HU194567B - Process for production of derivatives of 6-substituated methilen-penicillane acid - Google Patents

Abstract

Process for the preparation of 6- (substituted) methylenpenicillan and 6- (subst.) Hydroxymethylpenicillanic acids and their derivatives. b-lactamase inhibiting compounds of the formulas or a pharmaceutically acceptable acid addition salt or carboxylate salt thereof, wherein n is 0, 1 or 2, X3 is H or Br, R1 is H, is the residue of certain carboxy protecting groups or the residue of an in vivo readily hydrolyzable ester group R12 and R13 is H and the other is vinyl, certain aryl, arylthio, alkylthio, alkylsulfonyl or certain heterocyclyl, aminomethyl, thiocarboxamido or amidino groups, one of R2 and R3 is H and the other such R18 is H or certain acyl groups, intermediates useful in their preparation, processes for their preparation and their use, and pharmaceutical compositions containing them. Formulas (I) and (II)

Description

The present invention relates to novel 6- (substituted-methylene) -penicillanic acids, novel 6- (substituted-hydroxymethylene) -penicillanic acids, certain esters and their pharmaceutically acceptable salts, for the preparation of pharmaceutical compositions containing them as active ingredients and their use as beta-lactamase inhibitors. .

One of the most well-known and widely used classes of antibiotic compounds is the beta-lactam antibiotics. These compounds contain a 2-azetidinone (beta-lactam) central moiety linked to either a thiazolidine or dihydro-1,3-thiazine ring. When the central ring is attached to a thiazolidine ring, the compounds are referred to as penicillins, while the compounds containing the dihydrothiazine ring are cephalosporins. Typical examples of penicillins used in clinical practice are bis-cis-pylcillin (penicillin G), phenoxymethyl-penicillin (penicillin V), ampicillin and carbapenicillin; typical examples of cephalosporins used are cephalotin, cephalexin and cephalosporin.

Despite the fact that beta-lactam antibiotics are widely used as effective chemotherapies, they have the disadvantage that certain types are not active against certain microorganisms. It is believed that in many cases the resistance of the microorganism to the beta-lactam antibiotics results from the production of the beta-lactamase by the microorganism. It is an enzyme that cleaves the beta-lactam ring of penicillins and cephalosporins to produce products that have no antibacterial activity. Certain compounds are capable of inhibiting beta-lactamase enzymes and, when used in combination with penicillin or cephalosporin, such a beta-lactamase inhibitor can increase or enhance the antibacterial activity of cephalosporin or penicillin against said microorganisms. If the antimicrobial activity of the combination of a beta-lactamase inhibitor and a beta-lactamase antibiotic is significantly greater than the sum of the individual effects of the components, we are talking about enhancing the antibacterial activity.

The present invention relates to novel 6-substituted-methylene-peniciflanic acids, their 1-oxides, 1,1'-dioxides and readily hydrolyzable esters thereof in vivo. These novel penicillanic acids and their readily hydrolyzable esters in vivo are potential inhibitors of microbiological beta-lactamases. Accordingly, the present invention relates to a process for enhancing the efficacy of beta-lactam antibiotics using novel acids, their salts and certain readily hydrolyzable esters.

The invention further relates to a process for the preparation of 6-substituted-methylene-penicillanic acids, their 1-oxides and 1,1-dioxides as a synthetic intermediate containing a new carboxy protecting group.

The present invention also relates to a process for preparing 6- (substituted-hydroxymethylene) penicillanic acids, their 1-oxides,

1,1-dioxides, salts and esters thereof, which can be used both as synthetic intermediates and as beta-lactamase inhibitors.

European Patent Application No. 50,805 is a compound of general formula (III) wherein n is 0,1 or 2; |

R ¹ is a cyano group or a group containing a certain carbonyl moiety;

R ² is hydrogen, lower alkyl or halogen; and R ³ is hydrogen or a readily hydrolyzable group as effective beta-lactamase inhl. In the same description, oR oxo-penicillinic acid esters, their corresponding causes and sulfoxides are also described, as well as a process whereby the compound of general formula (III) is as described above and R * R ² C = P ( C ₆ H ₅ ) Prepared by reaction of ₃ phosphoranes.

British Patent GB 2,053,220A discloses, among other things, the 6-methylene-1,1-thloxycapnicillinic acid and its esters of the general formula (III), wherein n is 2, R 1 and R ² are independently hydrogen, the desired optionally substituted alkyl, aryl, optionally substituted cycloalkyl, an aralkyl, an optionally substituted amino group or the carbon atom or together Ri and ^R2 are seven membered carbocycle or heterocycle is substituted.

U.S. Pat. No. 4,287,181 discloses certain features

6-substituted penicillinic acid 1,1-dioxides and their esters, wherein the 6-substituent is of the formula XIII and, among others, R ³ is hydrogen or alkanoyl, R ⁴ is hydrogen, C 1-4 alkyl, phenyl or pyridyl. which are potent beta-lactamase inhibitors.

The present invention relates to a novel process of formula (I)

6- (substituted methylene) penicillinates wherein n is 0, 1 or 2,

R ¹ is hydrogen, C 2 -C 5 alkenyl, phenyl (C 1 -C 4) alkyl, or (C 1 -C 5) alkylcarbonyloxymethyl,

R ² and R ³ is a hydrogen atom and the other represents a chlorine atom, a hydroxymethyl group, a vinyl group, C1-4 alkylthio group, C1-4 alkylsulfonyl group, a furyl, thienyl, N-methyl-pyrrolyl, N -acetylpyrrolyl, a group of the formula (XLI), (XLII), (XX), (XXI), (XXII), (XXIV), (XXV), (XXVI), (XXXIV) or (XXXV), and p is 0 or 1, t is 0.1 or 2,

Xj is a sulfur atom or a group of formula XLVI,

R ¹ is hydrogen, C 14 alkyl, C 14 alkoxy, allyloxy, chloro, bromo or trifluoromethyl, and

R ⁿ is hydrogen, methyl or ethyl and salts thereof.

Prepared by the process of the present invention

Of the 194,567 compounds wherein R ¹ is R a and R ^a is C 2 -C 5 alkenyl or phenyl (C 14) alkyl, suitable intermediates for the preparation of compounds wherein R * is R ^b and R ^b is H ^v brain (C1-5) alkyl-carbonyl-oxy-methyl.

Compounds of formula (II) are suitable intermediates of formula (I)

6- (substituted-nictylene) -1,5-dioxopenyl / Tok. Plus, it's f'2. ^{Compounds of} formula ^{III in} which R ^{1 is} hydrogen or an easy in vivo hydro, ester moiety, as described above, for example, inhibitors of beta-lactamase, especially in combination with a beta-lactam antibiotic.

The compounds of the present invention, particularly preferred compounds (I) are those of formula I wherein n is 0 or 2, and R ² and R ³ is a hydrogen atom and the other represents a furyl group, a thienyl group, a hydroxymethyl group, methylsulfonyl N-methylpyrrolyl, (XX), (XXI), (XXIV) or (XXV).

Particularly preferred are carboxyl protecting groups, allyl or benzyl. The allyl group is particularly preferred because its preparation and removal is relatively selective.

Particularly preferred in vivo readily hydrolyzable ester residue groups are alkylcarbonyloxymethyl groups.

The compounds of formula (I) are useful for treating bacterial infections in a mammal, including a human, comprising administering to the mammal an antibacterially effective amount of a compound of formula (I) wherein R ¹ is as defined above.

Compounds of formula (I) wherein R * is hydrogen or group (XVII) may be used as potent inhibitors of beta-lactamase enzymes. Through this mechanism, these compounds increase the activity of beta-lactam antibiotics (penicillins and cephalosporins), especially against microorganisms that are partially or wholly resistant to beta-lactam antibiotics, because they produce enzymes (beta-lactamases) that are completely or they partially decompose beta-lactam antibiotics. By constructing such an inhibitor, the spectrum of action of the beta-lactam antibiotic can be broadened.

The compounds of the present invention are generally effective in enhancing the activity of beta-lactam antibiotics, but preferably in peninicillin or cephalosporin compounds such as amoxicillin, ainpicillin, apalcillinne, phenolycin, carbamycin, , cefalorammal, cefamandollal, cefaniandol naftiláttal, cefaparotlal, cefatrizínnel, cefazolinnal, cefbuperazonnal, cefoniciddel i cefmenoximmal, cefodizimmel, cefoperazonnaJ, ceforaniddel, cefotaxime, cefotiammal, cefoxitinnel, cefpiramiddal, cefpirommal, cefsulodinnal, ceftazidirnmal, ceftizoximmal, ceftriaxone, cefuroxime, cefacetriilel, cephalexin , cephalogilcin, cephalorodine. cephalotin, cefapyrin, cefradine, cyclacillin. epicillin, furazlocillin, hetacillin, lenampic swine, levopropylcillin, mecillinam, meslocillin, penicillin V, phenethylcillin, piperacillin, pirbenicillin, pivampicillin, sarm, and pharmaceutically acceptable salts thereof. The names given above for the beta-lactam compounds are USAN names, i.e. names accepted in the United States.

The beta-lactamase inhibitors of the present invention are also useful in the preparation of 7- (2- (2-aminoamino-4-liazolyl) -2- (methoxyimino) acetamido) -3- (5,6-dihydro-4-pyridinium). ) - Methyl -3-cetene-4-carboxylate (HR-810); With 7- (2- (2-amino-4-thiazolyl) -2- (methoxytinino) acetamido) -3 - ((N-methylpyrrolidinium) methyl) -3-cephem-4-carboxylate (BMY- 28.142); and 7- [D-2 - ((4-carboxy-5-imidazole-carboxamido) -2-phenylacetamido] -3- (4- / 2-sulfonatoethyl) pyridinium) -3-cephem-4 -kar1 in combination with onic acid.

Although the compounds of the invention may be administered separately from the beta-lactam antibiotics, a combination dosage form is preferred. A pharmaceutical composition for oral or parenteral administration comprises a beta-lactamase inhibitor of the general formula (1) in a weight ratio of 1: 3 to 3: 1 and a beta-lactam antibiotic in an amount sufficient to effectively treat bacterial infection of a mammal in a single or routine treatment.

Further, the compounds of formula (I) prepared by the process of the invention wherein R ¹ is hydrogen are capable of forming cationic salts and these salts of pharmaceutically acceptable cations are also within the scope of the invention. Suitable cations include sodium, potassium, ammonium, calcium, magnesium, zinc, and substituted ammonium salts of amines such as diethanolamine, choline, ethylenediamine, ethanolamine, N-methylglucamine. and procaine.

The compounds of the present invention are derivatives of penicillanic acid of formula (LI). In the penileillanic acid derivatives, the dashed substituent bonds indicate that the substituent is located below the plane of the bicycle. These are called alpha configuration substituents. In contrast, the bold substituent bonds indicate that the substituent is located above the plane of the bicyclic ring. Such substituents are referred to as beta configuration substituents. When the substituent in the formulas is bonded to the central lymphatic system by a normal solid line, this means that the substituent can be either above or below the plane of the bicyclic ring, i.e., in either the alpha or beta configuration.

In accordance with the invention, methods A, B, and C 3

194,567 can be prepared which are shown in the flowcharts. '

The Wittig salts of formula (LH) required for process A, or known compounds or conventional synthetic methods as described above, can be readily prepared from commercially available precursors.

Preparation of Wittig salts

The alcohols R ³ CH ₂ OH are converted to the corresponding chloromethyl compounds, typically by reaction of the alcohol with an equivalent amount of thionyl chloride in an inert solvent such as chloroform or dichloromethane at about room temperature. The product is isolated, for example, by neutralization of the reaction mixture and extraction.

The chloromethyl compound of formula R ³ CH ₂ Cl is then converted to the Wittig salt by reaction with an equivalent amount of triphenylphosphine. This reaction step is generally carried out in toluene or similar solvent at elevated temperature, preferably at reflux temperature. The desired product precipitates out and can be filtered off.

6-alpha-hydroxypenicillanic acid is a known compound, see, e.g., Hauser et al., Helv. Chim. Acta, 50, 1327 (1967). The acid is converted to the protected carboxy derivative of formula (IV). The quality of the carboxy protecting group is not critical. The only requirement is that the carboxy protecting group (i) is the oxidation reaction used to prepare the 6-oxo-penicillanic acid ester of formula (V) and the subsequent reaction with the Wittig reagent of formula (VI, R ¹ = R ^a ) It must be stable under the reaction conditions which result in the 6- (substituted-methylene) penicillanate;

(ii) be selectively removable from the resulting compound of formula (VI, R ¹ = R ^a ) so that neither the beta-lactam nor the 6-substituted-methylene group undergoes a chemical reaction under the reaction conditions used;

(iii) be stable in the oxidation of the compound of formula (VI, R ^1; = Ra) to the sulfone of formula (VII) or the corresponding sulfoxide. Examples of suitable carboxy protecting groups include tetrahydropyranyl, benzyl, benzhydryl, 2,2,2-trichloroethyl, allyl, tert-butyl and phenacyl. See also U.S. Patent Nos. 3,632,850 and 3,197,466; British Patent No. 1,041,985; Woodward et al., Journal of the American Chemical Society, 88, 852 (1966); Cbauvctte, 1971, Journal of Organic Chemistry, 36, 1259; Jorunal of Organic Chemistry, 29, 2006 (1964); and Cephalosporin and Penicillins, Chemistry and Biology, eds. Η. E. Flynn, Academic Press, Inc., 1972. Particularly preferred such groups are allyl, benzyl and 2,2,24

-trichloroethyl, the allyl group is very advantageous as it is easily prepared and selectively removable.

The oxidation of the carboxy-protected 6-alpha-hydroxypenicillanate of formula (IV) to the corresponding 6-oxo-penicillanate ester of formula (V) is generally carried out with an equivalent amount of trifluoroacetic anhydride and molar excess dimethylsulfoxide, methylene chloride. The reaction is preferably carried out at temperatures between about -80 ° _v -7t. The reaction mixture is quenched by addition of, for example, a tertiary amine such as, then partitioned between water and a water-miscible solvent, and then the organic phase is evaporated.

The 6-oxopenicillanate ester (V) is then reacted with the Wittig reagent (LII). This reaction is preferably carried out in a reaction solvent such as a hydrocarbon such as pentane, hexane, benzene, toluene, xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,2-dibromoethane or chlorobenzene; in an ether-type solvent such as tetrahydrofuran, dioxane, diethyl ether, 1,2-dimethoxyethane, or t-butyl methyl ether. The reaction is carried out at a temperature of about -100 ° C to + 50 ° C, preferably about -78 ° C to + 25 ° C.

The desired product of formula (VI, R ¹ = R ^a ) is isolated by conventional methods. R ^a is C 2 -C 5 alkyl or phenyl (C 1 -C 4) alkyl. For example, the reaction is quenched by the addition of aqueous ammonium chloride, and the reaction mixture is extracted with a water-immiscible solvent and the solvent is evaporated. If desired, the resulting product may be purified by conventional techniques known in the art, such as, for example, silica gel column chromatography.

Then (VI, ^R? = ^R) compound of formula wherein R ^a is as defined above carboxy-protecting group, (VI; R * = R ^b) to the acid of formula, or- converted in vivo easily hydrolyzable ester, wherein R ^b is hydrogen or Icylcarbonyloxymethyl. In general, the arboxyl protecting group 1 is removed from intermediate (VI,} V = Ra) and the corresponding carboxylic acid is prepared. The method used to remove the carboxy protecting group depends on the quality of the R ^a ester-forming group, but a suitable method is readily available in the literature.

As described above, a particularly preferred carboxy protecting group is the allyl group. This protecting group can be removed under both mildly acidic and mildly basic hydrolysis conditions, but it is particularly advantageous to remove the soluble P illadium (O) complex, for example te trakis (triphenylphosphine) palladium (O), as a catalyst. Jeffrey and McOmbie / J. Org. Chem., 47, 587-590 (1982). In a typically inert solvent such as dichloromethane, chloroform, ethyl acetate, the allyl ester is catalytically present in an amount of about -47 to the allyl ester.

194,567, mixed with 1-5 mol% of tetrakis / triphenylphosphine) palladium (O) catalyst and triphenylphosphine of approximately equivalent weight. An equimolar amount of the sodium or potassium salt of 2-ethylhexanoic acid relative to the starting allyl ester is added and the mixture is stirred at room temperature until the desired salt of formula VI, wherein R ¹ is sodium or potassium, is formed. The reaction is usually complete within 2 to 20 hours. The salt is then isolated, for example, by filtration.

If the process according to the invention is to produce sulfide oxides or sulfones for which n in formula I is 1 or 2, the sulfides of formula VI are oxidized using oxidizing agents known in the art to oxidize sulfoxides to sulfones. Any such oxidizing agent may be used, but preferably metal permanganates such as alkali metal permanganates and alkaline earth metal permanganates, organic peroxyacids such as organic peroxycarboxylic acids. Suitable reagents include sodium permanganate, potassium permanganate, 3-chloroperbenzoic acid and peracetic acid.

Preferred oxidizing agents are organic peroxyacids, with 3-chloroperbenzoic acid being a particularly preferred organic peroxyacid.

When the desired product is a compound of formula (I) wherein n is 1, i.e. a sulfoxide, about a molar equivalent of the starting sulfide (n is 0) and an oxidizing agent is used. When the desired product is a sulfone, wherein n is 2 in the formula (I), the sulfide is reacted with two moles equivalent of an oxidizing agent. Of course, the sulfoxide can also serve as a starting material for the preparation of the corresponding sulfone. In this case, at least about one molar equivalent of oxidizing agent must be used in the reaction.

If the compound of formula (VI, R '= R ^a ) wherein R ^a is as defined above is oxidized to the compound of formula VII by use of an organic peroxyacid such as a peroxycarboxylic acid, and finally reacting the compound of formula (VI, R '= R ^a ) with 2-4 molar equivalents of the oxidizing agent in the reaction solvent. Examples of suitable solvents include halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane; ethers such as diethyl ether, tetrahydrofuran and 1,2-dimethoxyethane. The reaction is generally carried out at a temperature of about -20 ° C to about 50 ° C, preferably about 25 ° C. The reaction time is usually about 2 to 16 hours. The product is generally isolated by evaporation of the solvent in vacuo. The product may be purified by conventional techniques known in the art.

Preferably, the above oxidation processes can be carried out on starting materials wherein the carboxy group is provided with ^the carboxy protecting group R as defined above. Removal of the carboxy protecting group from the sulfoxide or sulfone product is carried out according to the usual methods for the nature of the protecting group employed, see, for example, the procedures described above for compounds of formula (VI, R ¹ = R ^a ).

The present invention of Formula (la) compounds in which ^R1 is an ester group readily hydrolyzable in vivo, the ester by conventional methods and appropriate starting materials in which ^R1 is hydrogen, can be prepared preferably. The particular method of preparation will depend upon the quality of the ester-forming group, but the appropriate preferred method may be readily selected from the literature. When R * is an alkylcarbonyloxymethyl group, the compounds may be prepared from the corresponding starting material of the present invention wherein R ¹ is hydrogen, by alkylation with the appropriate halide. By halide and halogen we mean chlorine, bromine and iodine derivatives. The reaction is typically carried out by dissolving the compound of formula (I) wherein R ¹ is hydrogen or a salt thereof in a suitable polar organic solvent such as például, Ν-dimethylformamide and adding about 1 molar equivalent of the corresponding halide. When the reaction is complete, the product is isolated by conventional methods. Often it is sufficient to dilute the reaction mixture with excess water and extract the product with a water immiscible solvent and then evaporate the solvent. Commonly used starting materials are salts, alkali metal salts such as sodium and potassium salts, tertiary amine salts such as trictylamine, N-ethylpiperidine, Ν, Ν-dimethylaniline, and N-methylmorpholine. salts, quaternary ammonium salts such as tetramethylammonium salts and tetrabutylammonium salts. The reaction is usually carried out at a temperature of about 0 ° C to 100 ° C, usually about 25 ° C. The reaction time required depends on several factors, such as the concentration of reagents and the reactivity of the reagents. Accordingly, with regard to the halogen derivative, iodine derivatives react more rapidly than bromine derivatives, which react more rapidly than chlorine derivatives. If a chlorine derivative is used in the reaction, one molar equivalent of an alkali metal iodide is preferably added to the reaction mixture. This will speed up the reaction. Depending on the above factors, the reaction time is generally from about 1 to about 24 hours.

If process B is intended to provide a compound of formula II wherein n is 2, X ³ and R ¹⁸ are each hydrogen or VIII is prepared, the desired compound of formula IX is prepared. alpha-bromo-1,1-dioxopenicillanate ester starting material using an equimolar amount of a low molecular weight Grignard reagent such as methyl inagnesin bromide, ethylmagnesium chloride or butyl magnesium iodide in an ethereal solvent, preferably tetrahydrofuran or in diethyl ether at -80 ° C to 25 ° C, typically -78 ° C, to a Grignard reagent. After stirring for a few minutes, an equimolar amount of the aldehyde (LVI) of the general formula (LVI) was added to the reaction mixture.

194,567, which was further stirred until the reaction was complete. The reaction is usually complete at about the same temperature for about 10 minutes to about 4 hours. The ester of the compound of formula II wherein n is 2 can be isolated from the reaction mixture by conventional means. For example, the reaction is quenched by the addition of aqueous ammonium chloride solution and the product is extracted with a water immiscible solvent. For example, the product of formula II can be further purified by column chromatography on silica gel.

Dehydration of the secondary alcohol of formula II wherein n is 2, X ³ is hydrogen to give the corresponding 6- (substituted-methylene) -1,1-dioxopenicillanate compound of formula (VIH). Many methods known in the art for dehydrating secondary alcohols can be used in the above step of the process, but preferably the alcohol is converted to acetate with at least one molar equivalent of acetic anhydride and pyridine, and the reaction mixture is stirred at room temperature for about 1-10 hours. . The reaction is generally quenched by the addition of water and the compound of formula (II) - n is isolated by extraction and further purified if desired.

In the compounds of formula (II) or (VIII) obtained by the above process, R ¹ is either R ^a , a carboxy protecting group as defined above, or R ¹ ', an ester-forming group as defined above. These esters, when R ¹ is R ^a , can be converted to the corresponding carboxylic acids (R ^b is hydrogen) by the methods described above. Of course, if desired, the carboxylic acids of formula (VIII) may be converted into the corresponding derivative wherein R ¹ is as defined above; an easily hydrolyzable ester-forming group in vivo.

The starting 6-alpha-bromo-1,1-dioxopenicillanate esters of formula IX are typically prepared from 6,6-dibromo-1,1-dioxopenicillanic acid which is reacted with sodium bicarbonate followed by sodium bisulfite. the reaction mixture is acidified. The resulting 6-alpha-bromo-1,1-dioxopenicillanic acid is then converted to the ester of formula IX.

The starting esters of formula (X) used in process C are known compounds, for example described in U.S. Patent 4,234,579. In the process of the present invention, the starting ester of formula (X) is typically used in a reaction solvent in a low temperature organic solvent such as toluene, xylene, pentane, tetrahydrofuran, diethyl ether or a mixture thereof, with butyl lithium reagent such as butyllithium. , with tert-butyl lithium or methyl lithium, and lithium penicillin intermediate is prepared. This is reacted directly with an aldehyde in an equimolar amount of the compound of formula (LVI), wherein R ¹² and R ¹³ are as defined above, and the reaction mixture is carried out for about 1-4 hours, at about -100 ° C to 50 ° C, preferably -78 ° C. stirring. The reaction is then quenched and the bromohydrin intermediate of formula XI is isolated, for example, by partitioning between water and solvent and purifying by silica gel or Florisilium (magnesium silicate) chromatography.

Alternatively, the starting dibromo ester of formula (X) above is reacted with an equimolar amount of the low molecular weight Grignard reagent using the reagents and reaction conditions described in Method B to give the bromohydrin of formula (XI).

The bromohydrin (XI) can be acylated and the corresponding compound (XII) can be prepared. Typically, the acylation is carried out with an equimolar amount of acid chloride, acid bromide or the corresponding acid anhydride. The intermediate bromohydrin (XI) is reacted with an equimolar amount of an acylating agent and a tertiary amine such as pyridine, N-methylmorpholine or the like in an inert organic solvent such as dichloromethane, tetrahydrofuran or ethyl acetate at room temperature or at room temperature. The desired diester of formula (XII) can be isolated by known methods such as extraction and evaporation of the solvent and, if desired, purified by column chromatography.

The bromohydrin ester of formula XI or the bromide ester of formula XII can then be subjected to hydrogenolysis and the bromine atom removed. This reaction can be carried out using a wide variety of known reduction techniques and reducing agents, for example, reduction of bromohydrin with hydrogen in the presence of a noble metal catalyst, or reduction with certain organic tin hydrides.

Preferred organic tin hydrides in the process are dialkyl tin hydrides, trialkyl tin hydrides in which the alkyl groups are C1-C6 alkyl, and triaryl tin hydrides in which the aryl group may be phenyl or nitro, C1-C3 alkyl or C1-C3 alkyl; substituted phenyl. Particularly preferred are triphenyltin hydride and more preferably tributyltin hydride because they are inexpensive and highly effective reagents.

