CS248733B2 - Production method of the 6-(subst.)methlenphenicilan acids - Google Patents

Description

The present invention relates to novel 6- (subst.) Methylenepenicillanic acids, their esters and pharmaceutically acceptable salts thereof, to pharmaceutical compositions containing said compounds, to a process for their preparation and to their use as inhibitors / Mactamases and as intermediates for their production.

One of the most well known classes of antibacterial agents is widely used,. is a group of substances known as β-lactam antibiotics. These compounds are characterized by the presence of a core containing a 2-azetidine (/ lactam) ring not fused to either a thiazolidine or dihydro-1,3-thiazine ring. If the core contains a thiazolidine ring, the corresponding compounds are generally referred to as penicillins, whereas if the core contains a dihydrothiazine ring, such compounds are referred to as cephalosporins. Typical examples of penicillins commonly used in clinical practice are benzylpenicillin (penicillin G), phenoxymethylpenicillin (penicillin V), ampicillin and carbenicillin, typical examples of common cephalosporins are cephalothin, cephalexin and cefazoline.

Despite the widespread use and general acceptance of β-actam antibiotics as valuable chemotherapeutic agents, however, these substances have a major disadvantage in that some of them. they are not effective against certain microorganisms. In many cases, it is believed that this resistance of a particular microorganism to a given β-actam antibiotic is due to the β-actamase being produced by the microorganism. [Beta] -lactamases are enzymes that cleave the [beta] -actam ring of penicillins and cephalosporins to produce products lacking antibacterial activity. However, some substances have the ability to inhibit β-actamases and when used in combination with penicillin or cephalosporin, this may increase the antibacterial activity of this penicillin or cephalosporin against certain microorganisms. An increase in antibacterial activity is reported when the antibacterial activity of the / Mactamase Inhibitor / β-lactam antibiotic combination is significantly higher than the sum of the antibacterial activities of the individual components.

Accordingly, the invention describes new ones

6- (ssbst.) Methylenepenitinic acids, their 1-oxides, 1,1-oxides and their esters readily hydrolyzable in vivo. These novel penicillanic acids and their esters readily hydrolyzable in vivo are potent inhibitors. microbial / 3-actamas. Accordingly, a method of increasing the efficacy of β-lactam antibiotics using these novel acids, their salts and certain readily hydrolyzable esters is also disclosed.

The present invention further provides a carboxy-protected 6- (subst.) Methylenepenillanic acid derivatives, oxides and 1,1-dloxides thereof, which compounds are useful as intermediates.

European Patent Application 50,805 describes compounds of formula III

where n is 0, 1 or 2,

R1 is cyano or a carbonyl radical,

Ra represents a hydrogen atom, a lower alkyl group or a halogen atom, and

R 3 represents a hydrogen atom or an easily hydrolyzable group which are useful as α-lactamase inhibitors. In the same application, 6-oxopenicillanic acid esters, corresponding sulfoxides and sulfones, as well as a process for their use for the preparation of compounds of the formula III by reaction with a hypophosphite of the formula R 1 R 2 C = P (CeH 5) 3 are described.

British Patent Application 2,053,220 A discloses, inter alia, certain 6-methylene-1,1-dioxopenicillanic acids and esters of formula III wherein n is 2 and R 1 and R a are each independently hydrogen, optionally substituted alkyl, aryl, optionally substituted cycloalkyl, aralkyl or optionally substituted amino, or both, together with the carbon atom to which they are attached, form a three to seven membered carbocyclic or heterocyclic ring.

U.S. Pat. No. 4,287,181 discloses 1,1-dioxides and esters of certain 6-substituted penicillanic acids wherein the substituent at the 6-position is a radical of formula

OR3

R4-CH wherein R3 is hydrogen or alkanoyl and R4 is hydrogen, C1-C4alkyl, phenyl, benzyl or pyridyl, which are useful as inhibitors of i-lactamase .

The present invention discloses novel 6- (substituted methylenepenicillanic acid derivatives of formula I)

I ⁽ ° ^{) a} / CH ₃ R Г n Дхоь, (i) where n is 0, 1 or 2,

R 1 represents a radical R a or R ^b wherein R a represents a carboxyl function protecting group selected from the group consisting of tetrahydropyranyl, allyl, benzyl, d-nitrobenzyl, benzhydryl, 2,2,2-richlorethyl, tert-butyl and phenacyl radicals and R ^b means a hydrogen atom or an ester residue readily hydrolyzable in vivo, selected from the group consisting of 3-phthalidyl, 4-crotonolactonyl, χ-butyrolacton-4-yl, a radical of formula

II

O

I, -COCOR

-CO COOR

and

R4

CHOCOR 14 wherein each of R 4 and R 5 is each a hydrogen atom or a methyl group, R ⁶ is a C 1 -C 5 alkyl group and R 14 is a radical of formula

4 8:73 3

where Xz is a substituent in Peloza three known / З-lactam antibiotics: CEFARM losporinového type and R ¹⁵ represents a substituted-substituent in position 6 or 7 of the known / 8-lactam antiboitika penicillin or cephalosporin type, being especially preferred groups R1 as ⁴ · are the above penicillin residues wherein R 15 is

2-phenylacetamido,

2-phenoxyacetamido, D-2-amino-2-phenyl-acetyloidino, D-1, 4-imino-4-di-4-carboxylic acid,

2-carboxy-2-phenylacetylamido; 2-carboxy (2-thienyl) acetamido,

2-carboxy (3-thienyl) acetamido,

D-2- {4-elnyl-α, 2-dioxo-piperazine-ocarboyyl-amino} -72-phenylcetamido,

A Di2i [4-ethyl-2,3-dioxopiperazinocarbonylamino] 12i (4-hydroxyphenyl) acetamido group or

2,2-dimethyl-imidazolidinon 4lfenyll5-IL-nominal group one of R ² c R 3 c represents a hydrogen atom the other is a chlorine atom, a hydroxymethyl group, a vinyl group, clkylthioskupinu 1 GB 4 ctomy atoms. C 1 -C 4 alkylsulfonyl, furyl, thienyl, N-methylpyrrolyl,. N-acetylpyrrolyl, residue

R7C6H4,

R7C6H4S, -CH ^(R4) NR16R17, -CNR8R9,

II

S —CNR8R9,

NH

/ (O) p (o)

©

/ in which m is 2 or 3, p is 0 · or 1, t is 0, 1 or 2,

Xi represents a sulfur atom, an oxygen atom or an NR ¹¹ group,

R 7 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, allyloxy, hydroxyl, C 2 -C 5 carboxyalkoxycarbonyl, C 1 -C 5 alkylcarbonyl, phenyl, benzyl , naphthyl, pyridyl, NR ⁸ R ⁹ , CONR ⁸ R ⁹ , NHCOR ^w , nitro, chloro, bromo, trifluoromethyl or SR 8, each of R 8 and R 9 is each hydrogen, C 1 -C 4 alkyl , phenyl or benzyl,

R 10 represents a C 1 -C 6 alkyl, trifluoromethyl or phenyl group

R 11 represents a hydrogen atom, a methyl group, an ethyl group or an acetyl group

Group a

R 16 and R 17 are either hydrogen, C 1 -C 4 alkyl, C 2 -C 4 hydroxyalkyl, or R ¹⁶ and R 17 together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocyclic radical, preferably pyrrolidino, piperidino, morpholino, thiomorpholino or 4-methylpiperazino, and pharmaceutically acceptable acid addition salts of those compounds wherein R 2 or R 3 is a basic nitrogen atom, and pharmaceutically acceptable cationic salts of those compounds wherein R 1 is hydrogen or R2 or R3 contains a carboxyl group.

The above compounds wherein R 1 is the radical R ^and, are useful as intermediates for the preparation of those compounds in which R 1 represents a group R ^b. The latter are potent inhibitors of the [beta] -lactamase according to the invention.

Particularly preferred are those compounds of formula I wherein n is 0 or 2, one of R2 and R3 is hydrogen and the other is furyl thylsulfonyl, N-methylpyrrolyl, the rest of the group is thienyl, hydroxymethyl, phenyl group,

Particularly preferred carboxyl protecting groups for R ^a are allyl, benzyl, tert-butyl and 2,2,2-trichloroethyl, with allyl being particularly preferred for relatively ease of introduction and removal.

As ester radicals readily hydrolyzable in radicals R ^b , in vivo, i.e. as defined above, groups are particularly preferred

4 ·

R *

In particular, those in which R ⁴ and R ⁵ are hydrogen and R ⁶ is as defined above.

In addition to a method for producing compounds of Formula I, the invention also provides a method of treating a bacterial infection in a mammal, including a human, comprising administering to the mammal in need thereof an antibacterially effective amount of a compound of the formula wherein R ¹ is R ^b .

The invention further provides pharmaceutical compositions for the treatment of bacterial infections in mammals, including humans, comprising an antibacterially effective amount of a compound of formula I wherein R ¹ is R ^b .

Compounds of formula (I) wherein:

R ¹ represents the radical R ^b as defined above, being useful as inhibitors of β-lactamase enzymes. In this way, the compounds increase the efficacy of [beta] -lactam antibiotics (penicillins and oephalosporins), especially against those microorganisms which are identical or partially resistant to [beta] -lactam antibiotics due to the production of [beta] -lactamas degrading or partially degrading [beta] lactam antibiotics. In this way, the resist-lactam antibiospectrum of the ticks is increased.

The invention also provides a bacterial infection for a method of treating a mammal, including a human, by administering to a mammal in need of such treatment an antibacterially effective amount of penicillin or cephalosporin, in particular any of the aforementioned 1,448,733.

Although the compounds of the invention effectively enhance the activity of β-actam antibiotics in general, they are preferably combined with penicillin or cdfalosporin already established in clinical practice, such as amoxicillin, ampicillin, apalcilin, azlocilin, azthreonam, bacampicillin, carbenicillin, carbenicillin-indanyl , varbenicillin-phenyl, cefaclor, cefadroxil, -cephaloram, cefamandole, -cephamandole-naphat, cefaparol, cefatrizine, cefazoline, -cefbuperazone, cefonicide, cefmenoxim, cefodizime, cefoperazone, cforanimir, cforanef, ccefamef, ccefamef, -cefce cefsulodine, ceftazidime, ceftizoxime, ceftriaxone, -cefuroxime, cefacetril, cefalexin, cefaloglycine, cefaloridine, -cephalothin, sefapirin, -cefradine, cyclacilin, epicillin, furazloclinic, penetililin, lenetiline, len, , plperacillin, pirbenicillin, pivamcilin, sarmoxicillin, sarpicillin, suncilin, talampicillin and ticarcilin, including their pharmaceutically acceptable olí.

The invention further provides combinations of the β-lactamase inhibitors of the present invention

7- (2- (2-amino-4-thiaazlyl-2-methoxyiminoacetamido) -3- (5,6-dihydro-4-pyrindenium) methyl-3-cephem-4-carboxylate,

7- [2- (2-4-Methyl-4-thiaao-yl) -methylamino-acetamido] -3- (N-methylpyrrolidinium) methyl-3-cephem-4-ylcarbonylate and

7- [D- (2,4-carboxy-5-imidazolecarboxamido) -2-phenylacetamido] -3- [4- (2-sulfonatoethyl) pyridinium] -3-cephemocarboxylic acid.

Although the compounds of the invention may be administered separately from the lactam antibiotic, combined dosage forms are preferred. The pharmaceutical composition, whether for oral or parenteral administration, comprises the [beta] -lactamase inhibitor of the invention and the [beta] -actam antibiotic in a weight ratio of 1: 3 to 3: 1, the total amounts of these substances in the composition sufficient to cope successfully. bacterial infections - mammals in single or, more usually, multiple administrations.

