FI82250C - Process for the preparation of therapeutically active 6- (1-hydroxyethyl) -2-azacycloalkyl (alkylene) thio-2-penem-3-carboxylic acid compounds - Google Patents

Description

1 82250

The present invention relates to a process for the preparation of novel antibacterial compounds having 2-azetidinone. This invention relates to a process for the preparation of novel antibacterial compounds containing 2-azetidinone. This invention relates to a process for the preparation of novel antibacterial compounds containing 2-acetidinone. - i.e. lactam ring. The antibacterial compounds chemically prepared in accordance with this invention are identified as 2-substituted 6-α- (1-hydroxyethyl) -10 2-penem-3-carboxylic acid compounds.

Although certain 2-substituted 2-penem-3-carboxylic acid compounds have been reported in the past, there is a continuing need for new compounds with desirable antibacterial therapeutic properties.

The process of this invention provides novel compounds of formula I.

OH

20 T H

H ..... I -: ._ U S ^ -SB!

H3C Γ T

A-N

C02H

Or pharmaceutically acceptable salts thereof; wherein R is 30 35 2 2 82250 wherein A is alkylene of 2 to 4 carbon atoms, alkylene of 2 to 4 carbon atoms having an oxo substituent on one carbon atom, or alkylene of 2 to 4 carbon atoms, and whose one methylene group has been replaced by a ha-5 game or sulfur; B is carbonyl or methylene; R 2 is hydrogen, formyl or alkyl of 1 to 4 carbon atoms; alk is alkylene of 1 to 4 carbon atoms; and n is 0 or 10; provided that when B is methylene and A is alkylene of 2 to 4 carbon atoms, alkylene of 2 to 4 carbon atoms having one oxo substituent on one carbon atom which is not a carbon atom adjacent to the nitrogen atom of the group R, or alkylene having 2 to 4 carbon atoms and having a methylene group replaced by oxygen or sulfur, then R 2 is formyl.

Preferred compounds of formula I are those wherein A is alkylene, B is carbonyl, R 2 is hydrogen or methyl and n is 0. Particularly preferred are compounds wherein R is 2-pyrrolidon-3-yl, 2-pyrrolidon-4- yl, piperidin-2-on-3-yl, 1-methylpiperidin-2-on-3-yl or 2-piperidon-5-yl.

Also preferred are compounds wherein A is alkylene, B is methylene, R 2 is formyl and n is 0. Particularly preferred is a compound wherein R is 1-formyl-3-pyrrolidinyl or 1-formylpiperidin-3-yl.

Further preferred are compounds wherein A is carbonylethylene or carbonylpropylene, B is carbonyl, R 2 is hydrogen or methyl, provided that A's ethylene or propylene is attached to B; especially compounds wherein Rx is hydrogen and R is pyrrolidin-2,5-Dion-3-yl ·

Further preferred are compounds wherein A is 1-oxaalkylene, B is carbonyl, R 2 is hydrogen or methyl

II

3,82250 and n is 1, provided that the oxygen of 1-oxaalkylene is attached to B; especially compounds wherein Rx 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, 5- (1,3-oxazolidin-2-on-4-yl) methyl, or (1,3-oxazolidin-2-on-5-yl) methyl.

Included within the scope of this invention are the preparation of compounds wherein A is 1-oxaalkylene and B is carbonyl, R 2 is hydrogen or methyl and n is 0; especially when Rx is hydrogen and R is 3-methyl-perhydro-1,3-oxazolidin-2-on-5-yl.

Also within the scope of this invention is the preparation of compounds wherein A is 1-thiaalkylene, B is carbonyl, R 2 is hydrogen, or methyl and n is 1; especially when R 1 is hydrogen and R is (1,3-thiazolidin-2-on-4-yl) methyl.

The compounds of this invention may be used in pharmaceutical compositions comprising a compound of formula I and a pharmaceutically acceptable diluent or carrier; and can be used in a method of treating a bacterial infection in a mammal, comprising administering to the mammal 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 structure of formula 25 δ —- '' X 2

I I «“ N

A_N - 3 O 4 30

The ring structure of formula III is referred to throughout this specification as "2-penem" and the ring atoms are numbered as shown. The carbon atom bonded to ring carbon 6 is numbered 8.

4,82250

Likewise, throughout this specification, the abbreviation "PNB" refers to a p-nitrobenzyl group.

In the compounds of the formula I, the hydrogen at the bridgehead carbon atom 5 and the hydrogen remaining in the carbon 6 can be in the cis or trans configuration relative to one another. Both isomers as well as mixtures thereof are included within the scope of this invention. In pharmaceutical applications, the trans isomer is generally preferred and the cis isomer is readily converted to the trans isomer.

In general, the 5-position carbon has an absolute stereochemistry, which is denoted by R, using the R, S-stereochemical notation of Prelog-Ingold used in this patent application. Thus, for example, a compound of formula I wherein Rx is hydrogen and R is 2-pyrrolidon-3-yl is designated (5R, 6S-6 - [(R) -1-hydroxyethyl] -2- (2-pyrrolidon-3-yl). -yl) thio-3-carboxyl-2-penem.

As will be appreciated, various optically active isomers of the novel compounds are possible. This invention encompasses the preparation of such optically active isomers as well as mixtures thereof.

Compounds of formula I according to the invention are prepared from a compound of formula 25

OH

T H

Hitin C, J

f · '. ^ SR

CO 2 R 4 wherein R is as defined above and R 4 is p-nitrobenzyl is removed by hydrogenation of the group R 4 and, if desired, the resulting compound of formula I is converted into a pharmaceutically acceptable salt.

Il 5 82250

The starting materials and compounds of formula I used in the process of the invention can be synthesized according to Schemes A-C.

As shown in Scheme A, the compound of formula I can be prepared by the method of Yoshida et al., [Chem. Pharm, Bull., 29, (1981) p. 2899-2909] of a known dibromopenam compound of formula IV. The exchange reaction between di-bromopenam (IV) and t-butylmagnesium chloride takes place at a temperature between about 10 ° C and -40 ° C, preferably about -78 ° C, in a reaction inert solvent such as terahydrofuran, diethyl ether or toluene, preferably tetrahydrofuran. Other organometallic reagents may be used. The resulting reaction mixture is treated in situ with a suitable aldehyde, e.g. acetaldehyde, to prepare a 1-hydroxyethyl derivative. The aldehyde is added at a temperature between about -80 ° and -60 ° C, preferably about -78 ° C, using acetaldehyde.

The resulting bromohydroxypenam V is hydrogenated to remove the 6-bromo-20 substituent. A suitable hydrogenation catalyst is a noble metal catalyst such as palladium. The reaction is carried out in a protic solvent such as methanol-water (1: 1) or tetrahydrofuran-water (1: 1), preferably methanol-water (1: 1), at a pressure of about 1 to 4 atmospheres, preferably 4 atmospheres, and at a temperature between about 0 and 30 ° C, preferably about 25 ° C.

I '6 82250

Scheme A

Br HO B

O co2ch3 o '* co2ch3 IV v' PO * 0 \ 'C02ch3

VI

f 1

Rg-Sio I / "» • in t / · / y C0oCH,

VII ^ J

i f t

Rq-SiO Rn-SiO

/ / - · -] - 0AC, / / * · ~ "· ι—.

* 'R9 / "V" CO2ch3

IX VIII

7 82250

Scheme B

f »I § IX -> R9-fi0V - ^ S-C-SR10 R9

X

** f »i

^ F1? Ro-SiO S

^ rTT10 «- ^ 'rrr--

-lc ° 2 ™ 0 ^ -VrCo2MB

XII

XI

. J

I9 f9

R9-9 ° O Rg-SiO

[l-i — r ^ V'8 * 10 P I 1 — S "T" SR

‘P-K -

o 002PNB o COjPNB

XIII XIV

HO

<- / V ^ V "—n-n

O CO2PNB

XV

8 82250

Scheme C

f9

IX - ^ R9-SiO S

K \ li

Stuck j "-S-C — SR

XVA

R ^ | 9? 9 R9 “f1? § Rq — SiO e ’j3-r H Ä-

° CO, PNB I

C02PN3 XVII XV1 f9 I s' T If

R9 “S10 s-C-SR

I -1 R9 J, _n „%

fj ^ XIV

0 C02PNB XVI12 9 82250

The alcohol of formula VI formed may be protected by a trialkyl halosilane of formula R9 *

5 R -Si-Q

wherein each R 1 is alkyl of 1 to 6 carbon atoms, and Q is chlorine, bromine or iodine. Thus, dimethyl-t-butylchloro-10-risilane forms a hydroxyl trialkylsilyl protecting group in the presence of an amine proton acceptor such as imidazole in a polar, aprotic solvent such as N, N-dimethylformamide at a temperature between about 5 ° C and 40 ° C, preferably about 25 ° C. as shown in formula 15 VII.

