DE1805674C - Process for the production of ice propenylphosphonic acid - Google Patents

Description

The method according to the invention can be represented as follows:

PCl ₃ ^ 2R0H - * ■ [(RO) ₂ PCl]

(Π)

\ r CH = CCH ₁ OH

[CH s CCH ₂ OP (OR) J]
(III)

I "1 * 1 * '

I 11

L CH ₃ - CH = CH - P (OR), J LCH ₂ = C = CH - P (OR) ₂

(V) (IV)

CH ₃ - CH = CH - P (OH) ₂ (D.

Here, R denotes lower alkyl, such as isobutyl and oar. Glycols, such as ethane-pentyi, aryl, such as substituted phenyl, halophenyl diol, propanediol, butanediol and pyrocatechol, are also suitable. the u. «d o-Phenylene, lower aralkyl, such as substituted glycols, form a cyclic phosphorous acid diester-aralkyl, e.g. B. halobenzyl, lower alkenyl, such as chloride, each hydroxyl group of the glycols Propenyl and butenyl, or two R radicals mean chlorine atom of phosphorus trichloride replaced, an aryl or lower alkyl glycol radical, e.g. B. a. Any inert solvent can be used for this ethylene glycol or catechol derived conversion. Aromatic charcoal residue. Hydrogens, such as benzene, toluene, and xylene, are good ones

As from the reaction scheme given above, solvent; Pentaii, hexane, cydohexane, tetra "

zuerschen, phosphorus trichloride is first mixed with hydrofuran, methylene chloride and diethyl ether.

2 equivalents of an alcohol or about 1 equivalents are also used,

valent of a glycol in an inert solvent 60 However, the reaction is generally not

to a phosphorous acid diester chloride (TI) necessarily carried out in the presence of an acid binder

puts. As an alcohol one can have a primary, second- The presence of free hydrogen chloride can

Use dear or tertiary alcohol. Lower alkyl, however, lead to undesired side reactions. When

alcohols such as methanol, ethanol, propanol, butanol, acid binders come tertiary amines such as triethyl

fsopropanol or terf -butanol, aryl alcohols such as 65 amine, dimethylaniline, N-methylmorpholine, collidine,

Phenol, aralkyl alcohols such as benzyl alcohol and sub-pyridine and 2,6-lutidine, or oxides such as propylene

Substituted benzyl alcohol, and unsaturated alcohols, oxide, into consideration. In general, about 3 equi

such as allyl alcohol and niahalyl alcohol, are used valents of the amine

The phosphorus trichloride is initially retained in the solution when an inert atmosphere is applied solvent dissolved and the resulting solution to about.

Cooled to 0 to 25 ° C; the preferred temperature The propadienylphosphonic acid diester contains

range is about 0 to 10 ° C. A solution of about tende reaction mixture is then generally at 2 equivalents of the base is then treated with water at such a rate of room temperature to dissolve out amine hydrochloride added to the phosphorus trichloride solution; then will give that the reaction temperature is separated in the organic and aqueous layer. If with desired area is kept. The water-miscible solvent is left as a reaction solution mixture, generally used with agitation, about 20 to medium, the undissolved amine-60 Minutes on itself. Then a solution of io hydrochloride will be removed by filtration. the The amine and alcohol in general under organic layer is then reduced before stirring added at such a rate that step with a suitable desiccant such as the reaction temperature is maintained. Then magnesium sulfate or sodium sulfate, dried; the mixture is left an additional 20 to 60 minutes if a solvent such as benzene or toluene requires stand. The reaction tends to be exothermic 15 turns, the water can be azeotropic Course, but is easily removed by the rate of addition distillation. Preferably used the alcohol solution and external cooling creates a dry solution for the hydrogenation step, controlled. Instead of adding the amine in 2 parts, the propadienylphosphoic acid diester is then added

can also give all the amine at once to the catalytically hydrogenated, because the catalytic reduction gives phosphorus trichloride solution, and can then be stereospecific. so that only the cis-propenylsend add to the alcohol. The amine hydrochloride phosphonic acid diester is obtained in good yield. This generally precipitates during the addition, depending on the reduction in the terminal double bond of the solvent used. After the padienylphosphonic acid diesters have been terminated, the reaction mixture is selective, even if it has been added, if the solution is hydrogenated for 1 to 3 hours at room temperature for 1 to 3 hours after the addition of 1 equivalent of hydrogen. The uptake of hydrogen is generally rapid

