Claims:1. A substantially pure Dofetilide triamine intermediate or its salt thereof Formula I,

Formula I
or pharmaceutically acceptable salt thereof, has mono-nitro amine impurity of Formula-IA,

Formula-IA

less than 0.5 % when measured by HPLC.

2. A one pot process for the preparation of substantially pure Dofetilide triamine intermediate or its salt thereof Formula I,

Formula I
has mono-nitro amine impurity less than 0.5 % when measured by HPLC
the process comprises the steps of
a) condensing N-methyl-2-(4-nitrophenyl)ethanamine with 1-(2- chloroethoxy)-4-nitrobenzene in presence of potassium bicarbonate, sodium iodide and tetra butyl ammonium bromide in water,
b) adding palladium on carbon in methanol,
c) isolating 1-(4-aminophenoxy)-2-[N-(4-aminophenethyl)-N-methylamino] ethane

3. The process of claim 2, wherein 1-(4-aminophenoxy)-2-[N-(4-aminophenethyl)-N-methylamino] ethane, has purity more than or equal to 99% when measured by HPLC.

4. The process according to claim 2, wherein 1-(4-aminophenoxy)-2-[N-(4-aminophenethyl)-N-methylamino] ethane subsequently converted to Dofetilide or a pharmaceutically acceptable salt thereof.

5. The process according to claim 2, wherein palladium on carbon is 5 % w/w.

6. The process of claim 1 and 2, wherein the mono-nitro amine impurity is converted to Dofetilide triamine intermediate.
, Description:Field of Invention

The present invention relates to substantially pure N-Methyl-N-[2-(4-aminophenoxy) ethyl]-4-aminophenethylamine (referred herein after “Dofetilide triamine intermediate”) or its salt thereof, has mono-nitro amine impurity less than 0.5 % when measured by HPLC. In particular aspect of present invention provides an improved process for the preparation of Dofetilide triamine intermediate or its salt thereof.

Background of the invention

Dofetilide is chemically known N-[4-[2-[methyl [2-[4-[(methylsulfonyl)amino]phenoxy] ethyl]amino]ethyl]phenyl]-methanesulfonamide and is structurally represented by formula (I):

Formula I
Dofetilide is an antiarrhythmic drug with Class III (cardiac action potential duration prolonging) properties. Its empirical formula is C19H27N3O5S2 and it has a molecular weight of 441.6. Dofetilide approved in USA for indication under the trade name Tikosyn by Pfizer. Tikosyn is indicated for the maintenance of normal sinus rhythm (delay in time to recurrence of atrial fibrillation/atrial flutter [AF/AFl]) in patients with atrial fibrillation/atrial flutter.

US Patent No 4,959,366 described Dofetilide or a pharmaceutically acceptable salt thereof with its process for the preparation.

The reported process suffers various drawbacks including low yield, less purity and reaction takes longer time, thus reported process is not industrially feasible.
Thus, an object of the present invention is to provide an improved process for the preparation of substantially pure Dofetilide or its pharmaceutically acceptable salt thereof to overcome aforesaid problems and to provide simple, less time consuming process, which is very cost effective and industrially feasible.

Summary of the Invention

The present invention provides a substantially pure Dofetilide triamine intermediate or its salt thereof Formula I,

Formula I
or pharmaceutically acceptable salt thereof, has mono-nitro amine impurity of Formula-IA,

Formula-IA
less than 0.5 % as measured by HPLC.

In an another aspect, the present invention provides a one pot process for the preparation of substantially pure Dofetilide triamine intermediate or its salt thereof Formula I,

Formula I
has mono-nitro amine impurity less than 0.5 % when measured by HPLC
the process includes the steps of
a) condensing N-methyl-2-(4-nitrophenyl)ethanamine with 1-(2-chloroethoxy)-4-nitrobenzene in presence of potassium bicarbonate, sodium iodide and tetra butyl ammonium bromide in water,
b) adding palladium on carbon in methanol,
c) isolating 1-(4-aminophenoxy)-2-[N-(4-aminophenethyl)-N-methylamino]ethane,

In one another aspect of the present invention provides N-Methyl-N-[2-(4-aminophenoxy) ethyl]-4-aminophenethylamine, has purity more than or equal to 99% when measured by HPLC.
Description of the Invention

For purposes of the present invention, the following terms are defined below.

The intermediates and starting materials of the present invention may be used as free bases or its salts.

The salt used is pharmaceutically acceptable salt and it refers to inorganic or organic salt. Inorganic salt may include hydrochloride, hydrobromide, and the like; organic salt may include acetate, mesylate, tosylate, trifluoroacetate, fumarate, mandalate, lactate, glutamate, ascorbate, citrate and the like.

