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WO2019073427A1 - A process for the preparation of trientine dihydrochloride - Google Patents

A process for the preparation of trientine dihydrochloride Download PDF

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Publication number
WO2019073427A1
WO2019073427A1 PCT/IB2018/057873 IB2018057873W WO2019073427A1 WO 2019073427 A1 WO2019073427 A1 WO 2019073427A1 IB 2018057873 W IB2018057873 W IB 2018057873W WO 2019073427 A1 WO2019073427 A1 WO 2019073427A1
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formula
solvent
compound
amine
acid
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PCT/IB2018/057873
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French (fr)
Inventor
Milind Gharpure
Sanjay Kumar Sharma
Prakash PANSARE
Sandip SINORE
Kamlesh CHAVAN
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Piramal Enterprises Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/44—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers
    • C07C209/48—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers by reduction of nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/62—Preparation of compounds containing amino groups bound to a carbon skeleton by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/02—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C211/14—Amines containing amino groups bound to at least two aminoalkyl groups, e.g. diethylenetriamines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/24—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton
    • C07C255/25—Aminoacetonitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/20—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups

Definitions

  • the present invention relates to a process for the preparation of trientine dihydrochlonde, ⁇ , ⁇ '- bis (2-aminoethyl)- 1 ,2-ethanediamine dihydrochloride represented herein by compound of formula I.
  • Trientine chemically known as triethylenetetramine or N,N'-bis(2-aminoethyl)-l,2- ethanediamine belongs to the class of polyethylene polyamines.
  • Trientine dihydrochloride is a chelating agent which is used to bind and remove copper in the body in the treatment of Wilson's disease.
  • Trientine dihydrochloride formulation developed by Aton with the proprietary name SYPRINE, was approved by USFDA on November 8, 1985 for the treatment of patients with Wilson's disease, who is intolerant to penicillamine. Trientine dihydrochloride, due to its activity on copper homeostasis, is being studied for various potential applications in the treatment of internal organs damage in diabetics, Alzheimer's disease and cancer.
  • CS 197,093 discloses a process comprising reaction of triethylenetetramine with concentrated hydrochloric acid to obtain the crystalline tetra hydrochloride salt. Further reaction of the salt with sodium ethoxide in solvent ethanol, filtration of the solid sodium chloride which is generated in the process, followed by slow cooling and crystallization of the filtrate provided the dihydrochloride salt. Optionally, aqueous solution of the tetra hydrochloride salt was passed through a column of an anion exchanger and the eluate containing free base was treated with a calculated amount of the tetra hydrochloride, evaporated, and the residue was crystallized from aqueous ethanol to yield the dihydrochloride salt.
  • US patent 4,550,209 and US patent 5,225,599 disclose process for preparing linear triethylenetetramine and aminoethylethanolamine by condensation of ethylene diamine and ethylene glycol in the presence of a catalytically effective amount of a condensation catalyst selected from a metatungstate or mixtures thereof with one or more Group IV B metal oxides which includes zirconium trimethylene diphosphonate or metatungstate composites of titanium dioxide and zirconium dioxide.
  • a condensation catalyst selected from a metatungstate or mixtures thereof with one or more Group IV B metal oxides which includes zirconium trimethylene diphosphonate or metatungstate composites of titanium dioxide and zirconium dioxide.
  • CN 102924289 discloses a process for trientine dihydrochloride comprising reduction of ⁇ , ⁇ '- dibenzyl-,N,N'-bis[2-(l,3-dioxo-2H-isoindolyl)ethyl]ethanediamine using hydrazine hydrate to give N,N'-dibenzyl-,N,N'-bis(2-aminoethyl)ethanediamine, which, upon condensation with benzyl chloroformate gave N,N'-dibenzyl-,N,N'-bis[2-(Cbz-amino)ethyl]ethanediamine, and further reductive deprotection to give the desired compound.
  • US patent 8394992 discloses a method for preparation of triethylenetetramine dihydrochloride wherein tertiary butoxycarbonyl (boc) protected triethylenetetramine is first converted to its tetra hydrochloride salt using large excess of hydrochloric acid in solvent isopropanol, followed by treatment of the resulting tetra hydrochloride salt with a strong base like sodium alkoxide to produce the amine free base and sodium chloride salt in anhydrous conditions. The free amine is extracted with tertiary butyl methyl ether, followed by removal of sodium chloride salt and finally the amine free base is treated with hydrochloric acid in solvent ethanol to give trientine dihydrochloride.
  • boc tertiary butoxycarbonyl
  • patent provides polymorphs of triethylenetetramine salts and methods for their preparation. These polymorphs include polymorphs of triethylenetetramine disuccinate, triethylenetetramine tetra hydrochloride, and triethylenetetramine dihydrochloride.
  • PCT application 2017/046695 disclose process for preparation of trientine dihydrochloride by reacting tert- butyl-N-(2-aminoethyl)-N-2-[(2-aminoethyl)-(tert-butoxy)carbonyl]amino]ethyl ⁇ carbamate with hydrochloric acid.
  • the present invention provides a process for the preparation of trientine dihydrochloride, which is simple, efficient, cost effective, in reaction itself by designing optimum condition for reaction to reduce effluent load, environment friendly, commercially scalable for large scale operations quality of intermediates and finished product obtained from the improved process is better than that obtained with reported prior art processes.
  • An object of the present invention is to provide an improved process for the preparation of trientine dihydrochloride.
  • the present invention relates to an improved process for the preparation of trientine dihydrochloride.
  • the present invention relates to an improved process for the preparation of trientine dihydrochloride, wherein final compound of formula I resulted in good yield, preferably more than 70%.