Compounds of the invention wherein one of the radicals R @ 1 and R @ 3 contains a basic nitrogen atom can form acid addition salts. The invention includes such salts with pharmaceutically acceptable acids. Examples of said acids are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, citric acid, malic acid, tartaric acid, maleic acid, fumaric acid, gluconic acid, sugar acid, benzenesulfonic acid, p-toluenesulfonic acid, - p-chlorobenzenesulfonic acid and 2-naphthalenesulfonic acid.

Furthermore, those compounds of the invention in which R 1 is hydrogen form cationic salts and such salts with pharmaceutically acceptable cations are also within the scope of the invention. Examples of such cations are sodium, potassium, ammonium, calcium, magnesium and zinc cations, and amine cations derived from amines such as diethanolamine, -choline, -ethylenediamine, ethanolamine, N-methylglucamine and procaine.

The invention relates to penicillanic acid derivatives which correspond to the formula г Г

O'

In penicillanic acid derivatives, the attachment of a dotted line substituent (III) to a bicyclic nucleus means that the substituent is located below the plane of the nucleus and is said to be in the α-configuration. (F) means that the substituent is above the plane of the core. This latter arrangement is referred to as confguration. Binding of the substituent to the bicyclic nucleus by a normal solid line (----- herein means that the substituent may be either in the α-configuration or in the β-configuration).

The present invention provides a process for the preparation of the compounds of formula (I) and salts thereof, characterized in that the starting material of formula (V) is used

in which

R 1 is as defined above, and preferably represents a radical R ^a , reacted with a Wittig reagent of the formula

R2R3C = P (C6H5j3 in which

R @ 1 and R @ 3 are as defined above, in the presence of an inert organic solvent at a temperature in the range of from -100 to +50 [deg.] C., to give a compound of formula I wherein л is 0; of the formula I in which n is 1 or 2, the compound in which n is 0 is oxidized, preferably with an alkali metal or alkaline earth metal permanganate, with 3-chloroperbenzoic acid or peracetic acid, and / or to produce compounds formula I wherein R ¹ represents a group R ^b, cleaving off protecting groups ^{present, and} carboxyl function R to produce a compound of formula I wherein R ¹ represents a hydrogen atom, and this compound is then optionally reacted with compounds of formula Nou

R ^b O in kt-en

R ^b is as defined above except for a hydrogen atom, a

Q is chlorine, bromine or iodine, in the presence of a polar organic solvent, whereupon optionally the resulting compound of formula I is converted to its pharmaceutically acceptable acid addition salt or cationic salt.

The process according to the invention, including the preparation of the starting materials, can be described by the following reaction scheme:

Diagram

ÍO

..A (IV)

Лен 'COOR' COOR ¹ u-2

<

The Wittig salts of the general formula used in the process described above are either known or can be prepared in a simple manner from commercially available starting materials by conventional synthetic methods, for example as described below.

Preparation of Wittig salts

dj

The primary alcohol of formula R ³ CH ² OH is converted to the corresponding chloromethyl derivative, typically by reacting the alcohol with an equimolar amount of thionyl chloride in the presence of an inert solvent such as chloroform or methylene chloride at or near ambient temperature. The product is isolated, for example, by neutralization of the reaction mixture and extraction.

The chloromethyl derivative of the general formula R ³ CH ² Cl is then converted to the desired Wittig salt, for example by reaction with an equimolar amount of triphenylphosphine. This reaction is usually carried out in a solvent such as toluene at elevated temperature, preferably at reflux. · The desired product forms a precipitate which is filtered off.

6α-hydroxypenemic acid is a known compound - see, for example, Hauser et al., Helv. Chim. Acta, S0, 1327 (1967). This acid is converted to a carboxy-protected derivative of the general formula IV. The nature of the carboxyl function protecting group is not critical. The carboxyl function protecting group in the meaning of the symbol R ^and only the following requirements are imposed:

(1) it must be stable under the oxidizing conditions used to produce the 6-oxopenicillanic acid ester of formula (V) and subsequent reaction with a Wittig reagent to give 6- (subst.) Methylenepenilicilate of formula (I) in which R 1 is a residue R ^and ;

(ii) it must be selectively cleavable from a compound of formula I (R 1 = R ^a ) under conditions that substantially do not damage both the β-actam moiety and the 6- (subst.) methylene group; and (iii) it must be stable in the oxidation of a compound of formula I (R ¹ = R ^a ) to a sulfone of formula I or the corresponding sulfoxide.

Typical carboxyl protecting groups meeting the above requirements are tetrahydropyranyl, benzyl, benzhydryl, 2,2,2-trichloroethyl, allyl, tert-butyl and phenacyl. In this connection, reference is made to the following publications: U.S. Patent Nos. 3,632,850 and 3,197,466, British Patent 1,041,985, Woodward et al., Journal of the American Chemical Society, 88, 852 (1966), Chauvette, U.S. Pat. Journal of Organic Chemistry, 36, 1259 (1971), Sheehan et al., Journal of Organic Chemistry, 29, 2 006 (1964) and "Cephalospo248733"

W18 rin and Penicillins, Chemistry and Biology, ed. Η. E. Flynn, Academic Press, Inc., 1972. Of these, allyl, benzyl, and 2,2,2-trichloroethyl, and especially allyl, which are easy to introduce and selectively remove, are particularly preferred.

The oxidation of the carboxy-protected 6α-hydroxypenicillanate (IV) to the corresponding 6-oxopenicillanate (V) is usually accomplished by treatment with an approximately equimolar amount of trifluoroacetic anhydride and a molar excess of dimethylsulfoxide in the presence of an inert solvent such as chloroform or methylene chloride. The reaction is preferably carried out at a temperature of about -80 ° C to -70 ° C. The reaction mixture is neutralized, for example by adding a tertiary amine, such as triethylamine, and then isolating the reaction product, for example by shaking the reaction mixture between water and solvent. miscible with water, and evaporation of the organic layer.

The 6-xo-penicillinate of formula V is then reacted with a Wittig reagent of formula

R-R 3 - + CP (C 6 H 5 J 3

The reaction is preferably carried out in the presence of an inert organic reaction solvent, for example a hydrocarbon such as pentane, hexane, benzene, toluene or xylene, a halogenated hydrocarbon such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,2-dibromoethane, or chlorobenzene, an ether such as tetrahydrofuran, dioxane, diethyl ether, 1,2-dimethoxyethane or tert-butyl methyl ether. Although this reaction can be carried out over a wide temperature range of about -100 ° C to + 50 ° ^C! Preferably, the reaction temperature range is from about -78 ° C to about 100 ° C. Deň: 22 ° C.

The desired product of formula I (R 1 = R ^a] is isolated in known manner, for example by the reaction was quenched with aqueous ammonium chloride, extracted with a water immiscible solvent and the solvent is then evaporated. The resulting product is optionally purified by conventional methods known in the art, for example by chromatography on a silica gel column.

The ester of formula I (R ¹ = R ^a ) wherein R a is a carboxyl function protecting group as defined above can then be converted to the corresponding acid or ester of formula I (R 1 = R ^b ) wherein R ^b is hydrogen or an ester-forming radical readily hydrolyzable in vivo. Typically, the procedure is such that the intermediate of the general formula I (R ¹ = R a) deprotecting the carboxylic function to give the corresponding carboxylic acid. Specific . the method chosen to remove the protecting group depends on the nature of the ester residue R a ^, but the choice of a suitable method will not cause problems for those of ordinary skill in the art.

As mentioned above, a particularly preferred carboxyl protecting group Ra is allyl. Although this group can be cleaved with mild acid or alkaline hydrolysis to a satisfactory result, a particularly preferred method for cleaving is the use of a soluble palladium-O complex, namely tetrakis (tri-phenylphosphine) palladium (0) as a catalyst. This method has already been described by Jeffery and McCombie in J. Org. Chem., 47, 587-590 (1982). Typically, the methyl ester in an inert solvent such as ethylene dichloride, chloroform or ethyl acetate is mixed with a catalytic amount of tetrakis (triphenylphosphine) palladium (0), for example about 1 to 5, under a nitrogen atmosphere. % by weight of the complex, based on the α-ethyl ester, and about the equivalent amount of triphenylphosphine. To this mixture is added the sodium salt or potassium salt of 2-ethyl hexanoate in equimolar amount based on the starting allyl ester, and the resulting mixture is stirred at room temperature until precipitation of the desired salt, for example a salt of formula I in which R 1 is sodium or potassium. The reaction is usually complete in about 2 to 20 hours. The resulting salt is then isolated, for example by filtration.

If the sulfoxides or sulfones of the invention are to be prepared, for example a compound of formula I wherein n is 1 or 2, the sulfides of formula I (n = 0 O) are oxidized using any of a wide variety of oxidizing agents known in the art. Particularly preferred agents of this type are metal permanganates, such as the rock metal and alkaline earth metal permanganates, and organic pproxyacids such as organic peroxycarbonic acids. Suitable individual agents are sodium permanganate, permanganate. potassium, 3-chloroerbenzoic acid and per-acetic acid.

A particularly preferred class of oxidizing agents is organic oeroxyacids, with the preferred organic peroxyacid being 3-chloroperbenzoic acid.

If the desired oxidation product is a sulfoxide of formula I in which n has a value of 1, roughly equivalent amounts of the starting sulfide (n = OJ and oxidizing agent) are used. If the desired product is a sulfone, for example a compound of formula I, in which n has a value of 2, the starting sulfide is treated with two or more moles equivalents of the oxidizing agent, and of course, sulfoxides which can be used as starting materials for the preparation of the sulfones are: in which case at least an equimolar amount of oxidizing agent is used.

For example, if a compound of formula I (R ¹ = R ^a , n = 0), wherein R ^a is as defined above, is oxidized to the corresponding compound of formula I (R ¹ = R ^a , n = 2) using an organic peroxyacids such as peroxycarboxylic acids, the reaction is usually carried out by treating a compound of formula I (R ¹ = R ^a , n = 0) with an inert organic solvent of about 2 to 4 mol equivalents of the oxidizing agent. Typical solvents are chlorinated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane, and ethers such as diethyl ether, tetrahydrofuran and 1,2-dimethoxyethane. The reaction is normally carried out at a temperature of about -20 ° C to 50 ° C, preferably at about 25 ° C. At temperatures of about 25 ° C, reaction times of from about 2 to 16 hours are usually employed. The product is normally isolated by removal of the solvent (Evaporation in vacuo. The product can be purified by conventional methods known in the art.

In the aforementioned oxidations, a starting material is preferably used in which the carboxyl function is protected by the aforementioned protecting group carboxyl function R ^a . The carboxyl function protecting group is removed from the resulting sulfoxide or sulfoin by a normal procedure applicable to that protecting group, for example, as described above for compounds of formula I wherein R ¹ is R ^and an is 0.

