DE1805677A1 - Cis-propenyl compounds and processes for their preparation - Google Patents

Description

Cis propenyl compounds and method too their division

The invention "relates to the new cis-propenylphosphonic acid and their salts and esters obtained by selective hydrogenation of propynylphosphonic acid or its salts or esters is obtained »Cie-Propenylthiophosphonate, -phosphonsäureamide and D'hosphonsauredihalgenide are obtained by treatment the free acid with thionyl halide and reaction of the phosphonic acid dihalide with an alcohol »a Thiol or a primary or secondary amine «These cis-propenylphosphonic acid compounds are intermediates in the manufacture of antibacterial active (i) - (cis-1,2 ~ epoxypropyl) -phosphonic acid and their active (-) - enantiomers «.

The invention relates to new chemical compounds and methods for their production. It relates in particular to the new cis-propenylphophonic acid, its derivatives and processes 2UP making these connections,

{-.) - (Cis-1,2-apox; ypropyl) ~ phosphonic acid and its salts have

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ORIGINAL

$ 12,437

have very significant antibacterial activity against a large number of pathogens. The (i) - (cia-1,2-Bpoxy propyl) phosphonic acid and its salts also show antibacterial activity which is practically half the (-) isomer on a weight basis. These compounds actively cause inhibition the growth of both Gram-positive and Gram-negative pathogenic bacteria "They are active against species of Bacillus- * Eeoheriohia""Staphylococoi-, Salmonella and proteus pathogens and antibiotic-resistant strains thereof", examples of such pathogens are Bacillus subtilis, Escherichia eoli , Salmonella schottmuelleri, Salmonella gallinarum, Salmonella pullorum, Proteus vulgaris, Proteus mirabilis, Proteus morganii, Staphylococcus aureus and Staphylococcus pyogenes. The (-) and (^ - (cis-i ^ -Epoxypropyli-phosphonic acid and its salts can be used as an antiseptic to remove responsive organisms from pharmaceutical, dental or medical equipment or other areas subject to infection by such organisms , and also inhibit harmful bacterial growth in industrial paints. Similarly, they can be used to separate certain microorganisms from mixtures of microorganisms. They are useful in treating diseases which have been and are caused by bacterial infections in humans and animals particularly valuable here because they are active against many strains of pathogens that are resistant to previously available antibiotics.

The salts of (-) and (i) - (cis-1,2-epoxypropyl) -phosphon ~ acids are suitable as protective agents for industrial applications because they are effective against undesired bacterial

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growth in the white water, like ee in paper mills and in Paints used inhibit »ζ. Β · in polyvinyl acetate paints.

If (-) and (£) - (οΐ8-1 ₍ 2-Εροχνρτορν1) -ραθΒρ1ιοη8 & ι * τβ or their salts are used to combat bacteria in humans or low animals, they can be administered orally in dosage forms in fora of capes or tablets or ale These formulations can be prepared using diluents, granulating agents, preservatives, binders, taste-improving agents and coating agents as are used for such purposes.

The (-) - (ci6-1,2-EpOx? Propvl ^ phosphoric acid mentioned below rotates plane-polarized light counterclockwise (to the left as seen by the observer) when the rotation of the disodium hall in water (constant concentration) at 405 mu is measured »

The term "ice", as it is used in the description of the 1,2-Gpoxj'proprlphosphonsäureverbindungen, means that each of the hydrogen atoms of the carbon atoms 1 and 2 of propylphosphonic acid are on the same side of the oxide ring. The term "ice" is unambiguous in the designation of the cis-propenylphosphonic acid compounds according to the invention.

One of the goals according to the invention is the provision of new intermediates which are necessary for the synthesis of the (-) (cis-1,2-epoxypropyl) -piiBoplionic acid compounds are suitable Bind Another task is provision

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of Processes but Preparation of the New Intermediates, Other features of the invention will be apparent from the following description.

The inventive oie-propenylplioBphone acid compounds can through.the formula

H H V

- C = 0 - P - Y

are represented, in which X is oxygen or sulfur Y -OE, -SRf halogen or -HR ₁ E ₂ Z -OR, -SR, halogen or IR ₁ Rg R is hydrogen or a hydrocarbon radical R ₁ and R _{2 is} hydrogen or a hydrocarbon freet or an acyl radical · Included in the formula I and a preferred feature of the invention are the organic and inorganic salts of those compounds in which R is hydrogen. The substituents Y and Z can be the same or different in each specific compound

For the sake of simplicity, the structural formulas of the new compounds according to the invention are planned in the manner shown above Formula described because the configuration is adequately defined by the name cis-propenylphosphonic acid. For the sake of completeness, the room configuration can be structurally like are shown below

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SAD ORIQINAt

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• H H

Bending room configuration let a critical feature of the inventor use, because earlier described 'tropenylphosphonic acids combine in the trans configuration or as mixtures of cis and trans isomers are present »while the invention available compounds in the cis-lorm and practical are free of trans configurations.

if R, E ₁ and / or E ^ in formula I represent a carbon only off residue, such a residue can be aliphatic, cycloaliphatic, aoyl, araliphatic, aromatic or a heterocyclic radical which can optionally be further substituted.

For example, it can be aliphatic, such as substituted or unsubstituted alkyl, alkenyl or alkynyl * Representative examples are alkyl, such as methyl, propyl, isopropyl, t-butyl, hexyl, octyl, decyl, dodecyl, haloalkyl, such as chloroethyl, fluoropropyl, bromoethyl and Diohloräthyl _s Acylosyalkyl as Acetoximethyl, Propionoxiäthyl "and Bengsoyloxiäthyl, Eydroxipropyl» aminomethyl, aminoethyl, Alkylamxiioalkyl as dimethylaminomethyl or Diäthylaainopropyl »p-Iitrobenzoylaminomethyl, Carboalkoximethyl, cyanoethyl, Sulfoniamidoäthyl, phthalimidomethyl and Methöximethyl * alkenyl such as allyl, methallyl, vinyl, propenyl, hexenyl, Octadlenyl ; Alkynyl like propargyl, ithynyl or chloroethynylj Cycloalkyl like cyclohexyl, Oyclohexenyl or Oyclo-? L. If R "R ₁ or R _{2 are} aliphatic, they contain roughly 1 to 6 carbon atoms, ie they are substituted

· »5 - ^
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tuted or unsubstituted monoalkyl or alkenyl radicals.

Examples of R, R ₁ and / or R ₂ with araliphatic radicals are aralkyl, such as benzyl, phenethyl, phenylpropyl, p-halobenzyl and o-, m- or p-alkoxibenzyl »Hitrobenavl, aminophenätlayl, Pyräyläthyl» Furylmethyl or Thienylpropyl,

R, R ₁ and / or R ₂ can also represent an aryl group, such as phenyl »haphthyl or substituted phenyl or eaphthyl, for example p-chlorophenyl, o-hitropihenyl, o, p-dihalophenyl» cyano phenyl, methoxyphenyl, aminophenyl or tolyl » 3) The aryl radicals are preferably mononuclear aromatic radicals. If R, R ₁ and / or R _{2 are} heterocyclic, they can be heteroaromatic * such as pyridyl, furyl »ihienyl, thiazolyl or pyrazinyl, or on the other hand they can also represent a hydrogenated heterocyclic» as for example in tetrahydrofuryl and piperasinyl »

If both Y and 2 mean -OR or -SR, they can together be connected to form a cyclic ester from type

XO X O ^

W or -P ^ V ₉ -

where W is derived from a compound having two Hy & ro Contains xyl or awei thio groups * Examples of W are

-CH ₂ CH ₂

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The compounds of formula I that are acidic, i.e. H. the Free acids and Konoeeters, can form salse and Bolohe salts form a preventive aspect of the invention because they are particularly useful for the production of the ' (iKciB-1,2-Epoxipropyl) -phoaphonaäureverbindungen are ·

As will be understood by any person skilled in the art, the free phophonic acid compounds form both organic and inorganic salts and both are included in the invention. Examples of such saiae are inorganic metal salts, such as the sodium, aluminum, potassium, ammonium, and calcium salts. Magnesium, silver or Bieensalse. Typical organic sales include those with primary, secondary, or tertiary amines such as monoalkylamines, dialkylamines, trialkylamines, and nitrogen-containing heterocyclic amines. Typical examples of Aainsalee are a-phenethylamine, diethylamine, biäthylenetriamine, quinine, brucine, Lye in, protamine, arginine, procaine, xthanolamine, morphine, beneylamine, xthylenediamine,!, H'-bibenzylethylenediamine, diethanolamine, piperaein, n-piperlaaminoethyl Ethanol, 2-amino-2-methyl-i-propanol, theophylline, set of amino acids and H-methyIglucamine, both the mono- and the dibaelach Salee can be produced with monovalent cations

R. and / or R ₂ in Formula I can also represent acyl salts, preferably lower alkanoyl, such as acetyl, propionyl or butyryl, or monocyclic aroyl, such as benzoyl, halo-likeyl, p-nitrobenzoyl, puroyl or thienoyl, R ₁ and Rp can also be linked to one another with the formation of a cyclic ring with the substance of -HR ^ R ₂ all part of the ring, as in morpholinyl, thiamorpholinyl or pipea-idyl.

