HU194248B - Process for producing 2-azacycloalkyl-peneme derivatives and pharmaceutical compositions containing them - Google Patents

Abstract

Certain 2-azacycloalkylthio-2-penem-3-carboxylic acid compounds are useful as antibacterial agents for the treatment of mammals and have the formula or a pharmaceutically acceptable salt thereof, wherein RA is alkylene of 2 to 4 carbon atoms, alkylene of 2 to 4 carbon atoms, wherein a carbon atom has an oxo substituent, or alkylene of 2 to 4 carbon atoms wherein a methylene group is replaced by oxygen, S (O) m or N-R3; B is carbonyl, thiocarbonyl, methylene or imine; R1 is hydrogen or an ester group R 2 is hydrogen, formyl, alkylcarbonyl, N-alkyl-aminocarbonyl, N-alkylaminosulfonyl, aminosulfonyl, aminocarbonyl, alkoxycarbonyl of 2 to 5 carbon atoms, alkylsulfonyl, alkyl or alkyl substituted by aminocarbonyl, alkyl-S (O ) m-, hydroxyl, amino, alkylcarbonylamino, formamido or alkylsulfonylamino wherein each alkyl has 1 to 4 carbon atoms; R3 is hydrogen, methyl, formyl, methylcarbon yl or methylsulfonyl; alk is alkylene of 1 to 4 carbon atoms; n is zero or one and m is zero, one or two.

Description

The process of the present invention is for the preparation of a family of antibacterial agents containing a 2-azatidinone (beta-lactam) ring. Chemically Prepared Antimicrobial Agents of the Invention 6a-1-Hydroxyethyl-2-substituted-2-penem-3-carboxylic acid compounds

Although certain 2-substituted 2-penem-3-carboxylic acid compounds have been disclosed previously, there is a continuing need for new compounds having the desired antibacterial therapeutic activity.

No. 57,176,988. Japanese Patent Publication No. 6,198,125 discloses, inter alia, 6- (1-hydroxyethyl) -2-penem derivatives substituted at the 2-position by a heterocyclic group, including 3-pyrrolidinylthio or 3-piperidinylthio.

EP 70204 is incorporated herein by reference. European Patent Publication No. 6,123,198 discloses a 6- (1-hydroxyethyl) -2-substituted-2-penem derivative having 2-substituents including cyclohexylthio, 3-pyrrolidinylthio and 4-piperidinylthio.

The process of the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R is a group of formula (I) wherein A is C 2-4 alkylene, C 2-4 alkylene having carbon atoms. one of which is substituted with an oxo group, or wherein a methylene group is replaced by an oxygen or sulfur atom, and B is a carbonyl group or a methylene group,

R _{2 is} hydrogen, formyl or C 1 -C 4 alkyl, alk C 1 -C 4 alkylene, and n is 0 or 1, provided that A is not butylene, B is methylene, R _{2 is} hydrogen, alk is methylene or ethylene. .

The compounds of the formula (II) or pharmaceutically acceptable salts thereof, wherein R is as defined above for formula (I), are also included within the scope of the compounds of this invention.

Among the compounds of formulas I and II, those in which A is alkylene B is a cabonyl group, R _{2 is} hydrogen or methylene and n = 0. Particularly preferred are compounds in which R 1 is hydrogen and R is 2-pyrrolidione -3-yl, 2-pyrrolidon-4-yl, piperidin-2-one-3-yl, 1-methyl-piperidin-2-one-3-yl or 2-piperidin-5-yl -group.

Also preferred are compounds in which the alkylene, B is methylene, R ₂ -CHO, and n ^s is 0. Particularly preferred is a compound wherein R is hydrogen and R is 1-formyl-3-pinolidinŐ group or a l-formyl-piperidine-3 -yl.

Further preferred are compounds wherein A is a carbonyl ethylene or carbonylpropylene group, B is a carbonyl group, R _{2 is} hydrogen or methyl, provided that the ethylene or propylene group at position A is attached to B. particularly preferred are those compounds wherein R 1 is hydrogen and R is pyrrolidin-2,5-dione-3-yl.

Preferred are further those compounds, wherein A 1 oxaalkilén group, B is carbonyl, R ₂ is hydrogen or methyl, with the proviso that the oxygen of 1 -oxaalkilén group bind to B, particularly preferred are compounds. wherein R (3-methyl-1,3-oxazolidin-2-one-4-yl) methyl, (3 methyl-1,3-oxazolidin-2-one-5-yl) -ethyl, (13oxazolidine) 2-one-4-yl) methyl or (1 ', 3'-oxazolidin-2-one-5-yl) methyl.

The present invention encompasses the preparation of those of compounds in which the 1-oxaalkilén group, B is carbonyl, R ₂ is hydrogen or methyl and n = 0; it is particularly preferred that R 1 is hydrogen and R 3 is methyl perhydro-1,3-oxazolidin-2-one-5-yl.

The invention encompasses those compounds in which the 1-tiaalkilén group, B is carbonyl, R ₂ is hydrogen or methyl and n = 1; Particularly preferred, when R _(a hydrogen atom and R (l, 3-thiazolidin-2οη-4-yl) methyl group.

The present invention also provides a pharmaceutical formulation comprising as active ingredient a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, in addition to generally acceptable diluents and carriers.

The compounds of formulas (1) and (II) may be useful as antibacterial agents. These compounds can be derived from the bicyclic core of formula (III). The parent compound of formula (III) has the designation 2-penem and the numbering of the ring atoms is represented by the formula. The carbon atom to which the carbon atom in the ring is attached to is 6 is designated as 8. As used herein, the abbreviation PNB refers to a p-nitrobenzyl group.

Both the hydrogen atoms on the bridgehead carbon 5 and the hydrogen atoms on the carbon atoms of the compounds of formula I can be either cis or trans. The present invention encompasses both isomers and mixtures thereof. The trans isomer is generally preferred for pharmaceutical use, but the cis isomer can be easily converted to the trans isomer.

The absolute stereochemistry of carbon 5 may generally be designated R by the term R, S stereochemistry as Prelog-Ingold. For example, the compound of formula (II) wherein R 1 is hydrogen and R 2 is pyrrolidon-3-yl is (5R, 6S) -6 / (R) -1-hydroxyethyl / -2- ( 2-pyrrolidon-3-yl) -thio-3-carboxyl-2-penethane.

As is evident, many optically active isomers are possible with new compounds. The present invention encompasses these optically active isomers and mixtures thereof.

According to the invention, a compound of formula (IA), which is a carboxyl protecting group which is easily removed by the hydrogenolysis of R4, is subjected to hydrogenolysis.

The compounds of formula 01 may be synthesized as described in lines 1-3.

As shown in Formula 1, a compound of formula (Π) can be prepared from the known dibromopenam of formula (IV) by the method described by Yoshida et al., Chem. Pharm. Bull. 29, 2899-2909 (1981). The dibromopenam of formula (ΓΥ) is firstly reacted with tert-butyl magnesium chloride at a temperature of -90 to -40 ° C, preferably about -78 ° C, in an inert solvent such as tetrahydrofuran, diethyl ether or toluene, preferably tetrahydrofuran. Other organometallic compounds may also be used, and the resulting reaction mixture is treated in situ with the appropriate aldehyde, for example, with acetaldehyde to give the 1-hydroxyethyl derivative.

194,248 in the Decade. The aldehyde is added at -80 to -60 ° C, preferably at -78 ° C for acetaldehyde.

The resulting bromo-hydroxypenam of formula (V) is hydrogenated to remove the 6-bromo substituent. 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, or preferably 1: 1 methanol-water, 1.01-4.05, preferably 4.05 bar. pressure and from 0 to 30 ° C, preferably at about 25 ° C.

The resulting alcohol of formula VI may be protected by a trialkyl halosilane of formula 2 wherein R _{9 is C} 1-6 alkyl in each respect and Q is chloro, bromo or iodo. Thus, dimethyl-tert-butyl chlorosilane in the presence of a proton-acceptor amine such as imidazole,

In a volatile aprotic solvent such as Ν, Ν-dimethyl-urea, the trialkylsilyl hydroxyl protecting group represented by formula (VII) is formed at a temperature between 5 and 40 ° C, preferably at 25 ° C.

Treatment of the compound of formula (VII) with mercuric acetate in acetic acid at a temperature of about 90 ° C results in the olefin of formula (VIU).

In order to obtain the desired azetidinone of formula IX, the olefin of formula VIII is ozonized in an inert solvent such as dichloromethane at a temperature of -80 to -40 ° C, preferably -78 ° C. Treatment of the reaction product with an alkanol such as methanol yields azetidine of formula IX.