Compounds of formula I wherein R ¹ is an ester-forming moiety readily hydrolyzable in vivo can be prepared directly from the corresponding compounds wherein R ¹ is a hydrogen atom using conventional esterification techniques. The particular embodiment depends on the exact structure of the ester-forming moiety, but the choice of a suitable method will not cause difficulties for the skilled person. When R ¹ is a radical selected from the group consisting of a 3-phthalidyl radical, a 4-crotonolactonyl radical, a γ-butyrolacton-4-yl radical and a radical of the formulas

R ⁴ —COCOR ⁶

R ⁵ a

R ⁴

-COCOOR ⁶ wherein R ⁴ , R ⁵ and R ⁶ are as defined above, such compounds may be prepared by alkylation of the corresponding compound of the invention wherein R ¹ is hydrogen with a halide of formula

R ^b Q is a 3-phthalidyl halide, 4-crotonolactonyl halide, t-butyrolacton-4-yl halide or a compound of formula

QCl-t 4 - CR R ^ ¹ G QCOCOR or »· 1 R * and 1 1, n n ' qcocoa X;! ! c ŽP 1 κ

wherein Q is a halogen atom and R ⁴ , R ⁵ and R ⁶ are as defined above. The terms "halogen" and "halide" refer to chlorine, bromine and iodine atoms, and derivatives thereof. The reaction is typically carried out by dissolving a salt of a compound of formula I wherein R ¹ is hydrogen in a suitable polar organic solvent, for example N, N-dimethylformamide, and about one mole equivalent of the corresponding halide is added to the solution. -genidu formula R ^b Q After virtually complete reaction the product is isolated by standard techniques. It is often sufficient to simply dilute the reaction mixture with excess water, extract the product with a water-immiscible organic solvent and then evaporate the solvent. Commonly used starting material salts are alkali metal salts such as sodium and potassium salts, tertiary amine salts such as triethylamine, N-ethylpiperidine, N, N-dimethylaniline and N-methylmorpholine, and quaternary ammonium salts such as tetrabutylammonium and tetramethylammonium salts. salts. The reaction is conducted at a temperature ranging from about CD 0-100 ° C, usually at about 25 ^o C. The reaction time required к completion of the reaction varies depending upon numerous factors such as · the concentration of the reactants and the reactivity of the reagents. Thus, as for the halogen derivatives, iodide reacts faster than bromide and it reacts faster than chloride. When using a chloro derivative, it is sometimes advantageous in practice to add up to one mol equivalent of an alkali metal iodide, thereby accelerating the reaction. In view of the above factors, reaction times of from about 1 to about 24 hours are generally employed.

As mentioned above, the compounds of formula I, wherein R 1 is hydrogen, and salts thereof, in combination with β-lactam antiboitics, exhibit synergistic activity in antibacterial in vitro assays. This efficacy is demonstrated by the measurement of minimum inhibitory concentrations (MICs) in µg / ml against a number of microorganisms. The following section describes the procedure recommended by the International Collaborative Study on Antibotic Sensitivity Testing (Ericcsoin and Sherris, Acta. Pathologica et Microblologia Scandinav, Supp. 217, section B: 64-68 [1971]), at. using brain and heart infusion agar, and a device allowing repeated inoculation. Overnight culture in test tubes is diluted 100-fold and used as a standard inoculum [20,000-10,000 cells in about 0.002 ml are plated onto the agar surface; each dish contains 20 ml of brain and heart infusion agar). Two-fold dilutions of the test substance are used, with an initial test compound concentration of 200 U / g / ml. The experiment is evaluated after an 18 hour incubation at 37 ° C, with individual colonies not taken into account. The sensitivity (MIC) of the test organism is considered to be the lowest concentration of the test compound or a combination of compounds capable of causing complete growth inhibition when evaluated with the naked eye.

Those compounds of formula I wherein R ¹ is hydrogen, and salts thereof, in combination with known / Mactam antibiotics are useful as industrial antimicrobial agents, for example, in water treatment, sewage and sludge treatment, paint and wood protection, as well as for topical applications as disinfectants. When using the disclosed compounds for such applications, it is often advantageous to mix the active ingredient with a nontoxic carrier such as a vegetable or mineral oil or a softening cream. Similarly, they may be dissolved or dispersed in liquid diluents or solvents such as water, alkanols, glycols or mixtures thereof. In most cases, it is expedient to use concentrations of the active ingredient ranging from about 0.1 to 10% by weight, based on the total composition.

As mentioned above, the compounds of formula I wherein R1 is Rb are of greater importance as potent inhibitors of microbial (Maktams), thereby enhancing the antibacterial activity of [beta] -lactam antibiotics (penicillins and cephalosporins) against numerous microorganisms, in particular against microorganisms which produce / Maktamasu. the ability of these compounds to increase the effectiveness / .beta.-lactam antibiotics may · demonstrate experiments in which are determined the MIC values of the antibiotic alone, and the actual compound of the formula I wherein. R ¹ is hydrogen, and these values are then compared with the MICs found for the combination of the antibiotic in question with a compound of formula I, where R1 represents a hydrogen atom If the antibacterial activity of the combination is significantly higher than would be expected based on the efficacy of the individual components, The MIC values of these combinations are measured using the method described by Barry · and Sabath in "Manual of Climate Microbiology", ed. Lenette, Spaulding and Truant, 2nd edition, 1974, American Society of Microbiology.

Compounds of formula (I) wherein R ¹ is a hydrogen atom or an ester moiety readily hydrolyzable in vivo increase the antibacterial activity (β-1 β-β 1) of the direct antibiotic in vivo, i.e., reduce the amount of antibiotic required to protect the test. To determine such activity, acute experimental infections are induced in mice by intraperitoneal inoculation with a standardized culture of the test organism suspended in 5% of the gastrointestinal mucin of the pig. for the mouse to receive a lethal dose of the organism [lethal dose means the minimum inoculum of the organism needed to reliably kill 100% of the infected untreated control mice). A group of infected mice is then orally or intraperitoneally administered with different doses of the test compound in combination with an antibiotic. After completion of the test, the efficacy of this combination is determined by counting the surviving animals in the group treated with the given dose of the combination. Efficacy is expressed as a percentage of surviving animals at a given dose or, calculated as a PD 50 value (dose protecting 50% of the test animals from infection).

The ability of the compounds of the invention to enhance the efficacy of β-lactam antibiotics against β-lactamase producing bacteria makes these compounds suitable for co-administration with β-lactam antibiotics in the treatment of bacterial infections in mammals, particularly humans. For the treatment of a bacterial infection, the compound of the invention may be mixed with a β-lactam antibiotic or, when R ^b is CH (R ⁴ ) OCOR ^U , where R 4 and R 14 are as defined above, the β-lactam antibiotic is chemically bound to a compound of the invention, whereby both are applied simultaneously. Alternatively, the compound of the invention may be administered as a separate agent during treatment with the β-lactam antibiotic. In some cases, it is preferable to pre-medicate a patient with a compound of the invention before initiating treatment with a β-lactam antibiotic.

When using a compound of formula

I, in which R ¹ is a residue of R b as defined above, to enhance the efficacy of an β-lactam antibiotic, with a mixture of this compound with a β-lactam antibiotic, or a compound of the invention itself when R ^b is CH (R ⁴ ) OCOR ^{14 is} preferably applied in the form of a composition comprising standard pharmaceutical carriers or diluents. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, the β-lactam antibiotic and / or the aforementioned compound of the invention normally comprises about 5 to 80% by weight of a pharmaceutically acceptable diluent.

When the compounds of the invention are combined with another .beta.-lactam antibiotic, the compounds may be administered orally or parenterally, i.e., intramuscularly, subcutaneously, or intraperitoneally. Although the dosage used in human medicine is ultimately determined by the attending physician, normally the ratio of the daily doses of the compound of formula I, wherein R ¹ is a residue of R ^b , and the β-lactam antibiotic, is in the weight range of about 1: 3 to 3: 1. Further, when a compound of the invention is used in combination with a β-lactam antibiotic, the daily oral dose for each component normally ranges from about 10 to 200 mg per kilogram body weight, and the daily dose of each component parenterally administered is normally about 10 to 40 mg / kg body weight. These daily doses are usually administered in several divided doses. In some cases, the attending physician may prescribe doses beyond those limits, if necessary.

It is understood that some β-lactam compounds are effective when administered orally or parenterally, while others are only effective when administered parenterally. Thus, if a compound of the invention is to be used simultaneously (i.e., in a mixture) with a? -Lactam antibiotic effective only for parenteral administration, a combination formulation suitable for parenteral administration will be required. If the compound of the invention is to be used simultaneously (in admixture) with a β-lactam antibiotic effective for both oral and parenteral administration, combination formulations suitable for either oral or parenteral administration may be prepared. Furthermore, it is possible to orally administer the compositions containing the active compounds according to the invention and to administer parenterally (S-lactam antibiotic).

The invention is illustrated by the following non-limiting examples. Proton and C ¹³ nuclear magnetic resonance spectrum in the examples were measured at 60, 90, 250 or 300 MHz using a solution of the product in deuterochloroform, deuterium oxide, or acetone-d perdeuterodi sulfoxide, and peak positions are expressed in ppm versus tetramethylsilane. Signal shapes are indicated by the following abbreviations:

s singlet d doublet dd doublet doublet t triplet q quartet m multiplet w wide signal.

Example 1

6a-Hydroxypenicillanic acid esters

A. Allylester

A solution of 85 g of 6α-hydroxypenicillanic acid [prepared by the method of Hauser et al. in Helv. Chim. Acta, 50, 1327 (1967)] in 300 ml of DMF, 34 ml (0.39 mol) of allyl bromide, 54 ml (0.39 mol) of triethylamine and 2 g of sodium bicarbonate are added, followed by stirring at room temperature for 15 hours. water was added and the resulting mixture was extracted with ethyl ether. The combined ether layers were washed with saturated sodium bicarbonate solution and water, dried over magnesium sulfate and concentrated in vacuo. 43 g of crude product are obtained, which is purified by silica gel column chromatography using a 9: 1 mixture of chloroform and ethyl acetate as eluent. 22.75 g (23%) of the desired allyl ester is obtained.

⁴ H-NMR (CDCl3, δ ppm):

1.42 (s, 3H);

1.60 (s, 3H);

4.45 (s, 1 H),

4.5 to 5.0 (m, 3H);

5.2 to 6.2 (m, 4H).

B. Pivaloyloxymethyl ester

A mixture of 9 g (0.041 mol) of 6α-hydroxypenicillanic acid, 40 ml of dimethylformamide,

7.4 ml (0.041 mol) of diisopropylethylamine, 6 ml (0.041 mol) of chloromethyl pivalate and

Sodium iodide (6.15 g, 0.041 mol) was stirred at room temperature for 15 hours, water was added and the mixture was extracted with ethyl ether. The extracts were dried and concentrated to give 9 g of crude ester, which was purified by silica gel column chromatography using chloroform / ethyl acetate (9: 1) as eluent. The appropriate fractions were combined and evaporated to give 4.384 g (32%) of the desired product.

C. Benzyl ester

To a mixture of 20 g (0.092 mol) 6α-hydroxy2487 33

26 pemcilanové. of acid, 12.9 ml (0.092 mmol) of triethylamine, 1.105 g (0.013 mol) of sodium bicarbonate and 200 ml of dimethylformamide are added 12.0 ml (0.101 mol) of benzyl bromide. The reaction mixture was stirred at room temperature for 20 hours, then partitioned between ethyl acetate and water and adjusted to pH 2.0 with 6 N hydrochloric acid. The layers were separated, the aqueous layer was extracted twice more with ether, the combined ethereal layers were washed with sodium bicarbonate solution and water, dried and the solvent was evaporated. The residue was crystallized from a mixture of hot chloroform -a. hexane 9.1 g. colorless crystals, m.p. 165-167 ° C.

D. (5-Methyl-2-oxo-1,3-dioxol-4-yl) methyl estr

Mixture 15:. g (0.078 mol) of (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl bromide and 18.7 g (0.078 mol) of sodium 6α-hydroxyponicilanate in -255 ml of dimethylformamide were added for 4 hours. The mixture is stirred at room temperature, then poured onto ice and worked up as described above. - The desired title ester is obtained.

Example 1 a-d 2

Esters of 6-oxopenicillanic acid

A. Allyl-6-oxopropacylate

A mixture of 2.84 ml (0.04 mol) of dimethylsulfoxide, 3.67 ml (0.026 mol) of trifluoroacetic anhydride and 50 ml of methylene chloride was stirred at -78 DEG C. for 10 minutes. C. A solution of 5.14 g of allyl-6α-hydroxypenicillanate - in 10 ml of methyl chloride is then added at -78 DEG C. and the resulting mixture is stirred at -78 DEG. Stir for 40 minutes. At the above temperature, 7.24 ml (0.052 mol) of triethylamine are added, the reaction mixture is allowed to gradually warm to room temperature and then water is added. After extraction with methylene chloride, the combined organic layers were washed three times with water. dried and the solvent evaporated in vacuo. This afforded 5.1 g (100%) of the title compound as a yellow oil;

1 H-NMR - (doutoruchlurufurm, S-value in ppm):

1.60 (s, 6H),

4.75 - (im, - 2H);

4.82 (s, -1H),

5.1 to - $ 6 (m, 3H)

5.82 (s, 1H).