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If Y and / or Z in formula I are halogen, that is added halogen, chlorine, bromine or fluorine "

According to the invention, the cis-propenylphosphonic acid and their salts and esters synthesized by selective hydrogenation of a cis-propynylphosphonic acid as follows is shown structurally i

! - CSC - P - OH - - t G ₃ CC - C - P - OH

Although written as a free acid, the process can be used in can also be carried out in the same way with salts, alkyl and aryl esters. It can also be used with unsaturated esters, like the alkenyl or alkynyl esters or with aralkyl esters are used, although these are at least due to the hydrogenation can be partially reduced during the reaction «

The step of selectively reducing propynylic acid or a salt or an ester thereof for the preparation of propenylphosphonic acid or the corresponding salts or esters is easily done by using the propynyl connection in the presence of a suitable hydrogenation catalyst, such as a noble metal or a Raney nickel catalyst, hydrogenated., Carrying out the hydrogenation gives the best yields of the desired Propenyl compound if hydrogenation is stopped xtf * as soon as one mole of hydrogen per mole of the starting propynyl compound has been added to prevent full saturation of the unsaturated bond au “For this Reduction are particularly suitable as a catalyst 5 # iges

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BATH ORIGINAL

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Palladium-on-Caloiu & carbonate or Raney-Kickel. These catalysts, which contain a small amount of added poisoning agents, reduce their activity, and can also be used to carry out the selective hydrogenation. Hiekel can be poisoned by adding a small amount of zinc acetate and / or an organic base such as piperidine, morpholine or quinoline. These poisoned catalysts are particularly suitable for the reduction of the pure propynylphosphonic acids. The particular catalyst and the amount required for the hydrogenation depends largely on the purity of the propynyl compound to be reduced, but in general an amount of about 1 to 5 % of catalyst is sufficient to carry out this selective reduction.

For example, alkenols such as methanol, ethanol or xsopropanol are used as solvents, but the solvent is not critical. Positive hydrogen pressure from about 1.4 to 7 * 0 atm (20 - 100 p »s«, i.g *) are preferred, but higher or lower pressures can also be used without any negative effect.

Typical examples of selective catalytic hydrogenation the corresponding propynylphosphonic acid compound obtained Propenylphosphonic acid compounds are lower alkyl esters, such as methyl, ethyl, propyl, tert-butyl, isosropyl and hexyl; and aryl esters such as phenyl, naphthyl, 5-jolyl, p-halophetiyl and hydroxyphenyl or pyridyl; Alkali and alkaline earth salts are the sodium, potassium, calcium and Magneaiumaalzej examples of amine salts are benzylamine, ^ Phenethylamine, ammonium, xthylenediaain, piperaziu, quinine

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12437/0

and like salts.

The oia-propenylphoaphoneauredihalides (formula I, where Y and Z are halogen) are obtained by treating the cis ~ propenylphosphonic acid with 2 moles of a halogenating agentB, such as a thionyl halide, for example thionyl chloride, bromide or fluoride, phoephorpentaehloria _? Phoaphonyl fluorobromide and the like. This process can be carried out by bringing the reactants together in suitable organic solvents, such as in benzene, toluene, xylene, pentane * ether or methylene chloride "The time and temperature of the reaction are not critical and good results are obtained" at temperatures from about -10 ° C to the reflux temperature of the solvent.

Compounds according to the invention in which Y and / or ZO hydrocarbon and / or S-means hydrogen, is obtained by reacting the cis-propenylphosphoneiuredihalide, in particular of dichloride or dibromide, with a suitable alcohol or thiol in the presence of a tertiary base, such as triethylamine * dimethylaniline * byyridine or collidine · Am alkyl, aryl, aralkyl, alkenyl or Alkynyl alcohol or thiol is used to make the appropriate Phoaphonat or thiophosphonat au obtained. If you use 2 moles of alcohol or thiol, you get the diphosphonate or di-dithiophosphonate while 1 mole gives the monoester. ■

The reaction is generally used at atmospheric pressure and at a temperature of -10 ° 0 to the boiling point of the reaction solvent. In the absence of tertiary base violent reaction conditions are employed, for example, from about 100 ° iemperatüren "Q

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stop for several hours and then remove the hydrohalic acid

Any inert organic solvent such as ethyl ether, benzene, toluene, ethyl acetate or methylene chloride can be used as the solvent. Examples of compounds according to the invention prepared in this way are di-ethyl-cis-propenylphosphonate, bibenzyl-cis-propenylphosphonate, diallyl-cis-propenylphosphonate, diphenyl-cis-propenylphosphonate, di-tbutyl-cis-propenylphoaphonate, di-ethiophenylphoaphonate, biaethallyl-di-thiophosphonate, biaethallyl -propenyldithiophosphonat, Biäthyl-cis-propenyldithlophosphonat _r dihexyl-cis-propenyldithiophosphonat, ithyl-cis-proponylphoaphonochloridat, BeneyJ-cis-propenylphoephonofluoridat _r Aayl-cis-propenylphoaphonobromidat _v allyl-cis-propenylthiophosphonochloridat, p-chlorophenyl-cis-propenylthiophoaphonochloridat and ß-Hethoxyaethyl -cis-propenylphonochloridate,

The phoephonic acid halides and thiophoephone acid halides been easily converted into the corresponding monoesters of cis-eropetiylphosphonic acid and cis-propenylthiophoephonic acid by adding the halides in aqueous solution a pH of about 4.5 oia 8.0 heated for a short time If the halogen is a fluoride, the removal of the Fluorine-accelerated by the presence of hydroxylamine ".

According to another aspect of the invention, the cie-propenylphosphonamides and -phoaphonodiaaide of Äorael I (Y and / or Z are NE ₁ R ₂ ) prepared by the cie-propenylphosphonic acid dihalide with ammonia or a primary or secondary amine in the presence of a tertiary base which acts as a hydrogen chloride acceptor. In this way, the substituted cis-Propenylphos-

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. Phonic acid halidamides (Formula I, T · halogen; 2 ■ prepared by treating cia-propenylpkoephonellureaihalide with 1 part of ammonia or a primary or secondary amine. Typical amines that can be used are aliphatic amines such as methylamine and dläthjrlamine, hydrazine and substituted Hydraein, hydroxylamines and substituted hydroxylamines, heterocyclic amines such as morpholine and pyrrolidine, aromatic amines such as aniline and substituted anilines, for example H-methylaniline, heteroero-metallic amines such as imidasol or pyrrole, guanidine and subtle guanidines, aralkylamines, such as beeneylamines the use of a tertiary base as hydrogen chloride acceptor is required, the requirement n * oh of a tertiary base does not exist if 2 moles of Adnonlak or the primary or secondary amine are used to absorb the hydrogen chloride.

■■■. ·· ■ ·

Though no solvents are required for this reaction are, such are prevented. Typical solvents are for example ether, dioxane, tetrahydrofuran, hexane, Beneol, toluene or ethylene chloride.

The reaction temperatures can range from about -10 ° C up to the boiling point of the solvent »whereby the lower temperatures of about 0 ° 0 are avoided« MBn the reaction can also start at one temperature run from about 0 ° C for about 1 hour and then quit at higher temperatures up to about 85 to 90 ° C.

The O-Buhstituierten-lf-eubetituierten cis-Fropenylphosphonamidate (formula I, Y ^ OR; Z = -KB ₁ R ₂ ) are obtained from the phosphonohalide amides by treating the latter with a suitable alcohol, preferably in the presence

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909850/1738

BATH ORIGINAL

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a tertiary base * The alcoholysis takes place at atmospheric pressure and preferably at temperatures of about 25 Mb • 50 ° Ü carried out. The temperature is not critical »however has a temperature in the range of about -10 ° 0

proven practical at the boiling point of the solvent. But you can also get these compounds by one ammonia or a primary or secondary Amiu bit an O-substituted oia-propenylphOBphouBaurelialogenid converts, whereby the O-substituted-H-substituted cis-eropenylpho & phonamidate receives

If a thiol in the method described above using the same reaction conditions, so are the ois-eropenylthiophosphonoamidates according to the invention obtain·

Typical compounds according to the invention in which T in Formula I O-hydrocarbon or S-hydrocarbon and Z -BRiHg. mean, are

Β, Η-diethyl-O-methyl ciB-propenylphosphonamidate B, iI-I) ibenzyl-O> -benzyl ois-propenylphosphonamidate, H, H-diphenyl ~ S-methyl cis-propenylthionophosphonamidate and H, IT-diethyl ~ S-allyl cis-propeaylthiophosphonamidate.

