CS248746B2 - Production method of the 6-(subst.)methylenpenicilan acids - Google Patents

Description

BACKGROUND OF THE INVENTION The present invention relates to novel 6- (substituted methylenepeniclianoic acids, their esters and pharmaceutically acceptable salts), to pharmaceutical compositions containing said compounds, to processes for their production and to their use as inhibitors / Mlaiktamiases and as intermediates for - their production.

One of the most well known classes of antibacterial agents that are widely used is the class of substances known as β-lactam antagonists. These compounds are characterized by the presence of a 2-laizeitide-4-Ooc-4-ring-containing nucleus (¢ l acetoam) ring non-fused to either thiazolidone or di-hydro-β-thio. tihiaizinoivý circle. If the core contains thiiaizolidinový ring -označují the respective compounds -General like- -peniciliny, -zatímco when the nucleus contains ^dihydrΌt'h: ial Zimová ring -označují Such compounds as cefalooporin.y. Typical examples of penicillins commonly used in clinical practice are beerylperinilcillin (penicillin G), phenoxymethylpeinicillin (penicillin V), ampicillin and canbertclinin. Typical examples of common cephalospinins are cephalinin, cephalexin, and cephalexin.

Despite the widespread use and widespread acceptance of lactic antibiotics as valuable chemotherapeutic agents, however, these substances have the major disadvantage that some of them are not effective against certain microorganisms. It is believed that in numerous cases this resistance of the respective microorganism is present. the β-lactam antibiotic, caused by the fact that the microorganism produces β-lactonase and α-lactamases are enzymes that cleave the β-actam ring of the β-c-linins and the cflosporins to formation of non-showing antibacterial activity. Some substances, however, have the ability to inhibit (lactamase), and when the inhibitor (MAC) is used in combination with -penicillin or -floapolymer, to increase the antibacterial activity of this penicillin or cephalbisporin against certain microorganisms. The increase in efficacy of the active ingredient when the antibacterial activity of the combination of an inhibitor of macitalmase and a lactam antibiotic is significantly higher than the sum of the antibacterial activities of the individual components.

Accordingly, the invention discloses novel 6- (substituted methylenepentanedioic acid), their 1,1-diol and their esters readily hydrolyzable in vivo.

These novel pen-α-lactic acids and their esters readily hydrolyzable in vivo are potent inhibitors of microbial β-lactamas. Accordingly, a method for enhancing the activity of lactam antibiotics using these novel acids, their salts and certain easily hydrolyzable esters is also disclosed.

Furthermore, the present invention provides derivatives of 6- (carbo) -tetyl-carboxylic acid-protected 6-carboxylic acids and their 1,1-dioxide, which compounds are useful as intermediates.

In European published patent application no. No. 50,805 discloses compounds of formula III

forms a three to seven-membered carbocyclic or heterocyclic ring.

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

ORR 4 -CH wherein, inter alia, R 1 represents a hydrogen atom or an alianianoyl group and R 4 represents a hydrogen atom, a (C 1 -C 4) alkyl group, a phenyl group, a benzyl group or a pyridyl group, which are useful as inhibitors -lactamases.

The present invention describes novel 6- (substituted methylenepenilicic acid derivatives) of the general formula ## STR6 ## in which n is 0, 1 or 2,

R 1 is cyano or a certain carbomyyl radical,

R2 is hydrogen, lower alkyl or 'halogen';

R 3 represents a hydrogen atom or an easily hydrolyzable group which are useful as inhibitors of ε-lactamase. The same application discloses 6-olo-o-olmcianoic acid esters, the corresponding sulfoxides and sulfoines, as well as a process for their use in the preparation of compounds of formula III by reaction with a phosphate of formula

RtRa ^^ - ^ PÍCeHsla ·

British Patent Application No. 2,053,220 AO discloses, inter alia, certain 6-methylene-1 H -dioiltopenicillanic acids and esters of formula (III) above wherein n is 2 'and R ₂ and R _{2 are} either independently of one another. in each case represent a hydrogen atom, an optionally substituted alkyl group, an aryl group, an optionally substituted cycloalkyl group, an alkyl group or an optionally substituted amino group, or both together with the carbon atom ¹ which is bonded

where n is 0 or 2,

R ¹ represents a radical R a or R ¹ ', wherein R a is a carboxyl function protecting group selected from the group consisting of tetrahydropyranyl, allyl, benzyl, 4-nitroibenzyl, benzhyldiryl, 2,2,6-trifluoromethyl, tert-butyl and a phenacytic residue and R b is a hydrogen atom or an ester residue readily in vivo selectable from the group consisting of 3-phthalidyl, 4-kirotonalakitonyl, β-butyrolacton-4-yl, a radical of formula.

-COCOR i _R j R ~ ⁶ and COCOOR '<- ^J H O) COR' ^W

Each of R ⁴ and R 5 is hydrogen or. methylovousskupiiu ,? R ⁶ represents an alkyl group having 1 to 5 carbon atoms and R ¹⁴ represents a radical of the formulas or in which:

X 2 represents a substituent at the 3-position of the known epithalosporin-type 4-akitaimic antibiotic and R 15 represents a substituent at the 6-position ^; or 7 -. known. or of the cetylisiporta type, wherein particularly preferred R ^k groups are the aforementioned peinicillin residues in which R ¹⁵ represents · 2. -phenylacetamido, 2-phenoxyacetaimido, D-2-amino-2-phenylacitamido, D-2Hamino-2- (4-hydroxyphenyl) aicetaimidloskuipine, 2-kairboxy-2-phenylacetamido, 2-kairboxy-2- (2-thieinyl) acetamido 1,2-carboxy-2- (3-thienyl) acetamido- ¹ , D-2- (4-ethyl-2H-4-iodo ⁾ -2- (2-carboxy-2- (3-thienyl) acetamide) boq D-2- (4-Ethyl-2-phenylacetamido) -2- [4-hydroxyphenyl] acetamido or 2,2-di-methyl-4-phenyl- [2,3-d] methyl] -2-phenylacetamido; 5-imidazolidmon-l- yl group, one of R ⁿ and Ri3 represents a hydrogen atom and the 'other of symboiů is a vinyl group-alkyteul foinylovou group having 1 to 4 carbon atoms, furyl, thieinylovou N-methionine ру nrol -yl or N-acetyls arolyl group, the residue

CH (R ⁴ ) NR ¹⁶ R 17,

CNR ⁸ R ⁹

AND

S /

AND

CNR8R9,

NH

8, with the proviso that when R ¹² or R ^{13 is a} radical of formula

and p is 0, then R ^{7 is} not hydrogen or methyl · in which formulas m is 2 · or 3,

P is 0 · or · 1, t is 0, 1, or 2,

Xt represents sulfur, oxygen or a radical NR ^11,

R 7 represents a hydrogen atom, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, an allyloxy group, a hydroxyl group, a carboxyl group, a C 2 -C 5 alkoxy carboinyl group, a C 1 -C 5 alkylcatonyl group, phenyl, benzyl, naphthyl, pyridyl, NR ⁸ R ⁹ , CONR ⁸ R ⁹ . NHCOR2 nitroalkyl, chlorine, bromine; trifluoromethyl or ¹ NR8 radical,

R 8a: R 9 independently; are each hydrogen, C1-C4alkyl, phenyl or benzyl,

R ¹⁹ is C 1 -C 4 alkyl, trifluoromethyl or phenyl,

R ¹¹ represents hydrogen, methyl, or ethyl group, and acetylovoiu

R16 and R17 are each independently hydrogen, C1-C4alkyl or C2-C4hydroxyalkyl, or R16 and R17 together with the nitrogen atom to which they are attached form a pyridoquino group , piperidio, morpholino, thiomorpholino or 4-methylpiperazino, and pharmaceutically acceptable acid addition salts of those compounds in which R'2 or R * 3 contain a basic nitrogen atom, or pharmaceutically acceptable cationic salts of the above compounds; wherein R 1 is hydrogen or R ¹² or R 13 contain a carboxyl group.

The above compounds wherein R ¹ is the radical R a are useful as intermediates for the preparation of those compounds wherein R ¹ is the radical R ^b . These latter compounds are potent inhibitors of the [alpha] -actamylisin of the invention;

Especially preferred are those compounds of formula I 'in which one of R2 and -from. R ³ is hydrogen and the other represents a furyl group, a thienyl group, a hydroxymethyl group, feinylovoiu group, meiil ^^^ J ^ l ^^^ lfonylovou a group, an N-methylpyrrolyol group, a residue of the formula

4 8749

Particularly preferred protecting groups karboxyloivé function value for R · R · ^and are allyl, benzyl ,, • tearc..bufylová group and 2 ', 2 ,, ^ - ^ L ^ J ^ ^ ichloire · aminobenzyl group, while particularly · the allyl group is preferred because of the relative ease of introduction and removal.

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

' ^C 2x' _r / H, r * _{1 e} R ^ _{1 c} / -CQCOR t and -cocooR II 0 R 5 R ⁵

and especially those in which R ⁴ and R ⁵ are hydrogen atoms. 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 formula I wherein R 1 is R ^b .

Furthermore, the invention provides pharmaceutical compositions for the treatment of bacterial infections in mammals, including humans, which contain an antibacterially effective amount of a compound of formula Γ wherein R ¹ is a residue R b.

Compounds of formula vzorce in which R 1 is the above-defined residue R b are useful as inhibitors of β-lactamase enzymes. In this way, the compounds increase the efficacy of the .alpha.-.alpha.-kkaim antibiotics (penicillins and cephalosporins), in particular against those microorganisms which are resistant or partially resistant to .beta.-lactoma antibiotics due to the production of enzymes (.beta.-lactamias). In this way, the spectrum of activity of the lactam antibiotics is increased.

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 penicillin or cephalosporin, in particular any of the following, and a compound of the formula ·.

Although the compounds of the invention effectively increase the activity of / Mactam antibiotics in general, they are preferably combined with penicillin or cephalosporin in clinical practice already established, such as amoxicillin, ampiciin, apalcilin, aizloclocin, aztheennam, baclaimpicillin, carbenicillin. , carbenicin-indanyl, carbeinicillin-phenyl, cefaclor, cefadroxil, cefaloram, cefatoindole ·, cefamandbl-naphiate, cefaparol, cefatirizine, cefazoline, cefbupeiiazone, cefobicide, cefménoxim, cefodizine col, cefodizin col, foxitin, cefpiramide, cefpirom, cefsutodine, cefitazazlite, iceftizoxime, cef traixone, cefuroxime, cefacetril, cefacexylin, cefidlbridtai, cefabothiin, cilcillinin, cilcillinin, cilcillinin, cefcillinin, cefcillinin, cefcillinin, cefcillinin, cefcillinin m-eciilnam, meslocillin, penicillin G, penicillin V, phenethicillin, piperacliin, pirbenicillin, pivampiciin, saT-moxicillin, sarpicillin, suncilin, talampicillin and tic.arc ilin, including pharmaceutically acceptable salts thereof.

The invention further provides a combination of the (Makitaimas) inhibitors of the present invention with 7- (2- (2-Amino-4-thiaisolyl) -2-nitro-α-amino) -3- (5,6,6,6- &lt; tb &gt; 4-Methyl-3-chloro-4-carbonylcylene, 7- ^methyl- 2- (1,2-dimethyl-4-methyl-4-carbonyl) -4-methyl-3-carboxylic acid 4-thiazolyl) 12-methyl-3-methyl-3- (N-methylpyrrolidin-4-yl) -4- (4-carboxy-5-imidiazolecarboxamido) -3- (N-methylpyrrolidinium); _1- thienyl} -3- [4- (2-sulfonatoethyl) pyridinium] -3-phenylphenyl-4'-carboxylic acid phenylation.

Although the compounds of the present invention may be administered separately from the β-lactiaimic antibiotic, combined dosage forms are preferred. The pharmaceutical composition, for oral or piarenteral administration, comprises a beta-lactamase inhibitor according to the invention and a beta-lactone antibiotic by a weight ratio of from 1: 3 to 3: 1, the total amounts of these substances in the composition sufficient to cope with bacterial infection. a mammal in a single or, more commonly, multiple administration.

The compounds of the invention wherein one of the radicals R12 and R13 contains a basic nitrogen atom may 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, mialeinic acid, fumaric acid, gluconic acid, · · sugar, benzenesulfonic acid, p-toluenesulfonic acid , p-chlorobenzenesuccinic acid, 2.alpha.-Cenuulfone (vol.

Further, plaque compounds of the invention in which R @ ¹ represents a hydrogen atom form canonical salts, and such salts with pharmaceutically acceptable cations also fall within the scope of the invention. Examples of such cationic agents include sodium, crumbly, aimonium, calcium, magnesium and zinc cations. and amine-derived lamionium cations such as diethanolamine, choline, ethylenedialmto, thainolaimine, N-methylglucamine and procaine.

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

In ilanoic acid warbler derivatives, the attachment of a dotted line substituent (IIIIII) to the bicyclic nucleus means that the substituent is below the plane of the nucleus and is said to be in the α-configuration. In contrast, the attachment of the sulbstituent to the bicyclic nucleus by a reinforced line (p *) means that the substituent is above the plane of the nucleus. This latter arrangement is referred to as the / Z-configuration. The attachment of a substituent to the bicyclic core by the normal solid line (----) herein means that the substituent may be either in the α-configuration or in the β-configuration.

The object of the invention is a process for the preparation of the compounds of the above general formula Г and their salts, characterized in that the compound of the general formula X

in which

R ¹ has the above meanings except hydrogen n is 0 or 2, is reacted with an equimolar alkylimagnesiumhlalogenidu having 1 to 4 carbon atoms in aUkylové part or an alkyllithium having one Iaz C4 carbon to the alkyl moiety, and an aldehyde of the formula R ¹² R ¹³ CO, wherein the aforementioned halide is the corresponding chloride, bromide or iodide and R ¹² and R ¹³ are as defined above, in the presence of an inert solvent at a temperature of from -100 to + 25 ° C, to form a compound of formula XI

in which

R @ ¹ , R @ ¹² , R @ ¹³ and as defined above, the compound is optionally acetylated on the free hydroxyl group with acetyl chloride, acetyl bromide or acetic anhydride in the presence of an equimolar amount of tertiary amine and in the presence of an inert organic solvent; hydrogenolyses in the presence of an inert solvent with organotin hydride or hydrogen in the presence of a noble metal catalyst, and the resulting compound of formula II

-4 O

ГГ) n / · '' 'fi Cn ·· ’

СЧ Z - ^{: í}

Π 1 I o COOR in which

R ¹ , R ¹² , R ¹³ and n are as defined above and

R @ ¹⁸ is hydrogen or acetyl, dehydrates or deacetylated, and optionally the resulting compound of formula ( ^{I) is} converted to its pharmaceutically acceptable acid addition salt or kiation salt.

The process according to the invention can be described by the following scheme:

4 8746.

