FI81584C - FOERFARANDE FOER FRAMSTAELLNING AV ANTIBAKTERIELLA 6-ALFA-HYDROXIETYL-2-SUBSTITUERAD-2-PENEM-3-CARBOXYLSYROR. - Google Patents

Description

1 81584

Process for the preparation of antibacterial 6-alpha-hydroxyethyl-2-substituted-2-penem-3-carboxylic acids 5

The invention relates to bacterial anti-penins substituted at the C-2 position by saturated sulfur-containing heterocycles of varying degrees of oxidation. JP-Kokai 58-43978 and application-EP-A-2210 and EP-A-70204 disclose 2-S-heterocyclic penems in which the heterocyclic group is a nitrogen-containing or aromatic heterocyclic group. These publications do not disclose or suggest a saturated sulfur-containing ring that is a C-2 gun-15 mass.

Thus, although certain 2-substituted-2-penem-3-carboxylic acid compounds have been disclosed in the past, there is a continuing need to find new compounds with the desired antibacterial therapeutic properties.

The invention relates to a process for the preparation of antibacterial 6-alpha-hydroxyethyl-2-substituted-2-penem-3-carboxylic acids of the formula wherein R is 3-tetanyl, 1-oxo-3-datanyl, 1,1- dioxo-3-thietanyl, 2-thiolanyl, 1-oxo-2-thiolanyl, 3-thiolanyl, 1-oxo-3-thiolanyl, 1,1-dioxo-3-thiolanyl, 3-hydroxy-4-thiolanyl, 1-oxo-3-hydroxy-4-thiolanyl, 1,1-dioxo-3-hydroxy-4-thiolanyl, 2-oxo-1,3-dithiolan-35-4-ylmethyl, 3-thianyl, 1-oxo-3 thianyl, 1,1-dioxo-3-thianyl, 4-thianyl, 1-oxo-4-thianyl, 1,1-dioxo-4-8158484 thianyl, 1,3-dithiolan-2-yl or 1,2 -ditiolan-4-yl; and Rx is hydrogen, and pharmaceutically acceptable salts thereof.

The invention also relates to the preparation of compounds of formula II in which R1 forms an in vivo hydrolysable ester.

Preferred are compounds wherein R is 1-oxo-3-thiolanyl, 1,1-dioxo-3-thiolanyl, 1-oxo-3-thietanyl, 1-oxo-3-thianyl, 1,1-dioxo-4 -thanyl or 4-thia-10-yl.

The present invention also provides a pharmaceutical composition comprising a compound of formula II and an acceptable diluent or carrier for treating a bacterial in-15 infection in a mammal.

The compounds of formula II are useful antibacterial agents. They are derivatives of a double-ring core with a core formula of 20 j 6_

---- III

• J M ^ 0 ^ 4 25

The nucleus of formula III is referred to throughout this patent application as "2-penem" and the ring yields are numbered as indicated. The number of the carbon atom associated with the ring carbon 6 is 8. Likewise, the abbreviation "PNB" is used throughout this application to denote a p-nitrobenzyl group.

In the compounds of formula II, the hydrogen of the crosslinking carbon 5 and the hydrogen remaining in the carbon 6 may be in either the cis or trans position relative to each other. treated

II

3,81584 The present invention encompasses both Isomers and mixtures thereof. In pharmaceutical applications, the trans isomer is generally preferred and the cis isomer can be readily converted to the trans isomer.

5 According to the stereochemical characterization of Prelog and Ingold R, S used in this patent application, carbon 5 generally has absolute stereochemistry. Thus, for example, a compound of formula II in which Rx is hydrogen and R is 4-thianyl is called (5R, 6S) -6- [(R) -1-hydroxyethyl] -2- (4-thianyl) thio-3 -carboxylic-2-penems.

As can be seen from the above, the new compounds can form various optically active isomers. The present invention encompasses such optically active Isomers as well as mixtures thereof. The present invention relates to penems having a moiety in the 2-position of the general formula R-S-.

compounds include those wherein R is 3-thietanyl, 1-oxo-3-thietanyl, 1,1-dioxo-3-thietanyl, 3-thiolanyl, 1-oxo-3-thiolanyl, 1,1-dioxo-3-thiolanyl -20β, 3-hydroxy-4-thiolanyl, 1-oxo-3-hydroxy-4-thiolanyl, 1,1-dioxo-3-hydroxy-4-thiolanyl, 3-thianyl, 1-oxo-3- thianyl, 1,1-dioxo-3-thianyl, 4-thianyl, 1-oxo-4-thianyl, 1,1-dioxo-4-thianyl or 2-oxo-1,3-dithiol-4- ylmethyl.

The present invention includes penems in which the 3-carboxyl group forms an ester with a non-toxic in vivo hydrolysable group (Rx). These esters are rapidly cleaved in mammalian blood or tissue, releasing the corresponding penem-3-carboxylic acid. Typical examples of such readily hydrolysable ester-forming residues are alkanoyloxymethyl having 3 to 8 carbon atoms, 1- (alkanoyloxy) ethyl having 4 to 9 carbon atoms, 1-methyl-1- (alkanoyloxy) ethyl having 5 to 10 carbon atoms , 3-6 to 35 carbon atoms, alkoxycarbonyloxymethyl, 4-7 4 81 584 carbon atoms, 1- (alkoxycarbonyloxy) ethyl, 5-8 carbon atoms, 1-methyl-1- (alkoxycarbonyloxy) ethyl, 3-9 carbon atoms, N- ( alkoxycarbonyl) aminomethyl, 1- (N-5-alkoxycarbonylamino) containing 4-10 carbon atoms, ethyl, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, carboxyalkylcarbonyloxymethyl containing 4-12 carbon atoms or -methyl-2-oxo-l, 3-dioxolen-4-yl) methyl. To prepare compounds of formula II wherein Rx is a group forming an in vivo hydrolysable ester, an acid of formula II (Rx is hydrogen) is reacted with a base to give the corresponding anion. Suitable cations include sodium, potassium, calcium, tetraalkylammonium and the like. The anion can be prepared by lyophilizing an aqueous solution of compound II, e.g., an aqueous solution containing tetrahydrofuran and sodium carbonate or tetrabutylammonium hydroxide.

The anion II formed is reacted with the corresponding chloride or bromide of Rx in an inert solvent such as acetone or dimethylformamide at a temperature of about 20 to 50 ° C, preferably 25 ° C.

Compounds of formula II wherein Rx is hydrogen or a salt formed by the compounds can be synthesized according to Schemes A-C.

As shown in Scheme A, a compound of formula II can be prepared according to the method of Yoshida et al., Chem. Pharm. Bull., 29, 2899-2909 (1981) for a known dibromopenam of formula IV. Dibromopenam (V) is reacted with tert-butylmagnesium chloride at a temperature between about -90 and -40 ° C, preferably about -76 ° C in an inert solvent such as tetrahydrofuran, diethyl ether or toluene, preferably tetrahydrofuran. Other organometallic reagents may be used. The resulting reaction mixture is treated in situ with the appropriate aldehyde, e.g. acetaldehyde

II

s 81584 when using a roxyethyl derivative. The aldehyde is added at a temperature between about -80 and -60 ° C, preferably at about -76 ° C / if acetaldehyde is used.

The resulting bromohydroxypenam V is hydrogenated to remove 6-5 bromo substituents. A suitable hydrogenation catalyst is a noble metal catalyst such as palladium. The reaction is carried out in a protic solvent such as 1: 1 methanol-water or 1: 1 tetrahydrofuran-water, preferably 1: 1 methanol-water at a pressure of about 1-4 atm, preferably 10-4 atm, and at a temperature of about 0-30 ° C, preferably about At 25 ° C.

6 81584

Scheme A

Br o H0 Br C ° 2CH3 0 'COjCHj

W V

0 \ C00CH3

VI

Rq 1 \ 9

Rg-Sio 7 CO-CH, VII 2 3 f \ s HQ “SiO p c,«

9 / Π RQ-S10

^ ^ CO-CH., «

II

7 81504

Scheme B

f IX—> * r ^ s-l-SR10 0J — m x Ϊ ’1

Ra-Sio · 91 V | 1 s "

HsJX_l k "γτΤ" * 10 ti? ^ co2pnb

0 cco-PNB

xii

, J

f »f *

* 11 H ^ s? Vf1 »M

i / jzty ·· —ijTztv '0 \ o2phb \

2 U C02PNB

xiii

XIV

HO T

0 co2pnb

XV

8 81 584

Scheme c IX VÖ i

Jutn imtr - S- C— SR

o ?? - "H

xva ^ f9 fa! / [h. », H-T"

cr f ti? > -0H

CO-PNB | co2pnb

^ 11 XVI

h *

S

.S-C-SR

i / 'Ti β W ^ (C6H5) 3 - »χΐν

0 C02PNB

xviii

II

9 81 i C 4

The alcohol of formula VI formed can be protected with a trialkyl halosilane of the formula *

5 R, -Si-Q

R * wherein R 1 is in each case alkyl having 1 to 6 carbon atoms and Q is chlorine, bromine or iodine. Thus, dime-10-style tert-butylchlorosilane is formed in the presence of an amine proton acceptor such as imidazole in a polar, aprotic solvent such as N, N-dimethylformamide at a temperature of about 5 to 40 ° C, preferably about 25 ° C, a trialkylsilyl hydroxyl of formula VII.

Treatment of VII with mercuric acetate in acetic acid at about 90 ° C gives olefin VIII.

To obtain the desired azetidinone IX, the olefin VIII is ozonated in a reaction in an inert solvent such as dichloromethane at a temperature of about -80 to -40 ° C, preferably about -76 ° C. The reaction product is treated with an alkanol such as methanol to give azetidine IX.

As shown in Scheme B, a compound of formula IX is treated with a trithiocarbonate salt of formula M * R 10 -SC (S) -S-, wherein R 10 is alkyl of 1 to 4 carbon atoms, preferably ethyl, and M is a metal such as sodium or potassium, to give a compound of formula X.

This conversion of compound IX to compound X is carried out in an organic solvent or water, preferably in a mixture of water and dichloromethane at a temperature in the range of about 0 to 35 ° C, preferably at about 25 ° C.

The compound of formula X is condensed with p-nitrobenzyl chlorooxalate in the presence of e.g. 1-4 carbon atoms in each tertiary alkylamine, e.g., alkyl, e.g. 35 ethyldiisopropylamine to give the compound of formula XI. This condensation reaction is carried out in a reaction in an inert solvent, preferably dichloromethane, at a temperature in the range of about 5-25 ° C, preferably about 10 ° C.

The resulting compound of formula XI is cyclized

a trialkyl phosphite in which the alkyl contains 1 to 4 carbon atoms, e.g. by means of triethyl phosphite in a reaction in an inert solvent such as trichloromethane at a temperature in the range from about 40 to 80 ° C, preferably at about 60 ° C

10 to obtain a penem.

The thiol group of XII is oxidized to the corresponding sulfoxide XII with an oxidant such as m-chloroperbenzoic acid in a reaction in an inert solvent such as dichloromethane at a temperature in the range of about -10 to -30 ° C, preferably -15 to -20 ° C.

The sulfoxide XIII is substituted with a mercaptide of formula RS, e.g. its sodium or potassium salt, which is reacted with the sulfoxide XIII in a polar organic solvent such as ethanol or aceto-nitrile at a temperature in the range of 35 to 50 ° C, preferably about. At 35 ° C.

The mercaptans of formula R-SH used as starting material and the thioacetates of formula R-S-C (O) CH3 used as starting material are known for many meanings of R, and hitherto unknowns can be prepared by analogous methods in the prior art. An overview is provided by J.L. Wardell, "Preparation of Thiols," in The Chemistry of the Thiol Group, edited by S. Patai, John Wiley & Sons, London, 1974, Chapter 4. See. see also Volante, 30 Tetrahedron Letters, 22, 3119-3122 (1981), which describes the conversion of alcohols to thiols and thiol esters by triphenylphosphine and dialkyl azodicarboxylate in the presence of alcohol and the appropriate thiolic acid.

When the groups R contain the group S (O) n and n is 1 or 35 2, the corresponding sulfide (n is zero), i.e. thioacetate o 11 81584 RSC (0) CH3 can be oxidized with about an equimolar amount of m-chloroperbenzoic acid to the sulfoxide (n is one) or with an additional amount of m-chloroperbenzoic acid to the sulfone (n is two) the mucus that tloacetate sulfur is oxidized.

The sulfoxide can also be oxidized to the sulfone with potassium permanganate in an aqueous solvent such as aqueous acetone at a buffered pH of about 7 at about 20-50 ° C, preferably at about 25 ° C. This method is particularly preferred when the group R contains a hydroxyl group. In addition, a cyclic sulfone containing double bonds can be easily isomerolda by the methods described by Prochazka et al., Collection Czech. Chem. Comm., 31, 3744 (1966).

Prior to the hydrogenolysis in which the acid protecting group (PNB) is removed, the compounds of formula XIV are preferably deprotected with a trialkylsilyl group to give a compound of formula XV. The trialkylsilyl group is removed with tetralkylammonium fluoride in an ether solvent such as tetrahydrofuran at a temperature in the range of about 15 to 40 ° C, preferably about 20 ° C.

The conversion of a compound of formula XV to a compound of formula II is carried out by a conventional hydrogenolysis reaction and in a manner conventional in this type of transformation. Thus, a solution of a compound of formula XV is stirred or shaken in a hydrogen atmosphere or in a atmosphere of hydrogen and an inert diluent such as nitrogen or argon with a catalytic amount of a hydrogenolysis catalyst, e.g. palladium-calcium carbonate catalyst or palladium-Celite catalyst. Common solvents for this hydrogenolysis include lower alkanols such as methanol, ethers such as tetrahydrofuran and dioxane, low molecular weight esters such as ethyl acetate and butyl acetate, water, and mixtures of these solvents. Usually, however, the conditions 35 are chosen so that the starting material is soluble. Hydro- 12 81 584 genolysis is usually performed at room temperature and a pressure of about 0.5 to about 5 kg / cm 2. The catalyst is usually present in an amount of about 10% by weight of the starting material, up to an amount corresponding to the starting material, if even larger amounts can be used. The reaction time is usually about one hour, and at the end of the reaction, the compound of formula II is isolated simply by filtration and removal of the solvent in vacuo. If palladium-calcium carbonate is used as the catalyst, the product 10 is often isolated as the calcium salt and when palladium-Celite is used the product is often isolated as the sodium salt.

