RU2153501C2 - Methods of preparing n-hydroxealkylaminomethylphosphonic acid, n-phosphonomethylaminocaproxylic acid and n- phosphonomethyl glycine or salts thereof - Google Patents

Abstract

FIELD: agriculture. SUBSTANCE: described are methods of preparing N-hydroxyalkylaminomethyl phosphonic acid I:

wherein n is integer of 2 to 6, N- phosphonometaminocarboxylic acid II:

and N- phosphonomethyl glycine III:

Description

 The invention relates to a method for producing N - hydroxyalkylaminomethylphosphonic acid or its salts. In one aspect, the present invention relates to a new and useful process for the preparation of N-hydroxyalkylaminomethylphosphonic acid or its salts from alkanolamine, formaldehyde and trialkylphosphite. In another aspect, the present invention relates to a method for producing N-phosphonomethylaminocarboxylic acid or its salts by catalytic oxidation of N-hydroxyalkylaminomethylphosphonic acid or its salts. And in another aspect, the invention relates to a method for producing N-phosphonomethylglycine, useful as a herbicide.

 N-hydroxyalkylaminomethylphosphonic acid or its salts are useful as starting material for agricultural chemical products.

 N-phosphonomethylaminocarboxylic acids or their salts are useful as agricultural chemicals. In particular, N-phosphonomethylglycine, also known by its common name glyphosate, is a highly effective and commercially important phytotoxicant useful in controlling a wide variety of weeds and crops. It is applied to the foliage of a very wide range of perennial and annual cereal plants and broadleaf plants to achieve the desired control. Industrial uses include weed control along roadsides, in waterways, along transmission lines, in storage areas and other non-agricultural locations. Typically, glyphosate is incorporated into the herbicidal compositions in the form of various salts thereof, which retain the anionic form of glyphosate in solution, preferably in water.

 The reaction of a primary amine with an aldehyde and a phosphite diester is disclosed in Fields, "The Synthesis of Esters of Substituted Amino Phosphonic Asids", J. Am. Chem. Soc., Vol. 74, pp. 1528-31 (1952). However, the reaction product contains significant amounts of undesired bis-phosphonomethylated product. Similarly, the reaction of a primary amine with formaldehyde and phosphorous acid is described in Moedritzer and Irani, "The Direct Synthesis of α-Aminomethylphosphonic Acids. Mannich-Type Reaction with Orthophosphorous Acids" J. Org, Chem., Vol. 31, pp. 1603-1607 (1966). As with Fields, the reaction product is primarily a bis-phosphonomethylated product.

Barsukov et al. , "Synthesis of New Complexons and Nheir Derivatives", Zhurnal Obshchei Khimii, Vol. 53, No. 6, pp. 1243-49 (1983) and Barsukov et al., "Synthesis of New Complexonsof Aliphatic Series and Investigation of Mechanism of Acidic Dissociation ", Zhurnal Obshchei Khimii, Vol. 55 N 7, pp. 1594-1600 (1985) disclosed a reaction of ethanolamine with paraformaldehyde and dimethylhydrophosphite with an amine / phosphite molar ratio of 1.0 and a formaldehyde / phosphite molar ratio of 1.0. Although it is stated in these articles that the product is a mono-phosphonomethylated compound, the reproduction of the reaction disclosed in the experimental part led to the production of a non-monophosphonomethylated product, i.e. ^{The 31} P-NMR spectrum of the material obtained by reproducing the Barsukov example showed a 0% yield of N- (2-hydroxyethyl) aminomethylphosphonic acid (see Example 5 in this description). Thus, the method described in the articles of Barsukov et al. Is not capable of producing N-hydroxyalkylaminomethylphosphonic acid on an industrial scale.

 A process for the preparation of N-hydroxyalkylaminomethylphosphonic acid or its salts, which is economical, commercially viable and can produce essentially only mono-phosphonomethylated product, is highly desirable.

 An object of the present invention is to provide an efficient and economical method for producing N-hydroxyalkylaminomethylphosphonic acid or its salts, which would be commercially viable. Another objective of the present invention is to provide a method for producing N-hydroxyalkylaminomethylphosphonic acid or its salts for use in the manufacture of N-phosphonomethylaminocarboxylic acid or its salts. Another objective of the present invention is to provide an effective and economical method for producing N-phosphonomethylaminocarboxylic acid or its salts for use as agricultural chemical products. And another objective of the present invention is to provide an effective and economical method for producing N-phosphonomethylglycine, which would be commercially viable.

 The present invention provides a method for producing N-hydroxyalkylaminomethylphosphonic acid or its salts, comprising contacting alkanolamine, formaldehyde and trialkylphosphite under suitable reaction conditions to produce a reaction mixture, and hydrolyzing the reaction mixture under neutral, acidic or alkaline conditions. In one embodiment, N-hydroxyalkylaminomethylphosphonic acid or its salts are catalytically oxidized to produce N-phosphonomethylaminocarboxylic acid or its salts.

 The present invention further provides a process for the preparation of N-hydroxyalkylaminomethylphosphonic acid or its salts, comprising contacting alkanolamine, formaldehyde and trialkylphosphite in the presence of alcohol under suitable reaction conditions to produce a reaction mixture, and hydrolyzing the reaction mixture under neutral, acidic or alkaline conditions. In one embodiment, N-hydroxyalkylaminomethylphosphonic acid or its salts are catalytically oxidized to produce N-phosphonomethylaminocarboxylic acid or its salts.

 In accordance with the present invention, there is provided a method for producing N-phosphonomethylglycine or its salts, comprising contacting ethanolamine, formaldehyde and trialkylphosphite under suitable reaction conditions to obtain a reaction mixture, hydrolyzing the reaction mixture under neutral, acidic or alkaline conditions to obtain N-hydroxyethylaminomethylphosphonic acid or its salts and the catalytic oxidation of N-hydroxyethylaminomethylphosphonic acid or its salts.