Diagram

(xj РУН, ЕяО 2

(хи)

The starting esters of the general formula (X) used in the process according to the invention are known (see, for example, U.S. Pat. No. 4,234,579). Typically, the starting ester X in an inert solvent such as toluene, xylene, pentane, tetrahydrofuran, ethyl ether, or a mixture of these solvents, is contacted at low temperature with an equimolar amount of alkyl lithium. , for example -n-buityllithium, t -buityllithium or methyllithila, to form an intermediate; a penicillin lithium derivative. · This intermediate is immediately treated with an equimolar .množstvím aldehyde of formula R ¹² R ^J3 CO where R ¹² and R ¹³ are as defined above, and the mixture is coarsened 1 to 4 hours at a temperature from -100 / -50 DO- ° C, preferably at a temperature of about -78 ° C. The reaction is then interrupted and the bromohydrin intermediate of the formula is intermediated

XI is isolated, for example by shaking between water and solvent, the lath optionally purified by chromatography of the extract obtained on silica gel or magnesium silicate.

Alternatively, the above starting dibrometer of formula (X) is reacted with an equimolar amount of a low molecular weight Grigniard reagent to form the bromohydrin of formula (XI).

Bromohydrin general formula XI can then be aicetylovat give the corresponding compound of formula XII wherein ^R18 is acetyl. The acetylation is typically carried out by reacting equimolar amounts of lacetyl chloride, acetyl bromide or acetic anhydride of the intermeldian bromohydrin of formula XI and a tertiary amine such as pyridine, N-methylmorpholine and the like in the presence of an inert organic solvent, preferably methylene chloride, tetrahydrofuran or tetrahydrofuran. at or below room temperature. The desired diester of formula (XII) is then isolated by known methods, such as extraction of the bales by evaporation of the solvent, and optionally purified, for example by column chromatography.

The intermediate bromohydrin-ester of Formula XI · bromo-or diester of formula XII may be ¹ к undergo cleavage hydrogeniolyse bromine atom. The hydrogenolysis is carried out using any of a number of known reducing agents and conditions, for example by treating the bromohydrin with hydrogen in the presence of a catalyst. a noble metal base, or that the bromohydrin is subjected to a reduction with the action of certain organotyrides.

Preferred organotin hydride reducing agents are dialkyl tin dihydrides, trialkyl tin hydrides containing in each alkyl moiety. in each case 1 to 6 carbon atoms, and triaryltin hydrides in which the aryl is phenyl, optionally substituted by a nitro group or an alkyl or alkoxy group having 1 to 3 carbon atoms. Particularly preferred reducing agents are triphenyltin hydride and tri-n-butyltin hydride, the latter being particularly preferred from an economic and efficiency point of view.

The reaction using these tin hydrides is usually carried out in the presence of an inert solvent. Suitable solvents for use in the reduction of organi-tin hydrides are those which substantially dissolve the starting materials of the formulas XI or XII but do not react with the reducing agent itself. Examples of such solvents include aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene and naphthalene, and ethers such as ethyl ether, iso-propyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane.

Benzene and toluene are particularly preferred solvents for economy and efficiency.

In order to carry out the hydrogenolysis using organotin hydride reducing agents, equimolar amounts of the biroimhydrin (XI) or the briomdiester (XII) and the hybrid are theoretically required. In practice, an excess of hybrid, for example from 5 to 50% of the art, is often used to ensure complete reaction.

The hydrocigenolysis of the organotin hydrides under the preferred conditions described above takes place virtually completely without the use of a catalyst, but is, however, accelerated by the use of a source of free radicals, for example by the action of radiation. or by adding a catalytic amount of azobisisobulyro.mil or -peroxides such as benzoyl peroxide. A preferred source of free radicals for this reaction is a catalytic amount of azobisisoibutyronitrile.

Typically, the compound of formula (XI) or (XII) is dissolved in an inert solvent and the solution is added in an inert atmosphere, such as nitrogen or argon, with an appropriate amount of oirgainocyanide and optionally a free radical source such as azobisisiobutyronitrile.

The resulting mixture is then stirred at a temperature ranging from about 0 ° C to the boiling point of the solvent. The reaction is - usually - completed in a few minutes to several hours, for example at a time ranging from 5 minutes (when operating at a boiling point of benzene) to about 20 hours (when operating at 0- ° C) ). The product of formula (II) is then isolated by methods known in the art, for example by evaporation of the solvent and chromatography of the residue on silica gel.

It has been found that the compounds of formula (II) formed by the above-described organiocin hydride debromfation are predominantly the β-isomers, i.e. substances in which the 6-R 12 R 13 'C (OR 18) substituent is in the /-configuration.

If the hydrogenation reaction is carried out by the action of hydrogen in the presence of a noble metal catalyst, the solution of the compound of formula (XI) or (XII) is expediently stirred or shaken under an atmosphere of hydrogen or a mixture of hydrogen and an inert diluent. nitrogen or argon, in the presence of a noble metal hydrogenolysis catalyst, suitable solvents for this hydrogenolytic reaction are those which substantially dissolve the starting material of formula XI or XII, but themselves hydrogenic or hydrogenolysis not subject. Těchto- Examples of solvents include ethers, such as' ethyl ether, tetrahydrofurane, 1,2-dioxane-a- dimeHhoxyethan esters, low molecular -Weight, IIIh ^^ about ¹ ethyl acetate, butyl a-, -tertiary amides such as N, N-dimethylformamide, Ν, Ν-dHmethylationtthymide, and N-methylpyrrolidione, water and mixtures thereof. Further, it is often desirable to buffer the reaction mixture so that the reaction proceeds at a pH of from about 4 to about 9, preferably about 6 to about 8. For this purpose, boron-ammonium, bicarbonate, and usually phosphate buffers. The introduction of gaseous hydrogen gas. Typically, the pressure of the reaction medium is such that the reaction is carried out in a closed vessel containing a compound of formula XI or XII, a solvent, a catalyst and hydrogen.

The pressure inside the container can be about 0.1 to 10 MPa. The preferred pressure range when the atmosphere inside the reaction vessel is substantially pure hydrogen is from about 0.2 to 5 bar. Hydrogenolysis is generally carried out at a temperature of from about 0 ° C to about 60 ° C, preferably from about 25 ° C to about 50 ° C. Using the preferred reaction temperatures and pressures, the hydrogenolysis generally takes several hours, for example about 2 to 20 hours. Preferred noble metal base catalysts used for this hydrogenolytic reaction are reagents known in the art. for this kind of transformations, for example nickel, palladium, platinum and rhodium catalysts. Palladium is particularly preferred in this respect. The catalyst is usually used in an amount of from about 0.01 to 25% by weight, preferably from about 0.1 to 10% by weight, based on the compound of formula XI. It is often expedient to apply the catalyst to the catalyst. inert carrier. A particularly preferred catalyst is palladium (II). Inert carriers such as carbon.

After practically complete hydrogenolysis, the desired product of formula (II) is then isolated by standard methods, for example by filtering off the catalyst and evaporating the solvent, and then optionally purified in a known manner, such as by crystallization by net chromatography.

If the starting material of formula XI or XII benzylésteir (R = R ¹ = benzyl) as described above may, when catalytic hydrogenolysis also occur to cleave the benzyl group and give the product specification of the formula II 'wherein R ¹ is hydrogen.

The 6- (Subsrt. Jhydroolecylhexylic acid or ester of formula (XII) or (II) wherein n is 0 may be oxidized using any of the methods known for converting sulfides to sulfones, for example using 3-chloroperbenzoic acid. However, a preferred method for obtaining sulfones of formula XI, XII or II is to use the corresponding 6,6-dibromo-1,1-dioxope. nicilianate of formula (X) wherein n has a value of 22 as the starting material in the process of the invention.

Oxidation of sulfides to sulfones can be accomplished using any of a wide variety of oxidizing agents known in the art for oxidizing suifoxides to. sultans. Particularly preferred agents of this kind are metal permanganates, such as alkaline permanganates. and alkaline earth metal permanganates, and organic peroxyalkanes, such as ^: organic peroxycarboxylic acids. Suitable individual agents are sodium permanganate, potassium permanganate, 3-chloroperbenzoic acid and peracetic acid.

An especially preferred class of oxidizing agents are organic acids Perek being preferred · organic peroxyacid is 3-chloro ^l orperbenzoová acid.

The alcohol of formula (II) is then dehydrated to give the corresponding 6- (subst.) Methylene-1,1-dioxopenicilate (II). Although a variety of methods known in the art for dehydrating secondary alcohols to olefins can be used to carry out this reaction step, the preferred method is to convert the alcohol by reacting with at least equimolar amounts of tertiary hydrochloride and pyridine on acetate, and Following stirring at room temperature for 1 to 10 hours to produce a large amount of the desired olefin. Water is usually added to the reaction mixture and the desired product is isolated by extraction and purified if necessary.

The products of formula (II) or (získané) obtained as described above are usually esters in which R ¹ is either a carboxyl function protecting group R ^a as defined above or an ester residue readily hydrolyzable in vivo R b, also defined above. Those esters wherein R1 is a residue R ^a, · optionally converted to acid .odpovídající kairboxyloivé · (b - hydrogen). If desired, however, the carboxylic acids of formulas (II) and (Γ) may be converted to the corresponding compounds in which R 1 represents an ester moiety readily hydrolyzable in vivo.

Thus, the ester of formula II · or nebo (R ¹ = = R ^a ), where R ^a represents the carboxyl group of the carboxyl-box function defined above, can be converted to. the corresponding acid or ester of formula (II) or (R 1 -R b) wherein R b is a hydrogen atom or an ester-forming moiety hydrolyzable in vivo. Typically, the carboxy function protecting group is removed from the compound (formula II) inejboo (R L = R a) to give the corresponding carboxylic acid. however, the method will not cause problems for those skilled in the art.

As noted above, a particularly preferred protecting group for the carboxyl function is R ^{and the} allyl group. Although this group can be cleaved off with mild acid by net alkaline hydrolysis to a satisfactory result, a particularly preferred method for cleavage consists in the use of a soluble β 1 -adium (O) complex, namely tetrakis triphenylphosphine pytata (O) as a catalyst.

This method has already been described by Jeffery and McCombie · in J. Oirg. Chem., 47, 587-590 (198-2). According to a typical embodiment of this method, the α-ethyl ester in an inert solvent, for example ethylene dichloride, chloroform or ethyl acetate, is mixed with a catalytic amount of tert-butyl ester (Γfr ^: phenolphenol). For example, about 1 to 5% molar of this complex, based on the allyl ester, and about an equivalent amount by weight of triphenylphosphine. To this mixture is added the sodium salt of 2-ethylhexanoate potassium in equimolar amounts relative to the starting allyl ester, and the resulting mixture is stirred at room temperature until precipitation of the desired salt is complete, for example the salt of formula Γ 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.

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

Compounds of formula (II) or (R ⁾ wherein R ¹ is an ester-forming moiety readily hydrolysable in vivo can be prepared directly from the corresponding compounds wherein R ¹ is hydrogen atom using conventional esiterification 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-crotonolactionylo radical, a χ-butyirolacton-4-yl radical and a radical of the formulas

R ⁴ —COCOR ⁶

AND

R ⁵ where

R4

I —COCOOR ^fi

AND

R5

R ^b Q i.e. 3-phthalidyl halide, 4-crotonol-aiktanyl halide, γ-buityrolacton-4-ylihalide or a compound of the general formula

R ⁴

QC0C0R ⁶ p or l _p

R ⁵

Λ

R ¹ 6 QCOCOOR

R ^S where

Q represents a halogen atom <a

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 pressure such that a salt of a compound of formula II or Г in which R ¹ is a hydrogen atom is dissolved in a suitable polar organic solvent, for example in N, N-dimethylformamide, and about one molar equivalent of the appropriate halo! du formula R ^b Q After virtually complete reaction the product is isolated by standard technikiaimi. 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 lamina salts such as triethylamine, N-ethylpiperiidine, Ν, dim-dimethylaniltoein and N-methylmorpholine, and quaternary ammonium salts such as tetrabutylaimoinium and tetraimethylammonium salts . The reaction is carried out at a temperature in the range of about 0 to 100 ° C, usually at about 25 ° C. The reaction time required to complete the reaction varies depending on a number of factors such as the design of the reactants and the reactivity of the reagents. The platicide pressure is a halogen derivative, iodide reacts faster than bromide and reacts ¹ faster than chloride. When using the chloro derivate, it is sometimes advantageous in practice to add up to one molequant of the alkali metal iodide, thereby quenching the reaction. In view of the above factors, reaction times of about 1 to 24 hours are generally used.

The starting aldehydes of formula R12R13QQ wh _e R12 _and R13 _IMA her · abovementioned meanings, are either commercially available or can Jei readily prepared from available starting materials by methods known in the art, for example:

1. Oxidation of the corresponding primary alcohols described above as necessary pre-curing of Wiitig reagents using, for example, oxidizing agents such as potassium bicarbonate, a mixture of chromic acid and pyridine, catalytic oxidation in the presence of noble metals, and Maingan oxide.

2. Reaction of the corresponding methyl-substituted aromatic hydrocarbon with, for example, selenium dioxide.

3. Reduction of the corresponding C 1 to C 4 alkoxy / ribonyl derivatives in the alkoxy portion of the metal hydride at low temperature in the presence of an ether solvent. Examples of suitable metal hydrides are lithium malimine hydride and diisobutylaluminum hydride.

4. Reaction of the respective aromatic hydrocarbon precursor with n-butyllithium and dimethylformamide.

As mentioned above, the compounds of formula (Γ), - where R 1 is a hydrogen atom, and Ia salts thereof, in combination with β-lactam antibiotics, have synergistic efficacy in the in vitro antibiotic tests. This efficacy is demonstrated by measuring the minimum inhibitory concentrations (MICs) in µg / ml against a number of microorganisms. The following section describes the procedure recommended by the Internailiniaiil Collaborative Study on Antibiotic Sensitivity Testing [Ericcson and Sheirrls, Acta, Plato · logica et Mloroblologia Sandinav, Supp. 217, section B: 64-68 (1971)] using brain-enriched agar. and the heart, and a device allowing repeated inoculation. Culture grown overnight in test tubes. It is used as a standard inoculum (20 -000 · - 10 - 000 cells in approx. 0.002 ml. applied to the surface of the agar; each dish contains 20 ml of agar with brain and heart infusion). 12-fold dilutions of the test substance are used, with an initial test compound concentration of 200 (4g / ml) when evaluated after incubation for 15 hours at 37 ° C, with no individual colonies taken into account. the lowest concentration of test compound or combination of compounds capable of causing complete inhibition of the growth of the organism when evaluated with the naked eye.

Those compounds of formula wherein R ¹ is hydrogen, and salts thereof, in combination with known -S-lactam antibiotics are useful as industrial antimicrobial agents, for example, in water treatment, waste treatment water and sludge, paint and wood protection, also in local applications as disinfectants. When using the compounds described for these 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, these compounds 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 of the total composition.

As already mentioned above, the compounds of the general formula Γ in which R 1 is the radical R b are much more important as potent inhibitors of microbial S-lactamias. In this way, these substances increase the aunibaicterial activity of β-lactam antibiotics (penicillins and -cephalosporanes) against numerous micro-organisms, in particular against S-lactamase-producing microorganisms.

