CS199670B2 - Method of producing derivatives of 7 beta-/p-hydroxy-phenylmalonamido/-3-substituted thiomethyl-1-oxadethia-3-cephem-4-carboxylic acids - Google Patents

Description

The present invention relates to a process for the preparation of 1-oxadethiationphalosporins, namely derivatives of N - (p-hydroxyphenylmalonamido) -3-substitutedthiomethyl-1-oxadethia-3-cephem-4-carboxylic acids of the general formula I

in which

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

In accordance with the invention, the compounds of formula (I) and pharmaceutically acceptable salts thereof are prepared by producing from a compound of formula (II):

in which

Ar ‘represents a protected p-hydroxyphenyl group α

COB ¹ and COB ² are as defined above, cleavage the protecting group in the Ar 'radical and optionally converting the obtained compound of formula I into its pharmaceutically acceptable salt by treatment with a base.

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) (JC 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. j, and in the Journal of the American Chemical Society, vol. 96, p. 7582 (1974) (BG Christensen et al.

In accordance with the 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 potency (1-thia jcephalosporins), the optically active products produced by the method of the invention are approximately four to eight times more antibacterially effective than the corresponding (1-thia However, the O-lactam ring of 1-oxacephalosporins is less stable (for use in clinical drugs) than the corresponding ring (1-thiajcephalosporins).

The compounds of formula (I) selected from the optically active substances prepared according to the 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,

2) higher stability / Hactam ring,

3) a narrower range of minimum inhibitory concentrations in relation to 6-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 χ / ml or more against Pseudomonas sp. and anaerobic bacteria such as Bacteroides fragilisj, bj higher efficacy 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 cephalosporins, usually containing up to 15 carbon atoms. Individual carboxyl groups in a molecule may be protected with 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 the 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.

Thus, specific examples of the aforementioned protecting groups include esters, including optionally substituted alkyl esters, for example tert-butyl, monohydroxy-tert-butyl or 2,2,2-trichloroethyl, acyloxymethyl, aralkyl esters, for example benzyl, p-tolylmethyl, p-nitrobenzyl. , p-methoxybenzyl ester, phthalidyl ester, diphenylmethyl ester, trityl and phenacyl ester, metal esters, e.g.

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, triethylamine and dlcyclohexylamine. 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 COB ¹ moieties are 5-indanyloxycarbonyl, phenoxycarbonyl or dimethylphenoxycarbonyl.

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

phthalidyl ester, acyloxymethyl ester, indanyl ester, phenyl ester, tolyl ester, dimethylphenyl ester and ethoxycarbonylmethyl ester group.

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.

Compounds of formula I that contain a p-hydroxyphenylmalonamido group at the 7-position 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. They also have a very high potency against Pseudomonas strains, including relevant 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.

Table A

The results of the potency assays of representative compounds of the invention are shown in Table A below. Table B shows the results obtained in analogous assays with comparative, closely related substances.

In vitro tests shall be carried out using the following micro-organisms:

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

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

(4) = Pscudomonas aeruginosa PS-24 (5 µ = E. coli EC-14

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

Antibacterial activity of the compounds of the invention in vitro ((g / ml) and in vivo (mg / kg)

-H

Test substance

B *

(5)

-CH2COOCH3

0.2

0.2

0.2

0.2

0.4

0.4

0.4

0.8

0.4

9.1

0.13

0.38

0.39

Table Β

Antibacterial potency of reference compounds in vitro (.mu.g / ml)

In vitro potency (1) (2) (3)

'CH CONH _Z> 100>100>100>100>100>100>100> 100

CH 2 OOCCH 3

COOH

12.5> 100> 100

7-7 oN.

CHJ

3.2> 100> 100

OO H

Thus, the compounds of formula I are 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 abovementioned salts, including alkali metal salts, are predominantly used. Acyloxymethyl, indanyl, phenyl, phthalidyl and the like esters are also suitable for oral administration. Compounds of formula I may also serve as intermediates for the addition of other useful compounds, whether or not within the scope of formula I.

