CS199669B2 - Method of producing derivatives of 7 beta-aryl-malonamido-3-substituted thiomethyl-1-oxadethia-3-cephem-4-carboxylic acids - Google Patents

Abstract

PURPOSE:Cephalosporin analogues of formula I (Ar is phenyl, p-acyloxyphenyl, 2-thienyl, 3-thienyl) and carboxyl derivatives thereof; for example, 7alphamethoxy-7beta-(alpha-phenyl-alpha-carboxyacetamido)-3-(1-methylt etrazol-5-yl) thiomethyl1-oxadethia-3-cephem-4-carboxylic acid.

Description

The present invention relates to a process for the preparation of 1-oxadethiationphalosporins, namely 7β-arylmalonamido-S-substituted-1-oxadetihia-3-cephem-4-carboxylic acid derivatives of the general formula I

(!) where

R represents an alkyl group having 1 to 5 carbon atoms, such as an acetyl, proplonyl, butyryl, isobutyryl or yaleryl group; and

COB ¹ and COB ^{2 each} independently represent a carboxyl group, optionally protected in the form of an ester, for example a phenyl ester, a xylyl ester, an indanyl ester, a phenacyl ester, an acetoxymethyl ester, a methoxymethyl ester or a phthalidyl ester, and their pharmaceutically acceptable base salts.

In accordance with the invention, the compounds of formula (I) above are prepared by producing an amine of formula (I) in which. Ar represents the remainder of the formula

199889

in which

СОВ ² is as defined above, acylated with an aryl malonic acid of formula III

АгСНСООН (III),

I сов ¹ in which

Ar and COB ¹ are as hereinbefore defined, or a reactive derivative thereof, from the compound of formula I in which COB ¹ and / or COB ² is a protected carboxyl group, optionally leaving one or more protecting groups and the resulting product of formula I, wherein COB ¹ and / or COB ² is a free carboxyl group is optionally converted by treatment with a base into a pharmaceutically acceptable salt.

Cephalosporin analogs containing an oxygen atom in the nucleus instead of sulfur are already described in the Journal of Heterocyclic Chemistry, Vol. 5, p. 779 (1968) (J. C. Sheehan and M. Dadic), in DOS No. 2 219 601 (1972), in the Canadian Journal of Chemistry, Vol. 52, p. 3996 (1974) (Saul Wolfe et al.), And in the Journal of the Americann Chemical Society, Vol. 96, p. 7582 (1974) (B. G. Christensen et al.).

In accordance with the present invention, various 1-oxadethiacephalosporins closely related to known (1-thia) -cephalosporins are prepared. In contrast to the data published by BG Christensen et al., Whose racemic 1-oxacephalosporins showed only about half the efficacy of (1-thia -cephalosporins). , the optically active products produced by the process of the invention are approximately four to eight times more antibacterially effective than the corresponding (1-thia cephalosporins). However, the lactam ring of 1-oxacephalosporins is less stable (for use in clinical drugs) than the corresponding ring (1-thia) cephalosporins.

The compounds of formula (I), selected from optically active substances prepared in the context of the present invention, do not have the aforementioned deficiency of 1-oxadethiacephalosporins.

Further, the compounds of formula I are characterized by the following properties:

1) .....

higher antibacterial activity against gram-negative organisms, higher stability / Mactam ring,

3) a narrower range of minimum inhibitory concentrations in relation to β-lactamase producing and non-producing bacteria;

4) less dependence on inoculum size,

5) higher efficacy against bacteria resistant to certain other cephalosporins (eg Enterobacteria, Serratia, indolpositive Proteus),

6) higher bactericidal character; and

7) higher blood levels.

In addition, the compounds of the formula I have the following advantageous properties:

(a) a wider spectrum of antibacterial activity (eg 3,6 y / ml or more against Pseudomonas sp. and anaerobic bacteria such as Bacteroides fragilis),

b) higher activity against β-lactamase producing organisms,

(c) increased blood stability; and

(d) lower blood protein binding.

The COB ¹ and COB ² moieties may be carboxyl or protected carboxyl groups common in the chemistry of penicillins and cephalosiporins, typically containing up to 15 carbon atoms. Individual carboxyl groups in a molecule may be protected by the same or different protecting groups. The protecting groups are usually cleaved to give the free carboxylic acids or salts thereof, so that the structure of the carboxyl function protecting groups can be varied within wide limits without departing from the scope of the invention. In other words, the structures of carboxyl function protecting groups have no specific meaning and mission other than to allow carboxyl function protection, cleavage of the protecting groups, and optionally salt formation. Preferred protecting groups are ester moieties.

As specific examples of the aforementioned examples of tert-butyl ester, monohydroxy-tert-butyl ester or 2,2,2-trichloroethyl ester, acyloxymethyl esters, aralkyl esters such as benzyl ester, p-tolylmethyl ester, p-nitrobenzyl ester, p-meithoxybenzyl ester, phthalenyl ester, phthalenyl ester, phthalenyl ester , metal esters, for example.

trimethylsilyl ester,.

dimethyl methoxysilyl ester, trimethylstannyl ester, and other easily cleavable aliphatic esters, as well as aromatic esters such as phenyl ester, tolyl ester,

- 3,4-dimethylphenyl ester, and

Of 5-indanylterer.

The compounds of formula I may also be in the form of pharmaceutically acceptable salts, including alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as magnesium, calcium and acyloxy calcium salts, and organic base salts such as procaine, trlethylamine and dicyclohexylamine. The individual carboxyl groups in the molecule may be free or in the form of salts or may be protected by the same or different groups.

The COB ¹ and COB ² moieties may preferably be free carboxyl groups or pharmaceutically acceptable salts thereof. Other preferred GOB1 moieties are 5-indanyloxycarbonyl, phenoxycarbonyl or dimethylphenoxycarbonyl.

However, some protecting groups for carboxyl functions are useful for changing the nature of the products as pharmaceuticals. In such cases, such protecting groups may be known groups commonly used in drugs in the art. These groups include the following pharmaceutically acceptable groups:

phthalidylester, acyloxymethyl, indanyl, phenylester, tolylester, dimethylphenynyster and ethoxycarbonylmethytystyryl groups.

For application in human or veterinary medicine, the compounds of the formula I are usually used in the form of salts. The most preferred salts are sodium or potassium salts, or salts with certain organic bases. These salts are selected with regard to their safety, solubility, stability and the like.

Specific examples of compounds of formula I include:

7β- [α- (2-thienyl) -α-carboxyacetamido] -7α-methoxy-3- (1-methyltetrazol-5-yl) -thiomethyl-1-oxadethia-4-carboxylic acid-4-carboxylic acid,

7β- [α- (3-thienyl) -α-carboxyacetamido] -7α-methoxy-3- (1-methyltetrazol-5-yl) -thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid,

7β- (α-phynyl-α-carboxyacetamido) -7α-methioxy-3- (1-methyltetrazol-5-yl) -thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid,

7β- (α-p-Hydroxyphenyl-α-carboxyacetamido) -7α-methoxy-3- (1-methyltetrazol-5-yl) -thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid,

7α- (α-β-acetoxyphenyl-α-carboxyacetamido) -7α-methoxy-3- [1-methyltetrazol-5-yl] -thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid,

7β- [ap-propionyloxyphenyl-α-carboxyacetamido) -7α-mythoxy-3- (1-methyltetrazol-5-yl) -thiomethyl-11-oxadethia-3-cep-4-carboxylic acid, and pharmaceutically acceptable salts thereof with bases, in particular sodium salts, and further esters, for example tert-butylestyrs, tert-amyl esters, 2,2,2-chloroethyl esters, acyloxymethyl esters, phthalidyl esters, diphenylmethyl esters, trityl esters.

benzyl esters, p-nitrobenzyl esters, p-methoxybenzyl esters, phynacylysters, phynylysters or indanyl esters and the like.

The compounds of the formula I having a phenylmalonamide, (2- (4-thienyl) -malonamide or (3-thienyl) -malonamide group at the -7- position) have a strong antibacterial activity, in particular against gram-negative microorganisms.

Compounds of formula I which contain at the 7-position p-hydroxyphenylmalonamido or p-acetoxyphenylmalonamido are potent antibacterial agents less inactivated in the living organism (due to their lower protein binding and higher blood levels) than the corresponding unsubstituted arylmalonamide derivatives. These substances also have a very enhanced activity against Pseudomonas strains, including the respective carbenicillin resistant strains.

The compounds of formula (I) are very potent antibacterial agents against Gram-negative organisms and their effect is associated with a small decrease in efficacy at larger inoculum size.

The results of the potency assays of representative compounds of the invention are shown in Table A. The following results are shown in Table B below: ana199689 logic tests with comparative, closely related compounds.

