Method for purifying triethylenetetramine

Abstract

A process for purifying impure triethylenetetramine to high purity triethylenetetramine is described. In particular, a process is described for preparing a relatively pure triethylenetetramine salt starting from a crude triethylenetetramine and a crude triethylenetetramine salt.

Description

[0001] Citations of Related Applications

[0002] This application claims the benefit of U.S. Provisional Patent No. 63 / 395,829, filed on August 7, 2022, the contents of which are incorporated herein by reference. Technical Field

[0003] Disclosed herein is a process for purifying crude triethylenetetramine into high purity triethylenetetramine. In particular, the present invention relates to a process for preparing triethylenetetramine salts starting from crude triethylenetetramine. Background Art

[0004] Trientine, chemically known as triethylenetetramine or N,N'-bis(2-aminoethyl)-1,2-ethylenediamine, belongs to the class of polyethylene polyamines. Trientine dihydrochloride is a chelating agent used to bind and remove copper from the body in the treatment of Wilson's disease. The U.S. FDA approved the trientine dihydrochloride formulation (developed by Aton, with the proprietary name SYPRINE) on November 8, 1985 for the treatment of patients with Wilson's disease who are intolerant to penicillamine. Trientine dihydrochloride is being studied for various potential applications in the treatment of various diseases involving copper-mediated pathways due to its activity on copper homeostasis. The disuccinate of triethylenetetramine (triethylenetetramine succinate; or TES) has excellent properties, including: i) high crystallinity in the solid state; ii) only a single known polymorph; iii) very high purity; iv) excellent ability to exclude relevant impurities during the crystallization process and v) long-term stability. U.S. Patent No. 7,582,796 relates to the synthesis of the disuccinate salt of triethylenetetramine.

[0005] Highly complex synthetic methods for preparing triethylenetetramine (TET) and the corresponding dihydrochloride and other salts have been disclosed. U.S. Pat. No. US 4,806,517 discloses the synthesis of triethylenetetramine from ethylenediamine and monoethanolamine using a phosphorus catalyst supported on titanium dioxide, while US 4,550,209 and US 5,225,599 disclose the catalytic condensation of ethylenediamine and ethylene glycol using catalysts such as trimethylene diphosphite zirconium or a metatungstate composite of titanium dioxide and zirconium dioxide for the synthesis of linear triethylenetetramine. US 4,503,253 discloses the preparation of triethylenetetramine by reacting an alkanolamine compound with ammonia and an alkyleneamine having two primary amino groups in the presence of a catalyst such as supported phosphoric acid, wherein the support consists of silica, alumina or carbon. US 7,960,591 discloses a method for preparing triethylenetetramine by hydrogenating ethylenediamine diacetonitrile (EDDN) over a catalyst. However, each of the above methods for preparing triethylenetetramine requires high temperature and high pressure. In addition, due to various possible side reactions and the associated impurities that arise therefrom, it is difficult to control the purity of the desired amine for each of the above methods. Chinese patent CN 102924289 discloses a method for trientine dihydrochloride, which comprises reducing N,N'-dibenzyl-, N,N'-bis[2-(1,3-dioxo-2H-isoindolyl)ethyl]ethylenediamine using hydrazine hydrate to form N,N'-dibenzyl-, N,N'-bis(2-aminoethyl)ethylenediamine, which generates N,N'-dibenzyl-, N,N'-bis[2-(Cbz-amino)ethyl]ethylenediamine when condensed with benzyl chloroformate, and further reducing and deprotecting to form the desired compound.

[0006] Czechoslovak patent CS197,093 relates to a process comprising reacting triethylenetetramine with concentrated hydrochloric acid to obtain a crystalline tetrahydrochloride salt. The salt is further reacted with sodium ethoxide in the solvent ethanol, the solid sodium chloride produced in the process is filtered, and the filtrate is then slowly cooled and crystallized to provide a dihydrochloride salt. Optionally, an aqueous solution of the tetrahydrochloride salt is passed through a column of an anion exchanger, and the eluent containing the free base is treated with a calculated amount of hydrochloric acid, evaporated, and the residue is crystallized from an ethanol aqueous solution to produce the dihydrochloride salt. However, the above process is not commercially viable because it is very long and cumbersome, requires the use of a strong base, involves filtering of sodium chloride, and results in a low yield (e.g., 60%).

[0007] U.S. Pat. No. US 8,394,992 relates to a process for preparing triethylenetetramine dihydrochloride, wherein tert-butyloxycarbonyl (boc) protected triethylenetetramine is first converted to its tetrahydrochloride using a large excess of hydrochloric acid in a solvent of isopropanol, followed by treatment of the resulting tetrahydrochloride with a strong base such as sodium alkoxide to produce the amine free base (TETA) and sodium chloride under anhydrous conditions. The free amine is extracted with tert-butyl methyl ether (TBME), followed by removal of the sodium chloride, and finally the amine free base TET is treated with hydrochloric acid in a solvent of ethanol to form trientine hydrochloride. However, the above process has the following disadvantages: a) a lengthy process, including treatment of the tetrahydrochloride with a base under anhydrous conditions to obtain the amine and its further conversion to TETA dihydrochloride, which includes many unit operations such as solvent extraction, washing of filtered solids, solvent concentration, crystallization, etc. at various synthesis stages; b) use of excess hydrochloric acid and anhydrous alcohol and ether solvents. c) a strict requirement to completely remove the sodium chloride formed in the process. If the salts are not carefully removed, the final product, trientine hydrochloride, is unlikely to pass the sulfated ash test (a test that indicates complete removal of inorganic impurities from the drug product).

[0008] Korean patent KR 20080022940 relates to a method for preparing triethylenetetramine dihydrochloride by dissolving triethylenetetramine free base in methanol, and forming the dihydrochloride by adding concentrated hydrochloric acid aqueous solution. After removing the methanol, the mixture is precipitated with isopropanol and then filtered to obtain a mixture of triethylenetetramine dihydrochloride and impurities. The impure hydrochloride is then recrystallized.

[0009] Some reports (Journal of Chemical Research 2005(4), 233-235; XP055551215)) relate to a process for preparing trientine dihydrochloride from technical grade triethylenetetramine free base and identify three impurities [N,N-bis-(2-aminoethyl)-1,2-ethylenediamine, 1,4-piperazinediethylamine and N-[2-(1-piperazinyl)ethyl]-1,2-ethylenediamine] that are commonly formed during its synthesis. The brief process lacks sufficient details for completely obtaining isolated material. In addition, there is no mention of conditions that may form the desired product or its impurities. Moreover, the obtained dihydrochloride is purified again by recrystallization from 95% ethanol, wherein the insoluble trihydrochloride is removed as an insoluble impurity during the recrystallization process.

[0010] European patent EP 3 350 154 B1 discloses an expensive process for the synthesis of triethylenetetramine dihydrochloride, comprising a single step of treating a Boc-protected amine with hydrochloric acid to form the desired dihydrochloride in substantially pure form and in good yield.

[0011] All of the foregoing references are incorporated herein by reference in their entirety. Summary of the invention

[0012] In some aspects, the present disclosure provides a method for preparing a high purity triethylenetetraamine diacid salt, comprising the following steps:

[0013] a) contacting impure triethylenetetramine (TET) with a diacid to obtain a crude solid; and

[0014] b) The crude solid is recrystallized to obtain high purity triethylenetetraamine diacid salt.

[0015] In some aspects, the high purity triethylenetetraamine dichloride is about 95% to about 99.95% pure. In some aspects, the high purity triethylenetetraamine dichloride is about 98% to about 99% pure. In some aspects, the high purity triethylenetetraamine dichloride is about 98.5% pure. In some aspects, the high purity triethylenetetraamine dichloride is high purity triethylenetetraamine disuccinate (TES). In some aspects, the diacid is selected from the group consisting of the following: succinic acid, malonic acid, oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid and its derivatives, dibenzoyltartaric acid, glutaric acid and adipic acid. In some aspects, the diacid is succinic acid. In some aspects, the impure triethylenetetramine (TET) is about 60% to about 95% pure. In some aspects, the impure triethylenetetramine (TET) is about 60% to about 70% pure. In some aspects, the impure triethylenetetramine (TET) is about 60% to about 65% pure.

