HRP921124A2 - Process for the production of aminoalkanophosphonic acids, salts and/or esters - Google Patents

Abstract

The present invention relates to a new process for obtaining alpha -aminoalkanephosphonic acids and/or salts or esters of general formula (I): <IMAGE> with R1, R2, which are identical or different, chosen from a hydrogen atom, a linear or branched alkyl group with one to six carbon atoms, or an alkali metal or alkaline-earth metal atom. R3 = a hydrogen atom or an alkyl, cycloalkyl, aryl or aralkyl group, it being possible for these groups to be optionally substituted by one or a number of heteroatoms, preferably halogen. R4 = a hydrogen atom or a linear or branched alkyl group with 1 to 4 carbon atoms.

Description

This invention relates to a new process for the production of aminoalkalinephosphonic acids, salts and/or esters of the general formula (I):

[image]

with R1, R2, identical or different, chosen from a hydrogen atom, a linear or branched alkyl group with one to six carbon atoms, one alkali or alkaline earth metal atom.

R3 = hydrogen atom, or alkyl, cycloalkyl, aryl, or arylalkyl groups, with the proviso that these groups may contain one heteroatom and may possibly be replaced by one or more atoms, preferably halogen.

R4 = hydrogen atom, alkyl group, linear or branched, with one to four carbon atoms.

Products of formula (I) are known and can be used as fungicides (European patent 0153284 and USP 4994447 and 4888330). Products for which R1, R2 and R4 are a hydrogen atom and R3 is ethyl is ampropyl, commercialized, and can be used in leaf processing or grain processing.

The approaches to these products described in the above-mentioned patents proved insufficient for their industrial production, due to the catalytic process using hydrogenation, due to conditions with high temperature and pressure and too long reaction times.

The aim of this invention is, therefore, to reach these compounds in a more economical way than the previously described ways.

Another goal of the invention is to produce formulas (I) with much milder hydrolysis conditions than the already known conditions and especially with a much slower reaction time.

In addition, a third object of the present invention is to use a process that allows better control of aqueous or gaseous outflow.

Finally, the aim of the invention is also to make compounds of formula (I) with optimal performance and purity.

The process of preparing aminoalkalinephosphonic acids or esters and salts R,S) 1 goes through three (acids) or four (esters, salts) stages that can be shown schematically as follows:

[image]

with R5=R1 and/or R2, or one alkali metal atom, preferably Na or K, and n=1 or 2.

The reaction a) between the primary amine and the carbonyl derivative (or one form of the carbonyl derivative, i.e. acetal, hemiacetal or dioxolane, which must be reacted in an acidic medium to form the carbonyl), can be written according to the scheme:

R3 — C — H + R4NH——— R3 — CH = NR4 + H2O

In cyclohexane, a reaction occurs between an aldehyde, eg propanal, and a primary amine, eg tertiobutylamine, at room temperature (20°C). Then the corresponding imine is obtained, for example tertiobutylpropanimine, which is only a transition compound. It can therefore be used without any additional treatment in the next reaction stage (stage b), but this leads to a high degree of impurity. Distilled imine leads to better selectivity, but in this case a good part (30%) of the synthesized imine is lost by distillation.

Carrying out stage a) in an organic solvent medium, water, which is the cause of a high degree of impurity, can easily be separated.

With a solution such as cyclohexane, 95% of the formed water is eliminated, while the use of dichloromethane allows the elimination of only 61% of the amount of formed water, toluene 83% and the toluene-soda mixture 92%.

The remaining water can be eliminated by azeotropic distillation, but at such a temperature (80°C with cyclohexane) that the imine degrades. Therefore, it is better to work in a cyclohexane solution, with simple decantation of the produced water.

Stage b) of the condensation of the obtained imine in a) on dialkylphosphate is written according to the reaction:

[image]

Stages a) and b) are carried out in an organic solvent such as cyclohexane, dichloromethane or toluene. The organic solution of the imine obtained in step a) is filtered into pure dialkyl phosphite or into an organic solution.

