US3595869A - Process for preparing a diastereomer of an optically active ester or amide of (cis-1,2-epoxypropyl)-phosphonic acid - Google Patents

Process for preparing a diastereomer of an optically active ester or amide of (cis-1,2-epoxypropyl)-phosphonic acid Download PDF

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US3595869A
US3595869A US729468A US3595869DA US3595869A US 3595869 A US3595869 A US 3595869A US 729468 A US729468 A US 729468A US 3595869D A US3595869D A US 3595869DA US 3595869 A US3595869 A US 3595869A
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epoxypropyl
phosphonate
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Richard F Shuman
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Merck and Co Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/65502—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a three-membered ring
    • C07F9/65505—Phosphonic acids containing oxirane groups; esters thereof

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  • This antibiotic can be produced by synthesis by procedures which result in the production of the racemic form consisting of a mixture of equal amounts of both the enantiomer, which is devoid of antibiotic activity and the enantiomer. While such mixtures are useful as antibiotics, methods have been sought whereby the content of the enantiomer might be increased or this isomer obtained in substantially pure form and free from the inactive form.
  • diastereomers of enantiomeric mixtures of esters or amides of (cis-1,2-epoxypropyl)-phosphonic acid, or salts of such esters or amides can be separated.
  • the individual diastereomers so obtained can then be cleaved to produce each of the enantiomeric forms of (cis-1,2-epoxypropyl)- phosphonic acid or salts thereof.
  • the separated diastereomers so obtained can be further cleaved to produce the enantiomeric isomers of (cis-l,2-epoxypropy1)-phosphonic acid and salts thereof.
  • the hydrocarbyl group can be a straight chain or branched chain alkyl, alkenyl, alkynyl group, a cycloalkyl group, a cycloalkenyl group, a cycloalkynyl group, an aryl group, an aralkyl group, or a heterocyclic group.
  • suitable hydrocarbyl groups that might be mentioned are alkyl, particularly lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl, pentyl and the like; alkenyl, particularly lower alkenyl such as vinyl, propenyl, butenyl, allyl, pentenyl and the like; alkynyl, particularly lower alkynyl such as ethynyl, propynyl, butynyl and the like; aryl such as phenyl and naphthyl; aralkyl, particularly lower alkyl substituted aryl such as benzyl, phenethyl, phenbutyl, naphthylenemethyl and the like; cycloalkyl, particularly cycloloweralkyl such as cyclobutyl, cyclopentyl, cyclohexyl and the like; heterocycles such as furan, pyrrole, thiophene, cycl
  • diastereomers which can be separated by the present invention are compounds of the formula and compound of the formula 0 X Y CHaCfi CH- wherein X and Y are the same as defined above.
  • compounds of the formulas shown in 2 and 3 above such as optically-active monoor disubstituted phosphonate, phosphonamidate, phosphondiamidate, phosphonodithioate, phosphonamidothioate, phosphonthioate, phosphonotrithioate, phosphonamidodithioate and phosphonodiamidothioate esters can be separated to obtain the individual diastereoisomers.
  • optically-active substituent or substituents of these compounds can be derived from an optically-active alcohol such as (
  • esters of enantiomeric mixtures of (cis 1,2 epoxypropyl)-phosphonic acid such as the monoor dimenthyl esters, the monoor dibornyl esters, the monoor didehydroabietyl esters and the like can be separated to obtain the individual diastereomers.
  • the diastereomer so obtained can then be cleaved to produce and (cis-1,2-epoxypropyl)-phosphonic acid or salts thereof.
  • esters can be readily prepared pursuant to methods known in this art, for example, by reacting an amine salt of (cis-1,2-epoxypropyl)-phosphonic acid with the appropriate quantity of alcohol in the presence of a suitable dehydrating agent, such as N,N-dicyclohexylcarbodiimide or N,N-dimethylcarbodiimide.
  • a suitable dehydrating agent such as N,N-dicyclohexylcarbodiimide or N,N-dimethylcarbodiimide.
  • the resulting mixture of the diastereomeric esters can then be separated from the reaction mixture and the individual diastereomers separated therefrom by crystallization, chromatography, ion exchange resin procedures or by inclusion or clathrate compounds.
  • substituted amides such as those derived from optically-active primary and secondary amines, such as u-phenethylarnine, fenchylamine, menthylamine and the like form diastereomeric monoor diamidates with mixtures of enantiomers of (cis-l,2-epoxypropyl)-phosphonic acid or derivatives thereof such as the phosphonamidic acid, the phosphonamidodithioic acid, the phosphonamidothioic acid and the phosphonodithioic acid or monoesters, monoamides or substituted monoamides thereof.
