DE1805678C - (plus minus) (ice 1,2 epoxypropyl) phosphonic acid compounds and antibacterial agents containing such compounds - Google Patents

Description

in which R and R _{1 are} hydrogen atoms or phenyl, O

C ₁ -C ₄ -alkyl or C ₂ -C 4 -alkenyl radicals be f

interpret, as well as the corresponding salts. "^ /

2. (dzXcis-l ^ -EpoxypropyO-phosphonic acid. 15 ³ \ ς / _

3. Pharmaceutically usable alkali salts, earth / \
alkali salts and amine salts of the compound according to H ^
Claim 2.

4. Antibacterial agent, characterized if R and / or R ₁ in the general formula net that it is the active ingredient (± H ^c 'sl »2-epoxypropyl> ao a C ₁ -C ₄ -AJkylrest, so this can for example phosphonic acid or a pharmaceutically usable methyl, propyl, isopropyl or tert-butyl radical thereof in a mixture with a pharmaceutical, if R and / or R _{1 is} a C _{2 -C 3} -alkenyl radical Contains chemical carrier, this can be, for example, allyl, vinyl or

Be propenyl radical.
»5 The free acid according to the invention and the monoesters

form salts which are more stable than the free acid;

the esters (except in special cases) are not as active as the salts. Examples of such salts

Many antibiotics are known; but these are metal salts, such as salts of sodium, aluminum,

generally only against a limited number of 30 potassium, calcium, magnesium, silver and iron,

Effective against pathogens, and certain strains also ammonium. Organic salts are e.g. B. Salts

these pathogens develop resistance from primary, secondary or tertiary amines, such as

against a certain antibiotic, so that this of monoalkylamines, dialkylamines, trialkylamines

Antibiotic is then no longer used to combat these nitrogen-containing heterocyclic amines.

resistant strains can be used. 35 Representative examples are salts of -x-phenethyl-

In the older, not state-of-the-art, tough amine, diethylamine, diethylenetriamine, quinine, brucine,

lenden Auslegeschrift 1768 965 are (-) - (cis-l, 2- lysine, protamine, argynine, procaine, ethanolamine,

Epoxypropyl) phosphonic acid, its salts and these morphine, benzylamine, ethylenediamine, N.N'-dibenzyl-

Antibiotic agents containing compounds ethylenediamine, diethanolamine, piperazine, N-amino

wrote that the growth of gram-positive and 4 ° äthylpiperazin.Dimethylaminoäthanol ^ -Amino ^ -me-

-inhibit negative microorganisms and oppose ethylpropanol-1, theophylline, esters of amino acids

some microorganisms are more effective than tetra- and N-methylglucamine. If the cation is monovalent

cyclin and chloramphenicol. can be both monobasic and dibasic

The invention relates to (±) - (cis-1,2-epoxy salts)

propyl) phosphonic acid compounds the general 45 basic residue of the salt is a biologically active amine,

Formula wiv; Erythromycin, oleandomycin or novobiocin,

H H be.

I I O is an example of compounds according to the invention

ρ / _ _nR bis-guanidine- (±) - (cis-1,2-epoxypropyl) -phosphonate,

^r \ ^UK 2 i 4 ° C

³ \ / ^r \ ^UK 50 F. 226 to 245 ° C.

OO ^R i ^Die (±) - (cis-l, 2-epoxypropyl) -phosphonic acid and

their salts can be used as antiseptic agents for pharmaceutical

in which R and R ₁ denote hydrogen atoms or phenyl, chemical, dental and medical aus-C ₁ -C ₄ -alkyl or C ₂ -C ₃ -alkenyl radicals, articles of armor or in technical paint, as well as the corresponding salts and also anti- 55 colors, e.g. B. in polyvinyl acetate latex paints, bacterial agents are used, which are used as active ingredient (±) -cis-epoxy-. They can also be used to separate propylphosphonic acid or a pharmaceutically certain microorganisms from mixtures with other reversible salts thereof in a mixture with a pharmaceutical microorganism. Contain the salts of the (±) - (ciszeutischen carriers. The 1,2-epoxypropyl) -phosphonic acid according to the invention are also available as Kon compounds are (rb) -Racemates. You can easily 60 serving agents for technical purposes through the usual racemate separation into the antibiotic usable, z. B. by the growth of undesirable (-) - (cis-l, 2-epoxypropyl) -phosphonic acid ter bacteria in the white water of paper mills and their salts are transferred, suppressing their superior.

antibiotic effectiveness in the published publication Wenn (±) - (cis-l, 2-epoxypropyl) -phosphonic acid

1,768,965 is shown. The (±) - (cis-l, 2-epoxypropyl) - 65 or their salts for combating bacteria

phosphonic acid and its salts are also used in anti-humans or lower animals themselves

bacterially effective due to their content of which they can be taken orally, e.g. B. in capsules or tablets, or

(-) - enantiomers. in liquid solution or suspension using

common diluents are given. The encryption can be at temperatures between about 0 and 90 ⁰ C, bonds moderately also be administered parenterally by injection, preferably between about room temperature and administered, usually as salts. 80 ° C, and pH values between about 3.0 and 11.0,

The (±) - (cis-1,2-epoxypropyl) according to the invention - preferably between about 4.0 and 6.0, carried out phosphonic acid compounds of the general formula 5 At pH values below about 4.0, the reaction should be below can be carried out by epoxidation of a cis-propenylphos- about 15 ° C to the decomposition Phonic acid compound of the general formula of the desired Epoxypropylphosphonsäureverbin-

suppression if possible. At higher

HH ^ r ^υ pH values (above 8.0) the peroxide decomposes into

H3C - C = C - P ^ - OR 10 considerable extent and must during the

\ Q £ settlement to be supplemented by fresh.

