DESC:Field of the Invention
The present invention relates to an improved process for the preparation of Trien hydrochloride, also known as Triethylenetetramine hydrochloride. Specifically the present invention relates to an improved process for preparation of Trien dihydrochloride, comprising treating triethylenetetramine with alcoholic hydrochloric acid resulting in good yields.
Background of the Invention
Trien or Triethylenetetramine, also commonly known as Trientine is chemically, N,N'-bis(2-aminoethyl)-1,2-ethanediamine dihydrochloride. It was approved by USFDA in November, 1985 and is marketed in the US in the form of oral capsules under the proprietary name, SYPRINE®.
Trientine dihydrochloride is a chelating compound and is indicated for the treatment of the patients suffering from Wilson’s disease, particularly in those who are intolerant to penicillamine, characterized by the excess accumulation of copper metal in human brain. The structural formula of trientine dihydrochloride is represented as follows:

Various synthetic methods for preparation of triethylenetetramine and the corresponding dihydrochloride salt have been disclosed in the prior art.
US 4,500,209, US 4,503,253, US 4,806,517, US 5,225,599 discloses various methods for preparing triethylenetetramine and salts thereof.
U.S. Patent No. 7,582,796 discloses process for the synthesis of Trientine dihydrochloride. The general route of synthesis reported basically involves synthesis of a dinitrile intermediate, 3,3'-(ethane-1,2-diylbis(azanediyl))dipropanenitrile followed by tert-butyloxycarbonyl (Boc) protection and reduction to form tert-butyl ethane-1,2-diylbis(2-aminoethylcarbamate). Deprotection of this intermediate resulted in a mixture of triethylenetetramine primary, secondary, tertiary or quaternary salt. Further, the tertiary or quaternary salts were converted to the desired secondary salt by use of sodium methoxide, hydrochloric acid, methyl tertiary butyl ether and precipitating with ethanol.
U.S. Patent No. 8,394,992 discloses a method for preparation of triethylenetetramine dihydrochloride wherein tertiary butoxycarbonyl (Boc) protected triethylenetetramine is first converted to its tetrahydrochloride salt using large excess of hydrochloric acid in solvent isopropanol, followed by treatment of the resulting tetrahydrochloride salt with a strong base like sodium alkoxide to produce the amine free base (TETA) and sodium chloride salt in anhydrous conditions. The free amine is extracted with tertiary butyl methyl ether (TBME), followed by removal of sodium chloride salt and finally the amine free base TETA is treated with hydrochloric acid in solvent ethanol to give trientine hydrochloride salt.
The method suffers from the following drawbacks:
a) Lengthy process comprising treatment of tetrahydrochloride salt with a base in anhydrous conditions to obtain the amine and its further conversion to TETA dihydrochloride, which includes a number of unit operations such as solvent extraction, washing of filtered solid, solvent concentration, crystallization at various stages of synthesis etc.
b) Use of excessive amounts of hydrochloric acid as well as anhydrous alcoholic and ether solvents.
c) Stringent requirement of complete removal of sodium chloride formed during the process.
If the salt is not scrupulously removed, the final product, trientine hydrochloride salt is unlikely to pass the sulphated ash test, which is indicative of incomplete removal of inorganic impurities from the drug product.
Indian patent application, 3708/CHE/2015 discloses a process for the preparation of triethylenetetramine dihydrochloride by reacting protected triethylenetetramine with sulfonic acid to form a corresponding sulfonic acid salt. The acid salt is converted to Trientine free base and followed by reaction with an acid to form a Triethylenetetramine dihydrochloride.
Indian patent application, 201741014337 discloses a method for preparation of triethylenetetramine dihydrochloride, wherein tertiary butoxycarbonyl (Boc) protected triethylenetetramine is treated with fumaric acid to obtain a difumarate salt thereof, followed by removing the Boc protecting groups by treating with concentrated HCl to form triethylenetetramine tetrahydrochloride. The tetrahydrochloride salt is then treated with suitable base to form trientine free base, which is subsequently blended with trientine tetrahydrochloride at a pH 7.0 to 8.5 to obtain trientine dihydrochloride salt.
Drawbacks of prior art:
1. A mixture of products and related impurities which require a tedious and uneconomical purification procedure which results Trientine in low yield.
