DD232706A5 - PROCESS AND PREPARATION OF 2-DIAXACYCLOALKYLTHIOPENEM DERIVATIVES - Google Patents

Abstract

Certain 2-dioxacycloalkylthio-2-penem-3-carboxylic acid compounds are useful as antibacterial agents for the treatment of mammals and have the formula I or a pharmaceutically acceptable salt thereof, wherein A is carbonyl, methylene or thiocarbonyl, B is alkylene of 2-5 carbon atoms, Alk alkylene of 1-6 carbon atoms, R 1 is hydrogen or a group resulting in an ester which is hydrolyzable in vivo, and n is 0 or 1.

Description

Process for the preparation of 2-dioxacycloalkylthiophenem

derivatives

Field of application of the invention

This invention is directed to a family of antibacterial agents containing a 2-azetidinone (β-lactam) ring. Chemically, the antibacterial agents of this invention are 6-oi-1-hydroxyethyl 1-2-subst. ^ -penem-S-carboxylic acid compounds identified.

Characteristic of the known technical solutions and object of the invention

Although certain 2-subst-2-penem-3-carboxylic acid compounds have previously been disclosed, there is a need for new compounds having desirable antibacterial therapeutic properties.

Explanation of the essence of the invention

The present invention is a compound of the formula

17MSU-02C42Q5

OH

HC

N

/ ^s \

1

S-R

COOR,

or a pharmaceutically acceptable salt thereof,

UIkI _n -

O - ^ O

A is carbonyl, methylene or thiocarbonyl, B is alkylene of 2-5 carbon atoms, alk alkylene of 1-6 carbon atoms,

R. hydrogen or a group which leads to an ester which is hydrolysable in vivo, and

η is zero or one.

Within the scope of the present invention is a compound of the formula

OH

H ▼

"mn ι Q

H ₃ C

H .S

S-R

.N

COOR ₁

II

or a pharmaceutically acceptable salt thereof, wherein ""

R and R are as defined above for compounds of formula I.

Preferred compounds of the formula I or II include those

wherein R _{1 is} hydrogen, B is ethylene, A is methylene and η is one; especially when R is 1,3-dioxacyclopent-4-ylmethyl or

I, S-dioxacyclopent-1-ylmethyl.

Preference is also given to compounds of the formula I or II in which R _{1 is} hydrogen, B is ethylene, A is carbonyl, η is one and alk is methylene, especially when R 2 is -Qxo-1 _/ 3-dioxacyclopent-4-ylmethyl.

Further preferred are compounds of formula I or II wherein R is hydrogen, B is propylene, A is methylene and η is zero; especially when R 1, S-dioxacyclohex-S-yl.

Further preferred are compounds of formula I or II, wherein R .. is hydrogen, B is propylene, A is carbonyl and η is zero; especially when R is 2-0xo-1,3-dioxacyclohex-5-yl.

Further encompassed by the present invention is a pharmaceutical composition, a compound of formula I or

II 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 or II.

The compounds of formulas I or II are useful as antibacterial agents and are derivatives of the bicyclic nucleus of the formula

-A-

In this specification, the nucleus of Formula III is identified by the term "2-penem", and ring atoms are numbered as shown. The carbon atom attached to the ring carbon 6 is numbered 8. Also in this specification the abbreviation "PNB" is used for the p-nitrobenzyl group.

The relationship between the hydrogen on the bridging carbon 5 and the residual hydrogen on the carbon 6 in compounds of formula I may be either ice or trans. The present invention includes both isomers and mixtures thereof. The trans isomer is generally preferred in pharmaceutical applications, and the cis isomer can be readily converted to the trans isomer.

In general, the carbon 5 will have the absolute stereochemistry designated by the stereochemical Prelog-Ingold R, S Rule R, which finds application in this application. Thus, for example, a compound of the formula II in which R 1, 3-dioxacyclohex-5-yl and R _{1 is} hydrogen, is (5R, 6S) -6 - / (R) -1-hydroxyethyl-2-yl (1, S-dioxacyclohex-S-yl) thio-3-carboxyl-2-penem.

Obviously, various optically active isomers of the new compounds are possible. The present invention includes such optically active isomers and mixtures thereof.

The present invention includes those penems in which the 3-carboxyl group is esterified with a non-toxic ester group which is hydrolyzed in vivo. These esters are secreted into mammalian blood or tissue to release the corresponding penem-3-carboxylic acid. Typical examples of such readily hydrolyzable ester-forming radicals are alkane

oyloxymethyl of 3 to 8 carbon atoms, 1- (alkanoyloxy) ethyl of 4 to 9 carbon atoms, 1-methyl-1 (alkanoyloxy) -

ethyl of 5 to 10 carbon atoms, alkoxycarbonyloxymethyl of 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy) ethyl of 4 to 7 carbon atoms, 1-methyl-1- {alkoxycarbonyloxy) -ethyl of 5 to 8 carbon atoms, N- (alkoxycarbonyl) aminomethyl with 3 to 9 carbon atoms, 1 - (N- / alkoxycarbonyl / amino) ethyl with 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, γ- butyrolactone-4-yl, carboxyalkylcarbonyloxymethyl having 4 to 12 carbon atoms or 5-methyl 2-oxo-1,3-dioxolen-4-yl-methyl.

