approximately between 0 C and room temperature, preferably at room temperature.

The subsequent cyclization of an obtained 4(R)-derivative of formula (VIII), into a 5(R)-penem of formula (I), may occur spontaneously or may be promoted, either thermally or by catalytic way, following known methods, for instance by heating in toluene according to the Woodward's procedure [J. Am. Chem. Soc., 101,6296 (1979); ibid., 101; 6301 (1979); ibid, 101, 6306 (1979); and ibid., 102,2039(1980)].

The optional salification and esterification steps as well as the optional conversion of a 5(R)-penem derivative of formula (I), wherein R2 is a carboxy protecting group into the corresponding 5(R)-penem derivative wherein R2 is hydrogen or cation may be performed by known methods.

In particular a 5(R)-penem of formula (I) wherein R2 is hydrogen, may be obtained, for example, from the corresponding compound wherein R2 is a carboxy protecting group, by hydrogenolysis, in particular, for instance, when R2 represents a p-nitro-benzyl group, or by hydrolysis, e.g. with a pH 7.5 phosphate buffer, in particular, for instance, when R2 represents an acetonyl group.

Also the optional conversion of a compound of formula (I) into another compound of formula (I) may be carried out according to the known methods of the organic chemistry.

According to the process of the present invention the chiral key intermediate of formula (II) is obtained by a method comprising: 1) converting a compound of formula (XIII)

wherein R3 is as defined above, into a compound of formula (XIV)

wherein R and R3 are as defined above; 2) oxidizing a compound of formula (XIV) to give a compound of formula (XV)

wherein R and R3 are as defined above, and 3) removing the N, 0 protecting group from a compound of formula (XV).

The conversion of a compound of formula (XIII) into a compound of formula (XIV) is performed by reaction with an excess of an appropriate base generally a strong, both organic and inorganic, base such as, for example NaH, LiH, KH, n-BuLi, t-BuLi, lithium-diisopropylamide or bis (trimethyl silyl)lithium amide, in a suitable solvent in accordance with known procedures, e.g. as reported by T. Durst, R.V.D. Elzen and R.

Legault in Can. J. Chem., 52,3206(1974), and by treatment of the resulting anion with an electrophile agent carrying the [R] moiety, in accordance with known procedures too.

An electrophile agent carrying the [R] unit may be any compound bearing an [R] moiety positively charged.

In particular, for example, to obtain a compound of formula (XIV) wherein R is an alkyl group the said electrophile agent may be the appropriate alkyl halide, e.g. chloride or bromine.

To obtain a compound (XIV) where R is acyl, it may be an appropriate activated acid, for example, an ester, an acyl halide, an acyl imidazole or an anhydride.

To obtain a compound (XIV) where R is carboxy it may be an appropriate activated formate, e.g.

chloroformate.

If desired or necessary a substituent R firstly introduced in the compound (XIV) may be converted into another substituent R by means of the usual reactions of the organic chemistry following known methods.

The oxidation of a sulphur compound of formula (XIV) to give a sulphone compound of formula (XV) may be carried out by the methods usually employed in the organic chemistry for this kind of oxidation e.g. by means of an inorganic or organic oxidizing agent preferably chosen from m-chloroperbenzoic acid or KMnO4.

The removal of the N, 0 protecting group in the compound of formula (XV) may be performed in a conventional way, in particular, for example, by mild hydrolysis, preferably acid hydrolysis.

From what reported above the compound of formula (XIII) results to be a new common chiral intermediate which is useful for the synthesis of any, that is anyway substituted, 5(R)-2-penem-3-carboxylic acid derivative.

In particular, according to the above procedure, a compound of fdrmula (XIII) may be, for example, converted into a compound of formula (XIV) wherein R is a group

wherein Rx is the residue of an acyl group, in particular C, -Ce alkyl or phenyl. The obtained acyl derivative may be subsequently reduced to give, according to the used reduction conditions, either a compound of formula (XIV) wherein R is a group

wherein Rx is as defined above and the carbon carrying the hydroxy group is in the R-configuration, or, respectively, a compound of formula (XIV) wherein R is a group

wherein Rx is as defined above and the carbon carrying the hydroxy group is in the S-configuration.

Starting from the so obtained optically active compounds of formula (XIV) and following the reaction sequences previously described in this application, through the corresponding optically active intermediates of formulae (VI) and (VII), optically active penems of formula (I) may be obtained wherein R is either a group of formula

wherein Rx is as defined above and the carbon carrying the hydroxy group is the R configuration, or, respectively, a group of formula

In particular, for example, 8(R), 6(S)-hydroxyethyl-5(R)-penems of formula (I) may be obtained which compounds, as single diastereoisomers, are not previously described in the art.

The said new chiral key intermediate of formula (XIII) may be prepared, according to the present invention, both starting from 6-amino penicillanic acid (6-APA) or penicillins and by a total synthetic way.

The chiral compounds of formula (XIII) wherein R3 is methyl may be prepared starting from 6-APA by the procedure herebelow illustrated in scheme II.

SCHEME II

The process reported in Scheme II comprises: a) transformation of the penicillanic acid (XVI) readily obtained from the 6-aminopenicillanic acid or penicillins with methods known perse, into the corresponding azide (XVII); b) rearrangement of the azide (XVII) in the presence of an alcohol R40H to give the urethane (XVIII), wherein R4 is a carboxy protecting group which may be readily split, for example, by reduction or by solvolysis or, alternatively, rearrangement of the azide (XIV), in the presence of an inert solvent to give the corresponding isocyanate intermediate; c) decarboxylation of the urethane (XVIII), to give the aldehyde (XIX), performed either under reducing or hydrolytic conditions or, alternatively aqueous acidic hydrolysis of the isocyanate intermediate to give the aldehyde (XIX); d) reduction of the aldehyde (XIX) to give the azetidinyl carbinol (XX) by the action of a reducing agent; e) conversion of the azetidinyl carbinol (XX) into the bicyclo-compound (XIII) wherein R3 is CH3 through the formation of the corresponding acetonide.

The sequence (a), (b), (c) is known under the name of Curtius degradation, a well known chemical method which allows the transformation of an acid into a 1 C-nor amine R-CH2COOH R-CH2-NH2 through the azide and the isocyanate intermediate [T. Curtius, J. Chem. Soc. (A) 60, 56 (1891)].

The corresponding intermediate 1C-nor amine is not isolated since it is unstable and, in the presence of water, it readily converts into the aldehyde (XIX):

The reduction of the aldehyde (XIX) to give the carbinol (XX) may be carried out by any of the methods usually employed in the organic chemistry for reducing the aldehydes to the primary alcohols in particular, for example, by an aqueous solution of sodium borohydride.

Examples of carboxy protecting groups R4 in the compound of formula (XVIII) are optionally halosubstituted lower alkyl groups, in particulartrichloroethyl; alkyl groups, especially benzvl and p-nitro-benzyl; lower alkyl groups, especially t-butyl, or acetonyl.

The conversion of the azetidinyl carbinol of formula (XX) into the bicyclic compound of formula (XIII: R3 = CH3) may be carried out by acetonidation according to known methods, for example by reaction with 2,2-dimethoxypropane in the presence of borontrifluoride in an organic solvent such as, for instance, methylene chloride, chloroform, diethyl ether, at a temperatu re from about -10"C to the room temperature.

The chiral compounds of formula (XIII) wherein R3 is hydrogen may be prepared starting from 6-amino penicillanic acid by the procedure herebelow illustrated in scheme (lil).

SCHEME III -

The process reported in the Scheme Ill comprises: a') esterification of the compound of formula (XVI) to give the penicillanate of formula (XXI) wherein R5 is a C1-C6 alkyl group or benzyl; b') coupling of the obtained penicillanate of the general formula (XXI) with a diazoacetate of the type N2CHCOOR6, wherein R6 is a C1-C6 alkyl group to give the secopenicillanate (XXII); c') isomerisation of the secopenicillanate (XXII) to give the azetidinone derivative (XXII A); or alternatively: a") oxidation/esterification of the compound of formula (XVI) to give the penicillanate S-oxide of formula (XXI A), wherein R5 is defined as above; b") condensation of the obtained penicillanate S-oxide of the general formula (XXI A) with a ketene dialkyl acetal of the type

wherein R6 is defined as above, to give the azetidinone derivative (XXII A); d') oxidative removal of the 1-substituent in the compound of formula (XXII A), obtained both through the sequence a')ob'-)ec') and the sequence a")ob"); e') reduction of the ester moiety COOR6 in the obtained compound of formula (XXIII) to give the azetidinyl carbinol (XXIV) and f') conversion of the azetidinyl carbinol (XXIV) into the bicyclo-compound (Xlil: R3 = H), byformation of the corresponding acetonide.

The conversion of the penicillanic acid of formula (XVI) into the corresponding penicillate of formula (XXI) may be obtained by reacting the compound (XVI), or a suitable derivative thereof, with an alcohol of formula R50H, wherein R5 is defined above, or a suitable reactive derivative thereof, according to the methods described in the organic chemistry.

The coupling between an obtained compound of formula (XXI) and a diazoacetate of formula N2CHCOOR6 may be performed as reported in the chemical literature for similar reactions [Tetr. Letters, 1972,4387].

The isomerisation of the isolated olefinic bond in a compound of formula (XXII) to give the compound (XXII A) may be obtained by the catalytic action of an inorganic or organic base in a suitable solvent such as, for example, chloroform, methylene chloride, diethyl ether in the cold or at room temperature.

The conversion of the penicillanic acid of formula (XVI) into the corresponding penicillanate S-oxide of formula (XXI A) may be obtained by well established methods in the organic chemistry, implying, for instance, the oxidation of the acid (XVI) followed by esterification to give the compound (XXI A) or, alternatively, the esterification followed by the oxidation.

The condensation reaction between a compound of formula (XXI A) and a ketene dialkyl acetal of formula

may be performed by the known methods reported in the literature for similar reactions [J.C.S. Chem.

Comm., 1972601].

The removal of the 1 -substituent from the compound of formula (XXII A) to give the compound of formula (XXIII) is carried out under oxidative condition in a suitable solvent such as, for instance, methylene chloride, acetone and at reduced temperature preferably varying between about -78"C and about +5"C.

The oxidative conditions are realized, for example, by the presence of ozone or Kin04 in basic media.

The reduction of the ester moiety -COOR6 in the compound of formula (XXIII) may be carried out by the methods usually described in the organic chemistry for the reduction of a carboxylic ester group to a primary alcohol, for example by the use of hydrides, preferably LiAIH4 or boranes, in a solvent such as for instance diethyl ether, tetrahydrofurane, dioxane and similar, at a temperature varying approximately between -20"C and +20"C.

The protection of the azetidinyl carbinol (XXIV) to give the compound XIII wherein R3 is hydrogen may be performed by known methods for example by reaction with 2,2-dimethoxy propane in acidic media and in an organic solvent such as, for instance, methylene chloride, chloroform, diethyl ether, at a temperature from about -10"C to room temperature.As already said the chiral key intermediate of formula (XIII), in addition to be prepared starting from natural 6-amino penicillanic acid or penicillins according to the methods illustrated in the scheme II and Ill, may also be obtained by total chemical synthesis according to the process illustrated in scheme IV SCHEME IV

The process reported in Scheme IV comprises: 1) conversion of a 2-oxo-azetidine-derivative of formula (XXV) wherein Lisa nucleofuge leaving group into a mixture of the enantiomers of formula (XXVIR) and (XXVls); 2) resolution of the obtained racemic mixture and esterification of the separated enantiomer (XXVIR) to give the 4(R)-ester derivative of formula (XXVII); 3) reduction of the optically active ester of formula (XXVII) or, alternatively, direct reduction of the optically active acid of formula (XXVIR), to give the optically active carbinol of formula (XXVIII); and 4) conversion of the obtained compound of formula (XXVIII) into the bicyclo compound of formula (Xlil: R3 = H or C-C6 alkyl) through the formation of the corresponding acetonide.

A nucleofuge leaving group L in a compound of formula (XXV) may be, for example, an acyloxy radical, preferably C,-C6 alkanoyloxy or benzoyloxy, a halogen or a sulphonyl group.

The conversion of a compound of formula (XXV) into the racemic mixture of the compounds (XXVIR) and (XXVlS) may be carried out by reaction with the di-salt, preferably sodium or potassium salt, of a thioglycolic acid derivative of formula

wherein each of the group R3 has the meanings given above.

The reaction may be carried out in a suitable solvent preferably chosen from the group of water, tetrahydrofurane, dimethylformamide, acetone, ethanol, acetonitrile or in a mixture of one or more of these solvents, at a temperature varying approximately from about 20at to about +20"C.

The resolution of the obtained racemic mixture of the enantiomeric acids (XXVIR) and (XXVls) is carried out by conventional way, e.g. by reaction with an optically active base, which may be, for instance, ephedrine, brucine, cinchonine, menthylamine, 1-phenylethylamine and similar to give a mixture of diastereoisomeric salts. After separation of the diastereoisomeric salts by known methods, e.g. by fractionate crystallization, the individual enantiomer of formula (XXVIR) is recovered by acidification of the corresponding salt.

Esterification of the free acid (XXVIR) by an alcohol of formula R6OH wherein R6 is as defined above, in a conventional manner, leads to the ester of formula (XXVII).

The reduction of the free acid of formula (XXVIR) or of its ester of formula (XXVII), to give the carbinol of formula (XXVIII), may be carried out by any of the methods usually employed in the organic chemistry to reduce a carboxylic ester into a primary alcohol, for example by reaction with a borane or a mixed hydride, LiAIH4 or NaBH4for instance, in an anhydrous inert solvent such as, for example, diethylether or tetrahydrofurane.

The conversion of the optically active carbinol of formula (XXVIII) into the optically active bicyclo compound (Xlil: R3 = H or C1-C6 alkyl) may be carried out by acetonidation of the amidic and alcoholic moieties according to known methods, for example by treatment with 2,2-dimethoxy propane in acidic media and in a solvent preferably chosen from methylene chloride, chloroform, diethyl ether at a temperature varying approximately between about -10 C and about +20"C.

The above indicated optical resolution of the racemic mixture of the enantiomers (XXVIR) and (XXVs) allows to obtain separately both the individual diastereoisomeric salt of the acid (XXVIR) and the diastereoisomeric salt of the acid (XXVls). The latter salt may be recycled by converting it into an enantiomeric mixture of the acids (XXVIR) and (XXVIs) from which, by the same procedure hereabove described, a further amount of the optically active ester of formula (XXVII) may be recovered.

The conversion of the diastereoisomeric salt of the acid (XXVls) into the enantiomeric mixture of the compounds (XXVIR) and (XXVls) may be carried by a step sequence comprising: a) liberating the free acid of formula (XXVls) from its diastereoisomeric salt by acidification in a conventional way; b) esterifying the free acid of formula (XXVls) by an alcohol of formula R6OH wherein R6 is as defined above, in a conventional manner; c) oxidizing the ester so obtained with a suitable, both inorganic and organic, oxidizing agent, such as, e.g., m-chloroperbenzoic-acidi or Kin04, in a known manner, to give the corresponding sulphone of formula (xXlx)

wherein each of the groups R3 and R6 has the meanings given above; d) reacting the sulphone (XXIX) with a di-salt of a thioglycolic acid derivative of formula

according to the same procedure previously indicated with reference to the analogous reaction of scheme IV.

The synthesis of the optically active key intermediate of formula (XIII) by the process illustrated in scheme IV allows to increase further the productivity of the whole process of the invention, due to the possibility of recycling, at an early stage of the synthesis, the enantiomer of 4(S)-configuration, namely the compound of formula (XXVIs).

