DE1924264A1 - Process for the preparation of phosphonic acid compounds - Google Patents

Description

Process for the preparation of phosphonic acid compounds

The present invention relates to a novel process for the preparation of {cis-i ^ -EpoxypropylJ-phosphonic acid and their salts and ester derivatives by reacting an IOrm ^ lphophonats with an appropriately substituted ethylid derivative.

The (i) - and (-) - (cis-1 _t 2-epoxypropyl) -phosphonic acid product according to the invention and its salts are anti-microbial agents which effectively inhibit the growth of both gram-positive and gram-negative pathogenic bacteria (-) - Form and especially its salts, such as the sodium and calcium salts, are effective against Bacillus, Escherichia, Staphylococci, Salmonella and Proteua pathogens and their antibiotic-resistant strains. Representative such pathogens are Bacillus aubtilis, Escherichia coli, Salmonella schottmuelleri, Salmonella gallinarum, Salmonella, pullorum, Proteus vulgaris, Proteus mirabilis, Proteus morganii, Straphylococcus aureus and Staphylococcus pyogenes. Thus, (-) - and (~) ~ (cia-1,2-Epo3: ypropyl) ~ phosphonic acid and its salts can be used as antiseptic agents for removing organisms that are sensitive to such agents.

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mechanisms of pharmaceutical, dental and medical ßöraten and other zones susceptible to infection by such organisms can be used. In a similar way you can they are used to separate certain microorganisms from mixtures of microorganisms be used. The salts are (-) - (gis-1,2-epoxypropyl) phosphonic acid 3 are particularly valuable because they are not only used in the treatment of diseases caused by bacterial inföctions May cause corrosion in humans and animals, application but also against reactive strains of pathogens are effective. The salts mentioned represent a preferred embodiment of the present invention, well they are effective when administered orally, although they can also be administered parenterally.

According to the present invention, (cis-1,2-epoxypropyl) -phosphonic acid and get their Kster derivatives (I, below) conveniently, by a Pormylplioaphonat with an Ethylid {II, below) is treated because on the methylene carbon atom (i.e. at the -CH carbon atom) a suitable, removable group carries as a substituent. The removable one bound to the ethylid Group can be any radical under the reaction conditions Undergoes cleavage in such a way that the formation of the epoxy product is made possible. Typical of such removable Groups are, for example, di-lower alkoxyphosphinyl or the sulfoxonium, ammonium, sulfonium or phosphonium cation; The following reaction equation illustrates the method according to the invention:

0 0

M®-CH® -OH ₃ + OCH-P (OR) ₂ -> CH ₃ -CH-OH - ^ (OR) ₂

II I

Here R denotes lower alkyl, such as methyl, ethyl, τι-propyl, Isopropyl, η-butyl, n-uayl and the like, lower alkenyl, such as

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SAD ORfGINAL

Allyl and the like, aryl such as phenyl, naphthyl and the like , or aralfcyl, such as bensyl, phenylethyl, menophthyl and the like, and H * di-thi-lower alkoxypliosphinyl, vrie Dime thoxyphoε phinyl, Bi & thoxyphosphinyl and the like, a di-lower alkylsulfonium cation or a di-arylaulfoniura cation, such as dialkylsulfonium and diphenylsulfonium and the like, a ri ~ low alkylammottium cation. like Triäthylammoniura and like, a di-lower alkyl sulfoxonium cation, such as dill thylsulfoxonium and the like, a l'ri-lower alkylpIiOG-phoniuia-cation, such as Triätliylphosphbonium and the like, or a tri-arylphoaphonium cation. like triphenylphophonium and der Gleichött.

The application of heat and the variety of solvent are not critical aspects of the invention .; When mixing the reactants, however, it is advantageous to add the pormyl phosphonate to a solution of the ethylide (II) at a temperature in the range from about the freezing point of the reaction, preferably 0 ° C, to about room temperature, "see below. As soon as the form-phosphonate-ileactant has been added, the reaction can then be facilitated by applying a little heat, for example by setting the temperature above room temperature up to about the boiling point of the ileaction mediumB, preferably to about 90 ° C is heated.

Bas ancestors can be any solvent or any in souls any solvent combinations are carried out in the bsw «who the starting materials are reasonably soluble and that or which are practically inert with respect to the reactants used

is or are. Suitable solvents include, for example Ethers such as diethyl ether, tetrahydrofuran and the like, or dimethylsulfocid-.

