Method for purifying triethylenetetramine

Abstract

Methods for the purification of impure triethylenetetramine to high-purity triethylenetetramine are described. In particular, methods for the preparation of relatively pure salts of triethylenetetramine starting from crude triethylenetetramine and crude triethylenetetramine salts are described. In some embodiments, the present disclosure provides methods for the preparation of high-purity triethylenetetramine diacid salts, the methods comprising: a) contacting impure triethylenetetramine (TET) with a diacid to result in a crude solid; and b) recrystallizing the crude solid to obtain high-purity triethylenetetramine diacid salts.

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 395,829, filed August 7, 2022, the contents of which are incorporated herein by reference.

[0002] FIELD OF THE INVENTION Disclosed herein is a process for the purification of crude triethylenetetramine to high purity triethylenetetramine. Specifically, the present invention relates to a process for the preparation of salts of triethylenetetramine starting from crude triethylenetetramine. [Background technology]

[0003] background Trientine (chemically known as triethylenetetramine or N,N'-bis(2-aminoethyl)-1,2-ethanediamine) belongs to the class of polyethylenepolyamines. Trientine dihydrochloride is a chelating agent used to bind and remove copper from the body in the treatment of Wilson's disease. A trientine dihydrochloride formulation (developed by Aton and trade name SYPRINE) was approved by the U.S. Food and Drug Administration (US FDA) on November 8, 1985, for the treatment of patients with Wilson's disease (who are penicillamine intolerant). Due to its activity on copper homeostasis, trientine dihydrochloride is under investigation for various potential applications in the treatment of various diseases involving copper-mediated pathways. The disuccinate salt of triethylenetetramine (triethylenetetramine succinate; or TES) has excellent properties, including: i) high crystallinity in the solid state; ii) only one known polymorph; iii) very high purity; iv) excellent ability to remove related impurities during crystallization; and v) long-term stability. U.S. Patent No. 7,582,796 refers to the synthesis of the disuccinate salt of triethylenetetramine.

[0004] Highly complex synthetic methods have been described for the preparation of triethylenetetramine (TET) and its corresponding dihydrochloride and other salts. U.S. Patent No. 4,806,517 discloses the synthesis of triethylenetetramine from ethylenediamine and monoethanolamine using a titania-supported phosphorus catalyst, while U.S. Patent Nos. 4,550,209 and 5,225,599 disclose the catalytic condensation of ethylenediamine with ethylene glycol to synthesize linear triethylenetetramine using a catalyst such as zirconium trimethylenediphosphonate or a metatungstate complex of titanium dioxide and zirconium dioxide. U.S. Patent No. 4,503,253 discloses the preparation of triethylenetetramine by the reaction of an alkanolamine compound, ammonia, and an alkyleneamine having two primary amino groups in the presence of a catalyst such as supported phosphoric acid (the support is composed of silica, alumina, or carbon). U.S. Patent No. 7,960,591 describes a process for producing triethyleneaminetetramine by hydrogenation of ethylenediaminediacetonitrile (EDDN) over a catalyst. However, each of the above methods for preparing triethylenetetramine requires high temperatures and pressures. Furthermore, due to various possible side reactions and the resulting associated impurities, it is difficult to control the purity of the desired amine for each of the above methods. Chinese patent CN102924289 discloses a process for trientine dihydrochloride, which involves reducing N,N'-dibenzyl-,N,N'-bis[2-(1,3-dioxo-2H-isoindolyl)ethyl]ethanediamine using hydrazine hydrate to form N,N'-dibenzyl-,N,N'-bis(2-aminoethyl)ethanediamine, which is condensed with benzyl chloroformate to yield N,N'-dibenzyl-,N,N'-bis[2-(Cbz-amino)ethyl]ethanediamine, and further reductive deprotection to form the desired compound.

[0005] Czechoslovak Patent CS197,093 describes a process for obtaining a crystalline tetrahydrochloride salt of triethylenetetramine by reacting it with concentrated hydrochloric acid. The dihydrochloride salt was obtained by further reacting the salt with sodium ethoxide in an ethanol solvent, filtering the solid sodium chloride produced in the process, followed by slow cooling and crystallization of the filtrate. If necessary, an aqueous solution of the tetrahydrochloride salt was passed through an anion exchange column, and the eluate containing the free base was treated with a calculated amount of hydrochloric acid and evaporated. The residue was crystallized from aqueous ethanol to obtain the dihydrochloride salt. However, the above process is not commercially viable because it is very lengthy and laborious, requires the use of a strong base, involves filtering the sodium chloride, and results in low yields (e.g., 60%).

[0006] U.S. Patent No. 8,394,992 describes a method for preparing triethylenetetramine dihydrochloride, in which tert-butoxycarbonyl (boc)-protected triethylenetetramine is first converted to its tetrahydrochloride using a large excess of hydrochloric acid in isopropanol, and then the resulting tetrahydrochloride is treated with a strong base such as sodium alkoxide under anhydrous conditions to produce the amine free base (TETA) and sodium chloride. The free amine is extracted with tert-butyl methyl ether (TBME), followed by removal of sodium chloride. Finally, the amine free base TET is treated with hydrochloric acid in ethanol to form trientine hydrochloride. However, the above method has the following drawbacks: a) a lengthy process involving the treatment of the tetrahydrochloride with a base under anhydrous conditions to obtain the amine, and then its further conversion to TETA dihydrochloride (which involves multiple unit operations at various synthesis stages, such as solvent extraction, washing of filtered solids, solvent concentration, and crystallization); b) the use of excess hydrochloric acid and anhydrous alcoholic and ether solvents. c) A strict requirement for the complete removal of sodium chloride formed during the process. If the salt is not properly removed, the final product, trientine hydrochloride, may not pass the sulfated ash test, which indicates the complete removal of inorganic impurities from a drug product.

[0007] Korean Patent KR20080022940 describes a method for preparing triethylenetetramine dihydrochloride by dissolving triethylenetetramine free base in methanol, and the dihydrochloride is formed by adding concentrated aqueous hydrochloric acid. 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.

[0008] Several reports (Journal of Chemical Research, 2005(4), pp. 233-235; XP055551215) describe methods for the preparation of trientine dihydrochloride from technical-grade triethylenetetramine free base and identify three impurities commonly formed during the synthesis: N,N-bis-(2-aminoethyl)-1,2-ethanediamine, 1,4-piperazinediethaneamine, and N-[2-(l-piperazinyl)ethyl]-1,2-ethanediamine. This brief method lacks sufficient details to completely isolate the material. Furthermore, no mention is made of the conditions under which the desired product or its impurities may form. The resulting dihydrochloride is then repurified by recrystallization from 95% ethanol, with the insoluble trihydrochloride being removed during the recrystallization process. European Patent No. EP 3 350 154 B1 describes an expensive process for the synthesis of triethylenetetramine dihydrochloride, which involves a single step of treating a Boc-protected amine with hydrochloric acid to form the desired dihydrochloride salt in substantially pure form and in good yield. All of the above references are incorporated by reference in their entirety. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] U.S. Patent No. 7,582,796 [Patent Document 2] U.S. Patent No. 4,806,517 [Patent Document 3] U.S. Patent No. 4,550,209 [Patent Document 4] U.S. Patent No. 5,225,599 [Patent Document 5] U.S. Patent No. 4,503,253 [Patent Document 6] U.S. Patent No. 7,960,591 [Patent Document 7] Chinese Patent No. 102924289 [Patent Document 8] Czechoslovak Patent No. 197,093 [Patent Document 9] U.S. Patent No. 8,394,992 [Patent Document 10] Korean Patent No. 20080022940 [Patent Document 11] European Patent No. 3350154 [Non-patent literature]