B. Pivaloyloxymethyl ester

A mixture of 0.36 ml (5.06 mmol) of dimethylsuloxide, 0.47 ml (3.29 mmol) of tri- anhydride

Iluoroacetic acid, 839 mg (2,53 mmol) of pivaloyloxymethyl-6α-hydroxy-prenicilate- and 5-ml-methylene chloride was stirred at -78 ° C for 30 min, then 0.92 was added. ml (6.58 mmol) of triethylamine. After working up the reaction mixture as described in Part A above, 788 mg (95 percent) of the desired ketone is obtained.

1 H-NMR (CDCl 3, δ values in ppm):

1.3 (s, 9H);

1.65 (s, 6H);

4.85 (s, 1 H),

5.8- (m, 3H).

Ex.ladder 3

Allyl-6´pE) - (2-pyridyl) methylenepenicilate

A mixture of 2.64 g (6.8 mmol) of 2-picolyl-triphenylphosphonium chloride and 0.265 g (6.8 mmol) of sodium amide in 6 ml of dry tetrahydrofuran was stirred at room temperature for 30 minutes. The resulting brown suspension was cooled to -78 ° C, a solution of 1.8 g (7.0 mmolU) of allyl-6-o-xenicenicilate in 4 mL of dry tetrahydrofuran was added in one portion, and the mixture was stirred at room temperature for 3 minutes. temperature - 78 ° C. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, the combined organic layers were washed three times with water, dried over magnesium sulfate, and concentrated in vacuo. 3.3 g of a red oil are obtained which, after purification by chromatography on a silica gel column, gives 1.35 g (60.7%) of the desired product as a yellow oil.

1 H-NMR (CDCl 3, δ ppm):

1.50 (s, 3H);

1.58 (s, 3H);

4.57 (s, 1 H),

4.65 (d, 2H).

5.15 to 6.15 (m, 3H)

6.17 (d, 1H, J = -1Hz),

6.87 (d, 1 H, J = 1 Hz),

7.2 to 7.4 (m, 2H)

7.60 (doublet triplet, 1H),

8.62 (doublet of doublets).

13 C-NMR (CDCl 3, δ in ppm):

26.04, 32.99, 62.77, 65.75, 70 (01, 70.54,

119.10, 123.24, 124.02, 125.86, 131.06, 136.34, 144.66, 149.94, 152.13, 167.54, 168.73.

instead of 2-picolyl-triphenylphosphonium chloride, the following compounds are obtained:

Example 4

Using the procedure of Example 3, but using the appropriate Wittig reagent of the formula w α Θ

6C ₆ A7 _S ) ₃ PCH ₂ Cl

CHj

Ctyj C00CH ₂ ^ CH ^ CH _of

R ³ Reaction Temperature Eluční Výě- ^ -NMR (deutero- time (° C) solvent- žek **) chloroform, values (minutes) body *) (%) δ in ppm)

Cl = 78 to +25

A 13 (E) E-isomer:

+3.2 (Z) 1.5 (s, 3H);

1.6 (s, 3H);

4.5 (s, 1 H),

4.65 (d, 2 H),

5.1 to 6.2 (m, 3H);

5.73 (d, IH);

6.82 (d, IH);

Z-isomer:

1.5 (s, 3H),

1.6 (s, 4H),

4.57 (s, 1 H),

4.7 (d, 2 H),

5.15 to 6.24 (m, 3H),

5.77 (s, 1 H),

6.37 (s, 1 H).

CH3S —78

CHO ^í)

В 16 i (E) Z-isomer:

(Z) 1.48 (s, 3H), (E + Z) 1.60 (s, 3H),

2.58 (s, 3H);

4.42 (s, 1 H),

4.60 (d, 2H).

5.0 to 6.0 (m, 3H);

5.58 (s, 1 H),

6.42 (s, 1 H);

E-isomer:

1.45 (s, 3H);

1.60 (s, 3H).

2.40 (s, 3H);

4.60 (s, 1 H),

4.80 (d, 2H), 5.0-6.1 (m, 3H),

5.72 (d, 1 H),

6.90 (d, IH).

³² 1.50 (s, 3H).

1.60 (s, 3H), 4.52 (s, 1H), 4.62 (d, 2H),

5.1 to 6.0 (m, 3H);

5.90 (d, 1H).

6.80 (d, 1 H),

9.73 (d, IH).

Yield of 4h-nMR [deuteros **) 'chloroform, values (° / o) δ in ppm)

R ³

Reaction Temperature Time (° C) (Minutes)

Elution Solvent * ·) '

2-quinolyl-78 (Z)

1.5 (s. 3H),

1.62 (s, 3H),

4.6 (s, 1 H),

4.7 (d, 2 H),

5.1 to 6.2 (m, 3H);

6.35 (d, IH);

7.0 (d, 1 H),

7.2 to 8.2 (m, 6H);

C2H5S - 78 (E, Z)

1.5 (s, 2.2H);

1.55 (s, O, 8H);

1.65 [s, 2.2H],

1.7 (s, 0.8H),

4.5 (s, 1 H),

4.5 to 4.8 (m, 2H);

5.1 to 6.1 (m, 4H);

6.8 (s, 0.26H);

7.15 (d, 0.74H),

7.4 (m, 5H).

(E) (s, 3H), (s, 3H), (s, 1 H), (d, 2 H),

1.45

1.55

4.55

4.65

5.2-6.1 (m, 3H);

6.15 (d. 1H);

6.75 (d, IH);

7.05 'to 7.75 (m,

3H),

C & H5 - 78 (Z)

1.5 (s. 3H),

1.6 (s, 4H),

4.6 (s, 1 H),

4.68 (d, 2 H),

5.1 to 6.1 (m, 3H);

5.77 (s, 1 H),

6.57 (s, 1 H),

7.2 to 7.64 (m, 3H);

7.64 to 8.16 (m, 2H);

—78 (E) (E)

1.52

1.62

4.60

4.69

5.1 to 6.3 (m, 3H);

6.1 (d. 1H);

7.03 (d, IH);

7.4 (s, 5H), (s, 3H), (s, 3H), (s, 1 H), (d, 2 H),

1.55

1.65

2.55

4.65 (s, 3H), (s, 3H), (s, 6H), (s, 1 H),

4.74 ' (d, 2H),

5.1 to 6.1 (m, 3H);

6.25 (d, 1H).

6.9 (s, 1 H),

7.0 (d, 1 H),

R ³

осн ₃ . OCHoCH = CH 2 x _{3 3} ^с '

ОСН ,.

Reaction gossip (—inutes) leptata PC) Elution orspray • tódto ·) Yield **) (%) ^X H-NMR (deuterium-,οοοΟοο—, throat δ in pp—) 3 —78 D 10 (E) (E) 1.5 (s. 3H), 1.6 (s, 4H), 3.85 (s, 3H); 4.55 (s, 1 H), 4.7 (d, 2 H), 5.1 to 6.1 (-, 3H), 6.2 (d. 1H). 7.0 to 7.5 (-, 3H), 8.2 (t, 1 H). 5 —78 A1 (E) 1.5 (s. 3H), 1.6 (s, 4H), 4.4 to 4.8 (-, 5H), 5.1 to 6.3 (-, 6H), 6.2 (d. 1H). 7.15 (d. 2H); 7.4 (d, 1 H), 8.15 (t, 1 H). 3 -78 (B) 27 Mar: E-isr-er: 1.5 (s. 3H), 1.6 (s, 4H), 2.6 (s. 3H); 4.6 (s, 1 H), 4.65 (-, 2H); 5.1 to 6.2 (-, 3H), 6.2 (d. 1H). 6.85 (d, IH); 7.0 - 7.7 (-, 3H). 5 —78 C 50 E-isr — eo: 1.5 (s. 3H), 1.6 (s, 3H) 4.55 (s, 1 H), 4.67 '(-, 2H), 5.0 to 6.2 (-, 3H), 6.15 (d. 1H); 6.95 (d, IH); 8.4 to 8.8 (-, 3H). 5 —78 C 13 E-isr — eo: 1.5 (s. 3H), 1.7 (s. 3H), 4.55 (s, 1 H), 4.7 (-, 2H). 5.1 to 6.2 (-, 3H), 6.2 (s. 1H). 6.5 to 7.0 (-, 3H), 8.5 (d, 1 H).

Legend: ________ _____________________________. _ | • '.Hříť (t'.Λ.γ Τ ^η $' * ί ^> ' _ι ϊ'γ ^, ν ·'; * ^; * ^ί ! Á '' ¹ '

*) A = hexane-ethyl acetate (9: 1)

A ¹ = heeaan-ethyl acetate (7: 3)

B = chloroform

= chloroform-ethyl acetate (9: 1) = chloroform-ethyl acetate (99: 1) ^{, a)} fro-yl-ethylene-tiphenylphosphorane in benzene.

Example 5

Thereafter, 6 (E.) - (2-pyridyl) -ethylenepenililate **) E-isr-R-R) is in the anhi-position to the β-lactate.

Z-sr-er-R3 is in the syn-position to the β-lactose

Dissolve 0.120 g of (0,38-oxyl) allyl-6 (E- (2-pyidyl) -ethylenepenillanate, 20 g of tetoakis (toiphenylphosphine) palladium (0) and 20 g of tripeyl 248483 phosphine in 3 ml of ethyl acetate and 0.76 ml (0.38 mmol) of a 0.5 M solution of sodium 2-ethylhexanoate in ethyl acetate was added under nitrogen and the mixture was stirred at room temperature for 2 hours, then the precipitate was filtered off, washed with ethyl acetate and dried in vacuo. This gave 57 mg (48%) of the title compound as a yellow solid.

1 H-NMR (deuterium oxide, δ in ppm):

1.55 (s, 6H);

4.33 (s, 1 H),

6.17 (d, 1H, J = 0.5Hz);

7.03 (d, 1H, J = 0.5Hz);

7.17 to 8.07 (m, 3H)

8.57 (m, IH).

IR (KBr):

433, 1756, 1 605 cm ¹ .

Example 6

The procedure is analogous to that of Example 5 using the corresponding allyl ester prepared in Example 4 as starting material. The following sodium salts are obtained:

COON &

R ³ Isomer Yield (%) Physical properties Cl (E) 95 yellow solid; @ 1 H-NMR (CDCl3) .delta. 1.50 (s, 3H), 1.58 (s, 3H), 4.3 (s, 1H), 5.83 (d, 1H), 7 1.1 (d, 1H); IR (CDCl 3) δ 1,573, 1,607, 1,688, 1,775, 3,460 cm ^-1 . Cl (OF) 89 IR (KBr): 1580, 1,609, 1,679, 1,753, 3,491 cm4 CH5S (E) 80 white solid; 1 H-NMR (dtuterium oxide, values <5 ppm): 1.48 (s, 3H); 1.56 (s, 3H); 2.50 '(s, 3H); 4.20 (s, 1 H), 5.88 (s, 1 H), 7.2 (s, 1 H); IC (Квг + есЬ ^ ка): 1 396, 1 606, 1 749, 2 926, 2 963, 3 552 cm-1. C6H5 (OF) 60 yellowish powder product. C6H5 ... (E) 80 white powder product; 1 H-NMR (deuterium oxide + perdeuterc) dimethylsulfoxide, values <5 ppm): 1.5 (s, 6H); 4.25 (s, 1 H), 6.1 (d, 1 H), 7.0 (d, 1H), 7.4 (s, (5H); IR (KBr) 1626, 1642, 1655, 1742, 3434 cm ^&lt; -1 & gt ^; .Ч ·· ⁴ . . ¹

The triphenylphosphine was dissolved in 1 ml of ethyl acetate, 0.52 ml of a 0.5 M solution of sodium 4-ethylhexanoate in ethyl acetate was added at room temperature, and the resulting mixture was stirred under nitrogen for 10 hours. Because only a very small amount of salt precipitates,

Example 6A

6-phenylthiomethylenepenilicic acid mg (0.26 mmol) atlyl-6-feyylthiome (mixture of isomers), 10 mg ttt-akis (triftnytphosphine) of patadium (0) and 10 mg

24873В

34

Dilute the reaction mixture with water and extract with methylene chloride. Aqueous layer. The mixture was acidified to pH 3.5 and extracted with methylene chloride. The dried extracts were concentrated in vacuo to give 63 mg (75%) of the desired free acid as a mixture of isomers.

