IL30918A - Process for the preparation of cis-1,2-epoxypropyl-phosphonic acid derivatives - Google Patents

Description

ii* a lDO·»o- *ainoΌ318SR-2,1-o«s Process for the preparation of cis-l,2-epoxypropyl-phosphonic acid derivatives MBRCft & CO. , C. 29131 ABSTRACT OF THE DISCLOSURE Novel (-) (cis-1 , 2-epoxypropyl) -phosphonic acid, and salts and esters thereof, are prepared by the epoxidation of the corresponding cis-properiylphosphonic acid compound. (-) (Cis-1 , 2-epoxypropyl) -phosphonic acid, and its salts and labile esters, have significant anti-bacterial activity.

Although many valuable antibiotics are known for the treatment of various diseases , such antibiotics are in general active against a limited number of pathogens, and certain strains of these pathogens develop resistance to a particular antibiotic so that the antibiotic is no longer active against such resistant strains. These shortcomings of the known antibiotics have stimulated further research to discover new antibacterial agents which are active against a wide range of pathogens and against strains of pathogens resistant to previously described antibiotics.

The present invention relates to novel anti-bacterial agents as well as to processes for their prepara-tion. It is concerned more particularly with novel epoxy-phosphonic acids, and more specifically with (-) (cis-1 , 2-epoxypropyl) -phosphonic acid compounds and mixtures of the (+) and (-) enantiomers , and with salts and esters thereof. It relates further to the preparation of such substances by the epoxidation of such cis-propenylphosphonic acid compounds . - 2 - 30918/2 It is an object of the present invention to provide mixtures of the (+) and (-) enantiomers of novel (cis-1.2-epoxypropyl)-phosphonlc acid compounds. A further object is provision of the (-) racemate of such compounds. It is another object provide procesees for making such substance's by the chemical epoxldation of cis-propenvl-phosphonio acid compounds. It is an additional object to provide (-) (cis-1.2-epox.vpropvl)-phosphonlc acid compounds that have a significant degree of antibacterial activity. Further ob eots will be apparent from the following detailed description of this invention.

The novel (-) (ols-1.2-epox.vpropy1)-phosphonic acid compounds of this invention are represented by the formula in which R and R.^ are independently hydrogen, metal (including ammonia) cations, organic cations, alkyl radicals optionally substituted with halogen, hydroxy, alkoxy, carbalkoxy, acyloxy, cyano, or pyridyl? lower alkenyl, or cycloalkyl radicals, phenyl radicals optionally substituted with nitro, halo, alkyl or alkylsulfonyl, aralkyl radicals optionally substituted with nitro, halo or alkyl} or ^ and R,, together represent either a group W attached to the oxygen atoms to form a cyclic ester of the formula 0 0 C- w - 3 - 30918/2 where W T H H < or a group e - Cv- C - CH, , or one of R or R, is a group 0 I H H - p C - CCH, or - PO,, (R0)~ where R is lower alkyl or an R 0 alkali or alkaline earth metal ion.

The structural formulas of the novel compounds of this invention are for convenience shown in the planar formula above because the configuration is adequately defined by the name (-) (ois-1.2-epox.vpropyl)-phoaphonic acid.

However, for the sake of completeness, the spatial configuration may be represented structural When R and/or R^ in formula I are alkyl they may be methyl, propyl, isopropyl, t-butyl, hexyl, octyl, decyl, dodecyl, · or substituted alkyl, for example, acyloxyalkyl such as aoetoxymethyl, proplonoxyethyl, and benzoylox ethyl, hydroxy-ethyl, hydroxypropyl, pyridylalkyl, carbalkoxymethyl, cyano-ethyl and methoxymethyl; where they are alkenyl they may be allyl, methallyl, vinyl, propenyl or hexenyl; where they are cycloalkyl they may be cyclohexyl, or cyclopropyl. When R is an optionally substituted lower alkyl or alkenyl, It preferably has from 1-6 carbon atoms. - 4 - 30918/2 Examples of R and/or representing an araliphatlc radical are benzyl, phenethyl, phenylpropyl, p-halobenzyl and p-nitrobenzyl.

R and/or ^ may also represent an aryl radical such as phenyl, or substituted phenyl, e.g. p-chlorophenyl, o-nitrophenyl, o,p-dihalophenyl, methylsulfonylphenyl, or tolyl.

Those compounds of formula I which are acidic, i.e. the free acids and the mono-esters, may form salts, and such salts constitute an especially preferred aspect of the invention because they are highly useful when the (-) ( cia-1.2-epox.vprop.vl)-phosphonic acid compounds are employed as antibacterial agents. They are more stable than the free phosphonic acid, and the esters are not (except in particular instances) as active as the salts.

As will be appreciated by those skilled' in this art, the free phosphonic acid compounds will form both organic and inorganic salts, and both are contemplated by this invention. Examples of such salts are inorganic metallic salts such as the sodium, aluminum, potassium, ammonium, calcium, magnesium, silver and iron salts.

Organic salts that may be mentioned as representative include the salts with primary, secondary or tertiary amines such as monoalkylamines , dialkylamines , trialkyl-amines and nitrogen containing heterocyclic amines.

Representative examples are salts with amines such as a-phenethylamine , diethylamine, diethylene triamine, quinine, brucine, lysine, protamine, arginine, procaine, ethanolamine, morphine, benzylamine, ethylenediamine, Ν,Ν'-dibenzylethylenedlamine, diethanolamine , piperazine, N-aminoethylpiperazine, dimethylaminoethanol , 2-amino-2-methyl-l-propanol, theophylline, esters of amino acids, and N-methylglucamine . Both mono- and di-basic salts may be prepared when the cation is monovalent. If desired, the basic moiety of the salt may be a biologically active amine such as erythromycin, oleandomycin or novobiocin.

Those salts which are pharmaceutically acceptable and substantially non-toxic may be employed when using the (i) ( cis-1, 2-epoxypropyl) -phosphonic acid as an anti-bacterial agent. Other salts which are not normally employed in pharmaceutical applications are useful as intermediates in forming the free acid and for making other salts by metathesis. In addition, the salts with optically active amines may be employed as intermediates in resolving the racemic (ί) (cis-1,2-epoxypropyl) -phosphonic acid into its optically active stereoisomers. esters which are readily hydrolyzed chemically or are converted biologically to the free acid or a salt. Such esters may be referred to as labile or biologically labile esters. They include compounds where the radicals R and/or (in Formula I above) represent lower alkenyl such as allyl or methallyl; acyl - examples of which are phenyl-acetyl, phenylpropionyl, p-chlorophenylacetyl, benzoyl and lower alkanoyl; substituted alkyl such as pyridylmethyl, p-dimethylaminoethyl, β-diethylaminoethyl, β-cyanoethyl , β-methoxymethyl, hydroxypropyl , acetoxymethyl, plvaloxy-methyl and propionoxymethy1; phenyl substituted with one or more electron withdrawing substituents such as nitro, alkylsulfonyl and aminosulfonyl , and the ester with catechol.

Also embraced by this invention are the pyro-phosphonates , anhydrides and isohypophosphates represented by the formulas or or I 12095 .30918/2 where R has the same, meaning as above, is loweralkyl or an alkali metal. or alkaline earth metal ion. Salts of compounds where R is hydrogen are especially preferred. 6 Representative examples of compounds of Formula II are 7 dipiperazlnium (-) ( cls_-l, 2-epoxypropyl)-pyrophosphonate , 6 dlsodium .(t) ( cls-1 , 2-epoxypropy 1 ) -pyrophosphonate , 9 dlbenzyl (ί) (cls-1 , 2-epoxypropy 1 ) -pyrophosphonate, and allyl (i) (cls-1 , 2-epoxypropyl) -pyrophosphonate; 11 the compound of Formula III is (ί) ( cis_- 1 , 2-epoxypropyl)- 12 phosphonic acid cyclic di-anhydride ; examples of the 13 compounds of Formula IV are sodium (-) ( cis-l^-epoxy-l'k propyl) -isohypophosphorlc acid disodium salt and potassium <-) (cls-1 , 2-epoxypropyl) -isohypophosphorlc Nacid dlbenzyl ' 16 ester. Although the di-anhydrides are conveniently 17 represented by Formula III above, they may also exist in 18 the forms 19 where n is a positive integer. These substances, and particularly those wherein R is a cation (i.e. salts) or 21 -an easTly-remoyable ester have antibacterial activity. 22 Specific representative examples of the compounds 23 of Formula I above, and salts thereof, which may be 2 prepared by the processes described hereinafter are: . {-) ( cis-1 , 2-epoxyprop l) -phosphonic acid, 1 diallyl (ί) ( cis-1, 2-epoxypropyl) -phosphonate , 2 dimethallyl (-) ( cj -l, 2-epoxypropyl) -phosphonate , 3 dibenzyl (-) ( cis-1, 2-epoxypropyl)-phosphonate , benzyl (-) (cis-1, 2-epoxypropyl) -phosphonate, decyl (,-) ( cis-1, 2-epoxypropyl)-phosphonate, 6 phenyl (-) ( cis-1, 2-epoxypropyl)-phosphonate , 7di(p-nitrophenyl) (-) ( cis-1, 2-epoxypropyl)-phosphonate , 9 cyclohexyl (-) (cis_-l, 2-epoxypropyl) -phosphonate, pentyl (ί) ( cls-1 , 2-epoxypropy 1) -phosphonate , U — p-amlnophon l ( ) — ( olo-lt 2-epoxypropy l)»phoophonate¾ 12 tolyl (ί) (cls-1, 2-epoxypropyl) -phosphonate , 13 — totrahydrofuryl (-) — (-c-l-s— -l-y-2— opoxypropyl) phoophonatoi ' 1*» dlsodlum (-) (cis-1, 2-epoxypropyl) -phosphonate , sodium (i) (cls-1, 2-epoxypropyl)-phosphonate , 16 potassium (ί) ( cis-1, 2-epoxypropyl)-phosphonate , 17 calcium (ΐ) ( cis-1, 2-epoxypropyl) -phosphonate , 18 aluminum (ί) ( cls-1 , 2-epoxypropy 1) -phosphonate , 19 benzyl ammonium (ί) ( cis-1, 2-epoxypropyl) -phosphonate, magnesium (i) ( is_-l, 2-epoxypropyl) -phosphonate, 21 a-phenethylammonium (-) (cis^-1, 2-epoxypropy l)-phosphonate 22 silver (-) (cis-1, 2-epoxypropyl) -phosphonate, 23 lysine (ί) (cis-1, 2-epoxyprop l) -phosphonate , 2 quinine (i) ( cis-1, 2-epoxypropyl) -phosphonate , procaine (-) ( cis-1, 2-epoxypropyl)-phosphonate , 6 dibenzylammonium (i) (cis-1, 2-epoxypropy l)-phosphonate, 7 ethylenedlammonium (-) (cis-1, 2-epoxypropyl) -phosphonate, 8 diethylenediammonium (ΐ) ( ci -l, 2-epoxypropyl )-phosphonat 9 disodium (-) ( cis-1, 2-epoxypropyl)-pyrophosphonate .

V 1 mono- and diplperazlnlum (-) (cls-1, 2-epoxypropy1)- 2 phosphonate, 3 cyclic ester of (ί) ( cls-1 ,2-epoxypropyl)-phosphonic acid 4 with catechol, cyclic ester of (-) ( cis-1, 2-epoxypropyl)-phosphonic acid 6 with ethylene glycol, -phosphonlc acid 8 with bis^ydroxyethyOamine, 9 bis-acetoxymethyl (ί) (cis_-l, 2-epoxypropy1) -phosphonate, 0 bis- -ethoxyethyl (-) ( cls-l 2-epoxypropyl)-phosphonate , 1 bis(phenylacetyl) (-) (cls-1, -epoxypropyl)-phosphonate, biB- + 2 (pyridylmethy])-(-) ( cis-1, 2-epoxypropy1) -phosphonate , 3^(methylsulfonylphenyl) (-) ( cis-1, 2-epoxypropyl) -phosphonate , ft-rH mpf-.hy 1 ami nnmphhy.1—(jL)—( ClS_-l,2 O OXy ro 1 ) -ph03phon¾te -, bis- + and/(β-hydroxyethyl) ( -) ( cls-1, -epoxypropy1) -phosphonate . 6 The (-) ( cis-1, 2-epoxypropy1) -phosphonl c acid 7 described herein and the salts and biologically labile 8 esters thereof, have significant antibacterial activity 9 against a large number of pathogens . They are useful 0 antimicrobial agents, which are active in inhibiting the 1 growth of both gram-positive and gram-negative pathogenic 2 bacteria. They are active against species of Bacillus , 3 Escherichia , Staphylococci , Salmonella and Proteus k pathogens, and antibiotic-resistant strains thereof.

Illustrative of such pathogens are Bacillus subtills , 6 Escherichia coll , Salmonella schottmuelleri , Salmonella 7 gal1.1narum,, Salmonella pu11o um, Proteus,, vulgaris , , 8 Pipoteus mira i,lls , Proteus .u r a ii , Staphylococcus aureus and Staphylococcus pyogenes. Thus, (-) (cis-l,2-epoxy- pharmaceutical, dental and medical equipment and other areas subject to infection by such organisms, and to inhibit harmful bacterial growth in industrial paints.

Similarly, they can be used to separate certain micro-organisms from mixtures of microorganisms . They are useful in the treatment of diseases caused by bacterial infections in man and animals and are particularly valuable in this respect, since they are active against many strains of pathogens resistant to previously available antibiotics.

The salts of (-) ( cis-l,2-epoxypropyl)-phosphonic acid are useful as preservatives in industrial applications since they effectively inhibit undesirable bacterial growth in the white water used in paper mills and in paints, e.g. in polyvinyl acetate latex paint.

When (t) (ci --l,2--epoxypropyl)-phosphonic acid or its salts or labile esters are used for combatting bacteria in man or lower animals, they may be administered orally in a dosage form such as capsules or tablets, or in a liquid solution or suspension. These formulations may be prepared using diluents , granulating agents, preservatives, binders, flavoring agents and coating agents known to those skilled in this particular art.

Alternatively, they may be administered parenterally by injection in a sterile vehicle, and for this it is normal to use a salt that is soluble in the liquid vehicle.

Representative examples of formulations are given below, it being understood that other salts and other pharmaceutical vehicles could be substituted for those illustrated.