[0010] [Non-Patent Document 1] Journal of Chemical Research, 2005(4), 233~235;XP055551215 Summary of the Invention [Means for solving the problem]

[0011] Summary of the Invention In some aspects, the present disclosure provides a method for the preparation of high purity triethylenetetramine diacid salt, the method comprising: a) contacting impure triethylenetetramine (TET) with a diacid to result in a crude solid; and b) recrystallizing the crude solid to obtain high-purity triethylenetetramine diacid salt Includes: In some embodiments, the high-purity triethylenetetramine diacid salt is between about 95% and about 99.95% pure. In some embodiments, the high-purity triethylenetetramine diacid salt is between about 98% and about 99% pure. In some embodiments, the high-purity triethylenetetramine diacid salt is about 98.5% pure. In some embodiments, the high-purity triethylenetetramine diacid salt is high-purity triethylenetetramine disuccinate (TES). In some embodiments, the diacid is selected from the group consisting of succinic acid, malonic acid, oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid and their derivatives, dibenzoyltartaric acid, glutaric acid, and adipic acid. In some embodiments, the diacid is succinic acid. In some embodiments, the impure triethylenetetramine (TET) is between about 60% and about 95% pure. In some embodiments, the impure triethylenetetramine (TET) is between about 60% and about 70% pure. In some embodiments, the impure triethylenetetramine (TET) is between about 60% and about 65% pure.

[0012] In some embodiments, the present disclosure provides a method of recrystallization, the method comprising: a) dissolving or partially dissolving said crude solid in a suitable solvent at elevated temperature, resulting in a solution or suspension; b) cooling the solution or suspension to form high purity triethylenetetramine diacid salt as crystals; and c) collecting the high purity triethylenetetramine diacid salt. Includes: In some embodiments, the suitable solvent is selected from the group consisting of polar protic solvents and polar aprotic solvents, or mixtures thereof. In some embodiments, the polar protic solvent is selected from water, C1-C8 alcohols, and C1-C8 polyhydric alcohols. In some embodiments, the alcohol is selected from the group consisting of methanol, ethanol, isopropanol, 1-propanol, ethylene glycol, propylene glycol, and butanediol. In some embodiments, the C1-C8 alcohol is methanol. In some embodiments, the polar aprotic solvent is selected from the group consisting of C1-C8 ethers, cyclic C4-C6 ethers, acetone, 2-butanone, dimethylacetamide, N-methylpyrrolidinone, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, dimethylpropylene urea, pyridine, sulfolane, and hexamethylphosphoric triamide. In some embodiments, the polar aprotic solvent is acetonitrile. In some embodiments, the mixture is water and acetonitrile. In some embodiments, the mixture is between about 2% and about 25% water. In some embodiments, the mixture is between about 5% and about 15% water. In some embodiments, the mixture is water and a C1-C8 alcohol. In some embodiments, the alcohol is selected from the group consisting of methanol, ethanol, isopropanol, and 1-propanol. In some embodiments, the alcohol is methanol. In some embodiments, the mixture is between about 2% and about 25% water. In some embodiments, the mixture is between about 5% and about 10% water. In some embodiments, the elevated temperature is between about 20°C and about the boiling point of the solvent or solvent mixture.

[0013] In some aspects, the present disclosure provides a method for the preparation of high purity triethylenetetramine diacid salt, the method comprising: a) dissolving impure triethylenetetramine (TET) in a suitable solvent to provide a first solution; b) adding a diacid to the first solution to form a second mixture; c) forming a precipitate of crude triethylenetetramine diacid salt in the second mixture; d) collecting the crude triethylenetetramine diacid salt; and e) optionally recrystallizing the crude triethylenetetramine diacid salt to obtain a high-purity triethylenetetramine diacid salt. Includes: In some embodiments, the high-purity triethylenetetramine diacid salt is between about 95% and about 99.95% pure. In some embodiments, the high-purity triethylenetetramine diacid salt is between about 98% and about 99% pure. In some embodiments, the high-purity triethylenetetramine diacid salt is about 98.5% pure. In some embodiments, the high-purity triethylenetetramine diacid salt is high-purity triethylenetetramine succinate (TES). In some embodiments, the diacid is selected from the group consisting of succinic acid, malonic acid, maleic acid, fumaric acid, malic acid, tartaric acid and their derivatives, dibenzoyltartaric acid, glutaric acid, and adipic acid. In some embodiments, the diacid is succinic acid. In some embodiments, the impure triethylenetetramine (TET) is between about 60% and about 95% pure. In some embodiments, the impure triethylenetetramine (TET) is between about 60% and about 70% pure. In some embodiments, the impure triethylenetetramine (TET) is about 60% pure. In some embodiments, the solvent is selected from the group consisting of C1-C8 alcohols, water, acetonitrile, and tetrahydrofuran, or mixtures thereof.

[0014] In some embodiments, the step of, if necessary, recrystallizing the crude triethylenetetramine diacid salt to obtain high purity triethylenetetramine diacid salt comprises: i) dissolving or partially dissolving said crude solid in a suitable solvent at elevated temperature, resulting in a solution; ii) cooling the solution to form high purity triethylenetetramine diacid salt as crystals; and iii) collecting the high purity triethylenetetramine diacid salt. The method is carried out by a method comprising: In some embodiments, the suitable solvent is selected from the group consisting of polar protic solvents and polar aprotic solvents, or mixtures thereof. In some embodiments, the polar protic solvent is selected from water, C1-C8 alcohols, and C1-C8 polyhydric alcohols. In some embodiments, the alcohol is selected from the group consisting of methanol, ethanol, isopropanol, 1-propanol, ethylene glycol, propylene glycol, and butanediol. In some embodiments, the C1-C8 alcohol is methanol. In some embodiments, the polar aprotic solvent is selected from the group consisting of C1-C8 ethers, cyclic C4-C6 ethers, acetone, 2-butanone, dimethylacetamide, N-methylpyrrolidinone, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, dimethylpropylene urea, pyridine, sulfolane, and hexamethylphosphoric triamide. In some embodiments, the polar aprotic solvent is acetonitrile. In some embodiments, the mixture is water and acetonitrile. In some embodiments, the mixture is between about 2% and about 25% water. In some embodiments, the mixture is between about 5% and about 10% water. In some embodiments, the mixture is water and a C1-C8 alcohol. In some embodiments, the alcohol is selected from the group consisting of methanol, ethanol, isopropanol, and 1-propanol. In some embodiments, the alcohol is methanol. In some embodiments, the mixture is between about 2% and about 25% water. In some embodiments, the mixture is between about 5% and about 15% water. In some embodiments, the elevated temperature is between about 20°C and about the boiling point of the solvent or solvent mixture.

