Tetraazadodecane-based chelating agents for the separation of rare earth elements and methods thereof

Abstract

The present invention relates to the use of compounds of general formula (I) for the separation of rare earth elements (lanthanides) by precipitation. [Case 1] JPEG2023551792000036.jpg38169 In the formula, R 1 is selected from the group consisting of H, -CH2COOH; R 2 , R 3 , R 4 , R 5 and R 6 are independently selected from the group consisting of H, OH, —NO2, —COOH, and phenyl; and / or R 2 and R 3 , or R 3 and R 4 , or R 4 and R 5 , or R 5 and R 6 forms a six-membered aromatic ring together with two adjacent carbon atoms of said aromatic ring. The present invention further relates to a method for separating rare earth elements by precipitation.

Description

Detailed Description of the Invention

[0001] [Technical field] The present invention relates to cyclen-based compounds suitable for the extraction and separation of rare earth elements (eg, from discarded electronic and electrical equipment, based on their different solubilities), and to methods for the separation of rare earth elements.

[0002] [Background technology] The rare earth elements (Scandium - Sc, Yttrium - Y, Lanthanum - La, Cerium - Ce, Praseodymium - Pr, Neodymium - Nd, Promethium - Pm, Samarium - Sm, Europium - Eu, Gadolinium - Gd, Terbium - Tb, Dysprosium - Dy, Holmium - Ho, Erbium - Er, Thulium - Tm, Ytterbium - Yb and Lutetium - Lu) are metals with very similar chemical properties. These elements are essential in many modern technologies. Nd and Dy are crucial for the powerful permanent magnets used in electric motors, wind turbines, and computer hard drives. Eu, Tb and Y are important components in the light-emitting phosphors in fluorescent lamps. Ce and Y are currently used in the most advanced light-emitting diode (LED) lighting technology. The number of industrial uses for the rare earth elements is expected to increase, and so will the overall consumption of rare earth elements. However, the extraction of these elements from primary ores is problematic. First, the majority of global production comes from just one country, China. For this reason, the European Union and the United States have placed some rare earth elements on their lists of critical raw materials. Second, processing and refining the individual elements to a degree suitable for the above-mentioned applications is energetically demanding, as well as generating large amounts of toxic and radioactive waste. An obvious solution is to recycle the rare earth elements from discarded equipment and electronic waste, which is generated in large quantities every year by developed countries. Despite this, only a few percent of the rare earth elements traditionally used are currently recycled. Although the separation of rare earth elements from other metals with sufficiently different properties is a solved problem, the separation of rare earth elements from each other remains technically and financially demanding. For these reasons, recycling rare earth elements is not profitable.

[0003] Historically, rare earth elements have been separated from each other by fractional crystallization, which requires thousands of iterations to obtain a pure product. Current industrial methods rely mainly on solvent-solvent extraction and, for high purity, on smaller scale ion exchange chromatography. None of these methods are selective for a particular element. Only solvent-solvent extraction offers the capacity to cover industrial demand. However, this method has several drawbacks. The requirement for a series of hundreds of extractors represents a large infrastructure with high investment and operating costs. Furthermore, this method requires the use of water-immiscible solvents and extractants, which are harmful to the environment. The development of simpler, more selective, and environmentally friendly alternative methods is highly desirable.

[0004] Precipitation and crystallization are industrially preferred purification methods due to their simplicity, efficiency and scalability to large quantities. Using these methods for the separation of rare earth elements is highly beneficial. However, the problem is finding chemicals that will create a sufficient difference in solubility between these elements. In recent years, several studies have demonstrated some progress in this field. Chelating ligands have been used to separate rare earth elements based on the different solubilities of their complexes in tetrahydrofuran. (See Bogart, JA et al. Angew. Chem. 2015, 127, 8340-8343 a Bogart, JA et al. PNAS 2016, 113, 14887-14892). Although light elements (La-Eu) were efficiently separated from heavy elements (Gd-Lu), separation of the two adjacent lanthanides was not demonstrated. The disadvantage of this method is the need to use organic solvents such as tetrahydrofuran, benzene or toluene, which are toxic and non-biological.

[0005] Another study demonstrated the possibility of separating rare earth elements using hydrothermal synthesis of crystalline borates with different crystal structures. (See Yin, X. et al. Nat. Commun. 2017, 8:14438). Separation was achieved between an aqueous solution and a solid phase, or between two crystalline solid phases that could be separated based on different crystal densities. However, the reaction conditions for the synthesis were very harsh, requiring the use of an autoclave, a temperature of 200 °C, and long crystallization times of 3-5 days. Moreover, even in this case, effective separation of two adjacent lanthanides was not demonstrated.

[0006] Yet another study demonstrated the selective precipitation of insoluble hydroxides of lanthanides from aqueous solutions with the aid of specially designed peptides. (See Hatanaka, T. et al. Nat. Commun. 2017, 8:15670). Some of the peptides showed selectivity for the precipitation of heavy lanthanides compared to light lanthanides. The separation of two adjacent lanthanides was not studied.

[0007] Thus, the background art lacks a suitable method for the separation of rare earth elements that is simple, efficient, scalable to large quantities, and at the same time does not require the use of toxic, non-biological solvents, or expensive equipment, or high temperatures and pressures.

[0008] DISCLOSURE OF THEINVENTION Chelators structurally derived from the macrocyclic cyclen (1,4,7,10-tetraazacyclododecane) are particularly suitable for complexing rare earth elements. In the background art, a number of such chelators have been prepared and investigated for use in biomedical applications. Complexes of gadolinium serve as contrast agents in magnetic resonance tomography and are useful for the complexation of radionuclides. 90 Y and 177Complexes with Lu have been used in targeted drugs for cancer treatment. For all these uses, it is desirable that the complexes are highly stable and soluble in water. In contrast, we have made the surprising discovery that some chelating agents derived from cyclen exhibit significant differences in the solubility of complexes with different rare earth elements. These differences are large enough that they can be practically used to separate these elements from each other. The separation is carried out by precipitation from an aqueous solution of the mixture of elements, and does not necessarily require the use of organic solvents. The separated solid phase can be redissolved and the precipitation process can be repeated to reach a higher degree of separation. The separated solid complexes can be decomposed back to free chelating agents and rare earth metal cations for further use. The mother liquor may also be used after its concentration and / or ultrafiltration and / or ion exchange chromatography to precipitate and separate the solid complexes of rare earth elements. This separation method is therefore very efficient, easy, biological and scalable to industrial scale, thus solving the problems of the background art mentioned above. Moreover, the method does not require any specialized and expensive equipment.

[0009] The subject of the present invention is the use of compounds of general formula (I) for the separation of rare earth elements (lanthanides) by precipitation,

[0010] [ka]

[0011] During the ceremony, R 1 is selected from the group consisting of: H; -CH2COOH; R 2 , R 3 , R 4 , R 5 and R 6 is independently selected from the group consisting of: H; OH; -NO2; -COOH; phenyl; and / or R 2 and R 3forms a six-membered aromatic ring together with two adjacent carbon atoms of the aromatic ring; and / or R 3 and R 4 forms a six-membered aromatic ring together with two adjacent carbon atoms of said aromatic ring; and / or R 4 and R 5 forms a six-membered aromatic ring together with two adjacent carbon atoms of said aromatic ring; and / or R 5 and R 6 forms a six-membered aromatic ring together with two adjacent carbon atoms of said aromatic ring.

[0012] The compounds of formula (I) form coordination compounds (complexes) with rare earth elements, and these coordination compounds differ considerably in water solubility, so that it is possible to separate them by precipitation.

[0013] The term "precipitation" refers to the displacement of a compound in a solid phase from a solution. Said solid phase may be in the form of a precipitate or in the form of crystals.

[0014] The rare earth elements are selected from scandium - Sc, yttrium - Y, lanthanum - La, cerium - Ce, praseodymium - Pr, neodymium - Nd, promethium - Pm, samarium - Sm, europium - Eu, gadolinium - Gd, terbium - Tb, dysprosium - Dy, holmium - Ho, erbium - Er, thulium - Tm, ytterbium - Yb and lutetium - Lu.

[0015] In one preferred embodiment, the substituent R 2 , R 3 , R 4 , R 5 and R 6 At most two of them are not H.

[0016] In one preferred embodiment, the substituent R 2 , R 3 , R 4 , R 5 and R 6One of them is other than H.

[0017] In one embodiment, R 2 and R 6 is independently H or OH.

[0018] In one embodiment, R 3 and R 4 forms a six-membered aromatic ring together with two adjacent carbon atoms of the aromatic ring, and at the same time, R 2 , R 5 and R 6 is H.

[0019] In one embodiment, R 2 , R 3 , R 4 , R 5 and R 6 is H.

[0020] In one embodiment, the group of general formula (I)

[0021] [ka]

[0022] is selected from the group including naphthalen-1-ylmethyl, naphthalen-2-ylmethyl and benzyl.

[0023] In one embodiment, R 2 , R 3 , R 5 and R 6 is H and R 4 is phenyl, H or COOH.