¹ H-NMR (CDCl 3, δ ppm):

1.5 (s, 2.1H),

1.55 · (s, 0, SH)

1.6 · (s, 2,1H '),

1.65 (s, 0.9H),

4.4 (s, 0.7H);

4.5 (s, 0.3H);

5.38 (d, 0.7H),

5.7 (s, 0.3H);

6.7 (s, 0.3H);

7.1 (d, 0.7H);

7.5 (m, 5 H).

Example 7

Allyll1,1-dioxo-6 (E) - (2-pyridyl) methylenepenililate

To a solution of 1.30 g (4.09 mmol) of allyl-6 (E) - (2-pyridyl) -methylenepenilicilane in 15 ml of methylene chloride was added 1.70 g (8.2 mmol) of m &lt; -1 &gt; chloroperbenzoic acid having a purity of 80-85% and the mixture was stirred at room temperature under nitrogen for 3 hours. After addition of saturated sodium thiosulfate solution and water, the mixture is extracted with methylene chloride, the organic layer is adjusted to pH 7.5 with saturated sodium bicarbonate solution, washed with water, dried over magnesium sulfate and the solvent is evaporated off under vacuum. 1.4 g (98%) of product are obtained in the form of a yellow oil which, after purification by silica gel column chromatography, · hexane / ethyl acetate (7: 3) as eluent, yields 0.78 g [55%]. ) of the title sulfone, in the form of colorless crystals.

@ 1 H-NMR (CDCl3, .delta. in ppm):

1.48 (s, 3H);

1.63 (s, 3H);

4.45 (s, 1 H),

4.73 (d, 2H).

5.1 to 6.2 (m, 3H),

5.77 (d, 1H, J = 0.5 Hz),

7.27 (d, 1H, J = 0.5 Hz),

7, li, to 8) l: (by, · 3H),

8; 6 (m, 1 H).

¹³ C-NMR · (deutero.chlor ofotime, · values - · δ; in · ppm:) ·:

18.53; · 20 (43, .63-, 18, · 64.25, · 66, .63, .. · 72.04, 119; 91, 124.64,. 126.03, 130 (68, 132 (83, 136.77, 150.31, 166.86, 168.11.

IC (KBr technology):

323, 58B; . 1759, 1.788, 3-437-cm! ·.

Example 8

Allyl-1,1-dioxo-6 (E) - (2-hydroxyoxydene) penicillanate

To a solution of 0.190 g (0.61 mmol) of allyl 1,1-dioxo-6 (E) -methylmethylenepenicilate in 4 mL of dry tetrahydrofuran at -78 ° C was added 0.61 mL (0.61 mmol) of 1M hexane. solution of diisobutylalumite nium hydride. The mixture was stirred at -78 ° C for 10 minutes, then diluted with methanol, stirred at room temperature for 20 minutes, and concentrated. After concentration of the filtrate in vacuo, 0.258 g of crude product is obtained, which is diluted with water and extracted with chloroform. The organic phase was dried over magnesium sulphate and the chloroform evaporated. 160 mg of material were obtained, which was further purified by silica gel column chromatography using a 4: 1 mixture of chloroform and ethyl acetate as eluent. This afforded 113 mg (60 percent) of the title compound.

^ -NMR ’(deuterochloroform, values <5 ppm):

1.40 (s, 3H).

1.60 (s, 3H).

2.60 (bs, 1H),

4.3 (m, 2H).

4.4 (s. 1H).

4.7 (d, 2H).

51 to 6.0 (m, 3H)

5.25 (d, IH);

6.38 (m, IH).

Example 9

Following the procedure of Example 7, using the appropriate 6-methylenepenicilanes (n = 0) (produced in Example 4) as starting materials, the following compounds were obtained:

ch ₃

C00CHnCH ₉ = CH

А X

R ³

Yield isomer or elution _(0/0) nldlo; silica gel

Physical properties;

¹ H-NMR (CDCl 3, Š Šppm) f

í ‘>

CHO (E) 22nd CHC13 1.42 (s, 3H); 1.60 (s, 3H); 4.50 (s, 1 H), 4.70 (d, 2H). 5.1 to 6.0 (m, 3H); 5.32 (s, 1 H), 7.1 (m. 1H); 9.73 (d, IH). 2-quinolyl *) (E) 28 CHC13 1.5 (s. 3H), 1.6 (s, 4H), 4.45 (s, 1 H), 4.7 (d, 2 H), 5.1 to 6.1 (m, 3H); 5.8 (d, 1 H), 7.3-8.5 (m, 7H). 6-chloro-2-pyridyl (E) 34 CHC13 1.5 (s. 3H), 1.6 (s, 4H), 4.45 (s, 1 H), 4.7 (d, 2 H), 5.1 to 6.3 (m, 3H); 5.75 (d, IH); 7.1 to 7.8 (m, 4H). v4x ^{, c / 73} λ (E) 8 (79% of crude product) CHC13 1.5 (s. 3H), 1.6 (s, 4H), 2.55 (s, 6H); 4.5 (s, 1 H), 4.7 (d, 2 H), 5.0 to 5.9 (m, 3H); 5.7 (d, 1 H), 6.9 (s, 1 H), 7.3 (d, 1 H). `осн _ч rY t 'in ⁴ (E) 47 hexane-ethyl acetate (1: 1) 1.4 (s. 3H), 1.6 (s, 3H); 3.8 (s. 3H), 4.4 (s. 1H). 4.65 (d, 2 H), 5.3 to 6.2 (m, 3H); 5.8 (d, 1 H),

7.4 (s, 1 H),

7.8 (d, 1 H),

8.35 (t, 1 H).

2.4: 8

36

R ³

Isomer Yield Elution-Physical Properties; (%) nidio at 1 H-NMR (CDCl 3, δ V ppm) graphics on silica gel

(Ε)

(Ε)

54 hexane-ethyl acetate (1: 1) 1.45 (s, 3H); 1.6 (s, 4H), 4.4 to 4.8 (m, 5H), 5.1 to 6.3 (m, 6H), 5.65 (d, IH); 7.15 (d. 2H); 7.7 (d, 1H). 8.15 (t, 1 H). 53 CHC13 1.5 (s. 3H), 1.64 (s. 3H); 2.64 (s, 3H); 4.48 (s, 1H). 4.74 (doublet of triplets, 2H) 5.3-5.5 (m, 2H); 5.8 (d, 1 H), 7.1 to 7.2 (m, 2H) 7.25 (d, IH); 7.6 (t, 1 H); IR (KBr): 1,588, 1,688, 1,728, 1,756, 1,795, 2,931, 2,976, 3,433. 40 chloroform-ethyl acetate (9: 1) 1.56 (s, 3H); 1.7 (s. 3H), 4.6 (s, 1 H), 4.85 (m, 2H). 5.2 to 6.2 (m, 3H); 5.8 (d, 1 H), 7.4 (d, IH) 8.5 to 9.0 (m, 3H). 99 no cleaning required 1.5 (s. 3H), 1.7 (s. 3H), 3.9 (s, 3 H), 4.5 (s, 1H) 4.75 (m, 2H). 5.2 to 6.3 (m, 3H); 5.7 (d, lH) 6.7 to 7.0 (m, 2H); 7.2 (d, 1H). 8.5 (d, 1H).

Legend: *) in the following experiment eluting the silica gel column with chloroform with 2% ethyl acetate gave the sulfone (n = 2) in 29% yield, and in 27% yield of the more polar fraction identified as the sulfoxide (n = 1).

Example 9A

Ally 1-6 (E) - [(1-Oxoquinolin-2-yl) methylene] -1,1-dioxopenicillanate

124 mg (0.313 mmol) of allyl-6 (E) - [(quinolin-2-yl) methylene] -1-oxopenicillanate [obtained as a by-product in the preparation of the corresponding sulfone - see case marked with *) in the previous example] are dissolved in 5 ml of methylene chloride and 195 mg (0.904 mmol) of 80% m-chloroperbenzoic acid are added to the solution. The mixture was stirred at room temperature for 48 hours, then diluted with water and extracted with methylene chloride. The extracts were washed with saturated sodium bicarbonate solution and water, dried and concentrated in vacuo to a yellow-colored oil which, after purification by silica gel column chromatography, afforded 45 mg (35%) of the title N-oxide as a yellow solid.

^! H-NMR (CDCl3, δ ppm):

1.45 (s, 3H);

1.6 (s, 3H);

4.45 (s, 1 H),

4.7 (m, 2H).

5.0 to 6.0 (m, 3H);

5.85 (d, 1 H),

7.3-8.0 (m, 7H).

Example 10

Sodium 1,1-dioxo-6 (E) - (2-pyridyl) methylenepenicilane

0.14 g [0.4 mmol] of allyl-1,1-dioxo-6 (E) - (2-pyridyl) methylenepenililate, 20 mg of tetrakis (triphenylphosphine) palladium (0) and 20 mg of triphenylphosphine are dissolved in 2 ml of ethyl acetate and 0.8 ml (0.4 mmol) of a 0.5 M solution of sodium 2-ethylhexanoate in ethyl acetate was added to the solution under nitrogen. The reaction mixture was stirred at room temperature for 5 minutes, then the precipitate was filtered off, washed with ethyl acetate and dried. 0.13 g (95%) of the desired salt is obtained as a yellow solid.

1 H-NMR (deuterium oxide, values <5 ppm):

1.50 (s, 3H);

1.60 (s, 3H);

4.23 (s, 1 H),

5.90 (d, 1H, J = 1Hz);

7.1 to 8.0 (m, 4H)

8.57 (m, IH).

IR (KBr):

590, 1,621, 1,770, 3,454 cm ¹ .

Example 11

Allyl-1,1-dioxo-6 (E) - (1-oxo-2-pyridyl) methylene penicillinate

To a solution of 100 mg (0.286 mmol) of allyl-1,1-dioxo-6 (E) - (2-pyridyl) methylene penicillanate in 5 ml of methylene chloride was added 120 mg (0.59 mmol) of m-chloroperbenzoic acid, the mixture was stirred for 3 days After stirring at room temperature, a saturated sodium thiosulfate solution was added thereto, and the resulting mixture was extracted with methylene chloride. The organic layer was neutralized with saturated sodium bicarbonate solution, washed with water and concentrated to dryness. 82 mg of a yellow oil are obtained which, after purification by silica gel column chromatography eluting with ethyl acetate, affords 22 mg (21%) of the title compound and 14 mg (13 percent) of the by-product 2,3-epoxypropanyl- 1,1-dioxo-6 (E) - (1-oxo-2-pyridyl) methylenepenicilate.

Allyl-1,1-dioxo-6- (E) - (1-oxo-2-pyridyl) methylenepenicilane:

⁴ H-NMR (CDCl3, δ ppm):

1.5 (s. 3H),

1.6 (s, 4H),

4.45 (d, 1 H),

4.7 (d, 2 H),

5.1 to 6.0 (m, 3H);

5.8 (s, 1 H),

7.1 to 8.4 (m, 5H).