The compound of formula II can be purified by methods conventional for beta-lactam compounds. The compound of formula II can be purified, for example, by column chromatography, gel filtration on Sephax or recrystallization.

Scheme C shows an alternative synthetic method. The azetidine of formula IX is reacted with a trithiocarbonate of formula M * R-S-C (S) -S-, wherein M is a metal such as sodium or potassium, by the method used above to prepare compound X.

The resulting trithiocarbonate XVa is treated with (p-nitrobenzyloxycarbonyl) (dihydroxy) methane in an aprotic solvent such as benzene, toluene or dimethylformamide, preferably benzene, at a temperature in the range of about 25 to 110 ° C, preferably about 80 ° C in formula XVI. to obtain alcohol.

The corresponding chloride XVII is prepared from alcohol XVI by treatment with thionyl chloride in a reaction in an inert organic solvent such as dichloromethane in the presence of a hindered amine acting as an acid acceptor such as 2,6-lutidine at a temperature in the range of about -10 to 75 ° C, preferably 0 ° C. .

Chloride XVII is reacted with a triarylphosphine-35 such as triphenylphosphine in an inert reaction

II

13 81 5 84 in a solvent such as tetrahydrofuran in the presence of a tertiary amine such as 2,6-lutidine at a temperature of about 25 ° C to give a compound of formula XVIII which is cyclized by refluxing in an aromatic solvent such as toluene to a penene of formula XIV.

Trithiocarbonate salts of formula M * R-S- (C-S) -S "are prepared from the appropriate mercaptan of formula R-SH or by treating thioacetate of formula RSC (O) CH3 with an alkali metal alkoxide and then carbon sulfide.

Using the above-mentioned method of Yoshida et al., The stereochemistry of penem carbon 6 and the associated hydroxyethyl group is of formula II. The most important stereochemical feature of the product obtained in the ring closure of Scheme B 15 or C is that the hydrogen in the 5-position of the penem ring is in the trans position with respect to the hydrogen of carbon 6 and has the alpha configuration. Stereochemistry can alternatively be described as 5R, 6S; 6- (R) -l-hydroxyethyl.

The compounds of formula II are acidic and form salts with basic substances. Such salts are considered to be within the scope of this invention. These salts can be prepared by standard methods, e.g. by combining the acidic and basic components, usually in a stoichiometric ratio, in an aqueous, non-aqueous or partially aqueous medium, depending on the circumstances. They are then isolated (depending on the conditions) by filtration, mixing with a non-solvent and filtration, evaporation of the solvent or, in the case of aqueous solutions, freeze-drying. Suitable basic substances for salt formation are of both the organic and inorganic type and include ammonia, organic amines, alkali metal hydroxides, carbonates, bicarbonates, hydrides and alkoxides, as well as alkaline earth metal hydroxides, carbonates, and 14-hydrides. dialkoxides. Representative examples of such bases include primary amines such as n-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine and octylamine, secondary amines such as diethylamine-5-one, morpholine, pyrrolidine and piperidine, tertiary amines such as tertiary amines such as methylmorpholine and 1,5-diazabicyclo [4.3.0] non-5-ene, hydroxides such as sodium hydroxide, potassium hydroxide, ammonium hydroxide and barium hydroxide, alkoxides such as sodium ethoxide and potassium ethoxide, hydrides such as calcium hydride and sodium hydride, potassium carbonate and sodium carbonate, bicarbonates such as sodium carbonate and potassium carbonate, and alkali metal salts of long chain fatty acids such as sodium 2-ethylhexanoate.

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

A pharmaceutically acceptable salt is one which, when formed with a compound of formula II, is a non-toxic, therapeutically useful drug and which, when metabolized, forms non-toxic degradation products.

As mentioned above, the compounds and salts of formula II are antibacterial agents. The in vitro activity of the compounds of formula II and their salts can be demonstrated by determining their minimum inhibitory concentrations (MICs) in pg / ml for various microorganisms. The method recommended by the International Collaborative Study on Antibiotic Sensitivity 30 Testing (Ericcson and Sherris, Acta Pathologica et Microbiology Scandinav., Supp. 217, Section B: 64-68 [1971]) and using brain-heart infusion agar has been used. (BHI) and an inoculum amplifier. Overnight cultured tubes were diluted 100-fold for use as a standard 35 inoculum (20,000-10,000 cells in approximately 0.002 ml of

II

is 815 34 was applied to the surface of the agar; 20 ml BHI agar / plate). Twelve double dilutions of test compound were used; the initial concentration of the test drug pool was 200 pg / ml. When the plates were read 18 hours at 37 ° C after incubation, single colonies were discarded. The sensitivity (MIC) of the testlor organism was considered to be the lowest concentration of compound at which growth could be completely inhibited when judged with the naked eye.

The compounds of formula II and their pharmaceutically acceptable salts are suitable for the treatment of bacterial infections in mammals, including humans. They can be used to treat infections caused by susceptible bacteria in a human subject, e.g., infections caused by susceptible strains of Staphylococcus aureuk-15.

When using a compound of formula II or a pharmaceutically acceptable salt thereof for the treatment of a bacterial infection in a mammalian subject, the compound may be administered orally or parenterally, i.e. intramuscularly, subcutaneously, intraperitoneally or intravenously. The compound may be administered alone or may be combined with a pharmaceutically acceptable carrier in accordance with standard pharmaceutical practice. The ratio of the proportions of active ingredient to carrier will, of course, depend on the chemical nature of the active ingredient, the porosity and stability, and also the intended dosage. However, in the antibacterial pharmaceutical composition of the invention, the ratio of pharmaceutically acceptable carrier to penem compound is generally in the range of 1:10 to 4: 1. For oral administration, the antibacterial penemic compound of this invention can be used in the form of tablets, capsules, lozenges, drills, powders, syrups, elixirs, aqueous solutions and suspensions, and the like. Lactose, sodium citrate and phosphoric acid salts can be used as carriers for tablets. In tablets ie 81584, various disintegrants such as starch and lubricants such as magnesium stearate, sodium lauryl sulfate and talc are commonly used. For oral administration in capsule form, useful diluents include lactose and high molecular weight polyethylene glycols. If aqueous suspensions are administered orally, emulsifying and suspending agents are added to the active ingredient. If desired, certain sweetening and / or flavoring agents may be added. For parenteral administration, sterile solutions are usually prepared, the pH of which is adjusted and buffered. For intravenous administration, the total concentration of solutes should be controlled to ensure the isotonicity of the product.

As mentioned above, the compounds of formula II can be used as antibacterial agents which act on susceptible organisms in a human subject. Ultimately, the prescribing physician will be able to evaluate the appropriate dose for a human subject, which can be expected to vary with the age, weight, and response of the patient, as well as the severity of the patient's symptoms. Generally, the compounds of formula II are administered orally at a dose of about 10 to about 200 mg / kg of body weight per day and parenterally at a dose of about 10 to about 400 mg / kg of body weight per day. But these values are illustrative only and in some cases it may be necessary to use doses outside these limits.

Antibacterial properties

The following table shows the minimum inhibitory concentration (MIC) pg / ml required to resist different types of microorganisms.

The first compound is the known penem compound Sch 29482 [Journal of Antimicrobial Chemotherapy, Vol. 9, Supplement C (1982)]. Other compounds are prepared according to the invention.

Il 17 81 554

H PH

^ 3 K_X

q ^ 7 ^ COOH

__MIC (μg / ml) 1_ • _Microorganism2_ _R_ 005 087 006 125 009 001 040 036 cis-1-oxo-3 - 44 0,1 1,56 44 0,1 44 '0,05 1,56 thianolyl trans- 1-ox-0.5 0.2 12.5 0.78 1.56 0.05 0.78 0.39 so-3-thianolyl 1,1-dioxo-44 0.05 3.12 0.1 0 .2 ΦΦ 0.1 0.1 3-thiolanyl 1,1-dioxo-0.2 0.39 12.5 3.12 3.12 0.2. 3.12 0.39 3-thianyl 3-thiol-44 0.1 1.56 1.56 1.56 44 0.78 0.2 nyl 3-thiol-0.05 0.2 3.12 1.56 1.56 0.05 0.78 0.39 nyl cis-1-oxo 0.2 0.78 25 0.39 0.78 0.2 0.39 1.56 so-3-diethanyl trans- 1- 0.05 0.2 12.5 0.2 0.39 0.1 0.2 0.39 oxo-3-tetanyl 1,1-dioxo-0.05 0.2 6.25 0.1 0.2 0.05 0.05 0.2 3-thanyl-4-thianyl ** ° '° 5 3.12 25 12'5 »12'5 °' 1 1.1-dioxo- * 0'2 6'25 3 ' 12 3.12 0.05 3.12 0.2 4-thianyl cis-1-oxo-4- '5 0.2 3.12 0.2 ° '35 * °' 2 O'1 thianyl trans-1- ok- ° '05 0-2 6 · 25 3,12 3 (12 05 3,12 0,1 so-4-thianyl-li Λ •, ° '1 ° '39 6'25 ° '78 0,78 0 .00.78 0.2 cis-1-oxo-3-thianyl, .0'10-39 12.5 3.12 3> 12 0; 1 3> 12 0.39 trans-1-ox- 'so-3-thianyl is 81584 MIC (pg / ml) 1 (cont'd) _Microorganism ^ _._ R_005 087 006 125 009 001 040 036 1.1-dioxo- M 0.05 3.12 0.1 .2 H 0.1 0.2 3-thiolanyl (less polar silyl ether) 1,1-dioxo-M 0.05 3.12 0.2 0.2 ph 0.1 0.1 3-thiolanyl -li (from more polar silyl ethers) 4-hydroxy-0.05 0.2 1.56 1.56 0.78 0.05 0.78 0.39 3-thiolanyl (less from the polar diastereomer A) 4-hydroxy- ΦΦ 0.05 3.12 3.12 3.12 0.01 3.12 0.78 3-thiolanyl (from the more polar diastereomer B) 1-oxo-0.1 0.2 12.5 1.56 3.12 0.2 l, 56 1.56 4-Hydroxy-3-thiolanyl (less from the polar diastereoisomer C) 1-oxo-0.05 0.2 3.12 0.2 0.39 0.1 0 .2 0.78 4-hydroxy-3-thiolanyl (from the more polar diastereomer D)

II

in O Ί r- ·

O I J o H

MIC (pg / ml) ^ (cont'd) - - - _ _Microorganism_ _R_005 087 006 125 009 001 040 036 1-oxo-0.1 0.2 25 0.78 1.56 0.2 0.78 1, 56 4-Hydroxy-3-thio-lanyl (less from the polar diastereomer E) 1-oxo-0.05 0.1 3.12 0.05 0.2 0.1 0.1 0.78 4-Hydroxy-3-thio-lanyl (from the more polar diastereomer F) 1,1-dioxo-0.1 0.39 6.25 1.56 1.56 0.39 1.56 0 .78 4-Hydroxy-3-thiolanyl (diastereomeric G) 1,1-dioxo-0.050.2 6.25 0.39 0.39 0.2 0.39 0.39 so-4-hydroxy roxy-3-thiolanyl (from diastereomeric H) 20 81 5 S 4 1 H 'indicates that the MIC was <0.025 2 the microorganism code is: 005 = Staphylococcus aureus 087 = Staphyloccous epidermidis 5 006 = Streptoccus faecalis 125 = Escherichia coli 009 = Klebsiella pneumoniae 001 = Pasteurella multocida 040 = Enterobacter aerogenes 10 036 = Haemophilus influenzae

The following examples and preparations are illustrative only.

Infrared (IR) spectra were run as potassium bromide tabs (KBr tablet), nujol mixture (nujol) or solutions in chloroform (CHCl 3), methylene chloride (CH 2 Cl 2) or dimethyl sulfoxide (DMSO) and the detection absorption bands are reported as either wavelengths; Nuclear magnetic resonance spectra (NMR) were measured at 60 MHz, unless otherwise indicated, from solutions of deuterium chloroform (CDCl 3), heavy water (D 2 O) or perdeuterium dimethyl sulfoxide (DMSO-d 6) or mixtures thereof. The positions of the peaks are reported in parts per million (ppm) in the field downstream of the tetramethylsilane. The abbreviations for the peak shapes are s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, b = broad and c = complex. The abbreviations "ss" and "sss" indicate that due to the diastereomers, the the proton appeared as 30 singlets and three singlets, respectively. In all examples and preparations, the abbreviation "PNB" means a p-nitrobenzyl group.

Il 21 81584

Example 1

Sodium (5R, 6S) -6-J (R) -l-hydroxyethyl-2- (l, l-dioxo-3-thiolanyl) thio-2-penem-3-carboxylate

The pH of a suspension of 350 mg of 10% palladium-5 diatomaceous earth in 75 ml of tetrahydrofuran and 75 ml of distilled water was adjusted to 8.3 with 0.02 M aqueous sodium bicarbonate solution. A solution of 350 mg of p-nitrobenzyl- (5R, 6S) -6-C (R) -1-hydroxyethyl: Q-2- (1,1-dioxo-3-thiolanyl) thio-2-penem-3) was added. carboxylate in 50 ml of tetrahydrofuran and 50 ml of water, and the resulting mixture was hydrogenated under a hydrogen pressure of 3.9 kg / cm for 75 minutes. An additional 350 mg of 10% palladium diatomaceous earth was then added to the reaction mixture and the pH of the suspension was adjusted to 7.0 with 0.02 M aqueous sodium bicarbonate solution. Mixture 2 was hydrogenated at 3.9 kg / cm 75 for 75 minutes, the catalyst was removed by filtration and the filtrate was evaporated in vacuo to remove tetrahydrofuran. The pH of the resulting aqueous solution was adjusted to 7, and the solution was extracted twice with 100 ml portions of ethyl acetate. The aqueous solution was then lyophilized to give 224 mg of the title compound as an amorphous solid (yield 82.5%).

The potassium chloride tablet run in the infrared spectrum of the title compound had absorbances at 2.92, 5.65 and 6.3 microns.

Example 2 The procedures of Example 1 and the corresponding compound of formula XV were used to give the corresponding sodium salts of formula II, wherein R is as in Table 1. The table also shows the infrared spectra of the products as a run potassium bromide tablet, unless otherwise indicated.