  • the present invention relates to an improved process for the preparation of trientine dihydrochloride, wherein final compound of formula I resulted in high purity, preferably
  • the present invention relates to a process for the preparation of trientine dihydrochloride, wherein intermediates as trientine salts resulted in high purity >95%.
  • the present invention relates to salts of boc -protected nitrile intermediate and its process. In another aspect, the present invention relates to a process for the preparation of trientine free base from trientine salts.
  • the present invention relates to a process for the preparation of trientine dihydrochloride from trientine free base.
  • the present invention relates to an improved process for the preparation of N,N'- bis(2-aminoethyl)-l,2- ethanediamine dihydrochloride here in after trientine dihydrochloride represented by the following formula I, comprising H
  • base can be selected from the organic base or inorganic base or mixtures thereof, wherein organic base may be selected from the group consisting of 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), pyridine, dimethylaminopyridine, dibutyl amine, triethyl amine, tributyl amine, diisopropyl amine, diisopropylethylamine, N-methylmorpholine and the like and inorganic base may be selected from the group consisting of hydroxides, carbonates and bicarbonates of alkali metals or alkaline earth metals selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate; or ammonia and the like.
  • base can be preferably potassium carbonate.
  • solvent can be selected from the group consisting of water, alcohols, ethers, amides, esters, nitriles, sulfoxides, ketones, hydrocarbons and halogenated hydrocarbons, wherein alcohol is selected from methanol, ethanol, iso-propanol.
  • ester is selected from ethyl acetate or isopropyl acetate
  • ketone is selected from the group consisting of acetone, methyl isobutyl ketone and methyl ethyl ketone
  • ether is selected from the group consisting of methyl tert-butyl ether, diisopropyl ether, diethyl ether tetrahydrofuran, 2-methyl tetrahydrofuran, cyclopentyl methyl ether and dioxane
  • halogenated solvent is selected from the group consisting of dichloromethane, chloroform, chlorobenzene and bromobenzene
  • hydrocarbons is selected from the group consisting of toluene, xylene and cyclohexane
  • nitrile is selected from acetonitrile or propionitrile
  • amide is selected from ⁇ , ⁇ -dimethylformamide or ⁇ , ⁇
  • solvent can be preferably nitrile, more preferably acetonitrile.
  • the reaction can be carried out at temperature from 0-80°C, preferably not more than 35°C.
  • in-situ herein after typically means “in the reaction mixture” or “not in isolated form” or “without drying”.
  • the formed compound of formula III can be taken in-situ for the next stage reaction.
  • the obtained compound of formula III reacted with di-tert-butyl dicarbonate, herein after Boc-anhydride in solvent to provide compound of formula IV.
  • the solvent can be selected from the group consisting of water, alcohols, ethers, amides, esters, nitriles, sulfoxides, ketones, hydrocarbons and halogenated hydrocarbons, wherein alcohol is selected from methanol, ethanol, iso-propanol.
  • ester is selected from ethyl acetate or isopropyl acetate
  • ketone is selected from the group consisting of acetone, methyl isobutyl ketone and methyl ethyl ketone
  • ether is selected from the group consisting of methyl tert-butyl ether, diisopropyl ether, diethyl ether tetrahydrofuran, 2-methyl tetrahydrofuran, cyclopentyl methyl ether and dioxane
  • halogenated solvent is selected from the group consisting of dichloromethane, chloroform, chlorobenzene and bromobenzene
  • hydrocarbons is selected from the group consisting of toluene, xylene and cyclohexane
  • nitrile is selected from acetonitrile or propionitrile
  • amide is selected from ⁇ , ⁇ -dimethylformamide or N,N-
  • the solvent used is preferably acetonitrile.
  • the compound of formula IV can be isolated after completion of the reaction.
  • the isolation of formula IV can be preceded by concentrating the obtained filtrate after completion of the reaction under vacuum preferably at temperature of about 40°C to provide crude solid of formula IV which is then treated with mixture of isopropanol and water under heating preferably at 75-80°C and followed by cooling at temperature 0-5 °C to provide compound of formula IV.
  • the obtained compound of formula IV can be dried by the conventional techniques available in the art to give yield >75%.
  • the obtained compound of formula IV reacted with reducing agent in the presence of liquid ammonia in solvent to provide compound of formula V in-situ.
  • the reducing agent can be selected from palladium on carbon, raney nickel, palladium hydroxide, platinum on carbon, platinum oxide, hydrazine hydrate and the like.
  • the reducing agent used is preferably raney nickel.
  • reaction mixture set under hydrogen pressure preferably at 6-7 Kg for 4-5 hours at temperature 25-30°C.
  • solvent can be selected from the group consisting of water, alcohols, ethers, amides, esters, nitriles, sulfoxides, ketones, hydrocarbons and halogenated hydrocarbons, wherein alcohol is selected from methanol, ethanol, iso-propanol.
  • ester is selected from ethyl acetate or isopropyl acetate
  • ketone is selected from the group consisting of acetone, methyl isobutyl ketone and methyl ethyl ketone
  • ether is selected from the group consisting of methyl tert-butyl ether, diisopropyl ether, diethyl ether tetrahydrofuran, 2-methyl tetrahydrofuran, cyclopentyl methyl ether and dioxane
  • halogenated solvent is selected from the group consisting of dichloromethane, chloroform, chlorobenzene and bromobenzene
  • hydrocarbons is selected from the group consisting of toluene, xylene and cyclohexane
  • nitrile is selected from acetonitrile or propionitrile
  • amide is selected from ⁇ , ⁇ -dimethylformamide or ⁇ , ⁇
  • the solvent used in the reaction is preferably isopropanol.
  • the obtained compound of formula V in-situ treated with an acid in solvent to provide compound of formula VI in-situ treated with an acid in solvent to provide compound of formula VI.
