NO167573B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE (5R, 6S,) - 6 - ((R) -1-HYDROXYTHYL) -2-AZACYCLOALKYLTIO-2-PENEM-3-CARBOXYL ACID DERIVATIVES. - Google Patents

Description

The present invention is directed to an analogue process

method for the preparation of a family of therapeutically active agents comprising a 2-azetidinone (β-lactam) ring. Chemically, the antibacterial agents produced according to the present invention are identified as 6-α-1-hydroxyethyl-2-substituted-2-penem-3-carboxylic acid compounds.

Although certain 2-substituted-2-penem-3-carboxylic acid compounds

parts previously described, there is a continuous need for new compounds with desirable antibacterial therapeutic properties.

The present invention relates to a method for

preparation of a compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein R is:

A is an alkylene with 2-4 carbon atoms, the alkylene with 2-4

carbon atoms where a carbon atom has an oxo substituent or alkylene with 2-4 carbon atoms where a methylene group is

replaced by oxygen or sulfur;

B is carbonyl or methylene;

R^ is hydrogen or forms an ester group which is hydrolysed

in vivo;

R 2 is hydrogen, formyl or alkyl of 1-4 carbon atoms;

alk is the alkylene of 1-4 carbon atoms; and

n is zero or 1,

with the proviso that when B is methylene and A is alkylene of 2-4 carbon atoms, then R 2 is formyl; and when B is methylene, A cannot have the meaning alkylene with 2-4 carbon atoms where one carbon atom

has an oxo substituent and said carbon atom is not in a neighboring position to nitrogen atoms in R, or the alkylene with 2-4 carbon atoms where a methylene has been replaced by oxygen or sulphur.

Preferred compounds of formulas I include those where A is alkylene, B is carbonyl, R 2 is hydrogen or methyl and n is zero. Particularly preferred are compounds where R is hydrogen and R is 2-pyrrolidon-3-yl, 2-pyrrolidon-4-yl, piperidin-2-on-3-yl, 1-methyl-piperidin-2-on-3- yl or 2-piperidon-5-yl.

Also preferred are compounds where A is alkylene, B is methylene, R2 is formyl and n is zero. Particularly preferred is the compound where R 1 is hydrogen and R 1 is 1-formyl-3-pyrrolidinyl or 1-formylpiperidin-3-yl.

Furthermore, compounds are preferred where A is carbonylethylene or carbonylpropylene, B is carbonyl, R 2 is hydrogen or methyl, with the proviso that ethylene or propylene in A is bound to B, especially the compounds where R 1 is hydrogen and R is pyrrolidine-2,5- dion-3-yl.

In addition, compounds are preferred where A is 1-oxaalkylene, B is carbonyl, R2 is hydrogen or methyl and n is 1, with the proviso that the oxygen of the 1-oxaalkylene is bonded to B, especially where R^ is hydrogen and R is (3- methyl-1,3-oxazolidin-2-on-4-yl)-methyl, (3-methyl-1,3-oxazolidin-2-on-5-yl)methyl, (1,3-oxazolidin-2-one -4-yl)methyl or (1,3-oxazolidin-2-on-5-yl)methyl.

Covered by the present invention is the preparation of compounds where A is 1-oxaalkylene and B is carbonyl, R 2 is hydrogen or methyl and n is zero, especially when R-^ is hydrogen and R is 3-methyl-perhydro-1,3-oxazolidine- 2-on-5-yl.

Also covered by the present invention is the production of compounds where A is 1-thiaalkylene, B is carbonyl, R2 is hydrogen or methyl and n is 1; especially when R 1 is hydrogen and R 1 is (i,3-thiazolidin-2-on-4-yl)methyl.

In JP 57-176988, with the exception of example 72, all the compounds exemplified there have groups which are bound to the exocyclic sulfur atom with substituents which cause the compounds to form zwitterions. The compound according to example 72 is in other respects very different from the compounds prepared according to the present invention, since the compound according to said example is unsubstituted in the 6-position.

Neither EP 2210 nor EP 70204 describes or suggests groups attached to the exocyclic sulfur atom, which has a carbonyl group adjacent to the ring nitrogen. The importance of the carbonyl substituent is that its presence in R makes this group neutral. Furthermore, EP 2210 only describes heterocyclic groups which are aromatic (ie ring structure with double bonds) attached to the exocyclic sulfur atom.

NO-patent 158,540 describes compounds with the general formula I where, however, R is not or comprises a heterocyclic group as in accordance with the present invention, but instead is an optionally hydroxy- or carboxy-substituted alkyl group.

The compounds produced according to the invention can form carboxylate salts since R is neutral, and not zwitterions. The chemical behavior and biological properties of zwitterionic compounds are completely different from those capable of forming carboxylate salts. The pharmacokinetic parameters and the serum protein binding capacity of compounds which can form carboxylate salts must be expected to be different from the corresponding properties of zwitterionic compounds. See Singhvi, S. M. et al., Chemotherapy 24:121-133 (1978) wherein the protein binding of cephalexin and cephradine, cephalosporins capable of forming zwitterions, and ampicillin, a penicillin capable of forming a zwitterion, is shown as well as the protein binding of other, non-zwitterion-forming compds.

A pharmaceutical preparation may comprise a compound of formula I and a pharmaceutically acceptable diluent or carrier, and a method of treating a bacterial infection in a mammal comprising administering an antibacterially effective amount of a compound of formula I.

The compounds of formula I are useful as antibacterial agents and are derivatives of the bicyclic nucleus with

the formula:

In this specification, the nucleus of formula III is identified by the name "2-penem" and the ring atoms are numbered as shown. The carbon atom attached to ring carbon atom 6 is given the number 8. In the present description, the abbreviation "PNB" is used for the p-nitrobenzyl group.

The relationship between the hydrogen atom on bridgehead carbon 5 and the remaining hydrogen atom on carbon atom 6 in compounds of formula I is trans, but the cis isomer can easily be converted to the trans isomer.

In general, carbon atom 5 will have the absolute stereochemical designation R using the Prelog-Ingold R, S stereochemical designation, which is used in the present application. Thus, for example, a compound of formula I is called where R^. is hydrogen and R is 2-pyrrolidon-3-yl, (5R,6S)-6-[(R)-1-hydroxyethyl]-2-(2-pyrrolidon-3-yl)thio-3-carboxyl- 2-penem.