The reaction using the above tin hydrides is generally carried out in the presence of a solvent in the reaction. Such solvents are those which dissolve the starting compounds of formula (XI) or (XII) but do not react with the tin anhydride blocking agent. Examples of such solvents are aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene and naphthalene; ether-type solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane and 1,2-dinethoxyethane. Particularly preferred economical and effective solvents are benzene and toluene.

The reduction process using organic tin hydride is theoretically using equimolar amounts of bromohydrin XI or bromide ester XII and hydride. In practice, in many cases an excess of hydride is used, for example an excess of 5 to 50% mole percent, to ensure complete reaction.

Reduction with organic tin hydrides

-611 leads to complete reduction under the preferred reaction conditions mentioned above without the use of a catalyst. However, the reaction is promoted using a free radical source such as ultraviolet light or a catalytic amount of azabis (isobutyronitrile) or a peroxide such as benzoyl peroxide. Preferably, a catalytic amount of azobis (isobutyronitrile) is used as the radical source in the reaction.

Typically, the compound of formula (XI) or (jellemző) is dissolved in the reaction solvent. The solution is maintained under an inert atmosphere, such as nitrogen or argon, and an appropriate amount of an organic tin hydride and, if desired, a free radical source such as azo-bis (isobutyronitrile) are added and the reaction mixture is preferably about 0 ° C and boiling point of the solvent. and stirring. The reaction is usually complete in a few minutes to several hours, for example at the boiling point of benzene, 5 minutes at 0 ° C and 20 hours. The compound of formula (II) X ³ is then isolated by methods known in the art. For example, the solvent is evaporated and the residue is purified by chromatography on silica gel.

X ^3, represented by the above-described organic tin hydride debromination process, is hydrogen, and the compounds are predominantly beta isomers, i.e., the substituent LV1I is in the beta configuration.

When the hydrogenolysis is carried out using hydrogen gas in the presence of a noble metal catalyst, a preferred embodiment is the solution of a compound of formula XI or XII in a hydrogen atmosphere or in a hydrogen gas mixed with or shaking them. Suitable solvents for the hydrogenation are those which dissolve the starting compounds of formula XI or XII and do not react with hydrogenation. Examples of such solvents include ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane; low molecular weight esters such as ethyl acetate and butyl acetate; tertiary amides such as Ν, Ν-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone, water and mixtures thereof. In addition, it is often advantageous to buffer the reaction mixture and to ensure that the reaction is carried out at a pH of about 4-9, preferably about 6-8. Borates, bicarbonates and phosphates may be used as buffers. The introduction of the hydrogen gas into the reaction mixture is usually carried out by carrying out the reaction in a sealed vessel containing the compound of formula (XI) or (XII), the solvent, the catalyst and hydrogen gas. The pressure inside the reaction vessel is about 1 to 100 kg / cm ² . If a clean hydrogen gas atmosphere is used in the reaction vessel, a pressure of about 2-5 kg / cm ^{2 is} preferred. The hydrogenolysis is generally carried out at a temperature from about 0 ° C to about 60 ° C, preferably from about 25 ° C to about 50 ° C. Hydrogenolysis is usually completed in a few hours, for example 2 to 20 hours, at the preferred temperature and pressure. Preferred noble metal catalysts for hydrogenolysis are those known in the art for carrying out this type of conversion, such as nickel, palladium, platinum and rhodium. Palladium catalysts are particularly preferably used. The catalyst is generally employed in an amount of from about 0.01% to about 25% by weight, preferably from about 0.1% to about 10% by weight, relative to the compound of formula (XI). Often, the catalyst is preferably applied to a pre-inoculated carrier; a palladium catalyst on an inert support such as carbon is particularly preferred.

When hydrogenolysis is substantially complete, the product of formula (11), wherein X ³ is hydrogen, is isolated by conventional means. For example, the catalyst is filtered off, the solvent is evaporated and its products are purified, if desired, by known methods such as crystallization or chromatography.

If the starting compound of formula (XI) or (XII) is a benzyl ester (R ¹ = R ^a = benzyl), the above catalytic hydrogenation process also removes the benzyl group and in the product of formula (H) X ³ and R ¹ is hydrogen.

The (XTL) or (II) (X ³ = hydrogen) 6- (substituted lúdroximetil) -pemeillánsav or ester corresponding to the known literature módszeekkel sulfoxides or sulfones of formula oxidizable. For example, as described above using 3-chloroperbenzoic • r.av this oxidation can be accomplished, and the megelető (XII) or of formula (II, X ³ is hydrogen) the sulfoxide or sulfone can be prepared: where in the formula n is I or 2. However, in the preferred process for the preparation of sulfones of formula XI, XII or II, the corresponding 6,6-dibromo-1,1-dioxopenicillanate esters of formula X, wherein In formula 1, n is 2, use starting material in process C.

The starting aldehydes of the general formula (LVL), wherein R ¹² and R ¹³ are as defined above, are either commercially available or can be readily prepared from commercially available starting materials by methods known in the art. For example, their methods of preparation known in the art include:

1. Oxidation of the corresponding primary alcohols described previously as Wittig reagent precursors. In the oxidation, for example, potassium dichlorate, chromic acid / pyridine, catalytic oxidation in the presence of carbon monoxide, manganese dioxide oxidation agents may be used.

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

3. Reduction of the corresponding C 1 -C 4 alkoxycarbonyl compound with metal hydride in an ether-type solvent at low temperature. Such alcahnas metal hydrides may be, for example, aluminum aluminum hydride and diisobutyl aluminum hydride.

4. Reaction of the corresponding aromatic hydrocarbon precursor with butyllithium with dimethylformamide.

-713

194 5 (> 7

As noted above, compounds of formula I of this invention (I), wherein ^R1 in the formula is hydrogen, and using the salts, beta-lactam antibiotics in combination showed synergistic activity in in vitro antibacterial tests. This activity can be determined by measuring the minimum inhibitory concentration (MIC) for various microorganisms in mcg / ml. The assay is a method recommended by the International Collaborative Study on Antibiotic Sensitivity Testing (Ericsson and Sherris, Acta Pathologica et Microbiologia Scandinav, Supp. 217, Section B: 64-68 / 1971 /), and BHI (brain heart infusion) agar. and uses an inoculum delivery device. Overnight tube cultures were diluted 100-fold and used as a standard inoculum (approximately 0.002 ml containing 20,000 10,000 cells was injected onto the agar surface; 20 ml HHI agar / plate). Twenty-fold dilutions of the test substance at an initial concentration of 200 mcg / ml were used. Single colonies were disregarded when 18-h cultures at 37 ° C were performed. Sensitivity of a given microorganism (MIC) was defined as the lowest concentration of test compound or combination that, when measured by the naked eye, caused complete inhibition of growth.

The compounds of the present invention in which R * in the formula (I) is hydrogen may also be used in combination with known beta-lactam antibiotics as industrial antibiotics. They can be used, for example, for water treatment, sludge control, paint preservation and wood protection as well as for local disinfection. For such use, these active ingredients are preferably used in admixture with a non-toxic carrier such as a vegetable or mineral oil or a softening cream. The active compounds may also be dissolved or dispersed in liquid diluents or solvents such as water, alkanols, glycols or mixtures thereof. In most cases, formulations containing from about 0.1% to about 10% by weight of active ingredient can be used with satisfactory results.

Compounds of formula I according to the invention (I), wherein in the formula described above, R ¹ is R ^b, as before, are particularly preferred as potential inhibitors of beta-lactamase enzymes. This mechanism increases the activity of beta-lactam antibiotics (penicillins and cephalosporins), particularly against microorganisms that produce beta-lactamase. The ability of the compounds of formula (I) to produce beta-lactam antibiotics according to the present invention can be determined by reference experiments in which the beta-lactam antibiotic is used alone. MIC values are determined for the beta-lactam alone and for the compound of formula (I) wherein R ¹ is hydrogen. Then, these values are compared to the MIC of a given antibiotic and the compound (1) of the general formula according to the invention wherein in formula R ¹ is H - MIC values observed for the combination of the application. If the aliquot of the combination is much larger than what would be expected at the bottom of the single effect of the two separate compounds, there is a case for synergistic enhancement of the effect. MIC values for the combinations were determined according to the method of Barry and Sabath (Manual of Clinical Microbiology, ed. Lenette, Spaulding and Truanl, 2nd ed., 1974, American Society for Microbiology).

The compounds of formula (I) according to the invention, wherein R ¹ is hydrogen or an easily hydrolyzable ester forming group in vivo, increase the activity of beta-lactam antibiotics in vivo. Therefore, they reduce the amount of antibiotic required in mouse spleen against infection of an otherwise lethal bacterial inoculum producing lactal lactamase. To determine this, a standard culture of the microorganism to be tested in 5% porcine gastric mucin was administered intraperitoneally and an acute experimental infection was established. The severity of the infection was standardized by administering a lethal dose of the microorganism to the mice (the lethal dose is the minimum amount of inoculum that causes one hundred percent death of infected and untreated control mice). The test compound of the present invention, prepared in accordance with the invention, was administered in combination with an antibiotic at various doses, either ip or po, to groups of infected mice. At the end of the assay, the activity of the mixture was determined

It seems that we counted the number of surviving animals among the animals treated with the given dose. Activity was determined as a percentage of the number of animals that survived a given dose or PD _SO (the dose that protects 50% of the infected animals).

The property of the compounds of formula (I) produced by the process of the present invention to increase the potency of beta-lactam antibiotics against beta-lactamase producing bacteria allows them to be used in combination with beta-lactam antibiotics for the treatment of bacterial infections in mammals and especially in humans. For the treatment of bacterial infection, the compound of formula (I) of the present invention may be administered in admixture with beta-lactam antibiotics to deliver the two active ingredients simultaneously. Alternatively, the compound of formula (I) prepared by the process of the present invention may be administered as a separate active ingredient during treatment with beta-lactam. In some cases, the treated unit is preferably pretreated with the compound of formula (I) prepared by the process of the invention, preferably at the beginning of the treatment with beta-lactam.

If prepared according to the invention a compound of formula (I) wherein the general lepleiben ^R1 is ^Rb, which is as in the above stated, the beta-lactam antibiotic is used hatásnövelésére, with the beta-lactam antibiotic of the invention 815, preferably with conventional pharmaceutical carriers or diluents

194,567 Pharmaceutical Formulations A pharmaceutical composition comprising a pharmaceutically acceptable carrier will generally contain from about 5% to about 80% by weight of the beta-lactam antibiotic and / or the compound of formula (I) produced by the process of the present invention.

When used in combination with another beta-lactam antibiotic, the compounds of formula (I) according to the invention may be administered orally or parenterally, for example, intramuscularly, subcutaneously or intraperitoneally. However, the treating physician will always determine the dose to be used for treating people. The ratio of the compound of formula (I) wherein R ¹ is R ^b as defined above to the daily dose of antibiotic beta 4-lactam is generally from about 1: 3 to about 3: 1 by weight. In addition, when the compound of formula I is used in combination with a beta-lactam antibiotic, the normal daily dose of each component is about 10-200 mg / kg body weight for oral administration and about 10-40 mg / kg body weight for parenteral administration. These daily doses are usually administered in divided doses. In some cases, your doctor will determine that a dose other than these should be used.

As is known to those skilled in the art, certain beta-lactam compounds are active at both oral and parenteral administration, while others are only active at parenteral administration. When the compounds of formula (I) according to the invention are administered simultaneously (i.e., mixed) with a beta-lactam antibiotic which is effective only for parenteral administration, it is necessary to prepare a combined form suitable for parenteral administration. When the compound of formula (I) of the present invention is administered simultaneously (i.e., mixed) with a beta-lactam that is also active for oral or parenteral administration, a combined form suitable for oral or parenteral administration should be prepared. It is also possible to administer the form of the compound of formula (I) according to the invention orally, while the beta-lactam antibiotic is administered parenterally, and it is possible to administer the form of the compound of formula (I), according to the invention, -lactam antibiotic is administered orally to the treated individual.

The following examples illustrate the invention. The process of the invention is not limited to the following examples. Proton and ¹ 3 (- Nuclear magnetic resonance spectra were recorded at 60, 90, 250 or 300 MHz, deuterochloroform (CDC1 _3), heavy water (D ₂ O), perdeuterodimethyl acetone (CD ₃ COCD ₂₎ or perdeutero dimethyl sulfoxide ( DMSO-d in solution ₆ ) and chemical shift in ppm relative to tetramethylsilane The following abbreviations are used: s singlet, d doublet, dd doublet, t triplet, qqvartet, b multiplet.

Example 1 '

6alpha-ffroxy penicillanate esters

A. A solution of allyl ester g (0.39 mol) in 6-alpha-hydroxypenylsilanoic acid * in 300 ml dimethylformamide with 34 ml (0.39 mol) allyl bromide, 54 ml (0.39 mol) triethyltinine and 2 g sodium hydrogen carbonate! reacted. The reaction mixture was stirred for 15 hours at room temperature and quenched with water. The reaction mixture was extracted with diethyl ether, and the organic layers were combined and washed with saturated sodium bicarbonate solution and water. Then m ignéziumszulfáton (MgSO _4), dried and concentrated in vacuo. 43 g of crude product are obtained, which is purified by silica gel column chromatography (9: 1 chloroform: ethyl acetate) to give 22.5 g (23%) of the allyl ester.

¹ H NMR (CDCl ₃ ) ppm (delta): 1.42 (s, 311), 1.60 (s, 311), 4.45 (s, HI), 4.5 5.0 (m, 311) ), 5.26.2 (m, 4H).

Mauser et al., Helv. Chim. Acta, 50, 1327 (1967).

B. (Pivaloyloxymethyl) ester g (0.041 mol) 6 alpha-hydroxy penicillanic acid, 40 ml rimethylformamide, 7.4 ml (0.041 mol) diisopropyl ethylamine, 6 ml (0.041 mol) diisopropylethylamine, A mixture of chloromethyl pivalate (6 mL, 0.041 mol) and sodium iodide (6.15 g, 0.041 mol) was stirred at room temperature for 15 hours and water was added. The reaction mixture was extracted with diethyl ether, and the organic phase was dried and evaporated. 9 g of crude ester are obtained, which is purified by column chromatography on isyl silica gel using chloroform / ethyl acetate (9: 1) as eluent to give 4.384 g (32%) of the ester.

C. Benzyl Ester g (0.092 mol) 6 alpha-hydroxypenicillanic acid, 12.9 g (0.092 mol) triethylamine 1.105 g (0.013 mol) sodium bicarbonate and 200 ml dimethylformamide 1.20 ml (0.101 mol) ) benzyl broinide was added. The reaction mixture was stirred at room temperature for 20 hours and then partitioned between diethyl ether and water. The aqueous phase was adjusted to pH 2 with 6N hydrochloric acid. The layers were separated and the aqueous layer was washed twice with ether. The combined ethereal phases are washed with sodium bicarbonate solution, then with water, dried and evaporated. The residue was recrystallized from hot chloroform / hxane to give 9.1 g of a colorless crystal. 165-167 ° C.

D. (5-Methyl-2-oxo-1,3-dioxol-4-yl) methyl ester g (0.078 mol) (5-methyl-2-oxo-1,3-dioxoM-yl) methyl bromide, 18.7 g (0.078 mole) of sodium phthalate bridge 9

A mixture of -917,194,567-oxypenicillanate in 225 ml of dimethylformamycl was stirred for 4 hours at room temperature and then poured onto ice and worked up as described above to give the desired ester as a product.

Example 2

6-Oxo-penicillinate esters

A. Allyl-6-oxopenicillinate

A mixture of 2.84 ml (0.04 mol) of dimethylsulfoxide, 3.67 ml (0.026 mol) of trifluoroacetic anhydride and 50 ml of dichloromethane is stirred at -78 ° C for 10 minutes, then at -78 ° C 5.14 g A solution of allyl-6-alpha-hydroxypenicillanate (0.02 mol) in dichloromethane (10 mL) was added. After stirring for 40 minutes, triethylamine (7.24 mL, 0.052 mol) was added at the same temperature, the temperature was gradually raised to room temperature, and the reaction was quenched with water. The reaction mixture was extracted with dichloromethane, the organic layers were combined and washed three times with water. The organic solution was dried and the solvent evaporated in vacuo. The desired product is obtained as a yellow oil. 5.1 g (100%).

¹ H-NMR (CDCl ₃ ) ppm (delta): 1.60 (s, 6H), 4.75 (m, 2H), 4.82 (s, 1H), 5.1-6.3 (m, 3H), 5.82 _'30 (s, lH).

B. (Pivaloyloxymethyl / ester

A mixture of 036 ml (5.06 mmol) dimethylsulfoxide, 0.47 ml 35 (3.29 mmol) trifluoroacetic anhydride, 839 mg (2.53 mmol) pivaloyloxymethyl-6-alpha-hydroxypenicillanate and 5 ml dichloromethane was added. After stirring for 1 minute at -78 ° C, triethylamine (0.92 mL, 6.58 mmol) was added. The reaction mixture was worked up according to the procedure under A to give 788 mg (95%) of the desired product (ketone).

11 ¹ H NMR (CDC1 ₃₎ ppm (delta): 1.3 (s, 9H), 1.65 (s, 6H), 4.58 (s, 1H), 5.8 (m, 3H).

!

Example 3 5

Allyl 6 (E // (2-pyridyl / CH / penicillanate

2.64 g (6.8 mmol) of (2-picolyl) triphenylphosphonium chloride foszfónium10 and 0.265 g (6.8 mmol) of sodium amide in 6 mL of dry THF was stirred at room temperature for 30 minutes and the resulting brown suspension 78 ^e Cool to C. To the stirred mixture at 78 ° C was added a solution of 1.8 g (7.0 mmol) of allyl-6-oxo-pcnicillanate in 4 mL of dry tetrahydrofuran and stirred for 3 minutes. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed three times with water, dried (MgSO ₄ ) and concentrated in vacuo. 3.3 g of a red oil are obtained, which is purified by column chromatography on silica gel to give 1.35 g (60.7%) of the desired product as a yellow oil.

1 H-NMR (CDCl 3) ppm (delta): 1.50 (s, 3H), 1.58 (s, 311), 4.57 (s, 111), 4.65 (d, 211), 5.15 δ , 15 (m, 3H), 6.17 (d, 1H, J = 1Hz), 6.87 (d, 1H, J = 1Hz), 7.2-7.4 (m, 2H), 7.60 (t, d, 1H), 8.62 (dd);

¹³ C-NMR (CDCl ₃ ) ppm (delta): 26.04; 32.99; 62.77; 65.75; 70.01; 70.54; 119.10; 123.24; 124.02; 125.86; 131.06; 136.34; 144.66; 149.94; 152.13; 167.54; 168.73.

Example 4

Following the procedure of Example 3, the following compounds were prepared using the appropriate Wittig reagent of formula (LVIII) instead of (2-picolyl) triphenylphosphonium chloride:

(LIX)

Time, minutes

Temperature, ° C

Cl 30 -78 - + 25

CH ₃ S.

eluent *

Yield ** ι H NMR (CDC1 ₃₎ ppm (delta):

13 (E) E-Isomer: 1.5 (s, 3H), 1.6 (s, 3H), 4.5 +3.2 (Z) (s, 1H), 4.65 (d, 2H), δ , -6.2 (m, 3H),

5.73 (d, 1H), 6.82 (d, 1H).

Z isomer: 1.5 (s, 311), 1.6 (s, 311), 4.57 (s, 111), 4.7 (d, 211), 5.15-6.24 (m, 311), 3.77 (s, 1H), 6.37 (s, 1H).

16 (E) Z-isomer: 1.48 (s, 3H), 1.60 (s, 3H),

2 (Z) 2.58 (s, 311), 4.42 (s, 111), 4.60 (d, 211),

15 (E + Z) 5.0-6.0 (m, 3H), 5.58 (s, 111), 6.42 (s, 1H).

E-Isomer: 1.45 (s, 3H), 1.60 (s, 3H), 2.40 (s, 3H), 4.60 (s, 1H0.4,80 (d, 2H), δ, 0-6.1 (m, 3H), 5.72 (d, 1H), 6.90 (d, 1H).

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R ³ Time, minute Temperature, C eluent * Production** % ¹ H-NMR (CDCl ₃ ) ppm (delta): CHO ^ 10 25 B 32 (E) 1.50 (s, 311), 1.60 (s, 311), 4.52 (s, 111), 4.62 (d, 211), 5.1-6.0 (m, 311), 5.90 (d, 1H), 6.80 (d, 1H), 9.73 (d, 1H). with telFormylmethylene triphenylphosphorane in benzene. 2-quinolyl 3 -78 B 80 (Z) 1.5 (s, 3H), 1.62 (s, 1H), 4.6 (s, 1H), 4.7 (d, 2H), 5.1-6.2 (m, 3H), 6.35 (d, 1H), 7.0 (d, 111), 7.2 8.2 (111.611). hydroxybenzenethio 1 -78 B 12 (E, Z) 1.5 (s, 2, 2H), 1.55 (s, 0.8H), 1.65 (s, 2, 2H, 0.1.7 (s, 0, 8H), 4.5 (s, 1H) ), 4.5-4.8 (m, 2H), 5.1-6.1 (m, 4H), 6.8 (s, 0.26H), 7.15 (d, 0.7411) , 7.4 (ηι, 5Π). (LX) 3 -78 B 20 (E) 1.45 (s, 3H), 1.55 (s, 3H), 4.55 (s, 1H), 4.65 (d, 2H), 5.2-6.1 (m, 3H), δ , 15 (d, 1H), 6.75 (d, 1H), 7.05-7.75 (m, 3H). phenyl 5 -78 THE 4 (Z) 1.5 (s, 3H), 1.6 (s, 3H), 4.6 (s, 1HO, 4.68 (d, 2H0, 5.1-6.1 (m, 3H), 5.77) (s, 1H), 6.57 (s, III), 7.2-7.46 (in, 3H), 7.648.16 (m, 2H). 30 <X) 1.52 (s, 3H), 1.62 (s, 3H), 4.60 (s, 1H), 4.69 (d, 2H), 5.1-6.3 (m, 3H), 6.1 (d, 1II), 7.03 (d, III) 7.4 (s, 511). (LXI) 3 -78 C 14 (E) 10 (E, Z) 1.55 (s, 311), 1.65 (s, 311), 2.55 (s, 611), 4.65 (s, 1H), 4.75 (d, 2H), 5.1-6.1, (m, 3H), 6.25 (d, 1H), 6.9 (s, 1H), 7.0 (d, 1H). (LXII) 3 -78 D (E) 1.5 (s, 3H), 1.6 (s, 3H), 3.85 (s, 3H), 4.55 (s, 111), 4.7 (d, 211), 5.1-6.1 (in, 3H), 6.2 (d, 1H), 7.0-7.5 (m, 3H), 8.2 (t, 1H). (LXIII) 5 -78 In ^{Figure 1} (E) 1.5 (s, 3H), 1.6 (s, 3H), 4.4-4.8 (m, 5H), 5.1-6.3 (in, 611), 6.2 (d, 111), 7.15 (d, 2H), 7.4 (d, III), 8.15 (t, III). (LXIV) 3 -78 B 27 E-Isomer: 1.5 (s, 3H), 1.6 (s, 3H), 2.6 (s, 3H), 4.6 (s, 1H), 4.65 (m, 2H), δ , 6.2 (m, 3H), 6.2 (d, 1H), 6.85 (d, 1H), 7.0-7.7 (m, 3H). (LXV) 5 -78 C 50 E-isomer: 1.5 (s, 311), 1.6 (s, 311), 4.55 (s, III), 4.67 (m, 211), 5.0-6.2 (in, 311), 6.15 (d, 1H), 6.95 (d, 1H), 8.4-8.8 (m, 3H). (LXVI) 5 -78 C 13 E-Isomer: 1.5 (s, 311), 1.7 (s, 311), 4.55 (s, 1H), 4.7 (ni, 211), 5.1-6.2 (m, 311) 6.2 (s, 1H), 6.5-7.0 (m, 3H), 8.5 (d, 1H).

A = hexane / ethyl acetate (9: 1)

Al = hexane / ethyl acetate (7: 3)

B = chloroform

C = chloroform / ethyl acetate (9: 1)

D = chloroform / ethyl acetate (99: 1) ** E-isomer (R ³ is anti-beta-lactam) Z-isomer (R ^{3 is} paused with beta-lactam)

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Example 5

Ndtrium-6 (E) - (2-pyridylmethylene penicillanate)

0.120 g (0.38 mmol) of allyl-6 (E) - (2-pyridyl) methylene / penicillanate, 20 mg of tetrakis (triphenylphosphine) palladium (0) and 20 mg of triphenylphosphine are dissolved in 3 ml of clilacetate and adding 0.76 ml (0.38 mmol) of a 0.5 M solution of sodium 2-ethylhexanoate in ethyl acetate under a nitrogen atmosphere. After stirring for 2 hours at room temperature, the precipitate was filtered off, washed with ethyl acetate and dried in vacuo. 57 mg (48%) of the desired compound are obtained as a yellow solid.

