HU194891B - Process for production of 6-/trisubstituated-methil/-penicillane acid and its derivatives - 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

This invention relates to novel 6- (trisubstituted-methyl) penicillanic acid derivatives which are useful as intermediates in the preparation of novel 6- (substituted-methylene) penicillanic acids, certain esters and their pharmaceutically acceptable salts. The latter can be used as beta-lactamase inhibitors.

European Patent Application 50,805 discloses a compound of formula III wherein n is 0, 1 or 2,

R ¹ is cyano or certain carbonyl moiety,

R ² is hydrogen, lower alkyl or halogen; and

R ³ is a hydrogen atom or a readily hydrolyzable group as a potent beta-lactamase inhibitor. In the same description, 6-oxo-penicillanic acid esters, their corresponding sulfones and sulfoxides, and a process for the preparation of the compound of formula (III) by the above compounds and R ¹ R ² C = P (C ₆ H ₅ ) are described. It is produced by the reaction of ₃ phosphoranes.

British Patent GB 2,053,220A discloses, among other things, the 6-methylene-1,1-dioxopenicillanic 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, together with the carbon atom or R ¹ and R ² represents a seven-membered carbocyclic or heterocyclic ring is substituted.

U.S. Pat. No. 4,287,181 discloses certain 6-substituted penicillanic acid 1,1-dioxides and their esters, wherein the 6-substituent is of the formula (XIII) and, inter alia, R ³ is hydrogen or alkanoyl, R ⁴ represents a hydrogen atom, a C 1-4 alkyl group, a phenyl group, a benzyl group or a pyridyl group, which are potent beta-lactamase inhibitors.

The Hungarian Patent Publication No. T / 37799 relates to novel 6- (substituted methylene) penicillinates of formula (I) wherein n is 0, 1 or 2,

R ¹ is R ^a or R ^ft , where R ⁶ is a carboxyl protecting group which may be tetrahydropyranyl, allyl, benzyl, 4-nitrobenzyl, benzhydryl, 2,2,2-trichloroethyl. , t-butyl and phenacyl, and R ^d is hydrogen or is readily hydrolyzed in vivo. an ester-forming group which may be selected from the group consisting of 3-phthalidyl, 4-crotonlactonib, gamma-butyrolacton-4-i ', XIV, XV, XVI and XVII; and

R ⁴ and R ⁵ are each hydrogen or methyl,

R @ 4 is C1 -C5 alkyl and

R ¹⁴ is a group of formula (XVIII) or (XIX) wherein X ² is the 3-position substituent of a known cephalosporin beta-lactam antibiotic, and

^R15 is a known cephalosporin or penicillin beta-lactam antibiotic 6- or 7-position substituent of the preparation. Intermediates for the preparation of these compounds are compounds of formula II.

The invention therefore relates salt method (II) of formula 6 (R ^L2, R ¹³ -substituted-hydroxymethyl) penicillanic acid, and pharmaceutically acceptable esters thereof, wherein in the formula a is 0 or 2, the invention

K ^{3 is} hydrogen or bromine,

R ¹ is hydrogen or R ', wherein

R ^is allyl, benzyl, (1-4C) alkylcarbonyloxymethyl or benzhydryl, and

R ^{8 is} hydrogen, C 2 -C 5 alkanoyl, C 2 -C 5 alkoxycarbonyl, pyrazinylcarbonyl or benzyl,

One of R ¹² and R ¹³ is hydrogen and the other is vinyl, phenyl, furyl, thienyl, N-methylpyrrolyl, Ν-acetylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl or (XXVI), ( XXVII), (XXXI), (XXXII), (ΧΧΧΙΪΙ), (XXXIV) or (XXXVI), t is 0, 1 or 2,

X 1 is sulfur or oxygen or = NR

R ⁷ is hydrogen, C 1-4 alkyl, C 1-4 alkoxy, or phenyl, and

R is hydrogen, methyl, ethyl, n-propyl or acetyl.

All of the compounds of formula (11) obtained by the process of the present invention are suitable intermediates for the preparation of the corresponding 6- (substituted methylene) -1,1-dioxopenicillanates of formula (I). In addition, compounds of formula II wherein R ¹ is hydrogen or a hydrolysable ester moiety which is readily hydrolysable in vivo can be used as beta-lactamase inhibitors, especially when used in combination with a beta-lactam antibiotic.

Particularly preferred compounds of formula (II) prepared according to the invention are those wherein n is 0 or 2,

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One of R ¹² and R ¹³ is hydrogen, the other is vinyl, 2-furyl,

2-thienyl, N-methylpyrrol-2-yl, N-acetylpyrrol-2-yl, XXXI, XXXII or XXXVI and R ¹⁸ is hydrogen or acetyl.

Particularly preferred are carboxyl protecting groups wherein R ^a is allyl or benzyl.

The allyl group is particularly preferred because its preparation and removal is relatively selective.

Compounds of formula (II) wherein R ¹ is hydrogen 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 this method, 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 clinical use with penicillin or cephalosporin compounds such as amoxicillin, ampicillin, carbonylcillin, indanIcarbenicl 11, cefamandole nafáttal, cefaparollal, cefatrizinnel, cefazolinnal, cefbuperazonnal, cefoniciddel, cefmenoximmal, cefodizimmel, cefoperazonnal, ceforaniddal, cefotaxime, cefotiammal, cefoxitinnel, cefpiramiddal, cefpirommal, cefszulodinnal, ceítazidimmai, ceftizoximmal, ceftriaxone, cefuroxime, cefacetrillel, cefaloxinnal, cefaloglicinnel, cefaloridinnel, cephalothim, cefapyrin, cefradine, cyclacil 1 inn, epicil 1 inn, furazlocil 1 inn, hetacillin, lenampicillin, levopiropylcillin, mecillin, meslocillin, penicillin G, pipicillin V, pi rbenicillin, pivampicillin, sarmoxicillin, carpicillin ,uncillin, talampicillin and ticarcillin, and pharmaceutically acceptable salts thereof. The names given for the above beta-lactam compounds are USAN names, i.e., the names accepted in the United States.

The beta-lactamase inhibitors produced by the process of the invention are also useful in the preparation of 7- (2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido) -3- (5,6-dihydro-4-pi) ridinium) methyl 3-cephem-4-carboxylate (HR810); 7- (2- (2-amino-4-thiazolyl) -2- (methoxyimino) 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 also in combination with carboxylic acid.

Although the compounds of the invention may be administered separately from the beta-lactam antibiotics, it is preferable to use a combined dosage form. In a pharmaceutical composition for oral or parenteral administration, a beta-lactamase inhibitor of the formula (II) and a beta-lactam antibiotic of a weight ratio of 1: 3 to 3: 1 are used in an amount sufficient to effectively treat bacterial infection of a mammal.

Further, the compounds of formula (II) obtained by the process of the invention wherein R ¹ is hydrogen are suitable for the formation of cationic salts and these salts with pharmaceutically acceptable cations are also within the scope of the invention. Suitable cations include sodium, potassium, ammonium, calcium, magnesium, zinc, and substituted ammonium salts with amines such as diethanolamine, choline, ethylenediamine, ethanolamine, glucamine and procaine.

The compounds of the present invention are derivatives of penicillanic acid. In the penicillanic acid derivatives, the dashed substituent bonds indicate that the substituent is located below the plane of the bicyclin. These are referred to as 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 attached to the central ring system by a bond marked with 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 alpha or beta configuration.

For example, the methods of the present invention provide the desired compounds by methods A and B.

If, according to Method A, the compound of formula II, wherein n is 2, X ³ and R ¹⁸ are each hydrogen, is prepared in the process of the invention, the desired 6-alpha-bromo of formula IX is desired. -1,1 dioxopenicillanate ester starting material using an equimolar amount of a small molecular weight Grignard reagent such as methyl magnesium bromide, ethyl magnesium chloride or butyl magnesium iodide in an ethereal solvent, preferably tetrahydrofuran or diethyl ether , From -80 ° C to 25 ° C, typically at -78 ° C, to a Grignard reagent. After stirring for a few minutes, an equimolar amount of the aldehyde V is added to the reaction mixture with stirring, which is further stirred until the reaction is complete. At the same temperature, the reaction is usually complete in about 10 minutes to 4 hours. The desired ester 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. The desired product of formula II can be further purified, for example, by column chromatography on silica gel.

In the compounds of formula (II) obtained by the above process, R ¹ is or R 0 is a carboxy protecting group as defined above. These esters, when R ¹ is R ', can be converted to the corresponding carboxylic acids (R ¹ is hydrogen) by the methods described above.

The starting 6-alpha-bromo-1,1-dioxopenicillinate esters of formula IX are typically prepared from 6,6-dibromo-1,1-dioxopenicillanic acid which is prepared with sodium bicarbonate and then with sodium hydrogen carbonate. sulfite and finally acidify the reaction mixture. 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 Method B are known compounds, for example, described in U.S. Patent 4,234,579. In the process of the invention, the starting ester of formula (X) is typically reacted in an organic solvent such as toluene, xylene, pentane, tetrahydrofuran, diethyl ether or a mixture thereof at low temperature with an equimolar amount of an alkyl lithium reagent such as butyl lithium, tert-butyl lithium or methyl lithium to form a lithium penicillin intermediate. This is reacted directly with an aldehyde of an equimolar amount of the formula (V) 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 about 50 ° C, preferably at -78 ° C. stirring. The reaction is then quenched and the bromohydrin intermediate XI is isolated, for example, by partitioning between water and solvent and purification by column chromatography on silica gel or Elorisil (magnesium silicate).

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

The bromohydrin of formula XI, when R ¹⁸ is as defined above, is not hydrogen, can be acylated and the corresponding compound of formula 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 a reaction 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 accomplished using a variety of known reduction techniques and reducing agents, for example, reduction of bromohydrin with hydrogen in the presence of a noble metal catalyst.

Preferred organic tin hydrides in the process are dialkyl tin anhydrides, trialkyl tin anhydrides in which the alkyl groups

C 1-6 alkyl groups, and trialkyl tin hydrides in which the aryl group may be phenyl or phenyl substituted with nitro, C 1-3 alkyl or C 1-3 alkoxy. 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 hydride reducing agent. Examples of such solvents are aromatic hydrocarbons such as benzene, toluene, xylene and chlorobenzene; ether-type solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane. 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 5 to 50% mole percent

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excess to ensure complete reaction.

The reduction with organic tin hydrides leads to complete reduction under the preferred reaction conditions described above, even without the use of a catalyst. However, the reaction is facilitated by the use of a free radical source such as ultraviolet light or a catalytic amount of azobisisobutyronitrile or a peroxide such as benzoyl peroxide. Preferably, a catalytic amount of azo-bis-isobutyronitrile is used as the radical source in the reaction.

Typically, the compound of formula (XI) or (XII) is dissolved in the reaction solvent. The solution is maintained under an inert atmosphere, such as nitrogen or argon, and an appropriate amount of organic tin hydride and, if desired, a free radical source such as azobis isobutyryl are added and the reaction mixture is preferably stirred at a temperature of about 0 ° C. The reaction is usually complete within a few minutes to several hours, for example at the boiling point of benzene, 5 minutes, 0 ° C, 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.

Most of the beta-isomers of the compounds of formula (II) wherein X ³ is hydrogen produced by the debromination process with organic tin hydride described above.

When hydrogenolysis is carried out using hydrogen gas in the presence of a noble metal catalyst, in a preferred embodiment, the solution of the compounds of formula (XI) and (XII) is hydrogenated or mixed with an inert diluent, e.g. . Suitable solvents for the hydrogenation are those which dissolve the starting compounds of formula (XI) or (XII) and which do not react with the 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, Ν, Ν-dimethylacetamide and N-methylpyrrolidone; water and mixtures thereof. In addition, it is often advantageous to buffer the reaction mixture and ensure that the reaction is carried out at a pH of from about 4 to about 9, preferably from about 6 to about 8. Borates, bicarbonates and phosphates may be used as buffers. Hydrogen gas is usually introduced into the reaction mixture 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. 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 generally complete within 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, of the compound of formula XI. Often, the catalyst is preferably applied on a pre-inert support, particularly preferably on a support inert support, such as carbon, palladium on catalyst.

When hydrogenolysis is substantially complete, the product of formula (II) wherein X ³ is hydrogen is isolated by conventional means. For example, the catalyst is filtered off, the solvent is evaporated and the product is 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 '= = = R ^a = benzyl), the above catalytic hydrogenation process also removes the benzyl group and in the product of formula (II) X ³ and R ¹ is hydrogen.