As will be appreciated, various optically active isomers of the new compounds are possible. The present invention encompasses the preparation of such optically active isomers as well as the mixture thereof.

The method according to the invention is characterized by the fact that a compound with the formula:

is converted to the corresponding compound of formula I by hydrogenolysis, where R4 is a carboxylic acid protecting group which is removed by hydrogenolysis, and optionally the pharmaceutically acceptable salt is formed in a manner known per se, or optionally a hydrolyzable ester of the carboxylic acid is produced.

The present invention comprises the preparation of the penems in which the 3-carboxyl group is esterified with a non-toxic ester group which is hydrolysed in vivo. These esters are rapidly cleaved in mammalian blood or tissue to release the corresponding penem-3-carboxylic acid. Typical examples of such easily hydrolyzable ester-forming residues are alkanoyloxymethyl with 3-8 carbon atoms, l-(alkanoyloxy)ethyl with 4-9 carbon atoms, l-methyl-l-(alkanoyloxy)ethyl with 5-10 carbon atoms, alkoxy-carbonyloxymethyl with 3-6 carbon atoms, 1-(Alkoxycarbonyloxy)-ethyl with 4-7 carbon atoms, 1-methyl-1-(Alkoxycarbonyloxy)-ethyl with 5-8 carbon atoms, N-(Alkoxycarbonyl)aminomethyl with 3-9 carbon atoms, l-( N-[Alkoxycarbonyl]ethyl with 4-10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl,'γ-butyrolacton-4-yl, carboxy-alkylcarbonyloxymethyl with 4-12 carbon atoms or 5-methyl-2-oxo-1,3- dioxolen-4-yl-methyl.

To prepare compounds of formula I where R 1 is a group that forms an ester that is hydrolyzed in vivo, the acid of formula I (R 1 is hydrogen) is reacted with a base to form the corresponding anion. Suitable cations include sodium, potassium, calcium, tetra-alkylammonium and the like. The anion can be prepared by lyophilization of an aqueous solution of I, for example an aqueous solution containing tetrahydrofuran, and sodium bicarbonate or tetrabutylammonium hydroxide.

The resulting anion of I is reacted with the corresponding chloride or bromide of R^ in a reaction-inert solvent such as e.g. acetone or dimethylformamide at 20 to 50°C, preferably 25<*>C. ;The compounds of formula I can be synthesized according to schemes A-C. ;As shown in scheme A, a compound of formula I can be prepared according to the method of Yoshida et al, Chem Pharm, bull., 29, 2899-2909 (1981), from the known dibromopename of formula IV. The dibromopename (IV) undergoes an exchange reaction with t-butyl magnesium chloride at a temperature of between -90 and -40°C preferably about -78°C in a reaction-inert solvent such as tetrahydrofuran, diethyl ether or toluene, preferably tetrahydrofuran. Other organo-metallic reagents can also be used. The reaction mixture is treated in situ with the appropriate aldehyde, e.g. eg acetaldehyde for the 1-hydroxyethyl derivative.The aldehyde is added in between

80 and -60°C, preferably approx. -78"C for acetaldehyde.

The resulting bromohydroxyvpenam V is hydrogenated for

to remove the 6-bromo substituent. A suitable hydrogenation catalyst is a noble metal catalyst such as e.g. palladium. The reaction is carried out in a protic solvent such as e.g. 1:1 methanol-water or 1:1 tetrahydrofuran-water, preferably 1:1 methanol-water, at a pressure of 1 to 4 atm, preferably 4 atm and a temperature of between 0 and 30°C_, preferably approx. 25°C.

The resulting alcohol of formula VI can be protected

with a trialkylhalosilane of formula:

where Rg at each occurrence is an alkyl group with 1-6 carbon atoms and Q is chlorine, bromine or iodine. Thus, dimethyl-t-butylchlorosilane forms in the presence of an amine proton acceptor, which e.g. imidazole, in a polar, aprotic solvent such as e.g. N,N-dimethylformamide in a temperature range of between 5 and 40°C, preferably approx. 25°C, a trialkylsilyl hydroxyl protecting

group as shown in formula VII.

Treatment of VII with mercuric acetate in acetic acid at a

temperature of approx. 90°C gives the olefin VIII.

To obtain the desired azetidinone IX, the olefin VIII is ozonized in a reaction-inert solvent such as e.g. dichloromethane at a temperature of between -80 and -40°C, preferably approx. -78°C. The reaction product is treated with an alkanol such as e.g. methanol to give the azetidine IX. As shown in scheme B, a compound of formal IX is treated with the trithiocarbonate salt with the formula M<+>RlQ-S-C(S)-S~ where R1Q is alkyl with 1-4 carbon atoms, preferably ethyl, and M is a metal such as e.g. sodium or potassium to obtain a compound of formula X. This conversion of IX to X is carried out in an organic solvent or water, preferably a mixture of water and dichloromethane, in a temperature range of 0-35°C, preferably approx. 25°C.

The compound of formula X is condensed with p-nitrobenzyl-chloro-oxalate in the presence of a tertiary alkylamine where each alkyl has, for example, 1-4 carbon atoms, which e.g. ethyl-di-isopropyl-amine, to obtain the compound of formula XI. This condensation is carried out in a reaction-inert solvent, preferably dichloromethane, in a temperature range of 5-25°C, preferably approx. 10°C.

The resulting compound of formula XI is ring-closed using a trialkyl phosphite where each alkyl has 1-4 carbon atoms such as e.g. triethyl phosphite in a reaction-inert solvent such as e.g. trichloromethane in a temperature range of 40-80°C, preferably approx. 60°C, to obtain the penem of formula XII.

The thio group in compound XII is oxidized to the corresponding sulfoxide XIII with an oxidizing agent such as e.g. m-chloro-perbenzoic acid in a reaction-inert solvent such as e.g. dichloromethane, in a temperature range of -10 to -30°C, preferably -20°C.