The second object of the invention concerns new optically active trans-6(S) substituted-5(R)-2-penem-3carboxylic acid derivatives of the following classes: a) compounds having the formula (I) reported above wherein Rand R, are, independently, C-C6 alkyl and R2 is hydrogen, C-C6 alkyl, an optionally nitro-substituted benzyl group or a pharmaceutically orveterinarily acceptable cation; b) compounds having the formula (I) reported above wherein R is C1-C6-alkyl, R1 is C1-C6 alkanoyloxymethyl and R2 is hydrogen, C,-C6 alkanoylmethyl, an optionally nitro substituted benzyl group or a pharmaceutically orveterinarily acceptable cation; c) compounds having the formula (I) reported above wherein R is C1-C6 alkyl, R, is C1-C6 alkoxy-carbonyl and R2 is hydrogen, C1-C6 alkyl, an optionally nitro-substituted benzyl group or a pharmaceutically orveterinarily acceptable cation; and d) compounds having the formula (I) reported above wherein R is C1-C6 alkyl; R1 isathienylmethyl group and R2 is hydrogen, C1-C6 alkyl, an optionally nitro-substituted benzyl group or a pharmaceutically or veterinarily acceptable cation.

Preferred compounds of the above class a) are those wherein Rand R1 are, independently, methyl, ethyl or propyl, in particular the species listed below: methyl (6S)-6-ethyl-(5R)-2-methyl-2-penem-3-ca rboxylate; methyl (6S)-6-ethyl-(5R)-2-ethyl-2-penem-3-ca rboxylate; methyl(6S)-6-ethyl-(5R)-2-propyl-2-penem-3-carboxylate; methyl(6S)-6-methyl-(5R)-2-methyl-2-penem-3-carboxylate; methyl(6S)-6-methyl-(5R)-2-ethyl-2-penem-3-carboxylate; methyl(6S)-6-methyl-(5R)-2-propyl-2-penem-3-carboxylate; methyl(6S)-6-propyl-(5R)-2-methyl-2-penem-3-carboxylate; methyl(6S)-6-propyl-(5R)-2-ethyl-2-penem-3-carboxylate; methyl(6S)-6-propyl-(5R)-2-propyl-2-penem-3-carboxylate; p-nitrobenzyl(6S)-6-ethyl-(5R)-2-methyl-2-penem-3-carboxylate; p-nitrobenzyl(6S)-6-ethyl-(5R)-2-ethyl-2-penem-3-carboxylate; p-nitrobenzyl(6S)-6-ethyl-(5R)-2-propyl-2-penem-3-carboxylate; p-nitrobenzyl(6S)-6-methyl-(5R)-2-methyl-2-penem-3-carboxylate; p-nitrobenzyl(6S)-6-methyl-(5R)-2-ethyl-2-penem-3-carboxylate; p-nitrobenzyl(6S)-6-methyl-(5R)-2-propyl-2-penem-3-carboxylate; p-nitrobenzyl(6S)-6-propyl-(5R)-2-methyl-2-penem-3-carboxylate; p-nitrobenzyl (6S)-6-propyl-(5R)-2-ethyl-2-penem-3-ca rboxylate; p-nitrobenzyl(6S)-6-propyl-(5R)-2-propyl-2-penem-3-carboxylate; (6S)-6-ethyl-(5R)-2-methyl-2-penem-3-carboxylic acid; (6S)-6-ethyl-(5R)-2-ethyl-2-penem-3-carboxyl ic acid; (6S)-6-ethyl-(5R)-2-propyl-2-penem-3-carboxylic acid; (6S)-6-methyl-(5R)-2-methyl-2-penem-3-carboxyl ic acid; (6S)-6-methyl-(5R)-2-ethyl-2-penem-3-carboxyl ic acid; (6S)-6-methyl-(5R)-2-propyl-2-penem-3-carboxyl ic acid; (6S)-6-propyl-(SR)-2-methyl-2-penem-3-carboxylic acid; (6S)-6-propyi-(5R)-2-ethyl-2-penem-3-carboxylic acid; (6S)-6-propyl-(5R)-2-propyl-2-penem-3-carboxylic acid; and the pharmcaceutically or veterinarily acceptable salts, in particular the sodium salts, of the free acids Preferred compounds of the class b) are those wherein;R is methyl, ethyl or propyl and R, is acetoxymethyl or propionyloxymethyl in particular the species listed below: p-nitrobenzyl (6S)-6-ethyl-(5R)-2-acetoxy-methyl-2-penem-3-carboxylate; p-nitrobenzyl(6S)-6-methyl-(5R)-2-acetoxy-methyl-2-penem-3-carboxylate; p-nitrobenzyl(6S)-6-propyl-(5R)-2-acetoxy-methyl-2-penem-3-carboxylate; p-nitrobenzyl(6S)-6-methyl-(5R)-2-propionyloxy-methyl-2-penem-3-carboxylate; p-nitrobenzyl(6S)-6-ethyl-(5R)-2-propionyloxy-methyl-2-penem-3-ca rboxylate; p-nitrobenzyl (6S)-6-propyl-(5R)-2-propionyloxy-methyl-2-penem-3-carboxylate; acetonyl(6S)-6-ethyl-(5R)-2-acetoxy-methyl-2-penem-3-carboxylate; acetonyl (6S)-6-methyl-(5R)-2-acetoxy-methyl-2-penem-3-ca rboxylate; acetonyl(6S)-6-propyl-(5R)-2-acetoxy-methyl-2-penem-3-carboxylate; acetonyl(6S)-6-methyl-(5R)-2-propionyloxy-methyl-2-penem-3-carboxylate; acetonyl (6S)-6-ethyl-(SR)-2-propionyloxy-methyl-2-penem-3-carboxylate; acetonyl(6S)-6-propyl-(5R)-2-propionyloxy-methyl-2-penem-3-carboxylate; (6S)-6-ethyl-(5R)-2-acetoxy-methyl-2-penem-3-carboxylic acid; (6S)-6-methyl-(5R)-2-acetoxy-methyl-2-penem-3-carboxylic acid; (6S)-6-propyl-(5R)-2-acetoxy-methyl-2-penem-3-carboxylic acid; (6S)-6-methyl-(5R)-2-propionyloxy-methyi-2-penem-3-carboxylic acid; (6S)-6-ethyl-(5R)-2-propionyloxy-methyl-2-penem-3-carboxylic acid; (6S)-6-propyl-(5R)-2-propionyloxy-methyl-2-penem-3-carboxyl ic acid; methyl (6S)-6-ethyl-(5R)-2-acetoxy-methyl-2-penem-3-carboxylate; methyl (6S)-6-methyl-(5R)-2-acetoxy-methyl-2-penem-3-ca rboxylate; methyl(6S)-6-pro pyl-(5R)-2-acetoxy-methyl-2-penem-3-ca rboxylate; methyl(6S)-6-methyl-(5R)-2-propionyloxy-methyl-2-penem-3-carboxylate; methyl(6S)-6-ethyl-(SR)-2-propionyloxy-methyl-2-penem-3-carboxylate; methyl(6S)-6-propyl-(SR)-2-prionyloxy-methyl-2-penem-3-carboxylate; and the pharmaceutically or veterinarily acceptable satls, in particular the sodium salts, of the free acids.

Preferred compounds of the class c) are those wherein R is methyl, ethyl or propyl and R, is methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl in particular the species listed below: p-nitrobenzyl (6S)-6-ethyl-(5R)-2-ethoxyca rbonyl-2-penem-3-ca rboxylate; p-nitrobenzyl(6S)-6-methyl-(5R)-2-ethoxycarbonyl-2-penem-3-carboxylate; p-nitrobenzyl(6S)-6-propyl-(5R)-2-ethoxycarbonyl-2-penem-3-carboxylate; p-nitrobenzyl(6S)-6-methyl-(5R)-2-methoxycarbonyl-2-penem-3-carboxylate; p-nitrobenzyl(6S)-6-ethyl-(5R)-2-methoxycarbonyl-2-penem-3-carboxylate; p-nitrobenzyl(6S)-6-propyl-(5R)-2-methoxycarbonyl-2-penem-3-carboxylate; p-nitrobenzyl(6S)-6-methyl-(5R)-2-propoxycarbonyl-2-penem-3-carboxylate; p-nitrobenzyl(6S)-6-ethyl-(5R)-2-propoxycarbonyl-2-penem-3-carboxylate; p-nitrobenzyl(6S)-6-propyl-(5R)-2-propoxycarbonyl-2-penem-3-carboxylate; (6S)-6-ethyl-(5R)-2-ethoxycarbonyl-2-penem-3-carboxyl ic acid; (6S)-6-methyl-(5R)-2-ethoxycarbonyl-2-penem-3-carboxylic acid; (6S)-6-propyl-(5R)-2-ethoxycarbonyl-2-penem-3-ca rboxylic acid; (6S)-6-methyl-(5R)-2-methoxycarbonyl-2-penem-3-carboxylic acid; (6S)-6-ethyl-(5R)-2-methoxycarbonyl-2-penem-3-carboxylic acid; (6S)-6-propyl-(5R)-2-propoxycarbonyl-2-penem-3-carboxylic acid; (6S)-6-methyl-(5R)-2-propoxycarbonyl-2-penem-3-carboxylic acid; (6S)-6-ethyl-(5R)-2-propoxycarbonyl-2-penem-3-carboxylic acid; (6S)-6-propyl-(5R)-2-propoxycarbonyl-2-penem-3-carboxyl ic acid; methyl (6S)-6-ethyl-(5R)-2-ethoxyca rbonyl-2-penem-3-carboxylate;; methyl(6S)-6-methyl-(5R)-2-ethoxycarbonyl-2-penem-3-carboxylate; methyl(6S)-6-pro pyl-(5R)-2-ethoxyca rbonyl-2-penem-3-ca rboxyl ate; methyl (6S)-6-methyl (5R)-2-methoxycarbonyl-2-penem-3-carboxylate; methyl(6S)-6-ethyl-(5R)-2-methoxycarbonyl-2-penem-3-carboxylate; methyl(6S)-6-propyl-(5R)-2-methoxycarbonyl-2-penem-3-carboxylate; methyl(6S)-6-methyl-(5R)-2-propoxycarbonyl-2-penem-3-carboxylate; methy-(6S)-6-ethyl-(5R)-2-propoxycarbonyl-2-penem-3-carboxylate; methyl(6S)-6-propyl-(5R)-2-propoxycarbonyl-2-penem-3-carboxylate; and the pharmaceutically or veterinarily acceptable salts, in particular the sodium salts, of the free acids.

Preferred compounds of the class d) are those wherein R is methyl, ethyl or propyl and R1 is 2-thienylmethyl, in particular the species: p-nitrobenzyl(6S)-6-ethyl-(5R)-2-thien-2'-yl-methyl-2-penem-3-carboxylate; p-nitrobenzyl(6S)-6-methyl-(5R)-2-thien-2'-yl-methyl-2-penem-3-carboxylate; p-nitrobenzyl(6S)-6-propyl-(5R)-2-thien-2'-yl-methyl-2-penem-3-carboxylate; (6S)-6-ethyl-(5R)-2-thien-2'-yl-methyl-2-penem-3-carboxylic acid; (6S)-6-methyl-(5R)-24hien-2'-yl-methyl-2-penem-3-carboxylic acid; (6S)-6-propyl-(5R)-2-thien-2'-yl-methyl-2-penem-3-carboxylic acid; methyll(6S)-6-ethyl-(5R)-2-thien-2'-yl-methyl-2-penem-3-carboxylate; Methyl (6S)-6-methyl-(5R)-2-thien-2 '-yl-methyl-2-penem-3-carboxylate; methy(6S)-6-propyl-(5R)-24h ien-2'-yl-methyl-2-penem-3-carboxylate; and the pharmaceutically or veterinarily acceptable salts, in particular the sodium salts, of the free acids.

All the above compounds can be prepared according to the general process which is the first object of the invention. The above new optically active trans-6(S)-substituted-5(R)-2-penem-3-carboxylic acid derivatives object of the invention have a high antibacterial activity both in animals and in humans against gram-positive and gram-negative bacteria such as staphylococci, streptococci, diplococci, Klebsiella, Escherichia coli, Proteus mirabilis, Salmonella, Shigella, Haemophilus and Neisseria.The compounds of the invention show also a high activity against the strong beta-lactamase producer microorganisms, such as, for example, Klebsiella aerogenes 1082 E, Escherichia coll Tem, Enterobactercloacae P99, and indole-positive Proteus and the like, as well as against Pseudomonas aeruginosa strains.

Owing to their high antibacterial activity either in animals or in humans against both Gram-positive and Gram-negative bacteria the compounds object of the present invention are useful in the treatment of the infections caused by said microorganisms, such as respiratory tract infections, for example, bronchitis, bronchopneumonia, pleurisy; hepatobiliary and abdominal infections, for example, septicemia; urinary tract infections, for example, pyelonephritis, cystitis; obstetrical and gynecological infections, for instance, cervicitis, endometritis; ear, nose and throat infections, for instance, otitis, sinusitis, parotitis.

The toxicity of the compounds of the invention is quite negligible and therefore they can be safely used in therapy.

The compounds of the invention may be administered, either to humans orto animals, in a variety of dosage forms, e.g., orally in the form of tablets, capsules, drops or syrups; rectally in the form of suppositories; parenterally, e.g., intravenously or intramuscularly (as solutions or suspensions), with intravenous administration being preferred in emergency situation; by inhalation in the form of aerosols or solutions for nebulizers; intravaginally in the form, e.g. of bougies; or topically in the form of lotions, creams and ointments. The pharmaceutical or veterinary compositions containing the compounds of the invention may be prepared in a conventional way by employing the conventional carriers or diluents used for the other cephalosporins.

Conventional carriers or diluents are, for example, water, gelatine, lactose, starches, magnesium stearate, talc, vegetable oils, cellulose and the like. Daily doses in the range of about 1 to about 100 mg per kg of body weight may be used, in various animal species, the exact dose depending on the age, weight and condition of the subject to be treated and on the frequency and route of administration.A preferred way of administration of the compounds of the invention is the parenteral one: in this case the compounds may be administered, for example to adult humans, in an amount ranging from about 100 mg to about 200 mg pro dose, preferably about 150 mg pro dose, 1-4 times a day, dissolved in a suitable solvent, such as, for example sterile water or lidocaine hydrochloride solution for intramuscular injections, and sterile water, physiological saline solution, dextrose solution or the conventional intravenous fluids or electrolytes, for intravenous injections.Furthermore, the compounds of the invention may be used as antibacterial agents in a prophylactic manner, e.g., in cleaning or as surface disinfecting compositions, for example, at a concentration of about 0.2 to 1% by weight of such compounds admixed with, suspended or dissolved in conventional inert dry or aqueous carriers for application by washing or spraying.

They are also useful as nutritional supplements in animal feeds.

Assessment of melting points was somewhat difficult in some cases as the compounds tend to retain the solvent. In these cases, after the indication of the melting points, the word "dec." (decomposition) was added. The abbreviations THF, AcOH and AcOEt were used to indicate, respectively, tetrahydrofuran, acetic acid and ethylacetate.

The following examples illustrate but do not limit the present invention.

EXAMPLE 1 2,2,-Dimethyl-3-carbonylazido-(5R)-penam

To a cooled (-1 5"C) solution of penicillanic acid (6.04 9, 30 mmole) in anhydrous THF (40 ml) is added a solution of Et3N (3.04 g, 4.18 ml, 30 mmole) in THF (5 ml) during 15 min. with stirring. After 15 min of additional stirring a solution of ethyl chloroformate (3.26 9, 2.86 mE,30 mmole) in THF (5 ml) is added dropwise. The reaction mixture is stirred during 90 min at a temperature from - 15 to - 10 C, then it is treated with the dropwise addition (30 min) of a solution of NaN3 (6 g, 92 mmole) in H2O (20 ml).The resulting mixture is stirred further for 45 min at - OaCthen it is worked up by diluting with cold water (150 ml) and extracting with benzene (4 x 100 ml).