  • acid can be selected from tartaric acid or sulfuric acid and the like.
  • acid can be selected from particularly L (+) tartaric acid or sulfuric acid to provide acid addition salts of formula VI.
  • solvent can be selected from the group consisting of water, alcohols, ethers, amides, esters, nitriles, sulfoxides, ketones, hydrocarbons and halogenated hydrocarbons, wherein alcohol is selected from methanol, ethanol, iso-propanol.
  • ester is selected from ethyl acetate or isopropyl acetate
  • ketone is selected from the group consisting of acetone, methyl isobutyl ketone and methyl ethyl ketone
  • ether is selected from the group consisting of methyl tert-butyl ether, diisopropyl ether, diethyl ether tetrahydrofuran, 2-methyl tetrahydrofuran, cyclopentyl methyl ether and dioxane
  • halogenated solvent is selected from the group consisting of dichloromethane, chloroform, chlorobenzene and bromobenzene
  • hydrocarbons is selected from the group consisting of toluene, xylene and cyclohexane
  • nitrile is selected from acetonitrile or propionitrile
  • amide is selected from ⁇ , ⁇ -dimethylformamide or ⁇ , ⁇
  • the reaction temperature is preferably 25-30°C.
  • the compound of formula VI can be isolated after completion of the reaction of the reaction by cooling at temperature 10-15°C.
  • the obtained compound of formula VI can be dried by the conventional techniques available in the art to give yield >75%.
  • the obtained compound of formula VI treated in solvent or mixture of solvents to provide compound of formula VII.
  • the compound of formula VI is treated preferably with water at temperature 90-95 °C to form compound of formula VII.
  • the formed compound of formula VII can be isolated by cooling the reaction mixture at temperature 25-30°C followed by treating with solvent, preferably isopropanol.
  • the obtained compound of formula VII can be dried by the conventional techniques available in the art to give yield >90%.
  • the compound of formula VII is treated preferably with ammonia in alcoholic solvent at temperature 25-30°C to form compound of formula VIII i.e trientine free base.
  • the alcoholic solvent is preferably methanol.
  • the formed compound of formula VII can be isolated by distillation of obtained filtrate after completion of the reaction under vacuum at temperature 45-50°C followed by degassing under vacuum at 50-55°C to provide compound of formula VIII.
  • the obtained compound of formula VIII can be dried by the conventional techniques available in the art to give yield >85%.
  • the obtained compound of formula VIII treated with hydrochloric acid in solvent to provide compound of formula I, i.e. trientine dihydrochloride.
  • the compound of formula VII is treated preferably with concentrated hydrochloric acid in alcoholic solvent.
  • the alcoholic solvent is preferably ethanol at temperature 10-15°C to provide compound of formula I, i.e. trientine dihydrochloride.
  • the formed compound of formula I can be isolated by cooling the reaction mixture at temperature 0-5 °C followed by seeding of crystals of trientine dihydrochloride at temperature 0-5°C to provide formula I.
  • the obtained compound of formula I can be dried by the conventional techniques available in the art to give yield >70%.
  • Acetonitrile (850 mL), potassium carbonate (473.7 gm) and ethylene diamine (100 gm) were added into the reaction vessel at 25-35 °C and cooled to 5-10°C.
  • the solution of chloroacetonitrile (266.3 gm) in acetonitrile (150 mL) was added into the reaction mixture and stirred for 10-12 hours at temperature not more than 35°C.
  • the reaction completion was monitored by using thin layer chromatography.
  • the obtained suspension was cooled to 5°C.
  • Boc-anhydride (762.6 gm) was added at temperature 5°C and maintained for about 1 hour. The reaction completion was monitored by using thin layer chromatography.
  • Example-3 Preparation of triethylene tetramine tartaric acid salt (Formula VII) from Boc- protected diamine tartaric acid salt (Formula VI).
  • reaction mixture of formula VI (20 gm) and demineralized (DM) water (20 mL) was heated at temperature 90-95°C under stirring for 14-16 hours. After completion of the reaction, the reaction mixture was cooled to 25-30°C followed by addition of isopropanol (100 mL) and distilled out isopropanol up to 2-3 volumes under vacuum at temperature 50-55 °C. Again isopropanol (60 mL) was added and distilled out isopropanol up to 2-3 volumes under vacuum at temperature 50- 55°C. The reaction mass was stirred at temperature 25-30°C for 1-2 hours. The obtained reaction mass was filtered, washed with isopropanol (40 mL) and dried under vacuum at 55-60°C to give the compound of formula VII. % Yield: 93.47%
  • Example-4 Preparation of triethylene tetramine free base (Formula VIII) from triethylene tetramine tartaric acid salt (Formula VII)
  • a reaction mixture of ethanol (45 mL) and formula VIII (9 gm) was cooled to 10-15°C under nitrogen atmosphere.
  • Concentrated hydrochloric acid (12.8 gm) was added into the reaction mixture at temperature 10-15°C for 30 minutes to adjust pH 7.0 to 8.5.
  • the reaction mixture was stirred at temperature 10-15°C for 30 minutes followed by cooling the reaction mixture at temperature 0-5 °C. Seed crystals of trientine dihydrochloride was added into the reaction mixture and maintained at temperature 0-5°C for 3-4 hours.
  • the reaction mass was filtered and wet cake was washed with ethanol (9 mL) and dried at temperature 45-50°C. % Yield: 70%

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Abstract

The present invention relates to an industrially feasible and economically viable process for preparation of trientine dihydrochloride of formula (I) in significantly high yield and purity.

Description

A PROCESS FOR THE PREPARATION OF TRIENTINE DIHYDROCHLORIDE
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of trientine dihydrochlonde, Ν,Ν'- bis (2-aminoethyl)- 1 ,2-ethanediamine dihydrochloride represented herein by compound of formula I.