In vitro assays are performed using the following microorganisms:

(1) = Escherichia coli JC-2 (2) = Enterobacter cloacae 233 (3) = Proteus vulgaris CN-329 (inoculum size 10 ⁸ , 5% horse blood added for esters) .The antibacterial efficacy values in this case are given in ( Ug / ml.

In vivo tests are performed in mice (intraperitoneal administration) using the following microorganisms:

(4) = Pseudomonas aeruginosa PS-24 (5) = Escherichia coli (EC-14)

Antibacterial activity values in this case are given in mg / kg.

AND

Table A Antibacterial activity of compounds of the invention in vitro (μ / kg) and in vivo (mg / kg)

Test substance In vitro potency in vivo

Active substance

In vitro efficacy (1) (2) (3)

Table В

Antibacterial activity of reference compounds in vitro (µg / ml)

> 100 > 100 > 100 6.25 > 100 > 100 1.56 > 100 > 100 0.2 > 100 > 100

> 100> 100> 100> 100

The compounds of the formula I are therefore novel substances with high antibacterial activity, and are useful as medicaments in human and veterinary medicine, and as disinfectants. For example, the compounds are conveniently administered orally or parenterally to humans or animals in a daily dosage of, for example, 0.05 to 50 mg per kilogram of body weight.

The compounds of formula (I) are usually supplied in ampoules containing sterilized microcrystals or lyophilisate, and are administered in the form of solutions prepared before use. Further, an effective amount of a compound of the invention may conveniently be administered orally or parenterally in association with pharmaceutically acceptable carriers, excipients, diluents or stabilizers in the form of pharmaceutical compositions such as ampoules, injections, ointments, solutions, tablets, powders and capsules. These compositions may be in unit dosage form. For parenteral administration, the above-mentioned salts, including alkali metal salts, are predominantly used. Acyloxymethyl, indanyl, phenyl, phthalidyl and the like esters are also suitable for oral administration. The compounds of formula I may also serve as intermediates for the preparation of useful compounds, whether or not within the scope of formula I.

In the acylation for the purposes of the invention, the amino group at the 7-position of the amine of formula II may be (activated with a silyl or stannyl group, or protected or activated with 1-haloalkylidene, 1-alkoxyalkylidene, alkylene, carbonyl, acyl if easily cleavable, as well as other similar groups for the actual acylation, and removal of these groups yields a compound of formula (I).

When the arylmalonic acid of formula III is used as the free acid, the acylation is carried out in a solvent, in particular a nitrile, ether, amide or halogenated hydrocarbon derivative or a mixture thereof, in the presence of a condensing agent such as N, N'-dialkylcarbodiimide such as N, N'-dicyclohexylcarbodiimide, or in the presence of a carbonyl compound such as carbonyldiimidazole in the presence of an acylamine such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, isoxazolinium salts such as N-ethyl-5-phenylisoxazolinium 3-sulfonate, N-tert-butyl-5-methylisoxazolollinumperchlorate and other similar condensing agents, at a temperature in the range of -10 to 70 ° C.

When an arylmalonic acid of the formula III is used in the acylation as a reactive derivative, an anhydride, for example a mixed anhydride with an alkylcarbonic acid, an aralkylcarboxylic acid, one of the hydrohalic acids (in fact an acid halide) may be used in this function. azoimide (i.e. an acid azide is used), phosphoric acid, phosphorous acid, sulfuric acid, sulfuric acid and hydrogen cyanide (an acid nitrile is used). Suitable are symmetrical intermolecular anhydrides, mixed anhydrides with aliphatic or aromatic sulfonic or carboxylic acids, special intramolecular anhydrides such as ketene, isocyanate and similar reactive anhydrides. Reactive esters such as enol esters, aryl esters such as pentachlorophenyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, benzotriazole esters, diacyliminoesters, reactive amides such as amides derived from imidazole or triazole, 2-ethoxy-1, 2-dihydroquinoline-1-amide, and formiminoderivatives such as N, N-dialkyliminomethyl esters, N, N-diacylanilines.

If desired, such acylating agents may be used in the presence of acid binders such as inorganic bases such as alkali or alkaline earth metal hydroxides, carbonates or bicarbonates, organic bases such as tertiary amines and aromatic bases, and alkylene oxides such as is ethylene oxide and propylene oxide, amides such as Ν, Ν-dimethylformates d, hexamethyltriophosphoric triamide, and other suitable acid binders, or molecular sieves, preferably in a solvent environment, in particular - ketones, esters, ethers, nitriles, amides, halogenated hydrocarbon derivatives or mixtures thereof.

The compounds of the formula I obtained can be converted into salts in the customary manner, or the carboxyl protecting groups present therein can be cleaved to give free carboxyl groups, or modified if necessary by introducing protecting groups or substituents.

For example, if a carboxyl group at the 4-position or a side chain carboxyl group at the 7-position is protected, the appropriate protecting groups may be cleaved in the conventional manner to give the desired compounds of formula I. For example, one of the following protecting groups may be cleaved. procedures :.

(1) highly reactive esters, amides and anhydrides can be easily hydrolyzed by treatment with acid or base;

2) 2-haloethyl, benzyl, methylbenzyl, nitrobenzyl and diarylmethyl esters can be cleaved by slight reduction, for example with tin, zinc or divalent chromium salts in the presence of acids, sodium dithionite or catalytic hydrogenation with hydrogen in the presence of a catalyst such as platinum, palladium or nickel;

3) benzyl-, methoxybenzyl-, p-methylbenzyl-, dimethoxybenzyl-, tert-alkyl-, trityl-, diarylmethyl- and cyclopropylmethyl esters can be cleaved by treatment with acids or solvolytically (for example by treatment with mineral acids such as hydrochloric acid, Lewis acids, for example chloride) aluminum, sulfonic acids such as p-toluenesulfonic acid or strongly acidic carboxylic acids such as trifluoroacetic acid or formic acid);

4) phenacyl-, ethynyl-, p-hydroxy-3,5-di-tert-butylbenzyl esters can be cleaved by treatment with a base (e.g., alkali metal thiophenoxides, inorganic bases, or basic salts).

As mentioned above, compounds of formula I containing one or more free carboxyl groups can be converted to the corresponding derivatives on the carboxyl group by introducing protecting groups or substituents in a manner known per se, such as to prepare esters with the corresponding alcohols. together with conventional condensing agents, diazo compounds, haloformates. and the like, for the preparation of salts by treatment with alkali metal hydroxides, alkali metal carbonates or alkali metal salts of alkanoic acids, or by treatment with organic bases or using ion exchangers.

The following examples illustrate the invention, but are not intended to limit the scope of the invention in any way. The results of elemental analyzes and the physical constants of the products in all these examples are nowhere in conflict with the stated structure. The products in these examples usually contain practically equal amounts of isomers at the asymmetric carbon at the position and the amide side chain. Both of these isomers are within the scope of the invention and, if desired, can be separated by chromatography or other conventional means. The nomenclature of the compounds is in accordance with the nomenclature disclosed in Japanese Publication No. 49-133594.

In the tables for NMR spectra, the abbreviations have the following meanings:

s = singlet d '= doublet t =' triplet q - quartet m '= multiplet w = broad signal

In addition, the following abbreviations are used in formulas and tables:

Me = methyl

Et = ethyl

Bu-butyl

Ph = phenyl

Py = pyridine

PMB = p-methoxybenzyl

Ac = acetyl

Tetr = 1-methyltetrazo-5-yl

The following Example A describes the preparation of the starting material of formula (II) by introducing a melhoxy group at the 7a position:

Example A (1) A solution of 600 mg of diphenylmethyl-4-amino-3- (1-methyltetrazol-1-yl) -1H-methyl-1-oxadethir-3-yl-4-carboxylate and 353 mg of 3,5-di-tert-butyl- Of 4-hydroxybenzaldehyde in a mixture of 15 ml of benzene and 5 ml of methylene chloride was heated under reflux for one hour, the water being removed by means of a molecular sieve in a Dean-Stark water separator. The obtained solution of diphenylmethyl-N- (3-di-tert-butyl-4-hydroxybenzal) amino-3- (1-methyltetrazol-1-yl) 1H-methyl-1-oxadiethyl-3-cephem-4-carboxylate was obtained. cooled to -10 ° C to -15 ° C, 1 g of anhydrous magnesium sulfate was added, followed by stirring 0.69 g of nickel peroxide, and the reaction mixture was stirred under cooling to -10 ° C to -15 ° C for 30 minutes and then 15 minutes at room temperature. After filtration, the solid was washed with benzene, to obtain a solution of diphenylmethyl-7- (3,5-di-tert-butyl-4-oxo-4-cyclohexadienylidenemethyl) imino-3- (1-methyltetrazzl-5-yl) thiomethyl-lioixadethta 10 ml of methanol was added to the 3-cephem-4-carboxylate, and the solution was allowed to stand for one hour at room temperature, after concentration to dryness under reduced pressure, the residue was chromatographed on 30 g of silica gel containing 10% water. ethyl acetate 4: 1.