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

To obtain the desired azetidinone IX, the olefin VIII is ozonated in a reaction-inert solvent such as dichloromethane at a temperature in the range of about -80 to 40 ° C, preferably about -78 ° C. The reaction product is treated with an alkanol such as methanol to give azetidine IX.

As shown in Scheme B, a compound of formula IX is treated with a trithiocarbonate salt of formula M * R 10 -SC (S) -S 'wherein R 10 is alkyl of 1 to 4 carbon atoms, preferably ethyl, and M is a metal such as sodium or potassium to give a compound of formula X30. This conversion IX to + X is carried out in an organic solvent or water, preferably a mixture of water and dichloromethane, at a temperature of about 0 to 35 ° C, preferably about 25 ° C.

A compound of formula X is condensed with p-nitro-35-benzyl chlorooxalate in the presence of a tertiary alkylamine having, for example, 1 to 4 carbon atoms in each alkyl, such as ethyl diisopropylamine, to give a compound of formula VI. This condensation reaction is carried out in a reaction-inert solvent, preferably dichloromethane, at a temperature of about 5 to 25 ° C, preferably about 10 ° C.

The resulting compound of formula XI is cyclized using a trialkyl phosphite having 1 to 4 carbon atoms in each alkyl, such as triethyl phosphite, in a reaction inert solvent such as trichloromethane at a temperature of about 40 to 80 ° C, preferably about 60 ° C to give a compound of formula XII. penem.

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

The sulfoxide of a compound of formula XIII is substituted with a mercaptide of formula RS 'using, for example, the sodium or potassium salt of a suitable mercaptide which is reacted with the sulfoxide XIII in a polar organic solvent such as ethanol or acetonitrile at a temperature of about -10 to -50 ° C. , preferably about -35 ° C.

The starting mercaptans of formula R-SH or the starting thioacetates of formula R-S-C (O) CH 3 are known for many meanings of R and those that are not known can be prepared by methods known in the art. For an overview, see J.L. Wardell, "Preparation of Thiols," in The Chemistry of the Thiol 30 Group, ed. S. Patai, John Wiley & Sons, London, 1974, Part 4. See also Volante, Tetrahedron Letters, 22, (1981) pp. 3119-3122, for the conversion of alcohols to thiols and thiol esters using triphenylphosphine and a dialkyl azodicarboxylate with an alcohol and a suitable thiol. -35 in the presence of acid.

li 11 82250

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

The 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 used in this type of conversion. Thus, a solution of a compound of formula XV is stirred or shaken in a hydrogen atmosphere, or in a hydrogen atmosphere mixed with an inert diluent such as nitrogen or argon, in the presence of a catalytic amount of a noble metal hydrogenation catalyst such as palladium on calcium carbonate or palladium on Celite. Suitable solvents for use in this hydrogenolysis include lower alkanols such as methanol; ethers such as tetrahydro-furan and dioxane; low molecular weight esters such as ethyl acetate and butyl acetate; water; and mixtures of these solvents. Usually, however, conditions are chosen under which the starting material is soluble, such as, for example, aqueous tetrahydrofuran. The hydrogenolysis is usually carried out at room temperature at a pressure of about 0.5 to about 5 kg / cm 2. The catalyst is usually present in an amount of about 10% by weight of the starting material up to an amount corresponding to the weight of the starting material, although larger amounts may be used. The reaction usually takes about an hour, after which the compound of formula I is recovered, simply by filtration, after which the solvent is removed in vacuo. If palladium on calcium carbonate is used as the catalyst, the product is isolated as the calcium salt, and if palladium on Celite is used, the product is isolated as the sodium salt.

i2 82250

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

An alternative synthetic method is shown in Scheme C. An azetidine of formula IX is reacted with a trithiocarbonate of formula M + R-S-C (S) -S "wherein M is a metal such as sodium or potassium using the method previously described to prepare compound X.

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

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

Chloride XVII is reacted with a triarylphosphine such as triphenylphosphine in a reaction inert solvent such as tetrahydrofuran in the presence of a tertiary amine such as 2,6-lutidine at a temperature of about 25 ° C to give a compound of formula XVIII which is cyclized by refluxing aromatics. In a solvent such as toluene to give a penem of formula XIV.

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

Using the previously mentioned method of Yoshida et al., The stereochemistry for the penem carbon 6 as well as the hydroxyethyl group attached to the carbon 6 is shown in Formula I. Thus, the essential stereochemistry for the Ring Closure-5 product when using Schemes B or C is one in which the hydrogen at the 5-position of the penem ring is in the trans position relative to the hydrogen on carbon 6 and in the α-configuration. Alternatively, the stereochemical structure may be represented in the form 5R, 6S; 6- (R) -l-hydroxyethyl.

The compounds of formula I are acidic and form salts with basic substances. Such salts are considered to be within the scope of this invention. These salts may be prepared by standard methods, such as by contacting the acidic and basic ingredients with one another, usually in a stoichiometric ratio, in an aqueous, non-aqueous or partially aqueous medium, as appropriate. They are then recovered by filtration, precipitation as an insoluble solvent and then filtration, evaporation of the solvent, or in the case of aqueous solutions, freeze-drying as deemed appropriate. Alkaline substances suitable for use in the formation of salts are of the organic or inorganic type and include ammonia, organic amines, alkali metal hydroxides, carbonates, bicarbonates, hydrides and alcoholates, as well as alkaline earth metal hydroxides, carbonates, hydrides and alcoholates.

Representative examples of such bases include primary amines such as -n-propylamine, -n-butyl-amine, aniline, cyclohexylamine, benzylamine, and octylamine; secondary amines such as diethylamine, morpholine, pyrrolidine and piperidine; tertiary amines such as triethylamine, N-ethylpiperidine, N-methylmordoline and 1,5-diazabicyclo [4.3.0] non-5-ene; Hydroxides such as sodium hydroxide, potassium hydroxide, ammonium hydroxide and barium hydroxide; alcoholates such as sodium 82250 and potassium methylate; 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 sodium 2-ethylhexanoate.

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

Pharmaceutically acceptable salts of the compounds of formula I include salts which do not have significant adverse side effects in commonly used amounts and include, for example, their sodium, potassium or calcium salts.

The antibacterial activity of the compounds of the formula I and their salts in vitro can be demonstrated by determining their minimum inhibitory concentrations (MIC values) in pg / ml against various microorganisms. The method to be followed is that recommended by the International Collaborative Study on Antibiotic Sen-20 Sitivity Testing (Ericcson and Sherris, Acta. Pathologica et Microbiologia Scandinav, Supp. 217, Section B, (1971) pp. 64-68) and using cerebrospinal infusion Tubes incubated overnight are diluted 100-fold for use as a standard 25 vaccine (20,000-10000 cells in approximately 0.002 ml are placed on an agar surface; 20 ml BHI agar / plate). single dilution of test compound after examination for 18 hours at 37 ° C. The susceptibility (MIC) of the test organism is considered to be the lowest concentration of compound that can be used in a single dilution of test compound at an initial concentration of 200 pg / ml of test compound. cause complete inhibition of growth with the naked eye estimates.

According to the above-mentioned method, 35 MIC values were determined in vitro for the compounds of the formula I in which the meanings of the substituent R are given below against microorganisms numbering 82250. The results are shown in the following Tables I and II. The table shows the following compounds of formula I:

Compound A: A compound prepared according to the invention wherein

5 _ / ~ V

R is - (^ O

"" B

Compound B: A compound prepared according to the invention wherein

10 R is II

B

Compound C is a preferred compound according to EP 70204, wherein the substituent R corresponds to a group

O

In Compound D, the substituent R is - ^ ^ ch3; Compound 20 is thus a close homologue to the preferred compound of EP 70204, wherein R is -p ,.

