HU182703B - Process for producing 2,2-dimethyl-penam-3-carboxylic acid-1 alpha-oxide - Google Patents

Abstract

The present invention relates to a process for the preparation of 2,2-dimethylpenam-3-carboxylic acid oxide as an intermediate compound for the preparation of 2,2-dimethylpenam-3-carboxylic acid 1,1-dioxide. In the process according to the invention, a 2,2-dimethyl-6,6-dibromophamam-3-carboxylic acid oxide derivative of the formula (III), wherein (R *) 'hydrogen or benzyl is hydrogenated, is obtained. (III) -1-

Description

The present invention relates to a process for the preparation of 2,2-dimethyl-penam-3-carboxylic acid 1,1-dioxide and its intermediates for the preparation of 2,2-dimethyl-penam-3-carboxylic acid 1 '<-oxide.

The intermediates of the present invention are useful as antimicrobial compounds and compounds that enhance the activity of several other '-lactam antibiotics, lactamase-producing bacteria, and 2,2-dimethyl-penam-2-carboxylic acid 1,1-dioxide and its readily hydrolyzable ester derivatives. can be used.

Lactam-type antibiotics are well known and widely used antimicrobial compounds. The compounds are characterized by a 2-azetidinone / '-lactam / ring fused to a thiazolidine or dihydro-1,3-thiazine ring. When the backbone contains a thiazolidine ring, the compound is a penicillin derivative; if the backbone contains a dihydrothiazine ring, the compound is called a cephalosporin. Examples of penicillins used in clinical practice include benzylpenicillin / penicillin G /, phenoxymethylpenicillin / penicillin V /, ampicillin and carbenicillin; commonly used cephalosporin derivatives include cephalotin, cephaloxin and cefazoline.

Although widely used and widely accepted as valuable chemotherapeutic agents, lactam-type antibiotics have the disadvantage that some of their agents are ineffective against certain microorganisms.

The resistance of certain microorganisms to a particular lactam-type antibiotic is obviously due to the fact that the microorganism cleaves the lactam ring of the penicillins and cephalosporins with the enzyme they produce, and the cleaved product has no antimicrobial activity. Certain compounds can inhibit lactamase enzymes and, if one ^; The use of a lactamase inhibitor compound in combination with penicillin or cephalosporin increases the antibacterial activity of penicillin or oephalosporin against certain microorganisms. The antibacterial effect is the increase in the ^one case be defined as the antibacterial compositions containing a lactamase inhibiting compound and / lactamase-type antibiotic is significantly greater than the sum of the components measured separately antibacterial activity.

Object of 180 042 Hungarian patent application comprises novel penicillin derivatives, a- ^r that antibacterial agent and also may be used to inhibit the mikrobiálls ejredetü lactamase enzymes compound zfel. These novel penicillin derivatives are 2,2-dimethylpenam-3U-carboxylic acid 1,1-dioxia derivatives and their readily hydrolyzable esters.

Hungarian Patent Application No. 180 042 relates to a process for the preparation of 2,2-dimethyl-pefcam-3-carboxylic acid 1,1-dioxide derivatives represented by the general formula I and their pharmaceutically acceptable salts, wherein they are hydrogen or 2-7 C 1 -C 4 alkanoyloxy-C 1 -C 4 alkyl, C 1 -C 4 alkoxycarbonyloxy-C 1 -C 4 alkyl, or 3-phthalidyl.

The above ester groups are readily hydrolyzed in vivo

-2182,703 and non-toxic are rapidly cleaved in mammalian blood or tissues, and upon cleavage, the corresponding free acid, i.e., the compound of formula I wherein R1 is hydrogen, is formed.

Compounds of formula I wherein R * is hydrogen or an in vivo hydrolyzable ester forming group are compounds having bactericidal activity and may be used to enhance the antibacterial activity of the ß-lactam antibiotics. compounds.

Compounds of formula I wherein R1 is a penicillin carboxyl protecting group. may be used as intermediates in the preparation of compounds of formula XA. Preferred carboxyl groups include, for example, benzyl, substituted benzyl, such as 4-nitrobenzyl.

