BE897183A - EASY-CLeavABLE CARBOXYL ESTERS AND THEIR USE IN THE SYNTHESIS OF PENEMS AND OTHER BETA-LACTAM ANTIBIOTICS - Google Patents

Description

       

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   DESCRIPTIVE MEMORY in support of a request for
PATENT OF INVENTION for "Easily cleavable carboxylic esters and their use in the synthesis of penems and other ss-lactam antibiotics" by the Company: FARMITALIA CARLO ERBA S. p. AT.



   Via Imbonati, 24
20159 MILAN (Italy). Priority of a patent application filed in the United Kingdom on July 1, 1982 under the number 82 19052. Inventors: Marco ALPESIANI, Angelo BEDESCHI, Bttore FERRONE,
Caraelo GANDOLFI.

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  Easily cleavable carboxylic esters and their use in the synthesis of penems and other ss-lactam antibiotics.



   The present invention relates to new carboxylic esters of sslactam antibiotics, a process for their preparation, as well as certain useful intermediates of this process.
 EMI2.1
 of.
The compounds of the present invention correspond to the general formula (I):
 EMI2.2
 wherein R. represents a hydrogen atom, a halogen atom or an organic group;
 EMI2.3
 R and are the same or different, each represents a hydrogen atom or an organic group;

   R4 represents an aromatic or heteroaromatic, monocyclic or bicyclic ring which is unsubstituted or substituted by one or more substituents chosen from a C 1 -C alkyl group C 1 -C alkoxy group formyl group, a phenyl group, a phenoxy group, a C2-C6 alkanoyl group, a benzoyl group, a (C1-C6) alkoxy group because
 EMI2.4
 bonyle, an amino group unsubstituted or substituted by one or two C-C alkyl mylamino, acyl (C-C) amino, benzoylamino, halogen and nitro groups;

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 EMI3.1
 the symbol-E-represents-0- X represents an oxygen or sulfur atom;

   and
 EMI3.2
 the symbol - Y a group completing,
 EMI3.3
 with the group-E- and the condensed azetidinone nucleus, the backbone of a 03-lactam antibiotic. The scope of the invention also includes the salts and all the possible isomers of the compounds of formula CI), for example, the geometric and optical isomers, as well as their mixtures.



   The alkyl, alkoxy, alkanoyl, alkoxycarbonyl, alkylamino and acylamino groups may be straight or branched chain groups. A halogen atom is, for example, a chlorine atom, a bromine atom or a fluorine atom. When substituted, an aromatic or hetero-aromatic, monocyclic or bicyclic ring preferably has 1 to 3 substituents. When R. is a halogen atom, it is preferably a chlorine atom, a bromine atom or an iodine atom.



   When PL is an organic group, it is, for example, an acylamino group, a free or protected amino group or a substituted or unsubstituted aliphatic hydrocarbon group. In particular, when R. is an acylamino group, it is preferably an substituted alkanoyl (C -C) amino group, in particular a substituted acetylamino group, preferably a) an arylacetamido group in which the aryl moiety is an aromatic homocyclic or heterocyclic radical which is unsubstituted or substituted by one or more substituents chosen from a C 1 -C alkyl group, a halogen atom, a hydroxy group and an amino group;

   or b) a phenoxyacetamido group; or c) a 2-aryl-2-methoxyimino-acetamido group in which the aryl moiety preferably represents a phenyl group, a

  <Desc / Clms Page number 4>

 2-furyl group, a 2-thienyl group or a 2-aminothiazol-4-yl group.



   When R, is a protected amino group, it is, for example, a straight or branched chain (C1-C6) alkoxy carbonylamino group, for example, a tert-butoxycarbonylamino group; or an imine,
 EMI4.1
 preferably a Schiff base with an aromatic aldehyde; or a substituted or unsubstituted acyl (C2-C6) amino group or alternatively a formylamino group, preferably a formylamino group, an acetamido group and a chloracetamido group.



   When R. is a substituted or unsubstituted aliphatic hydrocarbon group, it is, for example, a radical chosen from an alkyl group
 EMI4.2
 C1-C12 and a C rai i 4 / dical cycloalkyl group being unsubstituted or substituted by one or more substituents chosen from a hydroxy group, an amino group, a cyano group and a mercapto group, while the hydroxy, amino groups and mercapto can be free or in protected form; the preferred protective groups for the amino, hydroxy and mercapto groups are those known in the chemistry of peptides and antibiotics of lactam. When R. is a substituted or unsubstituted aliphatic hydrocarbon group, it is preferably an ethyl group or a 1-hydroxyethyl group.



   When R2 and / or R-represent an organic group, they are, for example, an alkyl group
 EMI4.3
 C.-C, a C1-C3 alkyl group. R and R ,, are the same or different, each preferably represents a hydrogen atom or a methyl group. When R4 is an aromatic monocyclic ring, it is, for example, a phenyl ring which is unsubstituted or substituted by one or more

  <Desc / Clms Page number 5>

 
 EMI5.1
 killers selected from a C1-C6 alkyl group preferably, a methyl group and a tert-butyl group; an amino group a nitro group; a halogen atom, preferably a chlorine atom a trihalo-C1-Calkyl group preferably, a trifluoromethyl group;

   a (C 1 -C 4) alkoxy carbonyl group, preferably a COOCH group a COOCH group; a C 1 -C alkanoyl group preferably an acetyl group; an amino (C2-C7) acyl group, preferably an acetylamino group 7 as well as a C1-C6 alkoxy group.



  When R4 is a heteroaromatic monocyclic ring, it is preferably a pyridine ring.



  When R4 is a bicyclic nucleus, it is preferably a quinoline nucleus.



  The skeleton of the above-mentioned ss-lactam antibiotic is preferably the skeleton of a penicillin, a cephalosporin, a penem, a carbapenem or a 1-oxa-l- dethiacephalosporin.



  Preferably, E represents in particular,
 EMI5.2
 Preferably, the symbol--Y./is a
 EMI5.3
 group chosen from:
 EMI5.4
 CH. Cl OCOCH.



  , - -where l CH3 CH3 CH3
 EMI5.5
 is a hydrogen atom or an organic group, better
 EMI5.6
 5 again, the group = C-which completes a nucleus
 EMI5.7
 with the condensed azetidinone nucleus and the group -When the latter represents -S-.



  When R 1 is an organic group, it is, for example, a substituted or substituted C 1 -C 6 alkyl group, preferably a methyl group.

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 unsubstituted or substituted by a substituent chosen from: a ') a halogen atom, for example, a chlorine atom or a bromine atom; b ') an acyloxy group, for example, an alkanoyl (C 2 -C 9) oxy group, in particular an acetoxy group; c ') a carbamoyloxy group unsubstituted or substituted by one or two substituents chosen from a C1-C4 alkyl group and a phenyl group; and d ') a group-S-Het in which Het denotes a saturated or unsaturated heteromonocyclic or heterobicyclic nucleus containing one or more heteroatoms chosen from a nitrogen atom, an oxygen atom and a sulfur atom.

   Preferably, this nucleus is chosen from the group comprising the thiazole, thiadiazole, tetrazole, triazine and tetrazolo-pyridazine nuclei and this nucleus is in turn unsubstituted or substituted by one or more substituents chosen, for example, from a cycano group;
 EMI6.1
 a C1-C1 alkyl group, preferably a C1-C1 alkyl group; a hydroxy group; an amino group a halogen atom, preferably a chloro atom
 EMI6.2
 re; a C1-C6 alkoxy group, preferably a C1-C4 alkoxy group a formyloxy group an acyl (C-C) oxy group; a carboxy group, an alkoxy (C1-C12) carbonyl group and a cari i bamoyl group unsubstituted or substituted by one or two C 1 -C alkyl groups.



   The preferred compounds of formula (I) are those in which: R1 is a hydrogen atom, a chlorine atom, a bromine atom, an amino group, a phenylacetamido group, a phenoxyacetamido group, a group

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2-amino-2-phenyl-acetamido, a 2- (2-amino-thiazol-4-yl) -2-methoxyimino-acetamido group, a C1-C4 alkyl group or a 1-hydroxyethyl group;

     R and R-j, which are the same or different, each represents a hydrogen atom or a C1-C6 alkyl group; R4 represents a phenyl group which is unsubstituted or substituted by 1,2 or 3 substituents chosen from a chlorine atom, a nitro group, a methoxy group, a C1-C4 alkyl group, an amino group, a formamido group and an alkanoyl group (C2-C3) amino; X represents an oxygen atom; the symbol-E-
 EMI7.1
 represents-S-or-0-and, when the symbol-E-
 EMI7.2
 represents the symbol - Y) a
 EMI7.3
 group chosen from:
 EMI7.4
 CH. Cl OCOCH.



  1 t 1 - -C- -where 1 CH. 1
 EMI7.5
 has the meaning defined above while, when
 EMI7.6
 that the symbol the symbol - Y / represents = C-CH-where the meaning defined 3 above; as well as their salts.



   More preferred compounds of formula (I) are those in which: R. is a hydrogen atom, a chlorine atom, a bromine atom, an amino group, a phenylacetamido group, a phenoxyacetamido group, a group
 EMI7.7
 2-amino-2-phenyl-acetamido, a 2-thiazol-4-yl group) a C1-C4 alkyl group or a 1-hydroxyethyl group; R2 and R3 each a hydrogen atom J R4 represents a phenyl group, a p-nitro-

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    (2-amino-phenyl, a p-aminophenyl group, a p-chlorophenyl group, a p-tolyl group, a p-tert-butylphenyl group or a p-acetamidophenyl group;

   X represents an oxygen atom; the symbol-E-re-
 EMI8.1
 present when the symbol -E -represented
 EMI8.2
 sente-S-, the symbol --- Y} represents a group
 EMI8.3
 chosen from:
 EMI8.4
 CH. Cl 1 - -C- - while CH. j that the symbol-E-represents-0-., zo represents = C-CH-and, in both cases, R-is a
 EMI8.5
 C1-Canon alkyl group substituted or substituted by a substituent chosen from: -S- or -0- and, a ") a chlorine atom or a bromine atom; b") an alkanoyl group (in C2-C9) oxy ;

   c ") a carbamoyloxy group unsubstituted or substituted by one or two substituents chosen from a C1-C4 alkyl group and a phenyl group, and d") a group-S-Het in which Het denotes a heteromonocyclic or heterobicyclic ring chosen from the group comprising the thiazole, thiadiazole, tetrazole, triazine and tetrazolopyridazine rings, this ring being, in turn, unsubstituted or substituted by one, two or three substituents chosen from a cyano group, a C1-C12 alkyl group, a group amino, a bromine atom, a chlorine atom, a hydroxy group, a C1-C12 alkoxy group, a formyloxy group, a C2-C12 acyloxy group,
 EMI8.6
 a carboxy group, an alkoxy group (in Cl-Cl2)

   carbol nyle and a carbamoyl group unsubstituted or substituted by one or two C1-C4 alkyl groups and their salts.