The protected p-hydroxyphenyl group, in the meaning of the symbol Ar lát, in the starting materials of the general formula II contains a corresponding readily cleavable group as a protecting group. Representative protecting groups include ester-forming groups [including C 1 -C 6 α-haloalkanoyl (for example, trifluoroacetyl or trichloroacetyl), C 1 -C 6 alkanoyl (for example, acetyl or formyl), ^-kethoxycarboxylic acid acyl residues C 4 -C 8 acids (e.g. acetoacetyl), C 2 -C 12 alkoxy carbonyl radicals (e.g. tert-butoxycarbonyl, cyclopropylmethoxycarbonyl, norbornyloxycarbonyl or

2,2,2-trichloroethoxycarbonyl group, C 8 -C 15 aralkoxycarbonyl radicals (for example, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-methylbenzyloxycarbonyl or diphenylmethoxycarbonyl) and similar acyl radicals], including the alkyl-forming groups [1] and the ether-forming groups [1] up to 6 carbon atoms (e.g., methyl, tert-butyl, cyclopropylmethyl, isobornyl, tetrahydropyranyl or methoxymethyl), aralkyl radicals (e.g., benzyl, p-methoxybenzyl, p-methylbenzyl, p-nitrobenzyl, diphenylmethyl or trityl and the like).

The preparation of the starting materials of the general formula (II) is described in our related Czechoslovak patent specification 199 669 and illustrated in the examples below.

In accordance with the invention, the protecting groups are cleaved, for example, by one of the following methods:

(1) cleavage of the acylated derivatives or ethers with an acid (e.g., mineral acid, Lewis acid, strong carboxylic acid or sulphonic acid) or base (e.g., sodium or potassium carbonate, sodium or potassium hydroxide or organic base) at room temperature or elevated temperature, optionally in the presence of a cationic binder, or

2) hydrogenation of p-nitrobenzyloxycarbonylderivatives or benzyloxycarbonylderivatives in a conventional manner with hydrogen in the presence of platinum or palladium.

The compounds of the formula I obtained can be converted into salts in the customary manner, or the carboxyl groups present in them can be cleaved to give free carboxyl groups, or the free carboxyl groups present can be modified 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. This cleavage may be accomplished, for example, by one of the following procedures:

1) highly reactive esters, amides and anhydrides are readily 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 ;

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

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

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 by treatment with the corresponding alcohols together with conventional condensation reagents, 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 on the asymmetric carbon at position a of the amidyl side chain. Both of these isomers are within the scope of the invention and can be separated, if necessary, by chromatography or other conventional means. The nomenclature of the compounds is in accordance with the nomenclature described in Japanese Patent Application Publication No. 49 · -133 594.

Example 1

To a solution of 193 mg of α-diphenylmethoxycarbonyl-p- (p-methoxybenzyl) oxyphenylacetic acid in 2 ml of methylene chloride at 0 ° 0 was added 0.0416 ml of triethylamine and 0.0256 ml of oxalic acid chloride, stirred for 30 minutes and the resulting solution 101.7 mg of diphenylmethyl-7H-amino-7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem-4-carboxylate and 0.024 ml were added to the solution at 0 ° C. After stirring for 30 minutes at 0 ° C, the mixture is diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated, and the residue is chromatographed on 20 g of silica gel containing 10% water, using a mixture of benzene and ethyl acetate ( 4: 1] as eluent to give 190.7 mg (yield 98%) of diphenylmethyl-7H- [α-β- (p-methoxybenzyl) oxyphenyl-α-diphenylmethoxycarbonyl lacetamido] -7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem-4-carboxylate as a colorless foam.

Company ID:

CHCl 3

V max

3420, 3325, 1792, 1730, 1700 (shoulder) cm ^-1 ;

NMR: δ ^CD113 (3.38 singlet-3.40 singlet) 3H,

3.70 singlet 3H,

3.77 singlet 3H,

4.20 singlet 2H,

4.47 singlet 2H,

4.68 singlet 1H,

4.95 singlet 2H,

5.00 singlet 1H.