^! 1 H-NMR (D ₂ O) ppm (delta): 1.55 (s, 6H), 4.33 (s, 1H), 6.17 (d, 1H, J = 0.5 Hz), 7.03 (d, 1H, J = 0.5 Hz), 7.17-8.07 (m, 3H), 8.57 (m, 1H);

IR (KBr): 3433,1765,1605 cm ^1st

6A. example

6- (Phenylthiomethylene) penicillanic acid mg (0.26 mmol) allyl-6- (phenylthiomethylene) penicillanate (isomeric mixture), 10 mg tetrakis (triphenylphosphine) palladium (0) - and 10 mg of trirnynylphosphine were dissolved in 1 ml of ethyl acetate and 0.52 ml (0.5 mol) of ethyl acetate-sodium 2-ethylhexanoate solution were added at room temperature, and the mixture was stirred under nitrogen for 10 minutes. Since very few salts are precipitated, the reaction is quenched with water and extracted with dichloromethane. The pH of the aqueous phase

Adjust to 3.5 and extract with dichloromethane. The extracts were dried and concentrated in vacuo. 63 mg (75%) of the free acid (isomeric mixture) product are obtained.

1 H NMR (CDCl ₃ ) ppm (delta): 1.48 (s, 3H), 1.63 (s, 311), 4.45 (s, 111), 4.73 (d, 211), δ , 6.2 (ni, 311), 5.77 (d, 111, J = 0.5 Hz), 7.27 (d, 111, J = 0.5 Hz), 7.1-8, 1 (m, 3H); 8.6 (m, 1H);

Example 6

Using the allyl esters described in Example 4 as starting material, Example 5 was used. The following compounds of formula (LXVII) were prepared according to the procedure of Example III:

R ³ isomer Production,% Physical constants chlorine (E) 95 yellow solid, ¹ H NMR (D ₂ 0) ppm (delta): 1.50 (s, 3H), 1.58 (s, 3H), 4.3 (s, 1H), 5.83 (d , 111), 7.1 (d. Iii); IR (KBr): 1580, 1609, 1679, 1753, 3491 cm ^-1 . chlorine (Z) 89 IR (KBr): 1580.1609, 1679.1753.3491 cm ^-1 . methylthio (E) 80 white solid, ¹ H-NME (D ₂ O) ppm (delta): 1.48 (s, 3H), 1.56 (s, 3H), 2.50 (s, 3H), 4.20 (s) , 1H), 5.88 (s, 1H), 7.2 (s, 1H); IR (KBr): 1396, 1606, 1749, 2926, 2963, 3552 cm ^-1 . phenyl (Z) 60 light yellow powder phenyl (E) 80 white powder, ¹ H NMR (D ₂ O / DMSO) ppm (delta): 1.5 (s, 611), 4.25 (s, 111), 6.1 (d, 111), 7.0 ( d, 1H), 7.4 (s, 5H); IR (KBr): 1626.1642, 1655,1742,3434 ^cm-first

^{, 3} C NMR (CDCl ₃ ) ppm (delta): 18.53, 20.43, 63.18, 64.25, 66.63, 72.04, 119.91, 124.64, 126.03, 130.68, 132.83, 136.77, 150.31, 166.86, 168.11.

IR (KBr): 1323.1586, 1759,1783,3437 ^cm-1

Example 7

Allyl 1,1-dioxo-6 (E) - (2-pyridyl) methylene / penicillanate

To a solution of 1.30 g (4.09 mmol) of allyl-6 (E) - (2-pyridyl) methylene / penicillanate in 15 mL of dichloromethane, 1.70 g (8.2 mmol) of 80-85% m-chloroperbenzoic acid of high purity was added and the mixture was stirred under nitrogen at room temperature for three hours. The reaction mixture was quenched by addition of saturated sodium sulfate solution and water, extracted with dichloromethane and adjusted to pH 7.5 with saturated sodium bicarbonate solution. The organic layer was washed with water, dried _(MgSO4) and the solvent evaporated in vacuo. 1.4 g (98%) of a yellow oil are obtained. The oil was purified by silica gel column chromatography (7: 3 hexane: ethyl acetate) to give 0.78 g (55%) of a colorless crystalline desired sulfone.

¹ H NMR (CDCl ₃ ) ppm (delta): 1.40 (s, 311), 1.60 (s, 3H), 2.60 (broad s, 1H), 4.3 (m, 2H) , 4.4 (s, 1H), 4.7 (d, 2H), 5.1 -6.0 (m, 3H), 5.25 (d, 1H), 6.38 (m, 1H).

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194,567

Example 8

III-1,1-Dioxo-6 (E) - (2-hydroxyethylidene) penicillanate

A solution of allyl-1,1-dioxo-6 (E) -formylmethylene-penicillanate (0.190 g, 0.61 mmol) in dry tetrahydrofuran (4 mL) at -78 ° C was treated with 0.61 mL (0.61 mmol) A 1M solution of diisobutylaluminum hydride in hexane was added. The reaction mixture was stirred for 10 minutes at -78 ° C, quenched with methanol and stirred for 20 minutes at room temperature and finally filtered. The filtrate was concentrated in vacuo. 0.258 g of crude product is obtained, amyl aqueous

The mixture was diluted, extracted with chloroform and the organic phase was dried over magnesium sulfate. The chloroform was evaporated to give 160 g of product, which was purified by column chromatography on fiber gel using 4: 1 chloroform / ethyl acetate as eluent. 113 mg (60%) of the desired product are obtained.

¹ H-NMR (CDCl ₃ ) ppm (delta): 1.40 (s, 311), 1.60 (s,

3H), 2.60 (broad s, 1H), 4.3 (m, 2H), 4.4 (s, 1H), 4.7 (d, 2H), 5.1-6.0 (m, 3H), 5.25 (d, 1H), 6.38 (m, III).

Example 9

Starting from the corresponding 6-methylenepenylanetane esters (n-O) described in Example 4, the following compounds of formula (LXVIII) were prepared according to the procedure of Example 7:

n = 2 formyl

R ³

2-quinolyl *

Isomer (E) (E)

Yield,% Silica gel eluent

Physical constants ¹ H NMR (CDCl ₃ ) ppm (delta):

chloroform 1.42 (s, 3H), 1.60 (s, 3H), 4.50 (s, 1H),

4.70 (d, 2H), 5.1-6.0 (m, 3H), 5.32 (s, 1H), 7.1 (m, 1H), 9.73 (d, 1H).

chloroform 1.5 (s, 311), 1.6 (s, 311), 4.45 (s, 11II), 4.7 (d, 2H), 5.1-6.1 (m, 3H), 5.8 (d, III),

7.3-8.5 (m, 7H).

6-chloro-2-pyridyl (E) chloroform

1.5 (s, 3H), 1.6 (s, 311), 4.45 (s, 11II). 4.7 (d, 2H), 5.1 -6.3 (m, 311), 5.75 (d, 111), 7.1-7.8 (m, 4H).

(LXI) (E) (79% crude) chloroform

1.5 (s, 3H), 1.6 (s, 3H), 2.55 (s, 6H),

4.5 (s, 1H), 4.7 (d, 2H), 5.0-5.9 (m, 3H), 5.7 (d, 1H), 6.9 (s, 1H), 7.3 (d, lH).

(LX11) (E) ₄₇ hexane / ethyl acetate j _{4 (s 3 H} ) ₎ j _{6 (s 3 Η} χ _{3> 8 (s 3 H)> 44} ^: V ( _S; 1H), 4.65 (d, 2H), δ , 3-6.2 (m, 3H),

5.8 (d, 1H), 7.4 (s, 1H), 7.8 (d, 1H),

8.35 (t, 1H).

(LX1II) (E) hexane / ethyl acetate (1: 1)

1.45 (s, 311), 1.6 (s, 311), 4.4-4.8 (m, 511), 5.1 -6.3 (m, 6H), 5.65 (d, 1H), 715 (d, 2H), 7.7 (d, 1H), 8.15 (t, 1H).

In another experiment, column chromatography on silica gel, eluting with 2% ethyl acetate in chloroform, afforded sulfone (n = 2) in 29% yield and sulfoxide (n = 1) in 27% yield.

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194,567

R ³

Isomer Production,% Silica gel eluent

Physical constants ¹ H NMR (CDCl ₃ ) ppm (delta):

(1X1V) (E) chloroform 1.5 (s, 311), 1.64 (s, 311), 2.64 (s, 3H),

4.48 (s, 1H), 4.47 (d, t, 2H), 5.3-5.5 (m, 2H), 5.8 (d, 1H), 7.1-7.2 ( m, 2H), 7.25 (d, 1H),

7.6 (t, 1H).

IR (KBr) cm -1: 1588, 1688, 1728, 1756, 1795, 2931, 2976, 3433.

(LXV) (LXVI) (E) (E) Chloroform / 1.56 (s, 3H), 1.7 (s, 3H), 4.6 (s, 1H), 4.85 / ethyl acetate (m, 2H) ), 5.2-6.2 (m, 3H), 5.8 (d, 1H), (9: 1) 7.4 (d, 1H), 8.5-9.0 (m, 3H) .

crude 1.5 (s, 3H), 1.7 (s, 3H), 3.9 (s, 3H), 4.5 (s, 1H), 4.75 (m, 211), 5.2 6.3 (tn, 311), 5.7 (d, III), 6.7-7.0 (m, 211), 7.2 (d, III), 8.5 (d, 111).

9A. example

Allyl-6 (E) -1- (1-oxo-quinolin-2-yl) -methylene-1,1-dioxopenicilland ²⁰

124 mg (0.313 mmol) of allyl-6 (E) - (quinolin-2-yl) -methylene) -1-oxopenicillinate (obtained by the procedure described in the asterisk note in the previous example as m- ₃ θ), 5 ml. To a solution of methylene chloride in dichloromethane was added 195 mg (0.904 mmol) of 80% m-chloroperbenzoic acid and the mixture was stirred for 48 hours at room temperature. The reaction was quenched with water and extracted with dichloromethane. The extract was washed with saturated sodium bicarbonate solution, then with water, dried and concentrated in vacuo. A yellow oil is obtained, which is purified by column chromatography on silica gel. 45 g (35%) of the desired N-oxide are obtained as a yellow solid 40.

¹ H-NMR (CDCl ₃ ) ppm (delta): 1.45 (s, 3H), 1.6 (s,

3H), 4.45 (s, 1H), 4.7 (m, 2H), 5.0-5.0 (m,

3H), 5.85 (d, 1H), 7.3-8.0 (m, 7H). 45

Example 10

Sodium 1,1-dioxo-6 (E) - (2-pyridyl / methylene) - 50 penicillanates

0.14 g (0.4 mmol) of allyl 1,1-dioxo-6 (E) - (2-plridyl / methylene) penicillanate and 20 mg of tetrakis (triphenylphosphine) palladium (0) and 20 mg of triphenylphosphine $ 5 were dissolved in 2 ml of ethyl acetate under a nitrogen atmosphere and 0.8 ml (0.4 mmol) of a 0.5 molar solution of sodium 2-ethylhexanoate in ethyl acetate was added.

After stirring for 5 minutes at room temperature, the precipitate was filtered off, washed with ethyl acetate and dried in vacuo. Yield: 0.13 g (95%) of a yellow solid sodium salt.

1 H-NMR (D ₂ O) ppm (delta): 1.50 (s, 3H), 1.60 (s, 3H), 4.23 (s, 1H), 5.90 (d, 1H, J = 1 Hz), 7.18.0 (m, 4H), 8.57 (m, 1H).

IR (KBr) cm ^-1 : 1590, 1621, 1770, 3454.

Example 11

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

A solution of allyl-1,1-dioxo-6 (E) - (2-pyridyl / methylene) penicillanate (100 mg, 0.286 mmol) in dichloromethane (5 mL) was treated with m-chloroperbenzoic acid (120 mg, 0.59 mmol) and the reaction mixture was stirred at room temperature for three days. The reaction mixture was quenched with saturated sodium thiosulfate solution and extracted with dichloromethane. The organic layer was neutralized with saturated sodium bicarbonate solution, washed with water, dried and evaporated. 82 mg of a yellow oil are obtained, which is purified by column chromatography on silica gel using ethyl acetate as eluent. 22 mg (21%) of the desired compound and 14 mg (13%) of the by-product, (2,3-epoxy-propanyl) -1,1-dioxo-6 (E) - (1-oxo-2-pyridyl) -methylene ) -enicillanate. Allyl 1,1-dioxy-6 (E) - (1-oxo-2-pyridyl / methylene) penicillanate:

¹ H-NMR (CDCl ₃ ) ppm (delta): 1.5 (s, 311), 1.6 (s, 3H), 4.45 (d, 1H), 4.7 (d, 2H), δ , 1-6.0 (m, 3H), 5.8 (s, 1H), 7.1-8.4 (m, 5H).

-1427 ... 194,567

Example 12

Starting with the appropriate allyl ester, the following compounds of formula (LX1X) were prepared according to the procedure of Example 10. When potassium 2-ethylhexanoate is used instead of sodium 2-ethylhexanoate, the potassium salts of the general formula are obtained as a product.

R ³ Isomer Production,% Physical constants

IIOCIIi (E) hydroxymethyl

2-quinolyl (E)

6-Chloro-2-pyridyl (E) (LXI) (E) (LXII) (E)

1-oxoquinolyl (E) (LXIH) (E + Z) (potassium salt) hygroscopic (LXVI) (E) 11-NMR (D ₂ O) ppm (delta): 1.5 (s, 311), 1 , 6 (s, 311),

4.24 (s, 1H), 4.30 (dd, 2H), 5.75 (s, III), 7.20 (d, 1H); IR (KBr) cm ^-1 : 1618.1674,1767,3408.3440 ¹ H-NMR (250 MHz, DMSO) ppm (delta):

1.45 (s, 3H), 1.48 (s, 3H), 3.82 (s, 1H), 5.96 (s, 1H), 7.55-8.55 (m, 7H);

IR (KBr) cm ^-1 : 1619.1771.3437 ¹ H NMR (250 MHz, DMOS) ppm (delta):

1.56 (s, 3H), 1.64 (s, 3H), 4.34 (s, 1H), 6.18 (s, 1H), 7.45-8.0 (m, 4H);

IR (KBr) cm ^-1 : 1624, 1771.3433 ¹ H-NMR (250 MHz, D ₂ O) ppm (detla):

1.52 (s, 3H), 1.60 (s, 3H), 2.5 (s, 6H), 4.32 (s, 1H), 6.16 (d, 1H), 7.35 (d) , 1H), 7.65-7.75 (m, 1H);

IR (KBr) cm ^-1 : 1629.1781.3403 ¹ H NMR (250 MHz, CDCl ₃ ) ppm (delta):

1.42 (s, 311), 1.48 (s, 311), 3.85 (s, 111), 3.95 (s, 311), 5.85 (d, III), 7.45 (d) , 1H), 7.45-8.0 (m, 2H),

8.22 (m, 1H);

IR (KBr) cm- ¹ : 1617.1767.3435

IRíKBrjcm ^-1: 1553, 1622, 1769.3413 ¹ H NMR (DMSO) ppm (delta):

1.35 (s, 6H), 1.4 (s, 1.4 Η), 1.44 (s, 6H), 1.48 (s,

1.4 H), 3.8 (s, 1H), 4.55 (d, 1H), 4.75 (d, 1H), 5.15-5.5 (m, 2H), 5.67 ( s, 0.6 H), 5.8 (s, 0.4 H), 5.8-6.0 (m, 0.5 H), 6.0-6.2 (m, 0.5 H) ), 6.757.0 (m, 2H), 7.4-7.6 (m, 1H), 8.2 (d, 0.5H)

IR (KBr) cm ^-1 : 1613.1760.3429 ¹ H-NMR (D ₂ O) ppm (delta): 1.8 (s, 3H),

1.9 (s, 3H), 4.56 (s, 1H), 7.2 (1H), 7.34 (1H), 7.62 (111), 8.68 (1H);

¹³ C-NMR (D ₂ O) ppm (delta): 20.9 22.7, 58.7, 54.6,68,7,74,6,113,9,115,9,134.0, 134.2,

154,6,155,1,169,4,173,7,475,6.

-1 529

194 56 ⁷

Example 13 (Pivaloyloxymethyl-6 (Ej - (methylthio) methylene] penicillanate

A mixture of 2.4 mmol (methylthiomethyl) triphenylphosphoml chloride, 2.4 mmol sodium amide in 5 ml dry tetrahydrofuran was stirred for 20 minutes at room temperature. To the yellow solution was added a solution of 788 mg (2.4 mmol) of pivaloyloxymethyl-6-oxo-pericarbanilate in 10 ml of dry tetrahydrofuran at -78 ° C and the mixture was stirred at -78 ° C for one minute and is poured into a solution of ammonium chloride. The mixture was extracted with ethyl acetate and the organic phase was dried (Na ₂ SO ₄ ). The solvent was evaporated in vacuo to give 774 mg of crude product which was purified by column chromatography on silica gel using chloroform as eluent. 220 mg (24.5%) of pure product are obtained.

1 H-NMR (CDCl 3) ppm (delta): 1.25 (s, 9H), 1.50 (s, 3H), 1.65 (s, 3H), 2.45 (s, 3H), 4.45 (s) , 1H), 6.85 (m, 3H), 7.0 (d, 1H).

Example 14 (Pivaloyloxymethyl) -6 (E) - (mH-sulfonyl) -methyl-n-penicillanate 1-oxide (Aj and the corresponding 1,1-dioxide (B)

To a solution of 215 mg (0.58 mmol) of (pivaloyloxymethyl) -6 (E) - (methylthiomethyl / methylene) penicillanate in 5 mL of dichloromethane, 375 mg (1.74 mmol) (3 equivalents) of 80% os-chloroperbenzoic acid was added and the mixture was stirred at room temperature for four hours. The reaction was quenched with water and saturated sodium biosulfate solution, neutralized with sodium bicarbonate and extracted with chloroform. The organic layer was washed three times with water, dried (MgSO ₄ ) and the solvent evaporated in vacuo. 200 mg of product mixture are obtained, which is purified by column chromatography on silica gel using chloroform / ethyl acetate (9: 1) as eluent. 25 mg of 1-oxide (A) and 45 mg

1,1-dioxide (B) is obtained.

(A): ¹ H NMR (CDCl ₃ ) ppm (delta): 1.21 (s, 9H), 1.3 (s, 3H), 1.7 (s, 3H), 3.1 (s, 3H), 4.7 (s, 1H),

5.8 (ABquart, 2H), 5.85 (d, 1H), 7.1 (d, 1H);

IR: (CHCl ₃ ) cm ^-1 : 1333, 1759, 1807, 2927, 2960.

(B): 1 H-NMR (CDCl 3) ppm (delta): 1.2 (s, 9H), 1.45 (s, 3H), 1.6 (s, 3H), 3.15 (s, 3H), 4.5 (s, 1H), 5.6 (d, 1H), 5.8 (AB quartet, 2H), 7.2 (d, 1H);

IR (CHC1 ₃₎ ^cin-1: 1324, 1758, 1800, 12929, 2956th Example 75

Allyl-6alpha - ((N-methylpyrrol-2-yl) -hydroxymethyl) -1,1-dioxopenicillanate

Allyl-6-alpha-bromo-1,1-dioxopenicillanate (520 mg, 1.48 mmol) was dissolved in dry tetrahydrofuran (10 mL) and cooled to -78 ° C. 0.52 ml of a 2.85M solution of methyl magnesium bromide in tetrahydrofuran is added and the reaction mixture is stirred for 5 minutes at -78 ° C. 162 mg (0.16 mL) of N-methylpyrrole-216 are then added

carboxaldehyde was added and the mixture stirred for 20 minutes at -78 ° C and then poured into a saturated solution of ammonium chloride. The mixture was extracted with ethyl acetate, the organic phase was dried (MgSO ₄ ) and the solvent was evaporated in vacuo. 466 mg of crude product are obtained, which is purified by silica gel column chromatography using chloroform / ethyl acetate (9: 1) as eluent. 180 mg (32%) of pure desired product are obtained.

¹ H-NMR (CDCl ₃ ) ppm (delta): 1.4 (s, 3H), 1.62 (s, 3H), 3.68 (s, 3H), 4.0 → 1.4 (m, 1 H), 4.42 (s, 11), 4.5 -4.8 (m, 311), 5.0 6.0 (m, 411), 6.06.7 (in, 311).

Example 16

Allyl-6 (N, N-methylpyrrol-2-ylmethylene) -1,1-dioxocycnicillanate

180 mg (0.47 mmol) of allyl-6alpha - (N-methylpyrrol-2-yl) -hydroxymethyl) -1,1-dioxopenicillanate are dissolved in 3 ml of tetrahydrofuran and 0.15 ml of acetic anhydride and 0.2 ml of acetic anhydride. ml of pyridine was added. After stirring for one hour at room temperature, the reaction was quenched with water. The mixture was extracted with ethyl acetate, the organic phase was dried and the solvent was evaporated in vacuo. 162 mg of product are obtained. The crude product was dissolved in dichloromethane, 0.15 mL of acetyl chloride and 0.2 mL of pyridine were added and stirred for 2 hours at room temperature. The reaction mixture was worked up according to the previous method to give 140 mg of crude product which was purified by column chromatography on silica gel. 72 mg (42%) of pure product are obtained. Recrystallization from ethyl acetate gave colorless needle crystals.

¹ H NMR (CDCl ₃ ) ppm (delta): 1.45 (s, 311), 1.65 (s, 311), 3.7 (s, 311), 4.4 (s, 311), 4 , 6-4.9 (m, 211),

5.1-5.6 (m, 4H), 6.6-7.0 (m, 2H), 7.5 (dd, 1H).

Example 17

Sodium 6 (E) - (N-methylpyrrol-2-yl) methylene [alpha] -1,1-dioxopenicillanate mg allyl 6 (E) - (N-methylpyrrol-2-yl) methylene) -1,1-dioxopenicillanate, 5 mg tetrakis (triphenylphosphine) palladium (0), 4 mg triphenylphosphine were dissolved in 1 ml dichloromethane and stirred under nitrogen for 5 minutes, then diluted with ethyl acetate (1 ml) and Sodium 2-ethylhexanoate (0.25 mL) was added and the reaction mixture was stirred at room temperature for 1 hour, filtered and the precipitate was washed with ethyl acetate and ether to give 30 mg of a yellow solid.

1 H-NMR (D ₂ O) ppm (delta): 1.50 (s, 3H), 1.60 (s, 3H), 3.65 (s, 3H), 4.10 (s, 1H), 5.4 (s, 1H),

6.1-6.5 (m, 1H), 7.0 (s, broad, 2H), 7.2-7.4 (m, 1H);

IR (KBr) cm ^-1 : 1568, 1616, 1660, 1745, 3465.

-1 631

194,567

Example 18

Using the aldehyde of formula (LXX), the starting compound of formula (LXXI) was prepared according to the procedure of Example 15.

R ¹³ Yield,% Silica gel eluent ¹ H-NMR (CDCl ₃ ) ppm (delta):

(LXXII) (LXXH) (LXXIII) Phenyl (LXXIV) (LXXV) (LXXV1) Vinyl (LXXV11) (LXXV111) (LXXIX) (LXXX) Raw LP 8 MP

6-alpha isomer: 1.4 (s, 0.39 Η), 1.5 (s, 2.61 Η), 1.62 (s,

0.3911), 1.7 (s, 2.6111), 3.0 (bs, 1H), 4.0-4.4 (m, 1H), 4.45 (s, 1H), 4.5 -4.9 (m, 2H), 5.1 -6.1 (m, 4H), 6.366.6 (m, 2H), 7.45 (m, 11T);

The 6-alpha mixture, 8R and 6-alpha, 8S isone

1.4 (§, 3H), 1.60 (s, 3H), 2.50 and 2.60 (s, 3H), 4.1 4.4 (m, 1H), 4.4 and 4.5 ( s, 1H), 4.6-5.0 (m, 311),

5.1-6.0 (in, 411), 6.0 7.2 (m, 411).

1.4 (s, 3H), 1.6 (s, 3H), 3.28 (bs, 1H), 3.8-4.2 (m,

1H), 4.35 (s, 1H), 4.45-4.8 (m, 3H), 5.0-6.1 (m,

4H), 7.3 (s, 5H).

Β 1.3 (s, 3H), 1.55 (s, 3H), 4.04 (bs, 1H), 4.35 (s, 1H),

4.5-4.85 (m, 3H), 5.1-6.1 (m, 4H), 7.1-7.4 (m, 1H),

7.6-8.0 (m, 1H), 8.2-8.7 (ρι, 2H).

Β 1.3 (s, 3H), 1.55 (s, 3H), 4.0 (m, 1H), 4.35 (s, 1H), ′

4.4-6.8 (m, 3H), 5.1-6.2 (m, 4H), 7.2 -7.5 (m, 2H),

8.2-8.6 (tn, 211).