H
H2N ^ N ^
H . 2HC1
Formula I
BACKGROUND OF THE INVENTION
The following discussion of the prior art is intended to present the invention in an appropriate technical context, and allows its significance to be properly appreciated. Unless clearly indicated to the contrary, reference to any prior art in this specification should not be construed as an expressed or implied admission that such art is widely known or forms part of common general knowledge in the field.
Trientine, chemically known as triethylenetetramine or N,N'-bis(2-aminoethyl)-l,2- ethanediamine belongs to the class of polyethylene polyamines. Trientine dihydrochloride is a chelating agent which is used to bind and remove copper in the body in the treatment of Wilson's disease.
H
H2N ^ N ^
H · 2HC1
Trientine dihydrochloride
Trientine dihydrochloride formulation, developed by Aton with the proprietary name SYPRINE, was approved by USFDA on November 8, 1985 for the treatment of patients with Wilson's disease, who is intolerant to penicillamine. Trientine dihydrochloride, due to its activity on copper homeostasis, is being studied for various potential applications in the treatment of internal organs damage in diabetics, Alzheimer's disease and cancer.
Various synthetic methods for preparation of triethylenetetramine (TETA) and the corresponding dihydrochloride salt have been disclosed in the prior art.
CS 197,093 discloses a process comprising reaction of triethylenetetramine with concentrated hydrochloric acid to obtain the crystalline tetra hydrochloride salt. Further reaction of the salt with sodium ethoxide in solvent ethanol, filtration of the solid sodium chloride which is generated in the process, followed by slow cooling and crystallization of the filtrate provided the dihydrochloride salt. Optionally, aqueous solution of the tetra hydrochloride salt was passed through a column of an anion exchanger and the eluate containing free base was treated with a calculated amount of the tetra hydrochloride, evaporated, and the residue was crystallized from aqueous ethanol to yield the dihydrochloride salt.
Other non-patented articles, Lancet 1972, 15, 853, Lancet 1975, 2(7946) and 1218, Proc. Roy. Soc. Med. 1977, 70(3), 10-12 discloses preparation of trientine dihydrochloride having melting point range 115-122°C. US patent 4,806,517 discloses the synthesis of triethylenetetramine from ethylene diamine and monoethanolamine using Titania supported phosphorous catalyst. The patent also discloses the preparation of titania supported phosphorous catalyst.
US patent 4,550,209 and US patent 5,225,599 disclose process for preparing linear triethylenetetramine and aminoethylethanolamine by condensation of ethylene diamine and ethylene glycol in the presence of a catalytically effective amount of a condensation catalyst selected from a metatungstate or mixtures thereof with one or more Group IV B metal oxides which includes zirconium trimethylene diphosphonate or metatungstate composites of titanium dioxide and zirconium dioxide. CN 102924289 discloses a process for trientine dihydrochloride comprising reduction of Ν,Ν'- dibenzyl-,N,N'-bis[2-(l,3-dioxo-2H-isoindolyl)ethyl]ethanediamine using hydrazine hydrate to give N,N'-dibenzyl-,N,N'-bis(2-aminoethyl)ethanediamine, which, upon condensation with benzyl chloroformate gave N,N'-dibenzyl-,N,N'-bis[2-(Cbz-amino)ethyl]ethanediamine, and further reductive deprotection to give the desired compound.
US patent 8394992 discloses a method for preparation of triethylenetetramine dihydrochloride wherein tertiary butoxycarbonyl (boc) protected triethylenetetramine is first converted to its tetra hydrochloride salt using large excess of hydrochloric acid in solvent isopropanol, followed by treatment of the resulting tetra hydrochloride salt with a strong base like sodium alkoxide to produce the amine free base and sodium chloride salt in anhydrous conditions. The free amine is extracted with tertiary butyl methyl ether, followed by removal of sodium chloride salt and finally the amine free base is treated with hydrochloric acid in solvent ethanol to give trientine dihydrochloride. Further, patent provides polymorphs of triethylenetetramine salts and methods for their preparation. These polymorphs include polymorphs of triethylenetetramine disuccinate, triethylenetetramine tetra hydrochloride, and triethylenetetramine dihydrochloride.
PCT application 2017/046695 disclose process for preparation of trientine dihydrochloride by reacting tert- butyl-N-(2-aminoethyl)-N-2-[(2-aminoethyl)-(tert-butoxy)carbonyl]amino]ethyl } carbamate with hydrochloric acid.
It is evident from the discussion of the processes for the preparation of trientine dihydrochloride of formula I, described in afore cited patent documents that the reported processes primarily involve purification of intermediates, purification of isolated final product, isolation at various stages, long reaction time cycle and low yields, which is not advisable from commercial point of view. Existing processes are suffering from drawbacks like tedious processes, loss of yield, loss of human hours and involvement of more inventories as well as unit operations.
Inventors of the present invention have developed an improved process that addresses the problems associated with the processes reported in the prior art. The process does not require additional purification steps and critical workup procedure. Accordingly, the present invention provides a process for the preparation of trientine dihydrochloride, which is simple, efficient, cost effective, in reaction itself by designing optimum condition for reaction to reduce effluent load, environment friendly, commercially scalable for large scale operations quality of intermediates and finished product obtained from the improved process is better than that obtained with reported prior art processes.
OBJECT OF THE INVENTION
An object of the present invention is to provide an improved process for the preparation of trientine dihydrochloride.
Another object of the present invention is to provide trientine dihydrochloride in high purity, preferably >99%, more preferably >99.5%. Another object of the present invention is to provide trientine dihydrochloride in high yield.
