FI71740C - In the preparation of therapeutically active penicillanic acid 1,1-dioxide as well as intermediates useful in penicillanic acid 1-oxides. - Google Patents

Description

1,71740 Penicillanic acid po-1-oxides useful as intermediates in the preparation of therapeutically active penicillanic acid 1,1-dioxide 5 Separated from application 781800 (Patent 66003)

The invention relates, as intermediates, to the therapeutically active penicillanic acid 1,1-dioxide of the formula (I).

"COOH

15 and penicillanic acid 1-oxides useful in the preparation of its pharmaceutically acceptable salts, which are characterized by their formula (II) or (III) o H - rH H n

20; - / S ^ CH3 = ^ CH

j— n -____ i 3 ._i i ch3

0 '"COOH 0 ^ N \ C0QH

(II) (III) 25

Penicillanic acid 1,1-dioxide and its readily hydrolyzable esters in vivo are useful antibacterial agents as well as agents that enhance the efficacy of several β-lactam antibiotics against many β-lactamase-producing bacteria. Penicillan-1-oxides are useful chemical intermediates in the preparation of penicillanic acid 1-1-dioxide and its esters and salts.

One of the best known and most widely used classes of antibacterial agents comprises so-called β-lactam antibiotics. These compounds are characterized in that their backbone contains a 2-azetidinone ring (fb-lactam) fused to either a thiazolidine or a dihydro-1,3-thiazine ring. When the backbone contains a thiazolidine ring, the compounds are referred to as penicillins, and when the backbone contains a dihydro-rotiazine ring, the compounds are referred to as cefa-5 losporins. Examples of clinically commonly used penicillins include benzylpenicillin (penicillin G), phenoxymethylpenicillin (penicillin V), ampicillin and carbenicillin; typical examples of common cephalosporins are cephalothin, cefalexin and cefat-10 soline.

Although β-lactam antibiotics are widely used and accepted as valuable chemotherapeutic agents, their major drawback is that some of them are not active against certain microorganisms. It is believed that in many cases the resistance of a particular microorganism to a particular β-lactam antibiotic depends on the β-lactamase produced by the microorganism. These are enzymes that break down the β-lactam ring of penicillins and cephalosporins to form compounds that do not have antibacterial activity. However, some agents have the ability to inhibit the action of β-lactamase, and when used as a β-lactamase inhibitor in combination with penicillin or cephalosporin, it enhances or enhances the antibacterial activity of penicillin or cephalosporin against certain microorganisms. When the combination of the γ-lactamase inhibitor and the β-lactam antibiotic has a substantially higher antibacterial activity than the sum of the activities of the components, the antibacterial effect is considered to be enhanced.

The compound of formula I, penicillanic acid 1,1-dioxide, is useful as an antibacterial agent. In addition, penicillanic acid 1,1-dioxide is a potent inhibitor of microbial β-lactamases.

The 1,1-dioxides of benzylpenicillin, phenoxymethylpenicillin 35, and some of these esters are described in U.S. Patent Nos. 3,976,466 and 3,536,698 and Guddal et al. in Tetrahedron Letters, No. 9 (1962) 381.

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Harrison et al., Journal of the Chemical Society (London), Perkin I, 1772 (1976), have described a number of penicillin 1,1-dioxides and -1-oxides, including methylphthalimidopenicillanate 1,1-dioxide. , methyl 6,6-dibromopenicillanate-5β-1,1-dioxide, methylpenicillanate-1β-oxide, methylpenicillanate-1β-oxide, 6,6-dibromopenicillanic acid 1'-oxide and 6, 6-dibromopenicillanic-l / 3-oxide.

The novel intermediates of formula II or III according to the invention are derivatives of penicillanic acid. Penicillanic acid has the formula: V S * CH3 I CH, <IV> 15 I --- N ---- «

O COOH

In Formula IV, the dashed line with which the substituent is attached to the bicyclic backbone indicates that the substituent is below the level of the bicyclic backbone. Such a substituent is said to have the o 2 configuration. The incorporation of a substituent into the bicyclic backbone by a solid line indicates that the substituent is above the level of the backbone. This is called the f> configuration.

A compound of formula I may be prepared by oxidizing a compound of formula II or III. Many different oxidants used in the art to oxidize sulfoxides to sulfones can be used in this process. However, particularly suitable reagents are metal permanganates, such as alkali metal permanganates and alkaline earth metal permanganates, as well as organic peroxyacids, such as organic peroxycarboxylic acids. Suitable reagents include sodium permanganate, 3-chloroperbenzoic acid and peracetic acid.