22 81 584

Table 1 _R__IR (microns) _ Yield 3-thiolanyl 2.94, 5.66 and 6.3 82 5 cis-1-oxo-3-thiolanyl 2.92, 5.65 and 6.27 78 (from the more polar isomer) trans -1-oxo-3-thiolanyl 2.92, 5.65 and 6.26 51 (of the more non-polar isomer) 2- (methylsulfinyl) 2.94, 5.65 and 6.3 67 ethyl 2- (methylsulfonyl) 2.94, 5.65 and 6.25 59 ethylmethylsulfinylmethyl 2.94, 5.66 and 6.26 78 methylsulfonylmethyl 2.94, 5.62 and 6.28 68 1-oxo-3-thianyl 2.93 , 5.65 and 6.26 74 1,1-dioxo-3-thianyl 2.94, 5.66 and 6.4 67 3-thietanyl 2.92, 5.65 and 6.26 87 20 cis-1- oxo-3-thianyl 5.66 (nujol) 98 trans-1-oxo-3-thianyl 5.66 (nujol) 92.8

Example 3 (5R, 6S) -6 - [(R) -1-hydroxyethyl] -2- (cis-1-oxo-4-25 thianyl) thio-3-carboxyl-2-penem

3.00 g (10% palladium-Celite 2 at 4.2 kg / cm 2 in prehydrate for 10 minutes in 130 ml of tetrahydrofuran and 120 ml of water were prehydrated. The pH was adjusted to 7.5 with 1N hydrochloric acid, then 6 , 20 g of 12 (12.4 mmol) of p-nitrobenzyl- (5R, 6S) -6- [(R) -1-hydroxyethyl] -2- (cis-1-oxo-4-thianyl) thio-2 penem-3-carboxylate and the suspension was hydrogenated for 0.5 h, 3.00 g of catalyst was added twice, the pH was adjusted to 7.0 and the reaction mixture was hydrogenated for 0.75 h, a final charge of 35 catalyst was added, the pH was adjusted to 7.3 and reaction mixture

II

23 81 5 84 at the wheel for 1/5 hour. The reaction mixture was filtered through a pad of Celite and washed with additional tetrahydrofuran-water (1: 1). Tetrahydrofuran was removed in vacuo. Insoluble matter was removed by filtration through Celite 5, and the pH of the filtrate was adjusted to 7.0. The aqueous portion of the filtrate was washed twice with ethyl acetate, concentrated to remove ethyl acetate residues, cooled in an ice bath, and the pH was adjusted to 2.3 with 6N hydrochloric acid. After thirty minutes, the precipitated solid was isolated by filtration. After drying the precipitate in vacuo to constant weight, 3.64 g (81% yield) of the title compound were obtained as a pepper-yellow solid, m.p. 149-151 ° C, (DMSO): + 153 ° C.

The NMR spectrum (250 MHz) of the title compound showed peaks at 1.16 (d, J = 6.2 Hz, 3H), 1.95-2.3 (m, 4H), 2.7- 3.0 (m, 4H), 3.3-3.4 (m, 1H), 3.79 (dd, J = 6.1, 1.4 Hz, 1H), 3.98 (m, 1H) , 5.20 (bs, 1H) and 5.71 (d, J = 1.4 Hz, 1H) ppm. The potassium-20 bromide tablet run on the infrared spectrum of the title compound had absorptions at 2950 (b), 2923, 1782, 1678, 1508, 1400, 1294, 1216, 1197, 1131, 949 and 935 cm-1. The ultraviolet spectrum of the dimethyl sulfoxide solution of the title compound had the following absorption maxima (extinction coefficient in parentheses): 267 (4840) and 337 (6720) nano-25 meters.

Example 4

Sodium (5R, 6S) -6-J (R) -1-hydroxyethyl] -2- (cis-1-oxo-4-thianyl) thio-2-penem-3-carboxylate

5.09 g (14.0 mmol) of the title compound obtained in Example 3 were suspended in 75 ml of water and cooled in an ice bath. The pH of the reaction mixture was adjusted to 7.00 by adding 13.0 ml (93% of theory) of 1.00 N aqueous sodium hydroxide solution. The homogeneous solution was lyophilized overnight to give 5.00 g (93% yield) of the title compound as a sandy solid (35%): + H1.4 °.

24 81 584

The NMR spectrum (250 MHz) of the DjO solution of the title compound had peaks at 1.29 (d, J = 6.4 Hz, 3H), 2.1-2.4 (m, 4H), 2.8-3.0 (m, 2H), 3.1-3.25 (m, 2H), 3.42 (m, 1H), 3.91 (dd, J = 5.9, 1.0 Hz, 1H), 4 .24 (qd, δ J = 6.4, 5.9 Hz, 1H) and 5.67 (d, J = 1.0 Hz, 1H) ppm.

The potassium bromide tablet run in the infrared spectrum of the title compound had absorptions at 3403, 2964, 2917, 1765, 1589, 1514, 1372, 1290, 1126, 1041, 1012, 988 and _936 cm. The ultraviolet-10 spectrum of the aqueous solution of the title compound had the following absorption maxima (extinction coefficient in parentheses): 259 (5530) and 322 (7260) nanometers.

Example 5

Calcium (5R, 6S) -6- (R) -1-hydroxyethyl] -2- (4-thianyl) thio-2-penem-3-carboxylate The hydrogenation procedure of Example 1 and 5% palladium on carbon were used. calcium carbonate catalyst in tetrahydrofuran-water 1: 1 and starting from p-nitrobenzyl (5R, 6S) -6- / hydroxyethyl-2- (4-thianyl) thio-2-penem-3-carboxylate to give the title compound in 100% yield. .

In the NMR spectrum (250 MHz) of the title compound, the heavy aqueous solution had peaks at 1.29 (3H, d, J = 6.4 Hz), 1.7 to 1.9 (2H, m), 2.3 to 2, Δ (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 (1H, d, J = 1.3 Hz) ppm.

The potassium bromide tablet run in the infrared spectrum of the title compound had absorptions at 3409, 1770, 1583 and 1385 cm -1.

Example 6 The procedure of Example 5 was used starting from p-nitrobenzyl- (5R, 6S) -6- [(R) -1-hydroxyethyl] -2- (1,1-dioxo-4-thianyl) thio-2-penem-3 carboxylate to give calcium (5R, 6S) - [(R) -1-hydroxyethyl] -2- (1,1-dioxo-4-thianyl) thio-2-penem-3-carboxylate in 93% yield. yield.

Il 25 81584

In the NMR spectrum of the product (250 MHz), the heavy water solution had peaks at 1.29 (3H, d), 2.15-2.4 (2H, m), 2.4-2.65 (2H, m), 3 , 2 - 3.45 (4H, m), 3.61 (1H, m), 3.95 (1H, dd), 4.26 (1H, m) and 5.68 (1H, d) ppm.

The potassium bromide tablets run on the product in the crown spectrum showed absorptions at 3421, 1767, 1588, 1382, 1286 and 1112 cm-1.

The procedure of Example 5 was used in a similar manner and starting from p-nitrobenzyl- (5R, 6S) -6-β (R) -1-hydroxy-10-ethyl] -2- (trans-1-oxo-4-thianyl) thio-2-penem -3-carboxylate to give calcium (5R, 6S) -6-C (R) -1-hydroxyethyl] -2- (trans-1-oxo-4-thianyl) thio-2-penem-3- carboxylate in 81% yield. As a potassium bromide tablet in the infrared spectrum of the product, the absorbances were at 1769, 1592, 1511, 1383, 1294, 1131 and 1021 cm -1.

In the NMR spectrum of the product (250 MHz), the heavy water solution had peaks at 1.29 (3H, d, J = 6.3 Hz), 1.85-2.1 (2H, m), 2.45-2.65 (2H, m), 2.85-3.0 (2H, m), 3.15-3.4 (2H, m), 3.63 (1H, m), 3.93 (1H, dd, J) = 6, 20 1 Hz), 4.26 (1H, qd, J = 6.3, 6 Hz and 5.68 (1H, d, J = 1 Hz) ppm.

Example 7

Sodium (5R, 6S) -6 - [(R) -1-hydroxyethyl] -2-Z (cis) -1-oxo-3-thiolanyl] thio-2-penem-3-carboxylate To a solution of 6.0 g of p-nitrobenzyl (5R, 6S) -6- (1R) -1-hydroxyethyl 2 - [(cis) -1-oxo-3-thiolanyl] -1thio-2-penem-3-carboxylate 100 ml in tetrahydrofuran, a suspension of 3.0 g of 10% palladium diatomaceous earth in 100 ml of water adjusted to pH 7.4 was added, and then 25 ml of tetrahydrofuran was added. The resulting mixture was hydrogenated at 4.2 kg / cm for 10 minutes, an additional 3.0 g of catalyst was added and the pH of the mixture was adjusted to 7.3 with dilute aqueous sodium bicarbonate solution. The mixture was hydrogenated at 4.2 kg / cm 3 for 25 minutes, then a further 4.0 g of catalyst 26 81 584 were added and the pH of the suspension was adjusted to 7.4 with dilute aqueous sodium bicarbonate solution. The mixture was hydrogenated at 4.2 kg / cm for 45 minutes, then the pH was adjusted to 6.9 with aqueous sodium bicarbonate and the catalyst was removed by filtration. The filtrate was concentrated in vacuo to remove tetrahydrofuran and the aqueous solution was washed with 200 mL of diethyl ether, 200 mL of ethyl acetate and 200 mL of diethyl ether. The solution was filtered and the pH of the filtrate was adjusted to 7.2. Freeze-drying of this solution gave 4.3 g (yield 93%) of the title compound as an amorphous solid.

The NMR spectrum (250 MHz) of the heavy aqueous solution of the title compound had peaks at 1.32 (d, 3H), 2.53 (c, 1H), 2.74-3.12 (c, 3H), 3.26 ( c, 1H), 3.83 - 4.09 (c, 3H), 4.27 (m, 1H) and 5.74 (2d, 1H) ppm.

The potassium bromide tablet run in the infrared spectrum of the title compound had absorptions at 2.93, 5.66 and 6.3 microns.

20 Example 8

Sodium (5R, 6S) -6 - [(R) -1-hydroxyethyl] -2 - [(trans) -1-oxo-3-thiolanyl] thio-2-penem-3-carboxylate The procedure of Example 7 was used and the starting material was p. -nitrobenzyl (5R, 6S) -6-[(R) -1-hydroxyethyl] -2-25 [trans] -1-oxo-3-thiolanyl] thio-2-penem-3-carboxylate to give the title compound in 80% strength. yield.

The NMR spectrum (250 MHz) of the heavy aqueous solution of the title compound had peaks at 1.32 (d, 3H), 2.27 (m, 1H), 2.78-3.18 (c, 2H), 3.47 (c, 2H). ), 3.66 (m, 1H), 3.97 (m, 1H), 4.22-4.43 (c, 2H) and 5.74 (d, 1H) ppm.

The potassium bromide tablet run in the infrared spectrum of the title compound had absorbances at 2.92, 5.65 and 6.26 microns.

Il 27 81 584

Example 9

Sodium (5R, 6S) -6 - [(R) -1-hydroxyethyl] -2- (2-oxo-1,3-dithiolan-4-ylmethyl) thio-2-penem-3-carboxylate was 110 mg of 10% palladium

Celite diatomaceous earth catalyst in 10 ml of water was adjusted to pH 7. A solution of 107 mg of p-nitrobenzyl- (5R, 6S) -6-i * (R) -1-hydroxyethyl-2- (2- oxo-1,3-dithiolan-4-ylmethyl) thio-2-penem-3-carboxylate in 10 ml of tetrahydrofuran, and the resulting reaction mixture was hydrogenated at room temperature and pressure at 3.5 kg / cm 3. Two additional batches of catalyst were added every hour. The catalyst was removed by filtration and the filtrate was evaporated to remove tetrahydrofuran. The remaining aqueous solution was washed with ethyl acetate and diethyl ether and filtered. The filtrate was lyophilized to give 60 mg of the title compound as a pale yellow powder.

IR (KBr): 1600, 1640 and 1778 cm -1.

NMR (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 unclear due to solvent failure).

Example 10 Preparation of diastereomers of sodium (5R, 6S) -6 - [(R) -1-hydroxyethyl] -2- (1,1-dioxo-3-thiolanyl) thio-2-penem-3-carboxylate and separation.

The procedure of Preparation F was repeated to give p-nitrobenzyl- (5R, 6S) -6-7 * (R) -1-tert-butyldimethyl-3-silyloxyethyl] -2- (1,1-dioxo-3-thiolanyl) thio-2- penem-3-carboxylate in 50.8% yield. The two isomers of the product were separated by column chromatography on silica gel eluting with ethyl acetate-hexane 1: 1.

28 81 584

The more non-halved diastereomer was obtained in 46.5% yield and its m.p. was 160.5-162 ° C. Its infrared-driven potassium bromide tablet had absorbances at 5.62, 5.97, 6.56 and 6.74 microns, and its 5 deuterium chloroform solution had NMR spectra (250 MHz) with peaks at 0.03 (s, 3H), 07 (s, 3H), 0.81 (s, 9H), 1.25 (d, 3H), 2.28 (m, 1H), 2.76 (m, 1H), 3.12 (c, 2H) ), 3.34 (m, 1H), 3.58 (m, 1H), 3.79 (m, 1H), 3.98 (m, 1H), 4.28 (m, 1H9, 5.32 ( q, 2H), 5.71 (d, 1H), 7.6 (d, 2H) and 8.21 (d, 2H) ppm.

The more polar isomer was obtained in 40.3% yield, m.p. 181.5 to 182 ° C, its infrared-driven potassium bromide tablet had absorptions at 5.62, 5.9, 6.6 and 6.67 microns and its deuterium chloro-15 form solution had NMR spectra (250 MHz) at 0, O 2 (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, 1H), 7.61 (d, 2H) and 8.21 (d, 2H) at 20 ppm.

p-Nitrobenzyl (5R, 6S) -6- [1R) -1-hydroxyethyl] -2- (1,1-dioxo-3-thiolanyl) thio-2-penem-3-carboxylate diastereomer from the more non-polar silyl ether diastereomer.

The more non-polar silyl ether was reacted according to Preparation A to give the corresponding 1-hydroxyethyl compound, m.p. 172-173 ° C, yield 80%. The potassium bromide tablet run in the infrared spectrum of the product had absorptions at 5.63, 5.94, 6.6 and 6.68 microns. The NMR spectrum (250 MHz) of the deuterium chloroform-perdeuterium dimethyl sulfoxide solution of the product had peaks at 1.32 (d, 3H), 2.3 (m, 1H), 2.76 (m, 1H), 3.15 (c, 2H), 3.34 (m, 1H), 3.59 (m, 1H), 3.78 (m, 1H), 4.09 (c, 2H), 5.1 (d, 1H), 5, 36 (q, 2H), 5.77 (d, 1H), 7.65 (d, 2H) and 8.22 (d, 2H) 35 ppm.