Example 12

Using the procedure of Example 10, the following compounds were also obtained by hydrolysis of the corresponding allyl esters:

O o p ,. \ /

L Π ς

--- h ₃

0 ^ ^J> COON.

Using potassium 2-ethylhexanoate instead of sodium 2-ethylhexanoate gives the corresponding potassium salts of the above formula.

R ³ Isomer Yield {%) Physical properties H0CH2 (E) 53 Δ-NMR (δ in ppm): 1.5 (s, 3H), 1.6 (s, 3H), 4.24 (s, 1H), 4.30 (dd, 2H), 5.75 (s, 1H), 7.20 (d, IH); IR (KBr): 1618, 1674, 1767, 3 408, 3440 cm ^-1 . 2-quinolyl (E) 76 1 H-NMR (250 MHz, CDCl 3, δ ppm): 1.45 (s, 3H), 1.48 (s, 3H), 3.82 (s, 1H) ,. 5.96 (s, 1H); 7.55-8.55 (m, 7H); IR (KBr): 1619, 1771, 3437 cm ^-1 . 6-chloro-2-pyridyl (E) 86 NMR-NMR (250 MHz, perdeuterodimethylsulfoxide, δ ppm): 1.56 (s, 3H), 1.64 (s, 3H), 4.34 (s, 1H), 6.18 (s, 1H) 7.45 to 8.0 (m, 4H); IR (KBr): 1624, 1771, 3433 cm ^1st Г Η. ,. ^{_л? 's} © у л /'<s (E) 75 Ш-NMR (250 MHz, deuterium oxide, δ ppm): 1.52 (s, 3H), 1.60 (s, 3H), 2.5 (s, 6H), 4.32 (s, 1H) 6.16 (d, 1H); 7.35 (d, 1H); 7.65-7.75 (m, 1H); IR (KBr): 1629, 1781, 3 403 cm ^-1 . ; i s (E) 55 Ш-NMR (250 MHz, CDCl 3, δ in ppm): 1.42 (s, 3H), 1.48 (s, 3H), 3.85 (s, 1H), 3.95 (s, 3H), 5.85 (d, 1H), 7.45 (d, 1H), 7.45-8.0 (m, 2H), 8.22 (m, 1H); IR (KBr): 1617, 1767, 3454 cm ^-1 . 1-oxo-2-quinolyl (E) 56 IR (KBr): 1553, 1622, 1769, 3413 ^cm-first

R ³

Isomer (E + Z)

оснхн = сщ χ, X,. (hygroscopic potassium salt) (E)

Yield (%) Physical properties ^* H-NMR (250 MHz, DMSO, δ values in ppm):

1.35 (s, 6H);

1.4 (s, 1.4H)

1.44 (s, 6H);

1.48 (s, 1.4H),

3.7 (s, 1H).

4.55 (d, 1H).

4.75 (d, 1H).

5.15-5.5 (m, 2H);

5.67 (s, 0.6H);

5.8 (s, 0.4H);

5.8 to 6.0 (m, 0.5H),

6.0 to 6.2 (m, 0.5H),

6.75 to 7.0 (m, 2H);

7.4 to 7.6 (m, 1H),

8.2 (d, 0.5H);

IR (KBr):

613, 1,760, 3,429 cm ¹ .

⁴ H-NMR (deuterium oxide, δ in ppm):

1.8 (s, 3H)

1.9 (s, 3H)

4.56 (s, 1H).

7.2 (IH)

7.34 (IH),

7.62 (IH),

8.68 (1H);

¹³ C-NMR (deuterium oxide, δ in ppm):

20.9, 22.7, 58.7, 64.6, 68.7,

74.6, 113.9, 115.9, 134.0,

134.2, 154.6, 155.1, 169.4, 173.7, 175.6.

Example 13

Pivaloyloxymethyl-6 (E) - (methylthio) methylene penicilate

A mixture of 2.4 mmol of (methylthiomethyl) triphenylphosphonium chloride and 2.4 mmol of sodium amide in 5 ml of dry tetrahydrofuran was stirred at room temperature for 20 minutes. A solution of 788 mg (2.4 mmol) of pivaloyloxymethyl-6-oxopenicillanate in 10 mL of dry tetrahydrofuran was added to the resulting yellow solution at -78 ° C, and the reaction mixture was stirred at -78 ° C for 10 min. ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was evaporated in vacuo. 774 mg of crude product is obtained which, after purification by silica gel column chromatography using chloroform as eluent, affords 220 mg (24.6%) of pure product.

⁴ H-NMR (CDCl3, δ ppm):

1.25 (s, 9H);

1.50 (s, 3H);

1.65 (s, 3H);

2.45 (s. 3H);

4.45 (s, 1H).

6.85 (m, 3H).

7.0 (s, 1H).

Example 14

Pivaloyloxymethyl-6 (E) -methylsulphonylmethylenepenicilate-1-oxide (A) and the corresponding 1,1-dioxide (B)

To a solution of 215 mg (0.58 mmol) of pivaloyloxymethyl-6 (E) - (methylthio) methylene penicillanate in 5 mL of methylene chloride was added 375 mg (1.74 mmol, 3 equivalents) of 80% m-chloroperbenzoic acid. The mixture was stirred at room temperature for 4 hours, then stirred with water, saturated sodium thiosulfate solution and sodium bicarbonate, and extracted with chloroform. The organic phase is washed three times with water, dried over magnesium sulphate and concentrated in vacuo. 200 mg of the product mixture are obtained. The crude mixture was purified by silica gel chromatography using a 9: 1 mixture of chloroform and ethyl acetate as eluent. 25 mg of 1-oxide (A) and 45 mg are obtained

1,1-diouid (B).

(A):

@ 1 H-NMR (CDCl3, .delta. in ppm):

1.21 (s, 9H);

1.3 (s, 3H);

1.7 (s. 3H),

3.1 (s. 3H);

4.7 (s, 1 H),

5.8 (AB quartet, 2H),

5.85 (d, 1 H),

7.1 (d. 1H);

IR (chloroform):

333, 1,759, 1,807, 2,927, 2960 cm -1.

(B):

1 H-NMR (CDCl 3, δ ppm):

1.2 (s, 8H),

1.45 (s, 3H);

1.6 (s, 3H);

3.15 (s, 3H).

4.5 (s, 1 H),

5.6 (d, 1 H),

5.8 (AB quartet, 2H),

7.2 (d. 1H);

IR (chloroform):

324, 1758, 1800, 2929, 2956 cm @ -1.

Example 1 and 15

The procedure described in Example 10 was repeated with 50 mg (0.12 mmol) of allyl-6- (3-allyloxy-2-pyridyl) methylene-1,1-di-oxopenicillanate using 5.2 mg of triphenylphosphine. 5.2 mg of tetrakis (triphenylphosphine) palladium (0) and 0.24 mmol of potassium 2-ethylhexanoate (2 mol equivalents calculated on the starting allyl ester) in 1.5 ml of ethyl acetate. The resulting mixture was stirred for 18 hours, then the ethyl acetate was aspirated by pipette and the residue was washed twice with 1 ml of ethyl acetate each time. This gives 43 mg of a dark colored solid which is 6 (E) - (3-hydroxy-2-pyryl) methylene-1,1-dioxo-penicillanic acid 1-potassium potassium salt.

U-i-NMR (1euteriumoxi1, δ in ppm):

1.56 (s, 3H);

1.62 (s, 3H);

4.27 (s, 1H); 6.00 (d, 1H);

7.29 (m, 2H).

7.80 (d, 1 H), 8.04 (d, 1 H).

Example 16

Allyl-6 (E) - (2-pyrimidinyl) methylenepenicilate

A. 2-Hydroxymethylpyrimidine

A suspension of sodium ethoxide, prepared from 7.44 g (323 mmol) of sodium metal and 300 ml of absolute ethanol, was cooled to room temperature, 18 g (163 mmol) of hydroxyacetyl-hydrochloride and 8.06 ml (81 mmol) were added. 3-dimethylamino-acrolein, and the mixture is heated to reflux. Dimethylamine is slowly distilled off, ethanol is added periodically to maintain the volume of the solvent. The reaction mixture was heated under reflux for 9 hours, then stirred at room temperature for 18 hours, after which time the solvent was evaporated under reduced pressure. The residue is applied to a silica gel column eluted with ethyl acetate / methanol (19: 1). Yield: 4.1 g (46% yield) of the desired product.

B. 2-Pyrimidinylmethyltriphenylphosphonium chloride

4.096 g (37.2 mmol) of 2-hydroxymethylpyrimidine are dissolved in 80 ml of methylene chloride and 8.6 ml (37.2 mmol) of thionyl chloride are added dropwise (exothermic reaction).

The mixture was stirred for 15 min. The mixture was stirred, then neutralized with saturated sodium bicarbonate solution and extracted with methylene chloride. The extracts were dried and the solvent was evaporated. 3.67 g of 2-chloromethylpyrimidine are obtained.

@ 1 H-NMR (CDCl3) .delta. In ppm):

4.82 (s, 2H).

7.3 (t, 1 H),

8.9 (d, 2 H).

A mixture of 3.565 g (27.7 mmol) of 2-chloromethylpyrimidine in 30 ml of toluene and 7.269 g (27.7 mmol) of triphenylphosphine was heated under reflux for 18 hours. The precipitate formed was filtered off and dried. 9.06 g (65% for two steps) of product are obtained.

C. A mixture of 2.187 g (5.6 mmol) of Wiittg's reagent prepared in Part B above, 218.4 mg (5.32 mmol) of sodium amide and 30 ml of dry tetrahydrofuran was stirred at room temperature for 1.5 hours and then added. at -78 ° C, the solution is added in one portion

1.44 g (5.65 mmol) of allyl-6-oxopenicillanate in 10 ml of dry tetrahydrofuran. The resulting mixture was stirred for 5 minutes, then poured into saturated ammonium chloride solution and extracted with chloroform. The organic phase was washed with saturated ammonium chloride solution and brine, dried over magnesium sulfate and the solvent was evaporated in vacuo. The oily residue is chromatographed on a silica gel column using a 9: 1 mixture of chloroform and ethyl acetate as eluent. 560 mg of pure product are obtained.

Ш-NMR (deuterochloroform, δ values in ppm):

1.5 (s. 3H),

1.6 (s, 4H),

4.6 (s, 1 H),

4.7 (m, 2H).

5.1-6.3 (m, 3H);

6.2 (d, 1 H),

7.0 (d, 1 H),

7.0 - 7.35 (m, 1H);

8.7 (d, 2 H).

Example 17

1,1-Diioxo-6 (E) - (2-pyrimidinyl) methylenepenicillanic acid allyl ester and potassium salt

A. 560 mg (1.69 mmol) of allyl-6 (E) - (2- (E) -imidinyl) methylenepenicillanate and 730 mg of 3-chloroperbenzoic acid (3.38 mmol) are dissolved in 10 ml of methylene chloride and the mixture is stirred in - The nitrogen atmosphere was stirred for 4 hours, diluted with water and extracted with methylene chloride, and the extracts washed with sodium thiosulfate solution, neutralized with sodium bicarbonate, and washed with brine, dried and concentrated in vacuo to give 460 mg of a crude oil which was purified Silica gel column chromatography eluting with chloroform / ethyl acetate (9: 1) gave 180 mg of the desired allyl ester as a light yellow solid.

1 H-NMR (CDCl 3, δ values in ppm):

1.45 (s, 3H),

1.65 (s, 3H);

4.5 (s, 1 H),

4.75 (m, 2H).

5.2-6.3 (m, 3H);

5.75 (s, 1 H),

7.1-7.5 (m. 2H);

8.9 (d, 2 H).