The combined extracts are washed with water (2 x 100 ml), with saturated aqueous NaCI solution (4 x 100 ml) and dried over Na2SO4. Evaporation of the solvent leaves an oily residue.

I.R. (CHCl3r cm-): 2150, 1780, 1710.

EXAMPLE 2 2',2',2'-Trichloroethyl-N(2,2,-dimethyl-(5R)-penam-3-yl)-urethane

To a solution of the azide (Example 1) in anhydrous benzene (100 ml) is added freshly distilled trichioroethanol (4.5 g; 30 mmole). The resulting mixture is heated at 70-75 C during 3-5 hrs, then it is cooled and evaporated in vacuo to yield a residue which is chromotographed over silica gel (100 g). Elution with C6H6-AcOEt 95:5 delivers a yellow solid which is crystallised from benzene (4.4 g, 42%).

m.p. . 162-4"C DSC 98% molar purity Elem. anal. (calc. for C,0H3CI3N203S): C 34.74 (34.55) H 3.73 (3.77) N 8.03( 8.05) S 9.07 (9.22) Cl 30.50 (30.60) [a]D= + 111.4"(C = 0.8, CHCl3) I.R. (CHC13, cm-'): 1780, 1743 N.M.R.(CDCl3,#): : 1.51 (3H,s) 1.57 (3H, s) 3.14 (1H, dd,J=2.5, 18Hz) 3.58(1 H, dd, J=5,18 Hz) 4.75 (2H, m) 5.12 (1H, dd, J=2.5, 6Hz) 5.45 (1H, br) 5.64 (1H, d, J=9 Hz) EXAMPLE 3 22-Dim eth yl-3-hydroxy-(5Rl-p enam

To a stirred suspension of the trichlorourethane (4.15 g, 11.9 mmole) in 90% AcOH (100 ml) is added Zn powder (25 g) at small portions during 30 min. at a temperature of 5 C. The resulting mixture is stirred further for 16-20 hrs at room temperature. The solid is then filtered with filter aid and washed liberally with benzene.

The combined filtrate and washings are washed with a saturated NaCI aqueous solution (4 x 50 ml) and dried over Na2SO4.

Evaporation of the solvent yields a yellow solid which is chromatographed over silica gel. Elution with C6H6-AcOEt 95:5 delivers the crystalline white title product (1.97 g, 90.7%) m.p.: 58-60 C [a]D = + 200.4 (C = 1.1, CHCl3) I.R. (CHCI3, cm-1): 3350, 1768 N.M.R. (CDCl3,#):: 1.49 (3H, s) 1.53 (3H, s) 3.02 (1H, dd, J=2.5, 18 Hz) 3.43(1 H, dd, J=5, 18 Hz) 4.00 (1H, br) 5.16(1 H, dd, J=2.5, 5Hz) 5.29 H, br) EXAMPLE 4 2,2-Dimethyl-3-hydroxy-(5R)-penam

2,2-Dimethyl-3-carbonylazido-(5R)-penam, prepared from 26.2 g (130 mmole) of penicillanic acid as described in the Example 1, is transposed to the corresponding isocyanate either by heating it in C6H8 (200 ml) at 70-75"C during 4 hours or by keeping it as neat under vacuum during 48 hrs.The crude isocyanate [IR (EtOH-free CH2C12): 2245, 1785 cm-1] so obtained is dissolved in dioxane (1000 ml) and added to a stirred mixture of H2O (3000 ml) and 2 N HCI (130 ml) over a period of 4 hrs. When the addition is over, the reaction mixture is stirred for an additional hour and, then it is extracted with methylene chloride (4 x 500 ml). The combined organic extracts are washed with a saturated NaCI aqueous solution, dried over Na2SO4 and evaported in vacuo to dryness.

The residue so obtained is taken up with benzene (100 ml) and AcOEt (10 ml), stirred for 1 hr and filtered.

The filtrate is eluted through a silica gel column (50 g).

Further elution with C6H6-AcOEt 90:10 yields the title compound (5.1 g, 22.6%).

EXAMPLE 5 {4R)-4-fss, ss-dimethyl-3-hydroxyethylthio)azetidin-2-one

To a cooled (ice bath) solution of 2,2-dimethyl-3-hydroxy-(5R)-penam (1.87 g, 10.8 mmole) in THF (25 ml) is added a solution of NaBH4 (440 mg, 22 mmole) in H2O (4 ml) during 15 min with stirring. The reaction mixture is worked up by adding cold 50% AcOH (1.5 ml) and by evaporating under vacuum to yield a residue which is taken up in CH2Cl2 (100 ml), washed with a saturated NaCI aqueous solution, dried over Na2SO4 and evaporated in vacuo to give a yellow oil. Purification by filtration through a short column of silica gel delivers the title compound as a water-clear oil (1.81 g, 95.7%).

[a]o = + 184.0 (C = 1, CHCI3) I.R. (CHCl3, cm-'): 3300, 1750 N.M.R. (CDCI3, b): 1.26 (3H, s) 1.38 (3H, s) 2.81 (lH,ddd,J = 1.5,2.5,18 Hz) 3.42(lH,ddd,J = 1.5, 5, 18 Hz) 3.56 (2H, s) 3.90 (1H, br) 5.00 H, dd, J = 2.5, 5 Hz) 7.58 (1H, br) EXAMPLE 6 2,2,5,6- Tetramethyl-(7R)-9-oxo-3-oxa-6thia- 1-azabicyclo-f5.2. Ol 7]nonane

To a cooled (-1 0"C) solution of (4R)-4-(ss,ss,dimethyl-3-hydroxyethylthio)azethidin-2-one (1.81 g, 10.3 mmole) and 2,2,-dimethoxy propane (3.8 ml, 3.2 g, 31 mmole) in CH2CI2 (20 ml) is added boron trifluoride etherate (0.25 ml). The reaction mixture is stirred at -10"C during 30 min and at ambient temperature for additional 2 hrs. The reaction is worked up by adding CH2Cl2 (100 ml), by washing with a saturated NaCI aqueous solution and by drying over Na2SO4.The solvent is evaporated in vacuo to yield a residue which is crystallised from hexane as a white solid (1.40 9, 63%): m.p.: 77-9 C DSC 99% molar purity Elem. anal. (calc.for C10H17NO2S): C 55.68 (55.78) H 7.99 (7.96) N 6.48( 6.51) S14.80(14.89) [a]D = + 137.62 (C = 1, CHCl3) I.R. (CHCl3, cm-'): 1740 N.M.R. (CDCl3, 5):: 1.20 (3H, s) 1.46 (3H, s) 1.55 (3H, s) 1.71 (3H, s) 2.65 (1H, dd, J = 2.5, 15 Hz) 3.18(lH,dd,J = 5,15Hz) 3.60(lH,d,J = 12 Hz) 4.14(1H,d,J = 12 Hz) 5.06(lH,dd,J = 2.5, 5 Hz) EXAMPLE 7 Ethyl α-[1-(1'α-methoxycarbonyl-2'-methylprop-2' -enyl)-2-oxoazetidin-(4R)-4-ylthio]acetate

To a stirred mixture of methyl penicillinate (5.35 g, 25 mmole) and Cu (acac)2** (1 g) in anhydrous benzene (100 ml) is added a solution of ethyl diazoacetate (3 g, 26 mmole) in benzene (10 ml) dropwise at 80"C. The reaction mixture is stirred for an additional hour, cooled and filtered. The filtrate is absorbed on the top of a silica gel column.Elution with toluene-AcOEt 98:2 delivers unreacted methyl penicillinate (2.56 g, 48%) followed by the oily title compound (1.9 g).

N.M.R.(CDCl3,#): 1.29 (3H, t, J = 7 Hz) 1.92 (3H, br s) 3.07 (1H, dd, J = 2.5,16Hz) 3.39 (2H, s) 3.49 (lH,dd,J = 5,16Hz) 3.80 (3H, s) 4.21 (2H, 9, J = 7 Hz) 4.80 (1H, s) 5.02 (1H, brs) 5.15 (1H, brs) 5.19 (1H, dd, J =2.5,5Hz) **(cupric acetylacetonate) EXAMPLE 8 Ethyl α-[1-(1'-methoxycarbonyl-2'-methylprop-1'enyl)-2-oxoazetidin-(4R)-4-ylthio]acetate

A solution of ethyl α-[1-(1'α-methoxycarbonyl-2'-methylprop-2'enyl)-2-oxoazetidin-(4R)-4-ylthio]acetate (1.9 g) in methylene chloride (40 ml) is treated with 2 drops of triethylamine.After standing overnight, the solvent is evaporated in vacuo to yield the title compound quantitatively.

N.M.R. (CDCl3,#): 1.28 (3H, t, J = 7 Hz) 2.03 (3H, s) 2.27 (3H, s) 3.02 (1H,dd, J = 2.5,16 Hz) 3.30 (2H, s) 3.44(1H,dd,J=5,16Hz) 3.81 (3H, s) 4.20 (2H, 9, J = 7Hz) 5.29 (1 H, dd, J = 2.5,5Hz) EXAMPLE 9 Ethyl α-[1-(1'-methoxycarbonyl-2'-methylprop-1'-enyl)-2-oxoazetidin-(4R)-4-ylthio]acetate

A solution of methyl penicillanate S oxide (2.31 g, 10 mmole) in dioxane (80 ml) is heated at 80 C in presence of a two molar excess of 1,1 -diethoxyethene under N2 for 24 hours. The cooled reaction mixture is evaporated in vacuo and the residue is chromatographed on silica gel. Elution with toluene AcOEt 98:2 delivers the title compound (2 g, 6.6 mmole, 66%).

EXAMPLE 10 Ethyl α-[2-oxoazetidin-(4R)-4- ylthio]acetate

Ethyl a-[1-(1 '-methoxycarbonyl-2'-methylprop-1 '-enyl)-2-oxoazetidin-(4R)-4-ylthio]acetate (1.5 9,5 mmole) dissolved in methylene chloride (150 ml) is cooled to -780C and treated with 5.2 mmole of 03.

Dimethyl sulfide is added and the stirred mixture is allowed to reach room temperature naturally. The solvent is evaporated in vacuo and the residue is taken up with methanol and stirred overnight at room temperature. The solvent is evaporated in vacuo and the residue is taken up with methylene chloride, washed with water, dried over Na2SO4 and evaporated in vacuo to yield the title compound.

[a]D = + 900 (C = 1.19, CHCl3) I.R. (CHCl3, cm-): 3330, 1770, 1730 N.M.R. (CDCl3,5): 1.33 (3H, t, J = 7Hz) 2.96(1 H, ddd, J = 15.5,2.5, 1.3 Hz) 3.40 (2H, s) 3.45 (1 H, ddd, J = 15.5,5.0, 1.7 Hz) 4.93 (1 H, dd, J = 2.5, 5.0 Hz) 7.05 (1 h, br) EXAMPLE 11 (4li)-('3-h ydroxyeth ylthio) azetidin-2-one

To a stirred solution of ethyl a-[2-oxo-(4R)-4-azetidinylthio]acetate (11.7 g, 0.062 mole) in anhydrous Et2O (250 ml) is added a suspension of LiAIH4 (1.77 g, 0.0466 mole) in 30 ml of Et2O at -20"C under nitrogen atmosphere.The reaction mixture is stirred between -20 C and 0 C for 2 hours, cooled again to -200C, treated with a suspension of Li AIH4 (1.77 g, 0.0466 mole) in 30 ml of Et2O and left overnight at room temperature.

Usual work up followed by thorough extraction with AcOEt gives 7.31 g of the crystalline title product (80% yield) M.p. 47 - 49 C [a]D = + 139" (C = 0.1, CHCl3) I.R. (CHCl3,cm'): 3300,1760 N.M.R. (CDCl3, b):: 2.60 (1H, s) 2.70-3.30 (2H, m) 3.25-3.5 (2H, m) 3.7-3.9 (2H, m) 4.81 (1H, dd, J1 = 2.5 Hz, J2 = 5 Hz) 7.32(1 H, s) EXAMPLE 12 2,2-Dimethyl-(7R)-9-oxo-3-oxa-6-thia- 1 azabicyclo[5.2. 0' 71 nonane

A solution of (4R)-4-(ss-hyroxyethylthio) azethidin-2-one (7.3 g, 0.0496 mole) and 2,2-dimethoxy propane (13.1 g 0.0125 mole) in dry ethanol-free CH2CI2 is cooled to -10"C and treated with the dropwise addition of BF3-Et2O (1 ml) under stirring. After 30 min of additional stirring, the reaction mixture is diluted with CH2Cl2 (70 ml), washed with cold saturated NaHCO3 aqueous solution (180 ml) and dried over Na2SO4.Evaporation of the solvent under vacuum gives a residue which, after crystallisation from Et2O-n-hexane at 0"C, yields the title product (6.7 g, 71%), m.p.: 93-4"C [a]D= 107 (C= 1,CHCl3) I.R. (CHCI3, cm-1): 1750 N.M.R. (CDCl3 b): 1.50 (3H, s) 1.73 (3H, s) 2.70 (1H, dd, J = 2,15 Hz) 2.71 (1 H, dt, J = 3, 14 Hz) 3.05(1H,dt,J = 5.5, 14 Hz) 3.20 (1 H, dd, J = 5, 15 Hz) 4.16 (2H, dd, J = 3, 5.5 Hz) 5.03 (1H, dd,J 2,5Hz).

EXAMPLE 13 a-[2-oxo-r4R, S)-4-azetidin ylthio] acetic acid

To a stirred 2N NaOH aqueous solution (470 ml) cooled to -4"C is added a 70% aqueous solution of thioglycolic acid (50 ml, 0.47 mole) diluted in 99% EtOH (400 ml) dropwise. After 5 min. of additional stirring, 4-acetoxy-azetidinone [K. Clauss etal., Liebig Ann. Chem. 1974, 539] (55 g, 0.426 mole) dissolved in 99% EtOH (100 ml) is added dropwise.

The resulting mixture is stirred at 0"C for 30 min. and at room temperature for 1 hour. After cooling to -5"C, the reaction solution is treated with the dropwise addition of a 2N HCI aqueous solution (490 ml). The resulting suspension is stirred in the cold for 1 hr. the precipitate is filtered off and washed with water.

The combined mother liquor and washings are evaporated to dryness in vacuo to yield a residue which is treated with 160 ml of H2O. The resulting suspension is filtered off and washed with little H2O. The combined precipitates are dried in vacuo at 45"C overnight. The title acid is obtained in 85% yield (58.5 g).

m.p.: 1300C(dec.) I.R. (KBr, cm-'): 3450,3300, 1745, 1710.

N.M.R. (CDCl3, b): 2.89 (1 H, dd, J = 2.5, 16 Hz) 3.38 (2H + 1H, s+m) 4.92 (1 H, q, J = 2.5,5Hz) 7.88 (1 H, br, exchange with D20) 9.66 (1 H, br, exchange with D2O) EXAMPLE 14 α-[2-oxo-(4R)-4-azetidinylthio]acetic acid D(+)-ephedrine salt To a solution of a-[2-oxo-(4R,S)-4-azetidinylthio]acetic acid (40 g, 0.248 mole) in 99% EtOH is added D(+)-ephedrine (45 g, 0.272 mole) at 70 C. The resulting hot solution is allowed to cool and to stand at room temperature overnight. A crystalline precipitate is formed which is filtered off, washed with little 99% EtOH and dried in vacuo at 40"C overnight to give the title salt (32.1 g).

M.P.: 160-2 C [a]D = + 109.68 (C = 0.1 EtOH 99%) EXAMPLE 15 α-[2-oxo-(4R)-4-azetidinylthio] acetic acid A solution of a-[2-oxo-(4R)-4-azetidinylthio] acetic acid D(+)-ephedrine salt (32.1 g) in distilled water is stirred with Amberlitee)lR-20 for 1 hour.