The novel N, H, Ii ^l, ii * -tetrasubBtituierten OILS- Fropenylphoephonodiamide be obtained from cis-Propenylphoaphottsäuredihalogemiden by tlmsetzung hit a molar amount of the latter compound with an amine · Get 2 The amine used may be ammonia or a primary or secondary amine * If you use an excess of amine to bind the hydrogen halide released, you can avoid the need to use a tertiary base in the reaction.

9098 5 0/17 38

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if desired, one can use an excess of a tertiary base along with an appropriate molar concentration of the amine reactant use. It goes without saying that 2 hole amines are used for the reaction with the biosphonic acid dihalo », genid and that you also need a base for the Neutralization of the hydrohalic acid, which occurs at the implementation is needed.

The reaction can take place at temperatures in the range of about -10 ° C to about 100 ° C in a suitable inert organic solvent. Used as an amine one if primary amine is used, lower temperatures are used preferred. However, with secondary amines it is often necessary to complete the "Means to heat"

The compounds according to the invention in which Σ in Pormol I denotes sulfur are obtained by a similar reaction like the one described above and uses oia-eropenylthiophoephonic acid dihalide as an exit connection. The latter connection is simply obtained "by adding ice- ' Xropenylphosphonic acid dihalide with phosphorus pentasulfide implements.

In addition to the process for the preparation of the bis-bropenylphosphonic acid halides and -phosphonoamides and -thioates discussed immediately before, these compounds can also be obtained by selective catalytic hydrogenation of the corresponding sropynylphosphonic acid halides, -phosphonoaaiöa and -phosphoric thioates. Although the catalytic hydrogenation of the kropynylphosphonates to the cis -sropenylphosphonates has been described in the same way as to the compounds in which X is the? Ora ^ XI is oxygen and J uad Z is OR, the process is also applicable to the sya "

x. ·, ■

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r ff # t f r t ι

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thesis of formula I Compounds in which at least one X ₉ T or 2 is a non-oxygen-containing best.Bie AuBgange propynyl compounds are obtained as described above by using a metal ^ acetylene Orignard reagent, such as metal acetylenemagneaium bromide with a corresponding chlorophosphonic acid amide , Chlorothiophosphonate or chlorophosphonic acid halide. The cis-propynylthiophoaphonate, -phosphonamides or -phosphonic acid halides obtained can be epoxidized directly into the corresponding (-) - (ele-1, 2-Epo ^ 5> propyl) -phophonic acid compounds or they are hydrolyzed, pre-evolved with mineral acid before they are epoxidized will.

The following examples illustrate the invention and are not to be interpreted restrictively «

example 1

Bi-n-cutyl-propyiiylphosphonat (10 g. 0.043 mol) are dissolved in 50 ml of methanol and in the presence of 3 g of a 55% palladium-on-calcium carbonate, which has been poisoned with lead acetate, at 2.80 kg / cm hydrogenated in a Parr apparatus · Vaohdem 4.73 attt (67.5 psig) hydrogen (theoretical 4 * 97 attt) (71 psig) have been taken up, the reactions! The filtrate is filtered to remove the catalyst and the catalyst is washed with methanol. The base filtrate is concentrated under reduced pressure, yielding B1-n-butyl-isopropenylphonate in the form of a pale yellow residue. The residue is distilled under reduced bridge, whereby di-n-butyl-cis-propenylphosphonate (8.49 g) which boils at 72 ° C. at 0.12 mm is obtained. Analysis of the product gives the formula C ₁₁ Hp ₅ OJP. The infrared spectrum of the compound shows the

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Absence of an acetyl ligament at 4.5 u and the presence of an Olefinbanäe at 6.12 / ι, as ei © for oie olefins is characteristic. The nuclear magnetic resonance spectrum also shows that the product in the ice confectionation is present

That used in the example di-n-butylpropynylphoephonat is obtained by mixing a solution of Methylacetylenmagnesiumbromid (0.5 mol) dissolved in a mixture au · 2 1 of benzene and 300 ml of tetrahydrofuran was added dropwise with stirring to a solution of 96.1 g (0.5 mol) of di-n-butylehlorphoaphonat in 1 l of benzene are · The methylacetylene-Grignerd reagent is added over the course of 3 hours and the reaction mixture is stirred vigorously during the addition »whereby the temperature is below about 28 ° C Holds · After the addition is complete, let the clear solution stand for about 16 hours at room temperature. 1 liter of aqueous ammonium chloride solution is added to the reaction mixture and the water layer is separated off and extracted twice with benzene Obtains oil weighing 61.5 g. The oil is distilled under reduced pressure, giving a first fraction with a boiling point of 111 ° C. at 0 _s 5 mm and then a clear, yellow liquid main fraction consisting essentially of di-n-butylpropynylphosphonate and 47.3 g weighs and boils at 102 ° C at 0.15 mm.

If this procedure is repeated using Dimethyi-u Di-tert-butyl, diphenyl or di-p-tolyl esters of liropynylphosphonic acid (obtained from the corresponding Chlorophosphonate and the

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this gives the corresponding eater of ois-propenylphosphonic acid.

B, eiapiel / 2

To a solution of 9 g (0.044 mol) of di-isopropylpropynylphosphonate in 50 ml of methanol, 1.5 g of a 55% Palladium-on-calcium carbonate catalysts made with lead acetate is poisoned, added and hydrogen is passed through the solution at a pressure of 2.80 kg / cm «Nach Absorption of 5.01 atmospheres of hydrogen (theoretically 5.02 atmospheres) (71.7 psig) the addition of the hydrogen is stopped and the reaction mixture is filtered off from the catalyst and the catalyst is washed with methanol. When concentrating the filtrate under reduced pressure gives 8.84 g of di-isopropyl-cis-propenylphosphonate. This material distilled at 0.15 mm at 42 to 43 ° C

The di-isopropyl propynyl phosphonate used in this example is according to the procedure described in Example 1 by reacting di-isopropyl chlorophosphonate made with methylacetylene magnesium bromide · The product Is obtained in the form of an oil with a melting point of 82 to 84 ° C at 0.4 to 0.45 mm. ·

Example 5

Dl-n-butyl-cis-propenylphosphonate (9.7 g) is refluxed in 80 ml of concentrated hydrochloric acid (12.4η) on an oil bath at 108-117 ° C. for 15 hours. The reaction mixture is allowed to cool to room temperature and concentrated then the solution with heating in a tar kuum _o Water ( 50 ml) is added to the residue and again

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fetches the Einäampfungs traversing s to give 6.19 g of a brown yiscosen obtained residue. The residue is dissolved in 25 ml of ethyl ether and the ether solution extracted with 3x, 10 ml of water. Shallow evaporation of the ither layer gives 2.56 g of a brown residue. When the aqueous extract is evaporated in vacuo, 3 43 g of a pale yellow are obtained , viscous oil · The residue obtained from the aqueous extract is purified by dissolving it in 25 ml of ether and extracting the ethereal solution with 12 ml of water. When the aqueous extract is evaporated in vacuo with heating, cis-propenylphoaphonic acid is obtained as a pale yellow, viscous oil. Infrared spectra of the yellow oil show the characteristic oil fin bands at 6.1 μ *

Example 4

Di-n-butylpropynylphosphon t (500 g, 2.15 mol) is dissolved in 2.5 1 of methanol in a Hyärierkolben * To this are added 50 g of 5 $ palladium on strength, -Calciumcarbonate, the piston is first filled with nitrogen and then with hydrogen with alternating evacuation and pressure pressure. The hydrogen pressure is set to 3.5 atmospheres. While shaking for 50 minutes, the temperature increases from 25 ° C to 45 ° C and it becomes 1.94. .-HbI .Hydrogen absorbed · HXq vigorous movement is stopped, the heater is vented and the kit is flushed with nitrogen. The catalyst is removed by filtration, washed with 200 ml of methanol and the methanol is evaporated in vacuo until the temperature of the residue has reached 100 ° O * The residue is di-n-ethyl-cis-propenyl phosphonate <· ■ - '

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Example 5

Salts of cis-propenylphosphonic acid are obtained by treating the free acid in ethanol with a base. It obtains metal salts by using metal oxides or hydroxides as bases, and amine salts by using suitable anines to obtain the monosale , the pH with the base is adjusted to 4.8 in the case of Metallealzen and 4 _f 2 in the case of Aainealaen; sur Heretellung the Diealise is 8.2 adjusting the pH to 8.8 at Hetallealcen and Aninsalsen · win su din the salts _t dae Xthanol removed by Terdaapfen in Talcuu "· So beispielawelse 2 g cie Propenylphoephonsäure in 50 al of ethanol old aqueous Fatritunhydroxid adjusted to a pH of 4.8. The mixture is concentrated to dryness in a cycle, whereby the nononatriuaeale of the ois-fropenylphophonic acid is obtained. If aqueous barium hydroxide is added to the above solution to pH 8.8 and the mixture is concentrated to dryness, the bis-sodium salt of cis-dropenylphosphonic acid is obtained the same way by adding benzylaain to the ethanolic solution of cis-propenylphosphonic acid up to a pH of 4.2 or 8.2. All of the aforementioned salts can be obtained in the same way using the appropriate base.

