DK156480B - PENICILLANIC ACID-1 OXIDES USED AS INTERMEDIATES IN THE PREPARATION OF THERAPEUTIC ACTIVE PENICILLANIC ACID-1,1-DIOXIDE DERIVATIVES - Google Patents

Description

DK 156480 B

The present invention relates to novel penicillanic acid 1-oxides for use as intermediates in the preparation of therapeutically active penicillanic acid 1,1-dioxide of formula I

5 h, V °> "ch3

—Y 'v | ^ -ch3 I

</ "\ oOH

10 or pharmaceutically acceptable salts thereof, the penicillic acid 1-oxides being characterized by the characterizing part of the claim.

The present compounds can be used as intermediates in the preparation of some of the novel penicillanic acid derivatives of formula I 'disclosed in the specification of Danish Patent Application No. 2514/78 which are useful as antibacterial agents.

One of the most well known and most commonly used classes of antibacterial agents is the so-called β-lac-tam antibiotics. These compounds are characterized in that they have a core consisting of a 2-azetidinone ring (β-lactam ring) condensed with either a thiazolidine ring or a dihydro-1,3-thiazine ring. When the core contains a thiazolidine ring, the compounds are usually referred to by the common name penicillins, while the compounds in which the core contains a dihydrothiazine ring are referred to as cephalosporins. Typical examples of penicillins commonly used in clinical practice are benzylpenicillin (penicillin G), phenoxymethylpenicillin (penicillin V), ampicillin and carbenicillin, and typical examples of common cephalosporins are cephalothin, cephalexin and cephalexin.

However, despite the widespread use and widespread recognition of the β-lactam antibiotics as valuable chemotherapeutic agents, they have the significant disadvantage that some members are not active against 2

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certain microorganisms. It is believed that this resistance of a particular microorganism to a given β-lactam antibiotic is in many cases due to the microorganism producing a β-lactamase. The latter are 5 enzymes that cleave the β-lactam ring into penicillins and cephalosporins to form products exposed to antibacterial action. However, certain substances have the ability to cure β-lactamases, and when a β-lactamase inhibitor is used in combination with a penicillin or cephalosporin, it may increase or enhance the antibacterial efficacy of the penicillin or cephalosporin to certain microorganisms. It is believed that there is an increase in antibacterial efficacy when the antibacterial effect of a combination of a β-lactamase inhibitor and a β-lactam antibiotic is significantly greater than the sum of the antibacterial effects of the individual components. .

In the description of Danish patent application no.

2514/78, novel penicillanic acid derivatives are new members of the class of antibiotics referred to as the penicillins, and as mentioned, they are useful as antibacterial agents, and more specifically, they are penicillanic acid-1,1-dioxide and hydrolyzable esters thereof in vitro. Furthermore, penicillanic acid 1,1-dioxide and its in vivo readily hydrolyzable esters are potent inhibitors of β-lactamase microbial and can thus be used to increase the effectiveness of β-lactam antibiotics.

1-1-Dioxides of benzylpenicillin, phenoxymethyl-penicillin and certain esters thereof are disclosed in U.S. Patent Nos. 3,197,466 and 3,536,698 and in an article by Guddal et al. In Tetrahedron Letters, no. 9, 381 (1962): Harrison et al., In the Journal of the Chemical Society (London), Perkin I, 1772 (1976), have described several different penicillin-1, 1-dioxides and 1-oxides, including methyl-phthalimidopenicillinate-1,1-dioxide, methyl-6,6-dibrompenicillinate-1,1-dioxide, methyl-penicilli-nat-la-oxide, methyl-penicillanate-13-oxide, 6,6-dibromo nicillanic acid 1a-oxide and 6,6-dibrompenicillanic acid-13-oxide.

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In the description of Danish patent application no.