¹ For best results, use

at least 1 mol, preferably at least 3 mol, are prepared with a chemical oxidizing agent, where R and R _{1 have} the above meanings. Peroxide per mole of the cis-propenylphosphonic acid is best at least one of the radicals R and R ₁ 15 compound.

not hydrogen. An oxidizing agent can be preferably used as a solvent

Peroxy compound, such as hydrogen peroxide, one that is compatible with water and / or with hydrogen peroxide organic or organic peracid, an organic alcohol such as lower alkanols. If necessary, can Use hydroperoxide or a peroxyimidate. the epoxidation in the presence of complexing

When using hydrogen peroxide takes 20 remedies to be carried out.

the reaction is preferably carried out in the presence of an excess after the end of the epoxidation

suitable inorganic peracid. The hydrogen peroxide is decomposed. (I) - (cis-l, 2-like inorganic acid to the reaction epoxypropyl) -phosphonsäureverbindung can by mixture and generate the peracid in the reaction separation of the inorganic compounds mixture itself by reaction with hydrogen 25 and subsequent recrystallization or Evaporation peroxide. The peracids are particularly suitable to be obtained from the reaction mixture to dryness. Tungsten, vanadium and molybdenum, either as used for the oxidation of the cis-propenyl

simple acids or as polyacids, including the phosphonic acid compound, an organic peracid. Heteropoly acids. The inorganic acids are such as peracetic acid, perbenzoic acid, a substituted one, generally in the form of neutral salts, perbenzoic acid, monoperphthalic acid, perform iron, such as alkali salts, e.g. B. as sodium or acid or peroxytrifluoroacetic acid, so one works potassium tungstate, ammonium wolf ramate, alkaline earth salts preferably at temperatures between about -10, such as calcium or barium ^{wolf ramate or and + 150 0} C. If necessary, you can use peroxy vanadate, heavy metal salts Use zinc anhydrides, such as zinc vanadate, as peroxyacid generators. This tungstate, tin tungstate, tin molybdate, aluminum peroxidation is preferably carried out in inert carbon tungstate or aluminum molybdate. One can also use hydrogen or halogenated hydrocarbons as an optically active compound, such as a salt, a solvent. The complex compound, an ester or a mixed reaction mixture is preferably buffered when using peracids anhydride, the hexavalent tungsten cation, which decompose when converted to strong tungstic acid or similar cations or acids, such as peroxytrifluoroacetic acid. of other transition metals, such as molybdenum or the cis-propenylphosphonic acid compounds,

Vanadium, use as a catalyst. Furthermore, complex compounds of such cations hydroperoxide can also be epoxidized by reaction with an organic one in a suitable solvent with polyamino compounds of the ethylene type. For this you can use any organic diamine, 1,3-diaminopropane or diethylene hydroperoxide, such as tert-butyl hydroperoxide, triamine either in a cumene hydroperoxide with a stirrer and amyl hydroperoxide. Use this reaction vessel or in bulk. The reaction is advantageous in an inert carbon. If catalysts of this type are used, hydrogen or halogenated hydrocarbons, the (cis-1,2-epoxypropyl) -phosphonate is kept as about -10 and + 10O ⁰ C, preferably between enantiomeric mixture, in which one of the two 50, 60 and 90 ° C. Enantiomers used as catalyst predominate. one preferably uses an oxide of a metal from the group

In addition to the simple peracids, heteropolymers Vb or VIb of the perion system, e.g. B. an oxide acids are used, such as the heteropoly tungsten of molybdenum, tungsten or vanadium, or a acids of arsenic, antimony and bismuth. Likewise, complex compound or a ligand of this memane Heteropolymolybdic acids and heteropoly- 55, such as molybdenum hexacarbonyl, in amounts of Chromic acids of sulfur, selenium or tellurium are about 0.01 to 5 percent by weight, based on the turn. You can also use more than two different propenyl compounds. One can also form an alkali heteroacid Use Group VI elements of the hydroxide or an organic base as a catalyst periodic table, e.g. B. use thiotellur tungsten.

acid and selenium molybdenum tungstic acid. Other other 60 Furthermore, the compounds according to the invention can be inorganic Catalysts are alkali carbonates that are made by making the cis propenyl carbonates and phosphates, such as sodium carbonate, phosphonic acid compound with hydrogen peroxide and Potassium bicarbonate, sodium phosphate and disodium- a nitrile that is treated as a peroxyimidic acid generator phosphate. serves. Suitable nitriles of this type are acetonitrile,

The catalyst is in amounts of at least 63 propionitrile and benzonitrile. You work with about min 0.1 to 30, preferably 0.25 to 5 percent by weight of at least 1 mole of peroxide and nitrile per mole of the olefin percent, based on the cis-propenylphosphonic acid compound. The implementation is generally in compound, applied. The reaction is expediently containing an aqueous or a lower alkanol

Solvent at pH values of about 7 to 9 suitably at room temperature with a low

guided. After the reaction has ended, an excess of epoxidation agent is carried out

schüssiges decomposed hydrogen peroxide, and however, the process durchgeführ at temperatures up to about 80 ⁰ C

product of the resulting organic amide. If a solvent is used, sol

separates It is advisable that the nitrile and the 5 cis-propenylphosphonate solution be soluble therein,

medium to be selected in such a way that the amide formed is

Reaction mixture insoluble, but the epoxide in it (±) - (cis-l, 2-epoxypropyl) -phosphonate directly!