  • optically-active primary and secondary amines such as u-phenethylarnine, fenchylamine, menthylamine and the like form diastereomeric monoor diamidates with mixtures of enantiomers of (cis-l,2-epoxypropyl)-phosphonic acid or derivatives thereof such as the phosphonamidic acid, the
  • diastereomers having optically-active amides examples include N,N'-biS-[(+)-ocphenethyl] (cis 1,2-epoxypropyl)-phosphonodiamidate, N,N' bis oc-phenethyl]-(cis-1,2-epoxypropyl)- phosphonodiamidothio ate, O-benzyl-N- -fenchylcis- 1,2 epoxypropyl) phosphonamidate, S-methyl-N-(+)- fenchyl-(cis-1,2-epoxypr0pyl) phosphonamidodithioate, N-methyl-N-(+)-a-phenethyl-S-ethyl (cis 1,2 epoxypropyl)-phosphonamidothioate and the like.
  • such diastereomers can be separated to obtain each diastereomer, which can then be converted to produce or enanti
  • the hydrocarbyl group can be any of the groups mentioned above.
  • the acid function of the R group mentioned above can be an acid group or function capable of forming salts with bases, particularly optically-active bases.
  • Examples of such acidic functions that might be mentioned are a carboxy, sulfonic acid, sulfinic acid, phosphonic acid, phosphonous acid substituent and the like.
  • Illustrative examples of such compounds that might be mentioned are 0,0'-carboxymethyl (cis-1,2-epoxypropyl)phosphonate.
  • these compounds can be reacted with an optically-active base to form the corresponding diastereoisomers, which can then be separated, for example, by fractional crystallization from suitable solvents such as lower alkanols or mixtures of such alcohols with other solvents or water.
  • bases that might be mentioned are nitrogenous bases or their acid salts such as quinine, brucine, a-phenethylamine, ocphenethylamine, amphetamine, L-(+) lysine, L- tyrosine hydrazide, L-threo-1-phenyl-2-amino-1,3- propanediol, L-a-fenchylamine, dehydroabietylamine, cobaltic tris(ethylenediamine)-triiodide, cobaltic tris-(ethylenediamine)-triiodide, iso-cholesterylamine, menthylamine, L-(+) arginine, [2.21-2- aminoparacyclophane, yohimbine, methylallyl- 4 phenylbenzylammonium bromide, methylallylphenylbenzylammonium bromide, 2,5 (octamethylene-l,8-dioxy)-aniline,
  • Such acid-substituted esters, thio-esters and amides can be prepared from anhydrides of (cis-1,2-epoxypropyl) phosphonic acid with strong acids [hydrogen halides; sulfuric, sulfinic and sulfonic acids; phosphonic, phosphoric and phosphinic acids; polyhalocarboxylic acids or others substituted with electron-withdrawing or electro-negative atoms or groups (halogen, sulfo, sulfonyl, sulfinyl, nitro, carbonyl)] by reaction with hydrocarbyl alcohols, thio alcohols, or amines; metal hydrocarbyl alkoxides, thio alkoxides, or amides wherein the hydrocarbyl portion also carries an acidic group or a group convertible to an acid.
  • the anhydrides of (cisl,2-epoxypropyl)-phosphonic acid can be formed in situ using dehydrating agents such as carbodiimides or anhydrides of strong acids such as sulfur trioxide, phosphorus pentoxide, trifluoroacetic anhydride; or by halogen metathesis from an acid halide to a metal salt of (cis-1,Z-epoxypropyl)-phosphonic acid giving (cis-1,2-epoxypropyl)-phosphonyl monoor dihalide.
  • dehydrating agents such as carbodiimides or anhydrides of strong acids such as sulfur trioxide, phosphorus pentoxide, trifluoroacetic anhydride
  • halogen metathesis from an acid halide to a metal salt of (cis-1,Z-epoxypropyl)-phosphonic acid giving (cis-1,2-epoxypropyl)-phosphonyl monoor dihalide.
  • acid-substituted esters can be prepared from metal salts of (cis-l,2-epoxypropyl)-phosphonic acid (alkali, alkaline earth and transition metal salts) and hydrocarbyl esters of strong acids or other hydrocarbyl derivatives having easily displaced groups or atoms and which contain an acidic group or a group convertible to an acid.
  • metal salts of (cis-l,2-epoxypropyl)-phosphonic acid alkali, alkaline earth and transition metal salts
  • hydrocarbyl esters of strong acids or other hydrocarbyl derivatives having easily displaced groups or atoms and which contain an acidic group or a group convertible to an acid.