The ability of the compounds to increase the efficacy of the β-lanaimine antibiotics can be demonstrated by experiments in which the MIC values of the antibiotic alone and the compound of the formula I, wherein R 1 is a hydrogen atom, are determined. these values are compared to the MIC values found for the combination of the antibiotic with a compound of formula I, wherein R 1 is a known hydrogen atom. - If the - antibacterial - efficacy of this - - - combination - is - considerably - higher than would be expected, on the basis of the efficacy of the individual components, it is considered to be. increase efficiency. The MIC values of the combinations are measured using the method described by Biiary and Sabath in "Ma.nual - of - Clinical Microbiology", ed. Lenette, Spauilding and - - Tnuarnit, 2nd edition, 1974, American Society - for Microbiology.

The compounds of the formula kde, - wherein - R 1 represents a hydrogen atom or an ester moiety - - readily - hydriblysible - in vivo, enhance the antibaiciteirial activity of the S-lactam antibiotics, i.e. they - suffer from - the amount of antibiotic required for protection of the experimental - mouse - over-the-deadly-inoculum of a certain β-lactamase-producing bacterium. In determining such efficacy, - in - - mice - intnaperitoneal - by inoculation with a standardized kuh ton of the test organism suspended in 5% of the gastric mass - pig - induces - an acute experimental - infection. - The severity of the infection is - standardized - so that the mouse - receives a lethal dose of the organism - (a lethal dose is understood - the minimum inoculum of the organism - - needed - - to - reliably - - to kill 100 - -% of infected untreated control mice).

Groups of infected mice are then administered orally-or into the aperture-inoine in various high doses of the test compound in combination with an antibiotic. Upon completion of the -test, the efficacy of this combination is determined by counting the surviving animals in the -treated-dose-combination group. Efficacy - is expressed as a percentage of - surviving animals - at a given dose - or is calculated as - value - PD 50 (dose - protecting 50 ·% of the test animals from - infection).

The ability of the compounds of the invention to enhance the efficacy of iMaiktam -antibiotics against β-lactamase-producing bacteria makes these compounds suitable for co-administration with S-li ₍ kI and a). The antibiotic may be admixed with a S-lactam antibiotic for the treatment of bacterial infections in humans, in particular humans. when R b is - CH (R ⁴ ) OCOR ¹⁴ - wherein R ⁴ and R 14 are as defined above, the β-lactam antibiotic is chemically bound to the compound of the invention Alternatively, the compound of the invention may be administered as a separate agent during treatment with the .alpha.-laictam lantiibloitic.

In some cases, it is advantageous to premedicate the patient with the compound of the invention before initiating treatment with the S-lactam antibiotic ern.

When a compound of formula (I ') is used, in which R1 represents a radical as defined above - R @ ^b - to increase the efficiency of the lactam248746 of its carbonyl titanium, a mixture of this compound with The compound of the invention, when R b is a CH 2 (R 4) OCOR ¹⁴ moiety, is preferably administered in the form of a composition comprising standard pharmaceutical carriers or diluents. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, an alpha lactamide, and / or the above compound of the invention normally contains about 5 to 80% by weight of a pharmaceutically acceptable diluent.

When the compounds of the present invention are combined with another .beta.-lactam antibiotic, the compounds may be administered orally or parenterally, i.e. by intramuscular, subcutaneous, or intraperialionic routes. Although used in human medicine is ultimately determined by the attending physician, normally the ratio of the daily doses of the compound of formula Γ, wherein R 1 is the radical of Rb and β-lactam antibiotic, is in the weight range of about 1: 3 to 3: 1. Further, for a compound of the invention in combination with a β-lactitic antibiotic, the daily oral dose for each component normally ranges from about 10 to 200 milligrams per kilogram of body weight, and the daily dose of each component is normally normal when administered pareinterly ¹ . ranges from about 10 to about 40 mg / kg body weight. These daily doses are usually administered in several doses. subdoses. In some cases, the treating physician may prescribe doses outside these limits, if necessary.

It is understood that some / Mactam compounds are effective when administered orally or parenterally, while others are only effective when administered parenterally. Thus, if the compound is. according to the invention to be used simultaneously (ie in a mixture) with a β-lactam anitibiotics effective only for parenteral administration, it will be necessary to prepare (a combination preparation suitable for parenteral administration). Compounds suitable for oral or parenteral administration may be prepared with a β-lactam antibiotic effective for both oral and parenteral administration, and compositions containing the active compounds of the invention may be orally administered and parenterally administered. of the invention and at the same time orally administering a β-1H-tamic antibiotic.

The invention is illustrated by the following examples, which are not intended to limit the scope of the invention in any way. Proton and C ¹³ nuclear .magnetická resonance spectra in the examples were measured at 60, 90, 250 or 300 MHz using the product solution in deuterochllorofonmui, deuteriurnoxidu, or perdeutenoacetonu DMSOd and peak positions are expressed in ppm estrous .oproti tetramethylsilane. The signal shapes are marked with the following abbreviations:

-s · singlet d doublet dd doublet of doublets t triplet q quartet rn multiplet w wide signal.

Example 1

Benzyl 6- (2-pyridyl) hydroxymethylene foamilate

A. Benzyl-6-bromo-6- (η 2 -pyridyl) hydroxylmethyl, ni.c.

A solution of 9.0 g (00-2 mol) of benzyl 6,6-dibnomo-penicilate in 200 ml of freshly distilled toluene is cooled to -78 ° C and added dropwise thereto with 9 ml of 2.2 M teq. Buityl III-pentane. The resulting mixture was stirred for 30 minutes, then 2.14 g (0.02 mol) of 2-pyridiinecarboxaldehyde was added and stirring was continued for 40 minutes. The reaction is quenched by the dropwise addition of acetic acid in toluene to the reaction mixture, after stirring for 30 minutes. The mixture was warmed to -10 ° C, diluted with 200 ml of toluene, washed five times with water and dried over sodium sulfate. The toluene solution was applied to a column of 1 kg of Florisil adsorbent and the column was eluted with toluene / ethyl acetate (2: 1). The combined solutions were evaporated and evaporated. under vacuum. 4.2 g were used in the next step.

B. 4.2 g of the brown syrup product of Part A were dissolved in 50 ml of benzene and 2.65 g of tributyltin hydride was added to the solution. The mixture was heated at reflux for 2 hours, then added

1.65 g of tert-butyl tin ethyltaide and refluxed overnight. The solvent was evaporated in vacuo, the residue was washed with hexane and applied to a column of 500 g of silica gel. Elution with 2: 1 toluene: ethyl acetate gave 425 mg of the title compound.

1 H-NMR (CDCl 3, δ ppm):

1.35 (s, 3H);

1.7 (s, 3H); 4.0 (dd, 1H);

4.5 (s, 1 H),

5.1 (s. 2H);

5.2 (d, 1 H,

5.4 (d, 1H); 7.0-7.8 (m, 3H);

8.5 (m. 1H).

Example 2 1,1-Diioxide-6- (2-pyridyl) hydroxymethylpeinicillanic acid

A. Benzyl 6- (2-pyridyl) hydroxymethyl-1,1-dioxopenicilainate

To a solution of 0.40 g of benzyl 6- (2-pyridyl) hydroxymethylpenicilate in 5 ml of methylene chloride was added 0.20 g of m-chloroperbenzoic acid and the mixture was stirred at room temperature for 1 h. According to thin film chromatography, the reaction mixture contains some sulfoxide. An additional 0.2 g of m-chloro per benzoic 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 chromatography on a silica gel column. Elution with 11: 9 ethyl acetate / hexane gave 60 mg of a yellow oil.

¹ H-NMR (deutenochloroform, δ values in ppmi):

1.25 (s, 3H).

1.5-2 (s, 3H),

4.1 (dd, 1 H),

4.5 (s, 1 H),

4.72 (d, IH);

5.5 (d, 2H).

5.8 (d, 1H),

7.1 - 8.0 (ni, 311),

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 for ¹ předhydrogeniovává 20 minutes under a hydrogen pressure of ¹ to 0.3 MPa. 130 mg of the benzyl ester prepared in Part A above in 4 ml of the same mixture of tetrahydrofuran and water are added to the resulting suspension. The mixture was hydrogenated at 50 psi for 30 minutes, an additional 129 µg of 10% palladium on was added. coal and hydrogenation at 50 psi were continued for 2 hours. The catalyst is filtered off, the solvents are evaporated off under vacuum and the residue is partitioned between water and ethyl acetate. Lyophilization of the aqueous layer gave 85 mg of the desired acid.

¹ H-NMR (deuitewiumoxide, δ in ppm):

1.3 (is, 3H),

1.5 (s. 3H),

4.4 (s. 1H).

5.0 - 5.35 (m, 2H),

5.9 (d, 1 H).

IR (KBr):

620, 1731, 3,407 cm ^-1 .

Example 3

Alyl-S (E) - (N-acetylpyrrol-2-yl) methylene-1,1-diioxopenicilainate

A. Allyl-6- (N-acetylpynrol-2-yl) thiazolio-thioxy-1,1-diox-openic illanate

210 mg (0.51 carniol) allyl 6- (N-acetylpyrrol-2-yl) hydroxymethyl-1,1-dioxiopeinicilainate are dissolved in 3 ml of tetrahydrofuran, 0.16 ml of acetic anhydride and 0.2 ml of pyridine are added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with water, extracted with methylene chloride, the extracts dried and basified. 171 mg (75%) of a yellow crystalline product are obtained.

⁴ H-NMR (δ in ppm):

1.4 (s. 3H),

1.6 (s, 3H);

2.15 (s, 3H).

2.55 (s, 3H);

4.15-4.3 (dd, 1H),

4.4 (s. 1H).

4.6—14.8 (m, 3Ή),

5.1 - 6.0 (im, 3H),

6.1-6.6 (m, 2H);

6.6-7.4 (im, 2H).

B. 170 mg (0.38 mmol) of Ν, diac-diacetate prepared! in part A was dissolved in methylene chloride and 47 mg (0.38 mimioil) of 1,5-diazabicyclo [4.3.0] non-5-ene was added to the solution.

The resulting mixture was stirred at room temperature for 1 h, then water was added and the mixture was extracted with methylene chloride. The extracts are dried and concentrated. 158 mg of an oil are obtained which, after purification by chromatography on silica gel with 2% ethyl acetate in chloroform, affords 108 mg of the desired product as a pale yellow oil.

‘H-NMR (CDCl 3, δ ppm):

1.5 (s. 3H),

1.6 (is, 3H); 2.55 (s, 3H);

4.4 (s, 1 H),

4.65 (d, 2 H),

5.0-6.0 (m, 4H),

6.3 (t, 1 H),

6.8 (dd, 1Ή),

7.2 (m, 1 H),

8.2 (d, 1 H).

240746

Example 4

Allyl-6 (E) -phenylmethyl-1,1-dioxopenicillanate and the corresponding (Z) -isomer

A. Using the procedure of Part A of the foregoing example, using 1.98 µm! allyl-6-phenylhydroxymethyl-1,1-dioxopemcianate, 4.2 mole of acetylchtarisde and 0.4 ml of pyridine gave 0.7 g (84%) of allyl-6-phenylacetoxymethyl-1,1-dioxo-penicillanate as a yellowish gum.

^f H-NMR (CDCl3, δ ppm):

1.3 and 1.4 (s, 3H),

1.62 (s, 3H);

2.08 and 2.2 (s, 3H),

4.2 (dd, 1 H),

4.4 (s. 1H).

4.5 (d, 1 H),

4.65 (d, 2 H),

6.25 (m, IH);

7.3 (m. 5H).

B. To a solution of 0.7 g (1.66 mmol) of the product prepared above in Part A in methylene chloride is added ^. 0.25 ml (1.67 mmol) of 1,5-diaza-bicyclo [5.4.0] undec-5-ene was added and the mixture was stirred at room temperature for 10 minutes. After adding water and the methylene chloride layers were separated, the organic extracts were washed 0, lN HCl, and brine, praying, dried over, sodium sulphate ¹ and the solvent evaporated. 660 mg of crude product are obtained, which is purified by chromatography on a 100 g silica gel column using chloroform as the eluent. 68 mg (11%) of the corresponding (Z) -isomer were obtained.

¹ H-NMR (CDCl 3, <5 ppm):

1.45 (s. 3H);

1.60 (s, 3H);

4.45 (s, 1 H),

4.68 (d, 2 H),

5.37 (id, 1H),

5.1-6.05 (m, 3H);

7.35 (d, IH);

7.45 (d, IH).

From the later eluted fractions, 100 mg (16.7%) of the (E) -isoisoimeir title compound was obtained as a colorless oil which crystallized on standing.

¹ H-NMR (dio-chloroformium, δ values in ppm):

1.4 (s, 3H),

1.58 (s, 3H);

4.45 (s, 1 H),

4.75 (d, 2 H),

5.45 (d. 1H);

5.2-6.2 (m, 1H),

7.36 (d, IH);

7.45 (s, 5H).

Example 5

A. Aillyl-6-bnoim-6- (2-metaolyl) hydroxymethyl-1,1-dioxiopenicilate

A solution of 8.84 g (20 mmol) of allyl 6,6-dibromo-1,1,1-dioxo-penticilainate in 100 ml of dry tetrahydrofuran was cooled to -78 ° C and treated with 7.0 ml (20 mmol) of meithylmagnesium bromide, a mixture of After stirring for 5 minutes, a solution of 2.26 g (20 mmol) of thtazole-2-carboixaldehyde in 10 ml of the same solvent was added dropwise at -78 ° C, and the resulting mixture was stirred for 20 minutes. After addition of 1.2 ml of acetic acid, the reaction mixture was poured into water and extracted with ethyl acetate and chloroform. The combined organic layers were dried over sodium sulfate and ¹ solvent evaporated in vacuo. 8.5 g of crude product are obtained in the form of a glassy mass.

This crude glassy material was purified by ¹ column chromatography on silica gel using chloroform / ethyl acetate (89: 11) as eluent.

6.2 g (72%) of pure product which was ideinitificin as the only isomer.

* H-NMR (CDCl3, δ ppm):

1.4 (is, 3H)

1.6 (s, 3H).

4.0 (bs, 1H),

4.42 (is, 1H);

4.6 (d, 2H).

5.3 (s. 1H).

5.55 (s, 1 H),

5.1-6.3 (m, 3H);

7.35 (d, IH);

7.75 (d, IH).

B. Benzyl-6-thromo-6- (2-thiazolyl) hydroxymethyl-1,1-diioxopenicillanate

The above procedure was repeated using benzyl 6,6-dihromo-1,1-dioxopeniciliainate instead of the allyl ester. The title compound is obtained in quantitative yield as an orange-colored foam.

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

1.32 (1H, 3H),

1.60 (mS, 3H),

4.5 (s. 2H);

5.2-5.8 (m, 4H);

7.3 (d. 1H).

7.4 (s. 5H);

7.8 (d, 1 H).