Example 2

In analogy to Example 1, 800 mg of diphenylmethyl-1H-amino-7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem-4-carboxylate was treated with α- p- (p-methoxybenzyl) oxyphenyl-.alpha.-methoxybenzyloxycarbonylacetyl chloride prepared from 1370 mg of the corresponding free acid and oxalic acid chloride in the presence of 190 mg of pyridine and 0.33 ml of triethylamine in 42 ml of methylene chloride, to give

1.45 g (almost quantitative yield) diphenylmethyl-7β- [η-β- (p-methoxybenzyl) oxyphenyl-α-methoxybenzyloxycarbonylacetamido] -7'-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl -1-oxadethia-3-cephem-4-carboxylate.

Company ID:

CHC13 in max

1792, 1725, 1700 (shoulder) cm ^-1 ;

NMR: δ ^{CDCl 3}

3.45 Singlet 3H / 2

3.48 singlet 3H / 2,

3.78 singlet 6H,

3.82 singlet 3H,

4.27 wide singlet 2H,

4.57 wide singlet 3H,

4.98 singlet 2H,

5.03 singlet 1H,

5.13 singlet 2H,

Example 3

To a solution of 376 mg of .alpha .- (p-benzyloxyphenyl) malonic acid monobenzyl ester in 4 ml of methylene chloride was added 105 .mu.l of triethylamine and 65 .mu.l of oxalic acid under ice-cooling, after stirring for 15 minutes under ice-cooling. diphenylmethyl-7β-amino-7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem-4-carboxylate and 60 µL of pyridine in 7 mL of methylene chloride. The mixture is poured into ethyl acetate at the above temperature, washed with 2N hydrochloric acid, water, 5% aqueous sodium hydrogen carbonate solution and again with water, dried over magnesium sulphate and evaporated. The residue is chromatographed on 20 g of silica gel containing 10% water, of benzene / ethyl acetate (10: 1) as eluent to give 390 mg of diphenylmethyl-7S- [ap- (benzyloxyphenyl) -1'-benzyloxycarbonylacetamldo] -7α-methoxy-3- (1-methyltetraz) ol-5-yl-thiomethyl-1-oxadethia-3-cephem-4-carboxylate as a colorless foam. NMR: δ ^{CDCl 3}

3.38 singlet 3H,

3.62 singlet 3H,

4.13 singlet 2H,

4.25 singlet 2H,

4.56 singlet 1H,

4.96 singlet 3H, ia

5.09 singlet 2H,

6.82 doublet (9 Hz) 2H,

6.84 singlet 1H;

Company ID:

Cl 2 HCl 3

V max

3411, 3326, 1789, 1722, 1700 (shoulder) ^cm-1; [α] D ^{23 -} 72.0 + 2 ° (c = 0.533, chloroform).

Example 4

To a solution of 170 mg of diphenylmethyl-7H- [N - p- (p-inethoxybenzyl) oxyphenyl-.alpha.-diphenylmethoxycarbonylacetamido] -7. Alpha.-methoxy-3- (1-methylthiazol-5-yl) thiomethyl-1- Oxadethia-3-cephem-4-carboxylate in 3.5 mL of methylene chloride was added at 0 ° C with 0.35 mL of anisole and 0.35 mL of trifluoroacetic acid, stirred at 0 ° C for 45 minutes, then the solvent was evaporated. . The residue was triturated with ether to give 91 mg (almost quantitative yield) of 7+ (? -Hydroxyphenyl-4-carboxyacetamido) -7? -Methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem- 4-carboxylic acid as a colorless powder. The product melts at 125-132 ° C with decomposition.