The 6- (substituted-hydroxymethyl) penicillanic acid or ester of formula (XII) or (II) (X ³ is hydrogen: om) can be oxidized to the corresponding sulfoxide or sulfone according to methods known in the art, for example by using 3-chloroperbenzoic acid as described above. the oxidation can be carried out to produce the corresponding sulfoxide or sulfone of formula (XII) or II (X ³ is hydrogen), wherein n in the general formula is 1 or 2. However, the compound of formula (XI), (XII) or (II) The preferred process for the preparation of the sulfones of Formula I is the use of the corresponding 6,6-diron-1,1-dioxopenicillanate esters of the general formula (X) wherein n is 2 as starting material.

The starting aldehydes of formula (V), wherein R ' ² 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 production methods known in the art include:

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1. Oxidation of the corresponding primary alcohols. In the oxidation, for example, potassium dichromate, chromic acid / pyridine, catalytic oxidation in the presence of precious metals, manganese dioxide oxidants may be used.

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

3. Reduction of the corresponding C 1-4 alkoxycarbonyl compound with a metal hydride in a low temperature ether solvent. Examples of suitable metal hydrides are lithium aluminum hydride and diisobutyl aluminum hydride.

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

As previously described, the compounds of formula (II) obtained by the process of the invention, wherein R ¹ is hydrogen, and their salts, when used in combination with beta-lactam antibiotics, show synergistic activity in in vitro antimicrobial assays. This activity can be determined by measuring the minimum inhibitory concentration (MIC) for various microorganisms in mcg / ml. The assay is the method recommended by the International Collaborative Study on Antibiotic Sensitivity Testing (Ericsson and Sherris, Acta. Pathologia Scandinav, Supp. 217, Secton B: 64-68 (1971)) and BHI (brain heaft infusion) agar and uses an inoculum transfer 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. The sensitivity of a given microorganism (HIC) was considered to be 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 wherein R ^{1 in the} formula (II) is hydrogen may also be used in combination with known beta-lactam 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, compositions containing from about 0.1% to about 10% by weight of active ingredient can be used with satisfactory results.

The compounds of formula (II) obtained by the process of the invention, wherein R ¹ is hydrogen as described above, are particularly preferred as potential beta-lactamase enzyme inhibitors. 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 (II) to produce beta-lactam antibiotics of the present invention can be determined from reference experiments using the beta-lactam antibiotic alone. The MIC values for the beta-lactam alone and for the compound of formula II where R is hydrogen are determined. Then, these values are compared with the respective MIC and antibioikum compound produced according to the present invention (II) - MIC values observed for the use of the combination of - where in the formula ^R1 is hydrogen. If the antibiotic effect of the combination is much greater than one would expect from the single effect of the two separate compounds, there is a case for synergistic enhancement of the effect. The MIC values for the combinations were determined by Barry and Sabath, Manual of Clinical Microbiology ed. Determined by Lenette, Spaulding and Truant, 2nd Edition, 1974, American Society for Microbiology.

Compounds of formula (II) prepared by the process of 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 the mouse against an otherwise lethal infection of a bacterium that produces lethal beta-lactamase. To determine this, a standard culture of the test organism in 5% porcine gastric mucin was administered intraperitoneally and an acute experimental infection was induced. The severity of 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 invention produced in accordance with the invention was administered in combination with an antibiotic at different doses ip or op to groups of infected mice. At the end of the assay, the activity of the mixture was determined by counting the number of surviving animals at the given dose.

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Activity was determined as a percentage of the number of animals that survived a given dose or at a PD ₅₀ (the dose that protects 50% of the infected animals).

The properties of the compounds of formula (II) produced by the process of the present invention in increasing the efficacy of beta-lactam antibiotics against beta-lactamase producing bacteria allow 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 (II) 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 (II) 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 subject is preferably pretreated with the compound of formula (II) prepared by the process of the invention, preferably at the start of treatment with beta-lactam.

If prepared according to the invention a compound of formula (II) wherein in formula R ¹ is hydrogen is used the beta-lactam antibiotic hatásnövelésére, with the beta-lactam compound according to the invention antibiotic is used, preferably in pharmaceutical carriers conventionally used or in the form of preparations with diluents. The 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 II prepared by the process of the invention.

When used in combination with another beta-lactam antibiotic of the present invention, the compounds of the formula (II) 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 (II) wherein R ¹ is hydrogen as defined above to the daily dose of the beta-lactam antibiotic is generally from about 1: 3 to about 3: 1 by weight. In addition, when the compound of formula (II) 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, the treating physician will determine when a dose other than these is required.

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 (II) of the present invention are administered simultaneously (i.e., mixed) with a beta-lactam antibiotic, a combined form suitable for parenteral administration should be prepared. When the compound of formula (II) 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 orally the form of the compound of formula (II) which is live by the method of the invention while parenterally administering the beta-lactam antibiotic and it is possible to administer the form of the compound (II) of the invention by parenteral administration. -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. The proton and 13: Nuclear magnetic resonance spectra were obtained next to 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 are given relative to tetramethylsilane _d6) solution and a value of chemical shift in ppm. The following abbreviations are used; s, singlet; d, doublet; dd, doublet of doublets; t, triplet; q, qvartett; m, multiplet; b, wide sign.

Example 1

A. To a mixture of 1.0 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 6-alpha-hydroxypenicillanate is obtained.

B. To a mixture of 1.0 6-alpha-hydroxypenicillanic acid in 50 mL of dioxane was added 0.5 mL of p-toluenesulfonic acid and 0.4 g of dihydropyran, and the reaction mixture was 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-hydroxypenicillinate is obtained.

Example 2

Benzyl-6-oxo-penicillanate

To a solution of 1.8 ml (0.025 mmol) of dimethylsulfoxide in 2 ml of dichloromethane 7

A solution of trifluoroacetic anhydride (2.12 ml, 0.015 mol) in dichloromethane (5 ml) was added dropwise at -60 ° C to -60 ° C. The reaction mixture was stirred for 20 minutes at -60 ° C and a solution of 350 mg (1.14 mmol) of benzyl 6-alpha-hydroxypenicillinate 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 3

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

A. Benzyl 6-bromo-6- (2-pyridyl) hydroxymethyl penicyl lanate

A solution of 9.0 (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 2M solution of pentane in t-butyllithium was added dropwise. The mixture was stirred for 30 minutes then

2.14 g (0.02 mol) of 2-pyridine carboxaldehyde are added. Stirring is continued for 40 minutes and the reaction is quenched by the dropwise addition of a solution of acetic acid in toluene. 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 was dried (MGSO ₄ ) and applied to a 1 kg Florisil column. The eluent was eluted with 2: 1 toluene / ethyl acetate and the product-containing fractions 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) obtained in (A) in 50 ml of benzene

2.65 g of tributyltin hydride are added. 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 500 g silica gel column. Elution with 2: 1 toluene / ethyl acetate gave 425 mg of the desired product.

1 H-NMR (CDCl ₃ ) ppm (delta) δ 1.35 (s, 3H),

1.7 (s, 3H), 4.0 (dd, 1Η), 4.5 (s, 1H),

5.1 (s, 2H), 5.2 (d, 1H), 5.4 (d, 1H), 7.0-7.8 (m, 3H), 8.5 (m, 1H).

Example 4

6 - ((2-Pyridyl) hydroxymethyl) penicillanic acid

-1,1-dioxide

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

0.40 for a solution of benzyl 6- (2-pyridylhydroxymethyl) penicillanate in 5 ml dichloromethane. g of m-chloropenobenzoic acid was added and the mixture was stirred at room temperature for 1 hour. Thin layer chromatography 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 silica gel column chromatography (11: 9 ethyl acetate / hexane) to give 60 mg of a yellow oily substance.

1 H-NMR (CDCl ₃ ) δ 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, 2H), 5.8 (d, 1H),

7.1-7.8 (m, 3H), 8.5 (m, 1H).

Β. A suspension of 118 mg of 10% Pd / C catalyst in 10 ml of tetrahydrofuran and 4 ml of water was 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 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 A was frozen to give 85 mg of the desired acid.

1 H-NMR (D 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, 1740.

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 5

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

(a) Potassium (6-alpha, 8R) -6- (thiazol-2-yl) -acetoxymethyl-1,1-dioxopenicillanate 1.0

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(b) ampicillin trihydrate 1.0 (c) lactose 0.5 (d) polyethylene glycol; gos molecular weight 4000 0.5

1375 mg of the mixture is filled into appropriately sized hard gelatin capsules to give each component a 250-250 mg active ingredient formulated 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 may be varied to provide a non-one weight ratio of, for example, 0.75, 1.5, 0.5, and 0.3 parts. Of this, 1700 mg of powder can be filled into capsules containing 225 mg of component (a) and 150 mg of component (b).

In a similar manner, 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 / penicanoloxymethyl) -6- {2-pyridyl} -. methylene (-1,1-dioxopenicyl lanate bridge with chloride).

Example 6

Allyl 6 - ((2-thiazolyl) acetoxymethyl) -1,1-dioxopenicillanate

0.5 g (1.29 mmol) of allyl-6 - ((2-thiazolyl) -hydroxymethyl) -1,1-dioxopenicillanate (0.396 g, 3.88 mmol) and acetic anhydride (0.307 g, 3.88 mmol) were added. Acidylated with pyridine in 5 ml of tetrahydrofuran according to the procedure of Example 20A. After stirring for 4 hours at room temperature, the reaction mixture was diluted with dichloromethane and washed with water until 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, 3H), 6, 65 (d, 1H), 7.4 (d, 1H), 7.8 (d, 1H).

Example 7

A. Potassium (6alpha-8S) -6 - ((pyrimidin-2-yl) -hydroxymethyl) -1,1-dioxopenicillanate

To a solution of 300 mg of allyl-6alpha - ((pyrimidin-2-yl) -hydroxymethyl) -1,1-dioxopenicillanate isomer in 4 ml of ethyl acetate is added 30 mg of tetrakis (triphenylphosphine) palladium (O), 30 mg of triphenylphosphine and the mixture is stirred under nitrogen until the components are dissolved (5 to 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, 250MHz (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, 1H), 4.89 (d, J = 2, 1H), 5.1 (d, J = 6, 1H), 6.33 (s , 1H), 7.48 (t, J = 4, 1H), 8.84 (d, J = 4, 2H).

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

300 mg of allyl-6alpha - ((pyrimidin-2-yl) -hydroxymethyl) -1,1-dioxopenicillanate are 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, 3H), 3.65 (s, 1H),

4.60 (dd, J = 2, J = 8, 1H), 4.75 (d, J = 2, 1H), 5.15 (d, J = 8, 1H), 7.47 (J, J) = 4H, 1H), 8.85 (d, J = 4.2H).

Example 8

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

785 mg (2.1 mmol) of allyl-6α-alpha- (pyrimidin-2-yl) -hydroxymethyl) -1,1-dioxopenicillanate are dissolved in 4 ml of dichloromethane and 0.45 ml (5.6 mmol) of pyridine and 53 ml (5.6 mmol) of acetic anhydride are added and the mixture is stirred at room temperature for 2.5 hours. The reaction mixture was then diluted with dichloromethane (30 mL), extracted with water (7 x 60 mL), triturated with dry magnesium sulfate and filtered. The solvent was evaporated in vacuo to give 813 mg (92%) of product.

1 H-NMR (DCD ₁₃ ) ppm (delta): 1.4 (s, 3H), 1.6 (s, 3H), 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), 5.7-6.3 (m, IH); 6.45 (d, 1H), 7.35 (t, 1H), 8.85 (d, 1H).

3. Allyl (6alpha, 8R) -6 - ((pyrimidin-2-yl) -acetoxymethyl) -1,1-dioxopenicyl lanate

By the above procedure, allyl-6alpha - (pyrimidine) is used

-2-yl (hydroxymethyl) -1,1-dioxopenicillin isomer is converted to the desired compound. Yield 88%.

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

1.6 (s, 3H), 4.45 (s, 1H), 4.50 (dd, J = 1, J = 8.1H), 4.75 (m, 2H), 4.8 (d) , J = 1, 1H), 5.25-5.6 (m, 2H), 5.7-

6.3 (m, 1H), 6.4 (d, J = 8, 1H), 7.55 (d, J = 6, 1H), 8.8 (d, J = 6, 1H) .

Example 9

Potassium (6alpha, 8S) -6 - ((pyrimidin-2-yl) -acetoxymethyl) -1,1-dioxopenicillanate

789 mg (1.86 mmol) of allyl (6 alpha, 8 S) -6 - ((pyrimidin-2-yl) -acetoxymethyl) -1,1-dioxopenicylate are dissolved in 4 ml of ethyl acetate and the procedure of Example 54 is prepared. is converted to the corresponding potassium salt. 342 (43%) of product are obtained, which is purified by A4PLC medium pressure liquid chromatography with 9: 1 water / acetonitrile as eluent. 105 mg of product 9

-9194891 two were obtained which were 83% pure by HPLC.