When a compound of formula II or III is oxidized to the corresponding compound of formula I metal permanganate account, the reaction is usually carried out by treating the compound of formula II or III in a suitable solvent system with about 0.5 to about 5 molar equivalents, preferably about 1 molar equivalent of permanganate. A suitable solvent-5 system is one that does not adversely affect the starting materials or the product, and water is usually used. If desired, a solvent which is miscible with water and does not affect the permanganate, e.g. tetrahydrofuran, can be added. The reaction is normally carried out at a temperature in the range of about -20 to 50 ° C, preferably about 0 ° C. At about 0 ° C, the reaction time is usually short, e.g., about one hour. Although the reaction may be carried out under neutral, basic or acidic conditions, it is most preferred to carry it out under substantially neutral conditions in order to avoid decomposition of the β-lactam ring system of the compound of formula I. Thus, it is often advantageous to buffer the reaction medium close to the neutral point. The product is recovered by conventional methods. Any excess permanganate is usually decomposed into sodium bisulfin-20, and then, when the product is precipitated, it is filtered. It is separated from the manganese dioxide by extraction into an organic solvent and evaporation of the solvent. If the product is dissolved at the end of the reaction, it is isolated by ordinary solvent extraction.

When a compound of formula II or m is oxidized to the corresponding compound of formula I with an organic peroxyacid, e.g. peroxycarboxylic acid, the reaction is usually carried out by treating a compound of formula II or III in a reaction inert solvent with about 30 molar equivalents, preferably about 1.2 molar equivalents of oxidant. . Suitable solvents include chlorinated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane, and ethers such as diethyl ether, tetrahydrofuran and 1,2-dimethoxyethane. The reaction is usually carried out at about -20 to 50 ° C, preferably at about 25 ° C. At about 25 ° C, the reaction time is generally about 2 to about 16 hours.

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The product is usually isolated by removing the solvent in vacuo. The product can be purified by conventional methods known in the art.

When a compound of formula II or III is oxidized to a compound of formula I with an organic peroxyacid, it is sometimes advantageous to add a catalyst such as a manganese salt, e.g. manganese acetylacetonate.

Penicillanic acid-10-oxide, i.e. the compound of formula II, can be prepared by debromination of 6,6-dibromopenisil-10-formic acid-10-oxide. Debromation can be performed by a conventional hydrogenolysis method. In this case, the 6,6-dibromo-penicillanic acid 1'-oxide is mixed or shaken under a hydrogen atmosphere or in a mixture of hydrogen and an inert diluent gas such as nitrogen and argon with a catalytic amount of a palladium / calcium carbonate catalyst. Suitable solvents for use in debromination include lower alkanols such as methanol, ethers such as tetrahydrofuran and dioxane, lower esters such as ethyl acetate and butyl acetate, water and mixtures of these solvents. Usually, a solvent in which the dibromo compound is soluble is selected. The hydrogenation is usually carried out at room temperature at a pressure of about normal pressure to about 345 kPa. The catalyst is generally present in an amount of from about 10% to about 100% by weight of the dibromo compound, although larger amounts may be used. The reaction time is generally about one hour, after which the compound of formula II is recovered simply by filtration and removal of the solvent in vacuo.

6,6-Dibromopenicillanic acid 10-oxide is prepared by oxidizing 6,6-dibromopenicillanic acid with 1 equivalent of 3-chlorobenzoic acid in tetrahydrofuran at 0-25 ° C for about one hour by the method described by Harrison et al., Journal of the Chemical Society (London) Perkin I, 1772 (1976) 6,6-Dibromopenicillanic acid is prepared by the method described by Clayton, Journal of the 35 Chemical Society (London), (C), 2123 (1969).

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Penicillanic acid 1-oxide, i.e. a compound of formula III, can be prepared by controlled oxidation of penicillanic acid. It can be prepared by treating penicillanic acid in an inert solvent at about 0 ° C with 1 molar equivalent of 5-chloroperbenzoic acid for about an hour. Typical solvents suitable for use include chlorinated hydrocarbons such as chloroform and dichloromethane, ethers such as diethyl ether and tetrahydrofuran, and lower esters such as ethyl acetate and butyl acetate. The product is isolated in the usual way.

Penicillanic acid is prepared as described in GB Patent No. 1,072,108.

As mentioned above, the compound of formula I is a moderately effective antibacterial agent. The in vitro activity of a compound of formula 15 I can be demonstrated by measuring the minimum inhibitory concentration (MIC) in μg / ml for various microorganisms. The method followed is that recommended by the International Collaborative Study on Antibiotic Sensitivity Testing (Ericsson and Sherris, Acta Pathologica 20 et Microbiologica, Scan. Supp, 217, Sections A and B: 1-90, 1970). It uses brain-heart infusion agar (BHI agar) and an inoculation device. The contents of the overnight tubes are diluted 100-fold and used as standard inocula (25,000,000-10,000 cells in approximately 0.002 ml; 20 ml BHI agar / dish) are applied to the agar surface. Test compounds are used in 12-fold dilutions and the initial concentration of test compound is 200 μg / ml. Individual colonies are not counted when readings are made after 18 hours of incubation at 37 ° C. The MIC value for each of the 30 test organisms is the lowest concentration at which the compound can visibly completely inhibit the growth of the test organism. The MIC values of penicillanic acid 1,1-dioxide against several different microorganisms are given in Table I of the parent application, i.e. FI patent publication 66003. FI patent publication 35003 describes in more detail the therapeutic properties and utility of the compounds of formula I.

