DE2615621A1 - Beta-lactam antibiotics - and beta-lactam precursors of penicillins and cephalosporins - Google Patents

Abstract

beta-Lactam precursors for penicillins and cephalosporins are prepared by (a) reaction of a condensation prod. of an L-cysteine-contg. protected polypeptide with a peroxy-activating agent selected from diazyl peroxides, diaroyl peroxides, aroyl perxyesters and their mixts. so as to activate the C-atom of the L-cysteine with is alpha to the S-atom; (b) substitution of the activated ring C-atom with bromide, iodide, alkysulphonate or arylsulphonate; and (c) removal of the substituent in the presence of a strong base in an aprotic medium to form the beta-lactam. Novel beta-lactam cpds. are those of formula (I): (where A is H or a group -S-CHR10-CO-R11; B is H or 1-7C alkyl, alkylthiomethyl (substd.)phenyl, 5-(protected amino)-5-carboxyvaleramido, 5-amino-5-carboxyvaleramido, carboaryloxy, carbalkoxy or trifluoroactyl; R6 is (esterified) OH or halogen; R7 and R8 are H, 1-4C alkyl or 1-4C alkoxy; R9 is -CR6R7R8, -CH8=CR7 R12 or R10 is H or 1-4C alkyl; R12 is H, 1-4C alkyl, 1-4C alkoxy, halogen, (substd.) phenyl (substd.) naphthyl; Z is halogen, CN NO2;-OR1 is CF3, alkylsulphonyl, arylsulphonyl, acyloxy or aroyloxy; and n is O, e.g. methyl12-/3-benzamido-2-oxo-4-(2-oxopropylthio)-1-azetidinyl/3-me- thyl-3-butenoate. The new process yields intermediates for antibiotic penicillins and cephalosporins active against staphylococci, streptococci and bacilli. Cpds. (I; A = -S-CHR10-CO-R11) are useful as intermediates for penicillins, cephalosporins and other beta-lactams with antibiotic activity. (I; A=H) and (II) are antibiotically active.

Description

ß-lactam antibiotics and intermediates and their manufacturing process The invention relates to new β-lactam precursors for cephalosporins, penicillins and ß-lactams as well as new ß-lactam antibiotics.

At present, penicillins and cephalosporins from mushrooms, mainly Penicillium chrysogenum or cephalosporium sp. And obtained as natural products.

It was assumed as a hypothesis that polypeptides, especially tripeptides, which in their structure contain the amino acids L-cysteine and D-valine, precursors are for penicillins or cephalosporins. The experimental Material, however, was not suited to the correctness of these hypotheses with sufficient Proof of accuracy.

On a process for the complete biosynthesis of penicillins and cephalosporins consists of readily available raw materials the production of natural penicillins and cephalosporins with the help of mushrooms extraordinary interest because of those in natural penicillins and cephalosporins feasible modifications of the structure due to the relative sensitivity their structure are very limited.

For this reason, great efforts must be made at present in the implementation the synthesis of modified penicillins and cephalosporins to protect a given Part of the chemical structure is undertaken against the reaction conditions, necessary to modify the other part of the chemical structure; this requires undesired additional reaction and separation steps to achieve modified penicillins and cephalosporins.

On the other hand, if a complete biosynthetic process is available for this would be available, it would be possible to be a direct precursor to what is desired Penicillin with the desired substitution before the formation of the 7-oxo-4-thia-1-azabicycl [3.2. ou to form heptane rings.

Such precursors are also important in terms of their implementation antibiotically effective ß-lactams with a high antimicrobial effect, in particular against Pseudomonas, of great interest.

The invention specifies new β-lactam precursors for penicillins, cephalosporins and antibiotic β-lactams of the formula I and the corresponding manufacturing processes.

in the formula: A is hydrogen or and B hydrogen or with R, R1, R9, R10 and R11 as defined below.

If A, B and R in formula I are hydrogen, the resulting compound corresponding to formula II represents with R13 as defined below represents a precursor for antibiotic active ß-lactams.

If A and B correspond to formulas Ia and Ib, respectively, the resulting compound is of formula III a precursor for penicillins, cephalosporins and antibiotic effective ß-lactams.

The compounds according to the invention are produced from a polypeptide which contains in its structure the condensation product of L-cysteine, in particular a dipeptide containing a trcysteinylvalyl dipeptide.

The L-cysteine residue is initially formed with the formation of the thiazolidine ring protected. Then the ring carbon atom adjacent to the sulfur atom becomes CH2 by reaction with a diacyl peroxide, a diaroyl peroxide, an aroyl peroxy ester or an acyl peroxyester activated, whereupon a ring closure adjoins to ß-lactam; included herein are those disclosed in U.S. Patent Application 567,046 of April 10, 1975 described ß-lactams included.