For the preparation of compounds of formula I or II wherein R _{1 is} a group which forms an ester which is hydrolyzed in vivo, the acid of formula I or II (R ₁ is hydrogen) with a base to form the corresponding anion implemented. Suitable cations include sodium, potassium, calcium, tetraalkylammonium and the like. The anion can be prepared by lyophilizing an aqueous solution of I or II, eg an aqueous solution containing tetrahydrofuran and sodium bicarbonate or tetrabutylammonium hydroxide.

The resulting anion of I or II is reacted with the corresponding chloride or bromide of R ₁ in a reaction inert solvent such as acetone or dimethylformamide at about 20 to about 50 ^° C., preferably at 25 ^° C.

The compounds of formula II can be synthesized according to Schemes A-C.

As shown in Scheme A, a compound of formula II can be prepared according to the procedure of Yoshida et al., Chem. Pharm. Bull., 2, 2899-2909 (1981) from the known dibromopenam of formula IV. The Dibrompenam (IV) undergoes an exchange reaction with t-butyl-magnesium chloride at a temperature between about -90 and -40 ° C, preferably about -78 ⁰ C, in a reaction-inert solvent such as tetrahydrofuran, diethyl ether or toluene, preferably tetrahydrofuran. Other organometallic

Reagents can also be used. The resulting reaction mixture is treated in situ with the appropriate aldehyde, e.g. with acetaldehyde for the 1-hydroxyethyl derivative. The aldehyde is added at about -80 to -60 ° C, preferably at about -78 ° C for acetaldehyde.

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

SCHEMA A

br

br

₂ CH ₃

IV

HO

O COoCH, 0

'CO ₂ CH ₃

R ₉ -SiO

CO ₂ CH ₃

J h-

R ₉ -SiO

OAc

-NH R ₉ -SiO

OAc

IX VIII

SCHEME B

- C-SR

.NH

PNB

XII

R ₉ -SiO

LrtMIM I ** "'

0 '

'CCO ₂ PNB

XI

R ₉ -SiO

0 l

R ₉ -SiO

10

CO ₂ PNB

I 1ι ·· ι · ι

XIII

HO

Il

or

.N U

SR

CO ₂ PNB

XIV

V S

-N.

SR

O'

CO ₂ PNB

XV

SCHEIiA C

R ₉ -SiO R,

.NH

Il

.S-C-SR

XVA

R ₉ -SiO

R.

S-C-SR Cl

CO ₂ PNB

XVII

R ₉ -SiO

IΛ

R "

S ti

S-C-SR

CO ₂ PNB> XIV

-S-C-SR

CO ₂ PNB

XVI

XVIIl

The resulting alcohol of the formula VI can by a trialkylhalosilane of the formula

"9

R ₉ -Si-Q

R ₉

each time R _{q is} an alkyl of 1 to 6 carbon atoms and Q is chlorine, bromine or iodine. Thus Dimethylt-butylchlorosilane forms in the presence of an amine proton acceptor such as imidazole, in a polar, aprotic solvent such as N, N-dimethylformamide, at a temperature in the range between about 5 and 40 ⁰ C, preferably at about 25 ° C, a Trialkylsilyl hydroxyl protecting group as shown in formula VII.

Treating VII with mercury (II) acetate in acetic acid at a temperature of about 90 ° C gives the olefin VIII.

In order to obtain the desired azetidinone IX, the olefin VIII in a reaction inert solvent such as Dichlorrnethan, treated with ozone at a temperature between about -80 and -40 ° C, preferably at about -78 ⁰ C. The reaction product is treated with an alkanol such as methanol to give the azetidine IX.

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

The compound of formula X is condensed with p-nitrobenzyl chlorooxalate in the presence of a tertiary alkylamine wherein each alkyl is e.g. 1 to 4 carbon atoms, such as ethyl-di-isopropylamine, to obtain the compound of formula XI. This agreement

preferably dichloromethane, at a temperature in the range of about 5 to 25 ° C, preferably at about 10 ⁰ C, is carried out densationsreaktion in a reaction inert solvent.

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

The thio group of compound XII is added 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 in the range of about -10 to -30 ° C, preferably -20 ° C. oxidized.

The sulfoxide XIII is reacted with the mercaptide of the formula R-S by use of e.g. sodium or potassium salt reacted with the sulfoxide XIII in a polar organic solvent such as ethanol or acetonitrile at a temperature in the range of about -50 to -10 ° C, preferably about -35 ° C.

The starting mercaptans of the formula R-SH or starting thioacetates of the formula RSC (O) CH ₃ are known for many of the meanings of R and those which are not known can be prepared by analogous methods known in the art. For review, see JL Wardell, "Preparation of Thiols," The Chemistry of the Thiol Group, S. Patai, John Wiley & Sons, London, 19, 74, Chapter 4. See also Volante, Tetrahedron Letters 2_2, 3119-3122 (1981). for the conversion of alcohols to thiols and thiolesters using triphenylphosphine and a dxalkyl azodicarboxylate in the presence of the alcohol and a suitable thiol acid.

_ 12 _

For compounds of formula XIV, the trialkylsilyl group is preferably removed before 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 ethereal solvent such as tetrahydrofuran at a temperature in the range of about 15 to 40 ° C, preferably at about 25 ° C.