Reaction of salts or esters of cis-propenyl is soluble

Another method for the preparation of the inventive phosphonic acid with one of the above-described

according to (±) - ( ^c ' ^s -l> 2-epoxypropyl) -phosphonic acid io oxidizing agent, preferably with a peroxy

compounds is the implementation of the cis-propenyl compound, established. This takes place at the same time

Phosphonic acid compounds with oxygen (or air) the oxidation of the phosphorus atom from the trivalent

in the presence of a suitable catalyst and one to the pentavalent state and the epoxidation dei

alkaline buffer. Examples of suitable catalysis-olefinic double bonds.

gates are alkali tungstates and vanadates, which 15 The esters of (iHcis-l ^ -EpoxypropyQ-phosphon-

Naphthenates of cobalt, iron, manganese and vanic acid can be introduced into the

dium and tert-butyl hydroperoxide, expediently in the case of free acid or in the mono- or di-salts

75 to 125 ° C. One preferably uses an inert one, e.g. B. by hydrolysis or by reducing

liquid solvent, e.g. B. a lower dialkylamide, splitting off of the ester group. The hydrolysis can be done with

such as dimethylformamide or Öimethylacetamid, or 20 a base or acid, enzymatically, by Lichi

a lower alkyl benzoate, such as benzoin catalyzed or by way of a trimethyl

ethyl acid ester. The reaction time is normal silyl derivative. The reducing

wise 15 to 25 hours. The ester group can be split off by hydrugen

Another method for oxidizing cis-prolysis or by chemical means, e.g. B. with sodium penylphosphonate compound is the reaction with 25 and a tertiary amine, take place. In each case of an oxidizing metal oxide or metal salt, the preferred method depends on the particular chromium trioxide or an alkali permanganate in an ester. The epoxidation process can also be based on alkaline solvents such as pyridine, Λ-picoline, the production of (±) - (cis-l, 2-epoxypropyl) -phos-piperidine or dimethylformamide. One can phonsäure at 0 or salts thereof work directly from one to 100 ⁰ C. You can also use an alkali hypo- cis-propenylphosphonic acid ester, halogenite, such as sodium and potassium hypochlorite or which can be easily oxidized, such as 3-crotyl-, hypobromite, as an oxidizing agent, expediently p-benzoquinonyl or p- Naphthoquinonyl ester. These moderately in an aqueous medium or an organic ester are epoxidized with a large excess of Oxydaschen base, such as pyridine or dimethylformamide, at control agents. The reaction product is 0 to 100 ⁰ C and a pH value above about 8.0. The cation contained in the reaction mixture can optionally be used with an epoxidation agent-speaking salt of (iHcis-l ^ -EpoxypropyO-phos, from which a phonic acid is formed in the reaction mixture.

Forms hypochlorite, such as. B. S ^ -Dimethyl-M-dichlorocis-propenylphosphonic acid is produced as follows: hydantoin. The product is then z. B. by ad- phosphorus trichloride is counter-sorption with tert-butanol the cations on a cation exchange * o was reacted by triethylamine and the obtained resin in the hydrogen ion form and recovering the di-tert-butyl chlorophosphite further with propargyl alcohol (±) - (cis-1,2-epoxypropyl) phosphonate compound from hol. From the phosphorous acid di-tert.-budem obtained Eluate obtained. tyl-mono-propynyl-ester is formed on heating

Furthermore, the epoxidation can be carried out by reaction under reflux of di-tert-propadienylphosphonic acid cis-propenylphosphonate in a suitable 45 tylester, from which the corresponding cis-donor olefin is obtained by hydrogenation with a water-inert solvent with ozone in the presence of a substance over palladium-carbon or a compound obtained propenyl ester. From this one splits to become pyrolytic, the one with ozone an equimolecular system table in the presence of p-toluenesulfonic acid isobutene tion compound forms, which is released with release. Salts of cis-propenylphosphonic acid are made by decomposed by oxygen in a very active form. 50 Conversion of the free acid in ethanol with bases This process is made in the cold at temperatures.

30 of bis-5O performed ⁰ C; Suitable donor- The diester of cis-propenylphosphonic acid is obtained

olefins are compounds such as stilbene and cyclo- man, by first converting the free acid in cis -pro-

witches. The reaction solvent must of course penylphosphonic acid dichloride converted and this

inert under the reaction conditions and then at 55 with 2 molar equivalents of an alcohol

Reaction temperature be liquid. Appropriate solution converts. The monoesters become the diesters

methylene chloride, pentane and hexane are medium. by splitting off one of the two ester groups with

After making the reactants in the cold a base. A monosalt of the monoester

has brought together, the mixture is left can by reacting the monoester with a

Gradually reach room temperature to produce the 60 equivalent of base.

Settlement to complete. The product you want. I ₁

is carried out by evaporating the solvent and cleaning Example 1

obtained by known methods. 2.2 g (0.018 mol) of cis-propenylphosphonic acid

Another method for preparing the (±) - (cis- dissolved in 10 ml of water. The pH of the aqueous

1,2-epoxypropyl) phosphonate compounds according to the 65 solution are obtained by adding 1.51 g (0.017 mol)

Invention, the epoxidation of cis-propenylphos sodium bicarbonate is adjusted to 5.5 to 6, so that

phonates is formed with an alkyl perborate or a sodium cis-propenylphosphonate. then