  • alkenes or alkynes can also be prepared from (cis-1,2-epoxypropyl)-phosphonic acid or metal salts thereof (alkali, alkaline earth and transition metals) via addition of the phosphonate anion through its oxygens to al kenes or alkynes wherein one of the carbons bearing the unsaturation is also substituted with an electron-withdrawing or an electronegative atom or group, such as cyano, nitro, carbonyl, sulfonyl, sulfinyl or phosphonyl.
  • the alkene or alkyene must carry an acid group or a group convertible to an acid (anhydride, cyano or ester).
  • acid substituted derivatives can be prepared from (cis-1,2-epoxypropyl)-phosphonic acid or basic salts thereof by condensation with alcohols, thio alcohols, or amines which also carry an acidic group or a group convertible to an acid.
  • Dehydrating agents such as carbodiimides, anhydrides of strong acids (sulfur trioxide, phosphorus pentoxide, trifluoroacetic anhydride) and other dehydrating agents, esterification catalysts or catalysts useful for amide formation and known to the art are used in this method.
  • metal salts of (cis- 1,2-epoxypropyl)-phosphonic acid preferably silver, but
  • alkali, alkaline earth and other transition metals are reacted with hydrocarbyl esters of strong acids (halides; sulfuric, sulfonic, sulfinic, phosphoric, phosphonic, phosphonic esters) or other derivatives having easily displaced groups or atoms and also carrying an acidic group or a group convertible to an acid.
  • hydrocarbyl esters of strong acids halides; sulfuric, sulfonic, sulfinic, phosphoric, phosphonic, phosphonic esters
  • Diastereomeric esters or amides of (cis 1,2-epoxypropyl)-phosphonic acid wherein the hydrocarbyl ester or amide carries an acidic function either free or as a salt may be converted to useful derivatives such as a salt by hydrolysis with water, caustic or acid solutions, by irradition with various forms of light, or by treatment with metal catalysts in a hydrogen atmosphere.
  • the hydrocarbyl group can be any of the groups mentioned above.
  • the basic function of the R substituent can be an amino group.
  • Illustrative examples of compounds having a basic function that might be mentioned are bis-Z-aminoethyl- (cis 1,2 epoxypropyl) phosphonate, 3 aminopropyl benzyl (cis 1,2 epoxypropyl) phosphonate, N,N- bis (2 aminoethyl) (cis 1,2 epoxypropyl) phosphondiamidate, 0,0 bis (4 aminobenzyl) (cis 1,2 epoxypropyl) phosphonate, and 8,8 bis (4 aminophenyl) (cis 1,2 epoxypropyl) phosphondithioate.
  • these basic derivatives can -be reacted with an optically-active acid to produce diastereomeric salts which can be separated by fractional crystallization from suitable solvents such as lower alkanols, particularly methanol, ethanol, propanol, isopropanol, aqueous mixtures of such alcohols, or mixtures with other suitable solvents.
  • suitable solvents such as lower alkanols, particularly methanol, ethanol, propanol, isopropanol, aqueous mixtures of such alcohols, or mixtures with other suitable solvents.
  • Optically-active acids useful in the above-described processes that might be mentioned are tartaric acid, gluconic acid, mannonic acid, lactic acid, malic acid, glutamic acid, mandelic acid, saccharic acid, trihydroxyglutaric acid, gulonic acid, alanine, serine, valine, aspartic acid, camphor-lO-sulfonic acid and the like.
  • the derivatives having a basic function can be reacted with an optically-active form of (cis-1,2- epoxypropyD-phosphonic acid and the resulting diastereomeric salts separated to obtain the individual diastereomers.
  • Such base-substituted esters, thio-esters and amides can be prepared from anhydrides of (cis-1,2-epoxypropyl)- phosphonic acid with strong acids [hydrogn halides; sulfuric, sulfinic and sulfonic acids; phosphoric, phosphonic and phosphinic acids; polyhalocarboxylic acids or others substituting with electron-withdrawing or electronegative atoms or groups (halogen, sulfo, sulfonyl, sulfinyl, nitro, carbonyl)] on reaction with hydrocarbyl alcohols, thio alcohols, or amines; metal hydrocarbyl alkoxides, thio alkoxides or amides wherein the hydrocarbyl portion also carries a basic group or a group convertible to an acid.
  • the anhydrides of (cis 1,2 epoxypropyl) phosphonic acid may be formed in situ using dehydrating agents such as carbodiimides or anhydrides of strong acids such as sulfur trioxide, phosphorus pentoxide, trifluoroacetic anhydride or by halogen metathesis from an acid halide to a metal salt of (cis 1,2 epoxypropyl)- phosphonic acid giving a (cis 1,2 epoxypropyl) phosphonyl monoor dihalide.