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   Particularly preferred compounds of formula (I) are those in which: R. is an ethyl group or a 1-hydroxyethyl group;
 EMI9.1
 R2 and R3 each represents a hydrogen atom; J R4 represents a phenyl group, a p-nitro-phenyl group, a p-aminophenyl group, or a p-chlorophenyl group; X represents an oxygen atom;
 EMI9.2
 the symbol-E-represents a sulfur atom;

   
 EMI9.3
 the symbol - y represents a group R? = C-where an acetoxymethyl group, a group
 EMI9.4
 carbamoyloxymethyl, a group (1-methyl-1, 2, 3, tetrazol-5-yl) -thiomethyl, a group (l-carboxy-
5-methyl-1,2,3,4-tetrazol-5-yl) -thiomethyl, a group [1- (2-carboxy) ethyl-1,2,3,4-tetrazol-5-yl] -thiomethyl, a group 2- (2-methyl-5-oxo-6-hydroxy-2, 5-dihydro-1,2,4-triazin-3-yl) -thiomethyl or a group [1- (2- dimethylamino) -ethyl-1 , 2, 3, 4-tetrazol-S-yl] -thiomethyl, and their salts.



   The salts of the compounds of formula (I) include the acid addition salts with inorganic acids, for example, nitric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid and phosphoric acid, or with organic acids, for example, acetic acid, propionic acid, glycolic acid, lactic acid, oxalic acid, malonic acid, malic acid, maleic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid and salicylic acid, as well as salts with inorganic bases, for example bases of alkali metals, in particular, bases of sodium or potassium, or with bases of alkaline earth metals, in particular,

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 calcium or magnesium bases, or with organic bases,

   for example, alkylamines, preferably triethylamine.



   It is well known that the removal of a conventional carboxy protecting group from a 03-lactam derivative, in particular from a bicyclic derivative, can be a critical reaction. The choice of an appropriate ester, that is to say an ester which can remain in complete safety following a multi-step process, while being easily cleaved at the end of the latter, is often the factor. crucial intervening in the success of a method of synthesis leading to a compound of formula (I) and this, whatever may be the insignificance of the first and the attraction of the second;

   hence the constant need to find new carboxy protecting groups in the chemistry of ss-lactam antibiotics. The esters of formula (I) and their salts provide a new family of carboxy protecting groups, generally cleavable under the moderate conditions required for the subsistence of the sensitive lactam moiety with an additional advantage resulting from the fact that the desired degree of reactivity can be modulated by the choice of the substituent (s) of the R4 nucleus. More specifically, the electron-attracting substituents (e.g. R4 = p-nitrophenyl) provide greater stability against acid hydrolysis, while the electron donating substituents (e.g. R4 = p- methoxyphenyl) reduce the stability of esters (II)

   compared to the basic nucleus (R4 = phenyl).



   As expected, the main advantage offered by the esters of formula (I) and their salts with respect to the conventional carboxy protecting groups known in the literature and commonly

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 used, for example, the benzyl, p-nitrobenzyl, tert-butyl, diphenylmethyl and the like groups resides in the softness of the conditions necessary for their cleavage.



   In addition, most of these esters resist ozonolysis and cold aqueous permanganate, unlike, for example, allyl esters, while their α-phosphoranylidene derivatives can easily undergo an internal Wittig reaction with a thioester-carbonyl of the type described. by Woodward et al., "J. Am. Chem. Soc." 100, 8214, 1978, unlike, for example, trichlorethyl esters.



   An eloquent example is offered by the synthesis of (sur, 6s) -6-ethyl-2- (1-methyl- 1, 2, 3, 4-tetrazol-5-yl) -thiomethyl-penem-3- acid carboxylic acid which the Applicant has not been able to obtain by catalytic hydrogenation of its benzyl or p-nitrobenzyl ester (a reduction in 2-methylpenem occurs rather) or by titration of its acetonyl ester with NaOH O, 1N (migration of the penem double bond in the exocyclic position) or else by hydrolysis of its tert-butyl ester with the intervention of trifluoroacetic acid or trimethylsilyl iodide (loss of the ss-lactam fraction).



  Finally, according to the present invention, this product was obtained with a high yield by extremely moderate acid hydrolysis of its 1-phenoxyethyl ester, that is to say by simple exposure to aqueous acetic acid, or even by stirring. with an aqueous solution of sodium metabisulfite.



   Another advantage offered by the esters of formula (I) and their salts, following their possibility of subsisting in different processes, while being however easily cleaved at the end of the latter, lies in their use in processes

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 concerning the interconversion between compounds of formula (I), interconversion which, under other conditions, would be impossible or would not be convenient to carry out on the corresponding free acids.



   An additional advantage offered by the use of these esters and their salts lies in the ease of esterification of their precursors of carboxylic acids, this esterification requiring no activation step as is the case for their conversion into prior art acyl halides. Another advantage over certain known reagents used for the protection of carboxylic acids lies in their low price, since both the preparation (see below) of most of the esters of formula (I) can be mass produced from extremely inexpensive materials such as acetylene, phenol and hydrogen chloride.

   As is known, the free acids originating from the cleavage of the esters of formula (I) exert 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. They also exert a high activity against the powerful micro-organisms producing ss-lactamase, for example, Klebsiella aerogenes 1082 E, Escherichia coli Tem, Enterobacter cloacae P 99, Proteus positive to indole and the like, as well as against strains of Pseudomonas aeruginosa.

   Consequently, these free acids and their pharmaceutically acceptable salts are useful in human and veterinary therapy.

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   The compounds of formula (I) can be prepared by a process comprising the steps consisting in:
 EMI13.1
 A) bring together a synthon of formula (II):
 EMI13.2
 
 EMI13.3
 in which R6 represents a radical deriving from an α-amino acid, an α-hydroxy acid, an α-keto acid or an α-alkenoric acid in which the amino, hydroxy and keto groups are free or protected by a protective group commonly used in the field of peptides,
 EMI13.4
 while R, R X have the meanings j 4 defined above, with another synthon, then treat the intermediate product thus obtained according to known methods
 EMI13.5
 per se, to obtain a compound of formula (I) or B) reacting an acid of formula (III)
 EMI13.6
 
 EMI13.7
 in which the symbols-E -, - Y have the
 EMI13.8
 meanings defined above,

   or a salt of this acid, with a halide of formula (IV):
 EMI13.9
 in which

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 EMI14.1
 Z represents a chlorine atom, a bromine atom or a fluorine atom, while R, and X have j 4 the meanings defined above, and possibly transform a compound of formula (I) into another compound of formula (I) and / or optionally transforming a compound of formula (I) into one of its salts; and / or, if desired, obtaining a free compound of formula (I) from one of its salts; and / or, if desired, separating a mixture of isomers of formula (I) into individual isomers.



   The compounds of formula (I) can be transformed into corresponding free carboxylic acids by a new process which also falls within the scope of the present invention.



   The second synthon (or building block) used in process A) indicated above can be any fragment which may be located in the structure of the compound of formula (I) provided that it does not contain the ester group
 EMI14.2
 which is already provided in process A) by the synthon of formula (II). Normally, the product of the reaction between the synthon of formula (II) and the second synthon, will be a compound which will be subjected to a complementary treatment.



   The preparation of a synthon of formula (II) consists in reacting a carboxylic acid of formula (V):
R6-COOH (V) in which R6 has the meaning defined above, or one of its salts, with a halide of formula (IV):

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 EMI15.1
 in which Z, R, R., R. and X have the meanings defined above.



   The process mentioned under A) above consists in treating the product of formula (II) according to general methods known per se to obtain a conventional ester of an acid of formula (III) (for example, its p-nitrobenzyl ester) from a conventional ester of an acid of formula (V). Among these methods, the preferred methods are those allowing the transformation, in several stages, of an ester of glyoxylic acid, that is to say a compound of formula (V) in which R6 represents HCO-, into a penem (see, among others, Woodward et al., "J. Am. Chem. Soc.", 101, 6296, 1979).



   A number of other methods are described, for example, by R. Bucourt in "Recent Advances in the Chemistry of ss-Lactam Antibiotics", Royal Soc. of Chemistry, Special Publ. no 38 (1980), 1-25.



   According to a preferred method of the invention,
 EMI15.2
 preferably, the carboxylic acid of which one chooses that of formula (V) from the group comprising tartaric acid, fumaric acid and glyoxylic acid.



   The reaction between a compound of formula (V) or one of its salts and a compound of formula (IV) can be carried out in an inert organic solvent, for example, dimethylformamide, dimethylsulfoxide, tetrahydrofuran or acetone, at a temperature between about -70 and about 140C, preferably between about -20 and about 500C.



  When, as free acid, a compound of

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 formula (V), the presence of an added organic or inorganic base is usually necessary.



  Among the suitable organic bases are, for example, pyridine, lutidine, collidine or an aliphatic tertiary amine such as triethylamine or ethyl-diisopropylamine; among suitable inorganic bases there are, for example, hydroxides of alkali metals or alkaline earth metals, for example, NaOH; carbonates or hydrogen carbonates. These bases are preferably used in approximately an equivalent molar amount.



   Among all the methods known per se with respect to the method mentioned under A) above, in a preferred method, one starts from a compound of formula (II) and leads to a compound of formula (I) in
 EMI16.1
 which the symbol-E-is a sulfur atom, tan-
 EMI16.2
 us say that the symbol - Y
 EMI16.3
 has the meaning defined above.

   This preferred method comprises the steps consisting in: represents = C-where R-lt) oxidize a compound of formula (II) in which R6 represents the radical deriving from L (+) tartaric acid, to obtain a compound of formula ( II) in which R6 is a formyl group;
21) condensing this compound or a hydrate, an acetal or even a hemi-acetal of this compound with an azetidinone of formula (VI):
 EMI16.4
 in which R., and R-have the meanings defined above, to obtain a compound of formula

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 (VII):
 EMI17.1
 in which
 EMI17.2
 R., X have the meanings defined J 4 above;
31) transform a compound of formula (VII) into a compound of formula (VIII):

   
 EMI17.3
 in which
 EMI17.4
 FL, X have the meanings defined above and Ph represents a phenyl group; and 4 ') cyclizing a compound of formula (VIII) to obtain a compound of formula (I) in which
 EMI17.5
 the symbol-E-represents-S- and the symbol-y R represents = C-where the defined meaning
Above.



   The step indicated under 1 ') above can be carried out with a suitable oxidizing agent, for example, lead tetracetate. The steps indicated under 2 '), 3') and 4 ') can be carried out according to well known methods, for example, those mentioned in the British patent application.

  <Desc / Clms Page number 18>

 published no. 8,005,476 to the Applicant.



   In particular, for example, step 2 ′) can be carried out:
A) by heating in an anhydrous inert solvent such as benzene or toluene, with simultaneous azeotropic distillation of the water formed, or
B) by treatment with molecular sieves at room temperature or
C) in an aprotic dipolar solvent such as tetrahydrofuran, in the presence of a basic catalyst such as triethylamine, at a temperature between room temperature and the boiling point of the solvent used.

   Step 3t) can be carried out, for example, by reacting the compound of formula (VII) with a halogenating agent to obtain the corresponding halide (preferably, the halogenation is carried out with thionyl chloride to obtain the chloride ), then reacting the halide obtained with triphenylphosphine, either at room temperature on an inert support, that is to say in the absence of a solvent, or in an inert organic solvent, for example, dichloromethane, tetrahydrofuran or dioxane, at a temperature between room temperature and about 70 C. It is possible to carry out step 4 ′), for example, by heating in an inert solvent, for example, benzene, toluene ,

   tetrahydrofuran, dioxane or dichloromethane, at temperatures varying between approximately 700C and approximately 150oC, preferably, working under a nitrogen atmosphere.