906 mg (yield 99.7%) of diphenylmethyl-73- (3,5-di-tert-butyl-4-hydroxybenzal) amino-7α-methoxy-3- is obtained.

- (1-methyltetrazzyl) thizmethyl-1-oxadethiol-3-cephem-4-carboxylate as a yellow foam. The substance is practically pure.

(2) To a solution of the above product in a mixture of 10 ml of methanol and 5 ml of tetrahydrofutane was added 315 mg of Girard reagent T, the reaction mixture was stirred at room temperature for one hour, then diluted with water and extracted with methyl chloride. The extract was washed with water, dried over sodium sulfate and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by freeze drying on 30 g of silica gel containing 10% water, eluting with a 1: 1: 1 mixture of ethyl acetate, benzene and methylene chloride. There was thus obtained diphenyl-7H-amino-7α-methoxy-3- (1-methyl-thiazol-5-yl) thiomethyl-1-oxadiethia-5-cephem-1-carboxylate. 469 mg; the total yield during this example was 73.6%. The substance melts with decomposition at 160 to 162 ° C.

Infrared spectrum:

max "3425, 3350, 1792, 1724 ^cm-first

NMR spectrum:

ξ CDC13.

2.00 wide singlet 2H

3.38 singlet 3H

3.87 singlet 3H

4.32 singlet 2H

4.73 singlet 2H

4.92 singlet 1H 7.00 singlet 1H

As can be seen from the above preparation, nickel peroxide has been found to be one of the best oxidizing agents of the phenolic intermediate when introducing the methoxy group to the 7a position of the 1-oxa- and also the 1-thiacephem ring.

The following examples illustrate the actual N-acylation of the invention, introduction and cleavage of protecting groups, and salt formation.

Example 1

To a solution of 103.9 ml of .alpha.-diphenylmethyloxybenzyl-.alpha.-phenyl-phthalic acid in 2 ml of methylene chloride is added 0.042 ml of triethylamine and 0.0256 ml of oxalic acid chloride after cooling to 0 DEG. The reaction mixture was stirred at 0 ° C for 10 minutes, then added to a solution of 101.7 mg of diphenylmethyl-7S-amino-7α-methoxy-3- while cooling to 0 ° C.

- (1-methyltetrazzyl) ylthio-1-oxa-1-oxa-99669 dethia-3-cephem-4-carboxylate and 0.0559 ml pyridine in 5 ml methylene chloride, stirred at 0 ° C for 1 hour, diluted by addition The solution was washed with dilute hydrochloric acid, water, aqueous sodium bicarbonate and water, dried over sodium sulfate and concentrated under reduced pressure. This was carried out with a 4: 1 mixture of benzene and ethyl acetate to give 121.2 mg (72.4%) of a colorless foam of diphenylmethyl-7R- (α-diphenylmethoxycarbonyl-α-phenylacetamido) -7α-methoxy-3. - (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem-4-carboxylate.

Infrared spectrum:

ν ^c _x ^b 3320, 1792, 1725, 1700 cm ^-1 .

NMR Spectrum:

£ CDCb.

3.40 singlet + 3.42 singlet 3H

3.69 singlet 3H

4.22 singlet 2H

4.45 singlet 2H

4.75 singlet IH

5.00 singlet IH

6.92 singlet 2H

7.85 singlet IH

Example 2

To a solution of 142 mg α-diphenylmethoxycarbonyl-α-β-acetoxyphenylacetic acid in 2 ml methylene chloride, after cooling to 0 ° C, 0.0416 ml triethylamine and 0.0256 ml oxalic acid dichloride are added. The reaction mixture was stirred at 0 ° C for 15 minutes, then treated gradually with a solution of 101.7 mg of diphenylmethyl-7α-amino-7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl- at 0 ° C. 1

oxadethia-3-cephem-4-carboxylate and 0.024 mL of pyridine in 4 mL of methylene chloride. After stirring for 15 minutes, ethyl acetate was added, the solution was washed with aqueous sodium bicarbonate solution, water, dilute hydrochloric acid solution and water, then the organic solution was dried over sodium sulfate and the filtrate was concentrated under reduced pressure. The residue is chromatographed on 20 g of silica gel containing 10% water. The fractions eluted with benzene / ethyl acetate (2: 1) gave 133.4 mg of diphenylmethyl 1- [4- (α-diphenylmethoxycarbonyl) -α-acetoxyphenylacetamido) -7α-methoxy-3- (1-methyltetrazol-5-yl). ) thiomethyl-1-oxadethia-3-cephem-4-carboxylate as a colorless foam. Yield 74.5%.

Infrared spectrum:

v ™ ^c _x ¹⁵ 3325, 1792, 1730 1700 (shoulder) cm ^-1 .

NMR Spectrum:

CDCls.

2.40 singlet 3H

3.40 singlet 3H

3.67 singlet 3H

4.17 singlet 2H

4.42 singlet 2H

4.73 singlet IH

4.98 singlet IH

Example 3

Under similar reaction conditions as in the preceding Example 2, the compounds summarized in the following overview are also obtained. The compounds prepared are potent antibacterial agents, as effective as the corresponding non-acylated phenolic derivatives. Compounds Nos. 1 to 10 are amorphous, Compounds Nos. 11 to 15 are foams.

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After deprotection of the carboxyl functions of the above products, the compounds are summarized as follows:

Number R Melting point IR: cm ¹ X ^: UV · λ C ^H _and ³ ° ^H nm (ε) ε (° C) nm 16 acetyl powder 1786, 1730. 274 9500 120—125 17 propionyl powder 1787 1758 1727 275 9500 ' 111—117 18 n-butyryl powder 1788, 1753, 1735. 274 9900 104 19 Dec isobutyryl powder 1788, 1755, 1730. 274 8900 104—112 20 May n-valeryl powder 1785, 1753, 1725. 274 9150 99—108 Example l 4 Example 5

To a solution of 25.4 mg of α-diphenylmethoxycarbonyl-α-hydroxyphenylacetic acid in 3 ml of methylene chloride was added 0.083 ml of triethylamine and 0.051 ml of oxalic acid dichloride while cooling to 0 ° C, followed by stirring for 0 minutes. ° C to a solution of 101.7 mg of diphenylmethyl-7 _; 1-amino-7α-methoxy-3- [1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem-4-carboxylate and 0.048 mL of pyridine in 4 mL of methylene chloride. The reaction mixture was stirred at 0 ° C for 30 minutes, diluted with ethyl acetate, washed with aqueous sodium bicarbonate, water, and concentrated. hydrochloric acid and again with water, the organic solution is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The residue is chromatographed on 20 g of silica gel containing 10% water, eluting with a 2: 1 mixture of benzene and ethyl acetate. 86.4 mg, (49.6%) of diphenylmethyl-4- (α-diphenylmethoxycarbonyl-α-hydroxyphenylacetamido) -7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3 was obtained. cephem-4-carboxylate as a colorless foam.

Infrared spectrum:

_in the 3585 ™, 3315, 1790, 1722, 1700 (shoulder) cm ⁴

NMR Spectrum:

CD CDCl 3 3.45 singlet-3.48 singlet 3H

3.72 singlet --- 3.75 singlet 3H

4.18 singlet 2H

4.45 · singlet 2H

4.67 singlet + 4.70 singlet IH

5.02 singlet IH

A mixture of 148 mg of .alpha .- (indan-5-yl) oxycarbonyl-.alpha.-phenylacetic acid and 0.25 ml of thionyl chloride was heated at 70 DEG C. for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in 2 ml of benzene and the solution was again concentrated to dryness. The residue was dissolved in 2 mL of methylene chloride and added to a solution of 101.7 mg of diphenylmethyl-73-amino-7o-methoxy-3- [1-methyltetrazol-5-yl) thiomethyl-1-oxadethia at 0 ° C. Of 3-cephem-4-carboxylate and 0.016 ml of pyridine in 4 ml of methylene chloride. The reaction mixture was stirred at 0 ° C for 30 min, then diluted with ethyl acetate, washed with aqueous sodium bicarbonate, water, dilute hydrochloric acid, and water again, dried over sodium sulfate, and concentrated under reduced pressure. The residue is chromatographed on 20 g of silica gel containing 10% water, eluting with a 4: 1 mixture of benzene and ethyl acetate. Yield: 116.1 mg (73.8%) of colorless foam-diphenylmethyl-7 - [- (indan-5-yl) oxycarbonyl-α-phenylacetamido] -7α-methoxy-3- (1-methyltetrazole) -5-yl) thiomethyl-1-oxadethia-3-cephem-4-carboxylate.

