NZ244927A - Process for the preparation of an alpha-aminoalkanephosphonic acid, salt or ester - 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): 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

New Zealand Paient Spedficaiion for Paient Number £44927 244927 Priority Dat3(s): . .&V.3 A i Complete Specification Filed: ?r?\ Class: Publication Date: P.EC 199^ P.O. Journcl, No: 1 wo d fi. t t tt i. * 1. »"♦ •*. / new zealand patents act, 1953 f NO, / _ 29°cr/y^ ' Date: complete specification PROCESS FOR THE PRODUCTION OF AMINOALKANEPHOSPHONIC ACIDS, SALTS AND/OR ESTERS / n We, RHONE-POULENCAGROCHIMIE, a French body corporate of 14-20 Rue I dig I Pierre Baizet,®P-9163"Lyoil 09, 69203 Lyun Ceifcx-*, France, hereby declare the 'VI, .°)3. eU^' invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- - 1 -(followed by page la) 2 4 4 -la- The present invention relates to a novel process 5 for obtaining a-aminoalkanephosphonic acids and/or salts or esters of general formula (I): RiO NHR4 _ 1 \ i 4 (I) P — CH—R3 /ii ■> R2O O with R, and 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 an alkaline-earth metal atom, or a quaternary ammonium group; 15 R3 = a hydrogen atom or an alkyl, cycloalkyl, aryl or aralkyl group, it being possible for these groups to be optionally substituted with one or more heteroatoms, preferably halogen; and R4 = a hydrogen atom or a linear or branched 20 alkyl group with 1 to 4 carbon atoms.

The products of formula (I) are known and can be used as fungicides (European Patent 0153284 and USP 4994447 and 4888330). The product for which Rj, R2 and R4 are a hydrogen atom and R3 an ethyl is ampropylfos, which is 25 commercially available and can be used in leaf or seed treatments.

The access routes to these products described in 2 4 4 9 2 the above patents have proved to be inadequate for industrial production of these products to be envisaged, especially because of catalytic process by hydrogenation, high temperature and pressure conditions and excessively 5 long reaction times.

One aim of the present invention is thus to lead to these compounds in a way which is more economic than the access routes described previously.

Another aim of the invention is to manufacture 10 the compounds of formula (I) with much gentler hydrolysis conditions than the conditions already known and, above all, with much shorter reaction times.

Moreover, a third aim of this invention is to use a process which makes possible a better control of the 15 aqueous and gaseous effluents.

Finally, another aim of the invention is to give compounds of formula (I) with an optimised yield and purity.

The present invention provides a process for preparing 20 compounds of formula (I) , as hereinbefore defined, which comprises: a) reacting an aldehyde R3CH0 (II) in which R3 is as hereinbefore defined, or a protected derivative thereof, with an alkyl amine fyNfy (III) in which R4 is alkyl of l to 25 4 carbon atoms, to produce an imine of formula (IV):- RjCH^NR* (IV) 24 4 0 2 7 in which R3 is as hereinbefore defined and R4 is alkyl of 1 to 4 carbon atoms; b) reacting the inline (IV) thus produced with a dialkyl phosphite of formula (V):- RlO > - H (V) R20 (!) in which Ri and R2 are the same or different and each is alkyl of 1 to 6 carbon atoms, to produce a compound of 10 formula (I) in which Rt , R2 and R, are each alkyl groups; c) hydrolysing the compound of formula (I) thus produced in the presence of sulphuric acid, to produce a compound of formula (I) in which R, and R2 are hydrogen and R4 is hydrogen or alkyl of 1 to 4 carbon atoms; and d) optionally reacting a compound of formula (I) produced by the hydrolysis stage c), with a compound of formula Rs0H where Rs is alkyl of 1 to 6 carbon atoms, alkali metal, alkaline-earth metal or a quaternary ammonium group to provide a compound of formula (I) in which R, and/or R2 is as defined above for Rs.

The process for the preparation of (R,S)-1-aminoalkanephosphonic acids or esters and salts passes through three (acids) or four (esters, salts) stages. The preferred process can be schematised in the following way: a) R3—C H +R4NH2 > R3—CH=NR4+H20 O 24 b) ^3 Rl°\ ch=nr4 + p-R2cj O h Ri<\ r2o o CHNHR4 I *3 c) RlO^ ^ p - chnhr4 + h2so4 r20 o r3 ho \ p / II ho o chnh2 I R* d) ho \ p / 11 ho o CHNH2 + nR5OH k R5°x /1 R5O O chnho 1 * r3 with R5 = R, and/or R2, preferably Na or K, and n = 1 or 2.

