NO133200B - - Google Patents

Description

The present invention relates to a new compound, cis-propenylphosphonic acid and salts thereof, for use as starting material in the production of (cis-1,2-epoxypropyl)-phosphonic acid with antibacterial action.

(-) (cis-1,2-epoxypropyl)-phosphonic acid and its salts have a

high degree of antibacterial activity against a large number of pathogenic bacteria. The ( t ) (cis-1,2-epoxypropyl)-phosphonic acid and its salts also have considerable antibacterial activity which, on a weight basis, is about half that of the (-)-isomer. These compounds are active in inhibiting the growth of both gram-positive and gram-negative pathogenic bacteria. They are active against pathogenic bacteria of species of Bacillus, Escherichia, Staphylococci, Salmonella and Proteus, and antibiotic-resistant variants thereof. Examples of such pathogenic bacteria are Bacillus subtilis, Escherichia coli, Salmonella schottmuelleri, Salmonella gallinarum, Salmonella pullorum, Proteus vulgaris, Proteus mirabilis, Proteus morganii, Staphylococcus aureus and Staphylococcus pyogenes. (-) and (t) (cis-1,2-epoxypropyl)-phosphonic acid and salts thereof can thus be used as antiseptics to remove susceptible organisms from pharmaceutical, dental and medical equipment and other areas that are exposed to infection by such organisms , and to inhibit harmful bacterial growth in industrial paints. Likewise, they can be used to separate certain microorganisms from mixtures of microorganisms. They are useful in the treatment of disorders caused by bacterial infections in humans and animals, and are particularly valuable in this respect as they are effective against many varieties of pathogenic bacteria that are resistant to previously available anti-biotics.

The salts of (-) and (-) (cis-1,2-epoxypropyl)-phosphonic acid are useful as preservatives in industrial applications as they effectively inhibit unwanted bacterial growth in waste water in papermaking

riches and in paints, e.g. in polyvinyl acetate latex paint.

When (-) and (t) (cis-1,2-epoxypropyl)-phosphonic acid and its salts are used to combat bacteria in humans and in lower animals, they can be administered orally in a dosage form such as capsules or tablets, or in liquid solution or suspension. These formulations can be prepared using diluents, granulating agents, preservatives, binding agents, flavoring agents and coating agents known in the art. The (-) (cis-1,2-epoxypropyl)-phosphonic acid discussed here rotates plane-polarized light in a counter-clockwise direction (to the left as seen from the observer) when the rotation of its disodium salt is measured in water (5% concentration) at k05 nm.

The designation cis used to describe the 1,2-epoxypropylphosphonic acid compounds denotes that each of the hydrogen atoms bound to carbon atoms 1 and 2 in the propylphosphonic acid is on the same side of the oxide ring. The expression "cis" is clear in the designation of the cis-propenyl-phosphonic acid compounds according to the invention.

An aim of the present invention is to provide new starting materials which are useful in synthesizing (+) (cis-1,2-epoxypropyl)-phosphonic acid and the (-)-enantiomer thereof.

The cis-propenylphosphonic acid according to the invention has the formula:

and the invention also includes the organic and inorganic salts of this compound.

The structural formula for the new compound according to the invention is for convenience shown as planar formulas above because the configuration is sufficiently defined by the name cis-propenylphosphonic acid. However, for the sake of completeness, the room configuration can be stated structurally as follows:

This space configuration is a critical feature of the present invention because previously described propenylphosphonic acid compounds have the trans configuration, or are mixtures of cis and trans isomers, while the present invention provides compounds in the cis form practically free of the trans form.

The salts of the compound of formula I constitute a particularly preferred embodiment of the invention because they are very useful in the preparation of (t) (cis-1,2-epoxypropyl)-phosphonic acid compounds.