2. The conversion of Trientine quaternary salt to the desired secondary salt suffer limitation such as application of high temperature, use of large volumes of solvent and repeated distillation and washing, making the process very tedious.
3. Use of highly toxic reagents or catalyst in excess quantity which makes the prior art processes uneconomical and not suitable for commercial scale.
4. Use of excess amount of hydrochloric acid may result in formation of inorganic impurities.
5. The main disadvantage of the known processes of Trientine is carrying out the reactions at more unstable conditions thereby obtaining the required product with low purity and low yields. Moreover maintaining reaction at higher temperatures is not preferable at commercial scale.
Hence there remains a need to develop an improved, commercially viable process for the preparation of triethylenetetramine dihydrochloride which overcomes the limitations of prior art.
The present inventors have surprisingly found an improved process for preparing trientine dihydrochloride, avoiding the direct addition of hydrochloric acid, resulting in higher yields, such process being commercially feasible. More particularly, the present invention is aimed at providing an improved efficient, commercially scalable process for the preparation of triethylenetetramine dihydrochloride from triethylenetetramine base comprising treating the free base with in-situ generated hydrochloric acid, thereby avoiding the use of high temperature and pressure, lengthy synthetic steps and use of multi-molar equivalents of hydrochloric acid.
Object of the Invention
An object of the invention is to provide an improved, commercially feasible process for preparing Trien dihydrochloride avoiding direct addition of hydrochloric acid, large volumes of solvents and higher reaction temperatures.
Another object of the invention is to provide efficient process for preparing triethylenetetramine dihydrochloride by overcoming the limitations of prior art.
It is also an object of the invention to provide a commercially viable, economic process for preparing trientine dihydrochloride directly from tertiary butoxycarbonyl (Boc) protected diamine compound, avoiding multiple unit operations and tedious purification steps at intermediate stages.
Summary of the invention:
In one embodiment, the present invention provides an improved, commercially feasible process for preparing trien dihydrochloride comprising reacting triethylenetetramine free base with alcoholic hydrochloric acid, avoiding direct addition of molar excess of hydrochloric acid and higher reaction temperatures.
In another embodiment, the improved process of the present invention for preparing trientine dihydrochloride comprises converting trientine tetrahydrochloride to trien free base, followed by treating the free base with alcoholic hydrochloric acid resulting in desired compound.
In yet another embodiment, the process of the present invention for preparing trientine dihydrochloride comprises treating trientine free base with hydrochloric acid generated during the reaction, thereby reducing impurities and resulting in higher yields, wherein the hydrochloric acid is generated in-situ on treating an acyl chloride with alcohol under reaction conditions.
In one preferred embodiment, the improved process of present invention comprises reacting acetyl chloride with methanol, wherein the hydrochloric acid quantitatively generated during the reaction is treated with trientine free base to form corresponding dihydrochloride salt.
In another preferred embodiment, the improved process of present invention comprises reacting acetyl chloride with ethanol, wherein the hydrochloric acid quantitatively generated during the reaction is treated with trientine free base to form corresponding dihydrochloride salt.
In another embodiment, the present invention provides a simple, convenient process for preparing trientine dihydrochloride directly from tertiary butoxycarbonyl (Boc) protected diamine compound, thereby avoiding multiple unit operations and purification steps at intermediate stages.
In yet another embodiment, the improved process of the present invention provides a crystalline form of Trientine dihydrochloride characterized by X-ray powder diffraction (XRPD) pattern having peaks expressed as 2? values at about 9.05, 13.43, 14.47, 14.79, 15.06, 16.70, 18.07, 20.41, 21.33, 21.76, 23.44, 24.13, 24.44, 25.13, 25.79, 26.86, 27.85, 28.32, 29.80, 30.19, 31.67, 32.85, 34.11, 35.02, 36.56, 38.60, 39.85, 43.70, 45.43, 46.32, and 48.90 ± 0.2º degrees.
Brief Description of Drawings
Figure 1 represents X-ray diffractogram (XRD) of Trientine dihydrochloride.
Figure 2 represents Infrared Spectrum of Trientine dihydrochloride.