The reaction a) between a primary amine and a carbonyl derivative (or a protected form of a carbonyl derivative, that is to say an acetal, a hemiacetal or dioxolane, which it is therefore appropriate to react in 20 acidic medium in order to generate the carbonyl) can be written according to the scheme: r3 - c — h + r4nh2 O * r3 — ch=nr4 + h20 24 4,9 The reaction is typically carried out in organic solvent, such as cyclohexane, dichloromethane, toluene and optionally in the presence of an alkali such as sodium hydroxide at room temperature (20°C). The imine of formula 5 (IV) product is an intermediate which can be introduced without any additional treatment into the following reaction stage (stage b). However this results in a high level of impurity, and if the imine is purified by distillation this results in a better selectivity though 10 the distillation causes the loss of a significant portion (typically about 3 0%) of the synthesised imine.

In one particular embodiment, propanal is reacted with tert-butylamine to provide the intermediate tert-propanimine.

If stage a) is carried out in organic solvent medium, the water formed, which is responsible for the high level of impurity, can be easily separated.

With cyclohexane, 95% of this water which is formed is removed, whereas the use of dichloromethane only 20 makes possible the removal of 61% of the quantity of water produced, toluene 83% and the toluene/sodium hydroxide mixture 92%.

The remaining water can be removed by azeotropic distillation but this has to take place at such a 25 temperature (80°C with cyclohexane) that the imine degrades. It is thus preferable to work in cyclohexane solvent with a simple separation of the water produced. 24 Stage b) of condensation of the imine obtained in a) with a dialkyl phosphite is written according to the reaction: Rt0 RiO \ 1 y p — H > . r20 o r20 o r3 r3—ch=nr4 + p — h > p chnhr4 4 / n / ii ■ Stages a) and b) are carried out in an organic 10 solvent medium such as cyclohexane, dichloromethane or toluene. The organic solution of imine obtained in stage a) is run onto the dialkyl phosphite, which is pure or itself in organic solution.

Stage c) of hydrolysis of the diester obtained, 15 and precipitation of the diacid obtained, is carried out according to the scheme: *l<\ hox p — chnhr4 +h2so4 > ,p — chnh2 /II I * L 4 / II I z r2o o r3 ho o r3 The diester compound obtained after stage b) can be isolated and used as it is. However, the compounds which 25 have proved more useful as fungicides are the acids and the salts, that is to say the compounds for which R, and/or R2 are chosen from hydrogen and the alkali or alkaline-earth 2 4 4 metals or quaternary ammonium groups, preferably alkali or alkaline-earth metals. As the acid is thus useful either as such or as an intermediate for obtaining the salts, this hydrolysis stage is thus practically always carried out 5 followed by the precipitation of the phosphonic acid obtained.

The conditions for the hydrolysis c) are gentler than those described previously. Indeed, this stage of acid hydrolysis of a l-aminoalkanephosphonic diester was already 10 known, as a basic reaction, but with use of hydrobromic acid, under pressure and at a temperature of the order of 175-180°C for a period of 48 hours.

The use according to the invention of 2 to 5 equivalents of sulphuric acid per mole of diester makes it 15 possible to carry out the hydrolysis in a few hours (4 to 6), at atmospheric pressure and at a temperature of the order of 120-140°C, for example 130-140°C.

Under these conditions, the two acid functional groups are released, as is the secondary amine which gives 20 NH2.

In an alternative embodiment it is possible to obtain compounds where R, is other than a hydrogen atom if the hydrolysis takes place at a lower temperature, for example in the region of 80°C. In that case, only the two 25 acid functional groups are generated.

The optional stage d) of salification or esterification of the diacid obtained in c) is written: 8 ho \ ho o r3 / U « P — CHNH2 + nR The examples which follow illustrate the present invention in a non-limiting way.