  • dehydrating agents such as carbodiimides or anhydrides of strong acids such as sulfur trioxide, phosphorus pentoxide, trifluoroacetic anhydride or by halogen metathesis from an acid halide to a metal salt of (cis 1,2 epoxypropyl)- phosphonic acid giving a (cis 1,2 epoxypropyl) phosphonyl monoor dihalide.
  • the base substituted esters can also be prepared from metal salts of (cis 1,2 epoxypropyl) phosphonic acid 6 (alkali, alkaline earth and transition metals) and hydrocarbyl esters of strong acids or other hydrocarbyl derivatives having easily displaced groups or atoms and also carrying a basic group (such as amino groups) or a group convertible to an amine.
  • metal salts of (cis 1,2 epoxypropyl) phosphonic acid 6 alkali, alkaline earth and transition metals
  • hydrocarbyl esters of strong acids or other hydrocarbyl derivatives having easily displaced groups or atoms and also carrying a basic group (such as amino groups) or a group convertible to an amine.
  • alkene or alkyne also carries basic (amino) groups or a group convertible to a base (cyano, nitro, amido, halo, mesyloxy, tosyloxy).
  • (Cis 1,2 epoxypropyl) phosphonic acid or basic salts can also be condensed with hydrocarbyl alcohols, thio alcohols, or amines which carry a basic (amino) group or a group convertible to an amine.
  • Dehydrating agents such as carbodiimides, anhydrides of strong acids (sulfur trioxide, phosphorus pentoxide, trifluoroacetic anhydride) and other dehydrating agents, esterification catalysts or catalysts useful for amide formation and known to the art.
  • metal salts of (cis 1,2 epoxypropyD- phosphonic acid can be reacted with hydrocarbyl esters of strong acids (halides; sulfuric, sulfonic, sulfinic, phosphoric, phosphonic, phosphonic esters) or other derivatives having easily displaced groups or atoms and also carrying a basic group (amino) or a group convertible to an amine.
  • hydrocarbyl esters of strong acids halides; sulfuric, sulfonic, sulfinic, phosphoric, phosphonic, phosphonic esters
  • Diastereomeric esters or amides of (cis 1,2 epoxypropyl)-phosphonic acid wherein the hydrocarbyl ester or amide carries a basic group either free or as a salt may be converted to useful derivatives (a salt of (cis-1,2- epoxypropyl) phosphonic acid) by hydrolysis with water, caustic or acid solutions, by irradiation with various forms of light, or by treatment with metal catalysts in a hydrogen atmosphere. If the basic group is an amine it may first be converted to a quaternary salt, a cyano, or a nitro group and then eliminated or hydrolyzed with the formation of a useful derivative of (cis 1,2 epoxypropyl)-phosphonic acid.
  • the white product disodium (cis-1,2-epoxypropyl)-phosphonate, is washed with 200 ml. of isopropanol and dried to constant weight.
  • This product has a rotation of Calcium (cis-1,2-epoxypropyl)-phosphonate monohydrate Bis- (trimethylammonium (cis-1,2-epoxypropyl) phosphonate (equivalent to 51.2 g. of dried salt, 0.2 mole) is dissolved in 250 ml. of water.
  • 35.2 g. (0.2 mole) of calcium acetate monohydrate dissolved in 250 ml. of water.
  • the resulting precipitate is filtered, Washed with 250 ml. of hot Water and dried to give calcium (cis-1,2-epoxypropyl)-phosphonate monohydrate,
  • Racemic bis- (Z-aminoethyl) (cis-1,2-epoxypropyl)- phosphonate Racemic monobenzylammonium (cis-l,2-epoxypropyl)- phosphonate (24.5 g., 0.1 mole) is dissolved in 125 ml. of methanol and passed at 10 ml. per minute over 500 ml. of strongly acidic ion exchange resin of the polystyrene type on the hydrogen (H+) cycle at 0 C.
  • the eflluent is collected in 200 ml. of anhydrous pyridine.
  • the column is Washed with 350 ml. of cold methanol and the Washes combined with the pyridine solution.
  • Bis- (Z-nitroethyl) (cis-1,2-epoxypropyl phosphonate A solution of sodium nitrite (20.7 g., 0.3 mole) and sodium cobaltinitrite (80.8 g., 0.2 mole) in 155 ml. of water is prepared at room temperature and 200 ml. of benzene is added. To this solution is added solid (cis-l,2-epoxypropyl)-phosphonyl 0,0 bis 2 ethylammoninum (+)-tartrate (0.1 mole).
  • Disodium (cis-1,2-epoxypropyl)-phosphonate Sodium methoxide (10.8 g., 0.2 mole) is dissolved in 100 ml. of ethanol. To this solution is added a solution of bis-(Z-nitroethyl) (cis-1,2-epoxypropyl)-phosphonate (28.4 g., 0.1 mole) in 150 ml. of ethanol. The resulting mixture is stirred for 3 hours and the white product, disodium (cis-1,2-epoxypropyl)-phosphonate, is filtered oif, washed with 100 ml. of ethanol and vacuum-dried at C.
