HU196412B - Process for production of penicillin-acid-penicillakiroloximethil-esthers - Google Patents

Abstract

FIELD OF THE INVENTION The present invention relates to an antibacterial compound of formula (III) wherein X is a compound of formula (b) wherein R2 in the formula (b) is hydrogen or a hydroxyl group for the preparation of penicillic acid penicillanoyloxymethyl derivatives. The process according to the invention is characterized in that the compound of formula (IV) wherein Y is chlorine, bromine or iodine is fumigated in a neutral solvent at room temperature with a compound of formula (V) wherein R a is C 1-4 alkyl and X is reacted with at least the same amount of the above compound at a temperature of -20 ° C to + 25 ° C. 196412 -1-

Description

The present invention relates to new penicillanic acid penicillanoyloxymethyl esters of the formula (I). These compounds show antibacterial activity.

Although the penicillin and cephalosporin derivatives, these beta-lactam backbone antibiotics are widely used to combat bacterial infections, some members of these two families of compounds are ineffective against certain resistant (resistant) microorganisms because they produce a beta-lactamase enzyme breaking down the beta-lactam backbone antibiotic converts these compounds to no antibacterial activity. Certain other compounds, on the other hand, are capable of inhibiting the beta-lactamase enzyme, and when combined with a penicillin or cephalosporir derivative, they increase the activity of the antibiotic against certain beta-lactamase producing microorganisms.

German Patent Publication No. 2,824,535, issued December 14, 1978, teaches that it is an effective inhibitor of penicillanic acid sulfone (inhibitors of the beta-lactamase enzymes. That disclosure also states that penicillanic acid Certain esters of sulfone are readily hydrolyzed in vivo to produce high concentrations of this beta-lactamase inhibitor In addition, British Patent Nos. 2,044,255 and 4,244,951 disclose that penicillanic acid —The halogenomethyl esters of the sulfone can be attached to the carboxyl group of an anti-bacterial penicillin derivative and the esters thus obtained are readily hydrolyzed under in vivo conditions to provide a penicillanic acid which inhibits the anti-bacterial penicillin derivative and the beta-lactamase enzyme.

British Patent Application 2,044,225 also teaches that the intermediate penicillanic acid sulfone chloromethyl ester is prepared by the catalytic amount of penicillanic acid sulfone in the presence of tetrabutylammonium sulfate in the presence of a catalytic amount of tetrabutylammonium sulfate. link. This application further describes that the tetrabutylammonium salts of certain anti-bacterial penicillanic acid derivatives can be coupled with penicillan sulfone-o-C-haloalkyl esters and that the resulting compounds readily hydrolyze in vivo the anti-bacterial penicillanic acid derivatives. penicillanate sulfone.

A compound of formula (I) wherein R is hydrogen, a compound of formula (a) or (b) wherein a compound of formula (a) or (b)

R2 is hydrogen or hydroxy, and

R 1 is azido, amino, 1-methoxycarbonyl-piper-2-ylamino or benzyloxycarbonylamino, the compounds of formula (II) wherein

R3 is an alkyl group having 1 to 4 carbon atoms and is reacted with at least one molar amount of iodochloromethane or bromochloromethane at a temperature of about -20 ° C to about + 25 ° C.

The compounds of formula (I) may be used as intermediates for the preparation of compounds which are readily hydrolyzed under in vivo conditions to β-lactam backbone antibiotics and to penicillanic acid sulfone which inhibits β-lactamase.

The present invention relates to a process of formula (III) wherein

X is a group of formula (b) wherein b is

R 2 is hydrogen or hydroxy to form compounds. The process of the present invention is carried out using a compound of formula (IV) wherein

Y is a chlorine, bromine or iodine compound in an inert solvent at room temperature of a compound of formula (V):

R5 is an alkyl group having 1 to 4 carbon atoms and is reacted with a compound.

One of the advantages of the process according to the invention. According to a preferred embodiment, the reaction is carried out in concrete or in dimethylformamide as a neutral solvent.

Compounds of formula (III) may also be prepared by reacting a compound of formula (VI) wherein

Y is a chlorine, bromine or iodine compound in an inert solvent at room temperature in a compound of formula VII wherein

E3 is an alkyl group having 1 to 4 carbon atoms and is reacted with a compound.

