Separation of rare earth elements

Abstract

This invention provides a method for isolating and purifying lutetium from irradiation targets containing other rare earth metals such as ytterbium. [Solution] A method for purifying lutetium comprises the steps of: providing a solid composition containing ytterbium and lutetium; and sublimating or distilling the ytterbium from the solid composition at a temperature of about 1196°C to about 3000°C to leave a lutetium composition containing a higher mass percentage of lutetium than that present in the solid composition.

Description

Description of related applications

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 004332, filed on 2 April 2020, the contents of which are incorporated herein by reference. [Technical Field]

[0002] The present invention broadly relates to the separation and purification of rare earth elements. More specifically, the present invention relates to the isolation and purification of lutetium from irradiation targets containing other rare earth metals such as ytterbium. [Overview of the Initiative]

[0003] In one embodiment, a method for purifying lutetium is provided, comprising the steps of: providing a solid composition containing ytterbium and lutetium; and sublimating or distilling the ytterbium from the solid composition under reduced pressure at a temperature of about 400°C to about 3000°C to leave a lutetium composition (i.e., a lutetium-enriched composition or sample) containing a higher mass percentage of lutetium than that present in the solid composition. In some embodiments, the temperature may be about 450°C to about 1500°C. In any of the above embodiments, the reduced pressure is about 1 × 10⁻⁶ -8 From approximately 750 Tor (approximately 1.33 x 10 -6 The pressure may be Pa to 100 kPa. In any of the above embodiments, the purification or distillation step may be carried out at a rate of about 10 minutes to about 100 minutes per gram of solid composition. In any of the above embodiments, the solid composition may contain Yb-176 and Lu-177.

[0004] In another embodiment, the method comprises the step of subjecting a sample containing Yb-176 and Lu-177 to sublimation, distillation, or a combination thereof to remove at least a portion of Yb-176 from the sample to form a sample concentrated with Lu-177.

[0005] In any of the above methods, the method may further include a step of performing chromatographic separation on the lutetium composition or a lutetium-enriched sample to further concentrate the lutetium in the composition or sample. In any of the above embodiments, the chromatographic separation may include column chromatography, plate chromatography, thin cell chromatography, or high-performance liquid chromatography.

[0006] In any of the above methods, the method may further include the steps of: dissolving a lutetium composition or a lutetium-concentrated sample in an acid to form a dissolved lutetium solution; adding a chelating agent to the dissolved lutetium solution and neutralizing it with a base to form a chelated lutetium solution containing both chelated lutetium and ytterbium; and performing chromatographic separation on the chelated lutetium solution to collect a purified chelated lutetium fraction, dechelating the lutetium to obtain purified lutetium. In any of the above embodiments, the purified lutetium may contain Lu-177 having a purity of more than 99% on an isotopic basis, a purity of more than 99.9% on an isotopic basis, a purity of more than 99.99% on an isotopic basis, a purity of more than 99.999% on an isotopic basis, or a purity of more than 99.999% on an isotopic basis. [Brief explanation of the drawing]

[0007] [Figure 1] Txy diagrams of lutetium and ytterbium at a constant pressure of 1 μTor (approximately 133 × 10⁻⁶ Pa). [Figure 2] Diagram illustrating the chamber for distillation / sublimation of ytterbium and lutetium. [Modes for carrying out the invention]

[0008] Various embodiments are described below. It should be noted that the specific embodiments are not intended to be an exhaustive description or to limit the scope to the broader embodiments described herein. One embodiment described with respect to a particular embodiment is not necessarily limited to that embodiment and may be implemented in any other embodiment.

[0009] As used here, "approximately" will be understood by those skilled in the art and will vary to some extent depending on the context in which it is used. Where there is an unclear use to those skilled in the art from the context in which the term is used, "approximately" will mean up to plus or minus 10% of a particular term.

[0010] Nouns in the context describing elements (in particular, in the context of the following claims) shall be interpreted to refer to both singular and plural subjects unless otherwise specified or unless the context clearly indicates otherwise. Unless otherwise specified, descriptions of ranges of values ​​herein are intended only as abbreviations for individually referring to each distinct value that falls within that range, and each distinct value is incorporated herein as if it were individually listed herein. All methods described herein may be performed in any appropriate order unless otherwise specified or unless the context clearly indicates otherwise otherwise. Any and all examples or illustrative language given herein (e.g., "etc.") are intended merely to better illustrate the embodiments and, unless otherwise specified, do not impose any limitation on the scope of the claims. Nothing in this specification should be interpreted as indicating that elements not described in the claims are essential.

[0011] Lutetium-177 (Lu-177) is used in the treatment of neuroendocrine tumors, prostate cancer, breast cancer, kidney cancer, pancreatic cancer, and other cancers. In the future, approximately 70,000 patients per year will require carrier-free Lu-177 during treatment. Lu-177 is useful for many medical applications because, upon decay, it releases low-energy beta particles suitable for tumor treatment. Lu-177 also emits two types of gamma rays that can be used for diagnostic testing. Isotopes possessing both therapeutic and diagnostic properties are called "theranostic." Not only is Lu-177 theranostic, but it also has a half-life of 6.65 days, allowing for the use of more complex chemicals and facilitating global distribution. Furthermore, Lu-177 possesses chemical properties that enable it to bind with many biomolecules for use in various treatments.

[0012] There are two main pathways for the production of Lu-177. One is the neutron capture reaction of Lu-176; Lu-176(n,γ)Lu-177. This production method is called carrier-added (ca)Lu-177. A carrier is an isotope of the same element (in this case, Lu-176), or a similar element that has the same chemical form as the target isotope. In trace chemistry, the target chemical element or isotope is at extremely low concentrations and therefore does not behave chemically as expected. In addition, isotopes of the same element cannot be chemically separated, so mass separation techniques are required. Therefore, the medical applications of Lu-177 produced by this carrier method are limited.

[0013] A second method for producing Lu-177 is to produce Yb-177 through the neutron capture reaction of ytterbium-176 (Yb-176) (Yb-176(n,γ)Yb-177). Yb-177 is then rapidly produced (1.911 hours t 1 / 2 It undergoes β-decay to become Lu-177. Yb-176 usually contains Yb-174 impurities, and the final product further contains Lu-175 impurities. This process is considered a "carrier-free" process. This process can occur as ytterbium metal or ytterbium oxide.

[0014] This disclosure describes a process for separating Yb and Lu obtained from a carrier-free process. This process includes a distillation / sublimation step to purify lutetium and remove excess Yb after irradiation. This process may then further include the purification of lutetium using a chromatographic separation process. Because the amount of material that can be processed is limited at any point during chromatographic separation, a process to concentrate Lu before chromatographic separation can increase the recovery rate of the Lu product to a much higher level than previously obtained. For example, the current process of chromatographic separation itself is limited to 20 milligrams of material per step, with a processing time of 30 minutes to 1 hour per step. A combination of distillation / sublimation and chromatographic separation allows for the use of larger materials and the isolation of the product by distillation, which can then be passed on to the chromatographic process. Processing 20 grams of sample by chromatography alone would require 1000 batches, resulting in significant material loss.

[0015] The separation of Yb and Lu can, at least in part, effectively utilize the difference in vapor pressure at specific temperatures and pressures. For example, at standard temperatures and pressures, the boiling point of Yb is 1196°C, while that of Lu is 3402°C. By utilizing the difference in vapor pressure at specified temperatures and pressures, Yb and Lu can be separated by sublimation and / or distillation. Figure 1 shows 1 μTor (approximately 133 × 10⁻¹⁰). -6 This is a Txy diagram of lutetium and ytterbium under constant pressure (Pa). In this diagram, the lower line (i.e., boiling point) represents the condensed phase composition at a given temperature, while the upper line (i.e., dew point) represents the gas phase. This graph was prepared using the assumption of ideal gas and ideal solution. This assumption is valid in terms of low pressure, high temperature, and the chemical similarity of the two components.

[0016] In sublimation, the solid phase of an element is directly converted to a gas phase by heating, and the gas phase can then be recovered for later use. In distillation, the solid is heated to its boiling point (through the liquid phase) and vaporized. The vaporized fraction can be recovered downstream after the vapor is condensed. In this case, ytterbium is vaporized (and can also be recovered downstream for later use), leaving a lutetium-enriched substance. This can be carried out on a larger scale, and therefore the amount of lutetium obtained can be increased. It should be noted that the recovered Yb can be recycled back into the reactor to produce more Lu in subsequent steps of this process.

[0017] Distillation / sublimation apparatuses generally comprise a high-vacuum chamber with appropriate gas, cooling, vacuum, power, and instrument feedthroughs. Referring to Figure 2, apparatus 100 has a suitable volume for housing a refractory crucible 190 suspended or supported within an RF induction heating coil 170 and a cold finger 160 having a collection substrate. The cold finger (cooling rod) 160, having a suitable end effector, is positioned directly above the crucible 190 and allows the crucible's open end to be opened to the vacuum system or sealed to the collection substrate. The apparatus has appropriate instruments for monitoring the chamber's vacuum pressure 140, the crucible temperature 180, and the cold plate temperature 120. Apparatus 100 is housed within a chamber 105 having an access port 110 to the crucible. Apparatus 100 also comprises a vacuum pump connection 150 and at least one port 200 for introducing an inert gas.