The sulfoxide in the compound of formula XIII is replaced with the mercaptide of formula R-S by, for example, using the sodium or potassium salt of the appropriate mercaptide which is reacted with the sulfoxide XIII in a polar organic solvent such as e.g. ethanol or acetonitrile in a temperature range from

-10 to -50°C, preferably approx. -35°C.

Starting mercaptans with the formula R-SH or starting thioacetates with the formula R-S-CtOJCH^ are known for many of the values of R and those that are not known can be prepared using analogous methods known in the art. For an overview see J.L. Wardell, "Preparation of Thiols", in The Chemistry of the Thiol Group, S. Patai, publisher John Wiley&Sons, London,

1974, Chapter 4. See also Volante, Tetrahedron Letters, 22, 3119-3122 (1981) for the conversion of alcohols to thiols and thiol esters using triphenylphosphine and a dialkylazodicarboxylar in the presence of the alcohol and an appropriate thiolic acid.

For the compounds of formula XIV, the trialkylsilyl group is preferably removed prior to the hydrogenolysis to remove the acid-protecting group (PNB) to obtain a compound of formula XV. The trialkylsilyl group is removed with a tetraalkylammonium

fluoride in an ether solvent, such as tetrahydrofuran,

in a temperature range of 15 to 40°C, preferably approx. 25°C.

Conversion of a compound of formula XV to a compound of formula I is carried out using a conventional hydrogenolysis reaction and is carried out in the usual manner for this type of conversion. Thus, a solution of a compound of formula XV is stirred or shaken under a hydrogen atmosphere, or hydrogen mixed with an inert diluent such as e.g. nitrogen or argon, in the presence of a catalytic amount of a noble metal hydrogenolysis catalyst, such as a palladium-on-calcium-carbonate or a palladium-on-"Celite" (a diatomaceous earth) catalyst. Suitable solvents for this hydrogenolysis are lower alkanols, such as methanol, ethers, such as tetrahydrofuran and dioxane; esters with low molecular weight, such as e.g. ethyl acetate and butyl acetate; water; and mixtures of these solvents. However, it is common to choose conditions under which the starting material is soluble, such as e.g. aqueous tetrahydrofuran. The hydrogenolysis is usually carried out at room temperature and at a pressure of 0.5 to 5 kg/cm. The catalyst is usually present in an amount from approx. 10% by weight based on the starting material up to an amount equal to the weight of the starting material, although larger amounts can be used. The reaction usually takes approx. 1 hour, after which the compound of formula I is simply recovered by filtration followed by removal of the solvent in vacuo. If palladium-on-calcium carbonate is used as catalyst, the product is isolated as the calcium salt and if palladium-on-Celite is used, the product is isolated as the sodium salt.

The compounds of formula I can be purified by conventional methods for β-lactam compounds. The compound of formula I can, for example, be purified by gel filtration on "Sephadex" or by recrystallization.

An alternative synthetic method is shown in scheme C. The azetidine of formula IX is reacted with a trithiocarbonate of the formula M<+>R-3-C(S)-S~, where M is a metal such as e.g. sodium or potassium using the procedure previously described to prepare X.

The resulting trithiocarbonate XVA is treated with

(p-nitrobenzyloxycarbonyl)(dihydroxy)methane in an aprotic solvent, such as e.g. benzene, toluene or dimethylformamide, preferably benzene, in a temperature range of 25-110°C, preferably approx. 80°C, to give the alcohol of formula XVI.

The corresponding chloride XVII is prepared from the alcohol

XVI by treatment with thionyl chloride in a reaction-inert organic solvent such as e.g. dichloromethane in the presence of a hindered amine which serves as an acid acceptor such as e.g. 2,6-lutidine in a temperature range of -10 to 75°C, preferably 0°C.

The chloride XVII is reacted with a triarylphosphine, which e.g. triphenylphosphine, in a reaction-inert solvent such as e.g. tetrahydrofuran, in the presence of a tertiary amine, such as 2,6-lutidine, at a temperature of approx. 25°C, to obtain the compound of formula XVII which is cyclized by reflux treatment in an aromatic solvent such as e.g. toluene to give the penem of formula XIV.

Trithiocarbonate salts of the formula M<+>R-S-(C=S)-s" are prepared from the appropriate mercaptan of the formula R-SH or by treating a thioacetate of the formula RSCtOJCH^ with an alkali metal alkoxide followed by carbon disulfide.

By applying the aforementioned method of Yoshida et al. the stereochemistry of carbon 6 in the penem as well as the hydroxyethyl group attached to carbon 6 is that shown

in formula I. Thus, the main stereochemistry of the product in the ring closure using schemes B or C is that where the hydrogen at the penemen ring position 5 is trans to the hydrogen on carbon 6 and in the α configuration. Alternatively, the stereochemistry can be described as 5R,6S; 6-(R)-1-Hydroxyethyl.

The compounds of formula I are acidic and will form salts with basic agents. The production of such salts is considered to be within the scope of the invention. These salts can

produced by standard techniques, such as bringing the acidic and basic components into contact with each other, usually in a stoichiometric ratio, in an aqueous, non-aqueous or partially aqueous medium, as appropriate. They are then recovered by filtration, by sweeping with a non-solvent followed by filtration, by evaporation of the solvent or in case of

from aqueous solutions by lyophilization, as appropriate. Basic agents which are suitably used in salt formation belong to both the organic and inorganic types, and they include

ammonia, organic amines, alkali metal hydroxides, carbonates, bicarbonates, hydrides and alkoxides, as well as alkaline earth metal hydroxides, carbonates, hybrids and alkoxides. Representative examples of such bases are primary amines, such as e.g. n-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine and octylamine; secondary amines, such as diethylamine, morpholine, pyrrolidine and piperidine; tertiary amines, such as triethylamine, N-ethylpiperidine, N-methylmorpholine and 1,5-diazabicyclo-[4,3,0]non-5-ene; hydroxides, such as sodium hydroxide, potassium hydroxide, ammonium hydroxide and barium hydroxide; alkoxides such as sodium ethoxide and potassium ethoxide; hydrides, such as calcium hydride and sodium hydride; carbonates, such as potassium carbonate and sodium carbonate; bicarbonates, such as sodium bicarbonate and potassium bicarbonate; and alkali metal salts of long-chain fatty acids, such as e.g. sodium 2-ethyl hexanoate.