In the compound E R is I I; thus, this compound is a close homologue of the preferred compound of EP 70204, wherein R is' 1 1

B

16 82250

Table I

Antibacterial MIC (pg / ml) in vitro compound

A__C__D__C / A D / A

5 (1) Staph, aur. 0.05 <0.025 0.10 0.5 2 01A005 (2) 01A052 0.05 0.05 0.05 1 1 (3) 01A110 0.10 0.05 0.10 1 1 (4) 01A400 0.05 <0.025 0.05 0.5 1 10 (5) Staph, epi. 0.20 0.20 0.20 1 1 01B087 (6) 01B111 0.05 <0.025 0.05 0.51 1 (7) 01B126 1.56 0.78 0.39 0.5 0.25 (8) Strep, faec. 3.12 3.12 6.25 1 2 15 02A006 (9) Strep, pyog. S0.025 <0.025 0.025 1 1 02C054 (10) 02C203 SO, 025 <0.025 <0.025 1 1 (11) Strep, agalact. 0.05 <0.025 0.05 0.5 1 20 02B006 (12) E. coli. 0.20> 50 1.56> 250 8 51A125 (13) 51A129 0.78> 50 6.25> 64 8 (14) 51A266 0.10> 50 0.78> 500 8 25 (15) 51A470-0 39 0.78 (16) Ps. > 50> 50> 50 1 1 52A104 (17) 52A663> 50> 50> 50 1 1 (18) Reg. pn. 0.20> 50 3.12> 250 16 30 53A009 (19) 53A031 0.20> 50 3.12> 250 16 (20) Kleb. Oxy. 0.20> 50 3.12> 250 16 53D024 (21) Past. mult. SO, 025 0.05 0.39 2> 16 35 59A001 (22) Serr. November. 1.56> 50 6.25> 32 4 63A017 17 82250

Table I (continued)

A C _D_ C /, A D / A

(23) Neiss sic. £ 0.025 0.20 0.78 --- ---

66COOO

5 (24) Ent. aerog. £ 0.025> 50 3.12> 2000 125 67A040 (25) Ent. cloac. 3.12> 50 12.5> 16 4 67B009 (26) Prov. stua. 1.56> 50 50> 32 32 10 77A013 (27) Prov. ret. 0.39> 50 25> 128 64 77C025 (28) Morg. Morg. 0.78> 50 50> 64 64 97A001 15 H. Infl .: 54A036 0.78 0.20 3.12 0.25 4 54A038 0.78 0.20 1.56 0.25 2 54A042 0.78 0, 20 1.56 0.25 2 54A051 0.78 0.39 1.56 0.5 2 20 54A012 0.78 0.20 0.78 0.25 1 54A078 0.78 0.39 1.56 0.5 2 54A081 0.78 0.20 1.56 0.25 2 54A070 0.39 0.39 1.56 1 4 18 82250

Table II

Antibacterial MIC (pg / ml) in vitro compound

_B__E__E / B

5 (1) Staph, aur. 0.10 0.05 0.5 01A005 (2) 01A052 0.10 0.05 0.5 (3) 01A110 0.10 0.05 0.5 (4) 01A400 0.10 0.05 0.5 10 (5) Staph, epi. 0.39 0.20 0.5 01B087 (6) OlBlll 0.10 0.10 1 (7) 01B126 1.56 1.56 1 (8) Strep, faec. 3.12 6.25 2 15 02A006 (9) Strep, pyog. <0.025 <0.025 1 02C054 (10) 02C203 <0.025 <0.025 1 (11) Strep, agalact. <0,025 0,05 2 20 02B006 (12) E. coli. 0.10 0.78 8 51A125 (13) 51A129 0.39 1.56 4 (14) 51A266 0.05 0.78 16 25 (15) 51A470 0.05 0.39 8 (16) Ps. > 50> 50 1 52A104 (17) 52A663> 50> 50 1 (18) Reg. pn. 0.10 6.25 62 30 53A009 (19) 53A031 0.20 1.56 8 (20) Reg. Oxy. 0.20 1.56 8 53D024 (21) Past. mult. 0.05 0.39 8 35 59A001 (22) Serr. November. 1.56 1.56 1 63A017 li 19 82250

Table II (breakdown)

_B_ E E / B

(23) Neiss slc. £ 0.025 0.20> 8

5 66COOO

(24) Ent. aerog. 0.05 1.56 31 67A040 (25) Ent. cloac. 1.56 6.25 4 67B009 10 (26) Prov. stua. 3.12> 50> 16 77A013 (27) Prov. ret. 1.56 25 16 77C025 (28) Morg. Morg. 3.12 50 16 15 97A001 H. Infl .: 54A036 0.20 3.12 16 54A038 0.20 NT --- 54A042 0.20 1.56 8 20 54A051 0.20 3.12 16 54A012 0.20 3 .12 16 54A078 0.20 3.12 16 54A081 0.20 1.56 8 54A070 1.56 6.25 4 25

Table I compares the MIC values obtained with a compound of formula I according to the invention, wherein R is 2-oxopiperidin-5-yl, and with compounds of the prior art, the corresponding substituent being cyclohexyl (compound C) or 1 methylpiperidin-4-yl. A comparison of the values obtained for compound A and compound C in column HC / A "shows that the activity of the compound according to the invention is up to several orders of magnitude higher than that of compound 35 C important Gram-negative pathogens E. coli, Klebsiella, Serratia, Enterobacter, Propidencia and Morganella against.

20 8 2 2 5 0

A similar comparison in column "D / A" shows that compound A prepared according to the invention has a significantly stronger potency against compound microorganisms E. coli, Klebsiella, Enterobacter, Providencia and Morganella than compound D.

Similarly, Table II compares the MIC values obtained with a compound of formula I according to the invention in which R is 2-oxopyrrolidin-3-yl and a closest known compound of structure 10E in which the corresponding substituent is 1-methylpyrrolidin-3-yl. yl. The values in column "E / B" indicate that the compound of the invention has a significantly stronger potency against important microorganisms E. coli, Klebsiella, Enterobacter, Providencia, Morganella and H. influenzae.

The compounds of formula I and their pharmaceutically acceptable salts are suitable for controlling bacterial infections in mammals, including man. They can be used to control infections caused by harmful bacteria in human patients, e.g., infections caused by harmful Staphylococcus aureus strains.

The compounds of this invention may be administered orally or parenterally, i. li-25 intramuscularly, subcutaneously, intraperitoneally or by intravenous injection; as such, alone or in combination with a pharmaceutically acceptable carrier in accordance with normal pharmaceutical practice.

The ratio of active substance to carrier depends on the chemical nature, solubility and stability of the active substance, as well as the intended dosage. Normally, the ratio of pharmaceutically acceptable carrier to penem compound is in the range of 1:10 to 4: 1. For the purpose of oral administration, the compounds of this invention may be employed in the form of tablets, capsules, troches, lozenges, powders, syrups, elixirs, aqueous solutions and suspensions, and the like. In the case of ti 2i 82250 tablets, useful carriers include lactose, sodium citrate and salts of phosphoric acid. Various disintegrants such as starch and glidants such as magnesium stearate, sodium lauryl sulfate and talc are commonly used in tablets. Useful capsule diluents include lactose and high molecular weight polyethylene glycols. If aqueous suspensions for oral use are required, the active ingredient is combined with emulsifying or suspending agents. Sweetening and / or flavoring agents may be added.

For parenteral administration, sterile solutions of the active ingredient are usually prepared and the pH of the solutions adjusted and buffered. For intravenous use, the total concentration of the solutions must be adjusted so that the preparation is isotonic. The prescribing physician will ultimately determine the appropriate dose for a particular human patient, and this can be expected to vary with the age, weight, and response of the individual patient, as well as the nature and severity of the patient's symptoms. The compounds of formula I are usually administered orally in doses ranging from about 10 to about 200 mg per kilogram of body weight per day, and parenterally in doses ranging from about 10 to about 400 mg per kilogram of body weight per day. 25 In some cases, it may be necessary to use doses that deviate from these limits.