In Scheme 2, the compound of Formula IX is treated with a tritocarbonate salt of M * R ₁₀ -SC (S) -S-, wherein R _{10 is C} 1-4 alkyl, preferably ethyl, and M is a metal. such as sodium or potassium in order to obtain a compound of formula (X). The conversion of the compound of formula IX to the compound of formula 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 from 0 to 35 ° C, preferably at a temperature of about 25.

The compound of formula (X) is condensed with p-nitrobenzyl chloroxalate in the presence of a tertiary alkylamine in which, for example, each alkyl group contains from 1 to 4 carbon atoms, such as ethyl diisopropylamine, and thus the compound of formula XI obtained. The condensation reaction is carried out in an inert solvent, preferably dichloromethane, at a temperature between 5 and 25 ° C, preferably at about 10 ° C.

The resultant product of formula XI is subjected to a ring closure reaction using trialkyl phosphite in which there are C1-C4 alkyl groups such as triethyl phosphite in inert solvent and trichloromethane at a temperature of about 40-80 ° C, preferably about 60 ° C. yielding the penem compound of formula XII.

The thio group of the compound of formula (ΧΠ) is treated with an oxidizing agent such as m-chloroperbenzoic acid in an inert solvent such as dichloromethane at a temperature of -10 ° C to -30 ° C, preferably -20 ° C. to a corresponding sulfoxide.

The sulfoxide group of the compound of formula (XDI) is displaced by a mercaptide group of formula RS-, for example, by reacting the sodium or potassium salt of the corresponding mercaptide in a polar organic solvent such as ethanol or acetonitrile at temperatures between -10 and -50 ° C, preferably At -35 ° C, the sulfoxide of formula (XIII) is reacted.

R-SH is used as the starting material of formula mercaptans or RSC (O) CH ₃ are known thioacetates of the formula R is a number of variants. Those which are not known can be prepared by analogous methods known to those skilled in the art. References in the literature can be found in JL Wardell's "The Making of Thiols" (John Wiley and Sons, London, 1974, Chapter 4) and in the series "Chemistry of the Thiol Group" edited by S. Patai. For more information, see Volante's announcement in Tetrahedron Letters. (22, 3119-3122, 1981), which deals with the conversion of alcohols with triphenylphosphine and dialkyl azodicarboxylate to thiols and thiol esters in the presence of the corresponding alcohol and a suitable thiol acid.

Preferably, the trialkylsilyl group of compounds of formula XIV is cleaved prior to hydrogenolysis to remove the acid protecting group (PNB) to give compound of formula XV. The trialkylsilyl group is removed in an ethereal solvent such as tetrahydrofuran, preferably at about 25 ° C, with tetraalkylammonium fluoride at a temperature in the range of 15-40 ° C.

Conversion of a compound of formula (XV) to a compound of formula (II) may be accomplished using conventional hydrogenolysis and may be carried out in the conventional manner. Thus, a solution of the compound of Formula XV is stirred or shaken under a hydrogen pressure of 1.01 bar, or a hydrogen atmosphere diluted with an inert diluent such as nitrogen or argon is used in a noble metal hydrogenolysis catalyst such as Pd / CaCO ₃ or Pd / Celite (diatomaceous earth). in the presence of a catalytic amount. Suitable solvents for this hydrogenolysis are 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.

In any case, it is customary to select conditions under which the starting material is soluble, such as aqueous tetrahydrofuran. Hydrogenolysis is usually carried out at room temperature, at pressures of 0.5 to 5 kg / cm ¹ . The catalyst is usually employed in an amount of 10 to 100% by weight of the starting material, although larger amounts may be used. The reaction is usually complete in one hour and the product of formula (II) is isolated by filtration and the solvent is removed in vacuo. If Pd / CaCO ₃ is used as the catalyst and the product's calcium salt is obtained, the Pd / Celite salt is isolated.

The products of formulas (I) and (U) can be purified by conventional methods for the beta-lactam compounds. For example, the product of formula (I) can be purified by gel filtration on Sephadex or by recrystallization.

Row 3 illustrates an alternative synthesis procedure. The azetidine of formula (IX) is reacted with thiocarbonate of formula M ⁺ -S- (OS) -S-, wherein M is a metal such as sodium or potassium using the procedure previously described for the preparation of compound (X). .

194 248

The resulting trithiocarbonate (XVa) is obtained in an aprotic solvent, benzene, toluene or dimethylformamide, preferably benzene, at a temperature in the range of 25-110 ° C, preferably at 80 ° C (treated with p-nitrobenzyloxycarbonyldihydroxymethane). ).

The corresponding chloride of Formula XVII is reacted with an alcohol of Formula XVI in an organic solvent such as dichloromethane in the presence of a tertiary amine, such as 2,6-lutidine, -10 and -75, in an organic solvent such as dichloromethane. ° C, preferably at 0 ° C.

The chloride of Formula XVII is reacted with triarylphosphine such as triphenylphosphine in an inert solvent such as tetrahydrofuran in the presence of a tertiary amine such as 2,6-lutidine at a temperature in the region of 25 ° C. The compound of formula (XVII) is obtained which is ring-closed in an aromatic solvent, such as toluene, under reflux to give penem of formula (XTV).

M ⁺ RS- (C = S) -S formula ^_ thiocarbonate salts can be prepared corresponding to the general formula R-SH mercaptan or an RSC (0) CH 3 thioacetate general formula by treatment with an alkali metal oxide, followed by reaction with carbon disulfide DOS.

Using the method previously quoted by Yoshida et al., The stereochemistry of the carbon atom of penem t and the hydroxyethyl group attached to the carbon atom of 6 are formed as described in formula II. Thus, using the process of Formula 2 or 3, the basic stereochemistry of the ring closure product is that the hydrogen at C 5 of the penis ring is trans-positioned and alpha-configurated with respect to C 6. Alternatively, 5R, 6S; 6- (R) -1-Hydroxyethyl is stereochemistry.

The compounds of formulas I and U are acidic in nature and form salts with basic agents. Such salts are also encompassed by the present invention. These salts may be prepared by standard techniques for combining the acidic and basic components, usually in stoichiometric proportions, in aqueous, anhydrous, or partially aqueous medium as it may be convenient.

The product may be recovered by filtration, precipitation, after filtration, by addition of a non-solvent, by evaporation of the solvent or, in the case of aqueous solutions, by lyophilization, as appropriate. The basic agents used in the salt formation may be organic or inorganic, and include ammonia, organic amines, alkali metal hydroxides, carbonates, hydrides and alkoxides, as well as hydroxides, carbonates, hydrides and alkoxides of alkaline earth metals. Representative representatives of such bases include primary amines such as n-propylamine, n-butylamine, aniline, dclohexylamine, benzylamine and octylamine; secondary amines include diethylamine, morpholine, pyrrolidine and piperidine; tertiary amines include triethylamine, N-methylpiperidine, N-methylmorpholine, and 1,5-diazabicyclo [4,3,0] non-5-ene; hydroxides such as sodium hydroxide, potassium hydroxide, ammonium hydroxide and potassium hydroxide; alkoxides and sodium ethoxide and potassium ethoxide; hydrides such as calcium hydride and sodium hydride; carbonates and potassium carbonate and sodium carbonate; bicarbonates such as sodium bicarbonate and potassium bicarbonate; and alkali metal salts of long chain fatty acids, such as sodium 2-ethylhexanoate.

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

Pharmaceutically acceptable salts of the compounds of formulas I and II are those which, at the usual dosage level, are free from significant deleterious side effects; these include the sodium, potassium and calcium salts of these compounds.

The in vitro antibacterial activity of the compounds of formula (I) and (II) and their salts is expressed in mcg / ml expressed as a minimal inhibitory concentration (MIC) on certain selected microorganisms. For these measurements, the procedure described in the International Collaborative Study on Antibiotic Sensitivity Testing (Ericsson and Sherris, Acta. Patologica et Microbiologica Scandinav., Supp. 217, Chapter B, pp. 64-68, 1971) was followed and brain-infusion (BHI) was performed. ) agar and inoculum replication device were used. Tubes grown overnight were diluted 100-fold for use as a standard inoculum (cell count between 20,000 and 10,000, approximately 0.002 mL, placed on agar surface; 20 mL of BHI agar was added per dish). Twelve dilutions of the test substance were used, the initial concentration of the test substance being 200 mcg / ml. Individual colonies are ignored when reading plates at 37 ° C for 18 hours. The susceptibility of the microorganism used for testing was considered valid if the lowest concentration of compound that caused complete inhibition resulted in a clear inhibitory ring visible to the naked eye.

The compounds of formulas I and II, and pharmaceutically acceptable salts thereof, are useful in the treatment of bacterial infections in mammals, including man. Their practical use may be in the treatment of bacterial infections in human subjects, such as those suspected of being caused by Staphylococcus aureus.