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

The pharmaceutically acceptable salts of formula I are those which are free from significant adverse side effects at ordinary levels of use and include, e.g. the sodium, potassium or calcium salts thereof.

In vitro antibacterial activity of the compounds of formula I and salts thereof can be demonstrated by measuring their minimal inhibitory concentrations (MIC) in mkg/ml against various microorganisms. The procedure followed is that recommended by the International Collaborative Study on Antibiotic Sensitivity Testing (Ericcson and Sherris, Acta. Pathologica et Microbiologia Scandinav, Supp. 217, Part B; 64-68 [1971]), and uses brain- heart infusion (BHI) agar and the graft reproduction device.

Tubes grown overnight are diluted 100-fold for use as standard inoculum (20,000 - 10,000 cells in approx.

0.002 ml is placed on the agar surface; 20 ml BHI agar/dish). Twelve 2-fold dilutions of the test compound are used, with an initial concentration of the test drug of 200 mg/ml. Single colonies are overlooked when the plates are read after 18 hours at 37°C. The sensitivity (MIC) of the test organism is accepted as the lowest concentration of compound capable of

complete inhibition of growth when assessed by the naked eye.

The compounds of formula I and the pharmaceutically acceptable salts thereof are suitable for combating bacterial infections in mammals, including humans. They will find

- use in combating infections caused by sensitive bacteria in humans, e.g. infections caused by sensitive strains of Staphylococcus aureus. The following examples and preparations are given for further illustration only. Infrared (IR) spectra were measured either as potassium bromide disks (KBr disk), Nujol "mulls" or as solutions in chloroform (CHCl^)/methylene chloride ( CH2Cl2) or dimethylsulfoxide (DMSO), and diagnostic absorption bands are given either in nm or wavenumber (cm^). Nuclear magnetic resonance (NMR) spectra were measured for solutions in deuterochloroform (CDCl^), perdeuteromethanol (CD^OD), or perdeuterodimethylsulfoxide (DMSO -dg), or mixtures thereof and peak readings are expressed in parts per million downstream from tetramethylsilane. The following abbreviations for shapes of the peaks are used: s, singlet; d, doublet; t, triplet; q, quartet; m, multi-spot, b, broad; c,- complex. The abbreviations "ss" and "sss" denote that a particular proton appeared as 2 or 3 singlets, respectively, depending on the presence of diastereoisomers. In the Examples and Preparations, the abbreviation "PNB" represents the p-nitrobenzyl group.

EXAMPLE 1

Sodium-(5R,6S)-6-[(R)-1-hydroxyethyl]-2-(2-pyrrolidon-3-yl)thio-2-penem-3-carboxylate

The pH of a suspension of 73 mg of 10% Pd on diatomaceous earth in a mixture of 20 ml of tetrahydrofuran and 20 ml of distilled water was adjusted to 8.3 with 0.02 M aqueous sodium bicarbonate solution. A solution of 73 mg of p-nitrobenzyl-(5R,6S)-6-[(R)-1-hydroxyethyl]-2-(2-pyrrolidon-3-yl)thio-2-penem-3-carboxylate in a mixture of 8 ml of tetrahydrofuran and 8 ml of water was then added and the resulting mixture was hydrogenated at 3.9 kg/cm<2>hydrogen for 75 min. Another 73 mg of 10% Pd on diatomaceous earth was then added and the pH of the mixture was adjusted to 7.0 with 0.02M aqueous sodium bicarbonate solution. The mixture was hydrogenated at 3.9 kg/cm for 75 min. The catalyst was then removed by filtration and the filtrate was concentrated in vacuo to remove tetrahydrofuran. The pH of the resulting aqueous solution was adjusted to 7.0 and the solution was extracted with two 15 mL portions of ethyl acetate. The aqueous solution was then lyophilized to give 38 mg (69% yield) of the title compound as an amorphous solid.

The infrared spectrum of the title compound as a potassium bromide disk had absorptions at 2.94, 5.65 and 6.3 nm.

EXAMPLE 2

The procedures of Example 1 were applied using appropriate compounds of formula XV to obtain the sodium salts of compounds of formula II, whose yield, infrared spectrum as potassium bromide disk (unless otherwise indicated) and R are as shown in Table 1.

EXAMPLE 3

Sodium (15R,6S)-6-[(R)-1-hydroxyethyl]-2-(pyrro.lidin-2,5-dion-3-yl)thio-2-penem-3-carboxylate

The procedures of Example 1 were used except that the starting pH was 7.5 and in the starting compound of formula XV R was pyrrolidin-2,5-dion-3-yl. The compound was obtained in 90% yield and had infrared spectrum absorptions, as potassium bromide disk, at 2.92, 5.63, 5.8 and 6.2 "mn.

EXAMPLE 4

The procedures of Example 3 were applied using the appropriate compounds of formula XV to obtain the sodium salts of the compounds of formula II whose yield, infrared spectrum in potassium bromide disk (unless otherwise indicated) and R are as shown in Table IA.

MANUFACTURE A

p-nitrobenzyl(5R,6S)-6-[(R)-1-hydroxyethyl]-2-(2-pyrrolidon-3-yl)thio-2-penem-3-carboxylate

To a solution of 118 mg (0.204 mol) p-nitrobenzyl(5R,6S)-6-[(R)-1-t-butyldimethylsilyloxyethyl]-2-(2-pyrrolidon-3-yl)-thio-2-penem-3 -carboxylate in 6 ml of tetrahydrofuran, 0.11 ml (2.04 mmol) of acetic acid and 0.612 ml (0.612 mol) of an IM solution of tetrabutylammonium fluoride in tetrahydrofuran were added. After stirring for 20 hours under nitrogen at room temperature, 50 ml of ethyl acetate was added and the resulting solution was washed with 40 ml of saturated aqueous sodium bicarbonate solution, 40 ml of water and 40 ml of saturated aqueous sodium chloride solution. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product (110 mg) was chromatographed on silica gel (50 g), eluting with 95 g ethyl acetate/methanol, to give 73 mg (77% yield) of the title compound as an amorphous solid.