[0015] In some aspects, the present disclosure provides a method for the preparation of high purity triethylenetetramine diacid salt, the method comprising: a) dissolving impure triethylenetetramine (TET) in a first solvent to provide a first solution; b) warming the first solution to a first temperature; c) adding a 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 triethylenetetramine diacid salt; and e) collecting the high purity triethylenetetramine diacid. Includes: In some embodiments, the high-purity triethylenetetramine diacid salt is between about 95% and about 99.95% pure. In some embodiments, the high-purity triethylenetetramine diacid salt is between about 98% and about 99% pure. In some embodiments, the high-purity triethylenetetramine diacid salt is about 98.5% pure. In some embodiments, the high-purity triethylenetetramine diacid salt is high-purity triethylenetetramine disuccinate (TES). In some embodiments, the diacid is selected from the group consisting of succinic acid, malonic acid, maleic acid, fumaric acid, malic acid, tartaric acid and their derivatives, dibenzoyltartaric acid, glutaric acid, and adipic acid. In some embodiments, the diacid is succinic acid. In some embodiments, the impure triethylenetetramine (TET) is between about 60% and about 90% pure. In some embodiments, the impure triethylenetetramine (TET) is between about 60% and about 70% pure. In some embodiments, the impure triethylenetetramine (TET) is about 65% pure. In some embodiments, the first solvent is selected from the group consisting of C1-C8 alcohols, C1-C8 polyhydric alcohols, acetonitrile, tetrahydrofuran, and water, and mixtures thereof. In some embodiments, the alcohol is selected from the group consisting of methanol, ethanol, isopropanol, 1-propanol, ethylene glycol, propylene glycol, and butanediol. In some embodiments, the first temperature is between about 50°C and about 95°C. In some embodiments, the first temperature is between about 65°C and about 80°C. In some embodiments, the second solvent is selected from the group consisting of C1-C8 alcohols, acetonitrile, tetrahydrofuran, and water, and mixtures thereof. In some embodiments, the second temperature is between about -5°C and about 25°C. In some embodiments, the second temperature is about 0°C.

[0016] In some aspects, the present disclosure provides a method for the preparation of high purity triethylenetetramine dihydrochloride or high purity triethylenetetramine tetrahydrochloride from impure triethylenetetramine, said method comprising: a) contacting impure triethylenetetramine (TET) with a diacid to result in a crude solid; b) recrystallizing the crude solid to obtain high-purity triethylenetetramine diacid salt; c) contacting the high purity triethylenetetramine diacid salt with an aqueous base to form high purity triethylenetetramine (TET); and d) converting the highly purified triethylenetetramine (TET) to its dihydrochloride salt by the methods described herein. Includes: In some embodiments, the high-purity triethylenetetramine diacid salt has a purity between about 95% and about 99.95%. In some embodiments, the high-purity triethylenetetramine diacid salt has a purity between about 98% and about 99%. In some embodiments, the high-purity triethylenetetramine diacid salt has a purity of about 98.5%. In some embodiments, the high-purity triethylenetetramine diacid salt is high-purity triethylenetetramine disuccinate (TES). In some embodiments, the diacid is selected from the group consisting of succinic acid, malonic acid, oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid and their derivatives, dibenzoyltartaric acid, glutaric acid, and adipic acid. In some embodiments, the diacid is succinic acid. In some embodiments, the aqueous base is selected from the group consisting of aqueous sodium hydroxide, aqueous potassium hydroxide, aqueous sodium carbonate, and aqueous potassium carbonate. In some embodiments, the impure triethylenetetramine (TET) has a purity between about 60% and about 90%. In some embodiments, the impure triethylenetetramine (TET) is between about 60% and about 70% pure. In some embodiments, the impure triethylenetetramine (TET) is about 60% pure.

[0017] In some embodiments, the present disclosure provides a recrystallization method, the recrystallization method comprising: i) dissolving or partially dissolving said crude solid in a suitable solvent at elevated temperature, resulting in a solution or suspension; i) cooling the solution or suspension to form high purity triethylenetetramine diacid salt as solid crystals; and iii) collecting the high purity triethylenetetramine diacid salt. The method is carried out by a method comprising: In some embodiments, the suitable solvent is selected from the group consisting of polar protic solvents and polar aprotic solvents, or mixtures thereof. In some embodiments, the polar protic solvent is selected from water, C1-C8 alcohols, and C1-C8 polyhydric alcohols. In some embodiments, the alcohol is selected from the group consisting of methanol, ethanol, isopropanol, 1-propanol, ethylene glycol, propylene glycol, and butanediol. In some embodiments, the C1-C8 alcohol is methanol. In some embodiments, the polar aprotic solvent is selected from the group consisting of C1-C8 ethers, cyclic C4-C6 ethers, acetone, 2-butanone, dimethylacetamide, N-methylpyrrolidinone, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, dimethylpropylene urea, pyridine, sulfolane, and hexamethylphosphoric triamide. In some embodiments, the polar aprotic solvent is acetonitrile. In some embodiments, the mixture is water and acetonitrile. In some embodiments, the mixture is between about 2% and about 25% water. In some embodiments, the mixture is between about 5% and about 10% water. In some embodiments, the mixture is water and a C1-C8 alcohol. In some embodiments, the alcohol is selected from the group consisting of methanol, ethanol, isopropanol, and 1-propanol. In some embodiments, the alcohol is methanol. In some embodiments, the mixture is between about 2% and about 25% water. In some embodiments, the mixture is between about 5% and about 10% water. In some embodiments, the elevated temperature is between about 20°C and about the boiling point of the solvent or solvent mixture.

[0018] In some embodiments, the present disclosure provides methods for the preparation of high purity triethylenetetramine (TET) by contacting a high purity triethylenetetramine diacid salt with an aqueous base to form high purity triethylenetetramine.

[0019] In some embodiments, the present disclosure provides methods for the preparation of high purity triethylenetetramine (TET) by contacting a high purity triethylenetetramine diacid salt with a material capable of performing ion exchange (e.g., an ion exchange resin) to form high purity triethylenetetramine. DETAILED DESCRIPTION OF THE INVENTION

[0020] Detailed Description of the Invention When describing the compounds and processes of the present invention, the terms used should be construed according to the following definitions, unless the context indicates otherwise. As used herein, the term "about" when referring to a measurable value such as a parameter, purity, amount, length of time, and the like, is intended to include a variation of ±10% or less from the particular value, preferably ±5% or less, more preferably ±1% or less, and even more preferably ±0.1% or less, insofar as such a variation is appropriate for practicing the disclosed invention. It should be understood that the value to which the modifier "about" refers is itself also specifically, preferably disclosed.

[0021] The literature processes for making various salts of triethylenetetramine require substantially pure (about 98% or higher) triethylenetetramine, which is difficult and expensive to produce. While technical grade triethylenetetramine would be a convenient and cost-effective starting material in the synthesis of its salts, it is typically contaminated with impurities (e.g., ethylenediamine, diethylenetriamine, piperazine and various derivatives, as well as branched polyamine impurities) that make it undesirable for producing a single pure salt.

[0022] In some embodiments, the present disclosure provides a cost-effective method for producing not only highly pure (98% or higher) triethylenetetramine but also various salts of triethylenetetramine. Highly pure (approximately 98% or higher) triethylenetetramine can be produced from inexpensive technical-grade (approximately 65% purity; approximately US$30 per kg) triethylenetetramine and, if necessary, converted to its salt form. For example, the highly pure triethylenetetramine so produced can be converted to its dihydrochloride salt using any of the methods described herein. In some embodiments, the present disclosure provides a commercially viable and cost-effective method for producing highly pure crystalline diacid salts of triethylenetetramine (including highly pure crystalline disuccinate salts) starting from technical-grade triethylenetetramine. Technical-grade (e.g., impure) triethylenetetramine (TET) can be obtained from the reaction of 1,2 diaminoethane reacted with ethanolamine and a catalyst.