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

Allyl (alpha, 8R) -6- (pyrimidin-2-yl) -acetoxymethyl-1,1-dioxopenicillanate (666 mg, 1.57 mmol) was converted to the desired potassium salt according to the above procedure and 339 mg Yield (51%). The product was purified by medium pressure liquid chromatography (MPLC) using water / acetonitrile 9: 1 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, 1H),

4.97 d, J = 2, 1H), 6.27 (d, J = 8.1H),

7.50 (t, J = 5.1H), 8.85 (d, J = 5.2H).

Example 10

Starting from the appropriate 6-R ' ³ CHOH-substituted-1,1-Cioxopenicillanate ester, the following acetate esters are prepared:

Formula VI

R ^{1 3} C g> C ₈ Production ³ H-NMR (CDCl ₃ ) ppm (delta): stereochemistry /She (XLI) 6alf a, 8S 100 1.43 (s, 311), 1.63 (s, 311), and 2.25 (s, 3H), 4.51 (m, 2H), 6at fa, 8R 4.79 (tn, 211), 5.43 (m, 2H), mix 5.98 (m, 1H), 6.65 (d, 1H), 7.5 (η, 3H), 7.98 (s, 1H), 8.20 (m, 211). (XLII) 60:40 69 1.4 (s, 811), 1.43 (s, 1.2H), 6alpha, 8S 1, 56 (s, 1, 211), 1.62 (s, and 1.811), 2.2 (s, 1.211), 2.3 (s, old wood, 8R 1, 811), 4.35 (m, 1H), 4.4 (s, mix 0.6H), 4.43 (s, 0.41!), 4.78 (d, 0.6H), 4.8 (d, 0.4H), 5.3-5.5 (tn, 2H), 5.8-6.05 (m, 1H), 6.3 (m, 1H), 7.45 (d, 111), 8.82 (d, 1H), 9.25 (m, 1H). (XI, KIC) 60:40 66 1.4 (s, 1.811), 1.5 (s, old wood, 8S 1.2H), 1.6 (s, 1.811), and 1.65 (s, 1.211), 2.2 (s, old wood 8R 1.2H), 2.26 (s, 1.811), mix 4.23 (dd, 0.411), 4.35 (dd, 0.611), 4.4 (s, 0.611), 4.45 (s, 0.4H), 4.68 (m, 211), 4.74 (d, 0.611), 5.0 (d, 0.411), 5.35 (m, 2H), 5.9 (m, 1H), 6.45 (m, 1H), 8.6 (m, 211), 8.75 (m, 1H). (LXIH) 92 dark gray viscous foam lyad ik Example 11 By the above procedure the corresponding 8-acetoxy- Of -3-allyl esters a (VII) General formula potassium salts live: _r 13 »Cg Yield (TI-NMR (CD3) delta): stereochemistry% (XLII) 65:35 57 (crude) Purified: 1.45 (s, 3H), 6-alpha-8S, 27 (chroma - 1.58 (s, 3H), 1.25 (s, 6alpha 8R graph 1.05H), 1.32 (s, 1.95H), mixing Asan * 4.25 (s, 0.65H), 4.28

* Using a C18 (Cig = monoctadecylsilicate) column.

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R ¹³ Cg, Ca Production ¹ H-NMR (D 2 O) ppm- (delta):

stereochemistry%

purified (s, 0.35H), 4.37 (dd, isomer-0.65H), 4.45 (dd, 0.35H), bloods 5.15 (d, 0.65H), 5.2 (d, 0.35H), 6.25 (d, 0.65H), 6.35 (d, O, 35H) 7.73 (m, 1H), 8.85 (m, 1H), 9.15 (m, 1H). (XLIV) 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), 6.5 ( d, 0.85H), 7.07. (s, 0.5H), 7.1 (d, 0.85H), 7.16 (s, 0.15H), 7.2 (d, 0.85H). IR (KBr cm ^-1 : 3409, 1786, 1740, 1620). (XLIII) 30:70 84 1.3 (s, 2.1H), 1.34 (s, 6alpha, 8S, (crude) 0.9H), 1.42 (s, 3H), 6alpha, 8R 43 (Chromatographed) 2.13 (s, 0.9H), 2.2 (s, 2.1H), 3.66 (s, 0.7H), 3.7 (s, 0.3H), 4.1 (dd, 0, 3H), 4.95 (d, 0.7H), 5.07 (d, 0.3H), 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): 3468, 1781, 1746, 1623 ^cm-first

Example 12

Potassium 6 - (/ imidazol-2-yl / hydroxymethyl) -1,1-dioxo-penicillanate

141 mg (0.38 mmol) of allyl 6 - (imidazol-2-yl) -hydroxymethyl) -1,1-dioxopenicillanate, mg of tetrakis (triphenylphosphine) palladium (0), mg of triphenylphosphine 0.76 ml (0.38 mmol) of potassium 2-ethylhexanoate in 2 ml ethyl acetate ELE _5Q mixture was stirred under nitrogen for one hour. The precipitated product was filtered off to obtain 143 mg (100%) of a yellow solid, which contained two isomers by HPLC.

IR (KBr): 3382, 1780, 1772 and 1615 cm ^-1 .

Example 13

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

A solution of 17.79 g (44 mmol) of benzyl 6-alpha-bromo-1,160-dioxopenicillanate in 250 ml of dry tetrahydrofuran was treated with an equimolar amount of methyl magnesium bromide (-78 ° C) and stirred for one minute. equimolar amounts thiazol-2-carb oxialdehidet ₅ g is added and stirring is continued for another minute. 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 a crude product are obtained which is a two spot stain by TLC. 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 mg of a less polar isomer and 0.5 g of a mixture of isomers (total yield 43%).

More polar isomer: Ή NMR _(CDCl3) ppm (delta): 1.25 (s, 3H), 1.55 (s, 3H), 4.3 (dd, IH);

4.45 (s, 1H), 4.65 (bs, 1H), 4.9 (d, 1H), 5.2 (m, 2H), 5.55 (d, 1H), 7.36 (m , 6H), 7.75 (d, 1H).

Less polar isomer: Ή NMR (CDC1 ₃₎ ppm (delta); 1.2 (s, 3H), 1.5 (s, 3H), 4.35 (m, 2H), 4.75 (d, 1H), 5.1 (m, 2H), 5.55 (d) , IH),

7.2 (m, 6H), 7.6 (d, 1H).

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Β. (Diphenylmethyl) -6 - ((2-thiazolyl) 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, 3H), 1.52 (s, 3H), 4.1-4.3 (m, 1H), 4.42 ( s, 1H), 4.76 (d, 1H), 5.45 (d, 1H), 6.82 (s, ΙΗ), 7.05-7.3 (m, 11H), 7.56 (d) , 1H). Less polar isomer: Ή NMR (CDC1 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, 1H), 7.2-7.4 (m, 1H), 7.75 (d, 1H) .

Example U.

Using the appropriate chloride R ³⁸ Cl or the corresponding acid anhydride and the corresponding 6-F. Starting from ¹³ CHO-substituted-1,1-dioxopenicylanate ester, the following compounds of formula VIII are prepared.

R ^a R ¹³ R ¹⁸ C ₈ stereo- chemistry ¹ H-NMR (CDCl 3) ppm (delta): benzyl (as described in 13.A. 2-Thiazo- methyl- (R) 1.3 (t, 3H), 1.4 (s, 1H), example more polar lil carbo 1.65 (s, 1H), 2.55 (q, 2H), 8-hydroxy product- nil 4.5 (s, 1H), 4.4-4.6 (m, starting from) 1H), 4.85 (d, 1H), 5.27 (s, 2H), 6.65 (d, 1H), 7.35 (m, 6H), 7.75 (d, 1H). Diphenylmethyl 2-Thiazomethoxy- (S) 1.25 (s, 3H), 1.3 (t, 3H), (Example 13B lil-carbo- 1.75 (s, 3H), 4.24 (q, less polar nil 2H), 4.36-4.60 (m, 1H), isomer (eb) 4.55 (s, 1H), 5.02 (d, 1H), 6.43 (d, 1H), 6.95 (s, 1H), 7.1-7.5 (m, 11H), 7.75 (d, 1H). Diphenylmethyl (a 2-Thiazomethoxy- (R) Copper solid foam Example 13.B. lil-carbo- richer muscle- nil vesicle) allyl 2-Thiazo- (XLV) (S) 1.4 (s, 2.1H), 1.5 (s, lil + 0.9H), 1.6 (s, 2.1H), 1.65 (R) (s, 0.9H) 4.4 (s, 0.7H), 4.5 (0.3H), 4.5-5.0 (m, 4H), 5.1-6.2 (m, 3H), 6.9 (d, 1H), 7.4 (m, 1H), 7.8 (d, 1H). allyl 2-Thiazo- isopropyl (S) 1.37 (m, 3H), 1.50, (m, lil picture (less) 3H), 1.65 (s, 3H), 1.82 carbo polar (s, 3H), 2.70 (m, 1H), nil 22% 4.61 (s, 1H), 4.7 (m, 1H),

benzyl

4.9 (tn, 2H), 5.12 (d, 1H), 5.41 (m, 1H), 5.6 (m, 1H), 5.8-6.5 (m, 1H), δ , 75 (d, 1H), 7.6 (d, 1H), 7.97 (d, 1H).

(R) 1.18 (m, 3H), 1.28 (m, 3H) polar-1.33 (s, 3H), 1.52 (s, sabb 41% 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, 1H), 7.63 (d, 1H).

2-Thiazobenzoyl lil

(S) 1.4 (s, 3H), 1.6 (s, 3H), 4.5 less (s, 1H), 4.4-4.6 (m, 1H), polar 5.1 (d, 1H), 5.2 (s, 2H), 6.7 (d, 1H), 7.2-8.2 (m, 12H). (P) 1.3 (s, 3H), 1.6 (s, 3H), less 4.5 (s, 1H), 4.6 (dd, 1H), polar 4.86 (d, 1H), 5.2 (s, 2H), 6.85 (d, 1H), 7.3-7.7 (tn, 9H), 7.8 (d, 1H), 8.15 (dd, 2H)

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Example 15

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

A suspension of 1.89 g of 10% Pd / C catalyst in 20 ml of THF / water (v / v) was saturated with hydrogen and 689 mg (1.4 mmol) of benzyl- (6alpha, 8R) -6 - (/ thiazole) was added. A solution of 2-yl (propionyloxy-methyl) -1,1-dioxopenicillanate in 13 ml of tetrahydrofuran and 7 ml of water 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 (MgSO ₄ ) and the solvent evaporated in vacuo. 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), δ , 05 (d, 1H), 6.68 (d, 1H), 7.4 (t, 7H),

7.55 (t, 1H), 7.58 (d, 1H), 7.7 (d, 1H),

7.95 (d, 1H).

IR (KBr) cm 3473, 1782, 1729, 1622.

Example 16

A. (6alpha, 8S) -6 - ((Thiazol-2-yl) -ethoxycarbonyloxy-methyl) -1,1-dioxopenicillanic acid

To a solution of 557 mg (0.954 mmol) of (diphenylmethyl) - (6alpha, 8S) -6- (thiazol-2-yl) -ethoxycarbonyloxy-methyl) -1,1-dioxopenicillanate in 5 ml of dichloromethane Anisole (0.62 mL, 5.72 mmol) was added. 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 to precipitate a precipitate. The precipitate was filtered off and dried. 211 mg (53%) of product are obtained. 1 H-NMR, 300 MHz, (CDCl ₃ ) ppm (delta):

1.40 (t, 3H), 1.53 (s, 3H), 1.67 (d, 3H),

4.28-4.42 (m, 3H), 4.50 (d, 1H), 4.92 (s, 1H), 6.58 (d, 1H), 7.55 (d, 1H),

7.93 (d, 1H).

IR (KBr) 3443, 1797, 1754 cm -1.

B. The (6alpha, 8R) -isomer diphenylmethyl ester starting material prepared in Example 14 is reacted according to the above procedure to give the (6alpha, 8R) -6 - (/ thiazol-2-yl) - (ethoxycarbonyloxy / methyl) -1,1-dioxopenici 11-acetic acid is prepared.

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), 7.55 (d, 1H),

7.90 (d, 1H).

IR (KBr) 3418, 1803, 1750 cm ^1st

Example 17

Using the appropriate allyl ester prepared in Example 14, starting material a

By the procedure of Example 12, the following potassium salts of formula (XII) are prepared.

