DK161331B - METHOD OF ANALOGY FOR THE PREPARATION OF 7BETA-SUBSTITUTED MALONAMIDO-1-OXADETHIA-7ALFA-METHOXY-3- (1-METHYLTETRAZOL-5-YL) THIOMETHYL-CEPHALOSPORINES - Google Patents

Description

in DK 1613b1 δ

The present invention relates to an analogue and process for the preparation of novel 7β-substituted malonamido-1-oxadethia-7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-cephalosporins having the following formula 5

OCH3 N-N

ToB2 CH3 17 wherein COB and COB are separately carboxy or carboxy protected as esters or pharmaceutically acceptable salts, the process being characterized by the characterizing part of the claim.

Cephalosporin analogs containing oxygen instead of sulfur in the nucleus are described in Journal of Heterocyclic Chemistry, Vol. 5, p. 779 (1968) by J.C. Sheehan and M. Dadic, German Patent Application No. 2,219,601 (1972), Canadian Journal of Chemistry, Vol. 52, p.

3996 (1974) by Saul Wolfe et al., And Journal of the American Chemical Society, Vol. 96, p. 7582 (1974) by B.G. Christensen et al.

The inventors of the present invention have now prepared various 1-oxadethiacephalosporins which are closely related to known 1-thiacephalosporins. Contrary to what is stated by B.G.

Christensen et al., Namely that their racemic 1-oxacephalosporins exhibited about half the strength of 1-thiacephalosporins, the other inventors of the above inventors made optically active products about 4-8 times as active as the corresponding 1-thiacephalosporins in their antibacterial properties. . However, the β-lactam ring of these 1-oxadethiacephalo-sporins was less stable when used as clinical medications than the 1-thiacephalosporins.

The present compounds (I) selected from the optically active compounds resolve this deficiency by 1-oxadethiacephalo-35 sporins.

Further, compounds (I) when compared to other 1-oxadethiacephalosporins exhibited the following characteristics:

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2 1) stronger antibacterial activity against Gram-negative bacteria, 2) higher stability of the / 3-1 actam ring, 3) narrower minimal in-concentration concentration of / J-lactamase-producing and non-producing bacteria, 5 4) less dependence of inoculum size, 5) higher efficacy against bacteria resistant to certain other cephalosporins (e.g. Enterobacteria, Serratia, indole-positive Proteus), 6) higher bactericidal contribution, and 7) higher bl odds. concentration.

In addition, compounds (I) have the following advantages: a) wider antibacterial spectra (e.g., 3.6 7 / ml or more against Pseudomonas sp., Anaerobic bacteria (Bacteroid fragi li s), b) higher potency against / Mactamase-producing bacteria, c) higher blood stability, and d) lower binding with serum proteins.

1 2

The groups COB and COB can be carboxy or carboxy protected as esters or pharmaceutically acceptable salts which are common in the chemistry of penicillins and cephalosporins and usually contain 20 up to 15 carbon atoms. The protecting groups may be the same or different for each carboxy in the molecule. Usually, the protective esterifying groups are removed to form free carboxy or salts at any desired step of the synthesis to prepare the compounds (I). Therefore, the structure of these carboxy protecting groups may be widely different without altering the main point of the invention.

In other words, their structures have no particular significance other than having to serve for protection, deprotection and any salt formation.

Examples of specific protecting groups are esters (comprising any substituted alkyl esters, e.g. t-butyl, monohydroxy-t-butyl, 2,2,2-trichloroethyl and acyloxymethyl esters, aralkyl esters , for example, benzyl, p-tolylmethyl, p-nitrobenzyl, p-methoxybenzyl, phthalidyl, di phenylmethyl, trityl and phenacyl esters, metal esters, for example trimethylsilyl, dimethylmethoxysilyl and trimethyl stannyl esters, and other readily removable aliphatic esters, as well as aromatic esters such as phenyl, tolyl, 3,4-dimethyl phenyl and 5-indanyl esters) and pharmaceutically acceptable salts (including alkali metal salts, e.g. and potassium salts, terrestrial potassium salts, for example magnesium, calcium and acyloxycalcium salts, and salts with organic bases, e.g.

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3 cain, tri ethylarnine and dicyclohexylamine). Each carboxy in the molecule may be free or protected by the same or different groups.

i p

Preferably, COB and COB may be free carboxy or pharmaceutically acceptable salts thereof. Other preferred COB * groups are 5-indanyloxy-carbonyl, phenoxycarbonyl or dimethylphenoxycarbonyl.