The solution of the diester produced in this way is direct and is somewhat exothermic; the exothermic reaction can be used in the second reaction step. A solution of about 1 equivalent Hert will be added to the reaction but, if desired, by external cooling control mixture. As a catalyst, Pd / C can be used propargyl alcohol and a base in the same way; but also Pd / CaCO ₃ , Raney nickel or solvents, such as those used in the first step, other hydrogenation catalysts can also be used. The solution of the alcohol and the den. After the reduction is complete, the Kauly's base is generally removed by filtration with stirring with such a sator. The hydrogenation is added at a rate that the reaction temperature expediently remains within the desired range under atmospheric pressure and at temperature. Performed after 35 room temperature. When the ester addition is complete, the mixture is allowed to stand in the group of an aralkyl group, such as benzyl, or generally, for about 1 to 2 hours to form substituted aralkyl group. like halobenzyl, is to ensure complete implementation. The formation of the hydrogenation also serves to remove the esters of the mixed phosphorous acid triesters is strong groups, so that directly the cis-propenylphosphonic acid exothermic; the reaction mixture will generally be obtained.

by external cooling during the addition of the Aiko- The free acid (I) can then from the diester (V)

hols chilled. by acid or base-acid hydrolysis or there,

The mixed phosphorous acid ester (III) formed in the second reaction step of the process where appropriate by pyrolysis in the absence of a solvent can be obtained. When acid is applied by heating in a propadienylphosphonic hydrolysis, that of the hydric acid diester (IV) is converted. The rearrangement can be followed by means of diesters obtained with an acid, preferably ultra-red spectra, which are recorded on samples of the reaction mixture of a strong mineral acid, such as hydrogen bromide. The hydrogen chloride or sulfuric acid, or an organically mixed phosphorous acid triester has a characteristic acid such as benzyl sulfonic acid or p-toluene-like band at 4.71 μ, while the propadienyl sulfonic acid is mixed. In the case of lower alkyl esters of phosphonic acid diesters, the mixture becomes a characteristic band when aqueous acids, such as chlorine, have at 5.1 μ. The rearrangement can e.g. B. by hydrogen or hydrogen bromide, can be used, heating the Reakttonsgemisches to about SO to generally heated to ^{boiling to vorgenom low-boiling 100 0} C or by boiling under reflux components, z. B. isopropyl chloride or isopropylmen. When the reaction mixture reaches higher levels of 55 bromide, distill off. The hydrolysis takes place at temperatures or in the presence of a strong base, lower temperatures; the reaction time, such as sodium, is heated, can a rearrangement but is usually longer. The distillation is continued for example into the α, / ί-propynylphosphonic acid diester for 1 to 2 hours after a constant temperature follows, which has also been achieved by hydrogenation in the cis-Pro-, then the reactpenylphosphonic acid diester is continued is convicted. For 60 tion mixture gradually concentrated in vacuo; In order to achieve a rapid and almost complete rearrangement into the free acid, the residue can be extracted with the propadienylphosphonic acid diester, the reac- a suitable solvent, such as ether or an ionic mixture, generally chloroform for about 1 to 3 hours, or the water can be removed heated. Preferably, the aforementioned will be converted.

Settlement in an inert atmosphere, such as nitrogen 65 when using a base-acid hydrolysis or helium, although a mixture of the cis-propenylphosphonic acid is not critical to the invention. In general, better diesters and aqueous bases, such as sodium hydroxide or Yields of the propadienylphosphonic acid diester potassium hydroxide, for about 1 to 2 hours in general

mine heated to reflux temperature. In the absence of a kaialytic amount of acid treatment with base, one of the two esters is heated. To allow rapid cleavage of the ester groups away. The reaction solution will then reach groups, but it is preferred that it be cooled and acidified by adding an acid such as chlorine- a catalytic amount of an acid, hydrogen or hydrogen bromide, is used. The 5 If a catalyst is used, a Tempe solution is then heated under reflux during temperature between 25 and 200 ° C to effect the alcohol formed, if it is a curse-ester cleavage suitable. The reaction also takes place in terms of alcohol, such as methanol or ethanol, at temperatures below 25 ° C; the reaction is distilled off by azeotropic distillation with water but the rate decreases at higher temperatures. The cis-propenylphosphonic acid is replaced by io. A temperature range from 85 to 200 ^° C. is preferred. Extracting the reaction mixture with one is preferred.