Il 29 81 504 p-Nitrobenzyl- (5R, 6S) -6- (R) -1-hydroxyethyl-2- (1,1-dioxo-3-thiolanyl) thio-2-penem-3-carboxylate a silate diastereomer from a more polar silyl ether diastereomer.

The more polar silyl ether was reacted according to Preparation A to give the corresponding 1-hydroxyethyl compound / m.p. 175-176 ° C, 76% yield. The potassium bromide tablet run in the infrared spectrum of the product had absorbances at 2.86, 5.6, 5.93, 6.59 and 6.68 ppm. The NMR spectrum of the deuterium chloroform-perdeuterium dimethyl sulfoxide solution showed peaks at 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, 2H), 5.78 (d, 1H), 7.64 (d, 2H) and 8.23 (d, 2H) ppm.

The title compound diastereomer derived from the pooled silyl ether diastereomer.

The p-nitrobenzyl-1-hydroxyethyl diastereomer obtained from the more non-polar silyl ether diastereomer was reacted according to Example 1 to give the title compound diastereomer in 96% yield.

The potassium bromide tablet run on the infrared spectrum of the product had absorptions at 2.93, 5.65 and 5.29 microns. The NMR spectrum (250 MHz) of the heavy aqueous solution of the product had 25 peaks at 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.

The title compound diastereomer from the more polar silyl ether diastereomer.

The p-nitrobenzyl-1-hydroxyethyl diastereomer obtained from the more polar silyl ether diastereomer was reacted according to Example 1 to give the title compound diastereomer in 95.5% yield. As a potassium bromide tablet in the infrared spectrum of the product, the absorbances at 35 were 2.94, 5.66 and 6.27 microns. The heavy water NMR spectrum (250 MHz) of the title compound had peaks at 1.35 (d, 3H), δ 81584 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.

Example 11 5-p-Nitrobenzyl- (5R, 6S) -6 - [(R) -1-tert-butyldimethylsiloxyethyl-N- (4-cis) -3-hydroxy-4-thiolanyl [7-thio-2-penemic acid] Preparation, separation and transformations of diastereomers of 3-carboxylate

To a solution of 0.272 g (0.002 mol) of cis-4-hydroxytoxythiolanyl-3-thiol in 10 ml of anhydrous ethanol cooled to -30 ° C under nitrogen was added 2 ml (0.002 mol) of an ethanolic solution of 1 M sodium ethoxide. After stirring for 30 minutes at -30 ° C, the mixture was cooled to -60 ° C and a solution of 1.08 g (0.002 mol) of p-nitrobenzyl- (5R, 6S) -6 - (-) was added. -1-tert-butyldimethylsiloxyethyl-2-ethylsulfinyl-2-penem-3-carboxylate in 30 ml of tetrahydrofuran cooled to -60 ° C. After 15 minutes at -60 ° C, a solution of 0.5 ml of acetic acid in 3 ml of tetrahydrofuran was added, the solution was allowed to warm to 25 ° C and concentrated in vacuo. The residue was dissolved in 100 ml of ethyl acetate, the resulting solution was washed with 20 ml of water, 20 ml of saturated aqueous sodium bicarbonate solution, 20 ml of water and 20 ml of saturated sodium chloride solution, dried over sodium sulfate and concentrated to dryness. . The residue was chromatographed twice on silica gel (250 g and 400 g, respectively) eluting with hexane-ethyl acetate 60:40 to give 0.4 g of the more non-polar diastereomer (diastereomer A), 0.56 g of the more polar diastereomer (diastereomer B) and 0, 12 g of a mixture of diastereomers (total yield 90.7%).

Diastereomer A

IR (KBR tablet): 2.86, 5.64, 6.0, 6.55 and 6.75 microns.

35 NMR (CDCl 3, 250 MHz): 0.04 (s, 3H), 0.07 (s, 3H), 0.83 (s, 9H), 1.25 (d, 3H), 2.47 ( d, 1 H), 3.0 (m, 2 H),

II

3i 8158 4 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.

Dlastereomer B

IR (KBr tablet): 2.86, 5.59, 5.95, 6.59 and 6.68 microns.

NMR (CDCl 3, 250 MHz): 0.04 (s, 3H), 0.07 (s, 3H), 0.83 (s, 9H), 1.25 (d, 3H), 2.35 (d, 1H), 3.02 (m, 2H), 3.2 (m, 2H), 3.67 (m, 1H), 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.

p-Nitrobenzyl (5R, 6S) “6 - [(R) -2-hydroxyethyl] -2/7cis) -3-hydroxy-4-thiolanyl] thio-2-penem-3-carboxylate derived from diastereomer A The methods of Preparation A were used starting from diastereomer A to give the title diol compound in 63.4% yield, mp 187-189 ° C (dec).

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

NMR (DMSO-d 6, 250 MHz): 1.28 (d, 3H), 2.74 (dd, 1H), 2.96 (dd, 1H), 3.13 (m, 2H), 3.63 (m, 1H), 3.89 (dd, 1H), 4.02 (m, 1H), 4.54 (m, 1H), 5.24 (d, 1H), 5.36 (q, 2H), δ , 74 (d, 1H), 5.81 (d, 1H), 7.69 (d, 2H) and 8.24 (d, 2H) ppm.

25 p-Nitrobenzyl (5R, 6S) -6-7 '(R) -1-hydroxyethyl] -2 - [(cis) -3-hydroxy-4-thiolanyl] thio-2-penem-3-carboxylate derived from diastereomer B The methods of Preparation A were used starting from diastereomer A to give the corresponding diol compound 30 in 77.3% yield, m.p. 206-207 ° C (decomposes).

IR (KBr tablet): 2.86, 2.91, 5.63, 5.98, 6.57 and 6.77 microns.

NMR (DMSP-d 6, 250 MHz): 1.17 (d, 3H), 2.73 (dd, 1H), 2.93 (dd, 1H), 3.1 (dd, 1H), 3.29 ( m, 1H), 3.64 (m, 1H), 35 3.86 (dd, 1H), 4.02 (m, 1H), 4.5 (m, 1H), 5.24 (d, 1H) , 5.37 (q, 2H), 5.77 (d, 1H), 5.79 (d, 1H), 7.69 (d, 2H) and 8.24 (d, 2H) ppm.

32 81584

Sodium (5R, 6S) -6 - [(R) -1-hydroxyethyl] -2- [[cis] -3-hydroxy-4-thiolanyl] thio-2-penem-3-carboxylate derived from diastereomer A The procedures of Example 1 were used and the starting material was p-nitrobenzyl- (5R, 6S) -6- [4 (R) -1-hydroxyethyl] -2- [(cis) -3-hydroxy-4-thiolanyl] thio-2-penemic acid. 3-Carboxylate derived from diastereomer A to give the corresponding sodium salt of formula II in 90% yield.

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

NMR (D 2 O / 250 MHz): δ 323H), 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 (5R, 6S) -6- (1R) -hydroxyethyl-2 - [(cis) -? 3-hydroxy-4-thiolanyl] -thio-2-penem-3-carboxylate derived from diastereomer B 1 and starting from p-nitrobenzyl (5R, 6S) -6- / 7R) -1-hydroxyethyl-2- (cis) -3-hydroxy-4-thiolanyl-thio-2-penem-3-carboxylate diastereomer B and the corresponding sodium salt of kaa-20a II was obtained in 87% yield.

IR (KBr): 2.93, 5.65 and 6.29 microns.

NMR (D 2 O, 250 MHz): 1.32 (d, 3H), 2.94 (m, 2H), 3.2 (dd, 1H), 3.34 (dd, 1H), 3.78 (m, 1H), 3.94 (dd, 1H), 4.27 (m, 1H), 4.66 (m, 1H) and 5.71 (d, 1H) ppm.

of p-nitrobenzyl (5R, 6S) -6- / 1R) -1-tert-butyl-metyylisilyylioksimetyyli7-2- (l-oxo-3-hydroxy-4-thio-benzoxolanyl) thio-2-penem-3-carboxylate Preparation and separation of isomers To a solution of 0.46 g (0.77 mol) of diastereomer B in 40 ml of methylene chloride cooled to -25 ° C under nitrogen was added dropwise over 15 minutes a solution of 0.142 g (0 , 77 mmol) of m-chlorobenzoic acid (85% activity) in 20 ml of methylene chloride. The solution was stirred for 10 minutes at -25 ° C after completion of the reaction, then 40 ml of methylene chloride was added.

II

33,81534 rids and 20 ml of water, the excess peracid was decomposed with sodium bisulfite and the pH of the mixture was adjusted to 7.5 with saturated aqueous sodium bicarbonate solution. The methylene chloride layer was isolated and washed with 30 ml of water and 30 ml of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on 250 g of silica gel eluting with ethyl acetate-methanol 92.5: 7.5 to give 0.136 g (yield 28.8%) of more non-polar sulfoxide (isomer E) and 0.210 g (44.5% of more polar sulfoxide (isomer)). F).

In a similar manner, 0.112 g (38%) of the more non-polar sulfoxide (isomer C) and 0.18 g (61.2%) of the more polar sulfoxide (isomer D) were obtained by oxidizing the diastereomer Aita with m-chloroperbenzoic acid.

The C-F infrared spectra of the isomers were run as potassium bromide tablets and the NMR spectra were run as perdeuterium dimethyl sulfoxide solutions at 250 MHz. The results are shown in Table 2.

20

Table 2

Isomer IR (micron NMR (ppm) δ C 3.06, 5.56, 0.01 (s, 3H); 0.04 (s, 3H); 5.85 and 6.61 0.78 (s, 9H); 1.22 ( d, 3H), 2.9 (dd, 1H), 3.15 (m, 2H), 359 (dd, 1H), 4.05 (m, 1H), 4.25 (m, 1H), 4.34 ( m, 1H), 4.79 (m, 1H), 5.34 (g, 2H), 5.75 (d, 1H), 6.03 (d, 1H), 7.7 (d, 2H), and 8.23 (d, 2 H); 34 81 584

Table 2 (continued)

Isomer IR (micron) NMR (ppm) D 3.0, 5.59, 5.96 0.01 (s, 3H); 0.04 (s. 3H); Δ 6.57 and 6.77 0.78 (s, 9H); 1.21 (d. 3H); 2.88 (m. 2H)? 3.27 (dd, 1 H); 3.77 (m, 1 H); 4.03 (c. 2H); 4.24 (m, 1 H); 4.63 (m, 1 H); 5.35 (q, 2 H); 5.73 (d, 1 H); 5.96 (d, 1 H); 7.7 (d. 2H); 8.23 (d. 2H); Δ 2.98, 5.58, 5.92 0.01 (s, 3H); 0.04 (s. 3H); 6.58, and 6.67, 0.78 (s, 9H); 1.2 (d. 3H); 2.9 (dd, 1 H); 3.08 (dd, 1 H); 3.35 (m, 1 H); 3.56 (dd, 1 H); 4.02 (m, 1 H); 4127 (m. 2H); 4.75 (m, 1 H); 5.32 (a. 2H); 5.78 (d, 1 H): 5.9 (d, 1 H); Δ 7.68 (d, 2 H); and 8.22 (d, 2 H).

F 2.96, 5.61, 5.98 0.01 (s, 3H); 0.04 (s, 3K); 6.58 and 6.69 0.77 (s, 9H); 1.2 (d, 3 R); 2.85 (m. 2H); 3.29 (dd, 1 H); 3.77 (m, 1 H); 4.0 (d. 1H); : 4.13 (dd, 1 H); 4.23 (m, 1 H); Δ 4.56 (m, 1R); 5.34 (q, 2K); 5.76 (d, 1 H); 5.98 (d, 1 H); 7.69 (d. 2H); and 8.22 (d, 2 H).

The corresponding p-nitrobenzyl- (5R, 6S) -6 - ['(R) -1-hydroxyethyl

Preparation of 17-2- (1-oxo-3-hydroxy-4-thiolanyl) thio-2-penem-3-carboxylate isomers from isomers C-F

The methods of Preparation A were used starting from isomers C-F to give the corresponding compounds of formula XV. As shown in Table 3, infrared spectra were run as potassium bromide tablets and NMR spectra as perdeuterium dimethyl sulfoxide solutions, and all melting points were associated with decomposition.

35

II

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36 81 584

Sodium (5R, 6S) -6 - / (R) -l-hydroksietyyli7 ~ 2- (1-oxo-

Preparation of 3-hydroxy-4-thiolanylthio-2-penem-3-carboxylate isomers from isomers C-F

The procedures of Example 1 were used starting from the corresponding isomers C-F of the compounds of formula XV and the corresponding sodium salts of the compounds of formula II were obtained. Table 4 shows the infrared spectra of the product compounds of formula II derived from isomers C-F as run potassium bromide tablets and the 10 NMR spectra as 250 MHz run heavy aqueous solutions, respectively.

Table 4

Isomer IR (micron) NMR (ppm) Yield (%) C 2.92, 5.66 and 1.31 (d, 3H); 3.11 46.3 6.27 (dd, 1 H); 3.26 (dd, 1 H); 3.44 (dd, 1 H); 3.84 (dd, 1 H)? 3.96 (dd, 1 H); 4.25 (n, 1 H); 4.4 (m, 1 H); 4.93 (m, 1 H); and 5771 (d, 1 H).

2 ° D 2.96, 5.67 and 1.3 (d, 3H); 3.0 63.3 - 6.28 (dd, 1 H); 3.1T (dd, 7H); 3.32 (dd, 1 H); 3.83 (m, 1 H); 3.94 (dd, 1 H); 4.24 (m. 2H); 4.7 (m, 1 H); and 5.68 (d, 1 H).

Δ 2.93, 5.67 and 31 (d, 3H); 60 6.3 3.14 (dd, 1 H) 3.28 (dd, 1 H); 3.55 (dd, 1 H); 3.8 (dd, 1 H); 3.96 (dd, 1 H); 4.26 (m, 1 H); 4.38 (m, 1 H); 4.92 (m, 1 H); and 5.74 (d, 1 H).

F 2.93, 5.65 and 1.3 (d, 3H); 3.03 47.1 6.30 (dd, 1 H); 3 ^ 16 (dd, 7 1H); 3.34 (dd, 1 H); 3.83 (m, 1 H); 3.93 (dd, 1 H); 4.28 (m. 2H); 4.68 (m, 1 H); and 5.71 (d, 1 H).

