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
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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 System
    • 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

Definitions

  • 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.

Abstract

A PROCESS FOR PREPARING A DIASTEREOMER OF AN OPTICALLYACTIVE ESTER OR AMIDE OF (CIS-1,2-EPOXYPROPYL) PHOSPHONIC ACID, WHICH COMPRISES SEPARATING ENANTIOMERS OR DIASTEREOMERS OF AN ESTER, AN AMIDE OR A SALT OF SAID ESTER OF AMIDE DERIVATIVE OF (CIS-1,2-EPOXYPROPYL)PHOSPHONIC ACID ENANTIOMERS. THE DERIVATIVES OF THE OPTICALLY-ACTIVE ISOMERS OF (CIS-1,2-EPOXYPROPYL) PHOSPHONIC ACID CAN THEN BE CONVERTED TO (CIS-1,2-EPOXYPROPYL)PHOSPHONIC ACID ENANTIOMERS OR A SALT THEREOF. (-) (CIS-1,2-EPOXYPROPYL) PHOSPHONIC ACID AND ITS SALTS ARE ACTIVE ANTIBIOTICS, WHICH ARE EFFECTIVE AGAINST VARIOUS GRAM-NEGATIVE AND GRAMPOSITIVE PATHOGENS.

Description

United States Patent Ofioe 3,595,869 Patented July 27, 1971 3,595,869 PROCESS FOR PREPARING A DIASTEREOMER OF AN OPTICALLY ACTIVE ESTER 01R AMIIDE OF (CIS-ll,Z-EPOXYPROPYL)-PHOSPHONIC ACID Richard F. Shuman, Westfield, N..li., assignor to Merck & (10., Inc, Rahway, NJ. No Drawing. Filed May 15, 1968, Ser. No. 729,468 Int. Cl. (307d N20 US. Cl. 260-297 3 Claims ABSTRACT OF THE DISCLOSURE BACKGROUND OF THE INVENTION It has been found that (cis-1,2-epoxypropyl)phosphonic acid is a valuable antibiotic which is active in inhibiting the growth of various Bacillus, Escherichia,
Staphylococci, Salmonella and Proteus pathogens and antibiotic resistant strains thereof. 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.
SUMMARY OF THE INVENTION It is an object of this invention to provide a process for separating enantiomeric mixtures of (cis-1,2-epoxypropyl)-phosphonic acid derivatives. Another object is to provide methods of separating enantiomeric mixtures of (cis-1,2-epoxypropyl)-phosphonic acids or amides. A further object is to provide diastereomers of (cis-1,2- epoxypropyl)-phosphonic acid esters and amides. Other objects will be apparent from the detailed description of this invention hereinafter provided.
In accordance with this invention, it is now found that 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.
In accordance with one embodiment of this invention, it is found that diastereomers of enantiomeric mixtures of (cis-1,2-epoxypropyl)-phosphonic acid derivatives of the general formula wherein X is oxygen or sulfur, Y is halo, OR, SR or NRR and Z is OR, SR or NR'R where R is a substituted or unsubstituted hydrocarbyl substituent containing an optically-active center, R is hydrogen or a hydrocarbyl group, and R is hydrogen, R, or a hydrocarbyl group, can be separated to obtain the individual diastereomers. 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. Thus, 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, pyridine, oxazole, imidazole, pyrimidine, indole, quinoline, isoquinoline and the like; heterocyclic alkyl; heterocyclic aryl and the like; and substituted derivatives thereof wherein the substituents can be hydroxy, halo, nitro, amino, carboxy, carbonyl, sulfo, sulfino, phosphino, phospho, phosphono and the like.