Example 6

6.1 g of cis-ropenylphosphonic acid, 60 ml of dry benzene and 9.0 ml of pyridine are placed in a 250 ml large-necked round bottom flask. The mixture is heated to 50 ° C, which Heat is dissipated and 13.2 g of thionyl chloride are added dropwise at such a rate that the

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The reaction mixture is kept at 50 ° C. The mixture is then cooled to room temperature and stirred at room temperature for 2 hours. The mixture is filtered and the filtrate is concentrated in vacuo at 35 ° C., 4 »5% inoe of cloudy oil being obtained. It is distilled, whereby nan cie-Fropenylphoephoneäuredichlorid with a boiling point τοη 6? - 69 ° 0/9 - 10 mn; * ξ ° : 1.4885 received.

BelBplel'7

A stirred mixture of PropenylphoephonaäurediGhlorid (0.1 mol) and triethylamine (0.2 mol) in 100 ml of benzene is cooled to 5 ° C. Benzyl alcohol (0 ₉ 1 mol) is added to the mixture at such a rate that the ' Temperature is maintained at 5 to 10 ° 0. When the addition is complete, the mixture is stirred for 1 hour at low temperature. The precipitated triethylamine hydrochloride is filtered off and the solvent is removed under reduced pressure, the residue obtained being beneyl-cis-propenylphosphonochloridate. Aqueous 1N sodium hydroxide is added and the mixture is stirred, a clear solution being formed. The solution is then acidified and extracted with n-butanol. After removing the solvent, sodium benzyl-cis-propenylphosphonate is obtained.

If this process is repeated using allyl alcohol, propargyl or phenol instead of benzyl alcohol, the allyl, propargyl or phenyl ether is obtained.

Example β

A stirred mixture of 0.1 mol of cis-propenylphosphonic acid dichloride and 0.1 mol of triethylamine in 100 ml of benzene is cooled to 5 ° C. 0.2 mol of benzyl mer-

- 20 -909850/1738

SADOHIOINAL

ι · ■ ··

12 437 «I.

captan is added at such a rate that the temperature is kept at 5 to 10 ° C. Broke termination the addition is the mixture for 1 hour at room temperature touched. The precipitated triethylamine hydrochloride salt is filtered off and the! solvent is removed under reduced pressure, whereby one dibenzyl-cis-propenyldithiophosphonate receives. The trithioate is obtained when using cis-propeuylthiophosphonic acid dichloride used as a starting compound.

In this experiment, ethyl mercaptan is used instead of benzyl mercaptan or tert-butylthiol is used, then one obtains diethyl- and di-t-butyl-cis ~ propenyldithiophosphonate.

Example 9

A stirred solution of cis-propenylphosphonic acid dichloride (0.1 mol) in 200 ml of absolute ether is cooled to 0 ° C and a solution of absolute ethanol (0.1 mol) and triethylamine (0.1 mol) in 50 ml is added dropwise given anhydrous ether. The rate of addition is set so that a reaction temperature between 0 to 5 ° C. is maintained; when the addition is complete, the reaction mixture is stirred in the cold for 1 hour. The triethylamine hydrochloride which has precipitated is then removed by filtration and the filtrate is concentrated under reduced pressure, whereby O-ethyl-cis-propenylphosphonochloridate is obtained. ■ '«''

Example 10

0.01 mol of cis-propenylphosphonic acid dichloride and 0.15 mol Phosphorus pentasulfide in 100 ml of dry xylene are refluxed for 5 hours. The solid precipitation will

- 21 -

9 0 Ö 8 5 0 y t 7 3 8

BATH

J J

* a

12 437 it

then filtered off and the filtrate is mixed with two 50 ml portions Washed with water and dried over sodium sulfate, The solvent is distilled off and the residue under distilled under reduced pressure, cis-propenylthiophosphonodichloride receives.

Example 11

0.2 Get ice-propenylphoaphone acid dichloride in 200 ml of ether are cooled to -13 ° C and this solution is under Stir a mixture dropwise. 0.4 moles of iryridine and 0.4 Hol ß-Bydroxypropionitril given. The temperature will kept below -10 ° C. The mixture is then poured onto 1 l of water and 500 g of bis; The watery smell comes from the ether separated and extracted with 3 ι 100 ml portions of ether. The combined ether filtrate and extracts are washed with water, with dilute hydrochloric acid and finally with water again washed. After drying the ethereal solution over anhydrous em sodium sulfate, this is filtered and concentrated to dryness in vacuo, bis (2-cyanoethyl) -cis-propenylphosphonate receives.

Bis ~ (2,2,2-trichloroethyl) -cis-propenylphonate is used in the same way obtained by adding 0.4 mol of trichloroethanol in 100 ml of ether used in the previous example.

Example I 12

0.2 mol of eollidin is added to a solution of 0.1 mol of cis-propenylphosphonaic dichloride in 50 ml of benzene. While cooling to 5 ^° G, a solution of 0.1 mol of phenol in 30 ml of benzene is added. The mixture is stirred for 1 hour at 5 to 10 ° C. A solution of 0.1 mol of iso-jupopanol in 50 ml of benzene is added. After another hour will be

■■; ■■■ ·· ■ - - ■ ·: --22 - ·

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the salts filtered and the filtrate concentrated to dryness, where nan receives the isopropylphenyl-cis-propenylphosphonate.

Example 13

A solution of 0.1 mol of cis-propenylphosphonic acid in dry ethyl acetate is treated with 0.2 mol of triethylamine and 0.2 mol of H-chloromethylphthalimide aneohliessend. the stirred mixture is kept overnight at 40 ° C and then boiled back for 30 minutes. The mixture is filtered and evaporated the piltrate to dryness to obtain bisphthalimidomethyl- ^ cie-propenylphosphonate.

Example U _%

A solution of ammonia (0.2 mol) and triethylamine (0.1 mol) is added dropwise to a stirred solution of propenyiphosphonic acid dichloride (0.1 mol) in dry benzene (200 ml), which is cooled to 5 ° C. given in dry benzene (100 ml). The rate of addition is controlled so that a reaction temperature between 5 to 10 ° C is maintained. After the addition is complete, the reaction mixture is stirred for 1 hour at 5 to 10 ° C., refluxed for several hours and then filtered while still in the heat in order to remove the trifithylamine hydrochloride salt. Concentrating the benzene filtrate to dryness gives cis-propenylphosphonodiamide.

If the procedure described above is used of 0.2 mol of Ν, Η-diethylamine repeated, one obtains Ti, H, H ', U »-Tetraethyl-cis-propenylphosphonodiamide.

- 23 -909850/1738

· T. 1 ♦ ·

12 437 2 (ί

B 6 in hall 15 '

A solution of 0.01 mol of cis-propenylthiophosphonodl chloride in 20 ml of benzene is added to a solution of 0.02 mol of methanol and 0.02 mol of triethylamine in 50 ml of benzene . The mixture is refluxed for 8 hours, and the filtrate is filtered Concentrated vacuum, whereby one consumes 0,0-dimethyl -cis-propenylthiophosphonate

In the same manner, with the use of 0.01 mole of methanol O-methyl-cis-propenylthiophoephonochloridat ·

Example 16

A. To a stirred solution of eie-propenylphosphonic acid * · »dichloride (0.1 mol) in dry Xther (200 ml), which on . 0 ° C is cooled, a solution of diethylamine (0.1 mol) and triethylamine (0.1 mol) in dry Xther is added dropwise. The addition rate is adjusted so 'that a Reaktionstemporatur is maintained between 0 to 5 ° C · Kaeh completion of the addition, the reaction mixture is stirred in the cold for an additional hour and then the triethylamine hydrochloride is filtered off. When the solvent is removed from the piltrate under reduced pressure, NIT-diethyl-cis-propenylphosphonosacid chloride * amide is obtained.