In the practical Uurdafülii-it is necessary, in order to bring about the formation of the (cis-1 _f 2 ~ Bpoxypropyl> -pho3phonaic acid ~ productGß oäei- of its ester derivative a, that the formyl-

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phosphonate reactant is added to a solution of the ethylide (II). For practical reasons, however, it is usually desirable to prepare the ethylide reactant in situ in a solvent which serves as a reaction medium for the condensation of the ethylide with the formylphosphonate reactant, e.g. B. in an ethereal solvent such as diethyl ether and the like. For example, the dialkylsulfonium and di-alkyleulfoxonium ethylides (Ha, below) can be prepared by simply adding an alkyl halide with a di-alkyl sulfide (reaction equation 1, below) or with a dialkylsulfox: id (reaction equation 2, below) Formation of the corresponding tri-alkyloulfoxonium or tri-alkylsulfonium halide "treated and the intermediate product thus obtained (Hb, below) is then treated with a suitable Baee, such as sodium methylsulfonylmethylide, to form the desired ethylide derivative (Ha). The thus obtained Compound is suitable for direct use in the process according to the invention and can be mixed directly with the formylphosphonate reactants in order to bring about the synthesis of the desired (cis-1,2-epoxypropyl) * -phophonic acid ester product:

(1) (R ¹ ) ₂ S + C ₂ H ₅ X-> (R ¹ J ₂ S ^ OH ₂ -CH ₃ X

θ base

(2) fR ² ) S0 -! -

Here, R is lliedrigalkyl, such as ethyl, or aryl, such as

Phenyl ²

anion.

Phenyl, and R ² lower alkyl, such as Xthyl and X "a Hslogen-

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The Tri-niearigelkylammonium-ethylid precursors are used for the process according to the invention sweckmäasigerweise on the way on the implementation of a tetra-low alkylene mottium halideB made with an organo-lithium reactant:

* (H ¹ ) Χ ^θ + R ³

H * (H ¹ ) ₄ Χ ^θ + R ³ M

Here, B * denotes an organic radical, such as alkyl, aryl, 2. B. phenyl and the like, or aralkyl, see e.g. benzyl and the like, and X * "is a halogenation, and R has the meaning given above. If desired, the triethylanaonium ethylide thus obtained can be obtained by recrystallization from a suitable solvent, e.g. by recrystallization from ether, getting cleaned"

The di-nledrigalkoxyphospninyl-ethylides, which are also used as starting materials for the inventive method, are synthesized by adding a bi-lower alkyl ethyl phosphonate is treated with a suitable base, e.g. with sodium methyleneulfonylmethylld:

CH ₃ -CH ₂ -J ((A) ₂ CH ₃ -OH ^ i (OR) ₂

Here, S has the meaning given above. Via the Bi-alkyl-BUlf ouiue- and Di-alkylaulf oxonium-ethylides are suitable

for the "nmlttelbar · application in the process according to the invention ao * kttnutm directly be rermlsoht with the fornylphoephonat-Beaktanten to the Synthesis of the fewtoeohten (oi «-1,2-lpojtypropyl) -fho« ihon »llur · - eater-> TQdttkf · »m

Di »erfinflWBfgOM» »rhalUmwi, tw — terfn (oiaw1,2-Bpoiy'-propyl) -i« »· in al» eelok * i solieri

or the named prayers can by hydrogenolysis, by treating with an aqueous solution of a mineral acid such as hydrochloric acid or sulfuric acid, with care buffered conditions or by treatment with trimothylchlorosylane and subsequent aqueous hydrolysis into the corresponding (18-1,2-epoxypropyl) -phosphonic acid.If desired, the cis-1,2-epoxypropyl) -phosphonic acid obtained in this way can then be converted by treatment old a watery one solution of a base, e.g. B. by treating with an aqueous solution of sodium hydroxide, lithium hydroxide or calcium hydroxide and the like, into their corresponding salt, such as the Alkali metal or alkaline earth metal salt.

The following examples illustrate the method by which (CiB-I ₉ S-BpOXyPrOPyI) -PhOePhOnSaUTe and its salts and ester derivative (1) can be obtained. However, the examples are representative only and are not to be construed as limiting, as other functionally equivalent reactants may be used in place of the reactants used therein to produce an identical (cis-1,2-spoxypropyl) phosphonic acid product and its corresponding hydrochloric acid. and to produce ester derivatives.

The (-) - (ois-1,2-epoxyproryl) -pho8phone acid, to which reference is made here, rotates linearly polarized light counterclockwise (to the left when viewed from the observer) when the rotation of its disodium salt in water (concentration 5 t) is measured at 405 ΐπμ.

The term oia used for the description of the 1,2-Bpoxypropylphoephonsäureverbindungen means that every * which is attached to the carbon atoms «1 and 2 of the PropylphoephoneMure “Umdeoem hydrogen atoms on the same side of the oxide ring • tea «.