The ß-lactam is then combined with an activating peroxy compound reacted to a ß-lactam sulfoxide, which then with sulfuric acid and a Dialkylacetamide for ring opening and formation of the corresponding ketosulfide for reaction is brought. The ketosulfide becomes a compound of formula VIII by a stepwise process Reaction with diazomethane, a Lewis acid and a peroxy activating agent implemented. The conversion of the compound of formula III to penicillin takes place through Oxidation to the corresponding sulfoxide, which reduces to the corresponding penicillin will. The penicillin can be converted into a cephalosporin by conventional ring expansion being transformed.

The conversion of the compound of the formula III to the compound of the formula II is made by desulfurization with a Raney nickel catalyst, the one or more steps for the removal of carboxyl and / or amino protective groups Connect according to known procedures. The amino group on the β-lactam ring can then be modified, for example by conventional acetylation Procedure.

The process according to the invention can be illustrated by the following reaction scheme: As already mentioned, the compounds of the formula III can be converted into penicillins or cephalosporins or into compounds of the formula II which are precursors of ß-lactams with antibiotic activity.

The following reaction path is used in the production of penicillins or cephalosporins: When antibiotically effective ß-lactams are produced, the following reaction route is used: The dipeptide or polypeptide used as the starting material can come from any source as long as the cysteine has the L-configuration and a second amino acid is valine or a substituted valine.

L-cysteine and valine containing suitable starting materials Tripeptides can be prepared by conventional methods.

Alternatively, the dipeptide can be used to create the compound of Formula IV by protecting the reactive sites on the sulfur and nitrogen of the L-cysteine molecule for example by reacting the L-cysteine with a ketone such as acetone to connect the Formula IV are implemented in which R4 and R5 are alkyl groups. The protected L-cysteine with nitrogen protected by acylation, whereby R1 can represent an alkyl, aryl or various alkoxy groups, then becomes with a suitable amino acid to the dipeptide of the formula V after a known condensation reaction implemented.

Among the examples of amino acids that correspond to L-cysteine Dipeptide that can be condensed include 3-hydroxyvaline, ß-alkoxyvaline, 2-amino-5-methyl -) - butenoic acid as well as vinyl glycine. The hydrogen atom of the carboxyl group of the second amino acid is thereby by a suitable acid protecting group according to a known method replaced so that the dipeptide can be further implemented according to the invention.

It should be emphasized that the sulfur and nitrogen atoms of L-cysteine is not protected from reaction with valine or another amino acid will measure. The dipeptide or polypeptide can initially be obtained by condensation of the Amino acids are made, followed by the sulfur and nitrogen atoms in the above described manner can be protected.

The peptide of formula V is then used to activate the ring carbon atom of the L-cysteine residue activated in such a way that the carbon atom subsequently with a chloride, Bromide, iodide, alkyl sulfonate, aryl sulfonate or an alkoxy or hydroxyl group can be substituted. Among the examples of suitable organic peroxides as Appropriate activating agents include diaroyl peroxides such as benzoyl peroxide, p-nitrobenzoyl peroxide or the like. and diacyl peroxides such as diacetyl peroxide or the like.

Ara.lperoxyester of the formula Ar-CO-O-O-R or acylperoxyester of the formula Alkyl-CO-O-O-R, in which Ar is a phenyl or substituted phenyl group and R is lower Alkyl group including methyl, ethyl, butyl, propyl, Hexyl or the like. mean.

For the sake of simplicity, the reaction is referred to below on the use of benzoyl peroxide explained. It should be noted that the reaction in the same way with other activating agents such as those mentioned can be carried out successfully.

The reaction is carried out in the absence of free oxygen in a inert atmosphere such as nitrogen and in an inert solvent such as carbon tetrachloride, Bromotrichloromethane, chloroform or ethylene dichloride at elevated temperature, usually in the range of about 25-100 ° C and preferably 65-75 ° C.

It is desirable to achieve a relatively complete Implementation to apply a stoichiometric excess of the peroxy compound The product corresponding to formula IV is obtained in the form of white crystals by filtration obtain. The filtrate can also be concentrated to obtain further amounts of product will.

Benzoyloxylation is highly stereospecific, with the one being desired Stereochemistry easily by pyrolytic cleavage of benzoic acid as well as by 1EI-Nt Spectrometry can be detected.

The conversion of the compound of formula VI to the compound of formula VITI can be done in two ways.

Preference is given to the direct route in which the compound of the formula VI with a non-aqueous solution of hydrogen chloride, hydrogen bromide or hydrogen iodide or an alkyl sulfonyl halide or an aryl sulfonyl halide in an inert solvent such as chloroform, carbon tetrachloride or dichloromethane is implemented. The reaction is always carried out under anhydrous conditions. The reaction temperature is about -25 to +25 0C, preferably about 0 ° C. At temperatures below about -25 0C, the reaction proceeds undesirably slowly, while at temperatures above runs about 25 0C less cleanly. The halogenated product is produced by evaporation of the solvent obtained.