[0016] In some aspects, the present disclosure provides a method of recrystallization, the method comprising the steps of:

[0017] a) dissolving or partially dissolving the crude solid in a suitable solvent at elevated temperature to obtain a solution or suspension;

[0018] b) cooling the solution or suspension to form high purity triethylenetetraamine dicarboxylic acid salt as crystals; and

[0019] c) collecting the high-purity triethylenetetraamine dichloride.

[0020] In some aspects, the suitable solvent is selected from the group consisting of the following: polar protic solvents and polar aprotic solvents or mixtures thereof. In some aspects, the polar protic solvent is selected from water, C1-C8 alcohols and C1-C8 polyols. In some aspects, the alcohol is selected from the group consisting of the following: methanol, ethanol, isopropanol, 1-propanol, ethylene glycol, propylene glycol and butanediol. In some aspects, the C1-C8 alcohol is methanol. In some aspects, the polar aprotic solvent is selected from the group consisting of the following: C1-C8 ethers, cyclic C4-C6 ethers, acetone, 2-butanone, dimethylacetamide, N-methylpyrrolidone, N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile and dimethylpropylene urea, pyridine, cyclopentane sulfone and hexamethylphosphoric acid triamide. In some aspects, the polar aprotic solvent is acetonitrile. In some aspects, the mixture is water and acetonitrile. In some aspects, the mixture is about 2% to about 25% water. In some aspects, the mixture is about 5% to about 15% water. In some aspects, the mixture is water and C1-C8 alcohol. In some aspects, the alcohol is selected from the group consisting of methanol, ethanol, isopropanol and 1-propanol. In some aspects, the alcohol is methanol. In some aspects, the mixture is about 2% to about 25% water. In some aspects, the mixture is about 5% to about 10% water. In some aspects, the elevated temperature is about 20°C to about the boiling point of the solvent or the mixture of solvents.

[0021] In some aspects, the present disclosure provides a method for preparing a high purity triethylenetetraamine diacid salt, comprising the following steps:

[0022] a) dissolving impure triethylenetetramine (TET) in a suitable solvent to obtain a first solution;

[0023] b) adding a diacid to the first solution to form a second mixture;

[0024] c) allowing the second mixture to form a precipitate of crude triethylenetetraamine diacid salt;

[0025] d) collecting crude triethylenetetraamine dioic acid salt; and

[0026] e) Optionally, recrystallizing the crude triethylenetetraamine diacid salt to obtain high purity triethylenetetraamine diacid salt.

[0027] In some aspects, the high purity triethylenetetraamine dichloride is about 95% to about 99.95% pure. In some aspects, the high purity triethylenetetraamine dichloride is about 98% to about 99% pure. In some aspects, the high purity triethylenetetraamine dichloride is about 98.5% pure. In some aspects, the high purity triethylenetetraamine dichloride is high purity triethylenetetraamine succinate (TES). In some aspects, the diacid is selected from the group consisting of the following: succinic acid, malonic acid, maleic acid, fumaric acid, malic acid, tartaric acid and its derivatives, dibenzoyltartaric acid, glutaric acid and adipic acid. In some aspects, the diacid is succinic acid. In some aspects, the impure triethylenetetramine (TET) is about 60% to about 95% pure. In some aspects, the impure triethylenetetramine (TET) is about 60% to about 70% pure. In some aspects, the impure triethylenetetramine (TET) is about 60% pure. In some aspects, the solvent is selected from the group consisting of: C1-C8 alcohols, water, acetonitrile, and tetrahydrofuran, or mixtures thereof.

[0028] In some aspects, the step of recrystallizing the crude triethylenetetraamine diacid salt as needed to obtain a high purity triethylenetetraamine diacid salt is performed by a method comprising the following steps:

[0029] i) dissolving or partially dissolving the crude solid in a suitable solvent at elevated temperature to obtain a solution;

[0030] ii) cooling the solution to form high purity triethylenetetraamine dicarboxylic acid salt as crystals; and

[0031] iii) collecting high purity triethylenetetraamine dichloride.

[0032] In some aspects, the suitable solvent is selected from the group consisting of the following: polar protic solvents and polar aprotic solvents or mixtures thereof. In some aspects, the polar protic solvent is selected from water, C1-C8 alcohols and C1-C8 polyols. In some aspects, the alcohol is selected from the group consisting of the following: methanol, ethanol, isopropanol, 1-propanol, ethylene glycol, propylene glycol and butanediol. In some aspects, the C1-C8 alcohol is methanol. In some aspects, the polar aprotic solvent is selected from the group consisting of the following: C1-C8 ethers, cyclic C4-C6 ethers, acetone, 2-butanone, dimethylacetamide, N-methylpyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, dimethylpropylene urea, pyridine, cyclopentane sulfone and hexamethylphosphoric acid triamide. In some aspects, the polar aprotic solvent is acetonitrile. In some aspects, the mixture is water and acetonitrile. In some aspects, the mixture is about 2% to about 25% water. In some aspects, the mixture is about 5% to about 10% water. In some aspects, the mixture is water and C1-C8 alcohol. In some aspects, the alcohol is selected from the group consisting of methanol, ethanol, isopropanol and 1-propanol. In some aspects, the alcohol is methanol. In some aspects, the mixture is about 2% to about 25% water. In some aspects, the mixture is about 5% to about 15% water. In some aspects, the elevated temperature is about 20°C to about the boiling point of the solvent or the mixture of solvents.

[0033] In some aspects, the present disclosure provides a method for preparing a high purity triethylenetetraamine diacid salt, comprising the following steps:

[0034] a) dissolving impure triethylenetetramine (TET) in a first solvent to obtain a first solution;

[0035] b) warming the first solution to a first temperature;

[0036] c) adding the diacid as a solid or as a solution in a second solvent to the first solution at a first temperature to form a second solution;

[0037] d) optionally, cooling the second solution to a second temperature to form a precipitate of high purity triethylenetetraamine diacid salt; and

[0038] e) collecting high-purity triethylenetetramine diacid.

[0039] In some aspects, the high purity triethylenetetraamine dichloride is about 95% to about 99.95% pure. In some aspects, the high purity triethylenetetraamine dichloride is about 98% to about 99% pure. In some aspects, the high purity triethylenetetraamine dichloride is about 98.5% pure. In some aspects, the high purity triethylenetetraamine dichloride is high purity triethylenetetraamine disuccinate (TES). In some aspects, the diacid is selected from the group consisting of the following: succinic acid, malonic acid, maleic acid, fumaric acid, malic acid, tartaric acid and its derivatives, dibenzoyltartaric acid, glutaric acid and adipic acid. In some aspects, the diacid is succinic acid. In some aspects, the impure triethylenetetramine (TET) is about 60% to about 90% pure. In some aspects, the impure triethylenetetramine (TET) is about 60% to about 70% pure. In some aspects, the impure triethylenetetramine (TET) is about 65% pure. In some aspects, the first solvent is selected from the group consisting of the following: C1-C8 alcohol, C1-C8 polyol, acetonitrile, tetrahydrofuran and water and their mixtures. In some aspects, the alcohol is selected from the group consisting of the following: methanol, ethanol, isopropanol, 1-propanol, ethylene glycol, propylene glycol and butanediol. In some aspects, the first temperature is about 50 ° C to about 95 ° C. In some aspects, the first temperature is about 65 ° C to about 80 ° C. In some aspects, the second solvent is selected from the group consisting of the following: C1-C8 alcohol, acetonitrile, tetrahydrofuran and water and their mixtures. In some aspects, the second temperature is about -5 ° C to about 25 ° C. In some aspects, the second temperature is about 0 ° C.