Hungarian Patent Application No. 180 042 relates to a process for the preparation of 2,2-dimethylpenam-3-carboxylic acid 1,1-dioxide derivatives of the structure IA and their pharmaceutically acceptable salts. The process involves the preparation of compounds of formula IA by the preparation of a compound of general formula II wherein

X is -S-, ~ 'S' * 'O or S-O, and

R 1 ^- is reacted with an oxidizing agent as defined above until, after substantially complete oxidation, the compounds of general formula I wherein R 1 is as defined above are obtained; optionally removing the carboxyl protecting group to give compounds of formula IA; and optionally reacting a compound of formula IA wherein R is hydrogen with a base to form a pharmaceutically acceptable salt.

The compounds of formula II as described above, wherein X is -xS * 'O or -S-O, are new compounds.

The compounds of the above formulas I and II are referred to as 2,2-dimethylpenam-3-carboxylic acid derivatives which are represented by formula IVA.

...... In formula IVA, the substituents linked to the bicyclic backbone by a dotted end line represent the substituents located below the bicyclic backbone. These substituents have the 't configuration. In contrast, the substituents bound to the bicyclic backbone by the drawn valence line are located above the base of the backbone. The latter have _t i -configuration.

Compounds of formula I are prepared by oxidation of compounds of formula II. The compound of formula II can be both 1Λ and 1 ^ oxide.

According to the invention, 2,2-dimethylpenam-1'-oxide of formula II 'is prepared. by hydrolyzing a 6,6-dibromo derivative of the Formula III wherein R ^{1 is} hydrogen or benzoylSOpbrt. '·,. "

Intermediate III (R) is preferably hydrogen. 'S _before 2,2-dimethyl-penam-3-carboxylic acid-lc <Under-oxide according to a preferred method of the invention

-3182,703 is obtained by cleaving the bromides of 2,2-dlmotyl-6,6-dibromo-penam-3-carboxylic acid 1'-oxide. Cleavage of bromine blocks is carried out by known hydrogenolysis reactions. For example, a solution of 2,2-dimethyl-6,6-dibromo-penam-3-carbonic acid-1-oxide is pressurized with hydrogen gas at atmospheric pressure or with a catalytic amount of stirring or shaking in the presence of palladium catalyst. The reaction mixture is preferably short-chain. alkanols such as methanol; ethers such as tetrahydrofuran or dioxane; low molecular weight esters such as ethyl acetate or butyl acetate; water or mixtures of the above. Preferably, the solvent in which the dibromo derivative is soluble is selected. Hydrophenolysis is generally carried out at room temperature, at atmospheric pressure and at 4.5 atmospheres. The catalyst is generally added in an amount of from 10% to 100% by weight of the dibromo derivative, although larger amounts may be used. The reaction usually takes about an hour. After completion of the reaction, the compound of formula II *, wherein B ^{1 is} hydrogen, is isolated by filtration under reduced pressure.

To produce 2,2-dimethyl-6,6-dibromo-oenam-N-carboxylic acid 1'-oxide, 2,2-dimethyl-6,6-dibromo-penam-5-carboxylic acid is oxidized with an equivalent amount of 3-chloroperbenzoic acid with tetrahydrofuran. in a reaction mixture at 0 ° to 25 ° C for about one hour. The reaction was carried out according to Harrison et al., J. Chem. Society, London, Perkin I., 1772,

1976: · Clayton's procedure for the preparation of 2,2-dimethyl-6,6-dibromo-penam-5-carboxylic acid is described by J. Chemical Society / London / C. 2123, 1969.

The compounds of formula IA and their salts prepared from the intermediates of the present invention are medium-potent antibacterial agents that inhibit the activity of microbial lactamase enzymes and enhance the anti-bacterial activity of -lactam-type antibiotics / penicillins and cephalosporins / enzymes, in particular opposite. These effects are described in Hungarian Patent Application Pl-630.

The invention is further illustrated by the following examples.

Infrared absorption spectra were determined in potassium bromide tablets or nujol, with absorption maxima at wavelengths / cm -1. The nuclear magnetic resonance spectrum was measured at 60 MHz in deuterium chloroform (CDCl3), deuterium dimethylsulfoxide (DMSO-cL) or deuterium oxidoan (DqO); the maximum is given in parts per million parts per ppm relative to tetramethylsilane or sodium 2,2-dimethyl-2-silapentane-5-sulfonate.