[0024] In a most preferred embodiment, said compound of general formula (I) is selected from the group consisting of: 2,2',2''-(10-benzyl-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2'-(4-(2-hydroxy-5-nitrobenzyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2,2'-(4-(4-carboxybenzyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2,2',2''-(10-(naphthalen-2-ylmethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2''-(10-(naphthalen-1-ylmethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2''-(10-([1,1'-biphenyl]-4-ylmethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid.

[0025] A further object of the present invention is a method for separating rare earth elements by precipitation, comprising the following steps o) and a): o) At least two different rare earth elements (M 3+ providing an aqueous solution of ions of the formula (I) and an aqueous solution of said compound of general formula (I) as defined above; a) At least two different rare earth elements (M 3+ ) with an aqueous solution of said compound of general formula (I) as defined above; the pH of the resulting solution is preferably in the range of from 5 to 9, more preferably in the range of from 6 to 8; 3+ causing the formation of complexes of ions with said compound of general formula (I), wherein at least one of said complexes formed is in the form of a precipitate or crystalline phase (thus forming a heterogeneous mixture containing at least one of said complexes in solid form, while said solution is enriched with the more soluble complexes).

[0026] Most preferably, said step a) is carried out at pH 7.

[0027] Preferably, step a) is carried out with constant stirring or shaking.

[0028] The compound of general formula (I) and the metal cation M 3+ The solubility of the resulting complexes with (in water or in the reaction mixture, respectively) is different for the various rare earth metal ions. For this reason, the precipitation preferably occurs only in the presence of one of the metal ions to be separated in the reaction mixture. The remaining complexes of the rare earth metal ions with the compound of general formula (I) remain dissolved in the reaction mixture.

[0029] For some combinations of two or more rare earth metal cations to be separated, the compound of general formula (I) and the metal cation M 3+ More than one complex with may be precipitated or crystallized from the reaction mixture. For example, an aqueous solution of four rare earth metal cations may, upon complex formation with the compound of general formula (I), result in the precipitation of two of the complexes formed, leaving the remaining two complexes in the solution mixture.

[0030] In either case, the reaction mixture is enriched with the more water-soluble complex or complexes.

[0031] Preferably, step a) is carried out for at least 1 minute, more preferably from 1 minute up to 5 days.

[0032] Preferably, step a) is carried out at room temperature (20 to 25° C.).

[0033] An aqueous solution is a solution, said solvent being selected from the group comprising water, a buffer solution (e.g., MOPS, 3-(N-morpholino)propanesulfonic acid), and / or a mixture of water and an organic solvent that is miscible with water.

[0034] When the solvent is a mixture of water and a water-miscible organic solvent, the preferred water content is at least 50% by volume, more preferably the water content is from 60% to 95% by volume, even more preferably from 70% to 85% by volume.

[0035] The organic solvent that is miscible with water may be, for example, acetonitrile, dimethylsulfoxide, N,N-dimethylformamide or a (C1-C4) alcohol, preferably acetonitrile, methanol and / or ethanol.

[0036] The starting aqueous solution of the compound of general formula (I) can be obtained by dissolving a previously prepared compound of general formula (I) in water, a buffer solution, and / or a mixture of water and an organic solvent miscible in water.

[0037] At least two different rare earth metals (M 3+ Said starting aqueous solution of ions of is preferably obtained by recycling discarded electronic and electrical equipment (for example by dissolving neodymium magnets in sulfuric or nitric acid or by burning neodymium magnets and then dissolving them in sulfuric, nitric or hydrochloric acid). Another example may be the dissolution of luminescent materials from fluorescent lamps in sulfuric, nitric or hydrochloric acid or in mixtures thereof, or in a mixture of HCl and hydrogen peroxide.

[0038] Preferably, all M in the reaction mixture in step a) 3+ The total molar concentration of the ions is in the range of 0.0001 mol / L to 1 mol / L, more preferably 0.001 mol / L to 0.1 mol / L, and most preferably 0.005 mol / L to 0.05 mol / L.

[0039] In a preferred embodiment, the molar ratio of the sum of rare earth metal ions to said compound of said general formula (I) ranges from 1:0.5 to 1:100.

[0040] b) Mechanical separation of said precipitate or said crystalline phase from said reaction mixture, preferably using precipitation, centrifugation or filtration.

[0041] Methods for separating heterogeneous mixtures containing solid and liquid phases are known to those skilled in the art.

[0042] The result of step b) is M 3+ ion, or M 3+ The solid complexes of rare earth metal cations and the mixture of the compound of general formula (I), which may further undergo optional steps c) and d). The remaining complexes of rare earth metal cations that have not precipitated / crystallized remain dissolved in the reaction mixture / mother liquor / filtrate / supernatant solution from which the solid phase was separated. In summary, the chemical equilibrium of the insoluble complexes is driven by their precipitation / crystallization, while the reaction mixture / mother liquor is enriched by the soluble complexes.

[0043] c) Optionally, redissolving the precipitate or the crystalline phase from step b) in water, in a buffer solution, in a mixture of water and a water-miscible organic solvent, or in an aqueous solution of an inorganic or organic acid (e.g., HCl or trifluoroacetic acid (pH ranging from 0 to 4), preferably an aqueous solution of HCl).

[0044] More preferably, this step may be carried out at a temperature of at least 30° C., even more preferably at a temperature ranging from 40° C. to 100° C. In this step, the solid complex is formed by mixing the free compound of general formula (I) and M 3+ It is redissolved and / or hydrolyzed into cations.

[0045] d) Optionally, adjust the pH of the solution from step c) (e.g., by using aqueous NaOH) to a pH value ranging from 5 to 9 and repeat steps a), b) and optionally c). By repeating the separation cycle, a higher degree of separation of the rare earth metal M can be achieved.

[0046] In one embodiment, the compound of general formula (I) can be separated from the reaction mixture in step c) after dissolving the precipitate or crystalline phase (meaning after hydrolysis of the specific complex). The separation of the compound of general formula (I) can be carried out, for example, using solid phase extraction (SPE) or by chromatography (for example, normal or reverse phase chromatography, ion exchange chromatography) or by sorption on activated carbon. The remaining solution therefore contains only the pure water-soluble salt of the separated rare earth metal cation.

[0047] In one preferred embodiment, the at least two different rare earth elements (M 3+ ) ions contain their water-soluble salts with inorganic or organic acids, preferably selected from the group comprising chloride, bromide, sulfate, nitrate, perchlorate, methanesulfonate, trifluoromethanesulfonate, formate, acetate, lactate, malate, citrate, 2-hydroxyisobutyrate, mandelate, diglycolate and / or tartrate.

[0048] A water-soluble salt is understood to have a water solubility of at least 0.5 g / 100 ml water at 25°C.

[0049] In one aspect of the present invention, additives can be used to improve the separation of rare earth elements, such as carboxylic acids (containing at least one carboxyl group and a (C1-C10) linear or branched hydrocarbon chain and / or a (C6-C10) aryl moiety) containing 1 to 11 carbon atoms, phosphinic acids (containing a (C1-C10) linear or branched hydrocarbon chain and / or a (C6-C10) aryl moiety) containing 1 to 10 carbon atoms, phosphonic acids (containing a (C1-C10) linear or branched hydrocarbon chain and / or a (C6-C10) aryl moiety) containing 1 to 10 carbon atoms, trifluoroacetic acid, 3-chlorobenzoic acid, chloride; dipicolinic acid, fluoride, glycine, glycolate, α-HIBA (α-hydroxyisobutyric acid), lactate, nitrate, phenylboronic acid, picoline. Preferably, the additive is selected from the group comprising acetate, trifluoroacetate, benzoic acid, 3-chlorobenzoic acid, 2-methylbenzoic acid, 3-methylbenzoic acid, 4-methylbenzoic acid, chloride, citrate, dipicolinic acid, fluoride, formate, glycine, glycolate, α-HIBA (α-hydroxyisobutyric acid), lactate, nitrate, phenylboronic acid, picolinic acid, pyridine, mandelic acid, salicylic acid, sulfate, thiocyanate, tributyl phosphate, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide. Preferably, sodium or potassium salts of the additive are used. In case of chiral centers in the molecule, the list of additives also includes optically active isomers, mixtures and racemates thereof.

[0050] It has been observed that the presence of additives increases the solubility of the heavier rare earth metal complexes with the compound of general formula (I), thus precipitating / crystallizing the lighter rare earth metal complexes with the compound of general formula (I) and keeping them in solution at the same time. In other words, the additives generally increase the solubility of the rare earth metal complexes with the compound of general formula (I), but their effect is relative, since they make the heavier rare earth metal complexes with the compound of general formula (I) more soluble. This results in a greater solubility difference between the lighter and heavier rare earth metal complexes. It should be understood that the mass of the complexes increases continuously along the lanthanide series (La to Lu), and therefore the presence of the additives usually increases the solubility of the complexes with the higher proton number rare earth elements more than the solubility of the complexes with the lower proton number rare earth elements. As a result, the efficiency of the separation is significantly improved by using the additives.