Another object of the present invention is to provide a process for the preparation of trientine dihydrochloride by using purer intermediates, preferably >95%. Another object of the present invention is to provide high purity salts of trientine and subsequently converted to trientine dihydrochloride.
SUMMARY OF THE INVENTION In one aspect, the present invention relates to an improved process for the preparation of trientine dihydrochloride.
In another aspect, the present invention relates to an improved process for the preparation of trientine dihydrochloride, wherein final compound of formula I resulted in good yield, preferably more than 70%. In another aspect, the present invention relates to an improved process for the preparation of trientine dihydrochloride, wherein final compound of formula I resulted in high purity, preferably
>99.5%.
In another aspect, the present invention relates to a process for the preparation of trientine dihydrochloride, wherein intermediates as trientine salts resulted in high purity >95%.
In another aspect, the present invention relates to salts of boc -protected nitrile intermediate and its process. In another aspect, the present invention relates to a process for the preparation of trientine free base from trientine salts.
In another aspect, the present invention relates to a process for the preparation of trientine dihydrochloride from trientine free base.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, there is provided a process for the preparation of compound of formula I comprising the steps of:
Figure imgf000006_0001
Formula I
a) reacting the compound of formula II,
Figure imgf000006_0002
Formula II
with base and chloroacetonitrile in solvent to provide compound of formula III in-situ;
Figure imgf000006_0003
Formula III
b) treating obtained compound of formula III with di-tert-butyl dicarbonate to provide compound of formula IV.
Boc
N CN
I
Boc
Formula IV
c) treating obtained compound of formula IV with reducing agent in the presence of liquid ammonia in solvent to provide compound of formula V in-situ.
Boc
H2N N
Boc
Formula V
d) reacting obtained compound of formula V with an acid in solvent to provide compound of formula VI.
Boc
I
H2N N 1
Boc . acid
Formula VI
e) treating obtained compound of formula VI in solvent or mixture of solvents to provide compound of formula VII.
H
,NH,
H2N
H
acid
Formula VII
f) treating obtained compound of formula VII in ammonia in solvent to provide compound of formula VIII.
H
-NH,
H2N
H
Formula VIII
g) treating obtained compound of formula VIII with hydrochloric acid in solvent to provide compound of formula I trientine dihydrochloride.
Accordingly, the present invention relates to an improved process for the preparation of N,N'- bis(2-aminoethyl)-l,2- ethanediamine dihydrochloride here in after trientine dihydrochloride represented by the following formula I, comprising H
NH2
Η,Ν N
H
Formula I
reacting the compound of formula II,
.NH9
H2N
Formula II
with base and chloroacetonitrile in solvent to provide compound of formula III in-situ;
H
N CN H
Formula III
In an embodiment, base can be selected from the organic base or inorganic base or mixtures thereof, wherein organic base may be selected from the group consisting of 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), pyridine, dimethylaminopyridine, dibutyl amine, triethyl amine, tributyl amine, diisopropyl amine, diisopropylethylamine, N-methylmorpholine and the like and inorganic base may be selected from the group consisting of hydroxides, carbonates and bicarbonates of alkali metals or alkaline earth metals selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate; or ammonia and the like. embodiment, base can be preferably potassium carbonate.
In an embodiment, solvent can be selected from the group consisting of water, alcohols, ethers, amides, esters, nitriles, sulfoxides, ketones, hydrocarbons and halogenated hydrocarbons, wherein alcohol is selected from methanol, ethanol, iso-propanol. n-butanol or iso-butanol; ester is selected from ethyl acetate or isopropyl acetate; ketone is selected from the group consisting of acetone, methyl isobutyl ketone and methyl ethyl ketone; ether is selected from the group consisting of methyl tert-butyl ether, diisopropyl ether, diethyl ether tetrahydrofuran, 2-methyl tetrahydrofuran, cyclopentyl methyl ether and dioxane; halogenated solvent is selected from the group consisting of dichloromethane, chloroform, chlorobenzene and bromobenzene; hydrocarbons is selected from the group consisting of toluene, xylene and cyclohexane; nitrile is selected from acetonitrile or propionitrile; amide is selected from Ν,Ν-dimethylformamide or Ν,Ν-dimethyl acetamide; sulfoxide is dimethyl sulfoxide; sulfone; or mixtures thereof.
In an embodiment, solvent can be preferably nitrile, more preferably acetonitrile.
In an embodiment, the reaction can be carried out at temperature from 0-80°C, preferably not more than 35°C.
In an embodiment, the term "in-situ" herein after typically means "in the reaction mixture" or "not in isolated form" or "without drying".
In an embodiment, preferably the formed compound of formula III can be taken in-situ for the next stage reaction.
In an embodiment, the obtained compound of formula III reacted with di-tert-butyl dicarbonate, herein after Boc-anhydride in solvent to provide compound of formula IV.
Figure imgf000009_0001
Formula IV
In an embodiment, the solvent can be selected from the group consisting of water, alcohols, ethers, amides, esters, nitriles, sulfoxides, ketones, hydrocarbons and halogenated hydrocarbons, wherein alcohol is selected from methanol, ethanol, iso-propanol. n-butanol or iso-butanol; ester is selected from ethyl acetate or isopropyl acetate; ketone is selected from the group consisting of acetone, methyl isobutyl ketone and methyl ethyl ketone; ether is selected from the group consisting of methyl tert-butyl ether, diisopropyl ether, diethyl ether tetrahydrofuran, 2-methyl tetrahydrofuran, cyclopentyl methyl ether and dioxane; halogenated solvent is selected from the group consisting of dichloromethane, chloroform, chlorobenzene and bromobenzene; hydrocarbons is selected from the group consisting of toluene, xylene and cyclohexane; nitrile is selected from acetonitrile or propionitrile; amide is selected from Ν,Ν-dimethylformamide or N,N-dimethyl acetamide; sulfoxide is dimethyl sulfoxide; sulfone; or mixtures thereof.