Example 5

In an analogous manner to Example 4, 1.45 g of diphenylmethyl-7 + [N - (p-methoxybenzyl) oxyphenyl -? - methoxybenzyloxycarbonylacetamido] -7? -Methoxy-3- (1-methyltetrazol-5-yl) thiomethyl- of 1-oxadethia-3-cephem-4-carboxylate in 8 ml of methylene chloride is treated at 0 DEG C. for 40 minutes with 4 ml of anisole and 4 ml of trifluoroacetic acid. In quantitative yield, 7+ (α-hydroxyphenyl-α-carboxyacetamido) -7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid melting on decomposition Mp 125-132 ° C. Example 6

To a solution of 100 mg diphenylmethyl-7 + [α- (p-benzyloxyphenyl) -α-benzyloxycarbonylacetamido] -7'-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem- 4-carboxylate in 2 ml of methylene chloride was added with ice-cooling 0.2 ml of anisole and a solution of 250 mg of aluminum chloride in 1.2 ml of nitromethane. After stirring for 2 hours under ice-cooling and stirring at room temperature for 1 hour, the reaction mixture is poured into a 5: 1 mixture of ethyl acetate and methanol, washed with 2N hydrochloric acid and saturated sodium chloride solution, dried over sodium sulfate and concentrated. The residue was washed with ether to give crude 7+ (? -Hydroxyphenyl-α-carboxyacetamido) -7? -Methoxy-3- (1-methyltetrazol-5-yl) thio14 methyl-1-oxadethia-3-cephem-4-carboxylic acid acid.

Company ID:

KBr max

1780, 1719, 1632 cm @ ^1st

Example 7

1) To a solution of 1.20 g of diphenylmethyl-7 + [α- (p-methoxybenzyljoxyphenyl-α-methoxybenzyloxycarbonylacetamido) -7, α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3- of cefem-4-carboxylate in 24 ml of methylene chloride is added 2.4 ml of anisole and a solution of 2.58 g of aluminum chloride in 12 ml of nitromethane at 0 DEG C. under nitrogen, after stirring at 0 DEG C. for 15 minutes. The filtrate was washed twice with 100 ml of methylene chloride, acidified with 2 N hydrochloric acid to pH 2.60 and poured onto a column of 60 ml of highly porous HP-20 polymer. 300 ml of water and eluted with methanol The concentrate was concentrated at room temperature, the residue was taken up in methanol and clarified with charcoal to give 595 mg (88.5% yield) of 7+ (? -Hydroxyphenyl-4-carbonylacetamido) -7a- methoxy-3- (1-methyltetrazol-5-yl) thiome ethyl-1-oxadethia-3-cephem-4-carboxylic acid as a powder · product decomposing at 125-132 ° C.

(2) The same product may be obtained by a procedure analogous to that in (1) above, where benzyl ether is also used instead of p-methoxybenzyl ether,

b) replacing the p-methoxybenzyloxycarbonyl group with a benzyloxycarbonyl group and / or using benzyl ester instead of the diphenylmethyl ester.

Example 8

To a solution of 359 mg of 7 + (N-p-hydroxyphenyl-α-carboxyacetamido) -7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethla-3-cephem-4-carboxylic acid in 7 mL of methanol was added. 1.73 ml of a solution of sodium 2-ethylhexanoate in methanol (2 mol / L) was added at room temperature. After stirring for 10 minutes, the reaction mixture was diluted with ethyl acetate, stirred for 5 minutes, filtered, washed with ethyl acetate and dried. 342 mg (yield 88.8%) of disodium salt of 7 / I- (AP-hydroixyfenyl- _l of carbonization xyacetamido) -7 «methoxy-3- (1-methyl-tetrazol-5-y1) thiomethyl-l-oxadetihia 3-chloro-4-carboxylic acid as a colorless powder melting at 170 ° C with decomposition.

Company ID:

nujol

V max

1768, 1675, 1608 cm ^-1 ;

UV:

. CH3OH

Λ max

273 nm (ε = 11100).