[0040] In some aspects, the present disclosure provides a method for preparing high-purity triethylenetetramine dihydrochloride or high-purity triethylenetetramine tetrahydrochloride from impure triethylenetetramine, comprising the following steps:

[0041] a) contacting impure triethylenetetramine (TET) with a diacid to obtain a crude solid;

[0042] b) recrystallizing the crude solid to obtain high purity triethylenetetraamine dicarboxylic acid salt;

[0043] c) contacting the high-purity triethylenetetramine dicarboxylic acid salt with an aqueous base solution to form high-purity triethylenetetramine (TET); and

[0044] d) converting the high purity triethylenetetramine (TET) into its dihydrochloride salt by the method described herein.

[0045] In some aspects, the high purity triethylenetetraamine dichloride is about 95% to about 99.95% pure. In some aspects, the high purity triethylenetetraamine dichloride is about 98% to about 99% pure. In some aspects, the high purity triethylenetetraamine dichloride is about 98.5% pure. In some aspects, the high purity triethylenetetraamine dichloride is high purity triethylenetetraamine disuccinate (TES). In some aspects, the diacid is selected from the group consisting of the following: succinic acid, malonic acid, oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid and its derivatives, dibenzoyltartaric acid, glutaric acid and adipic acid. In some aspects, the diacid is succinic acid. In some aspects, the alkali aqueous solution is selected from the group consisting of the following: sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, sodium carbonate aqueous solution and potassium carbonate aqueous solution. In some aspects, the impure triethylenetetramine (TET) is about 60% to about 90% pure. In some aspects, the impure triethylenetetramine (TET) is about 60% to about 70% pure. In some aspects, the impure triethylenetetramine (TET) is about 60% pure.

[0046] In some aspects, the present disclosure provides a recrystallization method, wherein the recrystallization method is performed by a method comprising:

[0047] i) dissolving or partially dissolving the crude solid in a suitable solvent at elevated temperature to obtain a solution or suspension;

[0048] i) cooling the solution or suspension to form high purity triethylenetetraamine dicarboxylic acid salt as solid crystals; and

[0049] iii) collecting high purity triethylenetetraamine dichloride.

[0050] In some aspects, the suitable solvent is selected from the group consisting of the following: polar protic solvents and polar aprotic solvents or mixtures thereof. In some aspects, the polar protic solvent is selected from water, C1-C8 alcohols and C1-C8 polyols. In some aspects, the alcohol is selected from the group consisting of the following: methanol, ethanol, isopropanol, 1-propanol, ethylene glycol, propylene glycol and butanediol. In some aspects, the C1-C8 alcohol is methanol. In some aspects, the polar aprotic solvent is selected from the group consisting of the following: C1-C8 ethers, cyclic C4-C6 ethers, acetone, 2-butanone, dimethylacetamide, N-methylpyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, dimethylpropylene urea, pyridine, cyclopentane sulfone and hexamethylphosphoric acid triamide. In some aspects, the polar aprotic solvent is acetonitrile. In some aspects, the mixture is water and acetonitrile. In some aspects, the mixture is about 2% and about 25% water. In some aspects, the mixture is about 5% to about 10% water. In some aspects, the mixture is water and C1-C8 alcohol. In some aspects, the alcohol is selected from the group consisting of methanol, ethanol, isopropanol and 1-propanol. In some aspects, the alcohol is methanol. In some aspects, the mixture is about 2% to about 25% water. In some aspects, the mixture is about 5% to about 10% water. In some aspects, the elevated temperature is about 20°C to about the boiling point of the solvent or the mixture of solvents.

[0051] In some aspects, the present disclosure provides a method for preparing high purity triethylenetetramine (TET) by contacting a high purity triethylenetetramine diacid salt with an aqueous base to form high purity triethylenetetramine.

[0052] In some aspects, the present disclosure provides a method for preparing high purity triethylenetetramine (TET) by contacting a high purity triethylenetetramine diacid salt with a material capable of ion exchange, such as an ion exchange resin, to form high purity triethylenetetramine. DETAILED DESCRIPTION

[0053] When describing the compounds and methods of the present invention, the terms used should be interpreted according to the following definitions unless the context indicates otherwise. When referring to measurable values ​​(such as parameters, purity, amount, time duration, etc.), the term "about" as used herein is intended to cover the specified value and + / -10% or less, preferably + / -5% or less, more preferably + / -1% or less and still more preferably + / -0.1% or less changes from the specified value, provided that these changes are suitable for making in the disclosed invention. It should be understood that the value referred to by the modifier "about" itself is also specifically and preferably disclosed.

[0054] Reference processes for preparing various salts of triethylenetetramine require substantially pure triethylenetetramine (about 98% or higher), which is difficult and expensive to produce. Technical grade triethylenetetramine would be a convenient and cost-effective starting material in the synthesis of its salts, however, it is often contaminated with impurities such as ethylenediamine, diethylenetriamine, piperazine and various derivatives, and branched polyamine impurities, making it unsuitable for the production of a single pure salt.

[0055] In some embodiments, the present disclosure provides a cost-effective way not only for producing high-purity (98% or more) triethylenetetramine but also for producing various salts of triethylenetetramine. High-purity (about 98% or more) triethylenetetramine can be produced from cheap industrial-grade (about 65% pure; about $30USD / Kg) triethylenetetramine, and optionally converted into its salt form. For example, the high-purity triethylenetetramine produced can be converted into its dihydrochloride using any method described herein. In some embodiments, the present disclosure provides a commercially viable and cost-effective method for producing high-purity crystalline diacids of triethylenetetramine (including high-purity crystalline disuccinates starting from industrial-grade triethylenetetramine). Industrial-grade (e.g., impure) triethylenetetramine (TET) can be obtained by reacting 1,2-diaminoethane with ethanolamine and a catalyst.

[0056] The purification process described herein provides a convenient, cost-effective and industrially feasible method for synthesizing triethylenetetramine dihydrochloride (1) which avoids the following: a) lengthy synthetic routes for protecting and deprotecting reactant amines and intermediates, b) excessive use of organic solvents, c) use of inorganic acids in multiple steps. Additional advantages of the purification process disclosed herein are avoidance of strong bases, controlled number of unit operations, and good yield of the desired dihydrochloride salt.

[0057] As used herein, the term "salt" or "pharmaceutically acceptable salt" refers to salts derived from pharmaceutically compatible organic and / or inorganic counterions of the referenced compounds.

[0058] As used herein, the term "Cx-y" when used in conjunction with a chemical moiety such as an alkyl, alkenyl, or alkynyl group is intended to include groups containing from x to y carbons in the chain. For example, the term "Cx-y alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group, including straight-chain alkyl and branched-chain alkyl groups containing from x to y carbons in the chain, including halogenated alkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl, etc. The term "Cx-y alcohol" refers to a substituted or unsubstituted saturated aliphatic alcohol group, including straight-chain alkyl alcohol and branched-chain alkyl alcohol groups containing from x to y carbons in the alkyl chain.

[0059] The alcohol and / or alcohol solvent is typically a short chain alcohol. The alcohol typically has the formula ROH, where R is a linear or branched C 1-8 Alkyl. C 1-8 The alkyl group is preferably unsubstituted. Examples of alcohols include methanol, ethanol, n-propanol, propanol, n-butanol, isobutanol, sec-butanol and tert-butanol. Methanol and ethanol are preferred. Methanol is more preferred.

[0060] Ethers and / or ether solvents are typically short chain ethers. Ethers typically have the formula RO-R', where R and R' are the same or different and represent a linear or branched C 1-8 Alkyl. C 1-8 The alkyl group is preferably unsubstituted. Preferred ethers include diethyl ether, diisopropyl ether and methyl tert-butyl ether (MTBE). 4-6 Cyclic ethers such as tetrahydrofuran and tetrahydropyran. Nitrile solvents are well known to those skilled in the art. Nitriles are generally short chain nitriles. Nitriles generally have the formula R-CN, wherein R represents a linear or branched C 1-6 Alkyl. C 1-6 The alkyl group is preferably unsubstituted. Preferred nitriles include acetonitrile.