The penicillanic acid derivatives disclosed in 2514/78 are compounds of the formula 5 -

0 'COOR

wherein R is hydrogen, 3-phthalidyl, 4-crotonolactonyl, γ-butyrolacton-4-yl or a group of the formula R3 R3 î î 5 I f 5

-C-O-C-R X or -C-O-C-O-R XI

I4 u

15 R R

Wherein R and R are each hydrogen, methyl or ethyl, and R 3 is alkyl of 1-6 carbon atoms and, when R 1, represents hydrogen, physiologically acceptable salts thereof, and it is thus only the compound of formula I 'wherein R is 20 hydrogen or pharmaceutically acceptable salts thereof, obtained directly from the subject penicillanic acid-1 oxides by oxidation as further described below.

According to the present invention, novel compounds of the formulas are provided

25 O O

H i o «h3 | V • v vx% S c y Nl_CH3 II _-CH3 m · 1_N-1 i_N-1 ^

30 cr '"' COOfl CT 'yCOOE

and base salts thereof.

The above compounds of formulas I, II and III are throughout the present description designated 35 as compounds or derivatives of penicillanic acid which may be reproduced by structural formula 4

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Ve w®3

-Γ rs IV

rCH3 5 -N-

^ ° COOE

In Formula IV, association of a substituent to the bicyclic nucleus with a broken union indicates that the substituent is below the plane of the bicyclic nucleus. Such a substituent is said to be in α configuration. Conversely, attaching a substituent to the bicyclic nucleus with a fully drawn line indicates that the substituent is located above the plane of the nucleus. This last configuration is referred to as β configuration.

Penicillanic acid 1,1-dioxide of formula I can be prepared by oxidation of a compound of formula II or III. For this, many different oxidizing agents known in the art of oxidizing sulfoxides to sulfones can be used. Particularly convenient oxidizing agents, however, are metal permanganates, such as alkali metal permanganates and alkaline earth metal permanganates, and organic peroxyacids, such as organic peroxycarboxylic acids. Suitable single oxidizing agents are sodium permanganate, potassium permanganate, 3-chloroperbenzoic acid and peracetic acid.

When a compound of formula II or III is oxidized to the corresponding compound of formula I using a metal permanganate, the reaction is usually carried out by treating the compound of formula II or III with from ca. 0.5 to approx. 5 molar equivalents of the permanganate, and preferably ca. 1 molar equivalent of the permanganate, in a suitable solvent system. A suitable solvent system is one which does not unintentionally react with either the starting materials or the product and water is generally used. If desired, a co-solvent which is miscible with water but which does not react with the permanganate such as tetrahydrofuran can be added. The reaction is usually carried out at a temperature in the range of approx. -20 to approx. 50 ° C, and preferably 5

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at about. 0 ° C. At about. 0 ° C, the reaction is usually substantially complete within a short period of time, e.g. Within 1 Hour. Although the reaction can be carried out under neutral, basic or acidic conditions, it is preferred to work under substantially neutral conditions to avoid decomposition of the β-lactam ring system in the compound of formula I. Indeed, it is often advantageous to buffer the reaction medium. to a pH near the neutral point. The product is extracted in a conventional manner.

Any excess permanganate is usually decomposed using sodium hydrogen sulfite, and then the product, if not in solution, is recovered by filtration. It is separated from manganese dioxide by extraction of it in an organic solvent and removal of the solvent by evaporation. Alternatively, the product, if present in solution, is isolated by the usual solvent extraction process.

When a compound of formula II or III is oxidized to the corresponding compound of formula I 20 using an organic peroxy acid, e.g. a peroxycarboxylic acid, the reaction is usually carried out by treating the compound of formula II or III with from ca. 1 to approx. 4 molar equivalents, and preferably approx. 1.2 equivalents of the oxidant in a reaction inert organic solvent. Typical solutions in the first part are 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 a temperature of from ca. -20 to approx. 50 ° C, and preferably at approx. 25 ° C. At about. Reaction times of about 25 ° C are generally used. 2 to approx. 16 hours. The product is usually isolated by removal of the solvent by evaporation in vacuo. The product can be purified by conventional means.

When oxidizing a compound of formula II

or III to a compound of formula I using an organic peroxy acid, it is sometimes advantageous to add a catalyst such as a manganese.