Suitable solvents, such as diethyl ether or Me- The obtained cis-propenylphosphonic acid can without

ethylene chloride, obtained and after evaporation of the further purification, for example with hydrogen per-

Solvent collected. The acid can be converted to (±) (cis-1,2-epoxypropyl) -phosphonic acid by means of oxide

Nuclear magnetic resonance spectroscopy and vapor phase 15 are set,

be characterized by chromatography. The method according to the invention proceeds with good results

If the ester group is of a secondary yield. Another advantage is that the whole thing

Alcohol, such as isopropyl alcohol, or a tertiary process in the same solvent

Alcohol, such as t-butyl alcohol !, can be derived for which can be.

Ester cleavage uses a non-aqueous system »0 B bis ο e 1 1
will. This is cheap because you don't have water and

inorganic salts from the reaction mixture ent- a) 750 ml of anhydrous benzene and 68.7 g (0.5 mol)

must go away. The cis-propenylphosphonic acid is except- phosphorus trichloride are in a 2 l three-

which is somewhat unstable in aqueous, acidic solutions. The cervical piston brought with a mechanical

Use of a non-aqueous system avoids »5 stirrers, thermometer, dropping funnel and drying

that some of the acid is equipped during the removal of the pipe. The solution is reduced to 5 ° C

Water decomposes. cools and over the course of 15 to 20 minutes

A mixture of dialkyl-cis-propenylphosphonic 50.6 g (0.5 mol) of triethylamine at 5 to 10 ° C,

dialkyl acid ester with a catalytic amount of a. The resulting mixture is stirred for 20 minutes.

Acid, such as p-toluenesulphonic acid, is in a gel 3o A solution of 50.6 g (0.5 mol) of triethylamine and

Suitable solvents, such as benzene, toluene, xylene or 30.0 g (0.5 mol) of isopropanol, are rubbed under

Tetralin, and preferably the original Reak course of 20 to 25 minutes at 5 to 10 ⁰ C trains

after the hydrogenation so long on return, and the mixture is left for 20 minutes.

Heated to flow temperature until the calculated amount stirs. Then a second portion of isopropanol is added

Olefin has escaped. The reaction mixture is then 35 (30.05 g; 0.5 mol) at the same temperature in the

cooled to room temperature, added cis-propenylphosphate from 20 to 25 minutes. The exothermic

phosphoric acid is deposited as an oil, which is in the organic reaction by means of an external cooling

Solvent usually only slightly soluble is controlled by methanol-ice bath. During the encore

and is separated from the solvent. Triethylamine hydrochloride also precipitates out. After completion

cis-Propenylphcsphonsäure can by evaporation 4 ° of the addition, the reaction mixture, the phospho-

of the organic solvent can be obtained. The rigsaure-diisopropylestewhlorid contains 90 minutes

Cleavage of the ester group can be stirred at 5 to 10 ° C for a long time, depending on the situation.

Solvent used - at the reflux temperature b) A solution of 50.6 g (0.5 mol) of triethylamine

temperature of the solvent carried out pasture; die and 28.03 g (0.5 mol) propargyl alcohol in 40 ml

however, the preferred reaction temperature is 45 anhydrous benzene is continuously stirred

the cleavage of tertiary esters, for example tert-butyl, added to the solution obtained in this way for 25 minutes ,

about 80 to 12d ° C. Higher temperatures are in The temperature of the reaction mixture is through

generally considered secondary esters such as isopropyl or external cooling 5-10 ⁰ C. To

Isobutyl ester, required. Acting as a catalyst at the end of the addition, the mixture is used for 1 hour

The acid used for ester cleavage can be stirred as a final 5 ° long. The resulting solution contains 2-propynyl

acid obtained product, d. H. cis-propenylphosphonophosphorous acid diisopropyl ester.