[0061] As used herein, when referring to an aqueous organic solvent, the term "aqueous solution" refers to a composition comprising water and the listed organic compound. For example, "aqueous methanol solution" refers to a composition comprising 1 to 99 wt.% water and the remainder methanol. In some embodiments, the aqueous phase may further include dissolved salts.

[0062] In some embodiments, the organic solvent aqueous solution is an alcohol aqueous solution or an acetonitrile aqueous solution. The organic solvent aqueous solution is preferably a methanol aqueous solution or an acetonitrile aqueous solution.

[0063] The purity of reagents and products can be determined by any analytical method known to those skilled in the art, such as ion chromatography, high pressure liquid chromatography (HPLC), proton nuclear magnetic resonance spectroscopy ( 1 HNMR), carbon nuclear magnetic resonance spectroscopy ( 13 C NMR), infrared spectroscopy (IR), powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), and melting point.

[0064] In some embodiments, the present disclosure relates to a unit dose of a pharmaceutical composition for treating a disease involving a copper-mediated pathway,

[0065] wherein the unit dose contains an effective amount of a TET salt formulated as a pharmaceutical composition for administration to a subject in need thereof, wherein the formulation of the composition and the amount of the TET salt in the unit dose are configured such that the unit dose is effective for treating a disease involving a copper-mediated pathway by removing or reducing the level of free copper (e.g., copper (I) or copper (II)) from the blood or tissues of the subject when the unit dose is administered to the subject, thereby reducing the severity of one or more signs or symptoms of the disease involving a copper-mediated pathway without causing side effects,

[0066] Wherein the TET salt has been prepared by a synthetic method comprising the following steps:

[0067] i) dissolving impure triethylenetetramine in a polar protic solvent or a polar aprotic solvent at a first temperature to form a dissolved impure triethylenetetramine solution;

[0068] ii) dissolving succinic acid in a protic solvent or a polar aprotic solvent, optionally at a second temperature, to form a dissolved succinic acid solution;

[0069] iii) optionally adding solid succinic acid or optionally adding a dissolved succinic acid solution to form a dissolved triethylenetetraamine succinate solution at a third temperature;

[0070] iv) cooling the dissolved triethylenetetraamine succinate solution to a fourth temperature, thereby forming solid triethylenetetraamine succinate (TES); and

[0071] v) collecting the solid triethylenetetraamine succinate (TES),

[0072] Wherein, the first temperature range is about 50°C to about 70°C,

[0073] Wherein, the second temperature range is about 50°C to about 70°C,

[0074] wherein the third temperature range is from about 50°C to about 70°C, and

[0075] Wherein, the fourth temperature range is from about 0°C to about 40°C.

[0076] In some embodiments, the polar protic solvent is methanol. In some embodiments, the polar aprotic solvent is acetonitrile. In some embodiments, the polar protic solvent will be a mixture of water and an alcohol such as methanol, ethanol, or 2-propanol.

[0077] Some methods involving ion exchange

[0078] In some embodiments, the present disclosure provides a method for preparing high-purity triethylenetetramine (TET) by contacting a high-purity triethylenetetramine diacid salt with a material capable of ion exchange to form high-purity triethylenetetramine. The material capable of ion exchange can be an ion exchange resin. The ion exchange resin can be cationic or anionic. In some embodiments, the method for preparing high-purity TET by a method involving an ion exchange resin includes contacting a TET salt with an ion exchange resin in acid form, and then filtering the ion exchange resin from the solution after a selected time (e.g., 1 minute-8 hours) at room temperature. In some embodiments, the ion exchange method for the preparation of high-purity TET can be similar to those disclosed in U.S. Patent No. US 4263145, which is incorporated herein by reference.

[0079] Example:

[0080] Example 1

[0081] 7.30 grams (30 mmol, corrected for purity) of technical grade (60% purity; Mallinckrodt Sigma-Aldrich) triethylenetetramine were dissolved in 50 mL of acetonitrile and warmed to 65°C with stirring. Separately, succinic acid (11.8 gm, 100 mmol) was dissolved in a warm (65°C) solution of 75 mL of acetonitrile:water (2:1). The warm succinic acid solution was added to the acetonitrile solution of triethylenetetramine over approximately 3 hours. After the addition was complete, the solution was cooled to room temperature over approximately 4 hours. The formation of a crystalline precipitate was observed to occur spontaneously at 40-45°C. Alternatively, crystallization can be initiated by seeding with a small amount (less than 500 mg) of preformed crystals at about 55°C or less. After cooling to 20°C, the suspension was stirred for an additional 2 hours and then the crystalline solid was filtered. The solid was washed with 30 mL of acetonitrile and dried to constant weight to obtain 10.11 g (88.3%) of crystalline triethylenetetramine disuccinate which was identical (PXRD, single crystal X-ray, 1 H and 13 C NMR).

[0082] Example 2

[0083] 7.30 grams (48.5 mmol, corrected for purity) of 97% pure triethylenetetramine (Mallinckrodt Sigma-Aldrich) were dissolved in 50 mL of acetonitrile and warmed to 65°C under stirring, and separately succinic acid (11.8 gm, 100 mmol) was dissolved in a warm (65°C) solution of 75 acetonitrile: water (2:1). The warm succinic acid solution was added to the acetonitrile solution of triethylenetetramine over approximately 3 hours. After the addition was complete, the solution was cooled to room temperature over approximately 4 hours. The formation of a second oily layer was observed to occur spontaneously at approximately 50°C. This layer appeared to be a mixture of crystalline and oily material. Under continuous stirring (approximately 2 hours) at 20°C, the precipitated material was completely converted into a large amount of crystalline material. The solid was isolated by filtration and washed with 30 mL of acetonitrile. After drying to constant weight, 17.09 grams of crystalline triethylenetetramine disuccinate were obtained. The product is identical to the prior art material (PXRD, 1 H and 13 C NMR).

[0084] Example 3

[0085] The method of Example 1 was repeated (all weights and volumes of materials and solvents were the same), except that methanol was used as the solvent instead of acetonitrile. The use of 60% pure triethylenetetramine (as in Example 1) resulted in the isolation of 9.51 g (83.0% yield, corrected for purity) of crystalline triethylenetetramine disuccinate.

[0086] Example 4

[0087] 7.30 grams (48.5 mmol, corrected for purity) of 97% pure triethylenetetramine (Mallinckrodt Sigma-Aldrich) were dissolved in 50 mL of methanol and stirred at 25°C. Over 30 minutes, a solution of succinic acid (11.8 gm, 100 mmol) in 100 mL of 60°C methanol was added to the solution. After adding about 25% of the succinic acid solution, precipitation of a second oily layer was observed. After the addition was complete, the suspension was cooled to 20°C over about 5 hours and stirred for another 18 hours. At this point, it was noted that the oily layer was converted into a crystalline precipitate. The product was isolated by filtration and washed with 75 mL of methanol. After drying to constant weight, 17.27 grams (93.2% yield) of crystalline product were obtained, which was identical in all respects to the material obtained from Example 1-3.

[0088] Example 5

[0089] 7.30 grams (30 mmol, corrected for purity) of 60% pure triethylenetetramine (Mallinckrodt Sigma-Aldrich) were dissolved in 50 mL of methanol and stirred at 25°C. Over 30 minutes, a solution of succinic acid (11.8 gm, 100 mmol) in 100 mL of 60°C methanol was added to the solution. After adding about 25% of the succinic acid solution, precipitation of a second oily layer was observed. After the addition was complete, the suspension was cooled to 20°C over about 5 hours and stirred for another 18 hours. At this point, it was noted that the oily layer was converted into a crystalline precipitate. The product was isolated by filtration and washed with 50 mL of methanol. After drying to constant weight, 9.27 grams (80.9% yield) of crystalline product were obtained, which was the same as the material obtained by Example 1-4.