The NMR spectrum of a deuterochloroform solution of the title compound had peaks at 1.32(d,3H); 2.0-3.2 (c,3H);

3.2-4.37 (c.5H); 5,3(q,2H); 5.6(d,1H); 6.64(b,1H); 7.6(d,2H) and 8.2(d,2H) ppm. The infrared spectrum of a dichloromethane solution of the title compound had absorption at 5.58, 5.85 and 6.57 mm.

MANUFACTURE B

The procedures from preparation A were used in use

of compounds of formula XIV to obtain compounds of formula XV whose properties and R are as shown in Table 2. The solvents in which the spectrum was measured are in parentheses.

MANUFACTURE C

p-nitrobenzyl-(5R,6S)-6-[(R)-1-hydroxyethyl]-2-(3-methyl-perhydro-1,3-oxazin-2-on-yl)thio-2-penem-3 -carboxylate

Tetrabutylammonium fluoride (1.25 mL of a 1M solution in tetrahydrofuran, 1.25 mmol) and acetic acid (0.25 mL) were added to a solution of p-nitro-benzyl-(5R,6S)-6-[(R)- 1-t-butyldimethyl-silyloxyethyl]-2-(3-methyl-perhydro-1,3-oxazin-2-on-5-yl)-thio-2-penem-3-carboxylate (0.24 g, 0, 39 mmol) in 2 ml anhydrous tetrahydrofuran. The resulting solution was stirred at 25°C under nitrogen for 20 hours. The reaction solution was then diluted with 100 ml ethyl acetate and washed with 10 ml water, two 20 ml portions of saline solution, 20 ml water and 20 ml saline solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The remaining solid was triturated with 5 mL of methanol, then 15 mL of diethyl ether was added and the resulting mixture was filtered to give 71 mg of the less soluble diastereomer as a light brown colored solid. The filtrate was concentrated in vacuo and the residue was chromatographed on silica gel

(75 g) and eluted with 9:1 ethyl acetate/methanol to give the more soluble diastereomer as a solid. Trituration of the solid with 1:1 diethyl ether/petroleum ether and filtration gave 52 mg of the more soluble diastereomer as a light brown colored solid. (Total yield 63%).

Less soluble diastereomer

(NMR(DMSO-dg, 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.

More soluble diastereomer

NMR (DMSO-dg, 250 MHz): 1.2 (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); 5.39 (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 Mm.

MANUFACTURE D

p-nitrobenzyl(5R,6S)-6-[(R)-1-t-butyldimethylsilyloxyethyl]-2-(pyrrolidon-3-yl)thio-2-penem-3-carboxylate

Sodium methoxide (27 mg, 0.5 mmol) was added to a solution of 80 mg (0.5 mmol) of 2-pyrrolidoh-3-yl-thide acetate in 5 ml of anhydrous ethanol cooled to -30°C. under nitrogen. After 30 minutes at -30°C, a solution of 300 mg (0.5 mmol) of crude p-nitrobenzyl-5R,6S)-6-[(R)-1-t-butyldimethylsilyloxyethyl]-2- ethylsulfinyl-2-penem-3-carboxylate from Preparation I in 5 ml of anhydrous tetrahydrofuran which had been cooled to -50°C. The resulting solution was stirred at -30°C for 60 minutes and 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 with 40 ml of saturated aqueous sodium bicarbonate solution, 40 ml of water and 40 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 product (370 mg) on silica gel (120 g) eluting with 1:1 chloroform/ethyl acetate gave 118 mg (41% yield) of the title compound as a viscous gum.

The infrared spectrum of a dichloromethane solution of the title compound had absorptions at 5.58, 5.86 and 6.58 mm. The NMR spectrum of a deuterochloroform solution of the title compound had peaks at 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.5H); 5.29 (q, 2H); 5.6 (d,lE); 6.6 (b, 1H); 7.55 (d,2H) and 8.16 (d,2H) ppm.

MANUFACTURE E

The procedures of Preparation D were applied using the appropriate thioacetate to obtain compounds of formula XIV, whose properties and R are as shown in Table 3.

MANUFACTURE F

The procedures from Preparation D were applied using purified p-nitrobenzyl-(5R,6S)-6-[(R)-1-t-butyldimethylsilyloxyethyl]-2-ethylsulfinyl-2-penem-3-carboxylate from Preparation H and the appropriate thioacetate to obtain compounds of formula XIV, whose properties and R are as shown in Table 3A.

MANUFACTURE G

p-nitrobenzyl(5R,6S)-6-[(R)-1-t-butyldimethylsilyloxyethyl]-2-(pyrrolidin-2,5-dion-3-yl)thio-2-penem-3-carboxylate

Sodium methoxide (54 mg, 1.0 mmol) was added to a solution of 87 mg (0.5 mmol) of pyrrolidine-2,5-dione-3-y1-thioacetate in 5 mL of anhydrous ethanol cooled to -35°C under nitrogen. After 40 minutes at -35°C, a solution of 300 mg (ca. 0.5 mmol) of crude p-nitrobenzyl-(5R,6S)-6-[(R)-1-t-butyldimethylsilyloxy-ethyl]-2 -ethylsulfinyl-2-penem-3-carboxylate in 5 ml of anhydrous tetrahydrofuran, which had been cooled to -50°C. The resulting solution was stirred at -40°C to -35°C for 60 minutes, 0.058 mL (1.0 mmol) of acetic acid was added and the solution concentrated in vacuo. The residue was dissolved in 50 ml of ethyl acetate and the resulting solution was washed with 40 ml of saturated aqueous sodium bicarbonate solution, 40 ml of water and 40 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 product (360 mg) on silica gel (120 g) eluting with 3:1 chloroform/ethyl acetate gave 123 mg (42% yield) of the title compound as a viscous gum.

The infrared spectrum of the title compound in a dichloromethane solution had absorptions at 5.56, 5.72 and 6.5 µm. The NMR spectrum of a deuterochloroform solution of the title compound had peaks at 0.04 (s, 3H), 0.08 (s, 3H), 0.86 (s, 9H),

1.25 (d, 3H), 2.54-4.54 (c, 5H), 5.3 (q, 2H), 5.7 (d, 1H),

7.6 (d, 2H) and 8.2 (d, 2H) ppm.

