NO833829L - PROCEDURE FOR THE PREPARATION OF N-PHOSPHONOMETHYLGYLINE - Google Patents

Description

This invention relates to a new process for the production of N-phosphonomethylglycine.

N-phosphonomethylglycine and certain salts are particularly effective as post-emergence herbicides. The commercial herbicide is in the trade as a preparation containing the isopropylamine salt of N-phosphonomethylglycine.

N-phosphonomethylglycine can be prepared in several ways. One

of these is, as described in US patent 3,160,632, to react N-phosphinomethylglycine (glycinemethylenephosphonic acid) with mercury(II) chloride in water at boiling temperature and then separate the reaction products from each other. Other methods are phosphonomethylation of glycine and reaction of ethyl glycinate with formaldehyde and diethyl phosphite. The latter method is described in US patent no. 3,799,758. There are also a number of patents relating to the production of N-phosphonomethylglycine, including US patents 3,868,407, 4,197,254 and 4,199,354.

From the state of the art, US patent 3,923,877 is particularly mentioned, which describes the reaction of 1,3,5-tricyanomethylhexahydro-1,3,5-triazine with an excess of disubstituted phosphite, whereby (RO)2P(0 )CH2NHCH2CN (R is hydrocarbyl or substituted hydrocarbyl) which is hydrolyzed to N-phosphonomethylglycine.

Since N-phosphonomethylglycine and certain salts are commercially important herbicides, improved processes for the preparation of these compounds are of considerable value.

The invention relates to a process for the production of N-phosphonomethylglycine, which comprises: (1) 1,3,5-tricyanomethylhexahydro-1,3,5-triazine is reacted with an acyl halide, preferably acyl chloride, forming the N-cyanomethyl-N-halomethylamide of the acyl halide, (2) the amide is reacted with a phosphite to form N-acylaminomethyl-N-cyanomethylphosphonate, and (3) this phosphonate is hydrolyzed to N-(phosphonomethyl)-glycine.

The method according to the invention can be illustrated using the following reaction core:

where R is an aliphatic or aromatic group as defined below, preferably C 1 -C 4 alkyl, more preferably methyl or ethyl, and X is chlorine, bromine or iodine, preferably chlorine. 1 2 0 0R where R and X are as defined above, and R and R are both aromatic groups or both aliphatic groups, preferably R<1>2 3 and R are Cj-Cg-alkyl, more preferably Cj-C^-alkyl , and R is an aliphatic group, preferably C 1 -C 8 -alkyl, more preferably C 1 -C 4 -alkyl, or R 1 is an alkali metal (M), preferably sodium or potassium.

in 2 +

where R, R and R 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, H+ is hydrochloric acid or hydrobromic acid, and OH is a strong base such as sodium hydroxide or potassium hydroxide, preferably an aqueous, aqueous-alcoholic or alcoholic solution. The hydrolysis is preferably carried out in the presence of a strong acid.

In the above reaction core, the group R is not directly involved in reaction step (a) between 1,3,5-tricyanomethylhexa-1 2 hydro-1,3,5-triazine and the acyl chloride. The groups R, R or R are not directly involved in reaction step (b) between the N-cyanomethyl-N-chloromethylamide reaction product of step (a) and phosphite. Group-12

neat R, R and R are removed in reaction step (c) when the phosphonate reaction product in reaction step (b) is subjected to hydrolysis. The nature of these groups is therefore not critical or decisive, although groups that will affect reaction steps (a) and (b) unfavorably

way, should obviously be avoided.

The group "C 1 -C 4 -alkyl" includes methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, sec-butyl and tert-butyl. The group "C 1 -C 8 -alkyl" includes the same radicals as C 1 -C 3 -alkyl plus the 6 pentyls and 16 hexyls.

The term "aliphatic group" is used herein in a broad sense and covers a large class of organic groups characterized by being derived from (1) an acyclic (open-chain) structure of the paraffinic, olefinic, and acetylene hydrocarbon series and their derivatives or ( 2) alicyclic compounds. The aliphatic group may have from

1 to 10 carbon atoms.

The term "aromatic group" is used herein in a broad sense and is distinguished from the aliphatic group and includes a group derived from (1) compounds having 6-20 carbon atoms and characterized by the presence of at least one benzene ring, including monocyclic, bicyclic and polycyclic hydrocarbons and their derivatives and (2) heterocyclic compounds of 5-19 carbon atoms, which are of similar structure and characterized by having an unsaturated ring structure containing at least one atom other than carbon, such as nitrogen, sulfur and oxygen, and derivatives of these heterocyclic compounds .