Example 1: Synthesis of aminopropanephosphonic acid 15 (diethyl phosphite route 1). hour, onto 3 mol (219 g) of tert-butylamine contained in a round-bottom flask at room temperature (20°C). At the end of the addition, 393 g of cyclohexane are added in order to 20 separate the water formed. 51.5 g of aqueous phase and 734.5 g of organic phase (d = 0.786) are then obtained. phase) are then withdrawn so as to have 0.75 mol (84.75 g) of produced imine which is then introduced, over one hour, 25 onto 0.75 mol (103.5 g) of diethyl phosphite heated at 60°C. a) 3 mol (174 g) of propanal are run, over one b) 183 g of the above reaction mixture (organic The total reaction mixture (286.5 g containing 2 4 4 9 2 ] 34% cyclohexane) is left at 60°C and then the temperature is raised to 80°C over one hour and the temperature is maintained for a further one hour before heating and stirring are stopped.

This gives degrees of conversion (DC) of the imine and the phosphite of 97 and 96% respectively and reaction yields (RY) of expected diester of 89% and of hydroxyl impurity ((EtO)2POCH(OH)Et) of 6%. c) Hydrolysis of the diester is carried out with 3 equivalents of sulphuric acid (96%) per mole of diester at a temperature of 140°C. The diester is run into the hot acid solution. After a reaction time of five hours, the diacid obtained in the aqueous phase is treated with methanol and then with triethylamine (NEt3) .

The following results are then obtained: RY of aminoalkanephosphonic acid/diester = 81% Purity of the aminoalkanephosphonic acid = 99%.

Example 2: Synthesis of aminopropanephosphonic acid (diethyl phosphite route 2). a) 2 mol (146 g) of tert-butylamine are introduced into a round-bottom flask at 20°C into which 2 mol (116 g) of propanal are run onto the amine at 20°C.

Af-fcer the propanal has been introduced, 250 g of cyclohexane are introduced in order to make separation possible. 35 g of aqueous phase and 477 g of organic phase ^4 4 9 2 (d = 0.78) are then obtained which are separated into two lots of 238.5 g. b) 179 g are withdrawn from one these lots so as to have 0.75 mol (84.75 g) of imine which is run onto 0.75 5 mol (103.5 g) of diethyl phosphite at 50°C over 40 minutes with stirring. The temperature is then increased to 60°C where it is maintained for 6 hours. After 278 g of the mixture obtained have been evaporated under laboratory vacuum at 70°C, the end result is 184 g of product which is 10 analysed by gas phase chromatography and NMR.

The balance is then the following: DC of the tert-butylpropanimine = 96% DC of the diethyl phosphite =97% 15 RY of diester = 90% RY of hydroxyl impurity = 7.2% The diester is then purified by basic washings (20% NaOH and then H20) in order to remove the hydroxyl 20 impurity ((EtO)2POCH(OH)Et). Several washings are necessary to restrict the remaining quantity of hydroxyl to 0.5 mol %. Indeed, by a single washing with water at 60°C for 1 h 40, 6% of this impurity is retained in the final mixture. c) The hydrolysis is carried out on a part of the 25 diester obtained, and purified to 95%, with 3 equivalents of sulphuric acid (96%) per mole of diester at a temperature of 140°C. The diester is run into the hot acid ^ 4 4 9 c j - ii - solution. After a reaction time of five hours, the diacid obtained in the aqueous phase is treated with methanol and then with triethylamine (NEt3) .

The following results are then obtained: RY of aminoalkanephosphonic acid/diester = 88% Purity of the aminoalkanephosphonic acid = > 99%.

Example 3: Synthesis of aminopropanephosphonic acid 10 (dimethyl phosphite route 1). a) 2 mol (146 g) of tert-butylamine are introduced into a round-bottom flask at 20°C into which 2 mol (116 g) of propanal are run onto the amine at 20°C. After the propanal has been introduced, 250 g of cyclohexane are introduced in order to make separation possible. 35 g of aqueous phase and 477 g of organic phase (d = 0.78) are then obtained which are separated into two lots of 238.5 g. b) 179 g are withdrawn from one of these lots so 2 0 as to have 0.75 mol (84.75 g) of imine which is run onto 0.75 mol (82.5 g) of dimethyl phosphite at 50°C over 40 minutes with stirring. The temperature is then raised to 60°C where it is maintained for 6 hours. After 257 g of the mixture obtained have been evaporated under laboratory 25 vaguum at 70°c, the end result is 164 g of product which is analysed by gas phase chromatography and NMR. *4 4 9 The balance is then the following: Degree of Conversion (DC) of the imine = 100% DC of the dimethyl phosphite (DMP) = 100% Reaction Yield (RY) diester/DMP = 90% 5 RY hydroxyl ((MeO)2POCH(OH) Et)/DMP = 4.8% Other impurities = 4.3%. c) The hydrolysis is carried out, starting from the diester obtained, with 3 equivalents of sulphuric acid 10 at 130°C for four hours. The acid obtained is then precipitated with methanol and triethylamine.