[0018] Generally, the initial purification process by distillation and / or sublimation proceeds as follows: The concentrated Yb-176 metal target is loaded into a 1 cm diameter quartz tube sealed at both ends. This quartz tube is then sealed in an inert overpack (e.g., aluminum) that is suitable for irradiation and impermeable to water and air. The sealed overpack is placed in a reactor and irradiated for several hours to several days (depending on the flux and batch requirements) to generate Lu-177 within the Yb-176 target. After irradiation, the irradiated Yb metal target is removed in an inert environment and placed in a refractory metal crucible (e.g., molybdenum or tantalum) and placed in a vacuum chamber where the pressure is reduced. The crucible is then heated by radio frequency (RF) induction. As the Yb metal sublimes from the heated crucible, it is deposited on a cold finger that is actively cooled for collection. As sublimation progresses, the crucible is heated to a higher temperature. At this stage of the process, the generated lutetium or lutetium oxide, trace amounts of ytterbium or ytterbium oxide, and trace contaminants remain in the crucible. Next, the contents of the crucible containing lutetium are dissolved in acid, removed from the crucible, and transferred to a chromatographic separation apparatus.

[0019] Accordingly, in a first embodiment, a method for purifying lutetium is provided. This method comprises the steps of providing a solid composition comprising lutetium and ytterbium, and sublimating or distilling the ytterbium from the solid composition under reduced pressure at a temperature of about 400°C to about 3000°C to leave a lutetium composition containing a higher mass percentage of lutetium than that present in the solid composition. As described above, the ytterbium sublimated / distilled from the solid composition can be reused as an additional irradiation target material.

[0020] According to various embodiments, the temperature for sublimation and / or distillation may be about 450°C to about 1500°C, or about 450°C to about 1200°C. Also, according to various embodiments, the pressure may be about 1 × 10⁻⁶ -8 From approximately 1520 Tor (approximately 1.33 x 10 -6It may be from about 203 kPa to about 267 kPa. In other embodiments, the temperature may be from about 450 °C to about 1500 °C, and the pressure may be from about 2000 Torr to about 1×10 -8 Torr (from about 267 kPa to about 1.33×10 -6 Pa), or the temperature may be from about 450 °C to about 1200 °C, and the pressure may be from about 1000 Torr to about 1×10 -8 Torr (from about 133 kPa to about 1.33×10 -6 Pa). In some embodiments, the separation includes distillation of ytterbium from a solid composition, and the pressure may be from about 1 Torr to about 1×10 -6 Torr (from about 133 Pa to about 133×10 -6 Pa), and the temperature may be from about 450 °C to about 800 °C. In some embodiments, the separation includes distillation of ytterbium from a solid composition, and the pressure may be from about 1×10 -3 Torr to about 1000 Torr (from about 133×10 -3 Pa to about 133 kPa), and the temperature may be from about 600 °C to about 1500 °C. In some embodiments, the separation includes distillation of ytterbium from a solid composition, and the pressure may be from about 1×10 -6 Torr to about 1×10 -1 Torr (from about 133×10 -6 Pa to 13.3 Pa), and the temperature may be from about 470 °C to about 630 °C.

[0021] In some embodiments, a heating and cooling rate over a period of 10 minutes to 2 hours may be used to ensure no bulging or non-uniform heating of the Yb sample of the subject containing lutetium. The temperature of the sample may be monitored indirectly through the crucible. In other embodiments, a vacuum is established to degas the sample prior to heating the crucible. This vacuum may be from about 5 minutes to 1 hour and may be about 1×10 -6 Torr (about 133×10 -6 Pa). A turbomolecular pump may be used to achieve a high vacuum level.

[0022] The time required for sublimation and / or distillation processes can vary widely and depend on the amount of substance in the sample, temperature, and pressure. This time can range from about one second to about one week. In some embodiments, the time-related factor is the rate of sublimation or distillation. In some embodiments, this rate may be about 10 minutes to about 100 minutes per gram of solid composition, or about 20 minutes to about 60 minutes per gram of solid composition. In one embodiment, the rate may be about 40 minutes per gram of solid composition.

[0023] In the sublimation / distillation process, a sample ("lutetium composition") is obtained in which lutetium is concentrated compared to the solid composition entering the process. The yield and purity can be measured in many ways. For example, in some embodiments, this process results in a ytterbium mass reduction of 1,000:1 to 10,000:1 of the solid composition. In other words, after the sublimation / distillation is complete, the amount of ytterbium in the sample is 1,000 to 10,000 times less than before the process. In some embodiments, the recovered lutetium composition (i.e., the contents of the crucible subjected to acid dissolution) may contain about 1% to 90% by mass of ytterbium relative to the total residual mass, which is then separated in a chromatographic process as described below. In other embodiments, the ytterbium recovered from sublimation / distillation is recovered in an amount of about 90% to 99.999% by mass of the ytterbium present in the solid composition. The purification process is also carried out to remove other trace metals and contaminants. For example, substances such as metals, metal oxides, or metal ions of K, Na, Ca, Fe, Al, Si, Ni, Cu, Pb, La, Ce, Lu (non-radioactive), Eu, Sn, Er, and Tm may be removed. In other words, the method comprises the step of removing at least a portion of Yb-176 from a sample containing Yb-176 and Lu-177 by sublimation, distillation, or a combination thereof, to form a Lu-177-enriched sample.

[0024] It has been found that purification can be performed to reduce Yb ​​by more than 1000:1 (i.e., a 1000-fold reduction in the amount of Yb present). This includes reductions greater than approximately 3000:1, greater than 8000:1, greater than 10000:1, and up to approximately 40000:1 (including that). However, higher reductions in Yb may be required to meet the purity requirements of some pharmaceuticals. Therefore, further purification may be performed before use in pharmaceutical applications. Such purification may be performed by the use of chelating agents and / or chromatographic separation.

[0025] The lutetium composition or lutetium-enriched sample described herein may be subjected to chromatographic separation to further concentrate the lutetium in the composition or sample. Such chromatographic separations may include column chromatography, plate chromatography, thin-film cell chromatography, or high-performance liquid chromatography. Exemplary processes for purifying lutetium may be those described in U.S. Patent No. 7,244403, U.S. Patent No. 9,816156, and / or the international publication PCT / EP2018 / 083215, all of which are cited herein in their entirety.

[0026] In one embodiment, the process may include the steps of dissolving the lutetium and ytterbium composition remaining in the crucible after sublimation in an acid, and applying the resulting solution to a chromatography column or plate. This may include plate chromatography material, chromatography column, HPLC chromatography column, ion exchange column, etc.

[0027] As an example, a dilute HCl solution of lutetium can be prepared (i.e., 0.01–5 N HCl). This can be applied to a solution-packed or dry ion-exchange column, and the lutetium can be eluted by additional washing with dilute HCl. This is because, generally speaking, easily treatable solutions are typically dilute solutions of strong acids, usually HCl, as stated in U.S. Patent No. 7244403. The resin bed may be in the form of a strong anion-exchange resin in a column, and contact is made by passing a solution through that column. In some embodiments, the resin is a strongly basic anion-exchange resin that is crosslinked by about 8%. First, an HCl solution is passed through the column to form an HCl-treated column, then an NaCl solution is passed through the HCl-treated column to form an NaCl-treated column, and then sterile water is passed through the NaCl-treated column. These preliminary steps help to elute sterile non-exothermic products. The resin may then be dried before applying the lutetium solution. In some embodiments, the anion exchange resin is generally in powder form, having particles of about 100 to about 200 mesh size. To accelerate the velocity of the solution flowing through the column, sterile gas pressure can be applied to the front of the column. This can be done by injecting a sterile gas, preferably air, into the upper end of the column to force the lutetium-177 solution through the column. The lutetium-177 recovered from such a process will be of higher purity than before column chromatography through the anion exchange column.

[0028] In another embodiment, the process may include the use of a cation exchange resin for purifying lutetium from a composition also containing ytterbium. As an example, generally as described in U.S. Patent No. 9,816,156, the method comprises the steps of loading a Lu / Yb mixture dissolved in a mineral acid into a first column packed with cation exchange material, exchanging protons in the cation exchange material with ammonium ions by using an NH4Cl solution, and washing the cation exchange material of the first column with water. The outlet of the first column is connected to the inlet of a second column, also packed with cation exchange material. Next, a water-chelating gradient is applied to the inlet of the first column, starting with 100% H2O and progressing to a 0.2 M chelating agent, to elute lutetium from the first and second columns. Examples of chelating agents include, but are not limited to, α-hydroxyisobutyrate [HIBA], citric acid, citrate, butyric acid, butyrate, EDTA, EGTA, and ammonium ions. The method may also include the steps of determining the radiation dose at the outlet of a second column to recognize the elution of the Lu-177 compound, collecting the first Lu-177 eluate from the outlet of the second column into a container, and then protonating the chelating agent to inactivate the chelating agent for complexing with Lu-177. This method may also include the steps of loading a final column packed with cation exchange material by continuously transporting acidic lutetium eluate to the inlet of the final column; washing away chelating agents with dilute mineral acid at a concentration of less than approximately 0.1 M; removing trace amounts of other metal ions from the lutetium solution by washing the cation exchange material of the final column with mineral acid at various concentrations ranging from approximately 0.01 to 2.5 M; and eluting Lu-177 from the final column with high-concentration mineral acid at approximately 1 M to 12 M. Finally, the eluate containing lutetium of a higher purity than that applied to the column can be collected, and the solvent and mineral acid can be removed by evaporation.

