BE898382A - Compounds (5R) -pénem and 2-thiacéphem and process for their preparation. - Google Patents

Abstract

The process for the preparation of derivatives (5R) -penem of general formula (I), or RI represents a hydrogen atom, R2 represents a hydrogen atom, y represents a hydrogen atom.

Description

       

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  "Compounds (5R) -pénem and 2-thiacéphem and process for preparing them" by the Company: FARMITALIA CARLO ERBA S. p. A., Via Imbonati, 24, l - 20159 MILAN. (Italy).
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  ---------- Priority of two patent applications filed in Great Britain, on December 8, 1982, under NO 8235058 and August 27, 1983, under NO 8323129.

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   The subject of the invention is a new process for the preparation of (5R) -penem compounds of general formula I and their acceptable salts for pharmaceutical and / or veterinary use:
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In this formula I, R represents a hydrogen atom or an organic group; R2 represents a hydrogen atom or a carboxy protecting group; Y represents a hydrogen or halogen atom or an organic group.



   The organic groups that R, may represent optionally include substituted aliphatic or cycloaliphatic groups. The aliphatic groups are preferably the alkyl groups having from 1 to 12 carbon atoms and the optional substituents can be one or more hydroxy, amino, cyano and / or mercapto groups. The hydroxy, amino and mercapto groups can be free or protected. Particularly preferable alkyl groups are methyl and ethyl, especially the latter, and a preferable substituent for such a group is a hydroxy group which may be free or protected.



  The l-hydroxyethyl group in configuration 6S, 8R or 6R, 8S is greatly preferable. The cycloaliphatic groups are preferably monocycloalkyl groups having from 4 to 7 carbon atoms. Cyclopentyl and cyclohexyl are especially preferred. The optional substituents are preferably chosen from alkyl groups having from 1 to 6 carbon atoms, for example methyl or ethyl groups, the hydroxy, amino and mercapto groups, the hydroxy, amino and mercapto groups being free or protected.

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   The carboxy protecting R2 group can be any of the groups which form, with half - C00- an esterified carboxy group. As examples of R2 groups protecting carboxy, mention may be made particularly of alkyl groups having from 1 to 6 carbon atoms, for example methyl, ethyl or t-butyl groups; halo-substituted alkyl groups having from 1 to 6 carbon atoms, for example 2,2,2-trichloroethyl; alkenyl groups having 2 to 4 carbon atoms, for example allyl; optionally substituted aryl groups, for example phenyl and p-nitro-phenyl;

   alkyl groups substituted by aryl, the alkyl part of these having from 1 to 6 carbon atoms and the aryl part being optionally substituted, for example benzyl, p-nitro- -benzyl and p-methoxy-benzyl; alkyl groups substituted by aryloxy, the alkyl part of these having from 1 to 6 carbon atoms, for example phenoxy-methyl; or groups like benzhydryl, o-nitro-benzhydryl, acetonyl, trimethylsilyl, diphenyl-t-butyl-silyl and dimethyl-! - - butyl-silyl. The definition of R2 as a carboxy protecting group also includes any residue such as acetoxymethyl, pivaloyloxymethyl or phthalidyl, leading to an ester group which is known to be hydrolyzable "in vivo" and to have favorable pharmacokinetic properties.



   When Y represents a halogen atom, it is preferable that it is a fluorine, chlorine or bromine atom.



   When Y represents an organic group, it is preferable that it be: a) a free or protected hydroxy group, b) a formyloxy group or an acyloxy group having from 2 to
6 carbon atoms, optionally substituted by a halogen atom, by an acyl group having from 2 to 6 carbon atoms, or by an amino, hydroxy or mercapto group, the amino, hydroxy or mercapto group being optionally in protected form;

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 c) an unsubstituted carbamoyloxy or substituted N-alkyl group;

   d) an alkoxy group having from 1 to 12 carbon atoms or an alkylthio group having from 1 to 12 carbon atoms, one or the other being optionally substituted by one or more halogen atoms, formyl groups, acyl groups having from 2 to 6 carbon atoms and / or amino, hydroxy or mercapto groups, the amino, hydroxy or mercapto groups being optionally in protected form; e) a 1-pyridinium group unsubstituted or substituted in the meta or para position by the group-CONH; f) a heterocyclylthio-S-Het group where Het meaning a saturated or unsaturated heterocycle ring containing at least one oxygen, sulfur and / or nitrogen atom, is preferably:

   A) a pentatomic or hexatomic heteromonocycle ring containing at least one double bond and at least one heteroatom of oxygen, sulfur and / or nitrogen, unsubstituted or substituted by one or more of: a ') alkoxy groups having from 1 to 6 carbon atoms, acyl-aliphatic groups having from 2 to 6 carbon atoms, hydroxy groups and / or halogen atoms; b ') alkyl groups having from 1 to 6 carbon atoms, unsubstituted or substituted by one or more hydroxy groups and / or halogen atoms; c ') alkenyl groups having from 2 to 6 carbon atoms,
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 unsubstituted or by one or more hydroxy groups and / or halogen atoms;

   d ') groups of general formula-S-R-in which R3 represents a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, or groups of general formula-S-CH-COOR. wherein R4 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a carboxy protecting group;

   

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 e ') groups of general formula- (CH) -COORj or -CH = CH-COOR.ou- (CH) -CNou- (CH) -CONH or 4 2m m 2 - (CH) -SO-H is zero, 1,2 or 3 and R4 is as defined above Rg f ') groups of general formula- (CH) -N, R5 in which m is as defined above and each of R5 and R, which may be the same or different, represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms or a
 EMI5.2
 aliphatic acyl group or, when one of R5 3 b is hydrogen, the other may also be an amino protecting group;

   B) a heterobicycle ring containing at least two double bonds in which each of the condensed heteromonocycle rings, being the same or different, is a pentatomic or hexatomic heteromonocycle ring containing at least one heteroatom of oxygen, sulfur or nitrogen, this heterobicycle ring being unsubstituted or substituted by one or more substituents of the chosen form a '), b'), c '), e') and f ') as defined above.



   In the above definitions A) and B), the preferred halogens are chlorine, bromine and iodine; preferred alkyl groups are methyl and ethyl; a preferred alkenyl group is allyl; a preferred aliphatic acyl group is acetyl; a carboxy protecting group may be any of the groups previously indicated for the substituent R2; the free sulfo and carboxy groups which may be present can be salified, for example as sodium or potassium salts.



  An heteromonocycle ring of class A) above can be, for example, an optionally substituted thiazolyl, triazolyl, thiadiazolyl, tetrazolyl or triazinyl ring. The preferred substituents of these rings are for example one or more substituents chosen from

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 the following: an amino, hydroxy, oxo group and a CC, - alkyl group, preferably methyl or ethyl, in which the Ci-c 6 -alkyl group may be optionally substituted with a substituent chosen from the following: carboxy, sulfo , cyano, carbamoyl, amino, methylamino or dimethylamino. A heterobicycle ring of class B above can be, for example, a tetrazolopyridazinyl radical optionally substituted by amino or carboxy.



   In formula l above, the amino, hydroxy or mercapto protecting groups which may be present may be those which are usually used in the chemistry of penicillins and cephalosporins for these functions. They can be, for example, optionally substituted acyl groups, especially halosubstituted, for example: acetyl, monochloroacetyl, dichloroacetyl, trifluoroacetyl, benzoyl or p-bromophenacyl; triarylmethyl groups, in particular triphenylmethyl; silyl groups, in particular
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 trimethylsilyl, dimethyl-t-butyl-silyl, diphenyl-t-butyl-- silyl or also groups such as t-butoxycarbonyl, p-nitrobenzyloxycarbonyl, 2,2, 2-trichloroethoxycarbonyl, benzyl, pyranyl and nitro.

   When, in particular the substituent RI of formula (I) is a hydroxyalkyl group, the preferred protective groups for the hydroxy function are p-nitro-benzyloxycarbonyl; dimethyl-t-butyl-silyl; diphenyl-t-butylsilyl; trimethylsilyl; 2,2,2-trichloroethoxycarbonyl; benzyl; p-bromo-phenacyl; triphenylmethyl and pyranyl. All the alkyl and alkenyl groups, including the aliphatic hydrocarbon half of the alkoxy, alkyl-thio and acyloxy groups, may be branched chain or straight chain.



   The pharmaceutically and / or veterinary acceptable salts can be both the salts obtained with acids, either inorganic acids such as hydrochloric acid or sulfuric acid or organic acids such as citric, tartaric acid, fumaric or methanesulfonic, and the salts with bases, or inorganic bases such as the hydroxides of an alkali metal
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 J

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 or of an alkaline earth metal, in particular sodium and potassium hydroxides, or organic bases such as triethylamine, pyridine, benzylamine or collidine. The preferred salts are the salts of the compounds of formula I in which R2 represents a hydrogen atom with one of the bases specified above, in particular with sodium hydroxide or potassium hydroxide.



   The compounds of general formula I which are obtained by the process of the invention are compounds known-described and claimed in the British patents of the applicant Nos. 2,043,639A and 8,210,410. They are powerful agents, with broad antimicrobial spectrum and they are therefore useful in the treatment of bacterial infections in warm-blooded animals, especially in men, by enteral or parenteral administration.



   The contraction for desulfurization of the 2-thiacéphem ring of general formula II
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 in which R1, R2 and Y are as defined above is a known process for the preparation of penems, but it has the disadvantage of a mediocre or contrary electivity stereos. Although the carbon atom at position 6 has the R configuration, desulfurization usually gives penems (5S) which are biologically inactive (HR Pfaendler et al., J. Am. Chem. Soc., 101, 1979, 6306 ) or a mixture of penems- (5S) and (5R) (A. Henderson et al., J. Chem. Soc. Commun., 1982,809).



  It has been observed and described in Tetrahedron Letters, 24, page 3283 (1983) that the penems- (5R) can be obtained from such desulfurizing contractions of the ring when the substituents R, R and Y and the solvent for

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 the execution of the process are suitably chosen.



  However, a more general stereoselective process, usable over the whole range of values of the substituents R ,, R and Y, is clearly desirable since it would eliminate the losses involved in the formation of the undesirable (5S) isomers and in their separation of the isomers- (5R) desired.



   The invention provides a process for the preparation of a penem (5R) having the general formula I as defined above, this process comprising the oxidation of a 2-thiacéphem having the general formula II defined above and in which the carbon in position 6 has the R configuration, leading to a sulfone having the general formula III
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 wherein R ,, R and Y are as defined above and the contraction of the sulfone ring by expulsion of sulfur dioxide; then, if desired, the conversion of the penem -f5R) resulting from general formula I into another compound of general formula I; and / or, if desired, converting the resulting compound of general formula I to a salt thereof;

   and / or, if desired, obtaining a free compound of general formula I above from a salt of the latter.



   Oxidation can be carried out using oxidizing agents commonly used to convert an organic sulfide to a corresponding sulfone. Preferred oxidizing agents are peracids such as m-chloroperbenzoic acid and peracetic acid. The reaction

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 is generally carried out in an inert solvent at a temperature ranging from 0 to 60 ° C., preferably from 4 to 30 ° C.



   The contraction of the sulfone ring, with loss of sulfur dioxide, can be carried out simply by heating in an inert organic solvent such as chloroform or benzene. The contraction of the ring can, in some cases, even occur spontaneously at room temperature. The R configuration of the carbon atom in position 6 in 2-thiacéphem II is retained during the whole process, so that only penems- (5R) are obtained.



   It should be noted that, although the loss of sulfur dioxide from thiosulfonates has been reported occasionally (see, for example, W. L. F. Armarego and E. E. Turner, J. Chem. Soc. 1956,1665; A. Padwa and R.



  Gruber, J. Org. Chem. 35, 1970, 1781), this reaction has almost no precedent when it comes to the yield and the smoothness of the operating conditions, and for the first time it was applied to the synthesis of p-lactam compounds. . The present invention also provides pathways for achieving the required compounds of formula II having the (5R) configuration.



   According to the invention, the compounds of general formula II are prepared by any of the routes represented below by the reaction scheme which follows in which: R, R and Y are as defined above, Z represents:
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 i) a group of formula SR7 in which R7 an alkyl group having from 1 to 8 carbon atoms, a phenyl or tolyl group or, preferably, a heterocycle group, especially a group
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 2-benzothiazolylthio or 1-methyl-tetrazol-5-yl-thio, ii) a group of formula SCOR8 in which Rn represents an optionally substituted lower alkyl group, preferably a methyl group,

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 / C0Rg iii)

   a group of formula'N curio
 EMI10.2
 wherein Rg and independently represent lower alkyl or aryl groups or together with the dicarboxyamino group form a heterocycle ring, preferably a succinimido or phthalimido group, or
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 0 il iv) a group of formula in which R7 il o
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 represents an optionally substituted lower alkyl or aryl group, preferably a methyl, phenyl or p-tolyl group; L represents a halogen atom, a sulfonyloxy-alkane group or a sulfonyloxy-arene group, preferably a methanesulfonyloxy group.

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   The compounds of general formula IV which are used as starting materials are known compounds or can be obtained from known compounds by methods known per se; the preparation of certain representative initial bodies is described in the examples which follow.



   The compound of general formula IV is first subjected to ozonolysis to give a compound of general formula VI. The hydroxy group is then converted to a group L and the resulting compound of general formula VIII is subjected to cyclization to give a compound of general formula II in which Y represents a hydrogen atom.



  If desired, the methyl group can then be halogenated to obtain a compound of general formula II where Y represents a halogen atom.



   According to a variant of the process, the compound of general formula IV can firstly be halogenated by methods known per se (using allyl, enene type, or by electrochemical halogenation, see Tetrahedron Letters, 1980,71 and 351 ; 1981,3193; 1982,2187). The resulting compound of general formula V is then subjected to ozonolysis; the hydroxy group of the resulting compound of general formula VII is then transformed into a group L and the resulting compound of general formula IX is subjected to cyclization to give a compound of general formula II.



   The group Y in the compounds of general formula V, VII, IX and II can, when it represents a halogen atom, be optionally transformed into any of the other groups that Y can represent with the exception of an atom of hydrogen. According to a preferred characteristic of the invention, this transformation is preferably carried out on the compounds of general formula II.



   The transformation into an L group of the hydroxy group of enol VI or VIII which can be in an equilibrium state with the corresponding cet-tautomer is preferably a mesylation. He was found with surprise

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 that, when this reaction is carried out in tetrahydrofuran instead of the halogenated hydrocarbons used everywhere, one obtains almost exclusively mesylates IX or VIII having the alkene Z geometry, which are best suited for the subsequent cyclization (a similar transformation carried out in dichloromethane usually provides a 1: 1 mixture of the E, Z isomers: see TW Doyle, et al. Can. J. Chem. 1977,55, 2873; MJ Pearson, J. Chem. Soc., Chem. Comm. 1981 , 947; PC Cherry et al. J. Chem. Soc., Chem. Comm. 1979,663).



  The cyclization of VIII or IX can be carried out in a single operation, by reaction with a sulphide or a hydrogen sulphide such as Na2S, NaHS, BU4NHS, or with H2S in the presence of a base such as triethylamine or pyridine.



  The cyclization of IX or VIII in which Z represents a group other than SR7 offers the clear advantage of releasing ZH by-products usually soluble in water, easily separable (for example phenylsulfinic acid, succinimide) instead R3SH by-products (for example mercaptobenzothiazole) which generally require chromatographic separation or precipitation in the form of heavy metal salts (Ag, Pb2 +).



   Against all reasonable expectations, which would have excluded the possibility of the halogenation of the 3-methyl group of the compounds II (Y = H) due to the presence of the half disulfide, a process has been found to effect this transformation with a high yield . We can thus obtain compounds II (Y = halogen) which are invaluable intermediates for the synthesis of highly active penem antibiotics I.

   A preferred halogenation reagent for this transformation is N-bromosuccinimide which is best used in the presence of an initiating radical such as azobisisobutyronitrile or benzoyl peroxide in the presence of acidic evacuators such as epoxides (e.g. propylene oxide), alkaline earth oxides (for example calcium oxide1 or molecular sieves,

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 in solvents such as benzene or carbon tetrachloride, ethyl formate at a temperature ranging from
 EMI14.1
 200C to 1300C.



   Compounds II (Y = halogen) can be converted into compounds II (Y = an organic group) by reactions known per se, for example: 1) a compound II (Y = Br or Cl) can be converted into a compound II (Y = OH free or protected) by mild alkaline hydrolysis or by reaction with the cuprous oxide / dimethylsulfoxide / water mixture or by reaction with a salt of a strong inorganic acid, for example a nitrate or a perchlorate, which makes it possible to 'thus obtaining a labile ester with said inorganic acid, ester which can be hydrolyzed, subsequently or in the same reactive medium, to yield the desired related alcohol.