The compounds of the present invention may be administered orally and parenterally, for example, intramuscularly, subcutaneously, intraperitoneally or intravenously, alone or via pharmaceutically acceptable excipients. The ratio of active ingredient to excipients will depend on chemical properties, solubility and stability, as well as the intended dosage. The ratio of pharmaceutically acceptable excipients to penem compounds is generally 1:10 to 4: 1.

For oral use, the compounds of the present invention may be formulated as tablets, capsules, lozenges, lozenges, powders, syrups, elixirs, aqueous solutions, suspensions, and the like. Lactose, sodium citrate, and phosphoric acid salts are used as carriers in the preparation of tablets. Many materials can be used to aid disintegration, such as starch. Lubricating agents such as magnesium stearate sodium allyl sulfate and talc are also commonly used in tablet formulation. Useful diluents in the preparation of capsules include lactose and high molecular weight polyethylene glycols. When aqueous suspensions are required for oral administration, the active ingredient is combined with emulsifying and suspending agents.

I can also add sweetening and flavoring agents. For parenteral administration, a sterile solution of the active ingredient is usually prepared, suitably pH adjusted.

194,248 configured and buffered. For intravenous use, the total concentration of the product should be checked to ensure that the solution remains isotonic. The dosage to be applied to a particular human patient will ultimately be determined by the prescribing physician and will depend upon the patient's age, weight, individual response and ultimately the nature and severity of the patient's symptoms.

The average daily dose of the compounds of formulas (1) and (Π) is 10-200 mg / kg body weight for oral administration and 10-400 mg / kg body weight for parenteral administration. In some special cases, it may be necessary to use doses above these limits.

The following examples and compositions serve merely to further illustrate and by no means limit the process of the present invention. Infrared spectra (IR) were measured either in KBr pastilles (KBr) or Nojul, and in chloroform solution (CHQ ₃ ), methylene chloride solution (CH ₂ Cl ₂ ) or dimethylsulfoxide (DMSO) and cut the absorption bands. micron or wave number (cm ^-1 ). The magnetic resonance spectra (NMR) was measured in deuterochloroform (CDC1 ₃₎ perdeuterometanolos (CD ₃ OD) or perdeutero dimetüszulfoxidos (DMSO-dj) solution, or a mixture thereof, and peak positions are expressed in ppm expressed as the area under tetramethylsilane. The shapes of the peaks are referred to as the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, b = wide, c = complex. The abbreviations "ss" and "sss" indicate that a given proton appeared as two or three singlets due to the presence of diastereomers. In the examples and formulations, the abbreviation PNB still refers to the p-nitrobenzyl group.

Example 1

Sodium (5R, 6S) -6 - ((R) -1-hydroxyethyl) -2- (2-pyrrolidon-3-yl) -thio-2-penem-3-carboxylate in ml of tetrahydrofuran and 20 ml of distilled water 10% Pd (Celite) (73 mg) was suspended in the mixture and adjusted to pH 8.3 with 0.02 M aqueous sodium bicarbonate. Then dissolved in tetrahydrofuran (8 ml) and water (73 mg), nyl (5R, 6S) -6 - ((R) -1-hydroxyethyl) -2- (2-pyrrolidon-3-yl) thio-2-penm-3-carboxylate is added and Hydrogenate at 85 atm for 75 minutes, then add another 73 mg of 10% Pd (Celite) and adjust the pH to 7 with 0.02 M sodium bicarbonate.

After hydrogenation at 3.85 atm, the catalyst was evaporated and the filtrate was distilled off in vacuo to remove tetrahydrofuran. Ph of the resulting aqueous solution

They were raised to 7 and extracted with ethyl acetate (2 x 15 mL). The aqueous solution was then lyophilized to give 38 mg (69% yield) of the title product as an amorphous solid.

The absorption spectrum of the title compound in the LR spectrum (KBr) was 2.94, 5.65 and 6.3 microns.

Example 2

Using the procedure described in Example 1, starting from the corresponding compounds of formula XV, the sodium salts of compounds of formula II are obtained, their yield, IR spectra, unless otherwise stated, and the R substituents are shown in I. Presents table.

1.That's the t R IR (micron) Yield (%) 2-pyrrolidone-4-yl 2.92, 5.68, 6.0 and 6.15 88 1-formyl-3-pyrrolidin-yl 2.92, 5.64, 6.03 and 6.3 89 (3-Methyl-1,3-oxazole- 2.94, 5.7 and 625 78 din-2-one-5-yl) methyl (3-Methyl-1,3-oxazolidin-2-one -4-yl) methyl 2.94, 5.7 and 6.28 90 2-piperidone-5-yl 5.64, 6.02 and 6.3 (DMSO) 93 piperidin-2-one-3-yl 2,94,5,66,6,6 / 06 and 6,25 79 pipeiidin-l-methyl-2- -οη-3-yl 2,93,5,64 and 6,15 98 1-formyl-piperidine -3-yl 2.9, 5.65 and 6.03 73 3-Methyl-perhydro-1,3-oxazin-2-one-5-yl (less soluble, diastereomer) 2.92, 5.63,5.99 and 6.08 57 3-Methyl-perhydro-1,3-oxazin-2-one-5-yl (from the more soluble diastereomer) 5.65 (DMSO) 84

Example 3

Sodium (5R, 6S) -6 - / (R) ethyl -14üdroxi / -2- (pinolidin-2,5-dione-3-yl) thio-2-penem-3-carboxylate

The procedure described in Example 1 was applied except that the pH was 7.5 and R was pyrrolidin-2,5-dione in the starting material (XV). The product was obtained in 90% yield and showed IR absorption (KBr) at 2.92, 5.63, 5.8 and 6 microns.

Example 4

The procedure of Example 3 was used using the appropriate compounds of formula XV to swallow the sodium salts of the compounds of formula II, the yield,? -Spectrum (KBr, unless otherwise stated), and the R substituents of the compound of formula IA. Presents table.

IA. Spreadsheet R IR (micron) Yield: (%) (1,3-oxazolidin-2-οη-4-yl) · methyl- 5.72 (b) 95 (1,3-oxazolidin-2-on-5-yl) methyl 5.72 (b) 87 (1,3-tiazoüdln-2-on-4-yl) methyl 5.65 100

S

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Example A p-Nitrobenzyl (5R, 6S) -6 - ((R) -1-hydroxyethyl) -2- (2-pyrrolidin-3-yl) · thio-2-penem-3-carboxylate

118 mg (0.204 mmol) of p-nitrobenzyl (5R, 6S) -6 - ((R) -1-tert-butyldimethylsilyloxyethyl) -2- (2-pyrrolidon-3-yl) To a solution of thio-2-penem-3-carboxylate in 6 mL of tetrahydrofuran was added 0.11 mL (2.04 mmol) of acetic acid and 0.612 mL (0.612 mmol) of 1 mL of tetrahydrofuran in tetrabutylammonium fluoride. After stirring at room temperature under nitrogen for 20 hours, ethyl acetate (50 mL) was added and the resulting solution was washed with aqueous saturated sodium bicarbonate solution (40 mL), water (40 mL) and brine (40 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product (50 mg) was chromatographed on silica gel (50 g) eluting with 95: 5 ethyl acetate: methanol to give 73 mg (77% yield) of the title compound as an amorphous solid.

The title compound NMR (CDC1 ₃₎ indicates whether the following peaks: 1.32 (d, 3H), 2.0 to 30 (c, 3H); 30 to 4.37 (c, 5H), 5.3 (q, 2H), 5.6 (d, 1H),

6.64 (b, 1H), 7.6 (d, 2H) and 8.2 (d, 2H).

The dichloromethane solution of the title compound exhibited an IR spectrum at 5.58, 5.85 and 6.57 microns.

Example B.

Using the procedure described in Example A, compounds of formula (XIV) were prepared from compounds of formula (XV) having IR,

NMR, yield, and R are shown in Table II. This is shown in the table. The solvents in which the spectra were recorded are shown in parentheses.