[0029] In a further embodiment, the process may include the steps of: dissolving a lutetium and ytterbium composition or a lutetium-enriched sample in acid to form a dissolved lutetium / ytterbium solution; adding a chelating agent to the dissolved lutetium / ytterbium solution; neutralizing with a base to form a chelated lutetium / ytterbium solution containing both chelated lutetium and ytterbium; and subjecting the chelate solution to chromatographic separation to collect a purified chelated lutetium fraction, dechelate the lutetium to obtain purified lutetium. This purified chelated lutetium fraction has a higher purity of lutetium than the lutetium in the dissolved lutetium / ytterbium solution. High levels of lutetium purity can be obtained using such chromatographic processes. For example, the purified lutetium obtained after chromatographic separation and separation may contain Lu-177 with a purity of over 99% on an isotopic basis. This contains Lu-177 in isotopic concentrations of over 99.9%, over 99.99%, over 99.999%, or over 99.9999%.

[0030] The chelating and chromatographic separation steps may be as described here and as described in the international publication PCT / EP2018 / 083215. Generally, the ytterbium metal or metal oxide target is irradiated to form Lu-177. This target is then dissolved in acid, a chelating agent is added, the solution is neutralized with a base to form a chelated metal, and chromatographic separation is performed, after which the purified metal is decomposed / dechelated from the chelating agent. However, due to the limitations of chromatography, starting with an impure source of lutetium (i.e., the irradiated ytterbium oxide target), the chromatographic efficiency is low, and even on an experimental scale, only a small percentage of purified lutetium is obtained in each chromatographic cycle. As mentioned above, using purified lutetium after distillation / sublimation offers the unexpected advantage of producing higher purity rare earth metals, particularly lutetium, on a larger scale and in a shorter time, which cannot be obtained by distillation or chromatography alone.

[0031] The initial dissolution of lutetium in acid can be carried out using hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, peroxosulfuric acid, perchloric acid, methanesulfonic acid, trifluoromethanesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, or any two or more mixtures thereof. The acid concentration can be about 0.01 M to about 6 M, and / or the base concentration is about 0.01 M to about 6 M. This includes concentrations of about 1 M to about 6 M and about 2 M to about 6 M. Next, a chelating agent (see below) is added together with a base (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, NH4OH, or alkylammonium hydroxide) to neutralize the acid and produce chelated lutetium. Then, HPLC is performed. This HPLC can be performed with a suitable column and elution with a suitable mobile phase. Each of these will vary in different method development scenarios. For example, the column may be a cation exchange column, an anion exchange column, a reversed-phase C18 column, etc., and the mobile phase may be any that is determined to allow separation. The mobile phase may be aqueous or organic solvent. Examples that are helpful for explanation include, but are not limited to, water, alcohols, alkanes, ethers, esters, acids, bases, and aromatic compounds. In various embodiments, the mobile phase may be water, methanol / water, methanol / trifluoroacetic acid / water, and / or a methanol mobile phase.

[0032] Examples of chelating agents include, but are not limited to, formula (I):

[0033] [ka]

[0034] The following are examples. In equation (I): X is H, OH, SH, CF3, F, Cl, Br, I, C1-C6 alkyl, C1-C6 alkyloxy, C1-C6 alkylthio, NH2, C1-C6 alkylamino, di(C1-C6 alkyl)amino, NO2, or C(O)OH. Y is N, CH, COH, CF, O, or N-oxide (N + -O - ) and Each Z is independently either C or N, but at least one Z is C. n is either 0 or 1. L is a covalent bond or -C(O)-, R 1 This is a benzyl which is optionally substituted with one or more substituents selected from H, C1-C6 alkyl, or NO2, OH, (-CH2P(O)(OH)2, -CH2P(O)(OH)(C1-C6 alkyl), C1-C2 alkyl)C(O)OH (the alkylenyl can optionally be substituted with C1-C6 alkyl), R 2 , R 3 , and R 4 Each of them individually either does not exist, or exists if possible with the valence of Z, and if it exists, R 2 , R 3 , and R 4 Each of these is individually H, F, Cl, Br, I, OH, SH, NH2, CN, NO2, COOR 5 , C1-C6 alkyl, C1-C6 alkyloxy, C6-C 10 Aryloxy, benzyloxy, C1-C6 alkylthio, C6-C 10 Arylthio, C1-C6 alkylamino, di(C1-C6 alkyl)amino, C1-C6 acylamino, di(C1-C6 acyl)amino, C6-C 10 Arylamino, or di(C6~C) 10 It is an aryl)amino, R 5 H or C1-C6 alkyl or C6-C 10 It is an aryl, or R 2 and R 3 , R 2 and R 4 , and / or R 3 and R 4These atoms may bond with each other to form a six-membered ring with an adjacent Z atom, where this six-membered ring is composed of OH, SH, CF3, F, Cl, Br, I, NO2, C(O)OH, C1-C6 alkyl, C1-C6 alkyloxy, C1-C6 alkylthio, NH2, C1-C6 alkylamino, di(C1-C6 alkyl)amino,

[0035] [ka]

[0036] One or more substituents may be substituted as needed.

[0037] Formula (I) is intended to include all its isomers, enantiomers, and diastereoisomers. In some embodiments, one Z is noncarbon. In other embodiments, two Zs are noncarbon. In other embodiments, rings containing a Z atom may include pyridinyl, pyrimidinyl, pyrrolyl, imidazolyl, indolyl, isoquinolinyl, quinolinyl, pyrazinyl, pyridinyl N-oxide, quinolinyl N-oxide, isoquinolinyl N-oxide, phenyl, naphthalyl, furanyl, or hydroxyquinolinyl. In some other embodiments, rings containing a Z atom are pyridinyl, pyridinyl N-oxide, quinolinyl N-oxide, isoquinolinyl N-oxide, or phenyl. In some embodiments, X is H, F, Cl, Br, I, CH3, or COOH. In other embodiments, R 1 These are H, -CH2COOH, -CH2CH2COOH, -CH(CH3)COOH, -CH2P(O)(OH)2, -CH2P(O)(OH)(C1~C6alkyl), or

[0038] [ka]

[0039] In some embodiments, L is a covalent bond. In some embodiments, R 1 These are H, OH, OCH3, NO2, F, Cl, Br, I, CH3, or COOH.

[0040] In some embodiments, Y is N, all Z is C, n is 1, and X is F, Cl, Br, I, CH3, CF3, OCH3, SCH3, OH, SH, NH2, or NO2. In further embodiments, X is F, Cl, Br, I, or CH3.

[0041] In some embodiments, Y is N, all Z is N, n is 1, and X is F, Cl, Br, I, CH3, CF3, OCH3, SCH3, OH, SH, NH2, or NO2. In further embodiments, X is F, Cl, Br, I, or CH3.

[0042] In some embodiments, Y is N-oxide (N + -O - ) where Z is carbon, n is 1, X is H, or X and its adjacent carbon, Z and R 1、2、または3 It forms a six-membered ring, optionally substituted with one or more substituents independently selected from the group consisting of OH, SH, CF3, F, Cl, Br, I, NH2, NO2, C(O)OH, C1-C6 alkyl, C1-C6 alkyloxy, C1-C6 alkylthio, C1-C6 alkylamino, or di(C1-C6 alkyl)amino.

[0043] In some embodiments, Y is C, all Z is C, n is 1, and X is H, NH2, or NO2. In some such embodiments, R may be OH or C1-C6 alkyloxy.

[0044] In some embodiments, Y is N, all Z are C, n is 1, X is H, or X and its adjacent carbon, Z and R 1、2、または3It forms a six-membered ring, optionally substituted with one or more substituents independently selected from the group consisting of OH, SH, CF3, F, Cl, Br, I, NH2, NO2, C(O)OH, C1-C6 alkyl, C1-C6 alkyloxy, C1-C6 alkylthio, C1-C6 alkylamino, or di(C1-C6 alkyl)amino.

[0045] In some embodiments, Y is N, all Zs are C, n is 1, and X is COOH.