Example 1

Preparation of 2,2-Dimethyl-penam-3-carboxylic acid 1-oxide In water, 1.4 g of a previously hydrogenated palladium catalyst containing 5% palladium were suspended in 1.39 g x 50 ml of tetrahydro. 2,2-dimethyl-6,6-dibromo-3-carboxylic acid benzyl ester 1'-oxide in furan is added. The reaction mixture was shaken for one hour at 25 DEG C. under hydrogen gas (about 41 atmospheres pressure) at 25 [deg.] C. and then strained. The filtrate was distilled off under reduced pressure to remove tetrahydrofuran, and the remaining aqueous phase was extracted with ether. The ether was removed from the ethereal extracts by distillation under reduced pressure to give 0.5 g of product as a distillation residue. It mainly contains 2,2-dimethyl-penam-3-carboxylic acid and 1,1'-oxide.

The 2,2-dimethyl-penam-3-carboxylic acid benzyl ester-1-oxide thus obtained was mixed with 2.0 g of 2,2-dimethyl-6,6-dibromo-penam-3-carboxylic acid benzyl ester-1-oxide. The mixture was dissolved in 50 ml of tetrahydrofuran. To the solution was added 4.0 g of 5% palladium-on-carbon calcium carbonate with 50 ml of water, and the reaction mixture was shaken overnight at 25 ° C under a hydrogen atmosphere of about 4 atmospheres. The reaction mixture is then filtered. the filtrate was extracted with ether. Distillation under reduced pressure of the extract, followed by chromatography on silica gel, elution with chloroform, gave 0.50 g of product.

This product was hydrogenated under a hydrogen gas pressure of about 3 bar in a 1: 1 mixture of water and methanol at 25 ° C with palladium calcium carbonate containing 5% palladium for 2 hours. After the reaction time, an additional 0.50 g of 5% palladium-on-calcium carbonate catalyst was added, and hydrogenation was also continued at 25 ° C overnight under hydrogen at 3 bar. The reaction mixture was filtered and extracted with ether and the extracts discarded. The aqueous solution was adjusted to pH 1.5 and extracted with ethyl acetate. Combine the ethyl acetate extracts. then dried over sodium sulfate and distilled under reduced pressure to give 0.14 g of 2,2-dimethylpenam-3-carboxylic acid 1-oxide as a distillation residue.

Nuclear magnetic resonance spectrum of the compound obtained / CDC1 _X / / EMSO-DR /: 1.4 / s, 3H / J 1.64 / s, 3H /; 3.60 (multiplet, 2H); 4.3 (singlet, 1H) and 4.54 (multiplet, 1H / ppm).

The infrared absorption spectrum of the test compound on KBr tablets prepared in 1795 and 1745 cm ^- * · wavelengths seems absorption maxima.

Example 2

Preparation of 2,2-Dimethyl-penam-3-carboxylic acid 1'-oxide in water, 1.0 g of 5% palladium on carbon pre-treated with hydrogen was suspended in 1.0 g of dissolved 2,2-dimethyl-6. 6-dibromo-penam-3-carboxylic acid LU-oxide is added to the suspension. The reaction mixture is shaken for 1 hour under hydrogen at a pressure of about 3 bar at 25 ° C. After filtration, the filtrate was distilled under reduced pressure to remove methanol. The aqueous solution obtained as a distillation residue was diluted with an equal volume of water, adjusted to pH 7 with ether, washed with ether to pH 2, then extracted with ethyl acetate.

-5182703

The ethyl acetate extracts were anhydrified with sodium sulfate and the solvent was distilled off under reduced pressure to give 2,2-dimethylpenam-3-carboxylic acid 1-oxide as a distillation residue.

The following examples illustrate the preparation of starting materials:

Example 5

The 2,2-dimethyl-6,6-dibromo penam-3-carboxylate-l-oxide Preparation ^x

The 2,2-dimethyl-6,6-dibromo penam-3-carboxylate-l-oxide ^v preparing BOW by Harrison et al. Chemical Society (London), Perkin I, 1772, 197 DEG-2,2-Dimethyl-6,6-dibromopenamic-3-carboxylic acid is reacted with 1 equivalent of 5-chloroperbenzoic acid in a mixture of tetrahydrofuran at 0 ° C to 25 ° C. temperature for one hour.