или ее солей, включающему (а) контактирование алканоламина, представленного формулой

где n находится в пределах от 2 до 6, формальдегида и триалкилфосфита при подходящих условиях времени и температуры для получения реакционной смеси, где молярное отношение алканоламина к фосфиту находится в пределах от примерно 1: 1 до примерно 15:1, и (b) гидролизование реакционной смеси в условиях нейтральной, кислотной или щелочной среды.The present invention relates to a method for producing N-hydroxyalkylaminomethylphosphonic acid represented by the formula

or its salts, including (a) contacting an alkanolamine represented by the formula

where n is in the range from 2 to 6, formaldehyde and trialkylphosphite under suitable conditions of time and temperature to obtain a reaction mixture, where the molar ratio of alkanolamine to phosphite is in the range from about 1: 1 to about 15: 1, and (b) hydrolysis of the reaction mixtures in a neutral, acidic or alkaline environment.

или ее солей, включающему (а) контактирование алканоламина, представленного формулой

где n находится в пределах от 2 до 6, формальдегида и триалкилфосфита в присутствии спирта, представленного формулой R(ОН)_m, где R представляет алкильную группу, имеющую от 1 до примерно 18 углеродных атомов, и m находится в пределах от 1 до 3, при подходящих условиях времени и температуры для получения реакционной смеси, где молярное отношение алканоламина к фосфиту составляет от 1:1 до примерно 5:1, и (b) гидролизование реакционной смеси в условиях нейтральной, кислой или щелочной среды.The present invention also relates to a method for producing N-hydroxyalkylaminomethylphosphonic acid represented by the formula

or its salts, including (a) contacting an alkanolamine represented by the formula

where n is in the range from 2 to 6, formaldehyde and trialkylphosphite in the presence of an alcohol represented by the formula R (OH) _m , where R is an alkyl group having from 1 to about 18 carbon atoms, and m is in the range from 1 to 3, under suitable conditions of time and temperature to obtain a reaction mixture, where the molar ratio of alkanolamine to phosphite is from 1: 1 to about 5: 1, and (b) hydrolysis of the reaction mixture in a neutral, acidic or alkaline environment.

или ее солей способы по настоящему изобретению дополнительно включают (с) каталитическое окисление N-гидроксиалкиламинометилфосфоновой кислоты или ее солей.To obtain N-phosphonomethylaminocarboxylic acid represented by the formula

or its salts, the methods of the present invention further include (c) catalytic oxidation of N-hydroxyalkylaminomethylphosphonic acid or its salts.

 Further, the present invention relates to a method for producing N-phosphonomethylglycine or its salts, comprising (a) contacting ethanolamine, formaldehyde and trialkylphosphite under suitable conditions of time and temperature to obtain a reaction mixture where the molar ratio of ethanolamine to phosphite is from about 1: 1 to about 15 : 1, (b) hydrolysis of the reaction mixture under neutral, acidic or alkaline conditions to obtain N-hydroxyethylaminomethylphosphonic acid or its salts and (c) catalytic oxidation of N- (2-hydroxyethyl ) Aminomethylphosphonic acid or salts thereof.

где n находится в пределах от 2 до 6. Примеры алканоламинов включают этаноламин, 3-амино-1-пропанол, 4-амино-1-бутанол, 5-амино-1-пентанол, 6-амино-1-гексанол и их смеси. Предпочтительным в настоящий момент алканоламином является этаноламин вследствие его легкой доступности и коммерческой значимости продукта, полученного с использованием этаноламина в качестве исходного материала.As used herein, the term “N-hydroxyalkylaminomethylphosphonic acid salts” means alkali or alkaline earth metal salts of N-hydroxyalkylaminomethylphosphonic acid, and the term “N-phosphonomethylaminocarboxylic acid salts” means alkali or alkaline earth metal salts of N-phosphonomethylaminocarboxylic acid. Thus, the products of hydrolysis and oxidation reactions may include acid, its salts, or any combination thereof, depending on the particular reaction and the selected reaction conditions. Alkanolamines that can be used in accordance with the present invention are represented by the formula

where n ranges from 2 to 6. Examples of alkanolamines include ethanolamine, 3-amino-1-propanol, 4-amino-1-butanol, 5-amino-1-pentanol, 6-amino-1-hexanol, and mixtures thereof. Currently preferred alkanolamine is ethanolamine due to its easy availability and commercial value of the product obtained using ethanolamine as a starting material.

 Formaldehyde can be used in accordance with the present invention in the form of paraformaldehyde or in the form of an aqueous solution of formaldehyde. Aqueous formaldehyde is commercially available as 37-50% (by weight) aqueous solutions which may contain methanol, ethanol or n-butanol.

Trialkylphosphites suitable for the method of the present invention are commercially available or can be easily prepared by conventional methods, such as by reacting PCl ₃ with an alcohol, including polyols. When using a polyol as a reagent, the phosphite product may have a cyclic structure, i.e. cyclic phosphite ester. See, for example, Ford-Moore et al., Org. Syn., Coll. Vol IV, p 955 and Cook et al., J. Chem. Soc., 635 (1949) on methods using PCl ₃ . Trialkylphosphites can be represented by the formula P (OR ′) ₃ , where R ′ represents an alkyl group. Alkyl groups of trialkylphosphites are unbranched or branched alkyl groups having from 1 to 18 carbon atoms and optionally substituted with —OH groups. Preferred alkyl groups are branched or sterically hindered groups or groups substituted with —OH. The most preferred alkyl groups are those having 2-6, in particular 3-4, carbon atoms. A preferred trialkyl phosphite is triisopropyl phosphite. Trialkylphosphites are preferred over dialkylphosphites because of the unexpectedly higher yields achieved using trialkylphosphites.

 Examples of suitable trialkylphosphites include, but are not limited to, tributylphosphite, triisopropylphosphite, trimethylphosphite, triethylphosphite, tridecylphosphite, triisodecylphosphite, triisooctylphosphite, trilaurylphosphite, 1-methyl-4-phospha-3,5,8-trioxo-3,2-trio-triabo-triab 5-phospha-4,6,9-trioxabicyclo - [3,3,1] -ionane and mixtures thereof. The amount of alkanolamine used in the method of the present invention can be expressed as the molar ratio of the starting alkanolamine to the starting phosphite. Over a wide range, the molar ratio of alkanoamine to phosphite is from about 1: 1 to about 15: 1. When the number of carbon atoms in the alkyl group of the trialkylphosphite is 2-6, the molar ratio of alkanolamine to phosphite is preferably from about 1.2: 1 to about 8: 1, and most preferably from about 1.5: 1 to about 2.5: 1. When the number of carbon atoms in the alkyl group of the trialkylphosphite is 1 or greater than 6, the molar ratio of alkanolamine to phosphite is preferably from about 1: 1 to about 10: 1, and most preferably from about 1.5: 1 to about 8: 1. The excess alkanolamine present in the process of the present invention also serves as a reaction solvent.