[0046] Examples of chelating compounds include, but are not limited to, 2,2',2”-(10-((6-fluoropyridine-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-((6-chloropyridine-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-((6-bromopyridine-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl )triacetic acid;2,2',2”-(10-((6-(trifluoromethyl)pyridine-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid;2,2',2”-(10-((6-methoxypyridine-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid;2,2',2”-(10-((6-methylpyridine-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid;2,2',2”- (10-((4,6-dimethylpyridine-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-(pyridine-2-ylmethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-(isoquinoline-1-ylmethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-(isoquinoline-3-ylmethyl)-1,4,7,10-te Traazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-(quinoline-2-ylmethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-((6-carboxypyridine-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-((6-methylpyrazine-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid;2,2',2”-(10-(pyrazine-2-ylmethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate;4-methyl-2-((4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)methyl)pyridine 1-oxide;2-methyl-6-((4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)methyl)pyridine 1-oxide;4-carboxy-2-((4,7,10-tris(carboxymethyl)-1 ,4,7,10-tetraazacyclododecane-1-yl)methyl)pyridine 1-oxide; 2-((4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)methyl)pyridine 1-oxide; 4-chloro-2-((4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)methyl)pyridine 1-oxide; 2-((4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)methyl)quinoline 1-oxide oxide; 1-((4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)methyl)isoquinoline 2-oxide; 3-((4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)methyl)isoquinoline 2-oxide; 2,2',2”-(10-(2-hydroxybenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate; 2,2',2”-(10-(2-hydroxy-3-methylbenzyl)-1,4,7,1 0-Tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-(2-hydroxy-4-methylbenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-(2-hydroxy-5-(methoxycarbonyl)benzyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-(2-hydroxy-5-nitrobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid;2,2',2”-(10-(2-methoxybenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-((3-methoxynaphthalene-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-((1-methoxynaphthalene-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-(2-carboxybenzyl)-1,4, 7,10-Tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-(3-carboxybenzyl)-1,4,7,10-Tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-(4-carboxybenzyl)-1,4,7,10-Tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-benzyl-1,4,7,10-Tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-(4-methylbenzyl)-1, 4,7,10-Tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-(2-methylbenzyl)-1,4,7,10-Tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-(4-nitrobenzyl)-1,4,7,10-Tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-((perfluoro Phenyl)methyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-(2-fluorobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-(2,6-difluorobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-(naphthalene-2-ylmethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid;2,2',2”-(10-(furan-2-ylmethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-(2-oxo-2-phenylethyl)-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'-(4,10-bis(2-hydroxy-5-nitrobenzyl)-1,4,7,10-tetraazacyclododecane-1 ,7-diyl)diacetic acid; 2,2'-(4-((6-carboxypyridine-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 6,6'-((4,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)bis(methylene))dipicolinic acid; 2,2'-(4-((6-methylpyridine-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2,2'-(4,10-bis((6-methylpyridine-2-yl)methyl)-1 ,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2-((4,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)methyl)pyridine 1-oxide; 2,2'-((4,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)bis(methylene))bis(pyridine 1-oxide); 2,2'-(4-((5-carboxyfuran-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 5,5'-(( 4,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)bis(methylene))bis(furan-2-carboxylic acid); 2,2'-(4,10-dibenzyl-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2,2'-(4-((perfluorophenyl)methyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2,2'-(4,10-bis((perfluorophenyl)methyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid;2,2'-(4-((1-methoxynaphthalene-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2,2'-(4-((3-methoxynaphthalene-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2,2'-(4-(2-carboxybenzyl)-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'-(4-(2-hydroxybenzyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2,2'-(4-(2-hydroxy-3-methylbenzyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2-((4,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)methyl)-6-methylpyridine 1-oxide; 2,2'-(4- (3-carboxy-2-hydroxybenzyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2,2'-(4-((8-hydroxyquinoline-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2,2'-(4-benzyl-10-(2-hydroxy-5-nitrobenzyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2-((7-benzyl-4,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl) Methyl)pyridine 1-oxide; 2,2'-(4-benzyl-1-((6-carboxypyridine-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2,2'-(4-(2-carboxyethyl)-10-((6-methylpyridine-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2,2'-(4-((6-bromopyridine-2-yl)methyl)-10-(2-carboxyethyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid;2,2'-(4-(2-carboxyethyl)-10-((6-chloropyridine-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2,2'-(4-(2-carboxyethyl)-10-((6-fluoropyridine-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2,2'-(4-(2-carboxyethyl)-10-(pyridine-2-ylmethyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2-((7-(2-carboxyethyl)-4,10-bis(carbo; Xymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)methyl)pyridine 1-oxide; 2-((4,10-bis(carboxymethyl)-7-(2-hydroxy-5-nitrobenzyl)-1,4,7,10-tetraazacyclododecane-1-yl)methyl)pyridine 1-oxide; 2-((4,10-bis(carboxymethyl)-7-((6-carboxypyridine-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1-yl)methyl)pyridine 1-oxide; 2,2 '-(4-((6-carboxypyridine-2-yl)methyl)-10-(2-hydroxy-5-nitrobenzyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid;2,2'-(4-((6-carboxypyridine-2-yl)methyl)-10-((6-chloropyridine-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid;2,2'-(4-((6-bromopyridine-2-yl)methyl)-10-((6-carboxypyridine-2-yl )methyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2,2'-(4-((6-carboxypyridine-2-yl)methyl)-10-((6-methylpyridine-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2,2'-(4-((6-carboxypyridine-2-yl)methyl)-10-(pyridine-4-yl(6-methylpyridine-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2,2'-(4-((6-carboxypyridine-2-yl)methyl)-10-((6-methylpyridine-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,7-di Luboxypyridine-2-yl)methyl)-10-methyl-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2,2'-(4-((6-chloropyridine-2-yl)methyl)-10-(phosphonomethyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid); 2,2'-(4-((6-bromopyridine-2-yl)methyl)-10-((hydroxy(methyl)phosphoryl)methyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid;2,2'-(4-((6-chloropyridine-2-yl)methyl)-10-((hydroxy(methyl)phosphoryl)methyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2,2',2”-(10-(2-oxo-2-(pyridine-2-yl)ethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-(pyrimidine-2-ylmethyl)-1,4,7,10- Examples include tetraazacyclododecane-1,4,7-triyl) triacetic acid; 2,2'-(4-(1-carboxyethyl)-10-((6-chloropyridine-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl) diacetic acid; and 2,2'-(4-((6-chloropyridine-2-yl)methyl)-10-(2-(methylsulfonamide)ethyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl) diacetic acid.

[0047] Following the purification of chelated lutetium by HPCL (see below), a dechelation process is carried out to obtain purified lutetium as a lutetium solution and / or ionic substance. In some embodiments, dechelation involves contacting the purified chelated lutetium fraction with an acid, which is hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, peroxosulfuric acid, perchloric acid, methanesulfonic acid, trifluoromethanesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, or any two or more mixtures thereof. The concentration of this acid may be about 0.01 M to about 6 M, and / or the concentration of the base is about 0.01 M to about 6 M. This includes concentrations of about 1 M to about 6 M and about 2 M to about 6 M.

[0048] As previously mentioned, the process described herein can be used for the separation of lutetium and ytterbium. However, if there is a difference in boiling / sublimation points and further purification is subsequently performed using chromatographic separation in the presence of various chelating agents, it can also be used for the separation of either rare earth metals and / or actinide metals. Rare earth elements that may be chelated for purification with the aforementioned chelating agents include cerium (Ce), dysprosium (Dy), erbium (Er), europium (Eu), gadolinium (Gd), holmium (Ho), lanthanum (La), lutetium (Lu), neodymium (Nd), praseodymium (Pr), promethium (Pm), samarium (Sm), scandium (Sc), terbium (Tb), thulium (Tm), ytterbium (Yb), and yttrium (Y). In some embodiments, the method comprises the chromatographic separation of rare earth elements from a mixture of at least two metal ions, at least one of which is Ce, Dy, Er, Eu, Gd, Ho, La, Lu, Nd, Pr, Pm, Sm, Sc, Tb, Tm, Yb, or Y.

[0049] The method may include a step of providing a mixture of at least one rare earth metal ion and at least one further metal ion (which may also be a rare earth metal ion, a transition metal ion, a non-transition metal ion, or an actinide ion). The metal ions in the mixture may be subjected to a reaction with at least one compound of the previously defined general formula (I) to form a chelate, which is then subjected to chromatographic separation such as column chromatography, thin-layer chromatography, or high-performance liquid chromatography (HPLC), where the stationary phase is silica (SiO2), alumina (Al2O3), or (C1-C1). 18 ) Derivatization reversed phase (C1~C 18 phenyl, pentafluorophenyl, C1~C 18The mobile phase is preferably an alkylphenyl or polymer reversed phase, and preferably contains one or more solvents selected from water, C1-C4 alcohols, acetonitrile, acetone, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, and aqueous ammonia, and the mobile phase may ultimately contain one or more additives for pH adjustment, such as acids, bases, or buffers; additives for pH adjustment are known to those skilled in the art. The chromatography step may be performed at least twice as needed to increase the purity of at least one separated metal chelate, and optionally, acid decomplexation is performed on at least one metal chelate obtained from the chromatographic separation to obtain uncomplexed rare earth metal ions. In some embodiments, the fractions / spots containing the metal chelates separated from chromatography are mixed with each other before repeating the chromatography step. In other embodiments, the mixed fractions containing the separated metal chelates are concentrated, for example, by evaporation, before repeating the chromatography step. These further metal ions may include Ce, Dy, Er, Eu, Gd, Ho, La, Lu, Nd, Pr, Pm, Sm, Sc, Tb, Tm, Yb, Y, and transition metals of the d block of the periodic table (groups IB to VIIIB). Non-transition metals are metals from the main group elements of the periodic table (group A), and actinides are chemical elements with atomic numbers from 89 to 103, ranging from actinium to lawrencium.

[0050] Examples of acids used for decomplexation / dechelation include, but are not limited to, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, peroxosulfuric acid, perchloric acid, methanesulfonic acid, trifluoromethanesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, and any two or more mixtures thereof. Following decomplexation / dechelation, the resulting mixture can be chromatographically treated to purify free rare earth metal ions from the molecule of the compound of general formula (I) or from the fragment obtained from the acid decomplexation.