Examples of diastereomers which can be separated by the present invention that might be mentioned 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. Thus, in accordance with the processes of this invention, 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. The optically-active substituent or substituents of these compounds can be derived from an optically-active alcohol such as (|)-oc phenethyl alcohol, (IL-() phenethyl alcohol, L-2,Z-dimethyl-S-hydroxy-6- phenyl-1,3-dioxane, quinine, morphine, methyl lactate, Z-butanol, menthol, borneol, hydrocortisone, L-threo-l-phenyl-Z-acetamido 1,3 propanediol, santalol, citronellol, nerolidol, linalool, dimethyl hydroxysuccinate, dehydroabietyl alcohol, (2,5-octamethylene-1,8-dioxy)- benzyl alcohol, dimethyl 6,6-dihydroxydiphenate, 2,2-5,5'-tetramethyl-3,3'-bis-(hydroxymethyl) bipyrrole, N phenylsulfonyl-N-carboxymethyl2-methyl-4-hydroxy-l naphthylamine, 4-(B hydroxyethylidene)- methylcyclohexane, methyl 3-hydroxy-2-tropanecarboxylate, 3-hydroxy-p-phenylene-l-decanone, cinchonine, cinchonidine and the like. Thus, 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.
These 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. 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.
Alternatively and pursuant to a further embodiment of this invention, 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. Examples of such diastereomers having optically-active amides that might be mentioned are 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. Thus, such diastereomers can be separated to obtain each diastereomer, which can then be converted to produce or enantiomer of (cis-l,2-epoxypropyl)-phosphonic acid or salts thereof.
Pursuant to a further embodiment of this invention, other suitable derivatives of (cis-1,2-epoxypropyl)-phos phonic acid antipodes which can be separated are optically-active salts of compounds of the formula wherein X is the same as defined above, Y represents 0R SR or NR R and Z represents 0R SR or NR R where R is a hydrocarbyl group containing an acidic function capable of forming salts with bases, R represents hydrogen, R or any hydrocarbyl group and R repre sents hydrogen or hydrocarbyl. 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. O-p-sulfophenyl hydrogen (cis-1,2-epoxypropyl)-phosphonate, bis-(2-sulfoethyl) (cis-1,2-epoxypropyl)-phosphonate, benzyl 2,2-dicarboxyethyl (cis-1,2-epoxypropyl)-phosphonate, or their salts. Thus, 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.
Specific illustrations of 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, fl-chloro 2,4,6-trimethyl-5-bromo-cis-cinnamoyl hydrazide, 4-(fl-aminoethylidene)-methylcyclohexane, 2,2, 5,5-tetramethyl-3,3'-diaminobipyrrole, 3- amino-p-phenylene-l-decanone, 6,6'-dinitrodiphenic acid dihydrazide, 6,6 dimethyl-2,2'-biphenyldiamine, L-2,Z-dimethyl-5-amino-6-phenyl-1,3-dioxane, lacthydrazide, l-menthyl carbazate, l-menthyl hydrazine, strychnine, quinidine, morphine, coniine, coniine, cocaine, cinchonine and cinchonidine or other bases such as p-biphenylyl-ot-naphthylphenylphosphine, pbiphenylyla-naphthylphenylphosphine, 2-phenyl-2-p-hydroxyphenyl l,2,3,4 tetrahydroisophosphinolinium bromide, 2 phenyl-Z-p-hydroxyphenyl-1,2,3,4-tetrahydroisophinolinium bromide, P-spiro-bis-l,2,3,4-tetrahydrophosphinolinium iodide, P-spiro-bis-l,2,3,4-tetrahydrophosphinolinium iodide, methylethylphenylbenzylphosphonium iodide, methylethylphenylbenzylphosphonium iodide, methylethylphenylbenzylarsonium iodide, methylethylphenylbenzylarsonium iodide, rnethylethylphenylphosphine, methylethylphenylphosphine, methylethylphenylarsine, methylethylphenylarsine, phenyl-o-tolylp-tolylstibine, phenyl-o-tolyl-p-tolylstibine, methylethyl-phenacylsulfonium bromide, methylethylphenacylsulfonium bromide, methylphenylsulfoxide and methylphenylsulfoxide.
