SI9200291A - New method for the production of aminoalkanphosphonic acids, their 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

A NEW PROCEDURE FOR THE ACHIEVEMENT OF AHINOALKANPHOSPHONIC ACIDS,

THEIR SALTS AND / OR ESTERS

A NEW PROCEDURE FOR THE PREPARATION OF AMINO-ALKANPHOSPHONIC ACIDS,

THEIR SALTS AND / OR ESTERS

The present invention relates to a novel process for the preparation of cCaminoalkanephosphonic acids and / or salts or esters of general formula (I):

RjO NHR ₄ \ and ⁴

P -CH - Ro / II ⁵

R ₂ CT 0 (I) with R *, R ₂ identical or different, selected from a hydrogen atom, a straight or branched alkyl group of one to six carbon atoms, and one atom of alkali or alkaline earth metals.

Ra = a hydrogen atom, or an alkyl, cycloalkyl, aryl or aralkyl group, these groups may contain one heteroatom and may be optionally substituted by one or more atoms, in particular halogen.

R ^ = hydrogen atom, unbranched or branched alkyl group, having 1 to 4 carbon atoms.

The products of formula (I) are known and used as fungicides (European patent 0153284 and USP 4994447 and

4888330). A product in which R *, R _z and R ^ are a hydrogen atom and

R »ethyl is ampropylphos, commercialized, which can be used to treat leaves or seeds.

It has been demonstrated that the methods of obtaining the products described in the aforementioned patents do not allow the industrial production of these products, especially due to catalytic processes by hydrogenation, high temperature and pressure conditions, and too long reaction times.

One object of the present invention, therefore, is to obtain these compounds in a more economical manner than the preparation methods described above.

Another object of the invention is to provide compounds of formula (I) under much milder hydrolysis conditions than already known and, in particular, with a much shorter reaction time.

Moreover, a third object of the present invention is to use a process that allows for better control of aqueous and gas fluids.

Finally, another object of the invention is to provide a compound of formula (I) in optimized yield and purity.

The process for the preparation of (R, S) 1 aminol can-phosphonic acids or esters and salts is carried out in three (acids) or four (esters, salts) stages, which can be schematized as follows:

a)

FU

H + R ₄ NH ₂

R ₃ _CH —NR ₄ + H ₂ O

b)

R ₃ -CH = NR ₄ +

R, 0 ¹ \

P / r ₂ oo

RlO ^

P / H r ₂ oo chnhr ₄ l

* 3

c) R.O

P

chnhr ₄ + H ₂ SO ₄ ->

HO r ₂ oo

p - chnh ₂

d)

CHNH ₂ + nR ₅ OH -P r ₅ oo chnh ₂

with R = = R _T and / or R _z , or an alkali metal atom, in particular Na or K, and n = 1 or 2.

The reaction a) between one primary amine and one carbonyl derivative (or a protected form of a carbonyl derivative, i.e. acetal, hemiacetal, or dioxolane and, therefore, an acidic reaction must be carried out in order to prepare the carbonyls) can be written as follows:

Ri_C _H ^J H

II + R ₄ NH ₂ _R 3 - CH— NR ₄ + H ₂ 0

The reaction between an aldehyde, for example propanal, and a primary amine, such as tert-butyl amine, is carried out in cyclohexane at room temperature (20 ° C). This gives the corresponding imine, for example tert-butylpropanamine, which is an intermediate only. It can therefore be used not to treat it further in the next stage of reaction (step b), but this leads to an increased percentage of contamination. Distilled imine provides better selectivity, but in this case, a good portion (30%) of the synthesized imine is lost due to distillation.

The water that is responsible for the increased percentage of contamination can be easily drained if step a) is carried out in an organic solvent.u.

A solvent such as cyclohexane removes 95% of this water, while using dichloromethane, only 61% of the amount of water produced is removed with toluene 83% and with a mixture of toluene sodium carbonate 92%.

The remaining water can be removed by azeotropic distillation, but to do so, a temperature (80 ° C with cyclohexane) must be selected so that the imine is degraded. Therefore, we prefer to work with cyclohexane as a solvent, and the water that is formed is easily cast.

The degree of b) condensation of the imine obtained in a) with d and al k which is Ι-phosphate is carried out after the reaction:

RiO R, 0 ¹ \ ¹ \

R 3 - CH =: NR ₄ + P --- H -> P -CHNHR,

Z 11 Z nt ⁴ r ₂ oor ₂ oor ₃

Steps a) and b) were realized in an organic solvent such as cyclohexane, dichloromethane or toluene. The organic solution of imine prepared in step a) was poured into dialka 1 phosphite, which was pure or in organic solution.