[0023] The purification method described herein provides a convenient, cost-effective, and industrially viable process for the synthesis of triethylenetetramine dihydrochloride (1), which avoids: a) lengthy synthetic routes for the protection and deprotection of the reactant amines and intermediates, b) excessive use of organic solvents, and c) the use of mineral acids in multiple steps. Additional advantages of the disclosed purification method are the avoidance of strong bases, the controlled number of unit operations, and good yields of the desired dihydrochloride salt.

[0024] 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 compound.

[0025] As used herein, the term "C" when used in combination with a chemical moiety (e.g., alkyl, alkenyl, or alkynyl) x~y" is intended to include groups containing x to y carbons in the chain. For example, the term "C x~y "Alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group containing x to y carbon atoms in the chain, including straight-chain and branched-chain alkyl groups, and includes haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl. x~y "Alcohol" refers to a substituted or unsubstituted saturated aliphatic alcohol group containing x to y carbons in its alkyl chain, including straight-chain and branched-chain alkyl alcohol groups.

[0026] The alcohol and / or alcohol solvent is typically a short-chain alcohol. The alcohol is typically of the formula ROH, where R is a straight or branched chain C 1~8 The C is an alkyl group. 1~8 The alkyl group is preferably unsubstituted. Examples of alcohols include methanol, ethanol, n-propanol, propanol, n-butanol, i-butanol, s-butanol and t-butanol. Methanol and ethanol are preferred. Methanol is more preferred.

[0027] The ether and / or ether solvent is typically a short-chain ether. The ether is typically of the formula RO-R', where R and R' are the same or different, and R and R' are straight-chain or branched C 1~8 represents an alkyl group. 1~8 The alkyl group is preferably unsubstituted. Preferred ethers include diethyl ether, diisopropyl ether, and methyl t-butyl ether (MTBE). 4~6 Cyclic ethers (e.g., tetrahydrofuran and tetrahydropyran) are also included. Nitrile solvents are well known to those skilled in the art. Nitriles are typically short-chain nitriles. Nitriles are typically of the formula R-CN, where R is a straight-chain or branched C 1~6 represents an alkyl group. 1~6The alkyl group is preferably unsubstituted.Preferred nitriles include acetonitrile.

[0028] As used herein, the term "aqueous" when referring to an aqueous organic solvent refers to a composition containing water and the described organic compound. For example, "aqueous methanol" refers to a composition containing 1% to 99% by weight water, with the remainder being methanol. In some embodiments, the aqueous phase may further contain dissolved salts.

[0029] In some embodiments, the aqueous organic solvent is aqueous alcohol or aqueous acetonitrile. The aqueous organic solvent is preferably aqueous methanol or aqueous acetonitrile.

[0030] Purity of reagents and products can be determined by analytical methods known to those skilled in the art, such as ion chromatography, high performance liquid chromatography (HPLC), proton nuclear magnetic resonance spectroscopy ( 1 H NMR), carbon nuclear magnetic resonance spectroscopy ( 13 C NMR), infrared spectroscopy (IR), powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and melting point).

[0031] In some embodiments, the present disclosure relates to a unit dose pharmaceutical composition for the treatment of a disease associated with a copper-mediated pathway, comprising: the unit dose comprises an effective amount of a TET salt formulated as a pharmaceutical composition for administration to a subject in need thereof, wherein the composition and amount of the TET salt in the unit dose formulation is configured such that the unit dose is effective in treating a disease associated with a copper-mediated pathway by removing or reducing the amount of free copper (e.g., copper(I) or copper(II)) levels from the blood or tissues of the subject, thereby reducing the severity of one or more signs or symptoms of the disease associated with a copper-mediated pathway without causing adverse effects when administered to a subject as a single dose; The TET salt is i) dissolving impure triethylenetetramine in a polar protic solvent or a polar aprotic solvent to form a dissolved impure triethylenetetramine solution at a first temperature; ii) optionally dissolving succinic acid in a protic solvent or a polar aprotic solvent to form a dissolved succinic acid solution at a second temperature; iii) optionally adding solid succinic acid or optionally said dissolved succinic acid solution at a third temperature to form a dissolved triethylenetetramine succinate solution; iv) cooling the dissolved triethylenetetramine succinate solution to a fourth temperature at which solid triethylenetetramine succinate (TES) forms; and v) collecting the solid triethylenetetramine succinate (TES). and prepared by a synthetic method comprising: the first temperature is in the range of about 50°C to about 70°C, the second temperature is in the range of about 50°C to about 70°C, the third temperature is in the range of about 50°C to about 70°C, The fourth temperature is in the range of about 0°C to about 40°C. 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 is a mixture of water and an alcohol (e.g., methanol, ethanol, or 2-propanol).

[0032] Certain methods involve ion exchange

[0033] 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 performing ion exchange to form high-purity triethylenetetramine. The material capable of performing ion exchange can be an ion exchange resin. The ion exchange resin can be a cation exchange resin or an anion exchange resin. In some embodiments, a method for preparing high-purity TET by a process involving an ion exchange resin includes contacting the TET salt with the acid form of the ion exchange resin, followed by filtering the ion exchange resin from the solution after a selected time (e.g., 1 minute to 8 hours) at room temperature. In some embodiments, the ion exchange method for preparing high-purity TET can be similar to the method described in U.S. Patent No. 4,263,145, which is incorporated herein by reference. [Example]

[0034] Example 1

[0035] 7.30 grams (30 mmol, corrected for purity) of technical grade (60% purity; Mallinckrodt Sigma-Aldrich) triethylenetetramine was dissolved in 50 mL of acetonitrile and warmed to 65°C with stirring. Succinic acid (11.8 grams, 100 mmol) was separately dissolved in 75 mL of a warm (65°C) solution of acetonitrile:water (2:1). The warm succinic acid solution was added to the triethylenetetramine acetonitrile solution over approximately 3 hours. After the addition was complete, the solution was allowed to cool to room temperature over approximately 4 hours. Spontaneous formation of a crystalline precipitate was observed between 40°C and 45°C. Alternatively, crystallization could be initiated by adding a small amount (less than 500 mg) of preformed crystals at approximately 55°C or lower. After cooling to 20°C, the suspension was stirred for an additional 2 hours before filtering the crystalline solid. The solid was washed with 30 mL of acetonitrile and dried to a constant weight to give 10.11 grams (88.3%) of crystalline triethylenetetramine disuccinate, which was identical (PXRD, single crystal X-ray, H and C NMR) to the reference material (U.S. Pat. No. 9,556,123, incorporated by reference in its entirety).

[0036] Example 2

[0037] 7.30 grams (48.5 mmol, corrected for purity) of 97% pure triethylenetetramine (Mallinckrodt Sigma-Aldrich) was dissolved in 50 mL of acetonitrile and warmed to 65°C with stirring. Succinic acid (11.8 grams, 100 mmol) was separately dissolved in a warm (65°C) solution of 75% acetonitrile:water (2:1). The warm succinic acid solution was added to the triethylenetetramine acetonitrile solution over approximately 3 hours. After the addition was complete, the solution was allowed to cool to room temperature over approximately 4 hours. The spontaneous formation of a second oily layer was observed at approximately 50°C. This layer appeared to be a mixture of crystals and an oily material. Continued stirring at 20°C (approximately 2 hours) allowed for complete conversion of the precipitated material to a large mass of crystalline material. The solid was isolated by filtration and washed with 30 mL of acetonitrile. After drying to a constant weight, 17.09 grams of crystalline triethylenetetramine disuccinate was obtained, which was identical to the prior art material (PXRD, H and C NMR).