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sait, e.g. manganiacetylacetonat.

g

Compounds of formula I ', wherein R is as defined above, can then be prepared by esterification of the compound of formula I. Which esterification method to be used can be readily determined by one skilled in the art and, of course, depends on the nature of the ester-forming group.

Penicillanic acid 1a-oxide, i.e. the compound of formula II can be prepared by debromating 6,6-dibromo-10-penicillanic acid 1-oxide. The debromination can be carried out using a conventional hydrogenolysis method. Thus, a solution of 6,6-dibrompenicillanic acid 1a-oxide is stirred or shaken under an atmosphere of hydrogen, or hydrogen mixed with an inert diluent such as nitrogen or argon, in the presence of a catalytic amount of palladium-p. -calci carbonate catalyst. Suitable solvents for this debromation are lower alkanols, such as methanol, ethers, such as tetrahydrofuran and dioxane, low molecular weight esters, such as ethyl acetate and butyl acetate, water, and mixtures of these solvents. However, conditions are usually chosen under which the dibromo compound is soluble. The hydrogenolysis is usually carried out at room temperature and at a pressure of approx. atmospheric pressure to about.0f35 MPa. The catalyst is usually present in an amount of about 10% by weight, calculated on the dibromo compound, and up to an equal weight amount as the dibromo compound, but larger quantities can be used. The reaction usually takes approx. 1 hour, after which the compound of formula II is simply recovered by filtration followed by removal of the solvent in vacuo.

6,6-Dibrompenicillanic acid la-oxide is prepared by oxidation of 6,6-dibrompenicillanic acid with an equivalent of 3-chloroperbenzoic acid in tetrahydrofuran at 0 to 25 ° C for approx. 1 hour following the method set forth by Harrison et al., Journal of the Chemical Society (London) Perkin I, 1772 (1976). 6,6-Dibrompenicillanic acid is prepared by the method of Clayton, Journal of the Chemical Society (London), (C) 2123 (1969).

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Penicillanic acid 1β-oxide, i.e. the compound of formula III, can be prepared by controlled oxidation of penicillanic acid. Thus, it can be prepared by treating penicillanic acid with a molar equivalent of 3-chloroperpenzoic acid in an inert solvent at ca.

0 ° C for approx. 1 hour. Typical solvents that may be used include chlorinated hydrocarbons such as chloroform and dichloromethane, ethers such as diethyl ether and tetrahydrofuran, and low molecular weight esters such as ethyl acetate and butyl acetate. The product is extracted by conventional means.

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

The compounds of formulas II and III are acidic and form salts with basic substances. Such salts are counted under the scope of the invention.

These salts can be prepared by conventional methods, such as contacting the acidic and basic components, usually in a molar ratio of 20: 1: 1, in an aqueous, non-aqueous or partially aqueous medium as the case may be. They are then recovered by filtration, by precipitation with a non-solvent followed by filtration, by evaporation of the solvent or, in the case of aqueous solutions, by lyophilization, as the case may be. Basic substances suitably used for salt formation belong to both the organic and inorganic type, and they include ammonia, organic amines, alkali metal hydroxides, carbonates, hydrogen carbonates, hydrides and alkoxides, and alkaline earth metal hydroxides, carbonates , hydrides and alkoxides. Representative examples of such bases are primary amines such as n-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine and octylamine, secondary amines such as diethylamine, morpholine, pyrrolidine and piperidine, tertiary amines such as triethylamine, N-methylmorpholine and 1,5-diazabicyclo [4,3,0] non-5-ene hydroxides such as sodium hydroxide

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lithium hydroxide, ammonium hydroxide and barium hydroxide, alkoxides such as sodium ethoxide and potassium ethoxide, hydrides such as calcium hydride and sodium hydride, carbonates such as potassium carbonate and sodium carbonate, hydrogen carbonates, 5 .

Preferred salts of the compounds of formulas II and III are sodium / potassium and triethylamine salts.