In an embodiment, the solvent used is preferably acetonitrile.
In an embodiment, the compound of formula IV can be isolated after completion of the reaction.
In an embodiment, the isolation of formula IV can be preceded by concentrating the obtained filtrate after completion of the reaction under vacuum preferably at temperature of about 40°C to provide crude solid of formula IV which is then treated with mixture of isopropanol and water under heating preferably at 75-80°C and followed by cooling at temperature 0-5 °C to provide compound of formula IV.
In an embodiment, the obtained compound of formula IV can be dried by the conventional techniques available in the art to give yield >75%.
In an embodiment, the obtained compound of formula IV reacted with reducing agent in the presence of liquid ammonia in solvent to provide compound of formula V in-situ.
Figure imgf000010_0001
Formula V
In an embodiment, the reducing agent can be selected from palladium on carbon, raney nickel, palladium hydroxide, platinum on carbon, platinum oxide, hydrazine hydrate and the like.
In an embodiment, the reducing agent used is preferably raney nickel.
In an embodiment, the reaction mixture set under hydrogen pressure preferably at 6-7 Kg for 4-5 hours at temperature 25-30°C.
In an embodiment, solvent can be selected from the group consisting of water, alcohols, ethers, amides, esters, nitriles, sulfoxides, ketones, hydrocarbons and halogenated hydrocarbons, wherein alcohol is selected from methanol, ethanol, iso-propanol. n-butanol or iso-butanol; ester is selected from ethyl acetate or isopropyl acetate; ketone is selected from the group consisting of acetone, methyl isobutyl ketone and methyl ethyl ketone; ether is selected from the group consisting of methyl tert-butyl ether, diisopropyl ether, diethyl ether tetrahydrofuran, 2-methyl tetrahydrofuran, cyclopentyl methyl ether and dioxane; halogenated solvent is selected from the group consisting of dichloromethane, chloroform, chlorobenzene and bromobenzene; hydrocarbons is selected from the group consisting of toluene, xylene and cyclohexane; nitrile is selected from acetonitrile or propionitrile; amide is selected from Ν,Ν-dimethylformamide or Ν,Ν-dimethyl acetamide; sulfoxide is dimethyl sulfoxide; sulfone; or mixtures thereof.
In an embodiment, the solvent used in the reaction is preferably isopropanol.
In an embodiment, the obtained compound of formula V in-situ treated with an acid in solvent to provide compound of formula VI.
Figure imgf000011_0001
Formula VI
In an embodiment, acid can be selected from tartaric acid or sulfuric acid and the like.
In an embodiment, acid can be selected from particularly L (+) tartaric acid or sulfuric acid to provide acid addition salts of formula VI.
In an embodiment, solvent can be selected from the group consisting of water, alcohols, ethers, amides, esters, nitriles, sulfoxides, ketones, hydrocarbons and halogenated hydrocarbons, wherein alcohol is selected from methanol, ethanol, iso-propanol. n-butanol or iso-butanol; ester is selected from ethyl acetate or isopropyl acetate; ketone is selected from the group consisting of acetone, methyl isobutyl ketone and methyl ethyl ketone; ether is selected from the group consisting of methyl tert-butyl ether, diisopropyl ether, diethyl ether tetrahydrofuran, 2-methyl tetrahydrofuran, cyclopentyl methyl ether and dioxane; halogenated solvent is selected from the group consisting of dichloromethane, chloroform, chlorobenzene and bromobenzene; hydrocarbons is selected from the group consisting of toluene, xylene and cyclohexane; nitrile is selected from acetonitrile or propionitrile; amide is selected from Ν,Ν-dimethylformamide or Ν,Ν-dimethyl acetamide; sulfoxide is dimethyl sulfoxide; sulfone; or mixtures thereof. In an embodiment, the solvent used in the reaction is preferably methanol.
In an embodiment, the reaction temperature is preferably 25-30°C.
In an embodiment, the compound of formula VI can be isolated after completion of the reaction of the reaction by cooling at temperature 10-15°C.
In an embodiment, the obtained compound of formula VI can be dried by the conventional techniques available in the art to give yield >75%. In an embodiment, the obtained compound of formula VI treated in solvent or mixture of solvents to provide compound of formula VII.
Figure imgf000012_0001
Formula VII
In an embodiment, the compound of formula VI is treated preferably with water at temperature 90-95 °C to form compound of formula VII.
In an embodiment, the formed compound of formula VII can be isolated by cooling the reaction mixture at temperature 25-30°C followed by treating with solvent, preferably isopropanol. In an embodiment, the obtained compound of formula VII can be dried by the conventional techniques available in the art to give yield >90%.
In an embodiment, the obtained compound of formula VII treated in ammonia in solvent to provide compound of formula VIII. H
N. NH2
H2N N'
H
Formula VIII
Trientine Free base
In an embodiment, the compound of formula VII is treated preferably with ammonia in alcoholic solvent at temperature 25-30°C to form compound of formula VIII i.e trientine free base.
In an embodiment, the alcoholic solvent is preferably methanol.
In an embodiment, the formed compound of formula VII can be isolated by distillation of obtained filtrate after completion of the reaction under vacuum at temperature 45-50°C followed by degassing under vacuum at 50-55°C to provide compound of formula VIII.
In an embodiment, the obtained compound of formula VIII can be dried by the conventional techniques available in the art to give yield >85%.
In an embodiment, the obtained compound of formula VIII treated with hydrochloric acid in solvent to provide compound of formula I, i.e. trientine dihydrochloride.