Usually, compounds (I) are delivered as salts for administration to humans or veterinary individuals. Most preferred salts are sodium or potassium salts or salts with certain organic bases. They are selected for safety, solubility, stability, etc.

Compounds (I) are potent antibacterial drugs against Gram negative bacteria and at the same time show less activity loss at higher inoculum size and show stronger anti-infective effect in vivo than expected from in vitro data due to their ability to achieve a higher blood concentration.

Compounds (I) which have β-hydroxyphenylmalonamido at the 7-position are potent antibacterial agents that are less deactivated in live animals because of their lower protein binding and because of their higher blood concentration than the corresponding unsubstituted arylmalonamido form. connections. They also exhibit highly intensified activity against Pseudomo-20 nas strains, including those resistant to carbenicillin.

Compounds (I) are novel compounds that exhibit strong antibacterial activity against Gram-positive and Gram-negative bacteria and are useful medications and veterinary drugs. Eg. they are usually administered orally or parenterally to humans or animals at a daily dose of e.g. 0.05 to 50 mg / kg body weight to treat or prevent bacterial infection.

The compounds (I) are usually supplied in small glass containing sterilized microcrystals or sterilized lyophilate and are given as solutions prepared before use. Furthermore, an effective amount of the compounds can usually be administered orally or parenterally with pharmaceutically acceptable carriers, thinners or stabilizers in the form of compositions such as e.g. small vials, injections, ointments, solutions, tablets, powders and capsules. They may be in unit dosage form. The salts, comprising alkali metal salts, are mainly used for parenteral administration. The acyloxymethyl, indanyl phenyl, phthalidyl esters, as well as similar esters, are also suitable for oral application.

The compounds (I) can e.g. is prepared by a process which

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4 is characterized by reacting an amine having formula (II) ° CH 3. "2Nj = 0i η 0 ^^ Η β (II) COB CH3 10 2 wherein COB has the meaning previously defined, with a p-hydroxyphenyl-substituted malonic acid having formula (III)

H0 \ VHC00H

In (III) COB1 wherein COB1 is as previously defined, or reactive derivatives thereof.

The amino group at the 7-position of the amine (II) may be activated by a silyl or stannyl group or be protected or activated by the 1-haloalkylidene, 1-alkoxyalkylidene, alkylene, carbonyl, easily leaving acyl or similar groups to the acylation.

When the arylmalonic acid (III) is used as the free acid, the acylation is carried out in a solvent (especially nitrile, ether, amide or halohydrocarbon or mixtures thereof as solvent) in the presence of a condensing reagent [e.g. Ν, Ν'-dialkylcarbodiimide (e.g., Ν, Ν'-di-cyclohexylcarbodiimide); carbonyl compound see (e.g. carbonyl di imidazole); acylamine (e.g., 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline); isoxazazolinium salt (e.g., N-ethyl-5-phenylisoxazolinium-3sulfonate, N-t-butyl-5-methylisoxazolium perchlorate) or other condensing reagent] at ca. -10 ° to approx. 70 °.

When the arylmalonic acid (III) is used in the form of a reactive derivative for the acylation, this may be an anhydride [e.g. mixed anhydride with 35 alkyl carboxylic acid, aral cool carbonic acid, hydrogen hal andenic acid (acid halide), hydrogen azide (acid azide), phosphoric acid, phosphoric acid, sulfuric acid, sulfuric acid, hydrogen cyanide (acid cyanide), symmetric interim)! acyl anhydride, mixed anhydride with al in fatty or aromatic, especially sulphonic or carboxylic acid, special intramolecular anhydride such as ketene, isocyanate or similar reactive anhydride], a reactive ester [e.g. an enol ester, aryl ester (e.g. pentachlorophenyl, p-nitrophenyl, 2,4-dinotrophenyl, benzotriazole ester)], a diacylimino ester, a reactive amide [e.g. amide with imidazole or triazole, reactive amide, e.g. 2-ethoxy-1,2-dihydroquinoline-1-amide] or a formiminoderate (e.g., N, N-dialkyliminomethyl ester, N, N-diacylaniline).

