HU194568B - Process for producing 2-/alkyl-thio/peneme derivatives - Google Patents

Abstract

The invention relates to a method of preparation of novel 2-alkylthio-2-penem-3-carboxylic acids which can be used in medicine as a remedy. The aim of the invention is the provision of new antibacterial drugs. The object of the invention to develop processes for the preparation of the novel 2-alkylthio-2-penem-3-carboxylic acids is obtained by hydrogenating a compound of the formula Igeloest, wherein R 1 is a carboxylic acid protecting group and R has the meaning given in the description, different meaning.

Description

The present invention relates to a process for the preparation of 6-a-hydroxyethyl-2-substituted-2-penem-3-carboxylic acids within the family of antibacterial agents containing a 2-azetidinone (beta-lactam) ring.

Although some 2-blycitrate-2-pcnene-3-carboxylic acid derivatives have been known previously, there is a continuing need for newer compounds with beneficial antibacterial properties.

The present invention relates to the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

R is 2- (methylsulfinyl) ethyl, 2- (methylsulfonyl) ethyl, (methylsulfinyl) methyl, (methylsulfonyl) methyl, 3-thietanyl, Ι- οχο-3-thietanyl, 1,1-diοχο-3-thietanyl, 2-thiolanyl, 1-oxo-2-thiolanyl, 3-thiolanyl, 1-oxo-3-thiolanyl, 1,1- dioxo-3-thiolanyl, 3-hydroxy-4-thiolanyl, 2-oxo-1,3-dithiolan-4-ylmethyl, 3-thiamyl, Ι-οχο-3-thianyl, 1,1 -dioxo-3-thianyl, 4-thianyl, 1-χχο-4-thianyl, 1,1-dioxo4-thianyl, 1,3-dithiolan-2-yl, or 1,2-dithiolan-4 -il-, and

R 1 is hydrogen, (C 1 -C 6) alkylcarbonyloxy (C 1 -C 4) alkyl, (C 1 -C 14) alkoxycarbonyloxy (C 14) alkyl, or one or two oxygen atoms and one carbonyl group. a five membered heterocyclic group optionally fused to a benzene ring or substituted with a C 14 alkyl group, which is bonded either through one of the carbon atoms of the heterocycle or through an alkylene group.

Preferred compounds of the invention are those wherein R is 2- (methylsulfinyl) ethyl, 2- (methylsulfonyl) ethyl, (methylsulfinyl) methyl, (methylsulfonyl) methyl, -thietanyl, Ι-οχο-3-thietanyl, 1,1-dioxo-3-thietanyl, 3-thiolanyl, 1-oxo-3-thiolanyl, 1,1-dioxo-3-thiolanyl, 3 -hydroxy-4-thianyl, 3-thianyl, Ι-οχο-3-thianyl, 1,1-dioxo-3-thianyl, 4-thianyl, 1-oxo4-thianyl, 1,1-dioxo4-thianyl or 2-oxo-1,3-dithiolan-4-ylmethyl.

Particularly preferred compounds of the invention are those wherein R is Ι-οχο-3-thiolanyl, 1,1-dioxo-3-thiolanyl, Ι-οχο-3-thietanyl, Ι-οχο-3-thianyl, -dioxo-4-thianyl ·, 4-thianyl.

The present invention also relates to the preparation of compounds of formula (II) and pharmaceutically acceptable salts thereof, which are a narrower group of compounds of formula I wherein R and R 1 are as defined for formula (I) above.

Preferred compounds of formula (II) are those wherein R is as defined for preferred compounds of formula (I).

Particularly advantageous are compounds of formula II wherein R is cis or trans-1-oxo-3-lolanyl, 1,1-dloxo-3-thiolanyl, cis or trans-1-oxo. 3-thietanyl, cis or trans-1-oxo-3-thianyl, 1,1-dioxo-4-thianyl, 4-thianyl or cis or Zrans-1-oxo-4-thianyl.

The present invention further encompasses the preparation of a pharmaceutical composition comprising a compound of formula (I) or (II) and a pharmaceutically acceptable diluent or carrier.

The compounds of the present invention having antibacterial activity of formulas I and II are considered to be derivatives of the bicyclic parent compound of formula III, the "2-pcncm" skeleton. The numbering of carbon atoms in the penem ring throughout this patent is the same as that given in formula (III). The carbon atom to which the ring carbon number 6 is attached is given the number 8. The p-nitrobenzyl group is referred to herein as "PNB".

The relative position of the hydrogen bonded to the bridged carbon number 5 of the penem ring and the residual hydrogen bonded to carbon number 6 in the compounds of formula I can be either cis or trans. The present invention encompasses both isomers as well as the cliocycles. From the therapeutic point of view, the use of trans isomers is generally more advantageous and the cis isomer can be easily converted to the corresponding trans isomer.

Generally speaking, the absolute spatial configuration of C 5 is R as defined by the Prelog-IngoId R, S stereochemical configuration designation used throughout this specification. For example, a compound of formula II wherein R 1 is hydrogen, R is 4-thianyl, (5R, 6S) -6 - [(R) -1-hydroxyethyl] -2- (4) -tianil) thio-3-carboxyl-2-penem.

Of course, various optically active isomers of the novel compounds of the invention are possible. The present invention encompasses all of these optical isomers as well as mixtures thereof.

Compounds of the invention include those wherein R is 2- (methylsulfinyl) ethyl, 2- (methylsulfonyl) ethyl, (methylsulfinyl) methyl, (methylsulfonyl) methyl- , 3-thietanyl, Ι-χχο-3-thietanyl, 1,1-diχχο-3-thetanyl, 3-thiolanyl, 1-oxo-3-thiolanyl, 1,1-dioxo-3-thiolanyl, , 2-thiolanyl, 1-oxo-2-thiolanyl, 3-thianyl, Ι-οχο-3-thianyl, 1,1-dioxo-3-thianyl, 4-thianyl, 1-oxo4-thianyl - 1,1-dioxo-4-thianyl, 1,3-dithiolan-2-yl, 3-hydroxy-4-thiolanyl, 2-oxo-1,3-dithiolan-4-ylmethyl, 1,2-dithiolan-4-yl, yl.

The present invention encompasses penem derivatives wherein the carboxyl group at the 3-position is esterified with a non-toxic R 1 group that undergoes hydrolysis in vivo. These esters are rapidly degraded in mammalian blood and other tissues, releasing the corresponding penem-3-carboxylic acid. Typical examples of such readily bisolidizable ester-forming groups are C 3-6 alkanoyloxymethyl groups, C 1-6 alkanoyloxyethyl groups, (C 1-6) alkylcarbonyl groups. oxyethyl groups, (C 14) alkoxycarbonyloxymethyl groups, (C 14) alkoxycarbonyloxyethyl groups, 3-l-thalidyl or (5-methyl) 2-oxo-1,3-dioxolen4-yl) methyl group. To prepare a compound of formula (I) or (II) wherein R _t is an in vivo hydrolyzing ester group, the acid of formula (I) or (II) (wherein R 1 is hydrogen) is reacted with a base to form the corresponding anion. .

194,563

F Suitable cations include sodium,

Potassium, calcium, tetraalkylammonium, and the like. The anion can be prepared by lyophilizing an aqueous solution of a compound of formula (I) or (II), such as an aqueous solution containing tetrahydrofuran and sodium bicarbonate or tetrabutylammonium hydroxide.

The anion derived from an acid of Formula I or Formula II, respectively, with an appropriate chloride of formula R, Cl or R ₍ - Br) or bromide, in a reaction-inert solvent such as acetone or dimethylformamide The reaction is carried out at a temperature of from 20 to 50 ° C, preferably 25 ° C.

Compounds of formula (II) in which R ₍₁₎ is hydrogen or salts thereof may be prepared as shown in the AC flow charts.

As shown in flow chart A, a compound of formula II is prepared by Yoshida et al., Chem. Pharm. Bull., 29, 2899-2909 (1981), starting from the known dichromopenem compound of formula (IV). The dibromopenam of formula (V) is reacted with tert-butyl magnesium chloride at a temperature of about -90 ° C to about 10 ° C, preferably about -76 ° C, in a reaction-inert solvent such as tetrahydrofuran, diethyl ether or toluene; preferably in tetrahydrofuran. Other organometallic reagents may also be used. The resulting reaction mixture is treated in situ with the appropriate aldehyde. For example, acetaldehyde is used to prepare the 1-hydroxyethyl derivative. The aldehyde is added to the reaction mixture at about -80 ° C to about -60 ° C, preferably at about -76 ° C for acetaldehyde.

The resulting bromo-hydroxypenam of formula (V) was obtained by a

Hydrogenate to remove the 6-bromo substituent. Suitable hydrogenation catalysts include noble metal catalysts such as palladium. The reaction is carried out in a protic solvent such as water and methanol or a 1: 1 mixture of water and tetrahydrofuran, preferably 1: 1 methanol: water. The reaction is conducted at a pressure of from about 0.1 to about 0.4 MPa, preferably at or near the upper pressure limit, and from about 0 to about 30 ° C, preferably at about 25 ° C.

rv

I

The alcohol of formula (VI) formed is a R ₉ -Si-O

By reaction with a trialkyl halo silane protected formula _R9 - wherein either R ₉ is the same or different, from 1 to 6 carbon atoms, any alkyl group, and Q is chloro litter, bromine or iodine. For example, dimethyl tert-bulyl chlorosilane in the presence of a proton acceptor amine such as imidazole in a polar aprotic solvent, such as Ν, Ν-dimethylformamide, at a temperature in the range of 5 ° C to 40 ° C, preferably about 25 ° C, it forms a silyl protecting group on the hydroxyl group as shown in formula VII.

Treatment of compound (VII) with mercury (II) acetate in acetic acid at about 90 ° C provides the olefin (VIII).

To produce the desired azetidinone of Formula IX, the olefin of Formula VIII is subjected to ozonization in a reaction-inert solvent such as dichloromethane. The reaction temperature is between 80 ° C and 40 ° C, preferably about -76 ° C. Treatment of the reaction product with an alkanol such as methanol yields the azetidinone derivative of formula IX.

Scheme B shows that when a compound of formula IX is prepared with a trithiocarbonate salt of M ⁺ R ₁₀ -S-C (S) -S- wherein R '' is a C 14 alkyl group, preferably ethyl, and M is a metal atom such as such as sodium or potassium, the compound of formula (X) is obtained. This conversion of the compound of formula IX to the compound of formula X is carried out in an organic solvent or water, preferably a mixture of water and dichloromethane, at a temperature between 0 ° C and 35 ° C, preferably at about 25 ° C.

The compound of formula (X) is condensed with oxalic acid chloride esterified with para-nitrobenzyl alcohol in the presence of a tertiary alkylamine. Tertiary alkyl amines include triple alkylated amine derivatives having any of the alkyl groups having 14 carbon atoms, such as ethyl diisopropylamine. The reaction product is a compound of formula XI. The above condensation reaction is carried out in a reaction-inert solvent, preferably dichloromethane, and the reaction temperature range

5-25 ° C, preferably within about 10 ° C.

The resulting compound of formula (XI) is ring-ringed with a trialkyl phosphite. The alkyl groups of said trialkyl phosphite may have 14 carbon atoms; a preferred example is triethyl phosphite. For other reaction conditions, the reaction medium must be inert to the reaction, so that chloroform may be used as a solvent. The reaction temperature is in the range of 40 to 80 ° C, preferably 60 ° C. The reaction product is a penem derivative of formula XII.

The thiol group of compound (XII) is oxidized to give the corresponding sulfoxide (XIII). For example, the oxidizing agent is n-chloroperbenzoic acid dissolved in an inert solvent such as dichloromethane. The reaction temperature may range from -10 ° C to -30 ° C; preferably -20 ° C.

The sulfoxide of formula (XIII) is converted to the mscapidide of formula (RS) by using, for example, the corresponding sodium or potassium (R) mercaptide salt, and the sulfoxide of formula (XIII) in a polar organic solvent such as ethanol or acetonitrile At a temperature of from -50 ° C to about -35 ° C, the mercaptide salt is reacted.

194,508

Mercaptans of formula R-SH and thioacetates of formula RSC (O) CH ₃ , which are used as starting materials for the preparation of the mercaptide reagent, are known for many different meanings of the R substituent and can be prepared by analogous methods known in the art. Relevant Synopsis Chapter by JL Wardell, 'I'reparation of Thiols', published by S. Patai, published by John Wiley and Sons, London, 1974, (4) Chapter). See also Volan et al., Tetrahedron Letters, 22, 3119- 3122 (1981), which describes the conversion of alcohols to lyols and thiolesters using triphenylphosphine and a dialkyl ester of azodicarboxylic acid directly in the alcohol and esterification in the presence of a suitable thiol acid.

When the R group contains a moiety of S (O) _n and n is 1 or 2, the corresponding thioacetate compound of the formula R-S-C (O) CH ₃ having a sulfide sulfur (n = 0) in its R group, approximately equimolar amounts of w-chloroperbenzoic acid can be oxidized to the corresponding sulfoxide (n = 1) or additional m-chloroperbenzoic acid to the corresponding sulfone (n = 2) without oxidizing the sulfur atom of the thioacetate.

The sulfoxide may also be oxidized to the sulfone using aqueous potassium permanganate; the aqueous medium may not be pure water, but may include aqueous acetone, the pH of which may be buffered! set to about 7. The oxidation is carried out at a temperature of from 20 to 50 ° C, preferably about 25 ° C. This procedure is particularly advantageous when the R group contains a hydroxy group.

In addition, cyclic sulfones containing double bonds can be easily isomerized by Prochazka et al., Collection Czech. Chem. Comm., 31, 3744 (1966).

For the compounds of formula (XIV), the triacylsilyl protecting group is conveniently removed before the carboxyl protecting group PNB is removed by hydrogenolysis. The intermediate is a desalkylsilylated but still contains a PNB protecting group (XV). The trialkylsilyl group is removed by a solution of tetraalkylammonium fluoride in an ether, preferably tetrahydrofuran. Deprotection is carried out at a temperature between 15 ° C and 40 ° C, preferably about 25 ° C.

The conversion of the compound of formula (XV) from the compound of formula (IJ) is accomplished by a conventional hydrogenolysis reaction which is carried out in the conventional manner. Thus, either a solution of the compound of formula (XV) may be stirred or shaken in a hydrogen atmosphere, or alternatively, the hydrogen gas may be mixed with an inert carrier gas such as nitrogen or argon and a catalytic amount of a hydrogenating precious metal catalyst such as calcium carbonate. palladium or palladium on celite. (Celite is a diatomaceous earth). Suitable media for the hydrogenation reaction include lower alcohols such as methanol, various ethers such as tetrahydrofuran and dioxane, low molecular weight esters such as ethyl and butyl acetate, water, and mixtures of these solvents. . However, the reaction conditions are usually chosen so that the starting material is soluble. Hydrogenation is generally carried out at room temperature; the pressure is between 0.5 and 5 bar. The catalyst is usually present in an amount of 10% by weight of the starting material and up to the same amount of starting material, but larger amounts may be used. The reaction time is usually about 1 hour, after which the compound of formula (1) is recovered from the mixture by evaporation of the solvent in vacuo after filtration of the mixture. When a palladium catalyst on a calcium carbonate support is used, the product is often isolated in the form of its calcium salt, and when palladium on a Celite support is used, the product is often obtained in the form of its sodium salt. The compounds of formula (I) or (II) may be purified by conventional procedures for beta-lactam derivatives. By way of example, the compounds of formula (I) or (II) may be purified by column chromatography, gel washing with Scphadcx or recrystallization.

Scheme C shows an alternative route for synthesis. The azetidine of formula (IX) is reacted with an M ⁺ R S-C (S) - S alkali metal trithiocarbonate, wherein fvT is an alkali metal ion such as sodium or potassium, as described above for the compound of formula (X) according to the procedure described for the preparation thereof.