   Preferred salts of this type are AgNO-, AgClO., NaNO-; 2) a compound II (Y = Br or Cl) can be converted into a compound II (Y = an unsubstituted carbamoyloxy group or
Substituted N-alkyl) by conversion to a compound II (Y = OH) as described above followed by reaction with an appropriate isocyanate; for example trichloroacetyl isocyanate is a preferred reagent for obtaining compounds II (Y = OCONH) followed by removal of the protection of the trichloroacetyl half on the first urethane adduct formed;

   3) a compound II (Y = Br or Cl) can be converted into a compound II (Y. = acyloxy) by reaction with a suitable salt of the corresponding carboxylic acid in an appropriate solvent or by catalysis by phase transfer, or by conversion into a compound II (Y = OH) followed by a conventional acylation; 4) a compound II (Y = Br or Cl) can be converted into a compound II (Y = S-Het) by reaction with the corresponding body HS-Het in the presence of a base, or with a preformed salt of HS- Het with a base, in a

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 suitable solvent such as tetrahydrofuran, acetone, acetonitrile or dimethylformamide. A suitable base is triethylamine; a suitable preformed salt
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 is a sodium salt, for example 1-methyl-1, 2, 3, 4- - sodium.



   Due to the pronounced propensity of 3-hydroxyrnethyl-2-thiacéphem-4-carboxylates to lactonize, it is preferable that in process 1) described above R2 represents a bulky group forming with the carboxy half bonded an ester having a relative inertia with respect to the nucleophilic attack by the neighboring hydroxy group, for example a tert-butyl ester. As a variant, it may be advantageous to remove the protection of the hydroxy group, starting from a protected form of the latter, after the operation of contraction of the ring towards the corresponding penem I, since the 2-hydroxymethylpenem- carboxylates do not lactonize easily.

   For example, a compound II (Y = Br) can be converted into a compound II (Y = ONO) which can be easily isolated, purified if necessary, desulfurized in corresponding penem I including the reducing hydrolysis (for example Zn / CH3COOH) easily provides the free hydroxy derivative.



   Because of the different stability of the penem and of the 2-thiacéphem nucleus with respect to the conditions required for the hydrolysis to ester-COOR, a clear advantage of the invention is that the hydrolysis of the ester is not compatible with a penem can be performed on the precursor 2-thiacéphem and the contraction of the ring can be performed on the free acid or on a salt using an organic or inorganic base, or on a different labile ester than l 'can be prepared in situ, if desired; for example a trimethylsilyl ester, t-butyldimethylsilyl, or t-butyldiphenylsilyl.



   The examples which follow are illustrations of the invention given without limiting intention.



  The abbreviations Me, But, Ph, Ms, pNB, THF, EtOAc, DMSO, MeCN, represent respectively the following bodies: methyl, t-butyl, phenyl, methanesulfonyl, p-nitro-

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 benzyl, tetrahydrofuran, ethyl acetate, dimethyl sulfoxide, acetonitrile. The NMR spectra were obtained either using a Hitachi-Perkin Elmer 60 MHz device or a Brucker 90 MHz device; the separation of the interior lines of the AB quartets relates to the spectra obtained with this latter device.



   Example 1
Diphenylmethyl 6,6-dibromopenicillanate
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6,6-dibromopenicillanic acid (90 g) in acetonitrile (450 ml) was treated with a
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 solution of diphenyldiazomethane (49 g) in the same solvent (150 ml) 1 hour at 20 C, the solid formed was collected by filtration and washed with small parts of cold ethyl ether, which gave 116 g of the product indicated in title. A second quantity (9 g) was obtained by evaporation of the mother liquors and by trituration with ethyl ether; 95% yield.



   A sample for analysis was obtained by crystallization from chloroform; p. f. 157-158 C;
 EMI16.3
 #max film) 1800, 1750 cm-1; 1.24 and 1.58 (each 3H, s, CMe2) '4, s, N. CH. CO), 5.80 (1H, s, N. CH. S), 6.71 (1H, s, OCH), and 7.30 ppm (10H, s, Ar).



  Found: C, 47, 80; H, 3.63; N, 2.64; S, 5, 95; Br, 30.49%.



  CH NO-. C, 48, 02; H, 3.64; N, 2.67; S, 6.10; Br, 30.43%.



  Example 2 6, 6-dibromopenicillanate detert-butyl
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 Method A)
6,6-dibromopenicillanic acid (100 g) in ethyl ether (1 liter) at 00C was treated sequentially with triethylamine (37 ml) and PCl5 (56 g). After 1 hour of stirring, the reaction mixture was evaporated under vacuum (dry benzene added and removed) and the crude acyl chloride dissolved in dichloromethane (200 ml) and stirred for 24 hours with tert-butanol (500 ml) in the presence of CaCO3 (50 g).



  The suspended salts were removed by filtration and the solution was washed with aqueous NaHCO3 (part of the unreacted starting material can be recovered by subsequent extraction from the acidified aqueous washes), bleached with charcoal and subjected to evaporation to give the title product which was then crystallized from diisopropyl ether,
 EMI17.1
 69 g (60%); p. f. 120-1210C, film) 1800 and 1740 cm; d) 1.98 (15H, s, But and Ci 05 (3H, s, 38 (1H, s, N. CH. CO), and 5.70 (1H, s, N. CH. S) ppm.



  Method B)
6,6-dibromopenicillanic acid (15 g) in dichloromethane (300 ml) was stirred overnight with 0-tert-butyl-N, N-diisopropyl-isourea (25 g).



  The reaction mixture was filtered and the solution washed.
 EMI17.2
 with aqueous NAHC03. Crystallization of the product from 3 diisopropyl ether gave the title compound, 8 g (47%).



  Example 3 6 &alpha; -bromo-6ss- [1 (R) -hydroxyethyl] -diphenylmethyl penicillanate
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Diphenylmethyl 6-dibromopenicillanate (120 g) in dry distilled THF (900 ml) under nitrogen at -75 ° C. was treated with a solution of ethylmagnesium bromide in ethyl ether (1 molar equivalent ).

   After 20 minutes at -75 ° C, acetaldehyde (25.7 ml) was added and the mixture was further stirred for 20 minutes at -750C. After blocking the reaction with an aqueous saturated NH 4 Cl solution (400 ml), the separation between water and ethyl ether followed by removal of the solvent left the crude product which was fractionated by chromatography on silica gel (benzene-ethyl acetate) and gave the title compound, 67 g (60%), as a foam, crystallizable (ether
 EMI18.1
 diisopropyl) to a solid; p. f. 65-70 C 1 max 3450, 1785 and 1740 cm-1; # (CDCl3) 1.22 and 1.60 (each 3H, s, CMe2), 1.29 (3H, d, J = 6Hz, CH3. CH ), 2.90 (1H, d, OH), 4.17 (1H, m, CH3. CH. OH), 4.58 (1H, s, N. CH. CO), 5.49 (1H, s , N. CH.

   S), 6.90 (1H, s, OCHPh2), and 7.3 (10H, s, Ar) ppm.



   Using a similar process and
 EMI18.2
 starting from tert-butyl 6,6-dibromopenicillanate, 6-bromo-6 - / 'tert-butyl was obtained with a yield of 65% after crystallization from the diisopropyl ether / hexane mixture;
 EMI18.3
 p. f. 93-950C (dec); J (CDCl) 1, 28 (3H, d, J = 6Hz, CH3. CH), 1.54 (12H, s, Bu and 65 (3H, s, Ci 65 (1H, s, CH. OH), 4 , 25 (1H, m, CH3. CH (OH). CH), 4.40 (1H, s, N-CH. CO), and 5.51 ppm (1H ,.s, N. CH. S) .



  Example 4 6-alpha 1-oxide - [1 (R) -hydroxyethyl] -diphenylmethyl penicillanate
 EMI18.4
 

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6 &alpha; -bromo-6ss- [1 (R) -hydroxyethyl] - - diphenylmethyl penicillanate (52 g) in 95% ethanol (400 ml) was hydrogenated to approximately 2 bars in the presence of Pd to 10 % / CaCO3 (25 g) and CaCO3 (11 g). The reaction mixture was filtered and evaporated to give a residue which was partitioned between brine and dichloromethane. Removal of the solvent left the crude diphenylmethyl penicillanate 6 &alpha; - [1 (R) -hydroxyethyl] -penicillanate which was oxidized with 85% MCPBA (17 g) in 500 ml of chloroform between 0-5 C for 1 hour .

   The filtered solution was washed with aqueous NaHCO 3 and the solvent was removed to leave the crude product, 40 g (88%), in the form of a foam, which can be used as it is or purified by chromatography on silica gel; #max (CHCl3 film) 1790 and 1750 cm-1; # (CDCl3) 0.94 1.67 (each 3H, s, CMe2), 1.37 (3H, d, J = 6Hz), 3.55 (1H, dd, J = 2 and 6.5 Hz, CH .CH.CH), 4.25 (1H, m, CH3. CH (OH). CH), 4.64 (1H, s, N. CH. CO), 4.98 (1H, d, J = 2 Hz, CH. CH. S), 6.98 (1H, s, OCHPh2), and 7.30 (10H, s, Ar) ppm.



   Using a similar process and
 EMI19.1
 starting from tert-butyl we obtained (75%) the 1-oxide of 6 &alpha; - [1 (R) -
 EMI19.2
 - of tert-butyl 3440, 1785 and 1740 cm-1.



   Example 5
6-alpha 1-oxide - [1 (R) -tert-butyldimethylsilyloxyethyl] -peni- - diphenylmethyl cillanate
 EMI19.3
 

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 EMI20.1
 6-alpha 1-oxide - [1 (R) -hydroxyethyl] - crude diphenylmethyl penicillanate, as obtained in Example 4 (40 g) was dissolved in DMF (350 ml) and stirred for 3 hours at 50-55 C in the presence of imidazole (18.5 g) and tert-butyldimethylsilyl chloride (27 g).



  The reaction mixture was partitioned between ethyl ether and brine and the organic layer was washed several times with water. Evaporation of the solvent and chromatography on silica gel provided the
 EMI20.2
 title product, 22 g; V film) 1790 and 1755 cm-1; # (CDCl3) 0.06 (6H, s, SiMe2), (13H, s, But and CH3), 1.3 (3H, d, J = 6Hz, CH3.CH), 1.7 (3H, s, CH3), 3.4 (1H, dd, J = 2 and 4.5 Hz, CH. CH.CH), 4.40 (1H, m CH3.CH.CH), 4.55 (1H, s, N . CH.CO), 4.88 (1H, d, J = 2, CH. CH.S), 6.9 (1H, s, OCHPh2), and 7.25 ppm (10H, s, Ar).



   Using a similar process and starting from 6-alpha 1-oxide - [1 (R) -hydroxyethyl] tert-butyl penicillanate, 6 & alpha 1-oxide was obtained - - [1 (R) -tert- -butyldimethylsilyloxyethyl ] -kotert-butyl penicillanate with a general yield of 55% from the precursor
 EMI20.3
 6 &alpha;-bromo;#max film) 1785 and 1750 cm-1; # (CDCl3) 0.06 (6H, s, Sire2), 88 (9H, s, 1, 25 and 1.66 (each 3H, s, Cyme2), 28 (3H, d, J = 6Hz, CH-. CH), 1, 45 (9H, s, 0Bu), 3, 5 (1H, dd, J = 2 and 5Hz, CH. CH. CH), 4, 4 (1H, s, N. CH. CO), 4.5 (1H, m, CH3. CH. CH), and 4.9 ppm (CHCl3 (1H, d, J = 2Hz, CH. CH. S).



  Example 6
 EMI20.4
 diphenylmethyl l-oxide
 EMI20.5
 

  <Desc / Clms Page number 21>

 
6-alpha 1-oxide - [1 (R) -hydroxyethyl] - - diphenylmethyl penicillanate was acylated with p-nitrobenzyl chlorocarbonate using N, N-dimethylaminopyridine as base and free ethanol-dichloromethane mixture as solvent, according to the process
 EMI21.1
 general, which gave the title product in the form of a foam; # (CDCl3) 0.96 and 1.70 (each 3H, s, CMe2), 1.52 (3H, d, J = 6Hz, CH3.CH), 3.83 (1H, dd, J = 2 and 6Hz , CH. CH.CH), 4.66 (1H, s, N. CH.CO), 4.99 (1H, d, J = 2Hz, CH.

   CH.S), 5.28 (2H, s, OCH2Ph), 5.35 (1H, m, CH3.CH.CH), 7.01 (1H, s, OCHPh2), 7.40 (10H, m, Ar), 7.55 and 8.26 ppm (each 2H, d, J = 8Hz, Ar).



   Following the same experimental process, 1-oxide of 6 &alpha; - [1 (R) -p-nitrobenzyloxycarbonyl-oxyethyl] -penicillanate was obtained.



   By following similar experimental procedures and using trichloroethyl chlorocarbonate in place of p-nitrobenzyl chlorocarbonate, we obtained: 1-oxide of 6 &alpha; - [1 (R) -p-nitrobenzyloxycarbonyloxyethyl] --tert-butyl penicillanate , 6 & alpha-1-oxide - [1 (R) -p-nitrobenzyloxycarbonyloxyethyl) - diphenylmethyl penicillanate.



  Example 7
 EMI21.2
 3 (S) - (1-methoxycarbonyl-2-methyl-1-prop-2-enyl) -azetidine- -L-1 (R) -hydroxyethyl! 7-4 (R) -benzothiazolyldithio-l - 2-one
 EMI21.3
 
A mixture of 6-alpha-1-oxide - [1 (R) -hydroxyethyl] -methyl penicillanate (5 g) and 2-mercaptobenzothiazole (3.04 g) was kept under reflux for 2 hours in toluene dry. The solvent has been removed

  <Desc / Clms Page number 22>

 under vacuum and the crude product was used as is for the next operation.



   By following a similar process we obtained:
 EMI22.1
 3 (S) - [1 (R) -tert-butyldimethylsilyloxyethyl] -4 thiazolyl-1- (1-methoxycarbonyl-2-methyl-1-prop-2-enyl) - (R) -benz - azetidine-2- one, from 1-oxide of 6 &alpha; - [1 (R) -tert- -butyldimethylsilyloxyethyl] -pénicillanate and extending the reaction time up to 6 hours;
 EMI22.2
 #max film) 1770 and 1744 cm-1 0.02 'ntcx-j and 0.04 (each 3H, s, SiMe2) 0.84 (9H, s, SiBut), 1.23 (3H, d, J = 6Hz, CH3. CH), 1.91 (3H, s, = C. CH-), 3.38 (1H, dd, J = 2 and 3.5Hz, CH.

   CH.CH), 3.69 (3H, s,
 EMI22.3
 (1H, m, 4.82 (IH, s, N.CH.CO), 5.07 (2H, m, CH2 = C), 5.42 (1H, d, J = 2Hz, CH.CH.S ), and 7.2-7.9 ppm (4H, m, Ar); 3 (S) - [1 (R) -hydroxyethyl] -4 (R) -benzthiazolyldithio-1- (1- -diphenylmethoxycarbonyl-2- methyl-1-prop-2-enyl) -azetidine-
 EMI22.4
 - from 1-oxide of 6 &alpha; - [1 (R) -hydroxyethyl] - -diphenylmethyl penicillanate; max 3400, 1765 and 1740 cm '; f nicx j'3 1.22 (3H, d, J = 6Hz, CH3.CH), 1.60 (3H, s, = C.CH3), 2.78 (1H, br s, OH), 3, 42 (1H, dd, J = 2 and 6 Hz, CH.CH.CH), 4.18 (1H, m, CH3.CHOH.CH), 4.93 (1H, s, N.CH.CO), 4.90-5.10 (2H, m, CH2 = C), 5.38 (1H, d, J = 2Hz, CH.

   CH.S), 6.89 (1H, s, OCHPh2), and 7.15-7.90 ppm (14H, m, Ar);
 EMI22.5
 3 (S) - [1 (R) -tert-butyldimethylsilyloxyethyl] -4 (R) -benzthiazolyldithio-1- (1-tert-butoxycarbonyl-2-methyl-1-prop- -2-enyl) -azetidine-2- one, from 1-oxide of 6 alpha - - [1 (R) - -tert-butyldimethylsilyloxyethyl] -penicillanate tert-butyl; reaction time 6 hours;

  <Desc / Clms Page number 23>

 
 EMI23.1
 cf (CDC1-) 0, 06 (6H, s, Sire2), 9 (9H, s, SiBut), 1, 26 (3H, d, J = 6Hz, CH3. CH), 1, 48 (9H, s, 0Bu), 1.95 (3H, s, = C. 3.40 (1H, dd, J = 2 and 4Hz, CH. CH. CH), 4.20 (1H, m, CH3. CH. 4, 71 (1H, s, N. CH. CO), 5, 1 (2H, br s, 5, 42 (1H, d, J = 2Hz, CH. CH.