The polymeric resin is filtered off with filter aid and washed with distilled water.

The combined filtrate and washings are evaporated in vacuo at 40"C to yield a residue which, on crystallisation from hot 99% EtOH, yields 13 g of the title compound.

[a]D = + 128 (C = 0.10, EtOH 99%) m.p.. 87-9 C.

EXAMPLE 16 Methyl a-[2-oxoazetidin-64RJ-4-ylthiol acetate

A suspension of a-[2-oxoazetidin-(4R)-4-ylthio] acetic acid (10 g, 0.062 mole) in absolute MeOH (200 ml) is stirred overnight in the presence of Amberlite R IR-120. The polymeric resin is filtered of and washed with MeOH. The combined filtrate and washings are evaporated in vacuo to give 10.8 g of the methyl ester (100%).

[(xJD = + 110 (C = 0.11, CHCl3); [a]D = +127a(C=O.1 1,EtOH) I.R. (CHCl3, cm-): 3330,1770,1730 N.M.R. (CDCl3,#): 2.96 (1H, ddd, J = 2.0, 2.5, 15 Hz) 3.41 (1H,ddd,J = 1.5, 5.0, 15 Hz) 3.42 (2H, s) 3.79 (3H, s) 4.94(1 H, dd, J = 2.5, 5.0 Hz) 7.35 (1H, br) EXAMPLE 17 (4R)-4-(3-hydroxyethylthio) acetidin-2-one

Methyl ct-[2-oxoazetidin-(4R)-4-ylthio] acetate is reduced to the title compound as described in the Example 11.

m.p.: 47-9 C [α]D= + 130"(C= 1,CHCI3).

EXAMPLE 18 2,2-Dimethyl-(7R)-(8S)-8-ethyl-9-oxo-3-oxa-6-thia- 1-azabicyclo [5.2. 0 1 7lnonane

To a stirred solution of di-iso-propylamine (40 ml, 0.276 mole) in anhydrous tetrahydrofurane (400 ml) is added a 15% n-BuLi solution in n-hexane (130 ml, 0.206 mole) dropwise at -70 C under N2.

After 15 min of additional stirring at -700C, a solution of 2,2-dimethyl-(7R)-9-oxo-3-oxa-6-thia-1 -azabicyclo [5.2.017]nonane (24.3 g, 0.130 mole) in tetrahydrofurane (150 ml) is added dropwise. The resulting yellowish solution is stirred at -70 C for 15 min and, then, quenched with the dropwise addition of an excess of ethyl bromide. The reaction mixture is allowed to reach the room temperature, then it is poured into ice-water and thoroughly extracted with CH2Cl2. The combined extracts are dried over Na2SO4 and evaporated in vacuo to give a residue which is crystallised from Et2O-n-hexane at 0 C to afford the title compound in 83% yield.

I.R. (CHCI3, cm-1): 1760 N.M.R. (CDC13, 5): 1.05 (3H, t, J = 7Hz) 1.51 (3H,s) 1.75 (3H, s) 1.89 (2H, m) 2.6-2.8 (2H, m) 2.9-3.5 (2H, m) 3.82 (1H, m) 5.05 (1 H, dd, J = 2.5 Hz) EXAMPLE 19 Z2-Dimeth yI-(7R)-(8S)-8-eth yl-9-oxo-3-oxa-6-thia- 1-azabicyclo [5.2. o- 7jnonane-6, 6-dioxide

To a stirred solution of 2,2-dimethyl-(7R)-(8S)-8-ethyl-9-oxo-3-oxa-6-thia-1-azabicyclo [5.2.0'-7]nonane (12 g, 0.056 mol) in 80% CH3COOH (400 ml) is added a solution of KMnO4 (17.60 g, 0.112 mole) in H2O (200 ml) dropwise at room temperature.After 2 hours of additional stirring the excess of KMnO4 is destroyed by adding H202, the precipitate is filtered off with filter aid and the filtrate is thoroughly extracted with CH2C12.

The combined extracts are washed with H2O, dried over CaCI2 and evaporated in vacuo to yield the solid title compound (11.8g).

I.R. (CHC13, cmw 1775, 1335, 1150, 1090.

EXAMPLE 20 (3S)-3-ethyl-(4RJ-4-('3-hydroxyethy/suIfonyI)azetidin-2-one

A solution of 2,2-dimethyl-(7R)-(8S)-8-ethyl-9-oxo-3-oxa-6-thia-1 -azabicyclo [5.2.017]nonane-6.6-dioxide (11.8 g) in CH3COOH (200 ml) and H20 (40 ml) is heated at reflux temperature for 105 min. The cooled resulting reaction mixture is evaporated in vacuo to yield the title compound (10.1 g).

EXAMPLE 21 (3S)-3-ethyl-(4R)-4-[α-tetrahydropyranylthio] azetidin-2-one

A mixture of (3S)-3-ethyl-(4R)-4-(ss-hydroxyethylsulfonyl)-azetidin-2-one (20.7 g, 0.1 mole) and 2tetrahydropyranthiol (12 g, 0.102 mole) [M.G. Missakian, R. Ketcham and A.R. Martin, J. Org. Chem., 39,2010 (1974)] in acetone (250 ml) is stirred with a 0.5 M NaOH aqueous solution (200 ml) during 1 hr at room temperature. The reaction mixture is saturated with NaCI and extracted with AcOEt several times. The combined extracts are washed with a saturated NaCI aqueous solution until neutral, dried over Na2SO4 and evaporated in vacuo to yield a residue which is purified by column chromatography on silica gel.Elution with toluene-hexane-AcOEt 70:25:25 gives the title product as an oil which crystallises on standing (19.3 g; 90% yield).

I.R. (CHCl3, cm 3300,2930, 2860, 1760.

N.M.R. (CDCl3, b): 1.04 (3H, t, J = 7 Hz) 1.60-1.90 (8H, br) 3.14(1 H, br m) 3.58(1 H, br m) 4.14 (1H, br m) 4.63 and 4.74(1 H, d, J = 2 Hz) 5.10 (1H, brm) 6.47 and 6.60(1 H, br, exchange with D2O) EXAMPLE 22 Methyl2-[(3'S)-3'-ethyl-(4'R)-4'[α-tetrahydropyranthio]-2'-oxo-azetidin- 1'-yl]-2- triphenylphosphoranylidene acetate

A mixture of (3S)-3-ethyl-(4R)-4-[a-tetrahydropyranthio]-azetidin-2-one (1 07 g, 5 mmole) and methyl glyoxylate (1 26 g, 12 mmole) in anhydrous tetrahydrofurane (40 ml) and anhydrous Et2O (10 ml) is cooled to 0-5"C under nitrogen atmosphere and treated with anhydrous triethylamine (0.70 ml, ~ 5 mmole).The obtained solution is stirred at room temperature for 24 hrs., diluted with AcOEt (50 ml), washed with a saturated NaCI aqueous solution (3x30 ml) and dried over Na2SO4. Evaporation of the solvent in vacuo yields an oil [1.1 g; IR (CHC6, cm-'): 3200 (broad), 2910,1760] which is dissolved in anhydrous tetrahydrofurane, cooled to -300C, treated under nitrogen atmosphere with pyridine (0.6 ml) and with the dropwise addition of a solution of thionyl chloride (0.45 ml) in anhydrous tetrahydrofurane (3 ml). The mixture is stirred at -20 C during 1/2 hr and at -5-0 C for additional 2 hrs. The precipitate is filtered and the filtrate is evaporated in vacuo from benzene several times.

The residue is dissolved in dry CH2Cl2 (50 ml), treated with triphenylphosphine (1.830 g) and stirred overnight at room temperature under N2 atmosphere. The solvent is evaporated in vacuo and the obtained residue is purified by column chromotography on silica gel, eluting initially with benzene/hexane AcOEt 70:25:25 and subsequently with benzene/hexane/AcOEt 70:10:40. The title compound is obtained as a white foam (1.36 g) I.R. (CHCl3, cm-1): 1740 EXAMPLE 23 Silver (3S)-3-ethyl- 1-methoxycarbonyltriphenylphosphoranylidenemethyl-2-oxo-azetidin-(4R)-4-yl thiolate

To a stirred solution of the phosphorane (561 mg, 1 mmole) in MeOH (6 ml), cooled with an external water bath is added a 0.25 M AgNO3 aqueous solution (4.2 ml) dropwise. After 5 min of additional stirring, the mixture is diluted with distilled water (5 ml) and carefully filtered by suction. The precipitate is washed with distilled water several times then with Et2O and dried on the filter. The yield is about 90%.

EXAMPLE 24 Methyl 2-[(3'S)-3-ethyl-(4'R)-4'-acetylthio-2'-oxo-azetidin- 1'-yl]-2-triphenylphosphoranylidene acetate

To a stirred solution of si Iver (3S)-3-ethyl-1-methoxycabonyltriphenylphosphoranylidenemethyl-2-oxo- azetidin-(4R)-4-yl thiolate (500 mg, 0.88 mmole) in acetonitrile (5 ml) is added acetyl chloride (1.32 mmole) dropwise. The mixture is stirred till the white AgCI precipitate separates neatly from the solution. This is then filtered through celite and washed liberally with AcOEt. The filtrate is washed with a saturated NaHCO3 aqueous solution (3x20 ml), and with a saturated NaCI aqueous solution (1 x20 ml), dried over Na2SO4 and evaporated in vacuo to yield a residue which is purified by flash column chromatography on silica gel.

Elution with benzene/hexane/AcOEt 70:25:25 yields 320 mg of the title compound.

EXAMPLE 25 Methyl (6S)-6-ethyl-(5R)-2-meth yI-2-p erem-3-carboxylate

A solution of methyl 2-[(3'S)-3-ethyl-(4' R)-4"-acetylthio-2'-oxo-azetidin-l '-yl]-2-triphenylphosphoranylidene acetate (320 mg) in toluene (150 ml) is heated at 85"-90"C during 10 hrs. under nitrogen atmosphere. The cooled mixture is absorbed on the top of a silica gel column and eluted with toiuene/AcOEt 19:1 to yield the title compound.

I.R.: (CHCI3, cm-1): 1780,1705 N.M.R. (CDC13, 5): 1.09 (3H, t, J = 7 Hz) 1.94 (2H, m, J = 7 Hz) 2.38 (3H, s) 3.69(1H, m,J = 7,1.7Hz) 3.85 (3H, s) 5.36(1H,d,J = 1.7 Hz) By proceeding analogously the following compounds are obtained: methyl (6S)-6-ethyl-(5R)-2-ethyl-2-penem-3-ca rboxylate; methyl(6S)-6-ethyl-(sR)-2-propyl-2-penem-3-ca rboxylate; methyl(6S)-6-methyl-(5R)-2-methyl-2-penem-3-carboxylate; methyl(6S)-6-methyl-(5R)-2-ethyl-2-penem-3-carboxylate; methyl(6S)-6-methyl-(5R)-2-propyl-2-penem-3-carboxylate; methyl(6S)-6-propyl-(5R)-2-methyl-2-penem-3-carboxylate; methyl(6S)-6-propyl-(5R)-2-ethyl-2-penem-3-carboxylate; methyl(6S)-6-propyl-(5R)-2-propyl-2-penem-3-carboxylate; EXAMPLE 26 p-nitrobenzyl-24r3'S)-3'-ethyl-(4'R)-4'-[a-tetrahydropyranylthioj-2'-oXo-azetidin- 1'-yl-2- triphenylphosphoranylidene acetate

To a solution of (3S)-3-ethyl-(4R)-4-[a-tetrahydropyranylthio]-azethidin-2-one (2.5 g, 11.6 mmole) in an anhydroustetrahydrofurane (100 ml) cooled to 100C is added anhydrous triethylamine (1.60 ml, 11.6 mmole) under nitrogen atmosphere, followed by the dropwise addition of a solution of p-nitrobenzylglyoxylate (5.63 g, 25 mmole) in anhydrous tetrahydrofurane (40 ml).After the addition is completed, the reaction mixture is stirred for 3 hrs. at room temperature and then it is quenched with a saturated NaCI aqueous solution (50 ml) and extracted with AcOEt (3x50 ml). The combined extracts are washed with a saturated NaCI aqueous solution (3x50 ml) and dried over Na2SO4.

Evaporation of the solvent in vacuo yields an oily residue [I.R. (film, cm-'): 3280 (broad), 2900, 1755] which is taken up in anhydrous tetrahydrofurane (150 ml), cooled under nitrogen atmosphere to -30"C, treated with dry pyridine (1.92 ml, 24 mmole) and with the dropwise addition of thionylchloride (1.45 ml, 20 mmole) dissolved in tetrahydrofurane (10 ml). The reaction mixture is stirred at 30aC during 1/2 hr. and at -5-O0Cfor additional 2 hrs. The precipitate is filtered and the filtrate is evaporated in vacuo from benzene several times.

The residue [I.R. (film, cm-'): 1760] is dissolved in dry CH2CI2 (150 ml) and stirred under nitrogen with triphenylphosphine (6.3 g, 24 mmole) overnight.

The solvent is evaporated in vacuo and the residue is purified by flash column chromatography on silica gel. Elution with benzene/hexane/AcOEt 70:25:25, yields the product as a yellowish foam (4.10 g).

I.R. (CHCl3,cm1): 1745.

EXAMPLE 27 Silver /3Sj-3-ethyl- 1-p-nitrobenzZloxycarbonyltriphenylphosphoranylidenemethyl-2-oXo-azetidin-{4R)-4-yl- thiolate

To a stirred solution of the phosphorane (900 mg, 1.35 mmole) in MeOH (6 ml) cooled with an external water bath a 0.25 M AgNO3 aqueous solution (6 ml) is added dropwise. After 5 min of additional stirring, the mixture is diluted with distilled water (5 ml) and carefuly filtered by suction. The precipitate is washed with distilled water several times, then with Et2O and dried on the filter. The yield is 920 mg.

EXAMPLE 28 p-nitrobenzyl2-f(3'S)-3-ethyl-(4'R)-4'.acetylthio-2'-oxo-azetidin- 1 '-yl]-2-triphenylphosphoranylidene acetate

To a stirred solution of silver (3S)-3-ethyl-1-nitrobenzyloxycarbonyltriphenylphosphoranylidenemethyl-2- oxo-azetidin-(4R)-4-yl thiolate (350 mg, 0.5 mmole) in acetonitrile (4 ml) is added acetyl chloride (0.8 mmole) dropwise. The mixture is stirred till the white AgCI precipitate separates neatly from the solution, then it is filtered through celite, washing liberally with AcOEt. The filtrate is washed with a saturated NaHCO3 aqueous solution (3x20 ml), with a saturated NaCI aqueous solution (1 x20 ml), dried over Na2SO4 and evaporated in vacuo to yield a residue which is purified by flash column chromatography on silica gel.

Elution with benzene/hexane/AcOEt 70:25:25 yields 195 mg, of the title compound.

I.R. (CHCI3, cm-1): 2900,1750,1705.

EXAMPLE 29 p-nitrobenzyl r6S)-6-ethyl-{5R)-2-methyl-2-penem-3-carboxylate

A solution of p-nitrobenzyl 2-[(3'S)-3-ethyl-(4R)-4'-acetylthio-2'-oxo-azetidin-1 '-yl]-2triphenylphosphoranylidene acetate (195 mg) in toluene (100 ml) is heated at85-900C under nitrogen atmosphere during 48 hrs.

The cooled mixture is adsorbed on the top of a silica gel column and eluted with toluene/AcOEt 19:1 to yield the title compound.

