RU2507195C1 - Method of obtaining asymmetric ethylene diamine-n,n-dipropionic acid - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining asymmetric ethylene diamine-N,N-dipropionic acid of formula

which can be applied as complex-forming agent in chemistry, biology and medicine. Method is realised through formation of intermediate zinc complex of asymmetric ethylene diamine-N,N-dipropionic acid of dichloride. Method consists in addition of equimolar amount of ethylene diamine to water solution of zinc chloride with further mixing of reaction mass at temperature 40-45°C, its dilution with water and addition of acrylic acid. After addition of acrylic acid reaction mass is mixed at temperature 55-60°C, cooled and intermediate product - zinc complex of asymmetric ethylene diamine-N,N-dipropionic acid of dichloride is separated in solid form. Complex is destructed by running its water solution at rate (3-20) cm³/min through column, filled with cationite in H-form. After that, column is washed first with water, and then with diluted aqueous ammonia, Target product is separated by evaporation in vacuum, dissolution of residue in distilled water, which is later removed in vacuum; residue is dried.

EFFECT: method makes it possible to simplify obtaining asymmetric ethylene diamine-N,N-dipropionic acid.

4 cl, 9 dwg, 4 ex

Description

The invention relates to methods for producing ethylenediaminocarboxylic acids, in particular asymmetric ethylenediamine-N, N-dipropionic acid, which can be used as a complexing agent to solve a number of problems in chemistry, biology, medicine, as well as a nodal compound for the synthesis of multifunctional ligands.

Asymmetric ethylenediamine-N, N-dipropionic acid (ac. EDDP) has the following asymmetric structure:

Asymmetric ethylenediamine-N, N-dipropionic acid is described previously in well-known publications. For example, it is known to use the tert-butyloxycarbonyl derivative of an asymmetric ethylenediamine-N, N-dipropionic acid as a starting material in the synthesis of biologically active compounds used in medicine (Y. YAN tt fl., A new ¹⁸ F-labeled BBN-RGD peptide heterodimer with a symmetric linker for prostate cancer imaging, AMINO ACIDS, 2011, 41 (2), 439-447). It is also known that asymmetric ethylenediamine-N, N-dipropionic acid in the form of dihydrochloride is obtained as an intermediate in the synthesis of the whitening agent used in photography (US 5352567, G07C 7/42, 1994).

A derivative of asymmetric ethylenediamine-N, N-dipropionic acid is its known binuclear nickel complex of the formula C ₁₆ H ₃₆ N ₄ Ni ₂ O ₁₂ (M. Badea, R. Olar, D. Marinescu / TTnorganic Chemistry Communications, 2009, vol. 12, P.555-557) having the following structure:

Asymmetric ethylenediamine-N, N-dipropionic acid belongs to the group of ethylenediamine-propionic acids, such as ethylenediamine-N, N′-dipropionic acid (sym. EDDP) (RU 2307828, С07С 227/04, 2008) and ethylenediamine-N, N, N ′, N′-tetrapropionic acid (EDTP) (RU 2308448, С07С 227/08, 2008), which, as is known, in contrast to it, have a symmetrical structure of the molecule:

Several publications are known regarding the production of symmetric ethylenediamine-N, N′-dipropionic acid.

Thus, an early 1950 publication described a process for preparing symmetric ethylenediamine-N, N′-dipropionic acid as a dihydrochloride (Arthur E. Martell, Stanley Chaberek, “The preparation and properties of some N, N-disubstituted ethylenediaminedipropionic acids.” J. Am. Chem. Sos., 1950, vol. 72, p. 5357-5361). In the cited work, the synthesis of this compound is carried out in several stages: in the first stage, ethylene diamine is reacted with acrylonitrile, then the resulting ethylene diamine-N, N′-dipropionitrile is hydrolyzed with concentrated hydrochloric acid, followed by treatment of the hydrolysis product. The processing of the hydrolyzate is multistage and includes the following stages: boiling, standing and evaporation of the reaction mixture, dissolving the dry precipitate in water, alkalizing the solution with ammonia water, extraction of the product with alcohol and other processing steps, in particular, purification by five-fold recrystallization from hot 80% ethyl alcohol . The yield of ethylenediamine-N, N′-dipropionic acid dihydrochloride in this case is 40%. The multi-stage and duration of the described process, as well as energy-intensive hardware design makes the known method uneconomical and industrially inapplicable. In addition, this method is not environmentally friendly due to the use of highly toxic acrylonitrile as a starting material.

