DESC:Field of Invention
The present invention relates to a process for the preparation of N-(2-(4-nitrophenoxy)ethyl)-N-methyl-2-(4-nitrophenyl)ethanamine and its conversion to dofetilide or pharmaceutically acceptable 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 a novel process for the preparation of 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 process for the preparation of N-(2-(4-nitrophenoxy)ethyl)-N-methyl-2-(4-nitrophenyl)ethanamine of Formula II,

Formula II
comprising the steps of,
a) reacting p-nitro phenol with 2-chloro-1,1-dimethoxyethane optionally in presence of base and nucleophilic catalyst in a solvent to obtain 1-(2,2-dimethoxyethoxy)-4-nitrobenzene,
b) treating 1-(2,2-dimethoxyethoxy)-4-nitrobenzene with acid to obtain 2-(4-nitrophenoxy)acetaldehyde,
c) condensing 2-(4-nitrophenoxy)acetaldehyde with N-methyl-2-(4-nitrophenyl) ethanamine in presence of reducing agent to obtain N-(2-(4-nitrophenoxy)ethyl)-N-methyl-2-(4-nitrophenyl) ethanamine of Formula II.

The present invention further provides N-(2-(4-nitrophenoxy)ethyl)-N-methyl-2-(4-nitrophenyl) ethanamine having HPLC purity of = 99%.

The present invention further provides a process of converting N-(2-(4-nitrophenoxy)ethyl)-N-methyl-2-(4-nitrophenyl) ethanamine to dofetilide or pharmaceutically acceptable salt thereof,

Description of the Invention
The pharmaceutically acceptable salt 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 base used in step (a) is selected from the group comprising one or more of organic or inorganic base. The organic base is selected from ammonia, dimethylamine, diethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene and triethylamine. The inorganic base is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium tert-butoxide and potassium hydroxide.

The nucleophilic catalyst used in step (a) is selected from potassium iodide and sodium iodide.

The solvent used in step (a) is selected from acetonitrile, propionitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, water, N,N-dimethylformamide; N,N-diethylformamide; dimethyl sulfoxide; hexamethyl phosphoramide; dimethylpropylene urea; sulpholane; N-methyl-2-pyrrolidone and mixture thereof.

The step (a) is carried out at a temperature from 0 °C to 100 °C, preferably at 30 °C to 100 °C for period of 1 to 10 hours, preferably 5 to 7 hours.

The step (b) is carried out in a suitable acid such as hydrochloric acid; at a temperature from 0 °C to 100 °C, preferably at 30 °C to 80 °C for period of 1 to 10 hours, preferably 1 to 3 hours.

The step (c) is carried out in an alcoholic solvent. The alcoholic solvent is selected from methanol, ethanol, isopropanol, n-propanol, butanol, isobutanol and propylene glycol and mixture thereof.

The reducing agent used in step (c) is selected from sodium borohydride, quaternary ammonium borohydride, lithium borohydride and Sodium cyanoborohydride.

The step (c) is carried out at a temperature from 0 °C to 100 °C for period of 1 to 10 hours, preferably 1 to 3 hours.

N-(2-(4-nitrophenoxy)ethyl)-N-methyl-2-(4-nitrophenyl) ethanamine can be converted to dofetilide or pharmaceutically acceptable salt thereof according to known methods in the art, e.g. US patent number US 4,959,366 and IN patent application IN 1288/MUM/2015.

The present invention is further illustrated by the following examples, 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: Synthesis of 2-(4-nitrophenoxy)acetaldehyde
The mixture of p-nitro phenol (10.0 g), 2-chloro-1,1-dimethoxyethane (10.7 g), potassium carbonate (19.8 g) and potassium iodide (5.9 g) in acetonitrile (100 ml) was refluxed for the period of 6 hour. The reaction mass was filtered and filtrate was collected. Aqueous hydrochloride (100 ml) was added to the filtrate and heated at temperature 50 °C for 2 hour. Reaction mass was cooled, extracted with dichloromethane (100 ml) and organic layer was distilled out to get title compound.
Yield: 9 g
Purity: 99 %