[0038] Example 3

[0039] The process of Example 1 was repeated (all weights and volumes of materials and solvents were identical), except that methanol was used as the solvent rather than acetonitrile. 60% pure triethylenetetramine was used (as in Example 1), resulting in the isolation of 9.51 grams (83.0% yield corrected for purity) of crystalline triethylenetetramine disuccinate.

[0040] Example 4

[0041] 7.30 grams (48.5 mmol, corrected for purity) of 97% pure triethylenetetramine (Mallinckrodt Sigma-Aldrich) was dissolved in 50 mL of methanol and stirred at 25°C. To this solution was added a solution of succinic acid (11.8 grams, 100 mmol) in 100 mL of methanol at 60°C over 30 minutes. Precipitation of a second oily layer was observed after approximately 25% of the succinic acid solution had been added. After addition was complete, the suspension was cooled to 20°C over approximately 5 hours and stirred for an additional 18 hours. At this point, conversion of the oily layer to a crystalline precipitate was noted. 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 was obtained, which was identical in all respects to the material obtained from Examples 1-3.

[0042] Example 5

[0043] 7.30 grams (30 mmol, corrected for purity) of 60% pure triethylenetetramine (Mallinckrodt Sigma-Aldrich) was dissolved in 50 mL of methanol and stirred at 25°C. To this solution was added a solution of succinic acid (11.8 grams, 100 mmol) in 100 mL of 60°C methanol over 30 minutes. After approximately 25% of the succinic acid solution had been added, precipitation of a second oily layer was observed. After addition was complete, the suspension was cooled to 20°C over approximately 5 hours and stirred for an additional 18 hours. At this point, conversion of the oily layer to a crystalline precipitate was noted. 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 was obtained, which was identical to the material obtained in Examples 1-4.

[0044] Example 6

[0045] 7.30 grams (48.5 mmol, corrected for purity) of 97% pure triethylenetetramine (Mallinckrodt Sigma-Aldrich) was dissolved in 50 mL of acetonitrile and stirred at 25° C. To this solution was added a solution of succinic acid (11.8 grams, 100 mmol) in 100 mL of acetonitrile at 70° C. over 30 minutes. After approximately 25% of the succinic acid solution had been added, precipitation of a second oily layer was observed. After addition was complete, the suspension was cooled to 20° C. over approximately 5 hours and stirred for an additional 18 hours. At this point, conversion of the oily layer to a crystalline precipitate was noted. 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 was obtained, which was identical in all respects to the material obtained from other examples.

[0046] Example 7

[0047] 7.30 grams (30 mmol, corrected for purity) of 60% pure triethylenetetramine (Mallinckrodt Sigma-Aldrich) was dissolved in 50 mL of methanol and stirred at 25° C. To this solution was added a solution of succinic acid (7.08 grams, 60 mmol) in 100 mL of methanol at 60° C. over 30 minutes. After approximately 50% of the succinic acid solution had been added, precipitation of a second oily layer was observed. After addition was complete, the suspension was cooled to 20° C. over approximately 5 hours and stirred for an additional 18 hours. At this point, conversion of the oily layer to a crystalline precipitate was noted. 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 was obtained, which was identical to the material obtained in other examples.

[0048] In a further embodiment of the present invention, crystalline salts of triethylenetetramine and organic diacids can be recrystallized to improve their purity. Thus, triethylenetetramine disuccinate with a purity of 97.6% can be recrystallized as follows to improve its purity to greater than 99%.

[0049] Example 8

[0050] Triethylenetetramine disuccinate (7.64 grams, approximately 20 mmol) of 97.6% purity (determined by GC / MS) was dissolved in 120 mL of 10% aqueous methanol with heating and stirring to produce a clear solution at 60°C. The solution was slowly cooled to 20°C over approximately 2 hours, and stirring was maintained at this temperature for an additional hour. The solution was further cooled to approximately 5°C and held at this temperature for an additional 2 hours. The solution was filtered, and the filter cake was washed with approximately 40 mL of methanol. The filter cake was dried under reduced pressure at 50°C to a constant weight. The product was obtained in a yield of 6.30 grams (84% recovery) with a purity of 99.6% (GC / MS).

[0051] In a further embodiment of the present invention, the crystalline salt of triethylenetetramine with an organic diacid can be converted to its free amine in high recovery and purity.

[0052] Example 9

[0053] Triethylenetetramine disuccinate (3.82 grams, approximately 10 mmol) of 99.95% purity (as determined by ion chromatography) was suspended in 40 mL of isopropyl acetate. The suspension was shaken with 20 mL of 3N aqueous sodium hydroxide to give a clear, two-phase liquid mixture. Solid sodium chloride was added to the aqueous layer to give 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 aqueous brine (50 mL). The isopropyl acetate was removed under reduced pressure to give 1.23 grams of triethylenetetramine with 99.2% purity (containing 0.4% isopropyl acetate; 83% recovery).

[0054] Example 10

[0055] Triethylenetetramine disuccinate (3.82 grams, approximately 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 to give 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 approximately 3 mL. The crude product was purified by flash column chromatography using a Biotage® KP-NH column with hexane / EtOAc (0% to 30% ethyl acetate gradient) as the mobile phase. After removal of the volatile solvents, triethylenetetramine was obtained in greater than 99% purity and approximately 75% to 90% recovery.

[0056] Example 11

[0057] Triethylenetetramine disuccinate (3.82 grams, approximately 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 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 approximately 3 mL. The crude product was distilled using a Kugelrohr apparatus. Triethylenetetramine was obtained with a purity of greater than 99% and a recovery of approximately 81%.