[0051] Said aqueous solution of at least one additive (preferably having a pH in the range of 6 to 8, more preferably pH 7) is added to said reaction mixture in step a) of the above separation process.

[0052] In one preferred embodiment, the molar ratio between the sum of rare earth metal ions in the reaction mixture in step a) and the additive ranges from 1:0.1 to 1:100, more preferably from 1:0.5 to 1:50, even more preferably from 1:1 to 1:10.

[0053] The use of said additive in step a) results in a larger and more unexpected increase in the separation factor.

[0054] In one embodiment, after precipitation of the complex (step b)), the additives can be removed from the reaction mixture, preferably using HPLC or ultrafiltration (e.g. using an ultrafiltration system having a membrane for nanofiltration) or ion exchange chromatography.

[0055] The rare earth metal complex present in the reaction mixture / mother liquor / filtrate / supernatant solution from which the solid phase has been separated in step b) may further undergo an optional step e) in which the reaction mixture / mother liquor / filtrate / supernatant solution from step b) is subjected to evaporation and / or ultrafiltration and / or ion exchange chromatography, thereby increasing the concentration of the rare earth metal complex with the compound of general formula (I) in the solution and / or decreasing the concentration of additives, causing the metal complex to precipitate or crystallize.

[0056] The ultrafiltration is preferred because it simultaneously removes the additives from the solution and increases the concentration of the metal complexes, which not only purifies the mixture but also shifts the precipitation equilibrium of the dissolved rare earth metal complexes towards precipitation, resulting in more precipitated / crystallized complexes.

[0057] BRIEF DESCRIPTION OF THE DRAWINGS Figure 1: HPLC chromatograms described in Example 28. From top to bottom: complex [La(L5)], free compound L5 and complex [La(L5)] after partial digestion in TFA.

[0058] [Example] I. Compound Synthesis Structures of commercially available synthetic precursors A and B

[0059] [ka]

[0060] Example 1. Synthesis of 2,2',2''-(10-benzyl-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (L1)

[0061] [ka]

[0062] Starting material B (1.00 g, 1.68 mmol), benzyl bromide (302 mg, 1.76 mmol), anhydrous potassium carbonate (1.16 g, 8.39 mmol) and acetonitrile (50 mL) were mixed in a 100 mL round-bottom flask equipped with a magnetic stir bar. The flask was capped and the mixture was stirred on a magnetic stirrer at room temperature for 48 h. The mixture was then filtered through a glass frit and the filtrate was concentrated by rotary evaporation. The resulting oily compound was purified using preparative HPLC (C18 reverse phase column, acetonitrile / water gradient with 0.1% TFA (trifluoroacetic acid) in the mobile phase). The fractions containing the product in the form of tert-butyl ester were collected, concentrated by rotary evaporation and further dried under high vacuum. The oily product was dissolved in TFA (10 mL) and stirred at room temperature for 24 h. TFA was then removed by rotary evaporation and the residue was purified using preparative HPLC (C18 reverse phase column, acetonitrile / water gradient with 0.1% TFA in the mobile phase). The fractions containing the product were collected, concentrated by rotary evaporation, redissolved in 5 mL water and lyophilized. The final yield was 304 mg of L1 as a white powder (0.507 mmol, 30% yield based on precursor B).

[0063] HRMS(ESI)m / z:[(M+H) + ](C 21 H 33 N4O6) Calculated value: 437.2395, Found value: 437.2392.

[0064] Elemental analysis: M 2.1TFA 1.1H2O; calculated: C(43.5), H(5.3), N(8.1), F(17.2); found: C(43.6), H(5.0), N(7.8), F(17.3).

[0065] Example 2. 2,2'-(4-(2-hydroxy-5-nitrobenzyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid (L2)

[0066] [ka]

[0067] Starting material A (2.00 g, 4.99 mmol) was dissolved in acetonitrile (25 mL). A solution of 2-(bromomethyl)-4-nitrophenol (579 mg, 2.50 mmol) in acetonitrile (100 mL) was slowly added dropwise over 2 h with stirring at room temperature. The reaction was stirred at room temperature for another 24 h. The mixture was then concentrated by rotary evaporation. The resulting oily compound was purified by preparative HPLC (C18 reverse phase column, acetonitrile / water gradient with 0.1% TFA in the mobile phase). Both starting material A and the double alkylation by-product were removed in this step. The fractions containing the product in the form of tert-butyl ester were combined, concentrated by rotary evaporation, and further dried under high vacuum. This oily product was dissolved in TFA (10 mL) and stirred at room temperature for 24 h. TFA was then removed by rotary evaporation and the residue was purified using preparative HPLC (C18 reverse phase column, gradient acetonitrile / water with 0.1% TFA in the mobile phase). Fractions containing the product were collected, concentrated by rotary evaporation, redissolved in 5 mL water and lyophilized. The final yield was 935 mg of L2 as a pale yellow powder (1.32 mmol, 35% yield based on 2-(bromomethyl)-4-nitrophenol).

[0068] HRMS(ESI)m / z:[(M+H) + ](C 19 H 30 N5O7) Calculated value: 440.2140, Found value: 440.2138.

[0069] Elemental analysis: M 2.35 TFA, calculated: C(40.2), H(4.5), N(9.9), F(18.9), found: C(40.3), H(4.5), N(9.7), F(19.2).

[0070] Example 3. Synthesis of 2,2'-(4-(4-carboxybenzyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid (L3)

[0071] [ka]

[0072] Starting material A (2 g, 4.99 mmol) was dissolved in acetonitrile (25 mL). A solution (100 mL) of 4-(bromomethyl)benzoate (614 mg, 2.85 mmol) in acetonitrile was slowly added dropwise over 2 h with stirring at room temperature. The reaction was stirred at room temperature for another 24 h. The mixture was then concentrated by rotary evaporation. The resulting oily compound was purified by preparative HPLC (C18 reverse phase column, acetonitrile / water gradient with 0.1% TFA in the mobile phase). Both starting material A and the double alkylation by-product were removed in this step. The fractions containing the product in the form of tert-butyl ester were collected and concentrated by rotary evaporation. The resulting oil was dissolved in methanol (25 mL). Lithium hydroxide monohydrate (290 mg, 6.91 mmol) was dissolved in water (25 mL) and added to the reaction mixture. The reaction mixture was stirred at room temperature for 4 h. The reaction was then quenched by the addition of TFA (787 mg, 6.91 mmol) and concentrated by rotary evaporation. The resulting oil was purified by preparative HPLC (C18 reverse phase column, gradient acetonitrile / water with 0.1% TFA in the mobile phase). Fractions containing the partially protected product (2x tert-butyl ester, 1x free carboxylic acid on the benzyl group) were collected and concentrated by rotary evaporation. The resulting oil was dissolved in TFA (15 mL) and stirred at room temperature for 24 h. TFA was then removed by rotary evaporation and the product was purified using preparative HPLC (C18 reverse phase column, gradient acetonitrile / water with 0.1% TFA in the mobile phase). Fractions containing the product were collected, concentrated by rotary evaporation, redissolved in 5 mL water and lyophilized. The final yield was 359 mg of L3 as a white powder (0.495 mmol, 17% yield based on 2-(bromomethyl)-benzoate).

[0073] HRMS(ESI)m / z:[(M+H) + ](C 20 H 31 N4O6) Calculated value: 423.2238, Measured value: 423.2237.

[0074] Elemental analysis: M 2.65 TFA, calculated: C(41.9), H(4.5), N(7.7), F(20.8), found: C(42.0), H(4.5), N(7.7), F(21.2).

[0075] Example 4. Synthesis of 2,2',2''-(10-(naphthalen-2-ylmethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (L4)

[0076] [ka]

[0077] Following the procedure of Example 1), compound B (250 mg, 0.420 mmol), 2-(bromomethyl)naphthalene (97.4 mg, 0.441 mmol), anhydrous potassium carbonate (290 mg, 2.099 mmol), and acetonitrile (15 mL) were mixed and reacted similarly to the procedure described for Example 1. The final yield was 181.4 mg of L4 as a white powder (0.255 mmol, 61% yield (based on precursor B)).

[0078] HRMS(ESI)m / z:[(M+H) + ](C 25 H 35 N4O6) Calculated value: 487.2551, Measured value: 487.2549.

[0079] Elemental analysis: M 1.8 TFA 1.0 H2O; calculated: C(48.4), H(5.4), N(7.9), F(14.4); found: C(48.2), H(5.2), N(8.1), F(14.7).

[0080] Example 5. Synthesis of 2,2',2''-(10-(naphthalen-1-ylmethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (L5)

[0081] [ka]

[0082] Following the procedure of Example 1), compound B (250 mg, 0.420 mmol), 1-(bromomethyl)naphthalene (97.4 mg, 0.441 mmol), anhydrous potassium carbonate (290 mg, 2.099 mmol), and acetonitrile (15 mL) were mixed and reacted in a similar manner to the procedure described for Example 1). The final yield was 202.3 mg of L5 as a white powder (0.285 mmol, 68% yield (based on precursor B)).