B. A stirred solution of tQrt.-butanol (0.1 mol) and triethylamine (0.1 mol) in 100 ml of anhydrous ether is mixed with a solution of ftyfl-methyl-cis-propenylphosphonic acid chloride amide (0.1 mol) in treated with anhydrous ether. The mixture is refluxed for 1 hour and the precipitated triethylamine hydrochloride is then filtered off. On concentrating the filtrate under reduced pressure

- 24 909850/1738

it «ft

• · · · β 4

12 437. 8ίΓ

one obtains Owt-Butyl-ITjir-Äiäthyl-eie-propenylphoephonamidat. .

The diamides are obtained from cia-propenylphosphonic acid dichloride according to the procedure described above when using 2 holes of a primary or secondary amine *

Example 17

Phosphorus trichloride (68.7 g, 0.5 mol) and 750 ml of anhydrous benzene are placed in a 2 liter three-necked flask equipped with a mechanical stirrer, thermometer, dropping funnel and a drying tube. The solution is cooled to 5 ° C. and triethylamine (50.6 g, 0.5 MbI) is added at 5 to 10 ° C. over the course of 20 minutes. The benzene solution is then stirred for 20 minutes. A solution of triethylamine (50.6 g, 0.5 mol) and tert-butanol (37.06 g, 0.5 mol) is made with stirring at 5 to 10 ° C in the course of 20 Minutes are added and the mixture is stirred for 20 minutes. A second portion of tert-butanol (37 _t 06 g, 0.5 mol) is then added at 5 to 10 ° C over a period of 20 minutes and the reaction mixture, which contains bit-butyl chlorophosphite, is 90 minutes at 5 to 10 ° C stirred,

Triethylamine (50.6 g, 0.5 mol) and propargyl alcohol (28.03 g * 0.5 mol) are dissolved in 40 ml of anhydrous benzene and the solution becomes the reaction mixture, which is di-t-butyl chlorophosphite contains, added with stirring over a period of 25 minutes, the reaction temperature through external cooling «wipe 5 and 10? C is held. The mixture containing di-t-butyl-2-propynylphosphite is

- 25 - - ■ -

JBAD ORIGINAL

β · # «ft

12 437 * β

Stirred at 5 to 10 ° C for 1 hour.

The seaction mixture containing di-t-butyl-2-propynyl phosphite is then heated to reflux and 1 hour under Held at reflux. You solution is then with a water bath cooled to room temperature and 185 ml of water are added in portions. The TriäthylarairLhydrochloriä dissolves calibrate in the aqueous layer and the organic layer is separated from the aqueous layer. You benzene solution is heated at atmospheric pressure and the water through azeotropic distillation removed. The remaining benzene solution contains di-t ~ bu: tylpropadienylphosphonBt.

If desired, the pure ester can be obtained by the solvent is removed and the ester is distilled in a high vacuum. The pure ester becomes nuclear magnetic through IR and nuclear magnetism Characterized resonance spectrum "

The dry, benzene solution of the di-t-butyl-propadienylphosphonate is at 20 to 25 ° C with a 5 $ palladium-on-carbon catalyst (5.0g) hydrogenated until hydrogen absorption commences. The catalyst is by filtering removed and washed 2 χ with 50 ml of benzene * After removal of the solvent in vacuo becomes di-tbutyl-cis-propenylphosphonate obtained, which is characterized by nuclear magnetic resonance and infrared spectra will. The crude ester can be distilled in a high vacuum getting cleaned"

Di_t ~ btttyl-cis-propenylphosphonate (1.0 mol) and p-toluenesulfoleic acid (0.005 mol> are dissolved in 235 ml of benzene and The solution is refluxed until the calculated Amount of isobutene has formed. To prove the iso-

* i098S0 / 173fr

BATH ORIGINAL,

· ■ «t

12 437

butene, a gas metering device is used. the tion is then brought to room temperature and Solvent removed in vacuo, leaving ale residue eie-propenylphosphonic acid is obtained.

Example 18

Its stirred mixture of 0.1 mol of cis-propenylphosphonic dichloride and 0.2 triethyiamine in 100 ml of benzene is cooled to 5 ° C. To the mixture are 0.2 mol Methyl alcohol is added at such a rate that the temperature is kept between 5 and 10 ° C, after the addition is complete, 1 hour at room temperature. stirs · The precipitated firiäthyiaminhydrochloridsale becomes then filtered off and the solvent is removed under reduced pressure, taking dimethyl cis-propenylphosphonate remains behind. Other Si-OB-esters of the cis-IropenylphoephoneKure, in which R is alkyl, alkenyl, alkynyl, aralkyl or Means aryl, substituted alkyl, aryl or alkenyl are obtained in the same manner using 0.2 Moles of alcohols R-OH.

At example 19

A stirred mixture of cis-propenylphosphonic acid dichloride (0.1 mol) and triethylamine (0.2 mol) in 100 ml of Benaol is cooled to 5 ° C. Benzyl alcohol is added to the mixture (0.1 mol) is added at such a rate that the temperature remains at 5 to 10 ° C. After the The reaction mixture is stirred for a further 1 hour at room temperature. The precipitated triethylamine hydrochloride salt is filtered off and the solvent is removed under reduced bridge, the monochloro-monobenzyl ester remaining. Bazu is aqueous in ITatrium

- 27 -S09850 / 1738

12 437 IT

hydroxide is added and the mixture is stirred to form a clear solution. The solution is then acidified and extracted with n-butanol. After removing the The solvent remains monobenzyl-cis-propenylphosphpnate return.

Example 20 To-

12.2 g of cis-propenylphosphonic acid are gradually increasing 200 ° C in a S tickst off atmosphere under one pressure heated by 200 mm of mercury and kept at this temperature for 48 hours. The heating is then interrupted The product obtained is bis (cie-propenyl) pyronnoephonic acid "

Cyclic β dianhydride of the cis-Propc

Exactly 1 mole of water is slowly added with vigorous stirring Given 1 mol of cis-propenylphosphonic acid dichloride, the Temperature kept below 10 ° C by external cooling will. After the development of heat has ended, the mixture is heated to 120 ° C under a pressure of 50 mm, until no more gas is evolved, the cyclic dianhydride of cis-propenylphosphonic acid being formed.

Cis-Pro penyiieohypopfaosph'oräure t

0.11 moles diethyl chlorophosphonate of the Pormal (produced by reacting ethanol with phosphorus oxychloride) with 0.1 mol of ethyl cis-propenylphosphonate in 150 ml of ethanol mixed. The mixture is for 5 hours Eaumtemperetur stirred and then with sodium hydroxide

- 28 -Ϊ09850 / 1738

BAD ORiQSNAi.

"Pll: ¹ " j ¹ : ·; ::: ¹ ; ': !!! ίίίΐιΙϊϊΙίΐΐΐιΐΐϊϊί ^ ϊϊΐΐΓΐΐϊϊιΤίί ^ ΐίΐΐ'ϊϊΐτ ™: ¹ : !!! ¹ !!! ¹ : ¹¹¹ ;:?. ■■■ ■■■. ■. . '! yy

12-437

brought a pH value of 9 and 6 hours at 80 ° 0 «rhitit. The solvent is removed in vacuo to give disodium salt of dae tfatriira-cis-propenylisohypophosphorsäur · receives.

The cis-propenylphosphonic acid esters of the invention (wherein Y and / or Z of the formula I -OR and R, as indicated above, mean) are hydrolyzed to the free acid as in Example 3 and before the epoxidation to (i) (cis-1,2-epoxypropyl) -phoaphonates converted into a salt; but you can also epoxidize the propenyl ester and the Eetergyuppe then remove, the salts are epoxidized directly · typical examples are given below, where ee it goes without saying that other salts and other esters can be epoxidized in the same way:

Cis-propenylphosphonic acid (2.2 g, 0.018 mol) is dissolved in 10 ml of water. The pH of the aqueous solution is adjusted to 5.5 to 6 by adding sodium bicarbonate (1.51 g, 0.17 mol), to obtain sodium cis-propenylphosphonate, latrium wolfraaiate dihydrate (0.55 g, 0.0017 mol) is added and the almost neutral solution is immersed in a water bath and heated to 55 ° C. The water bath is then removed and 2 ml of 30% hydrogen peroxide are added to the reaction mixture over the course of 10 minutes. The reaction is exothermic and the temperature rises to 65 ° C. during the addition of the peroxide. A further 1.6 ml of hydrogen peroxide are added. During the addition, oxygen is evolved and the temperature remains at 55 to 57 ° C without external heating · flat 20 minutes standing, the temperature falls to 53 ° C * The reaction mixture is then heated in a water bath to 55 ° C for a further 20 minutes, filtered and the Solution is freeze-dried, whereby one

- 29 §09850 / 1738 ^r

BAD QfilWJL

12 437. "

the monosodium salt of (i) {cis-1,2-epoxypropyl) -phoaplionic acid obtained as a white powder, which by its granular magnetic Resonance spectrum is characterized

Peroxytrifluoroacetic acid is prepared according to the method of Emmons (J. Am »Ohem» Soc. JS. 4 ^ 23 (1953). A solution of 2.8 g of peroxytrifluoroacetic acid in 20 ml of chloroform is then added to 5 g (0.022 mol) of benayiammonium oie propenyl phosphonate and 7 g of solid disodium hydrogen phosphonate in 30 ml of chloroform are added. The mixture is left to stand at 0 ° C. for 16 hours, the pesticides are then separated off by filtration. The pesticides are suspended in about 10 ml of methanol; the slurry is filtered and the methanolic piltrate is evaporated to the crystalline in vacuo, a solid residue of benzylammonium (i) - (cis-1 »2-epoxypropyl) -phoaphonate being obtained.The product is purified by recrystallization from 10 parts of 95% ethanol.