Π. Spreadsheet

R IR (micron) NMR (ppm) Yield (%)

2 piirolidon-4-yl 5.58, 5.87 and 6.58 (CH3Cl3) 1.3 (d, 3H), 2.0-4.42 (c, 8H), 5.3 (q, 2H), 5.3 (q, 2H), 5.68 (d, 1H) 605 (b, 1H) ), 7.56 (d, 2H) and 8.18 (d, 2H), CDC1 ₃₎ 87 1-formyl-3-pyrrolidinyl 5.57, 5.96 and 6.56 (CH3Cl3) 1.35 (d, 3H), 10-2.6 (c, 2H), 30 (b, 1H), 30-4.46 (7H), 5.3 (q, 2H), 5.64 ( d, 1H), 7.6 (d, 2H) and 8.2 (s and d, 3H), (CDCl ₃ ) 42 (3-Methyl-1,3-oxazolidin2-one-5-yl) methyl- 5,56,5,66 & 607 (CH 3 Cl 3) 106 (d, 3H), 2.4 (b, 1H), 2.9 (s, 3H), 3.17-3.92 (c, 5H), 4.04-4.86 (c, 2H) , 5.31 (q, 2H), 5.69 (d, 1H), 7.6 (d, 2H) and 8.2 (d, 2H) (CDCl ₃ ). 38 (3-methyl-1,3-oxazolilidin-2-on-4-yl) methyl 5,56,5,67 and 606 (CH 3 Cl 2) 105 (d, 3H), 2.2 (b, 1H), 2.89 (s) and 2.81-3.5 (c) (full 5H), 3.6-4.49 (c, 5H) 5.3 (q, 2H), 5.67 (d, IH), 7.56 (d, 2H) and 8.16 (d, 2H) (CDC1 ₃₎ 25 pyrrolidin-2,5-dione-3-yl 5.57, 5.75 and 6.54 (CH3) 1.3 (d, 3H), 2.1 (b, 1H), 2.5- 4.4 (c, 6H), 5.3 (q, 2H), 5.65 (d, 1H), 7.56 (d, 2H) and 8.16 (d, 2H) (CDCl3). 32 2-piperidone-5-yl 5.64 and 6.0 (Nujol) 1.18 (d, 3H), 1.74-2.8 (c, 4H), 3.05-3.75 (c, 4H), 4.03 (m, 1H), 5.25 (d, 1H) ), 5.37 (q, 2H), 5.78 (d, 1H), 7.66 (b, 1H), 7.7 (d, 2H), and 8.25 (d, 2H) (DMSO-). d _e , 250 MHz) 2.0 (b, 1H), 107 (d, 3H), 3.1 (m, 2H), 3.7 (dd, 1H), 3.8-4.67 (c, 4H), 5.31 (q, 2H), 5.68 (d, 1H), 7.1 (b, 1H), 7.6 (d, 2H) and 8.18 (d, 2H) (CDCl ₃ ) CD ₃ OD) 86 (1,3-oxazolidin-2-one-4-f) methyl 5,5,5,67, 5,91 and 608 (CH 3 Cl 3) ⁵⁷ (1,3-oxazoH-din-2-one-S-yl) -methyl- 508, 5.67 and 608 (CH3Cl3) 109 (d, 3H), 2.2 (b, 1H), 3.13.98 (c, 5H), 4.1 (m, 1H), 4.83 (c, 2H), 5.3 (q , 2H), 5.7 (d, 1H), 7.1 (b, 1H), 7.58 (d, 2H) and 8.17 (d, 2H) (CDCl ₃ ) DMSO-d ₆ ) 56

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Π. Τ 1 b Η ζ ι t

R IR (micron) NMR (ppm) Yield (%)

(1,3-thiazolidin-2-one 5,61,5,97, 6,06,6,6 and 1.18 (d, 3H), 3.13-3.46 (c, 3H) 64 -4-yl) methyl 6.7 (KBr) 3.62 (dd, 1H), 3.88 (dd, 1H), 4.02 (m, 1H), 4.1 (m, 1H), 5.25 (d, 1H), 5.38 (q , 2H), 5.76 (d, lH) 7.7 (d, 2H), 8.24 (d, 2H) and 8.42 (s, IH) (250 MHz, _DMS0-d6) piperidin-2-one-3-yl 5.56, 5.9, 6.0 and 6.56 (CH 3 Cl 2) 12 (d, 3H), 135-2.45 (c, 4H), 3.28 (c, 2H), 352-4.42 (c, 4H), 5.32 (q, 2H), 5.65 and 5.7 (2d, full 1H), 7.12 (b, 1H), 7.6 (d, 2H) and 8.2 (d, 2H) (CDCl ₃ ) DMSO-d ₆ ) 65 l-methyl-piperidin-2-on-3-yl 5.56, 5.92, 6.07 and 656 1.3 (d, 3H), 1.7-2.45 (c, 5H), 2.96 (s, 3H), 3.3 (m, 2H), 3,654.45 (c, 3H), δ , 3 (q, 2H), 5.6 (d, 1H, 7.57 (d, 2H) and 8.2 (d, 2H) (CDCl3) 1.12-2.33 (c) and 1.3 (d) (full 8H), 2.78-4.62 (c, 7H), 5.28 (q, 2H), 5.63 (d, 1H), 7.54 (d, 2H), 7, 98 (s, 1H) and 8.16 (2H) (CDCl ₃ ) 40 1-formyl-piperidin-3-yl- 5.57, 5.97 and 6.56 (CH ₂ Q ₂ ) 64

Example C p-Nitrobenzyl- (5R, 6S) -6 '/ (R) -1'-hydroxyethyl--2- (3-methylpyridro-1,3-oxazin-2-one-5-yl) thio-2-penem-3-carboxylate gg

From a 1 molar solution of tetrabutylammonium fluoride in tetrahydrofuran, 1.25 ml (1.25 mmol) and 0.25 ml of acetic acid were added 0.24 g (0.39 mmol) of p-nitrobenzyl (5R, 6S) - 6 - ((R) -1-tert-Butyldimethylsilyloxyethyl) -2- (3-methylpiperidro-1,3-oxazin-2-one-5-yl) thio-2-penem -3-carboxylate in 2 ml of anhydrous tetrahydrofuran. The resulting solution was stirred at 25 ° C under nitrogen for 20 hours. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (10 mL), brine (2 x 20 mL), water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The dry residue was stirred with methanol (5 mL), diethyl ether (15 mL) was added and the mixture was filtered to give 71 mg of the less soluble diastereomer as a light brown solid. The filtrate was concentrated in vacuo and the residue was chromatographed on silica gel (75 g), eluting with 9: 1 ethyl acetate / methanol to give the more soluble diastereomer as a solid. Trituration of the solid with diethyl ether / petroleum ether (1: 1) afforded after filtration 52 mg of the more soluble diastereomer as a light brown solid (63% overall).

Less soluble stereomer: NMR (DMSO-d ₆ ,

250 MHz): 1.2 (d, 3H), 2.86 (s, 3H), 3.4 (dd, 1H),

3.83 (dd, 1H), 3.9-4.1 (c, 3H), 4.25 (dd, 1H), 4.51 dd, 1H), 5.26 (d, 1H), 5.38 ( q, 2H), 5.8 (d, 1H), 7.7 d, 2H) and 8.26 (d, 2H) ppm. 55

The more soluble stereomer: NMR (DMSO-d *,

250 MHz): 12 (d, 3H), 2.86 (s, 3H), 3.35 (dd, 1H),

3.81 (dd, 1H), 3.9-4.1 (c, 3H), 4.29 (dd, 1H), 4.54 (dd, 1H), 5.26 (d, 1H), δ , 39 (q, 2H), 5.83 (d, 1H),

7.7 (d, 2H) and 8.26 (d, 2H) ppm.

IR (KBr): 2,92,5,61,5,85,5,91 and 6,61 microns. w

Example D p-Nitrobenzyl (5R, 6S) -6 - ((R) -1-tert-butyldimethylsilyloxyethyl) -2- (2-pyrrolidon-3-yl) thio-2-penem- Sodium methoxide 3 mg carboxylate (0.5 mmol) was added to a cooled solution of 80 mg (0.5 mmol) of 2-pyrrohdon-3-ylthioacetate in 5 mL of dry methanol under nitrogen at -30 ° C. After 30 minutes at -30 G, crude p-nitrobenzyl- (5R, 6S) -6- (R) -1-tert-butyldimethylsilyloxyethyl (300 mg, 0.5 mmol) was added. -2-Ethylsulfinyl-2-penem-3-carboxylate, prepared as described in Example I, was dissolved in 5 ml of anhydrous tetrahydrofuran and cooled to -50 ° C. The resulting solution was stirred at -30 ° C for 60 min, then acetic acid (0.029 mL, 0.5 mmol) was added and the solution was concentrated in vacuo. The residue was dissolved in ethyl acetate (50 mL) and the resulting solution was washed with saturated sodium bicarbonate solution (40 mL), water (40 mL) and brine (40 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. Chromatography of the crude product (370 mg) on silica gel (120 g, 1: 1 chloroform / ethyl acetate) gave 118 mg (41% yield) of the product as a viscous gum.

The dichloromethane solution of the title compound has an IR spectrum at 5.58, 5.86 and 6.58 microns. Nuclear Magnetic Resonance Spectrum (CDCl3) showed the following peaks: 0.06 (s, 3H), 0.1 (s, 3H), 0.84 (s, 9H), 1.24 (d, 3H), 1, 92-2.98 (c, 2H), 3.23-4.4 (c, SH), 5.29 (q, 2H), 5.6 (d, 1H), 6.6 (b, 1H) , 7.55 (d, 2H) and 8.16 (d, 2H) ppm.

