HU194897B - Process for preparing n-(phosphonomethyl)-glycine - Google Patents

Abstract

FIELD OF THE INVENTION The present invention relates to a novel process for the preparation of N- (phosphonomethyl) glycine such that a) 1,3,5-tris (cyanomethyl) hexahydro-1,3,5-triazine is calculated per mole of it. At 40 ° C to 110 ° C, from 3 to 10 moles of the acid halide of formula (III), wherein X 35 is a halogen atom having an atomic mass greater than R and a C 1-4 alkyl or ethoxy group, and b) a general formula IV. wherein X and R are as defined above, with 1 to 4 moles of a phosphite of formula V wherein R1 and R2 are C1-C4 alkyl and R3 is C1-C4 alkyl or lower alkyl; a potassium atom at a temperature of from 0 ° C to 110 ° C; and c) a phosphonate of formula VI, wherein R 'and R2 are inorganic acid, preferably salt, at a temperature of 0 ° C to 140 ° C as defined above, preferably salt hydrolysed in the presence of acid. H-N0 II-CH2-C-OHO-II-R-C-XO-) ORI-1R-RO-P-OR- (V) CH2 {- (OH) 2O (I) CH2CN · * R-C-N (sheet) ch2xo II. R-C-N ch2cn OR (VI) ch2p. ^ XOR2 -1-

Description

The present invention relates to a novel process for the preparation of N-phosphonomethylglycine.

Certain salts of N-phosphonomethylglycine are particularly effective, post-emergence (herbicidal) herbicidal formulations. One of the commercially available solid herbicidal formulations contains the active compound salt of N-phosphonomethylglycine with isopropylamine.

N-phosphonomethylglycine can be prepared by a variety of methods. One such method, as described in U.S. Pat. U.S. Pat. No. 4,600,129, N-phosphinomethylglycine (glycine methylene phosphonic acid) is heated to reflux with mercury (II) chloride and the reaction products are removed. Other suitable methods include phosphonomethylation of glycine and reaction of glycine ethyl ether with formaldehyde and diethyl phosphite 1. The latter method is disclosed in U.S. Pat. No. 3,799,758. U.S. Pat. A number of patents describing processes for the preparation of N-phosphonomethylglycine are also known. For example, U.S. Patent Nos. 3,868,407,4,197,254 and 4,199,354. U.S. Pat.

The process of the present invention is closely related to the process described in U.S. Patent No. 3,923,877. The process of US Patent No. 3,629,459, wherein 1,3,5-tris (cyanomethyl) hexahydro-1,3,5-triazine is reacted with excess double-substituted phosphite to give (RO) ₂ P (O) CH ₂ NHCH ₂ CN is prepared, wherein R is a hydrocarbon group or a substituted hydrocarbon group, and the latter is hydrolyzed to N-phosphonomethylglycine. A disadvantage of this process is that large amounts in the first step _[(RO?) P (O) CH _{2] 2} H _CH2 CN bis-N- (phosphonomethyl) -glicinonitril byproducts, but this compound can not be formed through hydrolysis of N - (phosphonomethyl) glycine, so that the yield of the first step is only about 6%.

Given the commercial importance of herbicidal compositions containing N-phosphonomethylglycine salts, new improved methods for preparing such compounds are of great importance.

The present invention relates to a novel process for the preparation of N-phosphonomethylglycine by:

a) 1,3,5-tris-cyanomethyl-hexahydro-1,3,

The 5-triazine is reacted with an acid halide, preferably an acid chloride, to give the N-cyanomethyl-N- (halomethyl) amide corresponding to the acid chloride used,

b) reacting the amide obtained in step a) with phosphite to form N- (acylaminomethyl) -N- (cyanomethyl) phosphonate; and

c) hydrolyzing the phosphonate obtained in step b) to N-phosphonomethylglycine of formula (I).

The process of the present invention is illustrated in Schemes A, B and C. 2

In Schemes A, III and IV

R is C1-C4 alkyl, preferably methyl or ethyl, or ethoxy;

X is a halogen atom having a mass greater than 35 atomic mass, preferably chlorine.

In Scheme B, R and X in formulas (V) and (VI) are as defined above in formulas (V) and (VI)

R ¹ and R ^{2 are C} 1 -C 4 alkyl and in the formulas V and VII R ^{3 is C} 1 -C 4 alkyl, or an alkali atom, preferably sodium or potassium.

In the formula of compounds of Scheme C

R ¹ , R ¹ and R ² are as defined above, and H ⁺ is a strong acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphonic acid or chloroacetic acid, preferably hydrochloric acid.

The hydrolysis is preferably carried out in the presence of a strong acid.