[0083] HRMS(ESI)m / z:[(M+H) + ](C 25 H 35 N4O6) Calculated value: 487.2551, Found value: 487.2553.

[0084] Elemental analysis: M 1.75TFA 1.3H2O; calculated: C(48.3), H(5.5), N(7.9), F(14.1); found: C(48.2), H(5.2), N(8.0), F(14.0).

[0085] Example 6. Synthesis of 2,2',2''-(10-([1,1'-biphenyl]-4-ylmethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (L6)

[0086] [ka]

[0087] According to the procedure of Example 1), compound B (300 mg, 0.50 mmol), 4-bromomethylbiphenyl (247.1 mg, 0.530 mmol), anhydrous potassium carbonate (348 mg, 2.52 mmol), and acetonitrile (18 mL) were mixed and reacted similarly to the procedure described for Example 1). The final yield was 285.2 mg of L6 as a white powder (0.385 mmol, 76% yield (based on precursor B)).

[0088] HRMS(ESI)m / z:[(M+H) + ](C 27 H 37 N4O6) Calculated value: 513.2713, Measured value: 513.2710.

[0089] Elemental analysis: M 1.8TFA 1.25H2O; calculated: C(49.7), H(5.5), N(7.6), F(13.9); found: C(49.9), H(5.1), N(7.3), F(13.5).

[0090] II. Separation of rare earth elements by precipitation from solution Example 7. Separation of a binary mixture of rare earth metals by precipitation from solution using L1.

[0091] The following stock solutions were pipetted into a 96-well plate: 1.5 μL of 100 mM rare earth chloride solution (M1) 2.5 μL of 100 mM aqueous solution of rare earth chloride salt 2 (M1) 3. 10 μL of a 100 mM solution of compound L1 in water.

[0092] 4. 20 μL of 3M MOPS (3-(N-morpholino)propanesulfonic acid) buffer pH=7.

[0093] 5. 50 μL water.

[0094] Two series of reaction mixtures were prepared. In one the rare earth metal was kept constant (Gd or Lu) and in the other the rare earth metal element was variable (except Pm). To each well of the plate, a glass ball with a diameter of 2 mm was added for mechanical stirring. The well plate was sealed with transparent adhesive tape to prevent evaporation and fixed on a shaker. The well plate was shaken at 900 rpm at room temperature for 5 days. The well plate was then centrifuged and 50 μL of supernatant was taken from each well for the determination of the metal concentration by ICP-OES (Inductively Coupled Plasma-Atomic Emission Spectroscopy). The absolute concentrations of both metals in the resulting supernatants and their ratios are summarized in Table 1. Values ​​of the M1 / M2 ratio greater than 1.0 or less than 1.0 indicate, respectively, the enrichment or removal of M1 relative to M2 in the solution and thus the degree of separation of the rare earths.

[0095] [Table 1]

[0096] Example 8. Separation of a binary mixture of rare earth metals by precipitation from solution using L1.

[0097] Similar to Example 7), two sets of reaction mixtures were prepared in 96-well plates with the following differences: the stock solution of 3M MOPS buffer had a pH of 8.5, a set of constant metals was either Er or Tm, each well plate slot was equipped with one PTFE-coated magnetic stir bar, the well plate was sealed with a silicon cover, and the reaction mixtures were stirred on a magnetic stirrer at room temperature for 2 days. The well plates were then centrifuged and the concentrations of the metals were determined using ICP-OES, similar to Example 7).

[0098] The concentrations of both metals and their ratios in the obtained supernatant are summarized in Table 2. Values ​​of M1 / M2 ratios greater than 1.0 or less than 1.0 indicate, respectively, the enrichment or removal of M1 relative to M2 in the solution and thus the degree of separation of the rare earths. It is clear from these results that some degree of separation is achieved even for mixtures of adjacent lanthanides (combinations Tm / Er and Er / Tm).

[0099] [Table 2]

[0100] Example 9. Separation of binary mixtures of rare earth metals by precipitation from solution using L6 A series of reaction mixtures were prepared by pipetting the following stock solutions into 2 mL plastic Eppendorf vials: 1.5 μL of 100 mM rare earth chloride solution (M1) 2.5 μL of 100 mM NdCl3 in water.

[0101] 3. 10 μL of a 100 mM solution of compound L1 in water.

[0102] 4. 20 μL of 3M MOPS (3-(N-morpholino)propanesulfonic acid) buffer pH=7.

[0103] 5. 50 μL water.

[0104] A PTFE-coated magnetic stir bar was added to each vial, and the vials were closed and stirred at 750 rpm at room temperature. After 18 hours, the stir bars were removed from the vials and the Eppendorf vials were centrifuged to separate the supernatant from the precipitate. An aliquot of 80 μL of the supernatant was removed from each vial and diluted by the addition of 40 μL of 1 M HCl and then analyzed by ICP-OES to determine the rare earth content in each solution. The measured concentrations were adjusted to reflect the concentration of each rare earth metal in the supernatant before dilution, as well as the M1 / Nd ratios, reported in Table 3.

[0105] [Table 3]

[0106] Example 10. Separation of selected industrially relevant binary mixtures of rare earth metals by precipitation from solution with L1, L2 and L3.

[0107] As in Example 7), three sets of reaction mixtures of two metals with either compound L1, L2, or L3 were prepared in a 96-well plate with the following differences: each well was equipped with one PTFE-coated magnetic stir bar, the well plate was sealed with a silicon cover, and the reaction mixture was stirred on a magnetic stirrer at room temperature for two days. Then, as in Example 7), the well plate was centrifuged and the concentration of the metals was determined using ICP-OES. The absolute concentrations of both metals and their ratios in the resulting supernatant are summarized in Table 4. Values ​​of the M1 / M2 ratio greater than 1.0 or less than 1.0 indicate, respectively, the enrichment or removal of M1 relative to M2 in the solution, and thus the degree of separation of the rare earths. From these results, it is clear that some enrichment is achieved for very different combinations of metals, and that the ligands L1, L2, and L3 have different selectivities for a given combination of metals.

[0108] [Table 4]

[0109] Example 11. Separation of Ho / Er mixtures by repeated precipitation from solution with compound L1.

[0110] The stock solutions were pipetted into round-bottom 2 mL Eppendorf tubes as follows: 1. 10 μL of 100 mM HoCl3 in water 2. 10 μL of 100 mM ErCl3 in water 3. 20 μL of a 100 mM solution of compound L1 in water.

[0111] 4. 60 μL of 2M MOPS buffer pH=7.

[0112] 5.140 μL water.

[0113] Nine identical reaction mixtures were prepared and divided into three groups, namely A, B, and C. Each tube was equipped with one PTFE-coated magnetic stir bar, sealed, and the mixtures were stirred on a magnetic stirrer at room temperature for 24 h. The tubes were then centrifuged, and the supernatants were carefully pipetted out and transferred to a new set of tubes. The precipitates from group A were dissolved by the addition of 200 μL of 0.1 M HCl. The concentrations of Ho and Er in the supernatants and redissolved precipitates from group A were determined by ICP-OES. The precipitates from groups B and C were further treated as follows: the precipitates were dissolved by the addition of 100 μL of 0.1 M HCl, and then the pH of the solution was raised from 1 to 7 by the addition of an equimolar amount of 0.2 M NaOH. The total volume was adjusted to 200 μL by adding water. The prepared mixtures were subjected to a second precipitation and stirred on a magnetic stirrer at room temperature for 24 h. The tubes were centrifuged again, and the supernatant was carefully pipetted out and transferred to a new set of tubes. Samples from group B were treated in the same way as the samples from group A described above, and the contents of Ho and Er in the supernatant and precipitate were determined by ICP-OES. The precipitates from group C were subjected to a third precipitation cycle similar to the procedure described above, and the contents of Ho and Er were subsequently determined. The absolute concentrations of both metals in the resulting supernatants and precipitates, as well as the values ​​of the separation factor Er / Ho, calculated according to the formula (concentration of Er in the supernatant / concentration of Er in the precipitate) / (concentration of Ho in the supernatant / concentration of Ho in the precipitate), are summarized in Table 5. The results show several important conclusions: 1-The examples of Ho and Er show that the separation method can also be used for adjacent lanthanides; 2-The precipitation can be repeated to obtain a higher degree of enrichment of one component; 3-The triplicate samples show good reproducibility of the process. The average separation factor value from all Er / Ho mixtures is 2.73, and is therefore comparable to or better than extractants used in industrial liquid-liquid extraction, where the separation factor value for two adjacent lanthanides is about 2.5 (see Xie, F. et al (2014), Miner. Eng. 56, 10-28).

[0114] [Table 5]

[0115] Example 12. Separation of Ho / Er mixtures by precipitation with compound L1 and repeated heating and dissolution of the precipitate.