The resulting trithiocarbonate of formula XVa is then obtained in an aprotic solvent such as benzene, toluene or dinethylformamide, preferably benzene, at a temperature between 25 ° C and 110 ° C, preferably around 80 ° C (p-nitrobenzyloxy). carbonyl) dihydroxymethane. The reaction product is the alcohol derivative XVI.

Treatment of the alcohol derivative (XVI) with thionyl chloride gives the corresponding chlorinated derivative (XVII). The reaction with thionyl chloride is carried out in an inert solvent such as dichloromethane in the presence of a spherically hindered amine compound at a temperature of -10 ° C to +75 ° C, preferably 0 ° C. The role of the basic amine compound is to bind the acid; for example, 2,6-lutidine may be useful for this purpose.

The chloro compound (XVII) is reacted with a triarylphosphine such as triphenylphosphine in a reaction-inert solvent such as tetrahydrofuran in the presence of a tertiary amine such as 2,6-lutidine at a temperature of about 25 ° C. In this way, the compound of formula (XV1I1) is obtained, which is then cyclized under reflux in an aromatic solvent such as toluene to give the penem derivative of formula (XIV).

194,568 δ

M ⁺ R-S (C = S) S- trithiocarbonate salts are prepared from the corresponding mercaptan R-SH or prepared by reacting a thioacetate RSC (O) CH ₃ with an alkali metal alkoxide and then with carbon. disulfide.

Using the aforementioned procedure, developed by Yoshida et al., The stereochemistry of the carbon atom of the penem 6 and the hydroxyethyl group attached thereto is as shown in formula II.

The stereochemistry of the product of the ring closures of Scheme B or C is essentially that the hydrogen atom attached to the C 5 carbon atom of the pcneingypyrrole is in the trans position.

Compared to hydrogen attached to carbon 6 and in the [mu] a configuration. Alternatively, stereochemistry may be characterized as follows: 5R, 6S; 6 - (R) -1-hydroxyethyl.

The compounds of formula (I) and (II) are acidic and form salts with bases. E salt; These salts may be prepared by conventional techniques, for example by the interaction of the acidic and basic components, which reaction is usually carried out in stoichiometric proportions and is carried out in aqueous, non-aqueous both aqueous and partially aqueous reaction media can be used. Recovery of the salts may be accomplished by filtration followed by filtration after precipitation with a non-solvent; by evaporation of the solvent, or - aqueous solution; in case of pouch - by lyophilization. Suitable bases for salt formation include both organic and inorganic type bases; Thus, they include ammonia, organic amines, alkali metal hydroxides, alkali metal carbonates, bicarbonates, hydrides, alkoxides, and alkaline earth metal hydroxides, carbonates, hydrides and alkoxides.

Suitable bases are represented by the following: primary amines such as n-propylamine, t-butylamine, aniline, cyclohexylamine, benzylamine and octylamine; secondary amines such as diethylamine, morpholine, pyrrolidine and piperidine; tertiary amines such as triethylamine, N-ethylpiperidine, N-methylmorpholine and 1,5-diazabicyclo [4,3,0] non-5-ene; hydroxides such as sodium hydroxide and potassium hydroxide, ammonium hydroxide and barium hydroxide; alkoxides such as sodium ethoxide and potassium ethoxide; such as calcium hydride and sodium hydride; carbonates such as potassium carbonate and sodium carbonate; bicarbonates such as sodium and potassium bicarbonate; and alkali metal salts of longer chain fatty acids, such as sodium 2-ethylhexanoate.

Preferred salts of the compounds of formulas I and II are sodium, potassium and calcium salts.

A pharmaceutically acceptable salt is one which is non-toxic, can be used as a drug substance, and its degradation products formed during metabolism are non-toxic.

As mentioned above, compounds of general formulas (I) and (II) and their salts are antibacterial agents. The in vitro activity of the compounds of formula (I) and (II) and their salts may be demonstrated by determining their minimum inhibitory concentration (MIC). MIC values are expressed as micrograms / ml and determined against a variety of microorganisms. Our assay was identical to that recommended by the International Collaborative Study on Antibiotic Sensitivity Testing (described in Ericsson and Sherris, Acta Pathologica and Microbiologica Scandinav., Supp. 217, Section B: 64-68 (1981)); brain-infusion (BHI) agar and an inoculum replicator were used in the experiments.

The contents of the tubes in which the inoculum colonies continued to grow overnight were diluted 100-fold and this dilution was used as a standard inoculum. Inoculation is carried out by applying 0.002 ml of an inoculum solution containing approximately 10,000 to 20,000 cells to the surface of the agar; 20 ml of BHI agar was placed in a dish. The test compound was applied at twofold dilution in twelve repetitions at a starting concentration of 200 micrograms / ml. Colonies developed in Petri dishes kept at 37 ° C were counted after 18 hours and colonies left alone were excluded. The lowest concentration at which the test compound, when judged by the naked eye, was able to completely inhibit bacterial growth is taken as the MIC of the experimental microorganism.

The compounds of formula (I) and (II) and pharmaceutically acceptable salts thereof can be used to combat bacterial infections in mammals and humans. They can be used to combat infections caused by certain susceptible bacteria, such as Staphylococcus aureus, in humans.

When a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, is used to combat a bacterial infection in a mammalian subject, the route of administration may be oral, parenteral, i.e., intramuscular, subcutaneous, intraperitoneal, or intravenous. The compound may be used alone or in combination with a pharmacologically acceptable carrier in accordance with standard pharmaceutical practice. The ratio of active ingredient to carrier will, of course, depend on the chemical nature, solubility and stability of the active ingredient, and on the intended dosage. In view of these general considerations, the ratio of the pharmaceutically acceptable carrier to the penem compound in the pharmaceutical compositions containing the antibacterial agent of the present invention will normally be from 1:10 to 4: 1. When administered orally, the antibacterial penetil of the present invention may be administered in the form of tablets, capsules, ointments, pills, powders, syrups, elixirs, aqueous solutions or suspensions, and the like. In the case of tablets, suitable carriers include lactose, sodium citrate and various salts of phosphoric acid. Various disintegration aids

194,568 materials such as starch, non-slip agents such as magnesium stearate, sodium dodecyl sulfate and talc are widely used. When administered orally in capsule form, lactose and high molecular weight polyethylene glycols can be used to dilute the active ingredient. When an aqueous suspension is formulated for oral administration, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and / or flavoring agents may be added. For parenteral administration, the active ingredient is usually formulated in a sterile solution and the pH adjusted or buffered. In the case of intravenous administration, the composition is rendered isotonic, taking into account the amount of all solutes.

Previously, it has been suggested that the compounds of formula (I) and (II) can be used as antimicrobial agents in human beings, as sensitive microorganisms. The prescribing physician will ultimately determine the appropriate dose for a transmitting person at a chat, and this will depend upon the individual's age, weight, individual drug sensitivity, and the nature and severity of the patient's symptoms. The normal daily dose of the compounds of formula (I) or (II) ranges from 10 mg / kg body weight to 200 ng / kg body weight for oral administration and from 10 mg / kg body weight to 400 mg / kg body weight for parenteral administration. These figures are provided for illustration purposes only and, in some cases, doses outside these limits may be required.

The following examples and descriptions of the preparation of certain materials are also intended to further illustrate the invention. Infra-red (IR) spectra were recorded using potassium bromide-containing pellets containing suspensions of nujol or solutions of chloroform, dichloromethane or dimethylsulfoxide. The absorption bands are given in micron or wave number (cnf ¹ ). Nuclear Magnetic Resonance (NMR) spectra were measured at 60 MHz, unless otherwise indicated, and solutions of deuterophosphorus (CDCl ₃ ), heavy water (D ₂ O), or deuterated dimethylsulfoxide (DMSO-d ₆ ) or mixtures thereof. We worked. The positions of the peaks were expressed in ppm, downstream of the internal standard chemical shift of fetrainethylsilane toward decreasing field strength. The following abbreviations are used to characterize the shape of the peaks: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, b = broad, c = complex. The abbreviations "ss" and "sss" indicate that the proton in question appears as two or three singlets, respectively, indicating the presence of diastereomers. Throughout the examples and the specification, the abbreviation "PNB" is used to denote the p-nitrobenzyl group.

EXAMPLE 1 Preparation of the sodium salt of (5R, 65) -6 - [(7R) -1-hydroxyethyl] -2- (1,1-dioxo-3-thioananyl) thio-2-pyricine-3-carboxylic acid

The catalyst, containing 10% palladium on 350 mg diatomaceous earth, was slurried in 75 mL of THF (75 mL) and adjusted to pH 8.3 with 0.02 M aqueous sodium bicarbonate. In a mixture of 50 ml of tetrahydrofuran and 50 ml of water was dissolved 350 mg of (57?, 6 S) -6 - [(R) -1-hydroxyethyl] -2- (1,1-dioxo-3-thiolanyl) thio-2 -penem-3-carboxylic acid p-nitrobenzyl ester and the solution are added to the above suspension. The resulting mixture was hydrogenated at 3.85 bar for 75 minutes. An additional 350 mg of 10% palladium catalyst on diatomaceous earth was added to the reaction mixture and the suspension was adjusted to pH 7.0 with 0.02 M sodium bicarbonate solution. The mixture was subjected to additional hydrogenation at 3.85 bar for 75 minutes, then the catalyst was removed by filtration and the filtrate was concentrated in vacuo to remove tetrahydrofuran. The remaining aqueous solution was adjusted to pH 7 and the neutral solution was extracted twice with 100 mL of ethyl acetate. The aqueous solution is then lyophilized; This gave 224 mg of the title compound as an amorphous solid. Yield: 82.5%.

The absorption spectra of the compound of the Cune were infrared at maxima of 2.92, 5.65, and 6.3 microns respectively.

Example 2

The procedure of Example 1 is followed; starting from the corresponding compound of the formula XV to give the corresponding salt of the compound of the formula II. In the compounds of formula (H) prepared, the meaning of the substituent R and the location of the characteristic infrared absorption bands are shown in Table 1 below. The recordings were made with potassium bromide pastilles; other cases are noted.

Table 7

R IR (micron) Yield%

3-thiolanil 2,94,5,66 and 6,382

-thiolanyl 2.92, 5.65 and 6.27 78 (the more polar isomer) trans-1-oxo-3-thiolanyl 2,92,5,65 and 6,26 51 (the less polar isomer)

2- (methylsulfinyl) -2.94, 5.65, and 6 (3161)

-ethyl

-611

Continuation of Table 1

R IR (micron) Yield% 2- (methylsulfonyl) - 2.94, 5.65 and 6.25 59 -ethyl methylsulfinylmethyl 2.94, 5.66 and 6.26 78 methylsulfonylmethyl 2,94,5,62 and 6,28 68 1 -οχο-3-thianyl 2.93, 5.65 and 6.26 74 1,1-dioxo-3-thianyl 2,94,5,66 and 6,4 67 3-Tetanyl 2.92, 5.65 and 6.26 87 cAz-1-oxo-3-thianyl 5.66 (nujol) 98 trans-1-oxo-3- -thienyl 5.66 (nujol) 92.8

Example 3 Preparation of (5R, 6S) -6-Hydroxyethyl] -2- (shak-η-o-4-thianyl) thio-3-carboxyl-2-penem

Palladium catalyst (3.00 g, 10% palladium on catalyst) was treated with a hydrogen gas (4.2 bar) in a mixture of 130 ml of tetrahydrofuran and 120 ml of water for 10 minutes. The pH was adjusted to 7.5 with 1N hydrochloric acid, and then 6.20 g (12.4 mmol) of (57?, 65) -6 - [(7?) - 1-hydroxyethyl] -2- ( cis-1-oxo-4-thianyl) thio-2-penem-3-carboxylic acid p-nitrobenzyl ester is added and the suspension is introduced with hydrogen gas for half an hour. Then 3.00 g of catalyst were added in two portions, the pH was adjusted to 7.0 and hydrogenation of the reaction mixture was continued for a further three-quarters of an hour. Subsequently, after addition to their final catalysts and adjustment of the pH to 7.3, the reaction mixture was hydrogenated for one and a half hours. The reaction mixture was filtered through a pad of Celite and washed with additional portions of a 1: 1 mixture of tetrahydrofuran and water. The tetrahydrofuran was evaporated in vacuo. Insoluble materials were removed by filtration through Celite and the filtrate was adjusted to pH 7.0. The aqueous phase separated from the filtrate was washed twice with ethyl acetate, partially evaporated to remove ethyl acetate, cooled in an ice bath and adjusted to pH 2.3 with 6N hydrochloric acid. After waiting for 30 minutes, the precipitate was collected on a filter. The resulting precipitate was dried under vacuum to constant weight to give 3.64 g of the mustard yellow solid. This corresponds to a yield of 81%. Melting point: 149-151 ° C, [ ^α] D = + 153 ° (measured in DMSO). The NMR spectrum of the title compound (deuterated dimethylsulfoxide solution, 250 MHz) contains the following peaks: 1.16 (d, J = 6.2 Hz, 3H), 1.95-2.3 (m, 4H). .

2.7-3.0 (τη, 4H), 3.3-3.4 (m, 1H), 3.79 (dd, J = 6.1, 1.4 Hz, 1H), 3.98 (m, 1H), 5.20 (broad singlet, 1H), 5.71 (d, J = 1.4 Hz, 1H) ppm. The infrared absorption spectrum (potassium bromide pastilization) of the title compound is characterized by the following absorption maxima: 2950 (wide), 2923, 1782, 1678, 1508, 1400, 1294, 1216, 1197,

1,131.949 and 935 ^cm-first The ultraviolet absorption spectrum of the dinethylsulfoxylated solution of the title compound is characterized by the following absorption maxima: (extinction coefficients in parentheses) 267 nm (4840), 337 nm (6720).

I

Example 4 Preparation of (57?, 6S) -6 - [(7?) - 1-Hydroxyethyl] -2- (cis-1-oxo + -thianyl) thio-2-penem-3-carboxylic acid sodium salt

5.09 g (14.0 mmol) of the compound of Example 3, cinnamon, are suspended in 75 ml of water and the suspension is cooled with an ice bath. The reaction mixture was adjusted to pH 7.00 with 1.0 N aqueous sodium hydroxide solution. This requires 13.0 ml of alkaline solution, which is 93% of the theoretical value. The homogeneous solution was lyophilized overnight. This gave 5.00 g (93%) of the title compound as a pale beige solid. l 'J _D (I1 ₂ O): + 111.4 °.

The nuclear magnetic resonance spectrum of a solution of the title compound in D ₂ O at 250 MHz excitation frequency shows the following peaks: 1.29 (d, J = 6.4 Hz, 3H), 2.1-2.4 (in, 4H), 2.8-3.0 (m, 2H), 3.1 3.25 (m, 211), 3.42 (m, 1H), 3.91 (dd, J = 5.9, 1.0 Hz) , 1H), 4.24 (qd, J = 6.4, 5.9, 1H), and 5.67 (d, J = 1.0 Hz, 1H) ppm.

The title compound exhibits an infrared absorption spectrum (KBr pastilles) at 3403, 2964, 2917, 1765, 1589, 1514, 1372, 1290, 1126, 1041, 1012, 888 and 936 cm ^-1 .

The ultraviolet absorption spectrum of the aqueous solution of the title compound is characterized by the following absorption maxima (extinction coefficients in parentheses): 259 nm (5530), 322 nm (7260).

Example 5 Preparation of (57?, 6S) -6 - [(7?) - 1-Hydroxyethyl] -2- (4-thianyl) thio-2-penem-3-carboxylic acid calcium salt

The hydrogenation process of Example 1 was carried out using a palladium catalyst containing 5% by weight of palladium on a silica gel carbonate support. The starting material is (57?, 6?) -6- (hydroxyethyl) -2- (4-thianyl) thio-2-penem-3-carboxylic acid p-nitrobenzyl ester, 1: 1 tetrahydrofuran. dissolved in water or suspended in the catalyst, the title compound was obtained in 100% yield.