In another known invention, to obtain ethylene diamine-N, N′-dipropionic acid having a symmetrical structure as a dihydrochloride, ethylene diamine is used as the starting compound, and the β-chloropropionic acid calcium salt is used as a carboxyalkylating reagent (RU 2307828, C07C 227/04, 2008 ) The carboxyalkylation process in this case is carried out at a temperature not exceeding 85 ° C and in the presence of calcium hydroxide at a pH of the reaction mass of 9.0-11.0. After cooling the reaction mass and its acidification with hydrochloric acid, the pH value is set at 1.0-1.5 and the target product is isolated by filtration, which is washed on the filter with ethyl alcohol. The yield of ethylenediamine-N, N′-dipropionic acid dihydrochloride is 40%. It is important to note that the main disadvantage of this known method is its relatively low yield, which is probably due to the ability of β-chloropropionic acid to participate in the side reaction of elimination under synthesis conditions.

As a prototype of the proposed method, the known method of obtaining asymmetric ethylenediamine-N, N-dipropionic acid in the form of dihydrochloride is selected. This method, as mentioned above, is an intermediate step in the synthesis of the whitening agent used in photography (US 5352567, G07C 7/42, 1994).

Asymmetric ethylenediamine-N, N-dipropionic acid in this method is obtained in two stages according to the following scheme:

To carry out this process in the first step, acrylic acid (2.1 mol) was added dropwise to an aqueous solution of N-acetylethylenediamine (1 mol) at room temperature, and then the reaction mixture was boiled for two hours. After that, diethyl ether was added to the resulting concentrated solution, the precipitate formed was filtered off, recrystallized in an aqueous methanol medium, washed with ether, and an intermediate product of N-acetylethylenediamine-N, N′-dipropionic acid of the formula:

In the second stage of the process, sodium hydroxide (2 mol) is added to an aqueous solution of the obtained intermediate product, boiled for 1 hour, cooled, and concentrated hydrochloric acid is added. The resulting sodium chloride is filtered off, the filtrate is concentrated under reduced pressure, ethanol is added, the target product, asymmetric ethylenediamine-N, N′-dipropionic acid dihydrochloride, is filtered off and recrystallized. The yield of asymmetric ethylenediamine-N, N-dipropionic acid dihydrochloride at this stage is 81%.

One of the main disadvantages of the prototype method (US 53525670) is the complexity of its implementation, associated primarily with the multi-stage process of synthesis, isolation and purification of intermediate and target products, which complicates the industrial implementation of the method. In addition, this process is fire and explosive, environmentally unsafe, because at each stage of isolation and purification it is envisaged to use a large number of organic solvents (explosive, flammable diethyl ether, methanol, ethanol), as well as the use of large amounts of concentrated hydrochloric acid (molar the ratio of N-acetylethylenediamine-N ′, N′-dipropionic acid to hydrochloric acid is 1: 7.3). The process is not economically viable, since N-acetylethylenediamine, which is an expensive reagent that is not commercially available for use in large quantities, is used as the starting product. Additionally, it should be noted that the considered method produces an asymmetric ethylenediamine-N, N-dipropionic acid in the form of its dihydrochloride, and does not isolate it as such in the form of an acid.

In order to create a technologically advanced, environmentally and economically acceptable process, a new method is proposed for producing asymmetric ethylenediamine-N, N-dipropionic acid (as. EDDP).

In the proposed new method for producing asymmetric ethylenediamine-N, N-dipropionic acid, the process is carried out through the formation of an intermediate zinc complex of asymmetric ethylenediamine-N, N-dipropionic acid dichloride, for which an equimolar amount of ethylene diamine is added to the aqueous solution of zinc chloride, after which the reaction mass is stirred at temperature 40-45 ° C, diluted with water and add acrylic acid, then the reaction mass is stirred at a temperature of 55-60 ° C, cooled and isolated in solid form, intermediate the product is the zinc complex of asymmetric ethylenediamine-N, N-dipropionic acid dichloride, which is destroyed by passing at a rate of (3-20) cm ³ / min of its aqueous solution through a column filled with cateonite in the H-form, after which the column is washed first with water, then with dilute aqueous ammonia and the target product is isolated by evaporation in vacuo of aqueous ammonia solutions to dryness, the residue of the obtained ethylenediamine-N, N-dipropionic acid is dissolved in distilled water, which is then removed in vacuum, and the target product is dried at.