   S), and 7.2-7.9 ppm (4H, m, Ar); 3 (S) - / 'l 7-4 thiazolyldithio-l- -prop-2-enyl) -azetidine-2-one v (film) 1772 and 1743 cm') 0.05 vmax (6H, s, Sire2), 80 (9H, s, SiBut), 1.29 (3H, d, J = 6Hz, CH-. 1.95 (3H, s, = C. Ci 3, 45 (1H, dd, J = 2 and 4Hz, CH. CH. CH), 4, 26 (1H, m, CH3. CH), 4, 95 (1H, s, N. CH. CO), 5, 08 (2H, ABq, separation of interior lines 5Hz, CH2 = C), 5.55 (1H, d, J = 2Hz, CH. CH. S), 6.93 (1H, s, OCHPh) and 7.1-8.0 ppm (14H, m, Ar); 3 (S) - / - 1 thiazolyldithio-1- -enyl) -azetidine-2-one, from l-oxide -pênicillanate 1) 1775 and 1745 cm '; J (CDCl-,) 1.48 max Jj (3H, d, J = 6Hz, CH-. 1.91 (3H, s, = C. Cl3), 3.69 (3H, s, 70 (1H, dd , CH. CH. CH) 4, 68 (s, 2H, OCH2) 4, 76 (1H, s, N. CH. CO), 5, 03-5, 30 (2H, m, CH2 = C), 5 , 23 (1H, m, CH3. CH. CH), 5.32 (1H, d, J = 2Hz, CH. CH.

   S), and 7.10-7.96 ppm (4H, Ar); and, analogously, starting from the corresponding tert-butyl and diphenylmethyl, 3 (S) - / - 1 thiazolyldithio-l- -2-enyl) -azetidine-2-one penicillanates

  <Desc / Clms Page number 24>

 
 EMI24.1
 3 thiazolyldithio-1- -prop-2-enyl) -azetidine-2-one and from 1-oxide of methyl-penicillanate, 3 (R) - / - l thiazolyldithio-l- 0, -enyl) -azetidine -2-one.



  Example 8
 EMI24.2
 3 (S) - / l methoxycarbonyl-2-hydroxy-1-prop-1-enyl)
 EMI24.3
 
The crude product 3 (S) - [1 (R) -hydroxyethyl-1- -4 (R) -benzthiazolyldithio-1- (1-methoxycarbonyl-2-methyl-1- -prop-2-enyl) -azetidine-2 -one as obtained in Example 6 was dissolved in dry dichloromethane (300 ml) and treated with an ozone stream at -700C until the thin layer chromatography shows that all the starting material had reacted. The solution was purged with nitrogen and then sodium metabisulfite (10 g) was added at -30 C. The mixture was allowed to warm up to room temperature during vigorous stirring and then filtered. .

   The solution was washed with 4% aqueous NaHCO3, dried over Na2SO4 and then evaporated. The residue was taken up in ethyl ether, the undissolved material was removed by filtration and the solution was evaporated to give the title crude product. An aliquot part was purified by flash chromatography on silica gel (using ethyl acetate- - cyclohexane mixture as eludant

  <Desc / Clms Page number 25>

 
 EMI25.1
 J (CDC1-.) 1.35 (3H, d, J = 7Hz, CH3. CH), 2.11 (3H, s, 2.75 (1H, br s, OH), 3.44 (1H, dd , J = 2, 0 and 5.0 Hz, CH. CH. CH), 3.79 (3H, s, OCH-), 26 (1H, m, CH3. CH. CH), 5.29 (1H, d, J = 2.0 Hz, CH. CH. S) and 7.25-7.95 ppm (4H, m, Ar).



  Following a similar process, we obtained: 3 (S) thiazolyldithio-ld-methoxycarbonyl-2-hydroxy-l-prop-1--enyl) -azetidine-2-one, starting from the crude product 3 (S) - / 'l thiazolyldithio-l- -; 9 (film) 3350, 1770 and - 1 max 1660 cm; J) 0.05 and 0.07 (6H, each s, Sire2), 0.87 (9H, s; SiBut), 1.27 (3H, d, J = 6.5Hz, CH3. CH), 2, 07 (3H, s, = C. Cl3), 3.33 (1H, dd, J = 2, 2 and 4, 2Hz, CH. CH. CH), 3.74 (3H, s, OCH-), 26 (1H, m, CH3-CH.



  5.36 (1H, d, J = 2.2Hz, CH. CH. S), 7.2-2.7, 9 (4H, m, Ar), and 12.37 ppm (1H, br s, OH); - - 3 (R) - / 'l thiazolyldithio-ld-methoxycarbonyl-2-hydroxy-l-prop-1- - from 3 (R) l (R) -tert- - - - (film) 3200, 1773, 1710, 1665 and 1620 cm 'cf (CDC1-.) 0, 20 (6H, s, Sire2), 94 (9H, s, SiBu), 52 (3H, d, J = 6Hz, CH3. CH), 2, 17 (3H, br s, = C. Ci 3, 6-3, 7 (4H, s + dd, OCH- and CH. CH. CH), 4, 4 (1H, m, 3 3'CH. CH) , 5, 25 (1H, d, CH. CH.

   S), and 7, 3-7, 9 ppm (4H, m, Ar) 3 (S) -7 - - starting from the crude product 3 - methoxycarbonyl-2-methyl-1-prop-2-enyl) v film ) 3400, 1770, 1730 and 1650 cm "; max 3 (S) - / 'l thiazolyldithio-l- - starting from the gross product

  <Desc / Clms Page number 26>

 
 EMI26.1
 3 (S) - / - l thiazolyldithio-l- -prop-2-enyl) -azetidine-2-one (CHC13 3400, 1775, 1735, 1700 sh, 1655 max and 1610 cm; V (CDC13) 0, 06 ( 6H, s, SiMe2), 82 (9H, s, Bu), 1, 26 (3H, d, J = 6Hz, CH-. 2, 08 (3H, s, = C. 3.33 (1H, dd, J = 2 and 5.5 Hz, CH. CH. CH), 4.18 (1H, m, CH3.5, 22 (1H, d, J = 2Hz, CH. CH. S), 6.86 (1H , s, OCHPh), 7, 2-7, 9 ppm (14H, m, Ar).; 3 (S) thiazolyldithio-1--enyl) -azetidine-2-one 50 (3H, d, J = 6Hz, CH3. CH), 2.14 (3H, s, = C. Ci 3.67 (1H, dd, J = 2, 2 and 5, 5Hz, CH. CH. CH), 3.82 (3H, s, OCH3), 62 (2H, ABq, J = 12 Hz, separation of interior lines 2Hz, OCH2), 5, 10-5, 40 (2H, m, CH3. CH.

   CH and CH. CH. S), 7.20-8.00 (4H, m, Ar), and 12.40 ppm (1H, br s, OH); and in an analogous manner, starting from the corresponding tert- and diphenylmethyl ester, 3 (S) (R) -trichloroethoxycarbonyloxyethyl7-4 thiazolyldithio-l- - 3 (S) - - l-prop-l-ennyl) -azetidine-2-one 3 (S) - / 'l thiazolyldithio-l- -prop-1-enyl) -azetidine-2-one.



  Example 9 3 (S) -methoxycarbonyl-2-methylsulfonyloxy-1-prop-1-enyl) - -

  <Desc / Clms Page number 27>

 
 EMI27.1
 
 EMI27.2
 A solution of 3-4 (130 mg, 0.3 mmol) in anhydrous dichloromethane (8 ml) was treated sequentially at -40 ° C. with triethylamine (0.043 ml; 0.3 mmol) and chloride. methanesulfonyl (0.024 ml; 0.31 mmol). The reaction was stopped after 5 minutes using a cold 2% aqueous NaHCO3 solution.



  Removal of the solvent from the organic layer gave the title crude product (quantitative yield), which was used as it was for the next operation.



  Following the same experimental process, we obtained: 3 (S) - / - l thiazolyldithio-l- '-l-prop-l-enyl) -azetidine-2-one, starting from 3 (S) - - / - 1 (R) -tert-butyl-dimethylsilyloxyethyl7-4 zolyldithio-1- - an aliquot of this product has been purified by. flash chromatography (silica gel eluting ethyl acetate-cyclohexane mixtures) and provided the pure title compound as a 1: 1 mixture of the E and Z isomers; (film) 1885, - 1730, 1363 and 1165 cm; (CDC13) 0.05 and 0.10 (each 3H, s, Sire2), 88 (9H, s, SiBut), 1.29 (3H, d, J = 6.5 Hz, CH3. CH), 2, 20 and 2.53 (3H, each s, = C. Ci 3, 18 and 3.29 (3H, each s, SO2CH3) '3.42 (1H, m, CH. CH. CH), 3.71 and 3.78 (3H, each s, 30 (1H, m, CH3. CH. CH), 5.59 and 5.64 (1H, each d, J = 2Hz, CH. CH. S), and 7.12 -7.96 ppm (4H, m, Ar).

  <Desc / Clms Page number 28>

 
 EMI28.1
 



  When tetrahydrofuran was used in place of dichloromethane as the solvent, the formation of the undesirable E-isomer was almost suppressed and the pure Z-isomer was collected; cf (CDC13) 0.05 (6H, s, Sire2), 88 (9H, s, SiBut), 1.29 (3H, d, J = 6, 6Hz, CH3. 2.53 (3H, s, = C Ci 3.29 (3H, s, 42 (1H, dd, J = 2 and 5Hz, CH. CH. CH), 3.71 (3H, s, OCH3) '4.30 (1H, m, CH3. CH. CH), 5.59 (1H, d, J = 2Hz, CH. CH. S), and 7.12-7.95 ppm (4H, m, Ar).



  Following this last process (use of tetrahydrofuran as solvent in the mesylation operation), we obtained: 3 (R) (R) -tert-butyldimethylsilyloxyêthy7-4 -1-prop-l- starting from 3 (R) - / 'l thiazolyldithio-l- - 1775, 1735, -1 1365 and 1165 cm; O (CDC13) 0, 18 (6H, s, SiMe2), 88 (9H, s, SiBu), 1, 42 (3H, d, J = 6, 5Hz, CH3. CH), 2, 33 (3H, s , = C. CH3), 3.05 (3H, s, SO2CH3) '3.45 (3H, s, OCH3), 3.62 (1H, dd, CH. CH. CH), 4.3, (1H, m, CH3. CH. CH), 5.40 (1H, d, J = 5Hz, CH. CH. S) and 7.15-7.85 ppm (4H, m, Ar) 3 (S) - / ' 1 - 1-diphenylmethoxycarbonyl-2-methylsulfonyloxy-1-prop- -1- starting from 3 (S) - / "1-hydroxyethyl 7-4 methoxycarbonyl2-hydroxy-1-prop-1-enyl); 9 (film ) 3400, 1775, 1730, 1365 and 1170 cm '; y max of 1, 22 (3H, d, J = 6, 5Hz, CH3. CH), 2, 43 (3H, s, = C. CH-), 3.13 (3H, s, SO2CH3) '3.35 (1H, dd, J = 2.5 and 4Hz, CH. CH. CH), 4.1 (1H, m, CH3.

   CH. CH), 5.40 (1H, d, J = 2.5 Hz, CH. CH. S), 6.85 (1H, s, OCHPh2) and 7, 1-7.9 ppm (14H, m, Ar )

  <Desc / Clms Page number 29>

 
 EMI29.1
 3 (S) - / - 1 thiazolyldithio-1-methylsulfonyloxy-1-prop-1-enyl) from 3 -4 - - film) 1775, 1725, 1370 and 1175 cm; cf (CDCl3) 0, 1 (6H, s, Sire2), 9 (9H, s, SiBut), 1, 28 (3H, d, J = 6Hz, CH3. CH), 2, 5 (3H, s, = C. Ci (3H, s, SOCH-), 3.35 (1H, dd, J = 2.5 and 5 Hz, CH. CH. CH), 4.20 (1H, m, CH3. CHCH), 5, 50 (1H, d, J = 2.5Hz, CH. CH. S), 6.9 (1H, s, OCHPh), 7, 1-7, 9 ppm (14H, m, Ar); 3 (S) - / - l thiazolyldithio-1- sulfonyloxy-1-prop-1-enyl) -azetidine-2-one, starting from 3 (S) - / - l - -1-prop-1-enyl) -azetidine-2 -one; 9 (film) 1773, max 1710, 1370 and 1165 cm ') 0.06 (6H, s, Sire2), 0.87 (9H, s, SiBut), 1.25 (3H, d, J = 6Hz, CH3 . CH), 1.49 (9H, si, 0But), 2.45 (3H, s, = C.

   Ci 3.25 (3H, s, S02CH3) '3.35 (1H, dd, J = 2.5 and 5Hz), 4.3 (1H, m, CH3. CH. CH), 5.60 (1H, d, J = 2.5 Hz, CH. CH. S), and 7.9 ppm (4H, m, Ar) 3 (S) - / * l - starting from 3 (S) - - / - 1 (R ) -trichloroethoxycarbonyloxyethyl7-4 zolyldithio-1- -; 1780, 1755 sh, rnax 1730, 1380, 1250 and 1167 cm-; cf (CDCl3) 1.48 (3H, d, J = 6Hz, CH. 2.52 (3H, s, = C. Ci 3.25 (3H, s, S02CH3) '3.72 (4H, s + dd , OCH- and CH. CH. CH), 4.68 (2H, s, OCH2), 2 (1H, m, CH3. CH. CH), 5.47 (1H, d, J = 2.5Hz, CH CH.

   S), and 7, 1-7.9 ppm (4H, m, Ar);

  <Desc / Clms Page number 30>

 
 EMI30.1
 and, analogously, starting from the corresponding tert-butyl and diphenylmethyl esters, there were obtained: 3 oxy-1-prop-1 (Z) -enyly-azetidine-2-one 3 (S) - / * 1 sulfonyloxy-1 -prop-l (Z) Example 10 3 (S) - / 'l dithio-l- -1-enyl) -azetidine-2-one
 EMI30.2
 
 EMI30.3
 When, in the reaction described in Example 8, the starting material was exposed to an excess (2 molar equivalents) of the methanesulfonyl chloride / / triethylamine mixture, the title product was obtained in powder form with a quantitative yield as a mixture of isomers (20%) Z (80%); V (film) - max 1780, 1730, 1360 and 1170 58 (3H, d, J = 6Hz, CH. 2, 22 and 2, 56 (3H, each s, = C. CH- E and Z isomers), 3 , 00 (3H, s, CH3SO2 the hydroxyethyl chain), 3.20 (1H, dd, J = 2, 2 and 4, 5Hz, CH. CH.

   CH), 3.28 (3H, s, CH3S02 on the crotonic appendage), 3.76 (3H, s, 11 (1H, m, CH3. CH. CH), 5.52 (1H, d, J = 2, 2Hz, CH. CH. S), and 7, 30-7, 95 ppm (4H, m, Ar).



  Following the same process but using THF as the solvent, the product 3 (S) (R) -methylsulfonyloxyethyl7-4 'l-diphenylmethoxycarbonyl-2-methylsulfonyloxy-l-prop-l- - was prepared and showed the spectral characteristics following /

  <Desc / Clms Page number 31>

 
 EMI31.1
 (film) 1777, 1728, 1360 and 1170 cm max
CH3) 1.50 (3H, d, J = 6Hz, CH3. CH), 2.52 (3H, s; = C. CH3), 2.9 (3H, s, CH3SO2 on the hydroxyethyl chain), 3, 23 (3H, s, CH3SO2 on the crotonic appendix), 3.62 (1H, dd, J = 2.5 and 5.5Hz, CH. CH.CH), 5.05 (1H, m, CH3.CH .CH), 5.45 (1H, d, J = 2.5Hz, CH. CH.S), 6.95 (1H, s, OCHPh2), and 7.10-7.95 ppm (14H, m, Ar).



  Example 11
 EMI31.2
 3 (S) thiazolyldithio-1-sulfonyloxy-1-prop-1-enyl) -azetidine-2-one
 EMI31.3
 
 EMI31.4
 The crude product 3 thylsilyloxyethy carbonyl-2-hydroxy-1-prop-1-enyl) (300 mg) in THF (5 ml) at -40 C was treated sequentially with triethylamine (170 µl) and anhydride trifluoromethanesulfonic (180 μl). The recovery and the chromatography gave the two distinct geometric isomers of the title product, in the form of foams:
 EMI31.5
 E isomer IU3.



  1135 cm *; J) 0.08 (6H, s, Sire2), 86 (9H, s, SiBu), 1.26 (3H, d, J = 6Hz, CH3.CH), 2.05 (3H, s, = C. CH3), 3.46 (1H, dd, 2.2 and 4Hz, CH.CH.CH), 3.81 (3H, s, OCH3), 4.28 (1H, m, CH3.CH.CH), 5.76 (1H, d, J = 2.2Hz, CH. CH.S), and 7.25-7.90 (4H, m, Ar); Z isomer (inter alia) # (CDCl3) 2.45 (3H, s, = C.CH3), 3.40 (1H, dd, J = 2 and 4Hz, CH. CH.CH), 3.64 (3H , s, OCH3), 4.30 (1H, m, CH3.CH.CH), and 5.65 ppm (1H, d, J = 2Hz, CH. CH.S).

