Process for preparation of trientine dihydrochloride

Abstract

The present invention provides a process for preparation of trientine dihydrochloride (1) comprising reaction of protected triethylene tetramine with hydrochloric acid in an aqueous system to yield the dihydrochloride salt wherein the formation of inorganic impurities and undesired salts is controlled significantly.

Claims

1. A process comprising preparing Trientine dihydrochloride directly and selectively in a single step reaction consisting of reacting a compound of Formula (6) with 1.6 to 2.1 molar equivalents of hydrochloric acid in an aqueous medium to produce the Trientine dihydrochloride without formation of Trientine tetrahydrochloride ##STR00003##

2. The process as claimed in claim 1, wherein the reaction temperature is maintained in the range of 80 to 110 C.

3. The process as claimed in claim 1, wherein the reaction mass obtained after completion of the reaction is concentrated, treated with ethanol, cooled and filtered to yield the Trientine dihydrochloride.

4. The process as claimed in claim 1, wherein the reaction is carried out at 80 to 110 C. in an autoclave or at atmospheric pressure.

5. The process of claim 1, wherein the Trientine tetrahydrochloride is subsequently converted to trientine free base and sodium chloride in presence of a strong base and an organic solvent.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) The present inventors, in their pursuit for developing a convenient, commercially viable and economical process for obtaining trientine dihydrochloride conforming to regulatory specifications, carried out extensive experimentation aimed at minimizing the synthetic steps as against the circuitous routes disclosed in prior art. Surprisingly, it was observed that a direct, single-step process for preparation of the dihydrochloride salt was possible when the reaction of tertiary butoxycarbonyl protected amine (6) with hydrochloric acid was carried out in an aqueous system at 80 to 110 C. in the pH range of 7-8. In this reaction, hydrochloric acid which was used in less than molar equivalent quantities with respect to the protected amine reactant, served the dual purpose of deprotection of the protecting group and formation of the salt, providing the selective dihydrochloride formation. It was also observed that the reaction could be carried out either at mild pressure in an autoclave or at atmospheric pressure.

(2) This novel strategy thus avoids lengthy, time consuming reaction sequence of preparing tetrahydrochloride salt from the protected diamine, its conversion to trientine free base, followed by re-conversion to the dihydrochloride salt by reaction with hydrochloric acid. Consequently, use of multi-molar equivalents of hydrochloric acid, excessive organic solvents and the multiple unit operations at intermediate stages are avoided to give a convenient and robust process for the dihydrochloride salt (1) which conforms to regulatory requirements.

(3) A noteworthy part of the embodied method was that there was no formation of sodium chloride during the process, due to which the unit operations for separation and filtration of the salt were eliminated and more importantly, problems associated with sulphated ash content, which hampered the purity of the final product; dihydrochloride salt were avoided.

(4) ##STR00002##

(5) In an embodiment, tert-butyl-N-(2-aminoethyl)-N-2-[(2-aminoethyl)-(tert-butoxy)carbonyl]amino]ethyl}carbamate of formula (6) was treated with concentrated hydrochloric acid.

(6) The amount of hydrochloric acid employed for deprotection of the amine group and subsequent dihydrochloride formation was in the range of 1.6 to 2.1 equivalents with respect to the tertiary butoxycarbonyl-protected diamine (6).

(7) It was noted that if, during the reaction eventually the pH was excessively higher or lower than the range of 7 to 8, there were problems in isolating the desired dihydrochloride salt resulting in substantial yield loss.

(8) The reaction mixture was heated in the temperature range of 80-110 C.

(9) The reaction was carried out at atmospheric pressure or in a pressure vessel (autoclave) wherein the pressure was maintained in the range of 2-10 Kg/cm.sup.2.

(10) After completion of the reaction as monitored by TLC, the aqueous reaction mixture was concentrated and ethanol was added to the residue. The resultant mixture was heated till a clear solution was obtained. Further cooling of the reaction mixture, filtration and drying yielded the desired compound, triethylenetetramine dihydrochloride (1) with yield around 80% and purity98% (purity within USP limits).