Stage c) hydrolysis of the diester obtained and the precipitations of the resulting diacids were carried out according to the scheme:

RiO Z II

P - CHNHR ₄ + HoSOa II I * ^z

R2O O Rj

HO

The diester compound obtained after step b) was isolated and used as such. However, a compound which has been shown to be more suitable as fungicides, the acids and salts, that is a compound for which Ri and / or R ₃ is selected from alkali or alkaline earth metal. Since acid, therefore, is suitable either as such or as an intermediate in salt production, it is practically always possible to realize this degree of hydrolysis followed by the precipitation of the phosphonic acid formed.

The hydrolysis conditions c) are milder than those described previously.

In fact, this step was already known as the elemental reaction of acid hydrolysis of 1-aminoalkanthosphonic ester, but using 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 (VI) acid per mole of diester enables the hydrolysis to be carried out in a few hours (4 to 6) at atmospheric pressure and temperature of the order of 120

140 ° C.

Under these conditions, two acidic functions are released as well as a secondary amine which again gives NH ₃ . The preparation of compounds in which R 2 is other than a hydrogen atom is possible if the reaction is carried out at lower temperatures, for example at about 80 ° C. In this case, only two acid functions are formed.

Eventual stage d) of conversion to salt - esterifiers is the diacids prepared in c) the following reaction is displayed:

HO

HO

P

II

CHNH _? + nRcOH->

and ^K 3

R ₅ o ^

P - CHNH _? / ii i ^with r ₅ oor ₃ where R ₌ = R _x and / or R ₂ , in particular Na or K, and π = 1 or

2. When n = 1, one of the two R _{= is} a hydrogen atom.

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

EXAMPLE 1 Synthesis of Aminopropanophosphonic Acid (Diethylphosphite 1 Procedure).

a) Add 3 moles (174 g) of propane, in one hour, to 3 moles (217 g) of tert-butylamine located in a flask at room temperature (20 ° C). At the end of the infusion, 373 g of cyclohexane was added to drain the resulting water. This is how we gain

51.5 g of aqueous phase and 734.5 g of organic phase (d = 0.786).

b) Then take 183 g of the preceding reaction mixture (organic phase) so as to have 0.75 mol (84.75 g) of the resulting imine, which is added to 0.75 mol (103.5 g) of diethyl phosphite heated at one hour 60 ° C.

The whole reaction mixture (286.5 g with 34% cyclohexane) was left at 60 ° C and then raised to 80 ° C for one hour and maintained for one hour before heating and stirring was inserted.

Thus, 97% and 96%, respectively, of the transformation (ST) of imine and phosphite and the yield of reaction (DR) are obtained with respect to the expected diester of 89% and to the impurity hydroxy (EtO) ₂ F'OCH (OH) Et) 6%.

c) Hydrolysis of the diester is achieved with 3 equivalents of sulfuric acid (96%) per mole of diester at temperature

140 ° C. Pour the diester into warm acidic solution. After five hours of the reaction, the resulting aqueous dioxide was treated with methanol followed by triethylamine (NEt ₃ ).

This gives the following results:

DR - aminoalkanephosphonic acid / diester = 81%

Purity of aminoalkanephosphonic acid = 99%.

EXAMPLE 2 Synthesis of Aminopropanephosphonic Acid (Diethylphosphite 2 Process).

a) Put 2 moles (146 g) of tert-butylamine at 20 ° C into the flask and then pour 2 moles (116 g) of propane at 20 ^θ 0 onto the amine.

250 g of cyclohexane were added at the end of the propanal addition to allow for leaching. This gives 35 g of the aqueous phase and 477 g of the organic phase (d = 0.78), which is divided into two parts

238,5 g.

b) Take 179 g from one of these portions in such a way that 0.75 moles (84.75 g) of imine are poured into 0.75 moles (103.5 g) of diethyl phosphite at 50 ° C and in 40 minutes stirring time. Then the temperature was raised to 60 ° C, leaving for 6 hours. Evaporation of 278 g of the resulting mixture in a laboratory vacuum at 70 ° C yields 184 g of the product whose analysis is performed by gas chromatography and NMR.

s

Thus the result is as follows:

ST tert-butylpropane at = 96%

ST Diet for 1-Phos-Fit = 97%

DR counting diester = 90%

DR calculated hydroxy impurity = 7.2%

The diester was then purified by washing with bases (NaOH 20% then water) to eliminate impurity hydroxy (EtO) withPOCH (OH) Et). Multiple rinses are needed to limit the amount of residual hydroxy impurity to 0.5 molar

%. After a single rinse with water at 60 ° C for 1 hour 40 minutes, 6% of this impurity remains in the final mixture.

c) One part of the obtained diester, purified to 95%, hydrolysis with 3 sulfuric acid (96%) per mole of diester at

140 ° C. The diester was added to the warm acidic solution for hours of the reaction, the resulting dichloromethane was treated with methanol then triethylamine (NEt ₃ ).

which we have equated to temperature. After five water phase with

Thus we obtain the following results:

DR calculated aminoalkanthosphonic k and sl and ησ / di ester = 88%

Purity of aminoalkanthosphonic acid => 99%.