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Be i β _± ρ 1 e 1 _. 1

(ois-i ^ -EpoxypropylJ-phosphonic acid and its calcium sala

Stage Ai diethyl formylphosphonate

1 equivalent of formic acid anhydride is given as sodium diethyl phosphite, which has been prepared by adding diethyl phosphite via sodium in dry ether with stirring and cooling. The mixture is then filtered to remove sodium acetate, and the remaining filtrate is an ethereal solution of diethyl formylphosphonate which can be used immediately for stage 0 of this example.

Stage B , i Piäthyl-gulfoxonium-äthylia,

Diethyl sulfoxide and a 2O # solution of ethyl iodide

Heated to 100 to 110 ° C for 2 days. After removing excess solvent in vacuo and cooling becomes triethylsulfoxonium iodide obtained as a crystalline solid, and said salt is purified by filtration with. Washed ether and dried over sodium sulfate * The purified triethylsulfoxonium iodide (10.0 g) is then with 1 equivalent Sodium methylsulfonyl methylide in 200 ml of dimethyl sulfoxide treated. Diethylsulfoxonium ethylide is obtained.

Level Ct ethyl (cie-1.2-epoxypgopyl) -phosphonate

1 equivalent of diethyl f onaylphosphonate is added with stirring 10 ° C to the solution of diethyl sulfoxo • rtium ethylide obtained in stage B given. The ether and the dimethyl sulfoxide become stripped in vacuo, and the residue is poured into egg water, extracted three times with ether and dried over sodium sulfate and evaporated. Diethyl (cis-1,2-epoxypropyl) phosphonate is obtained.

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Grade D: Hono-triäthTlQBBOniusi-aalz der (cie-1,2-epoxypropyl) -phosphoric acid

To a solution of 0.1 mol of dihenzyl - <(ole-.1,2-epo * ypropyl) -phoaphonate and 0.1 mol of triethylamine in 200 ml of ethanol 10 to 15 g of Baney hickel are added and the mixture is mixed with Hydrogen under a pressure of 2.61 kg / cm (40 p.s.i.) Shaken at room temperature until the absorption of water is practically complete. The test room will then filtered free of catalyst and evaporated the Piltrat Monotriethylammonium- (cie-1,2-epoxypropyl) ~ phos ~ is obtained phonate

Example 2

-i »2-epoxypropYl) -phoBphonat

Stage At triethylammonium ethylid

10 Hilllmol tetre-ethylammonium bromide in 20 ml Xther eu of a solution of 20 Hilllmol phenyllithium in Xther at 25 ° 0. After stirring for several hours, the solids are allowed to settle. The supernatant liquid is decanted off, washes the remaining solids once alt Xther and decants the solution again. Tri-ethylammonium ethylide is obtained as a crystalline pesticide.

Stage Bg Dimethyl-f cis-1.2 ~ epo3cvnropyl ) phosphonate

7.0 millimoles of dime thy l-formylphosphonate in 25.0 ml of Xther are slowly added to the triethylammoniumUB-ethylide obtained in step A while stirring at 0 ° 0 another half hour "boiled under Bückfluss The Xther is atmospheres pressure abdestllllert under, ι, _β aie reaction temperature ι 90 ° G reaches, but has not exceeded. The deficit is in

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Distilled in vacuo. Dimethyl (oiB-1,2-epoxypropyl) phosphonate is obtained.

B β i g ρ j Q 1 j

Dimethyl- (ois-> 1.2-eposypropTl) -nhosphotrate Stage ft »Di & tfryleulfonium-äthylia

A mixture of 80 pounds of diethyl sulfide and 20 # of ethyl bromide is heated to 105 ° C for 24 hours. Haeh the removal Oversized Löavmgsrittöls in a vacuum and cooling is triethylsulfoniua-'bromid ale crystalline feather recovered, and SaIs is then filtered and washed with. Purified with ether and drying over sodium sulfate. Dae Sriäthyleulfonium-broaid (10.0 g) is then given with 1 equivalent Sodium methyl sulfonyl methoxide in 200 al dimethyl sulfoxide treated to substitute diethyleulfonium-fethylid.

Level Bt Dimethyl- (eia-.t «2« "epoxypropyl) ~ pho8T? Honat

A solution of disethylaulfoniura-ethylid is mixed with 1 acetylene of the ether solution obtained according to Example 1, stage A added by diethyl forylplioaphonate. Ether and dimethyl sulfoxide are then stripped off in vacuo and the residue becomes Poured into ice water, extracted three times with ether, dried over sodium sulfate and evaporated. Dimethyl (cie-1,2-epoxypropyl) phosphonate is obtained.

Example 4 Dimethyl- (oia-1,. 2-enoxypropyl ) phosphonate Stage At Diathoxvpnoaphinyl-äthylia

1.0 mol of diethyl ethyl phosphonate slowly becomes 1.0 mol of Ha-

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trium methylsulfonyl methylide in 500 al dimethyl sulfoxide 20 ° 0 given »to a solution of diethoxyphosphinyl ethylide to manufacture.