  • the remaining orange oil is crude, racemic di-(tertiarybutoxycarbonylmethyl) (cis 1,2-epoxypropyl)-phosphonate from which excess tertiary-butyl chloroacetate is removed under vacuum at 40 C. and l4 mm. pressure.
  • Di- )-u-phenethylammonium (cis-1,2-epoXypropyl)-phosphonyl-'0,0-diacetate (49.7 g., 0.1 mole) is placed in 400 ml. of 80% aqueous isopropanol with 1 g. of 10% palladium-on-carbon.
  • the slurry is placed under p.s.i.g. of hydrogen in a stirred autoclave and vigorously stirred until 0.2 mole of hydrogen is consumed.
  • the batch is removed from the autoclave, heated to nearly complete solution at 75 C. and filtered to remove the palladium catalyst.
  • This salt can then be converted to disodium or calcium salts by the procedures described in Example 2.
  • EXAMPLE 7 Di- )-a-phenethylammonium (cis-1,2-epoxypropyl -phosphonyl-O, O-diacetate
  • a solution of 36.7 g. (0.1 mole) of racemic di-tertiary butyl (cis-l,Z-epoxypropyl)phosphonyl0,0'-diacetate in 250 ml. of isopropanol is added 24.2 g. (0.2 mole) of ()-a-phenethylamine and one drop of sulfuric acid.
  • the resulting solution is refluxed for 4 hours, cooled to room temperature and the slurry lfiltered.
  • the filtered white product is washed with 200 ml.
  • EXAMPLE 8 Di-( )-a-phenethylammonium (cis-1,2-epoxypropyl)-phosphonyl-O, O-diacetate
  • the combined mother liquors obtained by the process described in Example 7 are concentrated in vacuo to 0 ml.
  • To this solution is added 600 ml. of isopropanol and the solution is reconcentrated in vacuo to about 150 ml.
  • the precipitated white solids are filtered off, washed with 100 ml. of isopropanol and dried under vacuum at 40 C. to afford di-(-)-a-phenethylammonium (cis-1,2-epoxypropyl)-phosphonyl-0,0'-diacetate.
  • This product is converted to the ()-ot-phenethylammonium salt and to the calcium or disodium salts by the procedures described in Examples 6 and 2 respectively.
  • N-methylrnorpholine hydrochloride is removed by filtration and the mother liquors are concentrated to 50 ml. Fifty ml. of isopropanol is added and the solids recrystallized from the hot mixture. The white product, N-benzoylN- )-ot-phenethyl (cisl ,2-epoxypropyl) -phosphorochloroamidate, is filtered, washed with benzene and dried in vacuo at room temperature.
  • the aqueous layer is adjusted to pH 8.8 with sodium hydroxide.
  • Calcium acctate monohydrate (17.6 g., 0.1 mole) in 100 ml. of water is added to the reaction.
  • the precipitated product, calcium (cis-1,2-epoxypropyl)-phosphonate monohydrate, is filtered, washed with water and dried in vacuo at 60 C.
  • N-benzoyl-N-H-)-a-phenethyl cis-1,2-epoxypropyl -phosphorochloroamidate
  • the mother liquors from the isolation of N-benzoyl- N-(+)-ot-phenethyl (cis 1,2 epoxypropyl)-phosphorochloroamidate described in Example 9 are concentrated to dryness and the viscous concentrate then recrystallized from 100 ml. of hot benzene.
  • the white product, N-benzoyl-N-(+)-a-phenethyl (cis-1,2-ep0xypropyl)-phosphorochloroamidate is .filtered, washed with benzene and air-dried.
  • N-methylmorpholine hydrochloride is filtered oif and the filtrate stirred overnight with finely-powdered potassium ethanethiolate (13.3 g., 0.13 mole).
  • the reaction mixture is extracted with five 200 ml. portions of distilled water and the organic layer concentrated in vacuo to 50 ml. Fifty ml. of isopropanol is added and the solids recrystallized from the hot mixture.
  • the white product, N-methyl-N-(+)-aphenethyl S-ethyl (cis-1,2-epoxypropyl)-thiophosphoroamidate is filtered, washed with benzene and dried in vacuo at room temperature.
  • This product (26.8 g., 0.1 mole) is dissolved in 400 ml. of benzene and stirred for 18 hours with 30% hydrogen peroxide (40.8 ml., 0.4 mole).