The free phosphonic acid compounds will form both organic and inorganic salts, and both are included in the invention. Examples of such salts are inorganic metal salts, such as the sodium, aluminium, potassium, ammonium, calcium, magnesium, silver and iron salts. Organic salts which may be mentioned as representative include the salts of primary, secondary or tertiary amines such as monoalkylamines, dialkylamines, trialkylamines and nitrogen-containing heterocyclic amines. Representative examples are salts with amines such as α-phenethylamine, diethylamine, diethylenetriamine, quinine, brucine, lysine, protamine, arginine, procaine, ethanolamine, morphine, benzylamine, ethylenediamine, N,N<*->dibenzylethylenediamine, diethanolamine, piperazine, N- aminoethylpiperazine, dimethylamino-ethanol, 2-amino-2-methyl-1-propanol, theophylline, esters of amino acids, and N-methylglucamine. Both mono- and di-basic salts can be prepared when the cation is monovalent.

The compounds according to the invention can be synthesized by selective hydrogenation of a cis-propynylphosphonic acid, as shown structurally below:

Although an acid is used in the illustration, the method can just as well be applied to salts.

The step of selectively reducing the propynyl acid, salt or ester to form propenylphosphonic acid or the corresponding salt or ester is conveniently carried out by hydrogenating the propynyl compound in the presence of a suitable hydrogenation catalyst such as a noble metal or Raney nickel catalyst. When carrying out the hydrogenation to obtain maximum yields of the desired propene-yl bond, the hydrogenation is stopped when 1 mol of hydrogen per mol of starting propynyl compound is included to prevent complete saturation of the unsaturated bond. Catalysts that are particularly useful in this reaction are 5% palladium-on-calcium carbonate or Raney nickel. These catalysts containing a small amount of added poison to reduce their activity can also be used when carrying out the selective hydrogenation. thus the 5% palladium-on-calcium carbonate can be poisoned by adding a small amount of lead acetate, and Raney nickel can be poisoned by adding a small amount of zinc acetate and/or an organic base such as piperidine, morpholine, quinoline and the like. These poisoned catalysts are particularly useful in the reduction of pure propynylphosphonic acids. The particular catalyst and the amount required for the hydrogenation will depend in part on the purity of the propynyl compound being reduced, but generally an amount of catalyst between 1 and 5% is sufficient to effect this selective reduction.

As a solvent, lower alkanols such as methanol, ethanol or isopropanol are conveniently used, although the solvent is not critical. Positive hydrogen pressures of from 1.4 to 7j0 kg/cm overpressure are preferred, but again higher or lower pressures can be used without adverse effect.

Representative examples of cis-propenylphosphonic acid compounds produced by selective catalytic hydrogenation of the corresponding propynylphosphonic acid compound are alkali and alkaline earth metal salts such as sodium, potassium, calcium and magnesium salts and amine salts, for example benzylamine, phenethylamine, ammonium, ethylenediamine, piperazine and quinine salts.

cis-propanylphosphonic acid can also be obtained by saponification of cis-propenylphosphonic acid esters.

The following examples are given to illustrate the invention.

Example 1

10 g (0.043 mol) of di-n-butylpropynylphosphonate was dissolved in

50 ml of methanol and hydrogenated in the presence of 3 g of 5% palladium-on-calcium carbonate poisoned with lead acetate at 2.8 kg/cm in a Parr apparatus. After absorption of 95% of the theoretical amount of hydrogen, the reaction mixture was filtered to remove the catalyst,

and the catalyst was washed with methanol. The filtrate was concentrated under reduced pressure, whereby di-n-butyl-cis-propenylphosphonate was obtained in the form of a pale yellow residue. The residue was distilled

under reduced pressure, and 8.49 g of di-n-butyl-cis-propenylphosphonate boiling at 72°C at 0.12 mm was collected. The product had one

analysis which answered to C,,H_o0„P. The infrared spectrum of the product showed the absence of an acetylene bond at 4.5 µm and the presence of an olefinic band at 6.12 µm, which is characteristic of the cis-olefin. The NMR spectrum also showed that the product was of the cis configuration.