Figure imgf000013_0001
Formula I
Trientine dihydrochloride
In an embodiment, the compound of formula VII is treated preferably with concentrated hydrochloric acid in alcoholic solvent.
In an embodiment, the alcoholic solvent is preferably ethanol at temperature 10-15°C to provide compound of formula I, i.e. trientine dihydrochloride.
In an embodiment, the formed compound of formula I can be isolated by cooling the reaction mixture at temperature 0-5 °C followed by seeding of crystals of trientine dihydrochloride at temperature 0-5°C to provide formula I.
In an embodiment, the obtained compound of formula I can be dried by the conventional techniques available in the art to give yield >70%.
The process of the present invention as per the specific embodiment described above is illustrated in the following Scheme-I,
K2C03
H
C^ ^N Acetonitrile .NH,
N CN H,N
Chloroacetonitrile A 2
H
Formula II
Formula III
Boc anhydride
Isopropanol W ater
Figure imgf000014_0001
Formula IV Formula V
Methanol
Acid
H Boc
.N .NH, Water I
H7N N - N^ - NH,
H Isopropanol H2N' N
I
Boc
■ Acid
Formula VII
Formula VI
Ammonia
Solvent
H
H -NH2
NH2 Ethanol ¾N N
H2N 'N' H
H Con.HCl
Formula I
Formula VIII
Scheme-I
The invention is further illustrated by the following examples which are provided to be exemplary of the invention, and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLES
Example-1: Preparation of Boc-protected nitrile intermediate (Formula IV)
Figure imgf000015_0001
Formula TT
Formula 111 Formula IV
Acetonitrile (850 mL), potassium carbonate (473.7 gm) and ethylene diamine (100 gm) were added into the reaction vessel at 25-35 °C and cooled to 5-10°C. The solution of chloroacetonitrile (266.3 gm) in acetonitrile (150 mL) was added into the reaction mixture and stirred for 10-12 hours at temperature not more than 35°C. The reaction completion was monitored by using thin layer chromatography. The obtained suspension was cooled to 5°C. Into the reaction mixture Boc-anhydride (762.6 gm) was added at temperature 5°C and maintained for about 1 hour. The reaction completion was monitored by using thin layer chromatography. The reaction mass was filtered and washed with acetonitrile (400 mL). The filtrate was then concentrated under vacuum at 40°C. Into the obtained crude solid, isopropanol (1200 mL) and water (1800 mL) was added and stirred for 15 minutes. The reaction mixture was heated at temperature 75-80°C and maintained for 30 minutes followed by cooling the reaction mixture at temperature 0-5 °C for 1 hour. The reaction mixture was filtered and washed with 1 : 1 mixture of isopropanol (250 mL) and water (250 mL). The obtained product was dried under vacuum at temperature 50-55°C for 15 -18 hours. % Yield: 78.15% Example-2: Preparation of Boc-protected diamine tartaric acid salt (Formula VI)
Figure imgf000015_0002
Formula IV Formula V Formula VI
Into the hydrogenator vessel, isopropanol (300 mL), compound of formula IV (30 gm), liquid ammonia (150 mL, 25% in water) and Raney-Ni were added at room temperature. The reaction mixture was set under hydrogen pressure 6-7 Kg for 4-5 hours at temperature 25-30°C. After completion of the reaction, the reaction mixture was filtered under nitrogen atmosphere. The reaction mass was washed with isopropanol (180 mL) followed by distillation under vacuum at 45-50°C and stripped out with isopropanol (90 mL) under vacuum. Methanol (150 mL) and L (+) tartaric acid (26.64 gm) were added at temperature 25-30°C and stirred the reaction mixture at temperature 25-30°C for 12 hours. The reaction mixture was then cooled to 10-15°C and maintained for 1 hour. The obtained reaction mass was filtered, washed with methanol (60 mL) and dried under vacuum at 60-65°C for 8-10 hours. % Yield: 76%
Example-3: Preparation of triethylene tetramine tartaric acid salt (Formula VII) from Boc- protected diamine tartaric acid salt (Formula VI).
Boc
H ^NH2 Water
N Isopropanol H2N ^ Λ'^^ ^^ H2
H2N N
Boc *~ H
" Tartrate . Tartrate
Formula VI Formula VII
A reaction mixture of formula VI (20 gm) and demineralized (DM) water (20 mL) was heated at temperature 90-95°C under stirring for 14-16 hours. After completion of the reaction, the reaction mixture was cooled to 25-30°C followed by addition of isopropanol (100 mL) and distilled out isopropanol up to 2-3 volumes under vacuum at temperature 50-55 °C. Again isopropanol (60 mL) was added and distilled out isopropanol up to 2-3 volumes under vacuum at temperature 50- 55°C. The reaction mass was stirred at temperature 25-30°C for 1-2 hours. The obtained reaction mass was filtered, washed with isopropanol (40 mL) and dried under vacuum at 55-60°C to give the compound of formula VII. % Yield: 93.47%
Example-4: Preparation of triethylene tetramine free base (Formula VIII) from triethylene tetramine tartaric acid salt (Formula VII)
Figure imgf000016_0001
• Tartrate
Formula VII Formula VIII
A reaction mixture of ammonia in methanol (375 mL) and formula VII (50 gm) was stirred at temperature 25-30°C for 4-5 hours. After completion of reaction, the reaction mixture was filtered, washed with methanol (100 mL) and filtrate was distilled out under vacuum at 45-50°C. The reaction mass was degassed under vacuum at 50-55 °C for 30-60 minutes till constant weight was obtained. % Yield: 88.63%
Example-5: Preparation of Trientine dihydrochloride (Formula I) from triethylene tetramine free base (Formula VIII)
„ H
/ /v \ ^NH Ethanol H2N ^ " N — 2
H2N ^ ^ N ^ C011.HCI H . 2HC1