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. Alternatively, 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. They 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. In addition the alkene or alkyene must carry an acid group or a group convertible to an acid (anhydride, cyano or ester).
Additionally, 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.
In accordance with another method, metal salts of (cis- 1,2-epoxypropyl)-phosphonic acid (preferably silver, but
also 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.
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.
In accordance with another embodiment of this invention, other derivatives of (cis 1,2-epoxypropyl)-phosphonic acid antipodes which can be separated are optically-active salts of compounds of the formula wherein X is the same as defined above, Y" represents OR -SR or NR R Z" represents R SR or NR R where R, is a hydrocarbyl group containing a basic function capable of forming salts with opticallyactive acids, R is hydrogen, R or a hydrocarbyl group, and R is hydrogen or hydrocarbyl. The hydrocarbyl group can be any of the groups mentioned above. Thus, 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. Thus, 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.
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.
Alternatively, 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.
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.
Also, they can be obtained from (cis 1,2 epoxypropyl) phosphonic acid or salts thereof (alkali, alkaline earth and transition metals) via addition of the phosphonate anion through its oxygens to alkenes or alkynes wherein one of the carbons bearing the unsaturation is substituted with an electron-withdrawing or an electronnegative atom or group (cyano, nitro, carbonyl, sulfonyl, sulfinyl). In addition, the 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.
Additionally, metal salts of (cis 1,2 epoxypropyD- phosphonic acid (preferably silver, but also alkali, alkaline earth and other transition metals) 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.
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 following examples illustrate specific processes of this invention.
EXAMPLE 1 Monopyridinium mono-(-)-methyl (cis-1,2-
epoxypropyl)-phosphonate Racemic monobenzylammonium (cis-1,2-epoxypropyl)- phosphonate (24.5 g., 0.1 mole) .is dissolved in 125 ml. of methanol at 0 C. and the solution passed through 500 ml. of a strongly acidic polystyrene ion exchange resin (IR 120) on the acid (H+) cycle at a rate of 20 ml. per minute. The eflluent is dropped into 200 ml. of pyridine followed by 500 ml. of cold methanol wash. This solution is concentrated in vacuo to a volume of ml. To this concentrate is added 100 ml. of anhydrous pyridine followed by 200 m1. of anhydrous toluene in which are dissolved N,N-dicyclohexylcarbodiimide (20.6 g., 0.1 mole) and ()-methanol (15.6 g, 0.1 mole). The resulting solution is stirred at room temperature for 6 hours. The crystalized N,N'-dicyclohexylurea is filtered off, washed with 100 ml. of toluene, and the combined mother liquors are concentrated in vacuo to dryness at a maximum temperature of 40 C. Anhydrous toluene (300 ml.) is added and the solution is reconcentrated to dryness under vacuum at a maximum temperature of 40 C. One liter of petroleum ether is added dropwise to the vigorously-stirred oil over one hour. After stirring for an additional hour, the hygroscopic solids are filtered and transferred rapidly to a vacuum desiccator, where they are dried at 1 to 5 mm. to constant weight. The
monopyridinium mono-()-methyl (cis-1,2-epoxypropyl)-phosphonate melts at 145--175 C. with decomposition.
EXAMPLE 2 Bistrimethylammonium) cisl ,2-epoxypropyl phosphonate Disodium (cis-1,2-epoxypropyl)phosphonate Bis-(trimethylammonium) (cis-1,2-epoxypropyl)- phosphonate (equivalent to 51.2 g. of dried salt, 0.2 mole) is slurried in 250 ml. of methanol. To this slurry is added 21.6 g. of sodium methoxide dissolved in 250 ml. of methanol. The reaction is stirred for 2 hours at room temperature and then 500 ml. of isopropanol is added. The reaction mixture is concentrated in vacuo to 400 ml. and filtered. 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. To this solution is added 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,
(O=5%, 0.4 M ethylenediamine tetraacetic acid at pH 8.8)=l2.
