Claims:1) A process for the preparation of Trientine dihydrochloride of Formula I

I
comprising the steps of:
a. reacting the ethylene diamine of compound of Formula VIII

VIII
with chloroacetonitrile compound of Formula VII

VII
in the presence of base and in an organic solvent at temperature between 5°C – 50°C for a time duration ranging between 15 – 30 hours to get compound of formula VI followed by protecting with amine protecting groups (P) selected from benzyl or tertiary-butoxy carbonyl (t-BOC) in a suitable solvent at temperature ranging between 0°C -15 °C for a time duration ranging between 5 – 30 hours to get compound of formula V;

VI

V

b. reducing the compound of formula V in a suitable solvent at temperature ranging between 20-40°C for a time duration ranging between 15-30 hours to get diamino compound of formula IV followed by protecting with amine protecting group (P) selected from benzyl or tertiary-butoxy carbonyl (t-BOC) in a suitable solvent at temperature ranging between 20-40°C for a time duration ranging between 15-30 hours to get compound of formula III.

IV

III
c. treating compound of formula III with mineral acid in a suitable solvent at temperature ranging between 25°C-100°C for time duration ranging between 2-7 hours to get tetra hydrochloric acid salt of Trientine compound of formula II .

II
d. treating tetra hydrochloric acid salt of Trientine compound of compound of formula II with base in a suitable solvent to get Trientine dihydrochloride compound of Formula I with purity of 99%(by HPTLC) or more.
2) The process for the preparation of Trientine dihydrochloride of Formula I, according to claim 1, wherein the base used in step a. or step d or for treating the tetra hydrochloric acid is selected from inorganic base as sodium hydroxide, sodium carbonate, potassium carbonate, ammonia, ammonium hydroxide and calcium carbonate or organic base is selected from sodium methoxide, sodium ethoxide, potassium methoxide, triethyl amine and N-methylpyrrolidine.

3) The process for the preparation of Trientine dihydrochloride of Formula I, according to claim 1, wherein the mineral acid used in step c. is selected from hydrochloride, or mixture of hydrochloric acid & sulphuric or mixture of hydrochloric acid & phosphoric acid.

4) The process for the preparation of Trientine dihydrochloride of Formula I, according to claim 1, wherein the organic solvent selected from aromatic solvents as toluene, xylene or alcohol solvents as methanol, ethanol, isopropanol, n-propanol, butanol, or ester solvents as ethyl acetate, isopropyl acetate, butyl acetate or amide solvents as N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide or chlorinated solvents as dichloromethane, monochloromethane, trichloromethane, tetrachloromethane, dichloroethane or pyrrolidine solvents as dimethylpyrrolidine (DMP), N-methylpyrrolidine (NMP) or water and mixtures thereof.

5) The process for the preparation of Trientine dihydrochloride of Formula I, according to claim 1, wherein the reducing agents selected from Lithium Aluminium hydride (LAH), Nickel borohydride, Raney Nickel, Red-Al, Sodium borohydride, Tin hydrides, Sodium dithionite and Pd/C.

6) The process for the preparation of Trientine dihydrochloride of Formula I, according to claim 1, wherein amine protecting step of both step a and step b are carried as in-situ or isolating protected intermediate.

7) The process for the preparation of Trientine dihydrochloride of Formula I, according to claim 1, comprising the steps of:
a. crude Trientine protected with amine protecting group selected from the group such as benzyl or tertiary-butyl carbonyl (t-BOC) in presence of base in a suitable solvent at temperature ranging between 0 – 50°C for time duration ranging between 5 hrs - 20 hrs to get compound of formula III.

Trientine

III
b. treating compound of formula III with mineral acid or mixture thereof at temperature ranging between 25°C-100°C for time duration ranging between 2-7 hours to get Tetra hydrochloride salt of Trientine compound of formula II .

II
c. treating compound of formula II with base in a suitable solvent to get Trientine dihydrochloride compound of Formula I with purity of 99% (by HPTLC) or more .