EXAMPLE 3 Synthesis of Aminopropanopostonic Acid (Smoke 1 Process 1)

a) Pour 2 moles (146 g) of tertbutylamine into a flask at 200 ° C and then pour 2 moles (116 g) of propane at 2Q ° C onto the amine. At the end of the propanal introduction, 250 g of ci k 1ohexane was added to allow for leaching. This gives 35 g of the aqueous phase and 477 g of the organic phase (d = 0.78), which is divided into two parts of 238.5 g each.

b) From one of these portions we take 179 g so that we have

0.75 mol (84.75 g) of imine, which is poured over 40 minutes, while stirring at 50 ° C, to 0.75 mol (82.5 g) of dimethylphosphite.

The temperature was then raised to 6 ° C, leaving it for 6 hours. Evaporation of 257 g of the resulting mixture in a laboratory vacuum at 70 ° C yields 164 g of the product which is analyzed by gas chromatography and NMR.

Then the results are as follows:

Transformation rate (ST) of imine = 1007

ST dimethyl phosphite (DMP) = 1007

Reaction Yield (DR): Diester / DMP = 907

DR: hydroxy (MeO) ^ POCH (OH) Et) / DMP = 4.87

Other impurities = 4.37

c) With 3 equivalents of sulfuric (VI) acid, hydrolysis of the prepared diester is carried out at 130 ° C for four hours.

The resulting acid is then precipitated with methanol and triethylamine.

Thus we have:

DR: Aminopropane phosphonic acid / diester = 857

DR: Aminopropanophosphonic acid / dimethyl 1phosphite = 777

Purity of Aminopropanophosphonic Acid = 997..

EXAMPLE 4 Synthesis of Aminopropanophosphonic Acid (Dimethyl Phosphite 2 Process).

a) Put 3.5 mol (258 g) of tert-butylamine (d =

0.7). Pour 3.5 moles (203 g) of propanal (d = 0.8) per amine over 1 hour at 20 ° C. Then 461 g of cyclohexane is added to give an outflow that results in 60.5 g of the aqueous phase (thus removing 967 of the resulting water) and 860 g of the organic phase (d = 0.76).

b) In the second flask, 2.5 mol (275 g) of dimethyl phosphite and 275 g of cyclohexane are mixed. This mixture is heated to a temperature of 80 ° C. At this temperature, 614.3 g of the organic phase is introduced, which corresponds to 2.5 moles of imine. The inflow is carried out for one hour, during which time the cyclohexane containing one part of the propane formed during the degradation of imine is distilled.

The temperature was then maintained at 88 ° C for 4 hours. Distillation results in 178 g of cyclobeksan solution.

Then 955 g of the reaction mixture are taken. The substance balance shows a loss of 28 g. This reaction mixture (932 g, after sampling for analysis) yielded 517 g of the dry extract, which was analyzed by gas chromatography and NMR.

So we get:

ST dimethyl 1phosphite = 1007

DR: diester / dimethyl1phosphite = 947

DR: hydroxy / dimethyl phosphite = 27.

Distillation thus allowed a significant reduction in the formation of hydroxy (MeO) ₂ P0CH (OH) Et impurity.

c) The diester (470 g, 2.03 mol) prepared at 20 [deg.] C. in 30 minutes to a solution of 967 sulfuric (VI) acid (643 g, thus 6.3 mol or 3.1 eq. acid / mol) diestra). Then raise the temperature to 130 ° C and maintain it for five hours. After precipitation with methanol (1.6 ml / g solution) and triethylamine (340 g / mol diester) at 20 ° C and pH 5, the following is obtained:

DR: Aminopropanophosphonic acid / diester = 84%

DR: ami nopropanf osf onic k i sl i na / di meti 1 -f osf i t = 79%

Aminopropanophosphonic acid purity = 99.1%

EXAMPLE 5 Stages a) and b) with diethylphosphite (second solvent).