EXAMPLE 3 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. The methanol is completely removed in vacuo and ethyleneimine (8.6 g., 0.2 mole) is added. The reaction mixture is stirred at 50 C. for 3 hours, cooled and the pyridine removed to near dryness in vacuo to give an orange oil. Toluene (200 ml.) is added and the solution re-evaporated in vacuo under nitrogen to dryness to remove the remaining pyridine from the oily product, racemic bis-(Z-aminoethyl) (cis-1,2-epoxypropyl)-phosphonate.
EXAMPLE 4 (cis-1,2-epoxypropyl) -phosphonyl-0,0-bis-2- ethylammonium )-tartrate Racemic monobenzylammonium (cis-l,2-epoxypropyl)- phosphonate (22.6 g., 0.1 mole) is added to 4:1 isopropanol-water (240 ml.) at 70 C. containing dissolved (+)-tartaric acid (15.0 g., 0.1 mole). The solution is cooled to 0 C. and the precipitated (cis-1,2-epoxypropyl)-phosphonyl 0,0'-bis-2-ethylammonium (+)-tartrate is filtered off and Washed with 60 ml. of cold 4:1 isopropanol-water. The filtered product is recrystallized from 100 ml. of 4:1 isopropanol-water, filtered, the cake washed with ml. of 4:1 isopropanol-water and then dried to give pure (cis-l,2-epoxypropyl)-phosphonyl 0,0-bis-2-ethylammonium -tartrate.
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). The mixture is stirred for 2 hours and the .benzen layer containing the product is separated, washed with water and evaporated to dryness in vacuo to give bis-(Z-nitroethyl) (cis- 1,Z-epoxypropyl)-phosphonate in the form of an oil.
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.
EXAMPLE 5 Racemic di- (tertiary-butyl) (cis-1,2-epoxypropyl)-phosphonyl-0,0'-diacetate v Racemic disodium (cis-1,2-epoxypropyl)-phosphonate (18.2. g., 0.1 mole) is added to a mixture of tertiary-butyl chloroacetate (37.6 g., 0.025 mole) and finely-powered sodium carbonate (2 g.) in 100 ml. of dry benzene. The mixture is refluxed with stirring for 5 hours and then filtered to remove sodium chloride and sodium carbonate. The filtrate is evaporated in vacuo to remove the benzene. 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.
EXAMPLE 6 Di- -a-phenethylammonium (cis-1,2-epoxypropyl -phosphonyl-0,0-diacetate Racemic di-tertiary-butyl (cis 1,2-epoXypropyl)-phosphonyl-0,0'-diacetate (36.7 g., 0.1 mole) is dissolved in 250 ml. of isopropanol. To this solution is added (+)-aphenethylamine (24.2 g., 0.2 mole) and one drop of sulfuric acid. The resulting solution is refluxed for 4 hours, cooled to room temperature and the slurry filtered. The white product is washed with 200 ml. of isopropanol. The wet cake is crystallized from 300 ml. of hot aqueous isopropanol, the resulting mixture cooled to 0 C., filtered, washed with 100 ml. of cold aqueous isopropanol and dried in vacuo at 40 C. to obtain di(+)-a-phenethylammonium (cis-1,2-epoxypropyl)-phosphonyl- 0,0-diacetate.
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. The mother liquors are cooled to 0 C., filtered, and the white precipitated product, mono- -a-phenethylammonium (cis-l,2-epoxypropyl)- 9 phosphonate, dried in vacuo at 40 C., M.P. 135-137" C. dec
(C=5.0%, H O)=2.6. I
This salt can then be converted to disodium or calcium salts by the procedures described in Example 2.