I.R. (CHC13, cm-'): 1790, 1710 N.M.R. (CDCl3, 5): 1.07 (3H,t, J = 7.0 Hz) 1.91 (2H, m, J = 7.0,7.0 Hz) 2.36 (3H, s) 3.69 (1 H, m, J = 7.0,2.0 Hz) 5.34 (2H, dd, J = 14.0 Hz) 5.36(1H,d,J = 2.0 Hz) 7.63 (2H, d, J = 8.0 Hz) 8.22 (2H, d, J = 8.0 Hz) By proceeding analogously the following compounds are obtained: p-nitrobenzyl(6S)-6-ethyl-(5R)-2-ethyl-2-penem-3-ca rboxylate; p-nitrobenzyl(6S)-6-ethyl-(5R)-2-propyl-2-penem-3-carboxylate; p-nitrobenzyl(6S)-6-methyl-(5R)-2-methyl-2-penem-3-carboxylate; p-nitrobenzyl(6S)-6-methyl-(5R)-2-ethyl-2-penem-3-carboxylate; p-nitrobenzyl(6S)-6-methyl(5R)-2-propyl-2-penem-3-carboxylate; p-nitrobenzyl(6S)-6-propyl-(sR)-2-methyl-2-penem-3-carboxylate; p-nitrobenzyl(6S)-6-propyl-(5R)-2-ethyl-2-penem-3-carboxylate; p-nitrobenzyl(6S)-6-propyl-(5R)-2-propyl-2-penem-3-carboxylate.

EXAMPLE 30 r65)-6-ethyl-65R)-2-methyl-2-penem-3-carboxy/ic acid

A mixture of p-nitrobenzyl (6S)-6-ethyl-(5R)-2-methyl-2-penem-3-carboxylate (30 mg), 0.2 M NaHCO3 aqueous solution (2 ml), AcOEt (3 ml) and 10% palladium/carbon catalyst (60 mg) is stirred in a Brown-type automatic hydrogenator until the intake of NaBH4 solution ceases. The catalyst is filtered off, the residue is washed with a saturated NaHCO3 aqueous solution and with AcOEt. The aqueous phase is separated, washed with CH2C12 acidified with a 5% citric acid aqueous solution and extracted with CH2C12 several times.

The organic extracts are dried over Na2SO4, filtered and concentrated in vacuo to yield the title compound.

I.R. (KBr, cms 3300,1770,1660.

By proceeding analogously the following compounds are obtained: (6S)-6-ethyl-(5R)-2-ethyl-2-penem-3-ca rboxyl ic acid; (6S)-6-ethyl-(5R)-2-propyl-2-penem-3-carboxylic acid; (6S)-6-methyl-(5R)-2-methyl-2-penem-3-carboxylic acid; (6S)-6-methyl-(5R)-2-ethyl-2-penem-3-carboxyl ic acid; (6S)-6-methyl-(5R)-2-propyl-2-penem-3-ca rboxyl ic acid; (6S)-6-propyl-(5R)-2-methyl-2-penem-3-ca rboxylic acid; (6S)-6-propyl-(5R)-2-ethyl-2-penem-3-carboxylic acid; (6S)-6-propyl-(5R)-2-propyl-2-penem-3-carboxylic acid; By the usual salification procedure the sodium salts of all the above carboxylic acids, including the title compound of Example 30, are obtained.

EXAMPLE 31 p-nitrobenzyl 2-f(3' S)-3'-ethyl-(4'R)-4'-acetoxyacetylthio-2'-oxo-azetidin- 1 '-yl7-2- triphenylphosphoranylidene acetate

By the same procedure described in the Example 28, using silver (3S)-3-ethyl-1-p- nitrobenzyloxycarbonyltriphenylphosphoranylidenemethyl-2-oxo-azetidin-(4R)-4-yl thiolate (340 mg, 0.49 mmole) and freshly distilled acetoxy acetyl chloride (0.75 mmole) 216 mg of the title compound are obtained.

EXAMPLE 32 p-nitrobenzyl (GSJ-6-ethyl- lSRl-2-acetoxy-meth yl--p enem3-carboxylate

A solution of p-nitrobenzyl 2-[(3'S)-3'-ethyl-(4'R)-4'-acetoxyacetylthio-2'-oXo-azetidin-1 '-yl]-2triphenylphosphoranylidene acetate (216 mg) in toluene (110 ml) is heated under nitrogen atmosphere at 85-90"C during 30 hrs.

The cooled mixture is adsorbed on the top of a silica gel column and eluted with toluene /AcOEt 19:1 to yield the title compound.

I.R. (CHC13, cm-'): 1780, 1740, 1710 U.V. (EtOH, nm): 266,322 N.M.R. (CDCl3, 5): 1.09 (3H, t, J = 8 Hz) 1.93(2H,m,J =8,7Hz) 2.13 (3H, s) 3.80 (1 H, dt, J = 7,2Hz) 5.32 (2H, centre of ABq, Jgem= 15 Hz) 5.37 (2H, centre of ABq, Jgem= 14 Hz) 5.45 (1 H, d, J = 2 Hz) 7.95 (4H, centre of ABq, J = 9 Hz) By proceeding analogously the following compounds are obtained: p-nitrobenzyl (6S)-6-methyl-(5R)-2-acetoxy-methyl-2-penem-3-carboxylate; p-nitrobenzyl(6S)-6-propyl-(5R)-2-acetoxy-methyl-2-penem-3-carboxylate; p-nitrobenzyl (6S)-6-methyl-(5R)-2-propionyloxy-methyl-2-penem-3-carboxylate; p-nitrobenzyl (6S)-6-ethyl-(5R)-2-propionyloxy-methyl-2-penem-3-carboxylate; p-nitrobenzyl(6S)-6-propyl-(5R)-2-propionyloxy-methyl-2-penem-3-carboxylate.

EXAMPLE 33 p-nitrobenzyl 2-[{3'5)-3'-ethyl-r4'R)-4'-thien-2"-ylacetylthio-2'-oXo-azetidin- l ylJ-2- triphenylphosphoranylidene acetate

Proceeding by the same method of the Example 28, and using silver (3S)-3-ethyl-1-pnitrobenzyloxycarbonyltriphenylphosphoranylidenemethyl-2-oxo-azetidin-(4R)-4-yl thiolate (350 mg, 0.506 mmole) and freshly distilled thien-2-yl acetyl chloride (0.9 mmole) 224 mg of the title compound are obtained.

I.R.(CHCI3,cm-1): 1750,1680.

EXAMPLE 34 p-nitrobenzyl (6S)-6-ethyl-{5R)-2-thien-2'-yl-methyl-2-penem-3-carboxylate

A solution of p-nitrobenzyl 2-[(3'S)-3'-ethyl-(4'R)-4'-thien-2M-ylacetylthio-2'-oXo-azetidin-1 '-yl]-2triphenylphosphoranylidene acetate (224 mg) in toluene (110 ml) is heated at 85-90"C under nitrogen atmosphere during 24 hrs. The cooled mixture is adsorbed on the top of a silica gel column and eluted with toluene /AcOEt 19:1 to yield the title compound.

I.R. (CHCl3, cm-'): 1785, 1710, 1605, 1580, 1520 U.V. (EtOH, nm): 241,264,381 N.M.R. (CDCl3, 5): 1.04 (3H,t, J = 7 Hz) 1.89(2H,m,J =7,8Hz) 3.82 (1 H, dt, J = 8,1.8 Hz) 4.38 (2H, centre of ABq, Jgem= 17 Hz) 5.33(1H,d,J= 1.8 Hz) 5.40 (2H, centre of ABq, Jgem= 14 Hz) 6.95 and 7.24 (3H, m) 7.95 (4H, centre of ABq, Jgem= 9 Hz) By proceeding analogously the following compounds are obtained: p-nitrobenzyl(6S)-6-methyl-(5R)-2-thien-2'-yl-methyl-2-penem-3-carboxylate; p-nitrobenzyl(6S)-6-propyl-(5R)-2-thienyl-2'-yl-methyl-2-penem-3-carboxylate.

EXAMPLE 35 (6S)-6-ethyl-(5R)-24hien-2'-y!-methyl-2-penem-3-carboxyllc acid

A mixture ofp-nitrobenzyl (6S)-6-ethyl-(5R)-2-thien-2'-ylacetylthio-2-penem-3-carboxylate (35 mg), 0.2 M aqueous NaHCO3 solution (2.5 ml), AcOEt (4 ml) and 10% palladium/carbon catalyst (80 mg) is stirred in a Brown-type automatic hydrogenator until the intake of NaHCO3 solution ceases. The catalyst is filtered off and the residue is washed with a saturated NaHCO3 aqueous solution and with AcOEt.

The aqueous phase is separated, washed with CH2C12, acidified with a 5% citric acid aqueous solution and extracted with CH2C12 several times. The organic extracts are dried over Na2SO4, filtered and concentrated in vacuo to yield the title compound.

U.V. (EtOH, nm): 233,313 By proceeding analogously the following compounds are obtained: (6S)-6-methyl-(5R)-2-thien-2'-yl-methyl-2-penem-3-carboxyl ic acid; (6S)-6-propyl-(5R)-2-thien-2'-yl-methyl-2-penem-3-carboxylic acid.

By the usual esterification and salifaction procedures the methyl and ethyl esters and the sodium salts of all the carboxylic acids obtained in the above Example 35 were prepared, in particular: methyl(6S)-6-ethyl-(5R)-2-thien-2'-yl-methyl-2-penem-3-carboxylate methyl(6S)-6-methyl-(5R)-2-thien-2'-yl-methyl-2-penem-3-carboxylate methyl(6S)-6-propyl-(5R)-2-thien-2'-yl-methyl-2-penem-3-carboxylate.

EXAMPLE 36 p-nitrobenzyl 2-f(3' S)-3' -eth yl-(4'R)-4'-ethoxycarbon ylcarbonylthio-2 '-oxo-azetidin- 1 '-ylJ-2- triphenylphosphoranylidene acetate

Proceeding by the same method described in the Example 28, and using silver (3S)-3-ethyl-1-p nitrobenzyloxycarbonyltriphenyl phosphoranylidenemethyl-2-oxo-azetidin-(4R)-4-yl thiolate, (380 mg, 0.55 mmole) and commercial ethyl oxalyl choride (0.9 mmole) 255 mg of the title product are obtained.

EXAMPLE 37 p-nitrobenzyl(6S)-6-ethyl-(5R)-2-ethoxycarbon yl-2-penem-3-carboxylate

A solution of p-n itrobenzyl 2-[(3'-ethyl-(4' R)-4'-eth oxyca rbo nylca rbo nylth io-2'-oxo-azetidi n-l'yl]-2- triphenylphosphoranylidene acetate (255 mg) in toluene (125 ml) is kept under nitrogen atmosphere overnight, then heated at 80"C for few minutes.

The cooled mixture is absorbed on the top of a silica gel column and eluted with toluene/AcOEt 19:1 to yield the title compound.

I.R. (CHCl3, cm 1790, 1735, 1725 U.V. (EtOH, nm): 264,336 N.M.R. (CDCl3 b): 1.09 (3H, t, J = 8 Hz) 1.27 (3H, t, J = 7 Hz) 1.92 (2H, m, J = 8, 7 wiz) 3.92 (1H, dt,J =7,2Hz) 4.27 (2H, q, J = Hz) 5.38 (2H, collapsed ABq, Jgem - 1 Hz) 5.44(1H,d,J = 2 Hz) 7.93 (4H, centre of ABq, J = 8 Hz).

By proceeding analogously the following compounds are obtained: p-nitrobenzyl(6S)-6-methyl-(5R)-2-ethoxycarbonyl-2-penem-3-carboxylate; p-nitrobenzyl(6S)-6-propyl-(5R)-2-ethoxycarbonyl-2-penem-3-carboxylate; p-nitrobenzyl(6S)-6-methyl-(5R)-2-methoxycarbonyl-2-penem-3-carboxylate; p-nitrobenzyl (6S)-6-ethyi-(5R)-2-methoxycarbonyl-2-penem-3-carboxylate; p-nitrobenzyl(6S)-6-propyl-(5R)-2-methoxycarbonyl-2-penem-3-carboxylate; p-nitrobenzyl (6S)-6-methyl-(5R)-2-propxycarbonyl-2-penem-3-carboxylate; p-nitrobenzyl (6S)-6-ethyl-(5R)-2-propoxycarbonyl-2-penem-3-carboxylate; p-nitrobenzyl (6S)-6-propyl-(5R)-2-propoxycarbonyl-2-penem-3-carboxylate.

EXAMPLE 38 {6S)-6-ethyl-(5RJ-2-ethoxycarbonyl-2-penem-3-carboxylic acid

A mixture of p-nitrobenzyl (6S)-6-ethyl-(5R)-2-ethoxycarbonyl-2-penem-3-carboxylate (45 mg), 0.2 M NaHCO3 aqueous solution (3 ml), AcOEt (4 ml) and 10% palladium/carbon catalyst (100 mg) is stirred in a Brown-type automatic hydrogenator till 3 equivalents of hydrogen are adsorbed. The catalyst is filtered off, the residue is washed with a saturated NaHCO3 aqueous solution, and with AcOEt. The aqueous phase is separated, washed with CH2C12, acidified with a 5% citric acid aqueous solution and extracted with CH2C12 several times.

The organic extracts are dried over Na2SO4, filtered and evaporated in vacuo to yield the title compound.

U.V. (EtOH,nm) : 259,336.

By proceeding analogously the following compounds are obtained: (6S)-6-methyl-(5R)-2-ethoxycarbonyl-2-penem-3-carboxylic acid; (6S)-6-propyl-(5R)-2-ethoxycarbonyl-2-penem-3-carboxylic acid; (6S)-6-methyl-(5R)-2-methoxycarbonyl-2-penem-3-carboxylic acid; (6S)-6-ethyl-(5R)-2-methoxycarbonyl-2-penem-3-carboxylic acid; (6S)-6-propyl-(5R)-2-methoxycarbonyl-2-penem-3-carboxylic acid; (6S)-6-methyl-(5R)-2-propoxycarbonyl-2-penem-3-carboxylic acid; (6S)-6-ethyl-(5R)-2-propoxywarbonyl-2-penem-3-carboxylic acid; (6S)-6-propyl-(5R)-2-propoxycarbonyl-2-penem-3-carboxylic acid; By the normal esterification and salification procedures the methyl esters and the sodium salts of all the carboxylic acids obtained in the above Example 38 were prepared in particular:: methyl (6S)-6-ethyl-(5R)-2-ethoxyca rbonyl-2-penem-3-carboxyl ate; methyl(6S)-6-methyl-(5R)-2-ethoxycarbonyl-2-penem-3-carboxylate; methyl(6S)-6-propyi-(5R)-2-ethoxywarbonyl-2-penem-3-carboxylate; methyl(6S)-6-methyl-(5R)-2-methoxycarbonyl-2-penem-3-carboxylate; methyl(6S)-6-ethyl-(5R)-2-methoxywarbonyl-2-penem-3-carboxylate; methyl(6S)-6-propyl-(5R)-2-methoxycarbonyl-2-penem-3-carboxylate; methyl(6S)-6-methyl-(5R)-2-propoxywarbonyl-2-penem-3-carboxylate; methyl(6S)-6-ethyl-(5R}-2-propoxycarbonyl-2-penem-3-carboxylate; methyl(6S)-6-propyl-(5R)-2-propoxywarbonyl-2-penem-3-carboxylate.

EXAMPLE 39 Acetonyl 2{63' S)-3'-ethyl-64'R)-4'-[a-tetraDydropyranylthiol-2'-oXo-azetidin- 1 '-yll-2- triphenylphosphoranylidene acetate

To a solution of (3S)-3-ethyl-(4R)-4-[a-tetrahydropyranylthio]azetidin-2-one (861 mg, 4 mmole) and of acetonyl glyoxylate (1.4 g, 9.45 mmole) in anhydrous tetrahydrofurane (50 ml) is added an hydros triethylamine dropwise under nitrogen atmosphere.