a) Put 1 mole (73 g) of tert-butylamine at room temperature into the flask. Then add 1 mole (58 g) of propane in 15 minutes. After 45 minutes, 130 g of dichloromethane and 2 g were added

NaCl to perform the casting. This gives 13 g of aqueous

-phase (61% of the water that was formed was removed) and

247 g of the organic phase distilled at 4 g after removal

50 ° C for 20 minutes. Finished distillation gave 236 g of the reaction mixture.

b) Take 118 g of this mixture and pour it on 0,4 mol (55 ml)

g) diethylphosphite at 25 ° C. Then the sonic temperature in 15 minutes to 57 ° C to achieve gentle reverse distillation. This temperature was maintained for 3 hours.

Under these conditions, the following results are obtained:

ST tert-butylpropane = 91%

ST of diethylphosphite = 9S%

DR: diester = 76%

DR: hydroxy impurities = 15%

Claims (16)

PATENT APPLICATIONS 1. A process for the preparation of ot-aminoalkane-fostonic acid, its salt or an ester of the general formula (I): / H r ₂ o which R _x , R ₃ , identical or different, are selected from a hydrogen atom, a straight or branched alkyl group of one to six carbon atoms, and one atom of alkali or alkaline earth metals, R ₃ = a hydrogen atom, or an alkyl, cycloalkyl, aryl or aralkyl group, these groups may contain one heteroatom and may be optionally substituted by one or more atoms, in particular halogen, R * is a hydrogen atom, a branched or branched alkyl group of 1 to 4 carbon atoms, characterized in that it contains three (acids) or four (salts or esters) stages, the whole of these four stages is described by the following common scheme: a) R ₃ - C - H II (III) R ₃ _ CH = NR 4 + H ₂ O (IV) b) r ₃ ~ - CH = NR ₄ + RiO R, 0 ¹ \ Z? - H -ZP- CHNHR _4/11 1 ⁴ R ₂ 0 0 r ₂ o 0 r ₃ (IV) (V) (VI) c) R, 0 \ HO P__ Zil r ₂ o 0 chnhr ₄ 1 * 3 + H ₂ SO ₄ -P / u H0 ^x 0 CHNH- 1 r ₃ (VI) d) possibly ^H0 . R _s 0 a \ P— CHNHo + nRcOH Z P CHNH- z II l ^{Δ J} HO ⁷ 0 R ₃ r ₅ o ^z 0 1 r ₃ (la) (Ib) wherein R _{= is} equal to R _x and / or R21 or an alkali metal atom, in particular Na or K, and n is 1 or 2, provided that when n = 1, one of the two R = is a hydrogen atom. Process according to claim 1, characterized in that in step d), R is a sodium or potassium atom. Process according to claim 1, characterized in that steps a) and b) are carried out in a water-immiscible or slightly miscible organic solvent. Process according to claim 3, characterized in that the organic solvent is selected from the group consisting of cyclohexane, dicyclohexane or toluene. 5. The process according to claim 4, wherein the organic solvent is cyclohexane. Process according to claim 1, characterized in that the carbonyl compound is in unprotected form, ketone or aldehyde, or in protected form, acetal, hemiacetal or dioxolane. Process according to claim 6, characterized in that the carbonyl compound (II) is propanal. Process according to claim 1, characterized in that the amine (III) is selected from methyl, ethyl, propyl or isopropyl- or n-butyl or tert-butylamine. Process according to claim 8, characterized in that the amine (III) is tert-butylamine. Process according to claim 1, characterized in that step a) is carried out with a molar excess of amine (III) with respect to the carbonyl derivative (II) upon removal of water. A process according to claim 1, characterized in that in step b) the dialky is a 1-phostite compound (V) of dimethyl or diethyl l-phosph-f it. Process according to claim 1, characterized in that in step c) sulfuric acid (2 to 5 equivalents of acid per mole of diester (VI) is used at a temperature between 80 and 150 ° C. Process according to claim 12, characterized in that the reaction is carried out with about 3 equivalents of sulfuric acid at 130-14Q ° C. A process according to claim 1, characterized in that at pH = 5 at the end of step c) the aminoalkanophosphonic acid (Ia) formed is purified by precipitation in a strong organic or inorganic base. The process of claim 14, wherein the base is triethylamine. A process according to claim 1 for the preparation of a compound of formula (I) in which R _t and R ₃ together are not a hydrogen atom, characterized in that one mole of aminoalkanphosphonic acid (Ia) formed in step c) of about 1 is reacted or 2 moles of the compound R = 0H, where R _{= has the} same meaning as Ri or R ₃ .