Di- )-a-phenethylamn1onium (cis-1,2-epoxypropy1) -phosphonyl-0,0'-diacetate The combined filtrates obtained as described above are concentrated in vacuo to 150 ml. Isopropanol (600 ml.) is added and the solution reconcentrated in vacuo to 150 ml. The precipitated white solids are filtered, washed with 100 ml. of isopropanol and dried under vacuum at 40 C. to give di-(+)-a-phenethylammonium (cis-1,2-epoxypropyl -phosphonyl-0,0'-diacetate.
EXAMPLE 7 Di- )-a-phenethylammonium (cis-1,2-epoxypropyl -phosphonyl-O, O-diacetate To 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. of isopropanol. The washed filter cake is added to 300 ml. of hot 70% aqueous isopropanol and the resulting solution is cooled to C. to precipitate di-()- x-phenethylammonium (cis 1,2-epoxypropyl)-phosphonyl-O;O-diacetate. The product is removed by filtration, washed with 100 ml. of cold 80% aqueous isopropanol and dried in vacuo at 40 C.
The (ii-()-ot-phenethylammonium (cis-1,2-epoxypropyl)-phosphonyl-0,0-diacetate so obtained is converted to the mono-()-ot-phenethylammonium (cis- 1,2-epoxypropyl)-phosphonate monohydrate or to the calcium or disodium salts in accordance with the procedures described in Examples 6 and 2 respectively.
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.
EXAMPLE 9 N-benzoyl-N-(+)-a-phenethyl (cis 1,2-epoxypropyl)-phosphorochloroamidate In 400 ml. of benzene, racemic (cis-1,2-epoxypropyl) phosphonic acid dichloride (0.1 mole) is treated with N- methylmorpholine (20.2 g., 0.2 mole) and (+)-euphemethylarnine (12.1 g., 0.1 mole). The mixture is stirred at C. for 2 hours and then benzoyl chloride (14.1 g., 0.1 mole) is added and the mixture stirred an additional 2 hours. 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.
10 Calcium (cis-1,2-epoxypropyl)-phosphonate monohydrate N-benzoyl-N-(+)-u-phencthyl (cis-1,2-epoxypropyl)-phosphorochloroamidate (36.4 g., 0.1 mole) is placed in a solution of 50 ml. of Water, 50 ml. of acetic acid and 50 ml. of pyridine and the mixture heated at 60 C. for one hour. An additional 400 ml. of pyridine is added and the solution evaporated to ml. in vacuo. Water (300 ml.) is added and the mixture extracted with 3X ml. of methylene chloride. 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.
EXAMPLE .10
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.
Following the procedure of Example 9, this product is converted to the calcium salt of (cis-.l,2-epoxypropyl)-phosphonate monohydrate.
EXAMPLE 11 N,N'-bis-[(+)-ot-phenethyl] (cis-l,2-epoxypropyl)- phosphorodiamidate In 400 ml. of benzene, racemic (cis-1,2-epoxypropyl)- phosphonic acid dichloride (0.1 mole) is treated with N-methylmorpholine (20.2 g., 0.2 mole) and (+)-ocphenethylamine (24.2 g., 0.2 mole). The mixture is stirred at 60 C. for 5 hours. N-methylmorpholine hydrochloride is filtered off from the hot mixture. The warm benzene is removed in vacuo. The solid concentrate is dissolved in 200 ml. of hot methanol, the solution cooled to 0 C., and the white product, N,N-bis-[(+)-o-phenethyl] (cis-1,2-epoxypropyl)- phosphorodiamidate, is filtered, washed with methanol and dried at 40 C. in
vacuo.