[0058] Example 12

[0059] Triethylenetetramine disuccinate (3.82 grams, approximately 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 nearly quantitative recovery. Further embodiments Further embodiments of the present disclosure are presented as follows. Embodiment 1 a) contacting impure triethylenetetramine (TET) with a diacid to result in a crude solid; and b) Recrystallizing the crude solid to obtain high-purity triethylenetetramine diacid salt 1. A method for the preparation of high purity triethylenetetramine diacid salt, comprising: Embodiment 2 2. The method of embodiment 1, wherein the high purity triethylenetetramine diacid salt is between about 95% and about 99.95% pure. Embodiment 3 3. The method of embodiment 2, wherein the high purity triethylenetetramine diacid salt is between about 98% and about 99% pure. Embodiment 4 4. The method of embodiment 3, wherein the high purity triethylenetetramine diacid salt is about 98.5% pure. Embodiment 5 5. The method of embodiment 1, 2, 3 or 4, wherein said high purity triethylenetetramine diacid salt is high purity triethylenetetramine disuccinate (TES). Embodiment 6 2. The method of 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 derivatives thereof, dibenzoyltartaric acid, glutaric acid, and adipic acid. Embodiment 7 7. The method of embodiment 6, wherein the diacid is succinic acid. Embodiment 8 2. The method of embodiment 1, wherein the impure triethylenetetramine (TET) is between about 60% and about 95% pure. Embodiment 9 9. The method of embodiment 8, wherein the impure triethylenetetramine (TET) is between about 60% and about 70% pure. Embodiment 10 10. The method of embodiment 9, wherein the impure triethylenetetramine (TET) is between about 60% and about 65% pure. Embodiment 11 a) dissolving or partially dissolving the crude solid in a suitable solvent at elevated temperature, resulting in a solution or suspension; b) cooling the solution or suspension; and c) collecting the high purity triethylenetetramine diacid salt 2. The method of embodiment 1, wherein said recrystallization is achieved by: Embodiment 12 12. The method of 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. Embodiment 13 13. The method of embodiment 12, wherein the polar protic solvent is selected from water, C1-C8 alcohols and C1-C8 polyhydric alcohols. Embodiment 14 14. The method of embodiment 13, wherein the C1 to C8 alcohol is selected from the group consisting of methanol, ethanol, isopropanol, 1-propanol, ethylene glycol, propylene glycol, and butanediol. Embodiment 15 15. The method of embodiment 14, wherein the C1-C8 alcohol is methanol. Embodiment 16 13. The method of 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-methylpyrrolidinone, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, dimethylpropylene urea, pyridine, sulfolane, and hexamethylphosphoric triamide. Embodiment 17 17. The method of embodiment 16, wherein the polar aprotic solvent is acetonitrile. Embodiment 18 18. The method of embodiment 17, wherein the mixture is water and acetonitrile. Embodiment 19 19. The method of embodiment 18, wherein the mixture is between about 2% and about 25% water. Embodiment 20 20. The method of embodiment 19, wherein the mixture is between about 5% and about 15% water. Embodiment 21 13. The method of embodiment 12, wherein the mixture is water and a C1-C8 alcohol. Embodiment 22 22. The method of embodiment 21, wherein the alcohol is selected from the group consisting of methanol, ethanol, isopropanol, and 1-propanol. Embodiment 23 23. The method of embodiment 22, wherein the alcohol is methanol. Embodiment 24 22. The method of embodiment 21, wherein the mixture is between about 2% and about 50% water. Embodiment 25 25. The method of embodiment 24, wherein the mixture is between about 5% and about 20% water. Embodiment 26 13. The method of embodiment 12, wherein said elevated temperature is between about 20° C. and about the boiling point of said solvent or solvent mixture. Embodiment 27 a) dissolving impure triethylenetetramine (TET) in a suitable solvent to provide a first solution; b) adding a diacid to the first solution to form a second mixture; c) allowing the second mixture to stand or to stir to form a precipitate of crude triethylenetetramine diacid salt; d) collecting the crude triethylenetetramine diacid salt; and e) optionally, recrystallizing the crude triethylenetetramine diacid salt, if necessary, to obtain a highly pure triethylenetetramine diacid salt. 1. A method for the preparation of high purity triethylenetetramine diacid salt, comprising: Embodiment 28 25. The method of embodiment 24, wherein the high purity triethylenetetramine diacid salt is between about 95% and about 99.95% pure. Embodiment 29 26. The method of embodiment 25, wherein the high purity triethylenetetramine diacid salt is between about 98% and about 99% pure. Embodiment 30 27. The method of embodiment 26, wherein the high purity triethylenetetramine diacid salt is about 98.5% pure. Embodiment 31 31. The method of embodiment 27, 28, 29 or 30, wherein said highly pure triethylenetetramine diacid salt is highly pure triethylenetetramine disuccinate (TES). Embodiment 32 28. The method of embodiment 27, wherein said diacid is selected from the group consisting of succinic acid, malonic acid, maleic acid, fumaric acid, malic acid, tartaric acid and derivatives thereof, dibenzoyltartaric acid, glutaric acid and adipic acid. Embodiment 33 33. The method of embodiment 32, wherein the diacid is succinic acid. Embodiment 34 28. The method of embodiment 27, wherein said impure triethylenetetramine (TET) is between about 60% and about 95% pure. Embodiment 35 35. The method of embodiment 34, wherein said impure triethylenetetramine (TET) is between about 60% and about 70% pure. Embodiment 36 26. The method of embodiment 25, wherein said impure triethylenetetramine (TET) is about 60% pure. Embodiment 37 28. The method of embodiment 27, wherein the solvent is selected from the group consisting of C1 to C8 alcohols, water, acetonitrile and tetrahydrofuran, or mixtures thereof. Embodiment 38 a) dissolving or partially dissolving the crude solid in a suitable solvent at elevated temperature, resulting in a solution; b) cooling the solution; and c) collecting the high purity triethylenetetramine diacid salt 28. The method of embodiment 27, wherein said recrystallization is carried out by Embodiment 39 39. The method of 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. Embodiment 40 40. The method of embodiment 39, wherein the polar protic solvent is selected from water, C1-C8 alcohols and C1-C8 polyhydric alcohols. Embodiment 41 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. Embodiment 42 The method of embodiment 40, wherein the C1-C8 alcohol is methanol. Embodiment 43 40. The method of 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-methylpyrrolidinone, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, dimethylpropylene urea, pyridine, sulfolane, and hexamethylphosphoric triamide. Embodiment 44 44. The method of embodiment 43, wherein the polar aprotic solvent is acetonitrile. Embodiment 45 40. The method of embodiment 39, wherein the mixture is water and acetonitrile. Embodiment 46 46. The method of embodiment 45, wherein the mixture is between about 2% and about 50% water. Embodiment 47 47. The method of embodiment 46, wherein the mixture is between about 5% and about 20% water. Embodiment 48 46. The method of embodiment 45, wherein the mixture is water and a C1-C8 alcohol. Embodiment 49 49. The method of embodiment 48, wherein said alcohol is selected from the group consisting of methanol, ethanol, isopropanol, and 1-propanol. Embodiment 50 50. The method of embodiment 49, wherein the alcohol is methanol. Embodiment 51 49. The method of embodiment 48, wherein the mixture is between about 2% and about 50% water. Embodiment 52 52. The method of embodiment 51, wherein the mixture is between about 5% and about 20% water. Embodiment 53 39. The method of embodiment 38, wherein said elevated temperature is between about 20° C. and about the boiling point of said solvent or solvent mixture. EMBODIMENT 54 a) dissolving impure triethylenetetramine (TET) in a first solvent