Reaction step (a) is preferably carried out at a temperature between approx. 0 and approx. 150°C, more preferably between 40 and 110°C and most preferably between 75 and 85°C. This reaction step can be carried out at atmospheric, sub-atmospheric or super-atmospheric pressure, preferably at atmospheric pressure. The reaction is preferably carried out in a solvent for the acyl halide, such as ethylene dichloride, methylene chloride, tetrahydrofuran or toluene.

Three moles of the acyl halide are required for reaction with one mole of the 1,3,5-tricyanomethylhexahydro-1,3,5-triazine. An excess of acyl halide can be used to ensure complete reaction with the triazine. A large excess of the acyl halide can serve as solvent in this reaction step. The solvent or any excess acyl halide can be removed to isolate the N-cyanomethyl-N-chloromethylamide of the acyl halide in high yield. However, this amide is rapidly degraded thermally and by hydrolysis and should be kept in an inert atmosphere if isolated.

Most preferably, no excess of acyl halide is used, and the solvent used in reaction step (a) is also used as solvent in reaction step (b). Solvent thus does not need to be removed after completion of step (a) and it is used in reaction step (b).

In reaction step (b), (approximately) equimolar amounts of N-cyanomethyl-N-halomethylamide are most preferably reacted with the acyl halide and the phosphite. Less preferably, up to an excess of 2 mol can be used and least preferably up to an excess of 10 mol.

The reaction is exothermic and can be carried out at a temperature of between approx. 0 and approx. 150°C, more preferably between 40 and 100°C, most preferably between 75 and 85°C.

It is not necessary to use a solvent for the reaction, but any inert solvent can be used,

preferably solvent with a boiling point between approx. 40 and 100°C. Examples of such solvents are ethylene chloride, methylene chloride, tetrahydrofuran and toluene. Use of a solvent facilitates dispersion of the heat of reaction. Most preferably, the solvent is the one used in reaction step (a). Solvent that may be used in this reaction step will be removed after completion of reaction step (c), and the solvent is thus preferably one that can be removed by evaporation.

Alkali metal phosphites with the formula

1

where R and

as indicated and R 3 is an alkali metal, is reacted with N-cyanomethyl-N-halomethylamide under an inert atmosphere such as nitrogen. The alkali metal phosphite can be prepared by reacting an alkali metal alkoxide, alkali metal hydride or alkali metal with an equimolar amount of a disubstituted phosphite of the formula

where ^ R 1 and R 2 are as indicated. The reaction is carried out in an inert atmosphere such as nitrogen.

Alkali metal phosphites with the formula

where R 1 , R 2 and M are as indicated. Can, because tautomerism, have the following additional structural formula

1 2

where R and R are as indicated and M is an alkali metal.

In reaction step (c), one mol of the phosphonate reaction product from reaction step (b) is hydrolysed with 5 mol of water. The hydrolysis is carried out in the presence of a strong acid or base as indicated above. The hydrolysis is preferably acid-catalysed, preferably with an inorganic acid and most preferably with hydrochloric acid or hydrobromic acid. The hydrolysis gives the desired N-phosphonomethylglycine. Preferably, at least 2 mol of the acid are used. More preferably, a large excess over the amount of 2 mol is used. The preferred hydrochloric acid or hydrobromic acid can be used in concentrated or aqueous form.

The last reaction step is carried out at a temperature between approx. 0 and approx. 200°C, preferably between 50 and 125°C and most preferably between 100 and 125°C.

Atmospheric, subatmospheric or superatmospheric pressure can be used. Atmospheric pressure is preferably used during the hydrolysis.

The solid N-phosphonomethylglycine can be recovered by conventional methods in reaction step (c). Volatile, liquid products such as alcohols (methanol), chlorides (methyl chloride), acids (acetic acid), water, and excess acid can be removed by normal stripping techniques. The desired N-phosphonomethylglycine is extracted with high purity by dissolving it in water, adjusting the pH of the solution to between 1 and 2, and the product is crystallized from solution and removed by filtration.

The following examples will further illustrate the invention.

EXAMPLE 1

Preparation of N-cyanomethyl-N-chloromethylacetamide

17 g (0.0835 mol) 1,35,tricyanomethylhexahydro-1,3,5-tria-

zin was suspended in 150 ml of 1,2-dichloroethane in a round bottom flask.