[0051] In one preferred embodiment, chromatography is preferably C1-C 18 phenyl, pentafluorophenyl, C1~C 18 This is high-performance liquid chromatography (HPLC) performed using a stationary reversed phase selected from alkyl-phenyl or polymeric reversed phases, where the mobile phase consists of water and 0-40% (vol) of a water-miscible organic solvent. This organic solvent may be any one or more of methanol, ethanol, propanol, isopropanol, acetonitrile, acetone, N,N-dimethylformamide, dimethyl sulfoxide, or tetrahydrofuran. The solvent may also include a mobile phase further containing up to 10% (w / w) of an ion-pairing additive consisting of a cation and anion moiety, where the cation moiety is H + Li + na + , K + , Rb + , Cs + NH4 + , selected from the group including C1-C8 tetraalkylammonium, the anionic part is F - Cl - , Br - , I - , sulfates, hydrogen sulfates, nitrates, perchlorates, metal sulfonates, trifluoromethanesulfonates, (C2~C 18 Alkyl sulfonates, formate, lactates, (C2~C 18 The group includes alkyl)carboxylates, butyrates, malates, citrates, 2-hydroxyisobutyrates, mandelates, diglycolates, and tartrates.

[0052] In some embodiments, a solution containing a mixture obtained by a chelation step in the form of a salt (e.g., chloride, bromide, sulfate, nitrate, metal sulfonate, trifluoromethanesulfonate, formate, acetate, lactate, malate, citrate, 2-hydroxyisobutyrate, mandelate, diglycolate, tartrate), or a solid phase containing such a mixture (e.g., in the form of oxide, hydroxide, carbonate), is mixed with a solution of the compound of general formula (I) at a molar ratio of metal ions to the compound of general formula (I) of 1:0.5 to 1:100. This molar ratio includes 1:0.7 to 1:50, or 1:0.9 to 1:10. The concentration of the soluble component may be selected from a concentration range possible by the solubility of such compound in a given solvent at a given temperature, preferably a concentration range of 0.000001 M to 0.5 M. The solvent may be water, methanol, ethanol, propanol, isopropanol, acetone, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, or any mixture of two or more of these.

[0053] To counteract the protons released during complexation / chelation, organic or inorganic bases such as LiOH, NaOH, KOH, NH3 water, triethylamine, N,N-diisopropylethylamine, or pyridine may be added to the reaction mixture, and complexation / chelation may occur in the solution. 1 to 10 molar equivalents of base may be added per mole of compound of general formula (I). The mixture is stirred or shaken at room temperature or high temperature for up to 24 hours to obtain complete complex formation. For complex formation, the mixture may be stirred or shaken at approximately 40°C for 15 minutes. A considerably excess of compound of general formula (I) may be added to accelerate complex formation and shift the equilibrium toward chelate formation. Chromatographic separation of the chelate may be performed in the normal or reverse stationary phase. The normal phase may be silica or alumina. C1~C 18 , phenyl, pentafluorophenyl, (C1~C 18Various reversed phases may be used, including alkyl)-phenyl and polymer reversed phases.

[0054] The metal chelate solution may be centrifuged or filtered before chromatography, if necessary, to remove insoluble impurities or particulate matter such as dust. Separation may be performed using various chromatographic equipment, including column chromatography, thin-layer chromatography (TLC), and high-performance liquid chromatography (HPLC). Excess compounds of general formula (I) can also be separated during chromatography. In some embodiments, chromatographic separation is performed using C8, C8. 18 Alternatively, this may be carried out using HPLC with a reversed phenylhexyl phase. In some embodiments, the mobile phase may be water and 3-40% by volume methanol, ethanol, or acetonitrile. If necessary, 0.01-0.1 mol / L of buffer may be used in the mobile phase, where the buffer includes sodium acetate at pH=4.5, ammonium formate at pH=7.0, or ammonium acetate at pH=7.0.

[0055] By collecting and mixing fractions containing the desired metal chelate, a solution with a significantly concentrated content of the desired rare-earth metal chelate can be obtained compared to the original mixture of metal chelates before chromatography. This process can be repeated to further increase the purity of the product.

[0056] In one embodiment, the decomposition of the purified chelate is carried out by treating a chromatographically purified chelate solution with an organic or inorganic acid to decomplex the metal ions from the chelate. The organic or inorganic acid may be hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, peroxosulfuric acid, perchloric acid, methanesulfonic acid, trifluoromethanesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, or any two or more of these. In some embodiments, decomplexation / dechelation is carried out using HCl (0.01 to 12 mol / L) at 25°C to 95°C for a period of 5 minutes to 24 hours. Subsequently, secondary chromatographic purification may be performed to remove free chelating agent molecules (compounds of general formula (I)) from the rare earth metal ions. This can be done by column chromatography using a reversed stationary phase or by solid-phase extraction. The chelating agent can be retained on the reversed phase, while the free metal ions are eluted in the form of salts by the acid used to decompose the chelate.

[0057] Before repeating chromatographic separation, the concentration of the mixed fraction containing the separated metal chelate can be increased by partial evaporation of the solvent or by adsorption of the chelate onto a lipophilic substance such as the reverse phase. In some embodiments, the same reverse phase as in chromatographic separation is used. When an aqueous solution of the chelate is brought into physical contact with the reverse phase, the chelate is adsorbed thereon. The chelate can then be desorbed from the reverse phase with a stronger eluent, which contains a higher proportion of a water-miscible organic solvent than the original chelate solution, and the water-miscible organic solvent is methanol, ethanol, propanol, isopropanol, acetone, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, or any two or more of these. The strength of the eluent is controlled by the proportion of the water-miscible organic solvent in the mobile phase.

[0058] In some embodiments, a solution of a metal chelate of a compound of general formula (I) is concentrated in two steps by adsorption to a reversed phase: (i) a dilute aqueous solution of the chelate is passed through the reversed phase to adsorb the chelate. If the solution is a chromatographic fraction collected from the preceding chromatographic separation and therefore contains a water-miscible organic solvent, the solution is first diluted with distilled water before adsorption to reduce the strength of the eluent. The solution may be diluted with an equal or greater volume of water, thereby reducing the proportion of the water-miscible organic solvent to less than half of the original value. In the second step, the chelate is desorbed from the reversed phase with a stronger eluent containing a higher proportion of the water-miscible organic solvent. The mobile phase used in the chromatographic separation may be used as the eluent. In this case, secondary chromatographic separation can be performed directly. Alternatively, a stronger eluent is used in a smaller volume than the original volume of the adsorbed solution, and the desorbed metal chelate is collected directly. In this case, the concentration of the metal chelate is increased compared to the original solution. The advantage of this method is that it allows for the concentration of metal chelate solutions without requiring time-consuming evaporation, which is an undesirable operation, especially when working with radionuclides. Importantly, on a reversed-phase chromatography column, this method results in the sorption of metal chelates in a narrow bandwidth at the beginning of the column, followed by sharp peaks and more efficient chromatographic separation. This is in contrast to the broad peaks and poor separation that would result from the presence of a strong eluent in the previously collected fraction if it were used without being modified for another chromatographic separation. Furthermore, this method allows for rapid and continuous chromatographic separation of the previously collected chromatographic fraction. Rapid repetition of chromatographic purification allows for the acquisition of the desired metal chelate in a shorter time and with higher purity.

[0059] In the described process, the Yb metal collected from the distillation / sublimation process can be reused (i.e., recycled for irradiation) almost immediately, whereas if only a chelation process were used for separation, the Yb ions from chelation would need to be separated from the solvent and chelate and then converted into a suitable form for reactor irradiation, such as an oxide or metal. Thus, this process provides a more streamlined and environmentally friendly process that facilitates the recycling of input materials.

[0060] Generally, "substituted" refers to alkyl groups, alkenyl groups, alkynyl groups, aryl groups, or ether groups, as defined below, in which one or more bonds to hydrogen atoms within the group are replaced by bonds to non-hydrogen or non-carbon atoms. Substituents also include groups in which one or more bonds to carbon or hydrogen atoms are replaced by one or more bonds, including double or triple bonds, to heteroatoms. Therefore, substituents will be substituted by one or more substituents unless otherwise specified. In some embodiments, substituents are substituted by one, two, three, four, five, or six substituents. Examples of substituents include halogens (i.e., F, Cl, Br, and I); hydroxyl groups; alkoxy groups, alkenoxy groups, alkynoxy groups, aryloxy groups, aralkyloxy groups, heterocyclyloxy groups, and heterocyclylalkoxy groups; carbonyl (oxo); carboxyl; esters; urethanes; oximes; hydroxylamines; alkoxyamines; aralkoxyamines; thiols; sulfides; sulfoxides; sulfones; sulfonyls; sulfamides; amines; N-oxides; hydrazines; hydrazides; hydrazones; azides; amides; ureas; amidines; guanidines; enamines; imides; isocyanates; isothiocyanates; cyanates; thiocyanates; imines; nitro groups; and nitriles (i.e., CN).

[0061] As used herein, the “alkyl” group includes linear or branched alkyl groups having 1 to 20 carbon atoms, typically 1 to 12 carbon atoms, or in some embodiments, 1 to 8 carbon atoms. As used herein, “alkyl group” includes cycloalkyl groups as defined below. Alkyl groups may be substituted or unsubstituted. Examples of linear alkyl groups include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, sec-butyl, t-butyl, neopentyl, and isopentyl groups. Typical substituted alkyl groups may be substituted one or more times with halo groups such as amino, thio, hydroxyl, cyano, alkoxy, and / or F, Cl, Br, and I groups. As used herein, the term haloalkyl is an alkyl group having one or more halo groups. In some embodiments, haloalkyl refers to per-haloalkyl groups.