 The amount of formaldehyde used in the method of the present invention can be expressed as the molar ratio of the starting formaldehyde to the starting phosphite. Over a wide range, the molar ratio of formaldehyde to phosphite is from 1: 1 to about 5: 1, preferably from 1: 1 to about 2: 1, and most preferably from 1: 1 to about 1.5: 1.

The reaction of alkanolamine, formaldehyde and phosphite is carried out at a suitable temperature, which can vary widely. The reaction temperature is usually in the range of from about 50 ^° C to about 150 ^° C, preferably from about 60 ^° C to about 120 ^° C, and most preferably from about 70 ^° C to about 110 ^° C. The reaction of alkanolamine, formaldehyde and phosphite is carried out in the course of a suitable time, which can vary widely depending on various parameters, for example, the reaction temperature. The reaction time is usually in the range of the time required for the consumption of phosphite, to about 16 hours, preferably from about 2 hours to about 16 hours, and most preferably from about 4 hours to about 6 hours.

The reaction of alkanolamine, formaldehyde and phosphite can optionally be carried out in the presence of an alcohol solvent, where the alcohol is represented by the formula R (OH) _m where R is an alkyl group having from 1 to about 18 carbon atoms, and m is 1-3. The alkyl group R may be unbranched or branched and preferably is the same alkyl group as used in the trialkylphosphite starting material.

 Examples of suitable alcohols include, but are not limited to, methanol, ethanol, isopropanol, n-butanol, 2-butanol, isooctanol, decyl alcohol, isodecyl alcohol, lauryl alcohol, ethylene glycol, 1,2-propylene glycol, 1,3-propylene glycol, glycerol , 2-hydroxymethyl-2-methyl-1,3-propanediol, 1,3,5-trihydroxycyclohexane and mixtures thereof.

 When the reaction of alkanolamine, formaldehyde and phosphite is carried out in the presence of an alcohol solvent, the molar ratio of the starting alkanolamine to the starting phosphite is from 1: 1 to about 5: 1, preferably from 1.2: 1 to about 3: 1, and most preferably from about 1, 5: 1 to about 2: 1.

The hydrolysis reaction can be carried out under neutral, acidic or alkaline conditions by any of several conventional methods known to those skilled in the art. When the hydrolysis reaction is carried out under acidic conditions, the preferred method is to remove the excess alkanolamine from the reaction mixture together with any optional alcohol co-solvent, followed by hydrolysis of the reaction mixture in hydrochloric acid. The concentration of hydrochloric acid is preferably in the range of 6N.CHl to 12N.HCl (concentrated HCl). The reaction temperature of the acid hydrolysis is usually in the range of the boiling point of HCl to about 250 ^° C., preferably from 80 ^° C. to 120 ^° C. The reaction time is usually in the range of the time required for the hydrolysis to be performed, up to about 24 hours, preferably from about 2 hours to about 16 hours. Before the hydrolysis reaction is complete, N-hydroxyalkylaminomethylphosphonic acid can be recovered by any conventional method known to those skilled in the art, such as the method used in Example 1.

 When the hydrolysis reaction is carried out under alkaline conditions, a preferred method is to contact the reaction mixture with an alkali metal hydroxide or an alkaline earth metal hydroxide, preferably an alkali metal hydroxide. The concentration of alkali metal hydroxide or alkaline earth metal hydroxide is usually in the range of from about 15 wt.% To about 90 wt.%, Preferably from about 40 to about 60 wt.%, And most preferably is about 50 wt.%. The amount of alkali metal hydroxide or alkaline earth metal hydroxide used in the hydrolysis reaction can be expressed as the ratio of hydroxide equivalents to moles of starting phosphite. The ratio is usually from about 2: 1 to about 5: 1, preferably from about 2.5: 1 to about 4: 1, and most preferably 3: 1.

 In a preferred embodiment of the hydrolysis carried out under alkaline conditions, the alcohol formed during the hydrolysis, i.e. the alcohol corresponding to the alkyl groups in the trialkylphosphite is removed from the reaction mixture during hydrolysis by, for example, distillation. For example, when triisopropyl phosphite is used in the process, isopropyl alcohol is removed during hydrolysis. Hydrolysis under these conditions leads to an unexpectedly higher yield of N-hydroxyalkylaminomethylphosphonic acid as compared to hydrolysis without removing the resulting alcohol.

 Alkali metal hydroxides for use in the method of the present invention include lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide and cesium hydroxide. Because of their easy accessibility and ease of handling, sodium hydroxide and potassium hydroxide are preferred, and sodium hydroxide is particularly preferred.

 Alkaline earth metal hydroxides for use in the method of the present invention include beryllium hydroxide, magnesium hydroxide, calcium hydroxide, strontium hydroxide and barium hydroxide. Due to its easy availability, calcium hydroxide is currently preferred.

The temperature for the alkaline hydrolysis reaction is usually in the range of from about 80 ^° C to about 250 ^° C, preferably from about 80 ^° C to about 180 ^° C, and most preferably from about 120 ^° C to about 150 ^° C. The reaction time is usually in ranging from the time required to effect hydrolysis to about 48 hours, preferably from about 2 hours to about 24 hours, and most preferably from about 2 hours to about 16 hours. After the hydrolysis reaction is complete, N-hydroxyalkylaminomethylphosphonic acid or its salts can be recovered by any conventional method known to those skilled in the art, such as the method used in Example 1.

When the hydrolysis reaction is carried out under neutral conditions, the preferred method is to contact the reaction mixture with water. The concentration of hydrolyzable reagents, i.e. intermediate esters of N-hydroxyalkylaminomethylphosphonic acid in water is usually in the range from about 40 wt.% to about 50 wt.%, preferably from about 30 wt.% to about 15 wt.%. The temperature for the hydrolysis reaction in a neutral medium is usually in the range of from about 120 ^° C. to about 320 ^° C., preferably from about 180 ^° C. to about 260 ^° C. The reaction time is usually in the range of the time required for the hydrolysis to be carried out to about 24 hours, preferably from about 5 hours to about 15 hours. At the end of the hydrolysis reaction, N-hydroxyalkylaminomethylphosphonic acid or its salts can be recovered by any conventional method known to those skilled in the art.