The target product is further purified, for which it is recrystallized from hot water, precipitate ac. The EDDP is filtered off and washed on the filter with cold distilled water and methanol and dried.

Acrylic acid is added, preferably in a 6-10% excess of the stoichiometric amount relative to ethylenediamine.

The main significant difference of the proposed method from the prototype method is that the process is carried out through the formation of an intermediate zinc complex of asymmetric ethylenediamine-N, N-dipropionic acid dichloride, which, in turn, is obtained from an aqueous solution of zinc chloride, ethylene diamine and acrylic acid.

The main features of the proposed method are:

- the choice of starting reagents ethylene diamine, acrylic acid and an aqueous solution of zinc chloride and their specific molar ratio,

- a certain sequence of stages of the process,

- specific temperature conditions at all stages of the process,

- conditions for the selection of the target product.

Getting AC. EDDP is carried out through the formation of an intermediate, previously unknown compound - the zinc complex of asymmetric ethylenediamine-N, N-dipropionic acid dichloride (Zn [ac. EDDP] Cl ₂ ), the structure of which is confirmed and characterized by X-ray diffraction, mass spectrometry, IR and ¹ H-, ¹³ C-NMR spectroscopy, elemental analysis data (Fig. 1-4).

In the first stage, an equimolar amount of ethylene diamine (with a molar ratio of 1: 1) is added to an aqueous solution of zinc chloride with stirring at room temperature. The temperature of the reaction mass spontaneously rises to 85-90 ° C as a result of an exothermic reaction of complexation of zinc chloride (ZnCl ₂ ) with ethylene diamine (EDA). At the first stage of the process, a zinc complex of ethylenediamine dichloride is obtained in which Zn (II) is coordinated by two nitrogen atoms of two amino groups of ethylenediamine and has the composition C ₂ H ₈ N ₂ Cl ₂ Zn:

At the end of the temperature rise, the reaction mass is cooled to a temperature of 40-45 ° C to avoid polymerization at a higher temperature of the acrylic acid introduced into the reaction.

If the intermediate product is isolated by filtration before the introduction of acrylic acid into the obtained concentrated solution of Zn (II) of the ethylenediamine complex, the reaction mass is diluted with a volume of water, preferably equal to the volume of added acrylic acid. Otherwise (without dilution with water) the reaction mass thickens, which greatly complicates the isolation of the target product formed during the synthesis.

Preferably, to the resulting intermediate product, the ethylene diamine zinc complex, add acrylic acid in a 6-10% excess of the stoichiometric amount with respect to ethylene diamine (stoichiometric ethylene diamine: acrylic acid molar ratio is 1: 2), which compensates for its possible polymerization, and while the yield of the intermediate product is 58%. If stoichiometric amounts of ethylenediamine and acrylic acid are used, the zinc complex of ethylenediamine-N, N-dipropionic acid dichloride also forms, but the yield decreases and amounts to 52% (when all other conditions of the process are fulfilled, which is confirmed by the examples below).

The interaction of the zinc complex of ethylenediamine with acrylic acid is carried out in experimentally established temperature conditions, namely at a temperature of 55-60 ° C, which ensures maximum yield of the final product.

A certain sequence of component loading is also significant, since it involves the initial formation of a Zn (II) complex of ethylenediamine and the further interaction of acrylic acid with the amino group of ethylene diamine coordinated with Zn (II).

After cooling the reaction mass (to room temperature), the precipitate of the intermediate product — the zinc complex of ethylenediamine-N, N-dipropionic acid dichloride, can be isolated by known methods, but preferably by the most technologically advanced method — filtration.

To increase the degree of purity, the isolated intermediate product, the zinc complex of ethylenediamine-N, N-dipropionic acid dichloride, is additionally treated: the filter is washed with distilled water and methanol, and dried by known methods.