Calcium salt of (cis-1,2-epoxypropyl)-phosphonic acid N,N-bis-[(+)-ot-phenethyl] (cis 1,2 epoxypropyl)-phosphorodiamidate (33.9 g., 0.1 mole) is stirred with .200 ml. of pyridine and acetic anhydride (22.4 g., 0.22 mole) is added. The mixture is stirred for 20 minutes at 25 C. with cooling in an ice bath. Water (50 ml.) and acetic acid (50 ml.) are added and the mixture heated at 60 C. for one hour to hydrolyze the intermediate N,N- diacetylN,N-bis-[(+)-u-phenethyl] (cis 1,2- epoxypropyl)-phosphorodiamidate. An additional 400 ml. of pyridine is added and the solution evaporated to 100 ml. in vacuo. Water (300 ml.) is added and the mixture extracted with three 125 ml. portions of methylene ch10 ride. The aqueous layer is adjusted to pH 8.8 with sodium hydroxide. Calcium acetate monohydrate (17.6 g., 0.1 mole) in 100 ml. of water is added to the reaction. The precipitated product, calcium (cis-l,2-epoxypropyl)- phosphonate monohydrate, is filtered, washed with water and dried in vacuo at 60 C.
EXAMPLE 12 N-methyl-N-(+)-u-phenethyl S-ethyl (cis 1,2- epoxypropyl -thiophosphoroamidate In 400 ml. of benzene, racemic (cis-l,2-epoxypropyl)- phosphonic acid dichloride (0.1 mole) is treated with 1 1 N-methylmorpholine (10.1 g., 0.1 mole) and N-methyl- (+)-a-phenethylamine (13.6 g., 0.1 mole). The mixture is stirred at 25 C. for 2 hours. The 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.
EXAMPLE 13 Racemic bis-(2'thiohydroxyethyl) (cis-1,2-epoxypropyl -phosphonate Racemic monobenzylammonium (cis 1,2 epoxypropyl)-phosphonate (24.5 g., 0.1 mole) 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. The methanol is completely removed in vacuo and ethylene episulfide (12.0 g., 0.1 mole) is added. The reaction mixture is stirred in a nitrogen atmosphere at 25 C. for 18 hours and the pyridine removed to near dryness in vacuo to give an orange oil. Toluene (200 ml.) is added and the solution re-evaporated to dryness in vacuo under nitrogen to remove the remaining pyridine from the oily product, racemic bis-(Z-thiohydroxyethyl) (cis-1,2- epoxypropyl -phosphonate.
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. The 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. of aqueous solution is treated with (l- )-a-phenethylamine hydrochloride (31.5 g., 0.2 mole). The resulting slurry is heated to 80 C. and filtered hot to give bis-[(+)-mphenethylammonium] and (cis 1,2 epoxypropyl -phosphonyl-0,0'-bis- 2-ethylsulfonate) Cooling the hot, aqueous filtrate to 0 C. and filtering gives bis-[(+)-a-phenethylammoniurn] (cis-1,2- epoxypropyl) -phosphonyl-0,0'-bis- 2-ethy1sulfonate) Calcium (cis-1,2-epoxypropyl)-phosphonate monohydrate Bis a. phenethylammonium] (cis-1,2- epoxypropyl) phosphonyl 0,0-bis-(Z-ethylsulfonate) (59.7 g., 0.1 mole) is placed in one liter of water with calcium oxide (10.9 g., 0.195 mole) and stirred for 72 hours at C. 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. (0.1 mole), is added and the methanol completely removed in vacuo at less than C. in a nitrogen atmosphere to give racemic mono-( )-u-phenethylammonium benzyl (cis-1,2-epoxypropyl)-phosphonate mixed with sodium chloride and sodium bromide. Isopropanol (125 ml.) is added, the mixture heated to reflux and then filtered while hot. The filtrate is cooled to 25 C. and the product filtered, washed with isopropanol and air-dried at 25 C. to give mono- (+)-a-phenethylammonium benzyl (cis-1,2-epoxypropy1)-phosphonate having a high degree of optical purity.
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.