Infrared spectrum:

v ™ ^ 13 ί390, 3320, 1780, 1727 and 1700 · cm ¹

NM ^ - ^] ^ (^ 1 ^ t ^):

CDC13.

2.05 quintet (7 Hz) 2H

2.87 triplet (7Hz) 4H

3.48 singlet 3H

3.77 singlet 3H

4.23 singlet 2H

4.53 .singlet 2H

4.87 singlet IH 5.0 * 2 singlet IH

Example 6

To a solution of 97 mg of .alpha.-tert-butoxycarbonyl-.alpha .- (3-thienyl) acetic acid in 1 ml of methylene chloride was added, while cooling to 0 DEG C. under nitrogen, 0.042 ml of triethylamine and 0.026 ml of oxalic acid chloride. The reaction mixture was stirred at 0 ° C for 30 minutes, then poured into a solution of 101 mg of diphonylmethyl-7 at 0 ° C under nitrogen _; N-amino-7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem-4-carboxylate and 0.024 mL of pyridine in 3 mL of methylene chloride. The reaction mixture was stirred at this temperature for 90 minutes, diluted with methylene chloride, washed with 5% aqueous sodium bicarbonate solution, water, 2N hydrochloric acid solution and water, and dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is chromatographed on 5 g of silica gel containing 10% water, eluting with a 2: 1 mixture of benzene and ethyl acetate. 144 mg of diphenylmethyl (N - (C-butoxycarbonyl-1-thienyl) acetamido] -7? -Methoxy-3- [1-methyl-tetrazol-5-yl) -thiomethyl-1-oxadt-thia-3-cephem- are obtained. 4-carboxylate in the form of a colorless foam. The yield is quantitative.

Infrared spectrum:

in max13 1795, 1720, approx. 1700 cnr *

NMR Spectrum:

β CDC13.

6.96 singlet 1H

5 ^, 07 singlet + -5.05 singlet 1H

4.60 wide singlet 3H

4.30 broad singlet 2H

3.83 singlet 3H

3.53 singlet + 3.50 singlet 3H

1.41 singlet 9H

Example 7

To a solution of 176 mg of α-diphenylmethoxycarbonyl-α- (2-thienyl) acetic acid in 1 ml of methylene chloride was added under nitrogen, while cooling to 0 ° C · 0.055 ml of triethylamine and 0.34 ml of oxalic acid dichloride. The reaction mixture was stirred for 15 minutes while cooling to 0 ° C, then 101 mg of diphenylmethyl-7α-3-aminol-7α-methoxy-3-1-methyltetrazol-5-yl) thiomethyl-1 was added to the solution while cooling to 0 ° C. of oxadethia-3-cephem-4-carboxylate and 24 μΐ of pyridine in 3 ml of methylene chloride. The reaction mixture is stirred for 30 minutes, then diluted with ethyl acetate, washed with 5% sodium bicarbonate solution, water, 2 N hydrochloric acid solution and water, dried over sodium sulfate and concentrated under reduced pressure. The residue thus obtained is chromatographed on 10 g of silica gel containing 10% water, eluting with a 4: 1 mixture of benzene and ethyl acetate. 140 mg (85%) of diphenylmethyl-7 ₁ 3 [alpha] -diphenylmethoxycarbonyl-α- (2-thienyl) acetamido] -7'-methoxy-3- (1- · methyltetrazol-5lyl) thiomethyl-1-oxadtthia were obtained. 3-Cephem-4-carboxylate as a colorless foam.

Infrared spectrum:

in mx ^b 1785, 1720, approx. 1700 cm4

NMR Spectrum:

β CDCll.

6.93 singlet 2H

5.00 · singlet 2H

4.50 wide singlet 2H

4.15 · broad singlet 2H

3.80 singlet 3H

3.40 wide singlet 3H

Example 8

To a solution of 120 mg of 3-thienylmalonic acid monoindanyl ester in 1.5 ml of methylene chloride, 42 μΐ of triethylamine and 26 μΐ of oxalic acid dichloride are added under ice-cooling. The mixture was stirred for 15 minutes, then added to a solution of 116 mg of diphenylmethyl-17H-amino-7-methoxymethoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethial-3-cephem-4'-carboxylate in 3 ml of methylene chloride and 24 μΐ pyridine. The reaction mixture was stirred at 0 ° C for 1 h. After pouring into ethyl acetate, the organic solution was washed with 2 N hydrochloric acid, water, 5% aqueous hydrochloric acid, water, 5% aqueous sodium bicarbonate and water, dried The residue was chromatographed on 3 g of silica gel containing 10% water, eluting with a mixture of benzene and ethyl acetate to give diphenylmethyl-7 | 3- [a] in 140 mg (78%). - (3-thienyl) -N- (indan-5-yl) oxycarbonylacetamido] 17almethoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-methyl-4-carboxylate.

Infrared spectrum:

in S3 3400, 3327, 1789, 1736, 1712 cm @ ^-1 .

§ CDC13.

2.07 m 2H

2.87 wide triplet 4H

3.50 singlet 3H

3.77 'singleft 3H

4.24 singlet 2H

4.56 singlet 2H

4.97 singlet 1H 5.04 doublet (1 Hz) 1H

6.88 broad singlet 3H

[Α] D ²² · ^{-5 -} 68.2 + 1.1 ° (c = 10? 2? 3, CHCl 3).

Example 9

To a suspension of 370 mg of α- (5-indanyl) oxycarbonyl-α-β-hydroxyphenylacetic acid in 4 ml of methylene chloride at 0 ° C under nitrogen was added 139 µl of triethylamine and 85 µl of oxalic acid dichloride. A clear solution is obtained, which is stirred at 0 DEG C. for 20 minutes, and 203 mg of diphenylmethyl-7H-3-amino-7H-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1- is then added to the solution. oxadethia-3-cephem-4-carboxylate in a mixture of 5 ml of methylene chloride and 80 .mu.l of pyridine, and the mixture is stirred for 10 minutes. The reaction mixture was then washed with 2N hydrochloric acid, water, 5% aqueous sodium bicarbonate solution and water, and dried over anhydrous sodium sulfate to concentrate the filtrate under reduced pressure to give a yellow foam which was chromatographed on 50 g of silica gel containing 10% water. Elution with benzene / acetic acid (1: 1) is isolated as a crystalline residue, m.p. 114 DEG-116 DEG C. in a yield of 2.330 mg (71.5%) of diphenylmethyl-73-iota-p-hydroxyphenyl-.alpha. 5-indanyl) oxycarbonylcetamido-7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem-4-carboxylate.

Ultraviolet spectrum:

Тах ° ^ 272 (£ = 9500)

277 (£ = 10,300) 284 (ε = 9260) nm

NMR Spectrum:

fi CDsCOCDj.

2.1 multiplet 2H

2.87 triplet (7 Hz) 4H

3,413 singlet 3H

3.91 singlet 3H

4.31 singlet 2H

4.65 singlet 2H 5.07 singlet 1H 5.13 singlet 1H

6.92 broad singlet 3H

Infrared spectrum:

γ max ¹ '3590, 3335, 1789, 1736, 1722, 1700, 1601 cm * ¹

Example 10

To a suspension of 105 mg of 3-thienylmalonic acid monophenyl ester in methylene chloride, 42 μΐ of triethylamine and 26 μΐ of oxalic acid dichloride are added under ice-cooling. After stirring for 15 minutes, then at 0 ° C was added to a solution of 116 mg dlfenylmethyl-73-amino-7a-methoxy-3- _one (l-methyl-tetrazol-5-yl) thiomethyl-l-oxadeiihia-3-cephem

Of 4-carboxylate in 3 ml of methylene chloride and 24 μΐ of pyridine. The reaction mixture was stirred at 0 ° C for 1 hour, then poured into ethyl acetate, washed with 2 N hydrochloric acid, water, 5% aqueous sodium bicarbonate solution and water, and dried over anhydrous magnesium sulfate. The residue is chromatographed on 3 g of silica gel containing 10% water. Elution with a 8: 1 mixture of benzene and ethyl acetate gave 125 mg (76%) of diphenylmethyl-4- [4- (α-(3-thienyl) -afenoxycarbonylacetamido] -7α-methoxy-3- (1-methylte)). ((Razo-15-з11) hiomethyl-1-oxadethia-3-cephem-4-carboxylate as a colorless foam).

Infrared spectrum:

in m ”X ^b · 3406, 3341, 1789, 1740, 1711 cm ⁴

NMR Spectrum:

§ CDC13.