8) A process for the preparation of Trientine dihydrochloride of Formula I

I
comprising the steps of:
a. reacting the ethylene diamine of compound of Formula VIII

VIII
with chloroacetonitrile compound of Formula VII

VII
in the presence of potassium carbonate and in acetonitrile at temperature between 5°C – 50°C for a time duration ranging between 15 – 30 hours to get compound of formula VI followed by reacting with di-tertiary-butyl dicarbonate (BOC-Anhydride) at temperature ranging between 0 °C -15 °C for a time duration ranging between 5 – 30 hours to get compound of formula Va;

VI

Va
b. reducing the compound of formula Va with Raney Nickel in solvent ammonia dissolved in methanol at temperature ranging between 20-40°C for a time duration ranging between 15-30 hours to get diamino compound of formula IVa followed by reacting with di-tertiary-butyl dicarbonate (BOC-Anhydride) in ethyl acetate at temperature ranging between 20-40°C for a time duration ranging between 15-30 hours to get compound of formula IIIa.

IVa

IIIa
c. treating compound of formula IIIa with hydrochloric acid in isopropyl alcohol at temperature ranging between 25 °C-100 °C for time duration ranging between 2-7 hours to get Tetra hydrochloride acid salt of Trientine compound of formula II.

II
d. treating compound of formula II with sodium ethoxide in ethanol at temperature ranging between 25°C to reflux temperature for time duration ranging between 1-4 hours to get Trientine dihydrochloride compound of formula I with purity of 99% ( by HPTLC) or more.

9) The process for the preparation of substantially pure Trientine dihydrochloride of Formula I, comprising the steps of:
a. reacting the crude Trientine (having purity > 50%) with di-tertiary-butyl dicarbonate (BOC-Anhydride) in presence of triethyl amine in acetonitrile at temperature ranging between 0°C - 10°C for a time duration ranging between 5-15 hours to get compound of formula IIIa.

Trientine

IIIa
b. treating compound of formula IIIa with hydrochloric acid at temperature ranging between 25 °C-100 °C for time duration ranging between 2-7 hours to get tetra hydrochloric acid salt of Trientine compound of formula II.

II
c. treating tetra hydrochloric acid salt of Trientine compound of formula II with ethanolic solution of sodium ethoxide to get Trientine dihydrochloride compound of formula I with purity of 99% ( by HPTLC) or more.
, Description:FIELD OF THE INVENTION
The present invention relates to improved and commercially viable process for the preparation of Trientine dihydrochloride of formula I.

(I)
Trientine dihydrochloride (I) is a therapeutically useful chelating agent which is used to bind and remove excess copper in the body in order to treat Wilson's disease, particularly in those who are intolerant to penicillamine.

BACKGROUND OF THE INVENTION
Trientine, chemically known as triethylenetetramine belongs to the class of polyethylene polyamines. Triethylenetetramine, sometimes also refered as N,N'-Bis(2-aminoethyl)ethane-1,2-diamine; TETA; Trien.

Trientine dihydrochloride
(I)
Trientine dihydrochloride is a chelating agent which is used to bind and remove excess 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 are intolerant to penicillamine.

Triethylenetetramine may reportedly also be used in the synthesis of N-methylated triethylenetetramine, as reported in United States Patent No. 2,390,766, to Zellhoefer et al Synthesis of polyethylenepolyamines, including triethylenetetramines, from ethylenediamine and monoethanolamine using pelleted group IVb metal oxide- phosphate type catalysts was reported by Vanderpool et al. in United States Patent No. 4,806,517. Synthesis of triethylenetetramine from ethylenediamine and ethanolamine was also proposed in United States Patent No. 4,550,209, to Unvert et al United States Patent No. 5,225,599, to King et al. is said to be directed to the synthesis of linear Methylene tetramine by condensation of ethylenediamine and ethylene glycol in the presence of a catalyst.

A process for preparation of alkyleneamines in the presence of a niobium catalyst was said to be provided in European Patent No. 256,516, to Tsutsumi et al. United States Patent No. 4,584,405, to Vanderpool, reported the continuous synthesis of essentially noncyclic polyethylenepolyamines by reaction of monoethanolamine with ethylenediamine in the presence of an activated carbon catalyst under a pressure between about 500 to about 3000 PSIG., and at a temperature of between about 200°C to about 400°C.