When the organic solution reacts neutrally or slightly basic, more triethylamine (0.6 ml, 4.5 mmole) is added and the mixture is stirred at room temperature during 24 hrs. The reaction is then quenched with a saturated NaCI aqueous solution (25 ml) and extracted with AcOEt (3x25 ml). The combined extracts are washed with a saturated NaCI aqueous solution (3x25 ml) and dried over Na2SO4.

Evaporation of the solvent in vacuo yields an oily residue (900 mg) which is taken up in anhydrous tetrahydrofurane (30 ml), cooled under nitrogen atmosphere to -30"C, treated with dry pyridine (0.54 ml) and with the dropwise addition of thionyl chloride (0.34 ml) dissolved in tetrahydrofurane (5 ml).

The reaction mixture is stirred at -30 C during 1/2 hr. and at -5-O"C for additional 2 hrs. The precipitate is filtered off and the filtrate is evaporated in vacuo from benzene several times.

The residue (900 mg) is dissolved in dry CH2Cl2 (30 ml) and stirred under nitrogen atmosphere with triphenylphosphine (1.8 g) during 19 hrs. at room temperature. The solvent is evaporated in vacuo and the residue is purified by column chromatography on silica gel. The product is eluted by benzene/hexane/AcOEt 70:25:25 and obtained as a white foam (1.03 g), after evaporation of the elution solvent.

EXAMPLE 40 Silver (3S)-3-eth yl- 1-acetonyloxycarbon yltriphen ylphosphoranylldenemeth yl-2-oxo-azet'din-(4R)yl- thiolate

To a stirred solution of the phosphorane (257 mg, 0.44 mmole) in MeOH (3 ml) cooled with an external water bath is added a 0.25 M Ag NO3 aqueous solution (2 ml) dropwise. After 5 min. of additional stirring, the mixture is diluted with distilled water (3 ml) and carefully filtered by suction. The precipitate is washed with distilled water several times, then with Et2O and dried on the filter. The yield is 250 mg.

EXAMPLE 41 Acetonyl 2-f(3'S)-3'-ethyl-(4'R)-4'-acetoxyacetylthio-2'-oxo-azetidin- 1 '-yU-2-triphenylphosphoranylldene acetate

By proceeding as described in the Example 28, and using silver (3S)-3-ethyl-1 acetonyloxycarbonyltriphenylphosphoranylidenemethyl-2-oxo-azetidin-(4R)-4-yl4hiolate (220 mg, 0.36 mmole) and freshly distilled acetoxy acetyl chloride (0.6 mmole) 143 mg of the title compound are obtained.

EXAMPLE 42 Aceton yl (6S)-6-eth yl-(5R)-2-acetoxymeth yl-2-penem-3-carb oxylate

A solution of acetonyl 2-[(3'S)-3'-ethyl-(4'R)-4'-acetoxyacetylthio-2'-oXo-azetidin-1 '-yl]-2triphenylphosphoranylidene acetate (143 mg) in toluene (80 ml) is heated at 85-90 C under nitrogen atmosphere for 24 hrs. The cooled mixture is absorbed on the top of a silica gel column and eluted with toluene/AcOEt 19:1 to yield the title compound.

I.R. (CHC13, cm-l: 1790,1745,1715 U.V. (EtOH, nm): 323.

N.M.R. (CDCl3, 5): 1.03 (3H, t, J = 7 Hz) 1.94(2H, m,J = 7,8Hz) 2.06 (3H, s) 2.16 (3H, s) 3.67 (1H, dt,J = 8,2Hz) 4.67 (2H, s) 5.17 (2H, centre of ABq, J = 15 Hz) 5.30 (1 H, d, J = 2 Hz) By proceeding analogously the following compounds are obtained; acetonyl (6S)-6-methyl-(5R)-2-acetoxy-methyl-2-penem-3-carboxylate; acetonyl(6S)-6-propyl (5R)-2-acetoxy-methyl-2-penem-3-carboxylate; acetonyl(6S)-6-methyl-(5R)-2-propionyloxy-methyl-2-penem-3-carboxylate; acetonyl(6S-6-ethyl-(5R)-2-propionyloxy-methyl-2-penem-3-carboxylate; acetonyl(6S)-6-propyl-(5R)-2-propionyloxy-methyl-2-penem-3-carboxylate.

EXAMPLE 43 {6S)-6-ethyl-05R)-2-acetoxymethyl-2-penem-3-carboxylic acid

To a stirred solution of acetonyl (6S)-6-ethyl-(5R)-2-acetoxymethyl-2-penem-3-carboxylate (15 mg) in acetonitrile (5 ml) and water (1 ml) is added a 0.1 M NaOH aqueous solution (1 eq.) during 20 min. at 0 C under nitrogen atmosphere. The mixture if stirred for additional 10 min, then washed with CH2Cl2. The aqueous phase is separated, acidifed with a 5% citric acid aqueous solution and extracted with CH2C12 several times.

I.R. (CHCl3, cm 3300, 1775, 1745, 1680 U.V. (EtOH, nm): 254,315 N.M.R. (CDC6, b): 1.07 (3H, t, J = 8 Hz) 1.92(2H,m,J = 8 Hz) 2.13 (3H, s) 3.78(1H,dt,J =8,2Hz) 5.10 (2H, centre of ABq, Jgem= 14 Hz) 5.43 (1 H, d, J = 2 Hz) 9.16 (1H, br, exchange with D2O).

By proceeding analogously the following compounds are obtained: (6S)-6-methyl-(5R)-2-acetoxy-methyl-2-penem-3-carboxylic acid; (6S)-6-propyl-(5R)-2-acetoxy-methyl-2-penem-3-carboxylic acid; (6S)-6-methyl-(5R)-2-propionyloxy-methyl-2-penem-3-carboxylic acid; (6S)-6-ethyl-(5R)-2-propionyloxy-methyl-2-penem-3-carboxylic acid; (6S)-6-propyl-(5R)-2-propionyloxy-methyl-2-penem-3-carboxylic acid.

By the usual esterification and salification procedures the methyl and ethyl esters and the sodium salts of all the carboxylic acids obtained in the above Example 43 are prepared, in particular: methyl(6S)-6-ethyl-(5R)-2-acetoxy-methyl-2-penem-3-carboxylate; methyl(65)-6-methyl-(5R)-2-acetoxy-methyl-2-penem-3-carboxylate; methyl(6S)-6-propyl-(5R)-2-acetoxy-methyl-2-penem-3-carboxylate; methyl(6S)-6-methyl-(5R)-2-propionyloxy-methyl-2-penem-3-carboxylate; methyl(6S)-6-ethyl-(5R)-2-propionyloxy-methyl-2-penem-3-carboxylate; methyl(6S)-6-propyl-(5R)-2-prionyloxy-methyl-2-penem-3-carboxylate.

EXAMPLE 44 2,2,5,5-tetramethyl-(7R)-(8S)-8-acetyl-9-oxo-3-oxa-6thia- 1-azabicyclof5.2. 0tt71nonane

To a solution of di-iso-propylamine(2.02 g, 2.8 ml, 20 mmole) in anhydrous THF (15 ml) is added a 15% n-BuLi solution in hexane (9.5 ml, 15 mmole) during 15 min under stirring and N2 atmosphere at -700C. After 15 min of additional stirring, a solution of 2,2,5,5-tetramethyl-(7R)-9-oxo-3-oxa-6-thia-1- azabicyclo [5.2.0,7]nonane (1.40 g, 5.5 mmole) in THF (5 ml) is added during 15 min. The resulting reaction mixture is stirred at -70 C for 30 min, then it is treated with the dropwise addition of a solution of AcOEt (5 ml, 4.5 g, 50 mmole) in THF (5 ml).

After the addition is over, the mixture is stirred for 15 min at -70 C, for 1 hr at 0 C and then it is worked up by adding cold water (75 ml) and by extracting with CH2C12 (5x50 ml). The combined organic extracts are dried over Na2SO4 and evaporated in vacuo to yield a yellowish oil which is chromatographed over silica gel (50 g). Elution with CGHdAcOEt 95:5 gives the crystalline title product (1.04 9,62%) m.p. 65-72"C.

[a]D= = + 111.9 (C=1,CHCI3).

I.R. (CHCl3, cm1): 1750, 1720 N.M.R. (CDCl3 b): 1.22 (3H, s) 1.47 (3H, s) 1.57 (3H, s) 1.71 (3H,s) 2.33 (3H, s) 3.65(1H,d,J = 13 Hz) 3.91 (1 H, d, J = 2.5 Hz) 4.11 (1H,d,J = 13 Hz) 5.70 (1H, d,J = 2.5 Hz) EXAMPLE 45 2,2,5,5tetramethyl-(7R)-(8S)-8-[1'-(1' S)-hydroxyethyl]-9-oxo-3-oxa-6-thia- 1-azabicyclo[5.2.0,7]nonane

To a stirred 1 M THF solution of commercial Li-Selectride (3 ml, 3 mmole) cooled at -78"C is added 2,2,5-tetramethyl-(7R)-(8S)-8-acetyl-9-oxo-3-oxa-6-thia-1-azabicyclo[5.2.07]nonane (535 mg, 2.08 mmole) in THF (8 ml) dropwise and under N2.The resulting reaction mixture is stirred at -78"C for further 3 hrs and then it is quenched with H2O (1 ml) and 30% H202 (3 ml). After 1 hr of additional stirring at 0 C, the mixture is diluted with H2O (30 ml) and extracted with CH2CI2 (5x50 ml). The combined extracts are dried over CaCI2 and evaporated in vacuo to yield a solid residue which is chromatographed on silica gel (20 g). Elution with C6H6-AcOEt 95:5 affords unreacted starting material (160 mg, 11%). Elution with C6H6-AcOEt 90:10 affords the title product (355 mg, 66%) m.p.: 97-102"C.

Elemental analysis (calculated for C12H21NO3S): C 55.55 (55.57) H 8.12 (8.16) N 5.38(5.40) S 12.07 (12.36) [α]D= + 111.16 (C=0.8, CHCl3) I.R. (CHCl3, cm-1): 3400, 1740 N.M.R.(CDCl3,#) 1.21 (3H,s) 1.35 (3H, d, J = 7 Hz) 1.49 (3H, s) 1.55 (3H, 5) 1.71 (3H, s) 2.68 (1 H, br d, J = 5 Hz, exchange with D2O) 2.88(1 H, dd, J = 2, 5.25 Hz) 3.60(1H,d,J = 12 Hz) 4.16 (1H, d,J = 12 Hz) 4.17 (1H, br m) 5.02(1H,d,J = 2 Hz).

EXAMPLE 46 2,2,5,5-tetramethyl-(7R)-(8S)-[1'-( 1'R)-hydroxyethyl]-9-oxo-3-oxa-6-thia- 1-azabicyclo[5.2.0,7]nonane.

To a stirred 0.5 M THF solution of commercial K-Selectride (20 ml, 10 mmole) is added 2,2,5,5-tetramethyl (7R)-(8S)-8-acetyl-9-oxo-3-oxa-6-thia-1-azabicyclo[5.2.0,7]nonane( (1.44 9, 5.6 mmole) in anhydrous Et2O (125 ml) dropwise under N2 and at room temperature. The reaction mixture is stirred for 20 hrs and then it is worked up as in the example 45. The resulting residue is chromatographed on silica gel (50 g). Elution with C6H6-AcOEt 95:5 affords unreacted starting material (397 mg).

Elution with C6H6-AcOEt 90:10 affords the title compound (602 mg).

m.p.126-130 C [a] = +80 (c=1, CHCl3) I.R. (CHCl3, cm 3600,3460, 1740 N.M.R. (CDCl3, o) 1.18 (3H, s) 1.27 (3H, d, J = 6 Hz) 1.47 (3H, s) 1.58 (3H, s) 1.67 (3H, s) 2.85 H, dd, J = 2.2,4.0 Hz) 3.60(1H,d,J = 12 Hz) 3.62(1 H, br, exchange with D2O) 4.09(lH,d,J = 12 Hz) 4.22 (1H, br) 5.17(lH,d,J = 2.2 Hz).

EXAMPLE 47 2,2,5,5-tetramethyl-(7R)-(8S)-[1'-(1'R)-p-nitrobenzyloxycarbonyloxyethyl]-9-oxo-3-oxa-6-thia- 1-azabicyclo- [5.2.0,7]nonane.

To a stirred solution of 2,2,5,5-tetramethyl-(7R)-(8S)-[1 '-(1 'R)-hydroxyethyl]-9-oxo-3-oxa-6-thia-1 -azabicyclo- [5.2.0171nonane (1.50 9, 5.78 mmole) in EtOH-free CH2 Cl2 (30 ml) cooled to -15"C is added pnitrobenzylchloroformate (1.66 9, 7.7 mmole) followed by the addition of 4-N,N-dimethylaminopyridine (940 mg, 7.7 mmole) during 30 min. The reaction mixture is stirred at room temperature for additional 18 hrs, diluted with CH2Cl2 (150 ml), washed with a saturated NaCI aqueous solution (2x50 ml) and dried over Na2SO4. Evaporation of the solvent leaves a residue which is chromatographed in silica gel (100 9).

Elution with C6H6-AcOEt 97.5:2.5 affords the title product as a yellow oil (2.20 9,87%), I.R. (CHCI3, cm-1): 1750, 1520, 1350.

EXAMPLE 48 2,2,5,5-tetramethyl-(7R)-(8S)-[1'-(1'R)-p-nitrobenzyloxycarbonyloxyethyl]-9-oxo-3-oxa-6-thia- 1-azabicyclo [5.2.0,7]nonane-S,S-

To a stirred solution of 2,2,5,5-tetramethyl-(7R)-(8S)-[1 '-(1 'R)-p-nitrobenzyloxycarbonyloxyethyl]-9-oxo-3- oxa-6-thia-1-azabicyclo[5.2.01 7]nonane (2.20 g, 5.0 mmole) in CH2Cl2 (30 ml), cooled with a crushed ice/NaCI bath, is added m-chloroperbenzoic acid (12.5 mmole) at small portions with stirring. The resulting reaction mixture is stirred in the cold for 1 hr and at room temperature for additional 30 min.After dilution with CH2Cl2 (150 ml), the solution is washed with a 8% NaHCO3 aqueous solution (1 x50 ml), with a 10% NaHCO3 aqueous solution (1 x50 ml), with a 8% NaHCO3 aqueous solution (1 x50 ml), with a saturated NaCI aqueous solution (1 x50 ml) and dried over Na2SO4. Evaporation of the solvent in vacuo yields a non crystalline solid (2.3 g, 98%).

I.R. (CHCl3, cm-'): 1775, 1750, 1520 N.M.R. (CDCl3 b) 1.31 (3H, s) 1.45(3H,d,J = 7 Hz) 1.46 (3H, s) 1.55 (3H, s) 1.69 (3H, s) 3.44(lH,d,J = 14 Hz) 3.78(1 H, dd, J = 2.2 4.2 Hz) 4.16(1H,d,J = 14Hz) 4.92 (1H,d,J = 2.2 Hz) 5.27 (2H, s) 5.29 (1H, m) 7.51 (2H, d, J = 8 Hz) 8.22 (2H, d, J = 8 Hz) EXAMPLE 49 (3S)-3-[1'-(1'R)-p-nitrobenzyloxycarbonyloxyethyl]-(4R)-4-(α, α-dimethyl-3-hydroxyethylsulfonyl) azetidin-2one

With a procedure similar to that described in the example 20 the title compound is obtained.

I.R. (CHCl3, cm-1): 3400, 1780, 1750 N.M.R.(CDCl3,#) 1.31 (3H,s) 1.42 (3H, s) 1.45 (3H, d, J = 7 Hz) 3.60(1H,d,J = 12 Hz) 3.82 (1 H, dd, J = 2 Hz) 3.91 (1H,d,J = 12 Hz) 5.02 (1H, d,J = 2 Hz) 5.24 (2H, s) 5.26 (iH, m) 7.38(1 H, br) 7.52 (2H, d, J = 8 Hz) 8.18(2H,d,J = 8 Hz) EXAMPLE 50 (3S)-3-f1 '-(1 'R)-p-nitrobenzy/oxycarbonyloxyethy/1-(4R)-4-(a-tetrahydrop yranylthio)azetidin-2-one

With a procedure similar to that described in the Example 21, the title compound is obtained.