 The oxidation of N-hydroxyalkylaminomethylphosphonic acid or its salts is carried out in the presence of a catalyst. Suitable oxidation catalysts such as Raney copper and the catalysts described in US Pat. Nos. 4,810,426 and 5,229,936, which are incorporated herein by reference, are well known to those skilled in the art.

In US Pat. No. 4,810,426, the oxidation of N- (2-hydroxyethyl) aminomethylphosphonic acid is carried out with an alkali metal hydroxide in the presence of water and a suitable catalyst selected from cadmium, zinc, copper, palladium and platinum and their corresponding oxides, hydroxides and salts. The oxidation reaction is carried out at a temperature of 200-300 ^o C.

In US Pat. No. 5,292,936, the oxidation of N- (2-hydroxyethyl) aminomethylphosphonic acid is carried out with an alkali metal hydroxide in the presence of an effective amount of a Raney copper catalyst containing from about 50 ppm to about 10,000 ppm of an element selected from the group consisting of chromium titanium, niobium, tantalum, zirconium, vanadium, molybdenum, manganese, tungsten, cobalt, nickel and mixtures thereof. Of these, chromium, molybdenum, and mixtures of chromium and molybdenum are preferred. The oxidation reaction is carried out at a temperature of about 120-220 ^o C.

 Another particularly suitable type of oxidation catalysts are supported supported metal catalysts, such as those described in US Serial Application No. 08/269722 for US Patent and, in subsequent partial extension thereof, Application No. 08/407723, which are incorporated herein by reference. The supported mixed metal catalysts of the present invention are prepared by depositing from about 1 wt.% To about 50 wt.%, Based on the total weight of the catalyst, an element selected from the group consisting of copper, cobalt, nickel, cadmium and mixtures thereof, on a stable to hydroxides of the carrier containing from about 0.05 wt.% to about 10 wt.% binding (fixing) metal selected from the group consisting of platinum, palladium, ruthenium, silver, gold and mixtures thereof.

 Suitable hydroxide-resistant supports include titanium oxide, zirconia and coal. Coal is preferred. Activated carbon is even more preferred.

 The particulate binding metal deposited on a hydroxide-resistant support can be a noble metal. Noble metal means gold, silver, platinum, palladium, ruthenium, or mixtures thereof. Platinum or palladium are preferred. Platinum is most preferred. The amount of binder metal deposited on a hydroxide-resistant support can range from about 0.05 wt.% To about 10 wt.% Of the total weight of the catalyst. If less than about 0.05% by weight of a bonding metal is deposited on said support, this amount will be insufficient to create a satisfactory catalyst together with copper, cobalt, nickel and / or cadmium. On the other hand, when more than about 10% by weight of the total mass of the catalyst metal binder is deposited on the support, there is a tendency to increase crystallite sizes of the supported metal. The increased crystal sizes of the supported elemental metal sometimes lead to reduced performance of the catalyst. It is preferred to use from about 0.1 wt.% To about 5 wt.%, Based on the total weight of the metal binder catalyst. The currently preferred mixed supported metal catalyst is a carbon supported mixture of copper and platinum or palladium.

 Suitable hydroxide-resistant carriers containing a suitable binder material can be obtained on an industrial scale.

 The amount of metal deposited (i.e. copper, cobalt, nickel and / or cadmium) must be sufficient to cover at least some of the embedded particles of the binder metal. In addition to the coated particles, at least some particles of the deposited metal may be present, embedded in the carrier but not adhered to the binding metal. To measure the relative concentration of surface atoms in the catalyst, X-ray photoelectron spectroscopy (XPS) can be used. Using this method, it was found that in the catalysts of the present invention, the surface atomic ratio of the deposited metal to the binder metal preferably exceeds 2.0, and more preferably, the surface atomic ratio determined by XPS exceeds the corresponding atomic ratio in volume.

 A variety of methods can be used to deposit a binder metal on an alkali-resistant substrate and to deposit copper, cobalt, nickel and / or cadmium on a binder metal. But it is preferable to use metal deposition without the use of electrical energy. Electroless deposition of metal refers to the chemical deposition of a viscous metal coating onto a suitable substrate in the absence of an external source of electrical energy.

 Regardless of the method of deposition of a binding (fixing) metal on a substrate, the particle size of the metal is a critical parameter, since it determines the crystal size of the deposited copper, cobalt, nickel and cadmium. The crystallite size of copper, cobalt, nickel and cadmium. The crystallite size of copper, cobalt, nickel and cadmium should be less than about 500 angstroms, and in the case of copper, it is preferable that it be less than about 300 angstroms. Although the applicants would not want to be bound by any particular theory, it is assumed that the uniform distribution of the binding metal is most favorable for achieving high reaction yields, but does not necessarily accelerate the reaction. In addition, it is believed that it is important to have small, finely divided, finely divided particles of a binding metal.

In practice, a substrate containing a binding metal is introduced into and suspended in water. Then, a coating solution is prepared, for example, a copper coating solution, by mixing the solution in appropriate proportions, and the suspension of the substrate and water is carefully mixed at a temperature of from about 0 ^° C. to 30 ^° C. or higher in an open vessel. A coating solution containing a complexing agent and a reducing agent is added in small portions to the suspension, controlling the pH at each addition. After an appropriate period of time, the next portion of the suspension is slowly added. The amount of coating solution added depends on the required weight percent of the catalytic metal on the binder metal in the catalyst. At the end of the precipitation of the catalytic metal, a substantially colorless filtrate is obtained.

 Next, the finished catalyst is filtered off and washed with distilled water. Filtering should be performed in a neutral atmosphere, such as a nitrogen atmosphere, to avoid exposure of the catalyst to air. Washing the catalyst removes unreacted components, such as parts per million of impurities, and an unreacted reducing agent, such as formaldehyde. It was found that on the catalyst remains from about 0.5 to 1.5 wt. % alkali metal, which usually does no harm. The catalyst must be stored in such a way as to avoid exposure to oxygen, preferably it is kept under water.