  • the reaction mixture containing N-methyl-N-( -a-phenethyl S-ethyl (cis 1,2-epoxypropyl)-thiophosphoroamidate N,S,S-trioxide is stirred for 36 hours with 250 ml. of water and suspended calcium oxide (5.6 g., 0.1 mole).
  • the resulting calcium (cis 1,2-epoxypropyl)-phosphonate monohydrate is filtered, washed with water and dried.
  • the disodium salt is prepared similarly to the calcium salt except that sodium hydroxide (8.0 g., 0.2 mole) is used. After stirring at 25 C. for 36 hours, the aqueous layer is separated, washed with benzene and evaporated to dryness in vacuo to give disodium (cis-1,2-epoxypropyl)-phosphonate.
  • Racemic bis-(2'thiohydroxyethyl) (cis-1,2-epoxypropyl -phosphonate) is dissolved in 125 ml. of methanol and passed at 10 ml. per minute over 175 ml. of a strongly acidic ion exchange resin of the polystyrene type (IR 120) on the hydrogen (H cycle at C.
  • the eflluent is collected in 200 ml. of anhydrous pyridine.
  • the column is washed with 350 ml. of cold methanol and the washes combined with the pyridine solution.
  • Racemic disodium (cis 1,2 epoxypropyl)-phosphonyl- 0,0'-bis-(2-ethylsulfonate) The racemic bis-(2-thiohydroxyethyl) (cis-1,2-epoxypropyl)-phosphonate (25.8 g., 0.1 mole) is added to a solution of hydrogen peroxide (20.2 g., 0.6 mole) and sodium bicarbonate (16.8 g., 0.2 mole) in 500 ml. of water. The mixture is stirred for 18 hours at 0-5 C.
  • reaction mixture is concentrated to 250 ml., giving a solution containing racemic disodium (cis-1,2-epoxypropyl -phosphonyl-0,0-bis- 2-ethylsulfonate) Bis-[(+)-a-phenethylammonium] and (cis- 1,2 epoxypropyl) phosphonyl 0,0'-bis-(2-ethyl sulfonate)
  • a solution of disodium (cis-1,2-epoxypropyl)-phosphonyl-0,0'-bis(2-ethylsulfonate) (0.1 mole) in 250 ml.
  • the precipitated calcium (cis-1,2- epoxypropyl) phosphonate monohydrate is filtered, washed with water, slurried for one hour in 500 ml. of methanol, filtered, and the cake washed with methanol and dried.
  • EXAMPLE 14 Mono-( )-a-phenethylammonium benzyl (cis-1,2- epoxypropyl -phosphonate Racemic disodium (cis-1,2-epoxypropyl)phosphonate, 18.2 g. (0.1 mole), is dissolved in 500 ml. of anhydrous methanol at +5 C. To this cold solution is added benzyl bromide, 17.1 g. (0.1 mole). The solution is stirred for 18 hours at +5 C. to give a solution containing racemic sodium benzyl (cis-1,2-epoxypropyl)-phosphonate. ccphenethylamine hydrochloride, 15.7 g.
  • the diastereomer, mono (+)-a-phenethylammonium benzyl (cis-1,Z-epoxypropyl)-phosphonate, is obtained by concentrating the mother liquors to a final weight of g., filtering the crystalline precipitate and washing it with 10 ml. of very cold isopropanol.
  • the palladium catalyst is removed by filtration and the resulting solution of mono- (+)-u-phenethylammonium (cis-1,2-epoxypropyl)- phosphonate is stirred for 2 hours with magnesium oxide, 8.0 g. (0.2 mole), at 0-5 C.
  • magnesium oxide 8.0 g. (0.2 mole)
  • the excess magnesium oxide is filtered off and the mother liquors concentrated in vacuo to a weight of g.
  • One hundred ml. of methanol is added followed by the dropwise addition of cold ethanol (800 ml.) over 30 minutes. The temperature is maintained at 05 C. throughout.
  • the batch is filtered and the cake washed with 200 ml. of ethanol.
  • the product is air-dried to constant weight at 25 C. to give 15.7 g. of magnesium (cis-1,2-epoxypropyl)-phosphonate dihydrate.
  • EXAMPLE 16 Methyl mono-(+)-a-phenethylammonium (cis- 1,2-epoxypropyl)-phosphonate Racemic monobenzylammonium (cis-1,2-epoxypropy1)- phosphonate (24.5 g., 0.1 mole) is dissolved in 250 ml. of water at 5 C. This solution is passed through ml. of a strongly acidic cation exchange resin of the polystyrene type on the acid cycle at the rate of 15-20 ml. per minute. The effluent and succeeding 350 ml. of wash are collected in a flask maintained at 0-2 C.