Example 9

To a solution of 836 mg of 7/3 '- [, α-hydroxyphenyl-α-carboxyacetamido] -7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid in A mixture of 15 ml of methylene chloride, 15 ml of ethyl acetate and 10 ml of methanol is added to 950 mg of diphenyldiazomethane After stirring at room temperature for 30 minutes, the reaction mixture is concentrated under reduced pressure and the residue is washed with n-hexane. Elution with benzene / ethyl acetate (1: 1j) gave 1.270 g (95% yield) diphenylmethyl-7/3 ^1- (α-hydroxyphenyl-1-α-diphenylmethoxycarbonylacetamido) -7α-methoxy-3- (1 methyl tetrazol-5-ylthiomethyl-1-oxadethia-3-cephem-4-carboxylate.

Company ID:

CHC13

V max

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

Example 10

CH «

O

N-N

Λ „Λ

CH, (Ar = 4-p-methoxybenzyloxyphenyl,

COB ¹ = p-methoxybenzyloxycarbonyl,

COB ² = tert-butoxycarbonyl)

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 (1.5 equivalents) of triethylamine and 0.252 ml (1.5 equivalents) of oxalic acid, and the resulting mixture was stirred at 0-3 ° C for 2 hours to give a solution of the corresponding acid chloride.

To this acid chloride solution was added a solution of 786 mg of tert-butyl-7S-amino-7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-dethia- while maintaining the temperature at 3-7 ° C. Of 1-oxa-3-cephem-4-carboxylate in 25 ml of dichloromethane containing 239 μΐ (1.5 equivalents) of pyridine, the reaction mixture is stirred at 3 ° C for 30 minutes and then evaporated in vacuo. The residue was dissolved in a mixture of 150 ml of ethyl acetate, 15 ml of 6 N hydrochloric acid and 150 ml of ice-water, the resulting mixture was shaken and the organic layer was separated. The organic phase is washed with ice-water, aqueous sodium bicarbonate and again with water, dried and concentrated to a residue of 2.16 g. This residue, after chromatographic purification, yields 1.61 g (100% yield) of tert-butyl ester 7β. - [2- (4-p-methoxybenzyloxyphenyl) -2-p-methoxybenzyloxycarbonylacetamido] -7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid. constants of this product are listed in the following table under No. 1.

Another product is prepared in an analogous manner, the physical constants of which are also shown in the following table.

In the table below, each abbreviation has the following meanings:

PMB = ^1- p-methoxybenzyl

Bu = butyl s = singlet m = 'multiplet s and o Λί II'

N

X

0>

Dl dl .. o a >> <O O

PS o n n S> u

PQ

O

O pq

O o

at

OT what '£ £

what £ ~ 23 ¹⁰ ! CO £

l> p

UM HM r * U * H HM HH UM HM * "* (W HM HM HM UM Hrl hrl UM γΉ

UuHMCr *> ^ - uMHMulM> JMHM —j — umuImhUm-iumhmhmum— CDCD1gCMCMrHOJCM ^ JjCOCOCOCMCOCOCMCO ¹ ^

E> CO CO t t> CM l> t> CM I O OCOOOLOOmm I LO CO (N CO CO O O) v H W erf 0 0 CO CO ^ CO L O C3 r- ^ CO ^ 03 r-Γ co> - ' what 'Φ' ψ · φ m what '-' what what * φ 'Φ irf m in what in oo oo O Ή what what CO rH oV

CO rH co t> CO Ή pq

AFTER

P0

AND

O

O o

X

WHAT

O

O

WITH

AFTER

C after cq

X

AT

I o

o o

§

Oo

I o

o o

HERE

X what about

O

AFTER

PO k

Example 11

Cleavage of tetrahydropyranyl ether group

(1) To a solution of 5.65 g of diphenylmethyl 7 _J S - ( «- p-tetrahydropyranyloxyphenyl-.alpha.-difenylmethoxykarbonylacetamido) -7a-methoxy-3- (l-methyl-tetrazol-5-yl) thiomethyl-1-dethia-l-oxa Of 3-cephem-4-carboxylic acid in 50 ml of acetone at 0 ° C under nitrogen is added 1.25 ml of 6 N hydrochloric acid, the reaction mixture is stirred at room temperature for 25 minutes, then diluted with ethyl acetate, washed with water and After drying over sodium sulfate, it is evaporated. 4.37 g of crystalline N - (? - (? -Hydroxyphenyl-α-diphenylmethoxycarbonylacetamido) -7? -Methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-dethia-1-oxa-3-cephem) diphenylmethyl ester are obtained. -4-carboxylic acids.