Perphosphoric acid alkyl ester. This reaction is set to 0.55 ε (0.0017 mol) sodium tungstate

dihydrate and heats the almost neutral solution B eis ρ ie 1 3
in a water bath to 55 ° C. After removal of the water bath, 2 ml of 30 ° / ₀ strength hydrogen peroxide are added to the reaction mixture in the course of 10 minutes with 13.4 g (0.11 mol) of cis-Pro. The reaction is exothermic and the 5 penylphosphonic acid is charged. Then the temperature rises to 65 ^° C. when the peroxide is added. 125 ml of n-propanol are added while stirring. A further 1.6 ml of hydrogen peroxide are added to the solution. Here, 12.0 ml (11.89 g or 0.11 mol) of benzylamine, oxygen evolves from the solution, and this is added dropwise, and the mixture is kept at reflux temperature without the reaction mixture being heated to temperature. After 10 minutes heating is heated at 55 After 20 minutes long to 57 ⁰ C. io at reflux, the hot solution is filtered. If left standing, the temperature drops to 53 ° C. The benzylammonium-cis-propenylphosphonate is then added to the reaction mixture in a water bath. Further filtrate is heated to 55 ° C for 20 minutes in a 500 ml round-bottom flask equipped with a stirrer, thermometer, filtered and the solution and addition funnel are subjected to freeze-drying. Here you get entered. The solution is heated in an oil bath to 55 ° C, the monosodium salt of (U- (CiS-1,2-epoxypropyl) - 15 and phosphonic acid with 0.50 g of sodium tungstate dihydrate as a white powder. KMR spectrum is set. The value of the mixture is now 5.3 D ₄ O: 1.5 ppm 3 H (CH ₃ ); 2.6 to 3.8 ppm multiplet (determined on 0.1 ml solution in 1.9 ml water) H (epoxy); 4.7 ppm singlet H (HOD by dripping out 35 ml of 30% water exchange with phosphate within 15 minutes)

If the above reaction with 0.018 mol calcium> 0 55 and 6O ⁰ C holds. Then the reaction mixture

cis-propenylphosphonate or magnesium-cis-propenyl- held at 55 to 6O ⁰ C for another hour,

phosphonate is carried out as a starting material, so the pH value by the addition of aqueous Na-

calcium-i-hMcis-l ^ -epoxypropyO-phos- tronlauge is obtained as required in the range from 4.6 to 5.2 ge

phonate with the following X-ray diffraction values (is kept strong.

1st lines): ² 5 After removing the heat source, one drips

Layer line spacing (A) Relative! Intensity 20 ° / ₀ aqueous sodium sulfite solution to to the over-

12 to decompose 15 loo schüssige hydrogen peroxide, whereby one

, 'qo 4 5 keeps the temperature below 55 ° C. The mixture will

/ qc 45 concentrated in vacuo to 62 mi. You put 62 ml

, \ w γ'5 30 n-propanol and the mixture again narrowed in

'' Vacuum to 62 ml. Then another 62 ml

or Magnesium-d) - (^ is-K2-epoxypropyl) -pliosphon-propanol added, and the mixture is again

nat with the following X-ray diffraction value: strong evaporated to 62 ml. The mixture thus obtained

Line d (A) - 12.60. All other lines very faint. is diluted with 150 ml of absolute methanol and

35 stirred at room temperature for 1 hour. Be on it

B s 1 s ρ 1 e I 2 ^ _{6 un} IÖ _S the substances filtered. The filter residue

A filtrate equipped with a stirrer, thermometer, and pH electrode is washed with 50 ml of methanol, and the 2 liter three-necked flask equipped with the addition funnel is concentrated in vacuo to 62 ml with 150 g (0.655 mol) of monobenzylammonium. 62 ml of n-propanol are added and the cis-propenylphosphonate and 1.121 water are charged. 40 solution again to 62 ml. The solution thus obtained is then slowly added 6.0 g (0.018 mol) of sodium solution and cooled in an ice bath while stirring. After tungstate dihydrate has been added, the mixture is heated to 50 ° C. for 10 minutes, cooling for 1 hour is interrupted and the pH is adjusted to 5.0 with 2.5 η sodium hydroxide solution and the flask is kept at 0 ° C. for 16 hours until 5 , 5 a. Thereupon, in the course of 15 micro The crystalline product is filtered off, 150 ml of 30 ° / o "ges hydrogen washed 45 per 100 ml of cold n-propanol and added twice with grooves at 55 to 6O ⁰ C in Vaperoxid, wherein the pH Value, if required, dried in a vacuum at 60 "C. Pure benzylammonium- (+) - (cis-1,2-epoxypropyl> is obtained practically by adding sodium hydroxide solution to 4.8 to 5.2. After stirring for 1 hour at 55 ° C. this becomes phosphonate; mp = 148 cooled to 15O ⁰ C. by Umkristalli mixture to room temperature to give Sieren from n-propanol the melting point increases to 10% aqueous sodium bisulfite solution is added, up to 5 ° 155 to 157 ° C.

the iodine starch test is negative. The solids are _If the above process is filtered off with 0.11 mol, and the filtrate is evaporated in vacuo to Äthylendiatnmonium- or Piperazmium-cis-propenyl dryness and carried out by washing three times phosphonate, ethyladiammo with 10 ml of benzene is further obtained dried One sets nium- or Piperaanium- (cis-1,2-epoxypropyl) -phos-630 ml of methanol and 1250 ml of acetone to. After 55 phonat. After recrystallization from 70 ° / _o sodium stirring for 5 minutes at the reflux temperature of ethanol melts the salt which was filtered off one molecule Äthylenwird the insoluble matter and containing diamine with a hot, at 120 to 130 ° C (monohydrate). The mixture of acetone and methanol was washed. The anhydrous salt melts after precipitation from the filtrate is evaporated to dryness in vacuo, methanol by adding ethanol from 69 to l71 ° C. and the solids are slurried in 625 ml of acetonitrile at reflux for 20 minutes. The slurry, after recrystallization from 85% isopropanol, is then cooled to 25 ° C. That at 195 ° C.