R ¹³ R ¹⁹ C _n Stereochemistry ¹ H-NMR (0 ^ 0) ppm (delta):

2-Thiazolyl- (XLV) (S) +

(8)

2-thiazolyl isopropylidene (S) _{propyl-go forbo-%} ⁿⁱ production

1.46 (s, 3H), 1.65 (s, 3H), 4.35 (2S, 1H), 5.2 (d, 1H), 7.05 (d, 1H), 7.7-3 , 0 (m, 2H), 8.7-9.5 (m, 3H).

1 13 (D. 3H),. 1, 16 (D, 3H), 1 33 (s. 3H), 1, 45 (s, 3H), 2 65 (tn, 1H), 3.73 (s. 1H), 4 23 (Dd, 1H) , 4.93 (d , 1H) e 50 (D, 1H), 7.35 (tn, 2 H) ,

IR (KBr): 3777, 3472, 3447 3270, 1783, 1746, 1621 cm ^-1 .

-13194891 ¹ H-NMR (DMSO-d ₆ ) ppm (delta):

Example 17 (continued)

R ¹⁸

C is _a stereochemistry (R) 1.17 (d, 3H), 1.20 (d, 3H), ²⁷ 1.44 (s, 3H). 2.69 (m, 1H), yield

3.68 (s, 1H), 4.12 (dd, 1H), 4.92 (d, 1H), 6.59 (d, 1H), 7.84 (m, 2H),

IR (KBr): 3543, 3498, 3437, 3415, 3348, 3270, 3119,

Example 18

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

A solution of 8.84 g (20 mmol) of allyl-6,6-dibromo-1,1-dioxopenicillanate in 100 ml of dry tetrahydrofuran was cooled to -78 ° C and 7.02 ml (20 mmol) of methyl magnesium bromide was 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 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 chloroform / ethyl acetate ₄₅ 89:11 as the eluent and 6.2 g.

R ^a R ¹⁸ Production%

1917, 1735, 1745, 1718,

1619 cm ^"1 (72%) of pure material, which comprises an isomer.

1 H-NMR (CDCl ₃ ) ppm (delta): 1.3 (s, 3H), 1.6 (s, 3H), 4.0 (bs, 1H), 4.42 (s, 1H),

4.6 (d, 2H); 5.3 (s, 1H). 5.55 (s, 1H),

5.1-6.3 (m, 3H), 7.35 (d, 1H), 7.75 (d, 1H).

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

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

1 H-NMR (CDCl 3) ppm (delta): 1.32 (s, 3H),

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).

C. Following the procedure of point A, the following compounds of formula (XLV1) are prepared.

¹ H-NMR (CDCl ₃ ) ppm (delta):

benzyl (XLVII) 100 1.25 (s, 3H), 1.54 (s, , 3H) 3árga 4.5 (s, 1H), 5.02 (s, 2 H), foam 5.43 (s, 1H), 5.68 (s , 1H) 7.32 (Tr., 7H), 8.00 (m , 2K) benzyl (XLVIII) 88 yellow solid 1.4 (2s 4.0 (s, , 3H), 1.6 (s 1H), 4.9 (2, , 3H) 1H),

5.18 (m, 2H), 5.5-5.7 (m, 2H), 7.5 (S, 5H). 8.0 and 8.5 (2s, 1H).

-14194891

R ^a R ¹³ Production ¹⁴ 4-NMR (CDCl ₃ ) ppm (delta):

benzyl (XLI1I) 100 1.25 (s, 3J1), 1.52 (s, 3H), 4.45 (s, 0.75 II), 4.52 (s, 0.25H), 5.1-5.4 (m, 411), 7.5 (s, 5H), 8.6 (m, 2H), 9.0 (m, 111). benzyl (XLVIII) 38 1.33 (S, 3H), 1.60 (s, 3II), 4.38-4.73 (m, 3H), 5.0-6.0 (m, 5H), 7.10 (s, 1H). 8.51 (s, 111). Example 19 A. Where in the general formula R ' Reports A. Prepared in Example 181 compounds 25 is allyl, R ¹⁸ is acetyl by acylation, the following compounds of formula (XL1X) are prepared. group,

the

2-thiazolyl

Production ¹ HN-1R (CDCl ₃ ) ppm (dal):

colorless crystal 1.4 (s, 3II), 1.6 (s, 3H), .22 (s. 3I-I), 4.45 (3 , 1H). 4.65 (Ra. 2H), 5.4 (3, 1H), 5.2-6.3 (M. 3H), 6.7 (s, 1H), 7.4 (d, 1H) 7.8 (d, 1H).

¹⁵ C-N 1 R (COCl 3) ppm (delta):

13.4 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.

, 40 (s, 3H), 160 (9, 3H), 2.25 (s, 3H.), 4.48-4.70 (m,, 2-6, 2 (s, 5H), 6, 92 ( s, 1H), 8.83 (s, 1H).

(XLVIII) 59 (+ 21% isomer product)

B. Where in the general formula R 'is benzyl, R' ⁸ is acetyl.

R ¹³

Production y

SQ ¹ H-NMR (CDC1 _X) ppm (delta):

2-Thiazolyl 100 1.25 (a, 3I), 1.55 (s, 3H), vitreous

9: 1 Isomer-4.50 (s, 0.9H), 4.55 (s, 0.1H), Mixed

-1519489 '

R Production ¹ H-NMR (GOC 1,) ppm (delta):

Λ)

5.2 (ra, 2H), 5.40 (s, 0.9H),

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

6.60 (s, 0, 9H), 7.3 (m, 6H),

7.75 (d, 1H).

(XLVII) 100 1.3 (ε, 3H), 1.52 (s. 3H), yellow orange foam 2.25 (s, 3H), 4.54 (s, 1H),

5.02 (3, 2H), 5.52 (s, 1H), 6.8 (s, 1H), 7.3 (m, 7H), 7.9 (m, 2H).

(L) 19 (XLIII) 90

3: 1 mixture of isomers

1, 25 (s , 3H), 1.5 (s, 3H); 2:19, (s. 3H) . 3.95 (s, 3H) , 4.4 (ε, 1H), 5.15 (s . 2 H) , 5.45 (S , 1H) , 6.3 (s. 1H) , 7.35 (s, 5H) , 7.73 (s, 1H). 1, 25 (s , 2.25 H), 1, 3 5 (s, 0.75H), 1, 4 (s, 2, 25H) , 1, 42 (s, 0 .75 H), 2.2 (S, 2.25 l · I). 2.3 (s, 0 , 75 H) 4.45 (s , 0.75 H), 4.5 5 (s, 0.25 H).

C. Alternatively, the compounds of the above general formula were prepared according to the procedure of Example 18. 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, 1.3 equivalents of methyl magnesium bromide in the same solvent was added and the mixture was stirred for 5-10 minutes. Then, 1.3 equivalents of the appropriate ^{(R! 3} CHO)

R ³ R ¹ ^ Production

5.1-5.3 (m, 2H), 5.3 (s, 0.75 H),

5.6 (s. 0.25 H), 6.25 (s, 0.25 H)

6.4 (s, 0.75H), 7.3, 5H), 8.67) (m, 2H), 9.67 (s. 1H).

a solution of aldehyde in the same solvent was 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 and extracted with ethyl acetate. isolated by drying the organic solution and evaporating the solvent in vacuo.

In the general formula, R ¹⁸ is an acetyl group.

¹ H-NMR (CCCl ₃ ) ppm- (delta): ^{* 2} benzyl phenyl 100 Pale yellow foam allyl (L ¹ ) yellow oil 1.35 (s, 3H), 1.56 (s, 3H), 22 (s, 3H), 4.42 (s, 1H), 4.60-4.74 (m, 2H), 5.24-5.42 (m, 3II), 5.79-5.96 (m, 1H). .

-16194891

R ^a R ¹³ Production ¹ H-NMR (CDCl ₃ ) ppm (delta).

6.52 (s, 1H), 7.32-7.34 (d, 1H), 8.70-0.74 (d, 1H).

IR: 1810, 1760 cm ^1st

allyl (LII) 59 yellow oil benzyl (LIII) 59 benzyl (LIV) 22 benzyl (LV) 44 yellow foam allyl (LVI) 36 foam

1.42 (s, 3H), 1.62 (s, 3H), 2.28 (s, 3H), 2.48 (s, 3H),

4.5 (s, 1H), 4.6-4.8 (m, 2H), δ 18-5.47 (m, 2H), 5.82-6.0

(M, 1H), 6.3 (s, 1H), , 6.97 (s. 1H). IRISH: 1810, 1760, 1730 -1 cm. 1, 6 (θ. 3H), 1, 8 (s, 3H), 2, 2 (S < 3H), 2.3 (s, 6H), 4.4 (θ · w) 5.2 (d, 2 H) , 5.3 (S 1H), 6.4 (s, 1H), 7.3 (s, 5H). 1, 22 (s, , 3H) , 1.5 (s , 3H).

2.18 (5, 3H), 2.42 (s, 3H),

4.5 (s, 1H). 5.16-5.36 (m, 3H), 6.18 (s, 1H), 6.48 (s, 14), 7.4 (s, 5H).

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 (θ. 1H), 6.6 (s, 1H), 6, 8 (s, 1H), 7.3 (s, 5H).

, 40 (s, 3H), 1.60 (s, 3H), 2.27 (s, 3H), 2.65 (s, 3H), 4.20-4.8 (m, 3H), δ, 1-6.2 (m, 4H), 6.41 [s, 1H).

IR: 1815, 1760 cm ^1st

-17194891

Example 20

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

To a solution of 74.6 g (134 mmol) of benzyl 6-bromo-6 - ((thiazol-2-yl) -acetoxymethyl) -1,1-dioxopenicillanate in 850 mL of benzene, 43.99 g (151.2 g) tributyltin anhydride was added. 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 extracted with acetonitrile (2 x 250 mL). The acetonitrile solution was evaporated, the residue suspended in ether, filtered and the precipitate washed with ether. 33.28 g of colorless crystals are obtained. 2.8 g of additional product are obtained by evaporation of 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 column chromatography on silica gel using chloroform / ethyl acetate 9: 1 as eluent.

The product-containing fractions were concentrated, slurried in ethyl ether / ethyl acetate 4: 1 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),

4.80 (d, 1H), 5.2 (dd, 1H), 5.22 (q, 2H), 6.75 (d, 1H), 7.35 (s, 5H), 7.4 (d) , 1H), 7.8 (d, 1H).

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 18 were prepared to give the following debrominated compound (LVII):

R ^a R ¹³ Production % ¹ H-NMR (CDCl ₃ ) ppm (delta): benzyl (XLVII) 39 1.3 (s, 3H), 1.55 (s, 3H), 2.19 (s, 3H), k.5 (s, 1H), 4.79 (d, 1H) 5.2 (m, 3H), 6.79 (d, 1Ή), 7.32 (s, 7H), 7.9 (m, 2II). benzyl (L) 72 1.29 (s, 3H), 1.55 (s, 3H), 2.10 (s, 2H), 4.03 (s, 3H). 4.5 (s, 1H), /, 78 (d, 1H), 4.87 (dd, 1H), 5.25 (q, 2H), 6.53 (d, 1H). 7.38 (s, 5H), 7.89 (s, 1H). benzyl (XLIII) 45 1.3 (s, 3H), 1.55 (s, 3H),

yellow solid

4.45 (s, Η), 4.5-5.1 (m, 2H), 5.2 (m, 2H), 6.5 (dd, 1H), allyl (XLVIII) 70 oils

7.35 (s, 5H), 8.5 (m, 2H), 8.83 (m, 1H).

1, 44 (s. 3H), 1, 62 (s. 3H), 2.10 (s - 3H), 4.51 (s, 1H), 4,60- -4.80 '(<', 2II), 4.89 -4.91

(d, 1H), 5.26-5.42 (m, 3H), 5.35-5.99 (rn, 1H), 6.88-5.92 (d, 1H), 3.82 (s) , 1H).

IR: 1795, 1750 cm ^-1 .