Example-2: Synthesis of N-(2-(4-nitrophenoxy)ethyl)-N-methyl-2-(4-nitrophenyl) ethanamine
2-(4-nitrophenoxy) acetaldehyde (10 g) was added to N-methyl-2-(4-nitrophenyl) ethanamine (11.9 g) in methanol (50 ml) solution at temperature 25 to 35 °C. The reaction mixture was refluxed for the period of 2 hour, followed by cooling the reaction mixture to room temperature. The solution of sodium cyanoborohydride (3.4 g) in methanol (50 ml) and acetic acid (10 ml) was added into the reaction mixture. The reaction mixture was stirred for 30 minute at temperature 25 to 35 °C, followed by cooling to room temperature, the resulting precipitate was filtered off, the filtrate was treated with 20% aqueous solution of sodium hydroxide, the solid product was filtered off, washed with water to get title compound.
Yield: 9.2 g
Purity: 99.5 %

Example-3: Synthesis of dofetilide
N-(2-(4-Nitrophenoxy)ethyl)-N-methyl-2-(4-nitrophenyl)ethanamine (100 g) in methanol (1500 ml) containing 5% w/w palladium-on-carbon (10 g) was stirred at temperature 25 °C to 35 °C under hydrogen atmosphere for the period of 6 hours. The catalyst was filtered off, washed with methanol and evaporated to give brown color oil, which was crystallized with methyl tert-butyl ether (300 mL). The solid was collected by filtration, washed with water (100 mL) and dried under vacuum to get N-methyl-N-[2-(4-aminophenoxy)ethyl]-4-aminophenethylamine.
To the solution of N-methyl-N-[2-(4-aminophenoxy)ethyl]-4-aminophenethylamine (100 g) in acetonitrile (800 mL), N-methylmorpholine (116 mL) was added the solution of methane sulphonyl chloride (88.4 g) in acetonitrile (200 mL) drop wise at 0-5 °C. After completion of the reaction, water (1000 mL) was added. The reaction mass was extracted with and dichloromethane (1000 mL) and the organic layer was distilled off to get the residue. The residue was crystallized from mixture of isopropanol (1000 mL) and water (100 mL) to get dofetilide.
Yield: 90 g
Purity: 99.7 %
,CLAIMS:1. A process for the preparation of N-(2-(4-nitrophenoxy)ethyl)-N-methyl-2-(4-nitrophenyl)ethanamine of Formula II,

Formula II
comprising the steps of,
a) reacting p-nitro phenol with 2-chloro-1,1-dimethoxyethane optionally in presence of base and nucleophilic catalyst in a solvent to obtain 1-(2,2-dimethoxyethoxy)-4-nitrobenzene,
b) treating 1-(2,2-dimethoxyethoxy)-4-nitrobenzene with acid to obtain 2-(4-nitrophenoxy)acetaldehyde,
c) condensing 2-(4-nitrophenoxy)acetaldehyde with N-methyl-2-(4-nitrophenyl) ethanamine in presence of reducing agent to obtain N-(2-(4-nitrophenoxy)ethyl)-N-methyl-2-(4-nitrophenyl) ethanamine of Formula II.

2. The process according to claim 1, wherein the base is selected from the group comprising one or more of organic or inorganic base.

3. The process according to claim 3, wherein the organic base is selected from ammonia, dimethylamine, diethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene and triethylamine.

4. The process according to claim 3, wherein the inorganic base is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium tert-butoxide and potassium hydroxide.

5. The process according to claim 1, wherein the nucleophilic catalyst is selected from potassium iodide and sodium iodide.
6. The process according to claim 1, wherein solvent is selected from acetonitrile, propionitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, water, N,N-dimethylformamide; N,N-diethylformamide; dimethyl sulfoxide; hexamethyl phosphoramide; dimethylpropylene urea; sulpholane; N-methyl-2-pyrrolidone and mixture thereof.

7. The process according to claim 1, wherein step (c) is carried out in an alcoholic solvent.

8. The process according to claim 1, wherein reducing agent is selected from sodium borohydride, quaternary ammonium borohydride, lithium borohydride and Sodium cyanoborohydride.

9. The process according to claim 1, wherein N-(2-(4-nitrophenoxy)ethyl)-N-methyl-2-(4-nitrophenyl) ethanamine having HPLC purity of = 99%.

10. The process according to claim 9 further comprising the step of converting N-(2-(4-nitrophenoxy)ethyl)-N-methyl-2-(4-nitrophenyl) ethanamine to dofetilide or pharmaceutically acceptable salt thereof.