A. Capsules ( cis-1 , 2-epoxypropy1) -phosphonate monohydrate are mixed with sufficient lactose U.S. P. to fill a No. 0 gelatin capsule which holds approximately 475 mg. of solid. After a uniform blend is obtained, the solids are milled to a particle size of less then 10 microns, and the capsules filled by hand or by machine.

Each capsule contains the equivalent of 250 mg. of (-) ( cls-l,2-epoxypropyl)-phQBphonic acid.

B. Tablets Per Tablet Calcium (-) ( cis-1 , -epoxypropy1)- phosphonate monohydrate 352.5 mg.

Dicalcium phosphate 180 Lactose U.S. P. 179.5 Cornstarch 80 mg.

Magnesium stearate 8 mg.

The phosphonate is blended with the dicalcium phosphate, lactose and half of the cornstarch. The mixture is granulated with a 15% cornstarch paste and rough-screened. It is dried at 45°C. and screened through a No, 16 screen. The balance of the cornstarch and the magnesium stearate is added, and the mixture compressed into 1/2" diameter tablets, each weighing about 800 mg. A similar tablet is prepared by adding bis-acetoxymethyl (i) (cis-l,2-epoxypropyl) -phosphonate in place of the calcium salt in an amount equivalent to 250 mg. of the free acid.

C. Oral Liquid Form Per 1000 Ml.

Disodium (-) ( cis-l,2-epoxypropyl)- phosphonate 132.0 gm.

Sucrose 600.0 gm.

Glucose 250.0 gm.

Citric Acid 13.0 gm.

Sodium benzoate 1.0 gm.

Concentrated Orange Oil 0.2 ml.

Purified water, U.S.P. to make 1000.0 ml.

The sucrose and glucose are dissolved in about 400 ml. of water, with heating. The solution is cooled, the citric acid and sodium benzoate added, and then the orange oil. The solution is brought to a volume of about 900 ml. with water, and the disodlum (t) (cis-1,2-epoxypropyD-phosphbnate added. The solution is filtered and adjusted to a volume of 1000 ml.

The (-) ( cls-l,2-epoxypropyl)-phosphonlc acid is preferably employed as an antibacterial agent in the form of a salt or a biologically active ester. Good results are obtained in the treatment and control of bacterial Infections in adult humans by administration of from about 1-8 gm./day of (-) ( cis-l,2-epoxypropyl)-phosphonic acid equivalent, the actual weight being dependent on the particular salt or ester employed. When the higher dose levels are used, the salt or ester is chosen so that the cation is not unduly toxic at such levels. It will, of course, be understood that the optimum dose in any given instance will depend upon the such adjustments being within the skill of the practitioner in the field.

The mixtures of the (+) and (-) enantiomers the ( cls-1 ,2-epoxypropyl)-phosphonic acid compounds of this invention may be administered alone or in combination with other biologically active ingredients and especially with other antibacterial agents such as erythromycin, lincomycin, a penicillin, streptomycin, novobiocin, tylosin, gentamycin, neomycin, colistin, kanamycin, oleandomycin, triacetyl oleandomycin and spiramycin.

The antibacterially active (-) ( cis-1, 2-epoxy-propyl) -phosphonic acid, and its salts, may be resolved, if desired, into the (+) and (-) enantiomers thereof, as by formation of a salt with an optically active amine, separation of the diastereoisomers of such salt, and. regeneration of the (+) and (-) enantiomers of ( cis-1,2-epoxypropyl) -phosphonic acid. The antibiotic activity resides in (-) ( cls-1, 2-epoxypropyl) -phosphonic acid so that this acid and its salts possess essentially twice the antibacterial activity (on a weight basis) of the (i) ( cis-1, 2-epoxypropyl) -phosphonic acid compounds of the present invention.

In accordance with the process aspect of this invention, the (-) (oisrl, 2-epoxypropyl) -phosphonic acid compounds of Formula I hereinabove are prepared by the epoxidation of a cis-propenylphosphonate compound of the formula: H H 0 H-C-C = C- OR ..- 14 - 30918/2 with a chemical epoxidizlng agent, where R and ^ have the same meanings as in formula I. When R and/or ^ are cations, the compound is a mono- or di-salt. It is preferred, and is important for best results In this reaction, that a least one of R and ^ in formula V be other than hydrogen. The choice of epoxidizlng agent is not unduly critical although it should be one capable of epoxidizlng the cls-propenylphosphonate compound without undue destruction of the remainder of the molecule. It is preferred to carry out the epoxidatlon on a sal or ester derivative of the free phosphonic acid since the acid itself tends to.be unstable under the reaction conditions. In addition, it is further preferred to employ as the oxidizing agent a peroxy compound, such as hydrogen peroxide, an inorganic peracld, a perorganlo acid, an organic hydroperoxide or peroxy imidate as discussed hereinafter. However, other epoxidizlng agents ma also be used if desired, and examples of these are also discussed hereinbelow.

The compounds of formulae II, III and IV above are obtained by epoxidizlng the corresponding cJLg-propenyl-phosplafate compounds of the formulae i - 14a - 30918/2 or or 0 H H H,C *» C σ P - O 05(R2); OR One of the better methods of ©poxidlzing the ethylenic double bond of the olefin compound is by treating said compound with hydrogen peroxide. Although hydrogen peroxide alone may be used, it is greatly preferred to conduct the reaction in the presence of a suitable inorganic peracid since much better results are thereby obtained. In describing this invention the inorganic peracid is sometimes referred to as a catalyst, although the exact role of such peracid is not unequivocally established as a catalyst in the classical sense, and it may participate as an epoxidizing agent. Although the peracid itself may be added to the reaction medium, it is generally preferred that the inorganic acid be added to the reaction mixture and the peracid formed in situ by reaction with the hydrogen peroxide. Stated another way, acids of metal oxides which react with hydrogen peroxide to form peracids may be employed. Particularly useful catalysts are the peracids of tungsten, vanadium and molybdenum, either as the simple acids or polyacids , includ-ing the heteropolyacid forms. The inorganic acids are generally used in the form of neutral salts, such as an alkali metal, e.g. sodium or potassium tungstate, ammonium tungstate, alkaline earth metal salts such as calcium or barium tungstate or vanadate, a heavy metal salt, examples of which are zinc vanadate, zinc tungstate, tin tungstate, tin molybdate, aluminum tungstate and aluminum molybdate. Alternatively, the neutral salt can be formed in situ by adding a free acid, such as tungstic or vanadic acid, and adding sufficient base to form the desired salt.

In addition to the simple peracids, there may be used heteropolyacids, examples of which are the hetero-polytungstic acids of arsenic, antimony and bismuth.

In the same way heteropolymolybdic and heteropolychromic acids of sulfur, selenium or tellurium may also be utilized as catalyst. In general, the heteropolyacids of the acid-forming elements of group VI of the Periodic Table of Elements are satisfactory. More than two different hetero-acid forming elements of group VI may be present in the catalyst, examples being thiotelluro-tungstic acid and selenomolybdotungstic acid. As previously stated, these are preferably converted in situ above, are alkali metal carbonates, bicarbonates and phosphates, e.g. sodium carbonate, potassium bicarbonate, sodium phosphate and disodium hydrogen phosphate. At least about 0.1$ of catalyst (by weight of cis-propenylphosphonic acid compound) Is used for best results. Higher amounts are not harmful and up to about 30% by weight may be employed if desired. It is preferred to use from about 0.25 - 556 of inorganic peracid (by weight of propenyl-phosphonate) . When these catalysts are utilized the cls-propenylphosphonic acid compound of Formula I above is contacted with hydrogen peroxide (or an equivalent peroxide such as sodium or barium peroxide) in the presence of the catalyst and in a suitable liquid reaction medium. The reaction is conveniently brought about at temperatures of from between about 0° and 90°C, and preferably from between about room temperature and 80°C. and at a pH of between about 3.0 and 11.0, and preferably from about 4.0 to 6.0. At a pH below about 4.0, reaction temperatures belo about 15°C are desirable in order to avoid or minimize decomposition of the desired epoxypropylphosphonlc acid compound. At the higher pH levels, (i.e. above 8.0) the hydrogen peroxide decomposes at an appreciable rate and must be replaced during the reaction.

Good results are obtained by dissolving or suspending the cls-propenylphosphonlc acid compound in the solvent, adjusting to the desired pH, adding the catalyst and finally the hydrogen peroxide. The rate and temperature of the reaction may be readily controlled by rate of peroxide addition. For best results, at least at least about 3 moles of peroxide per mole of phosphonate. Larger excesses are not deleterious.

Water and/or alcohols compatible with hydrogen peroxide are preferably employed as solvent media, suitable alcohols being lower alkanols such as methanol, ethanol, propanol or butanol. If desired, chelating agents such as ethylenediamine tetraacetlc acid, ethylenediamine diacetlc acid, glycine or β-alanine may be present during the epoxidatlon reaction in order to sequester any heavy metals such as iron, nickel or copper which tend to catalyze the decomposition of hydrogen peroxide.

Upon completion of the epoxidatlon reaction, any excess hydrogen peroxide is decomposed. The (ί) ( cis-l,2-epoxypropyl)-phosphonic acid compound may be recovered by separation from inorganic compounds and subsequent crystallization or evaporation of the reaction mixture to dryness.

The (-) ( cis-l,2-epoxypropyl)-phosphonates of this invention may also be obtained by reaction of the cis-propenylphosphonate (V) with an organic peracid such as peracetic, perbenzoic, substituted perbenzoic, mono-perpththalic, performic or peroxytrifluoroacetic acid, preferably at temperatures of between about -10°C. and 150°C. Peroxyanhydrides may also be employed as a source of the peroxy acids if so desired. This peroxidation is preferably carried out in inert hydrocarbon solvents such as chloroform, methylene dichloride, benzene, toluene, pyridine or ethyl acetate. The reaction time is not critical and it is, of course, preferable to continue the peracid is utilized for best results. It is preferred that the reaction mixture be buffered when employing those peracids which will decompose during the reaction to strong acids, e.g. peroxytrif luoroacetic acid. Dlsodium hydrogen phosphate is an example of a suitable buffering agent. It should be pointed out at this juncture that use of an optically active organic peracid as the peroxidizing agent, such as percamphorlc acid, will afford a reaction mixture containing predominantly only one of the optical isomers of the ( cls-l,2-epoxypropyl)-phosphonic acid compound. Thus, for example, utilization of (+) per-camphoric acid as epoxidizing agent will produce pre-dominantly the (-) ( cis-l,2-epoxypropyl)-phosphonic acid compound. The desired products may be recovered by methods known to those skilled in this art, for instance by decomposition of excess perorganic acid and removal of the solvent or solvents.

Additionally, the cis-propeny lphosphonic acid compounds of Formula V may be epoxidized to the 1,2-epoxypropyl compounds of Formula I by reaction with an organic hydroperoxide in a suitable solvent medium. Any organic hydroperoxide may be employed although the more readily available ones such as t-butyl hydroperoxide, cumene hydroperoxide and amylene hydroperoxide are pre-ferred. The reaction is conveniently carried out in inert hydrocarbon or halogenated hydrocarbon solvent (similar to those used in the perorganic acid process discussed above) at a temperature of between about -10°C. to about 100°C, preferably from 60-90°C. As catalyst, there is preferably 1 the Periodic Table, such as molybdenum, tungsten or 2 vanadium, or a complex or ligand of these metals, as for 3 example molybdenum hexacarbonyl. An alkali metal hydroxide . or an organic base such as Triton B may also be used as catalyst although the metal oxides are more satisfactory. 6 Further, formation of the epoxides of this 7 invention can be brought about by treating the cis- 8 propenylphosphonic acid compound of Formula V above with 9 hydrogen peroxide and a nitrile which serves as a source of peroxyimidic acid, suitable nitriles being acetonitrile , 11 propionltrile and benzonitrile . At least about 1 mole of 12 peroxide and nitrile is used per mole of olefin, although 13 larger quantities of oxidants may be employed if desired. I1* The peroxidizing agent is the peroxyimidic acid formed in situ from the nitrile and hydrogen peroxide, which is 16 decomposed during reaction to an amide. The reaction 17 is generally conducted in an aqueous or lower alkanolic 18 solvent medium (the alcohol being one that is compatible 19 with hydrogen peroxide), and at a pH of about 7-9 . The pH may be maintained with an alkali metal bicarbonate buffer 21 or by other means such as the continuous addition of an 22 alkali metal hydroxide, e.g. sodium hydroxide. Time and 23 temperature are not critical actors. Upon completion of *f the reaction, any excess hydrogen peroxide is decomposed 5 by known methods and the desired product separated from 6 the organic amide by-product by techniques known to those 7 skilled in this art. It is convenient to employ a nitrile 8 and solvent such that the resulting amide is insoluble 9 and the epoxide is soluble in the reaction mixture. 0 A still further method for obtaining the ( ί) 1 - - - 1 invention is by reacting the cis-propenylphosphonate 2 compounds with oxygen (or air) in the presence of a suit- 3 able catalyst and a basic buffer. Examples of satisfactory *t catalysts are alkali metal tungstates or vanadates, the naphthenates of cobalt, iron, manganese or vanadium, or 6 t-butyl hydroperoxide. It is desirable to carry out the 7 oxidation at temperatures of about 75°C. to 125°C. since 8 the epoxidation proceeds only slowly at lower temperatures. 9 Although a reaction solvent is not absolutely necessary, 0 it is preferred to utilize an inert liquid solvent, 1 suitable examples of which are diloweralkyl amides such 2 as dimethylformamide and dimethylacetamide , or a lower 3 alkyl benzoate, e.g. ethyl benzoate. The reaction time ** is not critical, and periods of from about 15-25 hours are normally used in order to obtain maximum yields of 6 epoxyphosphonate . Upon completion of the reaction, the 7 desired product is recovered by known techniques from the 8 solvent after separation of the insoluble catalyst . 9 Still another procedure for peroxidizing the 0 olefinlc cis-propenylphosphonate compound is by reacting it with an oxidizing metal salt such as chromium trioxide or an alkali metal permanganate in a basic solvent, examples of which are pyridine, a-picoline, piperidine and dimethylformamide. The reaction time and temperature are not unduly critical. It is preferred to peroxidize at about room temperature, although temperatures of from about 0°C. to 100°C. may be used. The reaction, in which an excess of oxidizing agent is generally employed, is allowed to proceed until the maximum amount of (-) ( cis- l, 2-epoxypropyl)-phosphonate is formed, which may then be 1 An alkali metal hypohalite may also be employed 2 as the oxidant in the process Of this invention, and for 3 this purpose sodium or potassium hypochlorite or hypo- bromite are the most suitable. The epoxidation is con- 5 venlently brought about in an aqueous medium, or in a 6 organic base such as pyridine or dimethylformamide , at 7 temperatures of from about 0°C. to 100°C. and at a pH 8 above about 8.0. If desired, an epoxidizing agent capable 9 of generating hypochlorite in situ may be used, an example of such a compound being 5,5-dimethyl 1,3-dichlorohydantoin. 11 The desired product is then recovered by known techniques, 12 one suitable method being removal of cations by adsorption 13 on a cation exchange resin on the hydrogen cycle, and lt recovery of the (-) ( cis-1, 2-epoxypropyl)-phosphonate compound from the resin eluate. It is convenient to 16 recover a salt by collecting the resin eluate in the 17 presence of a base. 18 In addition, the epoxidation may be carried out 19 by reacting a cis-propenylphosphonate of Formula V in a suitable inert solvent with ozone in the presence of 21 either a donor olefin or a compound that forms a 1:1 22 adduct with ozone that decomposes to release oxygen in 23 a very active form. This process is conducted in the cold, 4 i.e. at temperatures of from -30°C. to -5C)°C, suitable 5 donor olefins being compounds such as stilbene and cyclo- 6 hexene.' The reaction solvent is, of course, one that is 7 inert under the reaction conditions and liquid at the 8 reaction temperatures, suitable solvents being methylene 9 chloride, pentane or hexane. After the reactants are 0 brought together in the cold, the mixture is allowed to 1 warm slowly to ambient temperature in order to complete the reaction. The desired product is recovered by removal of the solvent and purification by known techniques. In this particular embodiment of the invention, best results are obtained where the particular salt or ester of the cis-propenylphosphonlc acid compound is soluble in the reaction solvent. A dialkyl trioxide may also be the oxidant.