According to the alternative route to the compound of formula VIII hydroxylated or alkoxylated compound of the formula VII in which R8 is hydrogen or a C1 - C7 alkyl group, initially by hydrolysis of the compound of formula VI with an aqueous mixture of an ether such as dioxane or ethylene glycol or alkoxylation of the compound with a lower alkanol such as methanol, propanol or the like. manufactured. The hydrolysis or alkoxylation is done in a sealed Vessel at elevated pressure above about 1 bar (15 psi) and a temperature between about 100 and 150 ° C.

That by removing the solvent at a temperature below 25 0 product obtained is a crystalline and somewhat unstable at room temperature Material.

The product is then in one of the above-mentioned inert Solvents dissolved and at a temperature below about 25 00, preferably below 0 OC, held.

The hydroxylated or alkoxylated product is in the halogenated, alkylsulfonated or arylsulfonated product of the formula VIII by reacting with a halide donor in the presence of a weak base in one inert solvent implemented. Preferred halide donors include alkyl sulfonyl chlorides, -bromides or iodides such as methanesulfonyl chloride, methanesulfonyl bromide, ethanesulfonyl chloride, thanesulfonyl bromide or comparable arylsulfonyl chlorides, bromides, iodides, etc. like

When the reaction takes place at relatively low temperatures in the above Temperature range is carried out, the product is with the alkyl sulfonate or Aryl sulfonate is substituted in admixture with the halogen-substituted compound. if on the other hand, the reaction is carried out in the higher temperature range predominantly the halogenated product versus the alkyl or aryl sulfonated product. In In any case, the corresponding derivatives can follow the invention β-lactam product can be cyclized. Examples of suitable weak bases are for example Trialkylamines such as triethylamine or dimethylaniline or cyclic amines including Pyridine.

Examples of inert solvents include methylene chloride, Chloroform and dichloroethylene.

The reaction is carried out at a temperature between about -25 and 0 ° C performed to relatively high yields of the halogenated, alkyl or aryl sulfonated Product to achieve. The product is processed in a suitable manner, for example by evaporation and washing with water to remove excess amine and Acids, obtained.

The ring closure of the compound of the formula VIII to the β-lactam of the formula IX is carried out in the presence of a strong base in an aprotic medium. The bases suitable for this include alkali metal hydrides such as sodium hydride or Potassium hydride as well as alkali metal alkoxides such as potassium t-butoxide.

Suitable aprotic solvents include dimethylformamide, Dimethyl sulfoxide and dichloromethane. The reaction with the base can alternatively carried out in an inert solvent with a tetra-N-alkylammonium salt will. The inert solvents suitable for this purpose include those mentioned above Solvents.

Suitable tetra-N-alkylammonium salts include tetra-N-butylammoniumJ odid, tetra-N-ethylammonium iodide and tetra-N-ethylammonium bromide.

The reaction is carried out at a temperature between about 0 and 40 ° C, preferably carried out at about 25 ° C.

The conversion of the compound of formula IX into the compound of Formula X is made by reaction with a peroxy activating agent; For this include, for example, ozone, alkali metal periodates, hydrogen peroxide in acetic acid, Peroxyearboxylic acids of the formula R-CO-OOH, where R is an aromatic hydrocarbon radical means, such as peroxybenzoic acid, m-chloroperoxybenzoic acid or the like) or where R is an aliphatic hydrocarbon group such as methyl, ethyl, propyl, butyl, pentyl, Means hexyl or the like. The reaction takes place in an inert atmosphere such as nitrogen in Absence of oxygen in an inert solvent such as Carbon tetrachloride, bromotrichloromethane, chloroform or ethylene dichloride a temperature in the range from about 0 to -80 ° C and preferably -50 to -80 ° C carried out. To achieve a relatively complete reaction, it is desirable that peroxy activating agent to use in a ssoichiometric excess.

The product corresponding to formula X is obtained by chromatography.

The reaction of the compound of the formula X to the compound of the formula III is carried out by heating with a dialkyl acetamide of the formula made, in which R10 and R11 mean a Cl - C4-alkyl group, with an acid such as sulfuric acid, a sulfuric acid derivative such as methanesulfonic acid, toluenesulfonic acid or the like. and at a temperature between about 50 and 120 ° C, preferably between about 100 and 110 ° C, performed. The product is obtained by chromatography.

If from the compound of the formula III penicillins or cephalosporins are to be produced, this is with diazomethane to the represented by formula XII Epoxy epimer implemented. The reaction is in an inert solvent at a temperature between about 0 and 20 ° C, preferably between 0 and 15 ° C, in an inert solvent such as methanol, diethyl ether, dichloromethane, methylene chloride, Tetrahydrofuran or ethanol made. The product is chromatographed as Won oil.