The following examples and preparations are presented for illustrative purposes only. Infrared (IR) spectra were determined as either potassium bromide tablets (KBr tablet-30 ti), Nujol steps, or solutions in chloroform (CHCl 3), methylene chloride (CH 2 Cl 2), or dimethyl sulfoxide (DMSO), and diagnostic absorption bands are reported in either microns or microns. cm-1). Nuclear magnetic resonance (NMR) spectra were measured from solutions in deuterochloro-35 (CDCl 3), perdeuteromethanol (CD30D) or perdeuterodimethylsulfoxide (DMS0-d6) or mixtures thereof, and peak locations are reported in ppm from tetramethyl-222. The following abbreviations have been used for the shapes of the peaks: s singlet; d doublets: t triplets; q quartets; m mul-tipletti; b wide; c complexes. The abbreviations "ss" and "sss" 5 mean that a particular proton appeared as two or three siglets, respectively, due to the presence of diastereoisomers. In the examples and preparations, the abbreviation "PNB" as a whole denotes a 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 ΙΟ% Pd 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 hydrogen carbonate 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 was then added. in a mixture of 8 ml of tetrahydrofuran and 8 ml of water, and the resulting mixture was hydrogenated at 55 psi of hydrogen (379 kPa) for 75 minutes; then an additional 73 mg of 10% Pd diatomaceous earth was added and the pH of the mixture was adjusted to 7.0 with 0.02 M aqueous sodium hydrogen carbonate solution. The mixture was hydrogenated at 55 psi (379 kPa) for 75 minutes; then the catalyst was 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 165 ml portions of ethyl acetate. The aqueous solution was then lyophilized to give 38 mg (yield 69%) of the title compound as an amorphous solid.

In the infrared spectrum of the title compound as a potassium bromide tablet, the absorbances were at 2.94, 5.65 and 6.3 microns.

Example 2 The procedures of Example 1 were followed using the appropriate compounds of formula XV to give the sodium salts of the compounds of formula I, the yield, infrared spectrum of the potassium bromide tablet (unless otherwise stated) and R are shown in Table 1.

23 82250

Table 1 5 R 1R (microns) Yield (%) 2-pyrrolidon-4-yl 2.92, 5.68, 6.0 88 and 6.15 1-formyl-3-pyrrolidinyl 2.92, 5.64, 6.03 89 10 and 6.3 (3-methyl-1,3-oxazolidine-2.94, 5.7 and 6.25 78 2-on-5-yl) methyl (3-methyl-1,3-methyl oxazolidin-2,94, 5,7 and 6,28 90 2-on-4-yl) methyl 15-piperidon-5-yl 5,64, 6,02 and 6,3 93 (DMSO) piperidin-2-yl on-3-yl 2,94, 5,66, 6,06,79 and 6,25 l-methylpiperidin-2-one-3, 2,93, 5,64 and 6,15 98 2-yl-1-formylpiperidin-3 -yl 2.9, 5.65 and 6.03 73 3-methyl-perhydro-1,3-2.92, 5.63, 5.99 57 oxazin-2-on-5-yl and 6.08 ( of the less soluble diastereomer) 3-methyl-perhydro-1,3,5,65 (DMSO) 84 oxazin-2-on-5-yl (of the more soluble diastereomer) 30

Example 3

Sodium (5R, 6S) -6 - [(R) -l-hydroksletyyli] -2- (pyrrol-lidln-2,5-dłoń-3-yl) thio-2-penem-3-carboxylate

The procedures of Example 1 were followed except that the initial 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% yields and its absorption spectral spectra as potassium bromide 24,82250 ditablets were at 2.92, 5.63, 5.8 and 6.2 microns.

Example 4

The procedures of Example 3 were followed using the appropriate compounds of formula XV to give salts of the compounds of formula I, the yield, infrared spectrum of the potassium bromide tablet (unless otherwise stated) and R are shown in Table IA.

Table 1 A

10 R IR (microns) Yield (%) (1,3-oxazolidin-2-on-4-yl) methyl 5,72 (b) 95 (1,3-oxazolidin-2-on-5-yl) methyl 5.72 (b) 87 (1,3-thiazolidin-2-on-4-yl) methyl 5,65 100

Preparation A

20 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 mmol) of 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 a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran were added. After stirring for 20 hours under nitrogen, 50 ml of ethyl acetate were added and the resulting solution was washed with 40 ml of saturated aqueous sodium hydrogencarbonate 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 evaporated to dryness in vacuo. The crude product (110 mg) was chromatographed on silica gel (50 g) eluting with ethyl acetate-methanol (95: 5) to give 73 mg (77% yield) of the title compound as an amorphous solid.

Il 25 82250

The NMR spectrum of the 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, 1 H); 6.64 (b, 1 H); 7.6 (d. 2H); and 8.2 (d, 2H) ppm. In the infrared spectrum of the title compound 5 in dichloromethane solution, the absorbances were at 5.58, 5.85 and 6.57 microns.

Preparation B

The procedures of Preparation A were followed using compounds of formula XIV to give compounds of formula XV 10 having the properties and R shown in Table 2. The solvents in which the spectra were measured are in parentheses.

26 82250

Table 2 R IR (microns) NMR (ppm) Yield (%) 2-pyrrolidone-5.58, 5.87 and 1.3 (d, 3H); 87 4-yl 6.58 (CH 2 Cl 2) 2.0-4.42 (c, 58H); 5.3 (q. 2H); 5.68 (d, 1 H); 6.25 (b, 1 H); 7.56 (d. 2H); 10 and 8:18 (d, 2 H).

(CDCl 3) 1-formyl-3- 5.57, 5.96 and 1.35 (d, 3H); 1.8-42 pyrrolidinyl 6.56 (CH 2 Cl 2) 2.6 (c, 2H); 3.2 (b, 1 H); 3.3-4.46 (c, 7 H); Δ: 3 (q, 2 H); 5.64 (d, 1 H): 7.6 (d, 2 H); and 8.2 (s and d, 3H); (cdCl 3) 2 O (3-methyl-1,3,5,56, 5,66 and 1,36 (d; 3H); 2,4,3,8-oxazolidine-2 - 6.57 (CH 2 Cl 2) (b, 1H); 2.9 (s, ηη 5-yl) methyl-3H); 3.17-3.92 L (c, 5H); 4.0-4.86 (c, 2 H); 5.31 (q, 2 H); Δ 5.69 (d, 1 H); 7.6 (d. 2H); and 8.2 (d, 2 H).

(CDCl 3) (3-methyl-1,3,5,56, 5,67 and 1,35 (d, 3H); 2,2-oxazolidine-2 - 6.56 (CH 2 Cl 2) (b, 1H); 2.89 (s) on-4-yl) me- and 2'81-3.5 (c), style (total 5H); 3.6-4.49 (c. 5H); 5.3 (q, 2 H); 35 5.67 (d, 1 H); 7.56 (d. 2H); and 8.16 (d, 2 H).

(CDC13)

II

27 82250

Table 2 cont.

1 H IR (microns) NMR (ppm) Yield (%) pyrrolidine-2.5-5.57, 5.75 and 1.3 (d, 3H); 32 Dion-2-yl 6.54 (CH 2 Cl 2) 2.1 (b, 1H); Δ 2.5-4.4 (c, 6 H); 5.3 (q. 2H); 5.65 (d, 1H): 7.56 (d, 2H); and 8.16 (d, 2 H).

(CDCl 3) 2-piperidone-5- 5.64 and 6.0 1.18 (d, 3H); 86 yl (Nujol gradient) 1.74-2.8 (c, 4H); 3.05 - 3.74 (c, 4H); 4.03 (m, 1 H); 5.25 (d, 1 H); 5.37 (q, 2 H); 5.78 (d, 1 H); 7.66 (b, 1 H); 7.7 (d. 2H); and 8.25 (d. 2H).

20 (DMSO-d 6, 250MHz) (1,3-oxazolidine-5.5, 5.67, 2.0 (b, 1H); 1.27 57 2-on-4-yl) methyl 5.91 and 6 .58 (d. 3H); 3.1 (m, (CH 2 Cl 2) 2 H); 3.7 (dd, 1 H); 3.8-4.67 (c. 4H); Δ 5.31 (q, 2 H); 5.68 (d, 1 H); 7.1 (b. 1H); 7.6 (d. 2H); and 8.18 (d, 2 H). (cdci3 / cd3od) 30 35 28 82250

Table 2 cont.

R IR (microns) NMR (ppm) Yield (%) 1,3-oxazolidine-5.58, 5.67 and 1.29 (d, 3H); 56 2-on-5-yl) me- 6.58 (CH 2 Cl 2) 2.2 (b, 1H); Δ style 3.1-3.98 (C, 5H); 4.1 (m, 1 H); 4.83 (C, 2 H); 5.3 (q. 2H); 5.7 (d, 1 H); Δ 7.1 (b, 1 H); 7.58 (d. 2H); and 8.17 (d, 2 H). (CDCl 3 / DMSO-d 6) (1,3-thiazolidine-5.61, 5.97, 1.18 (d, 3H); 64-2-on-4-yl) me-6.06, 6.6 , 6.7 3.13-3.46 (C, style (KBr) 3H); 3.62 (dd, 1 H); 3.88 (dd, 1 H); 4'O 2 (m, 1 H); 4.1 (m, 1 H); 5.25 (d, 1 H); 5.38 (q, 2 H); 5.76 (d, 1 H); 7.7 (d. 2H); 8.24 (d. 2H); 8.42 (s, 1 H).