  <Desc / Clms Page number 32>

 



  Example 12 (7S, 6R) -7- [1 (R) -tert-butyldimethylsilyloxyethyl] -3-methyl- - 2-thiacéphem-4-carboxylate
 EMI32.1
 
A solution of triethylamine (0.5 ml) in dichloromethane (10 ml) was saturated at -50 ° C using hydrogen sulfide. After purging with nitrogen, 0.34 cm3 of this solution was added to a cold solution
 EMI32.2
 (-50 C) of 3 (S) - [1 (R) -tert-butyldimethylsilyloxyethyly- -4 (R) -benzthiazolyldithio-1- (1-methoxycarbonyl-2-methyl-sulfonyloxy-1-prop-1-enyl) -azetidine-2-one (75 mg; 0.121 mmol).



   The mixture was allowed to warm to room temperature and then washed with water, dried (Na2SO4), then evaporated. The separation of the new compound from minor impurities and the 2-mercaptobenzthiazole formed was carried out by chromatography on silica gel (eluents ethyl acetate-cyclohexane mixture), which made it possible to obtain the title compound in the form of crystals white (19 mg, 20%); p. f. 85-870C, ^ (EtOH) 223 (C = 4.773), 277 (6.335) and 326 (2.922) nm, #max (CHCl3 film) 1785 and 1730 cm-1; cf (CDCl3) 0.08 (6H, s, SiMe2), 0.88 (9H, s, SiBut), 1.25 (3H, d, J = 6Hz, CH3.CH), 2.22 (3H, s , CH3), 3.07 (1H, dd, J = 2.2 and 3.5 Hz, CH.

   CH.CH), 3.8 (3H, s, OMe), 4.36 (1H, m, CH3.CH.CH), and 4.62 ppm (1H, d, J = 2.2Hz, CH.CH .S).



  Found: C: 49.08; H: 6.96; N: 3.52; S: 15.16 then
 EMI32.3
 C16H27NO4 C: 49.32; H: 6.99; NOT ; S: 16.46%. When instead of H2S / NEt3 we used a solution of NaSH (equivalent 0.9 mole) in DMF with

  <Desc / Clms Page number 33>

 cold blocking (partitioning between H20 and EtOAc) at OOC which followed in the interval of one minute, the yield of pure crude product indicated as isolated titer was high up to 40-45%.



   When the above process was performed on the Z geometric isomer of the starting material, the yield was further increased (up to 60-65%). On the contrary, the E isomer made it possible to obtain only a very small quantity of the product indicated in title.



   Following the same experimental process, methyl (7R, 6R) -7- [1 (R) -tert-butyldimethylsilyloxy-ethyl] -3-methyl-2-thiacephem-4-carboxylate was obtained.
 EMI33.1
 starting from 3 (R) - [1 (R) -tert-butyldimethylsilyloxyethyl] - -4 (R) -benzthiazolyldithio-1- (1-methoxycarbonyl-2-methylsulfonyloxy-1-prop-1-enyl) -azetidine-2 -one; V (film) 1785 and 1725 cm; J (CDCOCD) 0, 03 and 0, 05 (each 3H, s, SiMe2), 84 (9H, s, SiBu), 1, 19 (3H, d, 6, 5Hz, CH-. 2, 08 (3H, s, 72 (3H, s, OCH3) '4, 11 (1H, dd, J = 5, 5 and 8, 0Hz, CH. CH. CH), 4, 20 (1H, m, CH. CH), and 5.01 ppm (1H, d, J = 5.5Hz, CH. CH. S).



  Example 13 (7S, 6R) -7- / l (R) -hydroxyethyl7-3-methyl-2-thiacéphem-4- - methyl
 EMI33.2
 
 EMI33.3
 The crude product 3 (S) (R) -hydroxyethyl / - -4 sulfonyloxy-1-prop-1-enyl) -azetidine-2-one (145 mg, 0.287 mmol) as obtained in Example 9 was dissolved in anhydrous dimethylformamide (2 ml) and treated at +20 C with a freshly prepared solution of NaHS (16 mg; 0.287 mmol) in the same solvent (1.6 ml).

  <Desc / Clms Page number 34>

 



  The mixture was stirred for 2 minutes and then partitioned between ethyl acetate and water.



   After repeated washing with water, the solvent was removed and left a residue which was purified by pressure chromatography on silica gel (using the ethyl acetate-cyclohexane mixture as eluent), which gave in the form of a white powder the pure product indicated in title with a yield of 45%;
 EMI34.1
 p (nujol) 3400, 1770 and 1720 cm max.



  1.37 (3H, d, J = 7Hz, CH. CH), 2.22 (3H, s, CH3), 40 max (1H, br s, OH), 3.12 (1H, dd, J = 2 , 0 and 4.5Hz, CH. CH. CH), 3.86 (3H, s, OCH3), 4.35 (1H, m, CH3. CH. CH), and 4.65 ppm (1H, d, J = 2.0Hz, CH. CH. S).



   Following a similar experimental process, we obtained: (7S, 6R) -7- [1 (R) -hydroxyethyl] -3-methyl-2-thiacéphem-4- -carboxylate from diphenylmethyl, starting from 3 (S) -
 EMI34.2
 - -1-enyl) -azetidine-2-one; At 281 (5, 900) and 326 (3, 670) nm; Y (KBr) max 3550-3250, 3080, 3060, 3020, 2960, 920, 2840, 1775, 1720, 1660 and 1490 cm; Cf (CDCl-) 1, 36 (3H, d, J = 6, 5Hz, CH), 2, 17 (3H, s, Ci 12 (1H, dd, J = 2, 0 and 5Hz, CH. CH. CH. CH ), 4, 36 (1H, m, CH-. CH), 4, 76 (1H, d, J = 2.0Hz, CH. CH.

   S), 6.97 (1H, s, OCH2 and 7.30 (10H, m, Ar); (7S, 6S) -7 - / 'l - of diphenylmethyl, starting from 3 (S) -ll -benzthiazolyldithio -l- sulfonyloxy-1-prop-1-enyl)

  <Desc / Clms Page number 35>

   - [1 (R) -hydroxyethyl] -4 (R) -benzthiazolyldithio-1 - # (CDCl3) 0.06 (6H, s, SiMe2) 0.83 (9H, s, SiBut), 1.27 (3H, d, J = 6.5Hz, CH3.CH), 2.05
 EMI35.1
 (3H, s, CH3), (1H, dd, J = 3.0 and 5.0Hz, CH.CH.CH), 4.32 (1H, m, CH3.CH.CH), 4.60 d, J = 3, OHz, CH.CH.S), 7, s, OCHPh), 'and ppm (10H, s, Ar);

   (7S, 6R) -7 - / - l - tert-butyl, starting from 3 (S) - / - l thiazolyldithio-1-oxy-1-prop-1-enyl) -azetidine-1-one 278 ( é = 6.300) and 327 nm (e = 2.560) max #max 1780 and 1720 cm; 0.12 (6H, s, Sire2), 0.88 (9H, s, SiBut), 1.25 (3H, d, J = 6Hz, CH3. CH), 1.52 (9H, s, 0But, 2 , 10 (3H, s, CH3), 3.02 (1H, dd, J = 2.5 and 5Hz, CH. CH. CH), 4.28 (1H, m, CH. CH. CH), and 4 , 53 ppm (1H, d, J = 2.5 Hz, CH. CH. S);
 EMI35.2
 (7S, 6R) -7 - / - 1 - methyl, starting from 3 (S) - / * 1 dithio-1--1-enyl) -azetidine-2-one; 9 1780, 1725, 1360 and max 1175 cm; 1.60 (3H, d, J = 6.5Hz, CH3. CH), 2.25 (3H, s, CH3), (3H, s, CH3SO2), 3.27 (1H, dd, J = 2 , 2 and 5Hz, CH.CH.CH), 3.83 (3H, s, OCH3), 4.70 (1H, d, J = 2, 2H, CH. CH.S) 5.24 ppm (1H, m, CH3.CH.CH).



  (7S, 6R) -7- [1 (R) -methylsulfonyloxyethyl] -3-methyl-2--thiacéphem-4-diphenylmethyl carboxylate, starting from 3 (S) - [1 (R) -methylsulfonyloxyethyl] -4 (R) -benzthiazolyldithio-1- (1-diphenylmethoxycarbonyl-2-methylsulfonyloxy-1- -prop-1-enyl) -azetidine-2-one;

  <Desc / Clms Page number 36>

 
 EMI36.1
 y (CHC1) 282 (F- = 7.080) and 330 (3.966) nm; m. y (CHC1. 1778, 1720, 1255 and 1170 cm '; ci max 1, 53 (3H, d, J = 6Hz, (3H, s, CH), 2, (3H, s, - J = 2, and 5 , CH. CH. CH), 4.67 (1H, d, J = 2.5Hz, 'CH. CH. S), 5.05 (1H, m, CH3. CH); 6, s, OCHPh), and 725 25 Ar); (7S, 6R) -7 - / 'l - methyl, starting from 3 ethyl / -4 (R) -benzthiazolyldithio-1 - methoxycarbonyl-2- -; vmax (film) 1787, 1760 sh, 1725 and 1250 max 6 1, (3H, d, J =. 23 s, CH3) 3, 30 (1H, dd, J = 2 and 7, CH. CH. CH), 3, (3H, s, OCH3) '4, 68 (1H, d, J = 2Hz, CH. CH.

   S), 4.78 (2H, s, 5.37 ppm (1H, m, CH); (7S, - diphenylmethyl, starting from 3 ethyl7-4 carbonyl-2-methylsulfonyloxY-1-prop-1-enyl ) - \ 1 1787, 1745, 1720 sh cm; 6 (CLCl) max 1) (3H, d, 2, (3H, s, dd, J = 2 1 3 y and 6.5 Hz, CH-CH-CH ), 4, d, J = 2Hz, CH. CH. S), 5.15 (2H, s, OCH2) '5.28 (1H, m, CH.

   CH), 6, 7, (12H, m, Ar) and 8, ppm (2H, d, J = 9Hz, Ar);

  <Desc / Clms Page number 37>

 
 EMI37.1
 and, similarly, we obtained: (7S, 6R) -7- * l - of tert-butyl (7S, 6R) -7 - / * l - of diphenylmethyl (7S, 6R) -7 - / - l - trichloroethyl (7S, 6R) -7 - / - l - trichloroethyl (7S, 6R) -7 - / - l - (7S, 6R) -7 - / - l - (7S, 6R) -7- / 'l - Example 14 3 (S) - / - l -succinimido-thio-l- -prop-2-enyl) -azetidine-2-one
 EMI37.2
 
 EMI37.3
 We dissolved (2.32 g) of 1-oxide of 6 <x - / "1 methyl in dimethylacetamide (35 ml) and treated with acetic acid (0.15 ml), purged with nitrogen, and heated for 3.5 hours at 105 ° C. in the presence of N-trimethylsilylsuccinimide (5 g).



  After cooling to room temperature, we have

  <Desc / Clms Page number 38>

 
3 1distribute the reaction mixture between ethyl acetate and cold water. The fractionation of the material obtained from the organic layer (chromatography on silica gel, ethyl acetate-cyclohexane) provided the title product in the form of a white foam; 1.2 g (43%);
 EMI38.1
 y 1770, 1735, 1710 sh, and - 1680 cm; 006 (6H, s, 87 (9H, s, SiBu), 3 2 1, (3H, d, J = CH), IJ84 (3H, s, = C. 85 (4H, s, CO, dd, J = 3 and 45Hz, CH. CH. CH), 3, (3H, s, OMe), 4, m, CH. CH), 4, s, N. CH. CO), 4, d, J = 2, CH . CH. and 5d00 (2H, br s, CH2 = C).



   By following a similar experimental process, we also obtained:
 EMI38.2
 3- -succinimido-thio-l- -1-prop-2-enyl) -azetidine-2-one, and 3- - (S) - / - l (R) -tert-butyldimethylsilyloxyethyl7-4 (R) - 1-prop-2-enyl) -azetidine-2-one, the two were isolated as raw materials and used as such in the following operations.



  Example 15
 EMI38.3
 3 (S) - / - l oxy-l-prop-l-
 EMI38.4
 

  <Desc / Clms Page number 39>

 
 EMI39.1
 A solution of 3 (S) dimethylsilyloxyethyl7-4 3 - (100 mg) in acetone (9 was treated with AgN03 (34 mg), followed immediately by an ethanolic slurry of potassium phthalimide (30 mg After stirring for 30 minutes at room temperature, the precipitate was collected, partitioned between water and EtOAc and purified by rapid chromatography on silica gel, which gave the title product (55% ); #max (movie)
 EMI39.2
 1780, 1745, and 1725 cm-1 s, SiMe2), (9H, s, Bu), 1.4 d, CH3.CH), 2.2 (3H, s, = C.CH3), 3.05 ( 3H, s, 34 CH. CH. CH), 3, (3H, s, OCH3) '4) 2 (1H, m, CH. CH. J = 2Hz, CH.; And; # (CDCl3) 0.1 (6H, zu ppm (4H, m, Ar).
 EMI39.3
 



  Example 16 3 (S) (R) -tert-butyldimethylsilyloxyêthy7-4 -succinimidothio-l- -prop-1-enyl) -azetidine-2-one
 EMI39.4
 
The title product was obtained by ozonolysis of 3 (S) - [1 (R) -tert-butyldimethylsilyloxyêthyl] - -4 (R) -succinimidothio-1- (1-methoxycarbonyl-2-methyl-1- -prop -2-enyl) -azetidine-2-one in dichloromethane according to the process described in Example 8, and was used as such in subsequent reactions. A sample was characterized by its dimethyl ketal (MeOH / dry HCl):

  <Desc / Clms Page number 40>

 
 EMI40.1
 J} 1730 and 1715 sh; J (CDCl) 0J04 and 0, each 3H, s, 90 (9H, s, SiBu), 1, (3H, d, J = 5Hz, (3H, s, CH), (4H, s, and 3, acun3H , s, ctalOCH), 24 dd, J = 2) 5 and 5Hz), 3) (3H, s, ester OCH), 20 (1H, m, CHL. CH.



  3 4, s, N. CH. CO), and 4, ppm (1H, d, J = 2.5Hz).
 EMI40.2
 



  Similarly, 3 -tert-butyldimethylsilyloxyethyl7-4 - - was obtained starting from 3 (S) (R) -tert-butyldimethylsilyloxyethy methoxycarbonyl-2-methyl-1-prop-2-enyl) Example 17 (7S, 6R ) -7 - / - l - methyl
 EMI40.3
 
 EMI40.4
 A solution of 3 carbonyl-2-methylsulfonyloxy-1-prop-1- (400 mg) in dimethylformamide (4 ml) was treated, with vigorous stirring, with finely ground NaSH (50 mg). As soon as the last reagent was dissolved, the reaction was blocked by partitioning between ethyl ether and water. The recovery of the product gave the title compound, identical to the sample described in Example 12.

  <Desc / Clms Page number 41>

 



  Example 18 (7S, 6R) -7- [1 (R) -tert-butyldimethylsilyloxyethyl] -3- -methyl-2-thiacéphem-4-carboxylate
 EMI41.1
 
 EMI41.2
 The product 3 (S) silyloxyethyl7 "4 -1-prop-2-enyl) -azetidine-2-one (0.8 g) in dichloro- -L-1 (R) -tert-butyldimethyl-methane was ozonized at -700C until thin layer chromatography shows complete conversion The excess ozone was purged with nitrogen and dimethyl sulfide (1 ml) was added.

   After 1 hour at room temperature, all volatile matter was removed in vacuo and the residue was reacted with equimolar amounts of triethylamine and mesyl chloride (CH2C12'-200C at 0 C) until that the conversion of enole to mesylates was deemed to be complete by CCM. The mixture was concentrated in vacuo and divided between ethyl acetate and a cold aqueous solution of NaHCO3. The organic layer was evaporated to give the crude mixture of mesylates E, Z which was treated without purification with NaHS in DMF, according to the process described in Example 13.

   Purification of the resulting product by chromatography on silica gel provided the title compound identical to the material obtained in Example 12.



   By a simular process, we obtained the
 EMI41.3
 (7S, 6R) -7-1-methyl-2-thiacephem-4-diphenylmethyl carboxylate starting from 3 (S) - / - 1 -4 -1-prop-2-enyl) -azetidine-2-one, and this product showed

  <Desc / Clms Page number 42>

 the same spectral characteristics as the material previously described (Example 13).



  Example 19
 EMI42.1
 (7S, 6R) -7 - / 'l - 2, 3, 4-tetrazol-5-yl) -thiacéphem-4-carboxylate
 EMI42.2
 
 EMI42.3
 The product 3 (S) - / - l silyloxyethyI7-4 2, 3, 4-tetrazol-5-yl) - - l-methoxycarbonyl-2- 2, 3, 4- -tetrazol-5-yl) -thiomethyl-1 -prop-2-enyl7-azetidine-2-one (120 mg) in solution in dichloromethane was subjected to the same reaction sequence as that of Example 17 (ozonolysis, mesylation, reaction with NaHS).

   The crude product was partitioned between ethyl acetate and aqueous NaHCO3, which removed the released mercaptotetrazole; the organic layer was washed several times with water, subjected to evaporation and the residue was fractionated by chromatography on silica gel to give the title product; 17 mg (17%); #max (film) 1787,1725, 1587,1360 and 1250 cm
 EMI42.4
 # (CDCl3) (6H, s, 0.89 (9H, s, SiBut), (3H, d, J = 6Hz, 15 (1H, dd, Jazz and 3) CH. H. 92 38 m, CH lines. H. CH), 446 14Hz) and 468 d, J = -2, CH. CH. S).