In reaction step a) illustrated in Scheme A above, the R group is not directly involved in the reaction of 1,3,5-tris (cyanomethyl) hexahydro-1,3,5-triazine with the acid chloride. Similarly, as illustrated in the above Reaction Scheme B, b) of reaction of R, R 'and R ² groups are not involved in the reaction product obtained in step a), N- (cyanomethyl) -N- (chloromethyl) - amide and phosphite. The R, R ¹ and R ² groups are removed in Step c) above, as illustrated in Scheme C, when the product of Step b) is hydrolyzed to the phosphonate VI. Therefore, R, R ^! The nature of the groups R ² and R ^{2 is} not critical, but it is necessary to avoid the use of groups which would interfere with the reactions of steps a) and b).

Examples of "C1-C4 alkyl groups" include methyl, ethyl, η-propyl, isopropyl, η-butyl, isobutyl, secondary butyl or tert-butyl.

In a preferred embodiment of step a) of the process according to the invention, the reaction is carried out at a temperature of from 40 ° C to 110 ° C, preferably from 75 ° C to 85 ° C. The reaction may be carried out at atmospheric pressure or at lower or higher pressures, preferably at atmospheric pressure. The reaction is preferably carried out in a solvent which dissolves the acid chloride used, such as 1,2-dichloroethane, dichloromethane, tetrahydrofuran and toluene.

One mole of 1,3,5-tris (cyanomethyl) hexahydro-1,3,5-triazine reacts with 3 moles of acid halide. An excess of the acid halide may be used to complete the reaction with the triazine. Large amounts of the acid halide may also serve as a solvent for this reaction. After the reaction, the solvent and any excess acid halide present may be removed to give the N-cyanomethyl-N-chloromethylamide of the acid corresponding to the acid halide in high yield. However, this amide is rapidly decomposed by heat and by hydrolytic action and should be kept in a neutral atmosphere if isolated.

Most preferably, the excess acid halide is not used and the solvent used in Step a) is also used as the solvent in Step b). Thus, it is not necessary to remove the solvent after step a) and the reaction mixture can be used directly in step b).

In a preferred embodiment of step b) of the process according to the invention, the N-cyanomethyl-N- (halomethyl) amide of the acid corresponding to the acid halide used and the phosphite are reacted in approximately equal amounts. It is less preferred to use up to 2 moles of phosphite, and even less preferably to use up to 10 moles of excess.

This reaction is exothermic and is carried out at a temperature of 0 ° C to 110 ° C, more preferably 40 ° C to 100 ° C, and most preferably 75 ° C to 85 ° C.

No solvent is required for the reaction, however, an inert solvent may be employed, preferably a solvent having a boiling point of from 40 ° C to 100 ° C. Examples of such solvents are 1,2-dichloroethane, dichloromethane, tetrahydrofuran and toluene. If a neutral solvent is used, it will absorb the heat generated by the reaction. Most preferably, the solvent used in Step (a) is used. Optionally, the solvent used in Step b) is removed after the completion of Step c), so it is preferable to use a solvent that can be distilled.

The alkali metal phosphites of formula (V) wherein

R ¹ and R ² are as defined above and

R ³ is an alkali metal and is reacted with N- (cyanomethyl) -N- (halomethyl) amides under a neutral atmosphere, such as nitrogen. The alkali metal phosphite can be prepared by reacting an equimolar amount of an alkali metal alcoholate, an alkali metal hydride or an alkali metal doubly substituted phosphite of formula VIII wherein R ¹ and R ² are as defined above. The reaction is carried out under a neutral atmosphere, such as nitrogen.

Alkali metal phosphites of formula IXa wherein

R ¹ , R ² and M are as defined above, in tautomeric equilibrium with compounds of formula IXb wherein R ¹ and R ² are as defined above and M is an alkali metal.

In a preferred embodiment of step c) of the process of the invention, the phosphonate obtained in step b) is hydrolyzed molar with 5 times the amount of water. Hydrolysis is carried out in the presence of a strong acid as defined above. The acid used is an inorganic acid, preferably hydrochloric acid or hydrobromic acid. Hydrolysis yields the desired N-phosphonomethylglycine. Preferably at least two moles of acid are used. Even more preferably, a large excess of acid is used relative to the two moles. The preferred hydrochloric or hydrobromic acid may be used in concentrated or diluted with water.

The hydrolysis is carried out at a temperature of from 0 ° C to 200 ° C, preferably from 50 ° C to 140 ° C, and most preferably from 100 ° C to 125 ° C.

The reaction may be carried out at atmospheric pressure or higher or lower. Preferably, atmospheric pressure is employed.

The solid N-phosphonomethylglycine formed in Step c) can be isolated by methods known per se. Volatile liquid products such as alcohols (e.g. methanol), chlorides (e.g. methyl chloride), acids (e.g. acetic acid), water and excess acid can be removed by distillation under reduced pressure. The N-phosphonomethylglycine is prepared in high purity by dissolving the crude product in water, adjusting the pH of the solution to 1-2, and filtering off the crystallizing material from the solution.