-18194891

36

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

Aj Allyl (Ll) 51 Less Polar Isomers + 11 More Polar Isomers Allyl (LU) 31 Yellow Oil

MP Isomer: 5.34-6.00 (m, 1H), 6.23-6.42 (m, 21-1), 6.62-6.77 (d, 111), 7.38-7. , 43 (d, 11-1), 8.54-3.70 (d, 1H). White Crystals »

IR (KBr), 1807, 1760 cm ^-1

1.46 (s, 3H), 1.64 (s, 3-14), 2.14 (s, 3H), 2.48 (s, 311),

4.5 (s, 1H), 4.6-4.9 (m, 3H), 5.2-5.26 (dd, 1H), 5.3-5.6 (m, benzyl (Lili) 43

She. p. : 194.5 -195.5 ° C benzyl (LIV) 16 colorless solid, isomeric benzyl (LV) 43

2 H), 5,8i 5-6.1 (m, 1H), 6.7 (d, 1H), 7 .0 (s, 1H). IRISH: 1810 , 1760 cm 1 • 1, 3 (s,: 3H), 1.53 (s, 3H), 2:12 (S < 31!), 1.35 (d, 6H), 4.5 (s, 1H), 4.75 (d, 1H), 5.2-5.4 (Dd, 3H) , 6.6 (d, 1H), 7.4 (s, 514 1, 23 (s, 311), 1, 55 (S, 311), 2.1 (s, 311), 2.4 (s, 3 Η), 4.5 (s, 1H) 4.8 (Dd, 11-1), 5.25 (q, 1 Η), 6.15 ( ³ 1 H), 6.5 (d, 1 H), 7.4 (s, 5H) i, 3 (s, 3I4), 1, 58 (s, 3H),

allil (LVI) 44

3: 1 mixture of isomers

2.14 (s, 3H), 2.48 (s, 3H), 4.52 (8, 114), 4.8 (d, 1H), 5.16 to 5.36 (AB q and dd, 3I4), 6, 7 (d, 1H), 7.0 (s, 114), 7.4 (s, 514). 1.37-1.40 (d, 3H), 1.58-1.60 (d, 3H), 2.12-2.14 (d, 314), 2.58 (s, 3H), 4.48 (s, 1H), 4.58-4.88 (m, 4H), 5.24-5.46 (m, 2H), 5.82-6.00 (m, 1H), 5, 64-6.67 (d, 0.75 Η), 7, 05-

-7.08 (d, 0.25 H): IR: 1810, 1765 cm @ ^-1

-19194891 is used to convert the arm of formula (LVIIIa) to the carboxylic acids, wherein R ^{e in} the general formula is hydrogen.

¹ H NMR (DMSO-d6) ppm (delta)

Example 21

Benzyl esters were prepared Example 20 A Pd / C catalyst hidroR ¹³ _R 18 Yield%

2-thia- acetyl 74 oxazolyl white solid material op. 145-155 ° C (dec.) (XLVII) acetyl 45

1.45 (s, 3H), 1.53 (s, 3H) 2.10 (s, 3H), 4.40 (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, 81 1 1 . 168, 7027, 170,803 (5. 1.53 (s, 3H), 1.65 (s, 3H), 2.17 (s, 3H), 4.54 (s, 1H). 4.87 (d. 1H), 5.13 (dd, 1H), 6.82 (d, 2H), 7.88 (d, 1Η), 8.07 (d, 1H), 9.20 (bs, 1H) •

¹³ C-kMR: 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.

(00) 1.45 (s, 3H), 1.57 (s, 3H), (XLIII) acetyl Go

2.15 (s, 3I-I), 4.33 (s, 1H), 5.24 (d, 1H), 4.76 to 5.2 (4H, closed, value 0 □ _2), 6.55 ( d, 1H),

8.65-8.8 (m, 2H). IR (KBr): 3416, 1785, 1618 cm ^-1 . 13 C NMR: 17, 6, 19, ¢. 20.4, 54.4

64.1, 56.7, 68.1, 144.2, 145.2, 145.5, 151, 2. 172.7, 172, 8.

(LUX) acetyl 85

1.48 (s, 3H),

155, (s, 3H), 2.15 (s, 3H), 2, 23 (s, 3H), 2, 32 (s, 3H),

-20194891

40

R ¹³ R ¹⁸ Yield ¹ H-HMR (d-sodiosulfoisophthalate) ppm (delta):

% (Liy) acetyl 87

4.3 (s, 1Η), 4.35 (dd, 1H), 5.2 (d, 1H), 6.6 (d, 1H).

IR'KBr): 1787, 1626, 1618 cm ^1st

1.48 (s, 3H), 1.6 (s, 3H) . 2.2 (s, 3H), 2.46 (s, 3H) . 4, 35 (s, 1H) 5.2 (d, 1H), 6.4 (s, 1H), 6.55 (d, 1H). IR (KBr): 1791, 1692, 1631 cm ¹ .

(LV) acetyl 57

B. The 6β-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 liquid chromatography, _C18 column, * a water / acetonitrile 9: 1 as eluent. The desired potassium salt is obtained in 60% yield.

¹ H-NMR (DMSO-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-first

* C _lg octadecyl silicate.

Example 22

A. Kumum-6-bromo-6 - ((thiazol-2-yl) -acetoxymethyl) -1,1-dioxopenicillanate mg (0.2 mmol) allyl-6-bromo-6 - (/ thiazole) 2-yl (acetoxymethyl) -1,1-dioxopenicillanate, prepared in Example 17, was converted to the desired product by reaction for 10 minutes according to the procedure of Example 18. 46 mg (48%) of a yellow solid are obtained. 1 H-NMR (D ₂ O) ppm (delta): 1.45 (s, 3H), 1.6 (s, 3H), 4.4 (s, 1H), 5.55 (s, 1H), δ , 85 (s, 1H), 7.72 (d, 1H), 7.86 (d, 1H).

B. Cadum-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) compound prepared in Example 18 are obtained.

1.5 (s, 3H), 1.6 (s, 3H), 2.2 (s,

3H), 2.45 (s, 3H), 4.35 (s, 1H),

4.9 (dd, 1H), 5.25 (d, 1H), 6.7 (d, 1H), 7.3 (s, 1H).

IR (KBr): 1787, 1657, 1626 cm ^1st

hydroxymethyl) -1,1-dioxopenicillanate is converted to the desired product using a reaction time of 20 minutes. 52% yield of the desired compound is a pale yellow solid.

1 H-NMR (DMSO-d ₆ ) ppm (delta): 1.35 (s, 3H), 1.47 (s, 3H), 3.75 (s, 0.4H), 3.83 (s, 0.6 H), 5.3 (d, 0.4 H), 5.32 (d, 0.6 H), 5.45 (s, 0.6 H), 5.5 (s, 0.4) H), 7.6-8.0 (m, 2H),

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

Example 23

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

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

To a solution of 9.971 g (24.99 mmol) of allyl-6,6-dibromopenicillanate in 150 ml of dry tetrahydrofuran at -78 ° C was 8.77 ml of a 2.85 mol (24.99 mmol) solution of methyl magnesium bromide in tetrahydrofuran. and stir for 15 minutes. A solution of thiazole-2-carboxaldehyde (2.824 g, 24.99 mmol) in tetrahydrofuran (5 mL) was added and the mixture was 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), and the extract was washed with water (2 x 250 mL), dried (MgSO4) and the solvent evaporated in vacuo.

-21194891 color, yields oils. This was purified by column chromatography on silica gel using chloroform / ethyl acetate 9: 1 as the 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), overall yield 46%.

The yellow foam?-NMR (CDCl 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).

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

To a solution of 200 mg (0.462 mmol) of the more polar isomer prepared in (A) in 1 mL of benzene was added 0.183 mL (0.693 mmol, 1.5 equivalents) of a benzene solution of tributyl tin hydride and refluxed for three hours and then overnight at room temperature. let it stand. 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

R ^{* 13} Production

The column was purified by column chromatography on silica gel. Chloroform eluant gave 75 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), 4.8.05, 4.3 (dd, 1H), 4.65 (s, 1H), 4.78 (m, 2H) ), 5.3-5.6 (m, 2H), 5.6-6.3 (m, 3H), 7.45 (m, 1H), 7.85 (m, 1H).

C. 73 mg (0.206 mmol) of the product obtained in B. are converted to the potassium salt according to the procedure of Example 12. 58 mg (80%) of the desired product are obtained as a yellow solid. 1 H-NMR, 300 MHz, (D ₂ O) ppm (delta):

_J5 1.36 (s, 3H), 1.55 (s, 3H), 4.11 (dd, 1H),

4.18 (s, 1H), 5.32 (d, 1H), 5.42 (d, 1H),

7.56 (d, 1H), 7.60 (d, 1H).

Example 24

A. Using the appropriate aldehyde R ¹³ CHO instead of thiazole-2-carboxaldehyde, the corresponding compounds of formula LIX are prepared.

• NMR '(CDCl 3) ppm (delta):

(XLIII) 20, Isomer A (white crystal) 13, 3 isomers (yellow oil)

The isomer 1.46 (s, 3H), 1.64 (s, 3H), 4.42 (d, 1H), 4.50 (s, 1H), 4.64 (m, 2H), 5.265.50 (m, 2H), 5.84 (s, 1H), 5.8-6.0 (m, 1H), 8.58 (d, 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,

144.4, 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, 1H), 5.91 (s, 1H), 8.57 (m, 2H), 8.78 (m, 1H), ¹³ C-NMR (COCl ₃ ): 26.27, 32 , 57, 64.30, 66.19, 69.94, 70.77, 72.38, 74.73, 119.70, 130.98,

-22194891

1 H-NMR (COCl ₃ ) ppm (delta), 13

Production

143.33, 144.57, 144.70, 152.04, 166.93, 167.99 ppm (LX) 25 (isomer A, 8S) (LX) 40 (isomer B, 8R)

1, 52 (s, 3H); 1.70 (s, 3H), 4.64 (s, 1H), 4.72 (m, 2H), 4.86 (d, 1H). 5.34-5.48 (m, 3H), 5.91 (s, 1H), 5.92-6.05 (m. 1 H), 7.39 (vol. 1H), 8.87 (d, an). 1, 52, {s , 3II) , 1.71 (s, 3H) , 4.61 (s, 1H), 4.72 (m, 2H), 4.98 (d, 1 Η), 5.30-5.52 (m, 3H), 5.90-6.04 (m, 1H) 6.10 's, 11-1) 7.40 (t, 1H), 8, 85

(XLVIII) foam (d, 1H).

, 49 (s, 31-1), 1.69 (β, 3H), 3.56 (d, 0.7H), 3.89 (d, 03H), 4.7 (m, 3H), δ, Δ (m, 3H), 5.9 (m, 2H), 7.53 (m, 3H), 8.14 (m, 3H).

(XLVII) 94 (isomers crude reve rée) (LXIV) used in the next step without purification. (LXV) orange oil, used in the next step without purification. (LXVI) golden oil, used in the next step without purification. (LXVII) orange oil, used in the next step without purification. (LXIII) 100 orange oil, used in the next step without purification. (LXVIII) golden oil, used in the next step without purification. (LXIX) golden oil, used in the next step without purification. (LXX) golden oil, used in the next step without purification. (LXXI) (3,5-dimethoate in the next step without purification til - and 3,6-di is used.

methyl mixture) (LXXII) (LXXIII) orange glass, used in the next step without purification.

orange glassy material, used in the next step without purification.

-23194891 ¹ H-NMR (CDCl 3) ppm (delta):

Β. By debromination of the above compounds, compounds of formula (LXI) are prepared.

Production %

(XLIII) 57 (From Isomer A, 3S) Oil (XLIII) 59 (From Isomer B, 8'S)

1.5 (s, 3.1), 1.7 (s, 3H), 4.05 (dd, 11), 4.35 (s, 1Η), 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).

, 5 (s, 3H), 1.8 (s, 3H), 4.15 (dd, 111), 4.25 (bs, 1H), 4.55 (s, 4.7 (m, 2H), 5.2-6.2 (m, 5H),

8.67 (bs, 211), 9.00 (bs, 1H).

(LX) 35 1.51 (s, 3H), 1.74 (s, 3H), 4.01 (From the isomer, BS) oil (dd, 1H), 4.44 (d, 1H) , 4.70, (d, 2H), 5.40 (m, 3H), 5.60 (d, 1H) 5.96 (m, 1H), 7.34 (t, 1H), 8.80 (d, 2H). (LX) 1. 52 (s, 3H), 1.78 (s, 3H), 4.23 (From B isomer, 3R) 65 (m, 2II), 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). (XLVIII) 100 1, 47 (s. 3H), 1.67 (s, 3H), 4.16 (m, 2H), 4, 64 (m, 3H), 5.47 (m, 4H). 5.94 (M, IH), 7.43 (m, 3H), 9.02 (m, 3H), (XLVII) 81 1, 42 (3rd 3H), 1.7 (s, 3H), 4.4 (not clean tapped) (Dd, 0 = 4 and 8, 1H), 4.5 (s, 1H), 4.65 (m, 2 H) , 5.2-6.3 (m, 3H), 5.6

(d, O = 4, 1H,) 5.6 (d, O = 8, 1H), 7.2-7.6 (m, 2H), 7.8-8.1 (m, 2H).

-24194891 (XLVII)

Production ¹ I-W (CDCl 3) ppm (delta): 36 (cleaning after) 1.45 (s, 3H), 1.55 (s, 3H), 4.5 (s, 1H), 4.65 (m, 2H), 5.2 - 6.4 (m, 5H), 7.2 - 7.6 (ra, 2H), 7.8 - 8.2 (m, 2H).