40 mL (0.563 mol) of acetyl chloride was added all at once and the reaction mixture was refluxed for 3 hours, then stripped under reduced pressure to give 26.9 g (79.85%) of N-cyanomethyl-N-chloromethylacetamide . The structure was confirmed by usual analytical methods (infrared analysis, proton nuclear magnetic resonance and mass spectroscopy).

EXAMPLE 2

Preparation of 0,0-dimethyl-N-cyanomethyl-N-acetylaminomethylphosphonate

The amide compound prepared in Example 1 (26.9 g, 0.2 mol) was diluted with 75 ml of dichloromethane. Trimethylphosphite (25.5 g, 0.206 mol) was added and the mixture was stirred at room temperature overnight, refluxed for 0.5 h and stripped under reduced pressure to give 34.9 g (79.32%) of the desired product. The structure was confirmed by infrared analysis (ir), proton nuclear magnetic resonance (nmr) and mass spectroscopy (ms).

EXAMPLE 3

Preparation of N-phosphonomethylglycine

The phosphonate reaction product of Example 2 (19.5 g, 0.09 mol) was combined with 100 mL (1.21 mol) of concentrated hydrochloric acid, refluxed for 3 hours and stripped under reduced pressure. The residue was dissolved in 30 ml of water, the pH was adjusted to 10 with 50%

sodium hydroxide, and the mixture was stripped under reduced pressure. The product was again dissolved in 30 ml of water, and the pH was

set to 1 with concentrated hydrochloric acid. The mixture was refrigerated overnight, and the next morning 5.4 g (98.3% purity by weight) of the desired product was isolated by filtration (35.49% yield). The structure was confirmed by ir, nmr and liquid chromatography (lc).

EXAMPLE 4

Preparation of N-phosphonomethylglycine

50 ml of 1,2-dichloroethane was heated to boiling in a 50 ml round bottom flask. Acetyl chloride (5.5 mL, 0.077 mol) and 3.4 g (0.0167 mol) of 1,3,5-tricyanomethylhexahydro-1,3,5-triazine were added simultaneously over 10 min while maintaining an excess of the acetyl halide in the reaction vessel. The mixture was refluxed for 0.5 hour after the addition was complete, after which it was stripped under reduced pressure. 5 mL of toluene and 6.6 mL (0.05 mol) of trimethylphosphite were added to the residue, and this mixture was refluxed for 15 min, stirred at room temperature for 2 h, and stripped under reduced pressure. 30 mL (0.36 mol) of concentrated hydrochloric acid was added to the residue, and the mixture was refluxed for 3 hours and stripped under reduced pressure, yielding 11.3 g of solids containing 47.9% by weight of the desired N-phosphonomethylgly- one, determined by lc. The structure was confirmed by C 1 3 and proton NMR. The overall yield of N-phosphonomethylglycine was 64%.

EXAMPLE 5

Preparation of 0,0-dimethyl-N-cyanoethyl-N-carboethoxyaminomethyl-phosphonate

Ethyl chloroformate (8 mL, 0.083 mol) dissolved in 8 mL of methylene chloride and 3.4 g of 1,3,5-tricyanomethylhexahydro-1,3,5-triazine (0.016 7 mol) were combined in a 50 mL round bottom flask equipped with a stirrer and return cooler. The mixture was refluxed for 1 hour and stripped under reduced pressure. The residue was dissolved in 5 ml of methylene chloride. Trimethylphosphite (5 mL, 0.042 mol) dissolved in 15 mL of methylene chloride was added. The reaction mixture was refluxed for 1 hour. To the cooled mixture was added 50 ml of water. The mixture was extracted 3 times with 50 ml of methylene chloride. The organic portions were combined and dried with magnesium sulfate and stripped under vacuum, which gave 6.9 g of the desired product, corresponding to a 50% yield. The structure was confirmed by ir, nmr and ms.

EXAMPLE 6

Preparation of N-phosphonomethylglycine

The phosphonate reaction product of Example 5 (4.9 g, 0.02 mol) was combined with 20 ml (0.24 mol) of concentrated hydrochloric acid, refluxed for 3 hours and stripped under reduced pressure. The residue was dissolved in 30 ml of water, the pH was adjusted to 10 with 50% sodium hydroxide, and the mixture was stripped under reduced pressure. The product was again dissolved in approx. 5 ml of water. The structure was confirmed by nmr and liquid chromatography (lc).