EXAMPLE 15 Magnesium (cis-1,2-epoxypropyl)-phosphonate dihydrate 'Mono u-phenethylammonium benzyl (cis-1,2- epoxypropyl)-phosphonate, 34.7 g. (0.1 mole) is dissolved in 600 ml. of water and 3 g. of powdered 10% palladiumon-charcoal is added. With shaking, the mixture is held under p.s.i.g. of hydrogen until uptake is complete and the pressure ceases dropping. 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. 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. The ether layer is removed and sodium hydroxide (4.0 g., 0.1 mole) is added to the aqueous solution of racemic dimethyl (cis-1,2-epoxypropyl)- phosphonate which is stirred for 12 hours at room temperature. To the resulting solution of racemic methyl sodium (cis-1,2-epoxypropyl)-phosphonate is added 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. of hot isopropanol, the solution cooled and the product filtered, washed with cold isopropanol and air-dried to give methyl momma-(+)- phenethylammonium (cis 1,2 epoxypropyl)-phosphonate having a high degree of optical purity.
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 In 400 ml. of benzene racemic (cis-1,2-epoxypropyl)- phosphonic dichloride (0.1 mole) is treated with 15.8 g. of pyridine and 6.82 g. of ethylene glycol. 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.
The combined filtrate and washings are evaporated to dryness in vacuo. The residue is crystallized from 75 parts of hot isopropanol to give mono [2-(N,N-diInCthy1-OL' phenethylammonium)ethyl (cis 1,2-epoxypropyl)-phosphonate.
(B) Disodium (cis-1,2-epoxypropyl)-phosphonate Solid mono [2- (N,N-dimethyl-u-(+)-phenethylammonium)ethyl] (cis 1,2 epoxypropyl) phosphonate (33.3 g.) is added to a solution of 5.4 g. of sodium methoxide in 83.2 ml. of methanol and the resulting mixture stirred until all of the solids dissolved. To the resulting solution is added a solution of 5.4 g. of sodium methoxide in 83.2 ml. of methanol, and then 83.2 ml. of absolute ethanol. After stirring for 2 hours at room temperature, the precipitated disodium salt of (cis-1,2-epoxypropyl)-phosphonic acid is removed by filtration, washed with cold methanol to remove the dimethylvinyl-2-(+)- phenylammonium methoxide, and dried to constant weight at 50 C. in vacuo. The product so obtained has a rotation 133 h w-14 o H2O) EXAMPLE 1:;
(A) 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. of cold methanol and the washes combined (200 ml.) is added and the solution re-evaporated in 4 vacuo under nitrogen to remove all traces of solvents from the crystalline product, racemic Z-aminoethyl (cis- 1,2-epoxypropyl -phosphonate.
(B) and 2-aminoethyl (cis-1,2-epoxypropyl)- phosphonate A solution of racemic 2-aminoethyl (cis-1,2-epoxypropyl)-phosphonate, 9.05 g. (0.05 mole), in 100 m1. of cold water is passed onto a jacketed glass column with an inside diameter of two inches and containing 800 ml. of 100-300 mesh sulfonated polystyrene resin which contains phenylalamine at its isoelectric point of pH 5.5 linked via sulfonamide bridges. The column is then washed at the rate of 30 ml. per minute with 3 liters of water. 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.
(C) Sodium Z-nitroethyl (cis-l,2-epoxypropyl)- phosphonate A solution of 10.35 g. of sodium nitrite and 40.4 g. of sodium cobaltinitrite in ml. of water is prepared at room temperature and 200ml. of benzene is added followed by 0.1 mole of 2-aminoethyl (cis-1,2-epoxypropyl)-phosph0nate. The mixture is stirred for 2 hours and the benzene layer is separated. The aqueous layer is extracted with four ml. portions of benzene. The combined benzene extracts are dried over sodium sulfate and evaporated to dryness to obtain sodium 2-nitroethyl (cis-1,2-epoxypropyl)-phosphonate.