 The currently preferred oxidation catalysts for use in the process of the present invention are those described in US Pat. No. 5,292,936 and supported mixed metal catalysts, with supported mixed metal catalysts being particularly preferred.

 The reactions of the present invention can be carried out at atmospheric pressure or in a closed reactor under pressure. When the reactions are carried out in a reactor under pressure, then usually the pressure is the vapor pressure of the reaction mixture under the reaction conditions.

EXAMPLES
General procedures; Trialkyl and dialkyl phosphites were supplied f. "Aldrich Chemical," if any. Phosphites that were not commercially available were synthesized from PCl ₃ and the corresponding alcohol by the method of Ford-Moore et al., Org. Syn. Coll. Vol. IV p. 955 or the method of Cook et al., Chem. Soc., 635 (1949). Formaldehyde was supplied f. "Aldrich Chemical" in the form of a 37% solution in water. Paraformaldehyde (91-93%) was obtained from f. "Hoechst Celanese Corporation". The yield of N-hydroxyalkylaminomethylphosphonic acids or their salts was determined by ³¹ P-NMR analysis in D ₂ O using methylene diphosphonic acid as an internal standard. Typically, NMR samples were prepared in D ₂ O containing concentrated HCl to give a sample with a pH of 0.7. NMR spectra were obtained on Varian VXR-300 or Varian VXR-400 spectrometers. Qualitative and quantitative mass spectra were obtained on Finnigan MAT90, Finnigan 4500, and VG40-250T spectrometers.

Example 1
This example illustrates the synthesis of sodium N- (2-hydroxyethyl) amino methylphosphonate using triethyl phosphite.

Triethyl phosphite (16.6 g, 0.1 mmol), paraformaldehyde (3.0 g, 0.1 mmol), and ethanolamine (48.8 g, 0, 0.05) were charged into a round-bottom flask equipped with a magnetic stirrer and a reflux condenser (reflux condenser). 8 mmol). The reaction mixture was heated to 100 ^° C. for 16 hours. By adding 2 equivalents of NaOH (16 g of a 50% solution) and heating to 120 ^° C. for 16 hours, alkaline hydrolysis of the intermediate esters was ensured. The reaction mixture was allowed to cool and concentrated in vacuo. Methanol (100 ml) was added, after which the solvent was again removed under vacuum. This was repeated several times until a white solid formed in the flask. The solid, a mixture of inorganic salts and sodium N- (2-hydroxyethyl) aminomethylphosphonate, was filtered and dried under vacuum, resulting in a 56% yield of sodium N-hydroxyethylaminomethylphosphonate. ³¹ P-NMR spectrum obtained in D ₂ O containing concentrated HCl (sample had a pH of 0.7): δ = 10.8 ppm (ppm), FAB-MS spectrum obtained in a glutathione / HCl matrix : M + H = 156.

 It is also possible to hydrolyze the intermediate esters under acidic conditions. Using this method, excess ethanolamine is first removed under vacuum to give a yellow oil. Concentrated HCl (50 ml) was added and the reaction mixture was refluxed for 16 hours. The solution was allowed to cool and concentrated in vacuo. Sodium hydroxide (2 equiv. As a 10% solution) was added and water was removed in vacuo to give an amber oil. Methanol (100 ml) was added and immediately removed by evaporation. This was repeated three times, whereupon a white solid precipitated. The solid, which was a mixture of inorganic salts and sodium N- (2-hydroxyethyl) aminomethylphosphonate, was collected by filtration, washed with ether and dried in vacuo to give 36% sodium N- (2-hydroxyethyl) aminomethylphosphonate.

Table 1 summarizes the reaction results with various molar ratios of triethyl phosphite, formaldehyde, and ethanolamine under various reaction conditions. All reactions presented in table 1 were performed in accordance with the above procedure. The yields of N- (2-hydroxyethyl) aminomethylphosphonic acid were determined by ³¹ P-NMR.

Example 2
This example illustrates the use of triisopropyl phosphite in the synthesis of N- (2-hydroxyethyl) aminomethylphosphonic acid.

Triisopropylphosphite (20.8 g, 0.1 mmol), paraformaldehyde (3.6 g, 0.12 mmol) and ethanolamine (48.8 g, 0.) Were charged into a round-bottom flask equipped with a magnetic stirrer and a reflux condenser (reflux condenser). 8 mmol). The reaction mixture was heated to 100 ^° C. for 16 hours. By adding 2 equivalents of NaOH (16 g of a 50% solution) and heating to 120 ^° C. for 16 hours, alkaline hydrolysis of the intermediate esters was ensured. The reaction mixture was allowed to cool and concentrated in vacuo. Water (30 ml) was added to the reaction mixture and a sample was taken for ³¹ P-NMR analysis. The yield (85%) of N- (2-hydroxyethyl) aminomethylphosphonic acid was based on moles of charged phosphite.

 Table 2 summarizes the results of a series of reactions carried out according to an experimental procedure similar to that described above, but with different trialkylphosphites and different ratios of reagents.

Example 3
This comparative example illustrates the use of various dialkyl phosphites in the synthesis of N- (2-hydroxyethyl) aminomethylphosphonic acid.

Diisopropyl phosphite (17 g, 0.1 mmol), paraformaldehyde (3.6 g, 0.12 mmol) and ethanolamine (48.8 g, 0.8 mmol) were charged into a round bottom flask equipped with a magnetic stirrer and a reflux condenser (reflux condenser). ) The reaction mixture was heated to 100 ^° C. for 16 hours. By adding 2 equivalents of NaOH (16 g of a 50% solution) and heating to 120 ^° C. for 16 hours, alkaline hydrolysis of the intermediate esters was ensured. The reaction mixture was allowed to cool and concentrated in vacuo. Water (30 ml) was added to the reaction mixture and a sample was taken for ³¹ P-NMR analysis. The yield (13%) of N- (2-hydroxyethyl) aminomethylphosphonic acid was based on moles of charged phosphite.

 Table 3 summarizes the results of a series of reactions carried out according to an experimental procedure similar to that described above, but with different dialkyl phosphites and different ratios of reagents.