Converting a compound of formula XV to a compound of formula II is accomplished using a conventional hydrogenolysis reaction, and is conventionally done for this type of conversion. Thus, a solution of a compound of formula XV under an atmosphere of hydrogen or hydrogen in admixture with an inert diluent such as 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, stirred or shaken. Suitable solvents for this hydrogenolysis are lower alkanols, such as methanol; Ethers, such as tetrahydrofuran and dioxane; low molecular weight esters such as ethyl acetate and butyl acetate; Water; and mixtures of these solvents. However, it is common to choose conditions under which the starting material is soluble, such as aqueous ethers, eg, aqueous tetrahydrofuran, at a pH of about 7-8. The hydrogenolysis is usually carried out at room temperature and at a pressure of about 0.5 to about 5 bar (about 0.5 to about 5 kg / cm ² ). The catalyst is usually present in an amount of about 10% by weight, based on the starting material, to an amount equal to the weight of the starting material, although larger amounts can be used. The reaction usually requires about one hour, after which the compound of formula II is recovered simply by filtration and subsequent removal of the solvent in vacuo. When palladium on calcium carbonate is used as the catalyst, the product is isolated as the calcium salt, and when palladium on celite is used, the product is isolated as the sodium salt.

The compounds of the formula I or II can be purified by conventional methods for .beta.-lactain compounds. For example, the compound of formula I can be purified by gel filtration on Sephadex or by recrystallization.

An alternative mode of operation is shown in Scheme C. The azetidine of formula IX is reacted with a trithiocarbonate of the formula M ⁺ RSC (S) -S ", wherein M is a metal such as sodium or potassium, using the procedure previously described for the preparation of X.

The resulting trithiocarbonate XVA is reacted with (p-nitrobenzyloxycarbonyl) (dihydroxy) methane in an aprotic solvent, such as benzene, toluene or dimethylformamide, preferably benzene, at a temperature in the range of about 25-11O ⁰ C, preferably at about 8O ⁰ C, treated 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 dichloromethane in the presence of a hindered amine serving as an acid acceptor such as 2,6-lutidine at a temperature in the range of about -100 75 ° C, preferably at ^{0 0} C prepared.

The 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 obtain the compound of the formula XVIII which is cyclized by refluxing in an aromatic solvent such as toluene to give the penem of formula XIV.

 4- ··

Trithiocarbonate salts of the formula M RS- (C =S) -S are prepared from the appropriate mercaptan of the formula R-SH or by treating a thioacetate of the formula RSC (O) CH ₃ with an alkali metal alcoholate,

followed by carbon disulfide.

By applying the aforementioned procedure of Yoshida et al. is the stereochemistry at the carbon 6 of the penem as well as the hydroxyethyl group at the carbon 6 shown in formula II. Thus, the major stereochemistry for the product of ring closure according to Schemes B or C is that where the hydrogen at the penem ring position is 5 trans to the hydrogen at carbon 6 and in of configuration. Alternatively, the stereochemistry may be as 5R, 6S; 6- (R) -1-hydroxyethyl.

The compounds of formula I or II are acidic and form salts with basic agents. Such salts are considered to be within the scope of this invention. These salts can be prepared by standard techniques, such as by contacting the acidic and basic components, usually in a stoichiometric ratio, in an aqueous, non-aqueous or partially aqueous medium, as appropriate. They are then recovered by filtration, by precipitation with a non-solvent followed by filtration, by evaporation of the solvent or in the case of aqueous solutions by lyophilization as appropriate. Basic agents which are suitably used in salt formation include both organic and inorganic types, and include ammonia, organic amines, alkali metal hydroxides, carbonates, bicarbonates, hydrides and alcoholates, and alkaline earth metal hydroxides, carbonates , hydrides and alcoholates. Representative examples of such bases include primary amines such as 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, O / non-5-ene; Hydroxides, such as sodium hydroxide, Rali-umhydö'xid, ammonium hydroxide and barium hydroxide; Alcoholates, such as sodium ethylate and potassium ethylate; Hydrides, such as calcium hydride and sodium hydride; Carbonates such as potassium carbonate and sodium carbonate; Bicarbonates, such as sodium bicarbonate

carbonate and potassium bicarbonate; and alkali metal salts of long chain fatty acids such as sodium 2-ethylhexanoate.

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

The pharmaceutically-acceptable salts of formula I or II are those which are free of substantial adverse side effects at the dose of ordinary use, and include e.g. the sodium, potassium or calcium salts of these.

The in vitro activity of compounds of formula I or II and their salts can be demonstrated by measuring their minimum inhibitory concentrations (MICs) in μg / ml versus a variety of microorganisms. The procedure followed is that recommended and used by the International Collaborative Study on Antibiotic Sensitivity Testing (Ericcson and Sherris, Acta., Pathologica et Microbiologia Scandinav, Supp. 217, Section B: 64-68 / 19,717), which uses brain heart infusion (BHI). Agar and the inocula replicating device. Overnight growth tubes are diluted 100-fold for use as a standard inoculum (20,000 to 10,000 cells in about 0.002 ml are placed on the agar surface, 20 ml BHI agar / plate). Twelve 2-fold dilutions of the test compound are used, with the starting concentration of the test drug being 200 μg / ml. Single colonies are discarded when plates are read after 18 hours at 37 ° C. The susceptibility (MIC) of the test organism is considered to be the lowest concentration of the compound capable of producing complete growth inhibition as judged by the naked eye.

The compounds of formula I or II and the pharmaceutically acceptable salts thereof are useful for controlling bacterial infections in mammals, including humans, e.g. infection

caused by susceptible strains of Staphylococcus aureus.