3.49 singlet 3H

3.78 singlet 3H

4.24 singlet 2H

4.55 singlet 2H

4.97 singlet 1H

5.03 singlet 1H

6.88 singlet 1H (-] d ²² · ⁵ —74.88 ± 1 ° (c = 1.005, CHCl 3)

Example 11

To a solution of 120 mg of 3-thioyl-amino-mono-3,4-dimethyl-phenyl ester. in 1.5 ml of methylene chloride, 42 µl of triethylamine and 26 µl of oxalic acid dichloride are added under ice-cooling, and after stirring for 15 minutes, the mixture is added to a solution of 116 mg of dipeoylmethyl-7,3-amioo-7α-methoxy-3- (1-methylethylletrazol-5-yl) of thiomethyl-1-oxazodethia-3-cephem-4-carboxylate in 3 ml of methylene chloride and 24 µl of pyridine, and the reaction mixture is stirred for one hour at 0 ° C. The reaction mixture was poured into ethyl acetate, washed with 2 N hydrochloric acid, water, 5% aqueous sodium bicarbonate solution and water, and, after drying with anhydrous magnesium sulfate, concentrated. The residue is chromatographed on 3 g of silica gel containing 10% water, eluting with benzene and ethyl acetate to give diphenylmethyl-70- [α- (3-thienyl) -α- (3,4-dimethyllenyl) oxycarboylacetamido] -7α'-methoxy 1-Methyltetrazole-ST-1H / thiomethyl-1H-oxadethiazole-3-cephem-4-carboxylate in a yield of 128 mg (72%).

Infrared spectrum:

³ in XT 3405, 3340, 1790, 1737, 1712 cm-1

NMR Spectrum:

£ CDC13.

2.22 singlet 6H

3.50 singlet 3H

3.76 singlet 3H

4.24 singlet 2H

4.56 singlet 2H

4.95 singlet 1H

5.03 doublet (1.5 Hz) 1H

6.87 singlet 1H

6.90 singlet 1H [α] ^{D 22} ° - 68.1 ° + 1.1 ° (c = 1.002, CHCl 3).

Example 12

210 µl of triethylamine and 130 μΐ of oxalic acid dichloride are added to a solution of 710 mg of 3-thienylmalonic acid monobenzhydryl ester in 5 ml of methylene chloride. The reaction mixture was stirred under continuous cooling for 15 minutes, then 510 mg of diphenylmethyl-70-amino-7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem was added under ice-cooling. -4-carboxylate in a mixture of 15 ml methylene chloride and 120 μΐ pyridine. After stirring for 30 minutes, the reaction mixture was poured into ethyl acetate, washed with 2 N hydrochloric acid solution, water, 5% aqueous sodium bicarbonate solution and water, and dried over magnesium sulfate, concentrated. The residue is chromatographed on silica gel containing 10% water, eluting with a 10: 1 to 4: 1 mixture of benzene and ethyl acetate. 834 mg of diphenylmethyl-70- [α- (3-thienyl) -α-diphenylmethoxycarbonylacetamido] -7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cefem-4- is obtained. carboxylate in the form of a colorless foam.

Infrared spectrum:

in max * ⁵ 1790, 1728, 1710 (shoulder) cm ^-1

NMR Spectrum:

£ CDCl3.30 singlet 3H

3.60 singlet 3H

4.09 singlet 2H

4.37 singlet 2H

4.79 singlet 1H

4.90 singlet 1H

6.86 singlet 2H

Example 13

To a suspension of 125 mg of p- (p-methoxybenzyloxy) phenylmalonic acid in 3 ml of methylene chloride, 55 μΐ of triethylamine and 26 μΐ of oxalic acid chloride are added under stirring at -15 ° C, and the resulting mixture is stirred at 0 ° C for 40 minutes. is added to a solution of 100 mg of diphenylmethyl-70-amino-7'-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem-4-carboxylate in 3 ml of methylene chloride and 63 μΐ of pyridine The reaction mixture was stirred at 0 ° C for 30 minutes, then diluted with ethyl acetate, washed with 2 N aqueous hydrochloric acid and water, and dried over sodium sulfate, concentrated. 212 mg of crude product is obtained, which is chromatographed on 20 g of silica gel, eluting with a 99: 1 mixture of ethyl acetate and acetic acid. 71 mg (45%) of diphenylmethyl-70- [ap- (p-methoxybenzyloxy) phenyl-α-carboxyacetamido] -7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-11-oxadethia-3-cef was obtained. em-4-carboxylate in the form of a foam.

Infrared spectrum:

v ™ x ^1! 3385, 3300—2400 wide belt,

1790, 1762, 1714, 1612 cm ¹

NMR Spectrum:

β CDC13.

3.43 singlet 3H / 2

3.46 singlet 3H / 2

3.74 singlet 3H

3.78 singlet 6H

4.22 wide singlet 2H

4.56 wide singlet 3H

4.96 singlet 2H

5.05 singlet 1H

The above product (40 mg) gave 0.2- [trifluoroacetic acid] and 0.4 ml of anisole at 0 [deg.] C. for 20 minutes at 7 [deg.] - ([alpha] -hydroxyphenyl-, [alpha] -carboxyacetamido) -7a-methoxy-3- (1- methyltetrazol-5-yl) -thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid.

Example 14 (I) An ice-cooled suspension of 1.5 g of diphenylmethyl-7β-amino-7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem-4-carboxylate and 1.4 g of .alpha.-hydroxyphenyl-.alpha.-phthalidyloxycarbonylacetic acid in 45 ml. of dichloromethane are added with stirring 635 .mu.l of pyridine and 390 .mu.l of phosphorus oxychloride, and stirring is continued for 85 minutes. The dichloromethane layer was washed successively with dilute hydrochloric acid, aqueous sodium bicarbonate solution, water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, filtered to remove insoluble material and concentrated. The residue was chromatographed on 12 g of silica gel containing 10% water, eluting with benzene / ethyl acetate (2: 1). 344 was obtained as an amorphous material

9

2S milligrams of diphenylmethyl 1-7 / 3- (α-p-hydroxyphenyl-α-phthalidyloxycarbonylacetamido) -7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem-4-carboxylate.

(II) In analogy to the reactions summarized in Table 1, the compounds listed in Table 2 are obtained.

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Example 15

To a solution of 1.722 g of 2- (4-p-methoxybenzyloxyphenyl) -2-p-methoxybenzyloxycarbonylacetic acid in 10.33 ml of dichloromethane was added 0.413 ml of triethylamine and 0.252 ml of oxalic acid chloride, and the mixture was stirred at 0-3 for 2 hours. ^QC to give a solution of the corresponding acid chloride. To a solution of 786 mg of tert-butyl 7 (S-amino-7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem-4-carboxylate in 25 ml of dichloromethane containing 239 µl) The acid chloride solution prepared above was added to the pyridine while maintaining the temperature at 3-7 ° C, and the mixture was stirred at 3 ° C for 30 minutes. The reaction mixture was evaporated in vacuo, the residue was dissolved in ethyl acetate (23 ml), shaken and organic layer. The mixture was separated, washed with ice-water, aqueous sodium bicarbonate solution and water, dried and concentrated to a residue of 2.16 g. Chromatographic purification of the residue gave 1.61 g (100%) of tert-butyl-7β. - [2- (4-p-methoxybenzyloxyphenyl) -2-p-methoxybenzyloxycarbonylacetamido] -7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem-4-carboxylate.

The physical constants of this product are listed in the following overview under number 1.

An additional five compounds are prepared in an analogous manner, the physical constants of which are listed in numbers 2-6 below.

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Example 16

To a solution of 121.2 mg of diphenylmethyl-N- (α-diphenylmethoxycarbonyl-phenylacetamido) -7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem-4-carboxylate 0.2 ml of anisole and 0.3 ml of trifluoroacetic acid are added in 2 ml of methylene chloride while cooling to 0 ° C. The reaction mixture was stirred with cooling to 0 ° C for one hour and then concentrated under reduced pressure. Trituration of the residue with ether isolated 46.5 mg of 7β- (α-carboxy-1-phenylacetamido) -7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem- 4-carboxylic acid in the form of a colorless powder. Yield 59.8%; mp 110-116 ° C.

Ultraviolet spectrum:

v “x ^0H 275.5 nm (ε = 9400).

[α] ²⁵ ° -19.4 ° + 2.8 ° (c = 0.211, СНзОН)

Infrared spectrum:

in max 1780, 1717, 1631 cm- ’

NMR Spectrum:

£ D2O + NaHCO3

3.46 singlet + 3.53 singlet 3H

3.99 singlet- | -4.02 singlet 3H

4.0-4.2 multiplet 2H

4.48 singlet 2H

4.53 singlet 1H

5.13 singlet 1H

7.38 singlet 5H

Example 17

To a solution of 133.4 mg of diphenylmethyl-7- (zz-diphenylmethoxycarbonyl-α-acetoxyphenylacetamido) -7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-11-oxadethia-3-cep-4-carboxylate in 2 ml of methylene chloride are added, while cooling to 0 ° C, 0.2 ml of anisole and 0.4 ml of trifluoroacetic acid. The reaction mixture was stirred for 45 minutes, concentrated, triturated first with ether / pentane and then with ether. 77 mg (91.9%) of 7? - (? -Carboxy-.alpha.-acetoxyphenylacetamido) -7? -Methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cef is isolated. em-4-carboxylic acid as a colorless foam, m.p. 110-115 ° C.