The second stage of the process is reduced to passing an aqueous solution of an intermediate product - a zinc complex of asymmetric ethylenediamine-N, N-dipropionic acid dichloride, through a column filled with cation exchange resin in the H-form, resulting in the destruction of the complex and adsorption of ethylene diamine-N, N- on the cation exchange resin. dipropionic acid. As cation exchange resin can be used: KU-2-8 cation exchange resin in H-form, Dowex 50W, Duolite and others. An aqueous solution of the complex is passed through a column filled with cation exchange resin at a speed of (3-20) cm / min. The choice of just such a high-speed regime makes it possible to achieve the maximum degree of complex destruction and absorption of the target product, a free ligand, on the cation exchange resin. In the case of establishing a transmission rate below 3 cm ³ / min, the duration of the process significantly increases; in case of exceeding the transmission rate, there is a loss of an intermediate product and a decrease in the amount of ac adsorbed on cation exchanger. EDDP. After passing the solution through a column filled with cation exchange resin, it is washed with water until there are no chloride ions and zinc cations formed when the zinc complex of ethylenediamine-N, N-dipropionic acid dichloride is destroyed. Then the column is washed with a dilute aqueous solution of ammonia for desorption from the cation exchanger of the target product - ethylenediamine-N, N-dipropionic acid. The collected washing eluates having a solution pH of 6.0-7.0 are evaporated in vacuo. In order to purify the target product from traces of ammonia, the residue obtained in the form of an oil is dissolved in distilled water, which is completely removed in vacuum. The resulting oil of asymmetric ethylenediamine-N, N-dipropionic acid, not containing impurities of ammonium ions, chloride ions and zinc cations, is dried, for example, in vacuum over calcium chloride. For additional purification of the product and obtaining in crystalline form, it is recrystallized from hot water. The precipitated yellowish crystalline precipitate of asymmetric ethylenediamine-N, N-dipropionic acid is filtered off and washed on the filter with cold distilled water and methanol, and dried.

To identify the intermediate zinc complex ac. EDDP of dichloride and the obtained target product (as such ac. EDDP) and were used: methods of X-ray diffraction analysis, mass spectrometry, IR and ¹ H-, ¹³ C-NMR spectroscopy, data of elemental analysis. The results of X-ray diffraction analysis and ¹³ C-NMR spectroscopy data reliably confirm that the proposed method produces exactly ethylenediamine-N, N-dipropionic acid (ac. EDDP), which has an asymmetric molecular structure.

The mass spectrum of the intermediate product, the zinc complex ac, is shown in Fig. 1 below. EDDP of dichloride, its ¹ H and ¹³ C NMR spectra (Figs. 2 and 3), as well as the IR spectrum (Fig. 4). The data of physical and chemical studies using the methods of IR, NMR spectroscopy and spectrometry confirm the structure of the complex corresponding to (ethylenediamine-N, N-dipropionato) zinc (II) dichloride. The intermediate compound, zinc complex ace. EDDP dichloride, has so pl. 217.0-218.0 ° C (decomposed). Found,%: C 28.30, 27.63; H 4.53, 4.76; N, 8.21; 7.33; Zn 18.75, 18.80; Cl 20.96, 21.10. C ₈ H ₁₆ N ₂ O ₄ Cl ₂ Zn. Calculated,%: C 28.22; H 4.74; N, 8.23; O 18.79; Zn 19.20; Cl 20.82.

Figure 5 below shows the mass spectrum of the compound under study, in which there is a peak belonging to the molecular ion 204.961, which actually corresponds to the molecular weight of ethylenediamine dipropionic acid.

The presence of five signals from five nonequivalent carbon atoms in the ¹³ C NMR spectrum of the test compound (Fig. 6) indicates the asymmetric nature of the structure of the molecule, which corresponds to the structure of asymmetric ethylenediamine-N, N-dipropionic acid (ac. EDD). It should be noted that if the molecule had a symmetric structure characteristic of ethylenediamine-N, N′-dipropionic acid (sym. EDDP), then the number of nonequivalent carbon atoms was four in the ¹³ C-NMR spectrum of sim. EDDP (Fig. 7), four signals would be observed.