Formula VIII Formula I
A reaction mixture of ethanol (45 mL) and formula VIII (9 gm) was cooled to 10-15°C under nitrogen atmosphere. Concentrated hydrochloric acid (12.8 gm) was added into the reaction mixture at temperature 10-15°C for 30 minutes to adjust pH 7.0 to 8.5. The reaction mixture was stirred at temperature 10-15°C for 30 minutes followed by cooling the reaction mixture at temperature 0-5 °C. Seed crystals of trientine dihydrochloride was added into the reaction mixture and maintained at temperature 0-5°C for 3-4 hours. The reaction mass was filtered and wet cake was washed with ethanol (9 mL) and dried at temperature 45-50°C. % Yield: 70%

Claims

WE CLAIM
1. A process for the preparation of trientine dihydrochloride of formula I;
Figure imgf000018_0001
Formula I
comprising the steps of:
a) reacting the compound of formula II;
H2N ^
Formula II
with base and chloroacetonitrile in solvent to provide compound of formula III in-situ;
H
N CN H
Formula III
b) treating compound of formula III with di-tert-butyl dicarbonate to provide compound of formula IV;
Boc
I
N CN
I
Boc
Formula IV
c) treating obtained compound of formula IV with reducing agent in the presence of liquid ammonia in solvent to provide compound of formula V in-situ;
Figure imgf000018_0002
Formula V
d) reacting obtained compound of formula V with an acid in solvent to provide compound of formula VI; Boc
I
. ^\ /\ ^ NH2
H2N ^ N ^ 2
2 I
Boc . acid
Formula VT
e) treating obtained compound of formula VI in solvent or mixture of solvents to provide compound of formula VII;
H
. V /\ ^ NII2
H2N N 2
2 H
• acid
Formula VII
f) treating obtained compound of formula VII in ammonia in solvent to provide compound of formula VIII;
H
H,N N 2
2 H
Formula VIII
g) treating obtained compound of formula VIII with hydrochloric acid in solvent to provide compound of formula I trientine dihydrochloride.
2. The process as claimed in claim 1, wherein the base used in step (a) is an organic or inorganic base.
3. The process as claimed in claim 2, wherein the organic base is selected from the group consisting of primary amines selected from methylamine, ethanolamine aniline, propyl amine, 2-propyl amine, butyl amine, and 2-amino ethano); secondary amines selected from Ν,Ν-diisopropyl amine, dimethylamine, diethyl amine, N-methyl propyl amine, pyrrole, and methylethanolamine; tertiary amines selected from triethylamine, N,N- dimethyl aniline, Ν,Ν-diisopropyl ethyl amine, trimethyl amine, pyridine, pyrimidine, and Ν,Ν-dimethylethyl amine; tetraalkylammonium and phosphonium hydroxides; Metal Alkoxides and Amides; and Metal Silanoates.
4. The process as claimed in claim 2, wherein the inorganic base is selected from the group consisting of alkali metal carbonates selected from potassium carbonate, sodium carbonate, and cesium carbonate; alkali metal bicarbonates selected from sodium bicarbonate, and potassium bicarbonate; alkali metal hydroxides selected from sodium hydroxide, potassium hydroxide, barium hydroxide, and lithium hydroxide; metal hydrides, metal alkoxides selected from sodium methoxide, sodium ethoxide, and potassium tert butoxide; metal amides or liquor ammonia.
5. The process as claimed in claim 1, wherein the solvent used in step (a) is selected from nitriles such as acetonitrile or proprionitrile.
6. The process as claimed in claim 1, wherein solvent used in step (c), (d), (f) and (g) is selected from alcohols such as methanol, ethanol, n-propanol, isopropanol.
7. A process as claimed in claim 1, wherein the solvent used in step (e) is water.
8. The process as claimed in claim 1, wherein the reducing agent used in step (c) is selected from palladium on carbon, Raney nickel, palladium hydroxide, platinum on carbon, platinum oxide, hydrazine hydrate.
9. The process as claimed in claim 1, wherein the acid used in step (d) is selected from L (+) tartaric acid or sulfuric acid.
10. The process as claimed in claim 1, wherein the trientine dihydrochloride has a purity greater than 99%; preferably 99.5% when determined by HPLC.
PCT/IB2018/057873 2017-10-12 2018-10-11 A process for the preparation of trientine dihydrochloride WO2019073427A1 (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4806517A (en) * 1986-01-21 1989-02-21 Texaco Inc. Method for making pelleted phosphated catalysts derived from group IVB transition metal oxides and catalysts thus prepared
US5225599A (en) * 1990-03-30 1993-07-06 Union Carbide Chemicals & Plastics Technology Corporation Selective production of linear triethylenetetramine and aminoethylethanolamine
US20060041170A1 (en) * 2004-07-19 2006-02-23 Marco Jonas Synthesis of triethylenetetramines
WO2017046695A1 (en) * 2015-09-18 2017-03-23 Emcure Pharmaceuticals Limited An improved process for preparation of trientine dihydrochloride

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4806517A (en) * 1986-01-21 1989-02-21 Texaco Inc. Method for making pelleted phosphated catalysts derived from group IVB transition metal oxides and catalysts thus prepared
US5225599A (en) * 1990-03-30 1993-07-06 Union Carbide Chemicals & Plastics Technology Corporation Selective production of linear triethylenetetramine and aminoethylethanolamine
US20060041170A1 (en) * 2004-07-19 2006-02-23 Marco Jonas Synthesis of triethylenetetramines
WO2017046695A1 (en) * 2015-09-18 2017-03-23 Emcure Pharmaceuticals Limited An improved process for preparation of trientine dihydrochloride

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