C. The above allyl esters were converted to the potassium salts of formula (LXII) according to the procedure of Example 12.

Production

Stereochemistry 1H-NMR (DMSO-d6) ppm (delta?

(XLIII) 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), 8.5θ (d, 2H), 8.72 (s, 1H).

IR (KBr): 3478, 17,

1607 cm ^-1 .

Production of ¹ K NMR (CDCl 3) (LKIV) 16 (Purified) Gold Foam (LXV) 68 (Isomeric Mix) (6B, 8R) (6B, 8S) Chromium

1.3 (s, 3H), 1.54 (s, 3H), 3.68 (s,

3H), 4.42 (s, 1H), 4.56 (m, 2H), 5.15.4 (m, 3H), 5.48 (d, 1H), 5.76-5.94 (m, 1H), 7-7.3 (m, 3H). , 7.54 (d, 1H).

8R isomer:

1.40-1.55 (m, 6H), 1.75 (s, 3H, 4.14.4 (m, 2H), 4.52 (m, 2H), 4.6 (dd,

1H), 4.Ί (d, 2H), 5.2-5.5 (m, 3H), 5.8-6.1 <m, 1H), 7.2-7.5 (m, 3H),

7.7-7.9 (m, 1H).

8S isomer:

1.4-1.55 (m, 6H), 1.64 (s, 3H), 4.14 (q, 1ΗΓ, 4.42 (q, 1H), 4.5 (s, 1H),

4.64 (m, 2H), 5.2-5.5 (m, 2H), 5.9 (d, 1H), 5.8-6.0 (m, 1H), 7.1-7.4 (m, 3H),

7.65 (m, 1H).

-25194891 ¹ H-NMR (CDCl ₃ ) ppm (delta) (LXVI) (LXVII) (LXIII) (LXIX) (LXX)

Production

7.5 (6β, 8R) (6β, 8S) Yellow Oil (6β, 8S) Yellow Oil 13 (6β, 8S) and (6β, 8R)

4: 1 mixture of (6β, 8S) (6β, 8R) (6β, 8S)

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

3H), 1.87 (m, 2H), 4.0-4.4 (m, 2H), 4.4-4.6 (m, 2H), 4.68 (d, 2H), 5.25.5 (m, 3H), 5.7 (m, 1H) , 5.84-6.00 (m, 1H), 7.2-7.3 (m, 3H), 7.66-7.8 (m, 1H).

1.0 (t, 3H), 1.40 (s, 3H), 1.64 (s,

3H1, 1.9 (m, 2H), 4.05 (m, 1H), 4.3 (m, 1H), 4.5 (s, 1H), 4.6-4.7 (m, 3H), 5.2-5.4 (tn, 4H), 5.6 ( d, 1H), 5.846.00 (m, 1H), 7.1-7.3 (m, 3H), 7.6 (m, 1H).

1.44 (s, 3H), 1.64 (s, 3H), 4.3 (dd, 1H), 4.65 (s, 1H), 4.66 (d, 2H), 5.25.6 (m, 3H), 5.62 (d, 1H) , 5.8-6.1 (m, 1H), 7.32-7.42 (m, 2H), 7.52-7.64 (m, 1H), 7.7-8.2 (tn, 1H).

1.38 (s, 2.4H), 1.48 (s, 0.6H), 1.6 (ε, 2.4H), 1.67 (s, 0.6H), 3.7 (s, 0.6H), 3.74 (s, 2.4H), 4.12 ( dd,

0.2H), 4.34 (dd, 0.8H), 4.4 (s, 0.2H),

4.44 (s, 0.8H), 4.63 (m, 2H), 5.1-5.36 (m, 3.2H), 5.42 (d, 0.8H), 5.8-6.0 (m, 1H), 6.8-7.3 (m, 2H) .

1.3 (s, 3H1, 1.56 (s, 3H), 3.0 (s,

3H), 4.45 (s, 3H), 4.6 (m, 2H), 4.66 (dd, 1H / 5.0 (d, 1H), 5.2-5.4 (m,

2H), 5.4 (d, 1H), 5.8-6.0 (m, 1H),

6.76 (s, 1H), 7.1-7.5 (m, 3H), 7.5-7.7 (tn, 2H).

1.5 (s, 3H), 1.68 (s, 3H), 3.28 (s,

3H), 4.36 (dd, 1H) , 4.44 (S, 1H), 4. 66 (M, 2H), 5.14 (d. 1H), 5. 24-5.5 {tn. 2 H) , 5.7 (d, 1H), 5.8-6.0 (tn, 1H), 6 .9 (S, IH), 7.2-7.5 ( m, 3H), 7.6-7.8 {m t ; h). 1.3 (s, 3H), 1.58 (s, 3H) , 2.25 (s, OH), 2.3 (s, 3H), 3.65 (s , 3H), 4.45 also, 1H), 4.54 (dd, 1H), 4 .6 (tn, 2H), 5.2- 5.4 (m, 3H), 5 .48 (d, 1H), 5.8-6 .0 (M. 1H), 6.77 (s, 1H), 7. 26 (d, 1H). 1:44 (s, '3H), 1.62 (s, 3H ), 2.18 (s,

-26194891

R

Production ¹ H-HMR (GDCl ^) ppm (delta) (6β, 8R) (ΉΧΧΙ)

A mixture of 3,5-dimethyl and 3,6-dimethyl compounds

9.6 two isomers (6β, 8S) + 14 two isomers (6B, BR)

3H), 2.26 (s, 3H), 3.62 (s, 3H), 4.34 (s, 1H), 4.4 (dd, 1H), 4.6 (d, 2H), 5.2-5.4 (m, 3H), 5.44 (d) , 1H), 5-8-6.0 (ra, 1H), 6.88 (s, 1H), 7.24 (m, 1H). 1.42 (s, 3H), 1.68 (s, 3H), 2.46 (s, 1.5H), 2.5 (s, 1.5H), 3.82 (s, 3H), 4.52 (s, 3H), 4.6 (2dd, 1H) , 4.7 (m, 2E), 5.2-5.7 (m, 4H), 5.8-6.05 (m,

1K), 7.0-7.3 (m, 2H), 7.4-7.7 (m, 1H). (8R) -isomers:

1.44 (s, 3H), 1.64 (s, 3H), 2.32 (s, 1.5H), 2.4 (s, 1.5H), 3.6 (s, 1.5H), 3.64 (s, 1.5H), 4.36 ( s, 1H), 4.4 (dd.

(EXXII) ¹³ (6β, 8S)

1H), 4.6 (m, 2H), 5.2-5.5 (m, 4H), 5 8- < 5.0 (m, 1H), 6.8-7.2 (ra, 2H), 7, 2-1 1.6 (m, 1H). 1.32 (S, 3H), 1.58 (s, 3H), 3.66 (s, 3H), 3.7 Δ (s, 3H), 4.46 (s, 1H), 4.52 (Dd, 1H) , 4.6 (d, 1H), 5.2-5.4 (m, 37), 5.5 (d, 1H), 5.8-6.0 (m, 1H), 6:48 (D, 1H), 6.86 (dd, 1H), 7.43 (d, 1).

(BXXIII)

10 1:46 (S. 3H), 1.66 (s, 3H), 3.66 (s. (6β, 8R) 3H), 3.8 (s, 3H), 4.4 (ra, 2H), 4.64 (D, 2 H) , 5.2-5.4 (ra, 3H), 5.62 (d, 1H), 5.82 -6.0 (m, 1H), 6.58 (d, 1H), 6.8 (Dd, 1H), 7.5 (d, 1H). 24 1:28 (S. 3H), 1.54 (s, 3H), 3.68 (s, (6β, 8S) 3H), 3.72 (s, 3H), 4.4 (s, 1H), 4.52 (Dd, 1H), 4.56 (m, 2H), 5.1-5.4 (ra, 3H), 5:48 (d, 1H), 5.76-5.9 (m, 1H), € .8 (Dd. 1H), 6.96-7.1 (m, 1H), 7.28 also, 1H). 15 1:46 (S, 3H), 1.66 (s, 3H), 3.7 (s. (6β, 8R) ΞΗ), 3.8 (s, 3H), 4.4 (s, 1H), 4.4 (Dd, 1H), 4.64 (d, 2H), 5.2-5.4 (m, 7H), 5.4 (d, 1H), 5.5 (d, 1H), 5.8-6U ', M 1H), 6.8-7.0 (m, 1H), 7.1-7.25 (m l.H), 7:28 (s, 1H).

-27194891

54

Production Stereo ¹ H-NMR (OMSO-d 6) ppm (delta):

% Chemistry (XLIII) (LX)

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).

8S (D ₂ 0): 1.32 (s, 3H), 1.54 (s, 3H), 4.18 (s, 1H), 4.14-4.19 (m, 1H), 5.19 (d, 1H),

5.25 (d, 1H), 7.45 (t. 1H), 8.75 (d, 2H).

(LX) Isomer B 95 8R (0 0) 144, {s , 3H), 1. 58 (s 4.18 (m, 1H), 4.12 (e, 1H), (D. 1H; . 5.49 (d, 1H), 7.46 1H), 8, 75 (d, 2 H). (XLVIII) 97 8R 1, 47 (s> 3H), 1.58 (s, 3H), 3, 79 (s, 1H), 4.13 (dd, 111) (D, 1H), 5.4 (d, 1H), 5.95 7.45 (T. 1H), 7.60 (t, 2H), 8, 03 (D, 2 H) , 8.16 (S, 1H). (XLVII) 85 8S 1, 43 (s, 3H), 1.67 (s, 3H), 4.27 (dd , 3 = 4 and 10 1H), 4.3 (ε, 11-1), 5.45 (d, 3 = 4, 1H), 6.57 (d, 3 = 10, 1H), 7.45 -7, 65 (m, 2H), 8.04 (t,

3 = 8, 2H).

IR (KBr): 3424, 1765, 1746, 1592 cin ^"first

(XLVII)

8R, 42 (s, 3H), 1.56 (s, 3H),

4.16 (s, 1H), 4.25 (dd, 3 = 4, and 8, 1H), 5.46 (d, 3 = 4, 1H), 5.5 (d, 3 = 8, 1H) ), 7.4-7.6 (m, 2H), 7.8-3.05 (m, 2I ()).

-28194891

Stereo- ¹ H-NMR (D 2 O) ppm (delta) chemistry

R

Production *

(IXIV) 87 (raw) 34 (cleaned) solid. 8S (LXV) 59 (6β, 8S) (IXV) 30 (6B, 8R) (IX VI) 40 (6B, 8R) (LXVI) 90 (6B, 8S) (IX VII) 75 - (LXIII) 22 yellow solid 98% pure, (HPLC) (6β, 8S)

1:26 (S, 3H), 1.48 (s , 3H), 3.76 (S, 3H), 4.16 (s , IH), 4:36 (dd , IH) , 5.3-5. 45 (m, 2 H) , 7.2 -7.3 (m, 2H), 7.3~7.6 (M, 2 H) . 1.4- 1:45 (M. 6H), 1.6 (s, 3H) 4.3 (S, IH), 4.3-4.75 (m, 3H)

5.4-5.6 (m, 2H), 7.3-7.5 (m, 2H), 7.6 (d, 1H), 7.7 (d, 1H).

1.3-1.5 (m, 3H), 1.58 (s, 3H), 1.65 (s, 3H), 4.25 (s, 3H),

4.3-4.5 (m, 2H), 4.65 (dd,

IH) , 5.56 (d, 1H) , 5.65 (d IH) , 7.4 (m, 2H), 7.6-7. 8 (M, 2 H) . 0.9 (t, 3H), 1.6 (s, 3H) f 1.72 (S, 3H), 1.8-2.0 (m, 2H) t 4:26 (S, 1H), 4.2-4.4 (m, 2H) r 4.65 (dd , 1H), 5.56 (d , IH), 5th 7 (D, 1H), 7.3-7.5 (m, 2H) r 7.67 (D, 1H), 7.79 (d. IH).

IR (KBr) cm ^-1 : 3423, 1748,

1599 • 0.95 (T, 3H) , 1.42 (s, 3H), 1.62 (S, 3H) 1-9 (m, 2H), 3:39 (S, IH) , 4.3 (m, 2H), 4.5 (Dd. IH) , 5. 4-5.6 (m, 2H), 7.3- ' 7.5 (M, 2H), 7 .6 (m, 1H), 7.7 (M, IH). IR (K1 Br) -1 cm : 347 3, 1756, 1604 1:44 (S, 3H) , 1.6 (s, 3H), 4:26 (S, 3H) , 4.32 (dd, 1H), 5:46 (D, IH) , 5.5 (d, 1H),

7.4-7.8 (m, 4H). IR (KBr) cm ^-1 : 3422, 1763, 1609th 1.44 (s , 3H), 1.64 (s, 3H), 3.84 (s , 3H), 4.22 (dd, 1H) r 4.28 (s , 1H), 5.4 (d, 1H), 5.5 (d, 1H) , 7.1 (m, 1H), 7.42 (D, IH), 7: 82 (d, 1H). IR (KBr) cm ' ¹ : 3442, 1762,

1743, 1589.