Nuclear Magnetic Resonance Spectrum (250 MHz, D ₂ O): 1.29 (3H, d, J = 6.2 Hz), 1.7-1.9 (2H, m),

2.3-2.5 (2H, m), 2.7-2.8 (4H, m), 3.30 (1H, tt), 3.90 (1H, dd, J = 6.0, 1 , 3 Hz), 4.24 (1H, m) and 5.65 (III, d, J = 1.3 Hz) ppm.

The infrared absorption spectrum of the title compound (KBr) comprises the following peaks: 3409, 1770, 1583 and 1385 ^cm-first

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Example 6

The procedure of Example 5 was followed, starting from (5R, 65) -6 - [(R) -1-hydroxyethyl] -2- (1,1-dioxo-4-thanyl) thio-2-pcncm-3. -carboic acid-p-nitrobenzyl ester is used. In this way, the calcium salt of (5R, 6S) -6 - [(R) -1-hydroxyethyl] -2 '(1,1-dioxo-4-thianyl) thio-2-penem-3-carboxylic acid is obtained. % yield.

Nuclear Magnetic Resonance Spectrum (non-aqueous solution; 250 MHz): 1.29 (3H, d), 2.15-2.4 (211, m), 2.4-2.65 (211, m), 3 2 to 3.45 (4H, ni), 3.61 (1H, m), 3.95 (1H, dd), 4.26 (III, in), and 5.68 (III, d) ppm.

The infrared spectrum (KBr pastilles) of the product obtained is characterized by the following absorption sites: 3421, 1767, 1588, 1382, 1286 and 1112 cm @ ^-1 .

Also following the procedure of Example 5, (5β, 65) -6- (R) -hydroxyethyl-2- (trans-1-oxo-4-thianyl) thio-2-penem'-3- using (5R, 65) -6 - ((R) -1-hydroxyethyl) -2- (trans-1-oxo-4-thianyl) thio-2-carboxylic acid as starting material The calcium salt of -penem-3-carboxylic acid was obtained in 81% yield, and a potassium bromide extrudate was obtained from the products, the spectrum of which was determined by infrared absorption spectra as follows: 1131 and 1021 cm ^-1 .

The D ₂ O solution of the product showed a NMR spectrum (250 MHz) with the following peak characteristics: 1.29 (311, d, J = 6.3 Hz), 1.85-2.1 (2Π, m), 2.452 , 65 (2ll, m), 2.85 3.0 (211, in), 3.15 3.4 (211, in),

3.63 (1H, m), 3.93 (HI, dd, J = 6.1 Hz), 4.26 (1H, qd J = 6.3, 6 Hz), and 5.68 (1H, d) , J = 1 Hz) ppm.

Example 7 Preparation of (5R, 65) -6 - [(R) -1-Hydroxyethyl] -2 - [(ds-1-oxo-3-thioanyl] thio-2-penem-3-carboxylic acid sodium salt

6.0 g of (5R, 65) -6 - [(17R) -1-hydroxyethyl] -2 - [(2 R) -oxo-3-thiolanyl] thio-2-penem 3-carboxylic acid To a solution of p-nitrobenzyl ester in 100 mL of telhydrofuran and 25 mL of water was added the hydrogenation catalyst as an aqueous suspension. The suspension contained 3.0 g of 10% palladium on charcoal in 100 ml of water and the pH was pre-adjusted to 7.4. After the catalyst slurry was added, 25 ml of tetrahydrofuran was added to the former. The reaction mixture was hydrogenated at 4.2 bar for 10 minutes, then another 3.0 g of catalyst was added and the reaction mixture was adjusted to 7.3 with dilute aqueous sodium bicarbonate solution. The mixture was hydrogenated at 4.2 bar for 25 minutes, after which another 4.0 g of catalyst was added and the slurry was adjusted to 7.4 with dilute aqueous sodium bicarbonate solution. The hydrogenation of the reaction mixture was continued at constant pressure for 45 minutes, then the pH was adjusted to 6.9 with aqueous sodium bicarbonate solution and the catalyst removed by filtration. The filtrate was concentrated in vacuo to remove tetrahydrofuran. The remaining aqueous solution was washed with 200 ml portions of diethyl ether, ethyl acetate and diethyl ether respectively. The solution was filtered and the filtrate was adjusted to 7.2 rc. Lyophilization of this solution afforded 4.3 g of the title compound as an amorphous solid. Yield 93%.

Heavy water solution of the title compound at 250 MHz. NMR: 1.32 (d, 311), 2.53 (c, ifi), 2.74 - 3.12 (c, 3H), 3.26 (c, 111), , 83-4.09 (c, 311), 4.27 (m, 1H) and 5.74 (2d, 111) ppm.

In the infrared spectrum (KB :) of the title compound, the absorption maxima are found to be 2.93, 5.66 and 6.3 microns.

(Example 5) (5R, 65) -6 - [(R) -1-Hydroxyethyl] -2- (trans) -1-oxo-3-thiolanyl] thio-2-penem-3- preparation of the sodium salt of the carboxylic acid

Example 7 Following the procedure of (5R, 65) -6 - ((R) -1-hydroxyethyl) -2 - [(trans) -1-oxo-3-thiolanyl] thio-2-penem Using 3-carboxylic acid p-nitrobenzyl ester, the title compound is obtained in 80% yield.

The heavy water solution of the title compound (250 MHz) showed the following peaks: 1.32 (d, 311), 2.27 (m, 111), 2.78, 3.18 (c, 2H), 3. 47 (c, 2H), 3.66 (m, 1H), 3.97 (m, 1H), 4.22 - 1.43 (c, 2H) and 5.74 (d, 1H) ppm.

In the infrared spectrum (KBr pastilles) of the title compound, the absorption maxima are found at 2.92, 5.65 and 6.26 microns.

Example 9 (5R, 65) -6 - [(R) -1-Hydroxyethyl] -2- (2-oxo-1,3-dithiolan-4-ylmethyl) thio-2-penem-3 Preparation of Sodium Carboxylic Acid Sodium is suspended in 10 ml palladium catalyst containing 10 mg palladium on Celite diatomaceous earth. The pH of the suspension is adjusted to 7. Subsequently, 107 mg of (5Λ, 65) -6 - [(R) -1-hydroxyethyl] -2- (2-oxo-1,3-dithioan-4-ylmethyl) thio-2-penem are dissolved in 10 ml of tetrabidrofuran. 3-Arm: N, N-Benzyl ester of onoic acid is added to the above suspension and the reaction mixture is stirred at room temperature.

Hydrogenate with 3.5 bar of hydrogen for 1 hour. At 1 hour intervals, two additional catalyst parts are added to the system. The catalyst was removed by birth and the filtrate was evaporated to remove tetrahydrolurane. The remaining aqueous solution was washed with ethyl acetate and diethyl ether and filtered. The filtrate was freeze-dried; resultant title compound 60 mg as a pale yellow powder IR (KBr): 1600, 1640.1778 cm ^1st

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Nuclear Magnetic Resonance Spectrum (D ₂ O, 250 MHz): 1.29 (3H, d, J = 6), 3.25-3.63 (2H, m), 3.72-4.12 (2H, m) ), 4.24 (1H, m), and 5.66 (1H, s) ppm. (Some peaks are covered by solvent.) (M, 1H), 3.78 (rn, 1H), 4.9 (c, 2H), 5.1 (d, 1H), 5.36 (q, 2H), 5.77 (d, 1H), 7.65 (d, 2H) and 8.22 (d, 2H) ppm.

Example 10 Preparation of the sodium salt of (57R, 6S) -6 - [(R) -1-hydroxyethyl] -2- (1,1-dioxo-3-thiolanyl) thio-2-penem-3-carboxylic acid separation

By repeating the procedure described in Preparation Example F, (57R, 6S) -6 - [(R) -1-butyldimethylsilyloxyethyl] -2- (1,1-dioxo-3-thiolanyl) -thio- 2-Penem-3-carboxylic acid p-nitrobenzyl ester was obtained in a yield of 50.8%. The product is obtained as a mixture of the two diastereomers; they were separated by column chromatography on silica gel using 1: 1 ethyl acetate: hexane as the eluent.

The less polar diastereomer was obtained in 46.5% yield, m.p. 160.5-162 ° C. Potassium bromide pastilles are used to produce infrared spectra; absorption maxima at 5.62, 5.97, 6.56 and 6.74 microns; the nuclear magnetic resonance spectrum (at 250 MHz radio frequency excitation) of a solution of deuterochloroform shows the following peaks: 0.03 (S, 3H), 0.07 (S, 311), 0.81 (S, 9Π), 1 , 25 (d, 311), 2.28 (ni, III), 2.76 (m, 1H), 3.12 (d, 2H), 3.34 (rn, 111), 3.58 (m, 1H), 3.79 (m, 1H), 3.98 (m, 1H), 4.28 (m, 1H), 5.32 (q, 2H), 5.71 (d, 1H), 7, Δ (d, 2H) and 8.21 (d, 2H) ppm.

The more polar isomer was obtained in 40.3% yield. Mp 181.5-182 ° C. Its infrared spectrum (KBr) has the following absorption maxima: 5.62, 5.09, 6.6, 6.67 microns. Nuclear Magnetic Resonance Spectrum (deuterochloroform solution, 250 MHz) is characterized by the following peaks: 0.02 (S, 3H), 0.05 (S, 3H), 0.82 (S, 9H), 1.24 (d, 3H), 2.24 (m, 1H), 2.71 (m, 1H), 3.14 (c, 2H), 3.33 (m, 1H), 3.71 (m, 1H), 3, 78 (m, 1H), 3.97 (m, 1H), 4.28 (m, 1H), 5.32 (q, 2H), 5.72 (d, 111), 7.61 (d, 2H). ) and 8.21 (d, 211) ppm.

(5R, 6S) -6 - [(7R) -1-Hydroxyethyl] -2- (1,1-dioxo-3-thiolanyl) thio-2-penem-3-carboxylic acid p-nitrobenzyl Preparation of the ester from the less polar silyl ether diastereomer

The less polar silyl ether derivative is reacted according to Preparation A to give the corresponding 1-hydroxyethyl compound, m.p. 172-173 ° C. Yield 80%. The infrared spectrum of the product (KBr pastilles) shows the following absorption peaks: 5.63, 5.94, 6.6 and 6.68 microns. The material dissolved in the deutero-chloroform / DMSO-d ₆ mixture had an NMR (250 MHz) spectrum.

. contains the following peaks: 1.32 (d, 3H), 2.3 (m, 1H), 2.76 (m, 1H), 3.15 (c, 2H), 3.34 (m, 1H), 3,59 (57R, 65) -6 - ((7R) -1-Hydroxyethyl] -2- (1,1-dioxo-3-thiolanyl) thio-2-penem-3-carboxylic acid Preparation of the nitrobenzyl ester from the more polar silyl ester diastereomer

Following Preparation A, the more polar silyl ether derivative is reacted. This gave the corresponding 1-hydroxyethyl compound, m.p. 175-176 ° C, yield 76%. The infrared absorption spectrum (KBr) is characterized by the following peaks: 2.86, 5.6, 5.93, 6.59 and 6.68 microns. NMR spectroscopy (rum uptake of Cl) Clj (Cl) ₃ ) ₂ SO at 250 MHz gives the following peaks at 250 MHz: 1.34 (d, 3H), 2.25 (m, 1H), 2.69 (m, 1H), 3.16 (c, 2H), 3.35 (m, 1H), 3.71 (m, 1H), 3.78 (m, 1H), 4.03 (m, 1H) , 4.16 (m, 1H), 4.88 (d, 1H),

5.35 (q, 2Π), 5.78 (d, 111), 7.64 (d, 211) and 8.23 (d, 2H) ppm.

Λ Preparation of the diastereomer of the less polar silyl ether diastereomer of the title compound

The 1-hydroxyethyl diastereomer with a para-nitrobenzyl protecting group, obtained from a less polar silylcellular diastereomer, was reacted as in Example 1 to give one of the diastereomers of the title compound in 96% yield. The infrared absorption spectra of the regions (KBr pastilles) show absorption maxima at 2.93, 5.65 and 6.29 microns. The high magnetic resonance spectrum (250 MHz) of a heavy water solution of the product showed the following peaks: 1.39 (d, 3H), 2.45 (m, 1H), 2.86 (m, 1H), 3.38 (c, 2H). ), 3.56 (m, 1H), 3.82 (m, 1H), 4.06 (m, 1H), 4.25 (m, 1H), 4.36 (m, 1H) and 5.82 (d, 1H) ppm.

Preparation of the diastereomer of the more polar silyl ether diastereomer of the title compound

The 1-hydroxyethyl diastereomer of the more polar silyl ether diastereomer, protected with para-nitrobenzyl, is reacted as in Example 1 to give the other diastereomer of the title compound in 95.5% yield. The infrared absorption spectrum of the product (KBr pastilles) shows absorption maxima at 2.94, 5.66 and 6.27 microns. The nuclear magnetic resonance spectrum (250 MHz) of the product's water side contains the following peaks: 1.35 (d, 3H), 2.3 (m, 1H), 2.76 (m, 1H), 3.44 (c, 3H). ), 3.88 (m, 1H), 3.99 (m, 1H), 4.19 (m, 1H), 4.32 (m, 1H), and 5.76 (d, 1H) ppm.

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194 56f ll. example

(5R, 65) -6 - [(7R) -1R-Butyldimethylsilyloxyethyl] -2 - [(2 ') -3-hydroxy-4-thiolanyl] thio-2-penem- Preparation, Separation and Conversion of 3-Carboxylic Acid p-Nitrobenzyl Ester Diastereomers

After cooling to 30 ° C, 0.272 g (0.002 mol) of cis-4-hydroxy-thiolanyl-3-thiol dissolved in 10 ml of anhydrous ethanol are added 2 ml of a 1 molar solution of NaOEt (= 0.002 mol of NaOEt) under nitrogen. The solution was stirred at -30 ° C for 30 minutes, then cooled to 60 ° C; 1.08 g (0.002 mol) of (5R, 65) -6- (7R) -1-butyl-dinethylsil-1-oxyethyl] -2-ethylsulfonyl; A solution of 2-penem-3-carboxylic acid p-nitrobenzyl ester is dissolved in 30 ml of tetrahydrofuran, cooled to -60 ° C and added to the former. After fifteen minutes, a mixture of tetrahydrofuran (3 ml) and acetic acid (0.5 ml) was added under isothermal conditions, the solution was allowed to warm to + 25 ° C and evaporated in vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with distilled water (20 mL), saturated aqueous sodium bicarbonate solution (20 mL), water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate and evaporated to dryness. The residue is chromatographed on silica gel twice (250 g, then 400 g of silica gel). Elution was carried out with 60:40 hexane / ethyl acetate. This gives 0.4 g of the less polar diastereomer (diastereomer A) and 0.56 g of the more polar diastereomer (diastereomer B), and 0.12 g of a mixture of diastereomers. However, the overall yield is 90.7%.

The diastereomer

IR (KBr): 2.86, 5.64, 6.0, 6.55 and 6.75 microns. NMR (CDCl ₃ , 250 MHz): 0.04 (s, 3H), 0.07 (s,

3H), 0.83 (s, 9H), 1.25 (d, 3H), 2.47 (d, 1H), 3.0 (m, 2H), 3.15 (m, 2H), 3, 68 (m, 1H), 3.78 (dd, 1H), 4.28 (m, 1H), 4.65 (m, 1H), 5.34 (q, 2H), 5.67 (d, 1H) )

7.64 (d, 2H) and 8.22 (d, 2H) ppm.

Diastereomer B

IR (KBr): 2.86, 5.59, 5.94, 6.59 and 6.68 microns. NMR (CDCl ₃ , 250 MHz): 0.04 (s, 3H), 0.07 (s,

311), 0.83 (s, 911), 1.25 (d, 311), 2.35 (ti, 111), 3.02 (m, 211), 3.2 (m, 2H), 3, 67 (m, III), 3.75 (dd, 1H), 4.28 (m, 1H), 4.59 (m, 1H), 5.34 (q, 2H), 5.67 (d, 1H) ), 7.62 (d, 2H) and 8.21 (d, 2H) ppm.