to provide a first solution; b) warming the first solution to a first temperature; c) adding a 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 triethylenetetramine diacid salt; and e) collecting the high purity triethylenetetramine diacid salt. 1. A method for the preparation of high purity triethylenetetramine diacid salt, comprising: Embodiment 55 55. The method of embodiment 54, wherein the highly pure triethylenetetramine diacid salt is between about 95% and about 99.95% pure. Embodiment 56 56. The method of embodiment 55, wherein the high purity triethylenetetramine diacid salt is between about 98% and about 99% pure. Embodiment 57 57. The method of embodiment 56, wherein the highly pure triethylenetetramine diacid salt is about 98.5% pure. Embodiment 58 58. The method of embodiment 54, 55, 56 or 57, wherein said highly pure triethylenetetramine diacid salt is highly pure triethylenetetramine disuccinate (TES). Embodiment 59 55. The method of embodiment 54, wherein said diacid is selected from the group consisting of succinic acid, malonic acid, fumaric acid, malic acid, maleic acid, tartaric acid and derivatives thereof, dibenzoyltartaric acid, oxalic acid, glutaric acid and adipic acid. Embodiment 60 60. The method of embodiment 59, wherein the diacid is succinic acid. Embodiment 61 55. The method of embodiment 54, wherein said impure triethylenetetramine (TET) is between about 60% and about 90% pure. Embodiment 62 62. The method of embodiment 61, wherein the impure triethylenetetramine (TET) is between about 60% and about 70% pure. Embodiment 63 63. The method of embodiment 62, wherein said impure triethylenetetramine (TET) is about 60% pure. EMBODIMENT 64 64. The method of embodiment 63, wherein the first solvent is selected from the group consisting of C1 to C8 alcohols, C1 to C8 polyhydric alcohols, acetonitrile, tetrahydrofuran and water, and mixtures thereof. Embodiment 65 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. Embodiment 66 55. The method of embodiment 54, wherein the first temperature is between about 50°C and about 95°C. Embodiment 67 67. The method of embodiment 66, wherein the first temperature is between about 65°C and about 80°C. Embodiment 68 55. The method of embodiment 54, wherein the second solvent is selected from the group consisting of C1 to C8 alcohols, acetonitrile, tetrahydrofuran, and water, and mixtures thereof. Embodiment 69 55. The method of embodiment 54, wherein the second temperature is between about -5°C and about 25°C. Embodiment 70 61. The method of embodiment 60, wherein the second temperature is about 0°C. Embodiment 71 a) contacting impure triethylenetetramine (TET) with a diacid to result in a crude solid; b) recrystallizing the crude solid to obtain high-purity triethylenetetramine diacid salt; c) contacting the high-purity triethylenetetramine diacid salt with an aqueous base to form high-purity triethylenetetramine (TET); and d) converting the highly purified triethylenetetramine (TET) to its dihydrochloride salt using any of the literature methods described herein. 1. A method for the preparation of high purity triethylenetetramine dihydrochloride, comprising: Embodiment 72 72. The method of embodiment 71, wherein the highly pure triethylenetetramine diacid salt is between about 95% and about 99.95% pure. Embodiment 73 73. The method of embodiment 72, wherein the highly pure triethylenetetramine diacid salt is between about 98% and about 99% pure. EMBODIMENT 74 74. The method of embodiment 73, wherein the highly pure triethylenetetramine diacid salt is about 98.5% pure. Embodiment 75 75. The method of embodiment 71, 72, 73 or 74, wherein said highly pure triethylenetetramine diacid salt is highly pure triethylenetetramine disuccinate (TES). Embodiment 76 72. The method of embodiment 71, wherein said diacid is selected from the group consisting of succinic acid, malonic acid, maleic acid, fumaric acid, malic acid, tartaric acid and derivatives thereof, dibenzoyltartaric acid, oxalic acid, glutaric acid and adipic acid. Embodiment 77 77. The method of embodiment 76, wherein the diacid is succinic acid. Embodiment 78 72. The method of embodiment 71, wherein the aqueous base is selected from the group consisting of aqueous sodium hydroxide, aqueous potassium hydroxide, aqueous sodium carbonate, and aqueous potassium carbonate. Embodiment 79 72. The method of embodiment 71, wherein said impure triethylenetetramine (TET) is between about 60% and about 90% pure. Embodiment 80 80. The method of embodiment 79, wherein said impure triethylenetetramine (TET) is between about 60% and about 70% pure. Embodiment 81 81. The method of embodiment 80, wherein said impure triethylenetetramine (TET) is about 60% pure. Embodiment 82 a) dissolving or partially dissolving the crude solid in a suitable solvent at elevated temperature, resulting in a solution or suspension; b) cooling the solution or suspension; and c) collecting the high purity triethylenetetramine diacid salt 72. The method of embodiment 71, wherein said recrystallization is carried out by Embodiment 83 83. The method of embodiment 82, wherein said suitable solvent is selected from the group consisting of polar protic solvents and polar aprotic solvents, or mixtures thereof. Embodiment 84 The method of embodiment 83, wherein said polar protic solvent is selected from water, C1-C8 alcohols and C1-C8 polyhydric alcohols. Embodiment 85 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. Embodiment 86 The method of embodiment 84, wherein the C1-C8 alcohol is methanol. Embodiment 87 84. The method of 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-methylpyrrolidinone, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, dimethylpropylene urea, pyridine, sulfolane, and hexamethylphosphoric triamide. Embodiment 88 88. The method of embodiment 87, wherein the polar aprotic solvent is acetonitrile. Embodiment 89 88. The method of embodiment 87, wherein the mixture is water and acetonitrile. Embodiment 90 90. The method of embodiment 89, wherein the mixture is between about 2% and about 25% water. Embodiment 91 91. The method of embodiment 90, wherein the mixture is between about 5% and about 10% water. Embodiment 92 The method of embodiment 83, wherein the mixture is water and a C1-C8 alcohol. Embodiment 93 93. The method of embodiment 92, wherein said alcohol is selected from the group consisting of methanol, ethanol, isopropanol, and 1-propanol. Embodiment 94 The method of embodiment 93, wherein the alcohol is methanol. Embodiment 95 93. The method of embodiment 92, wherein the mixture is between about 2% and about 25% water. Embodiment 96 96. The method of embodiment 95, wherein the mixture is between about 5% and about 10% water. Embodiment 97 97. The method of embodiment 96, wherein said elevated temperature is between about 20° C. and about the boiling point of said solvent or solvent mixture. Embodiment 98 1. A process for the preparation of highly pure triethylenetetramine succinate from impure triethylenetetramine, the process comprising: i) dissolving impure triethylenetetramine in a polar protic solvent or a polar aprotic solvent to form a dissolved impure triethylenetetramine solution at a first temperature; ii) dissolving succinic acid in aqueous acetonitrile to form a dissolved succinic acid solution at a second temperature; iii) adding the dissolved impure triethylenetetramine solution to the dissolved succinic acid solution at a third temperature to form a dissolved triethylenetetramine succinate solution; iv) cooling the dissolved triethylenetetramine succinate solution to a fourth temperature at which solid triethylenetetramine succinate (TES) forms; and v) collecting the solid triethylenetetramine succinate (TES). Including, the first temperature is in the range of about 60°C to about 70°C, the second temperature is in the range of about 60°C to about 70°C; the third temperature is in the range of about 60°C to about 70°C; The fourth temperature is in the range of about 0°C to about 25°C. method. Embodiment 99 99. The method of embodiment 98, wherein the polar protic solvent is methanol. Embodiment 100 99. The method of embodiment 98, wherein the polar aprotic solvent is acetonitrile.