Still another method for preparing the (-) ( cis-,l,2-epoxypropyl)-phosphonate compounds of the Invention is by epoxidation of the cis-propenyIphosphonate with an alkyl perborate or alkyl perphosphate . The reaction is conveniently carried out at room temperature, although temperatures of up to about 8o°C. are satisfactory, using a slight excess of epoxidizing agent. A solvent is not necessary, although if one is employed the cis-propeny1-phosphonate should be soluble in it. The alkyl perborate, such as cyclohexyl perborate, is conveniently prepared by known methods from an alkyl borate and hydrogen peroxide the alkyl perphosphate reagent may be obtained by reaction of a dialkyl phosphorochloridate [( alkyl 0) 2r- CI] with a lower alkyl hydroperoxide in the presence of an alkali metal hydroxide.

In accordance with an additional aspect of the invention, the {-) (cls-l,2-epoxypropyl)-phosphonates of Formula I above are prepared directly by reaction of cis-propenylphosphonous acid salts and esters with an oxidizing agent described above, and preferably with a peroxy oxidizing agent. Thus, the oxidation state of the phosphorus atom is changed from p111 to PV, and the olefinic double bond epoxidized in the one reaction.

The (i) (cis-l,2-epoxypropyl)-phosphonic acid, obtained in accordance with the above-described process may be utilized directly as antibiotic agents since they possess substantial antibacterial activity. In addition, the racemic mixture obtained on oxidation of the cis-propenylphosphonate may be resolved by formation of a salt with an optically active amine, such as a-phenethylamlne, separation of the two diastereomers by fractional . crystallization, and recovery of the salt of (-) ( cis-1,2-epoxypropyl) -phosphonic acid. This latter material and its salts possess a high degree of antibacterial activity.

The esters of (ί) ( cis-l,2-epoxypropyl)-phosphonic acid may be converted to the free acid or to mono or dl-salts of (-) (cis_-l,2-epoxypropyl) -phosphonic acid by a number of methods such as by hydrolysis, or reductive removal of the ester group. The hydrolysis may be with base or acid, be enzymatic, light-catalyzed or via a trimethylsilyl derivative. The reductive removal of the ester group may be by hydrogenolysis or chemical, as with sodium-tertiary amine. The preferred method in any given instance depends upon the particular ester involved and representative examples appear in the experimental portion hereof. It should be noted that in some cases the reaction conditions employed to effect the epoxidation of this invention will also lead to at least partial hydrolysis of certain esters. This may occur when the pH during the epoxidation is above about pH 6 because certain of the epoxide diesters described herein are hydrolyzed with base to monoesters at higher pHs. Similarly, as will be appreciated by those skilled in this art, the conversion of esters of (-) ( cls-l,2-epoxy- 30918/2 about without recovering the ester from the epoxldatlon mixture. Thus, for Instance, dlbenzyl cls-propenyl-phosphonate may be epoxldlzed at about pH 4.5 with hydrogen peroxide and sodium pertungstate to dlbenzyl (ί) (cis-1,2-epoxypropyl) -phosphonate, and this latter product converted by hydrogenolysis without isolation to disodlum (-) (cis-1,2-epoxypropyD-phosphonate . The epoxldatlon process of this Invention may also be applied to preparing (-) (cls-l,2-epoxypropyl)-phosphonic acid or a salt thereof directly from a cis-propenylphosphonic acid ester that is easily oxidized, such as the 3-crotonyl, p-benzoquinonyl and p-naphthoquinonyl esters. These are epoxldlzed as discussed above but employing a large excess of oxidizing agent. The reaction product thus obtained is the salt of (-) ( cis-1.2-epoxypropyl)-ph08phonic acid corresponding to the cation present in the reaction mixture.

EXAMPLE 1 Cls-propenylphosphonic acid (2.2 g., .018 mole) is dissolved in 10 ml. of water. The pH of the aqueous solution is adjusted to 5.5-6 by the addition of sodium bicarbonate (1.51 g. , .017 mole) to produce sodium cis-propenylphosphonate . Sodium tungstate dihydrate (0.55, g., .0017 mole) is added, and the nearly neutral solution is placed In a water bath and heated to 55°C The water bath is then removed, and 2 ml. of 30% hydrogen peroxide are added to the reaction mixture during 10 minutes. The reaction is exothermic, and the temperature rises to 65°C. during addition of the peroxide. An additional 1.6 ml. of hydrogen peroxide is added. Oxygen evolves from the solution during the addition, and the temperature remains at 55-57°C. without external heating. After standing 20 minutes, the temperature falls to 53°C. The reaction mixture is then heated in a water bath at 55°C. for an additional 20 minutes, filtered and the solution is freeze-dried to yield the mono-sodium salt of (ί) (cis-1,2-epoxypropyD-phosphonic acid as a white powder, which is characterized by NMR spectra. This product as well as the other salts and the other compounds of this invention represented by Formulas I-IV above, may also be identified as ( cis-l,2-epoxypropyl) -phosphonic acid compounds, but the (-) nomenclature is used because it is preferred over the d.2.nomenclature by those expert in this field of chemistry. In this system of nomenclature, the (-) isomer is the same as the -^isomer.

When the above reaction is carried out employing 0.018 moles of dipotassium cls-propen lphosphonate , calcium cis-propenylphosphonate or magnesium cls-propeny1-phosphonate as starting material, there is obtained dipotassium (-) ( cls-1, 2-epoxypropyl) -phosphonate , calcium (-) (cijs-1, 2-epoxypropyl) -phosphonate , and magnesium (-) ( cis-1, 2-epoxyprop l) -phosphonate , respectively. -r 25a - 30918/1 Some physical constants of monosodium/calcium and magnesium (i) (c^-l,2-epoxypropyl)-phosphonates are as follows: . N · ■ Monosodlum (-) (cis-1.2-epox.vprop.vl)-Phosphonate.

Nuclear Magnetic resonance (UMB1 Spectrum In DgO: 1.5 ppm 3H (CH^); 2.6-3.8 ppm multlplet 211 (epoxy 4.7 ppm singlet H (HOD by exchange with phosphate).

Calcium (-) ( cia-1.2-epox.vprop.vl)- hosnhonate.

X-ray diffraction data (4 strongest lines): Interplanar Spaolnz (A°) Relative Intensity 12.16 100 6.08 4.5 4.05 4.5 3.04 7.5 Magnesium (£) ( 4g-l,2-epoxy ropyl)-phosphonate.

X-ray diffraction data; One strong line d(A°)»12.60. All others very weak.

EXAMPLE 2 Cis-propenylphosphonic acid (.50 g., .041 mole) is dissolved in 0.5 ml. of water, and the solution neutralized to pH 5.5 by careful addition of ammonium hydroxide. Sodium tungstate (10 mg., .00034 mole) is added, and the mixture is heated to 55°C. on a water bath. Hydrogen peroxide (0.5 cc.) is added, and the heating continued for 1-1/2 hours. The reaction mixture is then cooled to room temperature, and the solvent removed by freeze-drying. The residue is dissolved in 50 ml. of methanol, and the insoluble inorganic material filtered off. Upon concentration of the solution, crystalline ammonium salt of (-) ( cis-1, 2-epoxypropy1) -phosphonic acid is obtained. The product is characterized by its infrared and NMR spectra.

When this procedure is repeated, and the aqueous solution neutralized with dimethylamine, triethylamine or pyridine, there is obtained dimethylammonium, tri-ethylammonium and pyridinium (-) ( cis-1,2-epoxypropyl) -phosphonate, respectively.

The same result is obtained when the foregoing procedure is repeated using an equimolar amount of potassium vanadate or of aluminum molybdate as catalyst instead of sodium tungstate.

EXAMPLE 3 To a two liter, 3-necked flask equipped with a stirrer, thermometer, pH electrode and addition funnel is charged 150 g. (0.655 mole) of monobenzylammonium cis-propenylphosphonate and 1.12 liters of water. Sodium tun state dih drate 6.0 . 0.018 mole is slowl added. After 10 minutes at 50°C, the pH Is adjusted to 5.0-5. 5 with 2 . 5 N sodium hydroxide. 150 Mi. of 30% hydrogen peroxide is added over 15 minutes at 55-6o°C. maintaining a pH of 4 . 8 to 5.2 by addition of sodium hydroxide as required. After stirring for 1 hour at 55°C, the mixture is cooled to room temperature while 10% aqueous sodium bisulfite is added to obtain a negative starch iodide test. The solids are removed by filtration, and the filtrate is concentrated to dryness in vacuo and further dried by washing with 3 x 10 ml. of benzene.

Methanol ( 630 ml.) and acetone ( 1250 ml.) are added.

After stirring at reflux for 5 minutes, the insolubles are removed by filtration and washed with hot acetone-methanol. The filtrate is concentrated to dryness in vacuo and the solids slurried with 625 ml. of acetonitrile at reflux for 20 minutes, and the slurry cooled to 25°C. The yellow product is collected by filtration and washed with acetonitrile at 25°C. The product is dried in vacuo at 6o°C. to afford (-) ( cis_-l, 2-epoxypropyl)-phosphonic acid as the monobenzylammonium salt. It is purified by recrystallization from 10 volumes of ethanol, m.p. 155-157°C.

Repeating this procedure with 0 .655 moles of a-picolinium cis-propenylphosphonate and aluminum cls-propenylphosphonate yields the a-picoline and aluminum salts of (-) ( cis-1 , 2-epoxypropy,l ) -phosphonic acid.

EXAMPLE 4 To a 2 0 ml. round-bottom flask equipped with a stirrer and an addition funnel is charged 13. 4 g. ( 0.11 V- n-propanol Is added with stirring. The resulting solution is treated dropwlse with 12.0 ml. (11.89 g., 0.11 moles) of benzylamine and heated to reflux. After refluxing for 10 minutes the hot solution is filtered to clarify it.

The filtrate containing benzylammonium cls-propenyl-phosphonate is charged to a 500 ml. round-bottom flask equipped with a stirrer, thermometer and an addition funnel. The solution is heated to 55°C. in an oil bath, and 0.50 g. of sodium tungstate dihydrate added. The pH of this mixture is 5.3 (0.1 ml. of solution in 1.9 ml. of water). 35 Ml. of hydrogen peroxide (30%) is added dropwise over a 15-minute period while maintaining the temperature between 55-60°C. The reaction is kept at 55-60°C. for an additional hour during which the pH of the solution is maintained at Ί.6 - 5.2 with aqueous sodium hydroxide as necessary.

The heat source is then removed and a 20% aqueous sodium sulfite solution is added dropwise to decompose excess hydrogen peroxide maintaining the temperature below 55°C. The mixture is then concentrated in vacuo to a volume of 62 ml. An equal volume (62 ml.) of n-propanol is added and the mixture again concentrated in vacuo to a volume of 62 ml. Addition of n-propanol (62 ml.) and concentration to 62 ml. is repeated once more. The mixture thus obtained is diluted with 150 ml. of absolute methanol and stirred at room temperature for 1 hour. At the end of this period, the insoluble solids are removed by filtration. The filtered solids are washed with 50 ml. of methanol and the combined filtrates concen-trated under vacuum to a volume of 62 ml. An equal volume (62 ml.) of n- ro anol is added and the resultin solution concentrated again to a volume of 62 ml. The solution obtained is stirred and cooled in an ice-bath. After cooling for 1 hour the stirring is stopped and the flask kept at 0°C. for an additional 16 hours. The crystalline product is then removed by filtration, washed with two 100 ml. portions of cold n-propanol and dried in vacuo at 60°C. to afford substantially pure benzylammonium (-) ( cis-1 , 2-epoxypropy 1) -phosphonate , m.p. 148-150°C. Re-crystallization from n-propanol raises the melting point to 155-157°C When the above procedure is repeated using 0.11 mole of ethylenediammonium and piperazinium cis-propenylphosphonate , there are obtained the ethylenedi-ammonium and piperazinium ( cjLs-1, 2-epoxypropyl)-phosphonates The salt containing 1 molecule of ethylenediamine melts at 120-130°C. (monohydrate) . after recrystallization from 70% ethanol; the anhydrous salt melts at 169-171°C. after precipitation from methanol by addition of ethanol. The salt containing 1 molecule of piperazine melts at 195°C. on recrystallization from 85% isopropanol.