 A comparison of the results in Tables 1 and 2 with the results in Table 3 clearly shows an unexpected increase in yields achieved using trialkylphosphites in the process of the present invention.

Example 4
This example illustrates the preparation of N- (2-hydroxyethyl) -aminomethylphosphonic acid by hydrolysis of intermediate phosphonic acid esters with NaOH using alcohol as a solvent. A solution of paraformaldehyde (4 g, 0.13 mol), ethanolamine (48.8 g, 0.8 mmol) and triisopropyl phosphite (20.8 g, 0.1 mmol) was stirred at 100 ^° C. for 16 hours. The reaction mixture was allowed to cool to room temperature and 8 ml of 50% (w / w) sodium hydroxide and 100 ml of isopropanol were added to it. The mixture was heated under reflux for 48 hours. The solution was concentrated in vacuo and 25 ml of distilled water was added to homogenize the mixture. The reaction mixture was analyzed by ³¹ P-NMR in D ₂ O at pH 0.7. N- (2-hydroxyethyl) aminomethylphosphonic acid was obtained in 80% yield.

Example 5
This comparative example, which illustrates the methodology proposed by Barsukov et al., "Synthesis of new complexones and their derivatives." Journal of General Chemistry, Vol. 53, No. 6, pp. 12243-49 (1983) for the preparation of N- (2-hydroxyethyl) aminomethylphosphonic acid using dimethylphosphite.

To a stirred solution of paraformaldehyde (9.8 g, 0.32 mol) and ethanolamine (20 g, 0.32 mol) at a temperature below 20 ^° C. under nitrogen was added dropwise dimethyl phosphite (36 g, 0.3227 mol) under nitrogen. ) The solution was heated to 80 ^° C. for 1 hour and then cooled to room temperature. A solution of 350 ml of benzene was extracted as described in the article. Then the benzene solution was passed through a column containing 1 kg of aluminum oxide and the column was eluted with 1 liter of benzene. The benzene solution was concentrated in vacuo to dryness and 250 ml of concentrated HCl was added. The solution was heated to 110 ^° C. for 6 hours. Analysis of the reaction mixture by ³¹ P-NMR showed a 0% yield of N- (2-hydroxyethyl) aminomethylphosphonic acid. This example demonstrates that, in contrast to the one described in the reference of Barsukov et al., The method proposed in the link of Barsukov and others does not produce N- (2-hydroxyethyl) aminomethylphosphonic acid.

Example 6
This example illustrates the use of an alcoholic solvent for the preparation of N- (2-hydroxyethyl) aminomethylphosphonic acid using trialkylphosphite.

A solution of paraformaldehyde (4.0 g, 0.122 mol), ethanolamine (12 g, 0.2 mol), triisopropyl phosphite (20.9 g, 0.1 mol) and 50 ml of isopropanol was stirred at 90 ^° C. for 16 hours. Isopropanol was removed in vacuo and 50 ml of concentrated HCl was added in one portion. The solution was heated under reflux for 6 hours, after which it was analyzed by ³¹ P-NMR.

 N- (2-hydroxyethyl) aminomethylphosphonic acid was obtained in 78% yield.

Example 7
This example illustrates the use of Raney copper catalyst containing chromium according to US Pat. No. 5,292,936 for the conversion of N- (2-hydroxyethyl) aminomethylphosphonic acid to N-phosphonomethylglycine.

In a 160 ml nickel autoclave equipped with a stirrer, N- (2-hydroxyethyl) aminomethylphosphonic acid (16.84 g, 0.11 mol), water (11.3 ml) and 45 wt.% Potassium hydroxide (48.7 g, 0.39 mol), as well as a Raney copper catalyst containing 943 ppm chromium (3.53 g). The autoclave was hermetically sealed and heated to 160 ^° C. under a pressure of 9.5 kg / cm ² with stirring of the liquid phase in the autoclave. After 1.85 hours, hydrogen evolution ceased. The yield of N-phosphonomethylglycine in the form of its potassium salt was 98.5%.

Example 8
This example illustrates the preparation of a supported mixed metal catalyst of the present invention.

Distilled water (169 ml) and wet 5% activated carbon platinum in powder form, supplied by Degussa Corporation of Ridgefield Park, NJ, were introduced into a one liter glass beaker equipped with a 5 centimeter Teflon-coated magnetic stirring bar on a magnetic stirring bar. which corresponded to 13.37 g of dry weight. A copper coating solution was prepared in a separate 1 liter beaker by adding the following components, most of which are supplied by MacDermid, Inc. of Waterbury, CT, with stirring in the following order: (1) 687 ml of deionized water; (2) 90 ml MACuPlex Ultra Dep 1000B ^* ; (3) 54 ml of MACuPlex Ultra Dep 1000A ^* ; (4) 18 ml MACuPlex Ultra Dep 1000D ^* ; (5) 5 ml of 37% (w / w) formaldehyde, ( ^* proprietary (proprietary) MacDermid products)
TOTAL VOLUME 854 ml
According to the product description with code N 17970 f. "MasDermid" the resulting aqueous solution contains the following active components, g / l:
Copper Sulfate - 4.0
Formaldehyde 6.0
Sodium hydroxide - 9.0
The excess EDTA chelant is 0.06 molar.

The resulting coating solution was filtered and then added to a suspension of 5% platinum on activated carbon by adding portions of 122 milliliters every 3 minutes at 40 ^° C. To check the degree of reaction, the pH was monitored. When the evolution of gases was too rapid, the time between additions was increased.

 After adding the coating solution, the catalyst was removed by filtration using a 4 liter vacuum flask, a funnel with a 350 ml coarse filter and a glass cap with nitrogen on top of the funnel. After filtering, the solid material was washed three to four times with 250 milliliter portions of deionized water. The yield on dry weight was 18.4 grams. Microanalysis of the catalyst showed elemental composition: 13.4 wt.% Copper and 3.4 wt.% Platinum (of the total weight of the catalyst). The average copper crystal size, determined from the broadening of the X-ray diffraction lines (XRD), was 157 angstroms.

Example 9
This example demonstrates another preparation of a supported supported mixed metal catalyst of the present invention.