The compound of Formula XII becomes that represented by Formula XIII Aldehyde epimer by reaction with a Lewis acid such as boron trifluoride etherate in an inert solvent such as tetrahydrofuran, diethyl ether, chloroform, dichloromethane or the like. The rearrangement of the aldehyde epimer is carried out at a temperature between about -30 and 25 OC. The product is made by extraction and evaporation obtain.

The conversion of the aldehyde epheres to the sulfoxide of the formula XIV takes place by reaction with one of the above peroxy activating agents and below the conditions given above, being in an inert solvent such as benzene heated to a temperature between about 60 and 100 0C and preferably 70-90 0C whereupon the sulfoxide product of Formula XIV is obtained.

The deoxygenation of the sulfoxide to the corresponding penicillin becomes by a known method including by reaction with a Lewis acid such as phosphorus tribromide in an inert solvent such as dimethylformamide at a Temperature between about 78 and -10 0C corresponding to that given in US Pat. No. 5,641,014 Conditions carried out. The reaction can go through initially Dissolve of the sulfoxide in dimethylformamide and then cooling the solution in one Dry ice-acetone mixture can be carried out. The cold mixture becomes a solution of phosphorus tribromide in benzene added. After about 5 - 10 min the cold reaction mixture becomes warmed up to about -10 0C. After about 5 - 10 minutes at this temperature, the Reaction mixture worked up to give the corresponding penicillin.

The conversion of the penicillin to a cephalosporin takes place through Ring expansion by a conventional method such as heating the penicillin in an inert solvent in the presence of dipyridine phosphate, preferably with about 0.5-2.5 equivalents of dipyridine phosphate at a temperature between about 75-135 ° C and preferably 90-100 ° C. The inert ones suitable for this Solvents include dioxane, n-butyl ether, isobutyl ether or the like. It should be noted that that the ring expansion can take place before the deoxygenation, if the cephalosporin from which sulfoxide is made.

In the production of the antibiotically active ß-lactam, the Verb ndurig of the formula III to a temperature between about 20 and 80 0C in the presence a desulfurization catalyst heated, whereby the compound of the formula XVI forms. The catalysts suitable for this include Raney nickel or the like.

The reaction is carried out in an inert solvent such as ethanol, acetone, Dioxane, methanol or tetrahydrofuran through to complete proof of sales Thin-layer chromatography carried out. The product is through Filtration won.

The compound of the formula XVI is converted into the compound of the formula XVII by removing the acyl or aroyo group with phosphorus pentachloride, phosphorus oxychloride or phosgene in an inert solvent such as benzene, toluene or methylene chloride, a weak base such as pyridine, N-methylmorpholine, dimethylaniline or the like.

and adding an alcohol such as methanol, ethanol, Isobutanol or the like. convicted. The reaction will take place at a temperature between about -50 and 0 0C.

The compound of formula II is obtained by removing the amino, hydroxyl (R¹) - or carboxyl protecting groups in the radicals R and R9 by conventional methods such as obtained by hydrogenolysis. The antibiotic ß-lactam is created by acylating the compound of Formula II by known conventional methods such as in U.S. Patent 3,159,617.

In the above formulas, R represents an organic carboxyl protecting group such as a C1-C4 alkyl group, a benzyl group, a diphenylmethyl group, a 4-methoxy-diphenylmethyl group, a 3,5-dimethoxybenzyl group, a 4-methoxybenzyl group, a 3,3,3-trichloroethyl group or the like.

R1 means C1 - alkyl groups, phenyl groups, substituted phenyl groups including halophenyl, lower alkylphenyl groups, lower alkoxy and phenyl groups, hydroxyphenyl groups, alkylthiomethyl groups, 5'-amino-protected-5'-carboxyvaleramino groups or 5-amino-5'-carboxyvaleramino groups, carboaryloxy groups such as a carbobenzyloxy group, Carboalkoxy groups such as a carbotrichloroethyloxy group, a trifluoroacetyl group or the like.

R2 and R3 denote hydrogen, a C1-C7-alkyl group, a phenyl group or a substituted phenyl group as indicated above.

R4 and R5 represent a C1-C4-alkyl group.

X is chloride, bromide, iodide, alkylsulfonyl or arylsulfonyl.

R9 means and if the penicillin is generated directly, or when the cephalosporin is generated directly, or a group when the β-lactam of Formula II is generated in which Z is halogen, cyano, nitro and -OR¹ is nitro, trifluoromethyl, alkylsulfonyl, alkylsulfonyloxy, acyloxy or aroyloxy and n is an integer from 0-4.

R6 represents a hydroxyl group or an ester derivative of a hydroxyl group such as an acyloxy, benzoyloxy, or alkoxy group or a corresponding halide.

R7 and R8 denote hydrogen, a C1-C4-alkyl group or a Cl - C4-alkoxy group, R10 represents hydrogen or a Cl - C4-alkyl group.