MANUFACTURE H

Purification of p-nitrobenzyl-(5R,6S)-6-[(R)-1-t-butyldimethylsiloxyethyl]-2-ethylsulfinyl-2-penem-3-carboxylate

8.0 g of the title penem sulfoxide prepared according to Preparation I was chromatographed on silica gel (500 g). Elution with hexane/methyl acetate (1:1) gave 4.6 g of purified title compound as a mixture of diastereomers.

MANUFACTURE I

p-nitrobenzyl-(5R,6S)-6-[(R)-1-t-butyldimethylsilyloxy-ethyl]-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 to a solution of 2.5 g (4.78 mmol) of p-nitrobenzyl-(5R,6S)- 6-[(R)-1-t-butyl 1-dimethylsilyloxyethyl]-2-ethyl-thio-2-penem-3-carboxylate in 125 ml of methylene chloride cooled to -20°C under a nitrogen atmosphere. The mixture was stirred at -20°C for 3 hours, then washed successively with two 70 ml portions of saturated aqueous sodium bicarbonate solution, 70 ml water and 70 ml saturated aqueous sodium chloride solution. The methylene chloride solution was dried with anhydrous sodium sulfate and concentrated in vacuo to a yellow foam of the title compound (2.2 g, 86% yield).

The infrared spectrum of the title compound as a dichloromethane solution had absorptions at 5.54, 5.86 and 6.53 nm. The NMR spectrum of the title compound as a deuterochloroform solution 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 (df 2H) and 8.18 (d, 2H) ppm.

MANUFACTURE J

p-nitrobenzyl-(5R,6S)-6-[(R)-1-t-butyldimethylsilyloxyethyl]-2-ethylthio-2-penem-3-carboxylate

p-nitrobenzyl-oxalyl chloride (5.85 g, 0.024 mol) was added to a mixture of 7.3 g (0.02 mol) of (3-ct-t-butyldimethyl-silyloxyethyl-4-ethylthio(thiocarbonyl)- thio-2-oxo-azetidine and 4.8 g (0.048 mol) calcium carbonate in 70 ml methylene chloride cooled to 10° C. under a nitrogen atmosphere.A solution of 4.17 ml (0.024 mol) diisopropylethylamine in 20 ml methylene chloride was added dropwise with at a rate such that the temperature was maintained below 12° C. The mixture was stirred for 60 min 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 resulting crude p-nitrobenzyl-(3-α-t-butyldimethyl-silyloxyethyl-2-oxo-azetidinyl)oxoacetate was dissolved in 300 ml of ethanol-free chloroform and the resulting solution was refluxed under nitrogen while a solution of 6.85 ml (0. 04 mol) of triethyl phosphite in 50 ml of ethanol-free chloroform was added dropwise over 2 hours.The resulting solution was refluxed for 16 hours and then concentrated in vacuo. The residue was chromatographed on silica gel (800 g), eluting with 95:5 toluene/ethyl acetate to give 5.5 g (53% yield) of the title compound as a yellow foam.

The infrared spectrum of the title compound as a dichloromethane solution had absorptions at 5.56, 5.89 and 6.54 pm. The NMR spectrum of the title compound as a deuterochloroform solution 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 intermediate (1-^azatidinyl)-oxo-acetate as a deuterochloroform solution 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)f7.5(d,2H) and 8.17(d,2H)ppm.

MANUFACTURE K

3-a-t-butyldimethylsilyloxyethyl-4-ethylthio-(thiocarbonyl)thio-2-oxo-azetidine

Ethanethiol (8.5 mL, 0.115 mol) was 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 atmosphere. After 15 minutes, 7.73 mL (0.12 mol) of carbon disulfide was added and the mixture was stirred at 0-5°C for 35 minutes. A solution of 15.0 g (0.0522 mol) of 4-acetoxy-3-t-butyldimethylsilyloxyethyl 2-azetidinone in 500 ml of methylene chloride was added, and the mixture was stirred vigorously at room temperature for 24 hours. The aqueous phase was separated and extracted with two 150 ml portions of methylene chloride. The combined methylene chloride fractions were washed with two 200 mL portions of water and 200 mL 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 99:1 chloroform/ethyl acetate to give 9.1 g (48% yield) of the title 1-trithiocarbonate as a yellow foam.

The infrared spectrum of the title compound in dichloromethane solution had absorptions at 5.62 and 9.2 mm. The NMR spectrum of a deuterochloroform 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) and 6.57 (b, 1H) ppm.

MANUFACTURE L

2-pyrrolidon-3-yl-p-toluenesulfonate

To a solution of 1.0 g (0.01 mol) of 3-hydroxy-2-pyrrolidone in 50 ml of methylene chloride cooled to 0°C under nitrogen was added 2.44 g (0.02 mol) of 4-dimethylaminopyridine, and so

1.9 g (0.01 mol) of p-toluenesulfonyl chloride. The resulting solution was stirred at 0°C for 30 minutes, then at room temperature overnight. The solution was washed with 50 mL 1N aqueous hydrochloric acid solution, 50 mL water and 50 mL saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo to an amorphous solid (2.1 g, 83% yield) of the title compound.

The NMR spectrum of a deuterochloroform solution of the title compound had peaks at 2.44 (s) and 1.83-2.64 (c) (total 5H); 3.1-3.44 (m, 2H); 4.86 (t, 1H); 7.33 (d, 2H) and 7.8

(d + b, 3H) ppm.

MANUFACTURE M

The procedures from preparation L were used with 1-formyl-3-hydroxypyrrolidine as starting material to obtain 1-formyl-3-pyrrolidinyl-p-toluenesulfonate in 82% yield. The NMR spectrum of a deuterochloroform solution of the product had peaks at 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.

In a similar manner, 3-methyl-perhydro-1,3-oxazin-2-on-5-yl-p-toluenesulfonate was prepared from the corresponding alcohol (81%). The NMR spectrum for a deuterochloroform solution had peaks at 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.