The compounds of formula (III) obtained by the process of the present invention contain a readily hydrolyzable ester group which, in vivo, provides a t-lactam backbone antibiotic and a penicillanic acid sulfone which inhibits the β-lactamase enzyme.

In contrast to British Patent Application 2,044,255, wherein the potassium salt of penicillanic acid sulfone in the presence of a catalytic amount of tetrabutylammonium sulfate is prepared by coupling with chlorododomethane to produce the penicillanic acid sulfone chloromethyl ester of the present invention. the corresponding acid tetraalkylammonium salt and the corresponding halide are used in molar amounts to give a surprisingly high yield of the condensed product.

According to a preferred embodiment of the process according to the invention, a compound of formula (IV) wherein:

Y is the above penicillanic acid sulfone halomethyl ester in an inert solvent of formula (V):

X and R3 are reacted with at least a molar amount of the above compound.

Neutral solvents or solvent mixtures used in the methods of the present invention should be capable of solubilizing reagents well without reacting significantly with the rags or product under the reaction conditions. Acetone is preferred, although many other aprotic water miscible solvents may be used, such as ethyl acetate, acetonitrile, dimethylformamide and hexamethylphosphoric acid amide.

The reaction time depends on the concentration of the reagents, the reaction temperature and the reactivity of the starting materials. When the reaction is carried out at a preferred temperature of about 25 ° C, the reaction is generally complete within 30-60 minutes.

The highest yield in this reaction can be achieved if at least the same amount of tetraalkylammonium salt is used molar to the halomethyl ester. This salt can also be used in an excess of 10-20% without significantly altering the quality of the product obtained.

After completion of the reaction, the solvent is distilled off, usually under reduced pressure, and the residue is purified by chromatography on silica gel.

The tetraalkylammonium salts of penicillanic acid and the sulfonic halomethyl esters of penicillanic acid are prepared by the procedures detailed below.

According to another preferred embodiment of the process of the present invention there is provided a compound of formula VI wherein

X and Y are the above penicillanic acid halomethyl esters of formula VII wherein

R3 is at least the same molar amount of the compounds described above.

The reaction is carried out in an inert solvent, which solvent is required to dissolve the reagents well, without substantially reacting with the reagents or product under the reaction conditions. Acetone is preferred, although other highly polar, water miscible, aprotic solvents such as dimethylformamide or hexamethylphosphoric acid amide may be used.

The reaction time depends on the concentration of the reagents, the reaction temperature and the reactivity of the starting materials. At temperatures between about 25 ° C to about 60 C ^Ü temperature reactions between 0 ° C and 60 ° C, and preferably. Within the preferred temperature range, the reaction is carried out over a period of about 1/2 hour to 4 hours. For convenience, the reaction is often carried out by allowing the reaction mixture to stand overnight so that the quality of the product is not impaired.

After completion of the reaction, the reaction mixture is diluted with water and a water immiscible solvent. The organic layer was evaporated and the residue was purified by column chromatography.

As noted above, British Patent Application No. 2,044,225 teaches that the penicillanic acid sulfone halomethyl esters produced by the process of the present invention can be coupled with various lactam backbone antibiotics which are in vivo antimicrobial agents. they show an effect by being absorbed in the body and then hydrolyzed, resulting in high concentrations of penicillanic acid sulfone and of the lactam backbone antibiotic in the blood and tissues. In addition, the above-mentioned British Application describes the use of a product obtained by coupling a penicillanic acid sulfone to a β-lactam backbone antibiotic.

The invention is further illustrated by the following non-limiting examples. Nuclear Magnetic Resonance Spectrum (NMR) spectra were recorded in deuterochloroform (CDCl3) at 60 MHz. Peak chemical shift values are reported in ppm units for tetramethylsilane or 2,2-din: ethyl-2-silapentane-5-sulfonic acid sodium salt. The following abbreviations are used for the shape of the peaks:

s: singlet; d: doublet; t: triplet; q: quartet; ni: multiplet.