Detailed description of the invention:
The present invention is directed to an improved process for the preparation of trientine dihydrochloride represented by a compound of formula VI.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described.
As used herein, the term “Trien” refers to “Triethylenetetramine”, “Trientine”, “N, N’-bis(2-aminoethyl)-1,2-ethanediamine” and are used interchangeably for the purpose of present invention.
The term “reaction conditions” as used herein, unless otherwise specified refers to the details under which a chemical reaction proceeds. Examples of reaction conditions include, but are not limited to, one or more of the following: reaction temperature, solvent, pH, pressure, reaction time, mole ratio of reactants, the presence of a base or acid, or catalyst, etc. Reaction conditions may be named after the particular chemical reaction in which the conditions are employed, such as, coupling conditions, amine group protecting conditions, deprotecting conditions, salt forming conditions, etc. Reaction conditions for known reactions are generally known to those skilled in the art.
Unless otherwise specified, the term “base” as used herein refers to alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tertiary butoxide, potassium tertiary butoxide, lithium tertiary butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; organic bases such as dimethylamine, diethylamine, diisopropylamine, diisopropylethylamine, diisobutylamine, triethylamine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMP), lithium diisopropylamide; lithium hexamethyldisilylazide (LiHMDS), sodium hexamethyldisilylazide (NaHMDS), potassium hexamethyldisilylazide (KHMDS), or mixtures thereof.
The term “solvent(s)” as used herein include without limitation, hydrocarbon solvents such as n-pentane, n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, xylene and the like; ether solvents such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane and the like; ester solvents such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate and the like; polar-aprotic solvents such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; chlorinated solvents such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; nitrile solvents such as acetonitrile, propionitrile, isobutyronitrile and the like; alcohol solvents such as methanol, ethanol, n-propanol, isopropanol (IPA), n-butanol, iso-butanol, t-butanol, ethane-1,2-diol, propane-1,2-diol and the like; polar solvents; formic acid, acetic acid or mixtures thereof.
The present inventors have surprisingly found that Trientine dihydrochloride may be prepared efficiently by an improved process having industrial application wherein use of excess of concentrated hydrochloric acid may be reduced, thereby reducing the extent of equipment corrosion and production costs.
In one embodiment, the present invention provides an improved, commercially feasible process for preparing trientine dihydrochloride, avoiding the direct addition of hydrochloric acid, thereby providing an economic and advantageous alternative for preparing trien dihydrochloride, overcoming the limitations of prior art processes.
More particularly, the present invention provides a commercially scalable process for the preparation of triethylenetetramine dihydrochloride from triethylenetetramine base comprising treating the free base with in-situ generated hydrochloric acid, wherein the hydrochloric acid is generated in-situ on treating an acyl chloride with an alcohol under reaction conditions.
In another embodiment, the process of the present invention for preparing triethylenetetramine dihydrochloride comprises converting trientine tetrahydrochloride to corresponding free base, followed by treating the free base with alcoholic hydrochloric acid resulting in desired compound.
In one aspect, the process of the present invention for preparing trientine dihydrochloride comprises:
a) Reacting ethylene diamine (I) with chloroacetonitrile (II) in presence of a suitable base and a solvent to obtain a solution containing dinitrile compound (IIIa), which is further treated with a diamino protecting reagent to form compound III,
b) Reducing the compound of formula III obtained from step-a) in suitable solvent to form a compound of formula IVa,

Wherein PG denotes amine protecting group,
c) Subjecting the compound IVa to deprotection to form triethylenetetramine tetrahydrochloride compound of formula IV,

d) Converting trientine tetrahydrochloride obtained from step c) to form trientine free base (V),

e) Treating the free base with alcoholic hydrochloric acid generated in-situ to form trientine dihydrochloride.