yellow product is filtered off and mixed with Example 4 at 25 ° C
Acetonitrile washed. After drying in vacuo at 60 ° C., the Moaobenzylammonium- «5 A 50 ml three-necked round-bottomed flask equipped with a stirrer, thermometer and dropping funnel salt of (dzl-Ccis-l ^ -EpoxypropyO-phosphonic acid recrystallization from 10 parts by volume of etha- (0.01 mol) cis-propenylphosphonic acid-monomethylfiol melts the substance in 30 ml methanol at 155 to 157 ° C. The pH value

9 10

is adjusted to 4.5 with 2.5 η sodium hydroxide solution. After reaching a pH value of 5.5 in their mono addition of 0.06 g of sodium tungstate dihydrate, the sodium salt is converted. The Mononatriumdas mixture at 55 ° C and heated at 55 to 60 ⁰ C is added dropwise salt from the solution by freeze-drying in the course of 5 minutes recovered ml 3; KMR spectrum in D ₂ O: 1.5 ppm 3 H 30% strength hydrogen peroxide added. The mixture 5 (CH ₃ ); 2.6 to 3.8 ppm multiple 2H (epoxy); 4.7 ppm is left to stand for 1 hour at 55 to 6O ⁰ C, and singlet H (HOD by exchange with phosphate),
additional hydrogen peroxide is added as required. 17th
added so that the iodine starch test remains positive. Then B e 1 s ρ 1 e I 7
Saturated sodium sulfite solution is added until the iodine starch reaction equipped with a stirrer and dropping funnel has become negative. The inorganic 10 50 ml round bottom flask is filtered off with 1.22 g (0.01 mol) of cis-pronic solids, and the penylphosphonic acid solution and 20 ml of water are charged, are concentrated to half their volume and 2 ml are added (0.01 mole) of 20 ° / ₀ sodium hydroxide solution to cooled. The resulting precipitate of the to produce the monosodium salt of the cis-propenylphosphonic sodium salt of (±) - ( ^c ' ^s -U2-epoxypropyl) -phos acid. The mixture is then treated with 3 ml phonsäure-methylester is filtered off, veisetzt with ethanol 15 30 ⁰ / pc alcohol and hydrogen peroxide anschliegewaschen and dried. The same result was stirred for 3 weeks at room temperature. This is obtained if, in place of the sodium wolfra, excess hydrogen peroxide is destroyed with sodium mat as a catalyst, zinc vanadate or sodium sulfite, and the solution is used to make a small volume of selenium molybdenum tungstate; KMR spectrum narrowed. The solution is then replaced by a poly (D ₂ O): 1.2 to 1.5 ppm doublet; 2.6 to 3.5 ppm of such sulfonic polystyrene ion exchange resin in the multiple; 4.7 ppm singlet. Hydrogen ion form passed at 0 ⁰ C and the eluate

If one trapped equimolecular in the presence of 0.01 mol of benzylamine in the above process,

Lare amounts of cis-propenylphosphonic acid ethyl ester with The eluate is evaporated to dryness in vacuo

If hydrogen peroxide is oxidized, the sodium and the residue are recrystallized three times from n-propanol

salt of (±) - (ris-l, 2-epoxypropyl) -phosphonic acid- as lized. The benzylamine salt of (i) - (cis-

ethyl ester; KMR spectrum (D ₂ O): 1.1 to 1.5 ppm 1,2-epoxypropyl) phosphonic acid, m.p. 152 to 155 ° C.

Quintuplet; 2.7 to 3.5 ppm multiples; 3.8 bis The disodium salt of cis-propenylphosphonic acid

4.2 ppm quintuplet; 4.8 ppm singlet. can be epoxidized in a similar way if one

0.02 moles of sodium hydroxide used. The epoxy

Example 5 ₃₀ tion product is made from the remaining olefin salt

1.53 mol of cis-propenylphosphonic acid diallyl ester by repeated recrystallization from ethanol or

are separated into 1000 ml of η-pro-n-propanol in a reaction flask; X-ray diffraction values (the four

panol added, whereupon one slowly draws 0.018 mol of the strongest lines):
Adding ammonium vanadate. The mixture is on
50 ⁰ C heated and the pH value with ammonium 35
hydroxide adjusted to 5.3. Then you put in
Run in 200 ml of 30% hydrogen peroxide over a period of 30 minutes, the temperature being raised to 50%
up to 6O ⁰ C and the pH value by adding a base,
holds to 5.0-5.3 if necessary. The mixture 40
is stirred for 45 minutes at 6O ⁰ C, then cooled to room temperature and treated with sodium sulfite,

until the iodine starch reaction is negative. The mixture is placed in a 100 ml round bottom flask with 5.0 g (0.022 mol)

is filtered and the filtrate is evaporated to dryness. Benzylammonium cis-l-propenylphosphonate and 30ml

1800 ml of a mixture of chloroform are charged to the residue. Then add 3.04 g (0.022 mol)

extracted from 2 parts of acetone and 1 part of methanol. Perbenzoic acid in 20 ml of chloroform. The solution

The hxtrakt is einge- to dryness in vacuo 12 hours 6Q ⁰ C and heated. Genincli

evaporates, whereby one (i-Mcis-l ^ -EpoxypropylJ-phos- then cooled and filtered. The solid product, mono-

Phonic acid diallyl ester obtained as an oil; Sdp. ₀ . _{s mm} ■ - 105 benzylammonium- (f Mcis-l ^ -epoxypropyO-phospho-

to 11TC; / 7? ° C = 1.4623. 50 nat, is obtained by recrystallizing from 10 dividers

95 ° / own ethanol cleaned. The pure material

Example 6 melts at 155-157 ° C.