   The reaction between a compound of formula (III) and a compound of formula (IV) can be carried out under the same experimental conditions as those mentioned above for the reaction between

  <Desc / Clms Page number 19>

 a compound of formula (V) and a compound of formula (IV). As indicated above, it is possible to transform a compound of formula (I) into another compound of formula (I) in which R. and / or Y have different meanings chosen from those already indicated.



   When a transformation of this type concerns the group Ru ′, it may be, for example, the transformation of a protected amino group into a free amino group and / or the transformation of a free amino group into a group acylamino, or a transformation of an alkyl group comprising a protected hydroxy group into an alkyl group comprising a free hydroxy substituent. When a transformation of this type concerns the radical Y, it can be, for example, the chemical modification of a substituent occupying position 3 of a cephalosporin or of a 2-thiacephem, or else the chemical modification of a substituting in position 2 a penem, or a penam.

   As a variant, the radicals E and Y can be modified to a degree completing, after this transformation, a bicyclic ss-lactam nucleus different from that of the starting point and chosen from the classes of penicillin, cephalosporne, penem, carbapenem or 1-oxa-1-dethiacephalosporin, a common example of this type of transformation being the enlargement of the nucleus of a penicillin to a cephalosporin.



   These transformations are processes known per se and they can be carried out in analogy with well-known processes, for example, under the same experimental conditions as those already mentioned in the literature for the transformation of a conventional ester (for example, the p-nitrobenzyl ester) of an acid of formula (III) into a

  <Desc / Clms Page number 20>

 same conventional ester of a different acid of formula (III).



   The optional salification of a compound of formula (I), as well as the transformation of a salt into a free compound and the separation of a mixture of isomers into the free compound can be carried out by conventional methods.



   For example, the separation of optical isomers can be carried out by salification with an optically active base or acid with subsequent fractional crystallization of the diastereomeric salts, this crystallization being followed by recovery of the optically active isomer or acids.



   The separation of a mixture of cis and trans geometric isomers can be carried out, for example, by fractional crystallization or by chromatography.



   The preparation of a free acid of formula (III) from an ester of formula (I) (which also falls within the scope of the present invention) is carried out by cleavage of the ester of formula (I). Preferably, the cleavage is carried out by hydrolysis, preferably by acid hydrolysis. Acid hydrolysis normally includes the use of different Lewis and Brönsted acids, mainly depending on the group R4 present in the starting ester.



   The conditions chosen for hydrolysis with Brönsted acids include trifluoroacetic acid, diluted in an inert organic solvent or without solvent (this acid is suitable, for example, when R4 is a phenyl nucleus substituted by groups attracting electrons such as the NO2 group), p-toluenesulfonic acid in benzene (a period of 1-2 hours at room temperature is generally sufficient when R4 is a nucleus

  <Desc / Clms Page number 21>

 unsubstituted phenyl); as well as formic acid.

   Preferably, with the more sensitive p-lactam substrates, inorganic acids (for example, boric acid) or carboxylic acids (for example, citric acid, oxalic acid, acetic acid) are used. and phthalic acid) lower, usually dissolved in a mixture of water and an organic solvent, for example, tetrahydrofuran. One can even often use a solution of NaSO 2 in a mixture of water and an organic solvent or a slightly acidic aqueous buffer when R 4 does not contain substituents attracting the electrons, while esters of formula (I) in which R4 is a phenyl nucleus substituted by electron donor groups (for example, OCH3), can be cleaved by simple exposure to water.

   Among the Lewis acids chosen which can intervene in the cleavage of esters of formula (I), there are, for example, AlCl3, BF3, ZnBr2,
 EMI21.1
 ZnCI,. They can be used in 4 d an inert organic solvent, for example, dichloromethane or nitromethane, or in a mixture of organic solvents, usually at a temperature varying between about -20 ° C. and about +30 ° C., preferably at a temperature of approximately OOC, the more reactive Lewis acids (for example AlC13) being necessary again when R4 contains substituents attracting the electrons, the less reactive Lewis acids (for example, ZnC12) being preferred in others conditions.

   In the particular case where R4 represents an o- or p-nitrophenyl group, for the cleavage of the ester, it is possible to use a chemical reduction (for example, with NH4Cl / iron powder) or catalytic (for example, with hydrogen / palladium carbon), since both the

  <Desc / Clms Page number 22>

 Cleavage of the intermediate esters of formula (I) in which R4 represents an o- or p-aminophenyl group is even easier. Halides of formula (IV) can be prepared by adding an acid of formula HZ in which Z has the meaning defined above, to a mixture of vinyl ether / thioether of formula (IX):
 EMI22.1
 in which R2, R3, R4 and X have the meanings defined above.

   This reaction can be carried out in the presence or in the absence of a dry inert organic solvent such as, for example, tetrahydrofuran, preferably in the absence of water or humidity, as well as at a temperature between approximately 50 and about +50 C, preferably between about -150C and about +30 C.



   The compounds of formula (IX) are known compounds or they can be prepared from known compounds according to general methods.



   Specific methods chosen include the addition of a phenol / thiophenol to an alkyne (see, for example, W. Reppe et al., "Annalen der Chemie" 601, 81, 1965); reacting a vinyl halide (e.g. vinyl chloride) or a vinyl ester (e.g. vinyl acetate) with a phenol thiophenol; the reaction of an alkyl aryl ether / thioether, substituted in position 2 of the alkyl chain with an appropriate group which moves away (for example, a halide, a mesyloxy group) with a base (see, among others, W. M.



  Lauer and M. A. Spielman, "J. Am. Chem. Soc.", 55 1572, 1933).

  <Desc / Clms Page number 23>

 



   The compounds corresponding to formulas (III), (V) and (VI) are known compounds or they can be prepared by known methods starting from known compounds.



   The invention also provides compounds corresponding to formula (II):
 EMI23.1
 in which
R6 represents a radical deriving from an α-amino acid, an α-hydroxy acid, an α-keto acid or an α-alkenoic acid where the amino, hydroxy and keto groups are free or protected by a protective group in common use in the field of
 EMI23.2
 peptides, while R and X have the siJ 4 definitions defined above.



   Preferred compounds of formula (II) are those in which R and R3 each represent a hydrogen atom R4 represents a phenyl group, a p-nitro-phenyl group, a p-chlorophenyl group, a p-aminophenyl group, a group p-tolyl, a p-tert-butylphenyl group or a p-acetamidophenyl group; X represents an oxygen atom; R6 represents the radical deriving from tartaric acid, fumaric acid or glyoxylic acid.



   The invention also provides compounds corresponding to formula (VII):

  <Desc / Clms Page number 24>

 
 EMI24.1
 
 EMI24.2
 in which fL, X have the meanings defi-
Rnies above.



   The invention also provides compounds corresponding to formula (VIII):
 EMI24.3
 in which
 EMI24.4
 R.,, and Ph have the meanings defined above.



   Particularly preferred compounds corresponding to formulas (VII) and (VIII) are those in which: R. represents an ethyl group or a 1-hydroxyethyl group; R2 and R3 each represents a hydrogen atom; X represents an oxygen atom;

     R4 represents a phenyl group, a p-nitro-phenyl group, a p-chlorophenyl group, a p-aminophenyl group, a p-tolyl group, a p-tert-butylphenyl group or a p-acetamido- group

  <Desc / Clms Page number 25>

 phenyl;

  
R5 represents an acetoxymethyl group, a carbamoyloxymethyl group, a (1-methyl-1, 2, 3, 4-tetrazol-5-yl) -thiomethyl group, a group [1- (2-
 EMI25.1
 dimethylamino) -ethyl-l, methyl, a group (1-carboxymethyl-1, 2, 3, 4tetrazol-5-yl) -thiomethyl, a group [1- boxy) or a group 2- dihydro-l, 2, Thus as mentioned above, in addition to the fact that they are useful in various chemical processes as indicated above, the compounds of formula (I) can be easily hydrolyzed to give the free carboxylic acids of formula (III) whose it was mentioned above.



  As already indicated, the acids of formula (III), as well as their acceptable salts in the field of pharmacy or in the veterinary field exert a high broad-spectrum antibacterial activity against most of the gramposititive and gram- negative in both animals and humans; therefore, they are useful in the treatment of infections caused by these microorganisms in humans and animals, for example, respiratory tract infections such as bronchitis, bronchopneumonia, pleurisy; hepatobiliary and abdominal infections, for example, pyelonephritis and cystitis; obstetric and gynecological infections, for example, cervicitis and endometritis;

   ear, nose and throat infections, for example, otitis, sinusitis and parotitis.



  As useful compounds due to their antibacterial activity, the invention also provides

  <Desc / Clms Page number 26>

 
 EMI26.1
 compounds corresponding to formula (Ia) below:
 EMI26.2
 
 EMI26.3
 in which R .. -E- and the symbol --- Y
 EMI26.4
 the meanings defined above; RI and J each represent a hydrogen atom; X 'represents an oxygen atom and RI represents a phenyl group, a 4-methylphenyl group, a group
 EMI26.5
 4-chlorophenyl, a 4-acetamidophenyl group or a 4-methoxyphenyl group, as well as their acceptable salts in the pharmaceutical or veterinary field and also pharmaceutical or veterinary compositions containing a compound of formula (Ia) or one of its salts as active ingredient.



   It has been found that the toxicity of the compounds of formula (Ia) is similar to that of the corresponding free carboxylic acids of formula (III) and that, therefore, they can be safely used in therapy.



   The compounds of formula (Ia) can be administered to mammals at dosage levels analogous to those adopted for the corresponding free carboxylic acids of formula (III). Preferably, the compounds of formula (Ia) are administered orally, although they can also be administered by other conventional methods, for example, parenterally, for example, by intramuscular or intravenous injection, or even by rectal route. When the compounds of formula (Ia) are, for example, penems, the levels of

  <Desc / Clms Page number 27>

 Dosage for oral administration in adult humans is between about 100 mg and about 200 mg per dose, one to four times a day, the exact dosage level depending on age, weight and patient's condition.



   As indicated above, the scope of the invention also encompasses a pharmaceutical or veterinary composition comprising a compound of formula (Ia) or a salt thereof in combination with an excipient which is acceptable from the pharmaceutical or veterinary point of view ( which can be a support or a diluent). Pharmaceutical or veterinary compositions containing the compounds of formula (Ia) or a salt thereof, are usually prepared by adopting conventional methods and they are administered in a form which is suitable from the pharmaceutical or veterinary point of view. Dosage forms used for oral administration can be, for example, tablets, capsules, sugar-coated or film-coated tablets, as well as liquid dispersions.

   The pharmaceutical forms used for parenteral administration, for example, intramuscularly or intravenously, can be, for example, solutions or suspensions; for intramuscular injections, suspensions or solutions can be used while, for intravenous injections, aqueous solutions can be used.



   The pharmaceutical forms used for rectal administration can be, for example, suppositories. The pharmaceutical forms contain the compounds of formula (Ia), as well as a pharmaceutically acceptable carrier and / or diluent. Solid forms for administration

  <Desc / Clms Page number 28>

 orally may contain, together with the active compound, diluents, for example, lactose, dextrose, sucrose, cellulose, corn starch and potato starch;

   lubricants, for example, silica, talc, stearic acid, magnesium stearate, calcium stearate and / or polyethylene glycols, binding agents, for example, starches, gum arabic, gelatin, methyl cellulose, carboxymethyl cellulose and polyvinyl pyrrolidone; disintegrating agents, for example, starch or alginic acid. Liquid dispersions for oral administration may be, for example, syrups, emulsions and suspensions. The syrups may contain, as a carrier, for example, sucrose or sucrose with glycerin and / or mannitol and / or sorbitol.