Templeton, et al, reported on the preparation of linear polyethylenepolyamides asserted to result from reactions employing silica-alumina catalysts in European Patent No. EP150,558.

Production of triethylenetetramine dihydrochloride was said to have been reported in Kuhr et al, Czech Patent No. 197,093, via conversion of triethylenetetramine to crystalline tetrahydrochloride and subsequently to triethylenetetramine dihydrochloride. "A study of efficient preparation of triethylenetetramine dihydrochloride for the treatment of Wilson's disease and hygroscopicity of its capsule," Fujito, et al, Yakuzaigaku, 50:402-8 (1990), is also said to be directed to production of triethylenetetramine.

Owing to various commercial viable process hurdles related to impurities formation and others, the existing methods of synthesis of triethylenetetramines, and polyethylenepolyamines, are found to be unsatisfactory. For instance, some of them often require higher temperatures. A method for production of more pure triethylenetetramines at high yield under more favorable conditions including, for example, at more manageable temperatures and pressures, would be still be desirable for industrially feasible & up scalable process. Further, according to present process, purification process is much efficient and simple over prior-art process as Tetra BOC protected Trientine is more stable than the diBOC protected Trientine and hence the purification is much efficient and simple with Tetra BOC protected Trientine for preparation of Trientine dihydrochloride (I).
SUMMARY OF INVENTION
Particular aspect of the present invention relates to an efficient process for the preparation of Trientine dihydrochloride of Formula I.

I
In one aspect of the present invention relates to process for the preparation of Trientine dihydrochloride of Formula I comprising the steps of:
a. reacting the ethylene diamine of compound of Formula VIII

VIII
with chloroacetonitrile compound of Formula VII

VII
in the presence of base and in an organic solvent at temperature between 5°C – 50°C for a time duration ranging between 15 – 30 hours to get compound of formula VI followed by protecting with amine protecting group (P) selected from benzyl or tertiary-butoxy carbonyl (t-BOC) in a suitable solvent at temperature ranging between 0°C -15 °C for a time duration ranging between 5 – 30 hours to get compound of formula V;

VI

V
b. reducing the compound of formula V in a suitable solvent at temperature ranging between 20-40°C for a time duration ranging between 15-30 hours to get diamino compound of formula IV followed by protecting with amine protecting group (P) selected from benzyl or tertiary-butoxy carbonyl (t-BOC) in a suitable solvent at temperature ranging between 20-40°C for a time duration ranging between 15-30 hours to get compound of formula III.

IV

III
c. treating compound of formula III with mineral acid in a suitable solvent at temperature ranging between 25°C-100°C for time duration ranging between 2-7 hours to get tetra hydrochloric acid salt of Trientine compound of formula II.

II
d. treating tetra hydrochloric acid salt of Trientine compound of formula II with base in a suitable solvent to get Trientine dihydrochloride compound of Formula I with purity of 99%(by HPTLC) or more.

In another aspect of the present invention relates to a process for the preparation of Trientine dihydrochloride of Formula I

I
comprising the steps of:
a. reacting the ethylene diamine of compound of Formula VIII

VIII
with chloroacetonitrile compound of Formula VII

VII
in the presence of potassium carbonate and in acetonitrile at temperature between 5°C – 50°C for a time duration ranging between 15 – 30 hours to get compound of formula VI followed by reacting with di-tertiary-butyl dicarbonate (BOC-Anhydride) at temperature ranging between 0°C -15 °C for a time duration ranging between 5 – 30 hours to get compound of formula Va;

VI

Va
b. reducing the compound of formula Va in a suitable solvent at temperature ranging between 20-40°C for a time duration ranging between 15-30 hours to get diamino compound of formula IVa followed by protecting with amine protecting group (P) selected from benzyl or tertiary-butoxy carbonyl (t-BOC) in a suitable solvent at temperature ranging between 20-40°C for a time duration ranging between 15-30 hours to get compound of formula IIIa.

IVa

IIIa
c. treating compound of formula IIIa with hydrochloric acid in isopropyl alcohol at temperature ranging between 25°C-100°C for time duration ranging between 2-7 hours to get Tetra hydrochloride acid salt of Trientine compound of formula II.