In the present context, the base wherever used in steps a) to e) is selected from alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tertiary butoxide, potassium tertiary butoxide, lithium tertiary butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; organic bases such as dimethylamine, diethylamine, diisopropylamine, diisopropylethylamine, diisobutylamine, triethylamine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMP), lithium diisopropylamide; lithium hexamethyldisilylazide (LiHMDS), sodium hexamethyldisilylazide (NaHMDS), potassium hexamethyldisilylazide (KHMDS), or mixtures thereof.
The solvent used in steps a) to e) is selected from hydrocarbon solvents such as n-pentane, n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, xylene and the like; ether solvents such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert- butyl ether, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane and the like; ester solvents such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate and the like; polar-aprotic solvents such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; chlorinated solvents such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; nitrile solvents such as acetonitrile, propionitrile, isobutyronitrile and the like; alcohol solvents such as methanol, ethanol, n-propanol, isopropanol (IPA), n-butanol, iso-butanol, t-butanol, ethane-1,2-diol, propane-1,2-diol and the like; polar solvents; formic acid, acetic acid or mixtures thereof.
In step a) ethylene diamine reacts with chloroacetonitrile in the presence of a base and suitable solvent to obtain a solution containing a dinitrile compound (IIIa). In preferred embodiments, the base used is potassium carbonate and solvent is acetonitrile. This reaction may be carried out at room temperature.
Further the solution containing compound IIIa is treated with a diamine protecting reagent to form compound III. Examples of diamine protecting reagent include without limitation, benzaldehyde, di-tert-butyldicarbonate (BoC2O), trifluoroacetamide, and the like. In preferred embodiments, the protecting reagent used is di-tert-butyldicarbonate to form tertiary butoxycarbonyl (Boc) protected dinitrile compound (III). The reaction may be carried at a temperature of about 0-5°C.
In step b), the compound of formula III is subjected to reduction, wherein the nitrile is reduced to form a protected diamine compound IVa. Reduction may be carried out suitable reducing agents selected from the group consisting of Pd-C, raney nickel, nickel-aluminum catalyst, sodium aluminium hydride, lithium aluminium hydride, sodium borohydride, di-isobutyl aluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, tin (II) chloride, zinc in acetic acid, ammonium chloride, zinc dust etc. Solvents are chosen based on the reducing agent used, and include, for example, alcohols such as methanol, ethanol and isopropanol, acetic anhydride, dimethylformamide (DMF), tetrahydrofuran, dimethoxyethane, toluene, and a mixture of alcohol and water. Alcohol solvents and mixtures of alcohol and water may optionally include liquid or gaseous ammonia. In preferred embodiments, reduction is carried out by hydrogenation using raney nickel in isopropanol in the presence of liquid ammonia at a temperature of about 15-25°C.
In step c), compound IVa is subjected to deprotection by treating with suitable acid in a suitable solvent. Suitable acid may be selected from organic or inorganic acids. Solvents used may be as described hereinbefore. In preferred embodiments, a tertiary butoxycarbonyl (Boc) protected diamine compound is subjected to deprotection by treating compound IVa with conc. hydrochloric acid in isopropanol to form triethylenetetramine tetrahydrochloride. The deprotection may be carried out at a temperature of about 20-60ºC.
In step d), the tetrahydrochloride salt of trientine is converted to trientine free base by treating with a base in suitable solvent. Preferably, trientine tetrahydrochloride is treated with sodium hydroxide in isopropyl alcohol at a temperature of about 15-20°C to form trientine free base.
In step e), the trientine free base obtained as a syrupy liquid is treated with alcoholic hydrochloric acid generated in-situ to form a dihydrochloride salt thereof, wherein the hydrochloric acid is generated in-situ by reacting an acyl chloride with an alcoholic solvent at a temperature of about -10 ± 3°C. Examples of acyl chloride include without limitation, acetyl chloride, propionyl chloride and the like. Examples of alcoholic solvents include methanol, ethanol and the like. The reaction takes place using one or more solvents described as hereinbefore. Preferably a mixture of dichloromethane and dimethylformamide are used to dissolve the crude trientine free base, which is further treated with alcoholic hydrochloric acid to form corresponding dihydrochloride salt. There is no need of pH adjustment in this step.
Hydrogen chloride in organic solvents is a useful reagent for many reactions, primarily ones involving formation of amine salts. A major drawback of the reported procedures stems from the large excess of the acid present in solution, the organic solvent commonly being saturated with gaseous HCl. Preparation of organic solutions containing stoichiometric amounts of the acid are difficult.
The present inventors report a simple and highly convenient method for the preparation and use of solutions of HCl in organic solvents. The solution prepared by the addition of stoichiometric amount of acetyl chloride to an inert organic solvent containing an equivalent amount of methanol.
The solutions may be prepared by the addition of either a stoichiometric amount of acetyl chloride to an inert organic solvent containing an equivalent amount of methanol (or ethanol), or by addition of a known amount of acetyl chloride to an organic solvent containing a molar excess of the alcohol.
In one preferred embodiment, the trientine free base is treated with hydrochloric acid quantitatively generated during the reaction by reacting acetyl chloride with methanol to form trientine dihydrochloride salt.
In another preferred embodiment, the trientine free base is treated with hydrochloric acid quantitatively generated during the reaction by reacting acetyl chloride with ethanol to form trientine dihydrochloride salt.
In preferred embodiments, the improved process of the present invention for preparing trientine dihydrochloride is illustrated in Scheme-I.