  <Desc / Clms Page number 43>

 
 EMI43.1
 



  Example 20 3 (S) - [1 (R) -tert-butyldimethylsilyloxyethyl] -4 (R) -phenylsulfonylthio-1- [1-methoxycarbonyl-2-methyl-1-prop-2-enyl] -
0.10-azetidine-2-one
 EMI43.2
 The product 3 (S) - [1 (R) -tert-butyldimethyl-
 EMI43.3
 silyloxyethyl] -4 (R) -benzthiazolyldithio-1- (1-methoxycarbonyl-2-methyl-1-prop-2-enyl) (2.6 g) in acetone (160 ml) and water ( 18 ml) was treated with vigorous stirring with silver nitrate (0.98 g), immediately followed by sodium benzene sulfinate (0.79 g) in water (60 ml). After 1 hour at room temperature, the white precipitate was removed by filtration and the filtrate was concentrated in vacuo and then partitioned between water and ethyl acetate.



  Removal of the solvent from the organic layer left the title product in the form of a yellowish powder (2.43 g, 98%), recrystallisable from cyclohexane (white sheets, mp 105-106 C), ir (KRr) 3080,3020, 2960, 2930, 2900,2860, 1770, 1750, 1330 and
 EMI43.4
 -1 1145; 0 (CDC1) 0.05 (6H, s, rible2), (12H, sd, SJ. And CH), 1. (3H, s, = C. 3.22 (1H, dd, J = 2.5Hz, (3H, s, OMe), 4.19 cm4358 (IH, s, N. CH.CO), 5.00 (2H, m, C = CH2), 5.37 (1H, d, J = 2Hz, CH . CH.S), 7.60 and 7.96 ppm (3 and 2H, each m, Ar).

  <Desc / Clms Page number 44>

 
 EMI44.1
 



  Found: C: 53, 69; H: 6.99; N: 2.70; S: 12.42% while CH-eNOgSiS: 53.77; H: 6.87; N: 2.74; S: 12.48%.



  Following the same process, we also obtained: 3 (S) - / - l sulfonylthio-1--enyl) -azetidine-2-one 3 (S) - / - l sulfonylthio-l- -2-enyl) -azetidine -2-one 3 (S) - / - l sulfonylthio-1- - 3 (S) -l sulfonylthio-1- -prop-2-enyl) -azetidine-2-one.



  Example 21 3 (S) -7-l sulfonylthio-l - / - l-methoxycarbonyl-2-methylsulfonyloxy- -1-prop-l
 EMI44.2
 

  <Desc / Clms Page number 45>

 Process A)
The material obtained in Example 20 (1 g) in dry dichloromethane was ozonized at -70 C. After purging with nitrogen, dimethyl sulfide (3.5 ml) was added and stirred the mixture for 3 hours at room temperature. After removing any volatile material in vacuo, the residue was partitioned between ethyl acetate and water. Evaporation of the solvent left the intermediate product 3 (S) - [1 (R) -tert-butyldimethyl-
 EMI45.1
 silyloxyethyl] -4 (R) -phenylsulfonylthio-1- (1-methoxycarbonyl-2-hydroxy-1-prop-1-enyl) -azetidine-2-one y 1778, 1658 and 1620 cm; el (CDC13) 0.08 max (6H, s, Sire2), 90 (9H, s, SiBu), 1.13 (3H, d, J = 6Hz, CH-. 1.90 (3H, s, = C .

   Ci 3, 12 (1H, dd, J = 2, 5 and 4Hz, CH. CH. CH), 3, 73 (3H, s, OMe), 4, 2; (1H, m, CH3.CH.CH) , 5.52 (1H, d, J = 2.5Hz, CH. CH.S), 7.4-8.0 (5H, m, Ar), and 13 ppm (1H, s, OH).



   This material was subjected to mesylation using triethylamine (272 l) and mesyl chloride (151 l) in dry THF (10 ml) according to the general process-see example 10-which allowed '' obtain the title product, foam, 550 mg after chromatography on silica gel; ir (film) 1780,1730, 1640,1370 and 1145 cm '; cf (CDC13) 0.05 (6H, s, Sire2), 0.80 (9H, s, SiBut), 0.97 (3H, d, J = 6Hz, CH3.CH), 2.50 (3H, s , = C. CH3), 3.15 (4H, m, SO2CH3 and CH. CH.CH), 3.76 (3H, s, OCH3), 4.13 (1H, m, CH3.CH.CH), 5.7 (1H, d, J = 2.8 Hz, CH. CH.S), and 7.6-8.0 ppm (5H, m, Ar).



  Procedure B)
 EMI45.2
 Product 3 (S) - / - l silyloxyethyl7-4 "l-methoxycarbonyl- (100 mg) in acetone-water mixture 9: 1 (10 ml) was treated sequentially with stirring using silver nitrate (34.3 mg) and an aqueous solution of sodium benzene sulfinate (26.6 mg in 4 ml).

  <Desc / Clms Page number 46>

 15 minutes of stirring at room temperature, the precipitated silver benzthiazol mercaptide was filtered off and the solution was partitioned between CH2Cl2 and water. Removal of the solvent left the title product (quantitative yield) in syrup form, which shared the same spectral characteristics as those of the sample obtained by procedure A).



   According to the same methodology, we obtained:
 EMI46.1
 3 (S) - / 'l -1-prop-l 3 sulfonyloxy-l-prop-l (Z) Example 22 (7S, 6R) -7 - / - l - methyl
 EMI46.2
 
 EMI46.3
 The product 3 (S) 4-silyloxyethyl-carbonyl-2-methylsulfonyloxy-1-prop-1 (Z) -enyl / -azetidine- - was left to react with NaHS in DMF according to the process described in Example 13, this which made it possible to obtain the product indicated in the same title as the material previously described.

   This preparation allows a simpler purification of the product since the by-product, sodium benzene sulfinate, is soluble in water and does not require chromatographic separation or fractional crystallization to be eliminated (unlike mercaptobenzthiazole for example).
 EMI46.4
 r

  <Desc / Clms Page number 47>

 
Following the same methodology, we obtained: (7S, 6R) -7- [1 (R) -tert-butyldimethylsilyloxyethyl] -3-methyl- -2-thiacephem-4-tert-butyl carboxylate; (7S, 6R) -7- [1 (R) -trichloroethoxycarbonyloxyethyl] -3-methyl- - 2-thiacéphem-4-carboxylate of trichloroethyl.



  Example 23
 EMI47.1
 3 (S) - / - l - -azetidine-2-one
 EMI47.2
 
 EMI47.3
 A solution of 3 carbonyl-2-methylsulfonyloxy-1-prop-1 (Z) -enyl / -azetidine- (R) -trichloroethoxycarbonyloxyéthyl7-4 (R) -acétyl-- 2-one (340 mg) in THF (5 ml ) was treated with thioacetic acid (43 µl).

   Five minutes later the mixture was evaporated and the crude reaction product was released from 2-mercaptobenzothiazole by chromatography, which gave the pure title compound, 280, as a colorless syrup. mg (96%); (film) 1775,1760 sh, 1730 br cm-1 #max # (CDCl3) 1.50- (3H, d, CH3.CH), 2.48 (3H, s, = C. CH3),
 EMI47.4
 2.62 (3H, s, COCH3), (3H, s, SO2CH3), 3.44 (1H, dd, CH.CH.CH), 3.83 (3H, s, OMe), 4.77 (2H , ABq, J = ll, 5Hz, separation of interior lines 2Hz), 5, 24 (1H, d, CH. CH. S), 5, 25 (1H, m, CH3. CH. CH).



  Example 24 (7S, - methyl

  <Desc / Clms Page number 48>

 
 EMI48.1
 
A solution of the product 3 (S) - [1 (R) -trichloroethoxycarbonyloxyethyl] -4 (R) -acetyldithio-1- [1-methoxycarbonyl-2-methylsulfonyloxy-1-prop-1 (Z) -enyl] - azetidine--2-one (140 mg) in THF (10 ml) was treated at 0 ° C. with a solution of hydrogen sulfide tetrabutylammonium (65 mg) in the same solvent.



   Recovery and chromatography provided the title product; (Et0H) 280 (E 4,974)
 EMI48.2
 max and 327 nm (2,262); p (film) 1787, 1760 sh, 1725 cm max # (CDCl3) 1.54 (3H, d, CH3.CH), 2.23 (3H, s, CH3), -1 (1H, dd, 2 and 7 , 5 Hz, CH. CH.CH), 3.84 (3H, s, OMe), 4.68 (1H, d, CH. CH.S), 4.78 (2H, s, OCH2CCl3), and 5 , 3H ppm (1H, m, CH3.CH.CH), followed by a certain amount recovered from the starting material.



  Example 25 (7S, 6R) -7- [1 (R) -tert-butyldimethylsilyloxyethyl] -3- methyl bromomethyl-2-thiacéphem-4-carboxylate
 EMI48.3
 
 EMI48.4
 The product (7S, dimethylsilyloxyethyl] -3-methyl-2-thiacéphem-4-carboxylate (0.52 g), propylene oxide (0.95 ml) and N-bromosuccinimide (0.52 g ) as well as azobisisobutyronitrile (0.05 g) in carbon tetrachloride (40 ml) were kept under reflux for 6 hours.

  <Desc / Clms Page number 49>

 



   The reaction mixture was cooled to room temperature and then filtered. The filtrate was evaporated in vacuo and the residue was purified by chromatography on silica gel with ethyl acetate-hexane as eluent, which gave the title product (80%) as a yellowish oil. );
 EMI49.1
 (CHcl) 282 and 336 nm; J (CHC13'Îllm) max. 3 max 1785, 1730 cm-1; c5. (9H, s, SiBut), 1) d, CH. OSi), 3, dd, J = 2, 0 and j 3, CH. CH. CH), 3, (3H, s, (2H, center ABq, s. I. L. 4Hz, J =
3 (1H, d, J = 2, OHz, CH. CH.s) ppm We found: C: 41.1; H: 5.64; N: 3.01; S: 13.55; Br: 17.20 while C16H26BrN704SiS2 requires C: 41.02; H: 5.59; N: 2.99; S: 13.69; Br: 17.06.



   By following a similar process we obtained:
 EMI49.2
 (7S, 6R) -7 - / 'l - of ter-butyl vmax (CHCl3) 283 and 332 nm; v (film) 1787 and 1720 cm max max 6 0, (6H, s, SiMe2), 0, 9 (9H, s, SiBut), 1, (3H, d, CH), (9H, s, OBut), 3, dd, J = 2, 5 and 4, CH. CH. CH), 4.35 (3H, m, and CH. CH), and 4.71 ppm (1H, d J = 25Hz, CH. CH. S); (7S, - p-nitrobenzyl; 6 (CDC13) lp45 (3H,
 EMI49.3
 d,. CH), 343 dd, J = 25 and 6 Hz, CH. CH. CH), 4, (2H, ABq, J = 12Hz, d, J = 2, Hz, CH. CH. S), 5, (5H, m, OCH2Ar and. CH); 7) and 7.2H, d, J = 8.5Hz, Ar), and 8.20 ppm (4H, d, J = 8, Ar);

  <Desc / Clms Page number 50>

 
 EMI50.1
 (7S, diphenylmethyl methyl-2-thiacéphem-4-carboxylate 6 145 (3H, d, CH3. CH), 3.32 (1H, dd, J = 3 and 6Hz, CH. CH. CH), 4, ' 8 (2H, ABq, J = 11. Hz, CBr), d, J = 3Hz, CH. CH. S), 5, (2H, s, OCH. M, CH-.

   CH), 6.97 (1H, s, OCHPh), 7.10 (10H, br s, Ar), 7.45 ppm (each 2H, d, J = 9Hz, Ar); (7S, 6R) -7- [1 (R) -tert-butyldimethylsilyloxyethyl] -3-bromomethyl-2-thiacéphem-4-carboxylate, diphenylmethyl;
 EMI50.2
 #max (film) 1790 and 1730 cm-1; # (CDCl3) 0.05 (6H, s, SiMe2), 0.8 (9H, s, SiBut), 1.22 (3H, d, J = 6.5 Hz,
CH3.CH), 3.10 (1H, dd, J = 2.7 and 4.5 Hz, CH.CH.CH), 4.05 (2H, s, CH2Br), 4.2 (1H, m, CH3.CH.CH), 463 (1H, d, J = 2.7 Hz, CH. CH.S), 6.92 (1H, s, OCHPh2), and
 EMI50.3
 7.05-7.40 ppm (10H, m, Ar); #max (CHCl3) 283 (E = 7.867) and 336 nm (f. = 3.533); and, in the same way:
 EMI50.4
 (7S, 6R) -7 - / - 1 methyl-2-thiacephem-4-trichloroethyl carboxylate (7S, 6R) -7 - / "1 methyl-2-thiacephem-4-carboxylate of trichloroethyl.



  Example 26 (7S, 6R) -7 - / - 1 - 2, 3, 4-tetrazol-5-yl) - methyl

  <Desc / Clms Page number 51>

 
 EMI51.1
 
A solution in THF of (7S, 6R) -7- [1 (R) - -tert-butyldimethylsilyloxyethyl] -3-bromomethyl-2--thiacéphem-4-carboxylate was kept overnight in the presence of 1 -methyl-1,2,3,4-tetrazol--5-sodium thiolate bihydrate (equivalent 3 moles).



  The recovery and the chromatography provided the title product with an oil yield of 85% in the form of an oil; #max (EtOR) 281 and 333 nm; #max (movie)
 EMI51.2
 1790 and 1725 cm-1; 0.10 (6H, s, SiMe2), (9H, s, But), 1.26 (3H, d, CH3.CH), 3.15 (1H, dd, J = 2.2 and 3.5 Hz , CH. CH. CH), 3.88 (3H, s, OMe), 3.92 (3H, s, N. CH3), 4.38 (1H, m, CH3.CH.CH), 4.46 (2H, ABq, separation of internal lines 14Hz, J = 14Hz), 4.68 (1H, d, CH. CH.S, J = 2.2Hz).



   By following a similar process we obtained:
 EMI51.3
 (7S, 6R) -7 - / - l - (l-methyl-1, 2, 3, 4-tetrazol-5-yl) - tert-butyl, starting from (7S, 6R) -7 - / - l - tert-butyl; (7R, 6S) -7-7'l - l, (R) -tert-butyldimethylsilyloxyethyl / -3--2-thiacéphem-4-carboxylate of diphenylmethyl.



  Example 27 (5aR, 6S) -6- [1 (R) -tert-butyldimethylsilyloxyethyl] -5a, 6-
 EMI51.4
 -dihydro-3H, -1,7-dione

  <Desc / Clms Page number 52>

 
 EMI52.1
 
7H-azeto (2,1-c] furo (3,4-e] -1,2,4-dithiazine-Procedure A): A solution of (7S, 6R) -7- [1 (R) -tert- butyl dimethylsilyloxyethyl] -3-bromomethyl-2-thiacéphem-4- methylcarboxylate (15 mg) in DMSO (2 ml) and water (1.5 ml) was stirred with Cu2O (50 mg) 50 C for 2.5 hours.



   The reaction mixture was partitioned between water and ethyl acetate. Evaporation and chromatography of the organic extracts gave the title product in the form of a white powder; V (CHC13 max 3
 EMI52.2
 film) 1800-1760 br (3H, s, (3H, s, 9H, (3H, d, CH3. (1H, dd, J = 2) CH. CH. CH), 444 m, CH3. CH.



  4) 62 (1 d, J CH. CH. 5), and 4) s, CHO)
 EMI52.3
 Procedure B): The 2-bromomethyl precursor product (250 mg) in the 2: 1 acetone-water mixture (35 ml) was stirred for 15 minutes at 00C with AgClO4 (153 mg). The reaction mixture was partitioned between HO / EtOAc and the organic layer was evaporated until leaving a residue.



  Chromatography on silica gel provided the title product, identical to the sample described below - under A).



  Example 28 (7S, 6R) -7- / - of tert-butyl

  <Desc / Clms Page number 53>

 
 EMI53.1
 
 EMI53.2
 (7S, 6R) -7- [1 (R) -tert-butyldimethylsilyloxy-ethyl-3-bromomethyl-2-thiacêphem-4-tert-butyl carboxylate (300 mg) in the mixture 2: 1 acetone- water (10 ml) was stirred for 15 minutes at 0 C with AgClO4 (150 mg).