Stage c) hydrolysis of the obtained diester, and precipitation of the obtained dibasic acid is carried out according to the scheme:

[image]

The diester compound obtained after step b) can be isolated and used as such. However, compounds that are more interesting as fungicides are acids and salts, i.e. compounds for which R1 and/or R2 are chosen from alkali or alkaline earth metals. Since the acid is interesting either by itself, or as a transition in obtaining salt, this stage of hydrolysis is almost always carried out, followed by precipitation of the resulting phosphonic acid.

Hydrolysis conditions c) are much milder than those previously described. In fact, that stage was already known as an elementary reaction, acid hydrolysis of aminoalkanophosphonic diester 1, but with the use of hydrobromic acid, under pressure and at a temperature of 175-180°C for 48 hours.

The use according to the invention of 2 to 5 equivalents of sulfuric acid per mole of diester enables hydrolysis in a few hours (4 to 6), with atmospheric pressure and a temperature of 120-140°C.

Under these conditions, the two acid functions are released as well as the secondary amine, which again gives NH2. Obtaining compounds where R4 is different from a hydrogen atom is possible, but at a lower temperature, eg around 80°C. In this case, only two acidic functions are created.

Possible stage d) of salification of esterification of the dibasic acid obtained in c) is written as follows:

[image]

with R 5 = R 1 and/or R 2 preferably Na or K, and n = 1 or 2. When n = 1, one of the two R 5 is a hydrogen atom.

The following examples illustrate this invention in a non-limiting manner.

Example 1:

Synthesis of aminopropanephosphonic acid (diethylphosphite route 1).

a) 3 moles (174 g) of propanal are squeezed over one hour into 3 moles (219 g) of tertiobutylamine, which is in a bottle at room temperature (20*0. At the end of pouring, 393 g of cyclohexane is added to separate the resulting water. Then 51.5 g of the aqueous phase and 734.5 g of the organic phase (d = 0.786) are obtained. ;b) Then 183 g of the previous reaction mixture (organic phase) is taken so that there are 0.75 moles (84.75 g) of the resulting imine, which is placed on 0.75 mol (103.5g) of diethylphosphite at a temperature of 60°C for one hour. The total reaction mixture (286.5 g to 34% cyclohexane) was left at 60°C, then the temperature was raised to 80°C for one hour, and held there for another hour, before stopping the heating and mixing. Then the percentage of transformation (TT) of imine and phosphite of 97 and 96%, and reaction effects (RR) in the diester of 89% and oxy impurity ((EtO)2POCH(OH)Et) of 6% are obtained. ;c) Diester hydrolysis is performed with 3 equivalents of sulfuric acid (96%) per mole of diester at a temperature of 140°C. The diester is immersed in a warm acid solution. After five hours of reaction, the dibasic acid obtained in the aqueous phase is treated with methanol and then with triethylamine (Net3). ;The following results are then obtained: ;RR in aminoalkalinephosphonic acid/diester = 81% ;Aminoalkalinephosphonic acid purity = 99% ;Example 2: ;Synthesis of aminopropanephosphonic acid (route diethylphosphite 2). ;a) 2 moles of 6146 g of tertiobutylamine are introduced into a flask at 20°C in which 2 moles (116) of propanal are poured onto the amine at 20°C. At the end of the introduction of propanal, 250 g of cyclohexane are added to allow decantation. Then 35 g of the aqueous phase and 477 g of the organic phase (d = 0.78) are obtained, which is divided into two parts of 238.5 g each. ;b) 179 g is taken from one of these two parts in order to obtain 0, 75 moles (84.75 g) of imine is poured onto 0.75 moles (103.5 g) of diethylphosphite at 50°C for 40 minutes with stirring. Then the temperature is increased to 60°C and this temperature is maintained for 6 hours. After evaporation in a laboratory vacuum at 70°C of 278 g of the resulting mixture, 184 g of the product is obtained, which is analyzed using chromatography in the aqueous phase and NMR. The result is then the following: TT tertiobutylpropanimine = 96% ;TT diethylphosphite = 97% ;RR in the diester = 90% ;RR in the hydroxy impurity = 7.2%. The diester is then purified by basic washes with NaOH 20% then H2O) to eliminate hydroxy impurities ((EtO)2POCH(OH)Et). More washing is required to limit the remaining hydroxy amount to 0.5 molar%. Indeed, with a single wash in water at 60°C for 1 hour 40, 6% of that impurity is retained in the final mixture. ;c) On one part of the obtained diester, and purified to 95%, hydrolysis is carried out with 3 equivalents of sulfuric acid (96%) per mole of diester at a temperature of 140°C. The diester is immersed in a warm acid solution. After five hours of reaction, the dibasic acid obtained in the aqueous phase is treated with methanol and then with triethylsmine (NE3). ;The following results are then obtained: ;RR in aminoalalnophosphonic acids ⇒ 99%. ;Example 3: ;Synthesis of aminopropanephosphonic acid (dimethylphosphite route 1). ;a) 2 moles (146 g) of tertiobutylamine are introduced into a bottle at 20°C in which 2 moles (116 g) of propanal are poured onto the amine at 20°C. At the end of the introduction of propanal, 250 g of cyclohexane are introduced to enable decantation. Then 35 g of the aqueous phase and 477 g of the organic phase (d = 0.78) are obtained, which are divided into two parts of 238.5 g each. ;b) On one of those two parts, 179 g is taken so that we have 0.75 mol (84.75 g) of the imine, which is poured into 0.75 mol (82.5 g) of dimethylphosphite at 50°C, 40 minutes with mixing. Then the temperature is raised to 60°C and this temperature is maintained for 6 hours. After evaporation in a laboratory vacuum at 70°C of 257 g of the obtained mixture, 164 g of the product is obtained, which is analyzed by chromatography in the gas phase and NMR. ;Then the result is as follows: ;Transformation percentage (TT) imine = 100% ;TT dimethylphosphite (DMP) = 100% ;Reaction effect (RR) diester/DMP = 90% ;RR hydroxy (MeO)2POCH(OH)Et)/ DMP = 4.8%; Other impurities = 4.3%. ;c) Starting from the obtained diester, hydrolysis is carried out with three equivalents of sulfuric acid at 130°C for 4 hours. Then, the resulting acid is precipitated using methanol and triethylamine.