2.2 g (0.018 mol) of cis-propenylphosphonic acid are obtained. A similar result is obtained with 0.022 Mo

dissolved in 10 ml of water. 0.15 g of sodium peracetic acid or performic acid is used in place of the dei

Tungsten dihydrate is added and the mixture is cooled to 55% perbenzoic acid.

to 10 ⁰ C. Then in the course of 15 minutes

3 ml of 30% strength hydrogen peroxide were added, 0.022 mol of procaine salt of cis-propenylphosphonic acid being added

keeps the temperature below 10 ^{0 C by cooling.} That used gives the procaine salt of the (±) - (cis

The mixture is left to stand for 120 minutes at 10 ^° C., 1,2-epoxypropyl) phosphonic acid. The salt, which;

and then the excess hydrogen peroxide contains 60 1 molecule of procaine, melts after the order

crystallize from 80% isopropanol at 121 by adding dilute sodium bisulfite solution

(until the iodine starch reaction is negative) decomposes. That up to 130 ⁰ C.

The reaction mixture is concentrated to about 3 ml, for example 9
Removal of insoluble substances filtered and the freezer

subjected to drying. The residue obtained is 65. According to the method of E mm ο η s (Journal ο

(± H ^c 'sl, 2-epoxypropyl) phosphonic acid. The American Chemical Society, Vol. 75, 1953, p. 4623

Peroxytrifluoroacetic acid is produced by dissolving it in the smallest possible amount. A solution

Water and addition of sodium bicarbonate up to 2.8 g of peroxytrifluoroacetic acid in 20 ml of chloro

Layer line spacing (A) B e i s ρ Relative intensity iel 8 14.04 100 5.36 27 5.14 21 3.01 41

Layer line spacing (Λ) Relative intensity 14.04 100 5.36 27 5.14 21 3.01 41

11 12

form becomes 5 g (0.022 mol) of benzylammonium-cis-benzylainmonium salt of ( _: l _-) - (cis-l, 2-epoxypropyl) -

propenyl phosphonate and 7 g of solid disodium phosphonic acid are obtained by removing the eluate

phate added in 30 ml of chloroform. This is allowed to evaporate to dryness in vacuo. The connection

Mixture stand at 0 ^° C. for 16 hours and then filtered by recrystallization from 10 parts by volume

the solids off. The solids are purified in 10 ml of 5% 95% ethanol; 155-157 ° C.
Slurried methanol, filtered the slurry

and the filtrate was evaporated to dryness in vacuo. Example 12
Benzylammonium-

(±) - (cis-1,2-epoxypropyl) phosphonate. The product A-provided with a stirrer 200 ml flask is charged with 10 parts by recrystallization from 95 ° / _o sodium io 8.3 g (0.05 mole) of disodium cis-propenylphosphonat ethanol cleaned; 155-157 ° C. and charged 100 ml of water. Then be slow. 75 ml of an SVo'gen aqueous sodium hypochlorite example 10 solution (0.05 mol) are added, and the mixture is stirred overnight at room temperature with a pH electrode, stirrer and dropping funnel. The aqueous 100 ml three-necked round-bottom flask provided with 11.4 g of solution is concentrated in vacuo to half its volume (0.05 mol) of benzylammonium cis-propenylphosphonate, whereupon the dinatrium (i) - (cis - and 4.5 g (0.05 mol) of tert-butyl hydroperoxide in 50 ml of 1,2-epoxypropyl) phosphonate charged by freeze-drying methanol. The mixture is obtained with concentrated; X-ray diffraction values (the four strongest soda lye to a pH value of 8.0 one-line):
posed and 5 ^! / _{Stirred for 2} hours at 35 to 40 ° C, »°
adding sodium hydroxide as needed to
keep the pH at 8.0. The mixture is then concentrated to a small volume in vacuo,
the pH is adjusted to 4.6 with sulfuric acid and
n-propanol added. The solids are filtered off, 25
the remaining methanol is concentrated in the

Vacuum removed and the volume of propanol- Example 13
mixture is brought to 25 ml. The mixture will

Left to stand at 0 ^{° C. for 16 hours.} The solid benzyl one with stirrer, thermometer, gas inlet tube

ammonium - (± ) - (cis-1,2-epoxypropyl) - phosphonate 30 and a three-necked round bottom flask equipped with a gas vent tube

is then filtered off and dried in vacuo; is with 12.2 g (0.1 mol) of cis-propenylphosphonic acid,

155-157 ° C. 100 ml dimethylformamide and 8 g sodium hydroxide

Used instead of the benzylammonium pills loaded. Then add 0.1 g of cobalt naphtha

cis-propenylphosphonates the diethylenetriamine, nat and 0.1 g of tert-butyl hydroperoxide and heated

1,6-hexamethylenediamine or ethylamine salt of this 35 the mixture to 100 ° C. Through the mixture is

Acid, the corresponding salts are obtained after passing air through ^{at 100 ° C. for 21 hours.} then

(iHcis-l ^ -EpoxypropyO-phosphonic acid. The 1 Mo- is the mixture to half its volume

Lekül diethylenetriamine-containing salt melts after being concentrated and treated with an equal volume of water

the recrystallization from isopropanol at 182 to diluted. After multiple extraction with chloro-

183 ° C. The 1 molecule 1,6-hexamethylenediamine is removed from the form to remove the dimethylformamide

holding salt melts after recrystallization from aqueous solution of disodium (iMcis-1,2-epoxy-

a mixture of 1 part water, 3 parts methanol propyl) phosphonate at 0 ° C by a cation

and 3 parts of isopropanol at 194 ° C. The monoethyl exchange resin passed in the hydrogen ion form

ammonium salt melts at 137 to 140 ^° C. and the run-off in an aqueous benzylamine solution

45 (0.1 mole benzylamine) was collected. The thus obtained

Example 11 Benzylammonium salt of (* Hcis-1,2-epoxypropyl) -

- A 500 ml phosphonic acid equipped with a stirrer and dropping funnel is removed by means of an impeller