be acidic, eliminating the need for other c) The reaction mixture obtained is gradual

To have to remove compounds from the mixture, heated to re-nut temperature and 1 hour at

and the result is a purer product. Since the heated as 82 to 84 ° C under reflux. The mixture will

Product formed cis-propenylphosphonic acid a 55 then cooled to room temperature and with 185 ml

is strong acid, the catalytic reaction of Wassei is added. The triethylamine hydrochloride dissolves

itself. Acids such as sulfuric acid, phosphoric acid and themselves in the aqueous layer, and the organic and

p-Toluenesulfonic acids can also be used and the aqueous layer can be separated. The benzor phase,

will. Additional catalysts that used which propadienylphosphonic acid diisopropylester

are acidic ion exchange resins and contains 60 is heated to reflux temperature, the

inert substances with catalyzing acidic surfaces, water is removed by azeotropic distillation,

such as sea sand, Stlicagel or acid washed d) The dried benzene solution is at 20 to

Clay. 25 ° C with 5 ⁰ / _? Pd-C catalyst (5.0 g) as long The ester cleavage can also take place in the absence of hydrogenation until the hydrogen absorption ceases Solvents can be carried out by the Lö- 65 catalyst is filtered off and twice with SOmI

solvent from which washed after the hydrogenation of propa-benzene. The filtrate is concentrated in a vacuum

dienylphosphonic acid diester is concentrated and gives cis-propenylphosphonic acid diiso-

removes and then the residue in the presence or propyl ester. By distillation at 0.15 mm, the

IO

pure diisopropyl ester with a temperature of 42 to 43 ° C.

e) 78.25 g of crude cis-propenylphosphonic acid diisopropyl ester and 315 ml of constant-boiling hydrochloric acid are placed in a three-necked flask with a capacity of 11 which is equipped with a mechanical stirrer, thermometer, horizontal cooler and collecting vessel is. The mixture is stirred and heated to boiling in an oil bath. The lower boiling components are distilled off, and the distillation continued at 90 to 91 ° C for 1 hour. The reaction mixture is then concentrated in vacuo: the oily residue is then dissolved in 100 ml of water, treated with 4.0 g of charcoal and filtered. The The pale yellow filtrate is concentrated in vacuo and the Rinsed residue with twice 100 ml of benzene. When the residue is concentrated in vacuo to constant weight, cis-propenylphosphonic acid is obtained. The ultra-red spectrum of the yellow oil shows the characteristic cis-olefin band at 6.1 μ. The acid is identified in the form of the dicydohexylamine salt a with a melting point of 208.5 to 2U ° C.

Example 2

a) 68.7 g (0.5 mol) of phosphorus trichloride and 750 ml of anhydrous benzene are placed in a three-necked flask with a capacity of 21, which is equipped with a mechanical stirrer, thermometer, dropping device and drying tube. The solution is cooled to 5 ⁰ C, and 50.6 g (0.5 MoO triethylamine are added over 20 minutes at 5 to 10 ⁰ C. The benzene solution is then stirred for 20 minutes. A solution of 50.6 g (0.5 MoO triethylamine and 37.06 g (0.5 mol) of t-butanol is added in Vertauf of 20 minutes with stirring at 5 to 10 ⁰ C, and the mixture is stirred for 20 minutes. A second portion of 37 , 06 g (0.5 MoO t-butanol is then added over 20 minutes at 5 to 1O ⁰ C, and the phosphorous-di-t-butyl-chloride-containing reaction mixture for 90 minutes at 5 to 10 ⁰ C stirred.

b) 50.6 g (0.5 mol) of triethylamine and 28.03 g (0.5 moles) of propargyl alcohol are dissolved in 40 ml of anhydrous benzene, and the solution is taken under Stir over the course of 25 minutes to the reaction mixture, the phosphorous acid di-t-butyl ester chloride while the reaction temperature is maintained at 5 to 10 ° C by external cooling. The resulting i-propinylphosphorous acid-di-t-bTttyl- se ester-containing mixture is for 1 hour at 5 to 10 ⁰ C stirred.