   The suspensions and the emulsions can contain, as support, for example, a natural gum, agar-agar, sodium alginate, pectin, methyl-cellulose, carboxymethylcellulose or polyvinyl alcohol.



   Suspensions or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, for example, sterile isotonic water, olive oil, ethyl oleate, glycols, for example , propylene glycol, and possibly an appropriate amount of lidocaine hydrochloride. Suppositories may contain, together with the active compound, a pharmaceutically acceptable carrier, for example, cocoa butter, polyethylene glycol, a surfactant based on a fatty acid ester of polyoxyethylene sorbitan or the lecithin. The examples

  <Desc / Clms Page number 29>

 ples below illustrate, but in no way limit the invention.



  Example 1 l-phenoxyl-chlorethane
 EMI29.1
 
At a temperature of OIC, while stirring, anhydrous hydrogen chloride was passed through homogeneous phenyl vinyl ether (26.5 g, 0.22 mole) until the theoretical amount was adsorbed (about 8 g). The mixture was purged with nitrogen and the product obtained (34.3 g) was used as it was for the next step.



  Nuclear magnetic resonance spectrum Ó parts per million (CDC13): 1.88 (3H, d, J = 5.5 Hz, CH-CH3),
6.08 (1H, q, J = 5.5Hz ,, CH,, 6, 8-7, 4 (5H, m, Ar).



  Example 2 1-Phenoxy-ethyl tartrate
 EMI29.2
 
For 30 minutes, a solution of L (+) tartaric acid (16.1 g, 0.11 mole) and triethylamine (30.8 cm3, 0.22 mole) in dimethylformamide (120 ml) was added dropwise. cm3) to a solution (ice-cold) of 1-chloro-1-phenoxyethane (34.5 g, 0.22 mole) in dimethylformamide (80 cm3).



  In a few minutes, a precipitate formed

  <Desc / Clms Page number 30>

 White. After one hour, the reaction mixture was poured into ice water (1: 1, 500 g) while stirring, then extracted three times with diethyl ether (3 x 200 cm3).



   The combined organic phase was washed
 EMI30.1
 with 4% aqueous NaHCO, then with brine, after which it was dried over NaSO, filtered through 4 and evaporated to obtain the title compound in the form of a light yellow oil (42 g , 98%).



    Infrared ray absorption spectrum # max
 EMI30.2
 (CHC13): 3450, 3060, 2970, 2930, 1740, 1590, 1490, 1115 cm '.



  Nuclear magnetic resonance spectrum o parts per million (CDC13): 62 and 1.64 (6H, each d, and COOCH (Ph) 4, and 4.60 (2H, each s, CH-OH), 6.53, 6, 6, 62 and 6, 64 (2H, each q, CH-CH), 6, 26 (10H, m, Ar).



  EXAMPLE 3 1-Phenoxyethyl Glyoxylate (Hydrate)
 EMI30.3
 
 EMI30.4
 Under a nitrogen atmosphere, lead tetracetate (46.1 g, 0.104 mole) was added in portions to an ice-cold, stirred solution of 1-phenoxyethyl tartrate (38, mole) in anhydrous tetrahydrofuran (250 ml).



   A white precipitate immediately formed.

  <Desc / Clms Page number 31>

 



   After one hour, the precipitate was separated by filtration and the filtrate was evaporated to obtain a brown oil which was dissolved in diethyl ether, which was washed successively
 EMI31.1
 with BAHCO. aqueous at 4% and brine, which was dried (NaSO.), discolored with z 4 carbon and filtered through celite.



   The filtrate was concentrated in vacuo to obtain a white slurry which gave the product
 EMI31.2
 pure by crystallization from di-isopropyl ether; white crystals melting point: 95-960c (26.2 g, 63%).



  Absorption spectrum of infrared rays (CHC1): 3540, 1745 cm-.



  Nuclear magnetic resonance spectrum J parts per million: 1.65 (3H, d, J = 5, and 7.5 Hz, LH 5.52 (2H, m, DO exchange, CH (OH) 2; 6.58 ( 1H, q, CH-CH3), 6, 93-7, 44 (5H, m, Ar).



  Example 4 1-Phenoxyethyl fumarate
 EMI31.3
 
While stirring at a temperature of 0-10 C, a solution of fumaric acid (8.7 g, 75 mmol) and triethylamine (21 ml, 150 moles) was treated

  <Desc / Clms Page number 32>

 in dry dimethylformamide (30 ml) with a solution of 1-phenoxy-1-chlorethane (23.3 g, 150 mmol) in the same solvent (30 ml). The reaction mixture was stored overnight in a refrigerator, then poured into ice water (200 ml) and extracted with ethyl ether.



  Evaporation of the solvent left the crude product which was crystallized from a mixture of ethyl ether and light petroleum to obtain white crystals with a melting point of 87-880C (16.1 g, 60% ).
 EMI32.1
 



  Nuclear magnetic resonance spectrum parts per million (CDC13): 1.60 (6H, d, J = 6.55 (2H, q, J = 5.5 Hz, CH-CH3) 6, vinyl and aryl protons).



  Example 5 1-Phenoxyethyl Glyoxylate
 EMI32.2
 
A stream of ozone in dry oxygen was passed through a solution of 1-phenoxyethyl fumarate (0.6 g in dichloromethane (20 ml) until a dark blue color appeared
 EMI32.3
 se.



   The solution was purged with nitrogen and silica gel (2 g) was added. The mixture was allowed to reach room temperature while stirring vigorously and, after one hour, was filtered. The filtrate was washed with dilute aqueous sodium hydrogen carbonate, dried (Na2SO4) and evaporated to thereby obtain the

  <Desc / Clms Page number 33>

 product under heading which is identical to the sample described in Example 3.



  Example 6 1-Phenoxyethyl 6-phenoxyacetamidopenicillanate
 EMI33.1
 
Triethylamine (200 µl, 1.43 mmol) was added to a solution of penicillin V (500 mg, 1.43 mmol) in tetrahydrofuran (5 ml). To this solution, while stirring at a temperature of 0 C, 1-phenoxy-1chlorethane (235 mg, 1.5 millimole) was added in acetonitrile (2 ml). After one hour at OoC, the reaction mixture was partitioned between ethyl ether and 4% aqueous NaHCO3.

   Evaporation of the solvents out of the dried organic layer (NaSO 4) left a syrup which was crystallized once in diisopropyl ether to thus obtain the product under heading in the form of a slightly waxy solid with a almost quantitative yield.
 EMI33.2
 



  Nuclear magnetic resonance spectrum parts per million (CDC13): 1, 44, 1, and 1.57 (6H, each s, gem-CH3) 1.68 (3H, d, J = 5.5 Hz, 4, and 4.43 (1H, each s, N-CH-CO) 4.53 (2H, s, OCH-CO)

  <Desc / Clms Page number 34>

   5, 45-5, 80 (2H, m, p-lactam protons) 6, 63 (1H, m, CH-CH3) 6, 76-7, 40 (11H, m, CONH and Ar).



  EXAMPLE 7 6-Phenoxyacetamidopenicillanic acid
 EMI34.1
 
For 30 minutes, a mixture of 1-hydroxyethyl 6-phenoxyacetamidopenicillanate (50 mg) and ZnCl2 (58 mg) was stirred at room temperature in dry ethanol-free dichloromethane. Then, ethyl acetate and 5% aqueous citric acid were added and the organic layer was washed several times with brine, dried (Na2SO4), filtered on "Hi-flow" and it was evaporated so as to obtain the expected penicillin V in the form of a white foam with an almost quantitative yield.

  <Desc / Clms Page number 35>

 



  Example 8 1-Phenoxyethyl 7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate
 EMI35.1
 
A solution of 7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid (1.04 g, 3 mmol) and triethylamine (0.42 ml, 3 mmol) in acetonitrile ( 5 ml) cold (OOC) to a stirred solution of 1-chloro-1-phenoxyethane (0.47 g, 3 millimoles) in the same solvent. A white precipitate immediately formed.



   After one hour at OOC, the reaction mixture was poured into ice water and extracted with ethyl ether (2 x 50 ml). We have
 EMI35.2
 dried the organic extracts (NaSO 4) and they were evaporated to obtain the crude product in the form of a solid with a quantitative yield. By crystallization from ethyl ether, an analytical sample was obtained; melting point: 90 C.



  Absorption spectrum of infrared rays 9 max (KBr): 3430-3270, 1780, 1715, 1650, 1600, 1580 and
1525 cm ".

  <Desc / Clms Page number 36>

 



  Nuclear magnetic resonance spectrum # parts per million (CDC13): 1.71 (3H, d, J = 5 Hz, CH-CH3)
2.03 (3H, s broad, 3-CH3) 3.33 (2H, ABq, J = 18 Hz, separation of internal lines 14 Hz,
2-CH2) 4.55 (2H, s, 0-CH2CO)
4.98 (1H, d, J = 6 Hz, 6-H)
5.87 (1H, dd, J = 6 and 9 Hz, 7-H)
 EMI36.1
 6, 69 (1H, q, J = 5 Hz, CH-CH3) 6, 8-7, 4 (11H, m, CONH and Ar).



  Example 9 7-Phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid
 EMI36.2
 Method a)
 EMI36.3
 1-Phenoxyethyl 7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate (50 mg) was dissolved in 3.5 ml of a 20% trifluoroacetic acid solution in dry dichloromethane. The mixture was stirred for one hour at -100C.



   By treatment (evaporation to dryness, partition of the residue between ethyl acetate

  <Desc / Clms Page number 37>

 and a dilute aqueous solution of NaHCO-, acidification of the latter and re-extraction with ethyl acetate), the product under heading was obtained with an almost quantitative yield.



  Method b)
The 1-phenoxyethyl ester (48 mg) was dissolved in dry benzene (3 ml) and stirred for 1.5 hours at room temperature with an equivalent molar amount of p-toluene sulfonic acid (10 mg ) and, after this period, thin layer chromatography revealed a complete transformation. The mixture was filtered to collect a powder (37 mg, quantitative yield) which, on thin layer chromatography was identical to an authentic sample of the product under heading.



  Method c)
 EMI37.1
 1-Phenoxyethyl 7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate (50 mg) was stirred in dry dichloromethane (2 ml) with ZnC12 (58.2 mg) for 15 minutes at temperature ambient and, at the end of this period, thin layer chromatography revealed a complete transformation. The reaction mixture was taken up in ethyl acetate, washed with dilute HCl solution, dried (Na2SO4) and evaporated to obtain the title product.



  Method d)
The 1-phenoxyethyl ester (50 mg) was treated in dimethylformamide (1 ml) with
 EMI37.2
 Na2S205 ml). After stirring for 0.1 M aqueous z z (116 hours at room temperature, the conversion to the title product was approximately 5%.



  Acetic acid (1 ml) was then added and the transformation reached 45-50% after 24 hours.

  <Desc / Clms Page number 38>

 



  When 0.1 ml of H-PO was added. at 85%, on thin layer chromatography and monitoring for 2 hours, a transformation of 80-85% was observed in the product under heading.