If necessary, these acylating reagents can be used in the presence of an acid receptor [e.g. inorganic base (e.g. hydroxide, carbonate or hydrogen carbonate of all potassium metals or terrestrial potassium metals), organic base (e.g. tertiary amine, aromatic base), alkylene oxide (e.g. ethylene oxide, propylene oxide), amide ( e.g., Ν, Ν-dimethylformamide, hexamethylphosphoric triamide), or other acid receptor] or a molecular sieve, preferably in a solvent (especially ketone, ester, ether, nitrile, amide or halohydrocarbon solvent or mixture thereof).

The compounds prepared can first be protected by the hydroxy group having a readily cleavable, protecting group and subsequently deprotected to form the desired p-hydroxyphenyl compounds. Representative protecting groups may be those which form ester [comprising Cj_ 20 α-haloalkanoyl (e.g., tri-fluoroacetyl, trichloroacetyl), Cj g g alkanoyl (e.g., acetyl, formyl), C ^ / / J-ketocarboxylacyl ( e.g. acetoacyl), C12 alkoxycarbonyl (e.g. tbutoxycarbonyl, cyclopropylmethoxycarbonyl, norbornyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl), C 1-6 alkoxycarbonyl (e.g. benzyloxycarbonyl, p Or p-methylbenzyloxycarbonyl, diphenylmethoxycarbonyl) and similar acyls] and ethers [comprising C 1-6 alkyl (e.g., methyl, t-butyl, cyclopropylmethyl, isobornyl, tetrahydropyranyl, methoxymethyl), C 1-8 aralkyl (benzyl, p-methoxy) -, p-methyl or p-nitrobenzyl, diphenylmethyl, trityl) and similar groups]. Preferably, the protecting group may be introduced into the step of the arylmalonic acid (III) or reactive derivatives thereof. The deprotection is carried out by e.g. 1) cleavage of acylates or ethers with an acid (e.g., mineral acid, Lewis acid, strong carboxylic acid, sulfonic acid), or base (sodium or potassium carbonate, hydroxide, organic base) at room temperature or elevated temperature, if or 2) hydrogenation of p-nitrobenzyl-oxycarbonyl or benzyloxycarbonyl with hydrogen and platinum or palladium in a conventional manner.

When the carboxy group is in the 4-position or in the side chain at the 7-position,

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If the compound is protected, the protecting group may be removed to form the free acid compounds (I) in conventional manner to remove the protecting groups. 1) readily hydrolyze highly reactive esters with an acid or base; 2) cleave 2-haloethyl, benzyl, methyl benzyl, nitrobenzyl and di arylmethyl esters by mild reduction (e.g. with tin, zinc or divalent chromium salts in the presence of acids, with sodium dithionite, by catalytic hydrogenation with hydrogen over catalyst, e.g., platinum, palladium, nickel), 3) benzyl, methoxybenzyl, methyl benzyl, dimethoxybenzyl, t-alkyl, triethyl, diarylmethyl and cyclopropylmethyl esters by the action of acids or by solvolysis (eg with mineral acids such as hydrochloric acid, Lewis acids, eg aluminum chloride, sulphonic acids, eg toluene-p-sulfonic acid , highly acidic carboxylic acids, e.g., trifluoroacetic acid, formic acid, if necessary in the presence of a cation acceptor, e.g., anisole), 4) phenacyl-, ethynyl-, p-hydroxy-3,5-di-t -butylbenzyl esters by the action of base (eg, all potassium metal thiophene oxides, inorganic base, basic salts) or by similar methods.

The compounds (I) with one or two free carboxy groups can be converted to salts by the action of all potassium hydroxides, carbonates or alkanoate salts or by the action of organic bases, ion exchange resins.

The following examples will illustrate in detail the present invention. In each example, the elemental analyzes and physical constants of the products are consistent with the given structures. In the following examples, the products usually contain an approximately equal amount of the isomeric compounds of α-asymmetric carbon in the amide side chain. The preparation of both the isomers is within the scope of the invention and, if necessary, is separated by chromatographic technique or other conventional methods. The nomenclature is in accordance with Japanese Specification No. 49-133594.

The following example illustrates the preparation of 7β-amino compounds.

Example 1 (1) For a solution of diphenylmethyl-7) 3-phenylacetamido-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem-4-carboxylate (955)

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7 mg) in methylene chloride (24 ml) is added phosphorus pentachloride (666 mg) and pyridine (0.258 ml) in nitrogen gas at -20 °. After stirring at -20 ° for 30 minutes and at room temperature for 30 minutes, the mixture is mixed with methanol (12 ml) at -20 ° and stirred at room temperature for 30 minutes.