c) The reaction mixture obtained is then heated to reflux temperature and under reflux Heated for I hour. The solution is then cooled to room temperature with a water bath, and 185 ml of water are added in parts. The triethylamine hydrochloride dissolves in the aqueous Layer, and the organic layer is separated from the aqueous layer. The benzene solution will heated under atmospheric pressure and the water removed by azeotropic distillation. The remaining benzene solution contains propadienylphosphate phonic acid di-t-butyl ester.

d) The dried benzene solution obtained is _{hydrogenated with 5 ° / 0} Pd-C catalyst (5.0 g) at 20 to 25 C until the absorption of hydrogen ceases. The catalyst is removed by filtration and

tS washed twice with 50 ml of benzene. When the solvent is removed in vacuo, di-t-butyl cis-propenylphosphonate is obtained. The raw ester is purified by high vacuum distillation.

Nuclear Magnetic Resonance Spectrum

(T for (CH ₃ ), C -1.49;

σ for cis CH, - 1.90 to 2.15;

σ for - CH = CH - 5.15 to 7.15;

Ultrared spectrum C - C 6.14 µ.

e) 1.0 mol of cis-propenylphosphonic acid di-t-butyl ester and 0.05 mol of cis-propenylphosphonic acid dissolved in 235 ml of benzene, and the solution is heated to the reflux temperature until the calculated Amount of isobutene is formed. A gas meter is used to detect isobutene. The reaction mixture is then cooled to room temperature, the solvent is removed in vacuo and cis-propenylphosphonic acid is obtained as a residue.

5 g of cis-1-propenylphosphonic acid and 30 ml of benzene are placed in a 500 ml three-necked flask equipped with a stirrer, thermometer, inlet funnel and horizontal condenser, which is equipped with a The collecting vessel is connected to the gas discharge pipe. The mixture is heated to reflux temperature and a crude cis-propenylphosphonic acid di-t-butyl ester solution (0.5 mol, 1250 ml) becomes added over the course of 90 to 110 minutes, at the same time distii'.iert and the volume of the reaction mixture kept between 15 and 150 ml by regulating the addition and the rate of distillation will. After the distillation has ended, the destination will continue until the end event approx. 100 ml The reaction mixture is au! Cooled room temperature and the Benzolphasi (upper layer) separated. Cis-propenyte is obtained phosphonic acid.

309 63001

Claims (1)

1 2 Claim · is characterized in that in each case known way Process for the preparation of cis-propenyl phosphonic acid, characterized by a) phosphorus trichloride with at least about 2 equinet, that one in each case known per se 5 valents of an aryl, lower alkyl, lower alkene nyl or lower aralkyl alcohol or about a) phosphorus trichloride is reacted with at least about 2 equivalents of an aryl or lower alkyl glycol vabnten of an aryl, lower alkyl, lower in an organic solvent,
alkenyl or lower alkyl alcohol or b) the phosphorous acid diester chloride obtained is reacted with about 1 equivalent of an aryl or lower propargyl alcohol, alkyl glycol in an organic solution c) the phosphorous acid diester propynyl obtained agent converts, ester is rearranged by heating, b) the phosphorous acid diester chloride obtained d) the propadienylphosphonic acid diester obtained Reacts with propargyl alcohol,! .jtalytically hydrogenated and c) the phosphorous acid diester -pro 15 e) the cis-propenylphosphonic acid diester obtained pinyl ester rearranged by heating, acid or base hydrolysed or pyrolyzed, d) the propadienylphosphonic acid obtained, step e) being omitted if propadidiester in step d) catalytically hydrogenated and di-lower aralkyl enylphosphonic acid e) the obtained cis-propenylphosphonic acid was set,
diester acidic or basic hydrolysed or ao pyrolyzed, step e) being omitted if cis-propenylphosphonic acid prepared in this way can Stage d) Propadienylphosphonic acid - !! - low- in (± Hcis-1,2-epoxypropyl) -phosphonic acid over »e- aralkyl ester was used. leads expanses. The latter connection is for free positive and gram-negative bacteria effective. she hat is a new compound, what advantages over The invention relates to a method for tetracycline and chloramphenicol possesses (see. Patent Production of cis-propenylphosphonic acid, the da- 1 768 965).