Distilled water (190 ml) and then 5 wt.% Platinum activated carbon supplied by Degussa Corporation, which corresponded to 16.42 g, were introduced into a two-liter glass beaker equipped with a 2.5 cm long Teflon-coated magnetic stirring rod on a magnetic stirring plate. dry mass. An aqueous solution of copper was prepared in a 4 liter beaker for coating by adding the following components with stirring: (1) 500 ml of deionized water; (2) NaKC ₄ H ₄ O ₆ • 4H ₂ O (tartrate) [29.99 g, 0.106 mol]; stirring until dissolved (3) In a separate beaker, 11.79 g of CuSO ₄ • 5H ₂ O (3 g of Cu), (0.047 mol) in 400 ml of deionized water were dissolved; (4) a solution of copper (3) was added to the obtained tartrate solution (2); (5) 13.60 g of 50% (w / w) NaOH [0.17 mol] was added; (6) 11.35 ml of 37% (w / w) formaldehyde [0.15 mol]
TOTAL VOLUME 1125 ml
The resulting coating solution was added to a suspension of 5 wt.% Platinum on charcoal in a total of approximately twelve portions of 79 milliliters, one each every 2.5 minutes. To check the extent of the reaction, the pH was monitored, and when the gas evolution was too violent, the addition of portions was delayed for a while. After adding a solution for coating the suspension, the catalyst was removed by filtration, as in example 8. The yield by dry weight was 20.03 grams. An analysis of the composition showed elemental composition: 14.5% copper and 3.8% platinum (based on total catalyst weight). The average crystal size of copper was 119 angstroms.

Example 10
This example illustrates the use of various trialkylphosphites in the synthesis of N- (2-hydroxyethyl) aminomethylphosphonic acid using a low molar ratio of ethanolamine to phosphite and alcohol removal during hydrolysis by distillation and unexpectedly high yield and selectivity when using trialkylphosphites with alkyl groups having 3-4 3-4 carbon atoms, in particular triisopropyl phosphite.

A solution of 37% aqueous formaldehyde (8.2 g, 0.1 mol) and ethanolamine (9.0 g, 0.15 mol) was stirred at room temperature for 1 hour, followed by the addition of triisopropyl phosphite (22 g, 0.1 mole). The reaction solution was heated at 80 ^° C. for 3 hours. Water (50 ml) and 16 ml of 50% NaOH were added to the reaction solution, and the mixture was distilled in a Dean-Stark apparatus for 3 hours at 150 ^° C. to hydrolyze the intermediate esters while removing water, isopropanol and ethanolamine. The resulting white precipitate was dissolved with additional 50 ml of water. Analysis of the reaction mixture by ³¹ P-NMR showed a 98% yield of N- (2-hydroxyethyl) aminomethylphosphonic acid and a 2% yield of bis-N- (2-hydroxyethyl) aminomethylphosphonic acid.

 Table 4 summarizes the results of reactions carried out in accordance with the experimental procedure described above, but with various trialkylphosphites.

Example 11
This example illustrates the preparation of N- (2-hydroxyethyl) -aminomethylphosphonic acid using 1.2 equivalents of ethanolamine in the reaction.

A solution of 37% aqueous formaldehyde (8.2% g, 0.1 mol) and ethanolamine (7.2 g, 0.12 mol) was stirred at room temperature for 2 hours, followed by the addition of triisopropyl phosphite (22 g, 0, 1 mol). The reaction solution was heated at 80 ^° C. for 3 hours. Water (50 ml) and 17 ml of 50% NaOH were added to the reaction solution, and the mixture was distilled in a Dean-Stark apparatus for 3 hours at 150 ^° C. to hydrolyze the intermediate esters while removing water, isopropanol and ethanolamine (in general 70 ml). The resulting white precipitate was dissolved with additional 50 ml of water. Analysis of the reaction mixture by ^31- NMR showed a 90% yield of N- (2-hydroxyethyl) aminomethylphosphonic acid and a 4% yield of bis-N- (2-hydroxyethyl) aminomethylphosphonic acid.

Example 12
This comparative example illustrates the preparation of N- (2-hydroxyethyl) aminomethylphosphonic acid using diisopropyl phosphite.

A solution of 37% aqueous formaldehyde (8.2 g, 0.1 mol) and ethanolamine (9 g, 0.15 mol) was stirred at room temperature for 1-2 hours, followed by the addition of diisopropyl phosphite (17 g, 0.1 mole). The reaction solution was heated at 80 ^° C. for 3 hours. Water (50 ml) and 16 ml of 50% NaOH were added to the reaction solution, and the mixture was distilled in a Dean-Stark apparatus for 3 hours at 150 ^° C. to hydrolyze the intermediate esters while removing water, isopropanol and ethanolamine (total removed the volume was 80-100 ml). The resulting white precipitate was dissolved with additional 50 ml of water. Analysis of the reaction mixture by ³¹ P-NMR showed a 49% yield of N- (2-hydroxyethyl) aminomethylphosphonic acid and a 6% yield of bis-N- (2-hydroxyethyl) aminomethylphosphonic acid. A comparison of the results in this example with the results using triisopropyl phosphite in Example 10 clearly showed an unexpected increase in yield achieved using trialkyl phosphite in the method of the present invention.

Example 13
This example illustrates the aqueous hydrolysis of intermediate N-hydroxyethylaminomethylphosphonic acid esters.

The reaction was carried out under conditions identical to those described in Example 11 using triisopropyl phosphite, except that after three hours of reaction, the reaction mixture was concentrated in vacuo to give a yellow oil. A portion of the oil (4.2 g) was transferred to a high pressure steel reactor and 20 ml of distilled water was added. The reactor was sealed and heated to 220 ^° C. for 10 hours. Analysis of the reaction mixture by ³¹ P-NMR showed partial hydrolysis (50%) to N-hydroxyethylaminomethylphosphonic acid.