-29194891

Production

Stereo ¹ H-NMR (D 6 O 4 ppm) chemistry

(1XVIII) (6β, 8S) and (6β, 8R) h: 1 a mixture of 1.4 (s, 2.4H) 1.54 (s, 0.6H) 1.62 (s, 2.4H), 1.64 (s, 0.6H), 3.72 (s, 0.6H), 3.75 (s, 2.4H), 4.2 (s, 0.2H), 4.2! (s, 0.8H), 4.32 (dd, 0.8H), 4.46 (dd, 0.2H), 5.26 (d, 0.8H), 5.3 (d, 0.2H), 5.38 (d 0.8H), 5.6 (d, 0.2H), 6.97 (s 0.8H), 7.00 (ε, 0.2H), 7.15 (s, 1H). IR (KBr) cm ^-1 : 3452, 1757, 1663. (LXIX) 93 (6β, 8S) 1.42 (s, 3H), 1.62 (s, 3H), 3.72 (s, 3H), 4.28 (s, 1H), 4.42 (dd, 1H). (LXIX) 88 (6β, ar.) 1.55 (s, 3H), 1.7 (s, 3H), 3.7 (s, 3H), 4.24 (s, 1H), 4.48 (dd, 1H), 5.4 (d, 1H), 5.63 (d, 1H), 7.2- 7.5 (m, 3H) 7.7 (d, 2H). IR (KBr) cm ^-1 : 3395, 1756, 1603. (LXX) 100 white, solid material (6β, 83) 1.3 (s, 3H), 1.5 (s, 3H), 2.1 (s, 3H), 2.16 (s, 3H), 3.7 (s 3H), 4.2 (s, 1H), 4.36 (dd, 1H), 5.36 ( d, 1H), 5.4 (d, 1H), 7.08 (s, 1H), 7.3 (s, IH). (LXX) 93 yellow, solid. material (6β, 8R) 1.46 (s, 3H), 1.6 (s, 3H), 2.22 (s, 3H), 2.26 (s, 3H), 3.68 (s, 3H), 4.12 (s, 1H), 4.46 (dd, 1H), 5.44 (d, 1H), 5.56 (d, 1H), 7.2 (s, 1H), 7.36 (s, 1H). (LXXIV) + (LXXV) 15 (6β, 8S) 1.32 (s, 3H), 1.54 (s, 3H), white, and 2.36 (s, 1.5H), 2.38 (s, solid (66, 8R) 1.5H), 3.76 (s, 3H), 4.2 (s, 30 material isomers a mixture of 1H), 4.36 (dd, 1H), 5.4 (d, 1H), 5.42 (d, 1H), 7.06-7.6 (m, 3H). IR (KBr) cm- ¹ : 3445, 1747, 1604.

-30194891 ¹ H- ¹ IMR (D ₂ O) ppm (delta)

Production

Stereochemistry

(LXXIV) 80 (6β, 81 ') 1.54 (s, 3H), 1.66 (s, 3H), yellow, 2.4 (s, 1.5H), 2.44 (s, solid 1.5H), 3 .77 (s, 3H), 4.22 <s (LXXV) material (6β, 8i) 1H), 4.54 (dd, 1H), 5.52 (d, 1H), 5.64 (d, 1H), 7.1-7.7 (m, 3H). IR (KBr) 1602nd cm ^-1 : 3412, 1757, (LXXII) 100 yellow, solid material (6β, 8S) 1.35 (s, 3.84 (s, 4.23 (s, 5.4 (d, 3H), 1.57 (s, 3H), 3H), 3.88 (s, 3H), 1H), 4.37 (dd, 1H), 1H), 5.44 (d, 1H), 6.48 (dd , 1H), 7.12 (d, 1H), 7.57 (d. 1H). 100 (6β, 8R) 1.48 (s, 3H), 1.6 (s, 3H), (LXXII) yellow, 3.78 (s, 3H), 3.86 (s, 3H), solid 4.16 (s, 1H), 4.5 (dd, 1H), material 5.48 (d, 1H), 5.58 (d, 1H), 6.96. (dd , 1H), 7.1 (d, 1H), 7.56 (d, 1H). (LXXII) 80 (6β, 8S) 1.35 (s. 3H), 1.56 (s, 3H), yellow, 4.24 (s. 1H), 4.38 (dd, 1HJ, solid 5.20 (d. 1H), 5.22 (d, 1H), material 7.04 (m, 1H), 7.22 (m, 1H), 7.48 (d, IR (KBr) < 1610th 1H). cm ^-1 : 3411, 1747, (LXXII) 87 (6B, 8R) 1.5 (s,: 3H), 1.63 (s, 3H), yellow, 3.78 (s, 3H), 3.84 (s, 3H), solid 4.18 (s, 1H), 4.5 (dd, 1H),

5.5 (d, 1H), 5.6 (d, 1H), 7.0 (dd, 1H), 7.2 (d, 1H), 7.42 (d, 1H).

Example 25

Allyl 6-alpha - ((N-methylpyrrol-2-yl) -hydroxy-55-methyl) -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 30

A solution of methyl magnesium bromide (2.85 M in tetrahydrofuran) was added and the reaction mixture was stirred at -78 ° C for 5 minutes. Then 162 mg (0.16 ml) of N-methylpyrrole-2-carboxaldehyde was added, and 20 minutes at -78 ° C for ₅ q

and poured into saturated ammonium chloride solution. 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 column chromatography on silica gel 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), 4.0-4.4 (m, 1H), 4.42 (s, 1H), 4.5-4.8 (m, 3H), 5.0-6.0 (m, 4H), 6.0-6.7 (m, 3H).

-31194891, the corresponding compounds of general formula (LXXVI) are prepared.

Example 26

Using the aldehyde R ¹³ CHO as starting material, Example 25 was used

R ¹³ Production Silica gel eluent ¹ H-NMR (CDCl 3) ppm (delta)

(LXXVI Γ) 30 THE 6-alpha isomer: 1.4 (s, 0.39H), 1.5 (s, 2.61H), 1.62 (s, 0.39H), 1.7 (s, 2.61H), 3.0 (broad, 1H), 4.0-4.4 (m, 1H), 4.45 (s, 1H), 4.5-4.9 (m, 2H), 5.16.1 ( m, 4H), 6.3-6.6 (m, 2H), 7.45 (m, 1H); (LXXVII) 6 THE 6-alpha-blend; 8R and 6-alpha, 8S isomer (LXXVIII) 38 THE 1.4 (s, 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, 3H), 5.1-6.0 (m, 4H), 6.0-7.2 (m, 4H). phenyl 78 THE 1.4 (s, 3H), 1.6 (s, 3H), 3.28 (bs, 1H), 3.8-4.2 (m, 1H), 4.35 (s, 1H), 4 , 45-4.48 (m, 3H), 5.0-6.1 (m, 4H), 7.3 (s, 5H). (LXXLX) 33 B 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, Ή), 7.6-8.0 (m, 1H), 8.2-8.7 (m, 2H). (LXXX) 35 B 1.3 (s, 3H), 1.55 (s, 3H), 4.0 (m, 1H), 4.35 (s, 1H), 4.4-6.8 (m, 3H), δ , 1-6.2 (m, 4H), 7.2-7.5 (m, 2H), 8.2-8.6 (m, 2H). (LXXXI) 50 B 1.25 (s, 0.75H), 1.35 (s, 2.25H), 1.55 (s, 3H), 3.3 (bs, 1H), 4.05 (dd, 1H), 4 , 3 (s, 1H), 4.3-4.8 (m, 3H), 5.0-6.2 (m, 4H), 6.8-7.4 (m, 3H). vinyl 21 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). (XLIV) 25 D 1.36 (s, 1.5H), 1.40 (s, 1.5H), 1.60 (s, 1.5H), 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). (LXXXII) 52 D 6-alpha, 8S isomer: 1.4 (s, 3H), 1.6 (s, 3H),

-32194891, 1 3

64

Production ¹ H NMR (CDCl ₃ ) ppm (delta) on silica gel * (LXXXXI) 42

4.38 (dd, 1H), 4.43 (s, 1H), 4.67-4.75 (m, 2H), 4.76 (d, 1H), 5.3-5.5 (m, 2H), 5.63 (d, 1H), 5.856.05 (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), 7.75 (d, 1H).

E 6 alpha, 8S isomer: 1.44 (s, 3H), 1.62 (s, 3H), 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,

13), 8.14 (m, 2H), IR:

3 '+ 82, 1802 cm' ¹ .

Example 18 (continued)

R ¹³ Rolled silica ^1H-NMR _(CDCl3) ppm (delta): % eluting * (LX) 57 crude A / minor Less polar 6-wall, 8 LP polar Isomer 83: 1.41 (s, 3H), 8 MP isomer / 1.6 (s, 3H), 4.45 (s, 1H), F / poláro- 4.4-4.8 (m, 4H), 5.2-5.6 sabb iso- (m, 3H), 5.7-6.3 (m, 1H), mer / 7.35 (t, 1H), 8.85 (d, 2 H) . 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 (η, 2H), 4.95 (d, 1H), δ , 2-5.6 (m, 3H), 5.7-6.3 (η, 1H), 7.35 (t, 1H), 8.85 (d, 1H), (XLII) 25Z, Fraction 1-D Fraction 1 ': 1.4 (s, 3H), (one 1.6 (s, 3H), 4.2-4.4 (m, isomer) 211), 4.5-5.0 (m, 3H), 12Z, Fraction 2 5.1-6.1 (m, 6H), 7.6 (d, cation (2 iso- 1H), 8.87 (d, 1H), 9.23 dare to mix) (s, 1H). (XLIII) 56 D 1.4 (s, 3H), 1.57 (s, 3H), 70:30 4.25 (m, 1H), 4.37 (s, isomeric 0.7H), 4.42 (s, 0.3H), smote 4.75 (m, 2H), 4.8 (d,

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66

Example 18 (continued)

R ¹³ Expanded Silica Gel (NMR (CDCl ₃ )) ppm (delta):

% eluent *

0.3H), 4.85 (d, 0.7H), 5.25-5.5 (m, 3H), 5.9 (Irish, 1H), 8.52 (m, 2H), 8.84 (ra, 1H). (LXXXIV) ** 22 D 1: 2 isomeric mixture 1.4 (s, 1H), 1.46 (s, 2F), 1.6 (s, 1H), 1.63 (s, 2H), 4.12 (m, 1H), 4.22 (m, 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 (η, 1H), 6.95 and 7.05 (s, 1H), 7.28 and 7.36 (s, 1H). (LXXXV) 35G 1.38-1.40 (d, 3H), 1.56-1.57 (d, 3H), 4.20-4.40 (m, 2H), 4.59-4.72 (m, 211). ), 4.86-4.88 (d, 0.5H), 5.04-5.06 (d, 0.5H), 5.26-5.42 (m, 2H), 5.505.62 (m). , 1H), 5.82-6.00 (π, 1H), 7.50-7.86 (m, 1Η), 7.90-8.08 (m, 1H), 9.02-9, 10 (m, 1H). IR (KBr) cm ^-1 : 1800. (XLIII) h6 A isomer mix 1.34 (s, 3H), 1.52 (s, 3H), 3.8 (s, 3H), 4.4 (m, 1H), 4.5 - 4.7 ( ^m , 2H), 4 , 9 (d, 1H), 5.2 - 5.5 (m, 3H), 5.66 (broad s, 1H), 5.7 - - 6.0 (m, 1H), 7.0 (dd) , 1H), 7.2-7.3 (m, 1H), 7.82 (d, 1H).

= Starting aldehyde: 1- (diethoxymethyl) imidazole-2-carboxaldehyde.

= A: chloroform / ethyl acetate (9: 1); B: ethyl acetate / chloroform (7: 5) C: chloroform / ethyl acetate (19: 1) D: chloroform / methanol (19: 1.) E: chloroform P: chloroform / ethyl acetate (1: 1) G: ethyl acetate.