(D) Disodium (cis-1,2-epoxypropyl)-phosphonate Sodium methoxide (5.4 g.) is dissolved in 100 m1. of ethanol. To this solution is added a solution of sodium 2- nitroethyl (cis-1,2-epoxypropyl) -phosphonate (0.1 mole) in ml. of ethanol. The resulting mixture is stirred for 3 hours and the white product, disodium (cis-1,2-epoxypropyl)phosphonate, is filtered oil, washed with ethanol (100 ml.) and vacuum-dried at 60 C. 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. Thus, 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,
and the column eluted with water. The combined eluates are neutralized to a pH of about 5.5 with sodium hydroxide solution, and after removal of the water in vacuo, the monosodium salt of cis-propenylphosphonic acid is obtained as an amophous residue. The product is characterized by infrared and NMR spectra. 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 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.
The 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:
To a mixture of 1.38 g. (0.01 mole) of ammonium salt of racemic (cis-1,2-epoxypropyl)-phosphonic acid, ml. of benzene and 1.6 ml. of pyridine at 0 C. there is added, over ten minutes with stirring, 3.0 g. (0.025 mole) of thionyl chloride. After stirring at room temperature for three hours, the solution is decanted from the gummy o precipitate and then concentrated in vacuo at room temperature. The residue is flask distilled. Racemic (cis-1,2- epoxypropyl)-phosphonic dichloride distills at 0.5 mm./ 3233 C.; N =1.5055.
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. Illustrative of such pathogens are Bacillus subtilis, Escherichia coli, Salmonella schottmuelleri, Salmonella gallanarum, Salmonella pullorum, Proteus vulgaris, Proteus mirabilis, Proteus morganii, Staphylococcus aureus and Staphylococcus pyogenes. Thus, (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. Similarly, 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.
Since 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.
When (cis-1,2-epoxypropyl)-phosph0nic acid or its salt are 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. These formulations can be prepared using suitable diluents, extenders,
15 granulating agents, preservatives, binders, flavoring agents, and coating agents known to those skilled in this art. (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 structural formula of this antibiotic substance has been shown in the planar formula for the sake of convenience. However, the antibiotic can also be depicted spatially as follows:
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.
If desired, 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.
What is claimed is:
1. The process which comprises reacting racemic (cis- 1,2-epoxypropyl)phosphonic acid with one mole of menthol in the presence of pyridine and N',N'-dicyclohexyldiimide, and separating the monopyridinium monomenthyl() (cis 1,2 epoxypropyl)phosphonate formed by crystallization from petroleum ether.
2. The process which comprises reacting racemic (cisl,2-epoxypropyl)phosphonic acid with ethyleneimine in the presence of pyridine, recovering racemic bis-(2-aminoethyl) (cis-1,2-epoxypropy1)phosphonate by evaporation of the reaction mixture, reacting this product with a molar equivalent of tartaric acid in aqueous isopropanol, cooling the resulting solution to about 0 C., and separating the precipitated (cis-l,2-epoxypropyl)- phosphonyl-O,0-bis 2-ethylamm0nium tartrate from said solution.
3. The process which comprises reacting racemic sodium (cis-1,2-epoxypropyl)phosphonate with tertiarybutyl chloroacetate in benzene in the presence of sodium carbonate, recovering racemic di-(tertiary-butoxycarbon- References Cited yl)(cis-1,Z-epoxypropyl)phosphonate from the resulting reaction mixture, heating this product with two molar equivalents of (+)-a-phenethylamine in isopropanol, re-
covering the precipitated product from the cooled solu- 5 NORMA MILESTONE Primary Examiner tion, dissolving said product in 70% aqueous isopropanol,
cooling said solution to about 0 C., and recovering the US. Cl. X.R. precipitated di-(+)-a-phenethy1ammonium (-)(C S-1,2- 260-448, 999
epoxypropy] -phosphonyl-0,0'-diacetate.
Gilman, H., Organic Chemistry, vol. I (1948) pp.
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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