Example 1

Chloromethyl ester of 6- (2,2-dimethyl-5-oxo-4-phenyl-1-imidazolidinyl) penicillanic acid (compound of formula I)

1.56 g of 6- (2,2-dimethyl-5-oxo-4-phenyl-1-imidazolidinyl) penicillanic acid (J. Org. Chem., 31, 897 (1966)), 20 ml of dichloromethane and 20 ml of water. The biphasic suspension was adjusted to pH 8.5 with tetrabutylammonium hydroxide, the organic layer was separated and the aqueous layer was washed with dichloromethane (2 x 20 mL), the combined organic layers were dried over sodium sulfate and the solvent was distilled off. 2.3 g of a foam were obtained.

The tetrabutylammonium salt obtained as described in the above paragraph was added to 15 ml of chloroiodomethane and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then chromatographed on a column of silica gel (100 g) eluting with ethyl acetate / hexane (1: 1) (10 mL fractions every 30 seconds). 195-230. fractions were combined and the solvent was distilled off.

This gave 440 mg of the desired product. Nuclear Magnetic Resonance Spectrum (CDCl3): 1.5 (s, 311), 1.58 (s, 611),

1.72 (s, 311), 4.58 (s, 1H),

4.67 (s, 1H), 4.73 1H, 1H),

54.54 (d, 1H), and 7.2-7.6 (ni, 5H, ppm).

Proceeding in a similar manner and starting from 6- (2,2-dimethyl-5-oxo-4- (p-hydroxyphenyl) -1-imidazolidinyl) penicillanic acid (J. Chem. Soc., 1920 (1971)) methyl 2,2-dimethyl-5-oxo-4- (p-hydroxyphenyl) -1-imidazolidiryl] penicillanic acid chloroethyl ester.

Example 2

Penicillanic acid 1,1-dioxide [6 '- (2,2-dimethyl-5-oxo-4-phenyl-1-imidazolidinyl) penicillanoyloxymethyl ester vegyület (compound of formula III)]

To a solution of 1.0 g of 6- (2,2-dinethyl-5-oxo-4-phenyl-1-imidazolidinib penicillanic acid tetrabutylammonium salt in a mixture of 10 ml of ethyl acetate and 3 ml of dichloromethane is added 470 mg A solution of penicillanic acid 1,1-dioxide chloromethyl ester in ethyl acetate (7 mL) was stirred for 45 minutes at room temperature, washed with water, brine and dried over sodium sulfate. The residue was chromatographed on silica gel (g), eluting with ethyl acetate / hexane (1: 1), and fractions (14 m) were collected every 30 seconds. Fractions (95-230) are combined and the solvent is distilled off to give the desired product.

In a similar manner, 646 mg of the tetrabutylammonium salt of 6- (2,2-dimethyl-5-oxo-4-p-hydroxyphenyl-1-imidazolidinyl) penicillanic acid and 281 mg of penicillanic acid 1,1 Starting from the iodomethyl ester, 210 mg of penieillanic acid 1,1-dioxide (6'-2,2-dimethyl-5-oxo-4-p-hydroxyphenyl-1-imidazolidinyl) penicillanoyl xxymethyl 1-ester is obtained.

Nuclear Magnetic Resonance Spectrum (CDCl 3) 1.4-1.8 (m, 18H), 3.48 (d, 2H),

4.4-4.9 (m, 5H), 5.56 (d, 1H),

5.9 (s, 211), 6.64 (d, 2H), and 7.18 (d, 2H) ppm.

Claims (2)

A process for preparing a compound of formula (III) wherein X is a group of formula (b): Wherein in formula (b) R2 is a hydrogen atom or a hydroxy group for the preparation of penicillanic acid penicillanoyloxymethyl derivates, wherein 30 a! a compound of formula IV wherein: Y is a chlorine, bromine or iodine compound in an inert solvent at room temperature of a compound of formula (V): 35 R: is alkyl having 1 to 4 carbon atoms, and X is reacted with at least the same amount of compound of the above compound at a temperature of ¹¹⁰ ° C to -20 ° C to + 25 ° C, or b to a compound of formula VI - where X is as defined above, in an inert solvent at a temperature of 0 to 60 ° C, _{r is} a compound of formula VII wherein Ra is a C 1-4 alkyl group and Y is a chlorine, bromine or iodine atom molar at least the same amount. 2. A process according to claim 1 wherein the inert solvent is acetone or dimethylformamide.