R11 means a C1-C4-alkyl group.

R12 means hydrogen, a C1 - C4 alkyl group or a C1 - C4-alkoxy group, halogen, an aryl group or a substituted aryl group, where the aryl group is understood to mean phenyl or naphthyl.

R13 is the one resulting after the protective group has been split off shape of Rg, with the amino, carboxy and hydroxyl protecting groups removed and that ß-lactam is in the form of the free acid or a physiologically suitable salt.

In the formulas given, the term C1-C7-alkyl group relates to straight-chain and branched hydrocarbon groups such as methyl, ethyl, n-propyl, Isopropyl n-butyl, isobutyl, t-butyl, n-amyl, sec-amyl, n-hexyl, n-heptyl, and the like.

Lower C1-C4-alkyl groups include the above-mentioned hydrocarbon groups understood that contain 1 - 4 carbon atoms.

Halophenyl includes mono- or dihalosubstituted phenyl groups understood as, for example, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 2,4-dichlorophenyl, 4-bromophenyl, 4-iodophenyl, 4-fluorophenyl, 3-fluorophenyl, 3,4-dichlorophenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl and the like.

Lower alkylphenyl groups are one or two lower C1 - C 4 alkyl groups mono- or

understood disubstituted phenyl groups, for example 4-methylphenyl, 4-isopropylphenyl, 2,4-dimethylphenyl, 3-n-propylphenyl, 4-n-butylphenyl, 4-t-butylphenyl, 2,6-dimethylphenyl and the like.

Lower C1 - C4 alkoxyphenyl groups are lower mono- and di-C1 - C4-alkylphenyl ether groups understood like for example 4-methoxyphenyl, 4-isopropoxyphenyl, 2,6-dimethylphenyl, 3-ethoxy-4-methoxy phenyl, 3,4-dimethoxyphenyl, 4-n-butoxyphenyl and the like.

Among nitrophenyl groups are mono-nitro-substituted phenyl groups such as 4-nitrophenyl.

Hydroxyphenyl groups include 4-hydroxyphenyl, 2,4-dihydroxyhenyl, Understood D-hydroxyphenyl and the like.

Cyanophenyl groups are understood to mean monocyano-substituted groups such as 4-carboxyphenyl, 3-carboxyphenyl and the like.

The term lower alkoxycarbonylphenyl groups refers to lower C1 - C4 alkyl esters of carboxyphenyl groups such as 4-methoxycarbonylphenyl, 4-ethoxycarbonylphenyl, 3-isopropoxycarbonylphenyl and the like.

Under carboxyamidophenyl groups are with the carboxyphenyl group Understood amides formed, for example 4-carboxyamidophenyl.

Under protected amino groups such as protected aminophenyl groups substituted amino functions are understood in which the substituting group from the number of those groups that are generally known as amino protecting groups can be used, for example chloroacetyl, phthaloyl, t-butyloxycarbonyl, 2,2,2-trichloroethoxy 2 2 -trichloroethoxy and the like.

Z2 the examples for those mentioned above Formulas acylamido groups shown include acetamido, propionamido, phenylacetamido, Phenoxyacetamido, 2-thienylacetamido, 2-furylacetamido, 2,6-dimethoxybenzamido, 3-thienylacetamido, 3-hydroxybenzamido, 4-nitrophenylacetamido, 4-chlorophenylacetamido, 3,4-dichlorobenzamido, phenylglycylamido, mandelamido, 4-methylphenoxyacetamido and the like. like

The penicillins obtainable according to the invention from their precursors and cephalosporins can be used in doses of 5 - 500 mg / kg body weight for destruction or inhibition of the growth of staphylococci, streptococci and bacilli are used will. The β-I, actame obtainable from the precursors according to the invention can also in doses of 5 - 500 mg / kg body weight for destruction or inhibition used by Pseudomonas.

The invention thus gives ß-lactam antibiotics and intermediates of the formula at. The intermediates where A means, are used for the production of penicillins, cephalosporins and ß-lactams with antibiotic effects.

The invention is explained in more detail below with the aid of examples.

Example I The example relates to the step of activating the ring carbon atom next to the sulfur atom in the thiazolidine ring with benzoyl peroxide. Under a nitrogen atmosphere, 1.5 g of a dipeptide of the formula mixed with 3.2 g of benzoyl peroxide in 70 ml of carbon tetrachloride and held at 70ob for 90 minutes. The mixture was then cooled to room temperature and the carbon tetrachloride removed in vacuo. After removing the carbon tetrachloride, 50 ml of acetone, 1 ml of acetic acid, 5 ml of water and 5.5 g of potassium iodide were added to the residue and stirred at room temperature for 30 minutes. The mixture was again concentrated by heating to about 25 ° C., after which ethyl acetate was added for extraction. The extract was washed with a sodium bisulfite solution and a sodium bicarbonate solution, dried over magnesium sulfate and concentrated to crystals, which were separated by filtration in a yield of 0.75 g and washed with a small amount of carbon tetrachloride.