The reaction mixture is diluted with water (6 ml), stirred for 30 minutes and concentrated under reduced pressure. The residue is dissolved in 5% aqueous sodium bicarbonate solution under ice-cooling and extracted with ethyl acetate. The extract is washed with water, dried over sodium sulfate and concentrated under reduced pressure. The precipitated crystals are collected by filtration and washed with ether to give diphenylmethyl-7β-amino-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethi-3-cephem-4-carboxylate (661 mg). Melting point 151 - 156 °. Yield: 86.5%.

IR: 7ClNx3 3420> 3345> 1790> 1718 '1630 cm-1 NMR: δ CDCl3 1.75, broad s, 2H, 3.81, s, 3H, 4.28, broad s, 2H, 4.50, d , (4Hz) 1H, 4.64 wide s, 2H, 4.98, s, (4Hz) 1H, 6.90, s, 1H, 7.20 -7.70, m, 10H.

UV: CH CH₂] S SO 286 nm (e = 8695).

[.alpha.] D @ 25-232.8 ± 7.6 ° (c = 0.360, (CH3) 2 SO).

The following example illustrates the introduction of 7or-methoxy.

25

Example 2 (1) A solution of diphenylmethyl-7β-amino-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem-4-carboxylate (600 mg) and 3,5-di -t-Butyl-4-hydroxybenzaldehyde (353 mg) in a mixture of benzene (15 ml) and 30 methylene chloride (5 ml) is heated under reflux for 1 hour while removing water by molecular sieve in a Dean Stark water -udskiller. The resulting solution of diphenylmethyl-7> 3- (3,5-di-t-butyl-4-hydroxybenzal) amino-3- (1-methyltetrazol-5-yl) thio-methyl-1-oxadethi-3-cephem -4-carboxylate is cooled at -10 to -15 °, mixed with anhydrous magnesium sulfate (1 g) and then with nickel peroxide (0.69 g) with stirring, and stirred at -10 to -15 ° for 30 minutes and at room temperature for 15 minutes. The reaction mixture is filtered and the solid is washed with benzene. For the resulting solution of diphenylmethyl-7- (3,5-di-t

8 DK 161331B

ethyl 4-oxo-2,5-cyclohexadienylidenemethyl) imino-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem-4-carboxylate is added to methanol (10 ml) and the solution is allowed to stand at room temperature. for 1 hour and concentrated to dryness under reduced pressure. The residue is chromatographed on silica gel (30 g) containing 10% water and eluted with a mixture of benzene and ethyl acetate (4: 1) to give diphenylmethyl-7 / 1- (3,5-di-t-butyl) 4-hydroxybenzal) amino-7α-methoxy-3-carboxylate (906 mg) as a practically pure yellow foam. Yield: 99.7%.

(2) To a solution of the above product in a mixture of methanol (10 ml) and tetrahydrofuran (5 ml), add Girard T reagent (315 mg) and stir the mixture for 1 hour at room temperature, dilute with water and extract with methylene chloride. The extract is washed with water, dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue is purified by chromatography on silica gel (30 g) containing 10% water 15 and eluted with a mixture of ethyl acetate: benzene: methylene chloride (1: 1: 1) to give diphenylmethyl-7 / J-amino-7a-methoxy-3- (1-methyl-tetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem-4-carboxylate (469 mg). Total yield for this example: 73.6%, mp 160 - 162 ° (decomp.).

IR: δax 3 3425, 3350 '1792' 1724 cm NMR: δCDC13 2.00, broad s, 2H, 3.38, s, 3H, 3.87, s, 3H, 4.32, s, 2H, 4 , 73, s, 2H, 4.92, s, 1H, 7.00, s, 1H.

25

As can be seen from the above example, nickel peroxide has been found to be one of the best oxidation reagents for the phenolic intermediate for introducing a methoxy group at the 7a position in 1-oxa and also 1-thia cephem rings.

30

Example 3

To a solution of α-diphenylmethoxycarbonyl-α-β-hydroxyphenyl acetic acid (254 mg) in methylene chloride (3 ml) is added triethylamine (0.083 ml) and oxalyl chloride (0.051 ml) at 0 °. After stirring for 15 minutes, the mixture is added to a solution of di-phenyl methyl-7β-amino-7α-methoxy-3- (1-methyltetrazol-5-yl) -thiomethyl-1-oxadethia-3-cephem-4 carboxylate (101.7 mg) and pyridine (0.048 ml) in methylene chloride (4 ml) at 0.