EXAMPLE 5 To a 250 ml. flask equipped with stirrer and addition funnel there is charged 13.4 g. of cis-propenyl-phosphonic acid and 125 ml. of n-propanol. (+) a-Phen-ethylamlne is added to the propanol solution dropwise to a pH of 5.7 - 5.8 (about 14 grams are required). The resulting solution is warmed to 55°C. and to it there is added a solution of 0.5 g. of sodium tungstate and 0.1 g. of disodium ethylenediaminetetraacetic acid in 6 ml. of slowly over a 15-minute period at a rate to maintain the temperature between 55 and 60°C. When the hydrogen peroxide addition is complete, the solution is stirred at 55-60°C. for one hour. It is then cooled to -5°C. and stirred at this temperature for 2 hours. The resulting solid is recovered by filtration and washed with 60 ml. of cold n-propanol. This product is predominantly (+) a-phenethylammonium (-) ( cjLs-l,2-epoxypropyl)-phosphonate , m.p. 1'33-135°C. It is further purified by heating in a mixture of 40 ml. of isopropanol and 10 ml. of water at 75°C. and then cooling the solution slowly to about 0°C. The solid product is recovered by filtration, washed with cold isopropanol to afford substantially pure (+) a-phen-ethylammonium (-) ( cis-l,2-epoxypropyl)-phosphonate , m.p. 135-136°C.

EXAMPLE 6 To- a 100 ml. round-bottom 3-necked flask fitted with a stirrer, thermometer and addition funnel is added 3.2 g. (0.01 mole) dibenzyl cis-propenylphosphonate in 50 ml. of n-propanol. Sodium tungstate dihydrate (0.06 g.) is added and the mixture heated to 55°C Hydrogen peroxide 30/5 (3 ml.) (0.03 moles) is added dropwise over 15 minutes while the temperature is maintained at 55-60°C. The mixture is aged at 55-60° for 1 hour. Additional hydrogen peroxide is added as needed to give positive reaction with starch iodide test paper. The reaction is then quenched by the addition of a saturated solution of sodium sulfite to destroy excess hydrogen peroxide. The mixture is nc nt ed to 2 v lume inorganic salt removed by filtration. The solvent is removed in vacuo and the dibenzyl ester of (-) ( cls-1,2-epoxypropyD-phosphonic acid isolated as an oil.

When the above process is repeated using 4.32 g. of di (L) menthyl cis_-propenylphosphonate as starting material, there is obtained predominantly di menthyl (-) ( cls-1 , 2-epoxypropy 1) -phosphonate together with a lesser amount of di (^) menthyl ( + ) (cis_-l, 2-epoxypropy 1)-phosphonate.

When 0.01 mole of di-(p-chlorobenzyl) or di(p-nitrobenzyl) cis-propenylphosphonate is used as starting material, there are obtained the di-(p-chlorobenzyl) and di-(p-nitrobenzyl) esters of (ί) ( cis-1, 2-epox propy 1)-phosphonic acid. The cyclic esters of (-) (cis-1,2-epoxypropyD-phosphonic acid with catechol and with propylene glycol are obtained when the above procedure is used with 0.01 mole of the cyclic esters of cis-propenyl-phosphonic acid with catechol and propylene glycol.

EXAMPLE 7 To a 50 ml. round-bottom 3-necked flask fitted with a stirrer, thermometer and addition funnel is added 1.5 g. (0.01 mole) of monomethyl cis-propenylphosphonate in 30 ml. of methanol. The pH is adjusted to 4.5 with 2.5 N sodium hydroxide. Sodium tungstate dihydrate (0.06 g.) is added and the mixture heated to 55°C.

Hydrogen peroxide 30 (3 ml.) is added dropwise over 15 minutes at 55-60°C. The mixture is aged for one hour at 55-6o°C. Hydrogen peroxide is added as needed to maintain 30918/2 . · * ·' starch iodide test. The inorganic solids are removed by filtration, the solution evaporated to one-half volume . and chilled. The solid sodium methyl (-) (cis-1,2-epoxypropyl) -phosphonate thus obtained is separated by filtration, washed 'with ethanol and dried. NMR Spectrum (D2°) 1.2-1.5 ppm doublet; 2.6-3.5 ppm multiplet; 4.7 ppm singlet. The same result is obtained when zinc vanadate or sodium seleno molybdotungstate is used as catalyst in place of sodium turigstate.

·. When an equlmolar amount of n-butyl cjLs-propenyl-phosphonate, ethyl cis-propenylphosphonate or phenyl cis-propen lphosphonate is treated with hydrogen peroxide as . .described above, there is obtained the sodium salt of n-buty.l (ί) (cis-l,2-epoxypropyl).-phosphonate , ,ethyl (-) (cis-1, 2-epoxypropyl) -phosphonate (NiR Spectrum (D20) 1,1- 1.5 ppm quintuplet; 2.7-3.5 ppm multiplet;. 3.8-4.2 ppm quintuplet; 4.8 ppm singlet) and phenyl (ί) (cis-1,2-epoxypropyl) -phosphonate, respectively.

' . ., . · EXAMPLE 8 J 1.53 Mole of di-allyl cis-propenylphosphonate is added to 1000 ml. of n-propanol in a reaotion flask, and 0.018 mole of ammonium vanadate added slowly. The mixture is heated to 50°C. and the pH adjusted to 5.3 with ammonium hydroxide. 200 Ml. of 30% hydrogen peroxide is then added over a 30 minute period, holding the temperature at 50-60°C. and the pH at 5.0-5.3 by addition of base* j as. necessary. The mixture is stirred for an additional **5 minutes at 60°C, then cooled to room temperature and sodium sulfite added to a negative starch iodide test.

The mixture is filtered, and the filtrate concentrated to dryness. The residue is extracted with 1800 ml. of 2:1 1 dryness in vacuo to afford an oil of diallyl (-) ( cis- 2 l 2-epoxypropyl)-phosphonate boiling point I05-115°0 at 0.5 mm ϋ¾7=1.4623 3 The di-methallyl, diphenyl and ditolyl esters 4 of (ί) ( cis-1 ,2-epoxypropy1 ) -phosphonlc acid are prepared in the same manner from the corresponding esters of cis- 6 propenylphosphonic acid. 7 EXAMPLE 9 8 2.2 Grams (0.018 mole) of cis-propenylphosphonic 9 acid is dissolved in 10 ml. of water. 0.15 Grams of sodium tungstate dihydrate is added and the mixture 11 chilled to 5-10°C. 3 Ml. of 30% hydrogen peroxide are 12 added over a 15-minute period, maintaining the temperature 13 below 10°C. by external cooling. The mixture is then l1* allowed to stand at 10°C. for 120 minutes. Excess hydrogen peroxide is decomposed by the addition of a dilute aqueous 16 solution of sodium bisulfite (to a negative starch—iodide 17 test). The reaction mixture is concentrated to a volume 18 of about 3 ml., filtered to remove insoluble material and 19 then freeze-dried to afford a residue of (-) (cis-1.2-epoxy- 20 propyl) -phosphonlc acid. This latter product may be 21 converted to1 the mono-sodium salt by dissolving in a 22 minimum quantity of water and adding sodium bicarbonate 23 to a pH of 5.5. The solution is then freeze-dried to 2^ afford the mono-sodium salt.

EXAMPLE 10 6 When the procedure of Example 6 is repeated using 7 0.01 moles of di-hexyl cjLs-propenylphosphonate , di- 8 ( -carbethox hen l) cis- ro en l hos honate pivalox - propenylphosphonate instead of the starting material of Example 6, and 0.8 grams of aluminum tungstate as catalyst, there is obtained the di-hexyl, di-(p-carbethoxyphenyl) , pivaloxymethyl and bis-acetoxymethyl esters of (-) ( cls-l,2-epoxypropyl)-phosphonic acid.

EXAMPLE 11 To a 50 ml. round-bottom flask fitted with a stirrer and addition funnel is added 1.22 g. (0.01 mole) of cis-propenylphosphoriic acid and 20 ml. of water. 2 Ml. (0.01 mole) sodium hydroxide solution (20%) is added to form the mono-sodium salt of cis-propenylphosphonic acid. The mixture is treated with 3 ml. of 30% hydrogen peroxide. The mixture is stirred at room temperature for 3 weeks.

The excess hydrogen peroxide is quenched with sodium sulfite and the solution is concentrated to a small volume. The solution is then passed over the ion exchange resin Dowex 50 on the hydrogen cycle at 0°C. and the eluate collected anths pcesence of 0.01 mole of benzylamine. (Dowex 50 is a polysulfonated polystyrene ion exchange resin.). The eluate is concentrated to dryness in vacuo and the solid recrystallized three times from n-propanol to give the benzylamine salt of (-) ( cis-l,2-epoxypropyl)-phdsphonic acid. The disodlum salt of cls-propenylphos-phonic acid is epoxidized in similar fashion using 0.02 moles of sodium hydroxide; the epoxidized product is separated from the remaining olefin salt by repeated recrystallizations from ethanol or n-propanol.

Disodium (-) ( cis_-l,2-epoxypropyl)-phosphonate 30918/2 experiment n place of the hydrogen peroxide, and the mixture filtered to remove solids prior to the Ion exchange resin treatment. The X-ray diffraction data (4 strongest lines) are as follows: Interplanar Spacing (A°) Relative Intensify 14.04 100. .36 27. .14 21. 3.01 41 - a J experiment in pi ¾CP of the h drogen peroxide/ and the. <2 mixture filtered, to remove solids prior to tho ion -exchange* —resin treatment. . 4 EXAMPLE 12 To a 100 ml. round-bottom flask is charged 6 5 g. (0.022 moles) of benzy lammonium cis-l-propenyl- 7 phosphonate and 30 ml. of chloroform. To this is added 8 3.04 g. (0.022 moles) of perbenzoic acid in 20 ml. of 9 chloroform. The solution is heated at 6o°C. for 12 hours. 0 The mixture is then cooled and filtered. The solid 1 product, monobenzylammonium (-) ( cjLs-1, 2-epoxypropyl) -2 phosphonate is purified by recrystallization from 10 parts 3 of 95% ethanol. The pure material melts at 155-157°C.

A similar result is obtained when 0.022 moles 5 of peracetic acid or performic acid is used in place of 6 perbenzoic acid. 7 When 0.022 moles of the procaine or the diethanol-8 amine salt of cis-propenylphosphonic acid is used in the 9 above experiment, there is produced the procaine or 0 diethanolamine salt of (-) ( cis-1, 2-epoxypropyl)-phosphonic 1 acid. The salt containing 1 molecule of procaine melts at 2 127-130°C. on recrystallization from Bo% isopropanol. 3 EXAMPLE 13 4 Peroxytrifluoroacetic acid is prepared by the 5 method of Emmons (J. Am. Chem. Soc . 75. 4623 (1953). A 6 solution of 2.8 g. of peroxytrifluoroacetic acid in 7 20 ml. of chloroform is then added to 5 g. (0.022 moles) The mixture is allowed to stand for 16 hours at 0°C. The solids are then separated by filtration. The solids are slurried in about 10 ml. of methanol; the slurry is filtered and the methanol filtrate evaporated to dryness in vacuo to give a solid residue of benzylammonium (-) ( cis-l, 2-epoxyprop 1) -phosphonate . The product is purified by recryatallization from 10 parts of 95% ethanol.

With 0 .022 moles of disodium els-propenyl-phosphonate or dlethylammonium cis-propenylphosphonate as starting material, the corresponding salts of (i) ( cis-1,2-epoxypropyD-phosphonate are produced.

EXAMPLE 1*1 To a 100 ml. round-bottom 3-necked flask equipped with a stirrer, thermometer and an addition funnel is charged 6.4 g. ( 0 . 02 mole) dibenzyl cis-propenylph03phonate and 30 ml. of methylene dichloride. A solution of mono-perphthalic acid ( 3. 6 g., 0 . 02 moles) in 20 ml. of ethyl acetate is added slowly and the mixture heated to ^ 0°C .

The course of the reaction is followed by gas liquid chromatography of the dibenzyl ester or by titration of the peracid. The reaction is essentially complete in 24 hours. At the end of this time, the mixture is cooled to room temperature, the phthalic acid removed by filtration and the dibenzyl ( ί ) ( cis-l, 2-epoxypropyl)-phosphonate recovered by removing the solvent in vacuo. It is purified by recrystalliz tion from 95% ethanol.

When this experiment is carried out using 0.02 1 predominantly di-pyridylmethyl (-) ( cis-l,2-epoxypropyl)- 2 phosphonate. 3 EXAMPLE 15 When the procedure of Example 13, is repeated using 0.02 moles of dimethyl cis-propenylphosphonate, 6 diphenyl cis-propenylphosphonate or β-cyanoethyl cis- 7 propenylphosphonate , there is obtained dimethyl (-) ( cis- 8 1,2-epoxypropyl) -phosphonate, diphenyl (ί) ( cis-1 ,2- 9 epoxypropyl) -phosphonate and p-cyanoethyl (-) ( cls-1,2- 10 epoxypropyl ) -phosphonate , respectively. 11 EXAMPLE 16 12 it.3 Grams (0.02 moles) of ( + ) percamphoric acid 13 in 20 ml. of ethyl acetate is added slowly to 6.4 grams l1* (0.02 moles) of dibenzyl cis-propenylphosphonate in 30 ml. of chloroform. The mixture is heated for 22 hours at 16 60°C. and then cooled to room temperature and filtered to 17 separate any solid materials. The filtrate is extracted 18 with 3 x **0 ml. of 2.5 N sodium hydroxide, the organic 19 layer washed with water, dried over sodium sulfate and concentrated to dryness in vacuo to afford a residue 21 consisting predominantly of dibenzyl (-) (cis-1, 2- 22 epoxypropyl) -phosphonate . 23 The di-n-propyl and di-decyl esters of (-) ( cis- 24 l,2-epoxypropyl)-phosphonic acid are prepared according to 5 the above procedure from 0.02 moles of the corresponding 6 esters of cis-propenylphosphonlc acid.

EXAMPLE 17 To 0 . 022 moles of di-n-butyl cis-propenyl- phosphonate in 40 ml. of benzene in a suitable reaction flask is added 0.04 moles of performic acid solution.

The mixture is allowed to stand at room temperature for 16 hours. It is then cooled to 10°C. and any excess peracid decomposed with sodium bisulfite. Any insoluble materials are separated by filtration, and the filtrate concentrated to dryness in vacuo at about 35°C. to afford a residue of di-n-butyl (-) (cis-l, 2-epoxypropyl) -phosphonate . The bis-(p-hydroxyethyl) ester of ( ) ( cis-l, 2-epoxypropyl)- phosphonic acid is prepared by this procedure from bis- ( β-hydroxyethyl) cis-propenylphosphonate .