The yield is 63.4%. Melting point (with decomposition): 187-189 ° C.

IR (KBr): 2.83, 2.90, 5.61, 5.96, 6.58 and 6.71 microns.

NMR (DMSO-d6, 250 MHz): 1.28 (d, 3H), 2.74 (dd, 1H), 2.96 (dd, III), 3.13 (m, 211), 3, 63 (m, III), 3.89 (dd, 1H), 4.02 (m, 1H), 4.54 (m, 1H), 5.24 (d, 111), 5.36 (q, 211). ), 5.76 (d, 111), 5.81 (d, 111), 7.69 (d, 2H), and 8.24 (d, 211) ppm.

(57R, 65) -6 - ((7R) -1-Hydroxyethyl, -2-f (cf.rz) -3-hydroxy-4-thiolanyl) thio-2-cyclohexyl-3 derived from diastereomer B Preparation of p-nylcarbazyl ester of carboic acid

Using the method described in Preparation A, starting diastereomer B; the procedure affords the corresponding diol compound in 77.3% yield. Melting point (decomposition): 206-207 ° C.

Potassium bromide pastilles infrared spectra show the positions of the absorption peaks at 2.86, 2.91, 5.63, 5.98, 6.57 and 6.77 microns.

NMR _(DMSO-d6, 250 MHz): 1.17 (d, 3H), 2.73 (dd, IH), 2.93 (dd, IH), 3.1 (dd, IH), 3.29 (m, 1H),

3.64 (m, 111), 3.86 (dd, 1H), 4.02 (ni, 1H), 4.5 (m, 111), 5.24 (d, 111), 5.37 (q , 211), 5.77 (d, IfI), 5.79 (d, 1H), 7.69 (d, 2H), and 8.24 (d, 2H) ppm.

(57R, 65) -6 - [(R) -1-Hydroxyethyl] -2 - [(cis) -3-hydroxy-4-thiolanyl] thio-2-penem-3-carboxylic acid from diastereomer A - Preparation of the sodium salt

Following the procedure of Example 1, starting from (57?, 65) -6 - [(7?) -1-hydroxyethyl] -2 - [(cis) -3-hydroxy-4-thiolanyl from diastereomer A ] thio-2-penem-3-carboxylic acid p-nitrobenzyl ester is used. As a result, the corresponding sodium salt of the compound of formula (II) is obtained in 90% yield.

IR (KBr): 2.93, 5.65 and 6.31 microns.

NMR (D ₂ 0.250 MHz): 1.32 (d, 3H), 2.92 (m, 2H), 3.22 (m, 2H), 3.78 (m, 1H), 3.95 (dd, 1H), 4.27 (m, 1H), 4.7 (m, 1H) and 5.7 (d, 1H) ppm.

Sodium salt of (57?, 65) -6 - [(7?) -1-hydroxyethyl] -2 - [(cis) -3-hydroxy-4-thiolanyl] thio-2-penem-3-carboxylic acid derived from diastereomer B production

The procedure of Example 1 is followed, starting from (57?, 65) -6- (7?) -1-hydroxy-ethyl-2- (cis) -3-hydroxy-4 derived from diastereomer B p-nitrobenzyl ester of thiolanyl-thio-2-penem-3-carboxylic acid is used. As a result, the corresponding sodium salt of compound (II) is obtained in 87% yield.

(57R, 6S) -6 - [(R) -1-Hydroxyethyl] -2 - [(cis) -3-hydroxy-4-thiolanyl] thio-2-penem-3 from diastereomer A Preparation of p-nitrobenzyl ester of carboxylic acid

Following the procedure of Preparation Example A, starting from diastereomer A, the title diol compound is 10 (57?, 65) -6 - [(7?) - 1-butyldimethylsilyloxymethyl-2- (1-oxo-3). Preparation of p-nitrobenzyl ester of -hydroxy-4-thiolanyl) thio-2-pence-3-carboxylic acid and separation of its isomers

Diastereomer B (0.46 g, 0.77 mmol) in dichloro-1019 (40 mL)

Dissolve in 194,568 µmol methane and cool to -25 ° C under nitrogen atmosphere 0.142 g (0.66 mmol); A solution of m-chloroperbenzoic acid (87% activity) in dichloromethane (20 ml) was added dropwise over 15 minutes. After the addition of the meta-chloroperbenzoic acid was complete, the solution was stirred for 10 minutes at -25 ° C, and then 40 ml of dichloromethane and 20 ml of water were added. The excess peracid is decomposed with sodium bisulfite and the

Adjust to 7.5 with a saturated aqueous solution of sodium bicarbonate. The dichloromethane layer was separated and washed with water (30 mL), saturated aqueous sodium chloride (30 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is chromatographed on 250 g of silica gel eluting with 92.5: 7.5 ethyl acetate / methanol. Thus, 0.136 g of less polar sulfoxide (E isomer, 28.8% yield) and 0.210 g of less polar sulfoxide (F isomer,

44.5% yield). 20

Similarly, oxidation of diastereomer A with m-chloroperbenzoic acid yields 0.112 g of less polar sulfoxide (isomer C, 38%) and 0.18 g of more polar sulfoxide (isomer D, 61.2%). 25

The infrared absorption spectra of the C, D, E, F isomers were measured on potassium bromide pellets and their NMR spectra were recorded on their solutions with deuterated dimethyl sulfoxide at 250 MHz. The measurement results are shown in Table 2.

Of the C-F isomers, the corresponding (5R, 6R) -6H (R) -1-hydroxyethyl] -2- (1-oxo-3-hydroxy-4-thiothanyl) thio-2-penem-3- Preparation of p-nitrobenzyl ester of carboxylic acid

Preparation Method Λ is prepared using CF isomers as starting material to give the corresponding compounds of formula XV. The infrared absorption and NMR spectral data, melting point and yields of the prepared compounds are shown in Table 3. Infrared imaging was performed with potassium bromide pellets, NMR spectra were taken with DMSO-d ₆ solution of the compounds. At each of the measured melting points, the material decomposed.

Table 2

isomer Infrared absorption maxima (microns) Chemical shift values from NMR (ppm) C 3.06, 5.56, 5.85, 6.61 0.01 (s, 311), 0.04 (s, 311), 0.78 (s, 911), 1.22 (d, 3H), 3.9 (dd, 1H), 3.15 (m , 2H), 3.59 (dd, 1H, 0.45 (m, 1H), 4.25 (m, 1H), 4.34 (m, 1H), 4.79 (m, 1H), δ, 34 (q, 2H), 5.75 (d, 1H), 6.03 (d, 1H), 7.7 (d, 2H), 8.23 (d, 211) D 3,0,5,59,5,96,6,57,6,77 0.01 (s, 3H), 0.04 (s, 3H), 0.78 (s, 9H), 1.21 (d, 3H), 2.88 (m, 2H), 3.27 (dd) , 1H), 3.77 (m, 1H), 4.03 (c, 2H), 4.24 (m, 1H), 4.63 (m, 1H), 5.35 (q, 2H), δ , 73 (d, 1H), 5.96 (d, 1H), 7.7 (d, 2H), 8.23 (d, 2H) E 2,98,5,58,5,92,6,58,6,67 0.01 (s, 3H), 0.04 (s, 311), 0.78 (s, 911), 1.2 (d, 311), 2.9 (dd, 111), 3.08 (dd) , 111), 3.35 (m, 1H), 3.56 (dd, 1H), 4.02 (m, 1H), 4.27 (m, 2H), 4.75 (m, 1H), 5.32 (q, 2H), δ, 78 (d, 1H), 5.9 (d, 1H), 7.68 (d, 2H), 8.22 (d, 2H). F 2,96,5,61,5,98,6,58,6,69 0.01 (s, 311), 0.04 (s, 311), 0.77 (s, 911), 1.2 (d, 3H), 2.85 (m, 2H), 3.29 (dd) , 1H), 3.77 (m, 1H), 4.0 (d, 1H), 4.13 (dd, 1H), 4.23 (m, 1H 4.56 (m, 1H), 5.34 (q, 2H), 5.76 (d, 1H), 5.98 (d, 1H), 7.69 (d, 2H), 8.22 (d, 211).

-1 121

194,568

Table 3

initial isomer Infrared absorption maximum (microns) NMR (ppm) melting point (° C) Yield (%) C 2,92,3,12,5,60,5,91, 6.59 . 1.2 (d, 3H), 2.9 (dd, 1H), 2.15 (m, 2H), 3.58 (dd, 1H), 3.94 (m, 1H), 4.04 (m , 1H), 4.34 (ni, 1H), 4.79 (m, III), 5.24 (d, III), 5.38 (q, 211), 5.78 (d, 111), 6.03 (d, 1H), 7.7 (d, 2H), 8.25 (d, 2H). 203-5 69.9 D 2,95,5,59,5,93,6,59 1.18 (d, 3H), 2.83 (m, 2H), 3.27 (dd, 1H), 3.78 (m, 1H), 3.9 (dd, 1H), 4.02 (c) , 2H), 4.63 (ni, III), 5.75 (d, 111), 5.38 (q, 211), 5.75 (d, 111), 5.93 (d, 1H), 7 , 71 (d, 211), 8.24 (d, 2H). 118-20 78.5 E 2,90,3,11,5,63,5,93, 6,58,6,68 1.17 (d, 3H), 2.9 (dd, 1H), 3.08 (dd, 1H), 3.35 (dd, 1H), 3.16 (dd, 1H), 3.88 (dd) . 1H), 4.02 (m, 1H), 4.28 (m, 1H), 4.74 (m, 1H), 5.23 (d, 1H), 5.37 (q, 2H), δ, 79 (d, 111), 5.98 (d, 111), 7.68 (d, 211), 8.24 (d, 2H). 216-19 42.9 F 2,86,3,12,5,62,5,95, 6,58, 6,70 1.18 (d, 3H), 2.85 (m, 2H), 3.28 (dd, 1H), 3.76 (ni, 1H), 3.86 (dd, 1H), 4.06 (c, 2H), 4.55 (ni, 111), 5.25 (d, 1H), 5.38 (q, 211 ) 5.77 (d, 111), 5.97 (d, 111), 7.7 (d, 211), 8.24 (d, 2H). 128-30 69.2

The isomer derived from CF isomers is (5R, 65) -6 - [(R) -1-hydroxyethyl, -2- (1-oxo-3-hydroxy-4-thiolanyl] -thio-2-pencin-3-carboxylic acid - Preparation of sodium salts

Starting from the compounds of formula XV obtained from the C-F isomers, the procedure of Example 1 gives the sodium salt of the corresponding compounds of formula II.

Table 4 shows infrared and NMR spectroscopy data for compounds of formula II from C-F isomers. The former were prepared on potassium bromide pastilles made of the substance to be examined, the latter were prepared at 250 MHz with a heavy water solution of the compounds.

Table 4

isomer Infrared absorption maximum (microns) NMR (ppm) Yield (%) C 2,92,5,66,6,27 1.31 (d, 311), 3.11 (dd, 111), 3.26 (dd, III), 3.44 (dd, 111), 3.84 (dd, 11II), 3.96 (dd) , III), 4.25 (ni, III), 4.4 (m, 111), 4.93 (in, 111), 5.71 (d, 1H). 46.3 D 2,96,5,67,6,28 1.3 (d, 3H), 3.0 (dd, 1H), 3.17 (dd, 1H), 3.32 dd, 211), 3.83 (m, III), 3.94 (dd, IFI), 4.24 (m, 2H), 4.7 (m, 1H), 5.68 (d, 111) 63.3 E 2,93,5,67,6,3 1.31 µl, 3H), 3.14 (dd, 1H), 3.28 (dd, 1H), 3.55 (dd, 1H), 3.8 (dd, 1H), 3.96 (dd) , 1H), 4.26 (m, 1H), 4.38 (m, 1H), 4.92 (m, 1H), 5.74 (d, 1H). 60 F 2,93,5,65,6,30 1.3 (c, 311), 3.03 (dd, 111), 3.16 (dd, III), 3.34 (dd, 8H), 3.83 (ni, 1H), 3.93 (dd) , 1H), 4.28 (m, 2H), 4.68 (m, 1H), 5.71 (d, 1H). 47.1

-1 223

194,568

(5R, 65) -6 - [(7R-1-Butyldimethylsilyloxy) -2- (1,1-dioxo-cis-3-hydroxy-4-thiolanyl) - Preparation of diastereomers of thio-2-penem-3-carboxylic acid p-nitrobenzyl ester

0.12 g (0.195 min) of F isomer 25 mL of acetone, 5 mL of distilled water, and 5 mL of pH 7 buffer (K ₂ HPO ₄ ) -NaOH; Dissolve in 0.05 M and add dropwise over 30 minutes to an aqueous solution of potassium permanganate (30 mL) containing potassium permanganate (15.4 mg, 0.097 mmol). Thin layer chromatography indicated the presence of starting material in the reaction mixture, and an additional 4 mg of potassium permanganate dissolved in 1 ml of water was added. The acetone was then removed by vacuum evaporation and the aqueous phase was extracted with ethyl acetate (3 x 50 mL). The combined ethyl acetate extracts were washed twice with 30 ml portions of water and then with 30 ml of a saturated aqueous sodium chloride solution. The washed extract was dried over anhydrous sodium sulfate and dried in vacuo. The residue was chromatographed on silica gel (50 g) with ethyl acetate / hexane (70:30). 0.1 g of the corresponding sulfone derivative is obtained in the form of a pale yellow foam. This is the diastereomer H, 81% yield. In a similar manner, oxidation of 95 mg of isomer D with potassium permanganate gave 76 mg of the sulfone derivative. (Diastereomer G, 78%).

Diastereomer G

IR (KBr): 2.88, 5.59, 5.98, 6.57 and 6.75 microns. NMR (CDCl ₃ , 250 MHz): 0.04 (s, 3H), 0.07 (s,

3H), 0.83 (s, 9H), 1.26 (d, 3H), 3.22 (b, 1H), 3.44 (c, 4H), 3.84 (dd, 1H), 4, 04 (m, 1H), 4.28 (m, 111), 4.73 (m, 1H), 5.34 (q, 2H), 5.68 (d, 1H), 7.63 (d, 2H) ) and 8.23 (d, 2H) ppm.

(m, 2H), 3.52 (τη, 2H), 3.94 (dd, 1H), 4.03 (m, 1H), 4.15 (m, 1H), 4.68 (m, 1H) , 5.25 (d, 1H), 5.38 (q, 2H), 5.78 (d, 1H), 6.46 (d, 1H), 7.7 (d, 2H) and 8.25 ( d, 211) ppm.

Compound XV of diastereomer A11:

IR (KBr): 2.89, 5.62, 6.00, 6.58 and 6.73 microns

Nmr _(DMSO-d6, 250 MHz): 1.18 (d, 311), 3.31 (m, 2H), 3.52 (dd, 1H), 3.75 (dd, 1H), 3.9 (dd, 1H), 4.03 (m, 1H), 4.14 (m, 1H), 4.66 (m, 1H), 5.24 (d, 1H), 5.39 (q, 2H) , 5.82 (d, 1H), 6.44 (d, 1H), 7.72 (d, 2H), and 8.25 (d, 2H) ppm.

(57R, 6S) -6 - [(7R) -1-Hydroxyethyl] -2- (1,1-dioxo-3-hydroxy-4-thiolanyl) thio-2-penem-3-k : Preparation of diastereomers of the sodium salt of ironic acid

Following the procedure of Example 1, starting from the compounds of formula (XV) from the diastereomers G and H, the corresponding compounds of formula (II) are obtained in 45.6% and 69.6% yield respectively.

Compound of formula II derived from diastereomer G:

IR (KBr): 2,92,5,64 and 6,29 microns.

, NMR (D ₂ O, 250 MHz): 1.33 (d, 311), 3.5 (c, 311), 3.78 (dd, III), 3.98 (dd, 111), 4.26 (c, 211), 4.62 (m,

H) and 5.73 (d, 1H) ppm.