After stirring for 30 minutes at 0 °, the mixture is diluted with ethyl acetate.

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9, washed with aqueous sodium bicarbonate, water, hydrochloric acid and water, dried over sodium sulfate and evaporated under reduced pressure. The residue obtained is chromatographed on silica gel (20 g) containing 10% water and eluted with a mixture of benzene and ethyl acetate (2: 1) to give diphenylmethyl-7β- (α-diphenylmethoxycarbonyl-ap-hydroxyphenyl-acetamido). ) -7a-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem-4-carboxylate (86.4 mg) as colorless foam, yield: 49.6%.

IR: ymx3 3585> 3315, 179 ° 1722> 1700> shoulder cm -1.

NMR: 6CDCl 3 (3.45, s + 3.48, s) 3H, (3.72, s + 3.75, s) 3H, 4.18, s, 2H, 4.45, s, 2H, (4.67, s + 4.70, s) 1H, 5.02, s, 1H.

Example 4 To a slurry of α- (5-indanyl) oxycarbonyl-ap-hydroxyphenyl acetic acid (370 mg) in methylene chloride (4 ml), triethylamine (139 µl and oxalyl chloride (85 µl)) is added at 0 °. nitrogen to form a clear solution. After stirring for 20 minutes at 0 °, the mixture is added to a solution of diphenylmethyl-7/1-amino-7a-methoxy-3- (1-methyltetrazol-5-20 yl) -thiomethyl-1 -oxadethia-3-cephem-4-carboxylate (203 mg) in methylene chloride (5 ml) and pyridine (80 μΐ) and the mixture is stirred for 10 minutes. The reaction mixture is diluted with ethyl acetate, washed with 2N hydrochloric acid, water, 5% aqueous. sodium bicarbonate solution and water, dried over sodium sulfate and concentrated under reduced pressure to give pale yellow foam which is chromatographed on silica gel (50 g) containing 10% water and eluted with a mixture of benzene and acetic acid (1: 1) to form diphenylmethyl 7j8 - [> - p-hydroxyphenyl-a- (5-indanyl) oxycarbonyl-acetamido] -7a-methoxy-3- (1-methyl-tetrazol-5-yl) for omethyl-1-oxadethi α-3-cephem-4-carboxylate as crystalline residue (230 mg, yield: 71.6%), which is recrystallized from a mixture of chloroform and ether to give pure crystals, melting at 114 DEG. 116 °.

UV; [Α] 272 = 9500 (284 = 9260) nm * 35 NMR: δCD3COCD3 δ, 1, m, 2H, 2.87, t, (7Hz) 4H, 3.43, s, 3H, 3.91, s , 3H,

4.31, s, 2H, 4.65, s, 2H, 5.07, s, 1H, 5.13, s, 1H, 6.92, wide s3H

IR: ¾ 3590, 3335, 1789, 1736, 1722, 1700, 1601 cm -1.

ΠΙοΧ

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10

Example 5

For a solution of diphenylmethyl-7β- [at- (p-benzyloxyphenyl) -α-benzyloxycarbonylacetamido] -7α-methoxy-3- (1-methyltetrazol-5-yl) thio-methyl-1-oxadethia-3-cephem -4-carboxylate (100 mg) in methylene chloride (2.5 ml) is added anisole (0.2 ml) and a solution of aluminum chloride (250 mg) in nitromethane (1.2 ml) under ice-cooling. After stirring for 2 hours under ice-cooling and for 1 hour at room temperature, the mixture is poured into a mixture of ethyl acetate and methanol (5: 1), washed with 2N hydrochloric acid and saturated brine, dried over sodium sulfate and concentrated.

The residue is washed with ether to give 7β- (ap-hydroxyphenyl-α-carboxyacetamido) -7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxa-dethia-3-cephem. 4-carboxylic acid (35 mg).

IR 1780 1719> 1632 cm -1.

max. Example 6

To a solution of diphenylmethyl-7β- [ap- (p-methoxybenzyl) oxyphenyl-2-di-phenylmethoxycarbonylacetamido] -7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3- cephem-4-carboxylate (170 mg) in methylene chloride (3.5 ml) is added anisole (0.35 ml) and trifluoroacetic acid (0.35 ml) at 0 ° and the mixture is stirred for 45 minutes at 0 °. After evaporation of the solvent, the product is triturated to give 7β- (ap-hydroxy-phenyl-α-carboxyacetamido) -7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem 4-carboxylic acid (91 mg) as colorless powder, yield: about quantitative, m.p. 125-132 ° (decomposition).