Il 37 81584 p-Nitrobenzyl- (5R, 6S) -6 - [* (R) -1-tert-butyl-dimethylsilyloxy] -2- (1,1-dioxo-cis-3-hydroxy-4-thiolanyl) thio- Preparation of diastereomers of 2-penem-3-carboxylate 5 To a solution of 0.12 g (0.195 mmol) of isomer F in 25 mL of acetone, 5 mL of water and 5 mL of pH 7 buffer (K 2 HPO 4 / NaOH, 0.05-m), a solution of 15.4 mg (0.097 mmol) of potassium permanganate in 30 ml of water was added dropwise over 20 minutes. Thin layer chromatography-10 showed still starting material in the reaction mixture and therefore an additional 4 mg of potassium permanganate dissolved in 1 ml of water was added. The acetone was then removed in vacuo and the aqueous layer was extracted three times with 50 mL portions of ethyl acetate. The combined ethyl acetate-15 extracts were washed with two 30 mL portions of water and 30 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on 50 g of silica gel eluting with ethyl acetate-hexane 70:30 to give 0.1 g (81% yield) of the corresponding sulfone (diastereomer H) as a pale yellow foam. In a similar manner, 95 mg of isomer D was oxidized with potassium permanganate to give 76 mg (78%) of the corresponding sulfone (diastereomer G).

Diastereomer G

IR (KBr tablet): 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, 1H), 4.73 (m, 1H), .34 (q, 2H), 5.68 (d, 1H), 7.63 (d, 2H) and 8.23 (d, 2H) ppm.

Diastereomer H

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

35 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), 4.02 (m, 1H) / 4.28 (m, 1H). 4.74 (m, 1H), 38 81 584 5.33 (q, 2H), 5.75 (d, 1H), 7.62 (d, 2H) and 8.22 (d, 2H) ppm.

Diastereomers of p-nitrobenzyl (5R, 6S) -6- (R) -1-hydroxyethyl] -2- (1,1-dioxo-cis-3-hydroxy-4-thiolanyl) thio-2-penem-5 3-carboxylate Preparation Preparation A was used starting from diastereomers G and H to give the corresponding compounds of formula XV in 64.2% and 59.7% yields, respectively.

Compound of formula XV derived from diastereomer G 10 NMR (DMSO-d 6, 250 MHz): 1.18 (d, 3H), 3.34 (m, 2H), 3.52 (m, 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), 78 (d, 1H), 6.46 (d, 1H), 7.7 (d, 2H) and 8.25 (d, 2H) ppm.

Compound of formula XV derived from diastereomer H IR (KBr tablet): 2.89, 5.62, 6.00, 6.58 and 6.73 microns.

NMR (DMSO-d 6, 250 MHz): 1.18 (d, 3H), 3.31 (m, 2H), 3.52 (dd, 1H), 3.74 (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), δ , 82 (d, 1H), 6.44 (d, 1H), 7.72 (d, 2H) and 8.25 (d, 2H) ppm.

Sodium (5R, 6S) -6 - [(R) -hydroxyethyl] -2- (1,1-dioxo-cis-3-hydroxy-4-thiolanyl) thio-2-penem-3-carboxylate Preparation of diastereomers of the compound The procedure of Example 1 and the compounds of formula XV derived from diastereomers G and H were used to give the corresponding sodium salts of the compounds of formula II in 45.6% and 69.6% yields, 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, 3H), 3.5 (c, 3H), 3.78 (dd, 1H), 3.98 (dd, 1H), 4.26 (c, 2H), 4.62 (m, 1H) and 5.73 (d, 1H) ppm.

Compound of formula II derived from diastereomer H IR (KBr): 2.94, 5.65 and 6.34 microns.

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

Il 39 81 584

Preparation A

p-Nitrobenzyl (5R, 6S) -6- [1 (R) -1-hydroxyethyl] -2- (1,1-dioxo-3-thiolanyl) thio-2-penem-3-carboxylate

To a solution of 185 mg (0.303 mmol) of p-nitro-5-benzyl- (5R, 6S) -6 - [(R) -1-tert-butyldimethylsilyloxyethyl] -2- (1,1-dioxo-3- thiolanyl) thio-2-penem-3-carboxylate in 6 ml of tetrahydrofuran, 0.175 ml (3.03 mmol) of acetic acid and 0.909 ml (0.909 mmol) of a 1-m tetrahydrofuran solution of tetrabutylammonium fluoride were added. After stirring for 20 hours under nitrogen, 50 ml of ethyl acetate were added and the resulting solution was washed with 25 ml of saturated aqueous sodium carbonate solution, 25 ml of water and 25 ml of saturated aqueous sodium chloride solution. The ethyl acetate solution was then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product (138 mg) was purified by chromatography on 50 g of silica gel eluting with chloroform-ethyl acetate 60:40 to give 72 mg (yield 47.5%) of the title compound as an amorphous solid.

The NMR spectrum of the deuterium chloroform solution of the title compound had peaks at 1.35 (d, 3H), 1.9-4.4 (s, 10H), 5.3 (q, 2H), 5.7 (d, 1H), δ , Δ (d, 2H) and 8.18 (d, 2H) ppm. The infrared spectrum of the dichloromethane solution of the title compound had absorbances at 5.56, 5.92 and 6.57 microns.

Preparation B

The methods of Preparation A were used to convert the corresponding compound of formula XIV to a compound of formula XV wherein R is as in Table 5. The IR absorption spectra of the product were run as dichloromethane solutions unless otherwise indicated and the NMR spectra as deuterium chloroform solutions unless otherwise indicated.

40 81 584

Table 5 R

- IR (micron) NMR (ppm) Yield (%) δ 3-thiolanyl 5,56,5-88 and 1,35 (d, 3H); 51 6756 1, 8-4.4 (c, 10H); 5.3 (q, 2H ;; 5.65 (d, 1H); 7.6 (d, 2H) y and 872 (d, 2H).

10 ois-1-oxo-3-thiolanyl 5,56,5.86 and l * 3 (d 3ΗΪ · 1 Q e, (polar isomer) 6 '„' '5.38 <” ΐ0ϋ) 1 5.3 (q, 2H), 5.7 (Cd, 1H); 7.6 (Cd, 2H) y and 8.2 (d, 2H).

Trans-1-oxo-3-thiolanyl 5,56,5,88 and 1.3 (d, 3H); 51 (poolittanan isomer) 6.58 1.86-4.56 (c, 10H); 5.3 (q. 2H); 5.72 (d, 1 H); 7.6 (d. 2H); and 8.2 δ (2H) 2- (methylsulfinyl) 5,56,5,9 and 1.35 (d, 3H); 67 ethyl 6.55 2.65 (S, 3H); 2.9-3.5 (c, 4H); 3.75 (M, 1 H); 4.2 (c. 2H); 5.34 (q, 2 H); : 5.7 (d, 1 H); 7.6 (d. 2H); and 8.2 (d. 2H).

2- (methylsulfonyl) 5,57,5,9 and 1,23 (d, 3H); 85 ethyl 6.58 3.0 (s, 3 H); , n 3.4 (s, 4 H); JU 3.8 (m, 1 H); 4.0-4.8 (c. 2H); 5.36 (q, 2H}; 58 (d, 1H); 7.74 (d, 2H); and 8.2 (d, 2H).

Il 4i 81584

Table 5 (continued) _IL. 1R (micron) NMR (ppm) Yield (%) δ methylsulfinyl-5,57,5,92 and 1,35 (d, 3H); 65 methyl 6.6 2.68 (S, 3H); 12 m 64-4.45 (q, 5H); 5.3 (q, 2 H) δ 5.7 (d, 1H); 7.56 (d. 2H); and δ 8/2 (d, 2H).

methylsulfonyl-5,6,5,86 and 1.36 (d, 3H); 34 methyl 6.57 3.08 (s, 3H); 3.8-4.8 (c, 5H), 5.42 (q, 2H); 5.8 (d, 1 H); 7.75 (d. 2H); 8.24 (d. 2H).

R IR (microns) NMR (ppn)) Yield (¾) 42 81 584 1-oxo-5,56,5,94 and 1,32 (d, 3H); 1.5-26 3-thianyl 6.58 4.38 (c, 12H); Δ 5.3 (q, 2E); 5.7 (d, 1 H); Δ ^ 6 (d, 2H); and 8.2 (dy 2H).

5,56,5,8 and I.JU, 3H) j 1.76-47 nvvll * (55 4'4 (C '12H) »V3 yY (9.2H); 5.68 '1U (d, 1 H)? 7.6 (d. 2R); and 8.2 (d * 2H).

3- data - 5,56,5,88 and 1,3 (d, 3H); 74 ηγγίι 6.56 3.38 (c, 4H); 3.68 (m, 1 H); 4.22 n (m, 1H)! 4.8 (m, 1 H); 5.3 (q. 2H); 5.6 (d, 1 H); 7.55 (d. 2H); and 8.16 (d, 2 H).

4-thianyl 3424, 1773 and 1.39 (3H, d), 90 1688 cm -1, 1.8-2.0 (3H, m); 2.3-2.5 (2 R, m); 2.6-2.85 (4H, m) y 3.23 (1H, tt) y 3.77 (1H, dd); 4.28 (1H, m); 5.23 (lB, d); 5.49 (1H, d); 5.68 (1H, d); 7.64 (2B, d); and $ .22 (2R, d).

(250MHz) - IR (micron) NMR (ppm) Yield (%) 43 81 584 1,1-dioxo-3530, 1772, 1.15 (3H, d, J = 7777 4-thianyl 1681, 1510, 6.2 Hz ); 1., 95-1344, 1290 *, 2.15 (2H, m); and 1115 cm-2.3-2.55 (2H, m); Δ (KBR tablet) 3.05-3.5 (4H, m); 3.58 (1 H, m); 3.89 (1H, dd, J = 5.8, 1.4Hz); 4.00 (1 H, m); 5.23 (1H (OH), d, J = 4.6 Hz); 5.28 n (1H, D, Jgem »14Hz); 5.43 (1H, d, Jgem <14Hz); 5.77 (1H, d, J = 1.4 Hz); 7.68 (2H, d, J = 8.6Hz) and 8.23 (2H, d, J = 8.6Hz) (DMSOd 6 250MHz) δ cis-1-oxo-3435, 2940, 1.17 (3H, d , J = 6.3 92 4-thianyl 2919, 2862 Hz), 1.95-2.3 (4H, (m.p. 206-1768, 1686, m), 2.7-3.0 (4H, m) 208UC) 1609, 1504 3.43 (1H, tt, J-11, 1378, 1343, 7Hz), 3.88 (1H, dd, J = 1324, 1298, 5.8, 1.3Hz): 4.01 1244 , 1204 (1H gdd, J = 6.3, 1129, 1043 5.8, 4.6 Hz), 5.21, 1016, 1005, (1H, d, J * 4.6 Hz), 994, JJL 5, 29 & 5 ^ 44 (2H, 730 cm-2. Both d, J = (KBr) 14.0 Hz); ** 5.77 (1H, d, J »1.3 Hz); 7.69 (2H, d, J 8.6 Hz), 8.24 (2H, d, J = 8.6

Hz) (DMSO-d 6, 250 MHz) 1 H IR (microns) RHR (ppm) Yield (%) 44 δ 1,584 trans-1 - 1.18 (3H, d, J = 92 oxo-4 - 6.2 Hz ); 1.8-1.95 thianyl (2H, m); 2.45-2.6 δ (2H, m); 2.79 (2 H, m); 3.04 (2 H, m); 3.62 (1 H, m); 3.90 (1H, dd, J = 5.7, 1.3 Hz); 4.02 (1 H, m); 5.23 (1H, broad -d, J = 14.0 Hz); 5.29 & 5.45 (2H, Xu both d, JAR = 14.0 Hz); Δ 5.78 (1H, d, J = 1.3 Hz); 7.70 (2H, d, J = 8.7 Hz); and 8.25 (2H, d, J = 8.7 Hz) (DMSO-d 6, 250 MHz) b cis-1-oxo-5.57, 5.91 1.35 (d, 3H); 83.4 3-thianyl and 6f5Q 1.4-3.96 (c, 11H); 4.18 (m, 1 H); 5.31 (q, 2 H); 5.69 (d, 1H, 7.58 (d, 2H); 20 and 8 and 22 (d, 2H) trans-1- 5.57, 5.9 1.34 (d, 3H); 3- and g 58 1 4-4.43 (c, 1H), 7 thianyl 5 3 (§ # 2H), 5.7 (d, 1H), 7.55 (d, 2H), and 8-14 ( d, 2H).

li 45 81584

Preparation G

p-Nitrobenzyl (5R, 6S) -6-f (R) -1-tert-butyldimethylsilyloxymethyl] -2-methylsulfinylmethylthio-2-penem-3-carboxylate 5 Sodium methoxide (27 mg, 0.5 mmol) was added to the solution. to 76 mg (0.5 mmol) of methylsulfinylmethylthioacetate in 5 ml of anhydrous ethanol cooled to -40 ° C under nitrogen. After ninety minutes at -40 ° C, a solution of 300 mg (0.5 mmol) of 10 p-nitrobenzyl- (5R, 6S) -6 - [(R) -1-tert-butyldimethylsilyloxyoxy] ethyl-2- ethylsulfinylthio-2-penem-3-carboxylate cooled to -50 ° C. The resulting solution was stirred for 65 minutes at -40 ° C, then 0.029 mL (0.5 mmol) of acetic acid was added and the solution was concentrated in vacuo. The residue was dissolved in 50 ml of ethyl acetate, and the resulting solution was washed successively with 25 ml of saturated aqueous sodium chloride solution. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Chromatography of the crude title product (20 mg) on silica gel (85 g) eluting with chloroform-ethyl acetate 80:20 gave 120 mg (42% yield) of the product as a viscous gum.

The infrared spectrum of the dichloromethane solution of the title compound had absorbances at 5.58, 5.9 and 6.6 microns. The NMR spectrum of the deuterium chloroform solution of the title compound had peaks at 0.03 (s, 3H), 0.05 (s, 3H), 0.83 (s, 9H), 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), and 8.18 (d, 2H) ppm.

30 Preparation D

The method of Preparation C was used to prepare compounds of formula XIV from the corresponding thioacetates wherein R is as defined in Table 6. The infrared spectra of the products of formula XIV were run as a dichloromethane solution and the 35 NMR spectra in deuterium chloroform unless otherwise indicated.