EXAMPLE 16 To a 100 ml. round-bottom 3-necked flask fitted with a pH electrode, stirrer and addition funnel is charged 11.4 g. ( 0.05 moles) benzylammonium cis-propenylphosphonate and 4. 5 g. ( 0.05 moles) of t-butylhydroperoxide in 50 ml. methanol. The mixture is adjusted to pH 8 . 0 with concentrated sodium hydroxide and stirred at 35-40°C. for 5-1/2 hours, adding sodium hydroxide as necessary to maintain pH 8. 0 . At the end of this time, the mixture is concentrated in vacuo to a small volume, the pH adjusted to 4.6 with sulfuric acid and n-propanol added. The solids are removed by filtration, the remaining methanol removed by concentration in vacuo and the volume of the propanol mixture adjusted to i25 ml. The mixture is aged ( cis-1 , 2-epoxypropy 1) -phosphonate Is collected by filtration and dried in vacuo.

Similar results are obtained using the diethylene-triamine, calcium, magnesium, 1 , 6 hexamethylenediamine or ethylamine salts in place of the benzylammonium cis-propenylphosphonate. The corresponding salt of (ί) ( cis-1, 2-epoxypropyl)-phosphonic acid is obtained. The salt containing 1 molecule of diethylenetriamine melts at 182-183°C. on recrysiallization from isopropanol; the salt containing 1 molecule of 1 , 6-hexamethylenediamine melts at 194°C. on recrystallization from 1 : 3 : 3 water:methanol: isopropanol,, the salt containing 1 molecule of ethylamine melts at 137-140°C.

EXAMPLE 19 A solution of 0. 01 g. of molybdenum hexa-carbonyl, 4. 8 g. ( 0.05 moles) of t-butyl hydroperoxide and 13.0 g. ( 0.05 moles) of bis ( β-ethoxyethyl) cls-propenylphosphonate in 100 ml. of benzene is placed in a 200 ml. round-bottom flask fitted with a thermometer, a reflux condenser and a stirrer. The temperature is raised gradually to 8o°C. and held at 8o°C. for one hour.

The, reaction mixture is then cooled to room temperature, filtered, and the t-butanol and benzene removed by concen-tration in vacuo. The residual product thus obtained is bis (β-ethoxyethyl) (-) (cis-1, 2-epoxypropy 1) -phosphonate .

When 0.05 moles of bis (methylsulfonylphenyl) cis-propenylphosphonate and di-(p-nitrophenyl) cis-propenylphosphonate are employed in the above experiment, the bis (methylsulfonylphenyl) and di-(p-nitrophenyl) EXAMPLE 20 To a 200 ml. round-bottom 3-necked flask fitted with a stirrer, reflux condenser and addition funnel Is added 0.01 g. molybdenum hexacarbonyl , 7.5 g. (0.05 moles) of cumene hydroperoxide, 5.0 g. (0.05 moles) of triethylamine, 6.8 g. (0.05 moles) of monomethyl cls-propenylphosphonate and 100 ml. of benzene. The reaction mixture Is heated slowly to 8o°C. and held at 75-80°C. with stirring for 1-1/2 hours. At the end of this time, it is cooled to 20°C, filtered, and the filtrate concentrated to dryness under reduced pressure. The remaining solid is triethylammonium methyl (-) ( cis-1,2-epoxypropyl)-phosphonate .

EXAMPLE 21 To a 500 ml. round-bottom 3-necked flask fitted with a stirrer and addition funnel is added 300 ml. of methanol, 61 g. (0.5 moles) of cls-propenylphosphonic acid and 40 grams of sodium hydroxide. Benzonitrile 52 grams (0.5 moles) is added and the mixture cooled to room temperature. 31* Grams of hydrogen peroxide (505?) is added slowly from the addition funnel. When the addition is complete, the mixture is stirred at room temperature for kO hours. The excess peroxide is then decomposed with a saturated solution of sodium sulfite (to a negative starch iodide test). The solution is evaporated to dryness and the residue extracted with 10 volumes of methanol. The methanol solution is filtered and evaporated to dryness. The residue is extracted with 2 x 20 ml. of water to from benzamide. The aqueous extracts are combined and passed over a column of Dowex 50 resin on the acid cycle at 0°C. The eluate containing the free phosphonlc acid is collected in the presence of 0.5 mole of benzylamine. The monobenzylammonium salt of (-) (cis-l,2-epoxypropyl)-phosphonlc acid is recovered by evaporating the eluate to dryness in vacuo. It is purified by recrystallization from 10 volumes of 95% ethanol.

EXAMPLE 22 A solution of 100 ml. of methanol, 15.6 g. (.0.05 moles) of dibenzyl cis-propenylphosphonate , 1.0 g. of potassium bicarbonate and 2.05 g. of acetonitrile are stirred at room temperature 3·* 6. (0.05 moles), of 50% hydrogen peroxide is added slowly and the mixture is stirred until a negative starch iodide test is obtained. The methanol is then removed by concentration in vacuo, the solids dissolved in water and extracted with chloro-form. The chloroform extracts are washed well with water to remove the acetamide, dried with magnesium sulfate, and concentrated to an oil in vacuo to afford dibenzyl (i) ( cls-l,2-epoxypropyl)-phosphonate.

When the above procedure is repeated using 0.05 moles of di-phenethyl cis-propenylphosphonate as starting material, there is obtained di-phenethyl (ί) ( cis-1, 2-epbxypropy1) -phosphonate .

EXAMPLE 23 To a 200 ml. flask fitted with stirrer is added and 100 ml. of water* 75 Ml. of aqueous sodium hypo-chlorite solution (5%) (0.05 moles) is added slowly and the mixture stirred at room temperature overnight. The aqueous solution is concentrated in vacuo to one-half its volume and then freeze-dried to afford disodium (ί) ( cis-1 , 2-epoxypropy1) -phosphonate .

EXAMPLE 24 A solution of 2 millimoles of cyclohexene in 5 ml. of methylene chloride is cooled to -4o°C. and treated with ozone until saturated. A previously cooled solution of 3.1 g. (10 millimoles) of dibenzyl cis-propenyl-phosphonate in 10 ml. of methylene chloride is added and the mixture allowed to warm slowly to room temperature.

The solvent is then removed by evaporation in vacuo to afford dibenzyl (ί) ( cis-1 , 2-epoxypropy1)-phosphonate .

The above reaction is repeated using equivalent molar amounts of stilbene in place of cyclohexene, and monomethyl cis-propenylphosphonate in place of the dibenzyl ester. On completion of the reaction, the solution is extracted with aqueous sodium hydroxide. The sodium salt of methyl (-) ( cis-1, 2-epoxypropy1) -phosphonate is recovered from the aqueous extract.

EXAMPLE 25 To a round-bottom 3-necked flask fitted with a stirrer, thermometer and gas inlet tube and vent is added 12.2 g. (0.1 mole) of cis-propenylphosphonic acid, 100 ml. of dimethylformamide and 8 g. of sodium hydroxide pellets. 0.1 G. of cobalt naphthenate and 0.1 g. of t-butyl hydroperoxide are added and the mixture heated to 100°C. Air is bubbled through the mixture at 100° for 21 hours. The mixture is then concentrated to one-half its volume and diluted with an equal volume of water. The mixture is repeatedly extracted with chloroform to remove dimethylformamide and the aqueous solution of disodium (i) ( cis-lt 2-epoxypropyl)-phosphonate is then passed over a column of Dowex 50 on the hydrogen cycle at 0°C. into an aqueous solution of benzylamine (0.1 mole of benzy lamine) . The resulting benzylammonium salt of (ί) ( cis-1,2-epoxypropyD-phosphonlc acid Is purified by recrystalliza-tion from 10 volumes of 9556 ethanol.

EXAMPLE 26 A mixture of 14.9 g. (0.1 mole) of dimethyl cis-propenylphosphonate and 31.8 (0.1 mole) of cyclohexyl-perborate are stirred at room temperature under a nitrogen atmosphere for 30 minutes . The temperature is then raised to 80°C. for 1 hour. The mixture is cooled to room temperature and quenched by the addition of 30 ml. of water. The organic phase is separated and the water layer extracted with 3 x 10 ml. of chloroform. The chloroform extracts are combined with the organic phase and the whole is evaporated to dryness In vacuo to afford a residue of dimethyl (-) ( cis-l,2-epoxypropyl)-phosphonate. The product is purified by distillation, b.p. 70-72°C./0.5 mm mercury.

EXAMPLE 27 To a round-bottom flask there Is charged 30.0 g. of diphenyl cls-propenylphosphonate in 300 ml. of chloroform. Dibutyi mono-t-butyl perphosphate (28.2 g., 0.1 mole) (made from dibutyi phosphonochloridate and l mole of sodium t-butyl hydroperoxide) in 150 ml. of chloroform is added at room temperature. The mixture is heated at the reflux temperature for 15 hours . The solvent is then removed by concentration in vacuo. The product, diphenyl (-) (cJLs-l,2-epoxypropyl)-phosphonate is obtained as an oil.

EXAMPLE 28 A. Methyl acetylene is passed into a refluxing ethereal solution of ethyl magnesium bromide (from 109 g. of ethyl bromide and 24 g. magnesium) until two layers are formed. The ether is then evaporated by heating in a stream of nitrogen until only the lower thick solution remains. This is then dissolved in 500 ml. of tetrahydro-furan and 200 ml. of benzene, and cooled with stirring in a dry ice-acetone bath. To this slurry of 1-propynyl magnesium bromide is added a solution of 217 g. of dibutylchlorophosphlte in 200 ml. of ether over a period of one hour while maintaining the temperature below - 0°C. The mixture is then allowed to come to room temperature and stirred for 4 hours. 180 Ml. of pyridine is added dropwise with stirring and the precipitated pyridine-magnesium bromide complex removed by filtration. The filtrate is concentrated to a thick solution and 600 ml. which is distilled under reduced pressure,. After a small forerun there is obtained dibutyl l-propynyl^phosphonite, b.p. 80-84°C./0.4 mm.

B. 96 Grams of dibutyl-l-propynylphbsphonite is heated under reflux with 100 ml. of water and 50 ml. of Dowex 50 resin (H+ cycle) for two hours. The mixture is then evaporated in vacuo to remove butanol and the slurry diluted with water and filtered. The resin is washed with 200 ml. of water which is added to the filtrate.

The combined aqueous solutions are then evaporated to a thick oil which is allowed to stand at 0°C. for eighteen hours. The resulting oily crystalline mass is broken up by the addition of 20 ml. of ethyl acetate and filtered. The resulting crystals are washed with ether containin a little ethyl acetate to afford 1-propynylphosphonous acid, m.p. 64-66°C.

C. A solution of 4 g. of 1-propynylphosphonous acid in 50 ml. of water is neutralized to pH 7 with sodium bicarbonate and hydrogenated at an initial pressure of 40 p.s.i. in the presence of 1 g. of Raney nickel catalyst.' The hydrogenation is stopped when one equivalent of hydrogen is taken up. The solution is filtered from catalyst and evaporated to give the sodium salt of cis-1-propenylphosphonous acid.

D. 0.5 Grams of the end product of Part C is dis-solved in 8 ml. of water. Sodium tungstate (0.13 g.) is added and the pH brought to 6.5 with sulfuric acid. 30% Hydrogen peroxide (0.8 cc.) is added and the mixture heated at 55°C for four hours, while maintaining the pH at 5.5 - 5.6 by the addition of 0.1 N sodium h droxide solu- 1 solid extracted with 50 ml. of methanol and filtered from 2 inorganic salts. The methanolic solution is evaporated to 3 dryness leaving a residue of sodium (t) ( cis-1 ,2-epoxy- 4 propyl) -phosphonate.

EXAMPLE 29 6 A. Di-2 ' -(methyl-2' -buten,oate)-cis-propenyl- 7 phosphonate is prepared by reacting together equlmolar 8 amounts of methyl-3-keto-butenoate, sodium hydride and 9 diethylether, and treating the resulting product with cis-propenylphosphonic dichloride. 11 To a solution of 31.8 g. (0.1 m) of di-2'- 12, (methyl-2'-butenoate)-cis-propenylphosphonate in 300 ml. 13 of n-propanol is added 0.6 g. of sodium tungstate l1* dihydrate and the mixture heated to 55°C. 90 Ml. of 30% hydrogen peroxide (0,9 m.) is then added over a 45- 16 minute period, maintaining the temperature at 55-60°C. 17 The mixture is stirred at this temperature for 3 hours 18 with hydrogen peroxide being added as needed to maintain 19 a positive starch-iodide test, and sodium hydroxide added as needed to maintain a pH' of 4.5 - 5.5. At the end of 21 this time excess peroxide is destroyed with saturated 22 aqueous sodium sulfite and the reaction mixture concen- 23 trated in vacuo to 1/2 its volume. It is then diluted to 24 its original volume with water to afford a solution con- 25 taining sodium (ί) ( cls-l,2-epoxypropyl)-phosphonate . 26 The product is purified by passing the aqueous solution 27 over Dowex 50 resin on the hydrogen cycle and collecting •2.8 the eluate in the presence of one molar equivalent of 1 salt is recrystallized from 95% ethanol to give substan- 2 tially pure material, m.p. 155-157°C. 3 B. The bis-p-benzoquinone ester of cis-propenyl- 4 phosphonic acid is prepared by reacting together 0.1 m. of cis-propenylphosphonic dichloride and 0.2 m. of mono- 6 carbobenzoxy hydroqulnone In the presence of trlethylamlne 7 and subsequent removal of the carbobenzoxy group by 8 hydrogenation. 9 When the procedure of Example 13 is repeated employing 3 g. of di-(p-benzoqulnony1-cis-propen 1- 11 phosphonate and 3.8 g. of peroxytrifluoroacetic acid, 12 there is obtained sodium (ί) ( cis-l,2-epoxypropyl)- 13 phosphonate. ' I1» EXAMPLE 30 To a stirred suspension of 0.35 ml. (0.0125 16 mole) of 90% hydrogen peroxide in 2.5 ml. of methylene 17 chloride cooled in an ice-bath there is added dropwise 18 over a ten-minute period 2.1 ml. (0.015 mole) of trifluoro- 19 acetic anhydride. The solution of peroxytrifluoroacetic 0 acid so obtained is stirred in the cold for an additional 1 1 minutes, and then is added over a period of 15-20 22 minutes, with vigorous stirring, to a mixture of 0.0005 3 mole of dibenzyl cis-propenylphosphonate , 10 ml. of M methylene chloride, 3.8 g. (0.045 mole) of dry sodium bicarbonate, and 5 g. of anhydrous magnesium sulfate. 26 After the addition is complete, the mixture is heated 27 under reflux with continued stirring for 30 minutes. ί 8 The reaction mixture is then stirred with 25 ml. of methylene chloride. The organic layers are combined, dried over anhydrous magnesium sulfate and evaporated in vacuo to give dibenzyl (-) (cis_-lf2-epoxypropyl)phosphonate.