(250 MHz, DMSO-d 6) piperidin-2-one-3, 5.56, 5.9, 1.3 (d, 3H); 65 δ 6.0 and 6.56 1.65-2.45 (c, 4H); (CH 2 Cl 2) 3.28 (c, 2H); 3.52-4.42 (c, 4 H); 5.32 (q, 2 H); 5.65 and 5.7 (2d, total 1H); 7.12 (b, 1 H); Δ 7.6 (d. 2H); 8.2 (d. 2H). (CDCI 3 / DMSO-d 6)?

II

29 82250

Table 2 cont.

R IR (microns) NMR (ppm) Yield (%) 1-methylpiper- 5.56, 5.92, 6.07 1.3 (d, 3H); 40 ridin-2-on-3-yl and 6.56 (CH 2 Cl 2) 1.7-2.45 (c, 5H); 2.96 (s. 3H); 3.3 (m. 2H); 3.65-4.45 (c. 3H); 5.3 (q. 2H); 5.6 (d, 1H); Δ 7.57 (d, 2 H); and 8.2 (d, 2H).

(CDCl 3) 1-formylpiper-5.57, 5.97 and 1.12-2.33 (c) 64-din-3-yl 6.56 (CH 2 Cl 2) and 1.3 (d) 15 (total 8H) ; 2.78-4. 62 (c, 7H); 5.28 (q, 2 H); 5163 (d, 1 H); 7.54 (d. 2H); Δ 7.98 (s, 1 H); and 8.16 (2H).

(CDClg)

Preparation C

25-p-n -benzoyl- (5R, 6S) -6 - [(R) -1-hydroxyethyl] -2- (3-methylperhydro-1,3-oxazin-2-on-5-yl) thio-2-penethyl mi-3-carboxylate

Tetrabutylanunonum fluoride (1.25 mL of a 1 M solution of tetrahydrofuran, 1.25 mmol) and acetic acid (0.25 mL) were added to a solution of p-nitrobenzyl- (5R, 6S) -6 [(R) -1-t -butyldimethylsilyloxyethyl] -2- (3-methylperhydro-1,3-oxazin-2-on-5-yl) thio-2-penem-3-carboxylate (0.24 g; 0.39 mmol) in 2 mL: in dry tetrahydrofuran. The resulting solution was stirred at 25 ° C under 35 nitrogen for 20 hours. The reaction solution was then diluted with 100 ml of ethyl acetate and washed with 10 ml of water and 20 ml of brine, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residual 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 a diastereomer which dissolved in 5 minutes as a pale tan solid. The filtrate was evaporated to dryness in vacuo and the residue chromatographed on silica gel (75 g) eluting with ethyl acetate-methanol (9: 1) to give the more soluble diastereomer as a solid. Trituration of the solid with diethyl ether-petroleum ether (1: 1) and filtration gave 52 mg of the more soluble diastereomer as a light tan solid (total yield 63%).

Less soluble diastereomer: NMR (DMSO-d 6 250 MHz): 1.2 (d, 3H); 2.86 (s. 3H); 3.4 (dd, 1 H); 3.83 (dd, 1 H); 3.9-4.1 (c. 3H); 4.25 (dd, 1 H); 4.51 (dd, 1 H); 5.26 (d, 1 H); 5.38 (q, 2 H); 5.8 (d. 1H); 7.7 (d. 2H); and 8.26 (d, 2H) ppm.

Better soluble diastereomer: NMR (DMSO-d 6, 250 MHz): 1.2 (d, 3H); 2.86 (s. 3H); 3.35 (dd, 1 H); 3.81 (dd, 1 H); 3.9-4.1 (c. 3H); 4.29 (dd, 1 H); 4.54 (dd, 1 H); 5.26 (d, 1 H); 5.39 (q, 2 H); 5.83 (d, 1 H); 7.7 (d. 2H); and 8.26 (d, 2H) ppm; 25 IR (KBr); 2.92, 5.61, 5.85, 5.91 and 6.61 microns.

Preparation D

p-Nitrobenzyl (5R, 6S) -6 - [(R) -1-butyldimethylsilyloxyethyl] -2- (2-pyrrolidon-3-yl) thio-2-penem-3-carboxylate Sodium methylate (27 mg, 0.5 mmol) was added to a solution of 80 mg (0.5 mmol) of 2-pyrrolidon-3-yl-thioacetate in 5 ml of dry 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) -lt-butyldimethylsilyloxyethyl] obtained in Preparation I was added. -2-ethylsulfinyl-2-penem-3-carboxylate in 5 ml of dry tetra-

II

82250 hydrofuran cooled to -50 ° C. The resulting solution was stirred at -30 ° C for 60 minutes, then 0.029 ml (0.5 mmol) of acetic acid was added and the solution was evaporated to dryness 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 hydrogencarbonate 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 evaporated to dryness in vacuo. Chromatography of the crude product (370 mg) on silica gel (120 g) eluting with chloroform / ethyl acetate (1: 1) gave 118 mg (41% yield) of the title compound as a viscous resin.

The infrared spectrum of the dichloromethane solution of the title compound had absorbances at 5.58, 5.86 and 6.58 microns. The NMR spectrum of the 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, (c, 5H); 5.29 (q, 2 H); 5.6 (d, 1 H); 6.6 (b, 1 H); 7.55 δ (d. 2H); and 8.16 (d, 2H) ppm.

Preparation E

The procedures of Preparation D were followed using the appropriate thioacetate to give compounds of formula XIV having the properties and R shown in Table 25 and 3.

32 82250

Table 3 R IR (microns) NMR (ppm) Yield (%) 1-pyrrolidone-5.58, 5.86 and 0.04 (s 3H) 31 4-yl 6.57 (CH 2 Cl 2) 0.09 (s, 3H); Δ 0.82 (s, 9 H); 1.25 (d. 3H); 2.1-4.42 (c. 7H); 5.29 (q, 2 H); 5.62 (d, 10H); 6.44 (b, 1 H); 7.57 (d. 2H)? and 8.16 (d, 2 H). (CDCl 2) 1 -formyl ± -3.58, 6.02 and 0.02 (s, 3H): 37 pyrrolidinyl 6.57 (CH 2 Cl 2) 0.09 (s, 3H); 0.85 (s, 9 H); 1.24 (d, 3 H); 0.08 - 2.42 (c, 2H); 3.3-4.47 (c, 207H); 5.28 (q, 2 H): 5.64 (d, 1 H); 7.55 (d. 2H); and 8.16 (d) and 8.18 (s), (total 3H).

25 (CDCl 3) (3-methyl-1,3-5.57, 5.66 5.9 0.05 (s, 3H); 49 oxazolidin-2 and 6.57 (CH 2 Cl 2) 0.1 (s, 3H); on-5-yl] methyl 0.85 (s, 9H); 1.26 (d. 3H); 2.89 (s. 3H); 3.12 - 3.89 (c, 5H); 4.04-4.8 (c. 2H); 5.3 (c. 2H); 5.67 (d, 1 H); Δ 7.6 (d. 2H); 8.2 (d. 2H).

(coci3) 33 8 2 2 5 0

Table 3 cont.

R IR (microns) NMR (ppm) Yield (%) 3-methyl-1,3,5,5,5,67, 5,88 0,02 (s, 3H); 48 oxazolidin-2 and 6.57 (CH 2 Cl 2) 0.08 (s, 3H); 5 on-4-yl) methyl-0.82 (s, 9H): 1.26 (d, 3H); 2.9 (s) and 2.8-3.5 (c), (total 5H); Δ 3.65-4.54 (c, 5 H); 5.3 (q. 2H); 5.69 (d, 1 H); 7.6 (d. 2H); and 8.2 (d, 2H). (CDCl 3) 3-methyl-1,3-5.62 and 6.0 0.04 (s, 3H); 34 oxazolidin-2- (Nujoy fraction) 0.08 (s, 3H): on-4-yl) methyl-0.84 (s, 9H); li 1.27 (d, 3 H); Δ 1.85-2.7 (c, 4 H); 3.34 - 3.84 (c, 4H); 4.28 (m, 1 H); 5.33 (q, 2 H); 5.69 (d, 1 H); 6.06 (b, 1 H); 7.63 (d. 2H); and 8.22 (d, 2 H).