C. The following compounds are prepared in an analogous manner to Part A:

R ^and benisyl benzyl benzyl allyl

R13

yield (%) ⁽¹ H-NMR (CDCl 3, δ 8 ppm)) 10Q (yellow foam) 1.25 (s, 3H). 1.54 (s, 3H); 4.5 (s, 1 H), 5.02 (s, 2H); 5.43 (s, 1 H), 5.68 (s, 1 H), 7.32 (m, 7H). 8.00 (m, 2H), 88 (yellow solid product) 1.4 (3s, 3H), 1.6 (β, 3H) 4.0 (s, 1 H), 4.9 (2s, 1 H), 5.18 (m, 2H); 5.5-5.8 (m. 2H); 7.5 (s. 5H); 8.0 and 8.5 (2s, 1H), 100 ALIGN! 1.25 (is, 3H); 1.52 (s. 3H); 4.45 (s, 0.75H), 4.52 (s, 0.25 °), 5.1-5.4 (m, 4H), 7.3 (s, 5H). 8.6 (m, 2H). 9.0 (m, 1 H), 38 1.38 (s, 1H), 1.60 (s, 3H), 4.38-4.73 (m, 3H), 5.0-6.0 (m, 5H), 7.10 (s, 1 H), 8.51 (s, 1H).

Example 1 a d 6

A. Acylation of the compounds obtained in the previous example, using the procedure described in Example 3, was prepared in a similar manner as follows:

A. When R ^a is allyl and R ¹⁸ is CH ₃ CO

R13 Yield (%)

2-thiazolyl (colorless crystals)

(+ 21% isomeric producti) • 1 H-NMR (deuterochloroform, δ in ppm)

1.4 (is, 3H); 1.6 (s, 3H);

2.25 (s, 3H); 4.45 (s, 1H).

4.65 (m, 2H), 5.4 (s, 1H), 5.2-6.3 (m, 3Ή), 6.7 (s, 1H),

7.4 (d, 1H), 7.8 (d, 1H), ¹³ C-NMR (ideo-quintoinophore, halide <5 in ppm):

18.4, 19.8, 20.4, 60.7, 63.1, 64.4,

66.5, 66.9, 73.3, 120.3, 120.4,

130.6, 143.6, 163.7, 165.5, 166.2,

168.6,

1.40 (s, 3H), 1.60 (s, 3H),

2.26 (s, 3H); 4.48-4.70 (m, 3H);

5.2-6.2 (m, 5H);

6.92 (s, 1 H), 8.83 (s, 1 H),

B. When R ^a is benzyl and R ¹⁸ is CH ₃ CO

2-thiaisolyil

100 (9: 1 glassy isolmer mixture)

N — N

100 (yellow-orange foam)

1.25 (s, 3H), 1.55 (s, 3H),

4.50 (s, 0.9H), 4.55 (s, 0.1H),

5.2 (m, 2H), 5.40 (br, 0.9H),

5.57 (s, 0.1H), 6.42 (s, O, 1H),

6.60 (s, 0.9H), 7.3 (m, 6H),

7.75 (d, 1 H),

1.3 (s, 3H), 1.52 (s, 3H),

2.25 (s, 3H), 4.54 (s, 1H), 5.02 (s, 2H), 5.52 (s, 1H),

6.8 (s, 1H); 7.3 (m. 7H);

7.9 (m, 2H).

1.25 (is, 3H), 1.5 s, 3H),

2.19 (s, 3H), 3.95 (s, 3H),

4.4 (s, 1H), 5.15 (s, 2H),

5.45 (s, 1H); 6.3 (s, 1H);

7.35 (s, 5H); 7.73 (s, 1H);

1.25 (s, 2.05 H), 1.35 (s, 0.75H), (3: 1 mixture of isomers) 1.4 (s, 2.25H), 1.42 (s, O , 75H),

2.2 (s, 2.25H), 2.4 (s, 0.75H), 4.45 (s, 0.75H), 4.55 (s, 0.25H),

5.1-5.3 (m. 2H);

5.3 (s, 0.75H), 5.6 (s, 0.25H), 6.25 (s, 0.25H), 6.4 (s, 0, 75H),

7.3 (s, 5H), 8.67 (m, 2H), 9.67 (s, 1H).

32

C. Alternatively, the compounds of the above formula are prepared by a reaction mixture prior to isolation of the product as follows:

To a solution of 1.0 equivalent of 6,6-dibromipenicillanic acid ester in tetrahydrofuran at -78 ° C was added 1.3 equivalents of methylmaginesium bromide (dissolved in stearate) solvent and stirred for 5-10 minutes. At a temperature between -78

When R18 is CH3CO degrees Celsius and -68 ° C, 1.3 equivalents of the appropriate aldehyde (R ¹³ CHO) in the same solvent is added and the reaction mixture is stirred for 30-60 minutes. After the addition of 1.3 equivalents of acetylchloride, stirring at -78 ° C is continued for 10 more minutes, then the reaction product is isolated by pouring the mixture into ice water, extracting with ethyl acetate, drying the extract. -and · evaporating · the solvent under vacuum.

R ^a R ¹³ benzyl C6H5 allyl you allyl GO benzyl l-Ts benzyl AND N_ = J benzyl 0 CH ₃ allyl A NN u> ^H 3

Yield (!%) 1 H-NMR (deuterochloroform, values in ppm) 100 ALIGN! light yellow foam 77 (yellow oil) 1.35 (s, 3H), 1.56 (s, 3H), 2.22 (s, 3H), 4.42 (s, 1H), 4.60-4.74 (m, 2H), 5.24-5.42 (m, 3H), 5.79-5, 96 (m, 1 H), 6.52 (s, 1 H), 8.70-8.74 (d, IH) ID: 1 810, 1 · 760 · c ^ - ‘ 59 (yellow ole j) 1.42 (s, 3H), 1.62 (s, 3H), 2.28 (s, 3H), 2.48 (s, 3H), 4.5 (s, 1HJ, 4.6-4, Δ (m, 2H), 5.28-5.47 (m, 2H), 5.82-6.0 (m, 1H), 6.3 (s, 1H), 6.97 (s, 1H) IR: 1 · 810, 1760, 1730 cm. ^-1 59 1.6 (s, 3H); 1.8 (s, 3H); 2.2 (s, 3H), 2.3 (s, 6H), 4.4 (s, 1H); 5.2 (d, 2H); 5.3 (s, 1H); 6.4 (d, 1H); 7.3 (s. 5H); 22nd 1.22 (s, 3H), 1.5 (, s, 3H), 2.18 (s, 3H), 2.42 (s, 3H), 4.5 (s, 1H); 5.16-5.36 (m, 3H); 6.18 (s, 1 H), 6.48 (s, 1 H), 7.4 (s, 5H). 44 (yellow mousse.) 1.26 (s, 3H), 1.5 (s, 3H), 2.2 (s, 3H); 2.4 (s, 3H); 4.4 (s, 1H); 5.16 (d, 2H); 5.3 (s, 1H); 6.6 (s, 1H); 6.8 (s, 1H); 7.3 (s, 5H);

1.40 (s, 3H), 1.60 (s, 3H), (foam) 2.27 (s, 3b), 2.65 (1S, 3H),

4.20-4.8 (m, 3H);

5.1-6.2 (m, 4H);

6.41 (s, 1H).

IR: 1815, 1760 cm -1

Example 7

А. Bemzyl-trans-(thiazol-2-yl) acetoxymethyl-1,1-dioxopenicillanate is suspended in a mixture of ethyl ether and ethyl acetate (4: 1), the suspension is filtered and the residue on the filter is washed with ether. 22.6 g of white solid are obtained.

To a solution of 74.6 g (134 mmol) of benzyl-6-benzo-6- (thiazol-2-yl) acetoxynyl-1,1-dioxopeiniciliainite in 850 ml of benzene is added

43.99 g (151.2 mmol) of tri-n-butyl tin hydride. The mixture was heated under reflux for 5.5 hours and then allowed to stand overnight. The solvent is evaporated in vacuo, the residue is taken up in hexane and the solution is extracted twice with 250 ml of acetonitrile each time. The acetonitrile layer is evaporated, the residue is stirred in ethyl ether, the suspension is filtered and the filter cake is washed with ether. 33.28 g of colorless crystals are obtained. An additional 2.8 grams of product is obtained after evaporation of the filtrate to dryness. The residue is taken up in benzene and after addition of 10 g of tri-n-butyltin hydride, it is refluxed for 1 hour. The reaction mixture is treated as in the first crop. The total yield of the product was 56.3%.

The first crop of the above product was purified by silica gel column chromatography using a 9: 1 mixture of chloroform and ethyl acetate as eluent. Fractions containing product were concentrated, the residue ^X H-NMR, (CDCl₃) in ppm:

1.25 (s, 3H).

1.53 (s, 3H);

2.1 (s. 3H),

4.58 (s, 1 H),

4.80 (d, IH);

5.2 (dd, 1 H),

5.22 (quartet, 2H),

6.75 (d, IH);

7.35 (s, 5H),

7.4 (d, 1 H),

7.8 (d, 1 H).

¹³ C-NMR (CDCl3):

17.7, 19.9, 20.5, 54.5, 63.06, 63.6, 63.8, 64.5,

68.1, 121.8, 128.8, 128.9, 134.3, 142.6, 164.6,

166.5, 169.2, 170.5.

B. By analogy to debromination of the other compounds of Example 6, the following products were obtained:

OCCCH ₃ \ /

R * - CH ₃ ^CH 3 COOR ^a

R ^a

R ¹³ yield

C%) ^£ H-NMR (CDCl in ppm) benzyl benzyl benzyl ¹

1.3 (s, 3H), 1.55 (s, 3H),

2.19 (s, 3H); 4.5 (s, 1H);

4.79 (d, 1H); 5.2 (g, 3H);

6.79 (Id, 1H); 7.32 (m, 7H);

7.9 (m. 2H)

1.29 (s, 3H), 1.55 (s, 3H),

2.10 (s, 3H), 4.03 (s, 3H),

4.5 (s, 1H); 4.78 (d, 1H);

4.87 (dd, IH),

5.25 (quartet, 2H),

6.53 (d, 1H); 7.38 (s, 5H);

7.89 (s, 1 H),

1.3 (s, 3H), 1.55 (s, 3H), (yellow solid 4.45 (s, 1H), 4.6-5.1 (m, 2H), product) 5.2 (m (2H), 6.6 (did, 1H),

7.35 (s, 5H); 8.6 (m. 2H);

8.83 (m, IH)

@ 1 H-NMR (CDCl3) .delta.

R ^a

R13 yield (%) iallyl allyl

(oil) 44 (s, 3H), 1.62 (s, 3H), 2.10 (s, 3H), 4.51 (s, 1H), 4.60-4.80 (m, 2H) ], 4.89-4.91 (d, 1H), 5.26-5.42 (m, 3H), 5.86-5.99 (m, 1H), 6.88-6.92 (d (1H),

8.82 (s, 1 H),

IC: 1,795, 1,750 cm * ¹ more polar isomer:

'allyl

(more polar) + 5.84—6.00 ·. (m, 1H), 6.28-6.42. (m, 2H), 6.62-2.77 (d, 1H), 7.38-7.48 (d, 1H), 8.64-8.70 (d, 1H), white crystalline product; IC (KBr technology):

807, 1760 cm @ -1, + 11 (less polar) (yellow oil) benzyl benzyl

1.46 (s, 3H), 1.64 (s, 3H),

2.14 (s, 3H), 2.48 (s, 3H),

4.5 (s, 1H); 4.6-4.9 (m, 3H);

5.2 - 5.26 (dd, IH),

5.3-5.6 (m, 2H),

5.86-6.1 (m, 1H);

6.7 (d, 1H); 7.0 (s, 1H);

IR: 1810, 1760 cm -1, 3 (s, 3H), 1.58 (s, 3H),

2.12 (s, 3H), 2.36 (d, 6H), m.p.

194.5-195.5 04 4.5 (s, 1H), 4.75 (d, 1H);

5.2-5.4 (dd, 3H).

6.6 (d, 1H); 7.4 (s, 5H); benzyl

1.28 '(s, 3H), 1.55 (s, 3H), (colorless 2.1 (s, 3H), 2.4 (s, 3H), solid product; 4.5 (s, 1h) 4.8 (dd, 1H), one isomer) 5.25 (quartet, 1H),

6.15 (s, 1H); 6.5 (d, 1H);

7.4 (s, 5H), allyl

1.3 (s, 3H), 1.58 (s, 3H),

2.14 (s, 3H), 2.48 (s, 3H),

4.52 (s, 1H); 4.8 (d, 1H);

5.16-5.36 (AB quartet and dd, 3H),

6.7 (d, 1H); 7.0 (s, 1H);

7.4 (s, 5H), 37-1.40 (d, 3H),

. ..

(mixture of isomers 1.58-1.60 (d, 3H), 3: 1 ratio) 2.12-2.14 (d, 3H),

2.58 (s, 3H); 4.48 (s, 1H);

4.58-4.88 (m, 4H),

5.24-5.46 (m, 2H);

5.82-6.00 (m, 1H);

6.64-6.67 (d, 0.75H),

7.05-7.08 (d, _t 2'5H O);

IR: 1810, 1765 cm @ -1

24874В

Example 8

A. (6a, 8R) -6- (1 H-Isol-1-yl) -popionyloxymethyl-lildio} xo-eneCainioic acid

A mixture of 1.89 g of 10% palladium on carbon catalyst and 20 ml of a 9: 7 mixture of tetrahydrofuran and water was saturated with hydrogen and a solution of 689 mg (1.4 mmol) of benzyl- (6a; 8R) was added. -6- (thiazol-4-yl) -propioinyloxymethyl-11-di-di-o-oenocyanate in 13 ml of tetrahydrofuran and 7 ml of water. The resulting mixture was hydrogenated at 20 psi for 20 minutes, the catalyst was filtered off and the filtrate was extracted three times with 200 ml of ethyl acetate each time. The extracts were dried over magnesium sulfate and the solvent was evaporated in vacuo. 330 mg of a yellow solid are obtained.

B, (6a, 8R) -6- (Ittoiazoil-2-yl) benzyloxymethyl-1,1-dioxo-diphenylethylic acid

Compound. the title compound is obtained in the above manner in a yield of 57% of the corresponding benzyl ester.

1 H-NMR (deuteirium oxide, δ in ppm):

1.38 (s, 3H);

1.55 (s. 3H);

4.25 (s, 1H,);

4.44 (dd, IH),

5.05 (d, IH);

6.68 (d, IH);

7.4 (t. 7H);

7.55 (t, 1 H),

7.58 (d, 1 H),

7.7 (di, 1 H),

7.95 (d, IH);

IR (KBr-tec tonic):

473, 1,782, 1,729, 1,622 cm.

Example 9

A. The benzylistery obtained above with hydrogenation according to Example 8 using palladium. the corresponding carboxylic acids of the general formula below, wherein R b represents a hydrogen atom, are converted to carbon as a catalyst.