  Example 10
 EMI38.1
 3 (S) -) - (1-methyl-1, [1-hydroxy-1-azetidin-2-one
 EMI38.2
 Step a)
Bromacetic acid (13.9 g, 0.1 mole) and sodium hydrogen carbonate (8.4 g, 0.1 mole) in water (100 ml) were added to the sodium salt of 1 -methyl-5-mercapto-tetrazole (17.14 g, 0.1 mole) in 95% ethanol (100 ml) and the mixture obtained was stirred for 2 hours at room temperature.



  The organic solvent was removed in vacuo, the resulting aqueous solution was acidified with 2N HCl, saturated with NaCl and extracted several times with ethyl acetate. The combined extracts were dried (NaSO) and evaporated to obtain a slurry which crystallized from diisopropyl ether, thus giving 16.4 g (94%) of (1-methyl-1, 2, 3) acid , 4-tetrazol-5-yl) -thioacetic in the form of white crystals, melting point: 112 C.

  <Desc / Clms Page number 39>

 
 EMI39.1
 Nuclear magnetic resonance spectrum parts per million (d 4, (3H, s, CH3) 4, 19 (2H, s, CH2) 10, 70 (1H, s, D20, OH exchange).



  Step b)
For 5 minutes, at a temperature of 0 C, a solution of the product of step a) (6.97 g, 0.04 mole) and triethylamine (0.56 ml, 0.04 mole) was stirred in dry dichloromethane (200 ml) and, at the end of this period, PC15 (8.33 g, 0.04 mole) was added in portions. After stirring for 30 minutes at OOC and after an additional hour at room temperature, the mixture was evaporated in vacuo to dryness, it was taken up in dichloromethane (60 ml), the insoluble materials were separated by filtration and added dropwise to a solution of pyridine (12.9 ml; 0.16 mole) in dichloromethane (100 ml) which had previously been saturated with H2S at 0 C.

   The mixture obtained was stirred for 70 minutes at 0 ° C., then it was freed from excess H2S by evaporation under vacuum. The residue was dissolved in dichloromethane
 EMI39.2
 and washed successively with 10% H 2 SO 4 and brine. After removing the solvent, 7.5 g (quantitative yield) of (1methyl-1, 2, 3, 4-tetrazol-5-yl) acid were obtained. Absorption spectrum of infrared rays max # max (nujol): 2540 and 1690 cm Nuclear magnetic resonance spectrum of parts
 EMI39.3
 per million (d-acetone): 6 4, s, CH3) 01 (3H, 4, 44 (2H, s, CH2) 7.57 (1H, s, D20 exchange, SH).

  <Desc / Clms Page number 40>

 



  Step c)
At a temperature of OOC, a solution of the product of step b) (4.1 g, 21.6 millimoles) in IN NaOH (21.6 ml, 21.6 miDimoles) was added dropwise. solution of 3 (S) - [1 (R) -tert- butyldimethylsilyloxyethyl] -4 (R, S) -acetoxy-azetidin- 2-one (4.1 g, 14.3 millimoles) in water (40 ml) and acetone (80 ml).



   The mixture was stirred for 2 hours at 100C and, from time to time, a few drops of IN NaOH were added thereto in order to maintain the pH between 7, 6 and 7, 9. By removing the solvent, it was extracted several times the aqueous solution with dichloromethane, the organic extracts were dried (Na2SO4) and evaporated in vacuo. Chromatography
 EMI40.1
 oily residue (SiO H as eluent) gave 2.5 g (42%) of (3S) - [1 (R) -tert-butyl-dimethylsilyloxyethyl] -4 (R) - (1-methyl-1,2 , 3,4-tetrazol-5-yl) -thioacetylthio-azetidin-2-one in the form of a colorless gum.
 EMI40.2
 



  Absorption spectrum of infrared rays J 1 max (CHC13): 1775 and 1690 cm "-.



  Nuclear magnetic resonance spectrum parts per million (CDC13): 0.06 (6H, s, Me2) 0.88 (9H, s, But) 1, 20 (3H, 6 Hz, CH-CH) 3, 2 and 4 Hz, CH-CH-CH) 4, (3H, s, N-CH3) 4.39 (2H, s, CH2) 5.34 (1H, d, J = 2 Hz, CH-CH-S) 6, 79 (1H, br s, exchange DO, NH).

  <Desc / Clms Page number 41>

 
 EMI41.1
 



  For C-HN0 Found: 32; H 6.58 N 16.67; S 15, 28 Calculated: 14; H 6.52; N 16.77; S 15, 36.



  Step d) For 7 hours, a solution of the product of step c) (0.835 g, 2 millimoles) and 1-phenoxyethyl glyoxylate was heated to reflux to one molecule of water (0.764 g, 3.6 millimoles) in benzene with azeotropic removal of the water formed during the reaction.



  Chromatography (SiO2; EtOAc / C6H12 as eluents) of the residue gave the title compound (mixture of four diastereoisomers) in the form of a white foam (501 mg, 41%).



  Infrared ray absorption spectrum v 1 max (CHC13): 3600-3100, 1765 and 1690 Nuclear magnetic resonance spectrum o parts per million (CDC13): 0, (6H, s, Me2) 0.87 (9H, s , Bu 1, 13 and 1, 18 (3H, each d, 1, (3H, 3, 3, 4, 30 (1H, 4, 15 and 4, each s, CH2) 4, s large, exchange D20, CH -OH) 5, 20-5, 35 (1H, m, CH-CH-S) 5, 40-5, 6, 30-6, 70 (1H, m, CH3-CH-OPh) 6, 80-7 , 40 (5H, m, Ar).

  <Desc / Clms Page number 42>

 
 EMI42.1
 



  Example 11 (4R) - (3S) - chloro-1-din-2-one.
 EMI42.2
 
 EMI42.3
 



  A stirred solution of (4R) 2, 3, 4-tetrazol-5-yl) thioacetylthioethyl] -1-methyl-azetidin-2-one (360 mg millimole) was successively treated in dry tetrahydrofuran (8 ml) at -35 ° C. under a nitrogen atmosphere with pyridine (0, ml; 0, millimole), then with thionyl chloride (0, ml; 0, 59 millimole). He was formed immediately-

  <Desc / Clms Page number 43>

 
 EMI43.1
 a white precipitate. After 5 minutes, the reaction mixture was heated to OIC, filtered and the solid was washed with dry tetrahydrofuran.



  The filtrate and the washing products were evaporated in vacuo until dry to obtain the title compound in the raw state in the form of a light yellow gum (370 mg; 100%).



  Infrared absorption spectrum \) 1 max (CHC13): 1785, 1700 cm Example 12 (4R) - (3S) - triphenylphosphoranylidene-1- (1-phenoxyethyl) carbonyl] -methyl-azetidin-2-one.
 EMI43.2
 
 EMI43.3
 



  While stirring, to a solution of (4R) - (1-methyl-1, (3S) chloro-1-tidin-2-one (360 mg was added

  <Desc / Clms Page number 44>

 pyridine (0.046 ml; 0.57 millimole), triphenylphosphine (300 mg; 1.14 millimole) and silica gel ("Kieselgel 60", 2 30-400 mesh; 2.2 g). The solvent was removed in vacuo and the residue allowed to stand for two hours at room temperature, after which time it was placed on top of a column of silica gel. By elution with mixtures of acetates
 EMI44.1
 ethyl tate / cyclohexane, the title compound was obtained as a white foam (283 mg; 58%).



  Infrared absorption spectrum 9 1 max (CHC13): 1755, 1690, 1620 cm Example 13 (5R, 6S) -6 - [(1R) -tert-butyldimethylsilyloxyethyl] - 2- (1-methyl-1,2 , 3,4-tetrazol-5-yl) -thiomethyl-penem- 1-phenoxyethyl 3-carboxylate
 EMI44.2
 
For 3 hours, under a nitrogen atmosphere, a solution of (4R) - was heated to reflux.
 EMI44.3
 (1-methyl-1 (3S)

  <Desc / Clms Page number 45>

 
2, 3, triphenylphosphoranylidene-1- (1-phenoxyethyl) -oxycarbonyl] -methyl-azetidin-2-one (282 mg; 0.33 millimole) in dry toluene (12 ml).



   Removal of the solvent and chromatography on silica gel (mixtures of ethyl acetate / toluene as eluents) gave the compound under heading (two diastereoisomers) under
 EMI45.1
 shape of an eraser; 120 mg Ultraviolet A (hexane) absorption spectrum: 334 nm. max Infrared ray absorption spectrum \) 1 max): 1790, 1705 cm-.



  Nuclear magnetic resonance spectrum o parts per million (CDC13): 0.05 (6H, s, Me2) 0.87 (9H, s, Bu) 1.19 (3H, d, J = 6 Hz, CH3-CH- OSi) 1.68 (3H, d, J = 5 Hz, 3.68 (1H, dd, J = 2 and 4 Hz, CH-CH-CH)
3.88 (3H, s, N-CH3)
4.21 (1H, m, CH3-CH-Osi)
4, 58 and 4, 64 (2H, each ABq, J = 13 Hz, separation of internal lines 14 and 7 Hz)
5.54 (1H, d, J = 2 Hz, CH-CH-S) 6.58 and 6.63 (1H, each q, J = 5 Hz,
CH3-CH-OPh)
6, 90-7, 40 (5H, m, Ar).



  For C22H35N5O5SiS2
 EMI45.2
 Found: C 63; H 6.24; N 12, 08 88 Calculated: C H 6, 11 N 12, 12; S 11, 10.

  <Desc / Clms Page number 46>

 



  Example 14 (SE, 6S) -6- [1 (R) -hydroxyethyl] -2- (1-methyl-1,2,3,4- tetrazol-5-yl) -thiomethyl-3-penem-3-carboxylate 1-phenoxyethyl
 EMI46.1
 Method A
For 5 hours, at 28oC, one stirred a
 EMI46.2
 solution of (5R 6S) silyloxyethyl] -2- 3, 4-tetrazol-5-yl) 1-phenoxyethyl thiomethyl-penem-3-carboxylate (22 mg; 0.038 millimole) in tetrahydrofuran (1 ml) water (1 ml) and acetic acid (3 ml).



  The mixture was concentrated in vacuo.



   By chromatography of the residue on silica gel, eluting with mixtures of ethyl acetate / toluene, the unreacted starting material was obtained first, then the title compound as white foam (4, 6 mg 26%).
 EMI46.3
 



  HAVE

  <Desc / Clms Page number 47>

 
 EMI47.1
 Max ultraviolet absorption spectrum 'Method B
At a temperature of OOC, a solution of the o-silylated penem ester (15 mg; 0.026 millimole) in dry tetrahydrofuran (0.5 ml) was treated.
 EMI47.2
 with tetrabutylammonium fluoride (20, 0, millimole). The resulting mixture was stirred for 3 hours at room temperature, then poured into water and extracted with ethyl acetate. The combined organic phase was dried (Na 2 SO) and evaporated to obtain a brown oil.



  By chromatography on silica gel, eluting with ethyl acetate / cyclohexane mixtures, the title compound was obtained in the form of a light yellow gum (1.8 mg; 15%).



  Ultraviolet absorption spectrum
 EMI47.3
 max 'Example 15 (SR tetrazol-5-yl) -thiomethyl-penem-3-sodium carboxylate
 EMI47.4
 

  <Desc / Clms Page number 48>

 
 EMI48.1
 Method a)
A solution of (5R, 6S) -6- [1 (R) tert-butyldimethylsilyloxyethyl] -2- (1-methyl-1,2,3,4tetrazol- 1-phenoxyethyl 5-yl) -thiomethyl-penem-3-carboxylate (69 mg; 0.12 millimole) in 0.4N aqueous oxalic acid (16 ml) and tetrahydrofuran (6 ml).