¹ H NMR spectrum of the obtained ac. EDDP is shown in Fig. 8. The IR spectrum (Fig. 9) contains absorption bands corresponding to the ionized carboxyl group (1625 cm ^-1 ) and the amino group (3050 cm ^-1 ). The resulting compound has mp 117.5-118.5 ° C. Based on the data of elemental analysis, it was found,%: C 46.71, 45.96; H 7.86, 8.06; N 13.41, 12.96. C ₈ H ₁₆ N ₂ O ₄ . Calculated,%: C 47.05; H, 7.90; N 13.72; O 31.33.

The undeniable evidence for the production of asymmetric ethylenediamine-N, N-dipropionic acid (ac. EDDP) was the results of x-ray diffraction analysis of the grown single crystal obtained by the described method of connection.

Below the invention is illustrated by examples, which in no way limit the possibility of implementing this method within the claimed scope of claims.

Obtaining an intermediate product - a zinc complex of asymmetric ethylenediamine-N, N-dipropionic acid dichloride Example 1.

To a solution of 45.0 g (0.33 mol) of zinc chloride in 22 cm ^{3 of} water, 19.8 g (22.2 cm ³ ) (0.33 mol) of ethylenediamine are added, while the temperature of the reaction mixture rises to 85-90 ° C due to an exothermic reaction. At the end of the temperature rise, the resulting suspension is cooled to 40 ° C with stirring, diluted with water in a volume of 48 cm, 50.4 g (48.0 cm) (0.70 mol) of acrylic acid are added, which corresponds to a 6% excess in in relation to ethylenediamine. The resulting reaction mass in the form of a solution is heated to a temperature of 60 ° C. The precipitate formed is filtered off, washed on the filter with cold distilled water and methanol, and dried. Obtain 65.0 g of the zinc complex of asymmetric ethylenediamine-N, N-dipropionic acid dichloride with a yield of 57%, so pl. 217.0-218.0 ° C (decomposed). Found,%: C 28.30, 27.63; H 4.53, 4.76; N, 8.21; 7.33; Zn 18.75, 18.80; Cl 20.96, 21.10. C ₈ H ₁₆ N ₂ O ₄ Cl ₂ Zn. Calculated,%: C 28.22; H 4.74; N, 8.23; O 18.79; Zn 19.20; C1 20.82.

Example 2

To a solution of 45.0 g (0.33 mol) of zinc chloride in 22 cm ^{3 of} water, 19.8 g (22.2 cm) (0.33 mol) of ethylenediamine are added, while the temperature of the reaction mixture rises to 85-90 ° C due to exothermic reaction. At the end of the temperature rise, the resulting suspension with stirring is cooled to a temperature of 45 ° C, diluted with water in a volume of 50 cm ³ , 52.3 g (49.8 cm) (0.73 mol) of acrylic acid are added, which corresponds to a 10% excess in relation to ethylenediamine. The resulting reaction mass in the form of a solution is heated to a temperature of 60 ° C, the precipitate formed is filtered off, washed on a filter with cold distilled water and methanol, and dried. Obtain 65.0 g of the zinc complex of asymmetric ethylenediamine-N, N-dipropionic acid dichloride with a yield of 58%, so pl. 218 ° C (decomposed).

Example 3

To a solution of 45.0 g (0.33 mol) of zinc chloride in 22 cm ^{3 of} water, 19.8 g (22.2 cm ³ ) (0.33 mol) of ethylenediamine are added, while the temperature of the reaction mixture rises to 85-90 ° C due to an exothermic reaction. At the end of the temperature rise, the resulting suspension is cooled to 45 ° C with stirring, diluted with water in a volume of 45 cm ³ , 475 g (45.2 cm) (0.66 mol) of acrylic acid are added, which corresponds to an equimolar amount with respect to ethylene diamine. The resulting reaction mass in the form of a solution is heated to a temperature of 55 ° C, the precipitate formed is filtered off, washed on a filter with cold distilled water and methanol, and dried. Obtain 59.4 g of the zinc complex asymmetric ethylenediamine-N, N-dipropionic acid dichloride with a yield of 52%, so pl. 218 ° C (decomposed).