R13

R ¹⁸ yield 1 H NMR (ρerdeutercidimeihyř · L (%) or sulfoxide deuteriurnoxid, 8 values in ppm)

2H1? Z? I? II

O 74 1.45 (s, 3H), 1.53 (s, 3H], || (white solid 2.10 (s, 3H), 4.48 (s, 1H),

CH ₃ C 'secretions' at 5.0 (dd, 1H), 5.41 (d, 1H), decomposition at 6.59 (d, 1H), 7.91 (m, 2H); 155 ° C

13 C-NMR: 17, 1,036, 19, 3,736, 20, 2,771, 53, 2,954, 62, 5,971, 62, 8,347, 63, 3,676, 64, 5,698, 122, 6,881,142 , 4,252, 164, 3,975, 167, 8,111, 168, 7,027, 170, 8,035,

O 45 1.53 (S, 3H), 1.65 [s, 3H], || 2.17 (s, 3H); 4.54 (s, 1H);

CH ₃ C 4.87 (d, 1H-1, 5.13 (dd, 1H)),

6.82 (d, 2H), 7.88 (d, 1H), 8.07 (d, 1H), 9.20 (bs, 1H),

13 C-NMR: 17.6, 20.09, 20.5, 54.5,

63.2, 63.6, 63.9, 65.5, 121.9

123.4 1 ^ 2611L _t 126.6, 135.3, 151.6,

166.6, 169.2, 169.3, 170.6

R13

R ¹ . ⁸ yield (%) Hf-NMR (ipeirdeuteiroidimethylsuilfoxiid or deuterium oxide, ό in ppm) O II CH ₃ C 60 (deuterium oxide): 1.45 (s, 3H), 1.57 (s, 3H), 2.15 (s, 3H), 4.33 (s, 1H), 5.24 (s, 1H), 4 75-5.2 (1H masked with deuterium oxide signal), 6.55 (d, 1H), 8.65-8.8 (m, 2H); IC (KBr): 3,416, 1,785, 1,618 cm ^-1 ; ¹³ C-NMR: 17.6, 19.8, 20.4, 54.4, 64.1, 65.7, 68.1, 144.2, 145.2, 145.5, 151.2, 172 , 7, 172.8, 0 II CH ₃ C 85 1.47 (s, 3H), 1.55 (s, 3H), 2.15 (s, 3H), 2.28 (s, 3H), 2.32 (is, 3H), 4.3 (s) 1 H, 4.85 (dd, 1 H), 5.2 (d, 1 H), 6.6 (d, 1 H); IR (KBr): 1787, 1626 1618 cm ^- ". 0 II CH ₃ C 87 1.48 (s, 3H), 1.66 ( _; s, 3H), 2.2 (s, 3H), 2.46 (s, 3H), 4.35 (s, 1H), 5.2 ( d, 1H), 6.4 (s, 1H), 6.55 (d, 1H); IR (KBir-technia): 1791, 1692, 1631, -, 0 II CH ₃ C 57 1.5 (s, 3H), 1.6 (s, 3H), 2.2 (s, 3H), 2.45 (s, 3H), 4.35 (s, 1H), 4.9 (dd, 1H) 5.25 (d, 1H), 6.7 (d, 1H), 7.3 (s, 1H) ¹ IR (KBr): 1787, 1657, 1626 on * ¹ .

В. The 6α- (Thiazol-2-yl) acetoxymethyl-1,1-dioxopenicillanic acid prepared in Part A above was converted to the corresponding potassium salt by treatment of the aqueous acid suspension with an aqueous solution of an equivalent amount of potassium bicarbonate . The product was purified by medium pressure liquid chromatography on a C _{(8 (C18} = oiktiaidecylsilikát) using a mixture of water and acetonitrile (9: 1) as eluent. Yield 60% to yield the corresponding potassium salt.

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

1.37 (s, 3H);

1.48 (s, 3H);

2.07 (s, 3H);

3.80 (s, 1 H),

4.92 (dd, IH),

5.12 (d, IH),

6.55 (d, IH);

7.89 (m, 2H);

IR (KBr):

454, 1788, 1630 cm ^-1 .

Example 10

Kaliu.m-6- (imidazoil-2-yl) hydroxymethyl-1,1-dioxopeiniciline

A mixture of 141 mg (0.38 mmol) of allyl-6- (imidazol-2-yl) hydroxymethyl 1,1-dioxopeinicilate (isomer mixture), 12 mg of tetrakis (tertiaryphosphine) palladium (0), 12 mg of triphenylfoisfin, 0, 76 ml (0.38 mmol) of potassium 2-ethylhexainoate and 2 ml of ethyl acetate were stirred under nitrogen for 1 hour. Filtration of the precipitated product gave 143 mg (100%) of a yellow solid which contained two isomers according to HPLC.

IR (KBr):

382, 1780, 1728 and 1615 cm ^-1 .

249746

Example 11

A. Potassium-6 = thromo-64-thiiazol-2-yl) acetoxymethyl-11,1-dioxophpeinicilate mg [0.2 mmol] ailyl-6-bromo-6- (thiiazol-2-yl) aietythioxymethyl-1,1 -dioxoipenici ^; The lainate is reacted for 10 minutes according to the procedure of Example 10, after which the reaction mixture is treated as described in this example. 46 mg (48%) of a yellow solid are obtained.

⁴ H-NMR (deuterium oxide, δ in ppm):

1.45 (s. 3H);

1.6 (s, 3H).

4.4 (sH),

5.55 (s, 1 H),

6.85 (s, 1 H),

7.72 (d, IH),

7.86 (d, IH).

B. 6-Bromo-6- (thiazol-2-yl) hydroxymethyl-1,1-dioxopenicillanate

Similarly, a 20 minute reaction of allyl-6-bromo-6- (thiazol-2-yl) hydroxymethyl-11,1-dtoxjopenicilaitate (220 mg) yielded the title salt in a yield of 52% as a pale salt. yellow solids.

⁴ HN MR (terodlime t) hysulphoxide, values in ppm):

1.35 (s, ⁽ 3 H),

1.47 (s, 3H);

3.75 (s, 0.4H);

3.83 (s, 0.6H),

5.3 (s, 0.4H),

5.32 (d, 0.6H),

5.45 (s, 0.6H);

5.5 (s, 0.4H);

7.6-8.0 (m, 2 H).

IR (KBr):

442, 1794, 1633 cm ^-1 .

Example 12

Potassium (6,3,8S) -6- (thiazol-2-yl) hydroxymethylpeniciianate

A. Allyl-6-bromo-6- (thiazol-2-yl) hydroxymethylpenitilicate

To a solution of 9.971 g (24.99 mmol) of allyl 6,6-dibromipenicillanate in 150 mL of dry tetrahydrofuran, cooled to -78 ° C, was added 8.77 mL of 2.85M under nitrogen. (24.99 mmol) of methylmagnesium isobromide in tetrahydrofuran and the mixture was stirred for 15 min. After addition of a solution of 2.824 g (24.99 mmol) of thiazoil-2-cariboxaldehyde in 5 ml of tetaahydirof rain, the mixture was stirred at -78 ° C for a further 20 min. ) glacial acetic acid. The mixture was stirred for 10 minutes and then allowed to warm to room temperature. The resulting mixture was poured into water and extracted twice with 250 ml of ethyl acetate each time. The extracts are washed twice with 250 ml of water each time, dried over magnesium sulphate and the solvent is evaporated off under vacuum. 10.36 g of an orange oil are obtained which, after purification by chromatography on a silica gel column, using a mixture. of chloroform and ethyl acetate (9: 1) as eluent gave 4.54 g of yellow solid material (simes isomer) and 0.443 grams of a yellow foam which formed only the more polar isomer. The total yield is 46%.

• 1 H-NMR (deuterochloroform, δ ppm) yellow foams:

1.56 (cis, 3H),

1.76 (s, 3H).

4.60 (s, 1 H),

4.7 (m, 2H).

4.9-6.4 (m, 6H).

7.45 (m. 1H);

7.8 (m. 1H).

B. Aily: 1-6- [1- (thiazol-2-yl) hydroxymethyl-, warbled ilanate

200 mg (0.462 mmol) of the more polar isomer prepared in Part A are dissolved in 1 ml of benzene and 0.183 ml (0.693 mmol; 1.5 equivalents) of tiri-n-buityl tin hydride in benzene is added. The mixture was heated at reflux for 3 hours, then allowed to stand overnight at room temperature, then the solvent was evaporated in vacuo. The residue is taken up in acetonitrile, the solution is washed with hexane and evaporated to a small volume. This concentrate was applied to a silica gel column from which the chloroform was eluted with 73 mg (45%) of the desired product.

⁴ H-NMR (CDCl3, δ vippm):

1.65 (s. 3H);

1.87 (is, 3H),

3.8-4.4 (m, 1H), 4.05-5.3 (dd, 1H),

4.65 (s, 1 H),

4.78 (m, 2H).

5.3-5.6 (m, 2H);

5.6-6.3 (m, 3H);

7.45 (m. 1H);

7.85 (m, IH).

C. 73 mg (0.206 mg) of the product prepared in Part V were converted to the potassium salt by the procedure of Example 10. Obtained mg (80%) of the title compound.

1 H-NMR (300 MHz, deuterium oxide, δ in pip.m):

1.36 (s, 3H).

1.55 (s. 3H);

4.13 (dd, IH),

4.18 (s, 1 H),

5.32 (d, IH);

5.41 (d, IH);

7.56 (d, 1 H),

7.60 (d, 1 H,

Example 13

A. Work is 'analogously' to Part A of Example 12 'by' the nar space thiazol-2-kaiiiboxalide.hydu using the appropriate aldehyde of formula ^R, 3CHO. The corresponding compounds of general formula are obtained

R13

yield (%) of isomer A (white crystals) isomier B (yellow oil) (isomer A, 8S) (isomer B, 8R) ^J H-NMR ( 'deuterochlorofonm, δ values in ppm): Isomer A:

1.46 (s, 3H), 1.64 (s, 3H),

4.42 (d, 1 H), 4.50 (s, 1 H),

4.64 (m, 2 H),

5.2-6.6.50 (m, 3H),

5.84 (s, 1 H),

5.8-6.0 (im, 1 H),

8.58 (s, 2H), 8.9 (s, 1H);

13 C-NMR (CDCl 3):

26.4, 32.5, 64.4, 66.1, 69.8,

70.9, 73.7, 74.9, 119.6, 131.0,

143.0, 144.3, 144.6, 152.1,

166.8, 167.8 ppm, isomer B:

1.45 (s, 3H), 1.63 '(cis -3Ή),

4.56 (s, HH); 4.65 (m, 214);

5.1-5.5 (m, 4H);

5.6-6.0 (m, 1 H),

5.91 (s, 1H); 8.57 '(m, 2H);

8.78 (m, IH);

¹³ C-NMR (CDCl3):

26.27, '32.57, 64.30, .'βδ ^,

69.94, 70.77, 72, 38, 74.73 ,.

119.70, 130.98, 143.30, 144.57,

144.70, 152.04, 166.00, 167.99 ppm,

1.52 (s, 3H), 1.70 (s, 3H),

4.64 (s, 1H); 4.72 '(im, 2H);

4.86 (id, 1 H),

5.34-5.48 (m, 3H);

5.91 (s, 1 H),

5.92-6.0 (m, 1H);

7.39 (t, 1 H), 8.87 (d, 2 H,

1.52 (s, 3H), 1.71 (s, 3H),

4.61 (s, 1H); 4.72- (m, 2H);

4.98 (d, IH);

5.30-5.52 (m, 3H),

5.90-6.04 (m, 1 H),

6.10 (s, 1H); 7.40 1H);

8.85 (d, 2HH);

R13 yield (% J @ ¹ H-NMR (CDCl3, ppm, ppm))

(foam)

1.49 (s, 3H), 1.69 (s, 3H),

3.56 (d, 0.7H), 3.89 (d, 0.3H),

4.7 (m, 3H, 5.5 (m, 3H))

5.9 (g, 2H) 7.53 (m, 3H),

8.14 (g, 3H),

(Isomer A, 8S)

(isomer B, 8R)

(foam]

1.52 (s, 3H), 1.70 (s, 3H),

4.64 (s, 1 H), 4.72 (m, 2 H),

4.86 (d, 1H),

5.34-5.48 (; m, 3H),

5.91 (s, 1 H),

5.92-6.05 (m, 1 H),

7.39 (t, 1 H), 8.87 (d, 2 H),

1.52 (s, 3H), 1.71 (s, 3H),

4.61 (s, 1 H), 4.72 (m, 2 H),

4.98 (d, IH);

5.30 - 5.52 (g, 3H),

5.90-6.04 (m, 1 H),

6.10 (s, 1 H), 7.40 (t, 1 H),

8.85 (d, 2H).

1.49 (s, 3H), 1.69 (s, 3H),

3.56 (d, 0.7H), 3.89 (d, 0.3H),

4.7 (g, 3H), 5.5 (m, 3H),

5.9 (m, 2H), 7.53 (g, 3H), 8.14 (g, 3H).

(crude product) mixture of isomers

B. Debromination of the above compounds by the procedure of Part V of Example 12 gives the following compounds:

R ¹³

(from A, 8S isomers)

(from isomeir B, 8S)

(from isomer A, 8S)

(from isomers B, 8R)

(8R)

(8S)

OH

->

- C H

¹ H-NMR (CDCl 3) δH NMR (CDCl 3)?

1.5 (s, 3H), 1.7 (s, 3H), (oil) 4.05 (dd, 1H), 4.35 (s, 1H),

4.5 (d, 1H); 4.65 (m, 2H); 5.25-5.45 (m, 3H);

5.55 (d, 1 H), 5.9-6.0 (m, 1 H),

8.6 (m, 2H); 6.85 (s. 1H);

1.5 '(s, 3H), 1.8 (s, 3H),

4.15 (dd, 1H); 4.25 (bs, 1H);

4.55 (s, 1H); 4.7 (m, 2H); 5.2-6.2 (im, 5H);

8.67 (bs, 2H), 9.00 (bs, 1H),

1.51 (s, 3H), 1.74 (s, 3H), (oil) 4.01 (dd, 1H), 4.44 (d, 1H),

4.60 (s, 1H), 4.70 (d, 2H), 5.40 (m, 3H), 5.60 (d, 1H), 5.96 (m, 1H), 7.34 (t 1 H, 8.80 (d, 2H).

1.52 (s, 3H), 1.78 (s, 3H),

4.23 (m, 2H), 4.64 (s, 1H), 4.71 (d, 2H), 5.30-5.46 (m, 3H),

5.53 (d, 1H); 5.90-6.04 (m, 1H);

7.34 (t, 1 H), 8.85 (d, 2 H),

100 1.47 (s, 3H), 1.67 (s, 3H),

4.16 (m, 2H), 4.64 (m, 3H), 5.47 (m, 4H), 5.94 (m, 1H),

7.43 (m, 3H), 8.02 (m, 3H), (without purification) (after purification)

1.42 (s, 3H); 1.7 (s, 3H);

4.4 (doublet of doublets, J = 4 and

8, 1H),

4.5 (s, 1H); 4.65 (m, 2H);

5.2-6.3 (m, 3H);

5.6 (d, J = 4, 1H);

5.6 (d, J = 8, 1H).