The compounds of the invention may be administered orally or parenterally, i. H. intramuscularly, subcutaneously, intraperitoneally or intravenously, alone or in combination with a pharmaceutically acceptable carrier. The ratio of active ingredient to carrier will depend on the chemical nature, solubility and stability of the active ingredient as well as the dosage considered. The ratio of the pharmaceutically acceptable carrier to the penem compound will normally be in the range of 1:10 to 4: 1. For oral administration, the compounds of this invention may be used in the form of tablets, capsules, lozenges, round pastilles, powders, syrups, elixirs, aqueous solutions and suspensions, and the like. In the case of tablets, carriers which may be used include lactose, sodium citrate and salts of phosphoric acid. Various disintegrants, such as starch, and lubricants, 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. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. Sweetening and / or flavoring agents may be added. For parenteral administration, sterile solutions of the active ingredient are usually prepared and the pHs of the solutions are properly adjusted and buffered. For intravenous use, the total solute concentration should be controlled to make the preparation isotonic. The prescribing physician will ultimately determine the appropriate dose for a given 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 or II will normally be administered orally at dosages in the range of about 10 to

about 200 mg / kg of body weight per day and used parenterally at doses of about 10 to about 400 mg / kg of body weight per day. In some cases it may be necessary to use dosages outside these limits.

embodiments

The following examples and preparations are given for further illustration only. Infrared (IR) spectra were measured either as potassium bromide compacts (KBr pellets), Nujol pellets or as solutions in chloroform (CHCl ,,), methylene chloride (CH ₂ Cl ₂ ) or dimethyl sulfoxide (DMSO), and diagnostic absorption bands are either in Microns or in wavenumbers (cm). Nuclear Magnetic Resonance (NMR) spectra were measured for solutions in deuterochloroform (CDCl-), perdeutero-water (D ₉ O) or perdeuterodimethylsulfoxide (DMSO-d _r ) or mixtures of these,

and peak locations are expressed in parts per million downfield of tetramethylsilane. The following abbreviations for peak shapes are used: S = singlet; d = doublet; t = triplet; q = quadruplet; m = multiplet; b = wide; w = weak; c = complex. The abbreviations "ss" and "sss" mean that a particular proton occurred as two or three singlets due to the presence of diastereoisomers. In the examples and preparations, the abbreviation "PNB" means the p-nitrobenzyl group.

example 1

Sodium (5R, 6S) -6 - / (R) -1-hydroxyethyl7 ~ 2- (1,3-dioxacyclohex-5-yl) thio-2-penem-3-carboxylate

The pH of a suspension of 41 mg of 10% palladium on diatomaceous earth in 8 ml of distilled water + 8 ml of tetrahydrofuran was adjusted to about 7.5 with 0.02 M aqueous sodium bicarbonate solution. A solution of 41 mg p-nitrobenzyl - (5R, 6S) -

6 / (R) -I-hydroxyethyl / -2- (1, S -dioxacyclohex-S-yl) thio-2-penem-3-carboxylate in 4 mL of tetrahydrofuran and 4 mL of distilled water was added and the resulting mixture became Hydrogenated at 3.85 bar (55 psi) of hydrogen for 75 minutes. Another 40 mg of 10% palladium on diatomaceous earth was added to the reaction mixture, and the pH of the suspension was adjusted to about 7.0 with 0.02 M aqueous sodium bicarbonate solution. The mixture was hydrogenated at 3.85 bar (55 psi) of hydrogen for 75 minutes, then the catalyst was filtered off and the filtrate 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 20 ml portions of ethyl acetate. The aqueous phase was then lyophilized to give 30 mg (96% yield) of the title product as an amorphous solid. The infrared spectrum of the title compound as Nujol slurry had an absorbance at 5.67 μm.

The procedures were repeated to obtain the title compound in 85% yield. The spectral data are as follows: NMR (D ₂ 0.250 MHz): 1.29 / 3H, d, J = 6.5 Hz /; 3.57 / "1H, m / 3,90 / 2H, m / 3,92 / 1H, dd, J = 6,0, 1,4 Hz / 4,24 / 1H, qd, J = 6.5, 6.0 Hz /; 4.29 / 2H, m /; 4.86 and 4.94 / 2H, both d, J ^ = O, 5 Hz /; and 5.68 / 1H, d, J = 1.4 Hz / ppm IR (KBr pellet): 3040 (b), 2966 (b), 2846 (w), 1770 (s), 1593, 1378, 1295, 1169, 1136, 1053, 1020 and 924 cm " ¹ . UV (H ₂ O) (extinction coefficient in parentheses): 254 (4470) and 320 (5240) nm.

Example 2

The procedures of Example 1 were followed using compounds of formula XV to obtain the corresponding compounds of formula II as the sodium salt, whose R and infrared spectrum properties are as shown in Table 1, with the medium in parentheses ,

Table 1

R IR (pm) Yield (%)

1,3-DiOXaCyCl-5,7 (Nujol Aufauf 80

pent-4-ylmethyl sludge)

1, 3-DiOXaCyCl 2, 2.93, 5.65 and 82

pent-2-ylmethyl 6,26 (KBr-Preßling)

2-0XO-1,3-dioxa- 2.94, 5.66 and 71

cyclopent-4-ylmethyl 6,28 (KBr-Preßling)

Production A

p-nitrobenzyl (5R, 6S) -6 - / (R) -1-hydroxyethyl / -2- (1,3-dioxacyclo-hex-5-yl) thio-2-penem-3-carboxylate

To a solution of 70 mg (0.12 mmol) of p-nitrobenzyl- (5R, 6S) 6 - / (R) -1-t-butyldimethylsilyl-oxyethyl-2- (1,3-dioxacyclohex-5-yl) ) Thio-2-penem-3-carboxylate in 4 ml of anhydrous tetrahydrofuran were added 0.07 ml (1.2 mmol) of acetic acid and 0.36 ml (0.36 mmol) of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran 40 ml of ethyl acetate were added and the resulting solution was washed with 25 ml of saturated aqueous sodium bicarbonate solution, 25 ml of water and 25 ml of saturated aqueous sodium chloride solution. The crude product (70 mg) was chromatographed on silica gel (35 g) eluting with 2: 1 chloroform / ethyl acetate to give 4 6 mg (82% yield) of the title product.