Example 4

65.0 g (0.19 mol) of the zinc complex of asymmetric ethylenediamine-N, N-dipropionic acid dichloride of the composition C ₈ H ₁₆ N ₂ O ₄ Cl ₂ Zn is dissolved in 150 cm ^{3 of} water with stirring at room temperature, after which the resulting solution pass at a speed of 3 cm ³ / min through a column (diameter 30 mm) filled to a column height of 250 mm with KU-2-8 cation exchanger in the N-form. Preparation of cation exchanger for work and its translation into the H-form is carried out by standard methods. When Cl ^- and Zn ²⁺ ions are absent in the eluates, the cation exchanger in the column is washed first with 50 cm3 of water, then 45-50 cm3 of a 10% aqueous ammonia solution at the same rate, collecting washing eluates from the column having a solution pH in a round bottom flask 6.0-7.0, which are then evaporated to dryness in vacuo. Distilled water was added to the resulting residue, which was removed in vacuo. The resulting oil of the target product is dried in vacuum over calcium chloride. 32.2 g of asymmetric ethylenediamine-N, N-dipropionic acid are obtained in a yield of 83%. In order to purify and obtain the product in crystalline form, it is recrystallized from hot water. The precipitated white-yellow crystalline precipitate is filtered off and washed on the filter with cold distilled water, methanol and dried. Obtain 30.6 g of asymmetric ethylenediamine-N, N-dipropionic acid with a yield of 78.6%. so pl. 117.5-118.5 ° C. Found,%: C 46.71, 45.96; H 7.86, 8.06; N 13.41, 12.96. C ₈ H ₁₆ N ₂ O4. Calculated,%: C 47.05; H, 7.90; N 13.72; O 31.33.

As can be seen from the above examples, the proposed method is simple to implement and technologically acceptable, cost-effective. The final product, asymmetric ethylenediamine-N, N-dipropionic acid, is obtained in 83% yield (assuming its zinc complex). The structure of the compound, asymmetric ethylenediamine-N, N-dipropionic acid, is confirmed by the results of X-ray diffraction analysis, IR and ¹ H-, ¹³ C-NMR spectroscopy, mass spectrometry, and elemental analysis data.

The manufacturability of the process is confirmed by the fact that the inventive method is a simpler and more technologically advanced method (we propose a two-stage production of ethylenediamine-N, N-dipropionic acid - synthesis of its zinc complex and its subsequent destruction using the ion exchange method), which allows to reduce the complexity, duration and energy consumption of the process .

In addition, at the main stages, the process is carried out in an aqueous medium without the use of organic solvents. Organic solvents (methanol only) are used in small quantities only at the stages of purification. The inventive method is more economical in comparison with the prototype, since it uses only low-cost reagents.

As a result of the process of the proposed method, asymmetric ethylenediamine-N, N-dipropionic acid is obtained, which can be used as a nodal compound for the synthesis of multifunctional ligands, as well as a complexing agent for solving problems of chemistry, biology, and medicine.

Claims (4)

1. The method of obtaining asymmetric ethylenediamine-N, N-dipropionic acid of the formula

characterized in that the process is carried out through the formation of an intermediate zinc complex of asymmetric ethylenediamine-N, N-dipropionic acid dichloride, which is carried out by adding an equimolar amount of ethylene diamine to an aqueous solution of zinc chloride, followed by stirring the reaction mixture at a temperature of 40-45 ° C, diluting it with water and the addition of acrylic acid, followed by stirring of the reaction mixture at a temperature of 55-60 ° C, cooling and solid separation of the intermediate product - zinc comp Lexa of asymmetric ethylenediamine-N, N-dipropionic acid dichloride, which is destroyed by passing its aqueous solution at a rate of (3-20) cm ³ / min through a column filled with cation exchange resin in the H-form, after which the column is washed first with water, then with a diluted aqueous solution ammonia and the target product is isolated by evaporation in vacuo, dissolving the residue in distilled water, which is then removed in vacuum, and the residue is dried. 2. The method according to claim 1, characterized in that the acrylic acid is added, preferably in a 6-10% excess of stoichiometric with respect to ethylenediamine. 3. The method according to claim 2, characterized in that the intermediate product is a zinc complex of asymmetric ethylenediamine-N, N-dipropionic acid dichloride - is isolated by filtration, washed on the filter with distilled water and methanol and dried. 4. The method according to claim 2, characterized in that the target product is further purified, for which it is recrystallized from hot water, the precipitate is filtered off and washed on the filter with cold distilled water and methanol and dried.

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