[α]D: + 52 (C=1, CHCl3) I.R. (CHCl3, cm-1): 3400, 2940, 2860, 1775, 1750 N.M.R. (CDCl3, 5) 1.45 (3H, d, J = 6.5 Hz) 1.3-2.1 (6H, m) 3.25 - 3.70 (2H, m) 4.04(1 H, m) 4.92 and 5.00 (1 H, dd, J = 7.2 Hz) 5.0 - 5.3 (2H, m) 5.27 (2H, s) 6.52 and 7.02 (1 H, br) 7.55 (2H, d, J = 8 Hz) 8.23 (2H, d, J = 8 Hz) EXAMPLE 51 p-nitrobenzyl 2-[(3'S)-3'-[(1"R)- 1"p-nitrobenzyloxycarbonyloxyethyl]-(4'R)-4'-(α-tetrahydropyranylthio)2' oxo-azetidin- 1 '-yl's-2-triphenylphosphoranylidene acetate

With a procedure similar to that described in the Example 25, the title compound is obtained as a non crystalline solid.

I.R. (CHCl3, cm-1): 1750,1745.

EXAMPLE 52 Silver (3S)-3-f(1 'RJ- 1 '-p-nitrobenzyloxycarbonyloxyethyll- 1-p-nitrobenzyloxycarbonyltriphenyl- phosphoranylidene-methyl-2-oxo-azetidin-(4R)-4-yl thiolate

With a procedure similar to that described in the Example 27, the title salt is obtained.

EXAMPLE 53 p-nitrobenzyl 2-[(3'S)-3'-[(1"-R)- 1"-p-nitrobenzyloxycarbonyloxyethyl]-(4'R)-4'thien-2"-ylacetylthio-2'-oxo- azetidin- 1'-yl]-2-triphenylphosphoranylidene acetate

Proceeding by the same method of the Example 33, the title compound is obtained in 65% yield.

EXAMPLE 54 p-nitrobenzyl (6S)-6-[(1'R)-1'-p-nitrobenzyloxycarbonyloxyl-2-thien-2'-yl-methyl-2-penem-3-carboxylate

Proceeding by the same method of the Example 34, the title compound is obtained in 70% yield.

I.R. (CHCI3, cm-1): 1790, 1750, 1710 N.M.R. (CDC13, 5) 1.48 (3H, d, J = 6.5 Hz) 3.91 H, dd, J = 7.2, 1.8 Hz) 4.36 (2H, ABq, J = 16 Hz) 5.24 (2H, bs) 5.38 (2H, ABq) 5.59 (1 H, d, J = 1.8 Hz) 6.93 (2H, m) 7.21(1H, dd) 7.56 (4H, m) 8.20 (4H, d)

Claims

1. A process for the preparation of an optically active trans-6-substituted-5(R)-2-penem-3-carboxylic acid derivative of formula (I)

wherein R and R, are equal or different organic groups and R2 is hydrogen, a cation or a carboxy protecting group, the process comprising: a) reacting an optically active 4(R)-azetidin-2-one-derivative of formula (II)

wherein R is as defined above and each group R3 is, independently, hydrogen or C1-C6 alkyl, with a thiol of formula A-SH wherein A is a residue making the S-A bond liable to the heterolytic action of soluble metal salts or of halogens, or a salt thereof, so obtaining an optically active 4(R)-thio-derivative of formula (Ill)

wherein A and R are as defined above; b) reacting a 4(R) compound of formula (III) with a glyoxylic acid derivative of formula OHC - COOR2 wherein R2 is as defined above so obtaining a 4(R)-derivative of formula (IV)

wherein R, A and R2 are as defined above; c) halogenating a 4(R)-carbinol of formula (IV) so obtaining a compound of formula (V)

wherein R, A and R2 are as defined above and X is a halogen atom; d) reacting a 4(R)-compound of formula (V) with a phosphine of formula P#3 wherein each of the groups 91 is, independently, an aromatic, heterocyclic or alkyl radical, so obtaining a 4(R)-phosphorane of formula (Vl)

wherein RA, R2 and 0 are as defined above; e) reacting a 4(R)-phosphorane of formula (VI) with a solution of a heavy metal salt of formula M"+ - Y"- wherein M"+ represents the cation of a heavy metal M of n valency and Y"- represents the anionic residue of the salt, so obtaining a 4(R)-mercapto salt of formula (VII)

wherein R, R2, , and Mn+ are as defined above; f) reacting a 4(R)-mercapto salt of formula (VII) with a reactive derivative of an acid or thioacid of formula

wherein R1 is as defined above and t is oxygen or sulphur so obtaining a 4(R)-derivative of formula (VIII)

wherein R, R1, R2, 9 and ,0 are as defined above; and g) cyclizing a 4(R)-compound of formula (VIII), and, if desired, salifying an obtained compound of formula (I) wherein R2 is hydrogen and/or, if desired, esterifying a compound of formula (I) wherein R2 is hydrogen or a cation and/or, if desired, obtaining a compound of formula (I) wherein R2 is hydrogen or a cation from one in which R2 is a carboxy protective group and/or, if desired, converting a compound of formula (I) into another compound of formula (I).

2. A process for the preparation of an optically active trans-6-substituted-5(R)-2-penem-3-carboxylic acid derivative having the formula (I) as defined in claim 1, comprising reacting a mercapto salt having the formula (VII) reported above in claim 1 with a reactive derivative of an acid orthioacid of formula

wherein R1 and 9 are as defined in claim land cyclizing the resulting compound having the formula (VIII).

3. A process according to claims 1 and 2 wherein the residue A characterizing the thiol A-SH and the compounds of formulae (Ill), (IV), (V) and (Vl) is a residue chosen from dimethyltert-butylsilyl, trityl, a-methoxy-ethyl, tetrahydropyran-2-yl, 4-methoxy-tetrahydropyran-4-yl, 2-oxa-bicyclo[3.3.0]octan3-yl and 2-oxa-bicyclo[3.3.0]oct-6,7-en-3-yl.

4. A process according to claim 1 and 2 wherein the metal cation M"+ characterizing the metal salt Mn±Yn- and the mercapto salt of formula (VII) is a cation of a heavy metal chosen from Ag, Hg, Au, Cu and Pb.

5. A 4(R)-compound having the formula (VIII) as defined in claim 1.

6. A process for the preparation of a 4(R)-compound having the formula (VIII) as defined in claim 1 comprising reacting a 4(R)-mercapto salt having the formula (VII) as defined in claim 1 with a reactive derivative of an acid orthioacid of formula

wherein R, and 14 are as defined in claim 1.

7. A process according to claim 6 wherein the 4(R)-mercapto salt of formula (VII) is the salt of a heavy metal chosen from Ag, Hg, Au, Cu and Pb.

8. A 4(R)-mercapto salt having the formula (VII) as defined in claim 1.

9. A 4(R)-mercapto salt according to claim 8 having the formula (VIIA)

wherein R2, r M and n are as defined above in claim 1, Rx is the residue of an acyl group and the carbon atom carrying the hydroxy group is in the R-configuration.

10. A 4(R)-mercapto salt according to claim 8 having the following formula (VIIB)

wherein R2, , M and n are as defined in claim 1, Rx is the residue of an acyl group and the carbon atom carrying the hydroxy group is in the S-configuration.

11. A 4(R)-compound according to claims 9 and 10 wherein Rx is C1-C6 alkyl or phenyl.

12. A 4(R)-compound according to claims 9 and 10 wherein Rx is methyl.

13. A compound of claims 8 to 12 wherein the salt is the salt of a heavy metal chosen from Ag, Hg, Au, Cu and Pb.

14. A process for the preparation of 4(R)-mercapto salt of formula (VII), as defined in any one of claims 8 to 13 comprising reacting a 4(R)-phosphorane having the formula (Vl) reported above in claim 1 with a solution of a heavy metal salt of formula Mn±Yn- wherein Mn+ and yn- are as defined above in claim 1.

15. A 4(R)-compound having the formula (Vl) as defined in claim 1.

16. A 4(R)-compound having the formula (Vl) as defined in claim 1, having the formula (VIA)

wherein R2, A and , are as defined in claim 1, Rx is the residue of an acyl group and the carbon atom carrying the hydroxy group is in the R-configuration.

17. A 4(R)-compound having the formula (Vl) as defined in claim 1, having the formula (VlB)

wherein R2, A and are as defined in claim 1, Rx is the residue of an acyl group and the carbon atom carrying the hydroxy group is in the S-configuration.

18. A 4(R)-compound according to claims 16 and 17 wherein Rx is C1-C6 alkyl or phenyl.

19. A 4(R)-compound according to claims 16 and 17 wherein Rx is methyl.

20. A 4(R)-compound of formula (VI) according to claims 15 to 19 wherein A is a residue chosen from dimethyltert-butylsilyl, trityl, a-methoxy-ethyl, tetrahydropyran-2-yl, 4-methoxy-tetrahydropyran4-yl, P-oxa- bicyclo[3.3.0]octan-3-yl and 2-oxa-bicyclo[3.3.0]oct-6,7-en-3-yl, and each group 0 is phenyl.

21. A process for the preparation of a 4(R)-compound of formula (VI) as defined in any one of claims 15 to 20 comprising reacting a 4(R)-compound having the formula (V) as defined in claim 1 with a phosphine derivative of formula P & wherein 0 is as defined above in claim 1.

22. A process according to claim 21 wherein the phosphine derivative is triphenylphosphine.

23. A process according to claim 21 wherein the halogen characterizing the compound of formula (V) is chlorine.

24. A4(R)-compound having the formula (V) as defined in claim 1.

25. A 4(R)-compound of formula (V) according to claim 24 wherein Xis chlorine and A is as defined in claim 20.

26. A process for the preparation of a 4(R)-compound of formula (V) as defined in claims 24 or 25 comprising halogenating a 4(R)-carbinol having the formula (IV) reported above in claim 1.

27. A process according to claim 26 wherein the group A characterizing the carbinol of formula (IV) is as defined in claim 20.

28. A 4(R)-compound having the formula (IV) as defined in claim 1.

29. A 4(R)-compound of formula (IV) according to claim 28 wherein the group A is as defined in claim 20.

30. A process for the preparation of a 4(R)-compound of formula (IV) as defined in claims 28 or 29 comprising reacting a 4(R)-compound having the formula (III) as defined in claim 1 with a glyoxylic derivative of formula OHC-COOR2wherein R2 is as defined in claim 1.

31. A process according to claim 30 wherein the group A characterizing the compound of formula (III) is as defined in claim 20.

32. A 4(R)-compound having the formula (III) as defined in claim 1.

33. A 4(R)-compound of formula (III) according to claim 32 wherein the group A is as defined in claim 20.

34. A process for the preparation of a 4(R)-compound of formula (III) as defined in claims 32 or 33, comprising reacting a 4(R)-compound having the formula (II) as defined in claim 1 with a thiol of formula ASH wherein A is as defined above in claim 1.

35. A process according to claim 34 wherein the group A characterizing the thiol A-SH is as defined in claim 20.

36. A4(R)-compound of formula (II)

wherein R and R3 are as defined in claim 1.

37. A process for the preparation of a 4(R)-compound of formula (II)

wherein Rand R3 are as defined in claim 1, comprising: a) converting a compound of formula (XIII)

wherein R3 is as defined above, into a compound of formula (XIV)

wherein R and R3 are as defined above; b) oxidizing a compound of formula (XIV) so obtaining a compound of formula (XV)

wherein R and R3 are as defined above; and c) removing the N,O protecting group from a compound of formula (XV).

38. A compound having the formula (XV) as defined in claim 37.

39. A process for the preparation of a compound of formula (XV) as defined in claim 38 comprising oxidizing a compound having the formula (XIV) as defined in claim 37.

40. A compound having the formula (XIV) as defined in claim 37.

41. A compound having the formula (XIII) as defined in claim 37.

42. A process for the preparation of a compound of formula (XIIIA)

comprising: a) submitting to the Curtius degradation the compound of formula (XVI).

so obtaining the aldehyde of formula (XIX)

b) reducing the aldehyde of formula (XIX) into the alcohol of formula (XX)

and c) submitting the obtained compound of formula (XX) to acetonidation.

43. A process for the preparation of a compound of formula (XIIIB)

comprising: a) converting the compound having the formula (XVI) reported above in claim 42 into a compound of formula (XXIIA)

wherein R6 and R6 are, independently, C1-C6 alkyl groups; b) oxidatively removing the 1-substituent in a compound of formula (XXIIA) so obtaining a compound of formula (XXIII)

wherein Re is as defined above; c) reducing a compound of formula (XXIII) so obtaining the compound of formula (XXIV)

and d) submitting the obtained compound of formula (XXIV) to acetonidation.

44. A process for the preparation of a compound having the formula (XIII)

wherein R3 is as defined above, comprising: a) reacting a 2-oxo-azetidine derivative of formula (XXV)

wherein Lisa nucleofuge leaving group, with a thioglycolic acid derivative of formula

wherein each group R3 is as defined in claim 1,so obtaining a mixture of enantiomeric compounds of formula (XXVIR) and (XXVIS)

wherein R3 is as defined above; b) separating the enantiomer of formula (XXVIR) from the enantiomer of formula (XXVIs) by resolution; c) esterifying the compound of formula (XXVIR) with an alcohol of formula R6OH where R6 is C,-C6 alkyl so obtaining a compound of formula (XXVII)

wherein R3 and Re are as defined above; d) reducing a compound of formula (XXVII) so obtaining a compound of formula (XXVIII)

wherein Rg is as defined above, and e) submitting the compound of formula (XXVIII) to acetonidation.

45. A process for the preparation of a compound having the formula (XIII) as defined in claim 37, comprising the acetonidation of a compound having the formula (XXVIII) reported above in claim 44.

46. A 4(R)-compound having the formula (XXVIII) as defined in claim 44.

47. A process for the preparation of a compound of formula (XXVIII) as defined in claim 46, comprising the reduction of a compound having the formula (XXVII) as defined in claim 44.

48. A 4(R)-compound having the formula (XX) as defined in claim 42.

49. A process for the preparation of a compound of formula (XX) according to claim 48, comprising reducing a compound having the formula (XIX) as defined in claim 42.

50. A 4(R)-compound having the formula (XIX) as defined in claim 42.

51. A process for the preparation of a compound having the formula (XIX) according to claim 50, comprising submitting to Curtius degradation a compound having the formula (XVI) as defined in claim 42.

52. A 4(R)-compound having the formula (XXIII) as defined in claim 43 or the formula (XXVII) as defined in claim 44.

53. A process for the preparation of a compound of formula (XXIII) according to claim 52, comprising the oxidative removal of the 1 -substituent in a compound having the formula (XXIIA) as defined in claim 43.

54. A process for the preparation of a compound of formula (XXVII) according to claim 52, comprising esterifying a compound having the formula (XXVIR) as defined in claim 44 with an alcohol of formula R6OH wherein R6 is as defined above in claim 44.

55. A 4(R)-compound having the formula (XXIIA) as defined in claim 43.

56. A process for the preparation of a compound of formula (XXIIA) according to claim 55, comprising the isomerization of a compound having the formula (XXII)

wherein Rg and R6 are as defined above in claim 43.

57. A compound having the formula (XXII) as defined in claim 56.

58. A process for the preparation of a compound of formula (XXII) according to claim 57 comprising reacting a compound of formula (XXI)

wherein R5 is as defined above in claim 43 with a compound of formula N2CH-COOR6 wherein R6 is as defined in claim 43.