7,7-7,6 (im, 2H),

7.8-8.1 (m, 2H);

1.45 (s, 3H), 1.55 (s, 3H),

4.15 (doublet of doublets, 1H),

4.5 (s, 1H); 4.65 (m, 2H);

5.2-6.4 (m, 5H);

7.2 - 7.6 (m, 2H);

7.8-8.2 (m, 2H).

C. Using the procedure of Example 10, the above reaction gave the following potassium salts of the prepared alkyl esters

R ¹³

(isoimer B)

(isomer A)

(isomer B),

yield (° / o) stereochemistry at C ₈

1 H-NMR (perd euiteroidilmethylsulfoxide, δ values in ppm)

75 8R 1.45 (s, 3H), 1.56 (s, 3H), 3.76 (s, 1H, 4.13 (dd, 1H), 5.05 (d, 1 H), 5.4 (d, 1 H), 8.58 (d, 2H); 8.72 (s, 1H); IR (Kbr-technique): 3 478, 1761, 1607 cm ' 82 8S 1.42 (s, 3H), 1.65 (s, 3H), 4.25 (s, .3, HJ, 4.27 (dd, 1H), 5.3 (d, 1H), - 5.35 (d, 1H), 8.6-8.7 (, m, 2H), 8.8 (m. 1H); 94 8S (deuterium oxide): 1.32 (s, 3H), 1.54 (s, 3H), 4.18 (s. 1H). 4.14-4.19 (m, 1H), 5.19 (d, 1 H), 5.25 (d, 1 H), 7.45 (t, 1H); 8.75- (d, 2H); 95 8R (deuterium oxide '): 1.44 (s, 3H), 1.58 (s, 3H), 4.12 (s, 1H), 4.18 (m, 1H), 5.22 (d, 1H); 5.49- (d, 1H); 7.46 (t, 1H); 8.75 (d, 2H); 97 8R 1.47 (s, 3H), 1.58 (s, 3H), 3.79 (s, 1H); 4.13 (dd, 1H); 5.2 (d, 1 H), 5.4 (d, 1 H), 5.95 (bs, 1H), 7.45 (t, 1H), 7.60 (t, 2H); 8.03 (d, 2H); 8.16 (s, 1 H),

Δ S 1.48 (s, 3H), 1.67 (s, 3H),

4.27 (doublet of doublets, J = 4 and 10, 1H),

4.3 (s, 1 H),

5.45 (d, J = 4, 1H).

5.57 (d, J = 10, 1H); 7.45-7.65 (m, 2H); 8.04 (t, J = 8, 2H);

IR (KBr - echi.in): 3 424,

765, 1746, 1592 cim'1,

Ή-NMR (perdeuterodimethylsulfoxide, δ values in pp | m) stereochemistry per Cg yield (1%)

8R

1.42 (s, 3H), 1.56 (s, 3H),

4.16 (s, 1 H),

4.25 (doublet of oak flights, J = 4 and

8, 1H),

5.46 (d, J = 4, 1H);

5.5 (d, J = 8, 1H).

7.4-7.6 (m. 2H);

7.8-8.05 (m, 2 H).

Example 14

A. 6- (Benzothiazol-2-yl) methylene-11-diioxopenilcianoic acid, mixture of E and Z isomers

To a solution of 400 mg (0.91 mL) of 6- (benzothiazol-2-yllacetoxymethyl-11-di-oxo-trimethylic acid) in 5 mL of water was added a solution of 0.15 g (1.82 mmol) of sodium bicarbonate in 2 mL of water and The resulting mixture was stirred for 2 hours, the mixture was subjected to freeze-drying at pH 7.55, the residue was taken up in 8 ml of water, acidified to pH 3.5 with dilute hydrochloric acid and extracted with ethyl acetate, dried over magnesium sulfate and solvent. According to NMR spectroscopy, the resulting product is a 60:40 mixture of E and Z isomers.

4 H-NMR (CDCl 3, δ ppm):

1.6 (s, 1, 1H),

1.65 ((5', 1.2H L 1.67 (s, 1.8H),

4.55 (s, O. ^ Н])

4.58 (s, 0.444))

5.38 (s, Ο, Η j)

5.74 (s, 1H, 2H)]

7.44 (s, О, 4%)

7.48 (ss 0.6Hj)

7.5 (m, 4H),

7.89 (d, J) »8.07 (d, 0.4H),

8.15 (d, 0.6 H).

B. The similar reaction of the corresponding 1,1-dioxopenicillanate acids substituted into consideration 6 radicals R1 · ³ CH (OCOCH ₃₎ as prepared 'above to give compounds having the following general and Z isomers.

in the form of a mixture

1.55 (s, 1.2H),

RR ¹³ (sodium salt)

ch ₃ 'COOH yield (%) (mixture of E and Z' isomers in ratio 60 ': 40)

1H-NMR (deuterium oxide, δ in ppm)

1.54 (s, 3H), 1.62 (s, 3H),

4.04 (s, 3H); 4.35 (s, 1H);

5.7 (s, 0.6H), 5.95 (s, 0.4H),

7.26 (s, 0.6H), 7.55 (s, 0.4H),

8.09 (s, 2H).

Example 15

Allyl-6 (E) - (N-methylpyrrol-2-yl) methylene-1 H -dioxopentiliniainate

IMIG 180 (0.47 min ^ n ^ il) · allyl 6ť- (N-meithylpyrrol-2-yl) hyd.n.oxy Me thy ⁱ - l ⁱ dixxioipe L-N-C was dissolved in lianátu 3 ml of tetrahydrofuran and 0.15 ml of acetic anhydride and 0.2 ml of pyridine are added to the solution. The mixture was stirred at room temperature for 1 hour, then stirred with water and extracted with ethyl acetate. The organic layer was dried and the solvent was evaporated in vacuo to give 162 mg of product which still contained the starting material. This product was dissolved in 3 ml of methylene-CH 2 OH and 0.15 ml of acttyl chloride and 0.2 ml of pyridine were added to the solution. The mixture was stirred at room temperature for 2 hours. then it is processed as described above. 140 mg of crude product are obtained which, after purification by silica gel column chromatography, affords 72 mg (42%) of the pure product.

After recrystallization from ethyl acetate, the product is obtained in the form of colorless needle crystals.

NMR-NMR (uterochloroform, δ in ppm):

1.45 (s, 3H);

1.65 (s, 3H);

3.7 (s, 3 H),

4.4 (s. 3H),

4.6-4.9 (m, 2H);

6.1-6.4 (s, 4H);

6.6 - 7.0 (m, 2H);

7.5 (dd, IH).

Example 16

Sodium 6 - (E) - (N-methylpyrrol-2-yl) methylene-1,1-diioxopenicillanate

A solution of 46 mg of α-yl-6 (EHN-methylpyrrolidin-2-yl) methylene-1,1-dioxopenicillanate, 5 mg of tetramethylcyclopentanilate (5-thiophenylphenylphosphine) .alpha.). and 4 mg of triphenylphosphine in 1 ml of methylene chloride was stirred under nitrogen for 5 minutes. The resulting mixture was diluted with 1 mL of ethyl acetate and 0.25 mL of a solution of sodium 2-ethylhexainoate in ethyl acetate was added. The reaction mixture was stirred at room temperature for 1 hour, then filtered and the filtered precipitate was washed with ethyl acetate and ethyl ether. 30 mg of a yellow solid are obtained.

Ή-NMR (leutilium oxide, δ in ppm):

1.50 (s, 3H);

1.60 (s, 3H).

3.65 (s, 3H);

4.10 (s, 1 H),

5.4 (s, 1 H),

6.1-6.5 (m, 1H);

7.0 (broad s, 2H),

7.2-7.4 (m, IH).

IC (КВг4ес girl):

568, 1,660, 1,745, 3,465 cm ⁴ .

Example 17

Ally! ^ - (2-f uranyl) meth.-methyl-l, ldlioxopeni cilanate, (E) - and (z) -isomers

To a solution of 310 mg (0.84 mmol) of allyl-6- [2- (2-furanyl) oxymethyl-1,1-dioxoperitinate in 5 ml of methylene chloride] was added 0.14 ml (1 mmol) of triethylamine -a · 0.1 ml (0.9-24 mmol) of trifluoromethylsulfonyl chloride, and the mixture was stirred at room temperature for 2 hours in a duomo atmosphere, diluted with water and extracted with methylene chloride. The solvent was evaporated in vacuo to give 330 mg of crude product which was chromatographed on a column (silica gel, using chloroform as eluent) to give 130 mg of purified product by liquid chromatography. a high-resolution mixture of (E) and (Z) -isomers in a 4: 1 ratio.

Ή-NMR (deuteI) OChloloToform, δ values in pipmj:

1.47 (s. 3H),

1.61 (s. 3H),

4.47 (s, 1 H),

4.75 (d, 2 H),

6.1-6.2 (m, 4H);

5.52 (dd, IH),

6.8 (m, 1H);

7.15 (d, IH);

7.6 (d, 1 H).

Example 18

Following the procedure of Example 17, the following compounds were always obtained using the appropriate hydroxy compounds:

eluent - reagent 1Η -NM R (d euter ochloiroform, at chromatographic value S in ppm)

R13

CH ₂ —CH-

r » ₃ н ₃ 'соссн ₂ сн = сц.

yield (%)

22 (E)

19 (Z) EthylCher (E) -isomer:

1.5 (s, 3H), 1.7 (s, 3H),

4.5 (s, 1H); 4.7 (d, 2H);

5.5 (d, 1 H),

5.1-6.2 (m, 3H),

Δ:: ^ ^ ^ ^, (nm,), δ (nm, 2H),

7.7-8.0 (m, 1H); 8.53-8.83 (im, 2H);

(Z) -isomer:

1.48 (s, 3H), 1.6 [s, 3H],

4.5 (s, 1H); 4.7 (d, 2H);

5.25 (s, 1 H),

5.1 - 6.2 (m, 3H);

6.88 (s, 1 H),

7.2-7.5 (m, 1H); 8.43-9.0 (im, 3H);

Eithyliaicetút / Isomer mixture:

/ hexane (1: 1) 1.45 (s, 3H), 1.62 (s, 3H),

4.5 (s, 1H); 4.7 (d, 2H);

5.2-6.2 (m, 4H);

6.75 (s, 0.3H),

72-7.5 (m, 1.7H), 7.6-7.85 (m, 1H), 8.5-8.83 (m, 2H);

Chloroform Sodium chloroform

1.45 (s, 3H); 1.6 (s, 3H);

4.4 (s, 3H), 4.7 (d, 2H), 5.0-6.2 (m, 3H),

5.25 (d, 1H); 7.0-7.65 (m, 4H);

1.45 (s, 3H); 1.65 (s, 3H);

3.7-4.2 (m, 1 H),

4.45 (s, 0.6H), 4.5 (s, 0.4H),

4.75 (d, 2 H),

5.1-6.4 (m, 7H).

Corresponding potassium salts with salts.

using potassium 2-ethylhexanoate Example 19

Using the procedure of Example 16, using the preceding examples, the following were obtained

R13

COChy ^C 6 ^H 5

CH ₂ = CH—

(potassium salt)

(potassium salt) о

СИ3 CH ₃

O Na isorneir yield IR spectrum. . (H-NMR (deuterium dioxide, ((%) (KBr-technique) δ in ppm))

3 - 1 (E) :( Z) 47 1 621, 1 678, 1 764, 2 979, 3 402, 3 47 1 cm ¹ (E) 56 1,622, 1,728,

764,343 «cm - ¹

(OF) 91 1565, 1619, 1667, 1759, 2950, 3453 cm 1 ^_ (E) 72 1,623, 1,778, 3,462 cm ¹ (OF) 91 1303, 1623, 1761, 3445 ^cm-1

(250MHz):

1.5 (s, 3H), 1.6 (s, 3H),

4.25 (s, 1H); 5.57 (s, O, 25H);

5.9 (s, 0.75H), 6.65 (m, 1H), 7.0 (d, 1H), 7.17 (d, 0.25H),

7.36 (s, 0.75H), 7.78 (m, 1H), (60 MHz):

1.56 (s, 3H), 1.65 (s, 3H),

2.68 (s, 3H); 4.25 (s, 1H);

5.88 - (s, 1H), 6.5 (t, 1H), 7.0 (d, 1H), 7.6-8.0 (m, 1H),

8.2 (-s, 1 H), (60 MHz):

1.45 (s, 3H), 1.55 (s, 3H),

4.17 (s, 1H), 5.5 (s, 1H), 7.0 (s, 1H), 7.27-7.6 (m, 3H), 70-8.1 (m, 2H) ,

1.55 (s, 3H), 1.62 (s, 3H),

4.23 (s, 1H), 6.05 (s, 1H), 7.4-8.8 (m, 5H),

1.55 - (s, 3H), 1.65 (s, 3H),

4.3 (s, 1 H), 5.6 (s, 1 H),

6.96 (£, 1H), 7.1-90 (m, 4H),

(E) + (Z) 93 1,623, 1,778, 3,448 cm ' ¹ 1.5 (s, 3H), 1.6 (s, 3H), 4.3 (s, 0.3H), 5.55 (s, 0.3H), 6.0 (- d, 0.7H), 6.95 (s, 0.3H), 7.2-7.8 (m, 4.7H), (E) 33 1,619, 1,773, 3,425 cm 1 1.55 (s, 3H), 1.60. (s, 3H) 4.2 (s, 1H); 5.8 (s, 1H); 70-7.9 (m. 4H) 25 1 620 1773 3,430 cm -1 1.59 (s, 3H), 1.60 (s, 3H), 4.22 (s, 0.6H), - 4.3 (s, 0.4H), 5.53 (s, 0.4H), 5.75 (s, 0.6H), 5.5-6.2 (au, 3H), (E) 77 1.5 (s, 3H); 1.6 (s, 3H); 2.5 (s, 3H); 4.28- (s, 1H); 6.05 (d, 1H); 7.2-7.35 (m, -2H); 7.4- (d, 1H); 7.67 (t, 1H); 13 C-NMR (deurterium oxide, δ in ppm '): 20.719, 22.436, 26.032, 68.386, 68.533, 74.489, .120.794, 128.334, 132.843, 140.670, 152.549, 163.012, 174.041, 175.657, '(E) 92 1,614, 1,770, 3,406 cm ~ 1 (deu.terium oxide + perdeuiteerodimethylsulphoxide): 1.5 (s, 3H), 1.6 (s, 3H), 4.1 (s, 1H), 5.9 (d, 1H), 7.5 (d, 1 H), 8.5-90 (M, 3H '),

Example 20 1,1-Xioxide-6 (E) -phenylmethyl-ethylenepicillanic acid

To a solution of 0.1 g (0.28 mmol) -allyl-G (E) -lenelmethylene-1,110-oxo-chloro-phenyl: 20 mg of triphenylphosphine and 20 mg of tetraks (triphenylphosphine) -halide (a) in 3 0.5 ml of 0.5M-methyl-2-methylhexaneate was added to the ethyl acetate, the mixture was stirred at room temperature for 1 hour and then allowed to stand in the refrigerator for 65 hours while allowing the mixture to stand for 65 hours. - does not precipitate any precipitate. Dilute the mixture with ethyl acetate and water, aqueous layer. The mixture was acidified to pH 1.8 with dilute hydrochloric acid and extracted with fresh ethyl acetate. The extracts were dried over sodium sulfate and the solvent was evaporated in vacuo to give 62 mg (69%) of the desired product which, after crystallization from acetone, resulted as yellow crystals.