The filtrate was concentrated and the resulting bl on silica gel chromatographed, a further 0.75 g of the product (mp 193-194 ° C.) being obtained became.

Based on the spectral data, the product had the following formula: Example II The example relates to the conversion of the product of Example I to the hydroxy substituted intermediate of the formula 150 mg of the benzoate in 10 ml of 70% strength aqueous dioxane were kept at 125 ° C. for 5 hours in a sealed test tube. After cooling to room temperature, the material was extracted with ethyl acetate and the extract dried over magnesium sulfate and concentrated to an oil.

The oil was then purified in a Florasil column, after which 55 mg of a white, crystalline product were obtained.

Since the concentrated product at room temperature 0 very quickly decomposed, the work-up was carried out at OC.

The spectral data consistently show that the Compound has the formula given in this example.

Example III The example concerns the conversion of the compound obtained in Example II into the compound of the formula The product obtained according to Example II was dissolved in dichloromethane and 40 drops of triethylamine at 0 ° C. The resulting composition was then admixed with 15 drops of methanesulfonyl chloride and left to stand in a freezer at -5 ° C. overnight. The resulting composition was added to ice, diluted with ether, washed with cold dilute hydrochloric acid and saturated sodium bicarbonate solution, dried and concentrated to a liquid.

Crystallization occurred upon addition of anhydrous ether to the composition forming a white solid with a melting point between 136.5 and 138 0C a. The NMR analysis of the product confirmed that given in the example above Structure.

Example IV The example relates to the direct generation of the Product of Example III from the product of Example I.

30 ml of CH2Cl2 were saturated with HCl at 0 ° C; afterward became 500 ml of the benzoate were added and the mixture was stirred for 1.5 h. The mixture was poured into ice and ethyl acetate poured. The extract was separated off and washed with water, saturated NaHCO 3 solution and saturated NaCl solution. After subsequent drying and concentration 405 mg of the product with a melting point of 136-137.5 became the solid 0C received.

Example V The example relates to the conversion of the product of Example IV to the β-lactam of the formula 6 mg of 57 fiiges NaH was added under a nitrogen atmosphere to a mixture containing 27 mg of the product of Example IV and a catalytic amount of tetra-N-butylammonium iodide (about 1 mg) in 10 ml of dry dichloromethane. The reaction was initially carried out at room temperature (about 25 ° C.), whereupon further dichloromethane was added after 1.5 h; it was then washed with dilute HCl, saturated NaHCO3 solution and saturated NaCl solution. The composition was then concentrated to an oil which was primarily a product and purified by chromatography. The NMR analysis of the product confirmed the structure given in the example above.

Example VI The example relates to the preparation of the compound of formula from the dipeptide of the formula 100 mg of the dipeptide (0.266 mmol) and 363 mg (2.5 equivalent) benzoyl peroxide were suspended in 3 ml carbon tetrachloride and placed in an oil bath previously preheated to 70 ° C. under a nitrogen atmosphere and with a condenser. Heating was continued for 1.5 hours, followed by cooling to room temperature and stirring for 10 minutes. Then 47 µl of trimethyl phosphite (0.0496 g) was added to the composition and stirred at room temperature for 30 minutes, a yellow oil being formed. The mixture was dissolved in 5.0 ml of pyridine and 0.5 ml of water and heated in a steam bath for 40 minutes: followed by heating for evaporation to give a brown oil. The brown oil was dissolved in trichloromethane; this solution was washed twice with 25 ml of water, four times with 25 ml of NaCl, three times with 25 ml of saturated NaHCO 3 solution and twice with 25 ml of saturated NaCl solution. The product was then treated with MgSO>; dried and left in a freezer overnight. Crystallization occurred and the crystalline product (130 mg, 82.5 μg yield) was separated off by filtration and washed in CC14. After repeated washing with CC14, the crystals remained light brown. The product can be converted into the corresponding β-lactams by the methods given in the above examples.

Example VII The example relates to a process for the preparation of the compound of the formula The thiazolidine dipeptide and benzoyl peroxide (2.8 g, 2.5 equivalents), consisting of the condensation product of L-cysteine and 2-amino-3-methyl-3-butenoic acid (1.76 g, 4.65 mmol), were in 60 ml of CC14 suspended under a nitrogen atmosphere and then placed in an oil bath at 75 ° C. After 1.5 hours the reaction mixture was cooled to room temperature and the composition evaporated by heating to dryness. A small amount of CC14 was added to the residue and the resulting composition was cooled or frozen. The product was filtered off and gave 818 mg of a substance with a melting point of 104-105 ° C., which was identified as benzoyl peroxide. The remaining yellow oil was dissolved in ethyl acetate, washed three times with 25 ml of a saturated aqueous sodium bicarbonate solution and once with 25 ml of a saturated aqueous sodium chloride solution, dried, evaporated and chromatographed, whereupon 926 mg of product were obtained. The product can be converted into the corresponding β-lactam by the processes mentioned in the examples given above.