59. A process for the preparation of a compound having the formula (XXIIA) according to claim 55 comprising reacting a compound of formula (XXIA)

wherein R5 is as defined above in claim 43 with a compound of formula

wherein R6 is as defined in claim 43.

60. A 4(R)-compound having the formula (XXVIR) as defined in claim 44.

61. A 7(R)-8(S)-9-oxo-3-oxa-6-thia-1 -aza-bicyclo[5.2.01,7]nonane derivative having the following formula (XIVA)

wherein R3 is as defined in claim 1, Rx is the residue of an acyl group and the carbon atom carrying the hydroxy group is in the R-configuration.

62. A 7(R)-8(S)-9-oxo-3-oxa-64hia-1-aza-bicyclo[5.2.01,7]nonane derivative having the following formula (XIVB)

wherein R3 is as defined in claim 1, Rx is the residue of an acyl group and the carbon atom carrying the hydroxy group is in the S-configuration.

63. A compound according to claims 61 and 62 wherein Rx is C-C6 alkyl or phenyl.

64. A compound according to claims 61 and 62 wherein Rx is methyl.

65. A compound of formula (XIVA) or (XIVB) according to claims 61 to 64 wherein each group R3 is methyl.

66. A process for the preparation of a compound having the formula (XIVA) as defined in claim 61 comprising the stereoselective reduction of a 7(R)-8(S)-8-acyl-9-oxo-3-oxa-6-thia-1 -aza- bicyclo[5.2.0'-7]nonane derivative of formula (XXX)

wherein R3 and Rx are as defined in claims 61 to 65, by means of a complex hydride of a weakly polarizing cation at ambient temperatures in a weakly solvating medium.

67. A process according to claim 66 wherein the complex hydride is a potassium or sodium or ammonium complex hydride.

68. A process according to claim 67 wherein the complex hydride is a potassium complex hvdride.

69. A process according to claim 68 wherein the potassium complex hydride is K-selectride(5

70. A process according to any one of claims 66 to 69 wherein the reaction temperature is comprised between +20"C and +40aC.

71. A process according to any one of claims 66 to 70 wherein the weakly solvating medium is diethyl ether.

72. A process for the preparation of a compound having the formula (XIVB) as defined in claim 62, said process comprising the stereoselective reduction of a compound having the formula (XXX) as defined in claim 66, by means of a complex hydride of a highly polarizing cation, at low temperatures in a highly solvating medium.

73. A process according to claim 72 wherein the complex hydride is a lithium complex hdride.

74. A process according to claim 73 wherein the lithium complex hydride is Li-selectride

75. A process according to any one of claims 72 to 74 wherein the reaction temperature is comprised between -80 C and -60 C.

76. A process according to any one of claims 72 to 75 wherein the highly solvating medium is a solvent chosen from tetrahydrofurane and dimethoxyethane.

77. A trans-6(S)-5(R)-2-penem-3-carboxylic acid derivative having the formula (I) as defined in claim 1 wherein R and R, are, independently, C1-C6 alkyl, and R2 is hydrogen, C-C6 alkyl, an optionally nitrosubstituted benzyl group or a pharmaceutically orveterinarily acceptable cation.

78. A compound of claim 77 wherein R and R, are, independently, methyl, ethyl or propyl.

79. A compound selected from the group consisting of: methyl(6S)-6-ethyl-(5R)-2-methyl-2-penem-3-carboxylate; methyl(6S)-6-ethyl-(5R)-2-ethyl-2-penem-3-carboxylate; methyl(6S)-6-ethyl-(5R)-2-propyl-2-penem-3-carboxylate; methyl(6S)-6-methyl-(5R)-2-methyl-2-penem-3-carboxylate; methyl(6S)-6-methyl-(5R)-2-ethyl-2-penem-3-carboxylate; methyl(6S)-6-methyl-(5R)-2-propyl-2-penem-3-carboxylate; methyl (6S)-6-propyl-(5R)-2-methyl-2-penem-3-carboxylate; methyl(6S)-6-propyl-(SR)-2-ethyl-2-penem-3-carboxylate; methyl(6S)-6-propyl-(5R)-2-propyl-2-penem-3-carboxylate; p-nitrobenzyl(6S)-6-ethyl-(5R)-2-methyl-2-penem-3-carboxylate; p-nitrobenzyl(6S)-6-ethyl-(5R)-2-ethyl-2-penem-3-carboxylate; p-nitrobenzyl(6S)-6-ethyl-(5R)-2-propyl-2-penem-3-carboxylate; p-nitrobenzyl (6S)-6-methyl-(5R)-2-methyl-2-penem-3-carboxylate; p-nitrobenzyl (6S)-6-methyl-(SR)-2-ethyl-2-penem-3-carboxylate; p-nitrobenzyl (6S)-6-methyl-(5R)-2-propyl-2-penem-3-carboxylate; p-nitrobenzyl (6S)-6-propyl-(5R)-2-methyl-2-penem-3-carboxylate; p-nitrobenzyl (6S)-6-propyl-(5R)-2-ethyl-2-penem-3-carboxylate; p-nitrobenzyl (6S)-6-propyl-(5R)-2-propyl-2-penem-3-carboxylate; (6S)-6-ethyl-(5R)-2-methyl-2-penem-3-ca rboxyl ic acid; (6S)-6-ethyl-(5R)-2-ethyl-2-penem-3-carboxylic acid; (6S)-6-ethyl-(5R)-2-propyl-2-penem-3-carboxylic acid; (6S)-6-methyl-(5R)-2-methyl-2-penem-3-carboxylic acid; (6S)-6-methyl-(5R)-2-ethyl-2-penem-3-ca rboxyl ic acid; (6S)-6-methyl-(5R)-2-propyl-2-penem-3-carboxyl ic acid; (6S)-6-propyl-(5R)-2-methyl-2-penem-3-carboxyl ic acid; (6S)-6-propyl-(5R)-2-ethyl-2-penem-3-carboxylic acid; (6S)-6-propyl-(5R)-2-propyl-2-penem-3-carboxylic acid; and the pharmaceutically or verterinarily acceptable salts of the free acids.

80. A trans 6(S)-5(R)-2-penem-3-carboxylic acid derivative having the formula (I) reported above in claim 1 wherein R is C1 -C6 alkyl, R1 is C1-C6 alkanoyloxymethyl and R2 is hydrogen, C1-C6 alkanoylmethyl, an optionally nitro-substituted benzyl group or a pharmaceutically orveterinarily acceptable cation.

81. A compound of claim 80 wherein R is methyl, ethyl or propyl and R1 is acetoxymethyl or propionyloxymethyl.

82. A compound selected from the group consisting of: p-nitrobenzyl(6S)-6-ethyl-(5R)-2-acetoxy-methyl-2-penem-3-carboxylate; p-nitrobenzyl(6S)-6-methyl-(5R)-2-acetoxy-methyl-2-penem-3-carboxylate; p-nitrobenzyl (6S)-6-propyl-(5R)-2-acetoxy-methyl-2-penem-3-ca rboxylate; p-nitrobenzyl (6S)-6-methyl-(5R)-2-propionyloxy-methyi-2-penem-3-carboxylate; p-nitrobenzyl(6S)-6-ethyl-(5R)-2-propionyloxy-methyl-2-penem-3-carboxylate; p-nitrobenzyl(6S)-6-propyl-(5R)-2-propionyloxy-methyl-2-penem-3-carboxylate; acetonyl(6S)-6-ethyl-(5R)-2-acetoxy-methyl-2-penem-3-ca rboxylate; acetonyl(6S)-6-methyl-(5R)-2-acetoxy-methyl-2-penem-3-carboxylate; acetonyl (6S)-6-propyl-(5R)-2-acetoxy-methyl-2-penem-3-carboxylate; acetonyl(6S)-6-methyl-(5R)-2-propionyloxy-methyl-2-penem-3-carboxylate; acetonyl (6S)-6-ethyl-(5R)-2-propionyloxy-methyl-2-penem-3-ca rboxylate; acetonyl(6S)-6-propyl-(5R)-2-propionyloxy-methyl-2-penem-3-carboxylate; (6S)-6-ethyl-(5R)-2-acetoxy-methyl-2-penem-3-carboxylic acid; (6S)-6-methyl-(5R)-2-acetoxy-methyl-2-penem-3-carboxylic acid; (6S)-6-propyl-(5R)-2-acetoxy-methyl-2-penem-3-carboxylic acid; (6S)-6-methyl-(5R)-2-propionyloxy-methyl-2-penem-3-carboxylic acid; (6S)-6-ethyl-(5R)-2-propionyloxy-methyl-2-penem-3-carboxylic acid; (6S)-6-propyl-(5R)-2-propionyloxy-methyl-2-penem-3-carboxylic acid; methyl (6S)-6-ethyl-(5R)-2-acetoxy-methyl-2-penem-3-ca rboxylate; methyl(6S)-6-methyl-(5R)-2-acetoxy-methyl-2-penem-3-carboxylate; methyl(6S)-6-propyl-(5R)-2-acetoxy-methyl-2-penem-3-carboxylate; methyl(6S)-6-methyl-(5R)-2-propionyloxy-methyl-2-penem-3-carboxylate; methyl(6S)-6-ethyl-(5R)-2-propionyloxy-methyl-2-penem-3-carboxylate; methyl(6S)-6-propyl-(5R)-2-propionyloxy-methyl-2-penem-3-carboxylate; and the pharmaceutically or veterinarily acceptable salts of the free acids.

83. A trans 6(S)-5(R)-2-penem-3-carboxylic acid having the formula (I) as defined in claim 1 wherein R is C,-C6 alkyl, R, is C1-C6 alkoxy-carbonyl and R2 is hydrogen, C1 -C6 alkyl, an optionally nitro-substituted benzvl group or a pharmaceutically or veterinarily acceptable cation.

84. A compound of claim 83 wherein R is methyl, ethyl or propyl and R1 is methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl.

85. A compound selected from the group consisting of: p-nitrobenzyl (6S)-6-ethyl-(5R)-2-ethoxyca rbonyl-2-penem-3-carboxylate; p-nitrobenzyl(6S)-6-methyl-(5R)-2-ethoxycarbonyl-2-penem-3-carboxylate; p-n itrobenzyl (6S)-6-propyl-(5R)-2-ethoxycarbonyl-2-penem-3-carboxylate; p-nitrobenzyl(6S)-6-methyl-(5R)-2-methoxycarbonyl-2-penem-3-carboxylate; p-nitrobenzyl (6S)-6-ethyl-(5R)-2-methoxyca rbonyl-2-penem-3-carboxylate; p-nitrobenzyl(6S)-6-propyl-(5R)-2-methoxycarbonyl-2-penem-3-carboxylate; p-nitrobenzyl (6S)-6-methyl-(5R)-2-propoxycarbonyl-2-penem-3-carboxylate; p-nitrobenzyl(6S)-6-ethyl-(5R)-2-propoxycarbonyl-2-penem-3-carboxylate; p-nitrobenzyl(6S)-6-propyl-(5R)-2-propoxycarbonyl-2-penem-3-carboxylate; (6S)-6-ethyl-(5R)-2-ethoxycarbonyl-2-penem-3-carboxylic acid; (6S)-6-methyl-(5R)-2-ethoxycarbonyl-2-penem-3-carboxylic acid; (6S)-6-propyl-(5R)-2-ethoxycarbonyl-2-penem-3-carboxylic acid; (6S)-6-methyl-(5R)-2-methoxyca rbo nyl-2-penem3-ca rboxylic acid; (6S)-6-ethyl-(SR)-2-methoxycarbonyl-2-penem-3-carboxylic acid; (6S)-6-propyl-(5R)-2-methoxycarbonyl-2-penem-3-carboxylic acid; (6S)-6-methyl-(SR)-2-propoxycarbonyl-2-penem-3-carboxylic acid; (6S)-6-ethyl-(5R)-2-propoxycarbonyl-2-penem-3-carboxylic acid; (6S)-6-propyl-(5R)-2-propoxycarbonyl-2-penem-3-carboxylic acid; methyl(6S)-6-ethyl-(5R)-2-ethoxycarbonyl-2-penem-3-carboxylate; methyl (6S)-6-methyl-(SR)-2-ethoxycarbonyl-2-penem-3-carboxylate; methyl (6S)-6-propyl-(SR)-2-ethoxycarbonyl-2-penem-3-carboxylate; methyl(6S)-6-methyl-(SR)-2-methoxycarbonyl-2-penem-3-carboxylate; methyl(6S)-6-ethyl-(5R)-2-methoxycarbonyl-2-penem-3-carboxylaté; methyl(6S)-6-propyl-(5R)-2-methoxycarbonyl-2-penem-3-carboxylate; methyl (6S)-6-methyl-(5R)-2-p ropoxyca rbonyl-2-penem-3-ca rboxyl ate; methyl(6S)-6-ethyl-(5R)-2-propoxycarbonyl-2-penem-3-carboxylate; methyl(6S)-6-propyl-(5R)-2-propoxycarbonyl-2-penem-3-carboxylate; and the pharmaceutically or veterinarily acceptable salts of the free acids.

86. A trans 6(S)-5(R)-2-penem-3-carboxylic acid having the formula (I) as defined in claim 1 wherein R is C1-C6 alkyl; R1 is a thienylmethyl group and R2 is hydrogen, C1 -Ce alkyl, an optionally nitrosubstituted benzyl group or a pharmaceutically orveterinarily acceptable cation.

87. A compound of claim 86 wherein R is methyl, ethyl or propyl and R, is 2-thienylmethyl.

88. A compound selected from the group consisting of: p-nitrobenzyl(6S)-6-ethyl-(5R)-2-thien-2'-yl-methyl-2-penem-3-carboxylate; p-nitrobenzyl(6S)-6-methyl-(5R)-2-thien-2'-yl-methyl-2-penem-3-carboxylate; p-nitrobenzyl(6S)-6-propyl-(5R)-2-thien-2'-yl-methyl-2-penem-3-carboxylate; (6)-6-ethyl-(5R)-2-thien-2 '-yl-methyl-2-penem-3-carboxylate; (6S)-6-methyl-(5R)-2-thien-2'-yl-methyl-2-penem-3-carboxylate; (6S)-6-propyl-(SR)-2-thien-2'-yI-methyl-2-penem-3-carboxylic acid; methyl(6S)-6-ethyl-(5R)-2-thien-2'-yl-methyl-2-penem-3-carboxylate; methyl(6S)-6-methyl-(SR)-2-thien-2'-yI-methyl-2-penem-3-carboxylate; methyl(6S)-6-propyl-(5R)-2-thien-2'-yl-methyl-2-penem-3-carboxylate; and the pharmaceutically or veterinarily acceptable salts of the free acids.

89. A process according to claim 1 for the preparation of a compound of claims 77 to 88.

90. A pharmaceutical or veterinary composition comprising a compound according to any one of the preceding claims 77 to 88 and a pharmaceutically orveterinarily acceptable carrier and/or diluent.

91. A compound or salt of Formula I as defined in claim 1 hereinbefore specifically mentioned.

92. A compound or salt of Formula 11, III, IV, V, VI, VII, VIII, XIII, XIV, XV, XIX, XX, XXIIA, XXIII, XXVIA, XXVII, XXVIII or XXII as hereinbefore defined and as hereinbefore specifically mentioned.

93. A process for the preparation of a compound or salt of Formula I according to claim 1 or 2 substantially as hereinbefore described with reference to any one of the Examples.

94. A process for the preparation of a compound or salt according to any one of claims 6, 14,21,26,30, 34,37,42,43,44,45,47, 49,51,53,54,56,58,59,66 or 72 substantially as hereinbefore described with reference to any one of the Examples.

95. A composition according to claim 90 substantially as herein before described.

96. A compound or salt according to any one of claims 77 to 88 for use in a method of treatment of the human or animal body by surgery or therapy or of diagnosis practical on the human or animal body.