-Ί1

194 248

This is an example

The procedure described in Example D is used starting from the appropriate thioacetate to give UI. Compounds of formula (XIV) having the properties described in the Table and having the substituent R are obtained.

IH. Spreadsheet

R IR (micron) NMR (ppm) Yield (%)

2-pyrrolidone-4-yl- 5.58, 5.86 and 6.57 (CH3Cl3) 0.04 (s, 3H), 0.09 (s, 3H), 0.82 (s, 9H), 1.25 (d, 3H), 2.14.42 (c, 710.5.29 ( q, 2H), 5.62 (d, IH), 6.44 (b, IH), 7.57 (d, 2H), and 8.16 (d, 210 (CDC1 ₂₎ 31 1-formyl-3-pyrrole dinyl- 5.58, 6.02 and 6.57 0.02 (s, 3H), 0.09 (s, 3H), 0.85 (s, 9H), U4 (d, 3H), 0.08-2.42 (c, 2H), 3.3 -4.47 (c, 7H), 5.28 (q, 2H), 5.64 (d, 1H), 7.55 (d, 2H) and 8.16 (d) and 8.1 (s). (full 3H) (CDCl ₃ ) 0.05 (s, 3H), 0.1 (s, 3H), 0.85 (s, 9H0.1.26 (d, 3H), 2.89 (s, 3H) ), 3.12-3.89 (c, 5H), 4.04-4.8 (c, 2H), 5.3 (q, 2H), 5.67 (d, 1H), 7.6 ( d, 2H) and 8.2 (d, 2H) (CDCl ₃ ) 37 (3-Methyl-1,3-oxazolidin2-one-5-yl) methyl- 5,57,5,66,5,9 and 6,57 (CH ₂ Cl ₂ ) 49 (3-Methyl-1,3-oxazolidin-2-one-4-yl) methyl- 5,56,5,67,5,88 and 6,57 (CH ₂ Cl ₂ ) 0.02 (s, 3H), 0.08 (s, 3H), 0.82 (s, 910.1.26 (d, 3H), 2.9 (s), and 2.8-3.5 (c) ) (full 5H), 3.65-4.54 (c, 5H), 5.3 (q, 2H), 5.69 (d, 1H), 7.6 (d, 2H) and 8.2 ( d, 2H) (CDCl ₃ ) 48 2-piperidone-5-yl 5.62 and 6.0 (Nujol) 0.04 (s, 3H), 0.08 (s, 3H), 0.84 (s, 910, 1.27 (d, 3H), 1.85-2.7 (c, 4H) 3.34 -3.84 (c, 4H), 4.28 (m, 1H), 5.33 (q, 2H), 5.69 (d, 1H), 6.06 (b, 1H), 7.63 ( d, 2H) and 8.22 (d, 2H) (CDCl ₃ , 250 MHz) 34 piperidin-2-on-3-yl 5.57, 5.98 and 6.56 (CH ₂ Cl ₂ ) 0.03 (s, 3H), 0.06 (s, 3H), 0.84 (s, 9H), 1.22 (d, 3H), 1.66-2.4 (c, 4H), 3 , 34 (c, 2H), 3.6-4.5 (c, 3H), 5.26 q, 2H), 5.56 and 5.62 (2d, full 1H), 6p (b, 1H), 7.54 (d, 2H) and 8.14 (d, 2H) (CDCl ₃ ) 29 l-methyl-piperidin-2-one -3-yl 5,57,5,93, 6.08 and 6.56 (CH ₂ C1 ₂₎ 0.03 (s, 3H), 0.06 (s, 3H), 0.82 (s, 9H), 1.22 (d, 3H), 1.6-2.36 (c, 4H) 2, 96 (s, 3H), 3.3 (m, 2H), 3.67-4.43 (c, 3H), 5.28 (q, 2H), 5.57 (d, 1H), 7.57 (d, 2H) and 8.18 (d, 2H) ₃ CDQ) 40 l-formyl-piperidin-3-yl 5.8, 5,98,6,58 (CH ₂ Cl ₂ ) 0.03 (s, 310, 0.06 (s, 3H), 0.82 (s, 9H), 1.1-2.3 (c) and 1.23 (d) (full 7H), 2, 8-4.5 (c, 7H), 5.26 (q, 2H), 5.62 (d, 1H), 7.54 (d, 2H), 7.98 (s, 1H) and 8.14 ( d, 2H) (CDCl ₃ ) 48

Example F.

The procedure described in Example D and purified p-nitro-benzyl- (5R, 6S) -6- (R) -1-tert-butyldimethylsilyloxyethyl / -2-ethylsulfinyl-2-penem Using 3-carboxylate (prepared as in Example H) and the corresponding thioacetate compounds, compounds of formula (XIV) having the properties and R substituents were prepared. Presents table. θθ

194 248

IIIA. Spreadsheet

R IR (micron) NMR (ppm) Yield (%)

(1,3-oxazolidin-2-one 5,57,5,67,5,92 and 638 0.03 (s, 3H), 0.06 (s, 3H), 0.82 40 -4-yl) methyl · (CHjClj) (s, 9H), 122 (d, 3H), 3.1 (2d, 2H), 3.72 (dd, 1H), 3.82-4.68 (c, 4H), 5.26 (q, 2H), 5.64 (d, lH), 5.98 (b, IH), 7.54 (d, 2H) and 8.16 (d, 2H) ₍₃ CDA) (L, 3-oxazolidin-2-one 5.6, 5.67, 5.92 and 638 0.03 (s, 3H), 0.06 (s, 3H), O, 82 48 -5-yl) methyl (CH ₂ Cl ₂ ) (s, 9H), 1.22 (d, 3H), 3.1-4.0 (c, 5H), 4.22 (m, 1H), 4.8 (m, 1H), 5.29 (q, 2H), 5.65 (d, 1H), 5.84 (b, 1H), 7.56 (d, 2H) and 8.16 (d, 2H) (CDCl 3) 0.03 (s, 3H), 0.06 (s, 3H), 0.82 (1,3-thiazolidin-2-one 5.56, 5.89 and 634 50 -4-yl) methyl (CHjClj) (s, 9H), 1.22 (d, 3H), 3.0-4.42 (c, 7H), 5.3 (q, 2H), 5.66 (d, 1H), 6.0 ( b, 1H), 7.56 (d, 2H) and 8.16 (d, 2H) (CDCl3) 3-Methyl-perhydro-1,3-oxazin-2-one-5-ylmethyl 0.05 (s, 3H), 0.08 (s, 3H), 0.84 (s, 9H), 127 (d, 3H), 3.0 (s, 3H), 3.37 (dd, 1H) ), 3.67 (dd, 1H), 3.8 (c, 2H), 4.14-4.34 (c, 2H), 4.47 (dd, 1H), 5.33 (q, 2H) , 5.72 (d, 1H), 7.62 (d, 2H) and 8.23 (d, 2H) (CDCl3, 250 MHz). 82

Example G p-Nitrobenzyl- (5R, 6S) -6- (R) -1-tert-butyldimethylsilyloxyethyl-2- (pyrrolidine-2,5-dione-3-yl) thio -2-Penem-3-carboxylate In 35 ml of anhydrous ethanol was dissolved 87 mg (0.5 mmol) of pyrrolidine-2,5-dione -3-ylthioacetate, 54 mg (1.0 mmol) of sodium metric time was added and the reaction mixture was cooled to -35 ° C under nitrogen. After four hours at this temperature, 300 mg / kb. 40 0.5 mmol / crude p-nitrobenzyl (5R, 6S) -6- (R) -1-tert-butyldimethylsilyloxyethyl / -2-ethylsulfinyl-2-penem-3-carboxylate A solution of 5 ml of anhydrous tetrahydrofuran and cooled to -50 ° C is added. The resulting mixture was stirred at -40 ° C to -35 ° C for 60 minutes, acetic acid (0.058 mL, 1.0 mmol) was added and evaporated in vacuo. The residue was dissolved in ethyl acetate (50 mL), and the resulting solution was washed with aqueous sodium bicarbonate solution (40 mL), water (40 mL), and brine (40 mL).

The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product (360 mg) was chromatographed on silica gel (120 g) eluting with chloroform: 3: 1 (3: 1) to give 123 mg (42% yield) of the title compound as a viscous gum.

In the IR spectrum of the compound of dm, dichloromethane in methane was found to have an absorption at 5,56,5,72 and 63 microns.