EXAMPLE 31 When the procedure of Example 13 is repeated using as starting material 0.022 moles of dibenzyiammonium or diethylenediammonium cis-propenylpyrophosphonate , . there is obtained dibenzylammonium or diethylenediammonium (-) (cis-1, 2-epoxypropyl) pyrophosphonate , respectively.

The disodium (-) (cis-1 , 2-epoxypropyl) pyrophosphonate is obtained from disodium cis-propenylpyrophosphonate using the procedure of Example 1.

EXAMPLE 32 When 0.02 m« of cis-propenylphosphonic acid cyclic di-anhydride is reacted with perphthalic acid by the procedure described in Example 14 , there is obtained (-) (cis-1 ,2-epoxypropyl) phosphonic acid cyclic di-anhydride. The product is purified by crystallization from anhydrous ethanol.

EXAMPLE 33 The disodium and diammonium salts of sodium and ammonium (-) (cis-1 , 2-epoxypropyl) isohypophosphoric acid are produced from the corresponding salts of cis-propenyl isohypophosphoric acid by treating the olefin compounds with hydrogen peroxide and sodium tungstate by the procedure of Example 1 (for the sodium salt) and Example 2 (for the ammonium salt) .

The cis-propenylphosphonic acid compounds employed as starting materials for the present invention itself is made from di-t-butyl phosphorochloridite by the procedure : ' Phosphorus trichloride (68.7 grams, 0.5 mole) and 750 ml. of anhydrous benzene are placed in a 2-liter, ■ 3-necked flask equipped with mechanical stirrer, thermometer, dropping funnel and a drying tube. The solution is cooled to 5°C. and triethylamine (50.6 grams, 0.5 mole) is added at 5°-10°C. during 20 minutes. The benzene solution is then stirred for 20 minutes. A solution of triethylamine (50.6 grams, 0.5 mole) and t-butanol (37.06 grams, 0.5 mole) is added with stirring during 20 minutes at 5°-10°C. , and the mixture is stirred for 20 minutes. A second portion of t-butanol (37.06 grams, 0.5 mole) is then added at 5°-10°C. over a 20 minute period, and the reaction mixture containing di-t-butyl phosphorochloridite is stirred for 90 minutes at 5°-10°C.

Triethylamine (50.6 grams, 0.5 mole) and propargyl alcohol (28.03 grams, 0.5 mole) are dissolved in 40 ml. of anhydrous benzene, and the solution is added to the reaction mixture containing di-t-butylphosphorochloridite with stirring during 25 minutes, maintaining the reaction temperature between 5°-10°C. by external cooling. The resulting mixture containing di-t-butyl-2-propynylphosphite is stirred at 5°-10°C. for one hour.

The reaction mixture containing di-t-butyl-2-pro- pynylphosphite is then heated to reflux, and the refluxing is continued for one hour. The solution is then cooled to room temperature with a water bath, and 185 ml. of water is added in portions. The triethylamine hydro- chloride dissolves in the aqueous layer, and the organic solution is heated at atmospheric pressure, and the water is removed by azeotropic distillation. The residual benzene solution contains di-t-butylpropadienylphosphonate . Where desired, the crude ester can be obtained by removing the solvent and distilling the ester under high vacuum; the pure ester is characterized by IR and NMR spectra.

The dried benzene solution of di-t-butyl-propadienyl- phosphonate is hydrogenated at 20 ° -25 EC . with 5 % palladium- on-carbon catalyst ( 5 . 0 grams) until hydrogen absorption ceases. The catalyst is removed by filtration and is washed with 2 x 50 ml. of benzene. Upon removal of the solvent in vacuo, di-t-butyl-cis-propenylphosphonate is obtained and is characterized by NMR and IR spectra.

The crude ester can be purified by high vacuum distillation · Di^t-butyl-cis-propenylphosphonate ( 1 . 0 mole) and para-toluene sulfonic acid ( OJO 05 mole) are dissolved in 235 ml. of benzene, and the solution is heated at reflux until the calculated amount of isobutene is formed. A gas metering device is employed to detect the isobutene. The reaction mixture is then cooled to room temperature, the solvent is removed in vacuo and cis-propenylphosphonic acid is obtained as the residue.

Salts of cis-propenylphosphonic acid are made by treating the free acid in ethanol with a base. The metal salts are obtained by employing a metal oxide or hydroxide as the base, and amine salts by employing the appropriate amine. In order to obtain a mono-salt, the pH is adjusted with the base to 4 . 8 for metal salts and 4 . 2 for amine salts; for di-salts the pH is adjusted to 8 . 8 for metal salts and 8 . 2 for amine salts. In order to recover the salt, the ethanol is removed by evaporation in vacuo.

Thus , for example , 2 g. of cis-propenylphosphonic acid in 50 ml. of ethanol is adjusted to a pH of 4.8 with aqueous sodium hydroxide. The mixture is concentrated to dryness in vacuo to afford moho-sodium cis-propenyl- phosphonate. When aqueous sodium hydroxide is added to the above solution to a pH of 8.8, and the mixture concentrated to dryness, di-sodium cis-propenylphosphonate is obtained. The mono- and di-benzylamine salts are obtained in the same fashion by adding benzylamine to the ethanolic solution of cis-propenylphosphonic acid to a pH of 4.2 6a? 8.2. Any of the other salts discussed hereinabove are obtained in the same manner using the appropriate base.

The diesters of cis-propenylphosphonic acid are obtained by first converting the free acid to cis-propenylphosphonic dichloride, and then reacting this dichloride with 2 molar equivalents of an alcohol represented by the formula R-OH, where R represents the alcohol residue of the resulting ester. The monb-esters are prepared from the di-esters by removal of one of the ester radicals with base. A mono-salt mono-ester may then be prepared by reacting the mono-ester with one equivalent of base. Representative examples for the foregoing reactions are given herein, and it is to be understood that other esters and salts are obtained in the same manner from the appropriate starting materials. (a) Into a .250 ml. three-necked round-bottomed flask there is added 6.1 g. of cis-propenylphosphonic acid, 60 ml. of dry benzene and 9.0 ml. of pyridine. The mixture is he ed t °C the h chloride added dropwise at such a rate as to keep the reaction mixture at 50°C. The mixture is then cooled to room temperature and stirred for 2 hours at room tempera- ture. The mixture is filtered and the filtrate concen- trated in vacuum at 35°C. to yield 4.5 g. of a turbid oil. It is distilled to afford cis-propenylphosphonic dichloride, b.p. 67-69°C./9-10 mm.; n ^ : 1.4885. (b) A stirred mixture of 0.1 mole of cis-propenyl- phosphonic dichloride and 0.2 mole of triethylamine in 100 ml. of benzene is cooled to 5°C. To the mixture there is added 0.2 mole of methyl alcohol at such a rate as to maintain the temperature at 5-10°C. When the addition is complete, the mixture is stirred at room temperature for 1 hour. The precipitated triethylamine hydrochloride salt is then filtered off and the solvent is removed at reduced pressure to leave dimethyl cis-propenylphosphonate . Other di-OR-esters of cis-propenyl-phosphonic acid where R is alkyl, alkenyl, alkynyl, aralkyl or aryl, substituted alkyl, aryl or alkenyl are prepared in the same manner using 0.2 mole of the alcohol R-OH. (c) A stirred mixture of cis-propenylphosphonic dichloride (0.1 mole) and triethylamine (0.2 mole) in 100 ml. of benzene is cooled to 5eC. To the mixture there is added benzyl alcohol (0.1 mole) at such a rate as to maintain the temperature at 5-10°C. When the addition is complete, the mixture is stirred at room temperature for 1 hour. Then the precipitated triethyl-amine hydrochloride salts are filtered off and the solvent is removed at reduced pressure to leave the monochloro-monobenz l ester. A ueous 1 sodium h doxide is added and the mixture stirred, during which time a clear solution forms. The solution is then acidified and extracted with n-butanol. Removal of the solvent leaves monobenzyl cis-propenylphosphonate .

Other mono-esters are obtained in the same fashion using the appropriate alcohol.

An alternate method for making esters is represented by the following : (d) 10 Millimoles of cis-propenylphosphonic acid in 20 ml. of water is treated with 2.3 g. of silver oxide. The solution is then concentrated under reduced pressure to dryness and the residue of silver salt is; washed with a small amount of dimethoxyethane and suspended in 10 ml. of this solvent. One gram of potassium carbonate and 2.55 g. of bromomethyl acetate is added and the mixture stirred for 18 hours at 25 °C. The reaction mixture is then filtered and the filtrate concentrated to dryness to give a residue of bis- (acetoxymethyl) cis-propenyl-phosphonate.

Esters may also be obtained in the following manner: (e) 0.2 Moles of cis-propenylphosphonic dichloride and 200 ml. of ether is cooled to -13°C. and to this solution with stirring is added dropwise a mixture of 0.4 moles of pyridine and 0.4 moles of β-hydroxypropionitrile with good stirring and maintenance of temperature below -10 °C. The mixture is poured onto 1 liter of water and 500 grams of ice. The aqueous layer is then separated from the ether and extracted three more times with 100 milliliter portions of ether. The combined ether extracts are washed with water, diluted with' hydrochloric acid and finally sodium sulfate, it is filtered and concentrated in vacuo to give bis- (2-cyanoethyl) cis-propenylphosphonate .

An alternate method of making alkenyl esters is the following. (f) A stirred mixture of 0.4 moles of cis-propenyl- phosphonic acid, 2.4 moles of vinyl acetate and 1.6 g. of mercuric acetate and 0.2 ml. of sulfuric acid is refluxed under nitrogen for 3 hours. Sodium acetate (0.83 g.) is added and the low boiling excess vinyl acetate is removed in vacuo. The product is obtained by vacuum distillation.

A method of preparing mixed esters is the following (g) A stirred solution of cis-l-propenylphosphonic dichloride (0.1 mole) in 200 ml. of ether is cooled to 0°C. and then treated dropwise with a solution of absolute ethanol (0.1 mole) and triethylamine (0.1 mole) in 50 ml. of anhydrous ether. The addition rate is controlled so as to maintain the reaction temperature between 0-5 °C. When the addition is complete, the reaction mixture is stirred in the cold for 1 hour more. The precipitate of triethylamine hydrochloride is then removed by filtration and the filtrate concentrated under reduced pressure to yield O-ethyl cis-propenylphosphonochloridate 0.1 Mole of O-ethyl-cis-propenylphosphonochloridate in 150 ml. of ether is cooled to 10 °C. and added dropwise with a mixture of 0.1 mole of benzyl alcohol and 0.1 mole of triethylamine in 40 ml. of ether. The temperature is maintained below about 10 °C. The reaction mixture is stirred for one hour, filtered and the filtrate concen-trated to dryness to afford O-ethyl-O-benzyl-cis-propenyl- Bis- (cis-propenyl) yrophosphonic acid: 12.2 G. of cis-propenylphosphonic acid is heated gradually to 200°C. under a nitrogen atmosphere at 200 mm. Hg. pressure, and maintained at this temperature for 48 hours. The heating is discontinued. The resulting product is bis (cis-propenyl) pyrophosphonic acid.

Cis-propenylphosphonic acid cyclic dianhydride : Exactly one mole of water is added slowly with vigorous stirring to one mole of cis-propenylphosphonic dichloride, keeping the temperature below 10°C. by external cooling. When the evolution of heat stops, the mixture is heated to 120°C. under 50 mm. pressure until no more gas is evolved to afford cis-propenyl- phosphonic acid cyclic dianhydride.

Cis-propenyl-isohypophosphoric acid : 0.11 M. of diethyl chlorophosphonate of the formula (C^H^O) j-P- CI (prepared by reaction of ethanol with phosphorus oxychloride) is mixed with 0.1 m. of ethyl ci -propenylphosphonate in 150 ml. of ethanol. The mixture is stirred at room temperature for 5 hours and then brought to pH 9 with sodium hydroxide and heated at 80 °C. for 6 hours. The solvent is removed in vacuo to afford sodium cis-propenylisohypophosphoric acid disodium salt.

When the epoxidation process of the invention leads to an ester of (cis-1 ,2-epoxypropyl) phosphonic acid, such ester may be converted to the free acid,, or preferably to a salt, by one of several methods, the method of choice depending upon the nature of the I R and/or ¾ h H p a hy radical to be removed. atifrynyfc or aralkyl moieties, the preferred method for removing them is by hydrogenolysis , as by the following procedure : A solution of 3.2 g. of dibenzyl (cis-1 , 2-epoxy- propyl) phosphonate in 250 ml. of methanol is hydrogenated at 40 psi at room temperature for 15 minutes in the presence of 800 mg. of 10% palladium on charcoal catalyst and 2 g. of potassium bicarbonate.

The solution is then filtered from the catalyst and evaporated to dryness in vacuo at room temperature to give potassium cis-1 , 2-epoxypropylphosphonate . , When R and/or R^ in Formula I is loweralkyl or aryl, the preferred methods for removing these groups is by ultraviolet light irradiation in the presence of base, by alkaline hydrolysis, or by enzymolysis as exemplified below: (I) 4,G. of diphenyl (-) (cis-1 , 2-epoxypropyl) phosphonate in 100 ml. of an aqueous 2% solution of trimethylammonium carbonate is irradiated in a quartz flask at 25-30 eC. for 4 hours with an ultraviolet light source. The solution is then evaporated to dryness and the residue extracted into anhydrous methanol. The solution is passed over a sulfonic acid resin column (IR 120 previously dehydrated with methanol) on the hydrogen cycle at 0-5°C. The effluent is collected and rapidly adjusted with cyclohexylamine to pH 5. Concentration, of the solution to dryness affords (-) (cis-1 , 2-epoxypropyl) -phosphonic acid monocyclohexylamine salt. (2) 7 Grams of diethyl (-) (cis-1 , 2-epoxypropyl) phosphonate is added to 75 ml. of 2% trimethylammonium carbonate solution is then concentrated to dryness in vacuo to give a residue of calcium (-) (cis-1 ,2-epoxypropyl) phosphonate.