The infrared spectrum of a dichloromethane solution of the title compound had absorptions at 5.58, 5.91 and 6.58 μm. The 250 MHz NMR spectrum of a perdeuterodimethylsulfoxide

Solution of the title compound had peaks at 1.17 (d, 3H); 3.54 (m, iH); 3.76-3.95 (c, 3H); 4.02 (m, 1H); 4.2 (m, 2H); 4.82 (q, 2H); 5.25 (d, 1H); 5.38 (q, 2H); 5.78 (d, 1H); 7.7 d, 2H); and 8.25 (d, 2H) ppm.

The procedure was repeated to give the title compound in 94% yield, m.p. 214-215 ° C (from tetrahydrofuran). The spectral data are as follows: NMR (DMSO-d-, 250 MHz): 1.17 / 3H, d, J = 6 Hz /; 3.53 / 1H, m /; 3.82 / 2H, m /; 3.90 / 1H, dd, J = 6, 1 Hz /; 4.01 / * 1H, m /; 4,20 / "2H, mj; 4,7 and 4,83 / 2H, both d, J ^ = 6 EzJ-, 5,26 /" 1H, d, J = EzJ; 5.31 and 5.45 / 2H, both d, J = 14 EzJ; 5.78 / "1H, d, J = 1 Hz /; 7.69 / 2H, d, J = 9 EzJ, and 8.24 / 2H, d, J = 9 SzJ ppm. IR (KBr compact): 3452, 2965, 2851. (w), 1776 (S), 1609 (w), 1520, 1502, 1376, 1220, 1194, 1176, 1135, 1119, 1047 and 1023 cm ^-1 .

Production B

The procedures of Preparation A were employed using compounds of Formula XIV to obtain the corresponding compounds of Formula XV whose R, yield and spectral properties, with solvent in parentheses, are shown in Table 2.

Table 2

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

1,3-DiOXaCyCl-5,59, "5,92 and 1,24 (d, 3H); pent-4-ylmethyl 6,58 (CH ₉ Cl ₉ ) 3,0-3,27 (m, 2H) ;

3.48-4.4 (c, 6H);

4 ^

(s, 1H); '5,3 (q, 2H); 5.6 (d, 1H); 7.55 (d, 2H); and 8,12 (d, 2H) (CDCl ₃ )

Table 2 (continued)

R IR (around) NMR (ppm) Yield (%) 1.3 Dioxacyclopent- 5.58 , 5.92 1.26 (d, 3H); 25 2-yl-methyl and 6.57 3.18 (d, 2H); (CH ₀ Cl ₀ ) 5.64-4.5 (c, 6H); 5.0 (t, iH); 5.3 (G, 2H); 5.6 (D, 1H); 7.6 (d, 2H); and 8.2 (d, 2H) (CDCl ₃ ) 2-0x0-1,3-dioxa 5.58 , 5.92 1.26 (d, 3H); 52 cyclopent-4-yl and 6.58 2.96 (d, 2H); methyl (CH ₉ Cl ₉ ) 3.7 cm, 1H); 4.0-5.0 (c, 4H); 5.3 (q, 2H); 5.62 (D, 1H); 7.58 (d, 2H); and 8,18 (d, 2H) (CDCl ₃ )

Production C

p-Nitrobenzyl (5R, 6S) -6 - / (R) -1-t-butyldimethylsilyloxyethyl / -2- (1,3-dioxacyclohex-5-yl) thio-2-penem-3-carboxylate

Sodium methylate (27 mg, 0.5 mmol) was added to a solution of 1, S-dioxacyclohex-S-yl-thioacetate (81 mg, 0.5 mmol) in 5 mL of anhydrous ethanol, cooled to -35 C, under nitrogen , After 45 min at -3 5 C, a solution of 300 mg (ca. 0.5 mmol) of crude p-nitrobenzyl- (5R, 6S) -6 - / (R) -1-t-butyldimethylsilyloxyethyl / -2- was added. ethylsulfiny1-2-penem-3-carboxylate in 5 ml tetrahydrofuran which had been cooled to -50 ⁰ C was added. the resulting solution was stirred at -3 5 ° C for 60 min, then 0.029 ml (0.5 mmol) The residue was dissolved in 50 ml of ethyl acetate and the resulting solution was washed successively with 25 ml of saturated aqueous sodium bicarbonate solution, 25 ml of water and 25 ml of saturated aqueous sodium chloride solution dried over anhydrous sodium sulfate and concentrated in vacuo Chromatography of the crude product (3 60 mg) on silica gel (100 g) eluting with chloroform gave 70 mg (24%).

Yield) of the title product as a viscous resin.