The NMR spectrum of the deuterochloroform solution shows the following peaks: 0.04 (s, 3H), 0.08 (s, 3H),

0.86 (s, 9H), 1.25 (d, 3H), 2.54-4.54 (c, 5H), 5.3 _β (q. 2H), 5.7 (d * 1H), 7.6 (d, 2H) δ 8.2 (d, 2H) ppm. 50

Example H Purification of p-nitrobenzyl (5R, 6S) -6- (R) -1-tert-butyldimethylsilyloxyethyl / -2-ethylsulfinyl-3-penem-3-carboxylate

8.0 g of the title compound prepared as described in Example I are chromatographed on 500 g of silica gel. Elution with 1: 1 hexane-ethyl acetate afforded 4.6 g of the title compound as a mixture of diastereomers.

Example I p-Nitrobenzyl (5R, 6S) -6 - ((R) -1-tert-butyldimethylsilyloxyethyl / -2-ethylsulfinyl-2-penem-3-carboxylate)

A solution of 970 mg (4.78 mmol, 85% purity) of m-chloroperbenzoic acid in 25 ml of methylene chloride was added.

2.5 g (4.78 mmol) of p-nitrobenzyl- (5R, 6S) -6- (R) -1-tert-butyldimethylsilyloxyethyl -2-ethylthio-2- penem-3-carboxylate in 125 mL of methylene chloride at -20 ° C under nitrogen. After stirring at -20 ° C for 3 hours, it was washed twice with successively 70 ml of saturated aqueous sodium bicarbonate solution, 70 ml of water and 70 ml of saturated aqueous sodium chloride solution. The methylene chloride solution was dried over anhydrous sodium sulfate and evaporated in vacuo to give 2.2 g (86% yield) of the title compound as a yellow foam.

. The IR spectrum of the dichloromethane solution shows absorbance at 5.54, 5.86 and 623 microns. Nuclear Magnetic Resonance Spectrum in the deuterochloroform solution showed peaks at 0.06.0.08, 0.1 and 0.12 (4a, full 6H), 0.8 (s,

194 248

9Η), 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, full 1H), 7.54 (d, 2H) and 8.18 (d, 2H) ppm.

Example J p-Nitrobenzyl (5R, 6S) -6- (R) -tert-butyldimethylsilyloxyethyl -2-ethylthio-2-penem-3-carboxylate in 10 ml methylene chloride 7.3 g (0.02 mol) of (3-alpha-tert-butyldimethylsilyloxyethyl-4-ethylthio) thiocarbonylthio-2-oxoazetidine and 4 8 g (0.048 mol) of calcium carbonate and then to the mixture

(0.024 mole) of p-Nitrobenzyl oxalyl chloride 5.85 g was added then 4.17 ml (0.024 mol) of diisopropyl ethyl amine in 20 ml of methylene chloride was added at a rate dropwise to the reaction mixture to a temperature below 12 ^vol C left. After stirring at 10 ° C for 60 minutes, the mixture was washed with ice-cold water (2 x 50 ml), dried over anhydrous sodium sulfate and evaporated in vacuo to give a crude p-nitrobenzyl (3-alpha-tert-butyldimethylsilyloxyethyl-2). -oxoazetidinyl) oxoacetate was dissolved in 300 ml of ethanol-free chloroform and the resulting solution was spun for 2 hours under nitrogen at reflux while dissolved in 50 ml of ethanol-free chloroform.

6.85 ml (0.04 mol) of triethyl phosphite are added. The resulting solution was spun at reflux for 16 hours and then concentrated in vacuo. The resulting residue was chromatographed on 800 g silica gel eluting with 95: 5 toluene / ethyl acetate to give 5.5 g (53% yield) of the title compound as a yellow foam.

The IR spectrum of the dichloromethane solution shows absorption at 5.56, 5.89 and 6.54 microns. Nuclear Magnetic Resonance Spectrum in the solution in deuterochloroform: 0.07 (s, 3H), 0.1 (s, 3H), 0.85 (s, 9H), 1.121.53 (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), 8.18 (d, 2H) ppm.

The NMR spectrum of the (1-azetidinyl) oxoacetate intermediate in deuterochloroform showed the following peaks: 0.06 (s, 6H), 0.8 (s, 9H) 1.14-1.62 (m, 6H). , 3.14-3.63 (m, 3H), 4.33 (m, 1H), 5.16 (3, 2H), 6.7 (d, 1H) and 8.17 (d, 2H) ppm.

Example K.

3-alpha-tert-butyldimethylsilyloxyethyl-4-ethylthio (thiocarbonyl) thio-2-oxoazetidine

To a cooled 0-5 ° Gra solution of 4.18 g (0.104 mol) of sodium hydroxide in 250 ml of water under nitrogen

Ethanethiol (8.5 mL, 0.115 mol) was added. After 15 minutes, carbon disulfide (7.73 mL, 0.12 mol) was added and the mixture was stirred at 0-5 ° C for 35 minutes. A solution of 4-acetoxy-3-tert-butyldimethylsilyloxyethyl-2-azetidinone (15.0 g, 0.0522 mol) in methylene chloride (500 mL) was added and the mixture was stirred vigorously at room temperature for 24 hours. The aqueous layer was separated and extracted with two 150 mL portions of methylene chloride. The combined methylene chloride extracts were washed twice with 200 mL of water and 200 mL of saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude title compound (18 g) was chromatographed on silica gel (500 g), eluting with chloroform: ethyl acetate (99: 1), and trithiocarbonate (9.1 g, 48% yield) as a yellow foam.

The IR spectrum of the title compound, taken in dichloromethane, shows absorption at 5.62 and 9.2 microns. Nuclear Magnetic Resonance Spectrum in the solution in deuterochloroform: 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), and 6.57 (b, 1H) ppm.

Example L 2 µg 2-pyrrolidon-3-yl-p-toluenesulfonate

To a solution of 3-hydroxy-2-pinolidone (1.0 g, 0.01 mol) in methylene chloride (50 ml) cooled to 0 ° C was previously 4.44 g (0.02 mol) of 4-dimethylaminopyridine, followed by the addition of 1.9 g (0.01 mol) of p-toluenesulfonyl chloride. The resulting solution was stirred at 0 ° C for 30 minutes and then at room temperature overnight. It was washed with 50 ml of 1N aqueous hydrochloric acid, 50 ml of water and 50 ml of a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo to give 2.1 g (83% yield) of the title compound.

The peaks in the NMR spectrum in deuterochloroform solution are 2.44 (s) and 1.83-2.64 (c) (full 5H), 3.1-3.44 (m, 2H), 4.86 ( t, 1H), 7.33 (d, 2H) and 7.8 (d + b, 3H) ppm.

Example 2g

The procedure described in Example L, using formyl 3-hydroxypyrrolidone as starting material, was obtained in 82% yield to give 1-formyl-3-pyrrolidinyl-p-toluene sulfonate. Its NMR spectrum, taken in de30 uterochloroform solution, shows the following peaks: 1.9-2.3 (c, 2H), 2.46 (s, 3H), 3.36 -3.78 (c, 4H), 5.1 (c, 1H), 7.32 (d, 2H), 7.77 (d, 2H), and 8.13 (d, 1H) ppm.

Similarly, sulfonate 3-methyl-ethylhydro-1,3-oxazin-2-one-5-yl-p-toluene 35 was prepared from the corresponding alcohol in 81% yield. In the NMR spectrum of a solution of deuterochloroform, the peaks were:

2.44 (s, 3H), 2.9 (s, 3H), 3.46 (m, 2H), 4.18 (m, 2H),

4.9 (m, 1H), 7.3 (d, 2H) and 7.74 (d, 2H) ppm.

Example N.

2-pyrrolidin-4-yl-p-toluenesulfonate

To a solution of 4-hydroxy-2-pinolidone (0.71 g, 7.02 mmol) in methylene chloride (35 mL) cooled to 0 ° C was previously 1.72 g (14.04 mol) in a nitrogen atmosphere.

4-dimethylaminopyridine was added followed by 1.34 g (7.02 mmol) of ptoluenesulfonyl chloride. The resulting mixture was allowed to warm to room temperature and stirred for 3 hours. Thereafter, 2x30 ml of 1N aqueous hydrochloric acid solution, 30 ml of saturated aqueous sodium bicarbonate solution and 30 ml of aqueous saturated sodium chloride solution were added.

Wash with 5X, dry over anhydrous sodium sulfate and evaporate in vacuo to give the title compound as an amorphous solid (1.5 g, 84%).

The NMR spectrum in deuterochloroform showed peaks at 2.46 (s) and 2.02-2.84 (c) (full, 5H), 3.2455, 3.86 (c, 2H), 5.17 (c, 1H), 7.1 (b, III), 7.34 (d, 2H), and 7.76 (d, 2H) ppm.

Example O

Using the procedure of Example N, starting from 5-hydroxymethyl-3-methyl-1,3-oxazolidine-210

-101

194,248 were used and 85% yield of (3-methyl-1,3-oxazotidin-2-one -5-yl) -methyl-p-toluenesulfonate. s, 3H), 2.82 (s, 3H), 3.16-3.8 (m, 2H), 4.12 (d, 2H), 4.66 (c, 1H), 7.33 (d, 2H) and 7.74 (d, 2H) ppm.