  Removal of the solvent, followed by H2O / EtOAc partition and recovery of the organic layer gave 250 mg (96%) of the title product;
 EMI53.3
 At 335 nm; Y (film) 3450, max 1785 and 1712 cm; of 071 (6H, s, 0) (9H, s, SiBu), 1) (3H, d, dd, J = 2.5 and 4.5Hz, CH.CH.CH), 4.25 (center of ABq , J = 13Hz, and 4.60 ppm (1H, d, J = 2.5Hz, (CHClCH.CH.S). Example 29
 EMI53.4
 (7S, 6R) -7- [1 (R) -tert-butyldimethylsilyloxyethyl] -3- - - tert-butyl
 EMI53.5
 
 EMI53.6
 (7S, 6R} silyloxyethyl-3-hydroxymethyl-2-thiacéphem-4-tert-butyl carboxylate (250 mg) in the mixture ethanol- - free dichloromethane (2.5 ml) was treated at −40 ° C. trichloroacetylisocyanate (80 µl).

   The mixture was allowed to warm to room temperature

  <Desc / Clms Page number 54>

 then it was washed sequentially with a 2% aqueous NaHCO3 solution and brine. Evaporation of the solvent from the organic layer gave the title product in quantitative yield;
 EMI54.1
 (ETOH) max 275 and 329 nm; 1 and; (CD3CN), (6H, s, (3H, d, CH) 1, (9H, s, J = 3 and 4Hz, CH. CH. CH), 4, (1H, m, CH. CH. d, J = 3Hz, CH. CH. and 5, 3 (center of ABq, CH
 EMI54.2
 Example 30 (7S, 6R) -7-'l - from tert- - to-
 EMI54.3
 
 EMI54.4
 A methanolic solution of tert-butyl (7S, 6R) -7l acetyl) was stirred with silica gel for 20 hours.

   The slurry was then loaded into a column of silica gel and the product was eluted with ethyl acetate; # (CDCl3) 0.1 (6H, s, SiMe2), 0.9 (9H, s, SiBut), 1.35 (3H, d, CH3.CH), 1.60 (9H, s, 0But), 3.1 (1H, dd, CH. CH.CH), 4.3 (1H, m, CH3.CH.CH) 4.75 (1H, d, J = 3Hz, CH. HS), and 5.0 ppm (center of ABq, OCH2CO).

  <Desc / Clms Page number 55>

 



  Example 31 (7S, 6R) -7- [1 (R) -tert-butyldimethylsilyloxyethyl] -3- -nitrooxymethyl-2-thiacéphem-4-carboxylate
 EMI55.1
 
 EMI55.2
 A solution of (7S, 6R) dimethylsilyloxyethyl] -3-bromomethyl-2-thiacéphem-4- -7- [1 (R) -tert-butyl-methyl carboxylate (200 mg) in acetone (20 ml ) was stirred for 20 minutes in the presence of AgN03 (100 mg). The reaction mixture was filtered and then fractionated by chromatography on silica gel to give the title product, 120 mg;
 EMI55.3
 (film) 1790, 173C), At and 337 nm;) ./ max 3 1640 and 1280 cm; (6H, s, 0, (9H, 3'2 s, SiBut), (3H, d, CH), 3) J = 2, CH. CH. CH), 3J85 (3H, s, OMe), 4, m, CH. CH. CH), 473 (1H, d, J = 2, CH.

   S), and 5) ppm (2H, ABq, J = 13) (CHC13) 280s. i. l. 29.5Hz, CH ONO); further elution then provided part of the lactone described in Example 27.



  Example 32 (7S, 6R) -7- [1 (R) -tert-butyldimethylsilyloxyethyl] -3--methyl formyloxymethyl-2-thiacéphem-4-carboxylate
 EMI55.4
 

  <Desc / Clms Page number 56>

 
 EMI56.1
 (7S, 6R) -7 - / '"l methyl silyloxyethyl (200 mg) in CH2Cl2 was treated at daily intervals with tetrabutylammonium formate (3 x 600 mg). After 3 days at 5 ° C., TLC showed that 80% conversion of the product had taken place (ethyl acetate / light petroleum 1: 2) Elution through a short column of silica gel gave the product
 EMI56.2
 indicated in title; J (CDCl3) 1 (6H, s, Sire2), (9H, s, SiBut), 1.35 (3H, d, CH3. CH), 3.20 (1H, dd, 2.5 and 7Hz, CH. CH. CH), 3, 9 (3H, s, OMe), 4.5 (1H, m, CH3. CH.

   CH), 4.74 (1H, d, 2.5Hz, CH. CH. S), 5.13 (center of ABq, CH20).



   Similarly, starting from the corresponding tert-butyl and diphenylmethyl esters, we have obtained:
 EMI56.3
 (7S, 6R) -7- * 1 tert-butyl formyloxymethyl-2-thiacéphem-4-carboxylate; (7S, 6R) -7 - / 'l - of (R) -tert-butyldimethylsilyloxyethyl7-3-diphenylmethyl and, in an analogous manner, the corresponding acetates were obtained: (7S, 6R) -7- [1 (R) -tert-butyldimethylsilyloxyethyl] -3- -acetoxymethyl-2-thiacéphem-4-carboxylate
 EMI56.4
 (7S, 6R) -7- [1 (R) -tert-butyldimethylsilyloxyethyl] -3- - tert-butyl;

   (7S, 6R) -7 - / * l - diphenylmethyl (7S, 6R) -7 - / "l - trichloroethyl.

  <Desc / Clms Page number 57>

 acetoxymethyl-2-thiacéphem-4-carboxylate Example 33 (7S, 6R) -7- [1 (R) -hydroxyethyl] -3-methyl-2-thiacéphem- -4-carboxylate
 EMI57.1
 
 EMI57.2
 (7S, 6R) -7- [1 (R) -tert-butyldimethylsilyloxyethyl] -3-methyl-2-thiacéphem-4-carboxylate (0.75 g) was added to a solution of tetrabutylammonium fluoride trihydrate (2.03 g) in acetic acid (1.23 ml) and THF (10 ml).



   The recovery after 20 hours gave the title compound (with a virtually quantitative yield), having the spectral characteristics described for the sample obtained in Example 13.



   Following a similar experimental procedure, we obtained: (7S, 6R) -7- [1 (R) -hydroxyethyl] -3-methyl bromomethyl-2-thiacéphem- -4-carboxylate, starting from (7S, 6R ) -7- - Methyl [1 (R) -tert-butyldimethylsilyloxyethyl] -3-bromomethyl-2- -thiacephem-4-carboxylate;
 EMI57.3
 #max (film) 1775, 1730 cm-1 max
 EMI57.4
 (3H, d, dd, CH. Br s, OH), 3, (3H, s, OMe), 4, m, CH. CH), 4, (2H, center of deABq, p./lines 4Hz, and 4, ppm (1H, d, J = 2, CH. CH. S); (7S, 6R) -7-'l 2, Methyl 3, 4- -tetrazol-5-yl) -thiomethyl-2-thiacéphem-4-carboxylate, starting from (7S, 6R) -butyldimethylsilyloxyethyl7-3- 2, 3, 4- -tetrazol-5-yl) -thiomethyl-2-thiacéphem-4-methyl carboxylate;

  <Desc / Clms Page number 58>

 
 EMI58.1
 v (KBr) 1765 and 1707 cm-1; J (CD-COCD-) 1, 30 (3H, max d, CH. 3, 39 (1H, dd, CH. CH.

   CH), 3.79 (3H, s, NCH3), 3.97 (3H, s, 0 (1H, m, CH. CH), 4.38 (2H, center of ABq, J = 16Hz, line separation internal 13Hz, CH2. S), 4.77 (1H, d, J = 2.2Hz, CH. CH. S) and 5.0 ppm (1H, br s, OH); and, similarly, we have also prepared the corresponding tert-butyl, diphenylmethyl and trichloroethyl esters.



  Example 34 (7S, 6R) -7- [1 (R) -methylsulfonyloxyethyl] -3-methyl- -2-thiacéphem-4-carboxylic acid
 EMI58.2
 
Diphenylmethyl (7S, 6R) -7- [1 (R) -methylsulfonyloxyethyl] - -3-methyl-2-thiacéphem-4-carboxylate was dissolved in cold trifluoroacetic acid (OOC, net). After 15 minutes of stirring at the same temperature, carbon tetrachloride was added and the solution was completely evaporated in vacuo without external heating.

   The residue was triturated in CCI. and collected, which made it possible to obtain the product indicated in title; (CHCl3) 281 and 326 nm; . "evils
 EMI58.3
 \) (CHC13) 3000-2300, 2970, 2930, 2850, 1775, 1710, max 1530 and 1170 cm; CF (CD3COCD3) 1, 58 (3H, d, CH), 2, 23 (3H, s, Me), 3, 16 (3H, s, S02Me), 3, 66 (1H, dd, J = 2 and 6Hz , CH. CH. CH), 4.85 (1H, d, J = 2Hz, CH. CH. S), and 5.30 ppm (1H, m, CH3. CH. CH).

  <Desc / Clms Page number 59>

 



   The same material was obtained by hydrolysis in TFA of the corresponding t-butyl ester, extending the reaction time to about 1 hour.



   Similarly, hydrolysis of the t-butyl or diphenylmethyl precursors gave the following products:
 EMI59.1
 Acid (7S, 6R) -7 - / - l - Acid (7S, 6R) -7 - / 'l cephem-4-carboxylic acid (7S, 6R) - - - acid (7S, -2-thiacéphem-4- carboxylic acid (7S, 6R) -7 - / - l 2, 3, 4- - Example 35 l, 1-dioxide of (7S, 6R) ethyl
 EMI59.2
 
 EMI59.3
 Procedure a) A solution of 117 mg of (7S, 6R) -t-butyldimethylsilyloxyethyl7-3-methyl-4-methoxycarbonyl- (R) -tert-butyldimethylsilyloxyethyl7-- 2-thiacephem in 5 ml of chloroform was treated with 220 mg m-chloroperbenzoic acid to OOC, with agitation.



  After 30 minutes, the reaction mixture was partitioned between dichloromethane and a 2% by weight aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was purified by chromatography

  <Desc / Clms Page number 60>

 short circuit to provide in the form of a syrup the title product (89 mg); Y max (CH2C12 film)
 EMI60.1
 1800, 1735 cm '; (CDC13) 0, 10 (6H, s, Me 0, 90 (9H, s, Bu 1, 27 (3H, d, CH3-CH), 2, 18 (3H, s, Ci 3, 81-3, 83 (1H, dd, + 3H, s, CH-CH-CH and 35 (1H, m, CH3-CH-CH), 5.05 (1H, d, J = 2.0Hz, CH-CH-S) ppm; max (hexane) 276 5.084) and 297 (sh, 745) nm.



  Procedure b) A solution of 500 mg of (7S, 6R) - - in 25 ml of chloroform was treated with 276 mg of 80% m-chloroperbenzoic acid at 20 C.
2Si), let the temperature rise to +20 C over 30 minutes and then a 4% by weight aqueous solution of sodium bicarbonate was added.



   The organic layer was dried over anhydrous sodium sulfate and the solvent was removed by evaporation. The residue was separated by chromatography on silica gel to provide in the following order: - 1,1-dioxide, in syrup, 35 mg; NMR and IR characteristic as above; - 2-oxide, in syrup, 60 mg; #max (CH2Cl2 film) 1795.1740 cm; J (CDCl3) 0.10 (6H, s, Me2Si); 0.90 (9H, s, ButSi), 1.24 (3H, d, CH3-CH), 2.35 (3H, S, CH3); 2.85-3.90 (1H, dd, + 3H, s, CH-CH-CH and OCH3), 4.35 (1H, m, CH3-CH-CH), 5.27 (1H, d, J = 2.5 Hz, CH-CH-S)
 EMI60.2
 ppm; (hexane) 276 (# 5.092) nm max - white powder, p. f. 90-930C, 330 mg y max (CH2C12 film) 1790, 1730 cm ";

   Jo, 10 (6H, s, Me2Si),

  <Desc / Clms Page number 61>

 0.90 (9H, S, ButSi) 1.28 (3H, d, CH3-CH), 2.24 (3H, s, Ci 3), 3.60 (1H, dd, J = 2.0 and 4 , 0 Hz, CH-CH-CH), 3.87 (3H, s, OCH3), 4.35 (1H, m, CH3-CH-CH), 4.67 (1H, d, J = 2.0 Hz, CH-CH-S) ppm; #max (hexane) 273 (# = 4.862), 309 (sh, # = 2.721) nm.



   The solution of 300 mg of the 1-oxide in 30 ml of chloroform was stirred for 1 hour at room temperature in the presence of. 160 mg of m-chloroperbenzoic acid. The reaction mixture was washed with a concentrated aqueous sodium bicarbonate solution and purified by flash chromatography (silica gel, cyclohexane: ethyl acetate as eluent), which made it possible to obtain an additional 280 mg of the product indicated in title.



   Example 36 (6S, 5R) -6- [1 (R) -tert-butyldimethylsilyloxyethyl] -2- -methylpenem-3-carboxylate
 EMI61.1
 A solution of 300 mg of 1,1-dioxide
 EMI61.2
 (7S, 6R) -7- [1 (R) -t-butyldimethylsilyloxyethyl] -3-methyl- -4-methoxycarbonyl-2-thiacéphem in chloroform was heated at 50 ° C for 5 hours. Removal of the solvent provided the title compound, free from stereoisomers, in approximately quantitative yield (250 mg); #max (CHCl3) 1795.1717 cm-1; # (CDCl3) 0.08 (6H, s, Me2Si), 0.89 (9H, s, ButSi), 1.23 (3H, d, CH3-CH) 2.33
 EMI61.3
 (3H, s, (1H, dd, J = 1.8 and 5.0 Hz, CH-CH-CH), 3.75 (3, s, (1H, m, 5.50 (1H, d, J = 1.8Hz, CH-CH-S); max (EtOH) 257.314nm.

  <Desc / Clms Page number 62>

 



   The above reaction occurred even at room temperature; for example after 16 hours of maintenance in chloroform the NMR analysis revealed a 1: 2 mixture of the title product and the starting material.



  Example 37 (7S, 6R) -1,7-dioxide [1 (R) -hydroxyethyl] -3-methyl-4--methoxycarbonyl-2-thiacephem
 EMI62.1
 
 EMI62.2
 A solution of 40 mg of (7S, 6R) -7- [1 (R) - -hydroxyethyl] -3-methyl-4-methoxycarbonyl-2-thiacéphem in 1 ml of chloroform was stirred at OC for 15 minutes in the presence 60 mg of m-chloroperbenzoic acid.



  Separation between ethyl acetate and an aqueous sodium bicarbonate solution and removal of the solvent left the title compound which was further purified by chromatography on silica gel; J (CDC13) 1.36 (3H, d, J = 6.4Hz, CH3-CH), 2.21 (3H, s, CH3), 3.80-3.88 (4H, m, CH-CH- CH and OCH-), 4.40 (1H, m, CH3-CH-CH), 5.08 (1H, d, J = 1.6Hz, CH-CH-S).



  Example 38 (6S, 5R) -6- [1 (R) -hydroxyethyl] -2-methylpénem-3- -carboxylate
 EMI62.3
 

  <Desc / Clms Page number 63>

 
When a solution of the compound prepared in Example 37 in an inert solvent (for example chloroform or benzene) was left to stand for a few days, or briefly heated to 50-80 C, the title compound became formed, free of diastomers, with a virtually quantitative yield.
 EMI63.1
 



  J (CDC13) 34 (3H, d, J = 6, 4Hz, CH3-CH) 2, 35 (3H, s, 3, 68 (1H, dd, J = 6, 6 and l, 5Hz, CH-CH- CH), 3.80 (3H, s, OCH 3 4.40 (1H, m, CH3-CH-CH), 5.56 (1H, d, J = 1.5Hz, CH-CH-S).



  Example 39 (6S, 5R) -6- [1 (R) tert-butyldimethylsilyloxyethyl] -2-
1, - (1-methyl-1, 2,3, 4-tetrazol-5-yl) methyl thiomethylpenem-3- -carboxylate
 EMI63.2
 
 EMI63.3
 A solution of (7S, 6R) -7- [1 (R) -tert- -butyldimethylsilyloxyethyl] -3- (1-methyl-1, 2, 3, 4-tetrazol- -5-yl) thiomethyl-2-thiacéphem -4-methylcarboxylate in chloroform was stirred at 0 ° C. with m-chloroperbenzoic acid (2.5 molar equivalent) for 30 minutes, then washed with aqueous NaHCO3. The dried organic layer was kept under reflux for a few hours (under TLC control).



   Evaporation of the solvent and chromatography on silica gel provided the title product; # (CDCl3) 0.07 (6H, s, SiMe2), 0.82 (9H, s, SiBut), 1.20 (3H, d, CH3-CH), 3.68 (1H, dd, 1.8 and 4Hz, CH.CH.CH), 3.80 (3H, s, N-Me), 3.81 (3H, s, OMe), 4.22 (1H, m, CH3-CH-CH), 4 , 69 (2H, center of ABq, J = 14 Hz, separation of interior lines 11.5 Hz, CH2S), and 5.54 ppm (1H, d, J = 1.8 Hz, CH-CH-S).