The result is then: RY of aininopropanephosphonic acid/diester = 85% 15 RY of aininopropanephosphonic acid/dimethyl phosphite = 77% Purity of aininopropanephosphonic acid = 99%.

Example 4: Synthesis of aminopropanephosphonic acid 20 (dimethyl phosphite route 2). a) 3.5 mol (258 g) of tert-butylamine (d = 0.7) are introduced into a round-bottom flask. 3.5 mol (203 g) of propanal (d = 0.8) are run onto the amine over one hour at 20°C. 461 g of cyclohexane are then added for 25 separation, which results in 60.5 g of aqueous phase (96% of the water formed is removed) and 860 g of organic phase (d = 0.76) . 24 4 b) 2.5 mol (275 g) of dimethyl phosphite and 275 g of cyclohexane are mixed in another round-bottom flask. This mixture is heated so as to have a temperature of 80°C. At this temperature, 614.3 g of organic phase are 5 introduced which corresponds to 2.5 mol of imine. The organic phase is run in over one hour during which cyclohexane is distilled which contains a propanal part formed by reversion from the imine. The temperature is then maintained at 88°C for 4 hours. The distillation results in 10 178 g of cyclohexane solution.

A reaction mixture containing 955 g is then drawn off. The material balance shows a loss of 28 g. This reaction mixture (9 32 g, after removals of samples for analyses) results in 517 g of dry extract which is analysed 15 by gas phase chromatography and NMR.

There is then obtained: DC of dimethyl phosphite = 100% RY diester/dimethyl phosphite = 94% 20 RY hydroxyl/dimethyl phosphite = 2%.

The distillation has thus made it possible to markedly reduce the formation of the hydroxyl impurity (MeO) 2P0CH (OH) Et. c) The diester (470 g, 2.03 mol) obtained is run into a 96% solution of sulphuric acid (643 g, i.e. 6.3 mol or 3.1 eq. acid/mole of diester) at 20°C over 30 minutes. 24 49 The temperature is then raised to 130°C where it is maintained for five hours. After precipitating, at 20°C and a pH of 5, with methanol (1.6 ml/g of solution) and triethylamine (340 g/mole of diester), there is obtained: RY of aminopropanephosphonic acid/diester = 84% RY of aminopropanephosphonic acid/dimethyl phosphite = 79% Purity of aminopropanephosphonic acid = 99.1%.

Example 5: Stages a) and b) with diethyl phosphite (other solvent). a) 1 mol (73 g) of tert-butylamine are placed in a round-bottom flask at room temperature. 1 mol (58 g) of propanal are then run in over 15 minutes. After 45 minutes, 130 g of dichloromethane and 2 g of NaCl are added in order to produce the separation. 13 g of aqueous phase (61% of the water formed is thus removed) and 247 g of organic phase are obtained which, after withdrawal of 4 g, is distilled at 50°C for 20 minutes. When the distillation is complete, the end result is 236 g of reaction mixture. b) 118 g of this mixture are withdrawn and run onto 0.4 mol (55 g) of diethyl phosphite at 25°C. The temperature is then raised over 15 minutes to 57°C so as to hav.e a slight reflux. This temperature is maintained for 3 hours. ^4 4 9 2 1 Under these conditions, the end results are the following: DC of the tert-butylpropanimine = 91% DC of the diethyl phosphite = 98% RY diester =76% RY of hydroxyl impurity = 15%. 244927

Claims (20)

WHAT WE CLAIM IS:

1. Process for the preparation of an a-aminoalkanephosphonic acid, salt or ester of general formula (I): RiO^ p— ch—r3 ,t. /ii l1) r20 0 10 in which Rj and R2/ which are identical or different, are 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, or a quaternary ammonium group; R3 is a hydrogen atom or an alkyl, cycloalkyl, 15 aryl or aralkyl group, it being possible for these groups to be optionally substituted with one or more heteroatoms; and R, is a hydrogen atom or a linear or branched alkyl group with 1 to 4 carbon atoms, which process comprises :-20 a) reacting an aldehyde R3CH0 (II) in which R3 is as hereinbefore defined, or a protected derivative thereof, with an alkyl amine R,NH2 (III) in which R4 is alkyl of 1 to 4 carbon atoms, to produce an imine of formula (IV):- 25 R3CH=NR4 (IV) in which R3 is as hereinbefore defined and R« is alkyl 24 4 9 17 to 4 carbon atoms; b) reacting the imine (IV) thus produced with a dialkyl phosphite of formula (V):- in which R, and R2 are the same or different and each is alkyl of 1 to 6 carbon atoms, to produce a compound of formula (I) in which R, , R2 and R, are each alkyl groups; c) hydrolysing the compound of formula (I) thus produced in the presence of sulphuric acid, to produce a compound of formula (I) in which R, and R2 are hydrogen and R, is hydrogen or alkyl of 1 to 4 carbon atoms; and d) optionally reacting a compound of formula (I) produced by the hydrolysis stage c), with a compound of formula R5OH where R5 is alkyl of 1 to 6 carbon atoms, alkali metal, alkaline-earth metal or a quaternary ammonium group to provide a compound of formula (I) in which Rj and/or R2 is as defined above for R5.

2. A process according to claim 1 which comprises hydrolysing in stage c) to produce a compound of formula (I) in which Ru R2 and R, are each hydrogen.

3. Process according to claim 1 or 2 which comprises in stage d) , reacting with RsOH, where Rs is an alkali or alk-aline-earth metal atom or a quaternary ammonium group to produce a compound of formula (I) in which Rj and/or R2 is RiO 244 92 - 18 - an alkali or alkaline-earth metal atom or a quaternary ammonium group.

4. Process according to claim 3 in which Rs is sodium or potassium. 5

5. Process according to any one of the preceding claims in which stages a) and b) are carried out in an organic solvent medium which is immiscible or substantially immiscible with water.

6. Process according to claim 5, in which the 10 organic solvent is cyclohexane, dichloromethane or toluene.

7. Process according to claim 6, in which the organic solvent is cyclohexane.

8. Process according to any one of the preceding claims, in which the aldehyde (II) is in unprotected, 15 aldehyde form, or in the protected, acetal, hemiacetal or dioxolane form.

9. Process according to claim 8, in which the aldehyde (II) is propanal.

10. Process according to any one of the preceding 20 claims in which the amine (III) is methyl-, ethyl-, propyl-, isopropyl-, n-butyl- or tert-butylamine.

11. Process according to claim 10, in which the amine (III) is tert-butylamine.

12. Process according to any one of the preceding 25 claims in which stage a) is carried out with a molar excess of amine (III) with respect to the carbonyl derivative (II), and with removal of water formed, in the formation of 244927 - 19 - imine (IV).

13. Process according to any one of the preceding claims in which in stage b), the dialkyl phosphite compound (V) is dimethyl or diethyl phosphite. 5

14. Process according to any one of the preceding claims in which in hydrolysis stage c), sulphuric acid is used in an amount of 2 to 5 equivalents of acid per mole of diester at a temperature of between 80 and 150°C.

15. Process according to Claim 14, in which the 10 hydrolysis reaction is carried out with approximately 3 equivalents of sulphuric acid at 120-140°C.

16. Process according to any one of the preceding claims in which the aminoalkanephosphonic acid formed by hydrolysis stage c) is purified at pH 5 by precipitating in 15 an organic or inorganic strongly basic medium.

17. Process according to Claim 16, in which the base is triethylamine.

18. Process according to any one of the preceding claims which comprises in stage d), reacting with 20 approximately l or 2 moles of a compound RsOH, where Rs is as defined in claim 1, per mole of compound of "(I*)— in which R, and R2 are hydrogen. 29 OCT 1392 _RECGIV~0

19. A process according to claim 1 which substantially as hereinbefore described with reference"tCf—- 25 any one of Examples 1 to 5.

20. A compound of formula (I), as defined in claim 1, when prepared by a process as claimed in any one of the preceding claims. oated this day of Ocfader 19 92 A. J. PARK & SON PER S, AGENTS FO DR THE APPLICANTS