  • This cold aqueous solution containing racemic (cis-1,2-epoxypropyl)-phosphonic acid is stirred with diazomethane (approximately 9.24 g., 0.22 mole prepared from N-methyL N-nitrosourea by standard methods) in 300 ml. of ether for one hour at -5 C.
  • diazomethane approximately 9.24 g., 0.22 mole prepared from N-methyL N-nitrosourea by standard methods
  • racemic methyl sodium (cis-1,2-epoxypropyl)-phosphonate is added u- (+)-phenethylamine hydrochloride (15.7 g., 0.1 mole).
  • u- (+)-phenethylamine hydrochloride is added to the resulting solution of racemic methyl sodium (cis-1,2-epoxypropyl)-phosphonate.
  • u- (+)-phenethylamine hydrochloride (15.7 g., 0.1 mole).
  • the resulting solution is concentrated in vacuo to dryness to give crude racemic methyl mono-a-(+)-phenethylammonium (cis-1,2-epoxypropyl)-phosphonate.
  • This salt is dissolved in 125 ml.
  • EXAMPLE 17 (A) Racemic 0,0-ethylene (cis-1,2-epoxypropyl)-phosphonate and racemic mono [2-(N,N-dimethyl-a-(+)- phenethylarnmonium) ethyl] (cis 1,2 epoxypropyl)- phosphonate
  • benzene racemic (cis-1,2-epoxypropyl)- phosphonic dichloride 0.1 mole
  • the resulting mixture is stirred at 40 C. for 18 hours.
  • the precipitated pyridine hydrochloride is removed by filtration, and the filtrate containing raoemic 0,0-ethylene-(cis-1,2-epoxypropyl)-phosphonate is heated at reflux for 2 hours with N,N-dimethyl-a-(+)-phenethylamine (0.1 mole).
  • the precipitated racemic mono [2 (N,N- dimethyl-a-(+)- phenethylammonium)ethyl] (cis l,2-epoxypropyl)-phosphonate is filtered off and air-dried.
  • the dried salt (10 g.) is dissolved in 20 ml. of hot 85% aqueous isop ropanol, and the solution is then cooled to room temperature. The solids are then filtered off, washed with cold 85% isopropanol and air-dried to constant weight to yield mono [2-(N,N-dimethyl-a-(+)- phenethylammonium)ethyl] (cis-1,2-epoxypropyl)- phosphonate.
  • Racemic 2-aminoethyl (cis-1,2-epoxypropyl)- phosphonate Racemic monobenzylammonium (cis-1,2-epoxypropyl)- phosphonate, 24.5 g. (0.1 mole) is dissolved in 125ml. of methanol and passed at ml. per minute over 500ml. of strongly acidic cation exchange resin (IR 120) on the hydrogen (H+) cycle at 0 C. The eifiuent is collected in 200 ml. of anhydrous pyridine. The column is washed with 350 ml.
  • the first 1.5 liters of effluent is collected separately, frozen and freeze-dried at l00250 microns of pressure.
  • the residue is partially resolved Z-aminoethyl (cis-1,2-epoxypropyl)-phosphonate.
  • the second 1.5 liters of effluent is treated similarly to give partially resolved Z-aminoethyl (cis-1,2-epoxypropyl)-phosphonate.
  • Each partially resolved fraction is passed over the resin column again in an identical manner. Lyophilization of the first 1.5 liters of eflluent from re-passing partially resolved 2-aminoethyl (cis-1,2-epoxypropyl)- phosphonate through the column. atfords product of a high degree of optical purity. Similarly, the ester is purified by repassing the product through the column to obtain product of a high degree of optical purity.
  • the product has a rotation Racemic (cis 1,2-epoxypropyl)-phosphonate acid and salts thereof can be prepared by selectively hydrogenating l-propynylphosphonic acid to produce ciS-propenylphosphonic acid, and epoxidizing this acid to produce racemic (cis-1,2-epoxypropyl)-phosphonic acid or salts thereof.
  • these processes can be carried out as follows:
  • the sodium salt of l-propynylphosphonic acid (1.2 g., .01 mole) [obtained by passing an aqueous solution of the ammonium salt through an ion exchange resin on the sodium cycle and drying the resulting efiiuent in vacuo] is dissolved in 30ml. of water containing 1.67 ml. of piperidine, 83 mg. of zinc acetate and 0.3 g. of Raney nickel and the mixture hydrogenated at 40 p.s.i. One equivalent of hydrogen is adsorbed during 1%. hours.
  • the catalyst is filtered off, the filtrate passed through a column containing 10 g. of Dowex 50 on the acid cycle,
  • Hydrogen peroxide (0.5 cc.) is heated, and the heating continued for 1 /2 hours.
  • the reaction mixture is then cooled to room temperature, and the solvent removed by freezedrying.