Ultraviolet spectrum:

Infrared spectrum:

in max 1782, 1728, 1635 cm ¹

NMR Spectrum:

β DiO + NaHCO 3

2.33 singlet 3H

3.47 singlet + 3.53 singlet 3H

3.99 singlet-j-4.02 singlet 3H ca. 4.13 broad singlet 2H 4.46 broad singlet 2H

5.13 singlet 1H

7.12 + 7.47 AB-quartet (8 Hz) 4H

Example 18

To a solution of 84.6 mg of diphenylmethyl-7 (S- (α-diphenylmethoxycarbonyl-α-hydroxyphenyl- _f- acetamido) -7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem- The 4-carboxylate in 2 ml of methylene chloride was treated with 0.1 ml of anisole and 0.3 ml of trifluoroacetic acid while cooling to 0 DEG C. The reaction mixture was stirred at 0 DEG C. for 45 minutes, followed by trituration of the residue obtained by concentrating the reaction mixture. under vacuum, first with a mixture of ether and n-pentane, and then isolate 7? - 3- (α-carboxy-α-hydroxyphenylacetamido) -7? -methoxy-3- (1-methyltetrazol-5-yl) thiomethyl with ether 1-oxadethia-3-cephem-4-carboxylic acid in a yield of 46.4 mg (89.9%) as a colorless powder, m.p. 117-122 ° C (dec.).

Ultraviolet spectrum:

λ max ^0H 276 nm (ε = 10,200) [α] _D ^{25 -} 15.3 ° + 2.6 ° (c = 0.216, methanol)

Infrared spectrum:

in mix 1780, 1719, 1632 cm ^-1

NMR Spectrum:

D2O + NaHCO3

3.45 singlet + 3.53 singlet 3H

4.00 singlet + 4.02 singlet 3H

4.08 singlet-j-4.13 multiplet 2H

4.45 singlet | -4.48 singlet 2-3H

5.12 singlet 1H

6.87 + 7.28 AB-quartet (8 Hz) 4H

Example 19

144 mg of diphenylmethyl-7β- [α-tert-butoxycarbonyl-α- (3-thienyl) acetamido] -7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3- cephem-4-m Karve ^{0H H} ax 275 nm (ε = 9300) [?] D ²⁵ -27.5 + 2.6 ° (c = 0.258, СНзОН) carboxylate in 0.3 ml of anisole under nitrogen with cooling 1.7 ml of trifluoroacetic acid are added to 0 ° C, the reaction mixture is stirred for 3 hours, then concentrated to dryness under reduced pressure and the residue is triturated with ether. After washing with ethyl acetate and ether, 61 mg (61%) of N - [? - carboxy-1- (3-thienyl) acetamido] -7? -Methoxy-3- (1-methyltetrazol-5-yl) thiomethyl- was obtained. 1-oxadethia-3-cephem-4-carboxylic acid as a yellowish powder melting after crystallization from acetone with decomposition at 118-125 ° C.

[α] _D ²⁵ -12.8 + 2.5 ° (c = 0.211, methanol)

Ultraviolet spectrum:

in m ^H and x ^0H 276 nm (€ = 10,200)

Infrared spectrum:

max 1780, 1705 ^cm-1

NMR Spectrum:

β D2O + NaHCO3

4.03 singlet 3H

4.11 singlet + 4.21 multiplet 2H

4.51 singlet-4.53 singlet 2-3H

5.15 singlet 1H

7.05—7.25 multiplet 1H

7.27 - 7.52 multiplet 2H

Example 20

To a solution of 140 mg diphenylmethyl-N - [α-diphenylmethoxycarbonyl-α- (2-thienyl) acetamido] -7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1'-oxadethia-3-cephem- Of 4-carboxylate in 2 ml of methylene chloride at 0 ° C under nitrogen are added 0.2 ml of anisole and 0.4 ml of trifluoroacetic acid. The reaction mixture was stirred at 0 ° C for one hour, concentrated under reduced pressure, triturated with ether and washed with ether to give 60 mg (70%) of 7β- [α-carboxy-α- (2-) thienyl) acetamido-7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid as a colorless powder, m.p. 104-109 ° C (decomposition) .

Ultraviolet spectrum:

in mlx ° ^H 275 nm (ε = 8800) (α] _D ^{24 -} 15.0 + 1.5 ° (c = 0.374, CH 2 OH)

Infrared spectrum:

in S 1785, 1715 cm ¹

NMR Spectrum:

β D2O + NaHCO3

5.15 singlet 1H

4.04 singlet 3H (3.54 singlet + 3.48 singlet) 3H

Example 2 1

To a solution of 116.1 mg of diphenylmethyl-N - [? - (5-indanyl) oxycarbonyl-α-phenylacetamido] -7? -Methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia To 3-cephem-4-carboxylate in 2 mL of methylene chloride was added 0.1 mL of anisole and 0.2 mL of trifluoroacetic acid, and the mixture was stirred with cooling to 0 ° C for 30 minutes. The reaction mixture is concentrated under reduced pressure, the residue is chromatographed on 10 g of silica gel containing 10% water, eluting the column with ethyl acetate containing 5% acetic acid. Crystallization from ether / pentane yielded 74.5 mg of colorless crystals of N - [? - [indan-5-yl] oxycarbonyl-α-phenylacetamido] -7? -Methoxy-3- (1-methyltetrazol-5yl) thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid. Yield 81.4%. The product melts with decomposition at 123-125 ° C.

Infrared spectrum:

ε S 1770, 1702 cm ^-1 [α] _D ²⁵ -8.4 ° + 1.4 ° (c = 0.286, СНзОН)

NMR Spectrum:

g CDC1S

2.07 singlet 2H

2.85 singlet · 4H

3.32 singlet + 3.43 singlet 3H

3.79 singlet 3H

4.25 singlet 2H

4.50 singlet 2H

4.69 singlet 1H

4.97 singlet 1H

Example 1 a d 2 2

To a solution of 105 mg diphenylmethyl-7β- [3 '- (3-thienyl) -α- (3,4-dimethylphenyl) oxycarbonylacetamido] -7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1 Oxadethia-3-cephem-4-carboxylate in 2 mL of methylene chloride was added 0.2 mL of anisole and 0.2 mL of trifluoroacetic acid under ice-cooling, and the reaction mixture was stirred for one hour before concentrating under reduced pressure. The residue was triturated with ether, the solid was filtered off and washed with ether. After drying, 64 mg (77%) of the powdered product are obtained. M.p. 110-113 ° C. The product is 7β- [a- (3-thienyl) -α- (3,4-dimethylphenyl) oxycarbonylacetamido] -7'-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethiaic acid -3-Cephem-4-carboxylic acid.

7.00—7.5 multiplet 3H

Infrared spectrum:

max max ¹³ 3400 (shoulder), 3325, 1787, 1737, 1704 cm -1 ¹ [a] _D ²³ —53.4 ° + 1.9 ° (c = 0.504, СНС1з)

Example 23

830 mg of diphenylmethyl-N - [[1- (3-thienyl) -t-diphenylmethoxycarbonylacetamido] -7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl] -oxadethia-3-cep-4 2-anisole and 2 ml of trifluoroacetic acid are added under ice-cooling with ice-carboxylate in 15 ml of methylene chloride. The reaction mixture was stirred at the above temperature for 1 hour and then concentrated under reduced pressure. The residue was washed with ether to give 383 mg of N - [? - (3-thienyl) -? - carboxyacetamido] -7? -Methoxy-3- [1-methyltetrazol-5-yl) thiomethyl-1-oxadethia powdered acid 110 DEG-114 DEG C. 3-carboxylic acid 4-carboxylic acid.

Example 24

To a solution of 100 mg diphenylmethyl-7R- [α-

- (3-thienyl) a-4 enoxycarbonylacetamido] -

-7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem-4-carboxylate in 2 mL of methylene chloride was added 0.2 mL of anisole and 0.2 mL of trifluoroacetic acid while cooling with ice. . The reaction mixture was stirred for 1 hour and then concentrated. Trituration with ether yielded 38 mg of 7β- [(3-thienyl) -α-phenoxycarbonylacetamido] -7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-11-oxadethia-3-cepemic acid powder. 4-carboxylic acid, which is pure by thin layer chromatography. The product melts at 108-111 ° C. The yield was 50%.