Similarly, using 4-hydroxymethyl-3-methyl-1β-oxazolidin-2-one as the starting alcohol afforded (3-methyl-1,3-oxazolidin-2-one-4-yl) methyl- (88% yield). p-toluenesulfonate. Nuclear Magnetic Resonance Spectrum in deuterochloroform, peaks at 2.45 (s, 3H), 2.77 (s, 3H), 3.66-4.52 (c, 5H), 7.32 (d, 2H) and 7.74 (d, 2H) ppm.

Similarly, using 4-hydroxymethyl-3-methyl-1,3-oxazolidin-2-one as the starting alcohol, (3-methyl-1,3-oxazolidin-2-one-4-yl) was obtained in 88% yield. ) methyl p-toluenesulfonate. In its NMR spectrum, recorded in deuterochloroform, the peaks were 2.45 (s, 3H), 2.77 (s, 3H), 3.66-4.52 (c, 5H), 7.32 (d, 2H). and 7.74 (d, 2H) ppm.

1-Formylpiperidin-3-yl-p-toluenesulfonate was also prepared in 75% yield from the corresponding alcohol. NMR peaks ₍₃ CDQ): 1.22 to 2.17 (c, 4H), 2.46 (s, 3H), 2.96 to 3.9 (c, 4H), 4.53 (m , 1H) 7.34 (d, 2H), 7.8 (d, 2H) and 7.93 (d, 1H).

Example P.

2-pyrrolidin-3-yl thioacetate

A mixture of potassium thioacetate (855 mg, 7.5 mmol) and crude 2-pyrrolidon-3-yl-p-toluenesulfonate (1.27 g, 5 mmol) in acetone (40 mL) was heated at reflux under nitrogen for about 20 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was taken up in a mixture of 50 ml of ethyl acetate and 50 ml of water and the ethyl acetate layer was washed with 40 ml of water and 40 ml of a saturated aqueous sodium chloride solution. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was chromatographed on silica gel eluting with ethyl acetate. 180 mg (25%) of the title compound are obtained. The NMR spectrum of a solution in deuterochloroform shows peaks at 2.38 (s) and 1.7-2.98 (c) (full, 5H) 2.27-3.6 (m, 2H), 4.17 (t 1 H) and 7.74 (b, 1H) ppm.

Example Q.

The procedure described in Example P was repeated in Example IV. The ptoluohsulfonates used as starting materials listed in the Table to give the corresponding thioacetates, the yield and the characteristics of their NMR spectrum in deuterochloroform solution are shown in the table.

ARC. P-Toluene (%) Production of the corresponding sulfonate thioacetate by NMR (ppm)

2-pyrrolidone 61 2.34 (s) and 2.0-4.4 (c) 4-yl- (full 8H) and 7.44 (b, 1H) 2.4 (s) and 1.63-3.06 (c) l-formyl-3- 95 pyrrolidinyl (full 5H), 3.14-4.26 (c, 4H0, and 8.14 (b, 1H) (3-methyl-l, 3- 77 2.38 (s, 3H), 2.82 (s, oxazolidines-2- 3H), 303-3.81 (c, 4H), -οη-5-yl) methyl and 4.57 (m, 1H), and (3-Metl-l, 3- 68 2.36 (s, 3H), 2.82 (s) and -oxazolyl-din-2-one- 2.75-3.45 (m) (full -4-yl) methyl 5H) and 3.64-4.57 (c, 3H).

Example R.

Pyrrolidin-2,5-dione-3-yl thioacetate

Maleic acid imide (5.0 g, 0.051 mol) was added to 10 ml (0.14 mol) of thioacetic acid at 0 ° C under a nitrogen atmosphere. The mixture was stirred at 0 ° C for 70 min and then filtered. The filtrate was diluted with ethyl acetate (70 mL) and the resulting solution was washed with aqueous saturated sodium bicarbonate solution (50 mL) and brine (50 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate and evaporated in vacuo to give 5.4 g of a yellow oil. The crude product was chromatographed on silica gel (350 g) eluting with ethyl acetate-hexane (1: 3) to give 3.81 g (43% yield) of the title compound as a white solid.

The NMR spectrum of the title compound, recorded in deuterochloroform, shows the following peaks: 2.38 (s) and 2.3-3.54 (m) (full 5H), 4.24 (m, 1H) and 8.86 (b, 1H) ppm.

Example S.

2-piperidone-5-yl-p-toluate] sulfonate

2-Piperidone-5-ol (0.575 g, 5 mmol) was dissolved in dimethylformamide (15 mL) and diluted with dichloromethane (50 mL). The solution is cooled to 0 ° C under nitrogen and 0.95 g (5 mmol) of p-toluenesulfonyl chloride and 1.22 g (10 mmol) of 4-dimethylaminopyridine are added. The solution was stirred at 0 ° C for 3 hours and then at 25 ° C for 20 hours. The reaction mixture was then diluted with dichloromethane (125 mL) and the solution was washed with 1N aqueous hydrochloric acid (20 mL), water (2 x 20 mL), and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was taken up in diethyl ether and filtered to give 0.8 g (60%) of a solid.

The NMR spectrum of the compound of dm in deuterochloroform showed the following peaks: 2.4 (s) and 1.67-2.6 (c) (full 7HX 3.43 (c, 2H), 4.86 ( m, 1H), 6.96 (b, 1H), 7.3 (d, 2H) and 7.76 (d, 2H) ppm.

-111

194 248

Example T.

2-piperidone-5-yl-thioacetate

A solution of 1.9 g (6 mmol) of tetrabutylammonium thioacetate and 0.807 g (3 mmol) of 2-piperidin-5-yl-para-toluenesulfonate in 15 mL of acetone was heated under reflux for 70 minutes under nitrogen. The solution was concentrated in vacuo and the residue was dissolved in ethyl acetate (75 mL). The ethyl acetate solution was washed sequentially with water (10 mL), brine (10 mL), water (10 mL), and brine (10 mL). The aqueous extracts were combined and washed with two 50 mL portions of ethyl acetate. The combined ethyl acetate layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was chromatographed on 100 g silica gel eluting with ethyl acetate to give the title compound (0.229 g, 44% yield) as a yellowish solid.

The NMR spectrum of the title compound in deuterochloroform shows the following peaks: -2.4 (s) and 1.64-2.68 (c) (full 7H), 2.73-4.1 (c). 3H) and 7.05 (b, 1H) ppm.

Example U (1,3-Oxazolidin-2-one-4-yl) methyl-p-toluenesulfonate In mL methylene chloride, p-toluenesulfonyl chloride (1.01 g, 0.0053 mole) was added (0.619 g, 0%). 0053 mol) of a solution of 2-oxo-1,3-oxazolidine-4-methanol and 1.30 g (0.0106 mol) of 4-dimethylaminopyridine at 0 ° C under a nitrogen atmosphere. After 1 hour at 0 ° C, an additional 0.121 g of p-toluenesulfonyl chloride was added and the reaction mixture was stirred at 0 ° C for 30 minutes and at 25 ° C for 1 hour. The solution was washed twice with 50 mL of 1 N aqueous hydrochloric acid, 50 mL of water, 50 mL of saturated aqueous sodium bicarbonate, and 50 mL of aqueous saturated sodium chloride. Finally, it was dried over anhydrous sodium sulfate and concentrated in vacuo. The title compound was obtained (1.22 g, 85% yield) as a white solid.

NMR (CDCl ₃ ): 2.45 (s, 3H), 3.87-4.54 (c, 5H), 6.18 (b, 1H), 7.3 (d, 2H) and 7.73 ( d, 2H) ppm.

Example V

Using the procedure described in Example U, the corresponding alcoholic starting material was converted to the tosylate, which is represented by Table R in terms of R group, yield and NMR spectra.

Table V.

R NMR (ppm) Yield (%)

(1,3-oxazolidine 2.46 (s, 3H), 3.54 84 -2-one-5-yl) methyl (M, 2H), 4.13 (d, 2H) 4.8 (m, 1H), 6.23 (b, 1H), 7.33 (d, 2H) and 7.8 (d, 2H) (1,3-thiazolidine 2.45 (s, 3H), 3.32 88 · * 2 οη-4-11) methyl (m, 2H), 3.86-4.32 (c, 3H), 6jO6 (b, 1H) 7.32 (d, 2H) and 7.74 (d, 2H)

EXAMPLE W 1-Methylpiperidin-2-one-3-ylmethyl-sulfosate

Methanesulfonyl chloride (0.8 mL, 0.01 mol) was added dropwise to 1.29a (0.01 mol) 1-methyl] -2-oxo-3-piperidinol and 2.44 g (0.02 mol). -dimethylaminopyridine in 50 ml of dichloromethane at 0 ° C under nitrogen. The resulting solution was stirred at 0 ° C for 15 minutes and then at 25 ° for 2 hours. The reaction mixture was then washed with 50 ml of a saturated aqueous sodium chloride solution containing 6.8 ml of a 6N aqueous hydrochloric acid solution. Dry over anhydrous sodium sulfate and evaporate in vacuo to give 1.8 g (87% yield) of the title compound as a thick oil.