In yet another embodiment, the present invention provides a simple, convenient process for preparing trientine dihydrochloride directly from tertiary butoxycarbonyl (Boc) protected diamine compound, thereby avoiding multiple unit operations at intermediate stages, wherein said process comprises reacting compound IVa with isopropanol hydrochloride, followed by treating with a base in a suitable solvent, and finally reacting with hydrochloric acid generated in-situ to form trientine dihydrochloride without isolating intermediates, thereby avoiding multiple purification steps and excess use of solvents. Suitable solvents and bases used may be as described hereinbefore.
In another embodiment, the present invention provides a process for preparing pure trientine dihydrochloride, said process comprising:
(a) dissolving crude trientine free base in one or more solvents;
(b) adding acyl chloride and an alcohol to the mixture of step (a);
(c) stirring the reaction mixture at -10 ± 5ºC;
(d) isolating trientine dihydrochloride by adding another solvent to the reaction mixture of step (c);
(e) Purifying the crude compound obtained from step (d) in one or more solvents to provide pure trientine dihydrochloride.
In the present context, the solvents in steps (a) to (e) used may be as described hereinbefore. Preferred solvents may be selected from acetone, acetonitrile, 1,4-dioxane, diethyl ether, dichloromethane, methanol, ethanol, isopropyl alcohol (IPA), n-propanol, n-butanol, ethyl acetate, N,N-dimethylformamide, methyl tertiary butyl ether, hexane, cyclohexane, toluene, tetrahydrofuran, water or the like.
In preferred embodiments, the crude free base is dissolved in dichloromethane and dimethylformamide in step (a). In step (b), the acyl chloride is preferably acetyl chloride, and the alcohol is selected preferably from methanol and ethanol. In steps (d) and (e), the preferred solvent is acetonitrile.
In yet another embodiment, the present invention provides a crystalline form of Trientine dihydrochloride characterized by X-ray powder diffraction (XRPD) pattern having peaks expressed as 2? values at about 9.05, 13.43, 14.47, 14.79, 15.06, 16.70, 18.07, 20.41, 21.33, 21.76, 23.44, 24.13, 24.44, 25.13, 25.79, 26.86, 27.85, 28.32, 29.80, 30.19, 31.67, 32.85, 34.11, 35.02, 36.56, 38.60, 39.85, 43.70, 45.43, 46.32, and 48.90 ± 0.2º degrees, as represented in Figure 1.
In a further embodiment, the present invention provides a process for preparing the crystalline form of Trientine dihydrochloride characterized by X-ray powder diffraction (XRPD) pattern having peaks expressed as 2? values at about 9.05, 13.43, 14.47, 14.79, 15.06, 16.70, 18.07, 20.41, 21.33, 21.76, 23.44, 24.13, 24.44, 25.13, 25.79, 26.86, 27.85, 28.32, 29.80, 30.19, 31.67, 32.85, 34.11, 35.02, 36.56, 38.60, 39.85, 43.70, 45.43, 46.32, and 48.90 ± 0.2º degrees, said process comprising:
a) Reacting ethylene diamine (I) with chloroacetonitrile (II) in presence of a suitable base and a solvent to obtain a solution containing dinitrile compound (IIIa), which is further treated with a diamino protecting reagent to form compound III,

b) Reducing the compound of formula III obtained from step-a) in suitable solvent to form a compound of formula IVa,