II
treating compound of formula II with sodium ethoxide in ethanol at temperature ranging between 25°C to reflux temperature for time duration ranging between 1-4 hours to get Trientine dihydrochloride compound of formula I with purity of 99% ( by HPTLC) or more.

In yet another aspect of the present invention relates to process for the preparation of substantially pure Trientine dihydrochloride of Formula I, comprising the steps of:
a. reacting the crude Trientine (having purity > 50%) with di-tertiary-butyl dicarbonate (BOC-Anhydride) in presence of triethyl amine in acetonitrile at temperature ranging between 0°C - 10°C for a time duration ranging between 5-15 hours to get compound of formula IIIa.

IIIa
b. treating compound of formula IIIa with hydrochloric acid at temperature ranging between 25°C-100°C for time duration ranging between 2-7 hours to get tetra hydrochloric acid salt of Trientine compound of formula II .

II
c. treating compound of formula II with ethanolic solution of sodium ethoxide to get Trientine dihydrochloride compound of formula I with purity of 99%
( by HPTLC) or more.

DETAILED DESCRIPTION
In one embodiment, the present invention provides an efficient process for the preparation of Trientine dihydrochloride of Formula I, comprising the steps of:
a. reacting the ethylene diamine of compound of Formula VIII

VIII
with chloroacetonitrile compound of Formula VII

VII
in the presence of base and in an organic solvent at temperature between 5°C – 50°C for a time duration ranging between 15 – 30 hours to get compound of formula VI followed by reacting with amine protecting group (P) selected from benzyl or tertiary-butoxy carbonyl (t-BOC) in a suitable solvent at temperature ranging between 0°C -15 °C for a time duration ranging between 5 – 30 hours to get compound of formula V;

VI

V
b. reducing the compound of formula V in a suitable solvent to get diamino compound of formula IV followed by reacting with amine protecting group (P) selected from benzyl or tertiary-butoxy carbonyl (t-BOC) in a suitable solvent to get compound of formula III.

IV

III
c. treating compound of formula III with mineral acid in a suitable solvent at temperature ranging between 25°C-100°C for time duration ranging between 2-7 hours to get tetra hydrochloric acid salt of Trientine compound of formula II .

II
d. treating tetra hydrochloric acid salt of Trientine compound of compound of formula II with base in a suitable solvent to get Trientine dihydrochloride compound of Formula I with purity of 99% (by HTPLC) or more.
The process steps according to present invention step a, step d or treating the tetra hydrochloric acid compound of formula II are carried in the presence of a base wherein base selected from the group consisting of from inorganic base as sodium hydroxide, sodium carbonate, potassium carbonate, ammonia, ammonium hydroxide and calcium carbonate or organic base is selected from sodium methoxide, sodium ethoxide, potassium methoxide, triethyl amine and N-methylpyrrolidine.
In one of the particular embodiment of the present invention, step a is performed in the presence of inorganic base selected from the group consisting of sodium hydroxide, sodium carbonate, potassium carbonate, ammonia, ammonium hydroxide and calcium carbonate whereas step d or treating the tetra hydrochloric acid compound of formula II in presence of organic base selected from sodium methoxide, sodium ethoxide, potassium methoxide, triethyl amine and N-methylpyrrolidine.
In still particular embodiment of the present invention, step a is performed in presence of potassium carbonate as base and sodium ethoxide is used as base in step d or for treating the tetra hydrochloric acid compound of formula II.
In one of the embodiment of the present invention, process step a is performed at temperature between 5°C – 50°C for a time duration ranging between 15 – 30 hours to get compound of formula VI followed by protecting with amine protecting group (P) selected from benzyl or tertiary-butoxy carbonyl (t-BOC) in a suitable solvent at temperature ranging between 0°C -15°C for a time duration ranging between 5 – 30 hours to get compound of formula V.
In a one of the particular embodiment of the present invention, step a is performed is performed at temperature between 10°C – 15°C for a time duration ranging between 20 – 24 hours to get compound of formula VI followed by reacting with di-tertiary-butyl dicarbonate (BOC- Anhydride) at temperature ranging between 5°C -30°C for a time duration ranging between 20-24 hours to get compound of formula Va.
In another embodiment of the present invention, step a is performed in suitable solvent selected from aromatic solvents as toluene, xylene or alcohol solvents as methanol, ethanol, isopropanol, n-propanol, butanol, or ester solvents as ethyl acetate, isopropyl acetate, butyl acetate or amide solvents as N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide or chlorinated solvents as dichloromethane, monochloromethane, trichloromethane, tetrachloromethane, dichloroethane or pyrrolidine solvents as dimethylpyrrolidine (DMP), N-methylpyrrolidine (NMP) or water and mixtures thereof.
In one of the particular embodiment of the present invention, step a is performed in acetonitrile as solvent.
In one of the embodiment of the present invention, step b is performed by reducing the compound of formula V in a suitable solvent at temperature ranging between 20-40°C for a time duration ranging between 15-30 hours to get diamino compound of formula IV followed by reacting with amine protecting group (P) selected from benzyl or tertiary-butoxy carbonyl (t-BOC) in a suitable solvent at temperature ranging between 20-40°C for a time duration ranging between 15-30 hours to get compound of formula III.