46 8 1 534

Table 6 R IR (microns) NMR (ppm). Yield (%) δ methyl-5,56,5.88 and 0.1 (s, 6H); 27 sulfonyl- 6.54 0.9 (s, 9H); lymethyl y 1.22 (d, 3, H) and Z 9 (e, 3H) i 3.64 (m, 1H); in 4.16 (c, 3H); 10 5.2 (q, 2 H)? 5.57 (dr 1H); 7.42 (d. 2H); δ 86 (df 2H) · 15 ^, 56.5.92 and S-1Sf26 yl) 6.56 0.85 (S, 9H); ethyl 1.26 (d, 3H); YY 2.66 (3H); 2.86 to 3.54 (C, 4H); 3:74 (h; 1H); 4, 2 (M, 1 H); Δ 5 (q »2H)} 5.7 (d, 1H); 7.6 (d. 2H); and e ^ td, 2H).

2- (methyl-5,56,5,9 and 0-03 (s, 3H); 0.06 34 lisulfo-6.58 (S, 3H); 0.8? 11) (s, 9H); 1,3-ethyl (d, 3H), -2- (s, 3H); 3.36 (s. 4H); 3.64 (m, 1 H); 4.2 (m. 1H); 5.28 (g, 2 H); 5.68 (d, 1 H); Δ 7.57 (d, 2 H); and 8.18 (d, 2 H).

Il 47 81584

Table 6 (continued) 1 H-IR (micron) NMR (ppm) Yield (%) 3-thiol-5,56,5,92 and 0,02 (s, 3H); 41.56.5, 0.06 (s, 3H), 0.82 (E, 9H); 1.25 '(d. 3H); 1.8-4.4 (c. 9H); 5.3 (q, 2 H); 5.66 (d, 1 H); 7.6 (d. 2H); 10 and 8 ^ 2 (d, 2H).

thianyl "- 5.57, 5.95 and 0.06 (s, 3H); 0.08 (S, 3H); 22 thianyl 6'58 o88 (s, 9H)» 1126 (d, 3H); 1 Δ δ 4.4 (c, UH); δ δ (q, 2 H); δ 5.7 (d, 1 H); 7.6 (d, 2 H);

R IR (microns) HMR (pptn) Yield <48 81 584 1.1-di ° k-5.56.5.88 and 0.03 (s, 3H); 0.06 42 6'54 (s »3H); 0.82 δ tianyyU fs, 9H); 1.24 (d. 3H); 1.8-4.42 (Cc, 11H); 5.3 (q. 2H); 5.7 (d, 1 H); 7.6 (d. 2H); and 8.2 Cd> 2H).

Δ 5.6 ~ 5.56.5 ^, 88 and 0.03 (s, 3H), -0.06 28 δ 6.56 (8.3H); 0.827 (g, 9H); 1.24 (d, 3 H), 3.4 (c, 4 H); 3.7 (m, 1 H); 4.23 (a, 1 H); 4.85 (X5 <® »1H); 5.3 (q. 2H); 5.63 (d, 1 H); 7.6 (d. 2H); and 8.2 (d, 2H).

4-thianyl («,), 37 0.92 (9H, s); Δ 1.40 (3H, d, J = 7Hz); 1.8-2.9 (8 H, m); 3.27 (1 H, in); 3.75 UH, dd, J 4 1.5 Hz); 4.3 (1H, m), 5.18 (1H, d, 25 * 13 Hz);

5.48 (1H, d, J • 13 Hz); AB

5.67 (1H, d, J = 1.5 Hz); 7.60 (2ff, d, J ».8 Hz); and δ.18 (2H, d, 30, 7 * 8Hz).

II

r IR (micron) NMR (ppin) Yield%), 49 81584 1,1-dioxo- 0/13 (3H, s); 60 so-4-thia-0.17 (3H, s); nyl 0.93 (9H, s); 1.33 (3H, d, 5J - 6Hz); 2.4-4.4 (8 H, m); 3.6 (1 H, m); 3.80 (1 H, dd); .4.3 (1 H, m); 5.17 (1H, d, J * 13 Hz); 5.47 (1H, d, J <13 Hz); 5.69 (1H, d, J = 1 Hz); 7.57 (2H, d, J = 8Hz); and 8.15 (2K, d, J = 8Hz).

15 cis-1-2S24, 2489 n ftA.

oxo-4-1782, 1682, {S '“} 68 thianyl 1606, 1511,, ¾ ft me; mol and 830 2.1-2.3 (2H, m); 20 (KBr tablet) C4H, (+) / 20 '3.05-3.2 (2H, ra); 3.27 (1 H, m); 3.73 (1H, dd, J = 4.2, 1.4 Hz); 4.27 (1H, gd, J = 6.3, 4.2 Hz); 5.21 & 5r4? (2H, 25 both d 1 = 13.7 Hz); At> 5.66 (1H, d, J <1.4 Hz); 7.62 (2H, d, J * 8.7 Hz); and 8.21 (2H, d, J * 8.7 Hz). (250 MHz).

_R IR (micron) NMR (ppm) Yield (%) so 81584 oxo-4-ο. S !; 41 tianyyii?; 12 IIS: 5 6Hz); 1.7-2. 2 (2H, m); 2.5 - 3.1 (6 H, m); 3.6 (1H, in); 3.74 (1H, dd, J = 4, 1.5 Hz); 4.2 (1 H, m); 10 ^, 13 ^ AR (13 Hz); 5.45 AB (1H, d, JAB = 13Hz); 5.67 (1H, d, J = 1.5 Hz); 7.57 (2H, d, J = 15Hz); and 8.15 (2H, d, J = 8Hz).

c, is "1: 5.58, 5.9 0.04 (s, 3H); 45.5 oxSo-3 and 6.58 0 06 (s 3H); 7 thianyl O 2 (ε> 9R) 1/24 (d, 3H), 1.3-3.98 (c, 10H), 4.23 (m, 1H), 5.24 (q, 2H), 5.64 (d, 1H), 7, Δ (d, 2H), and 8.15 (d, 2H).

Trans-1- 5.58, 5.92 0.03 (s, 3B); 41.3 oxo-3- and 6.58 0.07 (s, 3H); thianyl 0.83 (s, 9H); 1.22 (d. 3H); 1.4 - 3.56 (c, 8H); 3.7 (m. 1H); 3.78 - 4.46 (c, 2H); 5.26 (q, 2 H); 5.63 (d, 1 H); 7.52 (d. 2H); 8.12 (d. 2H).

II

si 81584

Preparation E

p-Nitrobenzyl (5R, 6S) -6-2 "(R) -1-tert-butyldimethylsilyloxyethyl] -2- (1-oxo-3-thiolanyl) thio-2-penem-3-carboxylate 5 30 mg was added. (0.552 mmol) of sodium methoxide to a solution of 100 mg (0.552 mmol) of 1-oxo-3- (methylcarbonylthio) thiolane in 5 ml of anhydrous ethanol cooled to -30 ° C under a nitrogen blanket. A solution of 330 mg (0.552 mmol) of p-nitrobenzyl (5R, 6S) -6 - [(R) -1-tert-butyldimethylsilyloxyethyl] -2-ethylsulfinyl-2-penem-3-carboxylate was added at 50 ° C. in 1 ml of tetrahydrofuran cooled to -50 [deg.] C. The resulting solution was stirred at -35 to -30 [deg.] C. for 60 minutes, then 0.032 ml (0.552 mmol) of acetic acid were added and the solution was concentrated in vacuo. The residue was dissolved in 50 ml of ethyl acetate and the solution was washed successively with 25 ml of saturated aqueous sodium bicarbonate solution, 25 ml of water and 25 ml of saturated sodium chloride solution. The ethyl 20 acetate layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Chromatography of the crude product (315 mg) on silica gel (100 g) eluting with ethyl acetate-methanol 92.5: 7.5 gave 53 mg (16%) of the more non-polar title compound isomer and 65 mg (20%) of the more polar title compound sulfoxide isomer.

The infrared spectrum of the dichloromethane solution of the more polar isomer of the title compound had absorbances at 5.56, 5.92 and 6.58 microns, and the NMR spectrum of the deuterium chloroform solution had peaks at 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), 7.6 (d , 2H) and 8.2 (d, 2H) ppm.

The infrared spectrum of the dichloromethane solution of the more non-polar isomer of the title compound had absorbances at 5.57, 5.92 and 6.57 microns and the NMR spectrum of the deuterium chloroform-35 solution had peaks at 0.04 (s, 3H), 0.08 (s, 3H): ), 0.8 (s, 9H), 1.23 (d, 3H), 1.8-4.56 (c, 9H), 5.26 (g, 2H), 5.66 (d, 1H) , 7.6 (d, 2H) and 8.2 (d, 2H) ppm.

52 81584

Preparation F

p-Nitrobenzyl (5R, 6S) -6-[(R) -1-tert-butyldimethylsilyloxyethyl] -2- (1,1-dioxo-3-thiolanyl) thio-2-penem-3-carboxylate To a solution of 76 mg (0.5 mmol) of 3-sulfonanethiol (1,1-dioxo-3-thiolanyl mercaptan) in 5 ml of ethanol cooled to -35 ° C under nitrogen were added to 27 mg (0.5 mmol) of sodium methoxide. After forty-five minutes at -35 ° C, a solution of 300 mg (0.5 mmol) of p-nitrobenzyl- (5R, 6S) -6-> f (R) -1-tert-butyldimethylsilyloxyethyl was added. P-2-ethylsulfinyl-2-penem-3-carboxylate in 5 ml of anhydrous tetrahydrofuran cooled 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 concentrated in vacuo and the residue was dissolved in 50 mL of ethyl acetate. The ethyl acetate solution was washed successively with 25 ml of saturated aqueous sodium bicarbonate solution, 25 ml of water and 25 ml of saturated aqueous sodium chloride-20 solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product (285 mg) was purified by chromatography on silica gel (100 g) eluting with chloroform-ethyl acetate 95: 5 to give 185 mg (yield (60%) of the title compound as a gum).

The infrared spectrum of the dichloromethane solution of the title compound had absorbances at 5.57, 5.88 and 6.58 microns. The NMR spectrum of the deuterium chloroform solution of the title compound had peaks at 0.06 (s, 3H), 0.1 (s, 3H), 0.85 (s, 9H), 1.26 (d, 3H), 2.0-4 .4 (c, 9H), 5.32 (q, 2H), 5.72 (d, 1H) - 7.6 (d, 2H) and 8.2 (d, 2H) ppm.

Il 53 81 584

Preparation G

p-Nitrobenzyl (5R / 6S) -6 - [* (R) -1-tert-butyldimethylsilyloxyethyl] -2-ethylsulfinyl-2-penem-3-carboxylate 5 A solution of 970 mg (4, 78 mmol, purity 85%) of m-chloroperbenzoic acid in 25 ml of methylene chloride was added to a solution of 2.5 g (4.78 mmol) of p-nitrobenzyl- (5R, 6S) -6 - [(R) -1-tert- butyldimethylsilyloxy-ethyl-2-ethylthio-2-penem-3-carboxylate in 125 ml of 10 methylene chloride cooled to -20 ° C under nitrogen. The mixture was stirred for three hours at -20 ° C and then washed successively with two 70 ml portions of saturated aqueous sodium bicarbonate solution, 70 ml of water and 70 ml of saturated aqueous sodium chloride solution. The methylene-15 nichloride solution was dried over anhydrous sodium sulfate, concentrated in vacuo to give 2.2 g (86% yield) of the title compound as a yellow foam.

The infrared spectrum of the dichloromethane solution of the title compound had absorbances at 5.54, 5.86 and 6.53 microns. The NMR spectrum of the deuterium chloroform solution of the title compound had peaks at 0.06, 0.08, 0.1 and 0.12 (4s, total 6H), 0.8 (s, 9H), 1.12-1.58 (m, 6H ), 3.1 (m, 2H), 3.86 (m, 1H), 4.3 (m, 1H), 5.3 (m, 2H), 5.67 and 5.78 (2d, total 1H ), 7.54 (d, 2H) and 8.18 (d, 2H) at 25 ppm.

Preparation H

p-Nitrobenzyl (5R, 6S) -6 - [(R) -1-tert-butyldimethylsilyloxyethyl] -2-ethylthio-2-penem-3-carboxylate 30 5.85 g (0.024 mol) of p- nitrobenzyloxalyl chloride to a mixture of 7.3 g (0.02 mol) of 3 - [* (R) -1-tert-butyldimethylsilyloxyethyl] -4-ethylthio (thiocarbonyl) thio-2-oxoazetidine and 4.8 g ( 0.048 mol) of calcium carbonate in 70 ml of methylene chloride cooled to 10 ° C under a nitrogen blanket. A solution of 4.17 ml (0.024 mol) of diisopropylethylamine in 20 ml of methylene chloride was added dropwise at such a rate that the temperature remained below 12 ° C. The mixture was stirred for 60 minutes at 10 ° C, then washed with two 50 ml portions of ice-cold water, dried over anhydrous sodium sulfate and concentrated in vacuo to a viscous oil. The crude p-nitrobenzyl (3-alpha-tert-butyldimethylsilyloxyethyl-2-oxoazetidinyl) oxoacetate formed was dissolved in 300 ml of ethanol-free chloroform, and the resulting solution was heated under reflux under nitrogen for 2 hours while adding dropwise under nitrogen. 85 ml (0.04 mol) of triethyl phosphite in 50 ml of ethanol-free chloroform. The resulting solution was heated under reflux for 16 hours and then concentrated in vacuo. The residue was chromatographed on 800 g of silica gel eluting with toluene-ethyl acetate 95: 5 to give 5.5 g (53% yield) of the title compound as a yellow foam.

The infrared spectrum of the dichloromethane solution of the title compound had absorbances at 5.56, 5.89 and 6.54 microns. The NMR spectrum of the deuterium chloroform solution of the title compound had peaks at 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 deuterium chloroform solution of the intermediate 4-ethylthio (thiocarbonyl) thioazetidine had peaks at 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), 7.5 (d, 2H) and 8, 17 (d, 2 H) ppm.

30 Preparation I

3 - [(R) -1-tert-Butyldimethylsilyloxyethyl] -4-ethylthio- (thiocarbonyl) thio-2-oxoazetidine

8.5 ml (0.115 mol) of ethanethiol were added to a solution of 4.18 g (0.104 mol) of sodium hydroxide in 250 ml of water cooled to 0-5 ° C under a nitrogen blanket.