Then we have:

RR in aminopropanephosphonic acid/diester = 85%

RR in aminopropanephosphonic acid/dimethylphosphite = 77%

Purity of aminopropanephosphonic acid = 99%.

Example 4:

Synthesis of aminopropanephosphonic acid (dimethylphosphite route 2).

a) 3.5 moles (258 g) of tertiobutylamine (d = 0.7) are introduced into the bottle. 3.5 moles (203 g) of propanal (d = 0.8) is poured onto the amine for one hour at 20°C. 461 g of cyclohexane are then added for decantation, leading to 60.5 g of the aqueous phase (96% of the water formed is eliminated) and 860 g of the organic phase (d = 0.76).

b) Mix 2.5 moles (275 g) of dimethylphosphite and 275 g of cyclohexane in another bottle. This mixture is heated to a temperature of 80°C. At this temperature, 614.3 g of the organic phase corresponding to 2.5 moles of imine are introduced. The outflow is carried out for one hour, during which cyclohexane is distilled, which contains part of the propanal that was formed by the retrogradation of the imine. Then the temperature of 88°C is maintained for four hours. Distillation leads to 178 g of cyclohexane solution.

Then the reaction mixture of 955 g is poured over. The result of the substance shows a loss of 38 g. This reaction mixture (932 g, after taking samples for analysis) leads to 517 g of dry extract which is analyzed by chromatography in the gas phase NMR.

Then we get:

TT of dimethylphosphite = 100

RR diester/dimethylphosphite = 94%

RR hydroxy/dimethylphosphite = 2%.

Distillation therefore allowed to significantly reduce the formation of hydroxy impurity (MeO)2POCH(OH)Et.

c) The diester (470, 2.03 moles) obtained is immersed at 20°C for 30 minutes in a solution of 96% sulfuric acid (643 g, therefore, 6.3 moles or 3.1 eq acid/mol diester. Then the temperature rises up to a temperature of 130°C, which is maintained for five hours.After precipitation, at 20°C and pH 5, using methanol (1.6 ml/g of solution) and triethiamine (340 g/mol of diester), the following is obtained:

RR in aioinopropanephosphonic acid/diester = 84%

RR in aminopropanephosphonic acid/dimethylphosphite = 79%

Purity of aminopropanephosphonic acid = 99.1%.