25

Example 7

In a process similar to that described in Example 6, diphenylmethyl-7β- [α-ρ- (p-methoxybenzyl) oxyphenyl-α-pmethoxy-benzyloxycarbonylacetamido] -7α-methoxy-3- (1-methyltetrazol-5-yl) ) -thio-methyl-1-oxadethia-3-cephem-4-carboxylate (1.45 g) with anisole (4 ml) and trifluoroacetic acid (4 ml) in methylene chloride (8 ml) at 0 ° for 40 minutes to form of 7β- (ap-hydroxyphenyl-α-carboxyacetamido) -7α-methoxy-3- (1-methyltetrazol-5-yl) -thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid, m.p. 125-132 ° (decompos! ng), yield: quantitative.

Example 8 1) For a solution of diphenylmethyl-7β- [Q1-p- (p-methoxybenzyl) oxy-phenyl-α-p-methoxybenzyloxycarbonyl-acetamido] -7α-methoxy-3- (1-methyl te-11

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trazol-5-yl) thiomethyl-1-oxadethia-3-cephem-4-carboxylate (1.20 g) in methylene chloride (24 ml) is added anisole (2.4 ml) and a solution of aluminum chloride (2.58 g) in nitromethane (12 ml) at 0 ° under nitrogen. After stirring for 15 minutes at 0 °, the mixture is poured into cold 5% aqueous sodium hydrogen carbonate solution (100 ml) and filtered to remove the resulting precipitate. The filtrate is washed twice with methylene chloride (2 x 100 ml), acidified with 2N hydrochloric acid to pH 2.60 and poured into a column of highly porous polymer HP-20 (60 ml) sold by Mitsubishi Chemical Industries, Ltd. . The column is washed with water (300 ml) and eluted with methanol. The eluate is concentrated under reduced pressure at room temperature. The residue is dissolved in methanol, treated with activated carbon and concentrated under reduced pressure to give 7β- (α-ρ-hydroxyphenyl-α-carboxyacetamido) -7α-methoxy-3- (1-methyl-tetrazol-5-yl) thiomethyl 1-oxadethia-3-cephem-4-carboxylic acid as powder (595 mg) decomposing at 125 - 132 °, yield: 88.5%.

2) The same product can be prepared by a process similar to that described in 1) above, in which a) p-methoxybenzyl ether is replaced by benzyl ether, b) p-methoxybenzyloxycarbonyl group is replaced by benzyloxy-carbonyl group, and / or c) di phenylmethyl ester is replaced by benzyl ester.

Example 9

To a solution of 7β- (ap-hydroxyphenyl-α-carboxyacetamido) -7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid (359 mg ) in methanol (7 ml) is added a solution of sodium 2-ethyl hexanoate in methanol (2 mol / liter; 1.73 ml) at room temperature.

After stirring for 10 minutes, the reaction mixture is diluted with ethyl acetate, stirred for 5 minutes, and filtered to collect separated solid, which is washed with ethyl acetate and dried to give the disodium salt of 7 / S- (o-p-hydroxyphenyl). [(Carboxyacetamido) -7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid (342 mg), yield: 88.8%, colorless powder, melting point decomposition from 170 °.

IR: γΝυίη ° χ1768 '1675' 1608 cm] -UV: fiCHSiax max 273 nm = 1110 °) · 35

Claims (1)

Wherein O CO and COB are individually carboxy or carboxy protected as esters or pharmaceutically acceptable salts, characterized in that a) is reacted with a carboxy or a carboxy. amine of formula and 3S-5S-VS in 3 O3 YLc "2SJI] on COb2 éH3 2 wherein COB has the above meaning, with a p-hydroxyphenyl-substituted malonic acid compound of formula H0 ~" ~ CHC00H I (ΠΙ) COB1 wherein COB1 has the meaning given above, or a reactive derivative thereof, or b) removes the protecting group on Ar 'with acid, base or by hydrogenation in a compound of formula pCH3 Ar' CHCONIL in J33L / V ™ COB2 CH3 wherein Ar 'is β-protected hydroxyphenyl and COB and COB have the meanings set forth above.