  <Desc / Clms Page number 64>

 
 EMI64.1
 



  Example 40 (7S, - of p-nitrobenzyl
 EMI64.2
 
 EMI64.3
 A solution of (7S, 6R) benzyloxycarbonyloxyethy
6R) -7 - / - diphenylmethyl carboxylate (200 mg) in dichloromethane (25 ml) was treated for 30 minutes at OOC with trifluoroacetic acid (0.4 ml). Evaporation in vacuum in the cold left the crude 2-thiacéphem-4- - carboxylic acid which was dissolved in the acetonitrile-dimethylformamide mixture (2: 1.10 ml) and treated with triethylamine (0.050 ml) and p-nitrobenzyl bromide (100 mg). After 1 hour at 25 ° C., the mixture was divided between ethyl acetate and
Aqueous NaHC03.



   The dried organic layer (MgSO 4) was concentrated and the residue was passed through a short column of SiO 2 (with ethyl acetate-light petroleum as
 EMI64.4
 eluents) for obtaining the pure product indicated in title, 150 mg (79%); cf (CDC13 1, 45 (3H, d, CH3. CH), 3, 43 (1H, dd, J = 2, 5 6 Hz, CH-CH-CH), 4, 45 (2H, ABq, J = 12 Hz, CH2Br), 4.80 (1H, d, J = 2.5Hz, CH-CH-S), 5.2-5.5 (5H, m), 7.47 and 7.60 (each 2H , d, Ar), and 8.20 ppm (4H, d, Ar).



  Example 41
 EMI64.5
 (7S, 6R) bromide -7 - / - ethyl / -4-diphenylmethoxycarbonyl-2-thiacéphem-3- -

  <Desc / Clms Page number 65>

 
 EMI65.1
 
A solution of (7S, 6R) -7- [1 (R) -tert- -butyldimethylsilyloxyethyl] -3-bromomethyl-2-thiacéphem- -4-diphenylmethyl carboxylate (310 mg) in dry acetone (15 ml ) was treated with pyridine (0.4 ml). After 20 hours at room temperature, the solvent was distilled off and the residue was purified by chromatography on silica gel.

   The product-containing fractions (eluted with the CH2Cl2-HOAc-MeOH 70:15:15 mixture) were collected and released from the solvents to leave the title compound in the form of a syrup; #max (CHCl3-film) 1790, 1715 cm-1; # (CDCl3) (inter alia) 1.32 (3H, d, J = 6.5Hz), 3.33 (1H, dd), 4.45 (1H, m), 5.0 (1H, d, J <2Hz),
 EMI65.2
 7.11 (1H, s); 283 and 337 nm (# 4,060).



  In an analogous manner, starting from (7S, 6R) -7 - / 'l - of p-nitrobenzyl, there was obtained: (7S, ethyl #max (CHCl3) - (pyridinium) -methyl bromide.



  Example 42 (7S, 6R) -7 - [- 1 (R) -tert-butyldimethylsilyloxyethyl] -4-carboxy-2-thiacéphem-3- (pyridinium) trifluoroacetate

  <Desc / Clms Page number 66>

 
 EMI66.1
 
A solution of diphenylmethyl ester (obtained in Example 41) in dichloromethane (10 ml) was treated with trifluoroacetic acid (2 ml) at OOC for 15 minutes.



   After evaporation in vacuo, the residue was taken up in a small amount of chloroform. Ethyl ether was added during stirring and then removed by decantation to leave the product indicated in the raw state.
 EMI66.2
 In title ; 3420, 1785, 1715 and 1635 br max cm-1 (inter alia) 1.30 (3H, d, J = 6.5 Hz), 3.23 (1H, dd), 4.38 (1H, m), 4.76 (1H, d) ppm; #max (CHCl3) 262 and 334 nm.



  Example 43
 EMI66.3
 Bromide of (7S, ethy -
 EMI66.4
 
 EMI66.5
 A solution of (7S, benzyloxycarbonyloxyéthy
6R) -7- [1 (R) -p-nitrobenzyloxycarbonyloxy-- p-nitrobenzyl carboxylate (460 mg) in DMF (5 ml) was stirred overnight in the dark in the presence of nicotinamide (200 mg). Most of the solvent was removed by distillation and the residue was taken up in

  <Desc / Clms Page number 67>

 tetrahydrofuran (150 ml). This solution was washed repeatedly with a solution of NaCl in 0.1 N HCl (2 x 50 ml) with brine (2 x 50 ml) dried (Na2SO4) and subjected to evaporation. The residue was loaded on top of a column filled with silanized silica gel (Merck, Art. 7719).

   The excess nicotinamide and impurities were eluted with EtOAc, then the product was collected by elution with EtOAc-HOAc (9: 1).



  Evaporation in vacuo left the title product; #max (CHCl3) 1800.1725, 1695 cm-1; # (deuteroacetone; 200 MHz) 1.67 (3H, d, J = 6.4 Hz, CH3-CH), 4.14 (1H, dd, J = 2.5 and 4.7 Hz, CH-CH- CH), 5.30 (1H, d, J = 2.5 Hz, CH-CH-S), 5.4-5.7 (7H, m, 2xCH2OAr, CH2N, and CH3-CH-CH), 7 , 7-8.4 (8H, m, Ar), and 8.0.8.7, 9.5 and 9.7 ppm (each 1H, br s, pyridinium).



   Similarly, by using isonicotinamide instead of nicotinamide, we have obtained:
 EMI67.1
 (7S, 6R) ethyl bromide -7-L-1 (R) -p-nitrobenzyloxycarbonyloxy - (4-carbamoylpyridinium) methyl.



  Example 44 (6S, 5R) -6- [1 (R) -hydroxyethyl] -2- (piridinium) methyl- -penem-3-carboxylate
 EMI67.2
 
A ¯¯¯¯¯¯¯ solution of (7S, 6R) -7- [1 (R) - -p-nitrobenzyloxycarbonyloxyéthyl] -4-p-nitrobenzyloxycar- -acetate bonyl-3- (pyridinium) methyl-2-thiacéphem / (prepared from the corresponding bromite by a conventional treatment with

  <Desc / Clms Page number 68>

 silver acetate or an ion exchange resin) in chloroform was treated with peracetic acid (2 moles equivalent) to OOC. The work and
 EMI68.1
 moderate heating, according to the general procedure described in Examples 37 to 39, gave: - / benzyloxycarbonyl-2- (6S, 5R) -6-y maux (KBr) 1795,1740, 1705 cm ';

     cf (CDCl + deuteroacetone) 1.4 (3H, d, J = 6.5 Hz, CH3-CH), 4.10 (1H, dd, J = 1.7 and 8 Hz, CH-CH-CH ), 5.20 and 5.31 (each 2H, s, OCH2Ar), 5.2 (1H, m, CH3-CH-CH), 5.77 (1H, d, J = 1.7 Hz, CH- CH-S), 6.05 (2H, ABq, J = 15 Hz, CH2N), 7.4-8.3 (11H, m, Ar) and 9.15 ppm (2H, d, J = 6 Hz, o-Pyr).



   This material (300 mg) in the tetrahydrofuran-water mixture (1: 1.40 ml) was treated with ammonium chloride (5 g) while stirring until a clear solution was obtained.



   After cooling to about 100C, iron powder (about 2.5g) was added during vigorous stirring; the reaction can be controlled
 EMI68.2
 by TLC (HO-MeOH-NaCl 9: 1: 1) following the development of the product as a faster.



  After about an hour, celite (3 g) was added and the whole was filtered through a glass vase, washed with demineralized water. Removal of the organic solvent, followed by washing with ethyl ether, left an aqueous solution of the title product and inorganic salts.



   The first was obtained pure after reverse phase chromatography and cold drying; Jr (D20), 200 MHz), 1.27 (3H, d, J = 6.5 Hz, CH3CH), 3.98 (1H, dd, J = 1.4 and 5.8 Hz, CH-CH- CH), 4.24 (1H, m, CH3-CH-CH), 5.69 (1H, d, J = 1.4 Hz CH-CH-S), 5.94 (2H, ABq, J = 14 , 9 Hz, CH2N), 8.10 (2H, t, J = 6.6 Hz, pyridinium mH), 8.61 (1H, bd, J = 7.7 Hz, pyridinium pH), 8.95 (2H , d, J = 6.6 Hz, pyridinium oH) ppm.

  <Desc / Clms Page number 69>

 



   In an analogous manner, starting from the compounds described in Example 43, there were obtained: (6S, 5R) -6- (1 (R) -hydroxyêthy1] -2- (3-carbamoylpyridinium) methylpenem-3-carboxylate; (6S, 5R) -6- [1 (R) -hydroxyethyl] -2- (4-carbamoylpyridinium) methylpenem-3-carboxylate.



  EXAMPLE 45 Sodium salt of (6S, 5R) -6- [1 (R) -hydroxyethyl] - -2- (1-methyl-1,2,3,4-tetrazol-5-yl) thiomethylpenern- 3- - carboxylic
 EMI69.1
 
 EMI69.2
 A solution of (7S, benzyloxycarbonyloxyethyl7-3- 2, 3, 4-tetrazol- -5-yl) of p-nitro-benzyl in chloroform was oxidized with m-chloroperbenzoic acid, as described in the example 37, to give the corresponding sulfone. Without purification, this material was heated to 600C in dry distilled tetrahydrofuran under a stream of nitrogen until the expulsion of SO2 was complete.

   Removal of the solvent and chromatography on silica gel gave
 EMI69.3
 le (6S, - (l-methyl-1, 2, 3, 4-tetrazol-5-yl) thiométhylpénem-3-
5R) -6-- p-nitrobenzyl carboxylate; # (CDCl3) 1.48 (3H, d, J = 7 Hz, CH3-CH) 3.84 (1H, dd, J = 2 and 5.5 Hz, CH-CH-CH), 3.96 (3H , s, NCH3), 4.69 (2H, ABq, J = 14 Hz, CH2S), 5.20 (1H, m, CH3-CH-CH), 5.24 (2H, s, OCH2Ar), 5, 27 (2H, ABq, J = 13 Hz, OCH2Ar), 5.61 (1H, d, J = 2 Hz), 7.51 and 7.82 (each 2H, d, J = 8 Hz, Ar), 8 , 02 ppm (4H, d, J = 8 Hz, Ar).

  <Desc / Clms Page number 70>

 



  Reaction of this material above with Fe / NH4Cl, according to the procedure described in Example 44, provided the title product; J (D20) 1.28 (3H, d, J = 6.5Hz), 3.87 (1H, dd, J = 1.4 and 6.3 Hz, CH-CH-CH), 4.10 (3H , s, NCH3), 4.19 (1H, m, CH3-CH-CH), 4.40 (2H, ABq, J = 16 Hz, CH2S), 5.59 ppm (1H, d, J = 1, 4 Hz, CH-CH-S); max (H2O) 315 nm.



  Example 46 (6S, 5R) -6- [1 (R) -tert-butyldimethylsilyloxyethyl] -2- -nitrooxymethylpenen-3-carboxylate
 EMI70.1
 
 EMI70.2
 A solution of (7S, dimethylsilyloxyethyl] -3-nitrooxymethyl-2-thiacéphem-4-carboxylate (prepared as described in Example 31) in chloroform was treated with m-chloroperbenzoic acid (2 molar equivalents , OC) to give 1-sulfone.

   Aqueous hydrogen carbonate was added for the extraction of m-chlorobenzoic acid and then the dried organic solution was gently put under reflux (control by TLC), to give a solution of the penem compound indicated in title; # (CDCl3) (inter alia) 5.64 (1H, d, J = 2 Hz, CH-CH-S) and 5.65 ppm (2H, ABq, J = 15 Hz, line separation
 EMI70.3
 indoor 46 Hz, CH20N02) - 1710 cm.



   In a similar way starting from
 EMI70.4
 (7S, 6R) -7 - / - l - of trichloroethyl:

  <Desc / Clms Page number 71>

 (6S, 5R) -6- [1 (R) -trichloroethoxycarbonyloxyethyl] -2- -nitrooxymethylpenem-3-carboxylate of trichloroethyl.



  Example 47 (6S, 5R) -6- [1 (R) -tert-butyldimethylsilyloxyethyl] -2- -hydroxymethylpenem-3-carboxylate
 EMI71.1
 
 EMI71.2
 A solution of (6S, -butyldimethylsilyloxyethyl] -2-nitrooxymethylpénem-3-
5R) -6- [1 (R) -tert-- crude methyl carboxylate (obtained from 45 mg of the corresponding precursor 3-bromomethyl-2-thiacéphem, in accordance with Examples 31 and 46) in dichloromethane (2 ml) was stirred for 5 minutes at 0 ° C with zinc powder (0.1 g) and acetic acid (0.1 ml).

   The reaction mixture was filtered and the solution was evaporated until the title crude product was obtained, which was purified by chromatography on silica gel (ethyl acetate- light petroleum 1: 4 to 1: 1); #max (CHCl3 film)
 EMI71.3
 1785, 1710 cm-1; # 0.07 (6H, s, SiMe2), (9H, s, SiBut), 1.23 (3H, d, CH3-CH), 3.70 (1H, dd, J = 1.8 and 4.5 Hz, CH-CH-CH), 4.25 (1H, m, CH3-CH-CH), 4.59 (2H, s, CH OH) and 5.57 ppm (1H, d, J = 1.8 Hz, CH-CH-S).



   By operating in an analogous manner on (6S, 5R) -6- [1 (R) -trichloroethoxycarbonyloxyethyl] -2- -nitrooxymethylpenem-3-carboxylate of trichloroethyl, complete unblocking of the protecting groups was accomplished and obtained thus after recovery with aqueous NaHC03 and phase inversion chromatography (with water as eluent)

  <Desc / Clms Page number 72>

 
 EMI72.1
 the sodium salt of the acid (6S, - 5R) -6 - / - l (R) -hydroxyethyl7-Jr (D20) 1.30 (3H, d, CH3-CH), 3.88 (1H, dd , J = 1 and 6.3 Hz, CH-CH-CH), 4.23 (1H, m, CH3-CH-CH), 4.63 (2H, ABq, J = 14.5 Hz, line separation 4 Hz, CH2OH), and 5.62 ppm (1H, d, J = 1Hz, CH-CH-S); #max (KBr) 1765 and 1610-1590 cm-1.



    Example 48
 EMI72.2
 Acid sodium salt (6S, 5R) -6 - / 'KR) -hydroxyethyl7- -
 EMI72.3
 
 EMI72.4
 A solution in chloroform of (7S, - of
2-carbamoyloxyethylpenem-3-carboxyliquetrichloroethyl was treated with m-chloroperbenzoic acid according to the general method of Example 37.

   After resumption, brief heating of the resulting 1-sulfone in an inert solvent (benzene) gave (6S, 5R) -6- [1 (R) -trichloroethoxycarbonyloxyethyl] - -2-carbamoyloxymethylpenem-3-carboxylate of trichloro- ethyl; # (CDCl3) 1.5 (3H, d, CH3-CH), 3.94 (1H, dd, J = 2 and 8 Hz, CH-CH-CH), 4.73 and 4.82 (each 2H, s, OCH2CCl3), 4.8 (1H, m, CH3-CH-CH) 5.25 (2H, ABq, J = 10Hz, CH2OCONH2), 5.62 (1H, d, J = 2 Hz, CH-CH -S).



   A THF solution of this material was treated with Zn powder (about 6 parts by weight) and a 1M aqueous solution NaH2PO4 during stirring. After 3 hours of stirring at 250C another part of Zn was added and the mixture was maintained

  <Desc / Clms Page number 73>

 stirring for 3 hours. Recovery and phase inversion chromatography provided the title product;
 EMI73.1
 J 1, 31 (3H, d, J = 6.5 Hz, CH3-CH), dd, J = 1.5 and 6 Hz, CH-CH-CH), 4.25 (1H, m, CH3-CH -CH), 5.19 (2H, ABq, J = 14.5 Hz, CH20CO) and 5.66 ppm (1H, d, J = 1.5 Hz, CH-CH-S).