Example VIII The example relates to the preparation of the compound of formula 52 mg of m-chloroperbenzoic acid in dichloromethane were added at -78 ° C. to 97 mg of the compound obtained in Example V. The reaction was carried out for about 3 hours after which time the mixture was warmed to room temperature. The resulting composition was diluted with more dichloromethane, washed three times with 10 ml of a saturated aqueous sodium bicarbonate solution and once with a saturated aqueous sodium chloride solution, dried and evaporated. After the chromatograph, 68 mg of product were obtained. The NMR analysis of the product confirmed the above structure.

Example IX The example relates to the preparation of the compound of formula To 32 mg of the compound obtained in Example VIII were added 1.5 g of dimethylacetamide and 20 mg of concentrated sulfuric acid in 2.3 ml of benzene. The resulting mixture was heated to 105 ° C. for 2 h. The resulting composition was poured into ethyl acetate, washed twice in 10 ml of a saturated aqueous sodium bicarbonate solution and once with 10 ml of a saturated aqueous sodium chloride solution, dried, evaporated and chromatographed. The NMR analysis of the product confirmed the structure given above.

Example X The example relates to the preparation of the compound of formula 77 mg of diazomethane in 4 ml of ether were added at 0 ° C. to 120 mg of the compound obtained in Example IX in 1.25 ml of Methanop. The reaction was carried out for 16 hours. The product was recovered by evaporation and purified by chromatography. The NMR analysis of the product confirmed the structure given above.

Example XI The example relates to the preparation of the compound of formula To 712 mg of the compound obtained in Example 10, 107 mg of BF3 were added. Et2O in 11 ml of tetrahydrofuran was added at -25 ° C. The reaction was carried out for 1.5 hours. The NWtR analysis of the product confirmed the structure given above.

Example XII The example relates to the preparation of the compound of formula 108 mg of m-chloroperoxybenzoic acid in dichloromethane were added at -78 ° C. to 219 mg of the compound obtained in Example XI. The reaction was carried out for about 2 hours. The reaction mixture was then heated to syn elimination and produce a single stereoisomeric sulfenic acid and methacraldehyde. This reaction proceeded smoothly in benzene at reflux (80 ° C.) and provided the penicillin sulfoxide in an overall yield of 21%. The product was obtained by evaporation and purified by chromatography and by recrystallization. The NMR analysis of the product confirmed the structure given above.

Example XIII The example relates to the preparation of the compound of formula The deoxygenation of the compound obtained in Example XII was carried out by reacting the sulfoxide from Example XII with phosphorus tribromide in 5 ml of dimethylformamide, which was carried out at 0 ° C. for about 10 minutes. The resulting composition was poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic phase was washed three times with 10 ml of water and once with a saturated aqueous sodium chloride solution, dried and evaporated to recover the product.

Example XIV The example relates to the preparation of the compound of formula Raney nickel (1.7 g) was added at room temperature to an ethanolic solution (10 ml) of the ketosulfide from Example IX (435 mg, 1.64 mmol) with stirring. Further amounts of catalyst (500 mg) were then added to the reaction mixture and the mixture was stirred for 45 and 65 minutes. After the consumption of the starting material had been detected by thin-layer chromatography, the suspension was filtered through Celite and washed with fresh ethanol (30 ml). The filtrate was evaporated in vacuo and the oily residue (275 mg) was chromatographed on silica gel to obtain three main products. The first two products were eluted as one product (74 mg) and identified as the saturated and d, ß-unsaturated desthiopenam (A and B). The third eluted product (C) was identified as the X, β-unsaturated ketosulfide (76 mg).

Raney nickel (500 mg) was added to an ethanolic solution (3 ml) of the ketosulfide (166 mg, 0.46 mmol). The solution was refluxed for 1.5 hours, then filtered through Celite and washed with fresh ethanol (15 ml). The filtrate was evaporated in vacuo and the oily residue was purified by preparative thin-layer chromatography; the desthiopenam (A) was treated as (51 (43 mg), which was crystallized from ether; mp 100-102.5 ° C.

Example XV The example relates to the preparation of the compound of formula The thiazolidine of formula D was condensed with p-methoxy-phenylglycine-trichloroethyl ester with 2-ethoxy-n-ethanolyl-carbonyl-dihydroquinoline (EEDQ) in methylene chloride at 0 ° C to a compound of the formula E: The conversion of the compound of the formula E to the compound of the formula F was carried out in the manner and sequence described in Examples I, II, II>III> IV, V, VIII, IX and XIV.

The final cleavage of the carboxyl protective groups took place through Reduction with zinc dust and acetic acid at 10 ° C and gave the antibiotic the Formula G.