The invention is illustrated by the following non-limiting examples.

Example 1

N- (Cyanomethyl) -N- (chloromethyl) acetamide [Formula (IVa)] g (0.0835 mol) 1,3,5-tris-cyanomethyl-1H-xahydro-1,3 5-Triazine is suspended in 150 ml 1,2-dichloroethane in a round-bottomed flask. Acetyl chloride (40 mL, 0.563 mol) was added all at once, the mixture was refluxed for 3 hours and the solvent was distilled off under reduced pressure. 26.9 g (79.85% yield) of N- (cyanomethyl) -N-chloromethylacetamide are obtained. The structure of the product was determined by standard analytical methods (IR, NMR and mass spectrum).

Example 2 (N-Cyanomethyl-N-acetyl) -aminomethyl-phosphonic acid dimethyl ester (Formula Via)

26.9 g (0.2 mol) of the amide obtained in Example 1 are dissolved in 75 ml of dichloromethane, 25.5 g (0.206 mol) of trimethyl phosphite are added and the mixture is stirred overnight at room temperature and refluxed for half an hour. and then the solvent was distilled off under reduced pressure. 34.9 g (79.32%) of the desired product are obtained. The structure of the product was determined using its IR, NMR and tR spectra 3

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Example 3

N- (Phosphonomethyl) glycine [Formula I]

19.5 g (0.09 mol) of the product obtained in Example 2 are refluxed with 100 ml (1.21 mol) of concentrated hydrochloric acid for 3 hours, and the solvent is distilled off under reduced pressure. The residue was dissolved in water (30 ml), the pH of the solution was adjusted to 10 with 50% sodium hydroxide solution, and the solvent was distilled off under reduced pressure. The residue was redissolved in water (30 mL) and the pH was adjusted to 1 with concentrated hydrochloric acid. The mixture was cooled overnight and the next day the desired product was filtered off. 5.4 g (35.49%) of 98.3% pure desired product are obtained. The structure of the product was determined by means of its IR spectrum, NMR spectrum and liquid chromatography.

Example 4

N-Phosphonomethylglycine (Formula 1)

50 ml in a 50 ml round-bottom flask

1,2-dichloroethane was heated to reflux, then acetyl chloride (5.5 mL, 0.077 mole) was added over 10 min, followed by concurrent addition of 3.4 g (0.0167 mole) of 1,3,5-tris- ( cyanomethyl) hexahydro-1,3,5-triazine in such a way that an excess of acid chloride is always present in the flask. The mixture was refluxed for half an hour and then the solvent was distilled off under reduced pressure.

To the residue was added toluene (5 mL) and trimethylphosphite (6.6 mL, 0.05 mol) and the mixture was refluxed for a quarter hour. After stirring for 2 hours at room temperature, the solvent was distilled off under reduced pressure. Concentrated hydrochloric acid (30 ml, 0.36 mol) was added to the residue, the mixture was refluxed for 3 hours, and the solvent was distilled off under reduced pressure. This gave 11.3 g of a solid which, according to liquid chromatography, contained 47.9% by weight of the desired N-thiomonomethylglycine. The structure of the product was determined using ¹³ C-NMR and ¹ H-NMR spectra. The total yield of N-isosonomethylglycine in the three steps was 64%.

Example 5 [N- (Cyanomethyl) -N- (ethoxycarbonyl) aminomethylphosphonic acid dimethyl ester [Formula VIb]

In a 50 mL round bottom flask equipped with stirrer and condenser, 8 mL (0.083 mole) of ethyl chloroformate was dissolved in 8 mL of dichloromethane and 3.4 g (0.0167 mole) of 1,3,5-tris tris was added. (cyanomethyl) hexahydro-l, 3,5-triazine. The mixture was refluxed for 1 hour and then the solvent was distilled off under reduced pressure. The residue was dissolved in dichloromethane (5 mL) and a solution of trimethylphosphite (5 mL, 0.042 mol) in dichloromethane (15 mL) was added. The mixture was refluxed for 1 hour, then cooled and water (50 mL) was added. The aqueous layer was extracted with dichloromethane (3 x 50 mL), the combined organic layers were dried over magnesium sulfate and the solvent was distilled off under reduced pressure. 6.9 g (50%) of the desired product are obtained. The structure of the product was determined by its IR, NMR and mass spectra.

Example 6

N- (phosphonomethyl) glycine] (formula I)

A mixture of 4.9 g (0.02 mol) of the phosphonate obtained in Example 5 and 20 ml (0.24 mol) of concentrated hydrochloric acid is refluxed for 3 hours and then concentrated under reduced pressure. The residue was dissolved in water (30 ml), the pH of the solution was adjusted to 10 with 50% sodium hydroxide solution, and the solvent was distilled off under reduced pressure. The residue was redissolved in about 5 mL of water. The structure of the product was determined by NMR and liquid chromatography.