Wherein PG denotes amine protecting group,
c) Subjecting the compound IVa to deprotection to form triethylenetetramine tetrahydrochloride compound of formula IV,

d) Converting trientine tetrahydrochloride obtained from step c) to form trientine free base (V),

e) Treating the free base with alcoholic hydrochloric acid generated in-situ to form trientine dihydrochloride;

f) Purifying the compound obtained from step d) in one or more solvents to provide pure, crystalline trientine dihydrochloride.
In preferred embodiments, the base in step a) is potassium carbonate, solvent is acetonitrile, and diamine protecting agent is di-tert-butyldicarbonate. Reduction in step b) is carried out by hydrogenation using raney nickel in isopropanol in the presence of liquid ammonia. In step c), compound IVa is subjected to deprotection by treating with conc. hydrochloric acid in isopropanol to form triethylenetetramine tetrahydrochloride. In step d), the tetrahydrochloride salt of trientine is converted to trientine free base by treating with sodium hydroxide in isopropyl alcohol. In step e), the trientine free base in a mixture of dichloromethane and dimethylformamide is treated with acetyl chloride and an alcoholic solvent to form the corresponding dihydrochloride salt. In step f), the crude dihydrochloride salt is purified using one or more solvents, preferably using acetonitrile to provide a pure, crystalline trientine dihydrochloride as represented in Figure 1.

Further the improved process of present invention for preparing trientine dihydrochloride and intermediates thereof is illustrated in the following examples. The following specific and non-limiting examples are to be construed as merely illustrative, and do not limit the present disclosure in any way whatsoever.
Examples:
Example 1: Preparation of compound III:
To a solution of chloroacetonitrile (II) (251.2g) in acetonitrile (600 ml), was charged potassium carbonate (803g), stirred at room temperature (RT) for 15 mins. Ethylene diamine (I) (100g) was slowly added into the reaction mass (RM) under stirring and maintained for 12-20 hrs at RT. The reaction was monitored by TLC. After completion of reaction, the RM was cooled to 0 ± 5°C, followed by slow addition of Boc anhydride (920 ml) and maintained it for 6 hours at same temperature. Further, the RM was stirred at RT for 12 hrs. After completion of reaction, the RM was filtered, washed with acetonitrile (200 ml) and distilled under vacuum at 40°C to give a crude gummy compound. To the crude compound, was added (35 vol), ethyl acetate (30 vol) and stirred for 15 minutes. The aqueous and organic layers were separated. Combined organic layers were washed with sodium chloride, followed by washing with water. Total organic layer was distilled under vacuum at 45°C to give a crude compound (III). To the crude compound, was charged isopropyl alcohol (10 vol) and stirred the RM for 15 mins at RT. The RM was cooled to 0 ± 5°C, and maintained for 1 hr. Filtered the mass and washed with isopropyl alcohol (3 vol), followed by drying in oven at 50°C for 3 hrs to give pure compound III. (Yield = 85.7%)
Example 2: Preparation of compound IVa:
In a clean and dry autoclave, was charged compound III (40g) obtained from Example 1, 25% liq. ammonia (100 ml), Raney Nickel (40g), and isopropyl alcohol (100 ml) at room temperature under nitrogen atmosphere and pressurized with hydrogen to 5.0 kg/cm2. The reaction mixture was maintained for 18-20 hours. Progress of reaction was monitored by TLC. After completion of reaction, the RM was washed with isopropyl alcohol (100 ml), filtered through high-flow bed twice and washing with isopropyl alcohol (1000 ml) under nitrogen. The filtrate was completely distilled under vacuum at 45°C to give crude compound. To the crude, was charged n-hexane (500ml) resulting in a solid, followed by drying at 50°C for 3 hrs in vacuum oven to give the compound IVa. (Yield = 85%)
Example 3: Preparation of Trientine tetrahydrochloride (IV):
To a clean and dry RBF and condenser fitted with mechanical stirrer, was charged isopropyl alcohol (10 ml) and compound IVa (2g) obtained from Example 2 at room temperature and cooled to 20°C. To the above RM, was added conc. HCl (2 ml), heated to reflux temperature (up to 60°C), maintained for 4 hours. After that reaction mass allowed to room temperature, then cooled to 0-5°C and stirred for one hour. After maintenance, the RM was filtered and washed with isopropyl alcohol (5 ml). The wet solid obtained was dried in hot air oven at 50°C for one hour to give dried compound IV. (Yield = 93%)
Example 4: Preparation of Trientine free base (V):
To a clean and dry RBF and condenser with mechanical stirrer, was charged 30% sodium hydroxide (50 ml) and cooled to below 20°C. Compound IV (5g) from Example 3 was charged lot-wise and allowed to cool to room temperature. To the above RM was charged isopropyl alcohol (25 ml), and stirred for 30 minutes. The organic and aqueous layers were separated. The aq. layer was extracted with isopropyl alcohol (10ml). Combined organic layers were dried with sodium sulfate and distilled under vacuum at 45°C to give crude compound (V).
Example 5: Preparation of Trientine dihydrochloride (VI):
In an RBF, was charged methanol (1 ml) and cooled to 0 ± 5°C. To this, was slowly added acetyl chloride (1.8 ml) and stirred for 60 minutes at -10°C to 3°C. To the above RM, was added dropwise a solution of compound V (2g) from Example 4 in dichloromethane (10 ml) and dimethylformamide (2 ml). The RM was maintained at -15°C for 20 minutes. The reaction mass allowed to room temperature to precipitate thick crude compound. To the crude compound was added acetonitrile (20 ml), stirred for one hour at 15 ± 5°C. Filtered the solid and washed with acetonitrile under nitrogen atmosphere, followed by drying under vacuum at 45°C to yield pure trientine dihydrochloride (VI).
The XRPD of trientine dihydrochloride is depicted in Figure 1 and IR spectrum is depicted in Figure 2.
,CLAIMS:We Claim,
1. An improved process for the preparation of triethylenetetramine dihydrochloride (VI), comprising:
a) Reacting ethylene diamine (I) with chloroacetonitrile (II) in presence of a base to obtain a compound (IIIa), which is further treated with a diamino protecting reagent to form a compound III;
b) Reducing the compound of formula III to form a compound of formula IVa;