PRODUCTION N

2-pyrrolidon-4-yl-p-toluenesulfonate

To a solution of 0.71 g (7.02 mmol) of 4-hydroxy-2-pyrrolidone in 35 ml of methylene chloride cooled to 0°C under nitrogen was added 1.72 g (14.04 mol) of 4-dimethylaminopyridine, followed by of 1.34 g (7.02 mmol) of p-toluenesulfonyl chloride. The resulting solution was allowed to warm to room temperature and was stirred for 3 hours. The solution was then washed with 2 x 30 mL 1N aqueous hydrochloric acid solution, 30 mL saturated aqueous sodium bicarbonate solution and 30 mL saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo to give an amorphous solid (1.5 g, 84% yield ) of the title compound.

The NMR spectrum of a deuterochloroform solution of the title compound had peaks at 2.46 (s) and 2.02-2.84 (c)

(total 5H); 3.24-3.86 (c, 2H); 5.17 (c, 1H); 7.1 (b, 1H);

7.34 (d, 2H) and 7.76 (d, 2H) ppm.

MANUFACTURE 0

The procedures from preparation N were applied using 5-hydroxymethyl-3-methyl-1,3-oxazolidin-2-one as the starting alcohol to obtain (3-methyl-1,3-oxazolidin-2-on-5-yl) methyl p-toluenesulfonate in 85% yield whose NMR spectra as a deutero-chloroform solution had peaks at 2.44 (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. In a similar way, with 4-hydroxymethyl-3-methyl-1,3-oxazolidin-2-one as starting alcohol, (3-methyl-1,3-oxazolidin-2-on-4-yl)-methyl- p-toluenesulfonate

in 88% yield with an NMR spectrum as a deuterochloroform solution peaking 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, 1-formylpiperidin-3-yl-p-toluenesulfonate was prepared from the corresponding alcohol in 75% yield. NMR (CDCl 3 ): 1.22-2.17 (C, 4H); 2.46 (s, 3H); 2.96-3.9 (c, 4H); 4.53 (m, 1H); 7.34 (d, 2H); 7.8 (d, 2H); 7.93 (d, 1H).

MANUFACTURE P

2-pyrrolidone-3-yl-thioacetate

A mixture of 855 mg (.7.5 mmol) potassium thioacetate and

1.2 7 g (5 mmol) of crude 2-pyrrolidon-3-yl-p-toluenesulfonate in 40 ml of acetone was refluxed under nitrogen for approx. 20 hours. The mixture was then filtered and the filtrate was concentrated in vacuo. The residue was partitioned between 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 saturated aqueous sodium chloride solution. The ethyl acetate solution was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was chromatographed on silica gel eluting with ethyl acetate to give 180 mg (23% yield) of the title compound.

The NMR spectrum of the title compound as a deuterochloroform solution had peaks at 2.38 (s) and 1.7-2.98 (c) (total 5H); 2.27-3.6 (m, 2H); 4.17 (t, 1H); and 7.74 (b, 1H) ppm.

MANUFACTURE Q

The procedures from Preparation P were used with the starting p-toluenesulfonates shown in Table 4 to obtain

the corresponding thioacetates whose yields and NMR spectra as deuterochloroform solutions are shown.

MANUFACTURE R

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

Maleimide (5.0 g, 0.051 mol) was added to 10 mL (0.14 mol) of thioacetic acid cooled to 0°C under nitrogen. The mixture was stirred at 0°C for 70 minutes and then filtered. The filtrate was diluted with 70 ml of ethyl acetate and the resulting solution was washed with 50 ml of saturated aqueous sodium bicarbonate solution and 50 ml of saturated aqueous sodium chloride solution. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated in vacuo to a yellow oil (5.4 g). The crude product was purified by flash chromatography on silica gel (350 g) eluting with 1:3 ethyl acetate/hexane to give 3.81 g (43%) of the title compound as a white solid. The NMR spectrum of the title compound as a deuterochloroform solution had peaks at 2.38 (s) and 2.3-3.54 (m) (total 5H); 4.24 (m, 1H) and 8.86 (b, 1H) ppm.

MANUFACTURE S

2-pxperidon-5-yl-p-toluenesulfonate.

2-piperidon-5-ol (0.575 g, 5 mmol) was dissolved in 15 mL of dimethylformamide and the solution was diluted with 50 mL of dichloromethane. The solution was 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 were 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 125 ml of dichloromethane and the solution was washed with 20 ml of 1N aqueous hydrochloric acid solution, two 20 ml portions of water and 20 ml of saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Diethyl ether was added to the residue and the title compound was obtained as the resulting solid product after filtration (0.8 g, 60% yield). The NMR spectrum of the title compound as a deuterochloroform solution had peaks at 2.4 (s) and 1.67-2.6 (c) (total 7H); 3.43 (c, 2H); 4.86.

(m, 1H); 6.96 (b, 1H); 7.3 (d, 2H) and 7.76 (d, 2H) ppm.

MANUFACTURE T

2-piperidon-4-yl-thioacetate

A solution of 1.9 g, 6 mmol) of tetrabutylammonium thioacetate and 0.807 g (3 mmol) of 2-piperidone-5-yl-toluenesulfonate in 15 ml of acetone was refluxed under nitrogen for 70 minutes. The solution was then concentrated in vacuo and the residue was dissolved in

75 ml ethyl acetate. The ethyl acetate solution was washed successively with 10 ml of water, 10 ml of saturated aqueous sodium chloride solution, 10

ml of water and 10 ml of saturated aqueous sodium chloride solution. The combined aqueous extracts were washed with two 50 mL portions of ethyl acetate. The combined ethyl acetate fractions were dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was chromatographed on silica gel (100 g) eluting with ethyl acetate to give 0.229 g (44%) of the title compound as a yellowish solid. The NMR spectrum of the title compound as a deuterochloroform solution had peaks at 2.4 (s) and 1.64-2.68 (c) (total 7H); 2.73-4.1 (c, 3H) and 7.05 (b, 1H) ppm.