The three-necked round bottom flask is cleaned with 300 ml of methanol, 61 g of 10 parts by volume of 95% ethanol; F. 155

(0.5 mol) cis-propenylphosphonic acid and 40 g Na- up to 157 ° C.

trium hydroxide charged After adding 52 g of 5 ° B eis ρ ie 1 14
(0.5 mol) of benzonitrile, the mixture is cooled to room temperature. 34 g of a mixture of 14.9 g (0.1 mol) of cis-propenylphos-50% hydrogen peroxide are then slowly added dropwise is stirred at room temperature 30 ml mixture for 40 hours at room temperature. Stirred for 55 minutes under nitrogen. Excess peroxide is then heated with saturated sodium for 1 hour at 80 ° C., and the mixture is cooled on space sulfite solution (until the iodine starch test is negative). temperature and interrupts the reaction by adding the solution is evaporated to dryness and the set of 30 ml of water. The organic phase is extracted residue with 10 parts by volume of methanol. separated and the aqueous layer three times with each The methanol extract is filtered and extracted to dryness 6 ° 10 ml of chloroform. The chloroform extracts evaporated. The residue is combined twice, each time with the organic phase, and the 20 ml of water is extracted to remove the DinatriunHi;) - whole is evaporated to dryness in vacuo. As (cis-1,2-epoxypropyl) phosphonate is obtained from the benzamide residue to separate (±) - (cis-l, 2-EpoxypropyI) -. The aqueous extracts become dimethyl phosphonate with one another. The product is combined durci and ^{purified at 0 0} C by a cation exchange resin ⁶ 5 distillation: Bp ₀ , _sm m = 70 to 72 ° C in the hydrogen ion form. The free nf ° C = 1.4345. The eluate containing phosphonic acid is obtained in a similar manner in the presence of di-n-propyl ester; Sdp. ". _sm m = HO to Hl ⁰ C collected by 0.5 mol of benzylamine. The mono nf = 1.4361.

1 OUO D / O -

13 14

Ex a ni el 15 ^au ^ ^e 'evaporated ⁿ small volume, to remove

filtered of solids, further concentrated and finally

Fractionated by conversion of equimolecular amounts of borrowed by vacuum distillation. The under

S-ketobutanecarboxylic acid methyller, sodium hydride at a pressure of 0.20 to 0.15 mm Hg from 138 to

and diethyl ether and reaction of the product with 5 141 ^C C passing fraction is 21.6 g and is

cis-propenylphosphonic acid dichloride becomes di-2 '- (me-

ethyl 2'-bulenoate) -cis-propenylphosphonate. phosphonic acid diphenyl ester; 44 to 46 ° C.

A solution of 31.8 g (0.1 mole) di-2 '- (methyl-.
2'-butenoate) -cis-propenylphosphonate in 300 ml η-Pro- Example 17
propanol is heated with 0.6 g of sodium tungstate dihydrate comparable io A solution of 16.6 g Dinalrium-cis-propenylsetzt and the mixture to 55 ⁰ C. Then sets pho ^r .phonal in 50 ml of water is added a solution can ml in the course of 45 minutes, 90 ° 3O / _O strength of 23 g of 85% m-chloroperbenzoic acid in 75 ml of hydrogen peroxide (0.9 mol) to give the Tem- methanol added. The reaction mixture is kept at 55 to 60 ° C. for 4 hours. The mixture is stirred at 25 to 40 ° C., the pH value of this temperature being stirred for 3 hours, after 15 using 50% strength aqueous sodium hydroxide solution between 5 and required further hydrogen peroxide is maintained Implementation v / ird the mixture obtained a positive iodine starch reaction and Na- at 50 to 55 ° C in vacuo to half its volume of trium hydroxide to maintain a pH value of to drive off the methanol The excess of 75 ml of water is then concentrated to half its volume, the mixture is again concentrated peroxide with saturated aqueous sodium sulfite, the solution is then destroyed, the reaction mixture is filtered in vacuo and the filtrate is dissolved with 26 g of calcium acetate 75 ml is concentrated to half its volume, water is added, the mixture is left to stand for 30 minutes, diluted with water, to its original volume and room temperature, and the solid sample is obtained ine solution, the sodium (1) - (cis-1,2-epoxy product filtered off and dried in vacuo. To which propyD-phosphonate contains. The product is poured, 8 g of calcium acetate is added to 25 ml of water, the aqueous solution is purified by a cation, the solution is cooled overnight, filtered and dried. Exchange resin in the hydrogen ion form is passed the solid filter residue in vacuo. The two and the eluate in the presence of a molar equivalent of solid products are combined and benzylamine is collected. The benzylic acid obtained in this way gives 32.8 g of a material, which is calcium ammonium phosphonate, which is crystallized from 95% ethanol salt of (: t) - (cis-1,2-epoxypropyl) -phosphonic acid, whereby a practically pure material is kept . The yield is 23.7% of theory; rial with a melting point of 155 to 157 "C. X-ray diffraction values (the four strongest lines):

Example 16

A solution of 5.25 g of cis-propenylphosphonic acid 35 Diphenyl ester in 250 ml of methylene chloride becomes 119 g Dinatnumphosphat added and the suspension stirred and then heated to reflux temperature. the

The solution boiling on the reflux condenser is used in Example 18

of 45 hours in small portions with 100 ml 2.5 mo- 4 °.

larer peroxytrifluoroacetic acid added. Then the * ° ^{ml of} peroxysuccinic acid would become a at 25 ° C