[0062] Cycloalkyl groups are cyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups, but are not limited to those listed below. In some embodiments, cycloalkyl groups have 3 to 8 ring members, while in other embodiments, the number of carbon atoms in the ring ranges from 3 to 5, 6, or 7. Cycloalkyl groups may be substituted or unsubstituted. Cycloalkyl groups further include polycyclic cycloalkyl groups such as norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and calenyl groups, but are not limited to those listed below, and fused rings such as dekalinyl. Cycloalkyl groups also include rings substituted with linear or branched alkyl groups as defined above. Typical substituted cycloalkyl groups include, but are not limited to, 2,2-;2,3-;2,4-;2,5-; or 2,6-disubstituted cyclohexyl groups, or monosubstituted, disubstituted, or trisubstituted norbornyl or cycloheptyl groups (which may be substituted with alkyl groups, alkoxy groups, amino groups, thio groups, hydroxyl groups, cyano groups, and / or halo groups), and may be monosubstituted or multiple substituted.

[0063] As used herein, the “aryl” or “aromatic” group is a cyclic aromatic hydrocarbon that does not contain heteroatoms. Aryl groups include monocyclic, bicyclic, and polycyclic ring systems. Therefore, examples of aryl groups include, but are not limited to, phenyl, azlenyl, heptalenyl, biphenylenyl, indacenyl, fluorenyl, phenantrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenyl, anthracenyl, indenyl, indanyl, pentarenyl, and naphthyl groups. In some embodiments, the aryl group contains 6 to 14 carbon atoms, or 6 to 12 or even 6 to 10 carbon atoms in the ring portion of the group. The phrase “aryl group” includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, etc.). Aryl groups may be substituted or unsubstituted. A heteroaryl group is an aryl group that contains a heteroatom in its ring.

[0064] The present invention, as described in general terms, will be more readily understood by referring to the following examples. These examples are provided for illustrative purposes and are not intended to limit the present invention. [Examples]

[0065] Overview: Description of sublimation / distillation apparatus This apparatus comprises a high-vacuum chamber with appropriate gas, cooling, vacuum, power, and instrument feedthrough. The apparatus has a suitable volume for housing a refractory crucible suspended or supported within an RF induction heating coil and a cold surface with a collection substrate. Cold fingers (cooling rods) with appropriate end effectors are positioned directly above the crucible, allowing the open end of the crucible to be opened to the vacuum system or sealed to the collection substrate. The apparatus has appropriate instruments for monitoring the chamber vacuum pressure, crucible temperature, and cold plate temperature.

[0066] Explanation of the sublimation / distillation process 1. Load the concentrated Yb-176 metal into a 1 cm diameter quartz vial, sealed at both ends, while either evacuated or containing an inert gas. 2. The quartz vial is sealed in an inert overpack (i.e., aluminum) that is suitable for irradiation and impermeable to water and air. 3. Place the sealed overpack inside the reactor and irradiate it for several hours to several days (depending on the flux and batch requirements). 4. Remove the overpack from the reactor. 5. Load the transport casks into the processing hot cell or isolator. 6. Open the quartz vial containing the irradiated metal and remove the irradiated Yb metal target. 7. Place the irradiated Yb metal target into a refractory metal crucible (e.g., molybdenum or tantalum). 8. Under an inert atmosphere (e.g., He, N2, Ar, etc.), approximately 1 × 10⁻⁶ -6 Tor (approx. 133 x 10 -6 Evacuate the chamber until a stable pressure of Pa is achieved. 9. Next, the crucible is heated to approximately 470°C by radio frequency (RF) induction heating. At this temperature, the direct sublimation of Yb is indicated by a slight pressure increase in the vacuum chamber, as a small leakage path for Yb vapor is created. As the Yb metal sublimes from the heated crucible, the Yb metal is selectively deposited onto a cold finger that has been actively cooled for collection and reuse in step 1. 10. Sublimation is continued for approximately 40 minutes per gram of starting material. Completion of this process is when the vacuum pressure is approximately 5 × 10⁻⁶ -6 Tor (approx. 667 x 10 -6 From Pa) to approximately 1 × 10 -6 Tor (approx. 133 x 10 -6 This is confirmed by a sharp decline to below Pa. 11. After sublimation is complete, the crucible is further heated to approximately 600°C for 10 minutes. At this stage, only trace amounts of lutetium, trace amounts of ytterbium oxide, and trace amounts of contaminants remain in the crucible. 12. Then, add dilute hydrochloric acid (about 2 ml of about 2 M) to the crucible to dissolve the residual substance, take it out with a pipette or syringe, and filter it through a 0.22 μm membrane when transferring it to the HPLC system for chelation and separation.

[0067] Example 1. An illustrative example of this process Into a quartz vial 176 Load Yb metal (10 g) and irradiate for 6 days to 176 Convert some of the Yb 177 To Lu. 176 Yb / 177 Transfer the Yb / Lu mixed sample to a crucible and place it in a vacuum chamber. Next, for about 24 hours, at an external pressure of about 1 × 10 -6 Torr (about 133 × 10 -6 Pa), heat the crucible to 1000 °C. During this time, a part of the 176 Yb in the crucible sublimes onto the cold finger in the vacuum chamber, 177 and Lu remains in the crucible. After that, 176 Yb can be reused for further irradiation.

[0068] Next, 177 Dissolve Lu in 0.5 M to 6 M HCl. Then, add a chelating agent to the dissolved 177 Lu and add NaOH to form a chelated 177 Lu at neutral pH. The chelated 177 Lu contains other impurities at this point. For example, this chelated 177 Lu will contain Yb and may contain K, Na, Ca, Fe, Al, Si, Ni, Cu, Pb, La, Ce, Lu (other than Lu-177), Eu, Sn, Er, and Tm. Next, for further purification, subject the chelated 177 Lu to a high-performance liquid chromatography (HPLC) system (a reverse-phase C18 column containing 12 - 14 volume % methanol), and then elute the chelated 177 Lu with a higher purity than when it was subjected to this column. The chelated 177 Lu is released from the chelating agent as a chloride salt by acidification with HCl.

[0069] While specific embodiments have been illustrated and described, it should be understood that modifications and alterations can be made therein in accordance with the ordinary art in the art without departing from the broader aspects of the art as defined in the following claims.

[0070] The embodiments described herein as illustrative may be properly implemented without any elements or limitations not specifically disclosed herein. Therefore, terms such as “comprising,” “including,” and “containing” should be interpreted broadly and without limitation. Furthermore, the terms and expressions used herein are for illustrative purposes only and not limiting, and the use of such terms and expressions is not intended to exclude any equivalent of the illustrated and described features or any part thereof, but it should be recognized that various modifications are possible within the scope of the claimed technology. Furthermore, the phrase “substantially consisting of” should be understood to include additional elements that do not substantially affect the elements specifically mentioned and the fundamental and novel features of the claimed technology. The phrase “consisting of” excludes any elements not specifically identified.

[0071] This disclosure is not limited in terms of the specific embodiments described herein. As will be apparent to those skilled in the art, many modifications and alterations can be made without departing from its spirit and scope. In addition to those listed herein, functionally equivalent methods and compositions within the scope of this disclosure will be apparent to those skilled in the art from the foregoing description. Such modifications and alterations are intended to fall within the scope of the appended claims. This disclosure is limited only by the terms of the appended claims, along with the scope of the complete equivalents to which such claims are entitled. It should be understood that this disclosure is not limited to any particular method, reagent, compound, composition or biological system, which may naturally vary. It should also be understood that the terms used herein are for the purpose of describing a particular embodiment and are not intended to be limiting.

[0072] In addition, if any feature or aspect of the present disclosure is described in relation to the Markush group, a person skilled in the art will recognize that the present disclosure thus describes any individual element or subgroup of elements of the Markush group.

[0073] As will be understood by those skilled in the art, for any and all purposes, particularly in terms of providing written explanations, all scopes disclosed herein also encompass any and all possible partial scopes and combinations of partial scopes. Any enumerated scope can be readily recognized as fully explaining and enabling that the same scope may be divided into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each scope described herein can be readily divided into lower thirds, middle thirds, upper thirds, etc. Also, as will be understood by those skilled in the art, all language such as “up to,” “at least,” “greater than,” and “less than” refers to a scope that includes the number mentioned and can later be divided into partial scopes as described above. Finally, as will be understood by those skilled in the art, a scope includes each individual element.

[0074] All publications, patent applications, issued patents, and other documents referenced herein are incorporated herein by reference as if each individual publication, patent application, issued patent, or other document were specifically and individually incorporated by reference. Definitions contained in the text incorporated by reference are excluded to the extent that they conflict with the definitions in this disclosure.