[0116] The experiment was carried out according to Example 11). The difference was that instead of dissolving the precipitate in acid and neutralizing it by adding a base, 200 μL of water was added to the precipitate and the suspension was stirred at 80 ° C for 24 hours. During this treatment, complete dissolution of the precipitate was not achieved, but a saturated solution was formed. After cooling to room temperature, the mixture was treated as if precipitation had normally occurred. The absolute concentrations of the metals in both the supernatant and the precipitate obtained, as well as the calculated values ​​of the separation factor Er / Ho according to the formula described in Example 11), are summarized in Table 6. The data can be directly compared with the data from Table 5, proving that partial dissolution of the precipitate has the same effect as repeated precipitation by the method of complete dissolution of the precipitate in acid followed by neutralization. The repetition of the cycle in this experiment also led to a higher concentration of one of the rare earth elements. The average separation factor value was 2.97.

[0117] [Table 6]

[0118] Example 13. Separation of Gd / Lu mixtures by repeated precipitation from solution with compound L1.

[0119] Stock solutions were pipetted into round-bottom 2 mL Eppendorf tubes as follows: 1. 10 μL of 100 mM GdCl3 in water 2. 10 μL of 100 mM LuCl3 in water 3. 20 μL of a 100 mM solution of compound L1 in water.

[0120] 4.33.3 μL of 3M MOPS buffer pH=7.

[0121] 5.127.6 μL of water.

[0122] Nine identical reaction mixtures were prepared and divided into three groups, A, B, and C. Each tube was equipped with one PTFE-coated magnetic stir bar, sealed, and the mixtures were stirred on a magnetic stirrer for 24 h at room temperature. The tubes were then centrifuged, and the supernatant was carefully pipetted out and transferred to a new set of tubes. The precipitate from group A was dissolved by adding 100 μL of 1 M HCl at room temperature for 30 min, and then diluted to 200 μL by adding 100 μL of water. The concentrations of Gd and Lu in the supernatant and in the redissolved precipitate from group A were determined by ICP-OES. The precipitates from groups B and C were further treated as follows: the precipitates were dissolved by adding 100 μL of 1 M HCl at pH 0 at room temperature for 30 min. The pH was then adjusted to about 7 by adding 50 μL of 2 M NaOH, and the total volume was adjusted to 200 μL by adding water. The prepared mixture was subjected to a second precipitation and stirred on a magnetic stirrer for 24 hours at room temperature. The tubes were then centrifuged again and the supernatant was carefully pipetted out and transferred to a new set of tubes. The samples from group B were treated the same as the samples from group A above, and the contents of Gd and Lu in the supernatant and precipitate were determined by ICP-OES. The precipitates from group C were subjected to a third cycle of precipitation, followed by the determination of the contents of Gd and Lu as in the procedure above. The absolute concentrations of both metals in the obtained supernatants and precipitates, as well as the calculated values ​​of the separation factor Lu / Gd according to the formula from Example 11) are summarized in Table 7. The average separation factor value was 43.7.

[0123] [Table 7]

[0124] Example 14. Separation of Y / Tb mixtures by repeated precipitation from solution with compound L2.

[0125] According to Example 11), an experiment was carried out with nine identical reaction mixtures containing Y, Tb and compound L2. The experimental procedure was identical to that of Example 11. The absolute concentrations of the metals in both the supernatant and the precipitate obtained, as well as the calculated values ​​of the separation factor Y / Tb according to the formula from Example 11), are summarized in Table 8. The average separation factor value was 3.34.

[0126] [Table 8]

[0127] Example 15. Separation of Eu / Yb mixtures by precipitation from solution using compound L5.

[0128] Stock solutions were pipetted into round-bottom 2 mL Eppendorf tubes as follows: 1.15 μL of 100 mM EuCl3 in water 2. 10 μL of 100 mM YbCl3 in water 3. 30 μL of a 100 mM solution of compound L5 in water.

[0129] 4. 90 μL of 0.5 M MOPS buffer pH=7.

[0130] Three identical reaction mixtures were prepared. Each tube was equipped with one PTFE-coated magnetic stir bar, sealed, and the mixture was stirred on a magnetic stirrer for 24 hours at room temperature. The tubes were then centrifuged, and the supernatant was carefully pipetted out and transferred to a new set of tubes. 100 μL of 1M HCl (to reach pH=0) was added to the precipitate, and the mixture was stirred until complete dissolution (overnight at room temperature, pH=0). The total volume of the solution was adjusted to 150 μL volume by addition of water. The supernatant was treated with 1M HCl to a total volume of 150 μL, pH=0.5. The concentrations of Eu and Yb in the supernatant and in the redissolved precipitate were determined by ICP-OES. The absolute concentrations of both metals in the resulting supernatant and precipitate, as well as the calculated separation factor Yb / Eu according to the formula from Example 11) are summarized in Table 9. The triplicate samples show good reproducibility of the process. The average separation factor value was 152.

[0131] [Table 9]

[0132] Example 16. Separation of Tb / Lu mixtures by precipitation from solution with compound L4.

[0133] The experiment was carried out according to Example 24 using three identical reaction mixtures containing Tb, Lu and compound L4. The experimental procedure was identical to that of Example 24, with the difference that dissolution of the precipitate in 100 μL of 1 M HCL was achieved within a few minutes. The absolute concentrations of the metals in both the resulting supernatant and precipitate, as well as the calculated separation factor Yb / Eu according to the formula from Example 11) are summarized in Table 10. The triplicate samples show good reproducibility of the process. The average separation factor value was 27.

[0134] [Table 10]

[0135] Example 17. Separation of Eu / Yb mixtures by precipitation from water / acetonitrile solutions using compound L5.

[0136] Three reaction mixtures with different acetonitrile contents (group A = 10%, group B = 20%, group C = 50%) were prepared in duplicate plastic round-bottom 2 mL Eppendorf tubes, respectively.

[0137] For group A, stock solutions were pipetted as follows: 5 μL of 100 mM EuCl3 in water; 5 μL of 100 mM YbCl3 in water; 10 μL of 100 mM compound L5 in water; 20 μL of 3 M MOPS buffer pH=7; 50 μL of water; 10 μL of acetonitrile.

[0138] For group B, stock solutions were pipetted as follows: 5 μL of 100 mM EuCl3 in water; 5 μL of 100 mM YbCl3 in water; 10 μL of 100 mM compound L5 in water; 20 μL of 3 M MOPS buffer pH=7; 40 μL of water; 20 μL of acetonitrile.

[0139] For group C, stock solutions were pipetted as follows: 5 μL of 100 mM EuCl3 in water; 5 μL of 100 mM YbCl3 in water; 10 μL of 100 mM compound L5 in water; 20 μL of 3 M MOPS buffer pH=7; 10 μL of water; 50 μL of acetonitrile.

[0140] Each tube was equipped with one PTFE-coated magnetic stir bar, sealed, and the mixture was stirred on a magnetic stirrer for 24 hours at room temperature. The tubes were then centrifuged, and the supernatant was carefully pipetted out and transferred to a new set of tubes. 100 μL of 1 M HCl was added to the precipitate, and the mixture was stirred until complete dissolution (overnight at room temperature, pH=0). The concentrations of Eu and Yb in the supernatant and in the redissolved precipitate were determined by ICP-OES. The absolute concentrations of both metals in the resulting supernatant and precipitate, as well as the calculated separation factor Yb / Eu according to the formula from Example 11) are summarized in Table 11. The results showed that separation by means of precipitation can be achieved even in mixtures of water and water-miscible organic solvents.

[0141] [Table 11]

[0142] Example 18. Use of additives to improve separation of ND / Dy mixtures by precipitation from solution with compound L5 The stock solutions were pipetted into plastic 1 x 1 cm cuvettes and reaction mixtures were prepared with the following concentrations: 1.11mM Chelator L5 2.5mM NdCl3 3.5mM DyCl3 4.500mM MOPS pH=7 5. The additive of interest was prepared in variable concentrations; where possible, stock solutions were prepared using NaCl solutions of the compound. + Prepared from salt form; if not, stock solutions were titrated to pH=7 with NaOH / HCl prior to addition (see Table 12 for additives and concentrations) These aqueous reaction mixtures were each brought to a total volume of 2.0 mL, with water added as necessary, and mixed by using a PTFE-coated stir bar on a magnetic stirrer. The cuvettes were sealed with clear tape to prevent evaporation overnight. The reaction mixtures were stirred for 18 h, at which point a 500 μL aliquot of each reaction mixture was transferred to a plastic 2 mL Eppendorf tube and centrifuged. The supernatants were carefully pipetted out and transferred to a new set of tubes. The precipitates were dissolved by the addition of 500 μL of 1 M HCl. The absolute concentrations of Nd and Dy in each supernatant and precipitate were determined by ICP-OES.

[0143] The absolute concentrations of the metals in both the resulting supernatant and precipitate, as well as the calculated separation factor Dy / Nd according to the formula from Example 11), are summarized in Table 12. When the supernatant Nd and Dy concentrations were recorded as 5 mM and the precipitate concentration was recorded as 0 mM, no precipitation was observed and therefore no separation was achieved by these conditions.