Β 1.25 (s, 0.7511), 1.35 (s, 2.2511), 1.55 (s, 3H), 3.3 (bs,

1H), 4.05 (dd, 1H), 4.3 (s, 1H), 4.3-4.8 (m, 3H), 5.06.2 (m, 4H), 6.8-7 , 4 (p, 3H).

1.4 (s, 3H), 1.6 (s, 3H), 3.0 (bs, 1H), 3.7-4.0 (m, 1H),

4.4-4.8 (m, 4H), 5.0 ~ 6.3 (m, 6H).

D 1.36 (s, 1.5H), 1.40 (s, 1.5H), 1.60 (s, 1.511), 1.65 (s, 1.5H), 3.7 (s, 3H) ), 4.0-4.5 (m, 2H), 4.4 (s, 1H),

4.5-4.8 (m, 2H), 5.0-6.0 (m, 4H, 6.7 (s, 1H), 6.85 (s, 1H).

D 6 alpha, 8S isomer: 1.4 (s, 311), 1.6 (s, 311), 4.38 (dd,

111), 4.43 (s, 111), 4.67-4.75 (m, 211), 4.76 (d, 1H),

5.3- 5.5 (m, 2H), 5.63 (d, 1H), 5.85-6.05 (m, 1H),

7.4 (d, 1H), 7.8 (d, 1H); 6-alpha, 8R Isomer: 1.36 (s, 3H), 1.60 (s, 3H), 4.22 (d, 1H), 4.4 (s, 1H), 4.65 (m, 2H) , 4.88 (s, 1H), 5.25-5.5 (m, 2H), 5.55 (d,

1H), 5.8-6.0 (m, 1H), 7.35 (d, 1H), 7.75 (d, 1H).

The (less polar isomer)

F (more polar isomer)

6-alpha, 8S isomer: 1.44 (s, 3H), 1.62 (s, 311), 3.68 (bs, 1H), 4.31 (dd, 1H), 4.5 (s, 1H) ), 4.74 (d, 2H), 4.86 (d, 1H), 5.4 (m, 3H), 5.9 (m, 1H), 7.5 (m, 3H), 8.02 (s, 1H), 8.14 (m, 2H), IR: 3482,

1802 cm ¹ .

Less Polar 6-alpha, 8S Isomer: 1.41 (s, 311),

1.6 (s, 3H), 4.45 (s, 1H), 4.4 ^ 1.8 (m, 4H), 5.2-5.6 (m, 3H), 5.7-6, 3 (m, 1H), 7.35 (t, 1H), 8.85 (d, 2H).

More Polar 6-alpha, 8R Isomer: 1.45 (s, 3H), 1.6 (s, 3H), 4.4 (s, 1H), 4.45 (dd, 1H), 4.7-4, 9 (m, 2H), 4.95 (d, 1H), 5.2-5.6 (m, 3H), 5.7-6.3 (m, 1H), 7.35 (t, 1H) , 8.85 (d, 1H).

-1 733

194 56 ''

13 Yield% silica gel eluent * 1 H-NMR (CDCl ₃ ) ppm (delta): (LXXXI) 25%, fraction 1 (one isomer) 12%, fraction 2 (mixture of 2 isomers) D Fraction 1: 1.4 (s, 3H), 1.6 (s, 3H), 4.2-4.4 (m, 2H), 4.5-5.0 (m, 3H), 5.1-6.1 (m, 6H), 7.6 (d, 1H), 8.87 (d, 1H), 9.23 (s, 1H). (LXV) 56 70:30 isomeric mixture D 1.4 (s, 311), 1 1.57 (s, 311), 4.25 (111, 111), 4.37 (s, 0.711), 4.42 (s, 0.311), 4.75 ( in, 2H), 4.8 (d, 0.3H), 4.85 (d, 0.7H), 5.25-5.5 (m, 3H), 5.9 (m, 1H), δ , 52 (m, 2H), 8.84 (m, 1H). (LXXXII ** 22 1: 2 isomeric mixture D I, 4 (s, III), 1.46 (s, 211), 1.6 (s, III), 1.63 (s, 211), 4.12 (ni, 1H), 4.22 (ni, 1H), 4.41 and 4.46 (s, 1H), 4.6-4.8 (m, 2H), 4.95 (d, 1H), 5.2-5.5 (m, 3H), 5.9 (m, 1H), 6.95 and 7.05 (s, 1H), 7.28 and 7.36 (s, 1H). (LXXXI1I) 35 G 1.38-1.40 (d, 3H), 1.56-1.57 (d, 3H), 4.20-4.40 (m, 2H), 4.59-4.72 (m, 2H) ), 4.86-4.88 (d, 0.5H), 5.04 -5.06 (d, 0.511), 5.26 -5.43 (in, 211), 5.505.26 (ni, 1H ), 5.82-6.00 (m, 1H), 7.50-7.86 (m, 1H), 7.90-8.08 (m, 1H), 9.02-9.10 (m). , 1H). IR (KBr) cm ^-1 : 1800.

Ά = chloroform / ethyl acetate (9: 1)

Β = ethyl acetate / chloroform (7: 5)

C = chloroform / ethyl acetate (19: 1)

D = chloroform / methanol (19: 1)

E = chloroform

F = chloroform / ethyl acetate (1: 1)

G = ethyl acetate.

♦♦ Starting aldehyde: 1- (diethoxy-ethyl) -imidazole-2-carboaldehyde.

Example 19 ™

The (E) and (Z) isomers of II-6 - ((pyran-2-yl) methylene) -1,1-dioxopenicillanate

To a solution of 310 mg (0.84 mmol) of allyl-6alpha- (furan-2-yl) -hydroxy-5-oxymethyl-1,1-dioxopenicillanate in 5 mL of dichloromethane, 0.14 mL (1 mmol) of triethyl amine and 0.1 ml (0.924 mmol) of trifluoromethylsulfonyl chloride were added and the mixture was stirred under nitrogen for 1 hour. The reaction was quenched with water and extracted with dichloromethane.

The organic layers were dried (MgSO ₄ ) and the solvent was evaporated in vacuo. Purification by silica gel column chromatography (eluent: chloroform) gave 130 mg of the crude product which was a 4: 1 mixture of (E) and (Z) isomers by high performance liquid chromatography.

1 H NMR (CDCl ₃ ) ppm (delta): 1.47 (s, 311), 1.61 (s,

3H), 4.47 (s, 1H), 4.75 (d, 2H), 5.1-6.2 (m,

4H), 5.52 (dd, 1H), 6.8 (m, 1H), 7.15 (d, 1H),

7.6 (d, 1H). 65

Example 20

III-6 - ((N-acetylpyrrol-2-yl) methylene) -1,1-dioxopenicillanate

A. Allyl 6 - ((N-acetylpyrrole-24H-acetoxymethylene) -1,1-dioxide penicillanate

210 mg (0.51 mmol) of allyl 6 - ((N-acylylpyrrol-2-yl) -1-hydroxymethyl) -1,1-dioxide penicillanate are dissolved in 3 ml of tetrahydrofuran, followed by 0.16 ml of acetic anhydride and 0.2 ml of acetic anhydride. ml of pyridine was added and the reaction mixture was stirred for 24 hours at room temperature. The reaction was quenched with water and extracted with dichloromethane. The extracts were dried and evaporated to give 171 mg (75%) of yellow crystals.

1 H-NMR (CDCl 3) ppm (delta): 1.4 (s, 3H), 1.6 (s, 3H), 2.15 (s, 3H), 4.15-4.3 (dd, 1H), 4.4 (s, 111), 4.6 4.8 (m, 311), 5.1 6.0 (111, 311), 6.1

6.6 (ni, 211), 6.6-6.7 (111, 2H).

B. 170 mg (0.38 mmol) prepared in (A)

Ν, Ν-Diacetate was dissolved in dichloromethane and 47 mg

-1 835

194,567 (0.38 min) 1,5-diazabicyclo [4,3,0] non-5-ene (DBN) was added. After stirring for 1 hour at room temperature, water was added and the mixture was extracted with dichloromethane. The extracts were dried and evaporated. Obtained as an oil (158 mg) which was purified by chromatography on silica gel in chloroform (2% ethyl acetate). 108 mg of a light yellow oily product are obtained.

¹ H-NMR (CDCl ₃ ) ppm (delta): 1.5 (s, 3H), 1.6 (s, 3H), 2.55 (s, 3H), 4.4 (s, 1H), 4.65 (d, 2H), 5.0-6.0 (m, 411), 6.3 (t, 111), 6.8 (dd, 111), 7.2 (rn, III),

8.2 (d, 111).

Example 21

Üil-6 (Ephenylmethylene β, 1-dioxopenicillanate and the corresponding (Zfizomer

A. Allyl-6-phenylhydroxymethylene-1,1-dioxopenicillanate (1.98 mmol) using acetyl chloride (4.2 mmol) and pyridine (0.4 mL), following the procedure of Example 20 (A), gave 0.7 g. (84%) of allyl-6- (phenylaceloxymethyl) -1,1-dioxopenicillanate was obtained as a yellow gum.

¹ H-NMR (CDCl ₃ ) ppm (delta): 1.3 and 1.4 (s, 311), 1.62 (s, 3H), 2.08 and 2.2 (s, 3H), δ 2 (dd, 1H), 4.4 (s, 1H), 4.15 (d, 1H), 4.65 (d, 2H), 6.25 (m, 1H), 7.3 (m, 5H). ).

B. To a solution of 0.7 g (1.66 mmol) of the product obtained in A in dichloromethane, 0.25 mL (1.67 mmol) of 1,5-dicabicyclo [5.4.0] ulecl-5-yl (DBLI). and the mixture was stirred for 10 minutes at room temperature. Water, dichloromethane was added to the reaction mixture, the layer was separated and the organic layer was washed with 0.1 N hydrochloric acid, brine and water. The extracts were dried (NaSO ₄ ) and the solvent was evaporated to give 660 mg of crude product. The product was purified by column chromatography on silica gel (100 g), eluting with chloroform, to give (Z) -isomer (68 mg, 11%).

¹ H-NMR (CDCl ₃ ) ppm (delta): 1.45 (s, 311), 1.6 (s, ²⁰ 3H), 4.45 (s, 1H), 4.68 (d, 211), 5.37 (d, III),

5.1-6.05 (m, 3H), 7.35 (d, 1H), 7.45 (s, 1H).

Further fractions contained 100 mg (16.7%) of the (E) -isomer. It is also an oily substance which crystallizes on standing.

¹ H-NiMR (CDCl ₃ ) ppm (delta): 1.45 (s, 3H), 1.58 (s, 3H), 4.45 (s, 1H), 4.75 (d, 2H), δ , 45 (d, 1H), _Ίη 5.2-6.2 (m, 3H), 7.36 (d, 1H), 7.45 (s, 5H).

Example 22

From the corresponding hydroxy compounds prepared in Example 18, following the procedure of Example 19, the following compounds of formula (LXXXIV) were prepared:

R ³ Production, % Silica gel, eluent ¹ H-NMR (CDCl ₃ ) ppm (delta): (LXXIV) 22 19 (E) diethyl ether (Z) E) -isomer: 1.5 (s, 3H), 1.7 (s, 3H), 4.5 (s, 1H), 4.7 (d, 2H), 5.5 (d, 1H) ), 5.1-6.2 (m, 3H), 7.3-7.5 (m, 2H), 7.7-8.0 (m, 1H), 8.53-8.83 (m , 2 H). (Z) -isomer: 1.48 (s, 3H), 1.6 (s, 3H), 4.5 (s, 1H), 4.7 (d, 2H), 5.25 (s, 1H), 5.1 -6.2 (in, 3II), 6.88 (s, 1H), 7.2-7.5 (m, 1H), 8.43-9.0 (m, 3H). (LXXV) 36 ethyl acetate / hexane (1: 1) Isomeric mixture: 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), 7.2-7.5 (m, 1.7H), 7.6-7.85 (m, 1H), 8.5-8.83 (m, 2H). (LXXVI) 14 chloroform i, 45 (s, 311), 1.6 (s, 311), 4.4 (s, 311), 4.7 (ti, 211), f, 0-6.2 (rn, 3H), δ , 25 (d, 1H), 7.0-7.65 (m, 4H). soybean meal 18 chloroform 1.45 (s, 3H), 1.65 (s, 3H), 4.7-4.2 (m, 1H), 4.45 (s, 0.06H), 4.5 (s, 0, 4H), 4.75 (d, 2H), 5.1 -6.4 (m, 7H).

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Example 23

19-22. Starting from the allyl 6-R ³ -methylene- (1,1-dioxo-penicillanates) prepared in Examples 1 to 9, the following sodium salts of the formula (LXXXV) are prepared according to the procedure of Example 17. The corresponding potassium salts are also prepared (potassium using ethyl hexanoate.

R ³ isomer Production, % IR (KBr) ¹ H-NMR (D ₂ O) ppm (delta): (LXXI1) 3: 1 (THIS) 47 1621, I6 ' ⁷ 8, 1764 2979,3402,3472 cm' ¹ (250 MHz): 1.5 (s, 311), 1.6 (s, 311), 4.25 (s, 1H), 5.57 (s, 0.25 H), 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). (LXXIII) (E) 56 1622, 172 8 cm ^-1 (60 MHz spectrum): 1.56 (s, 3H), 1.65 (s, 3H), 2.68 (s, 311), 4.25 (s, 1H), 5.88 (s, 111) , 6.5 (vol. III), 7.0 (d, 111), 7.6 8.0 (m, 111), 8.2 (s, HI). phenyl (Z) 91 1565.1619.1667, (60 MHz spectrum): 1.45 (s, 3H), 1.55 (s, 1759.2950.3453, 3H0.4.17 (s, 1H), 5.5 (s, 1H) ), 7.0 (s, 1H), cm ^-1 7.27-7.6 (m, 3H), 7.6-8.1 (m, 2H). (LXXIV) (E) 72 1633,1778,3462 cm ^-1 1.55 (s, 3H), 1.62 (s, 3H), 4.23 (s, 1H), 6.05 (s, 1H), 7.4-8.8 (m, 5H). (LXXIV) (Z) 91 1303.1623, 1761, 3445 cm ^-1 1.55 (s, 3H), 1.65 (s, 3H), 4.3 (s, 1H), 5.6 (s, 1H), 6.96 (s, 1H), 7.1-9 , 0 (m, 4H). (LXXV) (E) + (Z) 93 1623.1773.3448 cm ¹ 1.5 (s, .311), 1.6 (s, 311), 4.3 (s, 0.311), 5.55 (s, 0.311), 6.0 (d, 0.711), 6.95 ( s, 0.311), 7.2-7.8 (m, 4.7H). (LXXVI) (E) 33 1619, 177.3,3425 cm ^-1 1.55 (s, 3H), 1.60 (s, 3H), 4.2 (s, 1H), 5.8 (s, 1H), 7.0-7.9 (m, 4H). vinyl - 25 1620,1773,3430 ^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 (m, 3H). (LXIV) (potassium salt) (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, 111), 7.67 (t, 111). ¹³ C-NMR (D ₂ O) ppm (delta): 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. (LXV) (Potassium salt) (E) 92 1614.1770 cm ^-1 (D ₂ 0 + DMSO): 1.5 (s, 3H), 1.6 (s, 3H), 4.1 (s, 1H), 5.9 (d, 1H), 7.5 (d, 1H), 8.5-

9.0 (m, 3H).

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Example 24

6 (E) 4-methyl) penicillanate l, l-dioxide

0.1 g (0.28 mmol) of allyl-6 (E) - (phenylmethylene) -1,1-dioxopenicillanate, 20 mg of triphenylphosphine and 20 mg of tetrakis (triphenylphosphine) -Padium (O) were prepared in 3 ml of ethyl acetate. To this solution was added 0.57 mL of 0.5 M sodium 2-ethylhexanoate and the mixture was stirred at room temperature for one hour. Allow to stand in the refrigerator for 65 hours without precipitation. The mixture was diluted with ethyl acetate, water was added, the layers were separated and the pH of the aqueous phase was adjusted to 1.8 with dilute hydrochloric acid. The aqueous phase was extracted with fresh ethyl acetate. The extracts were dried (Na ₂ SO ₄ ) and the solvent evaporated in vacuo. 62 mg (69%) of yellow crystals (recrystallized from acetone) are obtained.

¹ H-NMR (CD ₃ COCD ₃ ) ppm (delta): 1.55 (s, 3H), 1.65 (s, 3H), 4.43 (s, 1H), 5.93 (d, 1H) , 7.37.9 (m, 6H), 8.7 (bs, 1H);

IR (KBr) cin ': 1327.1685, 1737, 1772, 2929, 2961, 3108, 3477.

Example 25

Potassium-6 (E) 4/1-methylimidazol-2 · [α] -ηιεΜέη) -1,1-dioxopenicillanide

A. III-64/1 Methylimidazol-2-yl) acetoxymethyl) -1,1-dioxopenicillanate

472 mg (1.23 mmol) of 6 - ((1-methylimidazol-2-yl) -hydroxymethyl) -1,1-dioxopenicillanate were acylated by the method of Example 20A and 392 mg (75%). yielding the desired acetoxy compound consisting of a mixture of two isomers.

¹ H-NMR (CDCl ₃ ) ppm (delta): 1.4 (s, 1.5H), 1.5 (s, 1.5H), 1.6 (s, 1.5H), 1.7 ( s, 1.5H), 2.2 (s, 3H),

3.7 (s, 1.5H), 3.75 (s, 1.5H), 4.0-6.0 (m, 8H),

6.3-6.5 (m, 1H), 6.8 (m, 111), 7.0 (ni, 111).

B. III-6 (E) 4/1-Methylimidazol-2-yl (methylene) -1,1-dioxopenicillanate

392 mg (0.920 mmol) of the product obtained in (A) in 5 ml of dichloromethane (0.115 ml) of 1,5-diazabicyclo [4.3.0.0] non-5-ene (DBN) are prepared according to the procedure of Example 20B. 53% yield to give the desired ester.

¹ H-NMR (CDCl ₃ ) ppm (delta): 1.5 (s, 311), 1.6 (s, 311),

3.7 (s, 3H), 4.35 (s, 1H), 4.7 (m, 2Η), 5.0-6.1 (m, 3H), 5.7 (d, 1H), δ , 9 (m, 1H), 7.1 (d, 1H),

7.2 (m, 1H).

C. 163 mg (0.45 mmol) of the compound prepared in (B) was converted to the desired potassium salt using the procedure described in Example 17 using potassium 2-ethylhexanoate instead of the corresponding sodium salt. 143 mg (87%) of product containing only the (E) isomer were obtained.

1 H NMR (DMSO-d 6) ppm (delta): 1.38 (s, 3H), 1.45 (s, 3H), 3.8 (s, 4H), 5.68 (s, 1H), 7, 15 (s, 1H),

7.35 (in, 211);

³ C NMR (DMSO-d ₆ ) ppm (delta): 18.5, 20.2, 32.5, 64.4, 66.2, 70.55, 115.2, 124.6, 129, 9

130.6, 141.2, 167.9, 169.0.

IR (KBr): 1614,1762,3428 ^cm-first

Example 26 mg (0.12 mmol) of <3-yl-6 - ((3-allyloxy-2-pyridyl) methylene) -1,1-dioxocycnicillanal according to the procedure of Example 10 5.2 mg triphenylphosphine 5.2 mg of tetrakis (triphenylphosphine) palladium (O) and 0.24 mmol of potassium 2-ethylhexanoate (2 times molar excess of starting allyl ester) in 1.5 ml of ethyl acetate. The reaction mixture was stirred for 18 hours. The ethyl acetate was removed by pipette and the residue was washed twice with 1 mL of ethyl acetate. 43 mg of a dark solid are obtained, which is the dipotassium salt of 6 (E) - (3-hydroxy-2-pyridyl / methylene) -1,1-dioxopenicillanic acid.

1 H NMR (d 6) ppm (delta): 1.56 (s, 3Π), 1.62 (s, 311), 4.27 (s, HI), 6.00 (d, 111), 7.29 ( ni, 211), 7.80 (d, 111), 8.04 (d, 111).

Example 27

Allyl 6 (E) 4/2-pirimidbül / methylene) penicillanic> IIITM

A. 2-Hydroxymethylpyrimidine

Sodium ethoxide slurry (7.44 g, 323 mmol) and dry ethanol (300 mL) was cooled to room temperature and hydroxyacelamidine hydrochloride (18 g, 163 mmol) and 8.06 g (81 mmol) were added.

3- (Dinethylamino) acrolein is added and the mixture is heated to reflux. Dimethylamine is slowly distilled off, while ethanol is added occasionally to maintain the volume constant. After boiling at reflux for nine hours, mix! Stir at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue was purified by silica gel column chromatography (19: 1 ethyl acetate: methanol) to give 41 g (46%) of product.

B. 2-Pyrimidinylmethyl-triphenylphosphonium chloride

2-Hydroxymethylpyrimidine (4.096 g, 37.2 mmol) was dissolved in dichloromethane (80 mL) and thionyl chloride (8.6 mL, 37.2 mmol) was added dropwise (exotherm). The reaction mixture was stirred for 15 minutes, then neutralized with saturated sodium bicarbonate and extracted with dichloromethane. The extracts were dried and the solvent was evaporated. 3.67 g of 2-chloromethylpyrimidine are obtained.

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N 194 567 * H NMR (CDC1 ₃₎ ppm (delta): 4.82 (s, 2H), 7.3 (t, 1H), 8.9 (d, 2H).

3.565 g (27.7 mmol) of 2-chloromethylpyrimidine and 7.269 g (27.7 mmol) of trilylcylisol are reacted at reflux for 30 hours in 30 mL of toluene. The precipitate formed is filtered off and dried. 9.06 g (69% yield in two steps) are obtained.

C. 2.187 g (5.6 mmol), 218.4 g (5.32 mmol) of sodium nitramide and 30 ml of dry tetrahydrofuran in the Wittig reagent prepared in B. are stirred at room temperature for 1.5 hours. A solution of allyl 6-oxopenicillanate (1.44 g, 5.65 mmol) in dry tetrahydrofuran (10 mL) was added in one portion at -78 ° C. After stirring for 5 minutes, the mixture was poured into a saturated solution of ammonium chloride and extracted with chloroform. The organic layer was washed with saturated ammonium chloride solution, saturated brine, dried (MgSO ₄ ) and the solvent evaporated in vacuo. The resulting oily product was purified by column chromatography on silica gel (9: 1 chloroform: ethyl acetate) to give 560 mg of pure product.

¹ H NMR (CDCl ₃ ) ppm (delta): δ, 5 (s, 3H), 1.6 (s, 3H), 4.6 (s, 1H), 4.7 (m, 2H), δ , 1-6.3 (m, 3H), 6.2 (d, 1H), 7.0 (d, 1H), 7.0-7.35 (m, 1H), 8.8 (d, 2H) ).

28. pclda

Allyl and potassium salt of 1,1-dioxo-6 (E) - (2-pyrimidinyl / methylene) penicillanic acid

A. 560 mg (1.69 mmol) of allyl-6 (E) - (2-pyrimidinyl) -ethylene) penicillanate and 730 mg (3.38 mmol) of 3-chloroperbenzoic acid are dissolved in 10 mL of dichloromethane and the mixture is treated with nitrogen. under atmospheric stirring for 4 hours. The reaction was quenched with water, extracted with dichloromethane and washed with sodium thiosulfate solution. It was then neutralized with sodium bicarbonate, washed with brine, dried and concentrated in vacuo. 460 mg of crude oily product are obtained. The oily product was purified by silica gel column chromatography (9: 1 chloroform: ethyl acetate). 180 mg of the desired light yellow solid allyl ester are obtained.

¹ H-NMR (CDCl ₃ ) ppm (delta): 1.45 (s, 3H), 1.65 (s, 3H), 4.5 (s, 1H), 4.75 (m, 2H), 5.2-6.3 (m, 3H), 5.75 (s, 1H), 7.1-7.5 (m, 2H), 8.9 (d, 2H).

B. The reaction of the above prepared allyl ester, triphenylphosphine, tetrakis (triphenylphosphine) palladium (O) and potassium 2-methylhydroxyalioate in Example 10 provided 89% of the desired potassium salt which was a pink solid.

¹ H-NMR (D ₂ O) ppm (delta): 1.6 (s, 3H), 1.68 (s, 3H), 4.4 (s, 1H), 6.1 (s, 1H), 7.48 (s, 1H), 7.54 (t, 1H), 8.88 (d, 2H);

¹³ C-NMR (D ₂ O) ppm (delta): 20.9, 22.7, 68.8, 68.9, 74.6, 124.5, 132.5, 139.9, 160.9, 163.2, 172.5, 175.5.

1R (KBr): cm -1 ^J 1560, 1615, 1771.3439.

Example 29

A. To a mixture of 1.0 g of 6-alpha-hydroxypenicillanic acid in 25 ml of dichloromethane was added 50 mg of diisopropylcarbodiimide and 0.5 ml of 2,2,2-trichloroethanol, and the reaction mixture was stirred overnight. The solvent was evaporated in vacuo and the crude product was purified by silica gel column chromatography. 2,2,2-Trichloroethyl-alpha-hydroxypenicillanate is obtained.