B. Using the procedure of Example -10, treatment of the above allyl ester with triphenylphosphine, tetrakis (triphenylphosphine) palladium (0) and potassium 2-ethylhexanoate afforded the desired potassium salt in 89% yield as a pale pink solid.

1 H-NMR (deuterium oxide, δ in ppm):

1.6 (s, 4H),

1.68 (s, 3H);

4.4 (s, 1H),

6.1 (s, 1 H),

7.48 (s, 1H).

7.54 (t, 1 H),

8.88 (d, 2 H).

¹³ C-NMR (deuterium oxide, δ values in ppm):

20.9 22.7, 68.8, 68.9, 74.6, 124.5, 132.5,

139.9, 160.9, 163.2, 172.5, 175.5.

IC (KBr - echnika):

560, 1,615, 1,771, 3,439.

Example 18

A. To 1.0 g of 6α-hydroxypenicillanic acid in 25 ml of methylene chloride was added 50 mg of diisopropylcarbodiimide and 0.5 ml.

2,2,2-richlarethanol. The mixture was stirred overnight, then the solvent was evaporated in vacuo and the crude product was purified by silica gel chromatography. 2,2,2-Richloroethyl-.alpha.-hydroxypenicillanate is obtained.

Β. To 1.0 g of 6α-hydroxypenicillanic acid in 50 ml of dioxane was added 0.5 g of p-tolenesulfonic acid and 0.4 g of dihydropyran, the mixture was heated to 50 ° C and then stirred at room temperature overnight. After evaporation of the solvent and purification of the product by silica gel column chromatography, 2-tetrahydropyranyl-6? -Hydroxypyricilate is obtained.

Example 19 Rensyl-6-oxopenicillanate

To a solution of 1.8 ml (0.025 mmol) of dimethylsulfoxide in 2 ml of methylene chloride at -60 ° C was added dropwise a solution of 2.12 ml (0.015 mol) of t-trifluoroacetanediamide in 5 ml of methylene chloride. The mixture was stirred at -60 ° C for 20 minutes, then a solution of 350 mg (1.14 mmol) of benzyl-6α-hydroxypenicillanate in 5 ml of methylene chloride was added and stirring at -60 ° C was continued for 60 minutes. . After the addition of 0.50 ml of methylamine, the cooling bath was removed, the reaction mixture was warmed to 0 ° C, poured into ice-water and extracted with methylene chloride. The organic layer was dried, concentrated to low volume in vacuo, diluted with benzene and washed three times with ice-cold water. The benzene layer was dried and the solvent was evaporated in vacuo to give 230 mg (67%) of the product as yellow crystals. According to the proton NMR spectrum measured in dchte-ochtorrformh, the product obtained is very pure.

Example 20

6- (2-Pyridyl) hydroxymethylpenicillanic acid 1,1-dioxide

A. Renzyl-6-2-pyridylthydroxymeCyllll, t-dioxopenicillanate

To a solution of 0.40 g of benzyl-6- (2-pyridyl) hydroxymethyl-2-pentene-laaneate in 5 ml of methylene chloride was added 0.20 g of m-tert-perbenzo-2448733ic acid and the mixture was stirred at room temperature for 1 hour. According to thin layer chromatography, the reaction mixture contained some sulfoxide. An additional 0.2 g of m-chloroperbenzoic acid was added and the mixture was stirred overnight. The reaction mixture was diluted with methylene chloride, washed successively with saturated sodium thiosulfate solution, water and saturated sodium bicarbonate solution, and the organic layer was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with sodium bicarbonate solution, water and brine, dried over sodium sulfate and the solvent was evaporated. 330 mg of the desired benzyl ester is obtained as a brown oil which is purified by silica gel column chromatography. Elution with a 11: 9 mixture of ethyl acetate and hexane gave 60 mg of a yellow oil.

1.H-NMR (CDCl3, δ ppm):

1.25 (s, 3H).

1.52 (s, 3H);

4.1 (dd, 1 H),

4.5 (s, 1 H),

4.72 (d, IH);

5.5 (d, 2H).

5.8 (d, 1 H),

7.1-8.0 (m. 3H);

8.5 (m. 1H).

B. A suspension of 118 mg of 10% palladium on carbon catalyst in 10 ml of tetrahydrofuran and 4 ml of water was prehydrogenated under 20 psi of hydrogen for 20 minutes. To the resulting suspension was added 130 mg of the benzyl ester prepared in Part A above in 4 mL of the same tetrahydrofuran-water mixture. The mixture was hydrogenated at 0.35 MPa for 30 minutes, then an additional 129 mg of 10% palladium on carbon was added and hydrogenation at 0.35 MPa was continued for 2 hours. The catalyst was filtered off, the solvent was evaporated in vacuo and the residue was partitioned between water and ethyl acetate. Lyophilization of the aqueous layer gave 85 mg of the desired acid.

4H-NMR (deuterium oxide, δ in ppm):

1.3 (s. 3H),

1.5 (s. 3H),

4.4 (s. 1H).

5.0 - 5.35 (m, 2H),

5.9 (d, 1 H).

IR (KBrr-echnika):

620, 1731, 3 407 cm -1.

C. If the above procedure was repeated except that only 175 mg of m-chloroperbenzoic acid (equimolar amount) was used in Part A, the isolated product was a mixture of the corresponding α- and / -sulfoxides.

Example 21

Injectable preparation

Equal parts by weight of icepiperazone-sodium and potassium 1,1-dioxo-6 (E) - (2-pyrazinyl) methylene-penenate are mixed with -20 parts by weight of water. Using methods common in pharmaceutical practice, the solution is sterile filtered, filled with vials, which are loosely sealed with rubber caps and lyophilized. The filling volume is such that each vial after lyophilization, which is now sealed under vacuum, contains 500 mg of each active ingredient. Prior to injection, 10 ml of sterile water for injection was injected into the vial via a syringe piercing the rubber stopper and the vial was shaken to dissolve all solids. The solution for injection in a volume of 1 to 10 ml is withdrawn from the vial through a rubber stopper using a syringe with a hypodermic needle.

Preparation

(I) 6-Chloro-2-methyl-pyridine-1-oxide

To a solution of 5.1 g: 40 mmol of β-chloro-4-picoline in 50 ml of methylene chloride was added 8.625 g of (40 mmol) of 80% m-clil (.-Tonnj® KWB acid) and the mixture was stirred for 15 min. The reaction was quenched by the addition of 0.5 ml of saturated sodium thiosulfate solution and the pH of the reaction mixture was adjusted to 7.5 with sodium bicarbonate solution, and the organic layer was washed with water, dried over sodium sulfate. The solvent was evaporated to give 4.84 g of the desired N-oxide.

1 H-NMR (CDCl 3 -values - δ in ppm):

2.6 (s. 3H);

7.0-8.0 (m, 3H).

(ii) 6-chloro-2-acetoxymethylpyridine

A solution of 4.8 g (0.035 mmol) of the above prepared N-oxide in 15 ml of acetic anhydride was heated at 100 DEG C. for 1 hour and then subjected to distillation under vacuum. 2.39 g of the desired product are obtained in the form of a colorless oil having a boiling point of 125 to 128 DEG C./93 mbar.

@ 1 H-NMR (CDCl3) .delta.

2.1 (s, - 3H)

5.1 (s. 2H);

7.0-7.8 (m, 3H).

(iii) The 6-chloro-2-pyridylmethanol product obtained in part (ii) was hydrolyzed for 1 hour in 10 ml of 2N hydrochloric acid at 70 ° C. The mixture was neutralized with potassium carbonate, then extracted with chloroform, dried and the solvent was evaporated. 1.87 g of crude alcohol are obtained which, after purification by silica gel column chromatography, yields 0.982 g of pure product.

¹ H-NMR (CDCl 3, δ ppm):

4.8 (s, 2H).

5.3 (bs, 1H),

7.0-7.8 (m, 3H).

(iv) 6-chloro-2-chloromethylpyridine

0.982 g (6.84 mmol) of 6-chloro-2-pyridylmethanol in 10 ml of methylene chloride was treated with 0.814 g of thionyl chloride at room temperature for 1 hour. The reaction mixture was neutralized with saturated sodium bicarbonate solution and extracted with methylene chloride. The extracts were dried and the solvent was evaporated, yielding 815 mg of the desired product as colorless crystals.

1 H-NMR (CDCl 3, δ ppm):

4.7 (s, 2H).

7.1-8.0 (m, 3H).

(v) Dissolve 815 mg (5 mmol) of the product prepared in part (iv) and 1.318 g (5. mmol) of triphenylphosphine in 10 mL of toluene and reflux for 6 hours to prepare a Wittig reagent. Filtration of the precipitated product gave 1.388 g (65%) of the title compound.

1 H-NMR (dimethylsulfoxide, δ in ppm):

5.5 (s, 1 H),

5.8 (s, 1 H),

7.2- 8.2 (m, 18H).

(vi) 4-Methoxypyridin-2-ylmethyltriphenylphosphonium chloride

Using the procedure of part (ii), use

2.1 g of 2-methyl-4-methoxypyridine-1-oxide starting material yielded 2.5 g of 2-acetoxymethyl-4-methoxypyridine contaminated with about 25% of 5-acetoxy-2-methyl-4-methoxypyridine. This mixture of products was dissolved in 10 ml of methanol containing 1.118 g (20.7 mmol) of sodium methoxide, and the mixture was heated under reflux for 1 hour with stirring. The methanol was evaporated in vacuo, the residue was diluted with water, neutralized with dilute hydrochloric acid and extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. 853 mg (41%) of 2-hydroxymethyl-4-methoxypyridine are obtained.

1H-NMR (Dichlorochloroform, δ in ppm):

3.9 (s, 3 H),

4.72 (s, 2H).

5.35 (bs, 1H),

6.7 (dd, 1 H),

6.95 (d, IH);

8.3 (d, 1 H).

The above hydroxymethyl compound was converted to 0.895 g (5.68 mmol) of 2-chloromethyl-4-methoxypyridine as described in (iv) above. This material was treated with an equimolar amount of triphenylphosphine in 10 mL of toluene for 20 hours at reflux. Filtration of the precipitated product gave 860 mg of the title compound as a yellow solid.

Preparation В

2-quinolinylmethyltriphenylphosphonium chloride

A solution of 6.26 g (0.036 mol) of 2-chloromethylquinoline and 9.20 g (0.035 mol) of triphenylphosphine in 80 ml of toluene was heated under reflux for 3 hours. The precipitated solid was collected on a filter and dried under vacuum to give 3.5 g (23%) of the product as a brown solid.

Preparation C

3-allyloxy-2-pyridylmethyltriphenylphosphonium chloride (i) 3-allyloxy-2-hydroxymethylpyridine

To a mixture of sodium methoxide and methanol, made from 1.43 g (62 mmol) of sodium metal and 100 ml of methanol, 5.9 g (31 mmol) of 3-hydroxy-2-hydroxymethylpyridine are added and the methanol is evaporated off under vacuum. The residue was dissolved in DMF (80 mL) and allyl bromide (3.0 mL, 34.7 mmol) in DMF (20 mL) was added over 20 min at room temperature. The mixture was stirred for 2 hours, then dimethylsulfoxide was distilled off in vacuo and the residue was partitioned between chloroform and water. The aqueous phase was adjusted to pH 7.5 and extracted three times with chloroform. The combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated. 3.48 g (68%) of the desired ether are obtained.

(ii) 3-allyloxy-2-chloromethylpyridine

To 3.43 g (20.8 mmol) of the product from Part A in 20 mL of methylene chloride was added 1.5 equivalents (2.5 mL) of thionyl chloride and stirred under nitrogen for 2 hours. The volatiles were removed in vacuo and the residue was shaken between methylene chloride and water. The pH of the aqueous layer was adjusted to 7.5 and the mixture was extracted with fresh methylene chloride. The combined extracts were washed with water and brine, dried over sodium sulfate and the solvent was evaporated in vacuo. 3.28 g (86%) of the desired product are obtained, which product is used as is in the following stage.