Wherein PG denotes amine protecting group,
c) Subjecting the compound IVa to deprotection to form triethylenetetramine tetrahydrochloride compound of formula IV;

d) Converting triethylenetetramine tetrahydrochloride to trientine free base (V) by treatment with a base;

e) Treating trientine free base with acyl chloride and an alcohol to form trientine dihydrochloride,
.
2. The process as claimed in claim 1, wherein the base in step a) and d) is selected from alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides, alkali metal alkoxides, alkali metal hydrides, alkali metal amides and organic bases;
the amine protecting agent in step a) is selected from benzaldehyde, di-tert-butyldicarbonate, trifluoroacetamide, and the like;
reduction in step b) is performed using reducing agents selected from Pd-C, raney nickel, nickel-aluminum catalyst, sodium aluminium hydride, lithium aluminium hydride, sodium borohydride, di-isobutyl aluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, tin (II) chloride, zinc in acetic acid, ammonium chloride, and zinc dust;
the deprotection in step c) is carried out using concentrated hydrochloric acid;
the acyl chloride in step e) is selected from acetyl chloride, propionyl chloride and the like; alcohol is selected from methanol, ethanol, and the like.

3. An improved process for preparing pure trientine dihydrochloride (VI), comprising:
(a) Reacting a compound of formula IVa with an acid to provide trientine tetrahydrochloride (IV);
(b) Converting trientine tetrahydrochloride (IV) to trientine free base (V) by treatment with a base;
(c) Treating crude trientine free base (V) with an acyl chloride and alcohol in one or more solvents to provide crude trientine dihydrochloride;
(d) Dissolving the crude compound from step (c) in one or more solvents to provide a pure trientine dihydrochloride (VI).

4. An improved process for preparing pure trientine dihydrochloride (VI), comprising:
(a) Dissolving crude trientine free base in one or more solvents;
(b) Adding acyl chloride and an alcohol to the mixture of step (a);
(c) Isolating trientine dihydrochloride by adding another solvent to the reaction mixture of step (b);
(d) Purifying the crude compound obtained from step (c) in one or more solvents to provide pure trientine dihydrochloride.

5. The process as claimed in claims 3 & 4, wherein the acid is selected from an organic acid or inorganic acid; base is selected from alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides, alkali metal alkoxides, alkali metal hydrides, alkali metal amides and organic bases; solvent is selected from acetone, acetonitrile, 1,4-dioxane, diethyl ether, dichloromethane, methanol, ethanol, isopropyl alcohol (IPA), n-propanol, n-butanol, ethyl acetate, N,N-dimethylformamide, methyl tertiary butyl ether, hexane, cyclohexane, toluene, tetrahydrofuran, and water; the acyl chloride is selected from acetyl chloride, propionyl chloride and the like; and alcohol is selected from methanol, ethanol, and the like.