The infrared spectrum of the title compound in dichloromethane solution had absorbances at 5.59, 5.9 and 6.57 μm. The NMR spectrum of the title compound in a deuterochloroform solution had peaks at 0.03 (s, 3H); 0.06 (s, 3H); 0.8 (s, 9H); 1.25 (d, 3H); 3.4-3.86 (c, 4H); 4.0-4.5 (c, 3H); 4.63 (d, 1H); 4.95 (d, 1H); 5.27 (q, 2H); 5.63 (d, 1H); 7.56 (d, 2H); and 8.18 (d, 2H) ppm.

The procedure was repeated to obtain the title compound in 65% yield, mp 133-134 ° C (from diethyl ether / petroleum ether). The spectral data are as follows: NMR (CDCl ₃ , 25OMHz): 0.04 (3H, s); 0.07 (3H, s); 0.83 (9H, s); 1.26 (3H, d, J = 6.3 Hz); 3.5-3.75 (3H, m); 3.75 (1H, dd, J = 4.0, 1.5 Hz); 4.2-4.4 (3H, m); 4.67 and 4.97 (2H, both d, J = 6.2 Hz); 5.21 and 5.42 (2H, both d, J ^ = 13.7 Hz); 5.67 (1H, d, J = 1.5 Hz); 7.61 (2H, d, J = 8.7 Hz); and 8.21 (2H, d, J = 8.7 Hz) ppm. IR (KBr compact): 2946, 2927, 2850, 1797 (S), 1697 (S), 1610, 1512, 1374, 1345, 1320, 1230, 1189, 1168, 1122, 1064, 1025, 982, 931, 835 , 801 and 772 cm " ¹ .

Production D

The procedures of Preparation C were followed using the appropriate thioacetate to obtain the corresponding compound of Formula XIV, where R, yield and spectral properties, with the solvents in parentheses, are shown in Table 3.

Table 3

IR (um) NM R (ppm) Yield (%)

1.3 Dioxacy-

clopent-4-yl-

methyl

1.3 dioxacyclopent-2-yl methyl

2-oxo-l, 3-dioxacyclopent-4-ylmethyl

5.6, 5.92 and 6.57 (CH ₂ Cl ₂ )

5.58, 5.9 and 6.57 (CH ₂ Cl ₂ )

5.58, 5.9 and 6.57 (CH ₂ Cl ₂ ) 2.9 3.7

4.0 5 (c, 4H); (Q, 2H); 5.6 (d, lH); 7.53 (d, 2H); and 8.14 (d, 2H); _(CDCl3)

5.25

5.6

7:53

41

0.03 (s, 3H); 0.06 (s, 3H); 0.83 (s, 9H);

1.23 (d, 3H); 2.97 - 3.22 (m, 2H); 3.5 4.4 (c, 5H); 4.83 (s, IH); 5.02 (S, IH); 5.26 (q, 2H); 5.6 (d, lH); 7.54 (d, 2H); and 8.13 (d, 2H) _(CDCl3)

0.03 (s, 3H);

0.06 (s, 3H),

0.82 (s, 9H),

1.24 (d, 3H);

3.17 (d, 2H); 3.63 - 4.5 (c, 5H); 5.02 (t, lH); 5.3 (q, 2H); 5.62 (d, lH); 7.58 (d, 2H); and

3.18 (d, 2H) (CDCl ₁ )

0.0 2 Ts, 3H); 0.06 (s, 3H); 0.8 2 (s, 9H); 1.23 (d, 3H); 2.92 (d, 2H); 3.7 (m, lH); 4.0 - 5.0

Production E

p-Nitrobenzyl (5R, 6S) -6 - / (R) -i-t-butyldimethylsilyloxyethyl / -2-ethylsulfinyl-2-penem-3-carboxylate

A solution of 970 mg (4.78 mmol, 85% pure) 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-butyldimethylsilyloxyethyl _J 7-2-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 bicarbonate solution, 70 ml of water and 70 ml of 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 the dichloromethane solution had absorptions at 5.54, 5.86 and 6.53 μm. The NMR spectrum of the title compound * as the 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 (d, 2H); and 8.18 (d, 2H) ppm.

Production F

p-Nitrobenzyl (5R, 6S) -6 - / (R) -1-t-butyldimethylsilyloxylethyl / -2-ethylthio-2-penem-3-carboxylate

-p-nitrobenzyloxalyl chloride (5.85 g, 0.24 mol) was added to a mixture of 7.3 g (0.02 mol) of (3-c <-t-butyldiynethylsilyloxyethyl-4-ethylthio (thiocarbonyl) thio 2-oxo-azetidine and 4.8 g (0.048 mol) of calcium carbonate in 70 ml of methylene chloride, cooled to 10 ° C., under a nitrogen atmosphere

4.17 ml (0.024 mol) of diisopropylethylamine in 20 ml of methylene chloride was added dropwise at a rate to keep the temperature below 12 ° C. The mixture was stirred at 10 ° C for 60 minutes, 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- (S-o-t-butyldimethylsilyloxyethyl) oxo-azetidine

yl) 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, then concentrated in vacuo. The residue was chromatographed on silica

chromatographed 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 the dichloromethane solution had absorptions at 5.56, 5.89 and 6.54 μm. The NMR spectrum of the title compound as the 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, 4-ethylthio (thiocarbonyl) thio-azetidinone as a deuterochloroform solution, had peaks at 0.06 (s, 6H); 0.8 (s, 9H); 1.14-1.62 (in, 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.