-34194891

Example 27

Preparation of Pivaloyloxymethyl Esters

A) To a solution of 470 mg (1.28 mmol) of potassium 6- (isothiazol-3-yl) methylene-1,1-dioxopenylglylanate in 2 mL of dimethylformamide was added 0.18 mL (1.28 mmol) of chlorine. methyl pivalate was added at room temperature. The mixture was stirred overnight, poured into water and extracted with ethyl ether (3 x 20 mL). The extracts were dried over anhydrous sodium sulfate and the solvent was evaporated to give 500 mg (88%) of a dark orange oil. The product was chromatographed on a silica gel column using chloroform-ethyl acetate 9: 1 as eluent. Pureoyloxymethyl-6- (isothiazol-3-yl) methylene-1,1-dioxopenicillanate (315 mg, 55%) was obtained as a clear oil.

1 H NMR (CDCl ₃ ), ppm, delta:

1.22 (m, 0.9H), 1.5 (s, 3H), 1.6 (s, 3H),

4.44 (s, 1H), 5.65 (s, 1H), 5.84 (AB, quartet, 2H), 7.36 (s, 1H), 7.38 (d, 1H),

8.72 (d, 1H).

B) By the above method, pivaloyloxymethyl 6 - [(3-methylbenzimidazol-2-yl) hydroxymethyl] penicillanate was prepared from the corresponding potassium salt as a tan solid in 61% yield.

1 H NMR (CDCl ₃ ), ppm, delta:

1.2 (s, 9H), 1.42 (s, 3H), 1.64 (s, 3H),

3.84 (s, 3H), 4.5 (s, 1H), 4.58 (dd, 1H),

5.46 (d, 1H), 5.6 (d, 1H), 5.82 (AB, quartet, 2H), 7.24 (m, 3H), 7.7 (m, 1H).

Example 28

Benziloxazol-2-carboxaldehyde

The title compound was prepared from methyl benzoxazole-2-carboxylate. Yield: 35% yellow oil.

1 H-Nuclear magnetic resonance spectrum (CDCl ₃ ), ppm, delta 7.3 -

8.1 (m, 4H), 10.0 (s, 1H).

The above starting material was prepared from 0-aminophenol in two steps. First, a molar equivalent of oxalyl chloride is reacted in m-dichlorobenzene at reflux (about 185 ° C) to give 2,3-dioxobenzoxazolidine in near quantitative yield. This is then reacted with a small excess of thionyl chloride under reflux in benzene, and the resulting 3-chloro-2-hydroxybenzoxazine is treated with an equivalent amount of sodium bicarbonate in methanol under reflux overnight to give the desired product. methyl benzoxazole-2-carboxylate, m.p. 101-102 ° C.

1 H-Nuclear Magnetic Resonance Spectrum (CDCl ₃ ), ppm, delta: 4.05 (s, 3H), 7.3-8.0 (m, 4H).

Example 29

i) Oxidation of 6-Methoxy-2-methylbenzothiazole

6-Methoxy-2-methylbenzothiazole (10.0 g, 55.9 mmol) was oxidized with 6.2 g (55.9 mmol) of selenium dioxide in 300 mL of dioxane for 6 hours to give 6.0 g of 6-methoxy- 2-Formylbenzothiazole is obtained and the crude product is purified by chromatography on silica gel using chloroform as eluent.

1 H NMR (CDCl ₃ ), ppm, delta:

3.9 (s, 3H), 7.1-7.5 (m, 2H), 8.0-8.3 (m, 1H), 10.1 (s, 1H).

Example 30

i) 2-Formyl-3-methylbenzimidazole

12.6 g (0.086 mol) of 3-methylbenzimidazole

To a solution of 100 ml of tetrahydrofuran at -78 ° C was added 34.3 ml of a 2.5 M solution of n-butyllithium in 30 minutes and the mixture was stirred for 20 minutes. 3-Methylbenzimidazole was prepared by reacting benzimidazole in dimethylformamide with an equivalent amount of sodium hydride and methyl iodide for 2 hours at room temperature. The mixture was poured into water, acidified with concentrated hydrochloric acid and extracted with ethyl acetate (95% yellow oil).

To the above mixture was added 6.95 ml (0.086 mol) of ethyl formate over 5 minutes and stirring was continued for another 1 hour. Acetic acid (4.92 mL, 0.086 mol) was added, the temperature was raised to 10 ° C, and the mixture was poured into water (300 mL) and extracted with EtOAc (3 x 200 mL). The extracts were dried over anhydrous sodium sulfate, the solvent was evaporated, and the resulting yellow residue was triturated with ethyl ether to give 4.4 g of a pale yellow solid, which was evaporated to a volume of one third to give a total of 1.65 g. 6.05 g (44%). 1 H-NMR (CDCl ₃ ), δ ppm:

4.1 (s, 3H), 7.1-7.45 (m, 3H), 7.6-8.0 (m, 1H), 10.1 (s, 1H).

ii) 3-Formyl-3-ethylbenzimidazole

The title product by the above procedure,

Obtained from 3-ethylbenzimidazole. Yield: 67% after purification by silica gel column chromatography.

1 H NMR (CDCl ₃ ), ppm (delta):

1.4 (t, 3H), 4.55 (q, 2H), 7.2-7.5 (m, 3H), 7.91 (m, 1H), 10.1 (s, 1H).

iii) By the above method, 2-formyl-3-n-propylbenzimidazole is obtained in 25% yield.

3-n-propyl-benzimidazole.

1 H NMR (CDCl ₃ ), ppm, delta:

0.8 (t, 3H), 1.78 (m, 2H), 4.4 (t, 2H),

7.1-7.5 (m, 3H), 7.6-8.0 (m, 1H),

10.1 (s, 1H).

The procedure described above gave 8.14 g (0.051 mol) of 3-methyl-5-phenylimidazole in 43% yield as 2-formyl-3-methyl-5-phenylimidazole as a colorless solid.

v) The above methods were prepared to give 2-formyl-3,5-trimethylbenzimidazole in 44% yield.

1 H NMR (CDCl ₃ ), ppm, delta:

2.4 (s, 6H), 4.0 (s, 3H), 7.15 (s, 1H),

7.6 (s, 1H), 10.0 (s, 1H).

The starting material 3,5,6-trimethylbenzimidazole is 5,6-dimethylbenzene 35

-35194891 is obtained by methylation of imidazole with methyl iodide and sodium hydride in dimethylformamide.

¹ H-Nuclear magnetic resonance spectrum (CDCl ₃ ), ppm, delta:

2.45 (s, 6H), 3.8 (s, 3H), 7.2 (s, 1H),

7.6 (s, 1H), 7.8 (s, 1H).

Example 31

Mixture of 1,5-dimethyl-2-formylbenzimidazole and 1,6-dimethyl-2-formylbenzimidazole

i) 1,2-Bis (5-methyl-benzimidazol-2-yl) ethylene glycol

A mixture of 15.0 g (0.1 mol) succinic acid in 29.32 g (0.24 mol) 3,4-diaminotoluene, 25 ml water, 15 ml ethanol, 25 ml concentrated hydrochloric acid and 10 ml 85% phosphoric acid After heating at 120 ° C for 40 hours, the reaction mixture was poured into water and acidified with concentrated hydrochloric acid. The reaction mixture was extracted with chloroform and the aqueous layer was made basic with sodium hydroxide and the resulting precipitate was collected by filtration. This was washed with a small amount of acetone and kept under vacuum for 18 hours. The residual moisture is separated by azeotropic distillation of the mixture with Bezol.

ii) 2.0 g (6.17 mmol) of the above product are dissolved in 50 ml of dimethylformamide and 0.592 g (12.3 mmol) of 50% sodium hydride are added portionwise over 30 minutes. After stirring for a further 30 minutes, methyl iodide (0.760 mL, 12.3 mmol) was added and stirring was continued for 18 hours at room temperature. The mixture was poured into water, acidified to pH = 2 with hydrochloric acid and extracted three times with chloroform. The aqueous phase was made basic with sodium hydroxide and extracted with chloroform to give 640 mg of an off-white solid, which was the 1,2-bis (1,5 / 6'-dimethylbenzimidazol-2-yl) ethylene a mixture of glycol isomers.

iii) To a suspension of the product obtained in the previous step (4.80 g, 12.5 mmol) in 160 mL of 1 N sulfuric acid was added 2.68 g (12.5 mmol) of sodium metaperiodate and the mixture was stirred for 18 hours at room temperature. The mixture was then adjusted to pH 7.5-8.0 with sodium bicarbonate, extracted with ethyl acetate, the extracts dried over anhydrous magnesium sulfate and the solvent was evaporated to give 3.77 g. A mixture of 5-dimethyl-2-formylbenzimidazole and the corresponding 1,6-dimethyl compound. The isomeric mixture was further processed without further purification.

iv) Methylation of 1-methyl-5-methoxy-2-formylbenzimidazole and 1-methyl by the methylation and 4 A mixture of 6-methoxy-2-formylbenzimidazole isomers was obtained, which was chromatographed on a silica gel column eluting with chloroform-ethyl acetate (19: 1).

- ^{methyl-6-methoxy-2-fc-r} rpil benzimidazole Ή NMR (Cl) C 1 -C ₃₎ ppm delta:

3.8 (s, 3H), 4.05 Is, 3H), 6.0-7.2 (m, 1H), 7.6-7.9 (m, 1H), 10.0 (s, 1H).

methyl-5-methoxy-2-formyl-benzimidazole Ή NMR (CDC1 ₃₎ ppm delta:

3.9 (s, 3H), 4.1 (s, 3H), 7.05-7.5 (m, 3H), 10.1 (s, 1H).

Claims (5)

Patent Claim Point A process for the preparation of compounds of formula II wherein n is 0 or 2, X ^{3 is} hydrogen or bromine, R ¹ is hydrogen or R ', wherein R is allyl, benzyl, (C1-C4) alkylcarbonyl oxymethyl or benzhydryl, and R ^{18 is} hydrogen, C 2 -C 5 alkanoyl, C 2 -C 5 alkoxycarbonyl, pyrazinylcarbonyl, or benzoyl, One of R ¹² and R ¹³ is hydrogen and the other is vinyl, phenyl, furyl, thienyl, N-methylpyrrolyl, N-acetylpyrrolyl, pyrimidinyl, pyrazinyl or pyridazinyl or ( XXVI), (XXVII), (XXXI), (XXXII), (XXXIII), (XXXIV) or (XXXVI), t is 0, 1 or 2, X 1 is sulfur or oxygen or = NR '', R ^{7 is} hydrogen, C 1-4 alkyl, C 1-4 alkoxy or phenyl, R is hydrogen, methyl, ethyl, n-propyl or acetyl, and the pharmaceutically acceptable salts thereof, wherein a) a compound of formula X wherein R ¹ is R 0 and n is as defined above, C 1 -C 4 alkyl-magnesium halide or C 1 -C 4 alkyl-lithium reagent and aldehyde of formula (V) - wherein the halide is chloride, bromide or iodide, and R ¹² and R ¹³ are as defined above in the reaction; in a solvent at a temperature of from -100 ° C to + 25 ° C, and if desired, forming the compound of formula XI wherein R ¹² , R ¹³ and n are as defined above and R ¹ R ^a is a compound of formula II, which R ' ⁸ is other than hydrogen and X' is bromine, The acid chloride or acid bromide of the formula R ¹⁸ Cl or R ¹⁸ Br or the corresponding sevanhydride in the presence of a tertiary amine in a reaction inert solvent; and, if desired, for the preparation of compounds of formula II wherein X ^{3 is} hydrogen, R ^{1 is} R ^a , R ¹² , R ¹³ , R ⁸ and na, a compound of general formula (II) formed is (II) wherein X ³ is bromine and is hydrogenated with R ¹ , R, R ¹³ , R ¹⁸ and the like in the above reaction solvent, using an organic tin hydride or noble metal catalyst and hydrogen gas; and the desired case; for the preparation of compounds of formula II wherein n is 2, the resulting compound of formula II wherein n is 0 with an alkali metal or alkaline earth metal permanganate, Oxidized with 3-chloroperbenzoic acid 1 or peracetic acid, or b) a compound of formula IX wherein R ¹ is R 'in equimolar amounts of 1- With C4 alkylmagnesium halide and an aldehyde of formula V where R ' ² and R ^{13 are} as defined above, in an ethereal solvent at a temperature of -80 to 25 ° C, and optionally, a compound of formula II where R ¹⁸ is other than hydrogen, π is 2, R ¹ is R ^a , and R ¹² and R ^{13 are} the above compounds of formula IV, wherein R ¹ is R 0, and R ¹² and R ^{13 are} as defined above. given, R ¹⁸ Cl or R ¹⁸ Br is acylated with an acid clod or acid bromide or an appropriate acid anhydride in the presence of an equimolar amount of terrieramine in an inert solvent and optionally from a compound of formula II obtained by a) or b). in which R ¹ is R is ^a carboxy protecting group which is cleaved and optionally converted to the resulting free compound ester or, if desired, the resulting free compound into a pharmaceutically acceptable salt thereof. 11 pages with drawing pictures