(11) Compound (6) was prepared following known methods by reaction of ethylene diamine (2) with chloroacetonitrile (3) using potassium carbonate as base and solvent acetonitrile to give 2-({2-[(cyanomethyl)amino]ethyl}amino) acetonitrile (4). Compound (4) was further treated with ditertiarybutyl dicarbonate and the resulting boc-protected dinitrile (5) was hydrogenated using Raney nickel, ammonia and isopropyl alcohol to yield compound (6).

(12) Alternatively, the preparation of compound (4) and its further reaction with ditertiarybutyl dicarbonate was carried out in-situ.

(13) The following examples are meant to be illustrative of the present invention. These examples exemplify the invention and are not to be construed as limiting the scope of the invention.

EXAMPLES

Example 1: Preparation of 2-([2-[cyanomethyl]-t-butyloxycarbonylamino]ethyl-t-butyloxy carbonylamino)acetonitrile (5)

(14) Potassium carbonate (481.9 g) was added to a stirred mixture of ethylenediamine (100.0 g) in acetonitrile (800 ml) and cooled to around 10 C. Chloroacetonitrile (263.8 g) was gradually added at same temperature and stirred at 25-30 C., till completion of the reaction, as monitored by HPLC. The mixture was cooled to 5-15 C. and Boc-anhydride (762.1 g) was added to it, followed by stirring at the same temperature. The temperature was raised to 25-30 C. and the mass was stirred till completion of the reaction, as monitored by HPLC.

(15) The reaction mass was filtered and the filtrate was concentrated. Toluene was added to the residue, and the mixture was heated to around 70 C. followed by cooling and filtration to give 2-([2-[cyanomethyl)-t-butyloxycarbonylamino]ethyl-t-butyloxycarbonylamino) acetonitrile (5).

(16) Yield: 506.8 g

(17) % Yield: 89.9%

Example 2: Preparation of t-butyl(N-2-aminoethyl)N-([2-[(2-aminoethyl)t-butyloxy)carbonylamino] ethyl) carbamate (6)

(18) Raney nickel (120.0 g) in isopropanol (100 ml) was charged into an autoclave, followed by a mixture of Compound 5 (200 g) in isopropanol (400 ml). Cooled ammonia solution prepared by purging ammonia gas in 1400 ml isopropanol, equivalent to 125 g ammonia was gradually charged to the autoclave and the reaction was carried out around 15-25 C. under hydrogen pressure of 2-5 Kg/cm.sup.2.

(19) After completion of the reaction, as monitored by HPLC, the mass was filtered, concentrated, and methyl tertiary butyl ether was added to the residue. The mixture was heated to around 50 C., followed by cooling of the mass, stirring, optional seeding with compound 6 and filtration to give tertiary butyl-(N-2-aminoethyl)N-([2-[(2-aminoethyl)-(tert-butyloxy) carbonylamino]ethyl) carbamate.

(20) Yield: 174 g

(21) % Yield: 85%

Example 3: Preparation of Triethylenetetramine Dihydrochloride (1)

(22) Concentrated hydrochloric acid (121.5 g) was gradually added to a stirred mixture of tertiary-butyl-N-(2-aminoethyl)-N-2-[(2-aminoethyl)-(tert-butoxy) carbonyl]amino]ethyl}carbamate (Compound 6, 200.0 g) and water (1400 ml) at 20-30 C. The reaction mixture was heated in the temperature range of 100-105 C. till completion of the reaction, as monitored by HPLC, with optionally distilling out water, if so required.

(23) The reaction mass was concentrated and ethanol (600 ml) was added to the residue, followed by heating till a clear solution was obtained. The reaction mixture was gradually cooled with stirring, filtered and dried to provide triethylenetetramine dihydrochloride (1).

(24) Yield: 88.9 g, (70%)

(25) Purity: 99%