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The following examples illustrate the invention. Infrared spectra (IR spectra) were measured as KBr tablets or Nujol mixture, and diagnostic absorption sites are reported in wavenumbers (cm). The nuclear magnetic resonance (NMR) spectrum was measured at 60 MHz in deuterochloroform (CDCl 3), perdeuterodimethylsulfoxide (DMSO-d) or deuterium oxide (DO) solutions, and the location of the peaks is reported in parts per million (ppm) of tetramethylsilane or sodium 2,2-dimethyl-2-silanepentane-5-sulfonate. Abbreviations are used for the shapes of the peaks 10: s is a singlet, d is a doublet-ti, t is a triplet, q is a quartet, m is a multiplet.

Example 1

Benzylpenicillanate 1,1-dioxide To a stirred solution of 6.85 g (24 mmol) of benzylpenicillanate in 75 ml of ethanol-free chloroform in an ice bath was added a total of 4.78 g of 85% pure pure acid at 2.7 g in several portions under nitrogen. . Stirring in an ice bath was continued for 30 minutes and then without external cooling for another 45 minutes. The reaction mixture was washed with aqueous alkali solution (pH 8.5), then saturated sodium chloride solution and dried and evaporated in vacuo to give 7.05 g of residue. Upon examination, the residue was found to be a 5.5: 1 mixture of benzylpenicillanate-1-oxide and benzylpenicillanate-1,1-dioxide.

To the 5.5: 1 mixture of sulfoxide-sulfone (4.85 g) obtained above in 50 ml of ethanol-free chloroform was added 3.2 g of 85% pure 3-chloroperbenzoic acid under nitrogen at room temperature with stirring. The reaction mixture was stirred for 2.5 hours, then diluted with ethyl acetate. The resulting mixture was added to water (pH 8) and the layers were separated. The organic phase was washed with water (pH 8), then saturated sodium chloride solution and dried over sodium sulfate. Evaporation of the solvent gave 3.59 g of the title compound. The NMR spectrum had absorbances: 1.28 (s, 3H), 1.58 (s, 3H), 3.42 (m, 2H), 4.37 (s, 1H), 4.55 (m, 1H) , 5.18 (q, 2H, J = 12 Hz) and 7.35 (s, 5H) ppm.

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Example 2

Penicillanic acid N-oxide To 1.4 g of prehydrated 5% palladium / calcium carbonate in 50 ml of water was added a solution of 1.39 g of benzyl 6,6-dibromopenicillanate-1 '. - oxide in 50 ml of tetrahydrofuran. The mixture was shaken under a hydrogen atmosphere at 310 kPa at 25 ° C for 1 hour, then filtered. Most of the tetrahydrofuran was evaporated from the filtrate in vacuo and the aqueous phase was extracted with ether. The Eet-10 grain extract was evaporated in vacuo to give 0.5 g of a substance consisting mainly of benzylpenicillanate lot oxide.

The benzyl penicillanate lct oxide obtained above and an additional 2.0 g portion of benzyl β »G-dibromopenicillanate-N-oxide were combined and dissolved in 50 ml of tetrahydrofuran. The solution was added to 4.0 g of 5% palladium / calcium carbonate in 50 ml of water, and the resulting mixture was shaken under a hydrogen atmosphere at a pressure of about 310 kPa at 25 ° C overnight. The mixture was filtered, the filtrate was extracted with ether. The extract was evaporated in vacuo, and the residue was purified by chromatography on silica gel, eluting with chloroform. 0.50 g of product is obtained, which is hydrogenated for two hours under a hydrogen pressure of about 310 kPa at 250 [deg.] C. in an aqueous methanol mixture (1: 1) in the presence of 5% palladium / calcium carbonate (0.50 g). A new batch of 0.50 g of 5% palladium / calcium carbonate was then added and hydrogenation was continued at 310 kPa at 25 ° C overnight. The reaction mixture was filtered, extracted with ether and the extracts discarded. The pH of the aqueous phase was adjusted to 1.5 and then extracted with ethyl acetate. The ethyl acetate extract was dried over sodium sulfate and evaporated in vacuo to give 0.14 g of penicillanic acid-10C oxide. The NMR spectrum (CDCl 3 / DMSO-d 6) showed absorbances: 1.4 (s, 3H), 1.64 (s, 3H), 3.60 (m, 2H), 4.3 (s, 1H) and 4.54 (m, 1 H) ppm. The IR spectrum of the product (KBr tablet) showed absorbances: 1795 35 and 1745 cm -1 * 91740