[0090] Example 6

[0091] 7.30 grams (48.5 mmol, corrected for purity) of 97% pure triethylenetetramine (Mallinckrodt Sigma-Aldrich) were dissolved in 50 mL of acetonitrile and stirred at 25°C. Over 30 minutes, a solution of succinic acid (11.8 gm, 100 mmol) in 100 mL of 70°C acetonitrile was added to the solution. After adding about 25% of the succinic acid solution, precipitation of a second oily layer was observed. After the addition was completed, the suspension was cooled to 20°C over about 5 hours and stirred for another 18 hours. At this point, it was noted that the oily layer was converted into a crystalline precipitate. The product was isolated by filtration and washed with 75 mL of acetonitrile. After drying to constant weight, 14.89 grams (80.4% yield) of crystalline product were obtained, which was identical in all respects to the material obtained from the other examples.

[0092] Example 7

[0093] 7.30 grams (30 mmol, corrected for purity) of 60% pure triethylenetetramine (Mallinckrodt Sigma-Aldrich) were dissolved in 50 mL of methanol and stirred at 25°C. Over 30 minutes, a solution of succinic acid (7.08 gm, 60 mmol) in 100 mL of 60°C methanol was added to the solution. After adding about 50% of the succinic acid solution, precipitation of a second oily layer was observed. After the addition was complete, the suspension was cooled to 20°C over about 5 hours and stirred for another 18 hours. At this point, it was noted that the oily layer was converted into a crystalline precipitate. The product was isolated by filtration and washed with 50 mL of methanol. After drying to constant weight, 8.47 grams (73.9% yield) of crystalline product were obtained, which was the same as the material obtained by the other examples.

[0094] In a further embodiment of the invention, the crystalline salt of triethylenetetramine and an organic diacid may be recrystallized to improve their purity. Thus, 97.6% pure triethylenetetramine disuccinate may be recrystallized as follows to improve the purity to greater than 99%.

[0095] Example 8

[0096] Triethylenetetramine disuccinate (7.64 g, about 20 mmol) of 97.6% purity (determined by GC / MS) was dissolved in 120 mL of 10% aqueous methanol solution under heating and stirring to produce a clear solution at 60°C. The solution was slowly cooled to 20°C over about 2 hours and kept stirring at this temperature for another 1 hour. The solution was further cooled to about 5°C and kept at this temperature for another 2 hours. The solution was filtered and the filter cake was washed with about 40 mL of methanol. The filter cake was dried to constant weight at 50°C under reduced pressure. The product was obtained with a purity of 99.6% (GC / MS) in a yield of 6.30 g (84% recovery).

[0097] In another embodiment of the present invention, the crystalline salt of triethylenetetramine and an organic diacid can be converted to the free amine with high recovery and high purity.

[0098] Example 9

[0099] Triethylenetetramine disuccinate (3.82 grams, about 10 mmol) of 99.95% purity (determined by ion chromatography) was suspended in 40 mL of isopropyl acetate. The suspension was shaken with 20 mL of 3N aqueous sodium hydroxide solution to obtain a clear two-phase liquid mixture. Solid sodium chloride was added to the aqueous layer to obtain a saturated solution. The layers were separated and the aqueous layer was extracted twice with 30 mL portions of isopropyl acetate. The combined organic layers were washed with saturated brine (50 mL). Isopropyl acetate was removed under reduced pressure to provide 1.23 grams of 99.2% pure triethylenetetramine (containing 0.4% isopropyl acetate; recovery was 83%).

[0100] Example 10

[0101] Triethylenetetraamine disuccinate (3.82 grams, about 10 mmol) of 99.95% purity (determined by ion chromatography) was suspended in 40 mL of isopropyl acetate. The suspension was shaken with 20 mL of 3N aqueous sodium hydroxide solution to obtain a clear two-phase liquid mixture. The layers were separated and the aqueous layer was extracted twice with 30 mL portions of isopropyl acetate. The combined organic layers were dried over solid sodium chloride and concentrated to a volume of about 3 mL. The product was purified by flash column chromatography using The crude product was purified by KP-NH column using hexane / EtOAc (0%-30% ethyl acetate gradient) as mobile phase. Triethylenetetramine was obtained with greater than 99% purity and about 75%-90% recovery after removal of volatile solvents.

[0102] Embodiment 11

[0103] Triethylenetetramine disuccinate (3.82 grams, about 10 mmol) of 99.95% purity (determined by ion chromatography) was suspended in 40 mL of isopropyl acetate. The suspension was shaken with 20 mL of 3N aqueous sodium hydroxide solution to obtain a clear two-phase liquid mixture. The layers were separated and the aqueous layer was extracted twice with 30 mL portions of isopropyl acetate. The combined organic layers were dried over solid sodium chloride and concentrated under reduced pressure to a volume of about 3 mL. The crude product was distilled using a kugelrohr apparatus. Triethylenetetramine was obtained with greater than 99% purity and about 81% recovery.

[0104] Example 12

[0105] Triethylenetetramine disuccinate (3.82 g, about 10 mmol) of 99.95% purity (determined by ion chromatography) was converted to the corresponding free amine by ion exchange chromatography using an anion exchange resin. After removal of the solvent, free triethylenetetramine was obtained in almost quantitative recovery.

[0106] Other Embodiments

[0107] Additional embodiments of the present disclosure are provided as follows:

[0108] Embodiment 1: A method for preparing high-purity triethylenetetraamine dichloride, comprising the following steps:

[0109] a) contacting impure triethylenetetramine (TET) with a diacid to obtain a crude solid; and

[0110] b) The crude solid is recrystallized to obtain high purity triethylenetetraamine diacid salt.

[0111] Embodiment 2: The method of embodiment 1, wherein the high purity triethylenetetraamine dicarboxylic acid salt is about 95% to about 99.95% pure.

[0112] Embodiment 3: The method of embodiment 2, wherein the high purity triethylenetetraamine dicarboxylic acid salt is about 98% to about 99% pure.

[0113] Embodiment 4: The method of embodiment 3, wherein the high purity triethylenetetraamine dicarboxylic acid salt is about 98.5% pure.

[0114] Embodiment 5: The method according to embodiment 1, 2, 3 or 4, wherein the high purity triethylenetetraamine diacid salt is high purity triethylenetetraamine disuccinate (TES).

[0115] Embodiment 6: The method according to embodiment 1, wherein the diacid is selected from the group consisting of succinic acid, malonic acid, oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid and its derivatives, dibenzoyltartaric acid, glutaric acid and adipic acid.

[0116] Embodiment 7: The method according to embodiment 6, wherein the diacid is succinic acid.

[0117] Embodiment 8: The method of embodiment 1, wherein the impure triethylenetetramine (TET) is about 60% to about 95% pure.

[0118] Embodiment 9: The method of embodiment 8, wherein the impure triethylenetetramine (TET) is about 60% to about 70% pure.

[0119] Embodiment 10: The method of embodiment 9, wherein the impure triethylenetetramine (TET) is about 60% to about 65% pure.

[0120] Embodiment 11: The method according to embodiment 1, wherein the recrystallization is accomplished by:

[0121] a) dissolving or partially dissolving the crude solid in a suitable solvent at elevated temperature to obtain a solution or suspension;

[0122] b) cooling the solution or suspension; and

[0123] c) collecting high-purity triethylenetetraamine dichloride.

[0124] Embodiment 12: The method according to embodiment 11, wherein the suitable solvent is selected from the group consisting of a polar protic solvent, a polar aprotic solvent, or a mixture thereof.

[0125] Embodiment 13: The method of embodiment 12, wherein the polar protic solvent is selected from water, C1-C8 alcohols and C1-C8 polyols.

[0126] Embodiment 14: The method of embodiment 13, wherein the C1-C8 alcohol is selected from the group consisting of methanol, ethanol, isopropanol, 1-propanol, ethylene glycol, propylene glycol, and butanediol.

[0127] Embodiment 15: The method of embodiment 14, wherein the C1-C8 alcohol is methanol.

[0128] Embodiment 16: A method according to embodiment 12, wherein the polar aprotic solvent is selected from the group consisting of: C1-C8 ethers, cyclic C4-C6 ethers, acetone, 2-butanone, dimethylacetamide, N-methylpyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, dimethylpropylene urea, pyridine, cyclopentane sulfone and hexamethylphosphoric acid triamide.