Example 5:

Stages a) and b) with diethylphosphite (second solvent).

a) Place 1 mole (73 g) of tertiobutylamine at room temperature in one bottle. Then 1 mole of propanal is poured in over 15 minutes. After 45 minutes, 130 g of dichloromethane and 2 g of NaCl are added to decant. Then 13 g of the aqueous phase are obtained (61% of the resulting water is therefore eliminated) and 247 g of the organic phase, which, after taking 4 g, is distilled at 50°C for 20 minutes. When the distillation is complete, 236 g of the reaction mixture is obtained.

b) Take 118 g of this mixture, which is poured onto 0.4 moles of diethylphosphite at 25°C. Then the temperature is raised to 57°C for 15 minutes so that a slight reverse flux is obtained. This temperature is maintained for 3 hours.

Under these conditions, the following results are reached:

TT of tertiobutylpropamine = 91%

TT diethylphosphite = 98%

RR diester = 76%

RR in hydroxy impurity = 15%.

Claims (16)

1. Procedure for preparing aminoalkalinephosphonic acid, salt or ester of the general formula (I): [image] in which R1, R2, identical or different, are selected from a hydrogen atom, an alkyl linear or branched group with one of six carbon atoms, one alkali or alkaline earth metal atom. R3 is a hydrogen atom, or an alkyl, cycloalkyl, aryl or arylalkyl group, and these groups can possibly be replaced by one or more heteroatoms, preferably halogens. R4 is a hydrogen atom, an alkyl group, linear or branched, with 1 to 4 carbon atoms, characterized by the fact that it contains three (acids) or four (salts or esters) stages, and the whole of these four stages can be written according to the following global scheme: [image] [image] R 5 is equal to R 1 and/or R 2 , or an alkali metal atom, preferably Na or K, and n equal to 1 or 2, provided that when n=1, one of the two R 5 is a hydrogen atom. 2. Process according to claim 1, characterized by the fact that in step d) R5 is a sodium or potassium atom. 3. Process according to claim 1, characterized by the fact that steps a) and b) are carried out in the middle of an organic solvent, little or not at all suitable for mixing in water. 4. The method according to claim 3, characterized in that the organic solvent is selected from the group consisting of cyclohexane, dichloromethane or toluene. 5. Process according to claim 4, characterized in that the organic solvent is cyclohexane. 6. The method according to claim 1, characterized in that the carbonyl compound is in the unprotected form, a ketone or aldehyde, or in the protected form, acetyl, semiacetyl or dioxolane. 7. Process according to claim 6, characterized in that the carbonyl compound (II) is propanal. 8. Process according to claim 1, characterized in that the amine (III) is selected from methyl-, ethyl-, propyl-, or isopropyl-, or n-butyl-, or tertiobutylamine. 9. Process according to claim 8, characterized in that the amine (III) is tertiobutylamine. 10. The process according to claim 1, characterized in that stage a) is performed with a molar excess of amine (III) in relation to the carbonyl derivative (II), with the elimination of the water formed. 11. The method according to claim 1, characterized by the fact that in stage b) the compound dialkylphosphite (V) is dimethyl- or dimethylphosphite. 12. Process according to claim 1, characterized by the fact that in stage c) sulfuric acid is used with 2 to 5 equivalents of acid per mole of diester (IV) at a temperature between 80 and 150°C. 13. The process according to claim 12, characterized in that the reaction is carried out with about 3 equivalents of sulfuric acid at 130°C to 140°C. 14. The process according to claim 1, characterized in that it is purified with pH = 5 at the end of stage c) the aminoalkalinephosphonic acid (Ia) created, by precipitation in the middle of a strong organic or mineral base. 15. The method according to claim 14, characterized in that the base is triethylamine. 16. Process according to claim 1 for obtaining a compound of formula (I) in which R1 and R2 are not together a hydrogen atom, characterized in that it activates a mole of aminoalkalinephosphonic acid (Ia) from step c) with approximately 1 or 2 moles of compounds R5OH, R5 has the same meaning as well as R1 or Rz.