A. Compound of Formula II from diastereomer H:

IR (KBr): 2.94, 5.65 and 6.34 microns.

NMR (D, O, 250 MHz): 1.32 (d, 3H), 3.54 (c, 311), 3.88 (dd, 1H), 3.97 (dd, 1H), 4.27 ( c, 2H), 4.63 (m,; H) and 5.73 (d, 1H) ppm.

H diastereomer

IR (KBr): 2.88, 5.58, 5.91 and 6.58 microns.

NMR (CDCl ₃ , 250 MHz): 0.04 (s, 3H), 0.07 (s, 3H), 0.83 (s, 9H), 1.26 (d, 3H), 3.08 (b) , 1H), 3.46 (c, 4H), 3.79 (dd, 1H), 4, O2 (m, 1H), 4.28 (m, 1H), 4.74 (m, 1H), δ , 33 (q, 2H), 5.75 (d, 1H), 7.62 (d, 2H) and 8.22 (d, 2H) ppm.

(57R, 65) -6 - [(R) -1-Hydroxyethyl] -2- (1,1-dioxo-3-hydroxy-4-thiolanyl) thio-2-penem Preparation of diastereomers of 3-carboxylic acid p-nitrobenzyl ester

Using Method A, starting from the G and H diastereomers, the corresponding compounds of Formula XV were obtained in 64.2% and 59.7% yield, respectively.

Compound XV of diastereomer G:

NMR _(DMSO-d6, 250 MHz): 1.28 (d, 3H), 3.34. t

Preparation of (57R, 6S) -6 - [(R) -1-lhydroxyethyl] -2- (1,1-dioxo-3-thiolanyl) thio-2-penem-3-carboxylic acid Preparation of -nitrobenzyl ester

185 mg (0.303 mmol) of (57R, 65) -6 - ((7R) -1-t-butyldiethylethylsilyloxyethyl J-2- (1,1-dioxo-3-thiolanyl) -thio-2-rim-3-carboxylic acid p-nitrobenzyl ester is dissolved in 6 ml of tetrahydrofuran and 0.175 ml (3.03 nmole) of acetic acid and 0.909 ml (0.909 mmole) of 1M tetrabutylammonium fluoride are added. After stirring for 20 hours under nitrogen, 50 ml of ethyl acetate were added to the reaction mixture and the resulting solution was washed with 25 ml of saturated aqueous sodium bicarbonate solution, 25 ml of water and 25 ml of saturated aqueous sodium chloride solution each. The ethyl acetate solution was then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 138 mg of crude product which was purified by chromatography on 50 g of silica gel, eluting with 60:40 chloroform / ethyl acetate.

-1 325

194,568 mixtures were used. This gave 72 mg (47.5%) of the title compound as an amorphous solid.

The NMR spectrum of a solution of the title compound in deuterochloroform contained the following peaks: 1.35 (d, 311), 1.9-4.4 (c, 1011), 5.3 (q, 211),

5.7 (d, 1H), 7.5 (d, 2H), and 8.18 (d, 2H) ppm.

The infrared absorption spectrum of a solution of the title compound in dichloromethane indicates maximum absorption at the following wavelengths: 5.56, 5.92, 10 and 6.57 microns.

Production Process B

The method of Preparation A is used to convert a suitable compound of Formula XIV to a compound of Formula XV wherein R is as defined in Table 5 below. Infrared absorption spectra and nuclear magnetic resonance spectra are reported for identification of the reaction product; the former was measured in a dichloromethane solution of the compounds, unless otherwise noted, and the latter was measured in a deuterochloroform solution of the compounds, unless otherwise noted.

3-thiolanyl cis-1-oxo-3-thiolanyl (more polar isomer) trans} -oxo-3-thiolanyl (less polar isomer)

2- (methylsulfinyl) ethyl

2- (methylsulfinyl) ethyl methylsulfinylmethyl methylsulfonylmethyl

1-oxo-3-lianyl t, 1-dioxo-3-thianyl

3-thietanyl

Table 5 it

Infrared absorption maxima (microns) NMR (Ppm) Yield (%) 5,56,5,88,6,56 1.35 (d, 3H), 1.8-4.4 (c, 10H), 5.3 (q, 211), 5.65 (d, 1H), 7.6 (d, 2H), 8.2 (d, 2H). 51 5.56, 5,86,6,56 1.3 (d, 311), 1.9 4.38 (c, 1011), 5.3 (q, 211), 5.7 (d, 1H), 7.6 (d, 2H), 8.2 (d, 2H). 51 5,56,5,88,6,58 1.3 (d, 3H), 1.86-4.56 (c, 1011), 5.3 (q, 211), 5.72 (d, 111), 7.6 (d, 2H), 8.2 (d, 2H). 51 5,56,5,9,6,55 1.35 (d, 3H), 2.65 (S, 3H), 2.9- 3.5 (c, 4H), 3.75 (M, 1H), 4.2. (c, 2H), 5.34 (q, 2H), 5.7 (d, 1H), 7.6 (d, 2H), 8.2 (d, 2H). 67 5,57,5,9,6,58 1.23 (d, 311), 3.0 (s, 311), 3.4 (s, 4H), 3.8 (m, 1H), 4.0-4.8 (c, 2H), δ , 36 (q, 2H), 5.8 (d, 1H), 7.74 (d, 2H), 8.2 (d, 2H). 85 5,57,5,92,6,6 1.35 (d, 3H), 2.68 (s, 3H), 3,644.45 (c, 5H), 5.3 (q, 2H), 5.7 (d, 1H), 7.56 (d, 2H), 8.2 (d, 2H). 65 5,6,5,86,6,57 1.36 (d, 3H), 3.08 (s, 3H), 3.844.8 (c, 5H), 5.42 (q, 2H), 5.8 (d, 1H), 7.75 (d, 2H), 8.24 (d, 2H). 34 5,56,5,94,6,58 1.32 (d, 3H), 1.5-4.38 (c, 12H), 5.3 (q, 2H), 5.7 (d, 1H), 7.6 (d, 2H), 8.2 (d, 2H). 26 5.56, 5.8,6.55 1.3 (d, 3II), 1.76 4.4 (c, 12H), 5.3 (q, 211), 5.68 (ti, 111), 7.6 (d, 211), 8.2 (d, 2H). 47 5,56,5,88,6,56 1.3 (d, 3H), 3.38 (c, 4H), 3.68 (m, 1H), 4.22 (m, 1H), 4.8 (m, 1H), 5.3 (q, 2H), 5.6 (d, 1H), 7.55 (d, 2H), 8.16 (d, 2H). 74

-1 427

194,568

Continuation of Table 5

Infrared Absorption Maxima NMR Spectrum (micron) (pp ^m ) (%)

4 Tianie 3424, 1773, 1688 cm ^-1 1.39 (311, d), 1.8-2.0 (3H, m), 2.3-2.5 (211, m), 2.6-2.85 (4H, m), 3, 23 (1H, tt), 3.77 (1H, dd), 4.28 (1H, m), 5.23 (1H, d), 5.49 (1H, d), 5.68 (1H, d) ), 7.64 (2Il.d), 8.22 (211, d) (250 MHz). 90 1,1-dioxo-4-thianyl 1.18 (3H, d, J = 6.2 Hz), 1.8-1.95 (2H, m), 2.45-2.6 (2H, m), 2.79 (2H, m) , 3.04 (2H, in), 3.62 (1H, m), 3.90 (1H, dd, J = 5.7, 1.3, lz), 4.02 (1H, m), δ, 23 (1H, broad d, J = 14.0 Hz), 5.29-5.45 (2H, both d, J = 14.0 Hz), 5.78 (1H, d, J = 1.3 Hz), 7.70 (2H, d, J = 8.7 Hz), 8.25 (2H, d, J = 8.7 Hz) _(DMSO-d6, 250 MHz)? 92 <tase-1-oxo-4-thianyl (m.p. = 206-208 ° C). 5.57, 5.91 and 6.58 1.35 (d, 3II), 1.4 3.96 (c, MII), 4.18 (m, 1H), 5.31 (q, 2H), 5.69 (d, 1H), 7, 58 (d, 2H) and 8.22 (d, 2 H). 83.4 trans-1 -οχο-4-thianyl 5.57, 9.9 and 6.58 ! , 34 (d, 311), 1.4 4.43 (c, 111), 5.3 (q, 2H), 5.7 (d, 1H), 7.55 (d, 2H) and 8.14 (d, 2H). 58.5 cis-1 -οχο-3-thianyl 3530, 1772, 1681, 1510, 1344, 1290, and 1115 cm @ ^-1 1.15 (3H, d, J = 6.2 Hz), 1.95-2.15 (2H, m), 2.3-2.55 (2H, m), 3.05-3.5 (4H, m) , 3.58 (1H, m), 3.89 (III, dd, J = 5.8, 1.4, 11z), 4.00 (111, m), 5.23 (1H (01J), d, J = 4.6Hz), 5.28 (1H, D, Jgem = 14Hz), 5.43 (1H, d, Jgem = 14Hz), 5.77 (1H, d, J = 1.4) Hz), 7.68 (2H, d, J = 8.6 Hz), 8.23 (2H, d, J = 8.6 Hz. _(DMS0-d6, 250 MHz). 77 trans-1 -οχο-3-thianyl 3435,2940,2919,2862, 1786,1686,1609,1504, 1378,1343,1324, 1298, 1244,1204,1129,1043 1016, 1005,994 and 730 cm ^-1 (KBr) 1.17 (3H, d, J = 6.3 Hz), 1.952.3 (4H, m), 2.7-3.0 (4H, m), 3.43 (1H, tt, J = 11, 7 Hz), 3.88 (1H, dd, J = 5.8, 1.3 Hz), 4.01 (1H, qdd, J = 6.3, 5.8, 4.6 Hz), 5, 21 (1H, d, J = 4.6 Hz), 5.29 and 5.44 (211, both dd, = 14.0 ten), 5.77 (J1, d, J = 1.3 Hz) 7.69 (2H, d, J = 8.6 Hz), 8.24 (2H, d, J = 8.6 Hz) _(DMSO-d6, 250 MHz). 92

-1 529

194,568

Preparation C (5R, 65) -6 - [(R) -1-Butyldimethylsilyloxymethyl] -2-methylsulfinylmethylthio-2-penem-3-carboxylic acid p- Preparation of nitrobenzyl ester _ □

76 mg (0.5 mmol) of thiocetic acid methylsulfonylmethyl ester in anhydrous ethanol are added, the solution is brought to 40 ° C, and 27 mg (0.5 mmol) of sodium methylate are added under a nitrogen atmosphere.

after 5 minutes at the same temperature, 300 mg (0.5 mmol) of (5R, 65) -6 - ((R) -1-butyldimethylsilyloxy) ethyl-2-ethylsulfinylthio-2 -penem-3-carboxylic acid p-nitrobenzyl ester prepared with 5 ml of tetraalidiophylalan,

Pour the solution cooled to -50 ° C. The resulting solution was stirred at -40 ° C for 65 minutes, then 0.029 mL (0.5 mmol) of acetic acid was added and the solution was concentrated in vacuo. The residue was dissolved in ethyl acetate (50 mL), and the resulting solution was washed successively with 25 mL of saturated aqueous sodium bicarbonate, 25 mL of water, and 25 mL of saturated sodium chloride.

The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The title compound (290 mg, crude product) was chromatographed on 85 g of silica gel using 80:20 chlorol / l / ethyl acetate as eluent. This gives 120 mg (42%) of product as a viscous, gummy material.

The infrared absorption spectrum of a solution of the title compound in dichloromethane shows the following absorption maxima: 5.58, 5.9 and 6.6 microns. The dculerochloroform solution of the title compound showed the following peaks at 0.03 (s, 3H), 0.05 (s, 3H), 0.83 (s, 9H0, 1.24 (d, 3H)). ), 2.7 (s, 3H), 3.7-4.22 (c, 4H), 5.28 (q, 2H), 5.68 (d, 1H), 7.56 (d, 2H) , 8.18 (d, 2H) ppm.

Production Method D

Following Preparation C, compounds of formula (XIV) are prepared starting from the corresponding thioacetates having the groups R in the following Table 6. The infrared absorption spectrum (dichloromethane solution) and NMR spectrum (unless otherwise indicated, deuterochloroform solution) of the prepared compounds of formula (XIV) are shown in Table 6.

Table 6 Methylsulfonylmethyl

2- (methylamino szulfinli) ethyl

2- (methylsulfonyl) ethyl

3 tiolanii

1-oxo-3-thianyl, 1-dioxo-3-thianyl

Infrared absorption maxima (microns)

5.56, 5,88,6,54

5,56,5,92,6,56

5,56,5,9,6,58

5,56,5,92,6,56

5.57, 9.95 and 6.58

5.56, 5.88 and 6.54

Nuclear Magnetic Resonance Spectrum (ppm)

Yield (%)

0.1 (s, 6H), 0.9 (s, 9H), 1.22 (d, 3H), 27

2.9 (s, 311), 3.64 (in, 1H), 4.16 (c,

3H), 5.2 (q, 2H), 5.57 (d, 1H), 7.42 (d, 2H), and 8.06 (d, 2H).

0.06 (S, 3H), 0.1 (S, 3H), 0.85 (S, 26

911), 1.26 (d, 311), 2.66 (3Π), 2.86 3.54 (C, 411), 3.74 (M, III), 4.2 (M,

1H), 5.3 (q, 2H), 5.7 (d, 1H), 7.6 (d, 2H), and 8.2 (d, 2H),

0.03 (s, 3H), 0.06 (s, 3H), 0.8 (s, 9H), 34

1.23 (d, 3H), 2.98 (s, 3H), 3.36 (s,

4Π), 3.64 (ni, 11II), 4.2 (m, III), 5.28 (q, 211), 5.68 (d, 111), 7.57 (d, 211), and δ. , 18 (d, 2H).

0.02 (s, 3H), 0.06 (s, 3H), 0.82 (s, 9H), 41 1.25 (d, 3H), 1.8-4.4 (c, 911), 5.3 (q, 211), 5.66 (d, 111), 7.6 (d, 211), and 8.2 (d, 2H).

0.06 (s, 3H), 0.08 (s, 3H), 0.88 (s, 22)

9H), 1.26 (d, 3H), 1.5-4.4 (c, UH),

5.3 (q, 2H), 5.7 (d, 1H), 7.6 (d, 2H),

8.2 (d, 2H).

0.03 (s, 3H), 0.06 (s, 3Π), 0.82 (s, 911), 42

1.24 (d, 3H), 1.8-4.42 (q, 11H), 5.3 (q, 2H), 5.7 (d, SH), 7.6 (d, 2H), 8.2 (d, 2H).