[0075] The present invention can be implemented in the following embodiments. Embodiment 1

[0076] A method for purifying lutetium, A step of providing a solid composition containing ytterbium and lutetium, and In an inert or reduced pressure environment, sublimating or distilling ytterbium from the solid composition at a temperature of about 400 °C to about 3000 °C to leave a lutetium composition containing a higher mass percentage of lutetium than that present in the solid composition. A method comprising the steps of. Embodiment 2

[0077] The method according to embodiment 1, wherein the temperature is from about 450 °C to about 1500 °C. Embodiment 3

[0078] The method according to embodiment 1 or 2, wherein the temperature is from about 450 °C to about 1200 °C. Embodiment 4

[0079] The method according to any one of embodiments 1 to 3, further comprising the step of recovering the ytterbium for reuse. Embodiment 5

[0080] The reduced pressure is from about 1×10 -8 to about 2000 Torr (about 1.33×10 -6 Pa to 267 kPa). The method according to any one of embodiments 1 to 4. Embodiment 6

[0081] The temperature is from about 450 °C to about 1500 °C, and the pressure is from about 2000 Torr to about 1×10 -8 Torr (about 267 kPa to about 1.33×10 -6 Pa). The method according to any one of embodiments 1 to 4. Embodiment 7

[0082] The temperature is from about 450 °C to about 1200 °C, and the pressure is from about 1000 Torr to about 1×10 -8 Torr (about 133 kPa to about 1.33×10 -6 Pa). The method according to any one of embodiments 1 to 4. Embodiment 8

[0083] The pressure is from about 100 Torr to about 1×10 -7 Torr (about 13.3 kPa to about 1.33×10 -5 Pa). The method according to any one of embodiments 1 to 4. Embodiment 9

[0084] The aforementioned pressure is approximately 10 Torr to approximately 1 × 10 -6 Tor (approximately 1.33 kPa to approximately 133 × 10 -6 The method according to any one of Embodiments 1 to 4, wherein the temperature is approximately 450°C to approximately 800°C. Embodiment 10

[0085] The aforementioned pressure reduction is approximately 1 × 10 -3 The method according to any one of Embodiments 1 to 4, wherein the pressure is from approximately 2000 Torr (approximately 0.133 Pa to 267 kPa) and the temperature is from approximately 600°C to approximately 1500°C. Embodiment 11

[0086] The method according to any one of Embodiments 1 to 10, wherein the sublimation or distillation step is performed over a period of time ranging from about 1 second to about 1 week. Embodiment 12

[0087] The method according to any one of Embodiments 1 to 10, wherein the sublimation or distillation step is performed at a rate of approximately 10 minutes per gram of solid composition to approximately 100 minutes per gram of solid composition. Embodiment 13

[0088] The method according to Embodiment 12, wherein the sublimation or distillation step is performed at a rate of approximately 20 minutes per gram of solid composition to approximately 60 minutes per gram of solid composition. Embodiment 14

[0089] The method according to Embodiment 13, wherein the sublimation or distillation step is performed at a rate of approximately 40 minutes per gram of solid composition. Embodiment 15

[0090] The method according to any one of Embodiments 1 to 14, which results in a ytterbium mass reduction of the solid composition from 1000:1 to 10,000:1. Embodiment 16

[0091] The method according to any one of Embodiments 1 to 14, wherein the lutetium composition contains about 1% to 90% by mass of ytterbium. Embodiment 17

[0092] The method according to Embodiment 4, wherein the ytterbium is recovered in an amount of about 90% to about 99.999% by mass of the ytterbium present in the solid composition. Embodiment 18

[0093] The method according to Embodiment 1, wherein the solid composition further comprises metals, oxides, or ions of K, Na, Ca, Fe, Al, Si, Ni, Cu, Pb, La, Ce, Lu (non-radioactive), Eu, Sn, Er, and Tm. Embodiment 19

[0094] The method according to Embodiment 1, wherein the ytterbium comprises Yb-176 and the lutetium comprises Lu-177. Embodiment 20

[0095] The method according to Embodiment 1, wherein the steps provided include reducing ytterbium oxide to ytterbium metal and irradiating the ytterbium metal to produce lutetium. Embodiment 21

[0096] The method according to Embodiment 1, wherein the ytterbium is Yb-176, the lutetium is Lu-177, and the composition comprising solid Yb-176, solid Yb-177, and solid Lu-177 is formed by a neutron capture reaction with Yb-176. Embodiment 22

[0097] The method according to Embodiment 21, further comprising the step of contacting a solid containing Yb-176 with a neutron source before the sublimation step to convert at least a portion of the Yb-176 into Lu-177 to form the solid composition. Embodiment 23

[0098] A method comprising the step of removing at least a portion of Yb-176 from a sample containing Yb-176 and Lu-177 by sublimation, distillation, or a combination thereof, to form a sample concentrated with Lu-177. Embodiment 24

[0099] The method according to any one of Embodiments 1 to 23, further comprising the step of performing chromatographic separation on the lutetium composition or a lutetium-enriched sample to further concentrate the lutetium in the composition or sample. Embodiment 25

[0100] The method according to Embodiment 24, wherein the chromatographic separation includes column chromatography, plate chromatography, thin-film cell chromatography, or high-performance liquid chromatography. Embodiment 26

[0101] The method according to any one of Embodiments 1 to 25, further comprising the steps of: dissolving the lutetium composition or a sample concentrated with lutetium in an acid to form a dissolved lutetium solution; adding a chelating agent to the dissolved lutetium solution and neutralizing it with a base to form a chelated lutetium solution containing both chelated lutetium and ytterbium; and performing chromatographic separation on the chelated lutetium solution to collect a purified chelated lutetium fraction, dechelating the lutetium to obtain purified lutetium. Embodiment 27

[0102] The method according to Embodiment 26, wherein the purified chelate lutetium fraction has a higher purity of lutetium than the purity of lutetium in the dissolved lutetium solution. Embodiment 28

[0103] The method according to Embodiment 26 or 27, wherein the purified lutetium comprises Lu-177 that is more than 99% pure on an isotopic basis. Embodiment 29

[0104] The method according to Embodiment 26 or 27, wherein the purified lutetium contains Lu-177 which is ultrapure by isotopic standards at 99.9%. Embodiment 30

[0105] The method according to Embodiment 26 or 27, wherein the purified lutetium comprises Lu-177 which is ultrapure by isotopic standards at 99.99%. Embodiment 31

[0106] The method according to Embodiment 26 or 27, wherein the purified lutetium comprises Lu-177 which is ultrapure by isotopic standards at 99.999%. Embodiment 32

[0107] The method according to Embodiment 26 or 27, wherein the purified lutetium comprises Lu-177 which is ultrapure by isotopic standards at 99.9999%. Embodiment 33

[0108] The chelating agent is of formula (I):

[0109] [ka]

[0110] It is a compound represented by the following: During the ceremony: X is H, OH, SH, CF3, F, Cl, Br, I, C1-C6 alkyl, C1-C6 alkyloxy, C1-C6 alkylthio, NH2, C1-C6 alkylamino, di(C1-C6 alkyl)amino, NO2, or C(O)OH. Y is N, CH, COH, CF, O, or N-oxide (N + -O - ) and Each Z is independently either C or N, but at least one Z is C. n is either 0 or 1. L is a covalent bond or -C(O)-, R 1 This is a benzyl which is optionally substituted with one or more substituents selected from H, C1-C6 alkyl, or NO2, OH, (-CH2P(O)(OH)2, -CH2P(O)(OH)(C1-C6 alkyl), C1-C2 alkyl)C(O)OH (where the alkylenyl can optionally be substituted with a C1-C6 alkyl), R 2 , R 3 , and R 4 Each of them individually either does not exist, or exists if possible with the valence of Z, and if it exists, R 2 , R 3 , and R4 Each of these is individually H, F, Cl, Br, I, OH, SH, NH2, CN, NO2, COOR 5 , C1-C6 alkyl, C1-C6 alkyloxy, C6-C 10 Aryloxy, benzyloxy, C1-C6 alkylthio, C6-C 10 Arylthio, C1-C6 alkylamino, di(C1-C6 alkyl)amino, C1-C6 acylamino, di(C1-C6 acyl)amino, C6-C 10 Arylamino, or di(C6~C) 10 It is an aryl)amino, R 5 H or C1-C6 alkyl or C6-C 10 It is an aryl, or R 2 and R 3 , R 2 and R 4 , and / or R 3 and R 4 These atoms bond to each other, forming a six-membered ring with the adjacent Z atom, where the six-membered ring consists of OH, SH, CF3, F, Cl, Br, I, NO2, C(O)OH, C1-C6 alkyl, C1-C6 alkyloxy, C1-C6 alkylthio, NH2, C1-C6 alkylamino, di(C1-C6 alkyl)amino,

[0111] [ka]

[0112] The method according to any one of Embodiments 26 to 32, wherein one or more substituents are optionally substituted. Embodiment 34

[0113] The method according to Embodiment 33, wherein X is H, F, Cl, Br, I, CH3, or COOH. Embodiment 35

[0114] R 1 However, H, -CH2COOH, -CH2CH2COOH, -CH(CH3)COOH, -CH2P(O)(OH)2, -CH2P(O)(OH)(C1~C6alkyl), or

[0115] [ka]

[0116] The method described in Embodiment 33. Embodiment 36

[0117] L is a covalent bond, R 1 The method according to Embodiment 33, wherein the compound is H, OH, OCH3, NO2, F, Cl, Br, I, CH3, or COOH. Embodiment 37

[0118] The method according to Embodiment 33, wherein Y is N, all Z are C, n is 1, and X is F, Cl, Br, I, CH3, CF3, OCH3, SCH3, OH, SH, NH2, or NO2. Embodiment 38

[0119] The method according to Embodiment 33, wherein Y is N, all Z are N, n is 1, and X is F, Cl, Br, I, CH3, CF3, OCH3, SCH3, OH, SH, NH2, or NO2. Embodiment 39