Infrared spectrum:

^c _m T 3400, 3325, 1788, 1745, 1705 cm ¹ [α] _D ²³ —61.3 ° + 2.0 ° (c = 0.517, СНС1з)

Example 25

To a solution of 150 mg diphenylmethyl-N-Ha-p-hydroxyphenyl 1-α- (5-indanyl) oxycarbonylacetamido] -7 α-methoxy-3- (1-methyl tetrazol-5-yl) thiomethyl-1-oxadethia-3- of cefem-4-carboxylate in 12 ml of methylene chloride at 0 ° C under nitrogen are added 0.4 ml of anisole and 0.4 ml of trifluoroacetic acid. The reaction mixture was stirred at 0 ° C for 20 minutes, then concentrated under reduced pressure, diluted with benzene and concentrated again. The residue was triturated with ether to give 7β- [α-p-hydroxyphenyl-α- (5-indanyl) oxycarbonylacetamido] -7α-methoxy-3- in a yield of 91 mg.

- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid. The product is obtained in powder form, m.p. 123 DEG-126 DEG C. (decomposition). Yield 76.5%.

Infrared spectrum:

v “Λ 3385, 1785, 1727, 1705, 1631, 1613, 1595 cm ^-1

Ultraviolet spectrum:

CH3OH

V max

271.5 (ε = 12,950)

276.5 (ε = 12,700) nm [] 1 ^ 2 = 4-1.3 ^ + 0.8 ° [lof] 436 ²² = —25.1- + 1.2 ° [αί] 54δ22 = —5.2 ° + 1.2 ° (¢ = 0.541, methanol)

Example 26

To a solution of 97 mg of diphenylmethyl-7 + [α- (3-thienyl) -α- (indan-5-yl) oxycarbonyl lacetamido] -7α-nitro-3- (1-methyltetrazol-5-yl) thiomethyl-1- oxadethia-3-cephem-4-carboxylate in 2 ml of methylene chloride was added with ice-cooling 0.3 ml of anisole and 0.3 ml of trifluoroacetic acid. The reaction mixture was stirred for one hour, then concentrated and the residue triturated with ether. The solid was washed with ether to give 7+ (η; --( 3-thienyl) -? - (5-indanyl) oxycarbonylacetamido] -7H-methoxy-3- ( 1-methyltetrazol-5-yl) thiomethyl-11-oxidethia-3-cephem-4-carboxylic acid, m.p. 111-113 ° C.

Infrared spectrum:

ν max ¹ '3406 (shoulder), 3335, 1789, 1744, 1704 cm ¹ [α] _D ^{23 -} 57.5 ° + 2.4 ° (c = 0.402, CHCl 3)

Example 27 (1) To a solution of 600 mg of diphenylmethyl-7 (3- (N-p-propionylcxyphenyl-α-diphenylmethoxycarbonylacetamido) -7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3- of cefem-4-carboxylate in 8 ml of dichloromethane was added with stirring under nitrogen at 0 ° C, 1.2 ml of anisole and 1.2 ml of trifluoroacetic acid were added, and the reaction mixture was stirred at 0 ° C for 50 minutes. The residue was triturated with a mixture of ether and petroleum ether, the precipitated powder product was filtered off and washed with the same solvent to give 353 mg (92.6%) of 7β- (p-propionyloxyphenyl-α-carboxyacetamido) -7a- methoxy-3- (1-methyltetrazol-5-yl) thlomethyl-1-oxadethia-3-cephem-4-carboxylic acid as a colorless powder, m.p. 111-117 ° C.

(2) To a solution of 888 mg of diphenylmethyl 7H- (α-p-acetoxyphenyl-af enacyloxycarbonylacetamido-7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl 11-oxadethia-3-cephem-4-carboxylate in dichloromethane (5 ml) was added with stirring and ice-cooling for 20 minutes.

3S

3β gives 1 ml of anisole and 2 ml of trifluoroacetic acid and the reaction mixture is concentrated. Trituration of the residue with ether gave a powdery N - ((p-acetoxyphenyl-af enacyloxycarbonylacetamido) -7? -Methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1 -) in a yield of 506 mg (71 percent). oxadethia-4 -cephem-α-k-arboxylic acid.

(3) Similarly, the reactions described in Tables A and B yield the compounds shown in Tables C and D.

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Example 28 (1)

To a solution of 727 mg of aluminum chloride in 7 ml of anisole was added 931 mg of diphenylmethyl-7β- (α-hydroxyphenyl-α-diphenylmethoxycarbonyl lacetamido) -7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1- oxadethia-3-cephem-4-carboxylate and the mixture was stirred under nitrogen at -15 ° C for 1 hour. The reaction mixture was diluted with methyl ethyl ketone, poured into ice water and acidified to pH 1.5 with 6 N hydrochloric acid. After saturation with sodium chloride, the organic layer was separated, washed with saturated sodium chloride solution and extracted with 5% aqueous sodium bicarbonate solution. The extract was clarified with 30 mg of activated carbon, the insoluble matter was filtered off, the filtrate was overlaid with ethyl acetate, acidified with 6N hydrochloric acid to pH 1.2, saturated with sodium chloride and extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated. In a yield of 400 mg (70.5%), 7β- (α-hydroxyphenyl-α-carboxyacetamido) -7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem was obtained -4-carboxylic acid in the form of a colorless foam.

(2)

Similarly, 640 mg of diphenylmethyl 1-7 / 3- (α-hydroxyphenyl-α-methoxybenzyloxycarbonylacetamido) -7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem-4- of carboxylate with 504 mg of aluminum chloride in 5 ml of anisole at -20 ° C gives 345 mg (yield 87.5%) of the same product as in (1), as a colorless foam.

Example 29

To a suspension of 400 mg of N, 3- (α-carboxy-α-phenylacetamido) -3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid in 20 ml of methylene chloride was added. 700 mg of diphenyldiazomethane are added and the reaction mixture is stirred at room temperature for 30 minutes. The residue obtained by concentration under reduced pressure is chromatographed on 40 g of silica gel containing 10% water, eluting with a 1: 1 mixture of benzene and ethyl acetate. 322 mg of diphenylmethyl-7β- (α-diphenylmethoxycarbonyl-α-phenyl) acetamido) -3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem-4-carboxylate are obtained. Yield 47.4%, melting at 107-109 ° C. In another embodiment, a yield of 95% was achieved.

Example 30

-5-yl) thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid in a mixture of 30 ml of acetone and 5 ml of methanol is added a solution of 17.6 mg of sodium acetate in 2 ml of methanol and stirred at room temperature for one clock. The reaction mixture was concentrated under reduced pressure and the residue was washed with acetone to give disodium salt of 3- [(α-carboxy-α-phenylacetamido) -3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia]. 3-cephem-4-carboxylic acid in a yield of 57 mg.

Infrared spectrum:

v max 3425, 1746, 1660 (wide belt), 1610 (wide belt), 1410 cm ¹ .

Example 31

From the products prepared according to the above examples in the form of free carboxylic acids, dissolution in aqueous sodium bicarbonate solution yields the corresponding sodium salts for which antibacterial activity has been monitored and determined. Said substances are more efficient than the corresponding substances containing sulfur instead of the oxygen atom at the 1-position of the cyclic system. The products are potent antibiotics against gram-negative bacteria resistant to common cephalosporins, and are also highly active against Pseudomonas aeruginosa.

Example 32

To a solution of 2.04 g of N- [N- (3-thienyl) -α-carboxyacetamido] -7H-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-oxadethia-3-cephem-4- of carboxylic acid in 20 ml of methanol, a solution of sodium 2-ethylhexanoic acid in methanol (2 mol per liter, 10 ml) was added at room temperature. The reaction mixture was stirred for 10 min. Stir, then dilute by adding 100 mL of ethyl acetate, stir the solution for 5 minutes, filter the precipitated solids, wash with ethyl acetate, and dry to obtain the disodium salt of 7, β- [α- [3-thioenyl) -α-carboxyacetamido] - 7-Methoxy-3- (1-methyl-tetraisol-5-yl) -thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid in a yield of 1.90 g (86.7%). The substance is a colorless powder with a decomposition temperature of 150 ° C.

Infrared spectrum:

max 1768, 1680, 1612 ^cm-first

Ultraviolet spectrum:

^ν x ^0H 271 nm (ε - 9420).

Example 33

To a solution of 359 mg of 7β-3- (α-p-hydroxyphenyl-α-carboxyacetamido) -7α-methoxyК a suspension of 50 mg of 7β- (α-carboxy-α-phenylacetamido) -3- (1-methyltetrazole199669)

-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid in 7 mL methanol at room temperature was added a solution of sodium 2-ethylhexanoic acid in methanol (2 mol per liter) , 1.73 mL). After stirring for 10 minutes, the reaction mixture was diluted with ethyl acetate, stirred for 5 minutes, and the precipitated solid was collected by filtration and washed with ethyl acetate. After drying, the disodium salt of 7β- (α-p-hydroxyphenyl 1-acetylaminoethyl) -7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia- 3-Cephem-4-carboxylic acid in a yield of 342 mg (88.8%). The substance is a colorless powder with a decomposition temperature of 170 ° C.