EXAMPLE 7

Preparation of 0,0-diethyl-N-cyanomethyl-N-acetylaminomethylphosphonate

5.6 g (0.05 mol) of potassium t-butoxide was suspended in 25 ml of tetrahydrofuran (dried over molecular sieve material) in a round bottom flask, and the suspension was cooled in a water bath. Then 6.44 ml (0.05 mol) of diethyl phosphite was added dropwise to the slurry over 5 min under nitrogen. This mixture was cooled in an ice bath, and 7.33 g (0.05 mol) of N-cyanomethyl-N-chloromethylacetamide diluted with 50 ml of tetrahydrofuran was added dropwise over 15 min. The mixture was warmed to room temperature and stirred for 3 hours. The mixture was filtered through dicalite and the tetrahydrofuran stripped under reduced pressure to give 9.0 g of the desired product. The structure was confirmed by ir, nmr,

_13

ms, C - no.

EXAMPLE 8

Preparation of phosphonomethylglycine

5.4 g (0.022 mol) of the compound prepared in Example 7 was combined with 30 ml (0.363 mol) of concentrated HCl, refluxed for 3 hours and then stripped under reduced pressure to give 10.8 g of the desired product , a brown semi-solid. The structure was confirmed by ir, nmr, C 13 nmr and liquid chromatography.

EXAMPLE 9

Preparation of 0,0-dimethyl-N-cyanomethyl-N-acetylaminomethyl-phosphonate

1.44 g (0.06 mol) of sodium hydride was slurried in 25 ml of tetrahydrofuran (treated over molecular sieve material) under dry nitrogen. 6.4 ml (0.05 mol) of dimethyl phosphite was added dropwise over 15 min. After hydrogen gas evolution had ceased, the mixture was cooled in an ice bath, and 7.33 g (0.05 mol) of N-cyanomethyl-N-chloromethylacetamide, diluted with 50 ml of dry tetrahydrofuran, was added dropwise over 15 min. The mixture was stirred overnight, filtered and stripped under reduced pressure to give 11.5 g of the desired product, a yellow oil.

13

The structure was confirmed by ir, nmr, ms, C -nmr and glpc techniques.

The compound in example 9 can be hydrolyzed to phosphonomethylglycine according to example 3.

Claims (15)

1. Process for the production of N-phosphonomethylglycine, comprisinga) reaction of 1,3,5-tricyanomethylhexahydro-1,3,5-triazine with an acyl chloride of the formula where X is chlorine, bromine or iodine, and R is an aliphatic or aromatic group, forming the N-cyanomethyl-N-chloromethylamide of the acyl chloride, which has the structural formula where X and R are as indicated above, b) reacting the amide formed in step (a) with a phosphite of the formula in which R 1 and R 2 are both aromatic groups or both are aliphatic groups, and R 3 is an aliphatic group or R 3 is an alkali metal, forming a phosphonate compound of the formula 1 2 in which R and R are as defined above, and c) hydrolysis of the phosphonate formed in step (b), which gives N-phosphonomethylglycine. 2. Method according to claim 1, where R is C 1 -C 4 -alkyl and X is chlorine. 3. Method according to claim 1, where R is C 1 -C 4 -alkyl, R is 2 3 C 1 -C 8 alkyl, R is C 1 -C 8 alkyl, R is C 1 -C 8 alkyl, sodium or potassium, and X is chlorine. 4. Method according to claim 1, where R is C 1 -C 6 -alkyl, R 1 is 2 3 C 1 -C 4 -alkyl, R is C 1 -C 4 -alkyl, R is C 1 -C 4 -alkyl, sodium or potassium and X is chlorine. 5. Method according to claim 1, where R is C1 -C1 -alkyl, R1 is C1 -C1 -alkyl, R 2 is C1 -C1 -alkyl, R 3 is C1 -C1 -alkyl and X is chlorine . 12 3 6. Process according to claim 1, where R, R , R and R are methyl and X is chlorine. 7. Method according to claim 1, where step (a) is carried out at a temperature between approx. 0 and approx. 150°C. 8. Method according to claim 7, where step (c) is carried out with an acid catalyst. 9. Process according to claim 8, where the acid catalyst is hydrochloric acid or hydrobromic acid. 10. Connection with the formula in which R is C 1 -C 4 alkyl or ethoxy, and X is chlorine, bromine or iodine. 11. Compound according to claim 10, where R is methyl and X is chlorine. 12. Compound according to claim 10, where R is ethoxy and X is chlorine. 13. Connection with the formula where R is C 1 -C 4 alkyl, and R 1 and R 2 are both C 1 -C 8 alkyl. 14. Compound according to claim 13, where R is methyl, R 1 is methyl 2 and R is methyl. 15. Compound according to claim 13, where R is ethoxy, R 1 is methyl 2 and R is methyl.