Claims

1. A method for preparing high-purity triethylenetetramine diate, wherein the method is a) A step of contacting impure triethylenetetramine (TET) with a diacid to obtain a crude solid as a result; and b) A step of recrystallizing the crude solid to obtain high-purity triethylenetetramine diate. It contains, and the high-purity triethylenetetramine diate has a purity between approximately 95% and approximately 99.95%. A method 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 their derivatives, dibenzoyl tartaric acid, glutaric acid, and adipic acid.

2. The method according to claim 1, wherein the high-purity triethylenetetramine diate has a purity of approximately 98.5%.

3. The method according to claim 1, wherein the diacid is succinic acid.

4. The method according to claim 1, wherein the impurity triethylenetetramine (TET) has a purity between about 60% and about 70%.

5. i) Dissolving or partially dissolving the crude solid at a high temperature in a solvent selected from a polar aprotic solvent or a polar protic solvent, thereby obtaining a solution or suspension; ii) A step of cooling the solution or suspension; and iii) Process for collecting high-purity triethylenetetramine diate The method according to claim 1, wherein the recrystallization is carried out by a method including the following.

6. The polar protic solvent is water, C １ ~C ８ Alcohol, C １ ~C ８ The method according to claim 5, selected from polyhydric alcohols and mixtures thereof.

7. Said C １ ~C ８ The method according to claim 6, wherein the alcohol is selected from the group consisting of methanol, ethanol, isopropanol, 1-propanol, ethylene glycol, propylene glycol, and butanediol.

8. The method according to claim 5, wherein the polar protic solvent is methanol.

9. wherein the polar aprotic solvent is C １ -C ８ ether, cyclic C ４ -C ６ ether, acetone, 2-butanone, dimethylacetamide, N-methylpyrrolidinone, N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, dimethylpropyleneurea, pyridine, sulfolane, hexamethylphosphoric triamide, and a mixture thereof, the method according to claim 5.

10. The method according to claim 5, wherein the polar aprotic solvent is an aqueous solution containing acetonitrile.

11. The method according to claim 5, wherein the aprotic solvent is acetonitrile.

12. The method according to claim 5, wherein the high temperature is between approximately 20°C and the boiling point of the solvent or solvent mixture.

13. a) A step of dissolving impure triethylenetetramine (TET) in a suitable solvent to obtain a first solution; b) A step of adding diacid to the first solution to form a second mixture; c) A step of allowing the second mixture to stand or be stirred to form a precipitate of crude triethylenetetraminediate; d) A step of collecting the crude triethylenetetramine diate; and e) If necessary, the crude triethylenetetramine diate is recrystallized to obtain a high-purity triethylenetetramine diate having a purity of more than 95%. Includes, A method for preparing high-purity triethylenetetramine diate from impure triethylenetetramine, wherein the diacid is selected from the group consisting of succinic acid, malonic acid, maleic acid, fumaric acid, malic acid, tartaric acid and their derivatives, dibenzoyl tartaric acid, glutaric acid, and adipic acid.

14. The method according to claim 13, wherein the high-purity triethylenetetramine diate has a purity between approximately 95% and approximately 99.95%.

15. The method according to claim 13, wherein the diacid is succinic acid.

16. The aforementioned solvent is C １ ~C ８ The method according to claim 13, selected from the group consisting of alcohol, water, acetonitrile, tetrahydrofuran, or a mixture thereof.

17. i) A step of dissolving or partially dissolving the crude solid in a suitable solvent at a high temperature to obtain a solution as a result; ii) A step of cooling the solution to form high-purity triethylenetetramine diate; and iii) Process for collecting high-purity triethylenetetramine diate The method according to claim 13, wherein the recrystallization is carried out by a process comprising, the suitable solvent being selected from a polar protic solvent, a polar aprotic solvent, or a mixture thereof.

18. The method according to claim 17, wherein the polar protic solvent is selected from water, methanol, or a mixture thereof.

19. The method according to claim 17, wherein the polar aprotic solvent is acetonitrile or an aqueous solution containing acetonitrile.

20. The method according to claim 18, wherein the solvent is methanol.

21. The method according to claim 17, wherein the high temperature is between approximately 20°C and the boiling point of the solvent or solvent mixture.

22. a) A step of dissolving impure triethylenetetramine (TET) having a purity of less than 90% (w / w) in a first solvent to form a first solution; b) A step of heating the first solution to a first temperature; c) A step of adding dioic acid as a solid or dioic acid as a solution in a second solvent to the first solution at a first temperature to form a second solution; d) If necessary, a step of cooling the second solution to a second temperature to form a high-purity precipitate of triethylenetetramine diate having a purity of more than 95%; and e) A step of collecting the high-purity triethylenetetramine diate. Includes, A method for preparing high-purity triethylenetetramine diate, wherein the diacid is selected from the group consisting of succinic acid, malonic acid, fumaric acid, malic acid, maleic acid, tartaric acid and their derivatives, dibenzoyl tartaric acid, oxalic acid, glutaric acid, and adipic acid.

23. The method according to claim 22, wherein the diacid is succinic acid.

24. The method according to claim 22, wherein the first solvent is selected from the group consisting of methanol, acetonitrile, tetrahydrofuran, water, and mixtures thereof.

25. The method according to claim 22, wherein the first temperature is between approximately 50°C and approximately 80°C.

26. The method according to claim 22, wherein the second solvent is selected from the group consisting of methanol, acetonitrile, tetrahydrofuran, water, and mixtures thereof.

27. The method according to claim 22, wherein the second temperature is between approximately -5°C and approximately 25°C.

28. a) A step of contacting impure triethylenetetramine (TET) with a diacid to form a crude solid; b) A step of recrystallizing the crude solid to obtain high-purity triethylenetetramine diate; c) A step of contacting the high-purity triethylenetetramine diate with an aqueous base to form high-purity triethylenetetramine (TET) having a purity of more than 95% (w / w); and d) A step of converting the high-purity triethylenetetramine (TET) to its dihydrochloride salt. Includes, A method for preparing high-purity triethylenetetramine dihydrochloride, wherein the diacid is selected from the group consisting of succinic acid, malonic acid, maleic acid, fumaric acid, malic acid, tartaric acid and their derivatives, dibenzoyl tartaric acid, oxalic acid, glutaric acid, and adipic acid.

29. The method according to claim 28, wherein the diacid is succinic acid.

30. The method according to claim 28, wherein the aqueous base is selected from the group consisting of aqueous sodium hydroxide, aqueous potassium hydroxide, aqueous sodium carbonate, and aqueous potassium carbonate.

31. i) A step of dissolving or partially dissolving the crude solid in a suitable solvent at a high temperature to obtain a solution or suspension as a result; ii) A step of cooling the solution or suspension to form high-purity triethylenetetramine diate; and iii) Process for collecting high-purity triethylenetetramine diate The method according to claim 28, wherein the recrystallization is carried out by the method described above.

32. The method according to claim 31, wherein the appropriate solvent is selected from the group consisting of polar protic solvents, polar aprotic solvents, or mixtures thereof.

33. The method according to claim 31, wherein the polar protic solvent is selected from water, methanol, or a mixture thereof.

34. The aforementioned polar aprotic solvent is C １ ~C ８ Ether, cyclic carbon ４ ~C ６ The method according to claim 31, selected from the group consisting of ether, acetone, 2-butanone, dimethylacetamide, N-methylpyrrolidinone, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, dimethylpropylene urea, pyridine, sulfolane, and hexamethyl phosphate triamide.

35. The method according to claim 34, wherein the polar aprotic solvent is acetonitrile or an aqueous solution containing acetonitrile, and the aqueous solution containing acetonitrile contains water in an amount between approximately 2% and approximately 25%.

36. The method according to claim 31, wherein the high temperature is between approximately 20°C and the boiling point of the solvent or solvent mixture.

37. a) A step of contacting impure triethylenetetramine (TET) with a diacid selected from the group consisting of succinic acid, malonic acid, maleic acid, fumaric acid, malic acid, tartaric acid and their derivatives, dibenzoyl tartaric acid, oxalic acid, glutaric acid, and adipic acid to form a crude solid; b) If necessary, recrystallize the crude solid to obtain high-purity triethylenetetramine diate; c) A step of contacting the high-purity triethylenetetramine diate with an ion-exchange solid to form high-purity triethylenetetramine (TET); and d) A step of converting the high-purity triethylenetetramine (TET) to its dihydrochloride salt. A method for preparing high-purity triethylenetetramine dihydrochloride, including [a specific compound / component].