[0129] Embodiment 17: The method of embodiment 16, wherein the polar aprotic solvent is acetonitrile.

[0130] Embodiment 18: The method of Embodiment 17, wherein the mixture is water and acetonitrile.

[0131] Embodiment 19: The method of Embodiment 18, wherein the mixture is about 2% to about 25% water.

[0132] Embodiment 20: The method of Embodiment 19, wherein the mixture is about 5% to about 15% water.

[0133] Embodiment 21: The method of embodiment 12, wherein the mixture is water and a C1-C8 alcohol.

[0134] Embodiment 22: The method of embodiment 21, wherein the alcohol is selected from the group consisting of methanol, ethanol, isopropanol and 1-propanol.

[0135] Embodiment 23: The method of Embodiment 22, wherein the alcohol is methanol.

[0136] Embodiment 24: The method of Embodiment 21, wherein the mixture is about 2% to about 50% water.

[0137] Embodiment 25: The method of Embodiment 24, wherein the mixture is about 5% to about 20% water.

[0138] Embodiment 26: The method of Embodiment 12, wherein the elevated temperature is from about 20°C to about the boiling point of the solvent or mixture of solvents.

[0139] Embodiment 27: A method for preparing high-purity triethylenetetraamine dichloride, comprising the following steps:

[0140] a) dissolving impure triethylenetetramine (TET) in a suitable solvent to obtain a first solution;

[0141] b) adding a diacid to the first solution to form a second mixture;

[0142] c) allowing the second mixture to stand or stir to form a precipitate of crude triethylenetetraamine diacid salt;

[0143] d) collecting crude triethylenetetraamine dioic acid salt; and

[0144] e) Optionally, the crude triethylenetetraamine diacid salt is recrystallized to obtain high purity triethylenetetraamine diacid salt as required.

[0145] Embodiment 28: The method of Embodiment 24, wherein the high purity triethylenetetraamine dicarboxylic acid salt is about 95% to about 99.95% pure.

[0146] Embodiment 29: The method of Embodiment 25, wherein the high purity triethylenetetraamine dicarboxylic acid salt is about 98% to about 99% pure.

[0147] Embodiment 30: The method of Embodiment 26, wherein the high purity triethylenetetraamine dicarboxylic acid salt is about 98.5% pure.

[0148] Embodiment 31: The method according to embodiment 27, 28, 29 or 30, wherein the high purity triethylenetetramine diacid salt is high purity triethylenetetramine disuccinate (TES).

[0149] Embodiment 32: The method of embodiment 27, wherein the diacid is selected from the group consisting of succinic acid, malonic acid, maleic acid, fumaric acid, malic acid, tartaric acid and its derivatives, dibenzoyltartaric acid, glutaric acid and adipic acid.

[0150] Embodiment 33: The method of embodiment 32, wherein the diacid is succinic acid.

[0151] Embodiment 34: The method of Embodiment 27, wherein the impure triethylenetetramine (TET) is about 60% to about 95% pure.

[0152] Embodiment 35: The method of embodiment 34, wherein the impure triethylenetetramine (TET) is about 60% to about 70% pure.

[0153] Embodiment 36: The method of Embodiment 25, wherein the impure triethylenetetramine (TET) is about 60% pure.

[0154] Embodiment 37: The method of embodiment 27, wherein the solvent is selected from the group consisting of: C1-C8 alcohols, water, acetonitrile and tetrahydrofuran, or mixtures thereof.

[0155] Embodiment 38: The method according to embodiment 27, wherein the recrystallization is performed by:

[0156] a) dissolving or partially dissolving the crude solid in a suitable solvent at elevated temperature to obtain a solution;

[0157] b) cooling the solution; and

[0158] c) collecting high-purity triethylenetetraamine dichloride.

[0159] Embodiment 39: The method according to embodiment 38, wherein the suitable solvent is selected from the group consisting of: a polar protic solvent, a polar aprotic solvent, or a mixture thereof.

[0160] Embodiment 40: The method of embodiment 39, wherein the polar protic solvent is selected from water, C1-C8 alcohols and C1-C8 polyols.

[0161] Embodiment 41: The method of embodiment 40, wherein the alcohol is selected from the group consisting of methanol, ethanol, isopropanol, 1-propanol, ethylene glycol, propylene glycol, and butanediol.

[0162] Embodiment 42: A method according to embodiment 40, wherein the C1-C8 alcohol is methanol.

[0163] Embodiment 43: A method according to embodiment 39, wherein the polar aprotic solvent is selected from the group consisting of: C1-C8 ethers, cyclic C4-C6 ethers, acetone, 2-butanone, dimethylacetamide, N-methylpyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, dimethylpropylene urea, pyridine, cyclopentane sulfone and hexamethylphosphoric acid triamide.

[0164] Embodiment 44: The method of Embodiment 43, wherein the polar aprotic solvent is acetonitrile.

[0165] Embodiment 45: The method of Embodiment 39, wherein the mixture is water and acetonitrile.

[0166] Embodiment 46: The method of Embodiment 45, wherein the mixture is about 2% to about 50% water.

[0167] Embodiment 47: The method of Embodiment 46, wherein the mixture is about 5% to about 20% water.

[0168] Embodiment 48: The method of Embodiment 45, wherein the mixture is water and a C1-C8 alcohol.

[0169] Embodiment 49: The method of embodiment 48, wherein the alcohol is selected from the group consisting of methanol, ethanol, isopropanol and 1-propanol.

[0170] Embodiment 50: The method of embodiment 49, wherein the alcohol is methanol.

[0171] Embodiment 51: The method of Embodiment 48, wherein the mixture is about 2% to about 50% water.

[0172] Embodiment 52: The method of Embodiment 51, wherein the mixture is about 5% to about 20% water.

[0173] Embodiment 53: The method of Embodiment 38, wherein the elevated temperature is from about 20°C to about the boiling point of the solvent or mixture of solvents.

[0174] Embodiment 54: A method for preparing high-purity triethylenetetraamine dichloride, comprising the following steps:

[0175] a) dissolving impure triethylenetetramine (TET) in a first solvent to obtain a first solution;

[0176] b) warming the first solution to a first temperature;

[0177] c) adding the diacid as a solid or in solution in a second solvent to the first solution at a first temperature to form a second solution;

[0178] d) optionally cooling the second solution to a second temperature to form a precipitate of high purity triethylenetetraamine dicarboxylic acid salt; and

[0179] e) collecting high-purity triethylenetetraamine dichloride.

[0180] Embodiment 55: The method of Embodiment 54, wherein the high purity triethylenetetraamine dicarboxylic acid salt is about 95% to about 99.95% pure.

[0181] Embodiment 56: The method of Embodiment 55, wherein the high purity triethylenetetraamine dicarboxylic acid salt is about 98% to about 99% pure.

[0182] Embodiment 57: The method of Embodiment 56, wherein the high purity triethylenetetraamine dicarboxylic acid salt is about 98.5% pure.

[0183] Embodiment 58: The method according to embodiment 54, 55, 56 or 57, wherein the high purity triethylenetetraamine diacid salt is high purity triethylenetetraamine disuccinate (TES).

[0184] Embodiment 59: The method of embodiment 54, wherein the diacid is selected from the group consisting of succinic acid, malonic acid, fumaric acid, malic acid, maleic acid, tartaric acid and its derivatives, dibenzoyltartaric acid, oxalic acid, glutaric acid and adipic acid.

[0185] Embodiment 60: The method of embodiment 59, wherein the diacid is succinic acid.

[0186] Embodiment 61: The method of Embodiment 54, wherein the impure triethylenetetramine (TET) is about 60% to about 90% pure.

[0187] Embodiment 62: The method of Embodiment 61, wherein the impure triethylenetetramine (TET) is about 60% to about 70% pure.

[0188] Embodiment 63: The method of embodiment 62, wherein the impure triethylenetetramine (TET) is about 60% pure.