(iii) 3.28 g (17.9 mmol) of the product of part (ii) was dissolved in 30 ml of toluene, and 4.69 g (17.9 mmol) of triphenylphosphine was added thereto, followed by stirring at reflux for 3 hours. After cooling at room temperature for 12 hours, the product was filtered off and washed with toluene to give 3.89 g (49%) of the desired Wittig reagent.

Preparation D

6-Methyl-2-pyridylmethyl-phenylphosphonium chloride (i) 6-Methyl-2-hydroxymethyl-pyrimidine

6-Methyl-pririne-2-carboxaldehyde (0.44 mmol) in methanol (50 ml) was reduced at 0-5 ° C with 20.6 mmol of sodium borohydride. After the reduction was complete, the mixture was neutralized to pH 7.5 with 2N sulfuric acid, filtered, the filtrate was concentrated and the residue was partitioned between chloroform and water. Evaporation of the solvent from the organic layer yielded 3.32 g of a red-black oil which was used in the next step.

(ii) 2-chloromethyl-6-methylpyridine

The above-prepared product (3.32 g, 0.27 mmol) in 20 ml of metheplene chloride was treated with 1.94 ml (27 mmol) of thionyl chloride at room temperature for 1 hour. The reaction mixture was neutralized with sodium bicarbonate and extracted with chloroform. Evaporation of the solvent gave 3.22 g of the oily product used in the next step.

(Iii) A solution of 3.22 g of oily material. of part - (ii) and 5.96 g of triphenylphosphine in 30 ml of toluene were refluxed for - 4 hours. After filtering off the precipitate, -3.93 g of Wittig reagent is obtained as a brown solid.

Preparation

2-pyrazinylmethpltriphenylphosphonium chloride (i) 2-eyrroxymethplpyrazine

To a solution of 11.29 g (79.2 mmol) of 2-pyrazinecarbonyl-1-ori (prepared by reaction of the corresponding 2-carboxylic acid with a molar excess of thionyl chloride at reflux ¹ ) in 100 ml of tetrahydrofuran 2.0 g - (52.6 mmol) of lithium aluminum hydride - 95% purity was added portionwise at -78 ° C over 20 minutes. The mixture was stirred for 10 minutes and then allowed to warm to room temperature. To the reaction mixture was added 2M sodium hydroxide, the mixture was filtered, and the residue on the filter was washed with methanol, and the filtrate was concentrated in vacuo to give 4.12 g of a dark solid which was used in the next step.

(ii) 4.12 g (37.9 mmol) of the dark solid obtained above were dissolved in methylene chloride, and 2.8 ml of thionyl chloride was added to the solution at 0 ° C. The mixture was warmed to room temperature, stirred for 30 minutes, then water was added thereto, the resulting mixture was neutralized and extracted with methylene chloride. 2.29 g of a yellow oil are obtained, which product is used as is in the following stage.

(iii) To 2.29 g of the above-prepared oil in 40 ml of toluene was added 4.70 g of triphenylphosphine and the mixture was heated to reflux for 3 hours. After usual work-up, 1.995 g of Wittig reagent is obtained as a brown solid.

Claims (5)

A process for the preparation of 6- (subst.) Methplenpenicillanic acids of the general formula I. where л has a value of 0, 1 or 2, R ¹ represents a radical R ^a or R ^b , wherein -R ^a represents a carboxyl function protecting group selected from tetrahydropyranyl, allyl, benzyl, 4-nitrobenzyl, benzhydryl, 2,2,2-trichloroethyl, tert-butyl and phenacyl the moiety -a R ^b is a hydrogen atom -or an ester moiety readily hydrolyzed in vivo, selected from the group consisting of a 3-phthalidyl moiety, a 4-crotonolactonyl moiety, a α-moiety residue, a moiety of formula ( AND) -COCOŘ R * i < -COCOOR r * ¢ 5 and R4 AND 1 —CHOCOR14 wherein each of R ⁴ and R ⁵ represents a hydrogen atom or a methyl group, R ⁶ represents an alkyl group having 1-5 carbon atoms and R ^u is a radical of formula wherein R 15 is 2-phenylacetamido, 2-phenoxyacetamido, D-2-amino-2-phenylacetamido, D-2-amino-2- [4-hydroxyphenyl) acetamido, 2-carboxy-2-phenylationamido, 2-carboxy-2 - (2-thienyl) acetamido, 2-carboxy-2- (3-thienyl) acetamido, D-2- (4-ethyl-2,3-dioxopiperazinocarbonylamino) -2-phenylacetamido or 2,2-dimethyl-4 -phenyl-5-imidazolidinon-1-yl, and one of R ² and R ⁵ is hydrogen and the other is chloro, hydroxymethyl, vinyl, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfonyl alkyl, lurylovou, thienyl, N-methylpyrrolyl, N-acetylpyrrolylovou group, the radical R ⁷ CsH4, ^R7 CeH4S, -CH (R4) NR ¹⁶ R ¹ 7, -CNR ⁸ R ^9, II p —CNR8R ⁹ , NH 54: characterized in that the starting material of the formula (V) in which m is 2 or 3, p is 0 or 1, t is 0, 1 or 2, Xi represents a sulfur atom, an oxygen atom or an NR ¹¹ group, R ⁷ is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, allyloxy, hydroxyl, carboxyl, C 2 -C 5 alkoxycarbonyl, C 1 -C 5 alkylcarbonyl, phenyl , benzyl, naphthyl, pyridyl, NR ⁸ R ⁹ , CONR ⁸ R ⁹ , NHCOR ¹⁰ , nitro, chloro, bromo, trifluoromethyl or SR ⁸ , each of R ⁸ and R ⁹ is each hydrogen, C1-C4alkyl, phenyl or benzyl, R ¹⁰ is C 1 -C 4 alkyl, trifluoromethyl or phenyl, R ¹¹ represents hydrogen, methyl, ethyl or acetyl group, and R ¹⁶ and R ^{17 are} either hydrogen, C 1 -C 4 alkyl, C 2 -C 4 hydroxyalkyl, or R ¹⁶ and R ¹⁷ together with the nitrogen atom to which they are attached form pyrrolidino, piperidino, morpholino, thiomorpholino or 4-methylpiperazino, and pharmaceutically acceptable acid addition salts of those compounds wherein R ² or R ³ contains a basic nitrogen atom, or pharmaceutically acceptable cationic salts of those compounds wherein R ¹ is hydrogen or the radical R ² or R ³ contains a carboxyl group characterized in that R ¹ has the above meaning and preferably represents a radical R ^a, is reacted with a Wittig reagent of the formula R ² R ³ d = P (G6H5) 3 where · R ² and R ³ are as defined above, ¹ in the presence of an inert organic solvent at a temperature in the range of from -100 to +50 ° C to give a compound of formula I wherein n is < Where appropriate, for the preparation of compounds of the formula I in which η: has. 1 or 2, the compound in which n is 0 is oxidized, preferably by an alkali metal or alkaline earth metal permanganate, 3-chloroperbenzoic acid or a percentage acid; or / and to produce compounds of the general formula IJ in which z ¹ is -R ^{b .} cleaves ^; Present # ohráhiěí 'group karboxylové- ftmkoe * R * ^B for ^one form ¹ of compound ¹ · vzorce- Г, * in which R * · signify hydrogen-in, and this · · · to compound · · then optionally subjected to ¹ Reaction with an elephant of the formula R ^b Q> in which R ^b is as defined above, except for the hydrogen atom a Q is chlorine, bromine or iodine; ¹ in presence of polar organic solvents: · · ¹ tědlaj then ⁵ · ⁵ or a compound of výslédhá vzorce- I * převedfe Na- their pharmaceutically acceptable acid addition salt or a salt katióniókou. 2. A process according to claim 1, wherein the corresponding starting materials are used to form compounds of formula (I) in which: R ^{1 and} n are as defined in claim 1, one of R ² · R ³ represents a hydrogen atom and the other represents a chlorine atom, a hydroxymethyl ^one group, a vinyl group, an alkylthio sl to 4 carbon atoms, alkylsulfonyl having 1 to 4 carbon atoms , furyl, thienyl, N-methylpyrrolyl, N-acetylpyrrolyl, residue R7C6H4, R7C6H4S, -CH (R4) NR ¹⁶ R! 7 -CNR ⁸ R 9, S —CNR8R9, NH 4, hydroxyl, carboxyl, C 2 -C 5 alkoxycarbonyl, C 5 -C 5 alkylcarbonyl, NR ⁸ R ⁹ , CONR ⁸ R 9, NHCOR ¹⁰ , nitro, chloro, bromo, trifluoromethyl or SR ⁸ , each of R 8 and R ⁹ is hydrogen, C 1 -C 4 alkyl, phenyl or benzyl; R 10 is C 1 -C 4 alkyl, trifluoromethyl or phenyl; RH represents a hydrogen atom, a methyl group, an ethyl group or an acetyl group and R ¹⁶ and R 17 are either hydrogen, C 1 -C 4 alkyl, C 2 -C 4 hydroxyalkyl, or R ¹⁶ and R 17 together with the nitrogen atom to which they are attached form pyrrolidino, piperidino, morpholino, thiomorpholino or 4-methylpiperazino, and pharmaceutically acceptable acid addition salts of those compounds wherein R 2 or R 3 contains a basic nitrogen atom, or pharmaceutically acceptable cationic salts of those compounds wherein R 1 is hydrogen or the radical R 2 or R 3 contains a carboxyl group. 3. Process according to claim 1, characterized in that starting materials are used the above formulas in which R is a residue R ^a, preferably allyl or benzyl, or one of R ² and R 3 represents hydrogen and the other is 2- pyridyl, N-oxo-2-pyridyl, 2-quinolyl, 3-allyloxy-2-pyridyl, 3-methoxy-2-pyridyl, 4-methoxy-2-pyridyl, 3-hydroxy-2- pyridyl, 6-methyl-2-pyridyl, 1-methyl-2-imidazolyl, 2-thiazolyl, 4,5-dimethyl-2-thiazolyl, 4-methyl-2-thiazolyl, 4-pyrimidinyl, 2-pyrimidinyl, 4,6-dimethyl-2-pyrimidinyl, 2-pyrazinyl, 2-methyl-1,2,4-triazol-3-yl or benzothiazol-2-yl, tetrahydrofuran is used as inert solvent and the reaction is carried out at a temperature from -78 ° C to 25 ° C, and the resulting compound of formula e I, in which n · is 0, is oxidized to the corresponding compound in which n is 2 by treatment with 3-chloroperbenzoic acid or potassium permanganate. 4. The method of claim 1, wherein the starting material is a Wittig reagent of the above formula wherein one of R2 and R3 is hydrogen and the other is 2-pyridyl, 3-allyloxy-2-pyridyl, 2-pyrazinyl, 2- ^benzyl, W- ^72, 5, p IV v where m is 2 or 3, p is 0 or 1, t is 0, 1 or 2, Xi is a sulfur atom or an oxygen atom, R7 is hydrogen, C1-C4alkyl, C1-C4alkoxy, allyloxy248733 -pyrimidinyl, 3-hydroxy-2-pyridyl, 4-methoxy-2-pyridyl or 2-thiazolyl. 5. A method according to any of claims 1 to 4, characterized in that the -se starting materials are used wherein R ¹ is allyl, which are converted to the corresponding product wherein R ¹ represents hydrogen, sodium potassium, no bo, treating the resulting allyl ester product with catalytic amounts of tetrakis (triphenylphosphine) palladium (0) and triphenylphosphine, and an equimolar amount of sodium or potassium salt of 2-ethylhexanoic acid in the presence of an inert solvent.