1 H-NMR (iperdeuteiroacetone ·, δ in ppm ·):

1.55 (s, 3H);

1.65 (s, 3H);

4.43 (s, 1 H),

5.93 (d, IH);

7.3-7.9 (m. 6H);

8.7 (bs, 1H).

1C (KBr - ech <n.ika):

327, 1685, 1737, 1772, 2 929, 2 961, 3 108, 3 477 cm -1.

Example 21

CaHum-6 (E) - (1-methylpyridine) aa ^, 1,1-2-yl (methylene-1,1-dioxopeinicilate)

A. Allyl-6- (1-methyl-imidazolyl-2lyl jacetoxymethyl-1,1-dimethyl-oxopeniciline)

472 mg (1.23 mmol) of allell31- (1-methyl-imidazol-2-yl): hydroxymethyl-1,1-dtoxene-p-enicillanate were acetylated according to the procedure of Example 3 to give 392 mg (75%) of the desired acetoxy compound. in the form of a mixture of two isomers.

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

1.4 (s, 1.5H)

1.5 (s, 1.5H);

1.6 (s, 1.5H)

1.7 (s, 1 H),

2.2 (s. 3H),

3.7 (s, 1.5H);

3.75 (s, 1.5H), 4.0-60 (m, 8H),

6.3-6.5 (m, IH),

6.8 (m, 1 H),

7.0 (m, IH).

B. Allyl-6 (E) - (1-merthy ^, lim-oazol-2-yl) methylene-1,1-d toxoiphenate cianianate

392 mg (0.920 mmol) of the product prepared in Part A above were converted according to Part B of Example 3 using 5 ml of methylene chloride and 0.115 ml of 1,5-diazabicyclo [4.3.0] non-5- in the yield. 53% of the title n-a ester.

H-NMR (leueeroCihlooO'foιrm _L, δ values in ppm):

1.5 (s. 3H),

1.6 (s, 4H),

3.7 (s. 3H),

4.35 (s, 1 H),

4.7 (m, 2H).

50-6.1 (m, 3H),

5.7 (d, 1 H),

6.9 (na, 1H).

7.1 (d. 1H).

7.2 (m, 1H).

C. 113 mm (0.44% by weight of the Hyleistsirui prepared in Part B with the procedure of Example 16) but converted to the title potassium salt by using β-β-β-2-γ-α-β-β-oxoate in place of the corresponding sodium salt The product consists of 143 mg (87% yield) of the individual (E) 4-homomer.

Example 22

)-Ά ^ α α Ε) - (--руу-юКО-пУ!) Methylenepenilicilic acid and potassium salt

A 560 mg (1.69 mmol) allyl.l3 (E) L (2-propyl ^{τlmi.dinylime! The:} leηpenic veronal-la and 730--Mg 3lChloi peιгbenzooιvé acid (3.38 mmol) was dissolved in 10 ml -methyleachloridu mixture in diusíkové -atmosféře -míchá 4 hours, then diluted with water, extracted with -a ^'has:! · hyleιnChilαιl chloride. the extracts were washed, thiosínainu - sodium neutralized -with -hydгogeauhličitanem -sodným and after washing with The sodium chloride was dried and concentrated in vacuo to give 460 mg of a crude oil which was purified by chromatography on a silica gel column to give 180 mg of the desired allyl ester as an eluent of chloroform-ethyl acetate (9: 1). · In the form of a pale yellow solid.

@ 1 H-NMR (CDCl3) .delta.

1.45 (s, 3H);

1.65 (s, 3H);

4.5 (s, 1 H),

4.75 (m, 2H).

6.2-6.3 (m, 3H);

5.75 (s, 1 H),

7.1-7.5 (m. 2H);

8.9 (d. 2H).

24874В

Example 23

L-llyl-6- (2-thiazolyl) acetylmethyl-1,1-dioxopenicillanate

Following the procedure described in Example 3, 0.5 grams (1.29 mmol) of allyl 6- (2-thiazioyl) hydroxymethyl-11-dioixoipenicillanate was acetylated with 0.396 g (3.88 mmol) of acetic anhydride and 0.307 grams [3.88 mmol] pyridine in 5 mL of tetrahydrofuran. The reaction mixture was stirred at room temperature for 4 hours, then diluted with methylene chloride and washed with water until neutral (pH 6.0-6.5). The organic phase was dried over sodium sulfate and the solvent was evaporated. 0.688 g of the desired acetate is obtained.

¹ H-NMR (CDCl 3):

1.52 (s, 3H);

1.70 (s, 3H);

2.35 (s, 3H);

4.4-4.6 (m, 2H);

4.6-5.0 (m, 3H);

5.2-6.4 (m. 3H);

6.65 (d, IH);

7.4 (d, 1 H),

7.8 (d, 1 H).

Example 24

Ailyl-6- (n-thiazolyl) methylene-1,1-dioxioxenicenic acid and its hydrolysis to the potassium salt

A. 0.688 g (1.29 mmol) of the acetoxy ester prepared above was mixed with 0.16 g (1.29 mmol) of 1,5-diazabicyclo [4.3.0] non-5-ene and 5 ml of methyl niobiloride. The resulting mixture was stirred at room temperature for 1 hour, diluted with methylene chloride, washed with water (2 x 50 ml), dried over sodium sulphate and the solvent was evaporated. The oily residue is chromatographed on a silica gel column using a mixture of equal parts of ethyl acetate and hexane as eluent. 0.189 g (39%) of a pale yellow oil is obtained.

Ή-NMR (deuterocihfloiroform, δ in ppm):

1.53 (s, 3H);

1.65 (s. 3H);

4.33 (s, 1 H),

4.55 (d, 2 H),

5.0-5.4 (m, 2H).

5.45 (s. 1H).

5.4-6.0 (m, 1 H),

7.1 (m. 1H);

7.75 (m, IH);

7.65 (d, IH).

B. Hydrolysis of the above prepared aildyl ester by the procedure of Part C of Example 21 afforded 84.7% yield of kialium 6- (2-thiaaoilyl) methylene-1,1-dioxiopenicilane resulting in a yellow solid.

¹ H-NMR (250 MHz, p-trimetodimethylsulfoside, δ ppm):

1.40 (s, 3H).

1.45 (s. 3H);

3.80 (s, 1 H),

5.83 (s, 1 H),

7.66 (s, 1 H),

8.04 (m, 2 H).

Example 25

The 8-acetoxy esters prepared in the preceding examples were converted to the corresponding 6-methylenderivatives using the procedure of Example 2 in Example 2, and then the aryl group was removed as described to give the corresponding potassium salt. The following compounds are obtained in this way:

‘\ ..... /

СО т-4 &

у} <£ у ,, 5

and

о X) φ й

II

O

CXJ

Ю

ID СЛ

You ’ф what-

Example 26

Injectable preparation

Equal parts by weight of cefoperazoine naphtha and calcium-1,1-dioxo-6 (E) - (2-pyrimidinyl) methylenepenicillanate are mixed with 20 parts by weight of water. Using methods common in pharmaceutical priaxia, the solution is sterile filtered, filled with vials, which are loosely sealed with rubber closures, and lyophilized. The filling volume is such that each vial after freeze-drying, which is now sealed under vacuum, contains 500 mg of each active ingredient. Before injection in a vial, 10 ml of sterile water is injected into the vial and the vial is shaken to dissolve all the 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

Allyl-6α-broim-1,1-dio-1-openicilanoate and allyl-6,6-dibiromepenilcilainate (i) 6a-birompenicilainoic acid 1,1-dioxide

To a suspension of 20.26 g (0.0517 mol) of 6,6-dibromopenilicillinic acid 1,1-dioxide in 80 ml of water was added portionwise 13 g (0.155 mol) of solid sodium bicarbonate and the vigorous gas evolution was controlled by the addition of ethyl acetate. 6.76 g (0.062 mol) of solid sodium bisulfite are then added portionwise, the mixture is stirred for 35 minutes, and then acidified to pH 1.0 with concentrated hydrochloric acid, diluted with ethyl acetate, and the organic phase is washed with brine. The residue was triturated with chloroform and the mixture was filtered to give 6.72 g of a light yellow solid, and an additional 3.2 g of product was obtained by concentrating the filtrate and treating the residue with chloroform.

(ii) To 6.352 g of the first isolated material in 20 ml of dimethylformaimide, add 1.76 ml (20.3 mmol) of allyl bromide, 2.83 ml [20.3 mmol] of tiriethylamine and 0.2 g of bicarbonate The mixture was stirred at room temperature under nitrogen for 15 hours. After. adding water, the mixture is extracted with ethyl ether, the extracts are washed with water, dried over sodium sulfate and the solvent is evaporated off under vacuum. 4.60 g (64%) of the desired ester are obtained in the form of an oil.

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

1.6 (s, 4H),

4.4 (s. 1H).

4.6 (d, 1 H),

4.7 (d, 2 H),

5.15 (d. 1H);

5.1-5.95 (m, 3H).

(iii) Allyl-6,6 dibrompenicilate

6,6-Dibroimpeinicillanic acid (0.417 mol) was esterified from above to give 140 g (84%) of the corresponding allyl ester as an oil.

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

1.5 (s. 3H),

1.65 (s, 3H);

4.6 (s, 1 H),

4.75 (m, 2H).

5.3-5.6 (m. 2H);

5.85 (s, 1H).

5.8-6.3 (m, IH).

Preparation В

2-formyl-1-methylimididazole (i) 2-hydroxyinethyl-1-methylimidiazole

A mixture of 50 g of 1-methylimidazole and 100 ml of 37% formaldehyde (density 1.08) is added to a 300 ml stainless steel auroclave and heated at 150 ° C (bath temperature) for 17 hours. The autoclave was cooled in ice, the mixture was removed, concentrated in vacuo and the residue stored at 4 ° C overnight. The resulting mixture of crystals and oil was filtered, the colorless crystalline product was washed with ethyl acetate and dried in vacuo. 14.60 g of the desired product are obtained. A second crop of 6.48 g was obtained by treating the mother liquors. The overall yield was 21.08 g (31%).

(ii) К solution of 4.96 g (43.9 mmol) of 2-hydroixymetÍhyl-1 in 50 ml met.hylimidazo.lu diotxa <nu was added 4.90 g (44.1 mmol) of ¹ leničitého mixture The mixture was stirred at 85-90 ° C for 5 hours, then at room temperature for 36 hours, at 85 ° C for 8 hours, and at room temperature for 15 hours, filtered and the solvent evaporated in vacuo. 4.81 g of crude aldehyde are obtained, which is distilled to give 2.11 g of the product in the form of colorless crystals, boiling point 65 DEG C./373 Pa.

C a i c

4-formylpyrimidine

To a solution of 10 g (0.106 mol) of 4-methylpyrimidine in 100 ml of dioixane at room temperature was added 11.8 g of selenium oxide and the mixture was heated at 100 ° C for 15 hours. Po at 1.4 (s, 3H)

248748 a further 2.5 g of sulfur dioxide were continued for 1 hour, the mixture was cooled, filtered and the filter cake was washed with ethyl acetate. The filtrate was combined with the washings and evaporated in vacuo to dryness. The remaining dark oil was taken up in methylene chloride, the solution was filtered and the solvent was evaporated. The residue was crystallized from a small amount of methylene chloride to give the title aldehyde.

¹ H-NMR (CDCl 3, δ values in ppim):

7.87 (dd, IH),

9.06 (d, 1 H),

9.43 (d, IH);

10.0 (is, 1H).

Preparation D

Difluylmethyl-6α-bromo-1,1-dioxoipenicil: nat

К solution of 21,577 g (0.1 mol) in 400 ml difenyldiazometihanu tetoalhydriofuranu dry over ¹ 30 minuit added portionwise

31.2 g (0.1 mol) of 6'-biroim-1,1-di'-oxo ₍ penicillanic acid. The reaction is mildly exoithermic. The reaction mixture is stirred for 1 hour, then the solvent is evaporated and the residue is evaporated. The resulting mixture was stored at 4 DEG C. After 18 hours, no crystals formed, and the mixture was concentrated in vacuo to give 51.2 g of a yellow solid, m.p. Elution with chloroform gave 14.86 g of a colorless glass.

^ -NMR (deuterochlorofiorm, δ in ppm):

1.26 (s, 3H);

1.57 (s, 3H);

4.55 (s, 1 H),

4.70 (d, IH),

5.13 (d, 1 H),

6.9 (s, 1 H),

7.27 (s, 10H).

Example * E

In e-thiazole-2-carboxaldehyde d

A solution of 10 g (0.074 mol) of freshly distilled benzothiazole (b.p. 82 ^DEG C./0.2 mm Hg) in 250 ml of tetrahydrofuran was cooled to -78 DEG C. under nitrogen, stirred at this temperature for 15 minutes, then stirred for 15 minutes. 2.5 M n-butyllithium (29.6 ml, 0.074 mol) was added dropwise over 1 min. Stirring is continued for a further 25 minutes, then 8.6 ml (0.111 mol) of dimethylformamide are added and the mixture is stirred for 1 hour. The reaction mixture was allowed to warm to room temperature, 200 g of ice were added and the solvent was evaporated in vacuo.

The aqueous residue is extracted five times with 100 ml of ethyl acetate each time, the extracts are dried over magnesium sulphate, concentrated to a small volume and the concentrate is chromatographed on a silica gel column. Elution of the column with a mixture of chloroform and ethyl acetate (96; 4) yielded

8.4 g of the desired aldehyde, m.p. 74.5-75 ° C.

1 H-NMR (CDCl 3, δ in ppm):

7.54 (m, 2H).

7.97 (m IH),

8.21 (m, IH),

10.1 (s, 1 H).

For. using the above procedure, the following aldehydes are prepared analogously.

starting material aldehyde

Yield * 1 H-NMR (deuiterochloroorm, (i%) Ho S) (ppm) amber oil boiling

120 - 122 ° C / 3333 Pa

CHO

4.2 (s, 3H); 8.05 (s, 1H);

10.00 (w, 1Ή),

starting material aldehyde yield ⁴ H-NMR (δ deuterochloroform, ( _; ° / o) S values in ppm)

лх)

(oc ^ h _£ ) _z

1.2 ((i, 6H), 3,6-quartel, 2Ή).

3.64 (quartet, 2H), 6.95 (s, 1H),

7.21 (d, 1H); 7.55 (d, 1H);

8.23 (d, 1H)) ** prepared in solid form in 37% yield by reaction of 1H-1H-triazine with methylbutylliodide in ethanolic sodium ethoxide ** prepared from iimidazole and ethyl orthoformate by the procedure of described by Curtis- et al., J. Org. Chem. 45, 4,038 (1980)

P p v r F F F F

Pyridine-2-carboxaldehyde

The pyrazine-2-carboxylic acid is esterified by refluxing with methanolic sulfuric acid for 5 hours. The methanol was evaporated in vacuo, the residue was diluted with methylene chloride and neutralized with sodium bicarbonate to give a residue. pH 7.5. Concentration of the dried organic layer afforded methyl pyrazine-2-carboxylate (84% yield) as an off-white solid which was recrystallized from isopropanol / ethyl ether to give yellow needle crystals.