(CDCl 3, 250 MHz) 34 82250

Table 3 cont.

R IR (microns) NMR (ppm) Yield (%) piperidin-2-one-5.57, 5.98 and 0.03 (s, 3H): 29 3-yl 6.56 (CH 2 Cl 2) 0.06 ( s, 3H): δ 0.84 (s, 9H); 1.22 (d. 3H): 1.66-2.4 (c, 4H); 3.34 (c, 2H); 3.6-4.5 (c, 3H); Δ 5.26 (q, 2 H); 5.56 and 5.62 (2d, total 1H); 6.5 (b, 1 H); 7.54 (d. 2H); 15 and 8.14 (d. 2H).

(CDCl 3) 1-methylpiper- 5.57, 5.93, 6.08 0.03 (s, 3H); 40 din 2-on-3-yl and 6.56 (CH 2 Cl 2) 0.06 (s, 3H); 0.82 (s. 9H); Δ 1.22 (d, 3 H); 1.6 - 2.36 (c, 4H); 2.96 (s. 3H); 3, 3 (m, 2 H); 3.67-4.43 (c. 3H); 5.28 (q, 2H); 5.57 (d, 1 H); 7.57 (d. 2H); and 8.18 (d, 2 H).

(cdci3) 30 35

II

35 82250

Table 3 cont.

R IR (microns) NMR (ppm) Yield (%) 1-formylpiper- 5.8, 5.98, 6.58 0.03 (s, 3H); 48 din-3-yl (CH 2 Cl 2) 0.06 (s, 3H); Δ 0.82 (s, 9 H); 1.1-2.3 (c) and 1.23 (d) (total.

7H); 2.8-4.5 (c. 7H); 5.26 (q, 10H); 5.62 (d, 1 H); 7.54 (d. 2H); 7.98 (s, 1 H), and 8, 14 (d, 2 H).

(CDCl3)

15 Preparation F

The procedures of Preparation D were followed using purified p-nitrobenzyl (5R, 6S) -6 - [(R) -1-butyldimethylsilyloxyethyl] -2-ethylsulfinyl-2-penem-3-carboxylate of Preparation H and the appropriate thioacetate-20. to give compounds of formula XIV having the properties and R shown in Table 3A.

Table 3A

1 H IR (microns) NMR (ppm) Yield (%) 1,3-oxazolidine-5.57, 5.67, 0.03 (s, 3H); 40 (2-on-4-yl) methyl-5.92 and 6.58 0.06 (s, 3H); li (CH 2 Cl 2) 0.82 (s, 9H); 1.22 (d. 3H); 3.1 (2d, 2 H); 3.72 (dd, 1 H); 3.82-4.68 (c, 4 H); 5.26 (q, 2 H); 5.64 (d, 1 H); 5.98 (b, 1 H); 7.54 (d, 2 H), 35 and 8.16 (d, 2 H).

(CDCl 3) 36 82250

Table 3A, cont.

1 H IR (microns) NMR (ppm) (Yield (%) (1,3-oxazolidine-5.6, 5.67, 5.92 0.03 (s, 3H); 48 2-on-5-yl) methyl and 6.58 (CH 2 Cl 2) 0.06 (s, 3H), δ 0.82 (s, 9H), 1.22 (d, 3H), 3.1-4.0 (c, 5H), 4.22 (m, 1H); 4; 8 (m, 1H); δ 5:29 (q, 2H); 5:65 (d, 1H); 5.84 (b, 1H); 7.56 (d, 2H ), and 8.16 (d, 2 H).

15 (CDCl 3) (1,3-thiazolidine-5.56, 5.89 and 0.03 (s, 3H); 50 2-on-4-yl) me- 6.54 (CH 2 Cl 2) 0.06 (s , 3H); style 0.82 (s, 9H); 1.22 (d. 3H); Δ 3.0-4.42 (c, 7 H); 5.3 (q. 2H); 5.66 (d, 1 H); 6.0 (b, 1 H); 7.56 (d. 2H); and 8.16 (d. 2H).

(CDCl3)

II

37 82250

Table 3A, cont.

1 H IR (microns) NMR (ppm) (Yield (%) 3-methyl-perhydro-0.05 (s, 82.1,3-oxazin-2-one-5-3H); s, 3H), 0.84 (s, 9H), 1.27 (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).

(CDCl 3, 250 MHz)

20 Preparation G

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

Sodium unethylate (54 mg, 1.0 mmol) was added to a solution of 87 mg (0.5 mmol) of pyrrolidine-2,5-dion-3-ylthioacetate in 5 mL of dry ethanol cooled to -35 ° C. protected by 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-butyldimethylsilyloxyethyl] -2- ethylsulfinyl 2-penem-3-carboxylate in 5 ml of dry tetrahydrofuran cooled to -50 ° C. The resulting solution was stirred at -40 ° C to -35 ° C for 6 minutes, 0.058 mL (1.0 mmol) of acetic acid was added and the solution was evaporated to dryness 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 hydrogen carbonate 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 evaporated to dryness in vacuo. Chromatography of the crude product (360 mg) on silica gel (120 g), eluting with chloroform / ethyl acetate (3: 1) gave 123 mg (42% yield) of the title compound as a viscous resin.

In the infrared spectrum of the title compound, the dichloromethane solution had absorbances at 5.56, 5.72 and 6.5 microns. The NMR spectrum of the 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.

Preparation H

Purification of p-nitrobenzyl (5R, 6S) -6 - [(R) -1-butyldimethylsiloxyethyl] -2-ethylsulfinyl-2-penem-3-carboxylate 8.0 g of the title penem sulfoxide, which was prepared according to Preparation I, chromatographed on silica gel (500 g). Elution with hexane-ethyl acetate (1: 1) gave 4.6 g of the purified title compound as a mixture of diastereomers.

Preparation I

p-Nitrobenzyl (5R, 6S) -6 - [(R) -1 -1-butylmethyl-2-silyloxyethyl] -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-30 nitrobenzyl (5R, 6S) -6 - [(R) -lt-butyldimethylsilyloxyethyl] -2-ethylthio-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 hydrogen carbonate 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 to dryness in vacuo to give the title compound as a yellow foam (2.2 g, 86% yield).

In the infrared spectrum of the title compound, the dichloromethane solution had absorbances at 5.54, 5.86 and 6.53 microns. In the NMR spectrum of the title compound in deuterochloroform solution, the peaks were at 0.06, 0.08, 0.1 and 0.12 (4s, total 54); 0.8 (s. 9H); 1.12 - 1.58 (m, 6H); 3.1 (m, 2 H); 3.86 (m, 1 H); 4.3 (m. 1H); 5.3 (m. 2H); 5.67 and 5.78 (2d, total, 1H); 7.54 (d. 2H); and 8.18 (d, 2H) ppm.

Preparation J

p-Nitrobenzyl (5R, 6S) -6 - [(R) -1-butylmethylsilyloxyethyl] -2-ethylthio-2-penem-3-carboxylate 15 p-Nitrobenzyl oxalyl chloride (5.85 g, 0.024 mol) was added to a mixture of 7.3 g (0.02 moles) of (3-at-butyldimethylsilyloxyethyl-4-ethylthio (thiocarbonyl) thio-2-oxoazetidine and 4.8 g (0.048 moles of calcium carbonate in 70 ml). methylene chloride cooled to 10 ° C under a nitrogen atmosphere A solution of 4.17 ml (0.024 mol) of diisopropylethylamine in 20 ml of methylene chloride was added dropwise at such a rate that the temperature was kept below 12 ° C. The mixture was stirred for 60 minutes at 10 [deg.] C., then washed with two 50 ml portions of ice-cold water, dried over anhydrous sodium sulphate and evaporated in vacuo to a viscous oil. ) oxoacetate was dissolved in 300 ml of ethanol chloroform and the resulting solution was boiled under nitrogen with dropwise addition of the solution over 2 hours, 6.85 ml (0.04 mol) of triethyl phosphite in 50 ml of ethanol-free chloroform. The resulting solution was boiled for 16 hours, then evaporated to dryness in vacuo. The residue was chromatographed on silica gel (800 g) eluting with toluene / ethyl acetate 95: 5 to give 5.5 g (53% yield) of the title compound as a yellow foam.