Example XVI The example relates to the preparation of the compound of Formula H The compound of the formula G was reacted with phosgene in an inert solvent with pyridine, whereupon methanol was added or precipitated and the hydrochloride of H was obtained.

Example XVII The example relates to the preparation of the compound of formula I. The compound of the formula H was reacted with 2-thienylacetyl chloride in pyridine to give the compound of the formula J whose carbonyl protective group was cleaved by reduction with zinc dust and acetic acid and whose protective group of the phenolic hydroxyl group was cleaved by reaction with boron tribromide at low temperature (-80 ° C.) in an inert solvent, whereupon the compound of formula I was obtained.

Claims (1)

Godparents 1. Compounds of formula I in which: A is hydrogen or a group B hydrogen or P ine organic carhoxyl protecting group; C1-C7-alkyl, alkylthiomethyl, phenyl, substituted phenyl, 5'-amino-protected utes-5'-carboxyvaleramino, 5'-amino-5'-carboxyvaleramido, carbonaryloxy, carbalkoxy and trifluoacetyl; R6 hydroxyl, an ester derivative of a hydroxyl group and a halide; R7 and R8 are hydrogen, C1-C4-alkyl and C1-C4-alkoxy; R9 one of the groups and R10 is hydrogen and C1-C4-alkyl; R11 C1 - C4 alkyl; R12 is hydrogen, C1-C4-alkyl, C1-C4-alkoxy, halogen, phenyl, substituted ihenyl, naphthyl and substituted naphthyl; Z is halogen, cyano and nitro; -OR1 trifluoromethyl, alkylsulfonyl. Arylsulfonyl, acyloxy and aroyloxy and n is an integer from 0-4. 2. Compounds according to claim 1, characterized in that A is the grouping and R9 the grouping mean. 3. Compounds according to claim 1, characterized in that A is hydrogen and B is the grouping and R9 = R13, where R13 is the orm of resulting after the protective group has been split off is. 4. Compounds according to claim 2, characterized in that R10 is hydrogen and R11 is methyl. 5. ß-lactams of the formula in which: R, R1, R6 and R7 are the same as in claim 1; and and R3 is hydrogen, C1-C4-alkyl and C1-C4-alkoxy and also hydroxymethyl; R4 and R5 C1-C4-alkyl and Z 'one of the groupings and 6. ß-lactams according to claim 5, characterized in that Z ' means. 7. ß-lactams according to claim 5, characterized in that Z ' means. 8. ß-lactams according to claim 5, characterized in that Z ' means. 9. Process for the preparation of β-lactam precursors for penicillins or cephalosporins, characterized by the reaction of a condensation product protected polypeptide containing protected L-cysteine with a peroxy activating agent, that of the diacyl peroxides, diaroyl peroxides, aroyl peroxy esters, acyl peroxy esters and their mixing is selected to activate the g position to the sulfur atom C-atom of the L-C: ystein residue, substitution of the activated ring C-atom with chloride, Bromide, iodide, alkyl sulfonate or aryl sulfonate as well distance of the ßubstituenten in the presence of a strong base in an aprotic medium Formation of ß-lactam. 10. The method according to claim 9, characterized in that the activated Ring carbon atom is substituted directly with the substituent. 11. The method according to claim 9, characterized in> that the activated ring carbon atom is substituted with a first substituent, the one Represents hydroxyl or alkoxy group, which is then replaced by chloride, bromide, iodide, Alkyl sulfonate or aryl sulfonate is replaced. 12. The method according to any one of claims 9-11, characterized in that that benzoyl peroxide is used as the peroxy activating agent. 13. Process for the preparation of the compounds according to claim 2, characterized by activating a compound of the formula in which R, R1, R4, R5 and R9 are the same as in claims 1 and 5, respectively, with a peroxy activating agent to give the corresponding sulfoxide and reacting the sulfoxide with a dialkyl acetamide in the presence of sulfuric acid or a sulfuric acid derivative to give the product of claim 2 . 14. Process for the preparation of the compounds according to claim 3, characterized by activating a compound of the formula in which R, R1, R4, R5> Z and n are the same as in claim 1 and 5, respectively, with a peroxy activating agent to give the corresponding sulfoxide, reaction of the sulfoxide with a dialkyl acetamide in the presence of sulfuric acid or a sulfuric acid derivative to give the corresponding ketosulfide product, desulfurization of the ketosulfide in the presence of a Raney-Nicke 1 catalyst, removal of the Ri CO - group from the desulfurized product in the presence of a weak base, elimination of existing amino, hydroxyl and / or carboxyl protective groups from the desulfurized product and acylation of the desulfurized product. 15. The method according to claim 14, characterized in that n = 0 is. 16. Use of the compounds according to any one of claims 1 -8 for Production of penicillins, cephalosporins and ß-lactams or antibiotics.