NMR (CDCl 3): 1.6-2.37 (c, 4H), 2.96 (s, 3H),

3.1-3.4 (c) and 3.24 (s) (full 5H) and 4.96 (m, 1H), 6.26 (b, 1H) ppm.

Similarly, 2-oxo-pyridin-3-ol was converted to piperidin-2-one-341-methylsulfonate in 25% yield. NMR (CDCl 3): 2.03 (c, 4H), 3.06-3.45 (c) and 3.25 (s) (full 51.4.46 (m, 1H), 6.26 (b, 1H) ppm.

Example X (1,3-Oxazolidin-2-one-4-yl) methylthioacetate 2-oxo-1,3-oxazolidin-4-ylmethyl 1.22 g (0.0045 mol) in acetone. p-toluenesulfonate and 1.71 g (0.0054 mol) of tetrabutylammonium thioacetate were spun under nitrogen for 90 minutes. The reaction mixture is evaporated to dryness and the residue is chromatographed on 250 g of silica gel. Elution with 4: 1 ethyl acetate / hexane gave 580 mg (75%) of the title compound.

NMR (CDCl 3): 2.38 (s, 3H), 3.06 (d, 2H), 3.844.67 (c, 3H) and 6.3 (b, 1H) ppm.

Example Y.

Following the procedure described in Example X, the corresponding ptosylates were converted to thioacetate having the meaning of the R group, the NMR epectrum in deuterochloroform and the yield of the compound of Example VI. This is illustrated in the table.

VI. Spreadsheet

R NMR (ppm) Yield (%)

(1,3-oxazolidine -2-one-5-yl) methyl 2.37 (s, 3H), 3.22 '(d, 2H), 3.47 (m, 2H), 4.7 (m, 1H) and 6.26 (b, 1H) 76 (1,3-thiazolidine -2-one-4-yl) methyl 2.4 (s, 3H), 3.13 (d, 2H), 3.32 (m, 2H), 3.93 (m, 1H) and 6.63 (b, H) 58 3-methyl-perhydro-1,3-oxazin-5-yl 2.4 (s, 3H), 2.98 (s, 3H), and 3.0 - 4.6 (c, 5H) 61

Example Z 1-Formyl-3-piperidinyrylthioacetate

A solution of 1.12 g (0.007 mole) of 1-formyl-3-piperidinyl ethanol sulfonate and 0.91 g (0.008 mole) of potassium thioacetate in 10 ml of dimethylformamide was treated with

194.248 was kept at 70 ° C for 20 hours. The reaction mixture was diluted with ethyl acetate (150 mL) and the resulting solution was washed four times each with water (50 mL) and brine (50 mL). It was dried over anhydrous sodium acetate and the solution was concentrated in vacuo. The residue was chromatographed on 125 g silica gel eluting with 4: 1 ethyl acetate-hexane to give 0.16 g (21% yield) of the title compound.

NMR (CDCl ₃ ): 1.13-2.3 (c) and 2.32 (s) (full 7H) 2.84-4.0 (c, 5H) and 7.9 (d, 1H) ppm.

AA. example

-methylpiperidin-2-one-3-yl-thioacetate

A mixture of 1.7 g (0.008 mol) of 1-methyl-2-oxo-3-piperidinyl methanesulfonate and 139 g (0.012 mol) of potassium thioacetate in 80 ml of acetone was refluxed under nitrogen for 20 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in a mixture of ethyl acetate (50 mL) and water (50 mL). The ethyl acetate layer was washed with water (50 mL) and saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium acetate, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate to give 600 mg (40% yield) of the compound of dm.

NMR (CDCl 3): 1.7-2.5 (c) and 2.38 (s) (full 7H), 3.0 (s, 3H), 3.36 (m, 2H) and 4.2 (m , 1H) ppm.

Similarly, piperidin-2-one-3-ylmethylsulfonate was converted to piperidin-2-one-3-yl-thioacetate in 56% yield.

NMR (CDCl3): 1.5-2.5 (c) and 2.36 (s) (full 7H), 3.32 (c, 2H), 4.13 (m, 1H) and 7.18 (b) , 1H) ppm.

Claims (9)

PATENT CLAIMS A process for the preparation of 2-azacycloalkylthiopenem derivatives of the formula (I), or a pharmaceutically acceptable salt thereof, which comprises: R is a group of formula (I) wherein C 2 -C 4 alkylene, C 2 -C 4 alkylene, in which one of the carbon atoms is replaced by an oxo group, or in which a methylene group is replaced by an oxygen atom or a sulfur atom, & Carbonyl group B or methylene group, R _{2 is} hydrogen, formyl, or (C 1 -C 4) -alkyl, alk (C 1 -C 4) -alkylene, and n is 0 or 1, with the proviso that A may not simultaneously represent butylene, B is methylene, R _{2 is} hydrogen, alkyl is methylene or ethylene. characterized in that a compound of formula IA, which is a carboxyl protecting group which is easily removed by R 4 hydrogenolysis, preferably p-nitrobenzyl, is subjected to hydrogenolysis. 2. A process according to claim 1 for the preparation of compounds of formula I wherein A is a C 2 -C 4 alkylene group, B is a carbonyl group, R _{2 is} hydrogen or methyl, n is 0, characterized in that it is based on appropriately substituted materials. The process for the preparation of a compound of formula I according to claim 1, wherein A is a C 2 -C 4 alkylene group, B is a methylene group, R _{2 is} formyl 5 and n is 0, which is based on appropriately substituted materials. A process for the preparation of a compound of formula I according to claim 1, wherein A is a carbonylethylene or carbonylpropylene group, B is a carbonyl group, R _{2 is a} hydrogen atom or a methyl group, With the proviso that the ethylene or propylene moiety at position A is bonded to substituent B and n and alk are as defined in claim 1, characterized in that they are derived from appropriately substituted materials. A process for the preparation of a compound of formula (I) according to claim 1 wherein A is 1-oxaalkylene or 1-thioalkylene, B is carbonyl, R _{2 is} hydrogen or methyl, n is 1 and alk is 1. A process according to claim 1, characterized in that it is based on appropriately substituted parent compounds. A process for the preparation of a compound of formula (I) according to claim 1 wherein A is 1-oxaalkylene, B is carbonyl, R _{2 is} hydrogen or methyl and n is 0, characterized in that it is initiated from appropriately substituted materials. Who. 7. A process for the preparation of a compound of formula (I) according to any one of claims 1 to 6 wherein R 2 is pyrrolidon-3-yl, 2-pyrrolidon-4-yl, piperidin-2-one-3-yl, 1-methyl -piperidin-2-one-3-yl, 2-pieridin-5-yl, 1-formyl-3-pyrrolidinyl or 1-formyl-piperidin-3-yl, pyrrolidine-2,5-dione -3-yl, 3-methyl-1,3-oxazolidin-2on-5-yl) methyl, (3-methyl-1,3-oxazolidin-2-one4-yl) methyl, ( 1,3-oxazolidin-2-one-5-yl) -ethyl, (1,3-thiazolidin-2-one) -methyl or 3-methyl-perhydro-1,3-oxazolidin-2-one-5-yl, starting from appropriately substituted materials. The process of claim 1 for the preparation of compounds of formula (II) or pharmaceutically acceptable salts thereof which are In formula 4Q, R 2-pyrrolidon-3-yl, 2-pyrrolidone · 4-yl, 1-formyl-3-pyrrolidinyl, pyrrolidin2,5-dion-3-yl, (3-methyl-1,3-oxazolidin-2-one-4-yl) methyl, (3-Methyl-1,3-oxazolidin-2-one-5-yl) methyl, 2-piperidin-5-yl, piperidin-2-one-3-yl, 1-methyl-piperidin-2 one-3-yl; 45 1-formyl-pieridin-3-yl, (13-oxazolidin-2-one-4-yl) methyl, (13-oxazolidin-2-one-5-yl) methyl, or (1, 3-Thiazolidin-2-one-4-yl) -methyl, starting with appropriately substituted materials. 9- A process for the manufacture of a medicament having antibacterial activity, wherein: 1-8. The compound of formula (I) and (Π), wherein R is as defined in claim 1, or a pharmaceutically acceptable salt thereof, prepared by the process of any one of claims 1 to 8 is formulated for oral or parenteral administration.