CLIAMS:
1. A substantially pure Dofetilide of Formula I, or pharmaceutically acceptable salt thereof,

Formula I
having Mono impurity of Formula-A, Trimer impurity compound of Formula-B and Tetramer impurity of Formula-C impurities

less than 0.5 % when measured by HPLC.

2. An improved process for the preparation of substantially pure Dofetilide or pharmaceutically acceptable salt thereof of Formula I

Formula I
having Monomer, Trimer and Tetramer impurities less than 0.5 % when measured by HPLC, the process includes steps of,
a) condensing N-methyl-2-(4-nitrophenyl)ethanamine with 1-(2-chloroethoxy)-4-nitrobenzene, in presence of potassium bicarbonate and sodium iodide in acetonitrile and dimethyl acetate to obtain N-(2-(4-nitrophenoxy)ethyl)-N-methyl-2-(4-nitrophenyl)ethanamine,
b) reducing N-(2-(4-nitrophenoxy)ethyl)-N-methyl-2-(4-nitrophenyl) ethanamine by palladium on carbon in methanol to obtain 1-(4-aminophenoxy)-2-[N-(4-aminophenethyl)-N-methylamino]ethane,
c) reacting 1-(4-aminophenoxy)-2-[N-(4-aminophenethyl)-N-methylamino] ethane with methane sulfonyl chloride solution in acetonitrile to obtain Dofetilide,
d) purifying Dofetilide obtained in step (c) to obtain substantially pure Dofetilide or pharmaceutically acceptable salt thereof.

3. The process of claim 2, wherein substantially pure Dofetilide or salt thereof, has Monomer, Trimer and Tetramer impurities less than 0.5% when measured by HPLC.

4. The process of claim 2, wherein substantially pure Dofetilide or salt thereof, has Monomer, Trimer and Tetramer impurities less than 1 % when measured by HPLC.

5. The process of claim 2, wherein step (d) involves conversion of the trimer and tetramer impurities to Dofetilide by adjusting pH ≥10.

6. The process of claim 2, wherein purification is carried out by acid base treatment.

7. The process of claim 2, wherein N-(2-(4-nitrophenoxy)ethyl)-N-methyl-2-(4-nitrophenyl)ethanamine, has purity more than or equal to 99% when measured by HPLC.

8. 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.
,TagSPECI:Field of Invention

The present invention relates to substantially pure Dofetilide or its pharmaceutically acceptable salt thereof, has monomer, trimer and tetramer impurities less than 0.5 % when measured by HPLC. In particular aspect of present invention provides an improved process for the preparation of substantially pure Dofetilide or its pharmaceutically acceptable salt thereof. In further aspect of the present invention provides the conversion of the trimer and tetramer impurities to substantially pure Dofetilide.

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 of Formula I,

Formula I
or pharmaceutically acceptable salt thereof, having Monomer impurity of Formula-A, Trimer impurity compound of Formula-B and Tetramer impurity of Formula-C impurities

less than 0.5 % as measured by HPLC.

In an another aspect, the present invention provides an improved process for the preparation of substantially pure Dofetilide of Formula I,

Formula I
having monomer, trimer and tetramer impurities 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 and sodium iodide in acetonitrile and dimethyl acetate to obtain N-(2-(4-nitrophenoxy)ethyl)-N-methyl-2-(4-nitrophenyl)ethanamine,
b) reducing N-(2-(4-nitrophenoxy)ethyl)-N-methyl-2-(4-nitrophenyl)ethanamine
by palladium on carbon in methanol to obtain 1-(4-aminophenoxy)-2-[N-(4-aminophenethyl)-N-methylamino]ethane,
c) reacting 1-(4-aminophenoxy)-2-[N-(4-aminophenethyl)-N-methylamino]ethane with methane sulfonyl chloride solution in acetonitrile to obtain Dofetilide,
d) purifying Dofetilide obtained in step (c) to obtain substantially pure Dofetilide or pharmaceutically acceptable salt thereof.

In one another aspect of the present invention provides the conversion of the trimer and tetramer impurities to Dofetilide by adjusting pH of reaction mixture from about 12 to 14

In one another aspect of the present invention Dofetilide or pharmaceutically acceptable salt thereof has purity more than 99% when measured by HPLC.

In one another aspect of the present invention provides N-(2-(4-nitrophenoxy)ethyl)-N-methyl-2-(4-nitrophenyl)ethanamine, has purity more than or equal to 99% when measured by HPLC.

In one another aspect of the present invention provides 1-(4-aminophenoxy)-2-[N-(4-aminophenethyl)-N-methylamino]ethane, 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 Monomer, Trimer and Tetramer impurities less than 0.5%, preferably more 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 of Formula I,

Formula I
or pharmaceutically acceptable salt thereof, having Mono impurity of Formula-A, Trimer impurity compound of Formula-B and Tetramer impurity of Formula-C impurities

less than 0.5 % when measured by HPLC.