Stage Bi Dimethyl- (eis-1,2-et? 03cypropyl) ~ phoeT) hqnat

2u of the solution of diethoxyphosphinylethylide obtained in stage A becomes a solution of 0.1 mol of dimethyl formyl phosphonate given in 65 ml of ether at 10 ° C in the course of 2 hours. The temperature of the mixture is held at 10 ° C for 4 hours and slowly increased to 60 ° 0 in the course of 5 hours. The solvent is then removed in vacuo and the residue in bis-water, the pH of which has been adjusted to 8, ge ~ pour. The mixture is extracted three times with ether. The ether is dried over sodium sulfate, and the filtrate is evaporated. The residue is a mixture of dimethyl propenyl phosphonate and dimethyl (cis-1,2-epoxypropyl) phosphonate, which is separated by vacuum distillation. Dimethyl (cie-1,2-epoxypropyl) phoephonate is obtained.

example 5

pimethyl- (cis «-1,2-epoxypropyl ^ -phosphonate

Stage A: friphenylphosphonium ethylid

A solution of 0.1 mol of methylsulfinyl-carbanion. in 200 ml Diaethyl sulfoxide is cooled to 10 ° C. and during the addition of 37.0 g (0.1 mol) of ethyl triphenylphoaphonium bromide roared. The reaction mixture is then stirred for an additional 15 minutes at room temperature. The product thus obtained is a solution of triphenylphosphonium ethylid.

Stage B: dimethyl (cis-1 »2-epoxy propyl) phosphonate

0.1 mol of dimethyl formylphosphate in 65 ml of ether to ground

- 10 -

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added to a solution of 0.1 mol of tri-phtenylphOBplionium ethylide in 250 ml of dimothyl sulfoxide, nnd the solution is kept at 0 ° C. After removing the solvent in vacuo, the residue is treated with egg water, the triphenylphosphine oxide is filtered and the mixture is extracted three times with ether. After drying over sodium sulfate and evaporation of the solvent, the residue contains a mixture of dimethyl propyl phosphonate and dimethyl (cis-1,2-epoxypropyl) phosphonate ₍ which is separated by vacuum distillation. Dimethyl (cis-1) is obtained , 2-epoxypropyl) phosphonate.

11 -

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Claims (8)

273 12c May 1969 P a t e η t a , η s ρ r , ti che / 1. yVerfnhren sum Heistellen vou (cis-1 _} 2-epoxypropyl) -plios- \ _y phonic acid and its salts and ester derivatives, characterized that a Pormylphoaphonat is treated with a: lthylid, which is on the metal ~ carbonT> 8toffatom has a suitable, removable group as a substituent, 2. The method according to claim 1, characterized in that d & cs ^ the more distant group a Phoaphinyl-, SuIfosronitun-, Ammonium, sulfonium, or phosphonium ion i3t. 3. The method according to claim 1 sum Establishing a connection the formula ?
CH ₃ -CH-CH-PCOE) ₂ in which S is alkyl, lower alkenyl, aryl or aralkyl, characterized by the fact that the e «* corresponding phosphonate with an ethylide of the formula treated, in the M ⁺ di-lower alkoxyphosphinyl, di-thi-lower alkylsulphonium cation _r di-arylsulphonium cation, 3? ri-lower alkylammonium cation, di-lower alkyl oil sulfoxonium cation or tri-arylphosphonite cation means 4. The method according to claim 5 »characterized in that daes S denotes lower alkyl and Μ ^φ bi-t-lower alkosyphosphinyl. 5. The method according to claim 3 _f gekennaeichnet that R - 12 - 9 0 9 8 8 4/1777 BATH ORIGINAL , 13 Niödrigalkyl and M ⁶ M-niedölkyLnulfcmium bfjrlmiben. 6. Vorfahz'en according to claim 3, characterized in that E mean lower alkyl and K® Tri-nledrigalkylacmonium ". 7 »Ancestors according to claim 3, characterized in that H is lower alkyl and Ι · 1 ^{Φ is} di-lower alkyl sulfoxoniua. 8. The method according to claim 3, characterized in that R lower alkyl and M * tri-arylphosphonium mean » 9 «The method according to claim 3, characterized in that the (cis-1,2-Bpoxypropyl) -phoaphonat in (cis-1 _t 2-Bpoxypropyl) -phoaplionic acid and then by treatment with an aqueous solution of a base in daa corresponding alkali metal or Erflalkali metal saijs transferred. 10 fesefateea a & @ h AmspriteSi 9> dadurcli gQkaBaaeiölmQt »ö ^ ss eau Sels et al Sics V3rtfei9.d@'&e Base WstifSisiahjöroxM nM daa isslsaf © is 909634/177 7