Infrared spectrum:

νmax 1768, 1675, 1608 cm ^-1 .

Ultraviolet spectrum:

™ ° ^H in 273 nm (ε = '11100).

Example 34

To a solution of 836 mg of 7H-β-hydroxyphenyl-α-carboxyacetamido] -7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem-4- of carboxylic acid in a mixture of 15 ml of methylene chloride, 15 ml of ethyl acetate and 10 ml of methanol is added 950 mg of diphenyldiazomethine. After stirring at room temperature for 30 minutes, the reaction mixture was concentrated under reduced pressure and the solid product was washed with n-hexane. Chromatography on 90 g of silica gel containing 10% water, eluting with a 1: 1 mixture of benzene and ethyl acetate gave diphenylmethy-7 ₍ 3- (α-hydroxyphenyl-α-diphenylmethoxycarbonylacetamido) -7α-methoxy-3- (1-methyltetrazodo-). 5-yl) thiomethyl-1-oxadethia-3-cephem-4-carboxylate in 1.270 g (95%) yield.

Infrared spectrum:

in max13 3585, 3315, 1790, 1722, 1700 (shoulder) cm -1.

Example 35

To a solution of 1.0 g of 7./3((ap-hydroxyphenyl-a-carboxyacetamido) -7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid In 6 ml of N, N-dimethylformamide, 832 mg of phthalidyl bromide was added under stirring and ice-cooling, the reaction mixture was stirred at room temperature for 1 hour and then poured into a mixture of ethyl acetate and aqueous sodium bicarbonate solution. The residue (1.39 g) is chromatographed on 42 g of silica gel containing 10% water, eluting with benzene / ethyl acetate (1: 1). . 1.06 g · powdered product (I COB1 ₍₌ i = ² = ftalidyloxykarbonyl COB) containing 282 mg of isomer a (less polar fraction) and 164 mg of isomer B (more polar fraction), differing in the configuration of the side chain. These isomers may be isolated by preparative chromatography TLC on silica gel using ethyl acetate as the solvent system.

(isomer A)

CD3COCD3

NMR: δ i (3.20 singlet + 3.23 singlet) 3H,

3.37 singlet 3H

4.40 wide singlet 2H

4.63 broad singlet 2H

5.05 broad singlet 2H 6.8-8.0 multiplet ^T p ^u i ^o i i. υ max

1790, 1750 · (shoulder), 1700 cm ⁴ .

(isomer B) - CD 3 COCD 3

SNMR: δ

3.17 broad singlet 3H

4.00 singlet 3H

4.20 - 4.65 multiplet 4H

5.03 wide singlet IH 6.7-8.4 multiplet

J ^p . _v rniio ² iu. in max

1790, 1750 (shoulder), 1700 cm ⁴ .

Example 36 (1)

To a solution of 550 mg of 7: 3- (α-hydroxy-phenyl-α-carboxyacetamido) (7α-methoxy (3 ((1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid)) in N, N-dimethylformamide (3 ml) was added with stirring and ice-cooling 0.2 ml of acetoxymeithyl bromide, the mixture was stirred at room temperature for 30 minutes, then diluted with ethyl acetate, washed successively with dilute hydrochloric acid, aqueous sodium bicarbonate, water The residue was chromatographed on 25 g of silica gel containing 10% water, eluting with benzene / ethyl acetate (1: 1) to give 285 mg of acetoxymethyl ester powder. 7β- (α-hydroxyphenyl-α-acetoxymethoxycarbonylacetamido) (7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-4 -cephem-4-carbo199669 xylic acid (I, COB ¹ = COB ²⁾ = acetoxymethoxycarbonyl).

CD3COCD3

NMR: δ (2.05 Singet - 3.32 singlet and 3.47 singlet) 3H (3.97 singlet + 3.98 singlet) 3H

4.33 broad singlet 2H

4.62 Ab-quartet

4.83 broad singlet 1H

5.03 singlet 1H

4.07 singlet 2H

4.23 AB-quartet (7 Hz)

7.03 A2B2 4H

Tp. u nui01.

1L ·. μ max

1790 (shoulder), 1760, 1690 ^cm-first

(2)

A small amount of monoacetoxymethyl ester is obtained from the alkaline wash liquids

(side chain) treated with diphenyldiazomethane to form diphenylmethyl ester 7β- (α-hydroxyphenyl-α-acetoxymethoxycarbonylacetamido) -7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem -4-carboxylic acids.

CH 3 OH

NMR: .delta

2.00 singlet 3H

3.47 singlet 3H (3.73 singlet -J- 3.77 singlet) 3H

4.17 singlet 2H

4.47 wide singlet 2H

4.53 broad singlet 1H

5.00 singlet 1H

5.73 singlet 2H.

6.5—7.0 multiplet

Tp. CHCls

IG. D max

1790, 1730, 1705 (shoulder) cm ⁴ .

Example 37

COOPh

/ sodaA ______sul

Ph - phenyl

Tetr = 1-methyltetrazol-5-yl

2.3 g of 7? - (apn-valeryloxyphenyl-.alpha.-phenoxycarbonylacetamide)? -Methoxy-S-1-methyltetrazd-S-yl] thiomethyl-1-oxadethiadec-cefem-.alpha.-carboxylic acid in 5 ml of ethyl acetate were added at 0 ° C; 3.38 ml of a 2.0 M solution of sodium n-ethylhexanoate in isopropanol was added, the reaction mixture was stirred at 0 ° C for 10 min and then diluted with ether. The precipitate formed was filtered off and washed with ether to give 1.72 g (yield). 73%) Sodium salts of 7β- (α-pn-valeryloxyphenyl-α-transcarbonylacetamido) -7α-methoxy-3- (Ι-methyltetrol-5-yl) thicmethyl-1-oxadethia-3-cephem-4 -carboxylic acids.

CD3C0CD3

NMR: δ

0.93 multiplet 3H

1.58 multiplet 4H

2.55 triple [7Hz] -H (3.33 singlet + 3.40 singlet) 3H

3.80-Si-3H

4.44 W-HH

4.99 singlet 1H

5.40 singlet 1H

7.02—7.70 multiplet 9H

Claims (6)

The object of the invention A process for the preparation of 7β-aryl-malon-cephem-4-carboxylic acid derivatives of the general amido-3-substituted-thiomethyl-1-oxadethia-3 of the formula I in which: Ar represents the remainder of the formula R represents an alkanoyl group having 1 to 5 carbon atoms, such as acetyl, propionyl, butyryl, isobutyryl or valeryl; and COB ¹ and COB ^{2 each} independently represent a carboxyl group, optionally protected in the form of an ester, for example phenyl, xylyl, indanyl, phenacyl, acetoxymethyl, methoxymethyl or phthalidylester, and their pharmaceutically acceptable base salts, characterized in that the amine is of formula II (1f) wherein COB ² is as defined above, acylated with an aryl malonic acid of formula III ArCHCOOH I (III), COB ¹ in which Ar and COB ¹ are as hereinbefore defined, or a reactive derivative thereof, from the compound of formula I in which COB ¹ and / or COB ² is a protected carboxyl group, optionally leaving one or more protecting groups and the resulting product of formula I, wherein COB ¹ and / or COB ² is a free carboxyl group is optionally converted by treatment with a base into a pharmaceutically acceptable salt. 2. A method according to claim 1, characterized in that as the starting compounds those of formula III wherein Ar is 3-thienyl and COB ¹ is defined as in point 1. Third ZJpůsíob according to claim 1, characterized in that as the starting compounds those of formula III, in which Ar represents a p-hydroxyphenyl group and the COB ¹ is defined as in point 1. 4. A process according to claim 1, wherein the starting materials are compounds of formula III wherein Ar is a radical of formula R is as defined in 1 a COB ¹ has the meaning as in point 1. 5. A method according to claim 1, characterized in that as the starting compounds those of formula III wherein COB ^{@ 1} is 5-indanyloxykarbonylovou, phenoxycarbonyl tolyloxycarbonyl or dimethylfenoxykarbonylovou group and Ar is defined as in point 1. 6. A method according to claim 1, characterized in that as the starting compounds those of formula II in which COB ² is benzyloxycarbonyl, p-methoxybenzyloxycarbonyl xykarbonylovou, p-methylbenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, benzhydryloxycarbonyl, t-butoxycarbonyl or 2 2,2-trichloroethoxycarboxylic acid.