B. To a mixture of 1.0 g of Oalpha-hydroxypenicillanic acid in 50 ml of dioxane is added 0.5 ml of p-toluenesulphonic acid and 0.4 g of dilydropyran and the reaction mixture is heated to 50 ° C and stirred overnight at room temperature. The solvent was evaporated and the product was purified by column chromatography on silica gel. 2-Tetrahydropyranyl-6-alpha-hydroxypenicillanate is obtained.

Example 30

Benzyl-6-oxo-penicillanate

To a solution of 1.8 ml (0.025 mmol) of dicinylsulfoxide in 2 ml of dichloromethane is added dropwise a solution of trifluoroacetic anhydride (2.12 ml, 0.015 mol) in 5 ml of dichloromethane at -60 ° C. The reaction mixture was stirred for 20 minutes at -60 ° C and a solution of 350 mg (1.14 mmol) of benzyl-alpha-hydroxypenicillanate in 5 ml of dichloromethane was added. After stirring at -60 ° C for 60 minutes, triethylamine (0.5 mL) was added and the cooling bath removed. The temperature was raised to 0 ° C and the mixture was poured into ice water. The mixture was extracted with dichloromethane, the organic phase dried, concentrated in vacuo to a small volume and diluted with benzene. The solution is then washed three times with ice water, the benzene phase is dried and the solvent is evaporated off under vacuum. Yield: 230 mg (67%) of a yellow crystalline product. ¹ H NMR (CDCl ₃ ) shows the product to be very pure.

Example 31

Benzyl-6 - (/ 2-pyridyl / hydroxymethyl) penicillanate

A. Benzyl 6-bromo-6-yl-2-pyridyl-hydroxymethyl-penicillanate

A solution of 9.0 g (0.02 mmol) of benzyl 6,6-dibromopenicillanate in 200 ml of freshly distilled toluene was cooled to -78 ° C and 9 ml of a 2 M solution of pentane in t-butyllithium was added dropwise. After stirring for 30 minutes, 2-pyridine carboxaldehyde (2.14 g, 0.02 mol) was added. Stirring is continued for 40 minutes and then the reaction is carried out with a solution of acetic acid in toluene

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We stop it by dropping 194,567. After stirring for one hour, the cooling bath was removed and the temperature was raised to -10 ° C. The mixture was then diluted with 200 mL of toluene and washed five times with water. The organic phase is dried (MgSO ₄ ) and applied to a column of 1 kg of florisil. Toluene / ethyl acetate was eluted with 2: 1 eluent and the fractions containing product were concentrated in vacuo. A brown syrup weighing 4.2 g is obtained and is used as starting material in the next step.

B. To a solution of the brown syrup (4.2 g) prepared in (A) in benzene (2.65 g) is added tributyltin hydride. The reaction mixture was refluxed for 2 hours, followed by addition of 1.65 g of tributyltin hydride. The reaction mixture was refluxed overnight and the solvent was evaporated in vacuo. The residue was washed with hexane and applied to a column of 500 g silica gel. Elution with toluene / ethyl acetate 2: 1 gave 425 mg of the desired product.

1 H NMR (CDCl 3) ppm (delta): 1.35 (s, 3H), 1.7 (s, 3H), 4.0 (dd, 1H, 4.5 (s, 111), 5.1 (s, 211), 5.2 (d, 1H), 5.4 (d, 1H), 7.0-7.8 (m, 3H), 8.5 (m, 1H).

Example 32

6-j (2-Pyridylhydroxymethyl) penicillanic acid 1,1-dioxide

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

To a solution of benzyl 6 - (2-pyridylhydroxymethyl) penicillanate (0.40 g) in dichloromethane (5 mL) was added m-chloroperbenzoic acid (0.20 g) and the mixture was stirred at room temperature for 1 hour. TLC analysis indicated that the reaction mixture contained little sulfoxide. An additional 0.2 g of m-chloroperbenzoic acid was added and the mixture was stirred overnight. The reaction mixture was then diluted with dichloromethane, washed with saturated sodium thiosulfate solution, water, saturated sodium bicarbonate solution and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with sodium bicarbonate solution, water, and brine and dried (Na ₂ SO ₄ ). The solvent was evaporated to give 330 mg of the desired benzyl ester. The brown oily product was purified by column chromatography on silica gel using ethyl acetate / hexane 11: 9 as the eluent to give 60 mg of a yellow oil.

¹ H-NMR (CDCl ₃ ) ppm (delta): 1.25 (s, 3H), 1.52 (s, 3H), 4.1 (dd, 1H), 4.5 (s, 1H), 4.72 (d, 1H),

5.5 (d, 211), 5.8 (d, 111), 7.1 7.8 (in, 311), 8.5 (m, 1H).

B. A suspension of 118 mg of 10% Pd / C catalyst in 10 ml of tetrahydrofuran and 4 ml of water is prehydrogenated for 20 minutes under 3 atmospheric hydrogen gas. To the suspension is added a solution of 130 mg of benzyl ester prepared in A in 4 ml of the same tetrahydrofuran / water mixture. The mixture was hydrogenated at 50 psi (3.5 kg / cm ² ) hydrogen for 30 minutes. A further 129 mg of 10% Pd / C catalyst was added and the hydrogenation was continued at 50 psi for a further two hours. The catalyst was filtered off, the solvent was evaporated in vacuo and the residue partitioned between water and ethyl acetate. The aqueous phase was frozen to give 85 mg of the desired acid.

¹ H-NMR (E 2 O) ppm (delta): 1.3 (s, 1H), 1.5 (s, 3H), 4.4 (s, 1H), 5.0-5.35 ( m, 2H), 5.9 (d, 1H).

IR (KBr) cm ^-1 : 1620,1731, 13407.

C. If the procedure described above is repeated, but using a total of 175 mg of m-chloroperbenzoic acid (one molar equivalent) in the reaction of step A, the product is a mixture of the corresponding alpha and beta sulfoxides.

Example 33

The following materials are blended in the specified weight ratio to give a uniform powder blend.

(the) potassium (6alpha _; 8R) -6 - ((thiazol-2-yl) -acetoxymethyl) -1,1-dioxopenicillanate 1.0 (B) ampicillin trihydrate 1.0 (C) lactose 0.5 (D) polyctylene glycol, average molecular weight 4000 0.5

1375 mg of the mixture is filled into appropriately sized hard gelatin capsules to give a 250 to 250 mg of active ingredient in each form. Capsules containing larger or smaller amounts of the active ingredient may also be made by varying the size of the capsule and the amount of powder loaded. The weight ratio of the active ingredients can be varied to provide a different weight ratio, such as 0.75, 1.5, 0.5 and 0.3 ingredients. Of this, 1700 mg of powder can be filled into capsules containing 225 shirts (a) and 150 mg (b).

Alternatively, other beta-lactamase inhibitors of the invention may be formulated with other suitable beta-lactam antibiotics for oral administration.

Ingredients (a) and (b) used in the above formulation process, for example, may be replaced by two parts by weight of 6- (D- / 2-amino-2-phenylacetamido / penicillanoyloxymethyl) -6- (2-pyridyl / methylene). -1,1-dioxopenicillinate hydrochloride.

Example 34

Injection

Equal parts of cefoperazone sodium and potassium 1,1-dioxo-6 (E) - (2-pyrazinyl) -methylene-penicillanate are mixed with 20 parts by weight of water. The solution is prepared by methods known in the pharmaceutical literature

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194,567 were sterilized and filtered, and then filled into vials. The vials are loosely sealed with rubber stoppers and frozen on trays and then sealed under vacuum. Each ampoule contains 500 mg of each active ingredient. Prior to injection, each ampoule is diluted in 10 ml of sterile water for injection through a rubber stopper and shaken to ensure dissolution. The solution for injection is taken in an amount of 1 to 10 ml through the rubber stopper using a syringe for injection under the skin.

I i

Example 35

III-6 - ((2-thiazolyl) -accoxymethyl) -1,1-dioxopenicillanate

0.5 g (1.29 mmol) of allyl 6 - ((2-thiazolyl) -hydroxymethyl) -1,1-dioxopenicillanate (prepared according to the procedure of Example 18), 0.396 g (3.88 mmol). acetic anhydride and 0.307 g (3.88 mmol) of pyridine were acetylated in 5 ml of tetrahydrofuran as described in Example 20A. After stirring for 4 hours at room temperature, the reaction mixture was diluted with dichloromethane and washed with water until neutral (pH 6.0-6.5). The organic phase is dried (Na ₂ SO ₄ ) and the solvent is evaporated. 0.688 g of the desired acetate is obtained.

1 H-NMR (CDCl ₃ ) ppm (delta): 1.52 (s, 3H), 2.35 (s, 3H), 4.4-4.6 (m, 2H), 4.6-5. 0 (m, 3H), 5.2-6.4 (m, 311), 6.65 (d, 1H), 7.4 (d, 1H),

7.8 (d, III).

Example 36

Hydrolysis of allyl-6 (2-thiazolylmethylene) -1,1-dioxopenicillanate and its potassium salt

A. The acetoxy ester prepared in Example 35 (0.688 g, 1.29 mmol) was treated with 0.16 g (1.29 mmol) of 1,5-diazabicyclo [4.3.0] non-5-ene (DBN) and 5 mL. dichloromethane and stirred for one hour at room temperature. The mixture was diluted with dichloromethane, washed with water ( ₂ x 50 mL) and dried (Na ₂ SO ₄ ). The solvent was evaporated to give an oily residue which was purified by silica gel column chromatography (1: 1 ethyl acetate / hexane). Yield: 0.189 g (39%) of a light yellow oil.

1 H NMR (CDCl ₃ ) ppm (delta): 1.53 (s; 311), 1.65 (s, 311), 4.33 (s, 111), 4.55 (d, 2H), δ , 0-5.4 (m, 2H), 5.45 (s, 1H), 5.4-6.0 (m, 1H), 7.1 (m,

1H), 7.75 (m, 1H), 7.65 (d, 1H).

B. The above allyl ester is hydrolyzed according to the procedure of Example 25 (C) to give potassium o (2-thiazolyl / methylene) -1,1-dioxopenicillanate as a yellow solid.

¹ H NMR 250 MHz (DMSO-d ₆ ) ppm (delta): 1.40 (s, 3H), 1.45 (s, 3H), 3.80 (s, 1H), 5.83 (s, 1H), 7.66 (s, 1H), 8.04 (m, 2H).

Example 37 (Tetrabutylammonium) -6- (D-2 - ((1-methyl-2- (methoxycarbonyl) vinylamino) -2-phenylacetamido) penicillanate

To 300 ml of chloroform was added 39.3 g of 6- (D- (2-amino-2-phenylacetanido)) penicillalic acid trihydrate, 50 ml of water were added and the pH was adjusted with 40% aqueous tetrabutylammonium hydroxide. Set to 8.5. The layers were separated and the aqueous phase was saturated with sodium sulfate and extracted with fresh chloroform. The initial chlorolbrine phase and the extracts were combined and concentrated to a volume of 250 ml. To the solution was added 150 ml of methyl acetoacetate and 30 g of anhydrous magnesium sulfate. The mixture is refluxed for three hours, then allowed to separate and the warm organic phase is decanted. The pure chloroform solution is allowed to cool and the desired compound precipitates in crystalline form. The desired product is obtained in 52% yield, m.p. 182-184 ° C (dec.).

¹ H-NMR (CDCl ₃ ) ppm (delta): 0.8-2.0 (m, 4H), 1.88 (s, 3H), 3.1-3.6 (m, 8H), 3, 6 (s, 3H), 4.17 (s, 111), 4.58 (s, 111), 5.05 (d, 1H), 5.38 5.6 (m, 211), 6.78 ( d, 111), 7.35 (s, 5H), 9.4 (d, 1Η).

Example 38 (Tetrabutylammonium) -6- (D- (2 - ((1-methyl-2-methoxycarbonyl-vinyl) -amino) -2- (4-hydroxyphenyl) -acetamido) penicillanate

To 300 ml of dichloromethane was added 41.9 g of 6- (2-amino-2- (4-hydroxyphenyl) -acetamido) penicillanic acid trihydrate, water (50 ml) was added and the mixture was adjusted to pH 40 with tetrabutylammonium is adjusted to 8.5 with hydroxide. The phases are separated, the aqueous phase is saturated with sodium sulfate and extracted with fresh dichloromethane. The dichloromethane solution and extracts were combined and concentrated in vacuo. The resulting oily material was crystallized by digestion with acetone. 44.6 g of tetrabutylammonium 6- (2-amino-2- (4-hydroxyphenyl) acetamido) penicillanate are obtained.

The resulting salt is suspended in 150 ml of methyl acetoacetate and the suspension is heated to about 65 ° C until a clear solution is obtained (8 minutes). The mixture is then allowed to cool and the precipitated solid is filtered off. The solid was washed with methyl acetoacetate and then with diethyl ether. 49.25 g of a batch of ethyl ammonium 6- (2- (1-methyl-2-methoxycarbonyl-vinyl) -amino) -2- (4-hydroxyphenyl) -acetamido) penicillanate are obtained, which is a crystalline solid. material.

Example 39

4. Potassium (6alpha, SS) -6 - ((pyrimidin-2-yl) -hydroxymethyl) -1,1-dioxopenicillanate

300 mg of the first eluted (according to the procedure of Example 18) allyl-6alpha - ((pyrimidin-2-yl) -hydroxymethyl) -1,1-di-2447

To a solution of 194,567 oxo-peucicillanate isomers in 4 ml of ciliate acetate was added 30 mg of tetrakis (triphenylphosphine) palladium (O), 30 mg of triphenylphosphine and the mixture was stirred under nitrogen until dissolved (5-10 minutes). A solution of potassium 2-ethylhexanoate (1.57 mL, 0.79 mmol) in ethyl acetate was added and the mixture was stirred at room temperature for 20 minutes. The mixture was filtered and the precipitate was washed with ethyl acetate. The solid was dried to give 53 mg of a yellow solid.

The filtrate was mixed with ethyl ether and a second precipitate formed. Its amount is 152 mg. total yield 69%.

¹ H-NMR, 250 MHz (DMSO-d ₆ ) ppm (delta): 1.33 (s, 3H), 1.44 (s, 3H), 3.77 (s, 1H), 3.95 (d) or d, J = 2, d = 6, lh), 4.89 (d, J = 2.1H), 5.1 (d, J = 6.111), 6.33 (s, 111), 7.48 (t, J = 4, 111), 8.84 (d, J = 4.2H).

1 H-NMR (CDCl 3) ppm (delta): 1.4 (s, 3II), 1.6 (s, 311),

2.2 (s, 3H), 4.45 (s, 3H), 4.45 (dd, 1H), 4.75 (m, 2H), 4.95 (d, 1H), 5.2-5.6 (m, 2H), 5.76.3 (m, 1H), 6.45 (d, 1H), 7.35 (t, 1H), 8.85 (d, 1H).

B. Allylphosphate, 8R) -6 - ((Pyrimidin-2-yl) -acetoxymethyl) -1,1-dioxopenicillanate

By the above procedure, the second eluted allyl-6alpha - (pyrimidin-2-yl) -hydroxymethyl) -1,1-dioxopenicillanate isomer (according to the procedure of Example 18) is converted to the desired compound. Yield 88%.

¹ H-NMR (CDCl ₃ ) ppm (delta): 1.4 (s, 311), 1.6 (s, 3H), 4.45 (s, 1H), 4.50 (dd, J = 1, J = 8.2H), 4.75 (m, 2H), 4.8 (d, J = 1.1H), 5.25-5.6 (m, 2H),

5.7 6.3 (m, III), 6.4 (d, J = 8.111), 7.55 (t, J = 6.1H), 8.8 (d, J = 6, III).

B. Potassium (6alpha, 8R) -6 - ((pyrimidin-2-yl) -hydroxymethyl) -1,1-dioxopenicillanate

300 mg of the second eluted (according to the procedure of Example 18), allyl-6alpha- (pyrimidin-2-yl-hydroxymethyl) -1,1-dioxopenicillanate is converted to the potassium salt by the above procedure. 236 mg (79%) of product are obtained.

¹ H-NMR, 250 MHz (DMSO-d ₆ ) ppm (delta): 1.30 (s, 1H), 1.42 (s, 311), 3.65 (s, 111), 4.60 (dd) , J = O 2, J = 8, 1H), 4.75 (d, J = 2, 1H), 5.15 (d, J = 8, 1H), 7.47 (t, J = 4H, 1H) ), 8.85 (d, J = 4.2H).

Example 40

A. Allyl-6alpha, 8S) -6 - ((pyrimidin-2-yl) -acetoxymethyl) -1,1-dioxopenicillanate

785 mg (2.1 mmol) of the first allyl (6-pyrimidin-2-yl) -hydroxymethyl) -1,1-dioxopenicillanate isomer (according to the procedure of Example 18) are dissolved in 4 ml of dichloromethane and 0.45 Pyridine (5.6 mmol) and acetic anhydride (0.53 mL, 5.6 mmol) were added and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was then diluted with dichloromethane (30 mL), extracted with water (7X60 mL), dried over magnesium sulfate, and filtered. The solvent was evaporated in vacuo to give 813 mg (92%) of product.

Example 41

A. Potassium (6alpha, 8S) -6ffpyrimidin-2-yl-acetoxymethyl-1,1-dioxopenicillanate

789 mg (1.86 mmol) of allyl (6 alpha, 8 S) -6 - ((pyrimidin-2-yl) acetoxymethyl) -1,1-dioxopenicillanate are dissolved in 4 ml of ethyl acetate and following the procedure of Example 39. to the corresponding potassium salt. 342 g (43%) of product were obtained, which was purified by MPLC, medium pressure liquid chromatography (9: 1 water / acetonitrile). 105 mg of product are obtained, which is 83% pure by HPLC.

B. Potassium (6alpha, 8R) -6 - ([pyrimidin-2-yl-acetoxymethyl] -1,1-dioxopenicillanate

666 mg (1.57 (mmol)) of allyl- (6 alpha, 8 R) -6 - ((pyrimidin-2-yl) -acetoxymethyl) -1,1-dioxopenicillanate were converted to the desired potassium salt according to the above procedure. The crude product was purified by medium pressure liquid chromatography (MPLC) using 9: 1 water / acetonitrile as eluent to give 162 mg of pure isomer.

¹ H-NMR, 250 MHz (DMSO-d ₆ ) ppm (delta): 1.34 (s, 3H), 1.44 (s, 3H), 2.17 (s, 3H), 3.65 (s) , 1H), 4.15 (dd, J = 2, J = 8.1 N), 4.97 (d, J = 2.1 H), 6.27 (d, .1 = 8.111), 7, 50 (I, J = 5.111), 8.85 (d, J = 5.2H).

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Example 42

Starting from the corresponding 6-R ¹³ ClIO-substituted-1,1-dioxopenicillanate ester (prepared according to the procedure of Example 18), the following acetate esters were prepared according to the procedure of Example 20 or 40:

Formula (LXXXVI)

R ' ³ c ₆ , c _is stereochemistry Production, % 11 H-NMR (CDCl ₃ ) ppm (delta): (LXXIX) A mixture of 6alpha, 8S and 6alpha, 8R 100 1.43 (s, 3H), 1.63 (s, 3H), 2.25 (s, 3H), 4.51 (m, 2H), 4.79 (m, 2H), 5.43 (ρι, 2H), 5.98 (m, 1H), 6.65 (d, III), 7.5 (in, 3H), 7.98 (s, 11II), 8.20 (m, 211). (LXXX1) 60:40 A mixture of 6alpha, 8S and 6alpha, 8R 69 1.4 (s, 8H), 1.43 (s, 1.2Π), 1.56 (s, 1.2H), 1.62 (s, 1.811), 2.2 (s, 1.2H), 2.3 (s, 1.8H), 4.35 (m, 1H), 4.4 (s, 0.6H), 4.43 (s) , 0.4H), 4.78 (d, 0.6H), 4.8 (d, 0.4H), 5.3-5.5 (τη, 2H), 5.8-6.05 (m, 1H), 6.3 (m, 1H), 7.45 (d, 1H), 8.82 (d, 1H), 9.25 (tn, 1H). (LXV) 60:40 A mixture of 6alpha, 8S and 6alpha, 8R 66 1.4 (s, 1.811), 1.5 (s, 1.211), 1.6 (s, 1.811), 1.65 (s, 1.211), 2.2 (s, 1.211), 2.26 (s, 1.811), 4.24 (dd, 0.4H), 4.35 (dd, 0.6H), 4.4 (s, 0) , 6H), 4.45 (s, 0.4H), 4.68 (m, 2H), 4.74 (d, 0.6H), 5.0 (d, 0.4H), 5.35 ( m, 2H), 5.9 (m, 1H), 6.45 (ni, 1H), 8.6 (m, 2H), 8.75 (m, 1H)

Example 43

In accordance with the procedure of Example 39, the 8-acetoxy-3-allyloxycarbonyl esters prepared in Examples 25A and 42 were converted to the potassium salt of formula (LXXXVII).

R ¹³ . Yield, 11 ¹ H NMR (D ₂ 0) ppm (delta):

scereoKemia / 0

(LXXXI) 65:35 6alpha, 8S, 6alpha, 8R blend 57 (nyres) 27 (purified by chromatography *) Purified: 1.45 (s, 3H), 1.58 (s, 3H), 1.25 (s, 1.05H), 132 (s, 1.95H), 4.25 (s, 0.65H), 4.28 (s, O, 35H), 4.37 (dd, 0.6511), 4.45 (dd, O, 35H), 5.15 (d, O, 65H), 5.2 (d, 0.35H), 6.25 (d, O) , 65H), 6.35 (d, 0.35H), 7.73 (m, 1H), 8.85 (m, 1H), 9.15 (m, 1H). (LXXVII) 6: 1 6alpha, 8S, 6alpha, 8R 64 1.44 (s, 3H), 1.5 (s, 3H), 1.62 (s, 3H), 2.2 (s, 0.4H), 2.24 (s, 2.6H), 3 , Δ (s, 3H), 4.27 (s, 1H), 4.4 (dd, 1H), 4.96 (d, 1H), 6.45 (d, 0.15H), 5.5 ( d, 0.85H), 7.07 (s, 0.5H), 7.1 (d, 0.8511), 7.16 (s, 0.15H), 7.2 (d, 0.8511). IR (KBr) cm ^-1 : 3409, 1786, 1740, 1620. (LXV) 30:70 6alpha, 8S, 6alpha, 8R 84 (crude) 43 (Chromatographed) 1.3 (s, 2, 1H), 1.34 (s, 0.9H), 1.42 (s, 3H), 2.13 (s, 0.9H), 2.2 (s, 2.1H) ), 3.66 (s, 0.711), 3.7 (s, 0.311), 4.1 (dd, 0.311), 4.95 (d, 0.711), 5.07 (d, 0.311), 6.24 (d, 0.3H), 6.36 (d, 0.7H), 8.7 (s, 2H), 8.8 (s, 0.7H), 8.83 (s, 0.3H). IR (KBr): 4468, 1781, 1746, 1623 cm ^-1 . ia (C = mono _I8 octadecyl silicate) column.

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Example 44

In accordance with the procedure described in Example 20B, the 8-acetoxy esters prepared in the Examples above and below are converted to the corresponding 6-ethyl-ethyl compounds, followed by the procedure of Example 39 to remove the allyl group and the potassium salt of formula LXXXVIII. wherein R ¹ is potassium.