-1 631

194,568

Continuation of Table 6

R Infrared absorption maxima (microns) NMR Spectrum Yield (ppm) (%) 3-thietanyl 5,56,5,88 and 6,56 0.03 (s, 3H). 0.06 (s, 3H), 0.82 (s, 911), 28 1.24 (d, 311), 3.4 (c, 411), 3.7 (ni, 1H), 4.23 (m, 111), 4.85 (ni, 111), 5.3 (q, 2ll), 5.63 (d, 1H), 7.6 (d, 2H), and 8.2 (d, 2H). 4-dithianyl 0.13 (6H, s), 0.92 (9H, s), 1.40 (311, d, J = 7Hz). 1.8-2.9 (811, ni), 3.27 (III, in), 3.75 (111, dd, J = 4, 1.5 Hz), 4.3 (III, m), 5, 18 (1H, d, J _AB = 13 Hz), 5.48 (1H, d, J _AB = 13 Hz), 5.67 (1H, d, J = 1.5 Hz), 7.60 (2H , d, J = 8Hz), and 8.18 (2H, d, J = 8Hz). l, l-dioxo-4-íianil 0.13 (3H, s), 0.17 (3H, s), 0.93 (911, s), 60 1.33 (3H, d, J = 611), 2.4 3.4 (811, ni), 3.6 (1H, ni), 3.80 (111, dd) .4.3 (III, in), 5.17 (1H, d, J = 13Hz), 5.47 (1H, d, J) = 13 Hz), 5.69 (1H, d, J = 1 Hz), 7.57 (2H, d, J = 8Hz) and 8.15 (2H, d, J = 8 µz). cis-1-oxo-4-thianyl 2924, 2489, 1782, 1682, 1606, 1511, 1487, 1328, 1196, 1110, 1055, 997, and 830 cm ¹ (KBr pastilles) 0.04 (3H, s), 0.07 (3H, s), 0.83 68 (9H, s), 1.25 (3H, d, J = 6.3 Hz), 2.1-2, 3 (2H, m), 2.45-2.7 (4H, m), 3.05-3.2 (2H, m), 3.27 (1H, ni), 3.73 (1H, dd, J = 4.2, 1.4 Hz), 4.27 (1H, qd, J = 6.3,4.2 Hz), 5.21 and 5.42 (2H, both dd, J _AB = 13.7 Hz) , 5.66 (1H, d, J = 1.4 (Hz), 7.62 (2H, d, J = 8.7 Hz), 8.21 (2H, d, J = 8.7 Hz). 250 MHz). trans-1 -οχο-4-thianyl 0.10 (611, s), 0.87 (911, s), 1.28 (311, 41 d, J = 61 Iz), 1.7-2.3 (211, in), 2.5 3, 1 (6H, m), 3.6 (1H, m), 3.74 (1H, dd, J = 4.1.5 Hz), 4.2 (1H, m), 5.13 (1H, d) , J _AB = 13 Hz), 5.45 (1H, d, J _A B = 13 Hz), 5.67 (1H, d, J = 1.5 Hz), 7.57 (2H, d, J = 8 Hz) and 8.15 (2H, d, J = 8 Hz). Cis-l-oxo-3-dithianyl 5,58,5,9,6,58 0.04 (s, 311), 0.06 (s, 311), 0.82 (s, 45.5) 9H), 1.24 (s, 3H), 1.3-3.98 (c, 10H), 4.23 (m, 1H), 5.24 (q, 2H), 5.64 (d. 1H), 7.5 (d, 2H), and 8.15 (d, 211). trans-1-oxo-3-thianyl 5,58,5,92,6,58 0.03 (s, 3H), 0.07 (s, 3H), 0.83 (s, 41.3) 9H), 1.22 (d, 3H), 1.4-3.56 (c, 8H), 3.7 (m, 1H), 3.78-4.46 (c, 2H), 5.26 (q, 2H), 5.63 (d, 1H), 7.52 (d, 2H), 8.12 (d, 211).

-1 733

194,563

Preparation E (57-, 65) -6 - [(7R) -1-t-Butyldimethylsilyloxyethyl] -2- (1-oxo-3-thiolanyl) thio-2-penem Preparation of 3-carboxylic acid p-nitrobenzyl ester

1-Oxo-3- (methylcarbonylthio) thiolane (100 mg, 0.552 mmol) was dissolved in anhydrous ethanol (5 mL) and the solution was cooled to -30 ° C and 30 mg (from 0.052 nin) of sodium melylate under N 2 O is added to the solution. After 75 min, 330 mg (0.552 mmol) of (57?, 6 S) -6 - [(7?) -1-t-butyldimethylsilyloxyethyl] -230 mg (0.552 mmol) in 5 mL of tetrahydrofuran -ethylsulfinyl-2-penem-3-carboxylic acid p-nitrobenzyl ester is added to the above solution by cooling the tetrahydrofuran solution to -50 ° C beforehand. After stirring for 60 minutes at -35 ° C to -30 ° C, acetic acid (0.032 ml, 0.552 mmol) was added and the solution concentrated in vacuo. The residue was dissolved in ethyl acetate (50 mL) and washed successively with saturated aqueous sodium bicarbonate solution (25 mL), water (25 mL), and brine (25 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product (315 mg) was chromatographed on 100 g of silica gel, eluting with 92.5: 7.5 ethyl acetate / methanol. This gives 53 mg of the less polar isomer of the title compound (16%) and 65 mg of the more polar isomer of the title compound (20%).

The infrared spectrum of the more polar isomer of the title compound (dichloromethane solution) shows the positions of the absorption peaks at 5.56, 5.92 and 6.58 microns, whereas the absorption spectra in the deuterochloroform solution showed 0.03 ( 3H), 0.08 (3H), 0.82 (s, 9H), 1.24 (d, 3H), 1.9-4.4 (c, 9H), 5.28 (q, 2H), 5.68 (d, 1H), 2.6 (d, 2H) and 8.2 (d, 2H) ppm.

The infrared spectrum of the less polar isomer of the title compound (dichloromethane solution) indicates the position of the absorption peaks at 5.57, 5.92, and 6.57 microns; 3H), 0.08 (s, 3H), 0.8 (s, 9H), 1.23 (d, 3H), 1.8-4.56 (c, 9H), 5.26 (q, 2H) ), 5.66 (d, 1H), 7.6 (d, 2H) and 8.2 (d, 2H) ppm.

Preparation F (5R, 65 ') - 6 - [(7R) -1-butyldimethylsilyloxyethyl] -2- (1,1-dioxo-3-thiolanyl) thio-2 Preparation of -penem-3-carboxylic acid nitrobenzyl ester mg (0.5 mmol) of 1,1-dioxo-3-thiolanyl mercaptan (3-sulfolane thiol) was dissolved in 5 ml of ethanol and the solution was heated to -35 ° C. After cooling to C, 27 mg (0.5 mmol) of sodium methyl acetate are added under a nitrogen atmosphere.

300 min (0.5 mmol) of (57?, 6 S) -6 - [(7?) -1-butyldimethylsilyloxyethyl] in 5 ml of anhydrous tetrahydrofuran at -35 ° C. 2-Ethylsulfinyl-2-penem-3-carboxylic acid p-nitrobenzyl ester was added by cooling the tetrahydrofuran solution to -50 ° C. The resulting solution was stirred for 60 minutes at -35 ° C and then 0.029 mL (0.5 mmol) of acetic acid was added. The solution was evaporated in vacuo and the residue was dissolved in ethyl acetate (50 mL). The ethyl acetate solution was washed successively with 25 mL of saturated aqueous sodium bicarbonate solution, 25 mL of water, and then 25 mL of saturated aqueous sodium chloride. The ethyl acetate layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product (250 mg) was purified by chromatography on silica (100 g) eluting with 95: 5 chloroform: ethyl acetate. The appearance of the title compound (185 mg, 60%) resembles that of a gum.

The dichloromethane solution of the title compound has infrared absorption maxima at 5.57, 5.88 and 6.58 microns. The deuterochloroform solution of the title compound had an NMR of 0.06 (s, 3H), 0.1 (s, 3H), 0.85 (s, 9H), 1.26 (d, 3H), 2.0 1.4 (c, 9H), 5.32 (q, 2H), 5.72 (d, 1H), 7.6 (d, 2H) and 8.2 (d, 2H) ppm.

Preparation G (57R, 65) -6 - [(7R) -1-butyldimethylsilyloxyethyl] -2-ethylsulfinyl-2-penem-3-carboxylic acid p-nitro- Preparation of -bczzyl ester

2.5 g (4.78 mmol) of (57?, 65) -6 - [(7?) - t-butyldimethylsilyloxyethyl] -2-ethylthio-2-penem-3- p-Nitrobenzyl ester of carboxylic acid is dissolved in 125 ml of dichloromethane and the solution is cooled to -20 ° C. A solution of 97 mg (4.78 mmol, 85% purity) of m-chloroperbenzoic acid in 25 ml of dichloromethane was added to the former solution. After stirring at -20 ° C for 3 hours, the mixture was washed twice with successively 70-70 ml of saturated aqueous sodium bicarbonate solution, followed by 70 ml of water and then 70 ml of saturated brine. The dichloromethane layer was dried over anhydrous sodium sulfate and concentrated in vacuo. 2.2 g of the title compound are obtained in 86% yield as a yellow foam.

A solution of the title compound in dichloromethane exhibits the following infrared absorption maxima: 5.54, 5.86, 6.53 microns. Nuclear Magnetic Resonance Spectrum in a solution of the title compound in Leuterochloroform: 0.06.0.08.08.1 and 0.12 (4s, 611 in total), 0.8fs, 9H), 1.12-J, 58 (m, 6H), 3.1 (m, 2H), 3.86 (m, H), 4.3 (m, 1H), 5.3 (m, 2H), 5.67 and 5.78 (2d, 1H total), 7.54 (d, 2H) and 8.18 (d, 2H) ppm.

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Production Method H i

(57R, 65) -6 - [(R) -1-t-Butyldimethylsilyloxyethyl] -2-ethylthio-2-penem-3-carboxylic acid p-nitrobenzyl- Preparation of ester

7.3 g (0.02 mol) of 3 - [(tert-butyldimethylsilyloxyethyl) -4-ethylthio (thiocarbonyl) thio-2-oxoazetidine and

Calcium carbonate (4.8 g, 0.048 mol) was partitioned between dichloromethane (70 ml) and the solution was bound to 10 ° C under a nitrogen atmosphere, and g-nitrobenzyl-oxalyl chloride (5.85 g, 0.024 mol) was added. A solution of diisopropylethylamine (4.17 mL, 0.024 mol) in dichloromethane (20 mL) was added dropwise to the mixture at a temperature below 12 ° C. The mixture was stirred at 10 ° C for 60 minutes, then washed twice with 50 ml of ice-cold water. The washed dichloromethane solution was dried over anhydrous sodium sulfate and concentrated in vacuo to give a viscous oil. The crude (3-tert-butyldimethylsilyloxyethyl-2-oxoazetidinyl) -oxalacetic acid p-nitrobenzyl ester thus obtained was dissolved in 300 ml of ethyl alcohol-free chloroform, and the solution was refluxed under nitrogen. while stirring over a period of two hours, 6.85 ml of triethylphosphite dissolved in 50 ml of ethanol-free chloroform are added dropwise. The resulting mixture was refluxed for 16 hours and then concentrated in vacuo. The residue was chromatographed on 800 g of silica gel eluting with 95: 5 toluene / ethyl acetate. This way

5.5 g (53%) of the title compound are obtained as a yellow foam.

In the infrared absorption spectrum of the title compound (dichloromethane solution), the peaks are at 5.56, 5.89 and 6.54 microns. The deutero-chloroform solution of the title compound has the following peaks: 0.07 (s, 3H), 0.1 (s, 3H), 0.85 (s, 9H), 1.12-1. 53 (m, 6H), 2.97 (q, 2H), 3.7 (m, 1H), 4.25 (m, 1H), 5.3 (q, 2H), 5.63 (d, 1H) ), 7.38 (d, 2H) and 8.18 (d, 2H) ppm.

The NMR spectrum of the 4-ethylthio (thiocarbonyl) thioazetidine intermediate in deuterochloroform shows the following peaks: 0.06 (s, 6H), 0.8 (s, 9H), 1.14-1. , 62 (m, 6H), 3.14-3.63 (m, 3H), 4.33 (m, 1H), 5.16 (s, 2H), 6.7 (d, 1H), 7, Δ (d, 2H) and 8.17 (d, 211) ppm.

Preparation I

Preparation of 3 - [(R) -1-butyldimethylsilyloxyethyl] -4-ethylthio (thiocarbonyl) thio-2-oxoazetidine

Ethyl mercaptan (8.5 ml, 0.115 mol) was added to a solution of sodium hydroxide (4.18 g, 0.104 mol) in water (250 ml) cooled under nitrogen at 05 ° C. After 15 minutes, carbon disulfide (7.73 mL, 0.12 mol) was added and stirred at 0-5 ° C for 35 minutes. 15 g (0.0522 mol) of 4-acetoxy-3 - [(R) -1-t-butyldimethylsilyloxyethyl] -2-azetidinone (500 g) in dichloromethane are then added and stirring was continued vigorously at room temperature for 24 hours. The aqueous phase was separated and extracted with dichloromethane (2 x 150 mL). The combined dichloromethane fractions were washed with distilled water (2 x 200 mL), brine (200 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting 18 g of crude product is chromatographed on 500 g of silica gel stationary phase. The eluent is a 99: 1 mixture of chloroform and cleacelate as eluent. The title compound (9.1 g) was a yellow foam. Yield 48%.

The infrared absorption spectrum of a solution of the title compound in dichloromethane exhibited maximum absorption at 5.62 and 9.2 microns. NMR of a solution of the title compound in deuterochloroform: 0.08 (s, 611), 0.8 (s, 911), 1.02-1.5 (in, 611), 3.0 3.48 ( in, 311), 4.12 (m, 111), 5.54 (d, 111), 6.57 (b, 111) ppm.

Process J

Preparation of 3-methylcarbonylthiothiolane

Methanesulfonyl chloride (0.8 mL, 0.01 mol) was tetrahydrothiophen-3-ol (1.04 g, 0.01 mol) and 2.44 g (0.02 mol).

A solution of 4-dimethylaminopyridine in 40 ml of dichloromethane was cooled to 0 ° C under nitrogen. After stirring at 0 ° C for 1.5 hours, then at room temperature for 2 hours, the mixture was washed successively with 30 ml of 1N aqueous hydrochloric acid, 30 ml of water and 30 ml of brine. The organic phase so treated was dried over anhydrous sodium sulfate and the solvent removed in vacuo to give an oil. This was 1.6 g of 3-methylsulfonyloxythiolane, analyzed. Yield: 88%.

1.6 g (8.8 mmol) of crude 3-methylsulfonyloxythiolane and 1.5 g (8.8 mmol) of potassium thioacetate are dissolved in 40 ml of acetone and the solution is refluxed under nitrogen for 20 hours. boil. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate (40 mL) and water (40 mL). The ethyl acetate layer was separated and washed with 30 mL of flavor followed by 30 mL of saturated sodium chloride solution. After drying over anhydrous sodium sulfate, the ethyl acetate side is evaporated in vacuo. Chromatography of the crude product on silica gel using dichloromethane as eluent. 40 mg of the title compound are obtained in 52% yield.

Nuclear Magnetic Resonance Spectrum in deuterochloroform solution of the title compound: 2.35 (s, 3H), 1.6-3.4 (c, 611), 4.1 (m, 1H) ppm.

Process for the preparation of K

Using the same procedure as in Production Method 1, 3-methylsulfonyloxythiolane and potassium thioacetate were used to react with 3-chloro

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thionane and 2- (methylthio) ethyl chloride reagents and potassium thioacetate, respectively, to give the corresponding methyl carbonylthio derivatives, 33% and

In 100% yield.

The NMR spectrum of the 3-nicylcarbonylthiol in the dichlorochlorophore / nos side was 2.36 (s, 311) and 1.4-3.68 (c, 9H) ppm.

Preparation L Preparation of (Methylcarbonylthio) methylsulfonylmethane

Dissolve 1.0 g (7.34 mmol) of methylcarbonylthio-methylthio-methane in 50 ml of dichloromethane and cool to 0 ° C. and 3.0 g (14.7 mmol, 85% purity) of w-chloroperbenzoic acid. After stirring for 20 hours at room temperature, the solution was washed twice with 30 ml of saturated aqueous sodium bicarbonate solution and then with 30 ml of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography using silica gel stationary phase and ethyl acetate as eluent. The title compound was obtained in a yield of 740 mg (60%) as a viscous gum.

Nuclear Magnetic Resonance Spectrum in deutero chloroform solution of the title compound showed 2.5 (s, 3H), 2.94 (s, 3H), 4.4 (s, 2H) ppm.

M production process

Following the procedure of Preparation L, 3-methylcarbonylthio-1,1-dioxothane was prepared in 32% yield and 2- (methylcarbonylthio) -1- (methylsulfonyl) ethane in 55% yield. yield.

Nuclear Magnetic Resonance Spectrum in a solution of 1,1-dioxothane in deuterochloroform had peaks at 2.36 (s, 3H), 1.7-3.37 (c, 9H) ppm.