After 15 minutes, 7.73 ml (0.12 mol) of

II

55 81 584 carbon disulfide and the mixture was stirred for 35 minutes at 0-5 ° C. A solution of 15.0 g (0.0522 mol) of 4-acetoxy-3 - [(R) -1-tert-butyldimethylsilyloxyethyl] -2-azetidinone in 500 ml of methylene chloride was added and the mixture was stirred vigorously. 24 hours at room temperature. The aqueous phase was isolated and extracted with two 150 ml portions of methylene chloride. The combined methylene chloride diffractions were washed with two 200 mL portions of water and 200 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude title product (18 g) was chromatographed on silica gel (500 g) eluting with chloroform-ethyl acetate 99: 1 to give 9.1 g (48% yield) of the title trithiocarbonate as a yellow foam.

The infrared spectrum of the dichloromethane solution of the title compound had absorbances at 5.62 and 9.2 microns. The NMR spectrum of the deuterium chloroform solution of the title compound had peaks at 0.08 (s, 6H), 0.8 (s, 9H), 1.02-1.5 (m, 6H), 3.0-3.48 (m , 3H), 4.12 (m, 1H), 5.54 (d, 1H) 2 O and 6.57 (b, 1H) ppm.

Preparation J

3-metyylikarbonyylitiotiolaani

0.8 ml (0.01 mol) of methanesulfonyl chloride was added to a solution of 1.04 g (0.01 mol) of tetrahydro-thiophen-3-ol and 2.44 g (0.02 mol) of 4-dimethylaminopyrr. -dine in 40 ml of methylene chloride cooled to 0 ° C under nitrogen. After stirring for 1.5 hours at 0 ° C and two hours at room temperature, the solution was washed with 30 ml of 1N aqueous hydrochloric acid solution, 30 ml of water and 30 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated in vacuo and concentrated. 1.6 g (88% yield) of an oil formed from 3-methylsulfonyloxithiolane were obtained.

A mixture of 1.6 g (8.8 nunol) of crude 3-methyl-35-sulfonyloxythiolane in 40 ml of acetone was heated under reflux for 20 hours under nitrogen. The mixture was then concentrated in vacuo and the residue was partitioned between 40 ml of ethyl acetate and 40 ml of water. The ethyl acetate layer was isolated and washed with 30 ml of water and 30 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was chromatographed on silica gel eluting with methylene chloride to give 740 mg (52%) of the title compound.

The NMR spectrum of the deuterium chloroform solution of the title compound had peaks at 2.35 (s, 3H), 1.6-3.4 (c, 6H) and 4.1 (m, 1H) ppm.

Preparation K

The same methods were used as in Preparation J, in which 3-methylsulfonyloxithiolane was reacted with potassium thioacetate and both 3-chloro-15-thiane and 2- (methylthio) ethyl chloride were reacted with potassium thioacetate to give the corresponding methylcarbonylthio derivatives, 33% and 100% yield, respectively.

The NMR spectrum of the deuterium chloroform solution of 3-methylcarbonylthiothian had peaks at 2.36 (s, 3H) 2 O and 1.4-3.68 (c, 9H) ppm.

Preparation L

(Methylcarbonylthio) (methylsulfonyl) methane

3.0 g (14.7 mmol, purity 85%) of m-chloroperbenzoic acid were added to a solution of 1.0 g (7.34 mmol) of 25 (methylcarbonylthio) (methylthio) methane in 50 ml of methylene chloride under cooling. 0 ° C. After stirring for 20 hours at room temperature, the solution was washed with two 30 ml portions of saturated aqueous sodium bicarbonate solution and 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 on silica gel eluting with ethyl acetate to give 740 mg (60% yield) of the title compound as a thick gum.

K

57 81 584

The NMR spectrum of the deuterium chloroform solution of the title compound had peaks at 2.5 (s, 3H), 2.94 (s, 3H) and 4.4 (s, 2H) ppm.

Preparation M

The methods of Preparation L were used to prepare 3-methylcarbonylthio-1,1-dioxothiane in 32% yield and 2- (methylcarbonylthio) -1- (methylsulfonyl) ethane in 55% yield.

The NMR spectrum of the deuterium chloroform solution of the 1,1-dioxothiane product had peaks at 2.36 (s, 3H) and 1.7-3.37 (c, 9H) ppm.

Preparation N

2- (methylcarbonylthio) -1- (methylsulfinyl) ethane 2.03 g (0.01 mol, purity 85%) of m-chloroperbenzoic acid was added to a solution of 1.5 g (0.01 mol) of 2- ( methylcarbonylthio) -1- (methylthio) ethane in 40 ml of methylene chloride cooled to -10 ° C. After stirring for two hours at -10 ° C, the solution was washed with two 30 ml portions of saturated aqueous sodium bicarbonate solution, 30 ml of water and 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 on silica gel eluting with 10: 1 ethyl acetate-methanol to give 680 mg (38% yield) of the title compound as an amorphous solid.

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

30 Preparation O

The methods of Preparation N were used to prepare 3-methylcarbonylthio-1-oxothiolane in 42% yield, 3-methylcarbonylthio-1-oxothianane in 91% yield and (methylcarbonylthio) (methylsulfinyl) methan-35 in 32% yield.

58 81 584 The NMR spectrum of the deuterium chloroform solution of the 1-oxothiolane product had peaks at 2.36 (s, 3H) and 1.77-4.76 (c, 7H) ppm.

The NMR spectrum of the deuterium chloroform solution of the 1-oxothane product had peaks at 2.36 (s, 3H) and 1.6-3.4 (c, 9H) ppm.

The NMR spectrum of the deuterium chloroform solution of (methylcarbonylthio) (methylsulfinyl) methane had peaks at 2.5 (s, 3H), 2.94 (s, 3H) and 4.4 (s, 2H) ppm.

The methods of Preparation N were used and 1,1-dioxo-4-methylcarbonylthiothiane was prepared in 43% yield from 4-methylcarbonylthiothian and two equivalents of m-chloroperbenzoic acid. Purification was performed by column chromatography on silica gel eluting with ethyl 15-acetate-hexane 1: 1. Analysis for C 7 H 12 ClO 3 S: Calculated C 40.37, H 5.81, Found C 40.62, H 5.58. The NMR spectrum of the deuterium chloroform solution of the product had peaks at 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 potassium bromide tablet run in the infrared spectrum of the product had absorptions at 1687, 1291 and 1116 microns.

The methods of Preparation N were also used to prepare 1-oxo-4-4-p-methylphenylsulfonyloxithiane from 4-p-methylphenylsulfonyloxytian. The cis and trans isomers formed were separated by column chromatography on silica gel eluting with 3% methanol-ethyl acetate. The cis-1-oxo-4-p-methylsulfonyloxytian isomer was more polar. The NMR spectrum (250 MHz) of the deuterium-30 chloroform solution of the cis isomer showed peaks at 2.0 (2H, m), 2.48 (2H, m), 2.50 (2H, s), 2.75 (2H, dddd), 3.07 (2H, ddd), 4.67 (1H, tt, J = 3,3,3,4 Hz), 7.41 (2H, d, J = 8Hz) and 7.85 (2H , d, J = 8 Hz) ppm.

Il 59 81584

Preparation P

3-klooritiaani

857 mg (4.5 mmol) of p-toluenesulfonyl chloride were added to a solution of 530 mg (4.5 mmol) of tetrahydro-5-rothiopyran-3-ol and 1.1 g (9 mmol) of 4-dimethylaminopyridine in 30 ml. methylene chloride cooled to 0 ° C under nitrogen. The solution was stirred at room temperature for 20 hours, then washed with two 30 ml portions of 1N aqueous hydrochloric acid, 30 ml of water and 10 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated in vacuo to give 400 mg (yield 33%). the impure title compound.

Preparation Q

15-p-Nitrobenzyl (5R, 6S) -6 - [(R) -1-hydroxyethyl] -2- (2-oxo-1,3-dithiolan-4-ylmethyl) thio-2-penem-3-carboxylate

A solution of 410 mg of p-nitrobenzyl- (5R, 6S) -6 - [(R) -1-tert-butyldimethylsiloxyethyl] -2- (2-oxa-20,3-dithiolan-4-ylmethyl) thio penen-3-carboxylate in 20 ml of tetrahydrofuran, treated with 0.383 ml of glacial acetic acid and 2.0 ml of a 1-m solution of tetrabutylammonium fluoride. This solution was stirred for about 24 hours at room temperature. The solvent was then removed in vacuo and the residue was dissolved in ethyl acetate. This solution was washed with dilute aqueous sodium bicarbonate solution, water and brine, then dried over anhydrous sodium sulfate, filtered and evaporated. The product was further purified by column chromatography on silica gel eluting with hexane-ethyl acetate 1: 1 and ethyl acetate alone.

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: nd) ppm.

35 IR (CH 2 Cl 2): 1792 cm -1.

60 81 584

Preparation R

of p-nitrobenzyl (5R, 6S) -6-t (R) -1-tert-butyl-dimetyylisiloksietyyli7-2- (2-oxo-l, 3-dithiol-4-yl-methyl) thio-2-Penem 3-carboxylate

A solution of 0.500 g of 4-mercaptomethyl-1,3-di-5-thiolan-2-one in 50 ml of dichloromethane was cooled to 0 ° C and then treated with 0.640 ml of diisopropylethylamine. After 1 hour at 0-5 ° C, the solution was added to a solution of 0.307 g of p-nitrobenzyl- (5R, 6S) -6 - [(R) -1-tert-butyldimethylsiloxyethyl] -10 (2-ethylsulfinyl-2-penem). -3-carboxylate in 20 ml of dichloromethane at 0-5 [deg.] C. The reaction mixture was stirred for one hour at 0-5 [deg.] C. and then washed successively with water and brine and dried over anhydrous sodium sulfate, after filtration the solution was evaporated to a gum. triturated with hexane-ethyl acetate 1: 1 to give the product 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: nd) ppm.

IR (CH 2 Cl 2): 1792 cm -1.

Preparation S

p-Nitrobenzyl (5R, 6S) -6-f (R) -1-hydroxyethyl] 25 2 - [(cis) -1-oxo-3-thiolanyl] thio-2-penem-3-carboxylate

To a solution of 20.1 g (0.0337 mol) of p-nitrobenzyl- (5R, 6S) -6- [2R] -1-tert-butyldimethylsilyloxyethyl] -2 - [(cis) -1-oxo -3-Thiolanylthio-2-penem-3-carboxylate in 50 ml of anhydrous tetrahydrofuran, 19.9 ml of acetic acid and 118.8 ml of a 1-m tetrahydrofuran solution of tetrabutylammonium fluoride were added. After stirring overnight at room temperature under nitrogen, the solution was concentrated in vacuo. The residue was dissolved in 500 ml of ethyl acetate, and the resulting solution was washed with three portions of 35,200 ml of water. The product started to crystallize from aqueous extracts and the ethyl acetate layer, so the crystallization

II

61 81584 was allowed to proceed to completion (30 minutes). The crystalline material was isolated by filtration, washed with water and ethyl acetate, then slurried in 200 ml of ethyl acetate, filtered to give 12.03 g (yield 74%) of crystalline product. The ethyl acetate and aqueous extracts were combined, the ethyl acetate layer was washed with 300 mL of saturated aqueous sodium bicarbonate, 200 mL of water and 200 mL of brine, dried over anhydrous sodium sulfate, concentrated in vacuo to give 4.6 g of less pure product. This material was recrystallized from ethyl acetate to give an additional 3.0 g of product, total yield 92.2%, m.p. 122-125 ° C.

The NMR spectrum (250 MHz) of the deuterium chloroform solution of the title compound had peaks at 1.37 (d, 3H), 2.57-2.95 (c, 4H), 3.15 (c, 1H), 3.62-3, 97 (c, 3H), 4.26 (m, 1H), 5.34 (q, 2H), 5.72 and 5.74 (2d, 1H), 7.63 (d, 2H) and 8.23. (d, 2H) ppm.

The infrared spectrum of the dichloromethane solution of the title compound had absorbances at 5.56, 5.86 and 6.56 microns.

The corresponding trans isomer of the title compound was prepared in 75% yield, m.p. 178.5-180 ° C using the method used for the cis isomer and starting from p-nitrobenzyl- (5R, 6S) -6 - [(R) -1-tert-butyldimethylsilyl-25-oxyethyl] -2- (trans) -1-oxo-3-thiolanyl / thio-2-penem-3-carboxylate

The NMR spectrum of the deuterium chloroform solution of the trans isomer had peaks at 1.4 (d, 3H), 2.22 (c, 1H), 2.62 (c, 1H), 2.8 (m, 1H), 3.03 ( c, 2H), 3.18 (c, 1H), 3.52 (m, 1H), 3.83 (m, 1H), 4.27 (c, 1H), 4.43 (c, 1H) , 5.36 (q, 2H), 5.76 (d, 1H), 7.64 (d, 2H) and 8.24 (d, 2H) ppm.

The infrared spectrum of the dichloromethane solution of the trans isomer had absorbances at 5.56, 5.88 and 6.58 microns.

62 8 1 5 8 4

Preparation T

p-Nitrobenzyl- (5R, 6S) -6- [1 [R] -1-tert-butyl-dimethylsilyloxy-ethyl] -2-2f (cis) -1-oxo-3-thiolanyl] thio-2 -penem-3-carboxylate 5 A solution of sodium ethoxide in ethanol (57.5 mL, 1 M solution, 0.0575 mol) was added to a mixture of 10.68 g (0.06 mol) of cis-3-methylcarbonylthio. -1-oxothiolane in 110 ml of absolute ethanol cooled to -30 ° C under nitrogen. The resulting solution was stirred for two hours at -30 ° C and then cooled to -60 ° C. To this cooled solution was added a solution of 32.4 g (0.06 mol) of p-nitrobenzyl- (5R, 6S) -6 - [(R) -1-tert-butyldiraethylsilylsoxyethyl] -2-ethylsulfinyl- 2-penem-3-carboxylate 200 in 15 ml of tetrahydrofuran cooled to -60 ° C. The resulting solution was stirred for one hour at -60 ° C, then a solution of 10 ml of acetic acid in 20 ml of tetrahydrofuran was added and the resulting solution was allowed to warm to room temperature and concentrated in vacuo.