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

4.1 (s, 4 H),

8.93 (m, 2H);

9.47 (m, IH).

Dissolve g (0.145 mol) of this methylle.ste.ru in 600 ml of dry tetrahydrofuran, cool the solution in 600 ml of dry tetrahydrofuran, cool the solution to -78 degrees Celsius and add dropwise over 15 minutes. 5.8 g of 98% Uthium dialuminium hydride in tetrohydrofuron. The mixture was stirred at -78 ° C for 30 minutes, then 20 mL of acetic acid was added and the resulting mixture was concentrated under reduced pressure. The residue was partitioned between 30 ml of 2N hydrochloric acid and chloroform, the combined organic layers were washed with water and, after drying, evaporated. 8.53 g of crude product are obtained, which product is purified by silica gel column chromatography. Elution with a 4: 1 mixture of methylene chloride and ethyl acetate yielded 5.02 g of the product as pale yellow needle crystals.

NMR-NMR (deuterochloroform, values <5 in -ppm):

Preparation H

2-Phenyl-1,2,3-triazole-4-carboxaldehyde (i) Acetone dicarboxylic acid (0.34 mol) is treated with sodium nitrite (0.58 mol) at 100 DEG-10 DEG C. at 0-10 ° C. Dilute nitric acid was then added to the reaction mixture to precipitate the product. The desired dioxime is obtained in 46% yield, m.p. d, 3-dioximino-2-oxopropane in the form of red-yellow crystals.

(ii) 0.158 mol of this dloxime was treated with equimolar amounts of phenylhydrazine hydrochloride and sodium acetate at 70 ° C for 30 minutes at 170 ° C. After the addition of 170 ml of water, the mixture is heated to 85 DEG C., concentrated to a volume of 250 ml and cooled. 24.7 g of the desired phenylhydrazone are obtained.

Ή-NMR (deuterochloroform, S-values in ppm):

7.3 (m. 5H);

7.9 (s, 1 H),

8.6 (s, 1 H),

10.5 (bs, 1H),

11.4 (bs, 1H),

12.3 (s, 1 H).

(iii) 24.7 g (0.119 mol) of the above-prepared dioxime-Oenylhydriazone were stirred at room temperature for 30 minutes with 500 ml of acetic anhydride, poured into water, stirred for 20 minutes and then filtered. The resulting crude product is recrystallized from a mixture of benzene and ethyl acetate to give 15.47 g (52%) of the monoacetate of formula

HON = CH-C (= NNHC ₆ H ₅ ) CH = NOCOCH 3 as a yellow powder.

Ή-NMR (deuterochloroform, acetone, δ in ppm):

8.38 (m, 2H),

8.7 (bs, 1H),

9.7 (s, 1 H).

1.85 (s, 3H);

7.09 (m, 5H);

248749

7.95 (s, 1H),

8.3 (s, 1 H),

10.9 (bs, 1H),

12.25 (s, 1 H).

(iv) A solution of 15.40 g (0.062 mol) of the above monoacetate and 22.16 g (0.068 mol) of cesium carbonate in 400 ml of tetrahydrofuran was stirred at room temperature for 1 hour, then filtered and the filtrate was concentrated. The yellow-colored residue was dissolved in 700 ml of hot isopropyl ether-cyclohexane (1: 2) and concentrated to 200 ml to give 9.41 g (80%) of 2-phenyl-1,2,3- triazole-4-carboaldehyde oxixime in the form of a yellow powder, which is used in the next step (vj Mix 9.41 g (0.0497 m-ol) of the oxime prepared above), 4.48 g of s-trioxane 300 ml of 2N hydrochloric acid are added

The 3.5-hour heat is heated to reflux under the dickern's chlar. The aqueous phase was extracted with ethyl ether, the combined ether layers were washed with water, dried over magnesium sulfate and the ether was evaporated in vacuo. 6 g of crystalline aldehyde are obtained,

@ 1 H-NMR (CDCl3) .delta.

7.6 (m. 3H);

8.25 (m. 3H);

10.25 (s, 1 H),

Mp 66-67 ° C,

P. Ρ τ a. V a H

5-Methylisoxazole-3-cyclohexylidehyd (i) Ethyl-5-methylthiol-3-yl-iso-3-yl-oxo-1-carboxylic acid;

A mixture of 0.16 mol of ethyl 4-dioxovalerate a

0.08 moles of hydphoylanine sulphate -se. 50 ml of ethanol and 70 ml of toluene are stirred at 40 DEG C. for 4 hours. The reaction mixture was poured into a mixture of toluene and water and an aqueous layer. The organic layers were combined, washed with brine and dried over sodium sulfate. After evaporation of the solvent in vacuo, a yellow liquid material is obtained which, by distillation, yields 14.68 g of product having a boiling point of 120 to 124 ° c / 4 kPa which crystallizes on standing. (Ii) 2.0 g (14.4 mmol) of the ethyl ester obtained above in 75 ml of toluene was reduced in nitrogen at -75 DEG to -70 DEG C. with an equimolar amount of 1M diisototyl monohydride in hexane. After stirring for thirty minutes, stirring was continued. The reaction was quenched by the addition of ammonium chloride solution and the mixture was allowed to warm to room temperature. and the solvent was evaporated. vacuum,. The residue was ·· ¹ '· s trituruije .horkým meth ^ Arnot, after .odpaření · · · solution was obtained. 0/85. - colorless oil,

@ 1 H-NMR (detrtercloCl3) (.delta. In ppm):

2.4 (s, 3H).

6.3 (d, 1 H),

9.0 (s, 1 H),

Claims (7)

OBJECT OF THE INVENTION 1, Method. for the preparation of O-methylenepenicillanic acids of the general formula Ί2 \. , Ss / 3.7 M 0 COOR where n is '0' or 2, R ^l represents a 'radical ^and R' or R ^b, where R * is a protecting group 'carboxy ^ b ^ o ^ xytové function selected from the group' consisting t.etτahydIr) pyr'anhlΌ.vý) and Hylov, henzylový,. The 4-methylsilylbutylbutyl, 2,2,2-lichloroethyl, tert -butyl, and phenacyl radical and Rb is hydrogen or an ester radical readily a hydrolyzable in-viva selected from the group consisting of 3-hydroxyidyl, 4-cretholactyl, 4-butyrolactolin-4-yl, or a radical of formula (I); R * R * I with I 6! R't - COCOR ^{/ C} OOCOOR α-CHOCOR, _S l _S ' R ^s R ⁵ · - · Λ * «ггэ 4У T? r * O ^ * * ^cy I ^c · 'z' Azo C o wherein each of R ⁴ and R 5 is an atoim hydrogen or methyl group, R ^G is a C 1 -C 5 alkyl group and R 14 is a radical of formula wherein: 2-carboxy-2-fenylaceIaιmidosk · ^up, aniline, 2-carboxy-2- (2-thienyl jacetamidoskupinu 2-knirboxy-2e (3-thienyl íaceitaimidoskupinu, D-2- (4-ethye22, ediΏιX'opιipe ^ι Razine ₁ ( _1- Benylamino-amino) -2-phenylacetonitrile; ^2,2-d dimethyl-4-phenyl-5-L-imiida'zolidlnon. ylovoiu group, one of R ¹² and R ⁿ is hydrogen and the other of these means symboťů viιnylcvcu group alkylsuffonyloivou group having from 1 to 4 carbon atoms, furyl, thienyl, N-methylpyrrigolyl or N-acetylpyrrolidinyl, the remainder CH. (4) NR ¹⁶ R ¹ 7 CNR ⁸ R ⁹ II p R 15 represents 2-phenylacetaimidoskuptou, D-2-aimino-2-enyla-cetamido, D-2-aminoe2- (4-hydroxyphenyl) acetamido, CNR ⁸ R ⁹ II NH / 240746 - N 41 ± -R or with the restriction that R ^{12 represents} or Where R @ ^{13 is} p, then R @ ^{7 is} not hydrogen or methyl, in which m is 2 or. 3, p is 0 or 1, t is 0, 1 or 2, Představuje, represents sulfur, oxygen or NR ¹¹ , R ⁷ represents a hydrogen atom, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, an allyloxy group, a hydroxyl group, a carboxyl group, a C 2 -C 5 alkoxycarbonyl group, a C 1-5 alkylcarbonyl group carbon atoms, phenyl, benzyl, naphthyl, pyridyl, NR ⁸ R ⁹ , CONR ⁸ R ⁹ , NHCOR ¹⁰ , mitro, chlorine, bromine, trifluoromethyl or NR ⁸ , R ⁸ and R ⁹ are each independently hydrogen, C 1 -C 4 alkyl, phenyl or benzyl; R ¹⁰ represents an alkyl group having 1 to 3 carbon atoms, a triethylamino group or a phenyl group, R ¹¹ is hydrogen, methyl, ethyl or acetyl ia R ¹⁶ and R ¹⁷ are each independently hydrogen, C 1 -C 4 alkyl or C 2 -C 4 hydroxyalkyl, or R ^1G and R ¹⁷ together with the nitrogen atom to which they are attached form a pyrrolidino group , piperidiino, a group, morpholinoskuipine, thiomorpholinoskuipine, or 4-methylpiperazinoquinoline, af arm and eutilic acid addition salts of those compounds in which R ¹² or R ¹³ contain a basic atom nitrogen or pharmaceutically acceptable cationic salts of the above compounds wherein R ¹ is hydrogen or R ¹² or R ¹³ contain a carboxyl group, characterized in that the compound of formula X wherein: R ¹ , R ¹² , R ¹³ and n are as hereinbefore defined, this compound optionally being acetylated on a free hydroxyl group with acetyl chloride, acetylbroimide or acetic anhydride in the presence of an equimolar amount of tertiary amine and in the presence of an inert organic solvent; It is lysed in the presence of an inert solvent with organotin hydride or hydrogen in the presence of a noble metal base catalyst to form the compound of formula II T ...... COOR (X) in which R ¹ has the above meanings except hydrogen n is 0 or 2, is reacted with an equimolar COMES n i s Pieces in mia o у 1 m.ag not siumhalogeniďu having 1 to 4 carbon atoms in the alkyl moiety or- alkyllithium 1 -C And the aldehyde of the formula R ¹² R ¹³ CO, wherein the aforementioned halide is the corresponding chloride, bromide or joidide and R ¹² and R ¹³ are as defined above, in the presence of an inert solvent at a temperature of from -100 to 100 ° C. -b 25 ° C to give a compound of formula XI wherein R ¹ , R ¹² , R ¹³ and n are as defined above and R ¹⁸ represents a hydrogen atom or an acetyl group, is dehydrated or deacetylated, and optionally the resulting compound of formula Г is converted to its pharmaceutically acceptable acid addition salt or cationic salt. 2. A process according to claim 1, wherein a corresponding substance substitution is used to form compounds of the general formula Г in which: R ^{1 and} n are as in point 1, one of R ¹² and R ¹³ (represents an atom of hydrogen, the other of which is vinyl, furyl, thienyl, N-methylpyrrolyl or N-acetylpyrrolyl), the remainder CH (R ⁴ ) NR ¹⁶ R ¹⁷ CNR ⁸ R ⁹ II p CNR ⁸ R ⁹ NH With the restriction that R ^{11 is 2} or R 13 is a radical of formula (U / pa) p is 0, then R7 is not hydrogen or methyl, in which formulas m is 2 or 3, p is 0 or 1, t is 1 or 2, Xi presents! sulfur or oxygen, R 7 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, allyloxy group, hydroxyl, carboxyl, C 2 -C 5 alkoxycarbonyl, C 1 -C 5 alkylcarbonyl , 'NR8r', CONR8R9, NHCOR10, nitroL, bromo, trifluoromethyl or NR8, R 8 and R ^{9 are each} independently hydrogen, C 1 -C 4 alkyl, phenyl or n-benzyl; R10 represents an alkyl group having 1 to 5 carbon atoms 4-carbon atoms, trifluoromethyl or phenyl, R11 represents a hydrogen atom, a 'methyl, ethyl or' acetyl group and a R16 and R17 independently either 'one another are each a hydrogen' atom, an alkyl group having 1 to 4 carbon atoms or hyd.roxyalkylovou group having 2 to 4 carbon atoms, or R 1 and R ^{1G 7} together with the nitrogen atom to which they are attached, it forms a piperidino group, a piperidino group, a scorpion, a thiomorpholino group. or a 4-methylpiperazino group, and pharmaceutically acceptable acid addition salts thereof, in which R 12 or R ¹³ contain a basic nitrogen atom or a pharmaceutically acceptable salt. The salts of the aforementioned compounds with no more than ¹ R 1 are known to be hydrogen or the radicals R ¹ - or R 13 contain. carboxy group. 3. The 'by' method. 1 or 2, characterized in that the reaction is carried out. with an amide of the general formula R @ ¹² R @ ¹³ CO @ - at -78 DEG C. in the presence of a titanium dioxide or ethyl ether. . 4. A process according to claim 3, wherein the starting aldehyde of formula R12RI3CO is one wherein R12 and R13 are hydrogen and the other is A 2-thiazolyl group, A 3-isothiazolyl group, a 5-methyl-3-oxazolyl group, a 1,2,4-thiadi-2-zol-N-yl group, a pyridazin-3-yl group, 1,2.3-thiadiazin-4-yl, 1.2.4-Oxadiazin-3-yl group 1.2.4-oxa-diazin-5-yl, 1,3,4-oxoxidazol-2-yl, 1-phenyl-5-methyl-2,2,3-triazin-4-yl group N-methyl-11,2,4,4-1,4-biphenyl-2-yl-5-yl-1,3-methyl-1H-diazin-4-yl, α-pyrimidinyl , 4.5dimethylthiazol-2-yl! Qvou group benzolhitizol ^ -yl or · l ^ - ^ t ^ e ^ N ^ ^ yln (n ^ _i ^ ^ i ^ ddai KLL-2-yl 'group, 5. A method according to claim 1 or 4, wherein the compound of formula (X) in which:. R ¹ represents allyl-lovoiu or benzyl, is reacted with methylmagnesium bromide and an aldehyde of formula R ^ R ^ CO, and · the compound of Formula II is obtained hydrogemolysou tri-n-butyltin hydride in benzene or toluene ja ^ k ^ of solvent at a temperature of from 0 ° C to the boiling point of the solvent. 6. The process of claim 4, wherein the starting material is an aldehyde of the above formula wherein one of R13 and R13 is hydrogen and the other is 2-thiazolyl or benzoithiazol-2-yl. group. 7. A process according to any one of claims 1 to 6, wherein starting materials in which R1 is an allyl group are converted to the corresponding products wherein R1 is hydrogen, sodium or potassium by reacting the resulting allyl ester product. with catalytic amounts of tetrakis (tert-butylphosphine) palladium (0) and triphenylphosphine, and an equimolar amount of sodium or potassium salt of 2-ethylhexanoic acid in the presence of an inert solvent.