R ³ Production, % R ¹ = allyl Production, % R ¹ = potassium ¹ II-NMR (CÜClj) ppm (dclti): NMRiCWlj ^1-yl) ppm (delta): (LXXIX) 100 yellow powder 1.50 (s, 1.5H), 1.54 (s, 1.5H). 1.65 (s, 3H), 4.58 (s, 1H), 4.80 (d, 2H), 5.30 (s, 1H), 5.50 (m, 2H), 6.00 (m , 1H), 7.10 (s, III), 7.5 (m, 3H), 8.02 (s, 0.5H), 8.25 (ni, 211), 8.87 (s, 0, 5H). 1: 1 E and Z isomeric mixture. 42 1.53 (s, 3H), 1.63 (s, 3H), 4.3 E isomer only (s, 1H), 5.7 (s, 1H), 7.2 (s, 1H), 7.4-8.0 (m, 5H), 8.7 (s, 1H). (LXXXI) Example 48 1.55 (s, 3H), 1.65 (s, 3H), 4.35

corresponding spatial (s, 1H), 5.12 (s, 1H), 7.52 (d, 1H), m / z 7.68 (d, 1H), 8.85 (m, 1H), 9.2 by-product (m, 111).

isolated as sulfur (LXXXIX) 53. Example B, initial material 46 1.48 (s, 3H), 1.62 (s, 3H), 4.52 (s, 1H), 4.60-4.80 (s, 2H), 5.31-5.44 (m, 2H), 5.74 (s, JH), 5.87-6.01 (m, 1H), 7.59 (s. H), 8.76 (s, 1H). 39 yellow, solid material 1.38 (s, 3H), 1.40 (s, 3H), 4.19 (s, 1H), 5.92 (s, 1H), 7.76 (s, 1H), 9.13 (s) , 1H). IR (KBr) cm ^-1 : 1775, 1620. (XC) 53. Example B, initial material 59 2.46 (s, 3H), 2.60 (s, 3H), 4/6 (s, 1H), 5.20-5.42 (m, 2H), 5.66 (s, 1H), δ , 80-6.02 (m, H), 7.38-7.42 (ni, 2H), 8.71 (m, 1H). IR: 1795 cm ^-1 . 50 3.5: 1 MP: LP isomer 1.40 (s, 3H), 1.48 (s, 3H), 4.20 (s, 1H), 5.91 (s, 1H), 7.40-7.60 (m, 1H), δ , 89 (m, 1H). IR (KBr) cm ^-1 : 1760.1610. (XCI) 95 1.52 (s, 3H), 1.63 (s, 3H), 2A6 (s, 3H), 4.5 (s, 1H), 4.66-4.52 (m, 2H), 5.34 -5.46 (m, 2H). 5.65 (s, 1H), 6.0 (m, 1H), 7.16 (s, 1H), 7.34 (s, 1H). IRcm ' ¹ : 1790, 1760, 1680. 84 1.38 (s, 3H), 1.36 (s, 3H), 2.33 (s, 3H), 4.16 (s, 1H), 5.89 (s, 1H), 7.3 (s) , 1H), 7.46 (s, 1H). IR (KBr) cm -1 ^] : 1773.1683, 1619. (LXXXIII) starting from the 8-hydroxy compound of Example 18 8 1.49 (s, 3H), 1.63 (s, 3H), 4.52 (s, 1H), 4.60-4.78 (m, 2H), 5.20-5.45 (m, 2H), 5.96-6.02 (m, 2H), 7.39 (s, 1H), 7.477.58 (m, 211), 9.12-9.21 (in, HI). 20 IR cm ' ¹ : 1870, 1625. (XCII) 64 oil 1.46 (s, 3H), 1.60 (s, 3H), 3.64 (s, 3H), 4.51 (s, 1H), 4.60-4.80 (m, 2H), δ , 24-5.46 (m, 2H), 5.62 (s, 1H), 5.80-6.02 (m, III), 7.32 (s, 1H). IR cm ^-1 : 1805. 58 1.42 (s, 3H), 1.48 (s, 3H), 2.52 (s, 3H), 4.25 (s, 1H), 5.87 (s, 1H> 7.18 (s, 1H) .1R (KBr) cm ^-1 : 1785.

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Example 45. Kdlium-6 - (/ imidazol-2-yl / 4iidroxi-ylmethyl) _-l> l di0xo penicillanate

141 mg (0.38 mmol) of the isomeric mixture of Example 18 - allyl 6 - (imidazol-2-yl) -hydroxymethyl) -1,1-dioxopenylanilate, 12 mg of tetrakis (triphenylphosphine) palladium (O) A mixture of 12 mg triphenylphosphine (0.76 mL, 0.38 mmol) and potassium 2-ethylhexanoate (2 mL) was stirred under nitrogen for 1 hour. The precipitated product was filtered off to obtain 143 mg (100%) of a yellow material, which contained two isomers by HPLC. IR (KBr): 3382, 1615 cm 1780.1728 and ^first

Ú4 according to two spots. The crude product was purified by column chromatography on silica gel using chloroform / ethyl acetate 96: 4 as eluent. 4.72 g of a more polar and 2.98 g of a less polar isomer and 0.5 g of a mixture of isomers (total yield 43%) are obtained. More polar isomer: ¹ H NMR (CDC1 ₃₎ ppm (delta):

1.25 (s, 3H), 1.55 (s, 3H), 4.3 (dd, 1H), 4.45 (s, 1H), 4.65 (bs, 1H), 4.9 (d) , 1H), 5.2 (m, 2H), 5.55 (d, 111), 7.35 (m, 611), 7.75 (d, 111).

Less Polar Isomer: ¹ H NMR (CDCl ₃ ) ppm (delta): 1.2 (s, 311), 1.5 (s 311), 4.35 (m, 211), 4.75 (d, 111), 5.1 (m, 211), 5.55 (d, JH), 7.2 (m, 6H), 7.6 (d, 1H).

Example 46

A. Benzyl 6 - ((2-thiazolyl) hydroxymethyl) -1,1-dioxopenicillanate

A solution of 17.79 g (44 mmol) of bis-benzyl-6-alpha-bromo-1,1-dioxopenicillanate in 250 ml of dry tetrahydrofuran is treated with an equimolar amount of methyl magnesium bromide (-78 ° C) and after stirring for one minute, equimolar thiazole-2-carboxaldehyde was added and stirring continued for a further 10 minutes. The reaction mixture was then treated with an equimolar amount of acetic acid and stirred for 5 minutes and then poured into 500 ml of water. The mixture was extracted with ethyl acetate, and the extracts were washed with water, dried (MgSO ₄ ) and the solvent evaporated in vacuo. 16.93 g (98%) of crude product are obtained, which is purified by TLC.

B. (Diphenylmethyl) -6 - ((2-liazolyl) -hydroxymethyl) -1,1-dioxopenicillanate

According to the above procedure, 20 mmol of diphenylmethyl-6-alpha-bromo-1,1-dioxopenicillanate is reacted and the product is purified by silica gel column chromatography using 9: 1 chloroform / ethyl acetate as eluent. 2,464 g of the less polar (LP) and 3,029 g of the more polar (MP) isomer are obtained.

More Polar Isomer: ¹ H NMR (CDCl ₃ ) ppm (delta): 1.06 (s, 311), 1.52 (s, 311), 4.1-4.3 (in, 111), 4.42 (s, III), 4.76 (d, III), 5.45 (d, III), 6.82 (s, HI), 7.05-7.3 (in, III), 7.56 ( d, 1H).

Less Polar Isomer: 1 H NMR (CDCl 3) ppm (delta): 1.2 (s, 3H), 1.65 (s, 3H), 4.35 (dd, 1H), 4.55 (d, 1H), 4 , 83 (d, 1H), 5.65 (dd, 1H), 6.95 (s, 1ΙΊ), 7.2-7.4 (m, 1111), 7.75 (d, 1H).

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Example 7

Using the appropriate chloride of formula R ¹⁸ Cl or the corresponding acid anhydride and starting with the corresponding 6-R ¹³ CHOH-substituted-1,1-dioxopenicillanate ester according to the procedure of Example 20, point A, the following (XCIII): Compounds of formula (I) are prepared.

R ^a R ¹³ Ris C ₈ stereochemistry ¹ H-NMR (CDCl ₃ ) ppm (delta): benzyl (starting from the more polar 8-hydroxy product of Example 46A) 2-thiazolyl Methylaminocarbonyl (R) 1.3 (t, 3U), 1.4 (s, 111), 1.65 (s, 1H), 2.55 (q, 2H), 4.5 (s, 1H), 4.4-4 , 6 (m, 1H), 4.85 (d, 111), 5.27 (s, 2H), 6.65 (d, 111), 7.35 (m, 6H), 7.75 (d, IH). Diphenylmethyl (from the less polar isomer of Example 46B) 2-thiazolyl Methoxycarbonyl (S) 1.25 (s, 3H), 1.3 (t, 3H), 1.75 (s, 3H). 4.24 (q, 2H), 4.36-4.60 (m, 1H), 4.55 (s, 111), 5.02 (d, III), 6.43 (d, 111), 6 , 95 (s, 1H), 7.1-7.5 (in, 1111), 7.75 (d, 1H). Diphenylmethyl (from the more polar isomer of Example 61B) 2-thiazolyl Methoxycarbonyl (R) Pink solid foam allyl 2-thiazolyl (XCIV) (S) + (R) 1.4 (s, 2.1H), 1.5 (s, 0.9H), 1.6 (s, 2.1H), 1.65 (s, 0.9H), 4.4 (s, 0.7H; 4.5 (0.3H); 4.5-5.0 (m, 4H); 5.1-16 (m, 311); 6.9 (d, 111); 4 (m, 11), 7, E (d, 111). allyl 2-thiazolyl Isopropylamino-carbonyl (S) 1.37 (m, 3H), 1.50 (m, 3H), 1.65

less polar (s, 3H), 1.82 (s, 3H), 2.70 (m, 1H),

22% 4.61 (s, 1H), 4.7 (m, 1H), 4.9 (m,

2H), 5.12 (d, 111), 5.41 (m, 111), 5.6 (m, 1H), 5.8-6.5 (m, 1H), 6.75 (d, 1H) ), 7.6 (d, 1H), 7.97 (d, 1H).

(R) 1.18 (m, 3H), 1.28 (m, 3H), 1.33 more polar (s, 3H), 1.52 (s, 1H), 2.6 (m, 1H),% 4.3-4.7 (m, 5H), 5.0-5.4 (m, 2H),

5.45-6.2 (m, 1H), 6.47 (d, 1H), 7.23 (d, 111), 7.63 (d, 1H).

benzyl 2-thiazolyl benzoyl (S) 1.4 (s, 3H), 1.6 (s, 3H), 4.5 (1, 1H), less polar 4.4-4.6 (m, 1H), 5.1 (d, 1H), 5.2 (s, 2H), 6.7 (d, 1H), 7.2-8.2 (m, 1211).

(R) 1.3 (s, 311), 1.6 (s, 3H), 4.5 (s, 1H), less polar 4.6 (dd, 111), 4.86 (d, 111), 5.2 (s,

2H), 6.85 (d, 1H), 7.3-7.7 (m, 9H), 7.8 (d, 1H), 8.15 (dd, 2H).

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Example 48

A. (6alpha, 8R) -6 - ((Thiazol-2-yl) -propionyloxymethyl) -1,1-dioxopenicillanic acid

A suspension of 1.89 g of 10% Pd / C catalyst in 20 ml of 9: 7 (v / v) tetrahydrofuran / water was saturated with hydrogen and 689 mg (1.4 mmol) of benzyl- (6alpha, 8R) -6- A solution of (thiazol-2-yl) -propionyloxymethyl-1,1-dioxopenicillanate in THF (13 mL) and water (7 mL) was added.

The reaction mixture was hydrogenated at 3 bar of hydrogen for 20 minutes. The catalyst was filtered off and the filtrate was extracted with ethyl acetate (3 x 200 mL).

The extracts were dried _(MgSO4) and the solvent evaporated in vacuo agent ^15. 330 mg of a yellow solid are obtained.

B. (6alpha, 8R) -6- (Thiazol-2-yl-benzoyloxymethyl) -1,1-dioxopenicillanic acid

The desired product was prepared according to the above procedure from the corresponding benzyl ester in 57% yield.

1 H-NMR (D ₂ O) ppm (delta): 1.38 (s, 3H), 1.55 (s,

3H), 4.25 (s, 1H), 4.44 (dd, 1H), 5.05 (d, 1H),

6.68 (d, IH), 7.4 (t, 7H), 7.55 (t, IH), 7.58 ₃₀ (d, IH), 7.7 (d, IH), 7.95 ( d, 1H).

IR (KBr) cm ^-1 : 3473.1782, 1729, 1622.

Example 49

A. (6alpha, 8S) -6- (Thiazol-2-yl) -ethoxy-carboxyl-oxy-methyl'-1,1-dioxo-penicillanic acid

557 mg (0.954 mmol) of (diphenylmethyl) -6alpha, 8S) -6 - ((thiazol-2-yl) -ethoxycarbonyloxy-methyl) -1,1-dioxopenicillanate were prepared in 5 ml of dichloromethane. To this solution was added 0.62 mL (5.72 mmol) of anisole. The reaction mixture was cooled to -5 ° C and 382 mg (2.86 mmol) of anhydrous aluminum chloride and 2 ml of nitromethane were added slowly over 15 minutes. The reaction mixture was diluted with ethyl acetate (50 mL), water was added and the pH was adjusted to 7.5. The aqueous phase was separated, acidified to pH 3 and extracted with ethyl acetate. The solvent was evaporated and the glassy residue was dissolved in diethyl ether. The solution was filtered. Hexane was then added and a precipitate formed. The precipitate was filtered off and dried. 211 mg (53%) of product are obtained.

¹ H-NMR, 300 MHz, (CDCl ₃ ) ppm (delta): 1.34 (t, 3H), 1.53 (s, 3H), 1.65 (s, 3H), 4.2-4, 4 (m, 3H), 4.44 (s, 1H), 5.04 (s, 1H), 6.67 (d, 1H), 7.53 (d, 1H), 7.90 (d, 1H).

IR (KBr) 34.18, 1803, 1750 cm @ -1.

B. The (6alpha, 8R) -isomer diphenylmethyl ester starting material prepared in Example 47 was reacted according to the above procedure with the appropriate (6alpha, 8R) -6 - ((thiazol-2-i)) - / ethoxycarbonyl. oxy (methyl) -1,1-dioxo-pcnicillanic acid is prepared.

Example 50

Using the appropriate allyl ester prepared in Example 47, the potassium salts of formula (XCV) were prepared as follows starting from the procedure of Example 45.

R ¹³ R ¹⁸ C ₈ stereochemistry ¹ H-NMR (D ₂ O) ppm (delta): 2-thiazolyl (XCIV) (S) 1.46 (s, 3H), 1.65 (s, 3H), 4.35 (2s, 1H), 5.2 (d, 1H), + 7.05 (d, 1H), 7.7-8.0 (m, 2H), 8.7-9.5 (m, 3H). (R) 2-thiazolyl Isopropylamino-carbonyl (S) 1.13 (d, 3H), 1.16 (d, 3H), 1.33 (s, 3H), 1.45 (s, 3H), 90% 2.65 (m, 1H), 3.73 (s, 1H), 4.23 (dd, 1H), 4.93 (d, production 1 H), 6.50 (d, 1 H), 7.85 (m, 2 H). IR (KBr): 3777, 3472, 3447, 3270, 1783.1746, 1621 ^cm-first (R) 1.17 (d, 3II), 1.20 ((1, 311), 1.44 (s, 311), 2.69 (ill, III), 27% 3.68 (s, 1H), 4.12 (dd, 1H), 4.92 (d, 1H), 6.59 (d, 1H), production 7.84 (m, 2H).

R (KBr): 3443.3498.3437.3415.3348.3270.3119, 917.1783, 1745, 1718, 10 cm @ ^-1 .

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Example 57

A. Allyl-6-bromo-6 - ((2-thiazolyl) -hydroxymethyl) -1,1-dioxo-penicillanate

A solution of allyl-6,6-dibromo-1,1-dioxopenicillanate (8.84 g, 20 mmol) in dry tetrahydrofuran (100 mL) was cooled to -78 ° C and methyl magnesium (7.02 mL, 20 mmol) was added. bromide is added. After stirring for 5 minutes, a solution of thiazole-2-carboxaldehyde (2.26 g, 20 mmol) in dry tetrahydrofuran (10 mL) was added at -78 ° C. Stirring was continued for a further 20 minutes and then 1.2 ml of acetic acid was added. The reaction mixture was poured into water and extracted with ethyl acetate and chloroform. The combined organic solutions were dried (Na ₂ SO ₄ ) and the solvent was evaporated in vacuo. 8.5 g of a crude glass product are obtained.

The crude product was purified by column chromatography on silica gel using 89:11 chloroform / ethyl acetate as eluent to give 6.2 g (72%) of pure material, digested with one isomer.

¹ H-NMR (CDCl ₃ ) ppm (delta): 1.3 (s, 3H), 1.6 (s, 3H), 4.0 (bs, 1H), 4.42 (s, III), δ , 6 (d, 2H),

5.3 (s, 111), 5.55 (s, 111), 5.1-6.3 (m, 311), 7.35 (d, 1H), 7.75 (d, 1H).

B. Benzyl 6-bromo-6 - ((2-thiazolyl) -hydroxymethyl) -1,1-dioxopenicillanate

Using b-benzyl-6,6-dibromo-1,1-dioxopenicillanate starting material instead of allyl ester, the desired compound was prepared by the above procedure. A yellow foamy solid is obtained in quantitative yield.

1 H-NMR (CDCl ₃ ) ppm (delta): 1.32 (s, 311), 1.60 (s, 3H), 4.5 (s, 2H), 5.2-5.8 (m, 4H), 7.3 (d, 1H),

7.4 (s, 5H), 7.8 (d, 1H).

Example 57 (continued)

C. Following the procedure of A, the following compounds of formula (XCVI) are prepared.

R ^a _R 13 Production, % ¹ H-NMR (CDCl ₃ ) ppm (delta): benzyl (XCVII) 100 yellow foam 1.25 (s, 311), 1.54 (s, 311), 4.5 (s, 1H), 5.02 (s, 1H), 5.43 (s, III), 5.68 (s, 1H), 7.32 (m, 7H), 8.00 (m, 211). benzyl (XCVIII) 88 yellow solid 1.4 (2s, 3H), 1.6 (s, 3H), 4.0 (s, 1H), 4.9 (2, 1H), 5.18 (m, 2H), 5.5-5.7 (m, 2H), 7.5 (s, 5H), 8.0 and 8.5 (2s, 1H). benzyl (LXV) 100 1.25 (s, 311), 1.52 (s, 311), 4.45 (s, 0.7511), 4.52 (s, 0.2511), 5.1 5.4 (ni, 411 ), 7.3 (s, 511), 8.6 (in, 211),?, 0 (m, 1H). allyl (LXXXIX) 38 1.38 (s, 3H), 1.60 (s, 3H), 4.38-4.73 (m, 3H), 5.06.0 (m, 5H), 7.10 (s, 1H) , 8.51 (s, 1H). Example 52 _R n Production, ¹H-NMR (CDCl ₃ ) ppm (delta):

A. The compounds of Example 51 were prepared as described in Examples 42 or 50

By acylation according to the procedure of Example 47, the following compounds of formula (XCIX) are prepared.

A Where R ^a is allyl, R ¹⁸ is acetyl. 55 ¹³ C-NMR (CDCl ₃ ) ppm (delta):

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.

_R ia yield, 'H NMR _(CDCl3) ppm (delta):

2-thiazolyl colorless 1.4 (s, 3H), 1.6 (s, 3H), 2.25 crystals (s, 3H), 4.45 (s, 1H), 4.65 (m,

2H), 5.4 (s, 1H), 5.2-6.3 (m, 3H), 6.7 (s, 1H), 7.4 (d, 1H),

7.8 (d, 1H).

(LXXXIX) 59 (+21% 1.40 (s, 3H), 1.60 (s, 3H), 2.25 isomer (s, 311), 4.48 4.70 (in, 311), (coins) ) 5.2 6.2 (m, 511), 6.92 (s, 111),

8.83 (s, III).

B. Where in the general formula R ^a is benzyl 65, R ¹⁸ is acetyl.

-3 161

194 567 _R13 Production, 1 H NMR (CDCl ₃ ) ppm (delta):

R ¹³ Production, 1 H-NMR (CDCl ₃ ) ppm (delta):

2-thiazolyl 100 1.25 (s, 3H), 1.55 (s, 3H), vitreous 4.50 (s, 0.9H), 4.55 (s, 0.1H), material 5.2 (m, 2H), 5.40 (s, 0.9H), 9: 1 iso- 5.55 (s, 0.1 II), 6.42 (s, 0, III), mercury mixture 6.60 (s, 0.911), 7.3 (m, 6Π), 7.75 (d, 1H). 5 10 (XCVII) 100 yellow orange- foam 1.3 (s, 3H), 1.52 (s, 3H), 2.25 (s, 3H), 4.54 (s, 1H), 5.02 (s, 211), 5.52 (s) , 111), 6.8 (s, 1H), 7.3 (m, 7H), 7.9 (m, 2H). 15 (XCVI1I) 19 1.25 (s, 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). 20 (LXV) 90 1.25 (s, 2.25H), 1.35 (s, O, 75H),

3: 1 iso- 1.4 (s, 2.2511), 1.42 (s, 0.7511), mercury mixture 2.2 (s, 2.25H), 2.3 (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, 0.2511), 6.25 (s, 0.2511),

6.4 (s, 0.7511), 7.3 (ni, 511),

8.67 (m, 211), 9.67 (s, 1H).

~ ~ ~ ————— - |

C. Alternatively, the compounds of the general formula above are prepared as described in Example 5. Prepared according to the procedure of Example 1B.

The acylation of the reaction mixture is carried out without prior isolation of the product according to the following general procedure.

To a solution of 1.0 equivalent of 6,6-dibromopenicillanate ester in tetrahydrofuran at -78 ° C was added 1.3 equivalents of methyl magnesium bromide in the same solvent and stirred for 5-10 minutes. A solution of 1.3 equivalents of the appropriate (R ¹³ CHO) aldehyde in the same solvent was then added at -78 ° C to 68 ° C and stirred for 30-60 minutes. Finally, 1.3 equivalents of acetic acid chloride were added to the reaction mixture with stirring (-78 ° C).

Stirring is continued for 10 minutes and the product is poured into ice water, extracted with ethyl acetate, and the organic solution is dried. and isolated by evaporation of the solvent in vacuo.

R in the general ^{formula, and} is acetyl.

R ^a r! 3 Production, % ¹ H-NMR (CDCl ₃ ) ppm (delta): benzyl phenyl 100 Pale yellow foam allyl (XC) yellow oil 1.35 (s, 3H), 1.56 (s, 3H), 2.22 (s, 3H), 4.42 (s, 1H), 4.60-4.74 (m, 2H), δ , 24-5.42 (m, 3H), 5.79-5.96 (ni, 1H), 6.52 (s, 1H), 7.32-7.34 (d, 1H), 8.70 -8.74 (d, 1H). IR: 1810.1760 cm ^1st allyl (XCI) 59 yellow oil 1.42 (s, 3H), 1.62 (s, 3H), 2.28 (s, 3H), 2.48 (s, 3H), 4.5 (s, 1H), 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: 1810.1760, 1730 cm @ -1. benzyl (C) 59 1.6 (s, 311), 1.8 (s, 311), 2.2 (s, 311), 2.3 (s, 611), 4.4 (s, III), 5.2 (d, 2H), 5.3 (s, 1H), 6.4 (s, 1H), 7.3 (s, 5H). benzyl (CI) 22 1.22 (s, 3H), 1.5 (s, 311), 2.18 (s, 311), 4.22 (s, 3H), 4.5 (s, 111), 5.16-5.36 (m, 311), 6.18 (s, 111), 6.48 (s, 1H), 7.4 (s, 5H). benzyl (CII) 44 yellow foam 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). allyl (XCI) 36 foam 1.40 (s, 311), 1.60 (s, 311), 2.27 (s, 311), 2.65 (s, 311), 4.20-4.8 (m, 311), 5.1 -6.2 (m, 4H), 6.41 (s, 111). IR: cm 1815.1760 ^first

-3 263

194,567

Example 53

A. Benzyl 6-beta - ((thiazol-2-yl) -acetoxymethyl} -1,1-dioxopenicillanate

74.6 g (134 mmol) of benzyl-6-bromo-6 - ((thiazol-2-yl) -acetoxynictyl) -! Tributyltin hydride (43.99 g, 151.2 mmol) was added to a side of 1-dioxopenicillanate, 850 mL of benzene. The mixture was refluxed for 5.5 hours and then allowed to stand overnight. The solvent was evaporated in vacuo and the residue triturated with hexane and then extracted with acetonitrile (2 x 250 mL). The acelonitrile solution is evaporated, the residue is suspended in ether, filtered and the precipitate is washed with ether. 33.28 g of colorless crystals are obtained. 2.8 g of additional product are obtained by evaporating the filtrate to dryness. The residue was dissolved in benzene and 10 g of tributyltin hydride were added. Reflux for one hour and process in the same way as the first precipitate. Total yield 56.3%.

The above first precipitate was purified by silica gel column chromatography (9: 1 chloroform / ethyl acetate). The product-containing fractions were concentrated, slurried in 4: 1 ethyl ether / ethyl acetate and filtered. The precipitate was washed with ether to give 22.6 g of a white solid.

1 H-NMR (CDCl ₃ ) ppm (delta): 1.25 (s, 3H), 1.53 (s, 3H), 2.1 (s, 3H), 4.58 (s, 1H), δ , 80 (d, 1H),

5.2 (dd, III), 5.22 (q, 211), 6.75 (d, III), 7.35 (s, 511), 7.4 (d, 111), 7.8 (d) , III).