6.4 g (0.02 mol) of dihenzyl cis-propenylphosphonate and 30 ml of chloroform are added to a 100 ml large-necked round bottom flask equipped with a stirrer, thermometer and dropping funnel. A solution of monoperphthalic acid (3.6 g, 0.02 mol) in 20 ml of ethyl acetate is slowly added and the mixture is heated to 40 ° C. The course of the reaction is followed by gas-liquid chromatography of the dibenzyl ester or by titration of the peracid * The reaction is practically complete in 24 hours. After this time the mixture is cooled to room temperature and the Perphthalsäur © _s to give the dibenzyl (£) was removed by filtration - (1-cis "2-epöxypropyl) ~ phosphonate after removal of the solvent in vacuo obtained. '· ■ ^ "^; = -'■" ■

■ - 30 -

73 8

ßAD ORIGINAL

t m mm

12 437

The cie-propenylphosphonamides, -thiophosphonates and -phoephoneUurehaiogenide (formula I ₉ in which at least one of T and Z represents _{-SR, halogen or BS 1} B ₂ ) are epoxidized and the (i) - (ciss-i, 2-epoxypropyl ) -connect in the same way as shown in the following example:

16.6 g of propyl-cis-propenylphosphonic acid fluoridate and 30 g of sodium hydrogen phosphate in 400 ml of methylene dichloride are placed in a three-shark round-bottomed flask. To do this, a Solution of 14 g of PeroxytrifluoressigsKure in 100 al methylene dichloride and the temperature is 12 hours Maintained 0 ° C. The mixture is then filtered; the solid residue containing propjl- (i) - (cis-1,2-epoxypropyl) -phosphonic acid fluoride is added to 100 ml of methanol. bit Sodium hydroxide brought to pH 4.5 to 5.5 and then treated with 6.9 g (0.1 mol) of hydroxylamine hydrochloride and then stirred for 7 hours at room temperature. she Mixture is filtered again and in vacuum to dryness concentrated. To this 90 ml of a 1: 2 methanol-Jceton-Hiechung are added and the mixture is 10 minutes under Maintained reflux, filtered, and the filtrate concentrated to dryness to give mouosodium aonopropyl (±) - (oie-1,2-epoxypropylj-phosphonate

15 g of peroxitrifluoroacetic acid in 110 ml of chloroform are added to 15.8 g (0.1 mol) of cis-propenylphosphonic acid dichloride and 30 g of sodium hydrogen phosphate in 400 ml of chloroform. The mixture is stirred for 11 hours at 0 ° C and the plague fabrics are collected by filtration. The solids containing (i) - (cis-1,2-epoxypropyl) phosphonic acid dichloride are added to 100 ml of water and the pH is _{adjusted to 4 f} 5 to 5.5 with sodium hydroxide and the mixture is made

io9850 / 1738

"6AD

Stirred for 6 hours at room temperature. t times this time the solution concentrated to dryness in vacuo. The Bückst and is extracted 3 χ with 30 ml of methanol »the methanol extracts are combined and evaporated to dryness in vacuo, whereby sodium (i) - (cis-1,2-epoxypropyl) phosphate is obtained.

To a mixture of 2.1 g (0.01 mol) of 8,8-diethyl-cis-propenlydithiophosphonate, 30 al n-propanol and 0 _ν 0β g sodium tungstate dihydrate at 55 ° C, 3 ml of 30 # hydrogen peroxide are added, the Peroxide is slowly added over a period of 20 minutes. The mixture obtained is stirred for 50 minutes at 55 ° C and then quenched to a negative starch yoke by adding a saturated solution of sodium sulfite. The solution is concentrated to about half the volume, 25 ml of fresh u-propanol are added and the mixture is concentrated again to about half the volume. 40 μl of methanol are added and the contaminants are removed by filtration. The filtrate is concentrated to to remove the solvent, giving ale residue S, S-diethyl (i) - (cis-1,2-epoxypropyl) -dithiophophonate.

0.06 g of sodium tungstate dihydrate are added to a mixture of 3.25 g of Η, Ν'-dibenzoyl-cie-propenylphosphonic acid diamide in 15 ml of methanol and the mixture is brought to 55.degree heated. 3 ml of 30% pure hydrogen peroxide are slowly added over the course of 15 minutes, and the mixture obtained is stirred at 55 ° C. for 1 hour. That during this Time added hydrogen peroxide is required to maintain a positive starch-iodine test. Hach end of Saturated, aqueous sodium sulfite is added for one hour

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give to destroy the remaining peroxide 2u. the mixture is filtered and evaporated to dryness under reduced pressure Pressure, whereby one H, H'-Dibenzoyl-Cij-fcis-i ^ -epoxypropyl) -phoaphousäurediamid receives. Inorganic salts are separated by dissolving the phosphonic acid diamide in methanol extracted and then removed the methanol.

In a 100 ml three-necked round bottom flask equipped with a Stirrer, thermometer and a dropping funnel, 6.4 g (0.02 mol) 0,0-dibenzyl-cis-propenylthiophosphonate and 30 ml Methylene dichloride is introduced · A solution is slowly added from monoperphthalic acid (3.6 g, 0.02 mol) in 20 ml of ethyl acetate given and the mixture is heated to 40 ° 0. The course of the reaction is followed by gas-plus-ear chromatography of the dibenzyl ester or by titration of the peracid · The onset is practically complete after 24 hours. After this time the mixture comes to room temperature cooled, the phthalic acid removed by filtration and the 0,0 ~ dibenzyl- (i) - {cis ~ 1,2-epoxypropyl) thiophosphonate obtained by removing the solvent in vacuo *

Di © (i) - (öie-i, 2-Bpo3cypropyl) -phosphonic acid compounds which have been prepared from the cis-propenylphosphonic acid compounds according to the invention can, if desired, be converted into the mono- and / or disalso the .. (i) - (cis-1 , 2-Bpoxypro- 'pyl) -phophonic acid can be converted according to the method described below; these salts have ant! bacterial activity:
a) for alkenyl, alkynyl, aralkyl or aryl esters:

A solution from 3 _? "2 g of dibenzyl (cis-1,2-epoxypropyl)" phosphonate in 250 ml of methanol is added at 2.80 kg / cm ² (40 psi) at room temperature for 15 minutes in the presence of 800 mg of a

- 33 Ö098 50/17 38

BATH

10 # Pal iBdiiim-auf-KohVPkiitalyaatn ^ s and 2 g hydrogenated bonate.