Reaction mixture cooled, and the insoluble inorganic solution of 8.4 g of Dinatnum-as-propenylphosphonat

niche salts are filtered off. The salts are added with ^In 20 ^{ml of water} . The mixture becomes 3V ₂ slun

washed a little methylene chloride and ^{stirred the wash the ha} room temperature, whereby the pH

liquids combined with the filtrate. The value obtained in this way ^{by adding a base} 4.6 and 5.1

tene F.ltrat (about 250 ml) w _e d in succession depending two ^holding · ^{Then the} ™ ^{rd Losun} ß ™ [room temperature overall

^cools times with 50 ml of aqueous 20 ° / _o strength sodium bisulfite ^{and with} 50 ° / _o aqueous sodium hydroxide solution

solution, twice with 50 ml 2.5 η wäünger sodium hydroxide solution, ^{ε! Ι3εη} pH value of 9 «ngestdlt. After adding

twice with 50 ml of water and finally once with ²⁵ $ β calcium acetate in 70 ml of water, the thick-

Washed 50 ml of saturated saline solution. The total 50 ^flüssl ß ^e mixture filtered. The solid filter residue

»-Ashering: the solution is ^{washed over anhydrous sodium- is washed with water} and at 50 C in a vacuum

sulfate dried and then dried in vacuo to an oil The product contains calcium- (±) - (cis-

evaporated, which crystallizes on standing. The 1,2-epoxypropyl) phosphonate in a yield of

Product, (iHcis-U-EpoxypropylVphosphonic Acid- ¹² 7 "^; X-ray diffraction values (the four strongest

diphenyl ester, has a melting point of 46 to 48 ^ C 55 lines):

The ds-propenylphos-SchfchÜHnen distance used as starting material (A) Relative intensity

Diphenyl phonic acid ester can be prepared as follows

are: 6.08 4.5:

30.0 gds-propenyliphosphonic acid dichloridine 150inl 4.05 _; 4.5

Ethyl ether are added dropwise with a solution of ^6o 3.04. 7.5- ■ · ....

33.87 g of phenol and 28.8 ml of pyridine in 200 ml of ethyl. -, _1Q .

ether added, the temperature of the reaction example Vf

mixture is kept at 5 to 10 ⁰ C. "After loading a solution of 15.0 g of cis-propenylphosphonic acid

When the addition is complete, the reaction mixture is stirred dimethyl ester in 80 ml of benzene with 1 g of Vanadylr

another 3 hours and then cools it down to 5 ° C. The 65 acetylacetonät added. 9.9 g are added to the solution

cooled solution is added after filtering off the freshly distilled ferL-Butyihydrpperoxid. The

Precipitation of pyridine hydrochloride with some reaction mixture is 8 hours under nitrogen

Ethyl ether washed. The Fütrat is heated in a vacuum 6O ⁰ C, then cooled to room temperature and

Layer line spacing (A) Relative intensity 12.16 100 6.08 4.5 4.05 4.5 3.04 7.5

3313 if

evaporated to dryness in vacuo to remove the benzene and excess oxidizing agent. The residue contains mainly (±) - (cis-l, 2-epoxypropyl> phosphonic acid dimethyl ester, bp _{0, s} = 70 mm ° to 71 ° C..

When the above method with the diethyl ester of cis-propenylphosphonic acid in the presence of 1 ml of glacial acetic acid and the reaction mixture is heated for 4 hours at 60 ⁰ C, there is obtained (± ^cis M l, 2-epoxypropyl) phosphonic acid diethyl ester; Bp 0.5 mm = 78 to 82 ° C; nf ° C = 1.4327.

Example 20

330 mg of anhydrous disodium (± Hcis-1,2-epoxypropyl) phosphonate is mixed with sufficient lactose to make a gelatin capsule fill, which holds approximately 475 mg of solids. Once mixed evenly, the solids will add up Grind particle sizes below 10 μ and the capsules Filled by hand or by machine.

Each capsule contains the equivalent of 250 mg (dr) - (cis-1,2-epoxypropyl) -phosphonic acid.

Example 21

mg per tablet calcium- (±) - (cis-l, 2-epoxypropyl) -

phosphonate monohydrate 352.5

Dicalcium phosphate 180

Lactose 179.5

Cornstarch 80

Magnesium stearate 8

The phosphonate wild mixed with the dicalcium phosphate, the lactose and half of the corn starch The mixture is granulated with 15% corn starch paste and roughly sieved. Then it is dried at 45.degree and sieved through a 1.19 mm mesh sieve. The remainder of the corn starch and the magnesium stearate are then added and the mixture becomes tablets with diameters of 12.7 mm pressed, each weighing 800 mg.

Example 22

1000 ml each
Disodium (± Kcis-1,2-epoxypropyl) -

phosphonate - - - 132.0 g

Sucrose 600.0 g

Glucose 250, supra

Citric acid 13.0 g

Sodium benzoate 1.0 g

concentrated orange oil ~ - 0.2 ml

made up to 1000.0 ml with purified water

The sucrose and glucose are dissolved in 400 ml of water with heating. The solution becomes

as cooled, whereupon the citric acid and the sodium benzoate and then the orange oil is added. The solution is diluted with water to a volume of 900 ml are made up, and then the disodium (±) - (cis-1,2-epoxypropyl) -phosphonate added the

Solution is filtered and brought to a volume of 1000 ml

309 629/249

Claims (1)

The structural formula of the (± claims: (cis-1,2-epoxypropyl) -phosphonic acid according to the invention can be given spatially \ S% \ as follows: 1. (±) - (cis-l, 2-Epoxypropyi) -phosphonic acid bonds of general Fonriel 5 H- / ^ V / H VHH ^X C C '''ο ¹¹⁰ H, C ^{/ X} * / H ₃ C \ H ₃ CC CP ^ OR \ . ^Χ ο ^{κ X} o _Rl " _and