   The mixture was neutralized with NaHCO3 and evaporated in vacuo to a low volume, then passed through a reverse phase column, eluting with water; thus, the title compound was obtained as an amorphous solid (8 mg; 18%).



  Max ultraviolet absorption spectrum (H20): 315 nm.



  Nuclear magnetic resonance spectrum # parts per million (D20): 1, 28 (3H, d, J = 6, 3 Hz)
3.87 (1H, dd, J = 1.4 and 6.3 Hz) 4.10 (3H, s)
4.19 (1H, m)
4.40 (2H, ABq, J = 16 Hz, internal line separation 13 Hz) 5.59 (1H, d, J = 1.4 Hz) Method b)
The 1-phenoxyethyl penem carboxylate (22 mg; 0.038 millimole) was dissolved in a 4: 2: 1 mixture of acetic acid / tetrahydrofuran / water and stirred for 16 hours at room temperature.

  <Desc / Clms Page number 49>

 



  Thin layer chromatography revealed a transformation greater than 80%. The mixture was neutralized with NaHCO - concentrated and passed through a reverse phase column to obtain the title product with a yield of 48%.



  Example 16 (+) (3, 4-trans) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) -
 EMI49.1
 thioacetylthio-3-ethyl-1- ethyl)
 EMI49.2
 [1-hydroxy-l- (l-phenoxy-Step a)
The thio-acid (1-methyl-1, 2, 3, 4-tetrazol-5-yl) -thioacetic (3 g, 15.8 mmol) was reacted, prepared as described in Example 10, steps ab , with (+) - trans-4-acetoxy-3-ethyl-azetidin-2- one (1.57 g, 10 millimoles) and IN NaOH (15, 8 ml) in a mixture of water and acetone.

   When the starting material had virtually disappeared, the mixture was partitioned between dichloromethane and water and the organic extracts were evaporated to obtain a syrup which was purified by chromatography on silica gel to obtain thus 1.13 g of (+) (3,4-trans) -4- (1-methyl-1,2,3,4-tetrazol-5-yl) -thioacetylthio-3-ethyl-azetidin-2-one in the form of a powder.

  <Desc / Clms Page number 50>

 
 EMI50.1
 Parts per million nuclear magnetic resonance spectrum (CDC13): 1.04 (3H, t, J = 5.0Hz, CH3-CH2) 1.84 (2H, m, CH3-CH2-CH) 3.21 (1H , m, CH2-CH-CH) 4.40 (3H, s, N-CH3) 4.40 (2H, s, CH2-S) 5.05 (1H, d, J = 2.0 Hz, CH- CH-S) 7.13 (1H, broad s, exchange with D20, NH)
 EMI50.2
 For CHN S Found: 37, 81 H 4, 42 N 23, 89 S 22, 28 Calculated:

   H 4, 56 N 24, 37 22, 32.



  Step b)
For 5 hours, in a Dean-Stark apparatus, a solution of (+) (3,4-trans) -4- (1-methyl-1,2,3,4-tetrazol-5-) was refluxed yl) - thioacetylthio-3-ethyl-azetidin-2-one (1, 1 g) and 1-phenoxyethyl glyoxylate to 1 molecule of water (l, g) in benzene (25 ml). Complete removal of the solvent gave the crude product which could be isolated in the pure state as a mixture of di-stereoisomers with a yield of 61% after chromatography on silica gel.



  Parts per million nuclear magnetic resonance spectrum (CDC13):
1.02 (3H, t, CH3-CH2-)
1.67 and 1.73 (3H, each d, 0-CH (OPh) CH3)
1.80 (2H, q, CH3CH2-
 EMI50.3
 3, 00-3, 40 (1H, m, CH2-CH-CH) 3, 97, 3, 98 and 3.99 (3H, each s, N-CH3) 5, 21, 5, 23 and 5, 31 (1H, each d, J = 2 Hz, CH-CH-S) 5.38 (1H, m, N-CH-OH) 6, 50, 6, 62, 6, 69 and 6.79 (1H, each q, OCH (OPh) CH)

  <Desc / Clms Page number 51>

 
 EMI51.1
 6, 90-7, 50 (5H, m, Ar).



  Example 17 (5,6-trans) -2-methyl-6-ethyl-penem-3-carboxylate of () -1-phenoxyethyl
 EMI51.2
 

  <Desc / Clms Page number 52>

 
 EMI52.1
 
 EMI52.2
 The compound under heading was obtained from () (3, 4-trans) 2, 3, 4-tetrazol-5-yl) (1-phenoxyethyl) and following the same experimental process as that described in Examples 11 , 12 and 13 (yields step I, 95%; step II, 63% step III, 70%).



  Absorption spectrum of ultraviolet rays âmax (CH30H): 332 nm. max Absorption spectrum of infrared rays V 1 max (CHC13): 1785, 1705 cm-.



  Nuclear magnetic resonance spectrum o per million (CDC13): 1.05 (3H, t, J = 7.0 Hz, 1, (2H, d, J 5 Hz, 1.81 (2H, m, 3.84 ( 1H, m, CH2-CH-CH) 3, 91 (3H, s, N-CH3) 4, 47-4, 82 (2H, each ABq, CH2S) 5, 39 and 5, 41 (1H, d, J = 2 Hz, CH-CH-S) 6, 59 and 6, 63 (1H, each q, Hz, OCH (OPh) 6, 90 and 7, 40 (5H, m, Ar).

  <Desc / Clms Page number 53>

 
 EMI53.1
 



  Example 18 (5, 24-tetrazol-5-yl) -thiomethyl-6-ethyl-penem-3-carboxylate of () sodium.
 EMI53.2
 
 EMI53.3
 



  Method a) The (5, 1, 2, 3, (+) millimole) carboxylate was dissolved in dioxane (3 cm 3) and the solution obtained was treated dropwise with a 0.2N aqueous metabisulfite solution ( 3 cm3). The mixture was vigorously stirred for 30 hours at 25 ° C.



   The solution was concentrated to a small volume and the pH was adjusted to 7.



   By chromatography in a reverse phase column and eluting with water, the compound under the heading was obtained (Rf = 0.32; tetrahydrofuran / phosphate buffer pH 7.4, 1: 1) in the form of a amorphous solid (19.8 mg; 57%) and with a certain amount of the unreacted starting material (5 mg).



  Absorption spectrum of ultraviolet rays max 20): 314 nm.

  <Desc / Clms Page number 54>

 



  Method b)
For several hours, at room temperature, the 1-phenoxyethyl penem carboxylate was stirred in a mixture of acetic acid, tetrahydrofuran and water (4: 2: 1).



   The control was carried out by thin layer chromatography. Treatment and purification, carried out as described in Example 15, gave the title compound.



  EXAMPLE 19 P-Nitrophenyl Vinyl Ether
 EMI54.1
 
For 2 hours, at room temperature, a mixture of p-nitrophenol (4.17 g, 30 mmol) and vinyl acetate (9 ml) in cyclohexane (9 ml) was stirred in the presence of mercuric acetate
 EMI54.2
 (0, g) and 98% H2SO4 (2 drops). The reaction mixture was poured into ice-cold 20% NaOH and stirred for a few minutes. Then, ethyl ether was added; the mixture was again stirred and, by filtration, the unreacted sodium nitrophenate was recovered.



   The organic layer was washed several times with water, dried (Na2SO4) and evaporated to obtain the title product (1-1.5 g). By chromatography on silica gel, an analytical sample was obtained in the form of a yellow powder.



  Nuclear magnetic resonance spectrum d parts per million (d 6-acetone):
 EMI54.3
 4, J = 6 and 2 Hz, H H

  <Desc / Clms Page number 55>

 
 EMI55.1
 4, J = 13 and 2 Hz, H 6, and 6 Hz, -
 EMI55.2
 7, and 8, each d, J = 9 Hz, Ar).



  By the same experimental method and starting from the appropriate phenol, the following vinyl esters were obtained and characterized, inter alia, p-acetamidophenyl vinyl ether Nuclear magnetic resonance spectrum parts per million (CDCl) 2, 18 (3H, s, CH )
 EMI55.3
 4, J = 6 and 1, H 4, J = 14 and 1.8 Hz, H H 6, and 14 Hz, HH H
 EMI55.4
 6, and 7, 29 (4H, each d, J = 9 Hz, Ar) Ether p-tert-butylphenyl-vinyl Nuclear magnetic resonance spectrum cç parts per million (CDCl) 1, 28 (9H, s, t-Bu )
 EMI55.5
 4, dd, J = 6 Hz and 1, '- = \ - 4, J = 13 and 1, H H 6, = 6 and 13 Hz, HH' =
 EMI55.6
 6, 82 and 7, each d, J = 9 Hz, Ar).



  P-methoxyphenyl vinyl ether Nuclear magnetic resonance spectrum Ó parts per million (CDCl) 3.60 (3H, s,
 EMI55.7
 10 J = 7 and 2 Hz, \ - H

  <Desc / Clms Page number 56>

 
 EMI56.1
 4.52 (1H, dd, J = 14 and 2 Hz, H 6, dd, J = 7 and 14 Hz, H. -
 EMI56.2
 6, s large, Ar) p-Chlorophenyl vinyl ether Nuclear magnetic resonance spectrum o parts per million (CDCl):
 EMI56.3
 4, 53 (1H, dd, J = 4, 9 and 1.8 Hz, H 4, J = 12 and 1.8 Hz, HH 6, 60 (1H, dd, J = 12 and 4, 1! 6, 91 and 7, 26 (4H, each d, J = 9 Hz, Ar).



  Example 20 1-p-nitrophenoxy-1-chlorethane
 EMI56.4
 
Dry hydrogen chloride was passed through a solution of p-nitrophenylvinyl ether (0.42 g, 2.5 mmol) in tetrahydrofuran until thin layer chromatography (cyclohexane / acetate ethyl, 3: 1) reveals the complete transformation into a less mobile material (partial cleavage of the product into p-nitrophenol on the silica gel plate).



   Removal of the solvent gave the product in quantitative yield.
 EMI56.5
 



  Nuclear magnetic resonance spectrum J parts per million (CDC13): 6,

  <Desc / Clms Page number 57>

 
1.91 (3H, d, J = 5 Hz, CH-CH3) 7, 17 and 8, 11 (4H, each d J = 9 Hz, Ar).



  Example 21 1-p-chlorophenoxy-1-chlorethane
 EMI57.1
 
Following the experimental process described in Example 20, the compound was obtained under heading.
 EMI57.2
 Nuclear magnetic resonance spectrum J parts per million (CDC1) 1, J =: 6, 95 and 7, 28 (4H, each d J = 9 Hz, Ar).



   We obtained and immediately used other (substitution) -phenoxy-1-chlorethanes including
 EMI57.3
 in particular p-acetylamino-phenoxy-1-chlorethane and p-tert-butyl-phenoxy-1-chlorethane.



  Example 22 1-p-nitrophenoxyethyl 7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate.
 EMI57.4
 

  <Desc / Clms Page number 58>

 



   A solution of 7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid (0.871 g, 2.5 mmol) and triethylamine (0.35 ml, 2.5 mmol) was added in acetonitrile (8 ml) to an ice-cold solution of 1-p-nitrobenzyloxy-1-chlorethane (2.5 millimoles) in a mixture of dichloromethane (3 ml) and acetonitrile (6 ml).