In the infrared spectrum of the title compound, the dichloromethane solution had absorbances at 5.56, 5.89 and 6.54 microns. The NMR spectrum of the title compound in 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, 2 H); 3.7 (m. 1H); 4.25 (m, 1 H); 5.3 (q 2 H); 5.63 (d, 1 H); 7.38 (d. 2H); and 8.18 (d, 2H) ppm.

The NMR spectrum of the intermediate (1-azetidinyl) oxoacetate in deuterochloroform solution showed peaks at 0.06 (s, 06 (s, 6H); 0.8 (s, 9H); 1.14-1.62 (m, 6H)). 3.14-3.63 (m, 3H), 4.33 (m, 1H), 5.16 (s, 2H), 6.7 (d, 1H), 7.5 (d, 2H); and 8.17 (d, 2H) ppm.

15 Preparation K

3-a-t-butyylidimetyylisilvylioksietyyli-ethyl-4-thio (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 disulphide 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 of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The crude title product (18 g) was chromatographed on silica gel (500 g) eluting with chloroform / ethyl acetate (99: 1) to give 9.1 g (48% yield 48%) of the title trithiocarbonate as a yellow foam.

Il 4i 82250

In the infrared spectrum of the title compound, the dichloromethane solution had absorbances at 6.62 and 9.2 microns. The NMR spectrum of the title compound in deuterochloroform solution had peaks at 0.08 (s, 6H); 0.8 (s. 9H); Δ 1.02-1.5 (m. 6H); 3.0-3.48 (m. 3H); 4.12 (m, 1 H); 5.54 (d, 1 H); and 6.57 (b, 1H) ppm.

Preparation L

2-pyrrolidone-3-yl-p-toluenesulfonate

To a solution of 1.0 g (0.01 mol) of 3-hydroxy-10si-2-pyrrolidone in 50 ml of methylene chloride cooled to 0 ° under nitrogen was added 2.44 g (0.02 mol) of 4-dimethylaminopyridine. , then 1.9 g (0.01 mol) of p-toluenesulfonyl chloride The resulting solution was stirred at 0 ° for 30 minutes, then at room temperature overnight The solution was washed with 50 ml of 1 N aqueous saline, 50 ml of water and 50 ml of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo to give the title compound as an amorphous solid (2.1 g, yield 83%).

The NMR spectrum of the title compound in deuterochloroform solution had peaks at 2.44 (s) and 1.83-2.64 (c) (total, 5H); 3.1-3. 44 (m, 2H); 4.86 (t, 1 H); 7.33 (d. 2H); and 7.8 (d + b, 3H) ppm.

Preparation M

The procedures of Preparation L were followed using 1-formyl-3-hydroxypyrrolidine as starting material to give 1-formyl-3-pyrrolidinyl p-toluenesulfonate in 82% yield. The NMR spectrum of the deuterochloroform solution of the product had peaks at 1.9-2.3 (c, 2H); 2.46 (s, 3 H); 3.36 - 3.78 (c, 4H); 5.1 (c, 1 H); 7.32 (d. 2H); 7.77 (d. 2H); and 8.13 (d, 1H) ppm.

3-Methyl-perhydro-1,3-oxazin-2-on-5-yl-p-toluenesulfonate (81%) was prepared in a similar manner from the corresponding alcohol. The deuterochloroform solution in the 35 NMR spectrum had peaks at 2.44 (s, 3H); 2.9 (s, 4282250 3H); 3.46 (m. 2H); 4.18 (ra, 2H); 4.9 (m, 1 H); 7.3 (d. 2H); and 7.74 (d, 2H) ppm.

Preparation 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 1.34 g (7.02 mmol) of p-toluenesulfonyl chloride. The resulting solution was allowed to warm to room temperature and stirred for 3 hours. The solution was then washed twice with 30 ml portions of 1N aqueous hydrochloric acid, 30 ml of saturated aqueous sodium hydrogen carbonate solution and 30 ml of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo to give the title compound as an amorphous solid. (1.5 g, 84% yield).

The NMR spectrum of the deuterochloroform solution of the title compound had peaks at 2.46 (s), 2.02-2.84 (c) (total 5H); 3.24-3. 86 (c, 2H); 5.17 (c, 1 H); 7.1 (b. 1H); Δ 7.34 (d, 2 H); 3a 7.76 (d, 2H) ppm.

Preparation 0

The procedures of Preparation N were followed using 5-hydroxymethyl-3-methyl-1,3-oxazolidin-2-one as the starting alcohol to give (3-methyl-1,3-oxazolidin-2-one-5-yield) in 85% yield. -yl) methyl p-toluenesulfonate having a peak in the MR spectrum of the deuterochloroform solution at 2:44 (s, 3H); 2.82 (s. 3H); 3.16-3.8 (m. 2H); 4.12 (d. 2H); 4.66 (c, 1 H); 7.33 (d. 2H); and 7.74 (d, 2H) ppm.

Similarly, 4-hydroxymethyl-3-methyl-1,3-oxazolidin-2-one as the starting alcohol was obtained in 88% yield as (3-methyl-1,3-oxazolidin-2-on-4-yl) methyl. li-p-toluenesulfonate having a peak in the NMR spectrum of the deuterochloroform solution 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.

Il 43 8 2 2 5 0

In a similar manner, 1-formylpiperidin-3-yl-p-toluenesulfonate was prepared in 75% yield from the corresponding alcohol. NMR (CDCl 3); 1.22-2.17 (C, 4H); 2.46 (s. 3H); 2.96-3.9 (c. 4H); 4.53 (m, 1 H); 7.34 (d. 2H); 7.8 (d. 2H); 7.93 (d. 1H).

Preparation P

2-pyrrolidone-2-yl-thioacetate

A mixture of 855 mg (7.5 mmol) of potassium thioacetate and 1.27 g (5 mmol) of crude 2-pyrrolidon-3-10 yl p-toluenesulfonate in 40 ml of acetone was boiled under nitrogen for about 20 hours. The mixture was then filtered and the filtrate was evaporated to dryness in vacuo. The residue was partitioned between 50 ml of acetyl acetate and 50 ml of water, and the ethyl acetate layer was washed with 40 ml of water and 30 ml of saturated aqueous sodium chloride solution. The ethyl acetate solution was dried over anhydrous sodium sulfate and evaporated to dryness 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 deuterochloroform solution of the title compound had peaks at 2.38 (s) and 1.7-2.98 (c) (total 5H); 2.27-3.6 (m. 2H); 4.17 (t, 1 H); and 7.74 (b, 1H) ppm.

25 Preparation Q

The procedures of Preparation P were followed using the p-toluenesulfonates shown in Table 4 as starting materials to give the corresponding thioacetates, the yield and NMR spectra of the deuterochloroform solutions shown in Table 4.

35 44 82250

Table 4 Sodium yield of the corresponding p-toluenesulfothioacetate (%) NMR (ppm) δ 2-pyrrolidon-4-yl 61 2.34 (s) and 2.0-4.4 (c) (total 8H); and 7.44 (b, 1H).

1-formyl-3-pyrro-95 2,4 (s) and 1,63-lidinyl 3.06 (c) (total

10 5H); 3.14-4.26 (c, 4H); and 8.14 (b, 1 H).

(3-methyl-1,3-oxazole-77 2.38 (s, 3H); 2.82-lidin-2-on-5-yl) methyl- (s, 3H): 3.03-3.81 yl (c, 4H); and 4.57 (m, 1 H).

(3-methyl-1,3-oxazo-68 2.36 (s, 3H); 2.82 (s) 1d-2-on-4-yl) me- and 2.75-3.45 (m) (tot.

style 5H); and 3.64-4.57 δ (c, 3H).

Preparation R

Pyrrolidine-2,5-Dione-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 hydrogencarbonate 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 ethyl acetate-hexane 1: 3 to give 3.81 g (43%) of the title compound as a white solid. The title compound

II

♦ s The NMR spectrum of the 82250 deuterochloroform solution had peaks at 2.38 (s) and 2.3-3.54 (m) (total 5 H); 4.24 (m, 1 H); and 8.86 (b, 1H) ppm.

Preparation S

2-Piperidon-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, 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 1 N aqueous hydrochloric acid, 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 evaporated to dryness in vacuo. Diethyl ether was added to the residue, and the title compound was obtained as a solid after filtration (0.8 g, yield 60%).