[0189] Embodiment 64: The method of embodiment 63, wherein the first solvent is selected from the group consisting of: C1-C8 alcohols, C1-C8 polyols, acetonitrile, tetrahydrofuran, and water, and mixtures thereof.

[0190] Embodiment 65: The method of embodiment 64, wherein the alcohol is selected from the group consisting of methanol, ethanol, isopropanol, 1-propanol, ethylene glycol, propylene glycol, and butanediol.

[0191] Embodiment 66: The method of Embodiment 54, wherein the first temperature is from about 50°C to about 95°C.

[0192] Embodiment 67: The method of Embodiment 66, wherein the first temperature is from about 65°C to about 80°C.

[0193] Embodiment 68: The method of embodiment 54, wherein the second solvent is selected from the group consisting of: C1-C8 alcohols, acetonitrile, tetrahydrofuran, and water, and mixtures thereof.

[0194] Embodiment 69: The method of Embodiment 54, wherein the second temperature is from about -5°C to about 25°C.

[0195] Embodiment 70: The method of embodiment 60, wherein the second temperature is about 0°C.

[0196] Embodiment 71: A method for preparing high purity triethylenetetramine dihydrochloride, comprising the following steps:

[0197] a) contacting impure triethylenetetramine (TET) with a diacid to obtain a crude solid;

[0198] b) recrystallizing the crude solid to obtain high purity triethylenetetraamine dicarboxylic acid salt;

[0199] c) contacting the high-purity triethylenetetramine dicarboxylic acid salt with an aqueous base solution to form high-purity triethylenetetramine (TET); and

[0200] d) Converting high purity triethylenetetramine (TET) into its dihydrochloride salt using any of the literature methods described in this specification.

[0201] Embodiment 72: The method of embodiment 71, wherein the high purity triethylenetetraamine dicarboxylic acid salt is about 95% to about 99.95% pure.

[0202] Embodiment 73: The method of Embodiment 72, wherein the high purity triethylenetetraamine dicarboxylic acid salt is about 98% to about 99% pure.

[0203] Embodiment 74: The method of Embodiment 73, wherein the high purity triethylenetetraamine dicarboxylic acid salt is about 98.5% pure.

[0204] Embodiment 75: The method of embodiment 71, 72, 73 or 74, wherein the high purity triethylenetetramine diacid salt is high purity triethylenetetramine disuccinate (TES).

[0205] Embodiment 76: The method of embodiment 71, wherein the diacid is selected from the group consisting of succinic acid, malonic acid, maleic acid, fumaric acid, malic acid, tartaric acid and its derivatives, dibenzoyltartaric acid, oxalic acid, glutaric acid and adipic acid.

[0206] Embodiment 77: The method of embodiment 76, wherein the diacid is succinic acid.

[0207] Embodiment 78: The method of embodiment 71, wherein the aqueous base solution is selected from the group consisting of an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, an aqueous sodium carbonate solution, and an aqueous potassium carbonate solution.

[0208] Embodiment 79: The method of embodiment 71, wherein the impure triethylenetetramine (TET) is about 60% to about 90% pure.

[0209] Embodiment 80: The method of embodiment 79, wherein the impure triethylenetetramine (TET) is about 60% to about 70% pure.

[0210] Embodiment 81: The method of embodiment 80, wherein the impure triethylenetetramine (TET) is about 60% pure.

[0211] Embodiment 82: The method according to embodiment 71, wherein the recrystallization is performed by the following steps:

[0212] a) dissolving or partially dissolving the crude solid in a suitable solvent at elevated temperature to obtain a solution or suspension;

[0213] b) cooling the solution or suspension; and

[0214] c) collecting high-purity triethylenetetraamine dichloride.

[0215] Embodiment 83: The method according to embodiment 82, wherein the suitable solvent is selected from the group consisting of: a polar protic solvent and a polar aprotic solvent or a mixture thereof.

[0216] Embodiment 84: A method according to embodiment 83, wherein the polar protic solvent is selected from water, C1-C8 alcohols and C1-C8 polyols.

[0217] Embodiment 85: The method of embodiment 84, wherein the C1-C8 alcohol is selected from the group consisting of methanol, ethanol, isopropanol, 1-propanol, ethylene glycol, propylene glycol, and butanediol.

[0218] Embodiment 86: A method according to embodiment 84, wherein the C1-C8 alcohol is methanol.

[0219] Embodiment 87: A method according to embodiment 83, wherein the polar aprotic solvent is selected from the group consisting of: C1-C8 ethers, cyclic C4-C6 ethers, acetone, 2-butanone, dimethylacetamide, N-methylpyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, dimethylpropylene urea, pyridine, cyclopentane sulfone and hexamethylphosphoric acid triamide.

[0220] Embodiment 88: The method of embodiment 87, wherein the polar aprotic solvent is acetonitrile.

[0221] Embodiment 89: The method of embodiment 87, wherein the mixture is water and acetonitrile.

[0222] Embodiment 90: The method of Embodiment 89, wherein the mixture is about 2% to about 25% water.

[0223] Embodiment 91: The method of Embodiment 90, wherein the mixture is about 5% to about 10% water.

[0224] Embodiment 92: A method according to embodiment 83, wherein the mixture is water and a C1-C8 alcohol.

[0225] Embodiment 93: The method of embodiment 92, wherein the alcohol is selected from the group consisting of methanol, ethanol, isopropanol and 1-propanol.

[0226] Embodiment 94: A method according to embodiment 93, wherein the alcohol is methanol.

[0227] Embodiment 95: The method of Embodiment 92, wherein the mixture is about 2% to about 25% water.

[0228] Embodiment 96: The method of embodiment 95, wherein the mixture is about 5% to about 10% water.

[0229] Embodiment 97: The method of Embodiment 96, wherein the elevated temperature is from about 20°C to about the boiling point of the solvent or mixture of solvents.

[0230] Embodiment 98: A method for preparing high-purity triethylenetetramine succinate from impure triethylenetetramine, the method comprising:

[0231] i) dissolving impure triethylenetetramine in a polar protic solvent or a polar aprotic solvent at a first temperature to form a dissolved impure triethylenetetramine solution;

[0232] ii) dissolving succinic acid in aqueous acetonitrile at a second temperature to form a dissolved succinic acid solution;

[0233] iii) adding the dissolved impure triethylenetetramine solution to the dissolved succinic acid solution at a third temperature to form a dissolved triethylenetetramine succinate solution;

[0234] iv) cooling the dissolved triethylenetetraamine succinate solution to a fourth temperature, thereby forming solid triethylenetetraamine succinate (TES); and

[0235] v) collecting the solid triethylenetetraamine succinate (TES),

[0236] wherein the first temperature range is from about 60°C to about 70°C,

[0237] wherein the second temperature range is from about 60°C to about 70°C,

[0238] wherein the third temperature range is from about 60°C to about 70°C, and

[0239] The fourth temperature range is from about 0°C to about 25°C.

[0240] Embodiment 99: A method according to embodiment 98, wherein the polar protic solvent is methanol.

[0241] Embodiment 100: The method of embodiment 98, wherein the polar aprotic solvent is acetonitrile.

Claims

1. A method for preparing high-purity triethylenetetraamine dicarboxylic acid salt, comprising the following steps: a) contacting impure triethylenetetramine (TET) with a diacid to obtain a crude solid; and b) recrystallizing the crude solid to obtain a high purity triethylenetetraamine diacid salt, wherein the high purity triethylenetetraamine diacid salt is about 95% to about 99.95% pure.

2. The method of claim 1 wherein the high purity triethylenetetraamine dicarboxylic acid salt is about 98.5% pure.

3. The method of claim 1, wherein the diacid is selected from the group consisting of succinic acid, malonic acid, oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid and its derivatives, dibenzoyltartaric acid, glutaric acid and adipic acid. The method of claim 3 , wherein the diacid is succinic acid.