A solution of 50 millimoles of diphenyl (-) (cis- 1, 2-epoxypropyl) phosphonate in 10 ml. of 30% ethanol- water is refluxed with a two-fold excess of barium hydroxide in a nitrogen atmosphere for 1-1/2 hours. The reaction is cooled, adjusted to pH 8 with 4 N sulfuric acid and extracted 3 times with ethyl acetate. The remaining aqueous slurry is stirred overnight at room temperature with 30 g. of sodium sulfate. The solids are removed by filtration and the filtrate evaporated to dryness to give (-) (cis-1,2-epoxypropyl) phosphonic acid, disodium salt.

Where R and/or R^ represent aryl or substituted aryl , the conversion to salts is conveniently effected by treatment with sodium in a tertiary amine, i.e. : G. of diphenyl ( +-) (cis-1 , 2-epoxypropyl) -phosphonate in 5 ml. of methanol is added to 100 ml. of trimethylamine. Small pieces of sodium are added gradually to a total of 2.0 gm. The solvents are removed by concen-tration, and the product is extracted into methanol. The methanol solution is then passed over a column of IR 120 resin on the hydrogen cycle which has been precooled to 5°C. The effluent is basified to pH 8.2 with phenethyl-amine and concentrated to give (-) (cis-1 ,2-epoxypropyl) -phosphonic acid as the bis-phenethylamine salt.

The (-) (cis-1 ,2-epoxypropyl) phosphonic acid referred to herein rotates plane-polarized light in a counterclockwise direction (to the left as viewed by the observer) when the rotation of its disodium salt is measured in water (5% concentration) at 405 πΐ .

The designation cis used in describing the 1,2-epoxypropylphosphonic acid compounds means that each of the ·¾ hydrogen atoms attached to carbon atoms 1 and 2 of the propylphosphonic acid are on the same side of the oxide ring.

A solution of 49.1 g. of the monobenzylammonium salt of racemic (cis-1 , 2-epoxypropyl) phosphonic acid in 490 ml. of water is cooled to 0-5 °C. and passed through a column containing 330 ml. of a sulfonic acid cation exchange resin of the polystyrene type (Dowex 50) on the acidic cycle, which has been previously cooled to 0-2 °C. The phosphonic acid salt is passed over the resin at a rate of 20-40 ml. per minute. The column is then washed with 660 ml. of 0-5°C. water at the same rate. The combined effluents are collected in an agitated mixture of 24.2 g. of (+) -a-phenethylamine in 100 ml. of water. The pH on the resulting solution is then adjusted to 4.8 by the dropwise addition of an aqueous solution of (+) -a-phenethylamine. The resulting solution is evaporated in vacuo to 95-100 ml. and sufficient isopropanol (about 320 ml.), preheated to 70°C. , is added so that the resulting solution contains about 20% water. The resulting solution is heated with agitation to 75-79 °C. and then quickly cooled to 60°C. and seeded with a small amount of mono-(+)-phenethylammonium (-) (cis-1 , 2-epoxypropyl) phosphonate. This solution is then cooled to 0-3eC. and stirred slowly for 16-24 hours, whereupon the crystalline diastereomer precipitates and is collected by filtration. The filter cake is washed with 40 ml. of cold isopropanol-water (9:1) and finally with 40 ml. of cold isopropanol. The crystalline product is then dried at 40°C. to constant weight in_ vacuo. The mono-(+)-phenethylammonium . (-) (cis-1 , 2-epoxypropyl) phosphonate so obtained melts at 129-132 °C. when the sample is inserted ■ '■ When the procedure of Example 28 D is repeated using as starting material an optically active cis- propenylphosphonite, which has been obtained by resolution of a mixture of enantiomers of an optically active cis- propenylphosphonite, there is obtained a mixture of enan- tiomers of (cis-1 ,2-epoxypropyl) phosphonate containing a predominance of one of the enantiomers.

Procedures such as those described in Examples 1, 2 and 4, i.e. those epoxidations employing a transition metal catalyst, may also be carried out using as catalyst an optically active salt, complex, ester or mixed anhydride of hexavalent tungsten cation, of tungstic acid or of similar cations and acids of other transition metals such as molybdenum and vanadium. In addition, complexes of such cations with polyamino compounds of the type ethylene- diamine, 1, 3-diaminopropane or diethylenetriamine , either in a stirred reactor or in a fixed bed, may be utilized as the catalyst. When catalysts of this type are employed the resulting (cis-1 ,2-epoxypropyl) phosphonate is obtained as a mixture of enantiomers in which one of the enantiomers is predominant.

Any departure from the above description which -conforms to the pre-s-ant invention—is. intcndod-Hse-r-be— inoluded wi-fchin the scope of the claims.

To a solution of 5*25 g. of diphenyl cigi-propenyl-phosphonate in; 250 ml, of methylene chloride is added 119 g. of dis dlum hydrogenphosphate and th resulting suspension stirred and .the heated to reflux. To the refluxing solution is added 100 ml. of 2.5K peroxytrifluoroacetic acid in small quantities over a period of 45 hours. The resulting reaction mixture is then cooled and filtered to remove the insoluble inorganic salts The salts are washed with a small volume of methylene chloride and: the washes added to the filtrate. The resulting filtrate (ca. 250 ml.) is hashed successively with 2 x 50 ml. portions of aqueous 20 sodium bisulfite solution, 2 x 50 ml. of 2.5N aqueous sodium hydroxide, 2 x 50 ml. of water, and finally 1 x 5 ml. of saturated sodium chloride solution. The washed solution is dried over anhydrous sodium sulfate and then evaporated in vacuo to an oil which crystallizes on standing. The product diphenyl {±) (ols-1.2^-epoxyprop.vl)phosphonate. is found to melt at 46~48°C, . The diphenyl cls-nropenvlphosphonate used above is prepared as follows: To 30.0 .! of ci£-propenylphosphonic dichloride in 150 ml. of ethyl ether is added dropwise a solution of 33.87 g. of phenol and 28.D ml. of pyridine in 200 ml. of ethyl ether while maintaining the reaction mixture at a temperature of 5-10°C. After the addition is complete the reaction mixture is allowed to stir fo 3 hours and then cooled to 5°0. The cooled solution is filtered to remove the precipitated pyridine hydrochloride which is washed with a small amount of ethyl ether. The filtrate is concentrated to a small volume in vacuo, filtered to remove solids and the filtrate con- base. The solution is then oooled to room temperature and .. brought to pH 9 with 50% aqueous sodium hydroxide. 25.90·· of oaloium acetate in †o ml* of water is added arid the resulting thick mixture filtered, The solid is washed with water and dried in vacuo at 50°0· to afford a produc containing calcium (±) (cis~1.2*-epoxypropyl)phosphonate in 12$ yield·: EXAMPLE 37 To a mixture of 8.3 g. of disodium cis-propenyl-phosphonate in 35 ml. of glacial acetic acid there is added 10 ml. of 40J¾ peroxyace ic acid containing 800 mg. of sodium acetate trihydrate. The resulting mixture is stirred at room temperature for 24 hours and then 200 mg. of 5 palladium on carbon added to decompose any remaining peracid* The mixture is stirred for 2 hours at room temperature and then filtered. The filtrate is freeze dried to afford a product containing' calcium (£) (cis-1 ,2-epoxypropyl)phosphonate in 24$ yield; E AMPLE 38 To a solution, of 15.0 g.. of dimethyl To a solution of 6 . 1 g. of cis-l -propenylphosphonic acid in 60 ml. of ethylacetate is added portionwise 6.06 g. of . d-phenethylamine. The resulting salt (mono-d-phenethyl- ■ , ammonium-cis-1 -propenylphosphona.te). partially precipitates out, The slurry is cooled to room temperature' and - 9.4 g. of m-chlor.o~ perbenzoic acid in 30 ml. of ethylacetate is added over a period of 1 0 minutes. The mixture is aged for three hours.

During this period the salt dissolves. To the clear solution a solvent mixture of 3 ml. water and 3 ml. propanol is addedo The solution. is cooled to 0°C. to -5°C Crystalline d-phenethyl- ammonium- 1-cis- 1 , 2-epoxypropylphosphonate monohydrate precipitates and is collected on a funnel, and the cake is washed with cold n-propanol.

■ The crude product is recrystallized from 90!# n-propanol , to give substantially pure material, m.p; 1 35— 1 37°C.

The above procedure may be carried out utilizing solvents such- as chloroform, methylene chloride, dichloroethano , acetic acid, ether, or acetone i place of the ethyl acetate, and organic peracids such.aa peracetic acid, pertrifluoroacetio, perbenzoic, perfuroic, monopersuccinic, and monoperphthalic acids in place of the cllorop.jerbenzoic acid.

' E AMPL 40 · Into a 2 Ο ml. three-necked flask equipped with dry ice cooled reflux condenser and gas inlet tube are charged 1 00 ml. of acetone, 1 2. 2 g. of cis-1 -propenylphosphonic acid, 1 2. 1.- ,· ;. ' introduced through the gas inlst tube with simultaneous irradiation with a 100 mercury lamp* aj&g temperature of the reaction mixture is maintained between 25° to 35°0· y external cooling. After six hours reaction time 4 ml* of water is added and the mixture cooled to -20°CU The crystalline solid is filtered and recrystallized from 80 isopropjanol to give d- 1 phenethylammonium-y-cis-1 ,2-epoxypropylphosphonate· The above procedure may be carried out using carbon tetrachloride, methylethyl ketone, ether, or tetrachlorp ethane as solvent Instead of acetone* B3CAMP1E 41 To a solution of 6.1 g. of cis-1-propenylphosphonic acid in 70 ml. of water are added 50 rag, of ethylenediamine tetraacetic acld-dlsodlum salt, 250 mg. of sodlumtungstate dihydrate and stirred until all dissolves. To the clea solution 8.9 g of sodiumperborate tetrahydrate is added portlonwise over a period of five minutes. She solution is warmed up to 50°G. and aged with agitation between 50*55°C« for one hour. The slight excess o sodiumperborate is decomposed by adding a few ml. of 10# sodiumbisulfite solution. The reaction mixture—free from perborate— is freeae dried to give a solid residue containing the sodium-dl-cla-l f2-epoxypropyl-phosphonate. . 12417 30918/1 the ammonium salt of (··) (cis-1, 2-epoxypropyl) phosphonic I acid. The salt is dissolved in 2 ml. of water, and the ■ specific rotation measured in a 0.5 decimeter tube. The I product has a specific rotation of -13.5° at 405 π\μ.

' To a methanolic solution of 252 mg. of the ammonium salt of (-) (ci3-l, 2-epoxypropyl) phosphonic acid, 7 which is obtained from the quinine salt as desbribed above, 8 is added 154 mg. of benzylamine. The solution is evaporated 9 . at 60°C. in a stream of nitrogen to remove ammdnia and the 0 residue is taken up in a small volume of methanol and cooled 1 to cause crystallization. The crystals are removed by 2 filtration and dried in air to give 122 mg. of the benzyl-3 amine salt of (-) (cis-1 , 2-epoxypropyl) hosphonic acid, m.p. 4 158~160°C., [a] 405 mu. = -9.1°.

EXAMPLE 3 6 The monoammonium salt of racemic (cis-1, 2-, 7 epoxypropyl) phosphonic acid (0.5 g. ,' .0032 mole) is 8 treated with (+) a-phenethylamine (0.35 g., .0028 mole) 9 in 20 ml. of methanol. The solution is. evaporated to a 0 syrup, the residue is redissolved in a small volume of 1 methanol and is seeded with crystals of the (+) a-phen-2 ethylamine salt of (-) (cis-1 , 2-epoxypropyl) phosphonic acid, 3 m.p. 139-140°C. Some crystals settle out of the solution 4 upon standing. Acetone (5 ml.) is added and the crystal-5, lization is allowed to continue. The crystals are then 6 filtered off and washed with acetone to yield the (+) 7 a-phenethylamine salt of (-) (cis-1 , 2-epoxypropyl) -. 8 phosphonic acid, m.p. 131~132°C. After two crystalliza-9 tions from methanol, 30 my. of the salt, m.p. 140-142°C. , 0 are obtained*. ■' .· ' . , 12417 30918/1 EXAMPLE 44 A solution of 49.1 g. of the monobenzylammonium salt of racemic (cis-1, 2-epoxypropyl) hosphonic acid in 490 ml. of water is cooled to 0-5°C. and passed through a column containing 330 ml. of a sulfonic acid cation exchange resin of the polystyrene type (DO EX 50) on the acidic cycle, which had been previously cooled to 0-2°C.

The phosphonic acid salt is passed over the resin at a" rate of 20-40 ml. per minute. The column is then washed with 660 ml. of 0-5°C. water at the same rate. The combined effluents are collected in an agitated mixture of 24.2 g. of (+) a-phenethylamine in 100 ml. of water. .

The pH on the resulting! solution is then adjusted to 4.8 by the dropwise addition of an aqueous solution of (,+') a-phenethylamine. The resulting solution is evaporated in vacuo to 95-100 ml. and sufficient isopropanol (about 320 ml.) , preheated to 70°C.f is added so that the resulting solution contains about 20% water. The resulting solution is heated with agitation to 75-79°C, and then quickly cooled to 60°C. and seeded with a small amount of mono (+) phenethylammonium (-) (cis-1 , 2-epoxypropyl) - phosphonate. This solution is then cooled to 0-3°C. and stirred slowly for 16-24 hours, whereupon the crystalline diastereomer precipitates and is collected by filtration.

The filter cake is washed with 40 ml. of cold isopropanol- water (9:1) and finally with 40 ml. of cold isopropanol w The crystalline product is then dried at 40°C. to constant weight in V^CUQ. . The mono (+) phenethylammonium (-) (cis-1, 2-epoxypropyl) phosphonate so obtained melts at 129-132°C. when the sample is inserted, at 125eC. and . 30918/1 heated. at 2°C. per minute. The product has a rotation ?8°C. [α]405 ιήμ (C = 5% , H20) = -2.6°. Recrystallization from aqueous isopropanol affords crystalline product melting at 133-136°C. and having the same rotation.

E AMPLE 45 1.1 Liters of an aqueous solution of 27.6 g. of racemic (cis-1/ 2-epoxypropyl) phosphonic acid prepared as described in Example^ 4 from 49.1 g. of monobenzylammonium salt is added to a slurry of 65,0 g. of quinine in 100 ml.. of water.' The resulting colution is concentrated iri vacuo to about 100 ml. and 400 nil. of' isopropanol is added.