(2) In a similar manner, by the twenty minute partial hydrolysis of the tetrahydropyranyl ether group in diphenylmethyl 7β- (α-tetrahydropyranyloxyphenyl-α-methoxybenzyloxycarbonylacetamido) -7'-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-dethia -oxa-3-cephem-4-carboxylic acid (970 mg) in 10 ml of acetone by treatment with 0.25 ml of 6 N hydrochloric acid at 0 ° C gives 820 mg of crystalline diphenylmethyl 7β- (α-hydroxyphenyl-α-methoxybenzyloxycarbonylacetamido) - 7α-Methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-dehia-1-oxa-3-cephem-4-carboxylic acid.

COB ¹ = - COOCH (C 6 H 5) 2

IC:

nujol

V max

NMR:

f CD 3 COCD 3 0 ppm

3.56, singlet, 3H,

3.86, singlet, 3H,

4.28, singlet, 2H,

4.58, singlet, 2H,

4.83, singlet, 1H,

5.10, singlet, 1H.

c oeL-c oo och

Company ID:

by nujol O max

3380, 3280, 1780, 1752, 1718, 1690 cm

NMR:

CD3OD In ppm

3.37, singlet, 3H,

3.70, singlet, 3H,

3.80, singlet, 3H,

4.13, singlet, 2H,

4.43, singlet, 2H,

5.00, singlet, 1H,

5.03, singlet, 2H.

3295, 1795, 1768, 1730, 1705, 1677 cm ^-1 ;

PBM = p-methoxybenzyl

Tetr = 1-methyltetrazol-5-yl (1) R = triethylsilyl

To a solution of 100 mg of 7β- (ap-triethylsilyloxyphenyl-α-methoxybenzyloxycarbonyl lacetamido} -7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid diphenylmethyl ester in 1 1 ml of trifluoroacetic acid is added at 0 DEG C., the reaction mixture is stirred at 0 DEG C. for 30 minutes and then concentrated to dryness in vacuo to give 52.5 mg of 7 / 2- (ap. -hydroxyphenyl-1-carboxyacetamido) -7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid.

Yield 93%. The product was identified by comparison with an authentic sample.

(2) R = tert-butyl (dimethyl) silyl

Analogous to (1j) with 100 mg of diphenylmethyl N - (? - tert -butyldimethylsilyloxyphenyl-? - methoxybenzyloxycarbonylacetamido) - 7a-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3- of cefem-4-carboxylic acid in 1 ml of anisole was treated with 1 ml of trifluoroacetic acid at 0 ° C for 30 minutes and the mixture was worked up analogously to (1j) to give 51.4 mg (91% yield) of the product identical to the product obtained in the previous paragraph (ij. Example 13)

COOH

Tetr = 1-methyltetrazol-5-yl

Ph = phenyl

To a solution of 200 mg of 7β- (ap-tert-butoxyphenyl-α-tert-butoxycarbonyl lacetamido] -7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid diphenylmethyl ester of acid in 2 ml of anisole is added 300 mg of aluminum chloride at -20 DEG C., the reaction mixture is stirred at 0 DEG C. for 1 hour, then diluted with 4 ml of ethyl acetate, stirred for 15 minutes and then acidified with 0.2. ml of 6 N hydrochloric acid in 2 ml of water, the separated organic layer was washed with saturated sodium chloride solution and extracted with 5% sodium hydrogen carbonate solution, and the extract was acidified with dilute hydrochloric acid to pH

1.5 and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried over magnesium sulfate and concentrated. 98 mg (yield

%) N - (α-hydroxyphenyl-α-carboxyacetamido) -7'-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid identical to the authentic sample prepared according to the previous example.