Example 4

........ Preparation of 2,2-Dimethyl-6,6-dibromopen-3-carboxylic acid benzyl ester

In 350 ml of H, N-dimethylacetamide, 54 g / 0.165 m / 2,2-dimethyl-6,6-dibromo-penam-3-carboxylic acid was dissolved and 22.9 ml / 0.165 m / triethylamine was added, followed by 40 minutes. stir the reaction mixture. Benzyl bromide (19.6 ml / 0.165 m / m) was then added and the mixture was stirred at room temperature for 48 hours. The precipitated triethylamine hydrobromide was removed by filtration and the filtrate was poured into 1500 ml of ice water of pH 2. Extract the mixture with ether and wash the extract with saturated aqueous sodium hydrogencarbonate and water and finally brine. The ethereal solution was then dried over magnesium sulfate and distilled under reduced pressure. Distillation residue gave an off-white product which was crystallized from isopropanol. Yield: 70.0 S (95%), m.p. 75-6 ° C, identical with the benzyl ester of 2,2-dimethyl-6,6-dibromo-penam-3-carboxylic acid.

In the infrared absorption spectrum studied in potassium bromide, the absorption maxima at 1795 and 1740 cnT ^{1 were} observed.

The nuclear magnetic resonance spectrum of the prepared compound in deuterochloroform is as follows: 1.53 (singlet 3H); 1.58 (singlet, 3H); 4.50 (singlet, 1H); 5.13 (singlet, 2H); 5.72 (singlet, horse); and 7.37 / singlet, 5H / ppm.

Example 5

Preparation of 2,2-dimethyl-6,6-dibromo-penam-3-carboxylic acid benzyl and ter-1-oxide

Dissolve 13.4 g / 0.03 m / 2,2-dimethyl-6,6-dibromo-penam-3-carboxylic acid benzyl ester in 200 ml of dichloromethane and stir at 6.12 g / 0.03 m / 100 ml. 3-chloroperbenzoic acid dissolved in dichloromethane was added at 0 ° C. Stirring was continued for 1.5 hours at the same temperature and the reaction mixture was filtered. The filtrate was washed with 5% sodium bicarbonate solution, followed by water, and finally dried over sodium sulfate. The solution was distilled under reduced pressure, after which 12.5 g of 2, .beta.-dimethyl-6,6-6182.703 were obtained as an oily distillation residue.

benzyl ester 1-dibromo-penam-5-carboxylic acid is obtained.

The oily product is crystallized from ether. After completion of the crystallization process, the suspension is filtered to give 10.5 g of the solid product 2,2-dimethyl-6,6-dibromo-penam-5-carboxylic acid benzyl ester 1-oxide.

The infrared absorption spectrum of a chloroform solution of the test compound prepared is observed the following absorption maxima at wavelengths of 1800 and 1750 ^cm-first

The product has a nuclear magnetic resonance spectrum in deuterochloroform of 1.5 (singlet, 5H); 1.5 (singlet, 5H); 4.5 (singlet, 1H); 5.18 (singlet, 2H); 5.2 / singlet, 1H / 7.5 and 7.5 / singlet, 5H / ppm.

Patent claims

Claims (4)

A process for the preparation of 2,2-dimethyl-penam-5-carboxylic acid-1-oxld of formula II ', characterized in that a 2,2-dimethyl-6,6-dibromo-penam-5 the carboxylic acid V-oxide derivative wherein K ¹ / H or benzyl is hydrogenated. 2. The process according to claim 1, wherein the starting material is 2,2-dimethyl-6,6-dibromopen-5-carboxylic acid 1-oxide. The process according to claim 1 or 2, wherein the hydrogenolysis is carried out in the presence of a catalytic amount of palladium catalyst on the carbonate. 4. A process according to claim 2 or 5 wherein the hydrogenolysis is carried out in a lower alkanol, a low molecular weight ester, water or a mixture thereof. 5 · A 2-4. A process according to any one of claims 1 to 5, characterized in that the hydrogenolysis is carried out at a pressure of 1 to 5.5 h · 1 drawing