The mixture is heated to 60°C, cooled to 0°C. and the precipitated crystalline quinine salt of (-) (cis-1 ,2-epoxypropyl) phonphonic acid in recovered by filtration and then dried. The product: molts at 195-196°C. and °C. has a rotation [a]405 mμ. (C = 5¾, MeOH) » -465.3° and 28°C. [a]D · (C « 5%, MeOH) <= -135.8°, . . ^ .. 12417 ■ ' . 30918/1 ' . 1 · EXAMPLE 46 2 When the process of Example44 is repeated using 3 (-) a-phenethylamine in place of the (+) a-phenethylamine, the mono- (-) a-phenethylammonium (+) (cis , 1,2-epoxy- 5 propyl) phosphonate is obtained. This product has a melting 6 point of 135-137°C. when the sample is inserted at 125°C. 28°C. 7 and heated at 10°C. per minute, and a rotation, [α]405 κιμ. 8 (C '=» 5%, H20) =-2.6°. 9 The mother liquors obtained after removing the 11 diastereomer in Example 46 are concentrated to 40 ml. 12 in vacuo and 50' ml. of 2-propanol added. The resulting 13 solution is then reconcentrated to about 50 ml. and cooled 14 to cause precipitation of the mono-(-) a-phenethylammonium i ' ■ ' ■ (-) (cis-1, 2-epoxypropyl) phosphonate, which is recovered ! 16 by filtration and dried. The product obtained is found to 17 melt with decomposition at 171-172°C. when the sample is 18 inserted at 165°C. and heated at 10°C. per minute. This 28°C. 19 product has a rotation, [α] 405 ηψ,. (C - 5%, HLO) β -15.5°: '• ■ '' ' 28eC« - i · ' : ' " ' and [a]D ' (C «= 5%, H20) = -5.5°. 21· EXAMPLE 47,· 22 An aqueous solution containing 27.6 g. of 23 racemic (cis-1, 2-epoxypropyl) phosphonic acid is prepared 24 as described in Example 44 from 49.1 g. of monobenzylammonium salt and is added to a mixture of 27.0 g. of (+) amphetamine 26 in 100 ml. of water and the solution is then dried in vacuo.

I 27 The dried product is dissolved with heating in 160 ml. of, 28 ethanol and the solution is cooled to precipitate cry- 29 stalline (+) amphetammonium (-) (cis-1, 2-epoxypropyl) - 30 phosphonate. This product is recovered by filtration and '■■. :· .■ ■ ' ■ - 70 - ":■ j .

! I . · ■ 30918/1 ' EXAMPLE .50 To an aqueous solution of 27.6 g. of racemic ( cis-1 , 2-epoxypropyl) hosphonic acid, prepared as des-cribed in Example44 from 49.1 g. of monobenzylammonium salt, is added (-) dehydroabietylamine (0.2 mole) in 200 ml. of water and this solution is concentrated in vacuo to about 200 g. To this concentrate is then added 800 ml. of isopropanol and the resulting mixture is heated to 60eC., cooled to 0°C. and the precipitated mono-(-) dehydroabietylammonium (-) (cis-1, 2-epoxypropyl) phosphonate is recovered by filtration and dried. The product is I . . · -■.'· found to melt at 195-196°C. and to have a rotation, %' H20) " +57·10 and tal 80?'. (C * 5%, - EXAMPLE 51 ' 2.75 Liters of an aqueous solution of 27.6 g. of racemic (cis-1, 2-epoxypropyl) hosphonic acid, prepared as described in Example 44 from 49.1 g. of monobanzylamine salt, is added to an aqueous solution containing 0.4 mole of sodium hydroxide and then 0.2 mole of (-) cobaltic tris- (ethylenediamine) -triiodide is added. The resulting solution is warmed to obtain a clear solution and then evaporated in vacuo to about 800 g. To this concentrate is then added 800 ml. of tetrahydrofuran and th'i resulting solution is cooled to 0°C. The precipitated (-) cobaltic tris- (ethylenediamine) -triiodide salt of (-) ( is-l,2-epoxypropyl) hosphonic acid is recovered by filtration and dried. The product is found to melt at 270-275"C. with decomposition. ! ·, 30918/1 1 EXAMPLE 52 . 2 An aqueous solution of 13.8 g. of racemic (cis- 3 1, 2-epoxypropyl) phosphonic acid, prepared as described in 4 Example 44 from 25 g. of monobenzylamine salt is added to 17.4 g. of L-arginine in 50 ml. of water. The resulting 6 solution is evaporated to dryness in vacuo and the 7 residue is slurried with 120 ml. of hot isopropanol. The 8 resulting isopropanol solution is cooled to 0°C. and 9 the precipitated L-arginine salt of (-) (cis-1 , 2-epoxy- 10 propyl) hosphonic acid is recovered by filtration and dried. The product so obtained is found to melt at 213.°C. 28°C with decomposition and to have a rotation, [11 05 ηm"μa.. 13 (C » 5 ,, H20) - +13.7° and [a] 8"0, (C » 5%, Η,,Ο) » 14', +4.5°.

EXAMPLE 53, · 16 1.1 Liters of an aqueous solution containing j 17 27.6 grams of racemic (cis-1 , 2-epoxypropyl) phosphonic acid j 18, prepared as described in Example 44 from 49.1 grams of 19 monobenzylamine salt is added to an aqueous solution of 16.1 g. of (+) -ct-phenethylamine and 11 2 g. of triethylamine 21 in.100 ml. of water. The resulting solution containing the 22 mixed amine salts is evaporated in vacuo to about 30 ml. 23 To this aqueous concentrate is added 160 ml. of n-propanol. 24 The resulting solution is cooled whereupon crystalline , 25 (+) ,- -phenethylammonium (-) (cis-1, 2-epoxypropyl) phosphonate 26 crystallizes and is recovered by filtration. The product so 27 obtained is recrystallized from 150 ml. of n-propanol at 0°C. 28 and the crystalline product is recovered by filtration. The 29 product is washed three tiiiusa with 5 ml. of cold (0°C.) n- 30 propanol and dried in vacuo at 40°C. to constant weight.

D' . 3 918/1 ;i (·Ι·) i i.l I : 111 Ui 'J.ain n. ni i n n (-} ) ,"» p'l uylioiiuto (11.1.0 (',.) no obtnin. . 3. and has a rotation fix/ = -2. ■ .. i.i-05 Lj. EXAMPLE 54 . To a solution of 76· °f mono-(+) a-phenothyl- 6 ammonium (-) ( is-l,2-opoxypropyl)pho3phonato. mono ydrate .7 in 3 litorn of wator In nddod ΧΠ 6.5 ml. of J?0j¾ aodituii t roaoti a final pK of 9.0. 9 To tho resulting solution in ndclod a solution of 33 ' g. of calcium acotato in 1.3 litors of wator over a period of 11 20 minutes. The resulting slurry ia stirred at 25°C . for 12 I4.5 minutes, filtered, the cake washed with I. liters of 13. water and finally vacuum-dried at 50°C. to afford the ll calciuTi salt of (-) (c_is-l,2-epoxypropyl)ph03phonic aoid , monohydrato. Tho product 30 obtained had a rotation, ' ,20°c. · ■· . ' '■ ■ '; ' ·. · ■ "■ 16 ¾/ (C = 0.I . M aqueous othylonodiamino tetra- ).05 ιημ. " 17 ■ -nod ic ucid at pil tt.ti) ~ -11.0°. ' 1» lSKMPLK 55. ·' 1 . To. a solution of sodium motho ide (1.3!?' g.) in' 20,· 20.8 ml. of methanol is addod 6.93 S» of mono-(+) - 21 phenethylamiionium (-) (cis-l,2-opoxypropyl)phosphonate 22 and tho mixture . atirvud until all of th solids disaolva. 23. To this solution is then added in a .nitrogen . atmosphere 2 a solution of 1,35 g, of sodium methoxide in 20. Θ ml. of. anhydrous! othanol. Λ gelatinous precipitate is formed . 2 . in th-.v ro ulbi'.T,;. nolubiOn, wh:i oh gradually bocomoa 2 glvmul r upon tho addition of ,'Ό.Η. lii'L. of abfjoliito ntUanol Af or stirring room, tomporatm'o for 2 hou s , tho 2 precipitated disodium salt of (-) (cis-l,e!-opoxypropyl)-30 phosp onio acid is removed by filtration-, washed with 30918/1 I "100 nil. ο absolute ot unol and dviod to constant weight. t . in vacu . Thn product .MO obt ined had a 3 rotation, fi ■ (C « >, Π,,Ο)· =·-1ί|.0.

J.,. EXAMPLE " 6 .

A solution of racemio mono-(+) a-phenot yl- 6 ammonium (cij3-l/2-epoxypropyl)pho3phonate (11.1 g», 0'.0)+ 7 mole) ill l£0 ml. of cold wator is passed through a jacketed 8 glass column with an inside diameter of two inches contain- 9 ing 800 ml. of 100-300 mosh nnlfonutod polystyrene rosin 10 which contains (-) phcmylalunino at its isoelectric point 11. of pH 5.5 linked via sulfonamide bridges. The' column is 12 then washed at the rate of 20 ml. per minute'' ith a total 13 of 3 litere of $f aqueous buffer composed of !j.:l acetic IJ4. acid-ammonium acetate at pH ίμθ. The first 1.5. liters of' 1 effluent is collected separately, frozen and lyophilized 16 -at IOO-250 microns of pressure. The residue is mono-(+) 17 a-phenethylammonium salt enriched in the (+) (cis-1 ,2- 18 opoxypropyl)phosphonato ion. 19 ; Tho second 1.5 li riivi of offluent aro troatod similarly to give mono-(+) a-phonothylammonium sal 21 enriched in (-) (£is-l,2-epoxypropyl)phosphonatG ion. 22 Each partially resolved phenethylammonium 2 .phosphonate is passed over the resin column again in .the 2 identical manner. Lyophilization of the first 1.5 liters' 5 of effluent from repassing partially resolved mono-(+) 26 a-phenethylammoniiuii (+) (c: -:L, 2-epoxypropyl)phosphonato 27 through tho rosin column givoa salt of a high dogroo of 8 o m purity. 2 Lyap li nation of tlm !Jocond 1,511 torn of · effluent from repassing partially resolved mono- (+) 30918/1 1 u-)»hi.mottiylaimnon ttiu (-) ( oi n -1 , ?.-opoxypropyl )phosphonato lii'ciui'. ' the) voiui.ii column . vo aul of a ig degro'o of 3 option! purity, k- ' ' EXAMPLE 57.' . A dry-packed chromatography column of one kilo- 6 gram of 250r mosh. (+) lactose hydrate is prepared in a 7 two inch I. glass column . Anhydrous raoomic mono-(+) 0 . a-phonotliylanQnoniuJii (cia -1 , P.-opoxypropyl)phosphonato 9 (11 , 0 g., 0, 0l|. luol'o) is diaaolvod in 100 ml, of anhydrous methanol and passed through the column. The column is .11, eluted with 3 liters of isopropanol, which, on evaporation 12 to £>0 ml, followed "by filtration and drying, gives mono-(+) 13 Q-phenethylamiaonium salt enriched in the (+) ■ (cis-1,2- II . epoxypropyl )phosphonate ion. , 1 ■ The oolumn is washed with 3 liters of anhydrous jl6 methanol, whioh, on evaporation to 25 ml. dilution with 17 5 ml. of water and 75 ml. of isopropanol followed by . 18 filtration and drying, givoa principally mono-(+) a-phon-, 19 othylamnonium (-) (cls -1,2-o oxypropyl )phosphonato mono- 20 hydrate. 21 In place of the (+) lactose chromatography column, 22 other chromatographic colunns of (+) sucrose, (+) maltose · 23 hydrate, (+) oollobiose, starch, cellulose, hi-micellulose, 2-j. acetylated cellulose, silica gel, kieselguhr, aluminum · 2 oxide, polyamide powder, ncotylatod polyamide powder,.' 26 celluloso oth rs, and thn liko can similarly bo uaod. 27 · :ΐι!ΧΑΜ.'.ι. 58 Finoly-ground rnnomi c mono- (H-) ii-p onOtityl- 29 ammonium (cis-l,2-epoxypropyl)phosp.honate (2.5. 9 g.', 0,1 mole) is added to 2' ml. of water containing finely-ground

Claims (1)

1. 80 A mixture according to Claim 1 Of parts of compounds the and A mixture according to Claim of unequal parts of and acid or of compounds A mixture according to Claim 1 of pharmaceutically acceptable salts of and A mixture according to Claim wherein the salts are alkal metal or dlsodlum salts or alkaline earth metal calcium A mixture according to Claim 1 amine salts of and A according Claim wherein the salts those with an optically active or A mixture according to Claim wherein the salts are those with A mixture according to wherein the salts are those with A mixture according Claim of o dlesters of and of the formula I Claim wherein are biologically labile acetoxymethyl or A mixture according to Claim or of and of the formula I in Claim wherein are monocyclic aryl or A mixture according to Claim 1 of compounds of and o the formulae 81 H H C C P 0 P C V OR OR V or o C C C P IV 0 OR which R and are defined in Claim An antibacterial composition a mixture according to intimately admixed with a pharmaceutically acceptable A process for preparing a mixture according to Claim which comprises reacting phosphonic acid or a derivative of the formula in which and have the same meaning as in Claim with an epoxldizihg if replacin R in the of I in Claim 1 thus by a different R or cation or A process according to Claim 15 for preparing a mixture according to Claim wherein both the starting material of formula V and the agent are optically A process according to Claim 15 for preparing a mixture according to Claim wherein the epoxidiaing agent used is optically A process preparing a mixture according to Claim wherein a mixture obtained according to Claim 17 is reacted wit an antipode o compound to form a mixture of diastereomeric salts of formula I in Claim 1 in and which at least one of and is optically from this acid or a compound hereo is if A process accordin to Claim for preparing a mixture accordin to Claim 3 wherein a starting material formula V is in which is an optically active cation or A process according to the diastereomeric compound the antipode is recovered the mixture prepared accordance with Claim A process according to any one of Claims 15 to wherein peroxy compound used as the epoxidiain A process according to Claim wherein hydrogen peroxide in the presence of an inorganic peracid is used as the peroxy compound A process to Claim wherein a perorganic acid is peroxy A process according to Claim wherein a loweralkyl hydroperoxide is used as the peroxy A process according to Claim wherein a salt of propenyiphosphonic acid is used as a starting according to Claim wherein an alkali metal salt is A process according to Claim wherein an amine a lami A process according to Claim wherein benzylammonium or is reacted with hydrogen peroxide in presence of A for preparation compounds accordin to Claim 13 which comprises reacting corresponding compound of the formula or with an epoxidizing Processes for the preparation of compounds according to Claim substantially as described herein with to insufficientOCRQuality