    

Claims (25)

 CLAIMS 1. Process for the preparation of (5R) -penem derivatives of general formula I:  EMI74.1  wherein R1 represents a hydrogen atom or an organic group; R2 represents a hydrogen atom or a carboxy protecting group and Y represents a hydrogen or halogen atom, characterized in that a 2-thiacephem derivative of general formula II is subjected:  EMI74.2  in which R ,, R and Y are as defined above, in solution in an inert organic solvent such as chloroform or benzene, at a temperature of 0 to 60 C, to an oxidation reaction using oxidizing agents peracids such as m-chloroperbenzoic acid or peracetic acid, to obtain the corresponding sulfone of general formula III:    EMI74.3    <Desc / Clms Page number 75>  in which Ru, rozet Y are as defined above, which is finally subjected to a desulfurizing contraction of the ring by expulsion of SO 2 using gentle heating in an inert organic solvent or by maintaining the room temperature so that the desired derivatives (5R) -penem of formula I are obtained exclusively and finally purified according to known methods.  2. Method according to claim 1 characterized in that the organic groups that R-can represent in the derivative (5R) -penem of formula I are optionally substituted aliphatic or cycloaliphatic groups.  3. Method according to any one of claims 1,2 characterized in that the aliphatic groups that RI can represent in the derivatives (5R) -penem of formula I are straight or branched chain alkyl groups having from 1 to 12 atoms carbon optionally substituted with one or more free or protected groups mercapto, amino, hydroxy or a cyano group.  4-tetrazol-5-yl) - (6S, 5R) -6 - / - methyl l-nitrooxymethylpenem-3-carboxylate, (6S, 5R) -6 - / 'l - of trichloroethyl, (6S, 5R) - 6 - / - l - methyl, the sodium salt of the acid (6S, 5R) -6 - / - l - the sodium salt of the acid (6S, 5R) -6 - / * l -2 -carbamoyloxymethylpénem-3-carboxylic.  4. Method according to any one of claims 1 to 3 characterized in that the preferred alkyl groups that R. can represent in the derivatives (5R) - - penem of formula I are methyl, ethyl, isopropyl, preferably ethyl and a preferred substituent for such a group is a free or protected hydroxy group, the protective group being a p-nitrobenzyloxycarbonyl, dimethyl-t-butyl-silyl, diphenyl-t-butyl-silyl, trimethylsilyl, 2 group. , 2, 2-trichloroethoxycarbonyl, benzyl, p-bromophenacyl, triphenylmethyl or pyranyl.  5. Method according to any one of claims 1, 2 characterized in that the cycloaliphatic groups that RI can represent in the (5R) -penem derivatives of formula I are monocycloalkyl groups having from 4 to 7 carbon atoms, preferably a cyclopentyl or cyclohexyl group, optionally substituted, with alkyl groups having from 1 to 6 carbon atoms or with one or more free or protected mercapto, amino or hydroxy groups.  <Desc / Clms Page number 76>    6. Method according to claim 1 characterized in that the carboxy protecting groups that R2 can represent in the derivatives (5R) -penem of formula I are straight or branched chain alkyl groups having from 1 to 6 carbon atoms, groups halo-substituted alkyl having 1 to 6 carbon atoms such as the 2,2,2-trichloroethyl group, alkenyl groups having 2 to 4 carbon atoms such as an allyl group, optionally substituted aryl groups such as a phenyl group or p-nitrophenyl, alkyl groups substituted by aryl in which the aryl part is optionally substituted such as a benzyl group, p-nitro-benzyl or a p-methoxy benzyl group,  aryloxy-substituted alkyl groups in which the alkyl part has from 1 to 6 carbon atoms such as a phenoxy-methyl group, or a benzhydryl, o-nitro-benzhydryl, acetonyl, trimethylsilyl, diphenyl-t-butyl-silyl, dimethyl group -t-butyl-silyl, acetoxymethyl, pivaloyloxymethyl or phthalidyl.  7. Method according to claim 1 characterized in that, when Y in the derivatives (5R) -penem of formula I represents a halogen atom, the latter is preferably a fluorine, chlorine or bromine atom.  8. Method according to claim 1 characterized in that, when Y in the derivatives (5R) -penem of formula I represents an organic group, the latter is: a) a free or protected hydroxy group; b) a formyloxy group or an acyloxy group having from 2 to 6 carbon atoms, optionally substituted by a halogen atom, by an acyl group having from 2 to 6 carbon atoms, or by an amino, hydroxy or mercapto group , the amino, hydroxy or mercapto group being optionally in protected form; c) a carbamoyloxy group unsubstituted or substituted by N-alkyl;    <Desc / Clms Page number 77>    EMI77.1  d) an alkoxy group having from 1 to 12 carbon atoms or an alkylthio group having from 1 to 12 carbon atoms, one or the other being optionally substituted by one or more halogen atoms, formyl groups, acyl groups having from 2 to 6 carbon atoms, and / or an amino, hydroxy or mercapto group being optionally in protected form;  e) an unsubstituted or substituted 1-pyridinium group  EMI77.2  meta or para position with the CONH2 group f) a heterocyclylthio-S-Het group where Het denoting a saturated or unsaturated heterocycle ring containing at least one heteroatom of oxygen, sulfur and / or nitrogen is preferably: A) a pentatomic or hexatomic heteromonocycle ring containing at least one double bond and at least one heteroatom of oxygen, sulfur and / or nitrogen such as a thiazolyl, triazolyl, thiadiazolyl, tetrazolyl, triazinyl, unsubstituted or substituted group by one or more: a ') alkoxy groups having from 1 to 6 carbon atoms, acyl-aliphatic groups having from 2 to 6 carbon atoms, hydroxy groups and / or halogen atoms;  b ') alkyl groups having from 1 to 6 carbon atoms, unsubstituted or substituted by one or more hydroxy groups and / or halogen atoms; c ') alkenyl groups having 2 to 6 carbon atoms, unsubstituted' or substituted by one or more hydroxy groups and / or halogen atoms; d ') groups of general formula-S-R where R-represents a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms; or groups of general formula - S-CH -COOR where R. represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms or a carboxy protecting group;    <Desc / Clms Page number 78>    EMI78.1  e ') groups of general formula- (CH) -COOR. or-CH = CH-COOR.or- (CH) -CN or 4 2 m - (CH) -CONHLou- (CH) -SO-H is zero, 1, mm J- 2 or 3 and R4 is as defined below -above ; # R6 where mf ') groups of general formula- (CH2) m # -N # R5 where m is as defined above and each of R5 and Ru, which may be the same or different, represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms or  EMI78.2  an acyl-aliphatic group or, when one of R5 and R6 is hydrogen, the other may also be an amino protecting group;  B) a heterobicycle ring containing at least two double bonds where each of the condensed heteromonocycles rings, the latter being the same or different, is a pentatomic heteromonocycle ring  EMI78.3  or hexatomic containing at least one heteroatom of oxygen, sulfur or nitrogen, this hetero-bicycle ring being unsubstituted or substituted by one or more of the substituents chosen between a '), b'), c '), el) and f ') defined above.  9. derivative (5R) -penem of general formula I, prepared according to claim 1, which is one of the following substances: (6S, 5R) -6- [1 (R) -t-butyldimethylsilyloxyethyl] -2-methyl - methyl penem-3-carboxylate, (6S, 5R) -6 [1 (R) -hydroxyethyl] -2-methylpenem-3-carboxylate,  EMI78.4  (6S, 5R) -6- [1 (R) -hydroxyethyl] -2-acetoxymethyl-penem-3- - p-nitrobenzyl, (6S, 5R) -6 - / - l - p-nitrobenzyl, (6S , SR) -6 - / - l -2- - 2, 3, 4-tetrazol-5-yl) thiomethyl penem-3-  <Desc / Clms Page number 79>  methyl carboxylate, (6S, 5R) -6- [1 (R) -hydroxyethyl] -2- (pyridinium) methylpenem carboxylate, (6S, 5R) -6- [1 (R) -hydroxyethyl] -2- (3 -carbamoylpyridinium) methylpenem-3-carboxylate, (6S, 5R) -6- [1 (R) -hydroxyethyl] -2- (4-carbamoylpyridinium) methylpenern-3-carboxylate,  EMI79.1  the sodium salt of the acid (6S, -2- 2, 3,  10. Process for the preparation of a 2-thiacéphem derivative of general formula II:  EMI79.2  in which R and R2 are as defined in claims 1 to 6 and Y is a halogen atom, as defined in claim 7, characterized in that a 2-thiacephem derivative of general formula II is treated where RI and R2 are as defined above and Y is a hydrogen atom, dissolved in an inert organic solvent such as benzene or carbon tetrachloride, at a  <Desc / Clms Page number 80>  temperature from 200C to 1300C,    using an appropriate halogenating agent such as N-bromosuccinimide or N-chlorosuccinimide in the presence of azobisisobutyronitrile or benzoyl peroxide and in the presence of acidic evacuators such as propylene oxide, alkaline oxides earthy or molecular sieves, to obtain the desired 2-thiacéphem compound of formula II where R., and R2 are as defined above and Y is a bromine or chlorine atom.    11. 2-thiacéphem derivative of general formula II prepared according to claim 10 which is any one of the following bodies: (7S, 6R) -7- [1 (R) -tert-butyldimethylsilyloxyethyl] -3- -bromomethyl-2 -methyl thiacéphem-4-carboxylate, (7S, 6R) -7- [1 (R) -tert-butyldimethylsilyloxyethyl] -3--diphenylmethyl-2-thiacéphem-4-carboxylate,  EMI80.1  (7S, 6R) -7 - / - l - of trichloroethyl, (7S, 6R) -7- / - of trichloroethyl, (7S, 6R) -7 - / - l - of tert-butyl, ( 7S, 6R) -7-'l-p-nitrobenzyl-2-thiacephem-4-carboxylate, (7S, (R) -tert-butyldimethylsilyloxyethyl7-3 - diphenyl bromomethyl-2-thiacephem-4-carboxylate, (7S, 6R) -7- [1 (R) -tert-butyldimethylsilyloxyethyl] -3- -bromomethyl-2-thiacéphem-4-carboxylate of diphenylmethyl.  12. Process for the preparation of a 2-thiacéphem derivative of general formula II:  <Desc / Clms Page number 81>    EMI81.1    EMI81.2  where R and R2 are as defined in claims 1 to 6 and Y is a hydroxy group, characterized in that a 2-thiacephem derivative of general formula II is reacted where R, and R2 are as defined above and Y is a halogen atom, prepared according to claim 10, dissolved in an acetone-water mixture (2: 1 v / v) for 15 minutes at a temperature of 0 C with a salt of a strong inorganic acid such as silver perchlorate, to obtain a labile ester of this inorganic acid which is then hydrolyzed in the same reaction medium until the desired 2-thiacephem compound of formula II is obtained where R. and R2 are such that defined above and Y is OH. 13. A compound prepared according to claim 12 which is (7S, 6R) -7 - / - l ethyl tert-butyl. 14. Process for the preparation of a 2-thiacéphem derivative of general formula II:  EMI81.3    EMI81.4  where R and R2 are as defined in claims (R) -tert-butyldimethylsilyloxy-1 to 6 and Y is an N- (trichloroacetyl) carbamoyloxy group or a carbamoyloxy group, characterized in that a derivative 2- is treated thiacéphem of general formula II, where R and R2 are as defined above and Y is a hydroxy group,  <Desc / Clms Page number 82>  prepared according to claim 12, in solution in dichloromethane, at a temperature of -40 C, with a trichloroacetylisocyanate, the mixture is brought to reaction at room temperature and then the desired 2-thiacephem derivative of formula II is isolated,  where R and R2 are as defined above and Y is an N- (trichloroacetyl) carbamoyloxy group which is subjected, if desired, to an operation for removing the protection of the trichloroacetyl half of the first urethane adduct formed by stirring for 20 hours its methanolic solution with silica gel so as to obtain the 2-thiacephem derivative of formula II, where R 1 and R 2 are as defined above and Y is a carbamoyloxy group.  15. Product prepared according to claim 14 which is one of the following:  EMI82.1  (7S, 6R) -7 - / - l - - tert-butyl, (7S, 6R) -7 - / - l -carbamoyloxymethyl-2-thiacéphem-4-carboxylate tert-butyl.  16. Process for the preparation of a 2-thiacéphem derivative of general formula II:  EMI82.2    EMI82.3  where R. and R2 are as defined in claims 1 to 6 and Y is a formyloxy or acetoxy group, characterized in that a 2-thiacephem derivative of general formula II is treated, where R, and R2 are as defined above and Y is a halogen atom, prepared according to claim 10, in solution in dichloromethane at a  <Desc / Clms Page number 83>  temperature of 5 C and at daily intervals for 3 days with a suitable solution of the corresponding carboxylic acid to obtain the desired 2-thiacéphem product of formula II where R- and R- are as defined above and Y is a formyloxy or acetoxy group.  17. Product prepared according to claim 16 which is one of the following:  EMI83.1  (7S, 6R) -7 - / 'l - methyl- - (7S, 6R) -7 - / - l -3- - diphenylmethyl, (7S, 6R) -7 - / - l - methyl, ( 7S, 6R) -7 - / - l - tert-butyl, (7S, 6R) -7 - / - l - diphenylmethyl, (7S, 6R) -7 - / 'l - de (R) -tert- butyldimethylsilyloxyethyl / -3-trichloroethyl.  18. Process for the preparation of a 2-thiacéphem derivative of general formula II:  EMI83.2    <Desc / Clms Page number 84>  in which R and R are as defined in claims 1 to 6 and Y is a group-S-Het as defined in claim 8, characterized in that a 2-thiacephem derivative of general formula II is reacted, where R, and R2 are as defined above and Y is a halogen atom, prepared according to claim 10, in solution in an appropriate organic solvent such as tetrahydrofuran, acetone, acetonitrile or dimethylformamide, for one overnight, at room temperature,  with the corresponding HS-Het body in the presence of a base such as triethylamine or with a preformed sodium salt of HS-Het to obtain the 2-thiacephem derivative of formula II where RI and R2 are as defined above and Y is SHet.  19. Product prepared according to claim 18 which is one of the following:  EMI84.1  (7S, 6R) -7 - / - l - 2, 3, 4-tetrazol-5-yl) methyl thiomethyl-2-thiacéphem- - (7S, - 2, 3, 4-tetrazol "5-yl) - tert-butyl, (7S, 6R) -7 - / 'l tetrazol / 1, 5- / pyridazine-6-yl) (R) -tert-butyldimethylsilyloxyethyl7-3--4-diphenylmethyl carboxylate.  20. Process for the preparation of a 2-thiacéphem derivative of general formula II:  EMI84.2    <Desc / Clms Page number 85>  where R and R2 are as defined in claims 1 to 6 and Y is a 1-pyridinium group, unsubstituted or substituted in the meta or para position with a CO-NH group, characterized in that a derivative is reacted 2-thiacéphem of general formula II, where R, and R2 are as defined in claims 1 to 6 and Y is a halogen atom, prepared according to claim 10, overnight at room temperature with pyridine, nicotinamide or isonicotinamide to obtain, after purification by chromatography on silica gel, the desired 2-thiacéphem product of formula II,  where R. and R2 are as defined above and Y is an unsubstituted pyridinium group or a pyridinium group substituted in the meta or para position by a CO-NH group.  21. Product of general formula II prepared according to claim 20, which is one of the following:  EMI85.1  Bromide of (7S, 6R) -7 - / 'l ethy - bromide of (7S, ethy - bromide of (7S, ethy - bromide of (7S, ethy - 22. Process for the preparation of a 2-thiacéphem derivative of general formula II:  EMI85.2    <Desc / Clms Page number 86>  in which R 1 and R 2 have the meanings given in claims 1 to 6 and Y is as defined in claim 8, characterized in that a compound of general formula IV:  EMI86.1  in which RI and R2 are as defined above and Z represents:  i) a group of formula SR7 in which R7 represents an alkyl group having from 1 to 8 carbon atoms, a phenyl or tolyl group, or, preferably, a heterocycle group, especially a 2-benzothiazololthio or 1-methyl group tetrazol-5-yl-thio, ii) a group of formula SCORE in which R8 represents an optionally substituted lower alkyl group, preferably a methyl group, iii) a group of formula  EMI86.2    EMI86.3  where Rg and independently represent aryl or lower alkyl groups, or together with the dicarboxyamino group constitute a heterocycle ring, preferably a succinimido or phthalimido group, iv) a group of formula  EMI86.4  where R7 represents an optionally substituted aryl or lower alkyl group, preferably a methyl, phenyl or p-tolyl group,  is first halogenated by methods known per se to give the compound of general formula V:  <Desc / Clms Page number 87>    EMI87.1  in which R1, R2 and Z are as defined above and Y is a halogen atom, and then subjected to ozonolysis to give a compound of general formula VII:  EMI87.2  transforming the hydroxy group into a group L, where L represents a halogen atom, a sulfonyloxy-alkane group or a sulfonyloxy-arene group, preferably a sulfonyl-oxymethane group to give a compound of general formula IX:  EMI87.3  which is then subjected to cyclization to give the desired compound of formula II.  <Desc / Clms Page number 88>    23. Process for preparing a 2-thiacéphem derivative of general formula II:  EMI88.1  where R, and R2 are as defined in claims 1 to 6 and Y is a hydrogen atom, characterized in that a compound of general formula IV:  EMI88.2  where R and R2 have the meanings given in claims 1 to 6 and Z is as defined in claim 22 is first subjected to ozonolysis to give a compound of general formula VI:  EMI88.3  converting the hydroxy group to a group L where L is as defined in claim 22, to give the compound of general formula VIII:    <Desc / Clms Page number 89>    EMI89.1  which is then subjected to cyclization by treatment with a salt. of H2S with an organic or inorganic base to obtain the desired 2-thiacéphem derivative of general formula II.  24. 1, 1-dioxide-2-thiacephem of general formula III:  EMI89.2  prepared according to claim 1, R., R and Y being as defined in claims 1 to 6.  25. 1, 1-dioxide-2-thiacephem of general formula III, which is one of the following:  EMI89.3  1, 1-dioxide of (.ethyl-3-methyl-4-methoxycarbonyl-2-thiacéphem, 1, 1-dioxide of (7S, 6R) -7-'l (R) -hydroxyethyl7-3-methyl- -