5. The method of claim 1, wherein the impure triethylenetetramine (TET) is about 60% to about 70% pure.

6. The method according to claim 1, wherein the recrystallization is performed by a method comprising the steps of: i) dissolving or partially dissolving the crude solid in a solvent selected from polar aprotic solvents or polar protic solvents at elevated temperature to obtain a solution or suspension; ii) cooling the solution or suspension; and iii) collecting high purity triethylenetetraamine dichloride.

7. The method according to claim 6, wherein the polar protic solvent is selected from water, C1-C8 alcohols, C1-C8 polyols and mixtures thereof.

8. The method of claim 7, wherein the C1-C8 alcohol is selected from the group consisting of methanol, ethanol, isopropanol, 1-propanol, ethylene glycol, propylene glycol, and butanediol.

9. The method of claim 6, wherein the polar protic solvent is methanol.

10. The method of claim 6, wherein the polar aprotic solvent is selected from the group consisting of C1-C8 ethers, cyclic C4-C6 ethers, acetone, 2-butanone, dimethylacetamide, N-methylpyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, dimethylpropylene urea, pyridine, sulfolane, hexamethylphosphoric triamide, and mixtures thereof.

11. The method of claim 6, wherein the polar aprotic solvent is an aqueous solution comprising acetonitrile.

12. The method of claim 6, wherein the aprotic solvent is acetonitrile.

13. The method of claim 11, wherein the aqueous solution comprising acetonitrile comprises about 5% to about 50% water.

14. The method of claim 6, wherein the elevated temperature is from about 20°C to about the boiling point of the solvent or mixture of solvents.

15. A method for preparing high-purity triethylenetetramine diacid salt from impure triethylenetetramine, comprising the following steps: a) dissolving impure triethylenetetramine (TET) in a suitable solvent to obtain a first solution; b) adding a diacid to the first solution to form a second mixture; c) allowing the second mixture to stand or stir to form a precipitate of crude triethylenetetraamine dicarboxylic acid salt; d) collecting the crude triethylenetetraamine dioic acid salt; and e) Optionally, recrystallizing the crude triethylenetetraamine diacid salt to obtain high purity triethylenetetraamine diacid salt.

16. The method of claim 15, wherein the high purity triethylenetetraamine dicarboxylic acid salt is from about 95% to about 99.95% pure.

17. The method of claim 15, wherein the diacid is selected from the group consisting of succinic acid, malonic acid, maleic acid, fumaric acid, malic acid, tartaric acid and its derivatives, dibenzoyltartaric acid, glutaric acid, and adipic acid.

18. The method of claim 17, wherein the diacid is succinic acid.

19. The method of claim 15, wherein the impure triethylenetetramine (TET) is about 60% to about 95% pure.

20. The method of claim 15, wherein the solvent is selected from the group consisting of C1-C8 alcohols, water, acetonitrile, tetrahydrofuran, or mixtures thereof.

21. The method of claim 15, wherein the recrystallization is performed by a process comprising: i) dissolving or partially dissolving the crude solid in a suitable solvent at elevated temperature to obtain a solution; ii) cooling the solution to form a high purity triethylenetetraamine dicarboxylic acid salt; and iii) collecting high-purity triethylenetetraamine dichloride, The suitable solvent is selected from polar protic solvents, polar aprotic solvents or mixtures thereof.

22. The method of claim 21, wherein the polar protic solvent is selected from water, methanol or a mixture thereof.

23. The method of claim 21, wherein the polar aprotic solvent is acetonitrile or an aqueous solution comprising acetonitrile.

24. The method of claim 23, wherein the aqueous solution comprising acetonitrile comprises about 2% to about 50% water.

25. The method of claim 22, wherein the solvent is methanol.

26. The method of claim 21, wherein the elevated temperature is from about 20°C to about the boiling point of the solvent or mixture of solvents.

27. A method for preparing high-purity triethylenetetraamine dichloride, comprising the following steps: a) dissolving impure triethylenetetramine (TET) in a first solvent to form a first solution; b) warming the first solution to a first temperature; c) adding the diacid as a solid or in solution in a second solvent to the first solution at a first temperature to form a second solution; d) optionally, cooling the second solution to a second temperature to form a precipitate of high purity triethylenetetraamine diacid salt; and e) collecting the high-purity triethylenetetraamine dichloride.

28. The method of claim 27, wherein the high purity triethylenetetraamine dicarboxylic acid salt is about 95% to about 99.95% pure.

29. The method of claim 27, wherein the diacid is selected from the group consisting of succinic acid, malonic acid, fumaric acid, malic acid, maleic acid, tartaric acid and its derivatives, dibenzoyltartaric acid, oxalic acid, glutaric acid, and adipic acid.

30. The method of claim 29, wherein the diacid is succinic acid.

31. The method of claim 27, wherein the impure triethylenetetramine (TET) is about 60% to about 90% pure.

32. The method of claim 27, wherein the first solvent is selected from the group consisting of methanol, acetonitrile, tetrahydrofuran, water, and mixtures thereof.

33. The method of claim 27, wherein the first temperature is from about 50°C to about 80°C.

34. The method of claim 27, wherein the second solvent is selected from the group consisting of methanol, acetonitrile, tetrahydrofuran, water, and mixtures thereof.

35. The method of claim 27, wherein the second temperature is from about -5°C to about 25°C.

36. A method for preparing high-purity triethylenetetramine dihydrochloride, comprising the following steps: a) contacting impure triethylenetetramine (TET) with a diacid to form a crude solid; b) recrystallizing the crude solid to obtain high purity triethylenetetraamine dicarboxylic acid salt; c) contacting the high-purity triethylenetetramine dicarboxylic acid salt with an aqueous base solution to form high-purity triethylenetetramine (TET); and d) converting the high-purity triethylenetetramine (TET) into its dihydrochloride salt.

37. The method of claim 36, wherein the high purity triethylenetetraamine dicarboxylic acid salt is from about 95% to about 99.95% pure.

38. The method of claim 36, wherein the diacid is selected from the group consisting of succinic acid, malonic acid, maleic acid, fumaric acid, malic acid, tartaric acid and its derivatives, dibenzoyltartaric acid, oxalic acid, glutaric acid, and adipic acid.

39. The method of claim 36, wherein the diacid is succinic acid.

40. The method of claim 36, wherein the aqueous base solution is selected from the group consisting of aqueous sodium hydroxide solution, aqueous potassium hydroxide solution, aqueous sodium carbonate solution, and aqueous potassium carbonate solution.

41. The method of claim 36, wherein the recrystallization is performed by the following steps: i) dissolving or partially dissolving the crude solid in a suitable solvent at elevated temperature to obtain a solution or suspension; ii) cooling the solution or suspension to form a high purity triethylenetetraamine dicarboxylic acid salt; and iii) collecting high purity triethylenetetraamine dichloride.

42. The method of claim 41, wherein the suitable solvent is selected from the group consisting of polar protic solvents and polar aprotic solvents or mixtures thereof.

43. The method of claim 41, wherein the polar protic solvent is selected from water, methanol or mixtures thereof.

44. The method of claim 41, wherein the polar aprotic solvent is selected from the group consisting of C1-C8 ethers, cyclic C4-C6 ethers, acetone, 2-butanone, dimethylacetamide, N-methylpyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, dimethylpropylene urea, pyridine, sulfolane, and hexamethylphosphoric triamide.

45. The method of claim 44, wherein the polar aprotic solvent is acetonitrile or an aqueous solution comprising acetonitrile, wherein the aqueous solution comprising acetonitrile comprises about 2% to about 25% water.

46. ​​The method of claim 41, wherein the elevated temperature is from about 20°C to about the boiling point of the solvent or mixture of solvents.

47. A method for preparing high-purity triethylenetetramine dihydrochloride, comprising the following steps: a) contacting impure triethylenetetramine (TET) with a diacid to form a crude solid; b) optionally recrystallizing the crude solid to obtain high purity triethylenetetraamine diacid salt; c) contacting the high purity triethylenetetramine diacid salt with an ion exchange solid to form high purity triethylenetetramine (TET); and d) converting the high-purity triethylenetetramine (TET) into its dihydrochloride salt.