¹³ C-NMR (CDCl ₃ ) ppm (delta): 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. In a similar manner, the products of Example 52 were prepared to give the following debrominated compound (Cili):

R ^a R ¹³ Production, % ¹ H-NMR (CDCl ₃ ) ppm (delta): benzyl (XCVI) 39 1.3 (s, 311), 1.55 (s, 311), 2.19 (s, 311), 4.5 (s, III), 4.79 (d, III), 5.2 (ni , 311), 6.79 (d, III), 7.32 (m, 7Η), 7.9 (ni, 2H). benzyl (XCVIII) 72 1.29 (s, 3H), 1.55 (s, 3H), 2.10 (s, 311), 4.03 (s, 3H), 4.5 (s, 111), 4.78 (d) , 111), 4.87 (dd, 1H), 5.25 (q, 2H), 6.53 (d, 1H), 7.38 (s, 5H), 7.89 (s, 1H). benzyl (LXV) 46 yellow solid 1.3 (s, 311), 1.55 (s, 311), 4.45 (s, 111), 4.6 5.1 (m, 2H), 5.2 (m, 211), 6, Δ (dd, 1H), 7.35 (s, 5H), 8.6 (m, 2H), 8.83 (m, 1H). allyl (LXXXIX) 70 oil 1.44 (s, 3H), 1.62 (s, 3H), 2.10 (s, 3H), 4.52 (s, 1H), 4.60 4.80 (m, 211), 4, 89 4.91 (d, 111), 5.26 5.42 (m, 3H), 5.86-5.99 (ni, 1H), 6.88-6.92 (d, 111), 8, 82 (s, 1H). IR: cm 1795.1750 ^first allyl (XC) 51 less polar isomer + 11 more polar isomer MPi isomer: 5.84-6.00 (m, 1H), 6.28-6.42 (m, 2H), 6.62-6.77 (d, 1H), 7.38-7.48 ( d, 1H), 8.64-8.70 (d, 111). White crystals. IR (KBr) 1807, 1760 ^cm-first allyl (XCI) 31 yellow oil 1.46 (s, 3H), 1.64 (s, 3H), 2.14 (s, 3H), 2.48 (s, 3H), 4.5 (s, 1H), 4.6-4 , 9 (in, 3H), 5.2-5.26 (dd, 1H), 5.3-5.6 (ni, 2H), 5.86-6.1 (in, 1H), 6.7 (d, 1H), 7.0 (s, III). IR: 1810, 1760 ^cm-first benzyl (C) 43 m.p. 194.5-195.5 ° C 1.3 (s, 3H), 1.58 (s, 3H), 2.12 (s, 3H), 2.36 (d, 6H), 4.5 (s, 1H), 4.75 (d) , 1H), 5.2-5.4 (dd, 3H), 6.6 (d, 1H), 7.4 (s, 511). benzyl (CI) 16 colorless solid, one isomer 1.28 (s, 311), 1.55 (s, 311), 2.1 (s, 311), 2.4 (s, 311), 4.5 (s, 111), 4.8 (dd, 111), 5.25 (q, 111), 6.15 (s, 111), 6.5 (d, 1H), 7.4 (s, 5H).

-33194 567

R ^a R ¹³ Production, % ¹ H-NMR (CDCl ₃ ) ppm (delta): benzyl (CH) 43 1 1.3 (s, 311), 1.58 (s, 311), 2.14 (s, 311), 2.48 (s, 311), 4.52 (s, 111), 4.8 (4 , 111), 5.16 5.36 (AB q and dd, 3H), 6.7 (d, 1H), 7.0 (s, 111), 7.4 (s, 5H). allyl (XCII) 44 3: 1 mixture of isomers 1.37-1.40 (d, 3H), 1.58-1.60 (d, 3H), 2.12-2.14 (d, 3H), 2.58 (s, 3H), 4, 48 (s, 3H), 4.58-4.88 (m, 4H), 5.24-5.46 (m, 211), 5.82-6.00 (in, 1H), 6,646.67 ( d, 0.7511), 7.05-8.08 (d, 0.25H); IR: 1810, 1765 ^cm-first Example 54 1 A. The benzyl esters prepared in Example 53 are converted to the carboxylic acids of formula (CIV) by the following procedure. According to the method of the invention, R ^b is hydrogen using Pd / C catalyst. R ¹³ r! 8 Production, % ¹ H NMR (DMSO-δ ₆ ) ppm (delta): 2-thiazolyl acetyl 74 white solid, m.p. 145-155 ° C (dec.) 1.45 (s, 3H), 1.53 (s, 3H), 2.10 (s, 3H), 4.48 (s, 1H), 5.0 (dd, 1H), 5.41 (d) , 1H), 6.59 (d, 1H), 7.91 (m, 2H). ¹³ C-NMR: 17.1036, 19.3736, 20.2771, 53.2954, 62.5971, 62.8347, 63.3676, 64.5698, 122.6881, 142.4252, 164.3975, 167 , 8111, 168,7027, 170,8035 (LCV11) acetyl 45 1.53 (s, 311), 1.65 (s, 311), 2.17 (s, 3H), 4.54 (s, 111), 4.87 (d, 1H), 5.13 (dd) , 1H), 6.82 (d, 1H), 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, 126.1, 126 , 6, 135.3, 151.6, 166.6, 169.2, 169.3, 170.6. (LXV) acetyl 60 (D ₂ 0) 1.45 (s, 3H), 1.57 (s, 3H), 2.15 (s, 3H), 4.33 (s, 1H), 5.24 (d, 1H); 4.75-5.2 (-1H closed, at D ₂ O), 6.55 (d, 1H), 8.65-8.8 (m, 2H). IR (KBr): 3416.1785, 1618 cm / ^{1st 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. (C) acetyl 85 1.48 (s, 3H), 1.55 (s, 3H), 2.15 (s, 3H), 2.28 (s, 3H), 2.32 (s, 3H), 4.3 (s) , 1H), 4.85 (dd, 1H), 5.2 (d, 1H), 6.6 (d, 111). IR (KBr): 1787.1626, 1618 ^cm-first (CI) acetyl 87 1.48 (s, 3H), 1.6 (s, 3H), 2.2 (s, 3H), 2.46 (s, 3H), 4.35 (s, 1H), 5.2 (d) , III), 6.4 (s, 1H), 6.55 (d, 1H). IR (KBr): 1791.1692, 1631 ^cm-first (CH) acetyl 57 1.5 (s, 311), 1.6 (s, 311), 2.2 (s, 311), 2.45 (s, 3H), 4.35 (s, III), 4.0 (dd) , III) .5.25 (d, 111), 6.7 (d, III), 7.3 (s, 111). IR (KBr): 1787, 1657, 1626 cm ^-1 .

-3 467

194,567

Example 54 (continued)

B. The 6-beta-thiazol-2-yl-acetoxymethyl-1,1-dioxopenicillanic acid prepared in A is converted to the corresponding potassium salt. The acid aqueous suspension of an equimolar amount of potassium bicarbonate in an aqueous solution and the product using medium pressure fofyadékkromatográfia, * C ₁₈ column, 9: 1 using a water / acetonitrile eluent. The desired potassium salt is obtained in 60% yield.

1 H-NMR (CDMSO-d 6) ppm (delta): 1.37 (s, 3H), 1.48 (s, 3H), 2.07 (s, 3H), 3.80 (s, 1H), 4, 92 (dd, 1H), 5.12 (d, 1H), 6.55 (d, 1H), 7.89 (m, 2H).

IR (KBr): 3454, 1788.1630 cm ^1st

* Ci ₈ octadecyl silicate.

Example 55

A. 6f (Benzothiazol-2-yl (methylene) -1,1-dioxopenicillanic acid, E and Z isomeric mixture

To a solution of 400 mg (0.91 mmol) of 6 - ((benzothiazol-2-yl) -acetoxymethyl) -1,1-dioxopenicillanic acid in 5 mL of water was added 0.15 g (1.82 mmol) of sodium hydrogen carbonate solution in 2 tl of water was added and the mixture was stirred for 2 hours. The reaction mixture was lyophilized (pH 7.55). The lyophilate was dissolved in 8 mL of water, adjusted to pH 3.5 with dilute hydrochloric acid and extracted with ethyl acetate. The organic solutions were combined, dried (MgSO ₄ ) and the solvent evaporated in vacuo. The product was found to be a mixture of (E) and (Z) isomers of 60:40 by NMR.

1 H-NMR (CDCl 3) ppm (delta): 1.55 (s, 1.2H), 1.6 (s, 1.8H), 1.65 (s, 1.2H), 1.67 (s, 1 , 8H), 4.55 (s,

0.6H), 4.58 (s, 0.4H), 5.38 (s, 0.4H), 5.74 (s,

0.6H), 7.44 (s, 0.4H), 7.48 (s, 0.6H), 7.5 (m,

4H), 7.89 (d, 1H), 8.07 (d, 0.4H), 8.15 (d, 0.6H).

B. By a similar procedure, the corresponding 6-R ¹³ -CH (OAC) substituted 1,1'-dioxo-penicillanic acids are converted to compounds of formula (CV) which are a mixture of isomers (E) and (Z).

13 Yield% ¹ H NMR (D ₂ O) ppm (delta) (XCVIII) (Na salt) 84 1.54 (s, 3H), 1.62 (s, 3H), 60:40 (E) <Z) 4.04 (s, 3H), 4.35 (s, 1H), isomer mixture 5.7 (s, 0.6H), 5.95 (s) 0.411), 7.26 (s, 0.6H), 7.55 (s, 0.4H), 8.09 (s, 2H).

Example 56

A. Potassium 6-bromo-6 - ((thiazol-2-yl) -acetoxymethyl) -1,1-dioxopenicillanate mg (0.2 mmol) 6-bromo-6 - (/ thiazole-2-yl) II-Acetoxymethyl) -1,1-dioxopenicillanate, prepared in Example 52, is converted to the desired product by reaction for 10 minutes according to the procedure of Example 45. Obtained as a yellow solid (46 mg, 48%).

¹ H-NMR (D ₂ O) ppm (delta): 1.45 (s, 3H), 1.6 (s, 3H),

4.4 (s, 1H), 5.55 (s, 1H), 6.85 (s, 1H), 7.72 (d, 1H), 7.86 (d, III).

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

According to the above procedure, 200 mg of the allyl-6-bromo-6 - (thiazol-2-yl) -hydroxymethyl) -1,1-dioxopenicillanate prepared in Example 51 are converted to the desired product in a reaction time of 20 minutes. 52% yield of the desired compound is a pale yellow solid.

1 H-NMR DMSO-d6 ppm (delta): 1.35 (s, 3H), 1.47 (s, 3H), 3.75 (s, 0.4H), 3.83 (s, 0.6H). , 5.3 (d, 0.4H), 5.32 (d, 0.6H), 5.45 (s, 0.6H), 5.5 (s, 0.4H), 7.6-8 , 0 (m, 211).

IR (KBr): 3442, 1794, 1633 cm ^1st

Example 57

Potassium (6bcla, 8S) -6 - ((thiazol-2-yl) -hydroxymethyl) penicillanate

A. Allyl-6-bromo-6 - ((thiazol-2-yl) -hydroxymethyl) penicillanate

9.971 g (24.99 mmol) of allyl-6,6-dibromopenicillanate

To a solution of 150 ml of dry tetrahydrofuran at -78 ° C was added 8.77 ml of a solution of 2.85 mol (24.99 mmol) of methyl magnesium bromide in tetrahydrofuran and stirred for 15 minutes. A solution of thiazole-2-carboxaldehyde (2.824 g, 24.99 mmol) in tetrahydrofuran (5 mL) was added and stirred at -78 ° C for 20 min. The reaction was quenched with glacial acetic acid (1.43 mL, 24.99 mmol) and stirred for 10 minutes and then allowed to warm to room temperature. The mixture was poured into water, extracted with ethyl acetate (2 x 250 mL), washed with water (2 x 250 mL), dried (MgSO ₄ ) and the solvent evaporated in vacuo. 10.36 g of an orange oil are obtained. This was purified by column chromatography on silica gel using 9: 1 chloroform / ethyl acetate as eluent to give 4.54 g of a yellow solid (mixture of isomers) and 0.443 g of a yellow foam (more polar isomer only). Total yield 46%.

The yellow foam: ¹ H NMR (CDC1 ₃₎ ppm (delta): 1.56 (s, 3H), 1.76 (s, 3H), 4.60 (s, 1H), 4.7 (m, 2H ), 4.9-6.4 (m, 6H), 7.45 (m, 1H), 7.8 (m, 1H).

-3 569

57, 194,557

B. Allyl-6beta - ((thiazol-2-yl) -hydroxymethyl) penicillanate

The more polar isomer prepared in A.

To a solution of 200 mg (0.462 mmol) in 1 mL of benzene was added 0.183 mL (0.693 mmol, 1.5 equivalents) of a benzene solution of tributyltin hydride and the mixture was refluxed for 3 hours and then allowed to stand overnight at room temperature. The solvent was then evaporated in vacuo and the residue was dissolved in acetonitrile and washed with hexane. The solution was concentrated to a small volume and purified by column chromatography on silica gel. Chloroform eluant gave 73 mg (45%) of the desired product.

¹ H-NMR (CDCl ₃ ) ppm (delta): 1.65 (s, 3H), 1.87 (s, 3H), 3.8-4.4 (m, 1H), 4.05-4, 3 (dd, 1H), 4.65 (s, 1H), 4.78 (m, 2H), 5.3-5.6 (m, 2H), 5.66.3 (m, 3H), 7 , 45 (m, 1H), 7.85 (ni, 111).

C. 73 mg (0.206 mmol) of the product obtained in B. are converted to the potassium salt according to the procedure of Example 45. 58 mg (80%) of the desired product are obtained as a yellow solid.

¹ H-NMR, 300 MHz, (D ₂ O) ppm (delta): 1.36 (s, 3H), 1.55 (s, 311), 4.1 (dd, III), 4.18 (s) , 111), 5.32 (d, 111), 5.41 (d, 111), 7.56 (d, 1H), 7.60 (d, 1H).

Example 58

A. Using the corresponding aldehyde R ³ CHO instead of thiazole-2-carboxaldehyde, the corresponding compounds of formula CVI were prepared according to the procedure of Example 57, A.

R ^{* 13} Production ¹ H-NMR (CDCl ₃ ) ppm (delta):

% (LXV) 20, Isomer A-A: 1.46 (s, 3H), 1.64 mer (white (s, 3H), 4.42 (d, 1H), 4.50 crystals) (s , 1H), 4.64 (m, 2H), 5.2613, Trust- 5.50 (in, 311), 5.84 (s, 1H), m / z (yellow 5.8 -6.0 (m) , Η), 8.5 δ (d, oil) 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 (s, 3H), 4.56 (s, 1H), 4.65 (m, 2H), 5.1-5.5 (m, 4H),

5.6-6.0 (m, 111), 5.91 (s, III), 8.57 (ni, 211), 8.78 (ni, 111).

R ¹³ Production % ¹ H-NMR (CDCl ₃ ) ppm (delta): ¹³ C NMR (CDCl ₃ ): 26.27, 32.57, 64.30, 66.19, 69.94, 70.77, 72.38, 74.73, 119.70, 130.98, 143 , 30, 144.57, 144.70, 152.04, 166.99, 167.99 ppm. (LXXX) 25 (Isomer A, 8S) 1.52 (s, 3H), 1.70 (s, 3H), 4.64 (s, 111), 4.72 (m, 211), 4.86 (d, 111), 5.34-5.48 (in, 3H), 5.91 (s, 1H), δ , 92-6.05 (m, 1H), 7.39 (t, 1H), 8.87 (d, 2H). (LXXX) 40 (B isomer, 8R) 1.52 (s, 3H), 1.71 (s, 3H), 4.61 (s, 1H), 4.72 (m, 2H), 4.98 (d, 1H), 5.30-5.52 (m, 3H), 5.90-6.04 (m, 1H), 6.10 (s, 1H), 7.40 (t, 1H), 8.85 (d, 2H). (LXXXIX) 83 foam 1.49 (s, 311), 1.69 (s, 311), 3.56 (d, 0.711), 3.89 (d, 0.311), 4.7 (m, 3H), 5.5 (m, 3H), 5.9 (m, 2H), 7.53 (m , 3H), 8.14 (ni, 3H). (XCV11) 94 (crude mixture of isomers) (CVII) (LXXV) Β. The above compounds were debroamed by the procedure of Example 57, B to give compounds of formula (C1X). r13 Production % ¹ H NMR (CDCl ₃ ) ppin (delta): (LXV) (From the isomer, 8S) 57 oil 1.5 (s, 3H), 1.7 (s, 3H), 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, 1H), 5.9-6.0 (m, 1H), 8.6 (m, 2H), 8, 85 (s, 111). (LXV) (From B isomer, 8S) 59 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 (in, 511), 8.67 (bs, 211), 9.00 (bs, III).

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R ¹³ Production % ¹ H-NMR (CDCl ₃ ) ppm (delta): (LXXX) (From the isomer, 8S) 1 35 oil 1.51 (s, 311), 1.74 (s, 311), 4.01 (dd, 111), 4.44 (d, 111), 4.60 (s, 1H), 4.70 (d, 2H), 5.40 (m, 3H), 5.60 (d) , 1H), 5.96 (m, 1H), 7.34 (t, 1H), 8.80 (d, 211). (LXXX) (From isomer B, 8R) 65 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, 1H), 8.85 (d, 2H). (LXXX1X) 100 1.47 (s, 311), 1.67 (s, 311), 4.16 (m, 2H), 4.64 (m, 3H), 5.47 (m, 4H), 5.94 (m , 1H), 7.43 (M, 3H), 8.02 (m, 3H).

R ¹³ Production, % ¹ H-NMR (CDCl ₃ ) ppm (delta): (XCVII) 81 1.42 (3.311), 1.7 (s, 311), 4.4 5 (not clean (dd, J = 4and8, 111), 4.5 (s, 111), 10 (XCVU) tított) 36 4.65 (m, 2H), 5.2-6.3 (m, 3H), 5.6 (d, J = 4, 1H), 5.6 (d, J = = 8, 1H), 7.2-7.6 (m, 2H), 7.8 8.1 (ιη, 211). 1.45 (s, 3H), 1.55 (s, 3H), 4.15 15 (CV1I) (LXXV) (cleaning after) (dd, 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. The allyl esters prepared above were converted to the potassium salts of formula CX according to the procedure of Example 45.

Example 58 (continued)

R ¹³ Production, % Stereochemistry ¹ H NMR (DMSO-d ₆ ) ppm (delta): (LXV) (Isomer A) 75 8R 1.46 (s, 3H), 1.56 (s, 3H), 3.76 (s, 1H), 4.13 (dd, 1H), 5.05 (d, 1H), 5.4 (d) , 1H), 8.58 (d, 2H), 8.72 (s, 1H). IR (KBr): 3478, 1761.1607 cm ^1st (LXV) (Isomer B) 82 8S 1.42 (s, 3H), 1.65 (s, 3H), 4.25 (s, 3H), 4.27 (dd, 1H), 5.3 (d, 1H), 5.35 (d) , 1H), 8.6-8.7 (m, 2H), 8.8 (m, 1H). (LXXX) (Isomer A) 94 8S (D ₂ 0): 1.35 (s, 3H), 1.54 (s, 3H), 4.18 (s, IH), 4,144,19 (m, IH), 5.19 (d, IH) , 5.25 (d, 1H), 7.45 (t, 1H), 8.75 (d, 2H). (LXXX) (Isomer B) 95 8R (D ₂ O): 1.44 (s, 3H), 1.58 (s, 3H), 4.12 (s, 1H), 4.18 (m, IH), 5.22 (d, IH) , 5.49 (d, 1H), 7.46 (t, 1H), 8.75 (d, 2H). (LXXX1X) 97 8R 1.47 (s, 3H), 1.58 (s, 311), 3.79 (s, 111), 4.13 (dd, III), 5.2 (d, 1H), 5.4 (d) , 1H), 5.95 (bs, 111), 7.45 (t, 1H), 7.60 (t, 2H), 8.03 (d, 2H), 8.16 (s, 1H). (XCVII) 85 8S 1.48 (s, 3H), 1.67 (s, 3H), 4.27 (dd, J = 4 and 10, 1H), 4.3 (s, 1H), 5.45 (d, J = 4, 1H), 5.57 (d, J = 10, 1H), 7.45-7.65 (m, 2H), δ, 04 (t, J = 8, 2H). IR (KBr): 3424, 1765, 1746, 1592 cm -1. (XCVII) 91 8R 1.42 (s, 311), 1.56 (s, 311), 4.16 (s, 111), 4.25 (dd, J = 4, and 8, 1H), 5.46 (d, J = 4, 1H), 5.5 (d, J = 8, 1H), 7.47.7 (m, 2H), 7.8-8.05 (m, 2H). (CVII1) (LXXV)

-37194 567

Preparation A. ((6-Chloropyridin-2-yl) methyl) triphenylphosphonium chloride (i) 6-Chloro-2-methylpyridine 1-oxide

To a solution of 5.1 g (40 mmol) of 6-chloro-2-picoline in 50 mL of dichloromethane was added 8.625 g (40 mmol) of 80% m-chloroperbenzoic acid and the mixture was stirred at room temperature for 15 hours. The reaction was quenched with 0.5 mL of saturated sodium thiosulfate solution, adjusted to pH 7.5 with sodium bicarbonate solution, and the organic phase was washed with water, triturated (MgSO ₄ ) and the solvent was evaporated. . 4.84 g of N-oxide are obtained.

¹ H-NMR (CDCl ₃ ) ppm (delta): 2.6 (s, 3H), 7.0-8.0 (m, 3H).

(ii) 6-Chloro-2- (acetoxymethyl) pyridine

A solution of 4.8 g of the above N-oxide (0.035 mmol) in 15 ml of acetic anhydride was heated to 100 ° C for 1 hour and then concentrated in vacuo. 2.39 g of the expected product are obtained. M.p .: 125-128 ° C (0.7 ml as a colorless oil).

¹ H-NMR (CDCl ₃ ) ppm (delta): 2.1 (s, 3H), 5.1 (s, 2H), 7.0-8.8 (m, 3H).

(iii) 6-Chloro-2-pyridylmethanol

The product obtained in (ii) is hydrolyzed in 10 ml of 2N hydrochloric acid for 1 hour at 70 ° C, then the mixture is neutralized (K ₂ CO ₃ ) and extracted with chloroform. The solvent was distilled off, the extract was dried and the crude alcohol (1.87 g) was purified by column chromatography over silica gel. 0.982 g of pure material is obtained.

¹ H NMR (CDCl ₃ ) ppm (delta): 4.8 (s, 2H), 5.3 (bs, 1H), 7.0-7.8 (m, 3H).

(iv) 6-Chloro-2- (chloromethyl) pyridine

To a solution of 6-chloro-2-pyridylmethanol (0.982 g, 6.84 mmol) in dichloromethane (10 mL) was added 0.814 g of thionyl chloride and reacted for 1 hour at room temperature. The mixture was neutralized with saturated sodium bicarbonate solution, extracted with dichloromethane, the extracts dried and the solvent was evaporated. 815 mg of a colorless crystalline product are obtained.

¹ H-NMR (CDCl ₃ ) ppm (delta): 4.7 (s, 2H), 7.1-8.0 (m, 3H).

(v) Wittig reagent was prepared by mixing 815 mg (5 mmol) of the product obtained in part (iv) and triphenylphosphine (1.318 g, 5 mmol) in toluene (10 mL) and refluxing for 6 hours. The precipitated product was filtered off to give 1.368 g (65%) of the desired product.

¹ II-NMR _(DMSO-d6) ppm (delta): 5.5 (s, 111), 5.8 (s, 1H), 7.2-7.8 (m, 18H).

(vi) / (4-Methoxypyridin-2-yl) methyl / triphenylphosphonium chloride

As described in (ii), starting from 2.1 g of 2-methyl- (4-ethoxypyridine-1-oxide), 2.5 g of 2- (acetoxymethyl) -4-methoxypyridine are obtained, which is Contains 5% Acetoxy-2-methyl-4-methoxypyridine impurity Dissolve in 10 ml of methanol containing 1.1 g (20.7 mmol) of sodium methoxide and stir at reflux for one hour. The methanol was evaporated in vacuo and the residue diluted with water, neutralized with dilute hydrochloric acid and extracted with chloroform, the organic phase was washed with saturated brine, dried (MgSO ₄ ) and evaporated in vacuo to 853 mg (41%) of 2-hydroxymethyl. pyridine is obtained.

1 H-NMR (CDCl ₃ ) ppm (delta): 3.9 (s, 3H), 4.72 (s, 2H), 5.35 (broad s, 1H), 6.7 (dd, 1H), 6.95 (d, 1H), 8.3 (d, 1H).

The resulting hydroxymethyl compound was converted to 2- (chloromethyl) -4-methoxypyridine according to the procedure of (iv) to give 0.895 g (5.68 mmol) of product. This reaction was carried out with equimolar amount of triphenylphosphine in 10 mL of toluene for 20 hours at reflux. The precipitate was filtered off to give 860 mg of the desired product as a yellow solid.

Preparation B ((2-Quinolinyl) methyl) triphenylphosphonium chloride

A solution of 6.26 g (0.035 mmol) of 2- (chloromethyl) quinoline, 9.20 g (0.035 mol) of triphenylphosphine in 80 ml of toluene is refluxed for 3 hours, and the precipitate is filtered off and dried under vacuum. 3.5 g (23%) of a brown solid are obtained.