IV

III
In one of the embodiment of the present invention, step b is performed by using the reducing agents selected from the reducing agents selected from Lithium Aluminium hydride (LAH), Nickel borohydride, Raney Nickel, Red-Al, Sodium borohydride, Tin hydrides, Sodium dithionite and Pd/C.
In another embodiment of the present invention, the crude Trientine (having purity > 50% ) is protected with amine protecting group selected from the group such as benzyl or tertiary-butoxy carbonyl (t-BOC) in presence of base in a suitable solvent at temperature ranging between 0 – 50°C for time duration ranging between 5 hrs - 20 hrs to get compound of formula III.
In the step of reacting the crude Trientine with amine protecting group (P) according to the present invention, it comprises the source of crude Trientine that may be obtained according to any of prior disclosed processes.

Trientine

III
In another particular embodiment of the present invention, reacting the crude Trientine with di-tertiary-butyl dicarbonate (BOC-Anhydride) in presence of triethylamine in acetonitrile at temperature ranging between 20 – 35°C for time duration ranging between 10 - 15 hours to get compound of formula IIIa.

Trientine

IIIa
The term "amine protecting group (P)" as used herein refers to any moiety that is used to protect at least one -NH- moiety and/or at least one -NH2 moiety by replacement of hydrogen. Any moiety that is, for example, relatively inert to reaction conditions under which a nitrile is reduced may be used. The resulting protected structure may be linear or cyclic, and may include one or more amine protecting groups. Examples of amine protecting groups useful in the present invention include, by way of example only, methyl carbamate, ethyl carbamate, benzyl carbamate, tert-butyl carbamate, tert-butyloxycarbonyl (BOC), cyclohexanone, 2,2,6,6-tetramethyl cyclohexanone, anthrone, an alkyl group, an aryl group, or an aromatic alkyl group. Other amine protecting groups suitable for use in the invention are described, for example, in Protective Groups in Organic Synthesis, Third Edition, T.W. Green and P.G.M. Wuts (Wiley-Interscience, 1999). Others will be known to those in the art.
The term "alkyl" includes saturated aliphatic groups, including straight-chain alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.), branched-chain alkyl groups (isopropyl, tert-butyl, isobutyl, etc.), cycloalkyl (alicyclic) groups (cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. The term alkyl further includes alkyl groups, which comprise oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone. The term "aromatic-alkyl" includes alkyl groups substituted with one or more aryl groups. The term "aryl" includes groups with aromaticity, including 5- and 6- membered single-ring aromatic groups that may include from zero to four heteroatoms as well as multicyclic systems with at least one aromatic ring. Examples of aryl groups include benzene, phenyl, pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isooxazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like. Furthermore, the term "aryl" includes multicyclic aryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, napthridine, indole, benzofuran, purine, benzofuran, deazapurine, or indolizine. Those aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles", "heterocycles," "heteroaryls" or "heteroaromatics". The aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Aryl groups can also be fused or bridged with alicyclic or heterocyclic rings which are not aromatic so as to form a multicyclic system {e.g., tetralin, methylenedioxyphenyl).
The term "imidazolidine derivative-forming amine protecting group reagent" as used herein refers to a reactant used to protect more than one -NH- moiety by formation of an imidazolidine derivative. Examples of imidazolidine derivative- forming amine protecting group reagents include, for example, but are not limited to, an aldehyde, a ketone, formaldehyde, a substituted aromatic aldehyde, a substituted aliphatic aldehyde, a substituted alkyl-aromatic aldehyde, a substituted aromatic ketone, a substituted aliphatic ketone, and a substituted alkyl-aromatic ketone.
The term "amine protecting group reagent" as used herein refers to a reactant used to protect at least one -NH- moiety or at least one -NH2 moiety including imidazolidine derivative-forming amine protecting group reagents. For example, the reagent di-tert-butyl dicarbonate (BOC-Anhydride) may be used to protect about two equivalents of -NH- moiety for every one equivalent of BOC--Anhydride used in a reaction. Amine protecting group reagents include, for example, BOC--Anhydride, an aldehyde, a ketone, formaldehyde, a substituted aromatic aldehyde, a substituted aliphatic aldehyde, a substituted alkyl-aromatic aldehyde, a substituted aromatic ketone, a substituted aliphatic ketone, and a substituted alkyl-aromatic ketone.
In one of the particular embodiment of the present invention, performing the step b by reducing the compound of formula Va with Raney Nickel in solvent ammonia dissolved in methanol at temperature ranging between 20-30°C for time duration ranging between 20-24 hours to get amine compound of formula IVa followed by reacting with di-tertiary-butyl dicarbonate (BOC-Anhydride)in ethyl acetate at temperature ranging between 20-30°C for a time duration ranging between 20-24 hours to get compound of formula IIIa.