  After stirring for 15 hours, the mixture was partitioned between ethyl acetate and 8% aqueous BAHCO. The dried organic phase was evaporated and the residue was crystallized from a mixture of acetone, ethyl ether and petroleum ether to obtain 0.74 g of the title ether as a white powder. Melting point: 92-106 C (mixture of diastereoisomers).



    Infrared ray absorption spectrum? max (KBr): 3420, 3280, 1775, 1720, 1685, 1515, 1345,
1255, 1220, 1110, 1060, 750 and 690 cm-1.



  Nuclear magnetic resonance spectrum o parts per million (CDC13):
 EMI58.1
 1, 73 (3H, d, CH-CH3) 2, 11 (3H, s,:) 3, 35 (2H, ABq, J = 18.5 Hz, internal line separation 14 Hz, S-CH2) 4, 50 and 4.53 (2H, each s, 0-CH2-CO) 4, CH-CH-S) 5, 81 (1H, m, NH-CH-CH) 6, 6-7, 4 (9H, m , Ar, and CONH) 8, 15 (2H, d, Ar).



  Starting from C-CH3-ethyl-3-cephem-4-carboxylic acid and the appropriate halide, a similar process gave the following esters:

  <Desc / Clms Page number 59>

 1-p-chlorophenoxyethyl 7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate; melting point: 129-143 C.



    Infrared ray absorption spectrum? max (KBr): 3410, 3260,1765, 1710, 1670, 1630, 1600,
1590, 1540, 1490, 1240, 1215 cm '.
 EMI59.1
 



  Nuclear magnetic resonance spectrum parts per million (CDC13): 1.67 (3H, 2.08 (3H, s,: C-CH) 3.36 (2H, ABq, J = 18 Hz, internal line separation 14 Hz ) 4.55 (2H, s, OCH2CO) 4.77 (1H, d, J = 4.5Hz, CH-CH-S) 5.84 (1H, dd, J = 4.5 and 8.0Hz , NH-CH-CH)
 EMI59.2
 6.66 (1H, q, CH-CH3) 6, 80-7, 40 (10H, m, CONH and Ar); 1-p-acetamidophenoxyethyl 7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate; melting point: 156-175 C Maximum infrared ray absorption spectrum (KBr): 3410,3260, 1770, 1710, 1670, 1600, 1535,
1510, 1490, 1240, 1210 cm.



  Nuclear magnetic resonance spectrum C parts per million (CDC13):
 EMI59.3
 1, 72 (3H, d, 2, 12 (3H, s,: C-CH) 2, 15 (3H, s, COCH3) 3, 55 (2H, ABq, J = 14.5 Hz, separation of internal lines 18.0 Hz) 4.58 (2H, s, 0-CH2CO)
 EMI59.4
 4, 98 (1H, d, J = Hz, CH-CH-S), 5, 87 (1H, dd, J = 8 and 4.5 Hz, NH-CH-CH) 6.56 (1H, 6, 87-7, 35 (11H, m, CONH and Ar).

  <Desc / Clms Page number 60>

 
 EMI60.1
 



  Example 23 1-p-aminophenoxyethyl 7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate
 EMI60.2
 
For 15 minutes, at room temperature, a solution of 1-p-nitrophenoxyethyl 7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate (51 mg, 0.1 millimole) was stirred in dichloromethane (3 ml) in the presence of zinc dust (100 mg) and acetic acid (5 drops). The metal was filtered off and the solvent was removed in vacuo to obtain the title product in quantitative yield.



    Absorption spectrum of infrared rays Q max max
 EMI60.3
 (CHC13): 3420, 1785, 1720, 1690, 1625, 16oo, 1510 - and 1490 cm. Nuclear magnetic resonance spectrum S parts per million (CDC13): 1.64 (3H, d, CH-CH3)
 EMI60.4
 2,:

   C-CH)

  <Desc / Clms Page number 61>

 
03 (3H, s, 3, 22 (2H, ABq, J = 17 Hz, separation of internal lines 6 Hz, S-CH2) 4, 03 (2H, s wide, NH2) 4, 51 (2H, s, 0 -CH2-CO) 4, 95 (1H, d, J = 4, 5 Hz, CH-CH-S) 5, 82 (1H, dd, J = zo and 8 Hz, NH-CH-CH)
 EMI61.1
 6.55 (1H, q, CH-CH3) 6.40 (10H, m, Ar and CONH) Example 24 (5R, 6S) -6- [1 (R) -tert-butyldimethylsilyloxyethyl] - 2-p-nitrobenzyloxycarbonyloxymethyl -penem-3-carboxy-l-phenoxyethylate
 EMI61.2
 Step a)
 EMI61.3
 ., af af r'la For one hour, at room temperature, glycolic acid (10 g), triethylamine (36.8 ml) and p-nitrobenzyl chlorocarbonate (19.8 g) in dichloromethane (100 ml).

   By treatment, filtration through a short column of silica gel (CH2Cl2 as eluent) and by crystallization from diisopropyl ether, 10.2 g of p-nitrobenzyloxycarbonyloxy-acetic acid with a melting point of 95-980C.

  <Desc / Clms Page number 62>

 



  Step b)
The product from step a) (5.4 g) was dissolved in dichloromethane (140 ml) in the presence of triethylamine (3 ml) and treatment was carried out at −15 ° C. with ethyl chlorocarbonate ( 2, 1 ml).



   After 20 minutes at room temperature, the mixture was again cooled, another portion of NEt3 (3 ml) was added and hydrogen sulfide was bubbled through the solution for 30 minutes at -15 ° C. treatment, extraction with
 EMI62.1
 NaHCO. and re-extraction with ethyl acetate after acidification, impure p-nitrobenzyloxycarbonyloxythioacetic acid was obtained which was used as it was without further purification.



  Step c)
The raw material from step b) was mixed with the 3 (S) - [1 (R) -tert-butyldimethylsilyloxyethyl] - 4 (R, S) -acetoxy-azetidin-2-one (2.81 g) in a mixture of water and acetone and the pH of the solution was brought to 7.5-5 by adding 1N NaOH. By treatment and chromatography after one hour, there was first obtained a certain amount of unreacted azetidinone, then 2.6 g of (3S) - [1 (R) -tert-butyldime-
 EMI62.2
 thylsilyloxyethyl] -4 (R) -p-nitrobenzyloxycarbonyloxyacétylthio-azétidin-2-one in the form of a syrup.



  Step d)
The teat material c) (700 mg) was refluxed with 1-phenoxyethyl glyoxylate to one molecule of water (600 mg) in benzene with slow azeotropic removal of the released water (DeanStark). After 4 hours, we evaporated properly
 EMI62.3
 the solvent to obtain 3 (S) dimethylsilyloxyethyl] -4 (R) -P-nitrobenzyloxycarbonyloxyacétylthio-l- [l-hydroxy-l-

  <Desc / Clms Page number 63>

 - [1 (R) -tert-butyl-bonyl] -methyl-azetidin-2-one in the form of a mixture of diastereoisomers.



  Step e)
1.1 g of the product from step were treated
 EMI63.1
 d) with pyridine (0.124 ml) and thionyl chloride (0.12 ml) in dry tetrahydrofuran (15 ml) for 30 minutes at 0 C. By filtration of the salt ("Hiflo" bed) and elimination of any volatile material, 3 (S) thylsilyloxyethyl] -4 (R) -p-nitrobenzyloxycarbonyloxyacetylthio-l- - [1 (R) -tert-butyldimé-methyl-azetidin-2-one-crude was obtained.



  Step f)
The material from step e) was treated with a solution of triphenylphosphine (1 g) and pyridine (0.12 ml) in dry tetrahydrofuran. Silica gel (4.6 g) was added and the solvent was removed. After allowing to stand for 2 hours, the powder was poured onto the top of a column of silica gel. By elution with a mixture of ethyl acetate and cyclohexane, 3 (S) - [1 (R) -tert-butyldimethylsilyloxyethyl] -4- (R) -p- was obtained.
 EMI63.2
 nitrobenzyloxycarbonyloxyacetylthio-1- [1-triphenylphosphoranylidene-1-methyl-azetidin-2-one in the form of a white foam.



  Step g)
320 mg of the material from step f) was heated for 4 hours in dry toluene at 95-960C. By removal of the solvent and chromatography, the product was obtained under the heading (120 mg).
 EMI63.3
 Nuclear magnetic resonance spectrum J parts per million (CDC13): 0.06 (6H, s, SiMe2) t 0.87 (9H, s, Bu) 1.22 (3H, d, CH-CHOSi)

  <Desc / Clms Page number 64>

 
 EMI64.1
 1, 63 and 1, each d, 3, 69 and 3, 71 (1H, each dd, J = 2 and 4.5 Hz, CH-CH-CH) 4, 22 (1H, m, CH3-CHOSi-CH ) 5.09 and 5.11 (1H, each d,: C-CHH-OCO) 5.26 (2H, s, 0-CH2-Ar)
 EMI64.2
 5, and 5, 51 (1H, each d,:

   C-CHH-OCO) 5.59 (1H, d, J = 2 Hz, CH-CH-S) 6, and 6.62 (1H, each q, CH3-CHOCO)
6, 84-7, 40 (5H, m, OC6H5) 7, 50 and 8, 20 (4H, each d, J = 9 Hz,
C6H4N02).



  Example 25 (5R, 6S) -6- [1 (R) -tert-butyldimethylsilyloxyethyl] - 2-hydroxymethyl-penem-3-carboxylate of 1-phenoxyethyl
 EMI64.3
 
For one hour, under a hydrogen atmosphere, a solution of (SR, 6S) -6- [1 (R) -tert-butyldimethylsilyloxyethyl] -2-p-nitrobenzyloxycarbonyloxymethyl-penem-3-carboxylate was stirred ( 120 ml) in ethyl acetate

  <Desc / Clms Page number 65>

 
 EMI65.1
 (6 ml) with 5% palladium-on-charcoal. The catalyst was filtered off and the solvent was removed. By chromatography of the residue (SiO 2 ethyl acetate / cyclohexane), it was obtained under heading.



  Max ultraviolet absorption spectrum (CHC13): 328 nm (C = 6236).



  3, r Nuclear magnetic resonance spectrum J parts per million (CDC13): 0.06 (6H, s, SiMe2) 0.87 (OH, s, Bu) 1, 20 1.62 and 1.64 (3H, each d, 3, 13 (1H, broad s, OH) 3, and 3.66 each dd, CH-CH-CH) 4.19 (11H, m, 4.54 and 4.55 (2H, each s, CH20H ) 6, 52 and 6, 55 (1H, each q, 3 H 6, 85-7, Ar).



  Example 26 (on, 6S) -6- 2-1-phenoxyethyl carboxylate
 EMI65.2
 

  <Desc / Clms Page number 66>

 
 EMI66.1
 
For 30 minutes, at OOC temperature, a solution of triphenylphosphine (60 mg) and diethyl azodicarboxylate (36 ml) in dry tetrahydrofuran (2 ml) was stirred, followed by treatment with a solution. from (5R, 6S) -
 EMI66.2
 6- [1 methylphenem-3-carboxylate 1-phenoxyethyl (30 mg) and 1-methyl-1, 2, sodium (22 mg) in dry tetrahydrofuran (1 ml).