Production G

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

Ethanethiol (8.5 mL, 0.115 mol) was cooled to 0-5 C to a solution of 4.18 g (0.104 mol) of sodium hydroxide in 250 mL of water under nitrogen atmosphere. After 15 minutes, 7.73 ml (0.12 mol) of carbon disulfide were added and the mixture was stirred at 0-5 C for 5 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 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 concentrated in vacuo. The crude title product (18 g) was eluted on silica gel (500 g) eluting with 99: 1 chloroform / ethyl acetate to give 9.1 g (48% yield) of the title trithiocarbonate as a yellow foam.

The infrared spectrum of the title compound in dichloromethane solution had absorptions at 5.62 and 9.2 μm. The NMR spectrum of the deuterochloroform solution of the title compound had peaks at 0.08 (s, 6H); 0.8 (s, 9H); 1.02-1.5 (m, 6H); 3, o-3.48 (m, 3H); 4.12 (m, 1H); 5.54 (d, 1H); and 6.57 (b, 1H) ppm.

Production H

1, S-dioxa'cyclohe'-xS-yl-p-toluene-u'lf ofi'ät """'' · -

p-Toluenesulfonyl chloride (38.1 g, 0.2 mol) was added to a solution of 20.8 g (0.2 mol) of glycerol formal (a mixture of 67

1,3-dioxan-5-ol and 33% 1,3-dioxolan-4-yl) methanol) in 200 ml of pyridine, cooled to 0 C, under nitrogen. The reaction mixture was stirred at 0 C for 0.5 h, then at 25 ° C for 20 h. The mixture was added to 500 ml of 6N aqueous hydrochloric acid solution, and the resulting mixture was extracted with four 200 ml portions of ethyl acetate. The combined ethyl acetate extracts were washed with two 200 ml portions of 1 N aqueous hydrochloric acid solution, two 200 ml portions of water and 200 M saturated aqueous sodium chloride solution, dried over wa water-free sodium sulfate and concentrated in vacuo to an oil. The crude product was dissolved in 500 ml of diisopropyl ether, whereupon the desired 1,3-dioxacyclohex-5-yl-tosylate crystallized. Filtration provided. 17.4 g of white crystalline: tosylate, mp. 91-92 ° C. An additional 4.3 g of crystalline tosylate was obtained from the mother liquors (overall yield 42%). The NMR spectrum of the title compound as the deuterochloroform solution had peaks at 2.45 (s, 3H); 3.54-4.13 (c, 4H); 4.26-4.6 (m, 1H); 4.75 (s, 2H); 7.3 (d, 2H); and 7.8 (d, 2H) ppm.

Production I

1,3-dioxacyclopent-4-ylmethyl p-toluenesulfonate

p-Toluenesulfonyl chloride (76.2 g, 0.4 mol) was added to a solution of 104.1 g (1 mol) of glycerol formal (a mixture of 67% 1,3-dioxacyclohex-5-ol and 33% (1.3%)). Dioxacyclopent-4-yl) methanol) in 1000 ml of pyridine cooled to 0 ° C under nitrogen. After standing at 0 C for 20 h, the reaction mixture was allowed to warm to room temperature and was added to 1500 mL of 6 N aqueous hydrochloric acid. The resulting mixture was extracted with four 500 mL portions of ethyl acetate ... The combined ethyl acetate extracts were washed with two 500 mL portions of 6 N aqueous hydrochloric acid solution, two 500 mL portions of water, and 500 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and in a vacuum

geengt. The oily product (78.4 g) consisted approximately of a 2: 1 mixture of 1,3-dioxacyclopent-4-ylmethyl-tosylate and 1, S-dioxacyclohex-S-yl-tosylate, which was purified in a subsequent step (Preparation K) was used.

Production J

1, S-dioxacyclohex-S-yl-thioacetate

A solution of 28.0 g (0.108 mol) of 1, S-dioxacyclohex-S-yl-p-tosylate and 24.6 g (0.216 mol) of potassium thioacetate in 500 ml of dimethylformamide was heated to 80 C under nitrogen for 20 h. The reaction mixture was then cooled to room temperature and diluted with 1000 ml of water. The resulting mixture was extracted with six 300 ml portions of ethyl acetate. The combined ethyl acetate extracts were washed with four 500 ml portions of water and 500 ml of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo to an oil. Distillation of the product afforded 6.25 g (36% yield) of the title T. dioic acid, bp 70 ° C (53 Pa or 0.4 mm).

The NMR spectrum of the title compound as the deuterochloroform solution had the peaks at 2.34 (s, 3H); 3,4-4,36 (c, 5H); and 4.8 (q, 2H) ppm.

The procedure was repeated to obtain the title compound in 49% yield, b.p. 85-89 ° C (93 Pa and 0.7 mm, respectively). NMR (CDDL _3, 25OMHz): 2.34 (3H, s); 3.7-3.85 (3H, m); 4.05-4.2 (2H, m); 4.79 (1H, d, J = 6.2 Hz); and 4.89 (1H, d,

^J gem ^{= 6} ' ^{2 Hz} > ~ PP ^m ·. _ '~' ^ """

- - 29 -

Production K

(1,3-dioxacyclopent-4-yl) methyl-thioacetate

A mixture of 78 g (0.3 mol) of 1, S-dioxacyclopent-1-yl-tosylate (from Preparation I) and 27.4 g (0.24 mol) of potassium thioacetate in 1500 ml of acetone was refluxed overnight under nitrogen. The reaction mixture was then concentrated in vacuo and the residue was dissolved in 500 ml of ethyl acetate + 500 ml of water. The aqueous layer was extracted with 500 ml of ethyl acetate. The combined ethyl acetate extracts were washed with two 500 ml portions of water and 500 ml of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue, which consisted of a solid suspended in an oil, was filtered. The filtrate was distilled under reduced pressure to give 20.8 g (54%) of 1,3-dioxacyclopent-4-yl-methyl-tosylate, b.p. 65-70 ° C (27 Pa or 0.2 mm).