IVa

IIIa
In one of the particular embodiment of the present invention, step c is performed by treating compound of formula IIIa with hydrochloric acid in a suitable solvent at temperature ranging between 25°C-100°C for time duration ranging between 2-7 hours to get Tetra hydrochloride acid salt of Trientine compound of formula II.

III

II
In another particular embodiment of the present invention, compound of formula III with hydrochloric acid in isopropyl alcohol at temperature ranging between 25°C-100°C for time duration ranging between 2-7 hours to get Tetra hydrochloride acid salt of Trientine compound of formula II.

III

II
In another particular embodiment of the present invention, compound of formula IIIa with hydrochloric acid in isopropyl alcohol at temperature ranging between 70°C-75°C for time duration ranging between 3-4 hours to get tetra hydrochloride acid salt of Trientine compound of formula II.

IIIa
In another embodiment of the present invention, treating tetra hydrochloric acid salt of Trientine compound of compound of formula II with base in a suitable solvent to get Trientine dihydrochloride compound of Formula I with purity of 99% (by HPTLC) or more.

II
In one of the particular embodiment of the present invention, treating tetra hydrochloric acid salt of Trientine compound of formula II with sodium ethoxide in ethanol at temperature ranging between 25°C to reflux temperature for time duration ranging between 1-4 hours to get Trientine dihydrochloride compound of formula I with purity of 99% ( by HPTLC) or more.
The purity of the samples of compounds of formula V/Va and compounds of formula III/ IIIa were measured using HPLC Chromatography. HPLC Chromatography was performed with Waters Alliance HPLC system (MILD, USA) that consists of quaternary pump equipped with a 2695 separation module with inbuilt auto injector and 2996 photodiode array detector. The output signal was monitored and processed using chromelean software version 6.8.

The purity of the samples of compounds of Trietnine tetrahydrochloride compound of formula II and Trientine dihydrochloride compound of formula I was measured using HPTLC Chromatography. HPTLC Chromatography is high performance thin-layer chromatographic plate (please see Chromatography <621>) having a 1.5-cm preadsorbent zone and coated with a 0.15-mm layer of chromatographic silica gel mixture (For Analytical method refer USP monograph).