[0144] [Table 12] JPEG0007606607000022.jpg221169

[0145] Example 19. Separation of Nd / Pr mixtures by repeated precipitation from solution using compound L5 and α-HIBA The stock solutions were pipetted into 4 mL glass vials and reaction mixtures were prepared with the following concentrations: 1.11 mM (1.1 equivalents) chelator L5 2.5mM (0.5eq)PrCl3 3.5mM (0.5 equivalent) NdCl3 4.20mM (4 equivalents) α-HIBA pH=6.5 5.500mM (50 equivalents) MOPS pH=7 Three aqueous reaction mixtures (numbers 1–3) were prepared in a total volume of 2 mL each and treated identically throughout the process. A PTFE-coated magnetic stir bar was added to each, and the reaction mixtures were stirred overnight at room temperature on a magnetic stirrer. After 18 h, 200 μL aliquots of the resulting suspension were taken from each vial and labeled as A1, A2, or A3, according to the reaction mixture number taken. The aliquots were then centrifuged in plastic Eppendorf centrifuge tubes. The supernatants were carefully pipetted from each and transferred to a new set of tubes. 200 μL of 1 M HCl was added to the precipitates, and the mixtures were stirred until completely dissolved (approximately 1 h at room temperature). The Nd and Pr contents of these precipitate and supernatant samples were determined by ICP-OES. The remaining 1800 μL reaction mixture was centrifuged in plastic Eppendorf centrifuge vials, and the supernatants were set aside. A sample of the supernatant was analyzed by HPLC-MS and the peak areas were compared to those of a standard 10 mM chelate solution; this allowed the calculation of the approximate concentration of chelate remaining in solution and therefore the amount of chelate precipitated. The total volume of the subsequent reaction was scaled according to this information, even though the net amount of chelate present was reduced so that the concentration of chelate in solution prior to precipitation was 10 mM. The precipitate was then dissolved by the addition of 25 molar equivalents of 1 M HCl and transferred to a clean 4 mL glass vial with a PTFE-coated magnetic stir bar. Four molar equivalents of α-HIBA were added to this vial, followed by 50 molar equivalents of 3 M MOPS pH=7, the calculated volume of water required, and 25 molar equivalents of 2 M NaOH to complete the neutralization of the reaction mixture. (Here, the final reaction volume was not as important as the final reaction concentration.) The reaction mixture was again stirred overnight at room temperature on a magnetic stirrer. After 18 h, the resulting suspension was treated in the same way as before, with 200 μL aliquots (labeled as B1, B2, B3) taken for ICP-OES determination of the Nd and Pr contents of the precipitate and the supernatant. The remaining 1600 μL reaction mixture was centrifuged and the supernatant was analyzed by HPLC-MS; the precipitate was treated as before to again obtain a reaction solution with an initial concentration of 10 mM chelate.For the third replicate treatment, the reaction mixture was stirred overnight and 200 μL aliquots (C1, C2, C3) were processed again after 18 h for ICP-OES determination of Nd and Pr contents in the precipitate and in the supernatant.

[0146] The absolute concentrations of the metals in both the supernatant and the precipitate obtained, as well as the calculated separation factor Nd / Pr according to the formula from Example 11), are summarized in Table 13. The triplicate samples show good reproducibility of the process. The average separation factor was 1.69.

[0147] [Table 13]

[0148] Example 20. Separation of Tb / Dy mixtures by repeated precipitation from solution using compound L5 and α-HIBA Three reaction mixtures were prepared according to Example 19 with the following changes: the rare earth elements were Tb and Dy, and 0.5 molar equivalents (5 mM reaction concentration) of α-HIBA was used. Otherwise, the experiment was carried out in the same manner as in Example 19.

[0149] The absolute concentrations of the metals in both the supernatant and the precipitate obtained, as well as the calculated separation factor Dy / Tb according to the formula from Example 11), are summarized in Table 14. The triplicate samples show good reproducibility of the process. The average separation factor was 2.32.

[0150] [Table 14]

[0151] Example 21. Separation of Nd / Pr / Tb / Dy mixtures by precipitation from solution using compound L5 The stock solutions were pipetted into 4 mL glass vials and reaction mixtures were prepared with the following concentrations: 1.38.5 mM (1.1 equivalents) chelator L5 Total LnCl content of 2.35 mM (1 equivalent) (from a stock solution containing Ln = a mixture of Nd, Pr, Tb, and Dy in a ratio of 3.3:1:1:1, Nd:Pr:Tb:Dy) 3.1750mM (50 equivalents) MOPS pH=7 The total reaction volume was 3.2 mL. A PTFE-coated stir bar was added to the vial, the vial was capped and stirred with an aluminum heating block on a magnetic stirrer at a temperature maintained at 40 °C. After 20 h, a 500 μL aliquot of the reaction mixture was removed from the vial. This was centrifuged in a 2 mL plastic Eppendorf centrifuge vial and the supernatant was carefully pipetted from this and transferred to a new set of tubes. The precipitate was dissolved by the addition of 500 μL of 1 M HCl and the absolute concentrations of Nd, Pr, Tb, and Dy in both the supernatant and precipitate were determined by ICP-OES.

[0152] The absolute concentrations of the four metals in the resulting supernatant and precipitate are summarized in Table 15. The mole percent composition of each phase is also provided, indicating minimal selectivity in precipitation under these conditions.

[0153] [Table 15]

[0154] Example 22. Separation of Nd / Pr / Tb / Dy mixtures by precipitation from solution using compound L5 and acetate The reaction mixture was prepared according to Example 21), with the difference being that sodium acetate buffer pH=5.8 was used instead of MOPS pH=7, an additional aliquot was taken for analysis after 2 days, and the precipitate portion of the solution was not subjected to ICP-OES analysis - only the supernatant was analyzed. Otherwise, the reaction was carried out as in Example 21).

[0155] The resulting absolute concentrations of the four metals in the supernatant are summarized in Table 16. The mole percent compositions of each are also provided, demonstrating the improved selectivity in precipitation under these conditions compared to Example 21).

[0156] [Table 16]

[0157] Example 23. Separation of Nd / Pr / Tb / Dy mixtures by precipitation from solution using compound L5 and α-HIBA The stock solutions were pipetted into plastic 1 x 1 cm cuvettes and reaction mixtures were prepared with the following concentrations: 1.16.7 mM (1.1 equiv.) chelator L5 Total LnCl content of 2.15 mM (1 equivalent) (from a stock solution containing Ln = a mixture of Nd, Pr, Tb, and Dy in a ratio of 3.3:1:1:1, Nd:Pr:Tb:Dy) 3.15mM (1 equivalent) α-HIBA (α-hydroxyisobutyric acid) 4.760mM (50 equivalents) MOPS pH=7 These aqueous reaction mixtures were each brought to a total volume of 1.5 mL, with water added as necessary, and mixed using a PTFE-coated stir bar on a magnetic stirrer. The cuvettes were sealed with clear tape to prevent evaporation overnight. The reaction mixtures were stirred for 18 h, at which point 500 μL aliquots of each reaction mixture were transferred to plastic 2 mL Eppendorf tubes and centrifuged. The supernatants were carefully pipetted out and transferred to a new set of tubes. The precipitates were dissolved by the addition of 500 μL of 1 M HCl. The absolute concentrations of the four metals in each supernatant and precipitate were determined by ICP-OES.

[0158] The absolute concentrations of the four metals in the resulting supernatant and precipitate, as well as the % composition of each phase, are summarized in Table 17. The improved selectivity of the method over Example 21) is demonstrated. Triplicate samples show good reproducibility.