The NMR spectrum of the deuterochloroform solution of the title compound had peaks at 2.4 (s) and 1.67-2.6 (c) (total 7H); 3.43 (c, 2 H); 4.86 (m, 1 H); 6.96 (b, 1 H); 7.3 (d, 2 H); and 7.76 (d, 2H) ppm.

Preparation T

25 2-Piperidon-5-yl-thioacetate

A solution of 1.9 g (6 mmol) of tetrabutylammonium thioacetate and 0.0807 g (3 mmol) of 2-piperidin-5-yl p-toluenesulfonate in 15 ml of acetone was boiled under nitrogen for 70 minutes. . The solution was then evaporated to dryness in vacuo and the residue was dissolved in 75 ml of 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 evaporated to dryness 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 deuterochloroform solution of the title compound 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.

Preparation U

10 (1,3-Oxazolidin-2-on-4-yl) methyl p-toluenesulfonate p-Toluenesulfonyl chloride (1.01 g, 0.0053 mol) was added to a stirred solution of 2-oxo-1,3-yl -oxazolidine-4-methanol (0.619 g, 0.053 mol) and 4-15 dimethylaminopyridine (1.30 g, 0.0106 mol) in 60 ml of methylene chloride at 0 ° C under a nitrogen atmosphere. After the mixture was at 0 ° C for 1 hour, 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 reaction mixture was then washed with two portions of 1N aqueous hydrochloric acid, 50 ml of water, 50 ml of saturated aqueous sodium hydrogencarbonate solution and 50 ml of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. title compound as a white solid (1.22 g, 85% yield). NMR (CDCl 3); 2.45 (s. 3H); 3.87-4. 54 (c, 5H); 6.18 (b, 1 H); 7.3 (d. 2H); and 7.73 (d, 2H) ppm.

Preparation V

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

II

35 47 82250

Table 5 1 H-NMR (ppm) Yield (%) (1,3-oxazolidin-2.46 (s, 3H); 3:54 84 2-on-5-yl) methyl (m, 2H); 4.13 (d, 2H); 4.8 (m, 1 H); 6.23 (b, 1 H); 7.33 (d. 2H); and 7.8 (d. 2H).

(1,3-thiazolidine-2.45 (s, 3H); 3.32 88 10 2-on-4-yl) methyl (m, 2H); 3.86-4. 32 (c, 3H); 6.06 (b, 1 H); 7.32 (d. 2H); and 7.74 (d, 2 H).

15 Preparation W

1-Methylpiperidin-2-on-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 of 0, 01 mol) and 20 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, dried over anhydrous sodium sulfate and evaporated in vacuo to a thick oil, the title compound (1.8 g, yield 87%).

NMR (CDCl 3); 1.6-2.37 (c. 4H); 2.96 (s. 3H); 3.1-3.4 (c) and 3.24 (s) (total 5 H); and 4.9 (m, 1H) ppm.

2-Oxo-piperidin-3-ol was similarly converted to piperidin-2-on-3-ylmethylsulfonate in 25% yield. NMR (CDCl 3): 2.03 (c, 4H); 3.06-3.45 (c) and 3.25 (s) (total 5H); 4.96 (m, 1 H); 6.26 (b, 1 H) ppm.

35 48 8 2 2 5 0

Preparation X

(1,3-oxazolidin-2-on-4-yl) methyl thioacetate A solution of 2-oxo-1,3-oxazolidin-4-yl methyl p-toluenesulfonate (1.22 g, 0.0045 moles) and 5 tetrabutylammonium thioacetate (1.71 g, 0.0054 moles) in 75 mL of acetone were boiled under nitrogen for 90 minutes. The reaction mixture was evaporated to dryness and the residue was chromatographed on silica gel (250 g). Elution of ethyl acetate with hexane (4: 1) gave 580 mg of the title compound 10 (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.

Preparation Y

Using the methods of Preparation X, the appropriate p-tosylate was converted to thioacetate, respectively, whose R 15 NMR spectrum in deuterochloroform and yield are shown in Table 6.

Table 6 1 H NMR (ppm) Yield (%) (1,3-oxazolidin-2.37 (s, 3H); 3.22 76 2 2-on-5-yl) methyl (d, 2H); 3.47 (m. 2H); 4: 7 (m, 1 H); and 6.26 (b, 1 H); (1,3-thiazolidine-2,4 (s, 3H); 3.13 (d, 58 2-on-4-yl) methyl-2H); 3.32 (m. 2H); 25 3.93 (m, 1 H); and 6.63 (b, 1 H).

3-methyl-perhydro-2,4 (s, 3H); 2.98 (s, 61 1,3-oxazin-5-yl 3H); and 3.0-4.6 (c, 5 H).

Preparation Z

30 1-Formyl-3-piperidinyl-thioacetate

A solution of 1-formyl-3-piperidinyl-p-toluenesulfonate (1.12 g, 0.007 mol) and potassium thioacetate (0.091 g, 0.008 mol) in 10 ml of dimethylformamide was heated at 70 ° C under nitrogen. protected for 20 hours-35 tia. The reaction mixture was diluted with 150 ml of ethyl acetate 49,82250 and the resulting solution was washed with four 50 ml portions of water and 50 ml of brine, dried over anhydrous sodium acetate and evaporated to dryness in vacuo. The residue was chromatographed on silica gel (125 g) eluting with ethyl acetate / hexane (4: 1) to give 0.16 g (21% yield) of the title compound.

NMR (CDCl 3): 1.12-2.3 (c) and 2.32 (s) (total 7H); 2.84-4.0 (c. 5H); and 7.9 (d, 1H) ppm.

Preparation AA

10 1-Methylpiperidin-2-on-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 boiled under nitrogen for 20 hours. . The reaction mixture was evaporated to dryness 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 of water and 50 ml of saturated aqueous sodium chloride solution, dried over anhydrous sodium acetate and evaporated to dryness in vacuo. Residue 20 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.

Piperidin-2-on-3-yl methylsulfonate was converted in a similar manner 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); 4.12 (m, 1 H); 7.18 (b, 1 H) ppm.

Claims (2)

50 A process for the preparation of a therapeutically active 6- (1-hydroxyethyl) -2-azacycloalkyl (alkylene) thio-2-penem-3-5 carboxylic acid compound of formula I OH Ϊ „H · '" C. „, ·. To prepare a pharmaceutically acceptable salt thereof, wherein R is 20 u R 25 wherein A is alkylene of 2 to 4 carbon atoms, alkylene of the formula wherein R 2 is N 2 υ CO 2 H 15 or a pharmaceutically acceptable salt thereof. 2 to 4 carbon atoms and having one oxo substituent on one carbon atom, or alkylene having 2 to 4 carbon atoms and one methylene group substituted by ha-Pella or sulfur, 30. is carbonyl or methylene, R2 is hydrogen, formyl or alkyl having 1 to 4 carbon atoms. - 4 carbon atoms, alk is alkylene of 1 to 4 carbon atoms, and n is 0 or 1, 35 provided that when B is methylene and A is alkylene of 2 to 4 carbon atoms, alkylene of 2 to 4 carbon atoms 51 82250 liatoms and having one oxo-substituent on one carbon atom, which carbon atom is not a nitrogen the carbon atom adjacent to the atom, or alkylene having 2 to 4 carbon atoms and the methylene group of which has been replaced by oxygen or sulfur, then R 2 is formyl, characterized in that the compound of the formula OH m JH h 3c nt O is as defined above and R 4 is p-nitrobenzyl, is removed by hydrogenation of the group R 4, and if desired, the resulting compound of formula 1 is converted into a pharmaceutically acceptable salt. Process according to Claim 1, characterized in that R is 2-pyrrolidon-3-yl, 2-pyrrolidon-4-yl, 1-formyl-3-pyrrolidinyl, pyrrolidin-2,5-dion-3-yl , (3-methyl-1,3-oxazolidin-2-on-4-25 yl) methyl, (3-methyl-1,3-oxazolidin-2-on-5-yl) methyl, 2-piperidone 5-yl, piperidin-2-on-3-yl, 1-methyl-lipiperidin-2-on-3-yl, 2-piperidon-5-yl, 1-formyl-piperidin-3-yl, (1,3 -oxazolidin-2-on-4-yl) methyl, (1,3-oxazolidin-2-on-5-yl) methyl or (1,3-thiazol-3-din-2-on-4-yl) methyl. 52 82250