MANUFACTURE U

(1,3-oxazolidin-2-on-4-yl)methyl p-toluenesulfonate

p-toluenesulfonyl chloride (1.0 g, 0.0053 mol) was added to a stirred solution of 2-oxo-1,3-oxazolidine-4-methanol -

(0.619 g, 0.0053 mol) and 4-dimethylamino-pyridine (1.30 g, 0.0106 mol) in 60 mL of methylene chloride at 0°C under a nitrogen atmosphere. After 1 hour at 0°C, 0.121 g more of p-toluene-

sulfonyl chloride added and the reaction mixture was stirred at 0°C for 30 minutes and at 25°C for 1 hour. The reaction solution was then washed with two 50 mL portions of 1N aqueous hydrochloric acid solution, 50 mL water, 50 mL saturated aqueous sodium bicarbonate solution and 50 mL saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo to a white solid of the title compound. (1.22 g, 85% yield).

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.

PRODUCTION V

Using the procedures of Preparation U, the appropriate starting alcohol was converted to the corresponding tosylate whose R, yield and NMR spectrum are shown in Table 5.

MANUFACTURE W

1-Methylpiperidin-2-one-3-yl-methylsulfonate

Methanesulfonyl chloride (0.8 mL, 0.01 mol) was added dropwise to a stirred solution of 1-methyl-2-oxo-3-piperidinol (1.29 g, 0.01 mol) and 4-dimethylaminopyridine (2.44 g, 0.02 mol) in 50 mL of methylene chloride at 0°C under nitrogen. The resulting solution was stirred at 0°C for 15 minutes and at 25°C

for 2.5 hours. The reaction mixture was then washed with 50 ml of saturated aqueous sodium chloride solution containing 6.8 ml of 6N aqueous hydrochloric acid solution, dried over anhydrous sodium sulfate and concentrated

concentrated in vacuo to a thick oil of the title compound (1.8 g, 87% yield). NMR (CDCl 3 ): 1.6-2.37 (c, 4H); 2.96

(p, 3H); 3.1-3.4 (c) and 3.24 (s) (total 5H) and 4.9 (m, 1H) ppm.

In a similar manner, 2-oxo-piperidin-3-ol was converted i

25% yield to piperidin-2-on-3-yl-methyl-sulfonate. NMR (CDCl 3 ): 2.03 (c, 4H); 3.06-3.45 (c) and 3.25 (s) (total 5H); 4.96 (m, 1H); 6.26 (b, 1H) ppm.

PRODUCTION X

( 1,3-oxazolidin-2-one-4- ylmethyl- thioacetate A solution of 2-oxo-1,3-oxazolidin-4-ylmethyl-p-toluenesulfonate (1.22 g, 0.0045 mol) and tetrabutylammonium- thioacetate (1.71 g, 0.0054 mol) in 75 mL of acetone was refluxed under nitrogen for 90 min. The reaction mixture was concentrated to dryness and the residue was chromatographed on silica gel (250 g). Elution with 4:1 ethyl acetate/hexane gave 580 mg of the title compound (75% yield). NMR (CDCl 3 ): 2.38 (s, 3H); 3.06 (d, 2H); 3.84-4.67 (c, 3H) and 6.3 (b, 1H) ppm.

MANUFACTURE Y

Using the procedures of Preparation X, the appropriate p-tosylate was converted to the corresponding thioacetate whose R, NMR spectrum in deuterochloroform and yield are shown in Table 6.

MANUFACTURE Z

I-formyl-3-piperidinyl-thioacetate

A solution of 1-formyl-3-piperidinyl-p-toluenesulfonate (1.12 g, 0.007 mol) and calcium thioacetate (0.91 g,

0.008 mol) in 10 ml of dimethylformamide was heated at 70°C under nitrogen for 20 hours. The reaction mixture was diluted with 150 ml of ethyl acetate and the resulting solution was washed with four 50 ml portions of water and 50 ml of brine, dried over anhydrous sodium acetate and concentrated in vacuum. The residue was chromatographed on silica gel (125 g) 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) (total 7H); 2.84-4.0 (c, 5H) and 7.9 (d, 1H) ppm.

MANUFACTURE AA

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

A mixture of 1-methyl-2-oxo-3-piperidinyl methanesulfonate (1.7 g, 0.008 mol) and potassium thioacetate (1.39 g, 0.012 mol) 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 50 ml of ethyl acetate and 50 ml of water. The ethyl acetate layer was washed with 50 ml water and 50 ml saturated aqueous sodium chloride solution, 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 title compound. NMR (CDCl 3 ): 1.7-2.5 (c) and 2.38 (s) (total 7H); 3.0 (s, 3H); 3.36 (m, 2H) and 4.2 (m, 1H) ppm.

In a similar manner, piperidin-2-on-3-yl methyl sulfonate was converted to piperidin-2-on-3-yl thioacetate in 56% yield.

NMR (CDCl 3 ): 1.5-2.5 (c) and 2.36 (s) (total 7H); 3.32 (c, 2H); 4.13 (m, 1H); 7.18 (b, 1H) ppm.

Claims (1)

Analogous method for the preparation of therapeutically active compounds of formula: or a pharmaceutically acceptable salt thereof, wherein R is: A is an alkylene with 2-4 carbon atoms, the alkylene with 2-4 carbon atoms where a carbon atom has an oxo substituent or the alkylene with 2-4 carbon atoms where a methylene group is replaced by oxygen or sulphur; B is carbonyl or methylene; R 1 is hydrogen or forms an ester group which is hydrolyzed in vivo; R 2 is hydrogen, formyl or alkyl of 1-4 carbon atoms; alk is the alkylene of 1-4 carbon atoms; and n is zero or 1, with the proviso that when B is methylene and A is alkylene of 2-4 carbon atoms, then R 2 is formyl; and when B is methylene, A cannot have the meaning alkylene with 2-4 carbon atoms where a carbon atom has an oxo substituent and said carbon atom is not adjacent to the nitrogen atom in R, or alkylene with 2-4 carbon atoms where the methylene is replaced by oxygen or sulphur, characterized by a compound with the formula: is converted to the corresponding compound of formula I by hydrogenolysis, where R4 is a carboxylic acid protecting group which is removed by hydrogenolysis, and optionally the pharmaceutically acceptable salt is formed in a manner known per se, or optionally a hydrolyzable ester of the carboxylic acid is produced.