The Lasting is then filtered off by the catalyst and evaporated to dryness at room temperature in vacuo, aßn receiving potassium cis-i, ^ - epoxypropylphosphonate

b) for aryl and ftiedrigaikylesteri

4 g of phenyl- (i) - (cia-1 _t 2-epoxypropyl) -iÄoephonat in 100 si of a 2? Cigen, aqueous solution of triaethylanmoniuocarbonat are irradiated in a quartz flask at 25 to 30 ° C for 4 hours with an ultraviolet lamp. The solution is then evaporated to dryness and the residue is extracted with water-free methanol. The solution is passed through a sulfonic acid acid (IR 120, previously made water-free with methanol) in the (H *) - Porm at 0 to 5 ° C. The end of the discharge is collected and quickly adjusted to pH 5 with oyolohexylamine. When the lueung is centered towards the vrootae, one obtains the monocyolohexylamineale of the (-) - (cie-1,2-epoxypropyl) -phoephonetture «

40 ml of a medium consisting of 0.8 ml of HahrbrUlie, 0.2 ml of yeast extract, 3 t of gerelose and 0.3 of Malm extract is adjusted to pH 7 and then in a 250 ml Brlenmeyer flask pressurized at 121 ° C. and 1.12 atmospheres (15 psi) The medium is then inoculated with a vaccine from an agar slant from ABpergillus niger, and the bottle on a mechanical shaker (220 revolutions / minute ) incubated at 28 ° Q until the cultures have grown well (2 to 4 days). 10 ml of the fermentation broth are then aseptically transferred to a centrifuge

- 34 -

8ADORiGlNAL

rf tm r

t f C · ·

12 457

3?

tubes, transferred and the cells were tabletted with 25,000 χ g · The excess material is discarded and the cells are again suspended in 4 ml of distilled water « 2 ml of this cell suspension is aseptically transferred into a sterile 20 χ 200 mm reagent which contains 2 γ sodium ethyl (i) - (is-1,2-epozypropyl) -phoaphonate Bas Glae contained in 2 ml of water is put on a mechanical for 20 hours Incubated shaker (220 revolutions per minute) at 28 ° C. the Cells are then removed by JSer centrifugation (25,000 χ g). The excess is evaporated to dryness in a yakuum, where »on sodium (i) - (cis-t, 2-epoxypropyl) phosphonate receives.

■ c) for substituted alkyl and aryl esters ;

0.1 Hol Bi- (acetoxymethyl) - (i) - (cis-i, 2-epoxypropyl) phosphonate are dissolved in 50 ml of Weaaer and desu are 0.1 Get calcium oxide given. The solution is heated to 20 to 30 ° C for 2 hours while stirring. She will then be in the takiium Icon-centered to dryness, all residue calcium- (±) _ ( a-1,2-epoxypropyl) -phosplionate is obtained.

d) _r i ÜR arylC "tor:

5 g of diplienyl (i) - (cie-1,2-epoxypropyl) -phosphonate in 5 ml of methanol were added to 100 ml of Triraothyläiain. Small Ifatriumotücke was slowly added thereto up to a total amount g VCRA 2.0. The lüaungamittol is removed by concentration and extracted from the product with Hechanol. The methanolxBcLiw Löaußg vird then üfccr a Süulc vou IR 120-Hare (Jn äty v'aeöerB ^ afrorm) fcfcÄßi: et _t iie vorgektüilt t.-cr. The abf3! Essende throws PhenEthylerainen to pH- ¥ crä 3.2 basic and concentrated, whereby the (i> - (cis-1,2-EBox ^ prop3rl) -pIiospaonaäuro as bis-phenethyl-

- 35 - '
909850/1738

Il

12 437

The (i) - (cie * -1,2-epoxypropyl) -phoBphonamidate, -thiophos- » Phonates and -phosphonic acid halides are converted into the antibacterial, active salts of (-) - (cis-i, 2-epoxypropyl) -phosphonic acid according to the methods described below:

The compounds of formula I in which one or both of Y and Z denote halogen and in particular chlorine or bromine, are easily converted into the corresponding phosphonates, by heating them in an aqueous medium at temperatures ranging from tree temperature to 50 ° C. The beds Results are obtained by heating in aqueous alkali hydroxide, e.g. B. sodium or potassium hydroxide, in one pH value from about 4.5 to 7.5 at 40 to 50 ° 0 for 3 t> is 5 hours. The Aikalimetallphosphonsäuresäuresalee obtained can be obtained by known processes · Trap X and / or Z in formula I denote fluorine, the fluoride is replaced by treating the phophonic acid fluoride with hydroxylamine in an aqueous medium, preferably at a pH of about 5.0 to 8.0

If X in formula I means sulfur (i.e. thiophosphonate), the sulfur is replaced by oxygen by treating the sulfur-containing compound with peroxyltrifluoroacetic acid or with bromine water, as the following example shows: To 0.1 mole of O, O-dibeneyl (i) - (cis-1,2-epoxypropyl ) thiopliosphonate and 30 g of disodium hydrogen phosphate in 400 ml of chloroform, 15 g of peroxytrifluorous acid in 100 ml of chloroform are added. The mixture is stirred at 0 to 15 ° C for 10 hours. The reaction mixture is then filtered and the filtrate is purified in vacuo Concentrated dry to give 0,0-dibenzyl (i) - (cis-1,2-epoxypropyl) -pnoQplicnat.

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12 '437

If Y and / or Z in formula I is -SR, then these thiophosphonates and ditmcphosplionates are converted into the phosphonates by. Eian she treated bit silver nitrateί

0.1 mol of S, S'-diethyl (i) - {ci3-l, 2-epoxypropyl) -dithiophosplionate in 100 ml of water are added to 0.2 mol of sodium nitrate in 200 ml of water 10 g of potassium chloride and 50 ml of water are poured in for minutes, the mixture is filtered and the precipitate is washed with water. cis-1 ^ -epoxypropyl-phosphonate is obtained, but also the combined filtrates and wastewater via a Dowöx-SO-Kationauotauschharö (in the Waasöjcstoff-.fvi ^! äi} lead from the column drainage, whether .es dlb Ci) - (CiS-IyS-BpOXyPrOPyI) -PhOSPhOnBaUrO contains, neutralize with one molar equivalent of Benzylandn, whereby Bsri3ylaffimonium ~ (^) - (CiS-I j2-epoxypropyl) -phosphonate

liedeutet .Y "UUED / Odei · Z in formula I is -NR ₁ H _2, they will be I'IioophonsäTireaiiide and Phospiionsäurediaiaide in the (i) -1,2-lpoxjrpropy; i) ~ ionate} p3iosp transferred by base ©

Get Sr *! Jjli ^T * F ^I

Hb.casaurediaraid in 100 si water vrerden with .0,1nUa-T? Ii5-drn.i: id ti brought the pH to 8.2 and the -Mi-L & - ·; ί · Μ! fifVande filtered at 50 ° C. You will then be on 10 ° f ijölcf'ujjbfe and'untöx Htihreti are 0.1-TIoI-

otijiuxat: r.ugeg <jl) in, The mixture is 1 hour at 10 hi-Λΐ ' 1i; ^! C £ 5irahtt .md the precipitated Galciuni- (i) * (jiv, • i. _I 2-.i-nocv; ci.-op37l) phosphonate by filtering

- 31 -

BATH

12 437

Palls desired, the ao obtained (i) ~ (cia-1,2-EpOXyPrOPyI) -P] IOaPiIOYiSaIXrOIiSaISa in their '*' optical Εηάή-tiomeron umgßlagaci-t by forming a SaIa with an optically active area, dio Oiastereomö- ^received: separates ren and regenerates the enantiomaren salts:

A solution of "49" 1 g of the Monobenzylamraoniurasalzea racemisehen (ci3-1 _r 2-epoxypropyl) -phosphon3äure in 490 ml water was 5 ° C is cooled and passed through a column to 0 ms, the 330 ml of a sulfoüsaureu Kafeionauatausöhharzeo v ^ om Polystyrene type (Dovsx 50) {± n äei ^s ' S & uxe £ ox m) contains * which was previously cooled to 0 ms 2 ° C The column is then washed with 660 ml of 0 to 5 ° C warm water at the same speed! 7iainin in 100 ml of water, stirred vigorously. The pH of the solution obtained is then brought to 4.8 by the dropwise addition of an aqueous solution of (+) α-phenethylaiain. The solution obtained is evaporated to 95 to 100 in vacuo ml and sufficient isopropanol (about 320ml), which was preheated to 70 ° C, \ vrird that the solution is about 20 % ' Water contains * The reading obtained is heated to 75 to 79 ° C with gentle agitation and then quickly cooled to 60 ° C and treated with a small amount of Honp ~ (+) - phenäthylaimaoniuia- '(-) - {cis-1,2 «Epo3rypropy; l) ^: --phosphQna t inoculated * This solution is then cooled to 0 to 3 ° C and slowly stirred for 16 to l for 24 hours» - whereupon the crystalline M-astereomeran precipitate and are collected by filtering . Of the. The filter cake is washed with 40 ml of cold isopropanol Viasser (9? L) and washed with 40 ml of cold isopropanol. The crystalline product is then washed at 40 ° C

909B50 / 1738

8AO

12 437

dried to constant weight in vacuo and then heated at 2 ° C per minute. The product shows a rotation / 2/405 rough ^ "^ ^ * ** 2 ^ ^β 2.6 °. Recrystallization from aqueous isopropanol gives a crystalline product which melts at 133 to 136 ° C. and shows the same rotation.