Example 7 [N- (Cyanomethyl) -N- (acetyl)] aminomethyl-phosphonic acid diethyl ester (Formula VIc)

Potassium tert-butylate (5.6 g, 0.05 mol) was suspended in a round-bottom flask (25 ml) in tetrahydrofuran (molecular sieve) and 6.44 ml (0.05 mol) was added dropwise under ice-cooling over 5 minutes. diethyl phosphite. A solution of 7.33 g (0.05 mol) of N- (cyanomethyl) -N- (chloromethyl) acetamide in 50 ml of tetrahydrofuran is added dropwise to the reaction mixture under ice-cooling for 15 minutes. The mixture was then allowed to warm to room temperature and stirred for 3 hours. The mixture was then filtered through diatomaceous earth and the tetrahydrofuran was distilled off under reduced pressure. 9.0 g of the desired product are obtained, which structure is determined by IR, ¹³ C-NMR and 1 H-NMR and mass spectra.

Example 8

N-phosphonomethylglycine] (formula I)

A mixture of 5.4 g (0.022 mol) of the product obtained in Example 7 and 30 ml (0.363 mol) of concentrated hydrochloric acid is refluxed for 3 hours and then concentrated under reduced pressure. This gave 10.8 g of the desired product as a brown, winter solid, which was determined by IR, ¹³ C-NMR and 1 H-NMR and liquid chromatography.

Example N- (Cyanomethyl) -N- (acetyl) -aminomethyl-phosphonic acid dimethyl ester (Formula Via)

Sodium hydride (1.44 g, 0.06 mol) was suspended in 25 ml of molecular weight dried tetrahydrofuran under a nitrogen atmosphere. 6.4 ml (0.05 mol) of dimethyl phosphite are added dropwise over a quarter hour, and when the evolution of hydrogen gas is complete, the mixture is cooled in an ice bath and 7.33 g (0.05 mol) of N- is added dropwise over a period of (cyanomethyl) -N- (chloromethyl) acetamide in 50 ml of anhydrous tetrahydrofuran. The reaction mixture was stirred overnight, the insolubles were filtered off and the filtrate was evaporated under reduced pressure. 11.5 g of the desired product are obtained in the form of a yellow oil.

The structure of the product has an IR spectrum of ¹³ C-10

It is determined by mass spectra of NMR and 1 H NMR and liquid chromatography.

The product obtained as described in this Example is hydrolyzed as described in Example 3 to give N-phosphonomethylglycine.

Claims (6)

PATENT CLAIMS A process for the preparation of N-phosphonomethylglycine, comprising: a) 1,3,5-tris-cyanomethyl-hexahydro-1,3, 5-Triazine is reacted with 3 to 10 moles of acid halide of formula III in an inert solvent, preferably chlorinated hydrocarbon, at a temperature of from 40 to 110 ° C, per mole thereof. X halogen of more than 35 atomic masses and ₃₀ R is C 1-4 alkyl or ethoxy, then b) the resulting amide of formula (IV) wherein X and R are reacted with 1-4 moles of phosphite of formula (IV) 1-4 moles per mole thereof as a special solvent, preferably in a chlorinated hydrocarbon R 1 and R ^{2 are C} 1 -C 4 alkyl and R ^{3 is C} 1 -C 4 alkyl or alkaline earth metal at -0 ° C to 110 ° C and c) the resulting phosphonate of formula VI, wherein R ¹ and R ^{2 are} hydrolyzed in a manner known per se in the presence of an inorganic acid, preferably hydrochloric acid, at a temperature of from 50 ° C to 140 ° C. 2. The process according to claim 1, wherein the starting material is a compound of formula III wherein R is C 1-4 alkyl and X is chloro. 3. A process according to claim 1 wherein the starting material is a compound of formula (III) and (V) wherein R is C 1-4 alkyl, X is chlorine, R ¹ and R ^{2 are C} 1-4 alkyl and R ^{3 is C} 1-4 alkyl, sodium or potassium. 4. A process according to claim 1 wherein the starting material is a compound of formula (III) or (V) wherein R is C 1-2 alkyl, X is chlorine, R 1 and R ^{2 are C} 1 -C 4 alkyl and R ^{3 is C} 1-4 alkyl, sodium or potassium. 5. A process according to claim 1 wherein the starting material is a compound of formula (III) and (V) wherein R, R ¹ , R ² and R ^{3 are C} 1-2 alkyl and X is chloro. 6. A process according to claim 1 wherein the starting material is a compound of formula (III) and (V) wherein R, R ', R ² and R ^{3 are} methyl; X is chlorine.