The term “substantially free” as used herein, unless otherwise defined, refers to Dofetilide, an intermediate thereof, or salt thereof that contains mono-nitro amine impurity less than 0.5%, preferably less than about 1%, most preferably less than about 3%.

The term “pure” as used herein the HPLC purity of the compound measured by using HPLC technique.

The present invention provides a substantially pure Dofetilide triamine intermediate or its salt thereof Formula I,

Formula I
or pharmaceutically acceptable salt thereof, has mono-nitro amine impurity of Formula-IA,

Formula-IA
less than 0.5 % when measured by HPLC.

The present invention provides a one pot process for the preparation of substantially pure Dofetilide triamine intermediate or its salt thereof Formula I,

Formula I
has mono-nitro amine impurity less than 0.5 % when measured by HPLC
the process includes the steps of
a) condensing N-methyl-2-(4-nitrophenyl)ethanamine with 1-(2-chloroethoxy)-4-nitrobenzene in presence of potassium bicarbonate, sodium iodide and tetra butyl ammonium bromide in water,
b) adding palladium on carbon in methanol,
c) isolating N-Methyl-N-[2-(4-aminophenoxy) ethyl]-4-aminophenethylamine

The step a) of the present invention involves the condensing of N-methyl-2-(4-nitrophenyl)ethanamine with 1-(2-chloroethoxy)-4-nitrobenzene in presence of potassium bicarbonate, sodium iodide and tetra butyl ammonium bromide in water. The reaction mixture is stirred for a period of 5 hours at temperature in between range of 90°C to 100°C. After completion of reaction, the reaction mass is cooled to temperature 30°C and isopropyl alcohol is charged into the reaction mixture followed by stirring for a period of 2 hours at temperature in between range of 25oC to 30oC. After 2 hours, the reaction mass is filtered and washed with water to get N-(2-(4-nitrophenoxy)ethyl)-N-methyl-2-(4-nitrophenyl)ethanamine in situ as wet material.

The step b) of the present invention involves addition of 5% w/w palladium on carbon in methanol to the wet material obtained in step a). The wet material is charged in methanol containing 5% w/w palladium on carbon and hydrogenated at temperature in between range of 25oC to 35oC for a period of 6 hours.

The step c) of the present invention involves isolation of N-Methyl-N-[2-(4-aminophenoxy) ethyl]-4-aminophenethylamine. After completion of reaction, the reaction mixture is filtered, washed with methanol. The filtrate is distilled to get brown color residue. Residue is treated with acetonitrile and water. The precipitate is filtered and washed with water and dried under vacuum to get pure N-Methyl-N-[2-(4-aminophenoxy) ethyl]-4-aminophenethylamine.

In another aspect of the present invention provides the conversion of the mono-nitro amine impurity to Dofetilide triamine intermediate.

In another aspect of the present invention provides the formation of N-(2-(4-nitrophenoxy)ethyl)-N-methyl-2-(4-nitrophenyl)ethanamine in situ.

In another aspect of the present invention provides Dofetilide triamine intermediate or salt thereof has purity more than or equal to 99% when measured by HPLC.

The compounds N-Methyl-N-[2-(4-aminophenoxy) ethyl]-4-aminophenethylamine or salt thereof may be converted into Dofetilide according to known methods in the art, e.g. US patent number US 4959366 and IN patent application IN 1288/MUM/2015.
The process of the present invention is depicted in the following Scheme 1:

Scheme 1

The present invention is further illustrated by the following example, which does not limit the scope of the invention. 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 application.

Examples

Example-1: Preparation of N-Methyl-N-[2-(4-aminophenoxy) ethyl]-4-aminophenethylamine : Key Intermediate of Dofetilide

Charged N-methyl-2-(4-nitrophenyl)ethanamine hydrochloride (100 gm), 1-(2-chloroethoxy)-4-nitrobenzene (93 gm) potassium bicarbonate (127.6 gm), sodium iodide (138.4 gm) and tetra butyl ammonium bromide (22.3 gm) in water (500 ml). The reaction mixture was stirred for a period of 5 hours at temperature 90 to 100°C. After completion of reaction, the reaction mass was cooled to temperature 30°C and isopropyl alcohol (250 ml) was charged into the reaction mixture followed by stirring for a period of 2 hours at temperature 25oC to 30oC. After 2 hours the reaction mass was filtered and washed with water (250 ml). Wet material was suspended into methanol (1.5 L) containing 5% w/w Pd/C (10 gm) and hydrogenated at temperature 25oC to 30oC for a period of 6 hours. After completion of reaction, the reaction mixture was filtered. The filtrate was washed with methanol and distilled to get brown color residue. Residue was treated with acetonitrile (300 ml) and water (800 ml) for a period of 2 hours. The precipitate was filtered, washed with water (200 ml) and dried under vacuum to get the titled compound (75.0 g)
Yield: 75 gm
HPLC purity: >99%