Example 3

Penicillanic acid-1 P> oxide

To a stirred solution of 2.65 g (12.7 mmol) of penicillanic acid in chloroform was added 2.58 g of 85% pure 3-chloroperbenzoic acid at 0 ° C. After 1 hour, the reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was dissolved in a small amount of chloroform. The solution was slowly concentrated until a precipitate began to form. At this point the evaporation was stopped and the mixture was diluted with ether. The precipitate was filtered, washed with ether and dried to give 0.615 g of penicillanic acid 1β-oxide, m.p. 140-143 ° C. IR spectrum (CHCl solution)

-1 J

there were absorbances: 1775 and 1720 cm. The NMR spectrum (CDCl 3 / DMSO-d 6) showed absorbances: 1.35 (x, 3H), 1.76 (s, 3H), 3.36

O

15 (m, 2H), 4.50 (s, 1H) and 5.05 (m, 1H) ppm. Based on the NMR spectrum, the product was about 90% pure.

When the chloroform-ether mother liquor was examined, it was found that it still contained penicillanic acid 1-oxide and some penicillanic acid 1-oxide.

20 Preparation A

6,6-Dibromopenicillanic acid 10-oxide

The title compound is prepared by oxidizing 6,6-dibromopenicillanic acid with 1 equivalent of 3-chloroperbenzoic acid in tetrahydrofuran at 0-25 ° C for about one hour by the method of Harrison et al., Journal of the Chemical Society (London) Perkin I (1976). ) 1772 have described.

Preparation B

Benzyl 6,6-dibromopenicillanate

To a solution of 54 g (0.165 moles) of 6,6-dibro-30 mipenicillanic acid in 350 ml of Ν, Ν-dimethylacetamide was added 22.9 ml (0.165 moles) of triethylamine, and the solution was stirred for 40 minutes. Benzyl bromide (19.6 mL, 0.165 mol) was added to the solution, and the resulting mixture was stirred at room temperature for 48 hours. The precipitated triethyl-35 amine hydrobromide was filtered and the filtrate was added to 1500 ml of ice water (pH 2). The mixture was extracted with ether, the extracts washed successively with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulphate and evaporated in vacuo to give an off-white solid which was recrystallised from isopropanol. 70.0 g (95% yield) of the title compound were obtained, m.p. 75-76 ° C. The IR spectrum (KBr tablet) had absorbances: 1795 and the 1740 cm -1 NMR spectrum (CDCl 3) had absorbances: 1.53 (s, 3H), 1.58 (s, 3H), 4.50 (s, 1H), 5.13 (s, 2H), 5.72 (s, 1H) and 7.37 (s, 5H) ppm.

10 Preparation C

Benzyl 6,6-dibromopenicillanate-1o. -oxide

To a stirred solution of 13.4 g (0.03 mol) of benzyl 6,6-dibromopenicillanate in 200 ml of dichloromethane was added at about 0 ° C a solution of 6.12 g (0.03 mol) of moles) of 3-chloroperbenzoic acid in 100 ml of dichloromethane. Stirring was continued for 1.5 hours at about 0 ° C, then the reaction mixture was filtered. The filtrate was washed successively with 5% sodium bicarbonate solution and water, dried over sodium sulfate and evaporated in vacuo to give 12.5 g of the oily title product, the oil was crystallized by trituration in ether. Filtration of the crystals gave 10.5 g of benzyl 6,6-dibromopenicillanate-11 * oxide. The NMR spectrum of the product (CDCl 3) had absorbances: 1.3 (s, 3H), 1.5 (s, 3H), 4.5 (s, 1H), 5.18 (s, 2H), 2 (s, 1H) and 7.3 (s, 5H) ppm.

Example 4

Penicillanic acid 1,1-dioxide To 2.17 g (10 mmol) of penicillanic acid-10-oxide in 30 ml of ethanol-free chloroform was added 1.73 g (10 mmol) of 3-chloroperbenzoic acid at about 0 ° C. The mixture was stirred for one hour at about 0 ° C and then for another 24 hours at 25 ° C. The reaction mixture was filtered and evaporated in vacuo to give penicillanic acid 1,1-dioxide.

Claims (1)

As intermediates, the therapeutically active penicillanic acid 1,1-dioxide of formula (I): 5 HOO: CH (I) f T-CH JN - 1 cr "vCooh and its pharmaceutically acceptable salts are useful in the preparation of penicillanic acid. l-oxides, characterized in that they have the formula (II) or (III) HO HO - CH Ξ '1 -> S Λ: v., s CH r! Nch r V CHJ u COOH Ox COOH 20 (ID ( III)