The residue was dissolved in 500 ml of ethyl acetate, the solution was washed with seven 300 ml portions of water, 250 ml of saturated aqueous sodium bicarbonate solution, three 300 ml portions of water and 200 ml of s 11a brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was chromatographed on 1.5 kg of silica gel eluting with ethyl acetate-methanol 95: 5. The pure product obtained was triturated in 150 ml of diethyl ether overnight to give 14.25 g of crystalline product. Another 5.0 g of crude product from chromatography was dissolved in 5 ml of methylene chloride and the solution was diluted with 150 ml of diethyl ether. After stirring overnight, 3.42 g of crystalline product were obtained (total yield 51.5%), m.p. 137-138 ° C.

The NMR-35 spectrum (250 MHz) of the deuterium chloroform solution of the title compound had peaks at 0.04 (s, 3H), 0.07 (s, 3H), 0.82 (s, 9H), 1.25 (d, 3H), 2 , 45-2.9 (c, 4H), 3.14 (c, 1H), 3.55-4.0 (c, 3H), 4.27 (m, 1H), 5.32 (q, 2H) )

II

63 81 584 5.67 and 5.7 (2D, 1H), 7.62 (d, 2H) and 8.2 (d, 2H) ppm. The infrared spectrum of the methylene chloride solution of the title compound had absorbances at 5.56, 5.92 and 6.58 microns.

The corresponding trans isomer was prepared using this method and starting from trans-3-methylcarbonylthio-1-oxothiolane to give p-nitrobenzyl- (5R, 6S) -6 - [(R) -1-tert-butyldimethylsilyloxyethyl]. -2 - [(trans) -1-oxo-3-thiolanylthio-2-penem-3-carboxylate.

The trans isomer was more non-polar than the cis isomer.

The NMR spectrum (250 MHz) of the deuterium chloroform solution of the corresponding trans isomer of the title compound had peaks at 0.06 (s, 3H), 0.1 (s, 3H), 0.86 (s, 9H), 1.3 ( 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, 2 H) ppm.

The infrared spectrum of the methylene chloride solution of the trans isomer had absorbances at 5.57, 5.92 and 6.57 microns.

Preparation U

20 Cis-3-methylcarbonylthio-1-oxothiane

A solution of 300 mg (1.04 mmol) of trans-1-oxo-3-p-methylphenylsulfonyloxytian and 396 mg (1.25 mmol) of tetrabutylammonium thioacetate in 20 mL of acetone was heated under reflux under nitrogen overnight. The reaction mixture was concentrated in vacuo and the residue was chromatographed on 80 g of silica gel. Elution with acetone-Toni-hexane 4: 1 gave 50 mg (25%) of the title compound.

The NMR spectrum of the deuterium chloroform solution of the title compound had peaks at 1.2-3.1 (c) and 2.28 (s) at 30 (total 10H) and 3.34 (c, 2H) ppm.

In a similar manner, starting from cis-1-oxo-3-p-methylphenylsulfonyloxytian, trans-3-methylcarbonylthio-1-oxothiane was obtained in 50% yield. The NMR spectrum of the deuterium chloroform solution of this trans isomer had peaks at 1.42-3.24 (c) and 2.22 (c) (total 11H) and 4.06 (c, 1H) ppm.

64 81 584

Preparation V

l-oxo-3-p-metyylifenyylisulfonyylioksitiaani

3.65 g (0.019 mol) of p-toluenesulfonyl chloride were added to a solution of 2.14 g (0.016 mol) of 1-oxo-5 3-thyanol and 3.9 g (0.032 mol) of 4-dimethylaminopyridine in 80 ml. methylene chloride cooled to 0 ° C under nitrogen. After thirty minutes at 0 ° C, the reaction mixture was stirred at room temperature overnight.

The solution was then washed with 50 mL of 1 N aqueous hydrochloric acid-10 solution, 50 mL of water and 50 mL of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was chromatographed on 1 kg of silica gel eluting with acetone-hexane 4: 1 to give 300 mg of the title compound, 1.4 g of a mixture of cis- and trans-title compound and 1.5 g of the title compound (total yield 70%). .

The NMR spectrum of the perdeuterium chloroform solution of the cis isomer of the title compound had peaks at 1.4-2.92 (c) and 2.46 (s) / total 9H), 3.4 (c, 2H), 4.54 (c, 1H), 7.36 (d, 2H) and 7.8 (d, 2H) ppm.

The NMR spectrum of the perdeuterium chloroform solution of the trans isomer of the title compound had peaks at 1.4-3.3 (c) and 2.44 (s) total 11H), 5.1 (c, 1H), 7.32 (d, 2H ) and 7.77 (d, 2H) ppm.

25 Preparation W

3-hydroxy-l-oxothiane

3.44 g (0.017 mol, purity 85%) of m-chloroperbenzoic acid were added portionwise to a solution of 2.0 g (0.017 mol) of Tian-3-ol in 60 ml of methylene chloride cooled to 0 ° C under nitrogen. The reaction mixture was stirred for 35 minutes at 0 ° C and then for two hours at room temperature. The mixture was concentrated in vacuo and the residue was chromatographed on 200 g of silica gel. Elution with ethyl acetate-methanol 9: 1 gave 2.14 g (94% yield) of a mixture of 35 cis- and trans-3-hydroxy-1-oxothane.

Il 65 81 534

Preparation X

4-Methylcarbonylthiothian The same procedures were used as in Preparation J, in which 3- (p-methylphenylsulfonyloxy) 5 thiolane was reacted with potassium thioacetate, and 4- (p-methylphenylsulfonyloxy) thian and 1.5 equivalents of potassium thioacetamide were reacted at 80 ° C in dimethyl and chromatographed on silica gel eluting with 10% ethyl acetate-hexane to give 4-methylcarbonylthiothiane in 69% yield. The NMR spectrum of the deuterium chloroform solution of 4-methylcarbonylthiothian showed peaks at 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.

Preparation Y

The same method as in Preparation X was used

and starting from trans-1-oxo-4-p-methylphenylsulfonyloxytyanine to give cis-1-oxo-4- (methylcarbonylthio) thiane. The NMR spectrum (250 MHz) of the deuterium chloroform solution of the product had peaks at 1.97 (2H, m), 2.33 (3H, s), 2.42 (2H, dddd), 2.66 (2H, ddd) , 3.02 (2H, m) and 3.56 (1H, tt, J = 11.1, 3.6 Hz) ppm.

The method of Preparation X was also used as the starting material for cis-1-oxo-4-p-methylphenylsulfonyloxytyanine to give trans-1-oxo-4- (methylcarbonylthio) thiane. The NMR spectrum (250 MHz) of the deuterium chloroform solution of the product had peaks at 1.83 (2H, m), 2.33 (3H, s), 2.65 (2H, m), 2.87 (4H, m) and 3, 80 (1H, m) ppm.

Preparation Z

Trans-1-oxo-4-p-methylphenylsulfonyloxythian was prepared from trans-1-oxo-4-hydroxytyan (see

Klein et al., Tetrahedron, 30, 2541 (1974)) using the methods of Preparation V and 1.5 equivalents of p-toluenesulfonyl chloride and 3 equivalents of 4-dimethylaminopyridine to give the title compound as a white solid in 83% yield. , sp. 99-102 ° C. The NMR spectrum of the deuterium chloroform solution had peaks at 1.94 (2H, m), 2.51 (3H, s), 2.6 (2H, m), 2.84 (4H, m), 4.80 (1H, m ), 7.41 (2H, d, J = 8 Hz) and 7.85 (2H, d, J = 8 Hz) ppn.

66 81 584

Prepared 4-p-methylphenylsulfonyloxytian from 4-hydroxytian (prepared from 4-oxothane by reduction with diisobutylaluminum hydride) using the methods of Preparation V and 1.2 equivalents of p-toluene-5-sulfonyl chloride. 0.1 equivalents of 4-dimethylaminopyridine and 1.2 equivalents of triethylamine and then silica gel column chromatography eluting with ethyl acetate-hexane 1: 1 gave the desired product in 95% yield. The NMR spectrum of the deuterium-chloroform solution of the product had 10 peaks at 1.8-2.2 (4H, m), 2.47 (3H, s), 2.5-3.1 (4H, m), 4.60 ( 1H, m), 7.35 (2H, d, J = 7 Hz) and 7.80 (2H, d, J = 7 Hz) ppm.

Preparation AA

Cis-1-oxo-3-methylcarbonylthiothiolane A solution of 25.5 g (0.093 mol) of trans-1-oxo-3-p-toluenesulfonyloxithiolane and 59 g (0.186 mol) of tetra-n-butylammonium thioacetate in 180 ml: in acetone, was heated under reflux for 1.5 hours under nitrogen. The reaction mixture was concentrated in vacuo and the residue was chromatographed on 800 g of silica gel. Elution with ethyl acetate gave 13.4 g (81% yield) of cis-1-oxo-3-methylcarbonylthiothiolane as a solid, m.p. 52.5 to 54 ° C.

The NMR-25 spectrum of the deuterium chloroform solution of the title compound had peaks at 2.06-3.26 (c) and 2.34 (s) (8H total) and 3.26-4.21 (c, 2H) ppm.

Similarly, trans-1-oxo-3-methylcarbonylthiothiolane was prepared from cis-1-oxo-3-p-toluenesulfonyl oxythiolane in 47% yield, and the NMR spectrum (250 MHz) of the deuterium chloroform solution of the trans isomer product showed peaks at 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.

Il 67 81 584 1-Oxo-3-p-methylphenylsulfonyloxithiolane

1.19 g (0.005 mol, purity 85%) of m-chloroperbenzoic acid were added portionwise over 5 minutes to a solution of 1.29 g (0.005 mol) of 3-p-toluene-5-bisulfonyloxithiolane in 40 ml of methylene chloride cooled to 0 °. To C in a nitrogen shield. After thirty minutes at 0 ° C, the reaction mixture was diluted with 125 mL of methylene chloride and the solution was treated with 20 mL of dilute aqueous sodium bisulfite to remove excess peracid. The pH of the mixture was adjusted to 7.5 with sodium bicarbonate, and the methylene chloride layer was washed with 20 mL of water and 20 mL of brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was chromatographed on 200 g of silica gel eluting with ethyl acetate-methanol 95: 5 to give 0.175 g of the more polar cis isomer and 0.92 g of the more polar trans isomer as oils (80% yield) which solidified. The trans isomer m.p. was 85-87 ° C; the cis isomer was a low melting point waxy solid.

The NMR spectrum of the deuterium coroform solution of the trans isomer of the title compound had peaks at 2.2 to 3.63 (c) and 2.5 (s) (total 9H), 5.42 (m, 1H), 7.34 (d , 2H) and 7.78 (d, 2H) ppm.

The NMR spectrum of the deuterium chloroform-25 solution of the cis isomer of the title compound had peaks at 1.95 to 3.23 (c) and 2.46 (s) (total 9H), 5.2 (c, 1H), 7.3 (d , 2H) and 7.76 (d, 2H) ppm.

Manufacture CC

3-p-Methylphenylsulfonyloxithiolane 0.95 g (0.005 mol) of p-toluenesulfonyl chloride was added to a solution of 0.52 g (0.005 mol) of thiolan-3-ol and 1.22 g (0.01 mol) of 4- dimethylaminopyridine in 20 ml of methylene chloride cooled to 0 ° C under nitrogen. After stirring for 1.5 hours at 0 ° C, the reaction mixture was allowed to warm to room temperature. After 4 hours at room temperature, the reaction was complete. The reaction mixture was diluted with 80 ml of methylene chloride and washed with 20 ml of dilute aqueous hydrochloric acid, 20 ml of water and 20 ml of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to an oil which solidified on standing (1.3 g, 100% yield), m.p. 56.5-58 ° C.

The NMR spectrum of the perdeuterium dichloromethane solution of the title compound had peaks at 1.5 to 2.52 (c) and 2.44 (s) (5H in total), 2.56 to 3.02 (c, 4H), 5.13 ( m, 1H), 7.28 (d, 2H) and 7.72 (d, 2H) ppm.

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Claims (5)

A process for the preparation of antibacterial 6-alpha-hydroxyethyl-2-substituted-2-penem-3-carboxylic acids of the formula H X H Λ_Pv-S'R H, C A process according to claim 1, characterized in that R 2 is hydrogen and R is 3-thietanyl, 1-oxo-3-thietanyl, 1,1-dioxo-3-thietanyl, 3-thiolanyl, 1- oxo-3 -thiolanyl, 11-dioxo-3-thiolanyl, 3-hydroxy-4-thiolanyl, 1-oxo-3-hydroxy-4-thiolanyl, 1,1-dioxo-3-hydroxy-4-thiolanyl, 3-thianyl , 1-oxo-3-thianyl, 1,1-dioxo-3-thianyl, 4-thianyl, 1-oxo-4-thianyl, 1,1-dioxo-4-thianyl, or 2-oxo-1,3- d: * - Iolan-4-ylmethyl. A process according to claim 2, characterized in that R is trans-1-oxo-3-thiolanyl. 3 M_ '—II 10. C00 R 1 where R is 3-thietanyl, 1-oxo-3-thietanyl, 1,1-dioxo-3-thietanyl, 2-thiolanyl, 1-oxo-2-thiolanyl, 3-thiolanyl, 1-oxo 3-thiolanyl, 1,1-dioxo-3-diolanyl, 2-oxo-1,3-dithiolan-4-ylmethyl, 3-thianyl, 1-oxo-3-thianyl, 1,1-dioxo-3 -thianyl, 3-hydroxy-4-thiolanyl, 1-oxo-3-hydroxy-4-thiolanyl, 1,1-dioxo-3-hydroxy-4-thiolanyl, 4-thianyl, 1-oxo-4-thianyl, 1 , 1-dioxo-4-thianyl, 1,3-dithiolan-2-yl or 1,2-dithiolan-4-yl; and R 1 are hydrogen, and their pharmaceutically acceptable salts, characterized in that a compound of formula II wherein R 2 is a protecting group for the carboxylic acid is hydrogenated in a solvent, under an atmosphere consisting of hydrogen or hydrogen. mixed with an inert diluent, in the presence of a hydrogenation catalyst of a noble metal at a pressure of about 0.5-5 kp / cm 2. 4. A process according to claim 2, characterized in that R is cis-1-oxo-3-thiolanyl. Process according to claim 2, characterized in that R is 1,1-dioxo-3-thiolanyl, trans-1-oxo-3-thianyl, cis-1-oxo-3-thianyl, trans-1- oxo-3-thietanyl, 1,1-dioxo-4-thianyl, 3-thianyl, trans-1-oxo-4-thianyl, cis-1-oxo-4-thianyl, or cis-1-oxo-3 -tietanyl. Il