[0159] [Table 17]

[0160] Example 24. Separation of Nd / Pr / Tb / Dy mixtures by repeated precipitation from solution using compound L5 and α-HIBA Reaction mixtures were prepared by pipetting the following aqueous stock solutions into 20 mL glass vials: 1.476 μL of 246 mM aqueous solution of chelator L5 2.606 μL of 175.5 mM LnCl3 in water (from a stock solution containing Ln = a mixture of Nd, Pr, Tb, and Dy in a ratio of 3.3:1:1:1, Nd:Pr:Tb:Dy) 3.41.6μL of 2560mM α-HIBA aqueous solution pH=6.5 4.4103 μL of water 5.1733 μL of 3.0 M MOPS pH=7 The total reaction volume was 7.0 mL. Three identical reaction mixtures were prepared. A PTFE-coated stir bar was added to each vial; the vials were capped and stirred at room temperature on a magnetic stirrer. After 18 hours, a 200 μL aliquot of the reaction mixture was taken from each vial. This was centrifuged in 2 mL plastic Eppendorf centrifuge tubes, and the supernatant was carefully pipetted from the sample and transferred to a new set of tubes. The precipitates were dissolved by the addition of 200 μL of 1 M HCl, and the absolute concentrations of each of the four lanthanides (Nd, Pr, Tb, and Dy) in each sample of supernatant and precipitate were determined by ICP-OES. The remaining reaction mixture from each vial was centrifuged individually in 15 mL plastic centrifuge tubes, and the precipitates were separated from the supernatant. The supernatant was discarded. Each precipitate was dissolved by adding 2 mL of 1 M HCl and heating to 80° C. for 1 hour. After dissolution, the acidic solutions were transferred to clean 20 mL glass vials each containing one PTFE-coated magnetic stir bar. To each solution, 2037 μL of water, 40.4 μL of 2560 mM α-HIBA aqueous solution pH=6.5, 1723 μL of 3 M MOPS aqueous solution pH=7, and 1000 μL of 2 M NaOH were added in sequence. The solutions were capped and stirred at room temperature on a magnetic stirrer. After 18 hours, 200 μL aliquots of the reaction mixture were again taken from each and processed for ICP-OES analysis as before. Again, the remaining reaction mixtures from each vial were individually centrifuged in 15 mL plastic centrifuge tubes to separate the precipitate from the supernatant. The supernatant was discarded. Each precipitate was dissolved by adding 1 mL of 1 M HCl and heating to 80° C. for 1 hour. After dissolution, the acidic solutions were transferred to clean 20 mL glass vials each containing one PTFE-coated magnetic stir bar. To each solution was added, in sequence, 3376 μL of water, 51.6 μL of 2560 mM α-HIBA aqueous solution pH=6.5, 1672 μL of 3 M MOPS aqueous solution pH=7, and 500 μL of 2 M NaOH. The solutions were capped and stirred at room temperature on a magnetic stirrer. After 18 hours, a final 200 μL aliquot of the reaction mixture was again taken from each vial and processed for ICP-OES analysis as before.

[0161] The absolute concentrations of the four metals in the resulting supernatants are summarized in Table 18. Triplicate samples show good reproducibility of the process.

[0162] [Table 18]

[0163] III. Isolation of components after separation by precipitation Example 25. Removal of additives from retentate after precipitation by ultrafiltration The stock solutions were pipetted into 20 mL glass vials and reaction mixtures were prepared with the following concentrations: 1.16.7mM Chelator L5 2.15.2 mM total LnCl content (from a stock solution containing Ln = a mixture of Nd, Pr, Tb, and Dy in a ratio of 3.3:1:1:1, Nd:Pr:Tb:Dy) 3. Variable concentration of additives The reaction solution was then titrated to pH 6.5 by the addition of aqueous NaOH (2M). The solution was stirred on a magnetic stirrer plate for 2 hours at room temperature, at which point the precipitate was separated from the solution by filtration through a 0.45 μm regenerated cellulose syringe filter. A sample of this solution was taken for HPLC analysis. The solution was then filtered in an ultrafiltration system with a nanofiltration membrane with a molecular weight cut-off of 100-250 Da (NFS membrane, Synder Filtration, CA, USA), 4 bar of N2 to pressurize the system, magnetic stirring, and continuous water addition to replace the filtered volume. The filtrate was collected in 1.5 mL fractions, and the chelates and additives present in these fractions were quantified by HPLC-DAD and compared to measurements of samples taken from the solution before ultrafiltration. The concentration of each component (chelate and additive) that passed through the ultrafiltration membrane (after taking into account the difference in dilution factor in preparing the samples for HPLC analysis) was taken as a percentage and calculated as the ratio of the peak area in the filtrate sample to the peak area in the initial solution. Table 19 summarizes these results for each additive used.

[0164] For samples with benzoic acid as an additive, the HPLC method was a gradient of 5% to 100% MeCN / HO (aqueous phase 0.01% HCOOH; 1 min equilibration period, 4 min gradient to 100% MeCN, 1 min wash, 0.5 min gradient to 5% MeCN, and 3.5 min re-equilibration period) on a Luna Omega Polar C18 column (150 × 4.6 mm, 5 μm); flow rate 1.0 mL / min; detection by diode array detector. For samples containing α-hydroxyisobutyric acid or acetic acid as additives, the HPLC method was: 5% to 50% MeCN / HO (aqueous phase 0.01 M phosphate buffer, pH = 2.5; 1 min equilibration period, 2 min gradient to 50% MeCN, 0.5 min gradient to 5% MeCN, and 1.5 min re-equilibration period); Phenomenex Kinetex C18 column (100 × 3 mm, 2.6 μm); flow rate 0.6 mL / min; detection by diode array detector. Peak areas of α-hydroxyisobutyric acid and acetic acid were integrated at 210 nm, and peak areas of lanthanide chelates and benzoic acid were integrated at 280 nm.

[0165] [Table 19]

[0166] Example 26. Use of ultrafiltration to remove benzoic acid from solution and precipitate the L5 complex from solution The stock solution was pipetted into a 20 mL glass vial and the reaction mixture was prepared: 1.938 μL of 196 mM chelator L5 in water (pH=4) 2.836 μL of 1000 mM benzoic acid in water (stock solution containing 1 equivalent of NaOH) 3. 8000 μL HO 4.952 μL of 175.5 mM LnCl3 in water (from a stock solution containing Ln = a mixture of Nd, Pr, Tb, and Dy in a ratio of 3.3:1:1:1, Nd:Pr:Tb:Dy) The reaction solution was then titrated to pH 6.5 by the addition of 2 M aqueous NaOH. The solution was stirred on a magnetic stir plate at room temperature for 1 h, and the precipitate was removed from the solution by filtration through a 0.45 μm regenerated cellulose syringe filter. From this filtered solution, 1 mL was reserved for elemental analysis as the "initial" solution, 1 mL was reserved as the "control" solution in a clean 4 mL glass vial with a PTFE-coated stir bar, stirred at 600 rpm at room temperature on a magnetic stirrer, and the remaining 9 mL was slightly diluted by the addition of 2 mL of H2O. The solution was then filtered in an ultrafiltration system with nanofiltration membranes with a molecular weight cut-off of 100-250 Da (NFS membranes, Synder Filtration, CA, USA), 4 bar of N2 to pressurize the system, magnetic stirring at 250 rpm, as well as continuous addition of water to replace the filtered volume. The filtrate was collected in an Erlenmeyer flask, and a total volume of 50 mL was filtered over 11 h. After this time, the "retained" reaction mixture, now having a volume of 10.5 mL and with some precipitate present, was transferred to a clean 20 mL glass vial and stirred with a PTFE-coated stir bar at 600 rpm on a magnetic stirrer for an additional 10 hours, similar to the control solution. After this additional time, samples of both the control and retained solutions from the ultrafiltration were prepared for elemental analysis by filtration through 0.45 μm nylon syringe filters. The initial, control, and retained solutions were then analyzed by ICP-OES for determination of absolute Nd, Pr, Dy, and Tb content.

[0167] The absolute Ln content of the samples is shown below: Table 20. The measured content of the control sample was not significantly different from the initial solution, indicating that no precipitation occurred during the additional reaction time for the control sample. However, the content of the retained sample was significantly lower than the initial and control samples, and the difference is greater than can be explained by the change in volume that occurred during the ultrafiltration process. Thus, these results show that by using ultrafiltration to remove additives from the reaction solution, soluble complexes can be precipitated without the use of energy-intensive evaporation methods.

[0168] [Table 20]

[0169] Example 27. Dissociation of the [La(L5)] complex in an acidic environment and the free ion La 3+ Isolation of free compound L5 from

[0170] Compound L5 and La 3+ A solution with complexes with ions was prepared by mixing the following solutions in a 2 mL round-bottom Eppendorf tube: 1. 10 μL of 100 mM LaCl3 in water.

[0171] 2. 10 μl of a 100 mM solution of compound L5 in water.

[0172] 3. 100 μL of 0.5 M MOPS buffer pH=7.

[0173] 4.880 μL water.

[0174] The reaction mixture was mixed thoroughly and left at room temperature for 10 minutes. Two 200 μL samples were then taken. One was directly analyzed by HPLC-MS (High Performance Liquid Chromatography-Mass Spectrometry). The second was acidified with 1 μL of TFA, mixed thoroughly and equilibrated at room temperature for 30 minutes (pH of the mixture was 3). The acidified sample was then analyzed by HPLC-MS. A third sample was prepared as a solution of 1 mM compound L5 in 50 mM MOPS pH=7 buffer as a reference and was also analyzed by HPLC-MS. The method of analysis was the same for all three samples (injection volume 1 μL, Phenomenex Kinetex C18 column, 100×3 mm, 2.6 μm; isocratic method with 23.5% acetonitrile, 76.5% water solution of 10 mM ammonium formate pH=7.0, flow rate 0.65 mL / min; detection by diode array detector at 280 nm and mass spectrometer). Chromatograms of all three samples at 280 nm are shown in Figure 1. They show clear differences in the retention times of the intact complex [La(L5)] and the free compound L5. The sample of [La(L5)] acidified with TFA showed a high retention time of both compound L5 and free La. 3+ ions; the latter cannot be detected directly by this method. The MS spectrum reveals these results: the peak at 6.4 min corresponds to the [La(L5)] complex (ion [(M+H) + ]: calculated 623.1; found 623.2), and the peak at 3.1 min is free compound L5 (ion [(M+H) + m / z for ]: calculated 487.3; observed 487.3). The retention time of free compound L5 (3.1 min) indicates that this compound is free La 3+ ions, which are not retained on the C18 reversed-phase column and elute within the dead volume of the system (2.7 min). Reducing the organic solvent used in the isocratic method also increases the difference in retention times of the species.