Process for the preparation of N

Preparation of 2- (methylcarbonylthio) -1-methylsulfinyl ethane

2-Methylcarbonylthio-1-methylthioethane (1.5 g, 0.01 mol) was dissolved in dichloromethane (40 mL) and cooled to -10 ° C. To the solution was added m-chloroperbenzoic acid (2.03 g, 0.01 mol, 85% purity). After stirring at -10 ° C for 2 hours, the reaction mixture is washed with 30 ml portions of saturated aqueous bicarbonate solution, water and saturated aqueous sodium chloride solution. After drying over anhydrous sodium sulfate and evaporation in vacuo, the residue was applied to a silica gel column and eluted with 10: 1 ethyl acetate / methanol to give the title compound (680 mg) as an amorphous solid. Yield: 38%.

The deutero-chloroform solution of the title compound had an NMR of 2.4 (s, 3H), 2.68 (s, 3H), and 2.76-3.46 (c, 4H) ppm.

O production process

Following the N production procedure, 3-methylcarbonylthio-1-oxothiolane was prepared with 43%, 3-ethylcarbonylthio-1-oxothiolane 91% and (methylcarbonylthio). - (nyltylsulfinylmale) in 32% yield.

The NMR spectrum of a solution of 1-oxothiolane in deuterochloroform indicates the following peaks: 2.36 (s, 3H), 1.77 - 1.76 (c, 7H) ppm.

The NMR spectrum of a solution of 1-oxothianium in deuterochloroform showed peaks at 2.36 (s, 3H) and 1.6-3.4 (c, 9H) ppm.

NMR spectrum of (methylcarbonylthio) methylsulfinylmethane also in deuterochloroform solution:

2.5 (s, 3H), 2.94 (s, 3H) and 4.4 (s, 2H) ppm.

Using the N production procedure, 1,1-dioxo-A-octylcarbonylthiothiol is obtained in 43% yield from 4-methylcarbonylthiothiane and 2 equivalents of m-chloroperbenzoic acid. The product was purified by column chromatography on silica gel using ethyl acetate / hexane 1: 1 as eluent. According to elemental analysis:

Calculated (for C ₇ H ₂ O ₃ S): C: 40.37%, H: 5.81%;

Found: C, 40.62; H, 5.58.

The product showed the following peaks in NMR spectroscopy in deuterochloroform: 2.15-2.5 (4H, m), 2.36 (3H, s), 3.02-3.2 (4H, m) and 3 , 74 (1H, tt, J = 8.4 Hz) ppm.

The product has an infrared absorption spectrum with potassium bromide paste uptake at 1687, 1291 and 1116 cin ' ¹ .

Likewise, the N-production process provides 1-oxo-A-p-methylphenylsulfonyloxythane starting from 4-p-methylphenylsulfonyloxythane. The cis and trans isomers formed in the reaction are separated by column chromatography. The column was eluted with silica gel eluting with 3% methanol in ethyl acetate. Cwz-1-oxo-4-p-methylethylsulfonyloxyethane has been shown to be the more polar isomer. The NMR spectrum (at 250 MHz) of a solution of the cAz isomer in deuterochloroform gives the peaks at 2.0 (2H, m), 2.48 (2H, m), 2.50 (3H, s), 2.75 (211, dddd), 3.07 (2H, ddd), 4.67 (1H, J = 8.3 3.4 Hz), 7.41 (2H, d, J = 8 Hz) and 7 , 85 (2H, d, J = 8Hz) ppm.

Process for the preparation of P

Preparation of 3-Chlorothianthane

Tetrahydrothiopyran-3-ol (530 mg, 4.5 mmol) and 4-dimethylaminopyridine (1.1 g, 9 mmol) were dissolved in dichloromethane (30 mL) and cooled to 0 ° C under nitrogen. To the cooled solution was added 857 mg (4.5 mmol) of p-toluenesulfonyl chloride. After stirring for 20 hours at room temperature, the solution was washed twice with 30 ml of 1N aqueous hydrochloric acid, 30 ml of water and 30 ml of a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. This gave 400 mg (33%) of the crude title compound.

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Preparation Q (5R, 65) -6 - ((R) -1-Hydroxyethyl) -2- (2-oxo-1,3-di-thiolan-4-ylmethyl) -thio-2-penem-3 Preparation of p-nitrobenzyl ester of carboxylic acid

410 mg of (57R, 6S) -6 - [(7R) -1-butyldimethylsilyloxyethyl] -2- (2-oxo-1,3-dithiolan-4-ylmethyl) - Thiopenem-3-carboxylic acid p-nitrobenzyl ester is dissolved in 20 ml of tetrahydrofuran and the solution is mixed with 0.383 ml of glacial acetic acid and 2.0 ml of 1M tetrabutylammonium fluoride solution. The resulting solution was stirred at room temperature for 24 hours. At this time, the solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with dilute aqueous sodium hydrogencarbonate solution, water and brine, dried over anhydrous sodium sulfate, filtered and replaced. The product was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 1: 1) followed by pure ethyl acetate.

NMR (CDCl ₃ ) DMSO-d ₆ : 1.23 (3H, d, J = 6), 2.92-3.25 (2H, m), 3.42-3.67 (4H, m), δ , 2 (2H, s), 5.30 (1H, d, J = 2) and 7.83 (4H, d, d) ppm.

Preparation R (5R, 65) -6 - ((R) -1-butyldimethylsilyloxyethyl) -2- (2-oxo-1,3-dithiolan-4-ylmethyl) ) -thio-2-penem-3-carboxylic acid p-nitrobenzyl ester

4-Mercaptomethyl-1,3-dithiolan-2-one (0.500 g) was dissolved in dichloromethane (50 mL), cooled to 0 ° C and treated with diisopropylethylamine (0.640 mL). The solution was kept at 0-5 ° C for 1 hour, then 0.307 g of (5R, 65) -6 - ((77) -1-t-butyldimethylsilyloxyacyl) -2- (ethylsulfinyl) ) To a solution of p-nitrobenzyl 2-penen-3-carboxylate in the same temperature in dichloromethane (20 ml) was stirred at 0-5 ° C for 1 hour, then washed successively with water and brine, anhydrous. After filtration, the solution was evaporated to give a sticky material which was triturated with 1: 1 hexane / ethyl acetate to give the title compound as a pale yellow amorphous solid.

NMR (CDCl ₃ , 60 MHz): 0.05 (3H, s), 0.08 (3H, s), 0.83 (9H, s), 1.23 (3H, d, J = 6), 3 , 28-3.52 (2H, m), 3.67-3.92 (2H, m), 4.02-4.67 (2H, m), 5.30 (2H, d, J = 4). , 5.68 (1H, s) and 7.8 (4H, d, d) ppm.

IR (CHjCl _2): 1792 cm- ^first

Preparation of (57R, 65) -6 - [(7R) -1-Hydroxyethyl] -2 - [(trans) -1-oxo-3-thiolanyl] thio-2-penem-3-carboxylic acid Preparation of p-nitrobenzyl ester

20.1 g (0.0337 mol) of (5R, 65) -6 - ((R) -1-t-butyldimethylsilyloxyethyl) -2 - [(cis) -1- Oxo-3-thiolanyl] -thio-2-penem-3-carboxylic acid p-nitrobenzyl ester is dissolved in 50 ml of anhydrous tetrahydrofuran and added to the solution.

Acetic acid (19.9 ml) and tetrabutylammonium fluoride solution (118.8 ml) in tetrahydrofuran were added. Stirring of the solution was carried out at room temperature overnight under N 2 O and concentrated in vacuo. The residue was dissolved in ethyl acetate (500 mL), and the resulting solution was washed with water (3 x 200 mL). The product began to crystallize from the aqueous extracts and the ethyl acetate phase, allowing the crystallization to complete (30 min). The crystalline material is filtered off, washed with water and ethyl acetate, then suspended in 200 ml of ethyl acetate and filtered. 12.03 g of crystalline product are obtained, corresponding to a yield of 74%. The ethyl acetate and aqueous extracts were combined, the ethyl acetate layer was washed with 300 mL of saturated aqueous sodium bicarbonate solution, 200 mL of water and 200 mL of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. 4.6 g of less pure product are thus obtained. This material was recrystallized from ethyl acetate to give 3.0 g of additional product, m.p. 122-125 ° C.

The deuterochlorochloroform solution of the title compound (250 MHz) has the following peaks: 1.37 (d, 3H), 2.57-2.95 (c, 4H), 3.15 (c, 1H). , 622.93 (c, 3H), 4.26 (m, 1H), 5.34 (q, 2H), 5.72 and 5.74 (2d, 1H), 7.63 (d). , 211) and 8.23 (d, 2H) ppm.

The dichloro-inclusion solution of the title compound has infrared spectra at 5.56, 5.86 and 6.56 microns.

The corresponding trans configuration of the title compound is prepared in 75% yield using the procedure for the cis isomer, starting from (5R, 65) -6- (7R) -1-butyldimethylsilyloxy-f. til] -2 - ((trans) -1-oxo-3-lyolanyl) -thio-2-penem -3-carboxylic acid p-toluenesulfonyl ester.

The solution of the trans isomer in deuterochloroform has the following NMR spectrum: 1.4 (d, 3H), 2.22 (c, 1H), 2.62 (c, 1H), 2.8 (m, 1H), 3.04 (c, 2H), 3.18 (c, 1H), 3.52 (111, 1H), 3.83 (m, 1H), 4.27 (c, III), 4.43 (c) , J H), 5.36 (q, 211), 5.76 (d, 111), 7.64 (ti, 211) and 8.24 (i, 2H) ppm.

The infrared absorption spectrum of a solution of the trans isomer in dichloromethane exhibits absorption bands of 5.56, 5.88, and 6.58 microns.

Preparation T (5R, 65) -6 - [(7R) -1-Butyldimethylsilyloxyethyl] -2 - [(cis) -1-oxo-3-thianyl] thio-2- preparation of penem-3-carboxylic acid p-nitro-butyl ester

10.68 g (0.06 mol) of cis-3-methylcarbonylthio-N-oxothiolane are dissolved in 110 ml of anhydrous ethanol, the solution is cooled to -30 ° C under nitrogen and 57.5 ml of IM (= 0.0575 moles) of a solution of sodium nitrate in ethanol. The resulting solution was stirred at -30 ° C (> n for 2 hours) and then cooled to -60 ° C

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194,568 jiik. To this cooled solution was 32.4 g (0.06 mol) of (57?, 65) -6 - [(7?) - 1-butyldimethylsilyloxyethyl] -2-ethylsulfonyl. - 2 - penem - 3 -carboxylic acid; A solution of the nitrobenzyl ester in 200 ml of tetrahydrofuran, previously cooled to -60 ° C, is poured. The resulting solution was stirred at -60 ° C for one hour and then treated with acetic acid (10 ml) and tetrahydrofuran (20 ml), allowed to warm to room temperature and then concentrated in vacuo. The residue was dissolved in ethyl acetate (500 mL) and washed with water (7 x 300 mL), saturated aqueous sodium bicarbonate (250 mL), water (3 x 300 mL), and brine (200 mL). After dehydration with anhydrous sodium sulfate, the ethyl acetate solution was evaporated in vacuo. The crude product

Chromatograph on 1.5 kg silica gel. The eluent was a 95: 5 mixture of ethyl acetate and methanol. The product thus obtained is triturated with 150 ml of diethyl ether and 14.25 g of crystalline product precipitates from the suspension at night. Chromatographic separation gave an additional 5.0 g of less pure product fraction which was dissolved in 5 ml of dichloromethane and diluted with 150 ml of diethyl ether. Stirring overnight gives 3.42 g of crystalline product. 137-138 ° C. This, afterwards, was combined with the crystalline main product, yielding 51.5% of total product.

The NMR spectrum of the title compound (deuterochloroform solution, 250 MHz) contains the following peaks: 0.04 (s, 3H), 0.07 (s, 311), 0.82 (s 9H), 1.25. (d, 3H), 2.45-2.9 (c, 4H), 3.14 (c, 1H), 3.554.0 (c, 311), 4.27 (m, III), 5.32 ( q, 2H), 5.67 and 5.7 (2d, 1H), 7.62 (d, 2H) and 8.2 (d, 2H) ppm.

The dichloromethane solution of the title compound has infrared spectra at 5.56, 5.92 and 6.58 microns.

The trans isomer of the title compound is obtained in a 25% yield using the same procedure using trans-3-ethylcarbonylthio-1-oxothiolane as starting material. The trans isomer is less polar than the cis isomer.

The NMR spectrum of the trans isomer of the title compound in deutero chloroform solution (250 MHz) has the following peaks: 0.06 (s, 3H), 0.1 (s, 3H), 0.86 (s, 9H), 13 (d, 3H), 2.25 (m, 1H), 2.82 (m, 1H), 2.94-3.33 (c, 3H), 3.55 (m, 1H), 3.82 (d, 1H), 4.33 (c, 1H), 4.45 (c, 1H), 5.36 (q, 2H), 5.76 (d, 1H), 7.66 (d, 2H) and 8.22 (d, 2H) ppm.

The infrared spectrum of a solution of the trans isomer in dichloromethane showed absorption maxima at 5.57, 5.92 and 6.57 microns.

U production process

Preparation of Cl-3-Methylcarbonylthio-1-oxothiane

Trans-1-oxo-3-p-methylphenylsulfonyloxyethane (300 mg, 1.04 mmol) and tetrabutylammonium thioacetate (396 mg, 1.25 mmol) were dissolved in acetone (20 mL) and the solution was stirred under nitrogen. heat to boiling and keep it boiling overnight. The reaction mixture was concentrated in vacuo and the resulting residue was chromatographed on silica gel (80 g). 50 mg of the title compound are obtained in 25% yield.

The deuterochloroform solution of the title compound had an NMR of 1.2-3.1 (c) and 2.28 (s) (total: 10H) and 3.34 (c, 2Η) ppm.

Similarly, starting with title oxo-3-p-methylphenylsulfonyloxyethane, trans-3-methylcarbonylthio-1-oxothiane was obtained in 50% yield. The NMR spectra of this trans isomer in deuterochloroform solution are as follows: 42, 3.24 (c) and 2.22 (s) (total III) and 4.06 (c, 11) ppm.

Process V

Preparation of -Oxo-3-p-methylphenylsulfonyloxyethane

2-Dimethylaminopyridine (2.14 g, 0.016 mol) and 4-dimethylaminopyridine (3.9 g, 0.032 mol) were dissolved in dichloromethane (80 ml) and the solution was 0 under nitrogen. After cooling to C, 3.65 g (0.019 mol) of p-toluenesulfonyl chloride are added. After standing at 0 ° C for 30 minutes, the reaction mixture was stirred at room temperature overnight. The solution is then washed successively with 50 ml of 1N aqueous hydrochloric acid, 50 ml of water and 50 ml of brine. The dichloromethane solution thus washed was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was chromatographed on 1 kg of silica gel using acetone / hexane (4: 1) as eluent. This gives 300 mg of the trans isomer of the title compound, 1.4 g of the mixture of its cis and trans isomers and 1.5 g of the cis isomer of the title compound. Overall yield: 70%.

Nuclear Magnetic Resonance Spectrum of the cis isomer of the title compound in a solution of deuterium chloroform:

1.4 - 2.92 (c) and 2.46 (s) (9H total), 3.4 (c, 211), 4.54 (c, 1H), 7.36 (d, 2H) and 7.8 (d, 2H) ppm.

NMR spectrum of the trans isomer of the title compound in a solution of deuterium chloroform

1.4 - 3.3 (c) and 2.44 (s) (1H total), 5.1 (c, 1H), 7.32 (d, 2H) and 7.77 (d, 2H) ppm.