Preparation C ((3-Allyloxy-2-pyridyl) methyl) triphenylphosphonium chloride) 3-Allyloxy-2-hydroxymethylpyridine

To a methanolic mixture of sodium methoxide (1.43 g, 62 min) in methanol (100 ml) was added 3-hydroxy-2-hydroxymethylpyridine (5.9 g, 31 mmol) and the methanol was evaporated in vacuo. The residue was dissolved in 80 mL of dimethyl sulfoxide and a solution of 3.0 mL (34.7 mmol) of allyl bromide in 20 mL of dimethyl sulfoxide was added over 20 minutes at room temperature. The mixture was stirred for two hours, the dimethyl sulfoxide was evaporated in vacuo and the residue partitioned between chloroform and water. The pH of the aqueous phase is adjusted to 7.5 and

-3 875

Extract 194,567 three times with chloroform. The organic layers were washed with water, brine, dried (MgSO ₄ ) and evaporated. 3.48 g (68%) of the desired ether are obtained.

(ii) 3-Allyloxy-2- (chloromethyl) pyridine

To a solution of the product of (i) (3.43 g, 20.8 mmol) in dichloromethane (20 mL) was added 1.5 equivalents (2.5 mL) of thionyl chloride and the mixture was stirred for 2 hours under nitrogen. The volatiles were evaporated in vacuo and the residue partitioned between dichloromethane and water. The aqueous phase was adjusted to pH 7.5 and extracted with fresh dichloromethane. The combined extracts were washed with water, brine, dried (Na ₂ SO ₄ ) and the solvent was evaporated in vacuo. 3.28 g (86%) of the desired product are obtained, which product is used in the next reaction without purification.

(iii) The product of (ii) (3.28 g, 17.9 mmol) is dissolved in 30 mL of toluene and 4.69 g (17.9 mmol) of triphenylphosphine is added. The mixture was refluxed for 3 hours and then stirred at room temperature for 12 hours. The precipitated product is filtered off and washed with toluene. 3.89 g (49%) of Wittig reagent are obtained.

D. Production

Allyl-6alpha-bromo-1,1-dioxopenicillanate (i) 6Alpha-bromo-1,1-dioxopenicillanic acid

To a suspension of 20.26 g (0.0517 mmol) of 6,6-dibromo-1,1-dioxopenicillanic acid in 80 ml of water is added 13 g (0.155 mol) of sodium bicarbonate. The vigorous gas evolution was controlled by addition of ethyl acetate. 6.76 g (0.062 mol) of solid sodium bisulfite were added portionwise and the reaction mixture was stirred for 35 minutes and then adjusted to pH 0.1 with concentrated hydrochloric acid. The acidic mixture was extracted with ethyl acetate, the organic phase was washed with brine, dried (Na ₂ SO ₄ ) and the solvent was evaporated in vacuo. The residue was triturated with chloroform and filtered to give 6.72 g of a yellow solid. Concentration of the filtrate and trituration of the residue with chloroform gives 3.2 g.

(ii) To the first precipitate of 6.352 g obtained in the above procedure, 1.76 ml (20.3 mmol) of n-yl bromide, 2.83 ml (20.3 mmol) of triethylamine and 0, were added in 20 ml of dimethylformamide. Sodium bicarbonate (2 g) was added and the mixture was stirred under nitrogen at room temperature for 15 hours. Water was added, the mixture was extracted with ethyl ether and the extracts were washed with water. The organic solution was dried (Na ₂ SO ₄ ) and the solvent was evaporated in vacuo. 4.60 g (64%) of the desired oily product are obtained.

¹ H-NMR (CDCl ₃ ) ppm (delta): 1.4 (s, 3H), 1.6 (s, 3H),

4.4 (s, 1H), 4.6 (d, 1H), 4.7 (d, 2H). 5.15 (d, 1H), 5.1-5.95 (m, 3H).

(iii) Allyl-6,6-dibromine penicillanate

The esterification of 6,6-dibromopenicillanic acid is carried out as described above. The 0.147 molar reaction gave 140 g (84%) of the allyl ester as an oil.

¹ H-NMR (CDCl ₃ ) ppm (delta): 1.5 (s, 3H), 1.65 (s, 311), 4.6 (s, 1110, 4.75 (in, 211), δ Δ 5.6 (m, 2H), 5.85 (s, 1H), 5.8-6.3 (m, 1H).

E. Preparation

2-Formyl-1-methylimidazole (i) A mixture of 2-hydroxymethyl-1-methylimidazole g 1-methylimidazole and 100 ml 37% formaldehyde (1.08 g / ml) was placed in a stainless steel reactor (300 ml). ml) and heated to 150 ° C (bath temperature) for 17 hours. The reactor was then cooled in ice and the mixture was concentrated in vacuo. The residue was allowed to stand overnight at 4 ° C. The crystalline mixture was filtered and washed with ethyl acetate. The colorless crystalline oil was dried in vacuo to give 14.06 g of product. Workup of the mother liquor gave an additional 6.48 g of product, overall yield 21.08 g (31%).

(ii) To a solution of 4.96 g (43.9 mmol) of 2-hydroxymethyl-1-methylimidazole in 50 ml of dioxane is added 4.90 g (44.1 mmol) of clenylene dioxide and the mixture is heated to 85-90 ° C. heat and stir at this temperature for 5 hours, then at room temperature for 36 hours. Finally, stirring was continued for 8 hours at 85 ° C and for 15 hours at room temperature. The reaction mixture was filtered, the solvent was evaporated in vacuo to give 4.81 g of crude aldehyde which was purified by distillation. M.p. 65 ° C / 2.8 mng, yield 2.11 g, colorless crystals.

F. Production

6-Methyl-2-pyridylmethyl-triphenyl-phosphonium chloride (i) 6-Methyl-2-hydroxymethyl-pyridine

6-Methylpyridine-2-carboxaldehyde (0.44 mmol) was reduced in methanol (50 mL) with sodium borohydride (20.6 mmol) at 0-5 ° C. After the reduction is complete, the mixture is neutralized with 2N sulfuric acid (7.5 µl), filtered, the filtrate is concentrated and partitioned between chloroform and water. The organic phase was evaporated to give 3.32 g of a red-black oil which was used directly in the next reaction step.

(ii) 2- (Chloromethyl) -6-methylpyridine

The above product (332 g, 0.27 mmol) was dissolved in dichloromethane (20 mL) and treated with thionyl chloride (1.94 mL, 27 mmol) at room temperature for 1 hour.

-3 977

194,567

The reaction mixture was neutralized (NaHCO ₃ ) and extracted with chloroform. The organic solvent was distilled off to give 3.22 g of an oily product which was used directly in the next step.

(iii) 3.22 g of product obtained in (ii) and

5.96 g of triphenylphosphine are dissolved in 30 ml of toluene and the mixture is refluxed for 4 hours. The precipitate was filtered off to give 3.93 g of a brown solid Wiltig-Crags.

Preparation G. (2-Pyrazinyl) methyl triphenylphosphonium chloride (i) 2-Hydroxymethylpyrazine

A solution of 2-pyrazinecarbonyl chloride (11.29 g, 79.2 mmol) (prepared by refluxing the corresponding 2-carboxylic acid and excess thionyl chloride at reflux temperature) in tetrahydrofuran (100 mL), Lithium aluminum hydride (95%, 2.0 g, 52.6 mmol) was added portionwise over 20 min. The mixture was stirred for 10 minutes and then allowed to warm to room temperature. The reaction was quenched with 2M sodium hydroxide, filtered, and the precipitate washed with methanol. The filtrate was concentrated in vacuo to give 4.12 g of a dark solid which was used directly in the next step.

(ii) The above dark solid (4.12 g, 37.8 mmol) was dissolved in dichloroethane and 2.8 mL of thionyl chloride was added at 0 ° C. The mixture was warmed to room temperature and stirred for 30 minutes and then water was added. The mixture was neutralized, extracted with dichloromethane to give 2.29 g of a yellow oil which was reacted directly in the next step.

(iii) The above 2.29 g of oil and 4.7 g of triphenylphosphine are dissolved in 40 ml of toluene and the reaction mixture is stirred at reflux for 3 hours. The mixture was worked up in the usual manner to give 1.995 g of Wittig reagent as a brown solid.

/ {. production

A solution of 4-formylpyrimidine (0.106 mol) in 4 ml of dioxane (100 ml) was treated with 11.8 g of selenium dioxide at room temperature and stirred for 15 hours at 100 ° C. Another 2.5 g of selenium dioxide was added and heating continued for another hour. The mixture was then cooled and filtered. The precipitate was washed with ethyl acetate, and the filtrate and washings were combined and evaporated to dryness in vacuo. The residual dark oil was dissolved in dichloromethane, the solution was filtered and the solvent was evaporated. The residue was recrystallized from a small amount of dichloromethane to give the desired aldehyde as a product.

M-NMR (CDCl 3) ppm (delta): 7.87 (dd, 1H), 9.06 (d, 1H), 9.43 (d, 1H), 10.0 (s, 1H).

Preparation 1 (Diphenylmethyl) -6-alpha-bromo-1,1-dioxopenicillanate

To a solution of 21.557 g (0.1 mol) of diphenyl diazomethane in 400 ml of tetrahydrofuran was added portionwise 30 ml of 6-alpha-bromo-1,1-dioxopenicillanic acid over 30 minutes. The reaction is slightly exothermic. After stirring for 1 hour, the solvent was evaporated and the residue was dissolved in 50 ml of ethyl acetate. Diethyl ether (400 mL) was added and the solution was allowed to stand at 4 ° C. No crystalline material precipitates in 18 hours. The mixture was concentrated in vacuo to give 51.2 g of a yellow solid which was purified by column chromatography on silica gel using chloroform as eluent. 14.86 g of a glassy colorless substance are obtained.

1 H-NMR (CDCl ₃ ) ppm (delta): 1.26 (s, 311), 1.57 (s, 311), 4.55 (s, 111), 4.70 (d, 1H), δ , 13 (d, 111),

6.9 (s, 111), 7.27 (s, 1011).

J. Preparation

A solution of benzothiazole-2-carboxaldehyde (0.074 mol) freshly distilled (b.p. 82 ° C / 2 torr) benzothiazole in 250 ml tetrahydrofuran was cooled to -78 ° C under nitrogen and stirred at this temperature for 15 minutes. Subsequently, 29.6 ml (0.074 mol) of a 2.5 molar butyl lithium solution was added dropwise over 15 minutes and the mixture was stirred for 25 minutes. Subsequently, 8.6 ml (0.111 mol) of dimethylformamide were added and the mixture was stirred for a further 1 hour. The reaction mixture was allowed to warm to room temperature, 200 g of ice was added and the solvent was evaporated in vacuo. The aqueous residue was extracted with ethyl acetate (5 x 100 mL), the extracts were dried (MgSO 4), concentrated to low volume and purified by silica gel column chromatography (94: 6 chloroform / ethyl acetate). 8.4 g of the desired aldehyde are obtained,

mp: 74.5-75 ° C.

¹ H-NMR (CDCl ₃ ) ppm (delta): 7.54 (m, 2H), 7.97 (m, 1H), 8.21 (m, 1H), 10.1 (s, 1H).

-4 079

194,567

J. Production (continued)

The following aldehydes were prepared by the above procedure.

Starting material aldehyde Production, % ¹ H-NMR (CDCl ₃ ) ppm (delta): (CXVI) (CXI) 98 oil b.p .: I20 I22 ° C / 25 torr (CXII) * (CXIII) 50 4.3 (s, 3H), 8.05 (s, 1H), 10.00 (s, 1H). (CXIV) ** (CXV) 82 1.3 (t, 6H), 3.6 (q, 2H), 3.64 (q, 2H), 6.95 (s, 1H),

7.11 (d, 1H), 7.55 (d, 1H), 8.23 (d, 111).

Reaction of 11II-1,2,4-triazine and methyl iodide in ethanolic sodium ethoxide afforded 37% yield as a solid.

** From imidazole and ethyl orthoformate, Curtis et al., J. Org. Chem. 45, 4038 (1980).

K. Preparation

The pyrazine-2-carboxylic acid was esterified with refluxing methanolic sulfuric acid for 5 hours. The methanol was evaporated in vacuo and the residue diluted with dichloromethane. The mixture was neutralized with sodium bicarbonate (pH 7.5) and the organic layer was dried and evaporated. Recrystallization from isopropanol / ether afforded a yellow needle crystalline product in 84% yield as a grayish solid, methyl pyrazine-2-carboxylate.

'H-NMIUCDCU) ppm (delta): 4.1 (s, 311), 8.93 (m,

2H), 9.47 (m, 1H).

Methyl ester (0.145 mol) was dissolved in dry tetrahydrofuran (600 ml), cooled to -78 ° C, and a solution of lithium aluminum hydride (98%, 5.8 g, in tetrahydrofuran) was added dropwise over 15 minutes. After stirring for 30 minutes at -78 ° C, acetic acid (20 ml) was added and concentrated in vacuo.

The residue was partitioned between 2N hydrochloric acid (30 mL) and chloroform. The organic layers were washed with water, dried and evaporated. 8.53 g of crude product are obtained, which is purified by silica gel column chromatography (4: 1 dichloromethane / ethyl acetate). 5.02 g of a light yellow needle crystalline product are obtained.

¹ H-NMR (CDCl ₃ ) ppm (delta): 8.38 (m, 2H), 8.7 (bs, 1H), 9.7 (s, 1H). 55

Preparation of L. fif.

2-Phenyl-1,2,3-triazole-4-carboxaldehyde (i) Acetone dicarboxylic acid (034 mol) in water (100 ml) was treated with sodium nitrite (0.58 mol) at 0 to 10 ° C and dilute nitric acid was added and 55 divorces. Yield: 46% of 13-dioximino-2-oxopropane as a brown crystalline solid.

(ii) 0.158 mol of dioxime in 170 ml of ethanol is treated with an equimolar amount of phenylhydrazine hydrochloride and sodium acetate at 70 ° C. After 30 min, the reaction was quenched with water (170 mL). The mixture was heated to 85 ° C and concentrated to 250 ml. After cooling, 24.7 g of phenylhydrazone are obtained.

¹ H-NMR (CD ₃ COCD ₃ ) ppm (delta): 7.3 (m, 5H), 7.9 (s, 1H), 8.6 (s, 1H), 10.5 (broad s, 1H ), 11.4 (br, III), 12.3 (s, 1H).

(iii) 24.7 g (0.119 mol) of dioxime-phenylhydrazole below are stirred with 500 ml of acetic anhydride at room temperature for 1 minute and then poured into water. The mixture is stirred for 20 minutes and filtered. The crude solid product was recrystallized from benzene / ethyl ether to provide 15.47 g (52%) as a yellow powder H0N = CH-, - (= (NNHC ₆ H, _S) CH = NOCOCH ₃ monoacetate obtained.

¹ H-NMR (CDCl ₃ , acetone): 1.85 (s, 3H), 7.09 (m, 5H), 7.95 (s, 1H), 8.3 (s, 1H), 10.9 (broad s, 1H), 12.5 (s, 1H).

(sheet) 15.40 g (0.062 mol) of the above monoacetate and

A mixture of cesium carbonate (22.16 g, 0.068 mol) in tetrahydrofuran (400 ml) was stirred at room temperature for 1 hour, filtered and the filtrate was evaporated. A yellow residue is obtained which is dissolved in 700 nd of hot 1: 2 isopropyl ether / cyclohexane and concentrated to a volume of 200 ml. 2-phenyl-1,2,3-triazole-4-carboxaldehyde (9.41 g, 80%) is a yellow powder. -oxime, which is used in the next step without purification.

(v) 9.41 g (0.0497 mol) of oxime, 4.48 g of s-trioxane and

300 ml of 2N hydrochloric acid are refluxed for 3.5 hours. The aqueous phase was extracted with ethyl ether. The combined organic solutions were washed with water, dried (MgSO ₄ ) and the ether evaporated in vacuo. 6 g of crystalline aldehyde are obtained.

-4 181

194 557 1 H-NMR (CDCl ₃ ) ppm (delta): 7.6 (m, 3H), 8.25 (m, 3Η), 10.25 (s, 1H);

M.p .: 66-67 ° C.

M. preparation

5-Methylisoxazole-3-carboxaldehyde (i) Ethyl 5-methylisoxazole-3-carboxylate

A mixture of 0.16 mol of ethyl 2,4-dioxo valerate, 0.08 mol of hydroxylamine sulfate, 50 ml of ethanol and 70 ml of toluene was stirred for 4 hours at 40 ° C and then cooled to 15-20 ° C. concentrated ammonium hydroxide. Stirring is continued for 60 hours at room temperature and the mixture is poured into water / toluene. The aqueous phase is extracted with toluene, the organic phases are combined, washed with brine, dried (Na ₂ SO ₄ ) and the solvent is evaporated off under vacuum. A yellow liquid is obtained which is distilled off to give 14.68 g (b.p. 120-124 ° C / 30 torr) of product which crystallizes on standing.

(ii) 2.0 g (14.4 mmol) of the above ethyl ester are reduced in 75 ml of toluene with an equimolar amount of 1 M diisobutylaluminum hydride in hexane under a nitrogen atmosphere. After stirring for 30 minutes at -75 to -70 ° C, the ammonium chloride solution was added, warmed to room temperature, and concentrated in vacuo. The residue was worked up with hot methanol, evaporated and 85 g of a colorless oily product were obtained.

1 H-NMR (CDCl 3) ppm (delta): 2.4 (s, 3H), 6.3 (d, 1H), 9.0 (s, 1H).

Claims (8)

Claims A process for the preparation of a compound of formula I wherein n is 0, 1 or 2, R ¹ is hydrogen, C 2 -C 5 alkenyl, phenyl (C 1 -C 4) alkyl, or (C 1 -C 5) alkylcarbonyloxymethyl, One of R ² and R ³ is hydrogen, the other is chloro, hydroxymethyl, vinyl, C 1-4 alkylthio, C 1-4 alkylsulfonyl, furyl, thienyl, N-methylpyrrolyl a group, N-acetylpyrrolyl, (XLI), (XLII), (XX), (XXI), (XXII), (XXIV), (XXV), (XXVI), (XXXIV) or (XXXV) ) and p is 0 or 1, t is 0, 1 or 2, Xj is a sulfur atom or a group of formula XLVI, R ⁷ is hydrogen, C 14 alkyl, C 14 alkoxy, allyloxy, chloro, bromo or trifluoromethyl; I R ¹¹ is hydrogen, methyl or ethyl, and their pharmaceutically acceptable salts, wherein a) a compound of formula (V) wherein: R ¹ is as defined above, preferably R ^a , i.e. C 2 -C 5 alkenyl or phenyl (C 14) alkyl, in an organic solvent inactivated by reaction with the Wittig reagent of formula LII, -100 to + 50 ° C. and a compound of formula (I) is prepared wherein n is 0 and, if it is desired to produce a compound of formula (I) wherein n is I or 2, the resulting compound is obtained wherein n is 0. , preferably oxidized with an alkali metal or alkaline earth permanganate, 3-chloroperbenzoic acid or peracetic acid, or (b) for the preparation of a compound of formula (I ') which is a narrower group of compounds of formula (I): R * is as defined above, n is 0 or 2, and One of R ¹² and R ¹³ is hydrogen and the other of R ² and R ³ is the same as, but not chlorine, hydroxymethyl, C 14 alkylthio, (XLI) and (XLII) with the proviso that when R ¹² or R ^{13 is a} group of formula XX and p is 0 then R ^{7 is} other than hydrogen or methyl, a compound of formula X wherein R 'is as defined above but is not hydrogen; is 0 or 2, egyenértéknyl amount (14 szénatomszáinú alkyl) magnesium halogcnid - wherein the halide is chloride or bromide (14) alkyl and the alkyl lithium reagent (LV1) an aldehyde of formula - wherein R ¹² and R ¹³ are present in an inert solvent at a temperature of -100 to + 25 ° C to give a compound of formula XI wherein R ¹² and R ¹³ , n and R ¹ are present in the presence of a tertiary amine in the presence of an equimolar amount of an acyl chloride or acyl bromide of the formula R ¹⁸ -Cl or R ¹⁸ -Br or the corresponding acid anhydride, wherein R ^{18 is an} acyl group; ) wherein R ¹² , R ¹³ , R ¹⁸ , n and R ^{1 are} as defined in this embodiment; and X ³ is a bromine atom, hydrogenated in an inert solvent with an organic tin hydride or noble metal catalyst and hydrogen gas to give the compound of formula II. wherein R ¹ , R ' ² , R ¹³ and na are as defined in this embodiment, X ³ is hydrogen and R ¹⁸ is hydrogen or acyl, dehydrated or deacylated, or c) for the preparation of compounds of the general formula VIII which are a narrower group of the compounds of the formula I, wherein R ¹ , R ¹² and R ^{13 are within} the scope of the present invention; 194,567 Β4 provided a compound of formula IX wherein R ¹ is as defined above, but with an equimolar amount of a C 1-4 alkylmagnesium halide other than hydrogen and an aldehyde of formula R ² R ³ CO (LVI) - R ¹² and R ¹³ as above - are reacted in an ether-type solvent at a temperature of -80 to 25 ° C to give the compound of formula II, wherein R *, R ¹² and R ^{13 are} as above, if desired R ^{18 is} C 1 or C ¹⁸ Br acylated with acyl chloride or acyl bromide or the corresponding acid anhydride 10 - R ¹⁸ is acyl - in the presence of an equimolar amount of tertiary amine in the reaction inert solvent; and the compound of formula (11 ') so prepared wherein R ¹⁸ is acyl and R R ¹² , R ¹³ are deacylated or dehydrated as above for the preparation of the compound of formula (II) above and, if desired, for the preparation of compounds of formula (I), (L) and (VIII) wherein R 'is R ^b , i.e., hydrogen or (C 1 -C 5) -alkylcarbonyl-oxymethyl, R ^{a is a} carboxyl protecting group and the resulting compound of formula (I), (Γ) or (VIII) R ^! is hydrogen, optionally reacted with a reagent of formula Rq wherein R ^{b is} other than hydrogen and Q is chloro, bromo or iodo in a polar organic solvent and optionally a free compound of formula I converting the compound into a salt thereof and optionally forming a compound of formula (I) wherein R ² or R ^{3 is} (XX), (XXI) or (XXII) wherein p is 0 and R ⁷ , and n and R ¹ is as defined above, N-oxidized. Process a) according to claim 1, characterized in that a starting material is used wherein R ¹ is R ^a , preferably allyl or benzyl, one of R ² and R ³ is hydrogen, the other is 2-pyridyl , N-oxo-2-pyridyl, 4-methoxy-2-pyridyl, 6-methyl-2-pyridyl, 1-methyl-2-imidazolyl, 2-thiazolyl, , 5-dimethyl-2-thiazolyl, 4-methyl-2-thiazolyl, 4-pyrimidinyl, 2-pyridinidinyl-45, 4,6-dimethyl-2-pyrimidinyl, 2-pyrazinyl , 2-methyl-1,2,4-triazol-3-yl or benzothiazol-2-yl, the reaction solvent used is tetrahydrofuran and the reaction is carried out at a temperature between -78 ° C and 25 ° C, and a compound of Formula (I) wherein n is 0; Oxidation with 3-chloroperbenzoic acid or potassium permanganate to give the corresponding compound in which n is 2. Process (b) according to claim 1, characterized in that the reaction with the aldehyde (LVI) is carried out at -78 ° C in the presence of tetrahydrofuran or diethyl ether. A process according to claim 3 for the preparation of a compound of formula (VIII) or (I ') wherein one of R ¹¹ and R ¹³ is hydrogen and the other is 1,3,4-thiadiazolyl, pyridazin-3-yl , 1,2,4-oxadiazin-3-yl, 1,2,4-oxadiazin-5-yl, 4-pyrimidinyl or 4,5-dimethylthiazol-2-yl. , characterized in that it is based on appropriately substituted materials. 5. b) according to claim 1, characterized in that the compound of formula (X) wherein R ¹ is allyl or benzyl, methyl magnesium bromide and the aldehyde of formula (LVI) is reacted, and (II) wherein X ³ is hydrogen is prepared by hydrogenolysis with tributyltin anhydride in benzene or toluene at a temperature between 0 ° C and the reflux temperature of the solvent. The process for the preparation of a compound of formula (I) according to claim 1, wherein one of R ² and R ³ is hydrogen, the other is 2-pyridyl, 3-allyloxy-2-pyridyl, 2-pyrazinyl-. 2-pyrimidinyl, 2-pyrimidinyl, 2-pyridinidyl, 3-hydroxy-2-pyridyl (or 4- methoxy-2-pyridyl, and R ¹ and n are as defined in claim 1, characterized in that the preparation of substituted phenylpyrazole type herbicides. A process for the preparation of a compound of formula (I ') or (VIII) according to claim 4 wherein one of R ¹² and R ¹³ is hydrogen and the other is 2-thiazolyl or benzothiazol-2-yl, characterized in that it is based on appropriately substituted materials. 8. A process according to any one of claims 1 to 3, wherein the starting compound wherein R ¹ is allyl is converted to the corresponding compound in which R ¹ is hydrogen, sodium or potassium, the catalyzed amount of tetrakis (triphenylphosphine) in the inhaled solvent being palladium (O) and equimolar triphenylphosphine and equimolar sodium or potassium 2-ethylhexanoate.