[0175] Example 28. Separation of Pr from L5 using C18 column separation The stock solution was pipetted into a 20 mL glass vial and the reaction mixture was prepared as follows: 1.1.00 mL of 100 mM PrCl3 in water 2. 0.60 mL of 218 mM L5 in water The pH of the reaction was titrated to 6 by adding NaOH (2M aqueous stock solution) via micropipette. The reaction was stirred by using a PTFE-coated stir bar on a magnetic stirrer for 30 minutes at room temperature. The resulting suspension was transferred to two 2 mL plastic Eppendorf centrifuge tubes and centrifuged. The supernatant was saved and analyzed by HPLC. The precipitate was dissolved by adding 0.15 mL of 1 M HCl to each Eppendorf tube. The dissolved solutions were combined and titrated to pH 2 by the addition of 2 M NaOH.

[0176] L5 and Pr present in the acidic solution were separated by reversed-phase chromatography using 1.01 g of fully end-capped C18 silica gel in a plastic SPE cartridge (2 cm diameter). After conditioning the reversed phase with MeCN and MeCN / H2O solutions, 1 mL of H2O was run through the column, followed by loading of the L5-Pr solution onto the column. The MeCN / H2O solution was used to elute the components from the column in 2 mL of 0% MeCN, 4 mL of 10% MeCN, 4 mL of 25% MeCN, and 4 mL of 50% MeCN. The eluted solution was collected in seven 2 mL fractions. All fractions were analyzed by HPLC-MS to determine the content of L5. The first two fractions were also analyzed by ICP-OES to determine the content of Pr. Subsequent fractions shown to contain L5 by HPLC-MS were not analyzed for Pr content by ICP-OES. This is because HPLC-MS samples of those fractions spiked with MOPS buffer pH=7 showed no evidence of L5-Pr complex formation, which would have been observed if Pr was present in those fractions with L5.

[0177] The distribution of L5 and Pr in the fractions is shown in Table 21, where the amount of each component present in each fraction is provided as a fraction of the total amount of the component found in the sum of the fractions, as well as the measured content of Pr (in mM) and L5 (as integral of the chromatographic peak area at 280 nm) found in each fraction. These results demonstrate that the chelating agent and free rare earth metal ions can be separated from each other after processing, the chelating agent can be recycled and reused, and the rare earth elements can be isolated in the form of an aqueous solution of a water-soluble salt.

[0178] [Table 21]

[0179] IV. Separation of Rare Earth Elements from NdFeB Magnets Example 29. Separation of rare earths from transition metals using ammonium oxalate A spherical nickel-coated NdFeB magnet (105 mg) was placed in a 4 mL glass vial and dissolved by the addition of 1.00 mL of concentrated nitric acid (~65%). The resulting solution was analyzed by ICP-OES to quantify the major components present (Table 22; step 1). To isolate the lanthanides Nd and Pr from this solution, the solution was treated with ammonium oxalate: 0.1 mL of nitric acid solution (content of about 1.6 M total dissolved metals) was added to an aqueous solution of ammonium oxalate (1.1 mL, 0.5 M; about 3.5 molar equivalents of ammonium oxalate to metals) in a 2 mL plastic Eppendorf vial. The solution was mixed thoroughly, which immediately gave a light green solution and a white precipitate, which was separated by centrifugation. The solution was analyzed by ICP-OES to quantify the metals present (Table 22; step 2); Nd and Pr were not detected in this solution, but precipitated as insoluble lanthanide oxalates. The precipitate was rinsed with water and then dissolved by adding 100 μL of concentrated nitric acid to a plastic Eppendorf vial. After 5 minutes, NaOH (1.0 mL, 2 M) was added to the solution to give the lanthanide hydroxide as a white precipitate. The precipitate was again isolated by centrifugation and rinsed with water before being dissolved in HCl (200 μL, 0.5 M). The solution of lanthanide chloride was analyzed by ICP-OES to determine its final composition (Table 22; step 3).

[0180] Table 22 shows the concentration of each component of the resulting solution after each step of the process, as well as the molar % composition. The method allows the isolation of a pure (99%) mixture of lanthanides from NdFeB magnets that consist of less than 10% lanthanides by molar composition.

[0181] [Table 22] [Brief description of the drawings]

[0182] [Figure 1]HPLC chromatograms as described in Example 28. From top to bottom: complex [La(L5)], free compound L5 and complex [La(L5)] after partial digestion in TFA.

Claims

1. Use of compounds of general formula (I) for the separation of rare earth elements by precipitation 【Chemistry 1】 During the ceremony, R １ is H; -CH ２ COOH; R 2 and R 6 are independently H or OH; R ３ , R ４ and R 5 is independently H; OH; —NO ２ -COOH; and phenyl; or The group of the general formula (I) 【Chemistry 2】 is selected from naphthalen-1-ylmethyl and naphthalen-2-ylmethyl; With the proviso that at most two of said substituents R 2 , R 3 , R 4 , R 5 and R 6 are other than H.

2. The substituent R ２ , R ３ , R ４ , R ５ and R ６ The use according to claim 1 , wherein one of is other than H.

3. R ２ , R ３ , R ４ , R ５ and R ６ The use according to claim 1 , wherein is H.

4. R ２ , R ３ , R ５ and R ６ is H, and R ４ The use according to claim 1 , wherein is phenyl, H or COOH.

5. 2. The use according to claim 1, wherein the compound of general formula (I) is selected from the group consisting of: 2,2',2''-(10-benzyl-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2'-(4-(2-hydroxy-5-nitrobenzyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2,2'-(4-(4-carboxybenzyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2,2',2''-(10-(naphthalen-2-ylmethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2''-(10-(naphthalen-1-ylmethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2''-(10-([1,1'-biphenyl]-4-ylmethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid.

6. A method for separating rare earth elements by precipitation, comprising the following steps o) to d): o) at least two different rare earth elements (M ３＋ ) and an aqueous solution of said compound of general formula (I) as defined in any one of claims 1 to 5; wherein said solvent is selected from the group comprising water, a buffer solution and / or a mixture of water and an organic solvent miscible in water, said water content being at least 50% by volume: a) the at least two different rare earth elements (M ３＋ ) with an aqueous solution of the compound of general formula (I) as defined in any one of claims 1 to 5 at a pH ranging from 5 to 9 to obtain the compound M ３＋ forming at least one complex of an ion with said compound of general formula (I) in the form of a precipitate or a crystalline phase; b) mechanical separation of said precipitate or said crystalline phase from the reaction mixture; c) optionally redissolving the precipitate or the crystalline phase from step b) in water, in a buffer solution, in a mixture of water and a water-miscible organic solvent, or in an aqueous solution of an inorganic or organic acid; d) Optionally, adjusting the pH of the solution from step c) to a pH value in the range of from 5 to 9 and repeating steps a), b), and optionally c).

7. 7. The method according to claim 6, wherein the compound of general formula (I) is isolated from the reaction mixture after dissolving the precipitate or crystalline phase in step c).

8. Rare earth metal ion M ３＋ 8. The process according to claim 6 or 7, wherein the molar ratio between the sum of and said compound of general formula (I) ranges from 1:0.5 to 1:

100.

9. In step a), at least two different rare earth elements (M ３＋ 9. The method according to claim 6, wherein the ion of is in the form of a water-soluble salt with an inorganic or organic acid.

10. At least one additive is added to the reaction mixture in step a), 10. The method of any one of claims 6 to 9, wherein the additive is selected from the group consisting of acetate, trifluoroacetic acid, benzoic acid, 3-chlorobenzoic acid, 2-methylbenzoic acid, 3-methylbenzoic acid, 4-methylbenzoic acid, citrate, dipicolinic acid, fluoride, formate, glycine, glycolate, α-HIBA (α-hydroxyisobutyric acid), lactate, nitrate, picolinic acid, mandelic acid, salicylic acid, tributyl phosphate, dimethylsulfoxide, N,N-dimethylformamide, and N,N-dimethylacetamide.

11. 11. The method according to claim 10, wherein the molar ratio between the sum of rare earth metal ions in the reaction mixture of step a) and the additive ranges from 1:0.1 to 1:

100.

12. The reaction mixture from step b) is subjected to evaporation and / or ultrafiltration and / or ion exchange chromatography after mechanical separation of the precipitate or the crystalline phase to obtain the M ３＋ 12. The method according to any one of claims 6 to 11, characterized in that it further comprises a step e) resulting in the precipitation or crystallization of at least one complex of an ion with said compound of general formula (I).

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