The present invention provides an improved process for the preparation of substantially pure Dofetilide or pharmaceutically acceptable salt thereof of Formula I,

Formula I
having Monomer, Trimer and Tetramer impurities less than 0.5 % when measured by HPLC,
the process includes steps of ;
a) condensing N-methyl-2-(4-nitrophenyl)ethanamine with 1-(2-chloroethoxy)-4-nitrobenzene in presence of potassium bicarbonate and sodium iodide in acetonitrile and dimethyl acetate to obtain N-(2-(4-nitrophenoxy)ethyl)-N-methyl-2-(4-nitrophenyl)ethanamine,
b) reducing N-(2-(4-nitrophenoxy)ethyl)-N-methyl-2-(4-nitrophenyl)ethanamine
by palladium on carbon in methanol to obtain 1-(4-aminophenoxy)-2-[N-(4-aminophenethyl)-N-methylamino]ethane,
c) reacting 1-(4-aminophenoxy)-2-[N-(4-aminophenethyl)-N-methylamino]ethane with methane sulfonyl chloride solution in acetonitrile to obtain Dofetilide,
d) purifying Dofetilide obtained in step (c) to obtain substantially pure Dofetilide or pharmaceutically acceptable salt thereof.
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 in acetonitrile and dimethyl acetate followed by addition of sodium iodide. The reaction mixture was stirred for a period of 10 hours at temperature in between range of 80 to 85°C. After completion of reaction, the reaction mass was cooled and water was 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 was filtered and washed with water and the wet material was suspended into isopropyl alcohol and stirred for a period of 1 hour. The material was filtered and washed with isopropyl alcohol to get pure N-(2-(4-nitrophenoxy)ethyl)-N-methyl-2-(4-nitrophenyl)ethanamine.

The step b) of the present invention involves reduction N-(2-(4-nitrophenoxy)ethyl)-N-methyl-2-(4-nitrophenyl)ethanamine by palladium on carbon in methanol and hydrogenated at temperature in between range of 25oC to 30oC. After completion of reaction, the reaction mixture was filtered and the filtrate was distilled to get residue. Residue was treated with hexane and filtered to get pure 1-(4-aminophenoxy)-2-[N-(4-aminophenethyl)-N-methylamino]ethane.

The step c) of the present invention involves reacting 1-(4-aminophenoxy)-2-[N-(4-aminophenethyl)-N-methylamino]ethane with methane sulfonyl chloride solution in acetonitrile at temperature in between range of 30°C to 35°C. The reaction mixture was stirred at 30 to 35°C for a period of 1 hour. After completion of the reaction water was charged into the reaction mixture and solvents were distilled out to obtain Dofetilide.

The step d) of the present invention involves the purification of Dofetilide obtained in step c) by means of acid base treatment, with sodium hydroxide and hydrochloric acid. The reaction mixture was stirred for a period of 1 hour at 7-8.5 pH and filtered to get crude Dofetilide. The crude Dofetilide is further dissolved in hot ethyl acetate to get clear solution followed by cooling to temperature in between range of 10 to150C. The precipitated product was filtered to get substantially pure Dofetilide.

In another aspect of the present invention provides the conversion of the trimer and tetramer impurities to Dofetilide at highly basic pH by using sodium hydroxide. The highly basic pH is ≥10.

In one another aspect of the present invention provides the conversion of the trimer and tetramer impurities to Dofetilide by adjusting pH of reaction mixture highly basic by addition of suitable base, wherein the suitable base is selected from the group comprising one or more of organic base comprising dimethylamine, diethylamine or triethylamine, ammonia and inorganic base comprising one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide and potassium t-butoxide.

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

In another aspect of the present invention provides N-(2-(4-nitrophenoxy)ethyl)-N-methyl-2-(4-nitrophenyl)ethanamine, has purity more than or equal to 99% when measured by HPLC.

In another aspect of the present invention provides 1-(4-aminophenoxy)-2-[N-(4-aminophenethyl)-N-methylamino]ethane, has purity more than or equal to 99% when measured by HPLC.

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-(2-(4-nitrophenoxy)ethyl)-N-methyl-2-(4-nitrophenyl) ethanamine

Charged sodium iodide (83.1 gm) to the stirring solution of N-methyl-2-(4-nitrophenyl)ethanamine (100 gm), 1-(2-chloroethoxy)-4-nitrobenzene (88.6 gm) and potassium bicarbonate (231.6 gm) in acetonitrile (500 ml) and dimethylacetate (500 ml). The reaction mixture was stirred for a period of 10 hours at temperature 80 to 85°C. After completion of reaction, the reaction mass was cooled & water (1.0 lit.) 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 (100 ml). Wet material was suspended into isopropyl alcohol (300 ml) and stirred for a period of 1 hour. The material was filtered and washed with isopropyl alcohol (100 ml) to get pure titled compound.
Yield: 120 gm (75 %)
HPLC purity: >99%

Example-2: Preparation of 1-(4-aminophenoxy)-2-[N-(4-aminophenethyl)-N-methyl amino]ethane

Charged 5 % Pd/C (50 % wet; 10 gm) to the solution of N-(2-(4-nitrophenoxy)ethyl)-N-methyl-2-(4-nitrophenyl)ethanamine (100 gm) in methanol (2.0 lit), and hydrogenated at temperature 25oC to 30oC. After completion of reaction, the reaction mixture was filtered. The filtrate was distilled to get residue. Residue was treated with hexane and filtered & dried to get pure titled compound.
Yield: 70.0 gm (85 %)
HPLC Purity: >99%.

Example-3: Preparation of Dofetilide

Charged methane sulfonyl chloride solution (93.3 gm of methane sulfonyl chloride solution in 200 ml acetonitrile) slowly to the solution of 1-(4-aminophenoxy)-2-[N-(4-aminophenethyl)-N-methylamino]ethane (100 gm) in acetonitrile (1.0 lit.) at temperature 30°C to 35°C. The reaction mixture was stirred at 30 to 35°C for a period of 1 hour. After completion of the reaction, water was charged into the reaction mixture and solvents were distilled out. After distillation, charged NaOH pellets to adjust the pH to more than10 and stirred for a period of 6 hours followed by adjusting the pH 7 to 8.5 using hydrochloric acid. The reaction mixture was stirred for a period of 1 hour and filtered to get crude Dofetilide. The crude Dofetilide was dissolved in hot ethyl acetate to get clear solution, followed by cooling to temperature 10 to 15 0C. The precipitated product was filtered to get pure titled compound.
Yield: 120 gm (78 %)
HPLC purity: >98 %