1 g of N ^^ K'jK ^ -Tetramethylpropynylphosphbnsäureamid is dissolved in 10 ml of methanol and hydrogenated at atmospheric pressure in the presence of 250 mg of 5 f * palladium-on-calcium carbonate-After the theoretical amount of hydrogen has been absorbed, the reaction mixture is filtered and the piltrate is concentrated to dryness in vacuo, * where Ν, ΪΓ, Ν ¹ , -H'-tetramethyl-cis-propenylphosphonic acid diamide is obtained as an oily residue «The infrared spectrum of the product shows the presence of the 6.12 ^ t band, which is characteristic of flae is cis -olefin.

The N, K, N ', N »-Tetramethylpropynylphoephonsäurediamid used as starting compound in the above-described process is obtained by slowly adding a solution of 0.1 mol of methylacetylene magnesium bromide in 500 ml of benzene and 100 ml of tetrahydrofuran with stirring to a solution of 0, 1 mol, Ν, Η ·, IP-tetramethylchlorophosphonic acid diamide in 200 ml of benzene. The addition is carried out over a period of 3 hours, keeping the temperature below 28 ° C. The clear solution obtained is left to stand for 15 hours at room temperature . 200 ml of aqueous ammonium chloride are added and the water layer is separated off and washed twice with benzene. The combined BenzollöBungfcTi are dried over anhydrous sodium sulfate and im

_ 39 -ϊ £ -

t * t y · · »

Ii »· ■. f · ■ »- τ

1 * «1 M

12 437 "

Valcmim concentrated to dryness, using Ν, ΪΪ, ΪΓ% ΪΡ me-bhylpropynylphoopiionsaurediamid receives ^

If the procedure described above is repeated Use of U, H - diethylpropynylphosphonaaaidate (obtained from NyN diethyl jjhoaphonamidodichioriaat and Methylacetylenmagneaiumbromid), this gives HyK-diethyl ~ cia ~ propenylphosphoTiamida t.

-. AO 8098 50/173 8

BATH ORIGINAL

12 437

Below are some metrics from connections according to of the invention:

link

crystalline mono - (+) - phenäthyIammonium - (-) - (cis-1,2-epoxypropyl) -phosphonate Physical key figures

P. 133-136 ° C

Quinine salt of (-) - <(ol8-1,2-epoxy- P> 150 ° C (decomp.) Propyl) phosphoric acid

ciii-propenyl phosphoric acid

ice-propenylphosphones & urediohloricl

ei 3-propenylphoaphorodichlo-

Diaciit oxymefchyl-O is- propenyl-

phon & b Oläth "j 1- c 1 β» pr openyiphosphonat DlIs opropy1 - gi s-propenylphosphonat

Ν, ίί, Κ ⁵ , N * -Tetramethyl-ois-propenylphoaphonsjiurediaraid l olefinic band at O ₃ I μ

Bp 67 ° - 69 ° C / 9-10 mm ng ⁰ - 1.4885

Bp 28-31 ° C / 0.5-0.25 ram

ng ⁷ »1.4450

Bp 72 ° C / 0.12 mm

Sdp. 142 ° C / 13 mm Sdpo 42 ° - 43 ° C / 0.15mm

IR: 6.12 u band Sdpi 71 ° C / 0.5 mm

BATH

I ·

4ft

Connection physical indicators

Ammonium salt of 1-propynylphos- · P. 200 ° - 205 ° C phonic acid

Dlethyl propynyl phosphonate bp 62 ° -76 ° G / 10 mm

di-n-butyl-propynyl-1-phos- Sdp. sol ⁰ C / 0.15 mm phonate

Dilsopropyl-propynyl-l-phoaphonate Sdp »82 ° - 84 ° C / 0» ¹ * -

0.45 mm

- 40b -

9098S0 / 1738

BAD ORiöiHÄL

Claims (1)

* f * t * t t I 437 October 28, 1968 Claims 1 · A cis-propenylphosphonic acid compound of the general Formula HH ^ r ^X H ₃ C - O * C - P - Y, ^ Z in which mean X oxygen or sulfur; , Y -OR, -SR, halogen or -NR ₁ R ₉ ; Z -OR, -SR, halogen or -NR ₁ E ₂ J R is hydrogen or a hydrocarbon radical; R- and R2 each hydrogen, a hydrocarbon radical or an acyl radical, and if R is hydrogen, the salts of the abovementioned compound. 2. A compound according to claim I, wherein the hydrocarbon radical is lower alkyl, substituted lower alkyl, Lower alkenyl, alkynyl, phenyl, substituted phenyl, Benzyl or substituted benzyl and the acyl radical is lower alkanoyl or bensoyl. 5. A compound of Claim 1 wherein X is oxygen and Y and Z mean -OR. 4. A compound according to claim 1, wherein X is oxygen, Y and Z —OR and R an aralkyl or lower alkenyl radical mean" 5. A compound according to claim 1, wherein X is oxygen and Y - 41 909850/1738 12 437 and Z represent halogen. 6. A compound according to claim 1, characterized * that it is cis-propenylphosphonic acid dichloride. 7 cis-propenylphosphonic acid and its salts, 8ο A mono-salt of the compound according to claim 7 # "9. A di-salt of the compound according to claim 7 # 10. An alkali salt of the compound according to claim 7 » 11 «Connection according to claim 7», characterized in that it is Natriura-cis-propenylphosphonate 12. An amine salt of the compound of claim 7. 13. A honöastin salt of the compound according to claim 7 14 «Compound according to claim 7, characterized in that it is benzylannaonium cia-propenylphosphonate. 15. A compound according to claim 7 characterized in _t, that it is a-Phenethylairaonium-Gis-propönylphosphonat. 16 »Connection according to claim 7, characterized in that it is ethylene diammonium cis ~ propenylphosphonate " 17. A compound according to claim 1, wherein Y and Z are linked by a methylene or arylene radical · 18. A compound according to claim 1, characterized in that - 42 9098 50/17 38 437 aie the cyclic eoter from cis-propenylphosphonic acid and propylene glycol is 19 »Compound according to claim I ₁ in which Y and 2 are connected to one another via a methylene or arylene bridge and Y or Z contains nitrogen. 20 * Process for the preparation of a cis-propenylphosphona acid compound the formula HH ^
- C «0 - P- where H- πηα R ^ each hydrogen? Medrigalkyl or aryl cycloutene or a salt of the compound identified by the formula "if one or both of R 1 and H _y denote carbon dioxide, by the fact that a compound of the formula -zorin H ^ and R. are as vorhei ^one called hydrogenated xT, · ' 2A * ancestor according to claim 20 »characterized in that cliLQ Hyilrienmg carried out in the presence of palladium 2 °. VOIfSlLt-SnIIaChAiIaPa ⁴ UCh 20, marked thereby, 9098 50/1738 © AD Hi- 437 the hydrogenation carried out in the presence of Raney-Wiclcel will" * 23 Process for the preparation of cia-Propönylphosphonsäuredihalogeniden, dadt'.reh marked that one cis-UPropenylphosphonic acid with a monyl halide implements, 24 »Method according to claim 23 for the production of cis * Propenylphosphonsätiredichlorid, thereby drawn, daaa one ois-propenylphosphonic acid with thionyl chloride implements. 25, method 2 for the preparation of an ester of cis-propenyiphosphonic acid, characterized by »that one cis-Propenylphosphoiigäurödihalogeriiä with an Al » converting alcohol, 26, method according to claim 25, characterized _? that the Phoöphonsänrsdihalogenid is Phoaphonsäureäichlorid. 27, process for the preparation of an ester of cis-5ropenylthiophosphonsäure, characterized geicennseichnet DASA one ciSfPropenylphosphonsäuredihalogenid.mit.einem ΦΜοΙ reacted. 28 «Method according to claim 27, characterized in that that the phosphonic acid dihalide PhoBphonaäurodichlorid is" 29, process for the preparation of an amide of cis-propönylphosphonic acid, thereby gelcenn.aeiö'.met, class man - 44- - ■■ -, ■ 909850/1738 0AD 437 Cio-Propenylphosphonsäiiredihalogenid ait «iutrn primary or secondary amine. 30 · The method of claim 29 "wherein _t is the Phosphonsäuredihalogenid Phoaphonaäuredichlorid. 31. The method sur preparation of a compound according to claim 1, characterized in that a _{Propinylphosphonaüureverbindung}} of Formula - 0 ίί C - P - Y in which X, Y and Z have the meaning given in Aasetzt 1 reacts with Waaoorstoff in the presence of a catalyst. 32. Process for the production of cia-propenylphosphonic acid or a salt thereof, characterized by the fact that a maximum of a compound according to Ans pinch 1, in much more at least one Y and % have a meaning other than OH, hydrolyzed, 33. The method according to claim 32, characterized in that theo the hydrolysis is carried out with mono-acid. ■ - 45 -909850/1738 6AO ORIGINAL