The invention was further defined by reference to the following examples describing in detail by the preparation of the compounds of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
EXAMPLES:
Example 1: Preparation of 2,2'-(2,2,11,11-tetramethyl-3,10-dioxa-5,8-diazadodecane-5,8-diyl)diacetonitrile compound of formula (Va)
20 g (0.33 mol) of ethylene diamine (VIII) was dissolved in 160 mL of acetonitrile at room temperature and added 97 g (0.69 mol) of potassium carbonate in to the reaction mixture. Reaction mixture was cooled to 10 to 15 °C and added 53 g (0.69 mol) of chloro acetonitrile (VII) drop wise over a period of 45 minutes. Continued the stirring for another 24 h at room temperature. After completion of the coupling reaction, cool the reaction mixture to 5-10°C, added 153 g (0.69 mol) of BOC anhydride and stirred at room temperature for another 24. After completion of the reaction, the mixture was filtered and the residue was washed with 40 mL of acetonitrile. Distil off the solvent under vacuum below 60°C. Finally, the crude material was purified using toluene yielded 86 g (72 %) of the product (Va) as colourless solid.
HPLC purity: 99 %

Example 2: Preparation of Tetra BOC protected Trientine compound of formula (IIIa)
20 g (0.06 mol) of compound (Va) formed in Example 1 ( and 60 mL of Methanol was charged in to an autoclave under nitrogen atmosphere. 20 g of Raney nickel was added to the autoclave followed by 200 mL of Methanolic ammonia (15 %) at room temperature. Reaction mixture was hydrogenated at 20 – 25°C for 24 h under a hydrogen pressure of 8-10 Kg/cm2 . After completing the reaction, the reaction mixture was filtered and washed the catalyst with with 100 mL of Methanol. The product was isolated by distilling out methanol below 50°C yielded 20 g of the crude compound (IVa) (HPLC purity 82 %). Crude product was dissolved in 60 mL of ethyl acetate and 38 g (3 mol) of BOC anhydride was slowly added to the reaction mixture. The reaction mixture was stirred at room temperature for another 24 h. The product was filtered and the and purified in methanol afforded 22 g (68 %) of the product (IIIa).
HPLC purity: 97 %

Example 2B: Preparation of Tetra BOC protected Trientine compound of formula (IIIa)
10 g (7 g, 0.047 mol) of 67 % crude Trientine was dissolved in 35 mL of acetonitrile and cooled the reaction mixture to 0 – 5°C. 25.8 g of (0.22 mol) of triethyl amine and 47 g (0.22 mol) of BOC anhydride was added slowly in to the mixture with stirring. Temperature of the reaction was raised to room temperature and maintained for another 12h. After completion of the reaction, the product was isolated and purified in Acetonitrile to yield 14 g (54 %) of tetraboc protected Trientine compound of formula (IIIa).
Purity: 99% (by HPLC)

Example 3: Preparation of Trientine Tetra hydrochloride compound of formula II
Dissolve 88 g (0.16 mol) of Tetra BOC protected Trientine (IIIa) in 700 mL of isopropyl alcohol at room temperature. 220 mL of conc. HCl was added in to the reaction mixture and raise the temperature to 70-75°C. Maintained the reaction mixture at the same temperature for 3-4h. Cooled the reaction mixture to 25-30 °C and filtered. The product was then washed with isopropyl alcohol and MTBE and dried at 40 – 45°C for 10h yielded 45 g (95 %) of Trientine Tetra hydrochloride (II) as a white to pale yellow solid.
Purity: 99% (by HPTLC)

Example 4: Preparation of Trientine dihydrochloride compound of formula I
3.3 g of sodium ethoxide was dissolved in 200 mL of dry Ethanol under nitrogen atmosphere. 10 g of Trientin tetra hydrochloride (II) was added in to it and reflux the reaction mixture for 2 h. Cool the reaction mixture to 0-10°C, filtered the product under nitrogen atmosphere and dried under vacuum yielded 4 g (53 %) of Trientine Dihydrochloride (I) as white to pale yellow solid.
Purity: 99% (by HPTLC)

While the foregoing pages provide a detailed description of the preferred embodiments of the invention, it is to be understood that the summary, description and examples are illustrative only of the core of the invention and non-limiting. Furthermore, as many changes can be made to the invention without departing from the scope of the invention, it is intended that all material contained herein may be interpreted as mere illustrative of the invention and not in a limiting sense.