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Process for preparation of Trientine Hydrochloride

IP.com Disclosure Number: IPCOM000244588D
Publication Date: 2015-Dec-23
Document File: 5 page(s) / 182K

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Abstract

Process for preparation of Trientine dihydrochloride salt (I by circumventing the formation of the corresponding tetrahydrochloride salt.

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Process for preparation of Trientine hydrochloride

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Trientine, chemically known as triethylenetetramine or N,N’-bis(2-aminoethyl)-1,2-ethanediamine belongs to the class of polyethylene polyamines. Trientine dihydrochloride is used in the treatment of Wilson's disease wherein it acts as a chelating agent for removing copper in the body.

Trientine dihydrochloride (I)                                                          

Described herein is the process for preparation of Trientine dihydrochloride (I), along with characterization details for the same (Scheme-1).

Scheme-1: Synthesis of Trientine dihydrochloride (I)

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

Potassium carbonate (481 g) was added to the stirred mixture of Ethylene diamine (100 g) and acetonitrile (100 ml), cooled to around 100C, followed by gradual addition of chloroacetonitrile (263.2 g) at the same temperature. The reaction mass was stirred at 25-300C, till completion of the reaction, as monitored by HPLC. After completion, the mixture was cooled and Boc-anhydride (760 g) was added to it, followed by stirring at the same temperature till completion of the reaction, as monitored by HPLC.

The reaction mass was filtered and the filtrate was concentrated. Addition of toluene to the residue, heating the mixture to around 700C, followed by cooling of the mass, stirring and filtration provided 2-([2-[cyanomethyl)-t-butyloxycarbonylamino]ethyl-t-butyloxycarbonylamino)acetonitrile (V).

Yield:   507 g (90 %)

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

Raney nickel (120 g) in isopropanol (100 ml) was charged into an autoclave, followed by addition of compound V (200 g) in isopropanol (400 ml). Cooled ammonia solution (W/W 9% ammonia in isopropanol) was charged into the autoclave and the reaction was carried out at around 300C under hydrogen pressure of 5 Kg/cm2. The reaction was monitored by HPLC.

After completion of the reaction, the mass was filtered, concentrated, and methyl tertiary butyl ether was added to the residue. The mixture was heated to around 500C, followed by cooling of the mass, stirring, optional seeding with compound VI and filtration to give tertiary butyl( N-2-aminoethyl)-N-([2-[(2-aminoethyl)-(tert-butyloxy)carbonylamino]ethyl)carbamate .

Yield:  174 g (85 %)

Example 3:          Preparation of Trientine dihydrochloride (I)

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 VI, 200.0 g) and water (1400 ml) at 20-300C. The pH of the reaction mass was adjusted between 7 and 8 and the reaction mixtur...