   The reaction mixture was fractionated by chromatography on silica gel to obtain 15 mg of the title product which, in the absorption spectrum of ultraviolet rays, in the absorption spectrum of infrared rays and in thin layer chromatography, was identical to the material obtained according to Example 14.


    

Claims (22)

 CLAIMS 1. Compound of general formula (I)  EMI67.1  wherein R1 represents a hydrogen atom, a halogen atom or an organic group; R2 and R3, which are the same or different, each represents a hydrogen atom or an organic group; R4 represents an aromatic or heteroaromatic, monocyclic or bicyclic ring, unsubstituted or substituted by one or more chosen substituents  EMI67.2  from a CC alkyl group, C1-C6 alkoxy group 'a formyl group, a phenyl group, a phenoxy group, a C2-C6 alkanoyl group' a benzoyl group, a bonyl (C1-C6) alkoxy group, a amino group unsubstituted or substituted by one or two C1-C6alkylformylamino, acyl (C2-C6) halo and nitro groups;  the symbol-E-represents-0 - S-or-CH2- X represents an oxygen or sulfur atom and  EMI67.3  the symbol --- Y} a group completing,  EMI67.4  with the group-E- and the condensed azetidinone nucleus, the backbone of a 03-lactam antibiotic; as well as its salts.  2. Compound of formula (I) according to claim 1, formula in which:  <Desc / Clms Page number 68>  R1 represents a hydrogen atom, a chlorine atom, a bromine atom, an amino group, a phenylacetamido group, a phenoxyacetamido group, a 2-amino-2-phenyl-acetamido group, a 2- (2 -aminothiazol-4-yl) -2-methoxyiminoacetamido, a C1-C4 alkyl group or a 1-hydroxyethyl group; R and R3, which are identical or different, each represent a hydrogen atom or a group  EMI68.1  C1-C6 alkyl;  R4 represents a phenyl group which is unsubstituted or substituted by 1, 2 or 3 substituents chosen from a chlorine atom, a nitro group, a group  EMI68.2  methoxy, a C 1 -C alkyl group, an amino group, a formamido group and a (C 1 -C) amino group; X represents an oxygen atom; the symbol-E represents when the symbol-E-  EMI68.3  represents-S-, represents a group  EMI68.4  chosen from  EMI68.5  CH. Cl r 3 1 1 3 is - -C- -where r CH1 CH1 CH  EMI68.6  represents an organic group, while when  EMI68.7  the symbol the symbol --- Y 5 ts represents = C-CH- or the meaning defined above; as well as its salts.  3. Compound of formula (I) according to claim 1, formula in which: R1 represents a hydrogen atom, a chlorine atom, a bromine atom, an amino group, a phenylacetamido group, a phenoxyacetamido group, a group 2 -amino-2-phenyl-acetamido, a group  <Desc / Clms Page number 69>    EMI69.1  2- a C1-C4 alkyl group or a 1-hydroxyethyl group; R and R3 each represents a hydrogen atom; R4 represents a phenyl group, a p-nitrophenyl group, a p-aminophenyl group, a p-chlorophenyl group, a p-tolyl group, a p-tert-butylphenyl group or a p-acetamidophenyl group;  EMI69.2  X represents an oxygen atom;  the symbol-E represents when the symbol-E-represents  EMI69.3  present it a group  EMI69.4  chosen from  EMI69.5  CHL Cl t - -when when "CH, CH3 3 the symbol-E-represents-0-., R z represents = C-CH- and in both cases, R-is an unsubstituted C1-C4 alkyl group or substituted by a substituent chosen from:    EMI69.6  ail) a chlorine atom or a bromine atom b ") an alkanoyl group (C 2 -C 6) c") a carbamoyloxy group unsubstituted or substituted by one or two substituents chosen from a C 1 -C 4 alkyl group and a group phenyl, and d ") a group-S-Het where Het denotes a heteromonocyclic or heterobicyclic nucleus chosen from the group comprising a thiazole nucleus, a thiadiazole nucleus, a tetrazole nucleus, a triazine nucleus and a tetrazolopyridazine nucleus, this nucleus being at its tower unsubstituted or substituted by one, two or three substituents chosen from a cyano group, a C1-C12 alkyl group, an amino group, a bromine atom, a chlorine atom, a group  EMI69.7  hydroxy,  a C1-Cl2 alkoxy group formylo group 1 1  <Desc / Clms Page number 70>  unxy, a C2-C12 acyloxy group, a carboxy group, a (C1-Cl2) carbonyl alkoxy group and a carbamoyl group unsubstituted or substituted by one or two C1-C4 alkyl groups as well as its salts.  4. Compound of formula (I) according to claim 1, formula in which R1 represents an ethyl group or a 1-hydroxyethyl group; R and R3 each represents a hydrogen atom; R4 represents a phenyl group, a p-nitrophenyl group, a p-aminophenyl group or a p-chlorophenyl group; X represents an oxygen atom  EMI70.1  the symbol-E-represents sulfur  EMI70.2  R t the group = C-where  EMI70.3  acetoxymethyl group, carbamoyloxymethyl group, group (l-methyl-12.33, group (l-carboxymethyl-12, thiomethyl, group [l- (2-carboxy) tetrazol-5-yl] -thiomethyl, group 2- oxo-6-hydroxy-2, methyl or a group [1- (2-dimethylamino) 5 tetrazol-5-yl] -thiomethyl; as well as its salts.  5. Compound according to claim 1 corresponding to formula (Ia):  EMI70.4    <Desc / Clms Page number 71>    EMI71.1  in which R .. -E- and the symbol - Y  EMI71.2  meanings defined in claim 1 R'andR're each represent a hydrogen atom j X'represent an oxygen atom and a phenyl group, a 4-methylphenyl group, a 4-chlorophenyl group, a 4-acetamidophenyl group or a 4-methoxyphenyl group, as well as its pharmaceutically or veterinary acceptable salts.  6. Method for preparing a compound of formula (I) according to claim 1 characterized in that it comprises the steps which consist in A) bring together a synthon of formula (II)  EMI71.3  in which R6 is a radical derived from an α-amino acid, an α-hydroxy acid, an α-keto acid or an aalkenoic acid in which the amino, hydroxy and keto groups are free or protected by a protective group commonly used in the field of peptides,  EMI71.4  Rj, and X having the meanings defined J 4 in claim 1, with another synthon, then treating the intermediate product thus obtained according to methods known per se;    or  EMI71.5  B) reacting an acid of formula (III)  EMI71.6    EMI71.7  in which the symbols -E ---- Y and R. have the  EMI71.8  meanings defined in claim 1,  <Desc / Clms Page number 72>  or a salt of this acid, with a halide of formula (IV):  EMI72.1  in which Z represents a chlorine atom, a bromine atom or  EMI72.2  a fluorine atom, while R and X have the J 4 meanings defined in claim 1; and optionally transforming a compound of formula (I) into another compound of formula (I) and / or optionally transforming a compound of formula (I) into one of its salts; and / or optionally obtain a free compound of formula (I) from one of its salts;    and / or optionally separating a mixture of isomers of formula (I) into individual isomers.    7. Method according to claim 6, for  EMI72.3  the preparation of a compound of formula (I) in which-E-represents a sulfur atom, while the  EMI72.4  , symbol --- Y) represents  EMI72.5  tion defined in claim 2, 3 or 4, characterized in that the process A) of claim 6 is carried out: 11) by oxidizing a compound of formula (II) in which R6 represents the radical deriving from L (+) tartaric acid, to obtain a compound of formula (II) in which R6 is a formyl group 21) by condensing this compound , a hydrate, an acetal or a hemi-acetal of this compound with an azetidinone of formula (VI):    EMI72.6    <Desc / Clms Page number 73>    EMI73.1  in which R-has the meaning defined in claim 1 and Rus the meaning defined in claim 2, 3 or 4, to obtain a compound of formula (VII):  EMI73.2    EMI73.3  wherein R. X have the meanings defined in claim 1, while Rus the meanings defined in claim 2, 3 or 4; 31) transform a compound of formula (VII) into a compound of formula (VIII):  EMI73.4    EMI73.5  in which R.  X have the meanings defined in claim 1, Rus the meanings defined in claim 2, 3 or 4 and Ph represents a phenyl group; and 41) cyclizing a compound of formula (VIII) to obtain a compound of formula (I) in which  EMI73.6  the symbol-E-represents-S- and the symbol  <Desc / Clms Page number 74>    EMI74.1  represents = C-where the meaning defined in claim 2, 3 or 4 and optionally transform a compound obtained of formula (I) into another compound of formula (I); and / or optionally converting a compound of formula (I) into one of its salts and / or optionally obtaining a free compound of formula (I) from one of its salts; and / or optionally separating a mixture of isomers of formula (I) into individual isomers.  8. Compound of formula (II):  EMI74.2  in which  EMI74.3  R, and X have the meanings defined in J 4 claim 1 and R6 is a radical derived from an o R-, R.a-amino acid, an a-hydroxy acid, an a-keto acid or an a-alkenoic acid where the amino, hydroxy and keto groups are free or protected.  EMI74.4   9. Compound of formula (II) according to claim 8, characterized in that R and X j 4 have the meanings defined in claim 3 and R6 is a radical derived from tartaric acid, fumaric acid or l glyoxylic acid.  10. Compound corresponding to formula (VII)  EMI74.5  mentioned above in claim 7, wherein R,, X have the meanings defined in claim 7.  11. Compound corresponding to formula (VIII)  EMI74.6  mentioned above in claim 7, wherein R. and X have the meanings defined in claim 7.  12. Process for the preparation of a compound of formula (III) or of a salt thereof:  <Desc / Clms Page number 75>    EMI75.1    EMI75.2  where the symbols-E- and R have the meanings-  EMI75.3  cations defined in claim 1, this process consisting in cleaving an ester of formula (I):  EMI75.4    EMI75.5  in which the symbols-E---Y./  EMI75.6  R4 and X have the meanings defined in the res R. dication 1.  13. Process for preparing a compound of formula (III) according to claim 12, characterized in that the cleavage of the ester of formula (I) is carried out by hydrolysis.  14. Method according to claim 13, characterized in that the hydrolysis is an acid hydrolysis.  15. The method of claim 14, characterized in that the acid hydrolysis is carried out with a Lewis acid or a Brönsted acid.  16. Method according to claim 15, characterized in that the Lewis acid is chosen  EMI75.7  from the group comprising A1C1-,,, j j and FeC13. 17. according to claim 15, characterized in that the Brönsted acid is chosen from the group comprising trifluoroacetic acid,  <Desc / Clms Page number 76>   BF., ZnBrl formic acid, oxalic acid, acetic acid and citric acid.  18. Pharmaceutical or veterinary composition containing an appropriate diluent and / or carrier and, as active principle, a compound corresponding to the formula (Ia) mentioned above in claim 5 or one of its pharmaceutically acceptable salts or veterinary.  19. A compound according to claim 1, 8, 10 or 11 specifically identified in this specification.  20. The method of claim 6, in substance as described in one or other of examples 1 to 6, 8, 10 to 14, 16, 17 and 19 to 26.  21. The method of claim 12, in substance as described in either of Examples 7, 9, 15 and 18.  22. A compound of formula (Ia) or a pharmaceutically or veterinary acceptable salt thereof according to claim 5 for use as an antibacterial agent.