  • the residue is dissolved in 50ml. of methanol, and the insoluble inorganic material filtered off. Upon concentration of the solution, crystalline ammonium salt of racemic (cis-1,2-epoxypropyl)-phosphonic acid is obtained.
  • ammonium salt so obtained can be converted to other salts in accordance with procedures known in this art.
  • the ammonium salt is converted to racemic (cis-1,2- epoxypropyl)-phosphonic dichloride as follows:
  • Racemic and levorotatory (cis-1,2-epoxypropyl)-phosphonic acid and salts thereof are useful antimicrobial agents, which are active in inhibiting the growth of both gram-positive and gram-negative pathogenic bacteria.
  • This antibiotic, and particularly its salts are active against Bacillus, Escherichia, Staphylococci, Salmonella and Proteus pathogens, and antibiotic-resistant strains thereof.
  • pathogens Bacillus subtilis, Escherichia coli, Salmonella schottmuelleri, Salmonella gallanarum, Salmonella pullorum, Proteus vulgaris, Proteus mirabilis, Proteus morganii, Staphylococcus aureus and Staphylococcus pyogenes.
  • (cis-1,2-epoxypropyl)-phosphonic acid and salts thereof can be used as antiseptic agents to remove susceptible organisms from pharmaceutical, dental and medical equipment and other areas subject to infection by such organisms.
  • they can be used to separate certain microorganisms from mixtures of microorganisms.
  • Salts of (cis-1,2-epoxypropyl)-phosphonic acid are also useful in the treatment of diseases caused by bacterial infections in man and animals and is particularly valuable in this respect, since they are active against resistant strains of pathogens. These salts are especially valuable, since they are effective when given orally, although they can also be administered parenterally.
  • the antibiotic and its salts are very active in inhibiting the growth of various species of Salmonella, it can be used as a disinfectant in washing eggs and areas subject to infection by Salmonella.
  • the salts of (cis-1,2-epoxypropyl)-phosphonic acid are also useful as bactericides in various industrial applications, for example, in inhibiting undesirable bacterial growth in the white water in paper mills and in paints such as polyvinyl acetate latex paint.
  • (cis-1,2-epoxypropyl)-phosph0nic acid or its salt When used for combatting bacteria in man or lower animals, they may be administered orally in a dosage unit form such as capsules or tablets, or in a liquid solution or suspension. Alternatively, the antibiotic can be administered parenterally by injection.
  • a dosage unit form such as capsules or tablets, or in a liquid solution or suspension.
  • the antibiotic can be administered parenterally by injection.
  • These formulations can be prepared using suitable diluents, extenders,
  • (cis-1,2-epoxypropyl)-phosphonic acid can be represented by the formula This substance is an acidic compound which is now believed to be more properly named as (cis-1,2- epoxypropyl)-phosphonic acid in accordance with present chemical nomenclature practice; the indicating, as does the letter I, that this phosphonic acid rotates planepolarized 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 mg.
  • the designation cis used in describing the 1,2- epoxypropylphosphonic acid compound means that the hydrogen atoms attached to carbon atoms 1 and 2 of the propylphosphonic acid are on the same side of the oxide ring.
  • the dextrorotatory enantiomer of (cis-1,2-epoxypropyl)-phosphonic acid can be converted to cis-propenylphosponic acid by heating with potassium thiocyanate in aqueous methanol.
  • the cis-propenylphosphonic acid thus obtained can be used as a starting material in the processes described herein to produce the levorotatory enantiomer of (cis-1,2-epoxypropyl)-phosphonic acid.
  • the (cis-1,2-epoxypropyl)-phosphonic acid can be converted to the antibacterially active enantiomer by splitting the epoxide ring of a salt of the compound by reaction with trifiuoroacetic acid to form the [l-hydroxy-2-(trifluoroacetoxy)propyl]phosphonate salt, reacting this compound with methanesulfonyl chloride in a mixture of methylene chloride and anhydrous pyridine to produce the [l-(methanesulfonyloxy)-2-(trifluoroacetoxy)propyl]phosphonate salt, and treating this product in methanol solution with sodium hydroxide to produce the (cis-1,2-epoxypropyl)- phosphonate salt.

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US729468A 1968-05-15 1968-05-15 Process for preparing a diastereomer of an optically active ester or amide of (cis-1,2-epoxypropyl)-phosphonic acid Expired - Lifetime US3595869A (en)

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AT300832B (de) 1972-08-10
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OA03052A (fr) 1970-12-15
GB1259798A (en) 1972-01-12
IE32801B1 (en) 1973-12-12
LU58639A1 (fi) 1970-01-13
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DE1924085A1 (de) 1970-01-15
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