The solid product was washed with ether to give 18.4 g of 1,3-dioxacyclohex-5-yl-tosylate.

The NMR spectrum of the title compound as the deuterochloroform solution showed peaks at 2.37 (s, 3H); -3.1 (d, 2H); 3,4-4,4 (c, 3H); 4.86 (s, H); and 5.02 (s, 1H) ppm.

Preparation of L (1,3-dioxacyclopent-2-yl) methyl thioacetate

A mixture of 5.0 g (0.03 mole) 2-bromomethyl-1,3-dioxacyclopentane and 5.13 g '/ (OyO4 5 mole) potassium thioacetate in 60 mL acetone was refluxed overnight under nitrogen. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was partitioned between 100 ml of ethyl acetate and 60 ml of water.

Splits. The aqueous layer was extracted with 50 ml of ethyl acetate and the combined ethyl acetate portions were washed with 50 ml of water and 50 ml of saturated aqueous sodium chloride solution. The ethyl acetate solution was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride to give 4.0 g (83% yield) of the desired thioacetate as an oil.

The NMR spectrum of the title compound as the deuterochloroform solution had peaks at 2.36 (s, 3H); 3.16 (d, 2H); 3.94 (c, 4H); and 5.0 (t, 1H) ppm.

Production M

2-Oxo-i, 3-dioxacyclopent-4-ylmethyl-thioacetate

Diisopropyl azodicarboxylate (3.9 mL, 0.02 mol) was added to a solution of 5.2 g (0.02 mol) triphenylphosphine in 50 mL anhydrous tetrahydrofuran, cooled to 0 C, under nitrogen. The solution was stirred at 0 C for 30 minutes, whereupon a precipitate formed. To this mixture was added dropwise at 0 C a solution of 1.18 g (0.01 mol) of glycerol carbonate and 1.4 ml (0.02 mol) of thioacetic acid in 20 ml of anhydrous tetrahydrofuran. The mixture was stirred at 0 C for 1 h, then at room temperature for 2.5 h. The mixture was concentrated in vacuo and the residue was partitioned between 70 ml of ethyl acetate and 70 ml of water. The ethyl acetate layer was washed with two 50 ml portions of saturated aqueous sodium bicarbonate solution, 50 ml of water and 50 ml of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, dried and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride to give 600 mg of impure material. Further purification of the impure product by chromatography on silica gel and elution with

3: 1 hexane / ethyl acetate afforded 220 mg (13% yield) of the desired thioacetate as an oil.

The NMR spectrum of the title compound as the deuterochloroform solution had peaks at 2.4 (s, 3H); 3.25 (d, 2H); and 3.94-5.07 (c, 3H) ppm.

Claims (9)

invention claim or a pharmaceutically acceptable salt thereof, wherein R A is carbonyl, thiocarbonyl or methylene, B is alkylene of 2 to 5 carbon atoms, alk is alkylene of 1 to 6 carbon atoms, R. is hydrogen or a group which results in an ester which is hydrolyzable in vivo, and η is zero or one, characterized by the step of converting a compound of the formula COOR. to the corresponding compound of formula I-by hydrogenolysis, wherein R is a carboxylic acid protecting group which is removed by hydrogenolysis. 2. The method according to item 1, characterized in that R. hydrogen, B is ethylene, A methylene, η one and alk methylene. 3. The method according to item 2, characterized in that R is 1, 3-dioxacyclopent-4-ylinethyl or 1, 3-dioxacyclopent-2-ylmethyl. 4. The method according to item 1, characterized in that R _{1 is} hydrogen, A is carbonyl, η is one and alk is methylene. 5. The method according to item 4, characterized in that R 2-oxo-i, 3-dioxacyclopent-4-ylmethyl. 6. The method according to item 1, characterized in that R _{1 is} hydrogen, B is propylene, A methylene or carbonyl and η
Is zero. 7. The method according to item 6, characterized in that R is 1,3-dioxacyclohex-5-yl or 2-0xo-1,3-dioxacyclohex-5-yl
is. 8. The method according to item 1, characterized in that the compound of formula I OH ^H 3 ^C .N- S-R COOR ₁ or a pharmaceutically acceptable salt thereof, wherein R is A is carbonyl, thiocarbonyl or methylene, B is alkylene of 2 to 5 carbon atoms. Alk alkylene having 1 to 6 carbon atoms, R _{1 is} hydrogen or a group which is an ester which is hydrolyzable in vivo and η is zero or one. 9. The method according to item 8, characterized in that R ^ is hydrogen and R 1, B-Dioxacyclopent ^ -ylmethyl, 1,3-dioxacyclopent-2-ylmethyl, 2-0xo-1,3-dioxacyclopent-4-ylmethyl, 1 , 3-dioxacyclohex-5-yl or 2-oxo-1,3-dioxacyclohex-5-yl.