The invention is further illustrated by means of the following examples and preparations. The IR spectra were measured on KBr slices or Nujol suspensions and the diagnostic absorption bands are indicated as b01 numbers (cm -1 ·). The NMR spectra were measured at 60 MHz for solutions in deuterochloroform (CDCl3), perdeuterodimethylsulfoxide (DMSO-dg) or deuterium oxide (D2O), and the peak values are expressed in parts per minute. million (ppm) to tetramethylsilane or sodium 2,2-dimethyl-2-silapentane-5-sulfonate. The following abbreviations for tip shapes are used: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet.

Example 1

Penicillanic acid la-oxide.

To 1.4 g of pre-hydrogenated 5% palladium-potassium carbonate in 50 ml of water was added a solution of 1.39 g of benzyl-6,6-dibrompenicillanate a-oxide in 50 ml of tetrahydrofuran. The mixture was shaken under a hydrogen atmosphere at ca. 310 kPa and 25 ° C for 1 hour and then filtered. The filtrate was evaporated in vacuo to remove the bulk of the tetrahydrofuran and then the aqueous phase was extracted with ether. The ether extracts were evaporated in vacuo to give 0.5 g of material which was found to be mainly benzylpenicillanate oxide.

The above-mentioned benzylpenicillanate-la-oxide was poured into an additional 2.0 g of benzyl-6,6-dibrompenicilla-nat-la-oxide and the mixture was dissolved in 50 ml of tetrahydrofuran. The solution was added to 4.0 g of 5% palladium-on-cal 9

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cium carbonate in 50 ml of water, and the obtained mixture is stirred under a hydrogen atmosphere at ca. 310 kPa and 25 ° C

overnight. The mixture was filtered and the filtrate extracted with ether. The extracts were evaporated in vacuo and the residue was purified by chromatography on silica gel eluting with chloroform. 0.50 g of material was thus obtained.

The latter material was hydrogenated at ca.

310 kPa and 25 ° C in water-methanol (1: 1) with 0.50 g of 5% palladium-pium-calcium carbonate for 2 hours. After this time, an additional 0.50 g of 5% palladium-β-calcium carbonate was added and hydrogenation was continued at 310 KPa and 25 ° C overnight. The reaction mixture was filtered and extracted with ether and the extracts discarded.

The remaining aqueous phase was adjusted to pH 1.5 and then extracted with ethyl acetate. The ethyl acetate extracts were dried (Na 2 SO 4) and then evaporated in vacuo to give 0.14 g of penicillanic acid la-oxide. The NMR spectrum (CDCl3 / DMSO-dg) showed absorptions at 1.4 (s, 3H), 1.64 (s, 3H), 3.60 (m, 2H), 4.3 (s, 1H) and 4.54 (m, 1H) ppm. The IR spectrum of the product (KBr disk) showed absorptions at 1795 and 1745 cm -1.

Example 2 Penicillanic acid 1a-oxide.

To 1.0 g of pre-hydrogenated 5% palladium-potassium carbonate in 30 ml of water was added a solution of 1.0 g of 6,6-dibrompenicillanic acid la-oxide. The mixture was shaken under a hydrogen atom sphere at about 310 kPa and 25 ° C for 1 hour. The reaction mixture was then filtered. and the filtrate was concentrated in vacuo to remove the methanol.

The remaining aqueous phase was diluted with an equal volume of water, adjusted to pH 7 and washed with ether. The aqueous phase was then acidified to pH 2 with dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extracts are dried (Na 2 SO 4) and evaporated in vacuo to give penicillanic acid la-oxide.

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Example 3

Penicillanic-Lfrs oxide.

To a stirred solution of 2.65 g (12.7 itimol) of penicillanic acid in chloroform at 0 ° C was added 2.58 g of 85% pure 5 3-chloroperbenzoic acid. After 1 hour, the reaction mixture was filtered and the filtrate was evaporated in vacuo.