Process W. Preparation of 3-Hydroxy-1-oxothiane

To a solution of 2.0 g (0.017 mol) of thiol-3-ol in 60 ml of dichloromethane cooled to 0 ° C under nitrogen was added small amounts of 3.44 g (0.017 mol) of 85% pure m-chloroperbenzoic acid. . The reaction mixture was stirred at 0 ° C for 35 minutes and then at room temperature for 2 hours. The mixture was concentrated in vacuo and the residue was purified by chromatography on 200 g of silica gel. Elution was carried out with a 9: 1 mixture of ethyl acetate and methanol. This gave 2.14 g (94%) of a mixture of cis and trans-3-hydroxy-1-oxothian.

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Process X

Preparation of 4-methylcarbonylthiothiane

Similarly to the procedure used for the preparation of J for the reaction of 3- (p-methylphenylsulfonyloxy) thiolane and potassium thioacetate, 1.5 (equivalents) of 4- (p-methylphenylsulfonyloxy) thi Reaction with thioacetate on dimethylformamide at 80 ° C afforded 4-methylcarbonylthiothiane after 69% purification by silica gel chromatography. Elution was carried out with 10% ethyl acetate in hexane. The NMR spectrum of the solution of 4-methylcarbonylthiothiane in deutochlorochloride was 1.62-2.2 (4H, m), 2.32 (3H, s), 2.5-2.8 (4H, m) and 3.52 (1H, tt, J = 9.3 Hz) ppm.

Y production process

Using process Y, starting from trans-1-oxo-4-p-methylphenylsulfonyloxyethane, cis-1-oxo-4- (methylcarbonylthio) thiane is obtained. Nuclear Magnetic Resonance Spectrum (250 MHz) in deutero chloroform showed 1.97 (2 (, m), 2.33 (3H, s), 2.42 (2H, dddd), 2.66 (3, 02 2H, M) and 3.56 (111 tt, J = 11.1 3.6 lys) ppm.

Likewise, the preparation of Zis-1-oxo-4- (methylcarbonylthio) thiane is also prepared from the cis-1-oxo-4-p-methylphenylsulfonyloxythane starting material by Method X. Nuclear Magnetic Resonance Spectrum (250 MHz) in deuterochloroform: 1.83 (2H, m), 2.33 (3H, s), 2.65 (2H, m), 2.87 (4H, m) and 3.80 (1H, m) ppm.

Process Z

Following the V preparation procedure, using 1.5 equivalents of p-toluenesulfonyl chloride and 3 equivalents of 4-dimethylaminopyridine from trans-1-oxo-4-hydroxytethane (see Klein et al., Tetrahedron, 30, 2541). (1974)), trans -S-1-oxo-4-p-methylphenylsulfonyloxythane was prepared. The title compound was obtained in 83% yield as a white solid, m.p. 99-102 ° C. Nuclear Magnetic Resonance Spectrum (250MIIz) in a solution of the compound in deuterochloroform: 1.94 (2H, ni), 2.51 (311, s), 2.06 (211, m), 2.84 (411, m). , 4.80 (111, nI), 7.41 (2H, d, J = 8Hz) and 7.85 (2H, d, J = 8Hz) ppm.

4-p-Methylphenylsulfonyloxyethane was prepared from 4-hydroxytethane (which was prepared from 4-oxothiane by reduction with diisobutylaluminum chloride) according to Preparation V, 1.2 equivalents of p-. toluene sulfonyl chloride was prepared using 0.1 equivalents of 4-dimethylaminopyridine and 1.2 equivalents of triethylamine. Purification of the termus was carried out by silica gel column chromatography, eluting with ethyl acetate / hexane 1: 1. In this way, the desired compound is obtained in 95% yield. Nuclear Magnetic Resonance Spectrum in a solution of the product in deuterochloroform: 1.8-2.2 (4H, m), 2.47 (3H, s). 2.5-3.1 (4H, m), 4.60 ( 1H, m) ₃ 7.35 (2H, d, J = 7Hz) and 7.80 (2H, d, J = 7 Hz) ppm.

Preparation AA Preparation of cAz-10xo-3-methylcarbonylthiothiolane!

25.5 g (0.093 mol) of trans-1S-1-oxo-3-p-toluenesulfo; Nyloxythiolane and 59 g (0.186 mol) of tetra- (n-butyl) -ammonium thioacetate are dissolved in 180 ml of acetone, brought to reflux under nitrogen and refluxed for 1.5 hours. The reaction mixture was concentrated in vacuo and the residue was chromatographed on silica gel (800 g). Elution was carried out with ethyl acetate. 13.4 g of the title compound are obtained

52.5-54 ° C as a solid. Yield 81%.

The deuterochloroform solution of the title compound had a NMR of 2.06-3.26 (c) and 2.34 (s) (total: 8H) and 3.26-4.21 (c, 2H) ppm.

Similarly, trans-1-oxo-3-methylcarbonylthiothiolane was prepared in a 47% yield from cis-1-oxo-3β-toluenesulfonyloxythiokine. NMR (250 MHz, solution of deuterochlorochloroform) of the prepared trans isomer: 2.1 (c, 1H), 2.36 (s, 3H),

2.9 (c, 3H), 3.17 (m, 1H), 3.36 (m, 1H) and 4.48 (m, 1H) ppm.

ΰΰ production process

Preparation of -Oxo-3-p-methylphenylsulfonyloxythiolane

3-p-Toluenesulfonyloxythiolane (1.29 g, 0.005 mole) was dissolved in dichloromethane (10 mL), cooled to 0 ° C under nitrogen, and 85% of 1.19 g (0.005 mole) over 5 minutes. of pure purity, - chloroperbenzoic acid is added. After standing at 0 ° C for 30 minutes, the reaction mixture was diluted with 125 mL of chloromethane and treated with 20 mL of dilute aqueous sodium bisulfite to decompose excess peracid. The mixture was adjusted to 7.5 with p.l. sodium bicarbonate, and the dichloromethane layer was washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is chromatographed on 200 g of silica gel. Elution using 95: 5 ethyl acetate / methanol. This gives 0.175 g of the polysaccharide cis isomer and 0.92 g of the less polar trans isomer in an 80% yield as an oil that solidifies on standing. The transisome has a melting point of 85-87 ° C and the cis isomer is a low melting point waxy substance.

The trans isomer on the deuterochloroform side gives the following NMR spectra: 2.2 3.63 (c) and 2.5 (s) (9H in total), 5.42 (m, 1H), 7.34 (d). , 2H) and 7.78 (d, 2H) ppm.

NMR of the title isomer of the title compound in deuterochloroform: 1.95-3.23 (c) and 2.46 (s) (9H total), 5.2 (c, 1H), 7.3 ( d, 2H) and 7.76 (d, 2H) ppm.

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CC production process

Preparation of 3-p-Methylphenylsulfonyloxythiolane

0.52 g (0.005 mol) of thiolal-3-ol and 1.22 g (0.01 mol)

4-Dimethylaminopyridine was dissolved in dichloromethane (20 ml), cooled to 0 ° C under nitrogen, and p-toluenesulfonyl chloride (0.95 g, 0.05 mol) was added. After stirring at 0 ° C for 1.5 hours, the mixture was allowed to warm to room temperature. After 4 hours at room temperature, the reaction is complete. The reaction mixture was diluted with dichloromethane (80 mL), washed with dilute aqueous hydrochloric acid (20 mL), water (20 mL), and brine (20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to give an oil which solidified on standing. Yield: 1.3 g, m.p. 56.558 ° C, 100% yield.

The title compound has a NMR spectrum in 1.5d-2.52 (c) and 2.44 (s) (511 in total), 2.56-3.02 (c, 4H), in 5-dereuterodichloromethane. , 13 (m, 111), 7.28 (d, 211) and 7.72 (d, 211) ppm.

Example 12 (5R, 65) -6 - ((R) -1-Hydroxyethyl) -2 - [(cz.rz) -1-oxo-3-thioanyl] thio-3-carboxyl-2- penem production

3.5 g of the sodium salt of (5R, 6S) -6 - [(R) -1-hydroxyethyl] -2 - [(trans) -3-oxothiolanyl] thio-2-penem-3-carboxylic acid are dissolved. In 30 ml of water. Ethyl acetate (20 mL) was added to the solution and the pH of the aqueous phase was adjusted to 3.25 by the addition of 6N hydrochloric acid. The aqueous phase was separated, cooled to 0 ° C, and adjusted to pH 2.6 with 6N aqueous hydrochloric acid. After 30 minutes, the precipitate was filtered off and washed with water (4 ml), diethyl ether (10 ml) and ethyl acetate (10 ml) and dried. This gave 1.77 g of the title compound as a white crystalline solid. Yield: 54%, m.p. 190 ° C (dec.).

Example 13 (5R, 6S) -6 - [(R) -1-Hydroxy-ethyl] -2- (R) -O-oxo-3-thiolanyl] -thio-2-penem-3- Preparation of Carboxylic acid 2-methyl-2-propylcarbonyloxymethyl ester

Prepare a solution of sodium salt of tetrabutylammonium sulphonic acid in the following manner:

To a solution of water (mL) and tetrabutylammonium hydrogen sulfate (0.678 g, 0.002 mol) was added sodium bicarbonate (0.168 g, 0.002 mol). To the solution thus prepared, 0.742 g (0.002 mol) of (5R, 65) -6 - [(R) -1-hydroxyethyl] -2- (cis) -1-oxo-3-thiolanyl [thio] -3-Carboxyl-2-penem was added and the resulting solution was extracted with 50 ml of chloroform. The aqueous phase was saturated with sodium sulfate and then extracted twice with 30 ml of chloroform. The combined chloroform extract was dried over anhydrous sodium sulfate and concentrated in vacuo. The tetrabutylammonium salt of the starting penem derivative is obtained in the form of a foam. The resulting tetrabutylammonium salt was dissolved in acetone (3 ml) and chloromethyl pivalate (0.32 g, 0.0022 mol) was added and the reaction mixture was stirred at 25 ° C overnight.

The mixture was diluted with ethyl acetate (125 mL) and the acetyl acetate solution was washed with water (2 x 30 mL), brine (25 mL), water (30 mL) and brine (30 mL) and dried over anhydrous sodium sulfate. The solution was concentrated in vacuo. The resulting brown solid was purified by chromatography on 300 g of silica gel, eluting with ethyl acetate-methanol (9: 1). 0.62 g of the title compound is obtained as a white solid. Yield: 66.4%. 125135 ° C (dec.).

IR (KBr): 2.96 (b), 5.60, 5.69, 5.91 and 6.75 microns.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 250 MHz): 1.23 (s, 9H), 1.35 (d, 3H), 2.5 (b, 1H), 2.6-2.9 (c, 4H) , 3.16 (m, 1H), 3.62-4.0 (c, 3H), 4.25 (m, 1H), 5.7 and 5.72 (2d, 1H), and 5.88 ( q, 211) ppm.

Example 14

Following the procedure of Example 13, but using alkylating agents other than chloromethyl pivalate, the corresponding ester derivatives of the title compound of Example 12 are prepared. Table 1A gives the physical characteristics and yields of the compounds of formula I prepared.

In all cases, the IR spectra were recorded in KBr pellets, the NMR spectra in il-chloroform solution at 250 MHz.

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Table 1Α *

Ri R _{t is a} derivative IR (micron) NMR (ppm) Ilozam (%) 3-phthalidyl bromide 2.93 (b), 5.59, 5.85, 5.90 and 6.72 1.26 and 1.28 (2d, 311), 1.88 (b, III), 2.56-2.94 (c, 4H), 3.14 (m, 1H), 3.62-3. 95 (c, 3H), 4.13 (c, 1H), 5.7 (c, 1H), 7.42 and 7.46 (2S, 1H), 7,587.95 (c, 4). 58 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl- bromide 2.9 (b), 5.48, 5.6, 5.91 and 6.67 1.5 (d, 3H), 2.2 (S, 3H), 2.6-2.95 (C 511), 3.16 (ni, 111), 3.64-3.96 (c, 3H), 4.22 (m, 1H), 4.98 (m, 211), 5.69 and 5.72 (2d, 1H). 41.3 1- (methylcarbonyloxy) -1-ethyl- chloride 2.92 (b), 5.57, 5.68, 5.90, and 6.67 1.35 and 1.36 (2d, 3H), 1.54 and 1.55 (2d, 311), 2.07 and 2.1 (2s, 311), 2.6 2.9 (c, 511), 3.14 (in, 111), 3.62-3.98 (c, 1H), 4.23 (m, 1H), 5.68 (c, 1H), 6.94 (c, 1H). 44.8 1- (ethoxycarbonyloxy) -1-ethyl- chloride 2.94 (b), 5.57 5.68, 5.91 and 6.68 1.32 (c, 611), 1.57 and 1.58 (2d, 311), 2.58-2.94 (c, 5H), 3.14 (ni, 1H), 3.6-4, 0 (c, 3H), 4.23 (c, 3H), 5.67 and 5.70 (2d, 1H), 6.85 (tn, 1H). 67 esterification is complete 96 hours

Claims

Claims (1)

A process for the preparation of compounds of formula I and pharmaceutically acceptable salts thereof, wherein: R is 2- (methylsulfinyl) ethyl, 2- (methylsulfonyl) ethyl, (methylsulfinyl) -ethyl, (ethylsulfonyl) -methyl, 3-thietanyl, Ι- οχο-3-thietanyl, 1,1-diοχο-3-thietanyl, 2-thiolanyl, 1-oxo-2-thiolanyl, 3-thiolanyl, 1-oxo-3-thiolanyl, 1,1- dioxo-3-thiolanyl, 3-hydroxy-4-thiolanyl, 2-oxo-1,3-dithiolan-4-ylmethyl, 3-thianyl, Ι-οχο-3-thianyl, 1,1-dioxo-3 -thianyl, 4-thianyl, Ι-οχο-4-thianyl, 1,1-dioxo4-thianyl, 1,3-dithiolan-2-yl, or 1,2-dithiolan4-yl, and R 1 is hydrogen, (C 1 -C 6) alkylcarbonyloxy (C 1 -C 4) alkyl, (C 14) alkoxycarbonyloxy (C 14) alkyl, or containing one or two oxygen atoms and one carbonyl group, five-membered, optionally benzo-substituted fused or C1-4 alkyl, heterocyclic group or through a carbon atom or a methylene hetero ring is attached, characterized in that one (I) compound wherein R _(jclcnlésc carboxyl-protecting group, preferably nitrobenzyl is hydrogenated and the resulting compound is converted with a base to a pharmaceutically acceptable salt or, if desired, an anion of a compound of formula (I) wherein R 1 is hydrogen A compound of formula R 1 Cl or R 1 Br containing a group R 1 is reacted with R 1 other than hydrogen as defined herein. 2. A process according to claim 1 for the preparation of a compound of formula (I) which is a narrower group of compounds of formula (I) and their cis, trans isomers and pharmaceutically acceptable salts thereof, wherein: R is 2- (methylsulfinyl) ethyl, 2- (methylsulfonyl) ethyl (methylsulfonyl) methyl, (methylsulfonyl) methyl, 3-thietanyl, Ι-οχο -3-thietanyl, 1,1-diol-3-thietanyl, 2-thiolanyl, 1-oxo-2-thiolanyl, 3-thiolanyl, 1-oxo-3-thiolanyl, 1,1-dioxo -3-thiol ⁴⁵ nyl, 3-hydroxy-4-thiolanyl, 2-oxo-1,3-dithiolan-4-ylmethyl, 3-thianyl, Ι-χο-3-thianyl, 1,1-dioxo- 3-thianyl, 4-thianyl, 1-oxo4-thianyl, 1,1-dioxo4-thianyl, 1,3-dithiolan-2-yl, or 1,2-dithiolan4-yl R 1 is hydrogen, (C 1 -C 6) alkylcarbonyloxy (C 14) alkyl, (C 14) alkoxycarbonyloxy (C 14) alkyl, or containing one or two oxygen atoms and one carbonyl group, a five membered heterocyclic group optionally fused to a benzene ring or substituted with a C 14 alkyl group which is either on one of the carbon atoms of the heterocycle or a They are bonded via 60 methylene groups, characterized in that they use appropriately substituted starting compounds of formula II.