[0120] Y is N-oxide (N + -O - ) where Z is carbon, n is 1, X is H, or X and its adjacent carbon, Z and R 1、2、または3 The method according to Embodiment 33, wherein a six-membered ring is formed, which is optionally substituted with one or more substituents independently selected from the group consisting of OH, SH, CF3, F, Cl, Br, I, NH2, NO2, C(O)OH, C1-C6 alkyl, C1-C6 alkyloxy, C1-C6 alkylthio, C1-C6 alkylamino, and di(C1-C6 alkyl)amino. Embodiment 40

[0121] The method according to Embodiment 33, wherein Y is C, all Z are C, n is 1, and X is H, NH2, or NO2. Embodiment 41

[0122] Y is N, all Z are C, n is 1, X is H, or X and its adjacent carbon, Z and R 1、2、または3 The method according to Embodiment 33, wherein a six-membered ring is formed, which is optionally substituted with one or more substituents independently selected from the group consisting of OH, SH, CF3, F, Cl, Br, I, NH2, NO2, C(O)OH, C1-C6 alkyl, C1-C6 alkyloxy, C1-C6 alkylthio, C1-C6 alkylamino, and di(C1-C6 alkyl)amino. Embodiment 42

[0123] The method according to Embodiment 33, wherein Y is N, all Zs are C, n is 1, and X is COOH. Embodiment 43

[0124] The chelating agent is 2,2',2”-(10-((6-fluoropyridine-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-((6-chloropyridine-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-((6-bromopyridine-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-((6-(trifluoro Methyl)pyridine-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate; 2,2',2”-(10-((6-methoxypyridine-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate; 2,2',2”-(10-((6-methylpyridine-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate; 2,2',2”-(10-((4,6-dimethylpyridine-2-yl)methyl)-1,4,7,10-teto Laazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-(pyridine-2-ylmethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-(isoquinoline-1-ylmethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-(isoquinoline-3-ylmethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-(quinoline-2-ylmethyl )-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-((6-carboxypyridine-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-((6-methylpyrazine-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-(pyrazine-2-ylmethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid;4-methyl-2-((4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)methyl)pyridine 1-oxide; 2-methyl-6-((4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)methyl)pyridine 1-oxide; 4-carboxy-2-((4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)methyl)pyridine 1-oxide; 2-((4,7,10-tris(carboxymethyl (L)-1,4,7,10-tetraazacyclododecane-1-yl)methyl)pyridine 1-oxide; 4-chloro-2-((4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)methyl)pyridine 1-oxide; 2-((4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)methyl)quinoline 1-oxide; 1-((4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)methyl)isopropyl Noline 2-oxide; 3-((4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)methyl)isoquinoline 2-oxide; 2,2',2”-(10-(2-hydroxybenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-(2-hydroxy-3-methylbenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-(2-hydroxy-4-methylbenzyl)-1 ,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-(2-hydroxy-5-(methoxycarbonyl)benzyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-(2-hydroxy-5-nitrobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-(2-methoxybenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid;2,2',2”-(10-((3-methoxynaphthalene-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-((1-methoxynaphthalene-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-(2-carboxybenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-(3-carboxybenzyl)-1,4 ,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-(4-carboxybenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-benzyl-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-(4-methylbenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-(2-methylbenzyl)-1,4 ,7,10-Tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-(4-nitrobenzyl)-1,4,7,10-Tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-(2-nitrobenzyl)-1,4,7,10-Tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-((perfluorophenyl)methyl)-1,4,7,10-Tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-(2-F Luolobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid; 2,2',2”-(10-(2,6-difluorobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid; 2,2',2”-(10-(naphthalene-2-ylmethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid; 2,2',2”-(10-(furan-2-ylmethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid;2,2',2”-(10-(2-oxo-2-phenylethyl)-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'-(4,10-bis(2-hydroxy-5-nitrobenzyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2,2'-(4-((6-carboxypyridine-2-yl)methyl)-1,4,7,10-tetraazacyclododecane -1,7-diyl)diacetic acid; 6,6'-((4,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)bis(methylene))dipicolinic acid; 2,2'-(4-((6-methylpyridine-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2,2'-(4,10-bis((6-methylpyridine-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2-((4,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; (Traazacyclododecane-1-yl)methyl)pyridine 1-oxide; 2,2'-((4,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)bis(methylene))bis(pyridine 1-oxide); 2,2'-(4-((5-carboxyfuran-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 5,5'-((4,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)bis(methylene))bis(furan-2- Carboxylic acid); 2,2'-(4,10-dibenzyl-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2,2'-(4-((perfluorophenyl)methyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2,2'-(4,10-bis((perfluorophenyl)methyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2,2'-(4-((1-methoxynaphthalene-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid;2,2'-(4-((3-methoxynaphthalene-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2,2'-(4-(2-carboxybenzyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2,2'-(4-(3-carboxybenzyl)-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 Acetic acid; 2,2'-(4-(2-hydroxybenzyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2,2'-(4-(2-hydroxy-3-methylbenzyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2-((4,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)methyl)-6-methylpyridine 1-oxide; 2,2'-(4-(3-carboxy-2-hydroxybenzyl)-1,4,7,10-tetra (Liazacyclododecane-1,7-diyl)diacetic acid; 2,2'-(4-((8-hydroxyquinoline-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2,2'-(4-benzyl-10-(2-hydroxy-5-nitrobenzyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2-((7-benzyl-4,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)methyl)pyridine 1-oxide; 2 ,2'-(4-benzyl-1-((6-carboxypyridine-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2,2'-(4-(2-carboxyethyl)-10-((6-methylpyridine-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2,2'-(4-((6-bromopyridine-2-yl)methyl)-10-(2-carboxyethyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid;2,2'-(4-(2-carboxyethyl)-10-((6-chloropyridine-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2,2'-(4-(2-carboxyethyl)-10-((6-fluoropyridine-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2,2'-(4-(2-carboxyethyl)-10-(pyridine-2-ylmethyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2-((7-(2-carboxyethyl)-4,10-bis(carboxymethyl)-1,4,7,10-te; tetraazacyclododecane-1-yl)methyl)pyridine 1-oxide; 2-((4,10-bis(carboxymethyl)-7-(2-hydroxy-5-nitrobenzyl)-1,4,7,10-tetraazacyclododecane-1-yl)methyl)pyridine 1-oxide; 2-((4,10-bis(carboxymethyl)-7-((6-carboxypyridine-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1-yl)methyl)pyridine 1-oxide; 2,2'-(4-((6-carboxypyridine-2-yl)methyl)-10-(2- Hydroxy-5-nitrobenzyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2,2'-(4-((6-carboxypyridine-2-yl)methyl)-10-((6-chloropyridine-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2,2'-(4-((6-bromopyridine-2-yl)methyl)-10-((6-carboxypyridine-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2,2'-(4-((6-carboxypyridine-2-yl)methyl)-10-((6-carboxypyridine-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2,2'-(4-((6-carboxy Luboxypyridine-2-yl)methyl)-10-((6-methylpyridine-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2,2'-(4-((6-carboxypyridine-2-yl)methyl)-10-(pyridine-4-ylmethyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2,2'-(4-((6-carboxypyridine-2-yl)methyl)-10-methyl-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2,2'-(4-((6 -Chloropyridine-2-yl)methyl)-10-(phosphonomethyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2,2'-(4-((6-bromopyridine-2-yl)methyl)-10-((hydroxy(methyl)phosphoryl)methyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; 2,2'-(4-((6-chloropyridine-2-yl)methyl)-10-((hydroxy(methyl)phosphoryl)methyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid;2,2',2”-(10-(2-oxo-2-(pyridine-2-yl)ethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2',2”-(10-(pyrimidine-2-ylmethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid; 2,2'-(4-(1-carboxyethyl)-10-((6- The method according to any one of Embodiments 26 to 33, wherein the compound is chloropyridine-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; or 2,2'-(4-((6-chloropyridine-2-yl)methyl)-10-(2-(methylsulfonamide)ethyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid. Embodiment 44;

[0125] The method according to any one of Embodiments 26 to 43, wherein the dechelation step includes contacting the purified chelated tetium fraction with an acid which is hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, peroxosulfuric acid, perchloric acid, methanesulfonic acid, trifluoromethanesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, or any two or more mixtures thereof. Embodiment 45

[0126] The method according to any one of Embodiments 26 to 44, wherein the base is lithium hydroxide, sodium hydroxide, potassium hydroxide, NH4OH, or alkylammonium hydroxide. Embodiment 46

[0127] The method according to any one of Embodiments 26 to 45, wherein the concentration of the acid is about 0.01 M to about 6 M, and / or the concentration of the base is about 0.01 M to about 6 M. [Explanation of Symbols]

[0128] 100 devices 105 Chamber 110 Accelerator Port 120 Cold Plate 140 Chambers 150 Vacuum pump connection 160 Cold Fingers, Cooling Rods 170 RF induction heating coil 190 Fireproof crucible 200 ports

Claims

[Claim 1] A method for purifying lutetium, A step of providing a solid composition containing ytterbium and lutetium, and A step of sublimating or distilling ytterbium from the solid composition at a temperature of about 400°C to about 3000°C in an inert or reduced-pressure environment, to leave a lutetium composition containing a higher mass percentage of lutetium than that present in the solid composition. A method comprising [a certain characteristic].

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