The residue is dissolved in a small amount of chloroform. The solution was concentrated slowly until a precipitate began to appear. At this point, the evaporation was quenched and the mixture was diluted with ether. The precipitate was removed by filtration, washed with ether and dried to give 0.615 g of penicillanic acid-13 oxide, m.p. 140-143 ° C. The IR spectrum of the product (CHCl

-1 J

absorbances at 1775 and 1720 cm, NMR spectrum 15 (CDCl3 / DMSO-dg) showed absorptions at 1.35 (s, 3H), 1.76 (s, 3H), 3.36 (m, 2H) , 4.50 (s, 1H) and 5.05 (m, 1H) ppm. According to the NMR spectrum, the product was approx. 90% pure.

A study of the chloroform-ether mother liquor revealed that it contained additional penicillanic acid β-20 oxide and, moreover, some penicillanic acid la-oxide.

Example 4

Penicillanic acid 1,1-dioxide.

To 2.17 g (10 mmol) of penicillanic acid 1-oxide in 30 ml of ethanol-free chloroform at ca. At 0 ° C was added 1.73 g (10 mmol) of 3-chloroperbenzoic acid. The mixture is stirred for 1 hour at ca. 0 ° C and then for another 24 hours at 25 ° C.

The filtered reaction mixture is evaporated in vacuo to give penicillanic acid 1,1-dioxide. Mp. 148-151 ° C.

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Preparation A

6,6-dibromopenicillanic acid la-oxide.

The title compound is prepared by oxidation of 6,6-dibrompenicillanic acid with 1 equivalent of 3-chloroperbenzoic acid in tetrahydrofuran at 0-25 ° C for approx. 1 hour following the method set forth by Harrison et al., Journal of the Chemical Society (London) Perkin I, 1772 (1976).

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Preparation B

Benzyl 6,6-dibromopenicillanate.

To a solution of 54 g (0.165 mole) of 6,6-dibromo-penicillanic acid in 350 ml of Ν, Ν-dimethylacetamide was added 22.9 5 ml (0.165 mole) of triethylamine and the solution was stirred for 40 minutes. 19.6 ml (0.165 mol) of benzyl bromide was added and the obtained mixture was stirred at room temperature for 48 hours. The precipitated triethylamine hydrobromide was filtered off and the filtrate was added to 1500 ml of ice water 10 adjusted to pH 2. The mixture was extracted with ether and the extracts were washed successively with saturated sodium hydrogen carbonate solution, water and brine. The dried (MgSO 4) ether solution was evaporated in vacuo to give an almost white solid which was recrystallized from isopropanol. 70.0 g (95% yield) of the title compound, m.p.

75-76 ° C. The IR spectrum (KBr disk) showed absorptions at 1795 and 1740 cm NMR spectrum (CDCl3) showed absorptions at 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.

Preparation C

Benzyl 6,6-dibromopenicillanate la-oxide.

To a stirred solution of 13.4 g (0.03 mole) of benzyl 6,6-dibrompenicillanate in 2Q0 ml of dichloromethane was added a solution of 6.12 g (0.03 mole) of 3-chloroperbenzoic acid in 100 ml of dichloromethane. at about. 0 ° C. Stirring was continued for 1.5 hours at ca. 0 ° C, after which the reaction mixture was filtered. The filtrate was washed successively with 5% sodium hydrogen carbonate solution and water, then dried (Na 2 SO 4). By removing the solvent by evaporation in vacuo, 12.5 g of the title product was obtained as an oil. The oil was strengthened by trituration under ether. Then, by filtration, 10.5 g of benzyl-6,6-dibrompenicillanate 1-oxide was obtained as a solid. The IR spectrum (CHCl 3) showed absorptions at 1800 and 1750 cm NMR spectrum of the product (CDCl

Claims (1)

Penicillanic Acid-1 Oxides for Use as Intermediates in the Preparation of Therapeutically Active Penicillanic Acid-1,1-Dioxide of Formula IH, V ° v. CH3 10 -η pharmaceutically acceptable salts thereof, characterized in that they have the formulas II or III in QHO = 5, £ H = lv * CH_ 3 3 I l '"' ™! TT PCH3 III λ-N-1 J-N - \ O "" COOH O '^ COOH 20 and its base salts 25 30 35