The di-n-butyl-propynylphosphonate used in this example was prepared by adding a solution of 0.5 mol of methylacetylene-magnesium bromide dissolved in a mixture of 2 liters of benzene and 300 ml of tetrahydrofuran dropwise with stirring to a solution of 96.1 g ( 0.5 mol) of di-n-butyl chlorophosphonate in 1 liter of benzene. The methylacetylene-Grignard reagent was added over 3 hours, and the reaction mixture was vigorously stirred during the addition while the temperature was maintained below ca. 28°C. After the addition was finished, the clear solution was allowed to stand at room temperature for approx. 16 hours. 1 liter of an aqueous ammonium chloride solution was added to the reaction mixture and the aqueous layer was separated and extracted twice with benzene. The benzene extracts were combined with the benzene layer, and the solvent was evaporated under reduced pressure, whereby di-n-butylpropynylphosphonate was obtained in the form of an oil weighing 6l.5 g. The oil was distilled under reduced pressure and gave an early fraction with a boiling point of 111° C at 0.5 mm and a clear yellow liquid main fraction consisting of 47.3 g of di-n-butylpropynylphosphonate boiling at 102°C at 0.15 mm.

When this procedure was repeated using the dimethyl, di-t-butyl, diphenyl, or di-p-tolyl ester of propynylphosphonic acid (obtained from the appropriate chlorophosphonate and methylacetylene Grignard reagent), the corresponding ester of cis-propenylphosphonic acid.

Example 2

To a solution of 9 g (0.044 mol) of di-isopropylpropynyl phosphonate in 50 ml of methanol was added 1.5 g of 5% palladium-on-calcium carbonate poisoned with lead acetate, and hydrogen was passed through the solution at 2.8 kg/ cm. After admission of 99.7%

of the theoretical amount of hydrogen, the addition of hydrogen was stopped, and the reaction mixture was filtered free of catalyst, and the catalyst was washed with methanol. Concentration of the filtrate under reduced pressure gave 8.84 g of di-isopropyl-cis-propenylphosphonate. This material distilled at 42-43°C at 0.15 mm.

The di-isopropylpropynylphosphonate used in this example was prepared according to the method described in example 1 by reacting di-isopropyl chlorophosphonate with methylacetylene magnesium bromide. The product was obtained in the form of an oil with a boiling point of 82 - 84°C at 0.4 - 0.45 mm.

Example 3

9.7 g of di-n-butyl-cis-propenylphosphonate was refluxed in 80 ml of concentrated (12.4 N) hydrochloric acid for 15 hours in an oil bath maintained at 108-H7°C. The reaction mixture was allowed to cool to room temperature after which the solution was concentrated in vacuo under heating. 50 ml of water was added to the residue and the evaporation process was repeated, yielding 6.19 g of a brown viscous residue. The residue was dissolved in 25 ml of ethyl ether, and the ether solution was extracted with 3 x 10 ml of water. Evaporation of the ether layer gave 2.56 g of a brown residue. Evaporation of the aqueous extracts in vacuo gave 3.43 g of a pale yellow viscous oil. The residue obtained from the water extract was purified by dissolving in 25 ml of ether, and extracting the ether solution with 12 ml of water. Evaporation of the aqueous extract in vacuo with heating gave cis-propenylphosphonic acid, a pale yellow viscous oil. Infrared spectra of the yellow oil showed the characteristic olefinic band at 6.1 u.

Example 4

Dissolve 500 g (2.15 mol) of di-n-butyl-propynylphosphonate in

2.5 1 methanol in a hydrogenation flask. To this is added 50 g of 5% palladium-on-calcium carbonate. The flask was filled first with nitrogen and then with hydrogen by alternate evacuation and pressure application. The hydrogen pressure was brought up to 3.5 kg/cm overpressure. During 80 minutes of shaking, the temperature was raised from 25°C to 45°C, and 1.94 mol of hydrogen was absorbed. Shake no was stopped, the reactor vented and controlled with nitrogen. The catalyst was removed by filtration, washed with 200 ml of methanol and the methanol evaporated in vacuo until the temperature of the residue reached 100°C. The residue was di-n-butyl-cis-propenylphosphonate.