6. A crystalline form of Trientine dihydrochloride (VI) characterized by X-ray powder diffraction (XRPD) pattern having peaks expressed as 2? values at about 9.05, 13.43, 14.47, 14.79, 15.06, 16.70, 18.07, 20.41, 21.33, 21.76, 23.44, 24.13, 24.44, 25.13, 25.79, 26.86, 27.85, 28.32, 29.80, 30.19, 31.67, 32.85, 34.11, 35.02, 36.56, 38.60, 39.85, 43.70, 45.43, 46.32, and 48.90 ± 0.2º degrees.

7. A process for preparing a crystalline form of Trientine dihydrochloride (VI) characterized by X-ray powder diffraction (XRPD) pattern having peaks expressed as 2? values at about 9.05, 13.43, 14.47, 14.79, 15.06, 16.70, 18.07, 20.41, 21.33, 21.76, 23.44, 24.13, 24.44, 25.13, 25.79, 26.86, 27.85, 28.32, 29.80, 30.19, 31.67, 32.85, 34.11, 35.02, 36.56, 38.60, 39.85, 43.70, 45.43, 46.32, and 48.90 ± 0.2º degrees, comprising:
a) Reacting ethylene diamine (I) with chloroacetonitrile (II) in presence of a base to obtain a compound (IIIa), which is further treated with a diamino protecting reagent to form a compound III;
b) Reducing the compound of formula III to form a compound of formula IVa;

Wherein PG denotes amine protecting group,
c) Subjecting the compound IVa to deprotection to form triethylenetetramine tetrahydrochloride compound of formula IV;

d) Converting triethylenetetramine tetrahydrochloride to trientine free base (V) by treatment with a base;

e) Treating trientine free base with an acyl chloride and an alcohol to form trientine dihydrochloride,

f) Purifying the crude compound obtained from step e) in one or more solvents to provide crystalline form of trientine dihydrochloride (VI).

8. The process as claimed in claim 7, wherein the base in steps a) and d) is selected from alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides, alkali metal alkoxides, alkali metal hydrides, alkali metal amides and organic bases;
the amine protecting agent in step a) is selected from benzaldehyde, di-tert-butyldicarbonate, trifluoroacetamide, and the like;
reduction in step b) is performed using reducing agents selected from Pd-C, raney nickel, nickel-aluminum catalyst, sodium aluminium hydride, lithium aluminium hydride, sodium borohydride, di-isobutyl aluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, tin (II) chloride, zinc in acetic acid, ammonium chloride, and zinc dust;
the deprotection in step c) is carried out using concentrated hydrochloric acid;
in step e) the acyl chloride is selected from acetyl chloride, propionyl chloride and the like; alcohol is selected from methanol, ethanol, and the like;
solvent in step f) is selected from acetone, acetonitrile, 1,4-dioxane, diethyl ether, dichloromethane, methanol, ethanol, isopropyl alcohol (IPA), n-propanol, n-butanol, ethyl acetate, N,N-dimethylformamide, methyl tertiary butyl ether, hexane, cyclohexane, toluene, tetrahydrofuran, and water.

9. An improved process for preparing pure Triethylenetetramine dihydrochloride (VI), comprising:
a) Reacting ethylene diamine (I) with chloroacetonitrile (II) in presence of potassium carbonate in acetonitrile to obtain a compound (IIIa), which is further treated with di-tert-butyldicarbonate to form compound III;

b) Reducing the compound III obtained in step a) with raney nickel in presence of ammonia in isopropanol to form compound IVa;

c) Subjecting compound IVa to deprotection by treatment with hydrochloric acid to form compound IV;

d) Converting compound IV by treatment with sodium hydroxide in isopropanol to form trientine free base (V);

e) Dissolving the crude trientine free base obtained in step d) in a mixture of dichloromethane and N,N-dimethylformamide, followed by treating with in-situ generated hydrochloride acid to form trientine dihydrochloride (VI);

Wherein the hydrochloric acid is generated in-situ by reacting acetyl chloride with methanol,
f) Purifying the compound obtained from step e) in acetonitrile to provide pure triethylenetetramine dihydrochloride.