Example 14

To a solution of 1.0 g of 7β- (α-p-hydroxyphenyl-α-carboxyacetamido) -7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cefem-4- of carboxylic acid in 6 ml of N, N-dimethylformamide was added with stirring and ice-cooling 832 mg of phthalidyl bromide, 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 organic layer was separated, washed with water and brine, dried (MgSO 4) and concentrated. The residue, 1.39 g, was chromatographed on 42 g of silica gel containing 10% water, eluting with benzene / ethyl acetate (1: 1j) to give 1.06 g of a powdered product (I, COB ¹ = COB ^2). = phthalidyloxycarbonyl-containing 282 mg of isomer A (less polar fraction) and 164 mg of isomer B (polar fraction) differing in side chain configuration These isomers can be isolated by preparative thin layer silica gel chromatography using ethyl acetate as the solvent system, (isomer A)

NMR:

g CD5COCD3 (3.20 singlet-t-3.23 singlet) 3H,

3.37, singlet, 3H,

4.40, broad singlet, 2H,

4.63, broad singlet, 2H,

5.05, broad singlet, 2H,

6.8—8.0, multlplet.

Company ID:

nujol

V max

1790, 1750 (arm), 1700 cm ¹ .

(isomer B)

NMR: δ ^{CD 3 COCD!}

3.17, wide singlet, 3H,

4.00, singlet, 3H,

4.20 - 4.65, multiplet, 4H,

5.03, broad singlet, 1H,

6.7-8.4, multiplet.

Company ID:

nujol

V max

1790, 1750 (shoulder), 1700 cm ^-1 . Example 15 (1) To a solution of 550 mg of 7β- (α-p-hydroxyphenyl-α-carboxyacetamido) -7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3- cefem-4-carboxylic acid in N, N-dimethylformamide (3 ml) was added with stirring and ice-cooling 0.2 ml of acetoxymethyl bromide, stirred at room temperature for 30 minutes, then diluted with ethyl acetate, washed successively with dilute hydrochloric acid, aqueous sodium hydrogencarbonate solution, water and brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was chromatographed on 25 g of silica gel containing 10% water, eluting with benzene / ethyl acetate (1: 1). 285 mg of 7 / 3- (α-β-hydroxyphenyl-1-α-acetoxymethoxycarbonylacetamido) -7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cefem acetoxymethyl ester powder was obtained. -4-carboxylic acid (I, COB COB = ^{1 2} = acetoxymethoxykarbonyl). NMR: δ ^CD3COCD3 (2.05 singlet-t-3.32 singlet- | -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.

Company ID:

nujol

V max

1790 (shoulder), 1760, 1690 cm ^-1 .

(2) A small amount of monoacetoxymethyl ester (side chain) is obtained from the alkaline wash liquors and treated with diphenyldiazomethane to form diphenylmethyl ester 7β- (α-hydroxyphenyl-α-acetoxymethoxycarbonylacetamido) -7 α-methoxy-3- (1- methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid.

NMR: δ ^{CDCl 3}

2.00, singlet, 3H,

3.47, singlet, 3H, (3.73 singlet + 3.77 singlet) 3H,

4.17, singlet, 2H,

4.47, broad singlet, 2H,

4.53, broad singlet, 1H,

5.00, singlet, 1H,

5.73, singlet, 2H,

6.5-7.0, multiplet.

Company ID:

CHCls max

1790, 1730, 1705 (shoulder) cm ^-1 .

Claims (1)

PREDM8T VYNALEZU A process for the preparation of 7β- (p-hydroxyphenylmalonamido) -3-substituted-thiomethyl-1-oxadethia-3-cephem-4-carboxylic acid derivatives of the general formula I. in which 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 or a phthalidyl ester, and pharmaceutically acceptable base salts thereof. II ch ₃ (ti) in which Ar 'is a protected p-hydroxyphenyl group and COB ¹ and COB ² are as defined above, cleaves the protecting group in the Ar' radical and the compound of formula I obtained is optionally converted by treatment with a base into its pharmaceutically acceptable salt.