Example 5

Salts of cis-propenylphosphonic acid are prepared by treating the free acid in ethanol with a base. The metal salts are obtained by using a metal oxide or hydroxide as the base, and the amine salts by using the appropriate amine. To obtain a mono-salt, the pH with the base is adjusted to 4.8 for metal salts and 4.2 for amine salts. For di-salts, the pH is set to 8.8 for metal salts, 8.2 for amine salts. To recover the salt, the ethanol is removed by evaporation in a vacuum. For example, 2 g of cis-propenylphosphonic acid in 50 ml of ethanol are adjusted to a pH of 4.8 with aqueous sodium hydroxide. The mixture is evaporated to dryness in vacuo to give mono-sodium cis-propenylphosphonate. When aqueous sodium hydroxide is added to the above mixture to a pH of 8.8, and the mixture is concentrated to dryness, disodium cis-propenylphosphonate is obtained. The mono- and dibenzylamine salts are obtained in the same way by adding benzylamine to the ethanolic solution of cis-propenylphosphonic acid to a pH of 4.2 or 8.2. Any of the other salts discussed herein are obtained in the same manner using the appropriate base.

The cis-propenylphosphonate esters can be hydrolysed to the free acid as in example 3, and transferred to a salt before epoxidation to (t) (cis-1,2-epoxypropyl)-phosphonates, alternatively the propenyl esters can be epoxidized and the ester group then removed. The salts are epoxyd directly. Representative examples are the following and other salts and esters are epoxidized in the same way: 2.2 g (0.018 mol) of cis-propenylphosphonic acid was dissolved in 10 ml of water. The pH of the aqueous solution was adjusted to 5.6-6 by the addition of 1.51 g, (0.017 mol) sodium bicarbonate to form sodium cis-propenylphosphonate. 0.55 g (0.0017 mol) of sodium tungstate dihydrate was added, and the next neutral solution was placed on a water bath and heated to 55°C. The water bath was then removed and 2 ml of 30% hydrogen peroxide was added to the reaction mixture over 10 minutes. The reaction was exothermic, and the temperature rose to 65°C during the addition of the peroxide. An additional 1.6 mm of hydrogen peroxide was added. Oxygen was evolved from the solution during the addition, and the temperature remained at 55-57°C without external heating. After resting for 20 minutes, the temperature dropped to 53°C. The reaction mixture was then heated on a water bath at 55°C for an additional 20 minutes, filtered, and the solution lyophilized to give the monosodium salt of (±) (cis-1,2-epoxypropyl)-phosphono- acid as a white powder that was identified by its NMR spectrum.

Peroxytrifluoroacetic acid was prepared by the method of Emmons (J. Am. Chem. Soc. 75, 4623 (1953). A solution of 2.8 g of peroxytrifluoroacetic acid in 20 ml of chloroform was then added to 5 g (0.022 mol) of benzylammonium cis-propenylphosphonate and 7 g of solid disodium hydrogenphosphonate in 30 ml of chloroform. The mixture was allowed to stand for 16 hours at 0° C. The solids were then separated by filtration. The solids were suspended in about 10 ml of methanol, the suspension was filtered and the methanol filtrate evaporated to dryness in vacuo to give a solid residue of benzylammonium-(t)-(cis-1,2-epoxypropyl)phosphonate The product was purified by recrystallization from 10 parts of 95% ethanol.

6.4 9 (0.02 mol) of dibenzyl-cis-propenylphosphonate and 30 ml of chloroform were introduced into a 100 ml 3-necked round flask equipped with a stirrer, thermometer and addition funnel. A solution of 3»6 g

(0.02 mol) of mono-perphthalic acid in 20 ml of ethyl acetate was added slowly and the mixture heated to 40°C. The progress of the reaction was followed by gas-liquid chromatography of the dibenzyl ester or by titration of the peracid. The reaction was largely complete after 24 hours. at this point the mixture was cooled to room temperature, the phthalic acid was removed by filtration and the dibenzyl-(t)-(cis-1,2-epoxypropyl)phosphonate was recovered by removing the solvent in vacuo.

Claims (1)

Chemical compound for use as starting material in the production of cis-1,2-epoxypropylphosphonic acid with antibacterial action, characterized in that it is cis-propenylphosphonic acid with the formula: or a salt thereof.