Claims (37)

1. The method of obtaining N-hydroxyalkylaminomethylphosphonic acid of the formula

or its salts, including: (a) contacting an alkanolamine of the formula

where n = 2 - 6,
formaldehyde and trialkylphosphite at 50-150 ^° C. to obtain a reaction mixture wherein the molar ratio of alkanolamine to phosphite is from about 1: 1 to about 15: 1, and (b) hydrolysis of said reaction mixture under a neutral, acidic or alkaline environment.  2. The method according to claim 1, in which reaction (a) is carried out in the presence of alcohol.  3. The method according to claim 1, in which the molar ratio of formaldehyde to phosphite is from 1: 1 to about 5: 1.  4. The method according to claim 1, in which the trialkylphosphite is triisopropylphosphite.  5. The method according to claim 1, in which the molar ratio of alkanolamine and phosphite is from about 1.2: 1 to about 8: 1 and the number of carbon atoms in the alkyl group of trialkylphosphite is 2 to 6.  6. The method according to claim 5, in which the trialkylphosphite is triisopropylphosphite.  7. The method according to claim 1, in which the molar ratio of alkanolamine and phosphite is from about 1: 1 to about 10: 1 and the number of carbon atoms in the alkyl group of the trialkylphosphite is 1 or greater than 6.  8. The method according to claim 1, in which the hydrolysis is carried out in an alkaline environment.  9. The method of claim 8, in which the hydrolysis is carried out in the presence of an alkali metal hydroxide or alkaline earth metal hydroxide.  10. The method of claim 8, in which the alcohol formed during hydrolysis is removed during hydrolysis.  11. The method according to claim 1, in which n = 2. 12. The method according to p. 1, in which the reaction temperature (a) is 70 - 110 ^o C. 13. The method of obtaining N-phosphonomethylaminocarboxylic acid of the formula

where n = 2 - 6,
or its salts, including the catalytic oxidation of N-hydroxyalkylaminomethylphosphonic acid or its salts obtained according to the method according to claim 1. 14. The method according to item 13, in which the oxidation is carried out by contacting N-hydroxyalkylaminomethylphosphonic acid or its salts with an alkali metal hydroxide in the presence of an effective amount of a Raney copper catalyst containing from about 50 to about 10,000 million ^-1 element selected from the group consisting of from chromium, titanium, niobium, tantalum, zirconium, vanadium, molybdenum, manganese, tungsten, cobalt, nickel and mixtures thereof.  15. The method according to item 13, in which the oxidation is carried out in the presence of an effective amount of a mixed metal catalyst deposited on coal.  16. The method according to clause 15, in which the catalyst is a mixture of Cu and Pt or Pd deposited on coal. 17. A method of producing N-phosphonomethylglycine or its salts, comprising: (a) contacting ethanolamine, formaldehyde and trialkylphosphite at 50-150 ^° C to obtain a reaction mixture where the molar ratio of ethanolamine and phosphite is from about 1: 1 to about 15: 1 , (b) hydrolysis of the reaction mixture under neutral, acidic or alkaline conditions to obtain N-hydroxyethylaminomethylphosphonic acid or its salts; and (c) catalytic oxidation of N-hydroxyethylaminomethylphosphonic acid or its salts.  18. The method according to 17, in which the trialkylphosphite is triisopropylphosphite. 19. The method of claim 17, wherein the oxidation is carried out by contacting the N-gidroksietilaminometilfosfonovoy acid or its salts with an alkali metal hydroxide in the presence of an effective amount of a Raney copper catalyst containing from about 50 to about 10000 ^-1 million of an element selected from the group consisting from chromium, titanium, niobium, tantalum, zirconium, vanadium, molybdenum, manganese, tungsten, cobalt, nickel and mixtures thereof.  20. The method according to 17, in which the oxidation is carried out in the presence of an effective amount of a mixed metal catalyst deposited on coal.  21. The method according to 17, in which the hydrolysis is carried out in an alkaline environment.  22. The method according to item 21, in which the hydrolysis is carried out in the presence of an alkali metal hydroxide or alkaline earth metal hydroxide.  23. The method according to item 21, in which the alcohol formed during hydrolysis is removed during hydrolysis.  24. The method according to 17, in which reaction (a) is carried out in the presence of alcohol.  25. The method according to 17, in which the molar ratio of ethanolamine and phosphite is from about 1.2: 1 to about 8: 1 and the number of carbon atoms in the alkyl group of trialkylphosphite is 2 to 6.  26. The method according A.25, in which the trialkylphosphite is triisopropylphosphite.  27. The method according to 17, in which the molar ratio of alkanolamine and phosphite is from about 1: 1 to about 10: 1 and the number of carbon atoms in the alkyl group of trialkylphosphite is 1 or greater than 6.  28. The method according to 17, in which the molar ratio of formaldehyde to phosphite is from 1: 1 to about 5: 1. 29. The method of obtaining N-hydroxyalkylaminomethylphosphonic acid of the formula

or its salts, including: (a) contacting an alkanolamine of the formula

where n = 2 - 6,
formaldehyde and trialkylphosphite in the presence of an alcohol of the formula
R (OH) _m ,
where R is an alkyl group having from 1 to about 18 carbon atoms;
m = 1 - 3,
at 50 - 150 ^o C to obtain a reaction mixture, where the molar ratio of alkanolamine and phosphite is from about 1: 1 to about 5: 1, and (b) hydrolysis of the reaction mixture in a neutral, acidic or alkaline environment.  30. The method according to clause 29, in which the trialkylphosphite is triisopropylphosphite.  31. The method according to clause 29, in which n = 2.  32. The method according to clause 29, in which the molar ratio of alkanolamine and phosphite is from 1: 1 to about 2: 1. 33. The method of obtaining N-phosphonomethylaminocarboxylic acid of the formula

where n = 2 - 6,
or its salts, including the catalytic oxidation of N-hydroxyalkylaminomethylphosphonic acid or its salts obtained according to the method according to clause 29. 34. The method according to p, in which the oxidation is carried out by contacting N-hydroxyalkylaminomethylphosphonic acid or its salts with an alkali metal hydroxide in the presence of an effective amount of a Raney copper catalyst containing from about 50 to about 10,000 million ^-1 element selected from the group consisting of from chromium, titanium, niobium, tantalum, zirconium, vanadium, molybdenum, manganese, tungsten, cobalt, nickel and mixtures thereof.  35. The method according to p, in which the oxidation is carried out in the presence of an effective amount of a mixed metal catalyst deposited on coal.  36. The method according to p. 29, in which the hydrolysis is carried out in an alkaline environment.  37. The method according to clause 36, in which the alcohol formed during hydrolysis is removed during hydrolysis.

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